[Developments in research on mycotoxins].
Since the early 1960's attention has been paid to mycotoxins by various disciplines of the National Institute of Public Health and Environmental Hygiene (RIVM) (Analytical Chemistry, Microbiology, Toxicology). A major part of the work is carried out at the request of the Chief Medical Office. The activities undertaken on behalf of the Chief Veterinary Officer concern investigations on the causes of fungal growth and toxin production as well as on the presence of aflatoxin B1 and the analytical possibilities of determining aflatoxin B1 in feeds and aflatoxin M1 in milk. Because of its structural relationship with aflatoxin B1, aflatoxin M1 is suspected of having carcinogenic properties. In order to be able to do chronic toxicity studies in rats, efforts are being made to synthesize approximately 25 g. of aflatoxin M1 in co-operation with the State University of Utrecht, which was found to be a time-consuming and extremely difficult job. From the point of view of the Chief Veterinary Officer, it is expected that the analytical and toxicological features of aflatoxin M1 will continue to be of interest in the near future.


Relation of serum magnesium levels and postdischarge outcomes in patients hospitalized for heart failure (from the EVEREST Trial).
Serum magnesium levels may be impacted by neurohormonal activation, renal function, and diuretics. The clinical profile and prognostic significance of serum magnesium level concentration in patients hospitalized for heart failure (HF) with reduced ejection fraction is unclear. In this retrospective analysis of the placebo group of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial, we evaluated 1,982 patients hospitalized for worsening HF with ejection fractions ≤40%. Baseline magnesium levels were measured within 48 hours of admission and analyzed as a continuous variable and in quartiles. The primary end points of all-cause mortality (ACM) and cardiovascular mortality or HF rehospitalization were analyzed using Cox regression models. Mean baseline magnesium level was 2.1 ± 0.3 mg/dl. Compared with the lowest quartile, patients in the highest magnesium level quartile were more likely to be older, men, have lower heart rates and blood pressures, have ischemic HF origin, and have higher creatinine and natriuretic peptide levels (all p <0.003). During a median follow-up of 9.9 months, every 1-mg/dl increase in magnesium level was associated with higher ACM (hazard ratio [HR] 1.77; 95% confidence interval [CI] 1.35 to 2.32; p <0.001) and the composite end point (HR 1.44; 95% CI 1.15 to 1.81; p = 0.002). However, after adjustment for known baseline covariates, serum magnesium level was no longer an independent predictor of either ACM (HR 0.94, 95% CI 0.69 to 1.28; p = 0.7) or the composite end point (HR 1.01, 95% CI 0.79 to 1.30; p = 0.9). In conclusion, despite theoretical concerns, baseline magnesium level was not independently associated with worse outcomes in this cohort. Further research is needed to understand the importance of serum magnesium levels in specific HF patient populations.


The implementation of the Mais Médicos (More Doctors) Program and comprehensiveness of care in the Family Health Strategy.
The Mais Médicos (More Doctors) Program is a Brazilian government program that aims to expand access to medical care and thus improve the quality of primary healthcare delivery. This study aims to analyze the perceptions of nondoctor members of the Family Health Strategy teams regarding comprehensiveness of care after the inclusion of doctors from the program. The study encompassed 32 poor municipalities in Brazil's five geographical regions. A total of 78 health workers were interviewed. The interviews were transcribed and analyzed using content analysis and the software Atlas.ti Version 1.0.36. The study found that the program led to: an increase in access to and accessibility of services provided under the Family Health Strategy; humanized care and the establishment of bonds - understanding, partnership, friendship and respect; going back to clinical approaches - dedicated time, listening attentively, and detailed physical examination; the desire and willingness to resolve problems; continuity of care; guarenteeing home visits; and coordination of multidisciplinary teams in networks. It was concluded that the Mais Médicos Program contributed to the enhancement of comprehensiveness, thus leading to improvements in primary health care delivery.


The protective effect of thymoquinone on tert-butylhydroquinone induced cytotoxicity in human umbilical vein endothelial cells.
2-tert-Butyl-4-hydroquinone (TBHQ) is used for inhibition of oxidative rancidity in the food industry. However, this antioxidant can stimulate cytotoxicity in human umbilical vein endothelial cells (HUVECs). Thus, potential protective effects of thymoquinone (TQ) against TBHQ-induced cytotoxicity were investigated. Cytotoxicity was evaluated via MTT, flow cytometry, DAPI staining and DNA fragmentation methods. The obtained results revealed that treatment of HUVECs with TQ enhanced the cell viability rate and it had potential to reduce the cytotoxicity effect of TBHQ in cells. Also, in a combined regime of TQ and TBHQ, apoptosis was reduced compared to the cells treated with TBHQ (p < 0.05). Similarly, TQ had a protective effect on DNA and chromatin fragmentation of the cells treated with TBHQ. Finally, it can be concluded that TQ could be used as a protective agent against cytotoxicity induced by TBHQ in HUVECs.


Mechanisms of cadmium resistance in anaerobic bacterial enrichments degrading pentachlorophenol.
The mechanisms of heavy-metal resistance used by adapted sulfidogenic and methanogenic enrichments degrading pentachlorophenol in the presence of cadmium (Cd) were studied. The enrichment cultures adapted to and readily tolerated bioavailable Cd concentrations up to 50 ppm while degrading an equal concentration of pentachlorophenol. Both cultures removed >95% of the Cd from solution. Transmission electron micrographs revealed (i). the presence of electron-dense particles surrounding the cells in the sulfidogenic enrichments and (ii). the unusual clumping of cells and the presence of an exopolymer in the methanogenic enrichments. Energy dispersive X-ray analysis showed that the sulfidogenic enrichments removed Cd by extracellular precipitation of cadmium sulfide, while the methanogenic enrichment culture removed Cd by extracellular sequestration of Cd into the exopolymer.


High-quality maple genome reveals duplication-facilitated leaf color diversity.
Acer truncatum is a horticultural tree species with individuals that display either yellow or red leaves in autumn, giving it high ornamental and economic value. 'Lihong' of A. truncatum is an excellent cultivar due to its characteristic of having autumn leaves that turn a bright and beautiful shade of red, while its closely related cultivar 'Bunge' does not. However, the molecular mechanism underlying the color change in the cultivar 'Lihong' is still unclear. Here, we assembled a high-quality genome sequence of Acer truncatum 'Lihong' (genome size = 688 Mb, scaffold N50 = 9.14 Mb) with 28,438 protein-coding genes predicted. Through comparative genomic analysis, we found that 'Lihong' had experienced more tandem duplication events although it's a high degree of collinearity with 'Bunge'. Especially, the expansion of key enzymes in the anthocyanin synthesis pathway was significantly uneven between the two varieties, with 'Lihong' genome containing a significantly higher number of tandem/dispersed duplication key genes. Further transcriptomic, metabolomic, and molecular functional analyses demonstrated that several UFGT genes, mainly resulting from tandem/dispersed duplication, followed by the promoter sequence variation, may contribute greatly to the leaf color phenotype, which provides new insights into the mechanism of divergent anthocyanin accumulation process in the 'Lihong' and 'Bunge' with yellow leaves in autumn. Further, constitutive expression of two UFGT genes, which showed higher expression in 'Lihong', elevated the anthocyanin content. We proposed that the small-scale duplication events could contribute to phenotype innovation.


Testosterone replacement therapy.
The aim of testosterone replacement therapy (TRT) is to improve symptoms and signs of testosterone deficiency including decreased libido, erectile dysfunction, depressed mood, anaemia, loss of muscle and bone mass, by increasing serum testosterone levels to physiologic range. TRT has been used in the last 70 years, and overtime, numerous preparations and formulations have been developed to improve pharmacokinetics (PKs) and patient compliance. The routes of delivery approved for use in the Western world include buccal, nasal, subdermal, transdermal and intramuscular (IM). The aim of this narrative review was to describe and compare all available and approved testosterone preparations according to pharmacology, PKs and adverse effects. We have performed an extensive PubMed review of the literature on TRT in clinical practice. Contraindications and monitoring of TRT were analyzed by comparing available guidelines released in the last five years. We provide a review of advantages and disadvantages of different modalities of TRT and how to monitor treatment to minimize the risks. TRT is associated with multiple benefits highly relevant to the patient. However, the recommendations given in different guidelines on TRT are based on data from a limited number of randomized controlled trials (RCTs), as well as non-randomized clinical studies and observational studies. This is the case for the safety of a long-term TRT in late-onset hypogonadism (LOH). No evidence is provided indeed on the effects of TRT on endpoints such as deterioration of heart failure suggesting a cautious approach to T replacement in older men with a history of heart failure. Clinicians must consider the unique characteristics of each patient and make the necessary adjustments in the management of LOH in order to provide the safest and most beneficial results.


Trends in Hospitalizations for Sickle Cell Disease Related-Complications in USA 2004 - 2012.
Sickle cell disease (SCD) affects 100,000 patients in the USA. However, no recent data was available for annual national trends in hospitalization rates, in-hospital mortality, hospital length of stay (LOS) and costs of SCD admissions due to its complications. This study was conducted to study the trends of hospitalization rates, in-hospital mortality, LOS and hospital charges due to SCD-related complications in African American (AA) patients from 2004 to 2012 in the USA. Complications included acute chest syndrome, splenic sequestration, bacterial pneumonia, sepsis, stroke, deep vein thrombosis (DVT) or pulmonary embolism, retinal circulation complications, priapism, disorders related to biliary stones, or those required blood transfusions. We obtained the study population from the Nationwide Inpatient Sample. Hospital admission rate rose steadily from 106 per 100,000 AA population in 2004 to 137 in 2012. Seasonal and trend decomposition revealed the highest hospitalization rate in January. Hospital LOS decreased from 7.1 ± 7.65 days in 2004 to 6.23 ± 6.42 days in 2012. Hospital charges increased from 15.35 (8.99 - 27.57) thousand dollars per admission in 2004 to 24.78 (14.37 - 45.24) in 2012. Medicaid remained the primary payer in the highest number of patients in 9 years. In-hospital mortality did not change significantly, being 1.03% in 2004 and 1.02% in 2012, with no significant seasonal variation in mortality. Most common complications were acute pain crisis and blood transfusion requirement. Biliary pathology was the only complication that decreased over time. Admissions for each complication were initially uprising with a decline from 2010 to 2012, except for DVT/pulmonary embolism with a significant uptrend. Overall, from 2004 to 2012, hospital admission rates and charges increased, and hospital LOS decreased, while in-hospital mortality remained unchanged.


Implantation defect in endometriosis: endometrium or peritoneal fluid.
Clinical observations indicate that an implantation defect occurs in women with endometriosis. Despite intense research, the role of alterations in endometrial receptivity and the peritoneal fluid microenvironment in the derangement of implantation in endometriosis remains controversial. In this review, the evidence for the altered endometrial receptivity and peritoneal environment are summarized, and their effects on the implantation defect in women with endometriosis are discussed. Recent studies on cell adhesion molecules and their ligands, apoptosis, homeobox genes and the direct action of gonadotrophin-releasing hormone analogues are reviewed with respect to their contribution to endometrial receptivity in endometriosis. The possible mechanisms by which an altered peritoneal environment of endometriosis may affect implantation, including cytokine concentrations, iron metabolism, biochemical factors and embryotoxicity are discussed.


Elucidating pathways to pediatric obesity: a study evaluating obesity polygenic risk scores related to appetitive traits in children.
Obesity polygenic risk scores (PRS) explain substantial variation in body mass index (BMI), yet associations between PRSs and appetitive traits in children remain unclear. To better understand pathways leading to pediatric obesity, this study aimed to assess the association of obesity PRSs and appetitive traits. This study included 248 unrelated children aged 9-12 years. DNA from the children was genotyped (236 met quality control thresholds) and four weighted polygenic risk scores from previous studies were computed and standardized: a 97 SNP PRS, 266 SNP pediatric-specific PRS, 466 SNP adult-specific PRS, and ~2 million SNP PRS. Appetitive traits were assessed using a parent-completed Child Eating Behavior Questionnaire, which evaluated food approach/avoidance traits and a composite obesogenic appetite score. BMI was directly measured and standardized by age and sex. Three associations were evaluated with linear regression: (1) appetitive traits and BMI, (2) PRSs and BMI, and (3) PRSs and appetitive traits, the primary association of interest. Expected positive associations were observed between obesogenic appetitive traits and BMI and all four PRSs and BMI. Examining the association between PRSs and appetitive traits, all PRSs except for the 466 SNP adult PRS were significantly associated with the obesogenic appetite score. Each standard deviation increase in the 266 SNP pediatric PRS was associated with an adjusted 2.1% increase in obesogenic appetite score (95% CI: 0.6%, 3.7%, p = 0.006). Significant partial mediation of the PRS-BMI association by obesogenic appetite score was found for these PRSs; for example, 21.3% of the association between the 266 SNP pediatric PRS and BMI was explained by the obesogenic appetite score. Genetic obesity risk significantly predicted appetitive traits, which partially mediated the association between genetic obesity risk and BMI in children. These findings build a clearer picture of pathways leading to pediatric obesity.


Infantile Refsum disease: an inherited peroxisomal disorder. Comparison with Zellweger syndrome and neonatal adrenoleukodystrophy.
Three patients affected by infantile Refsum disease are described with mental retardation, minor facial dysmorphia, chorioretinopathy, sensorineural hearing deficit, hepatomegaly, failure to thrive and hypocholesterolaemia. Initially, only an accumulation of phytanic acid was thought to be present. More recent findings showed a biochemical profile very similar to that found in classical Zellweger syndrome or neonatal adrenoleukodystrophy. Morphologically typical peroxisomes were absent in the liver. All three disorders are associated with multiple peroxisomal dysfunction. Because of these similarities pertinent clinical data of our three patients are compared with those of reported patients diagnosed as having infantile Refsum disease, neonatal adrenoleukodystrophy or Zellweger syndrome who survived for several years. Attention is drawn to the difference in severity of clinical features, ranging from infantile Refsum's disease to neonatal adrenoleukodystrophy and, finally, to Zellweger syndrome.


FISTA-NET: Deep Algorithm Unrolling for Cerenkov luminescence tomography.
Cerenkov luminescence tomography (CLT) is a highly sensitive and promising imaging technique that can be used to reconstruct the three-dimensional distribution of radioactive probes in living animals. However, the accuracy of CLT reconstruction is limited by the simplified radiative transfer equation and ill-conditioned inverse problem. To address this issue, we propose a model-based deep learning network that combines the neural network with a model-based approach to enhance the performance of CLT reconstruction. The Fast Iterative Shrinkage Thresholding Algorithm (FISTA), a traditional model-based approach, is expanded into a deep network (known as FISTA-NET). Each layer in the network represents an iteration of the algorithm steps, and connecting these layers can form a deep neural network. In addition, different from the traditional FISTA, the key parameters in FISTA, such as gradient step size and threshold value, can be learned through training data without manual production. To evaluate the performance of FISTA-NET, numerical simulation experiments were conducted, which demonstrate its excellent positioning and shape recovery abilities.Clinical Relevance-This indicates that FISTA-NET strategy can significantly improve the quality of CLT reconstruction, which is further beneficial to the assessment of disease activity and treatment effect based on CLT.


CD44 regulation of endothelial cell proliferation and apoptosis via modulation of CD31 and VE-cadherin expression.
CD44 has been implicated in a diverse array of cell behaviors and in a diverse range of signaling pathway activations under physiological and pathophysiological conditions. We have documented a role for CD44 in mediating vascular barrier integrity via regulation of PECAM-1 (CD31) expression. We now report our findings on the roles of CD44 in modulating proliferation and apoptosis of microvascular endothelial cells via its modulation of CD31 and VE-cadherin expression and the Hippo pathway. In this report, we demonstrate persistent increased proliferation and reduced activations of both effector and initiator caspases in high cell density, postconfluent CD44 knock-out (CD44KO), and CD31KO cultures. We found that reconstitution with murine CD44 or CD31 restored the proliferative and caspase activation rates to WT levels. Moreover, we have confirmed that the CD31 ecto-domain plays a key role in specific caspase cascades as well as cell adhesion-mediated cell growth and found that CD31 deficiency results in a reduction in VE-cadherin expression. Last, we have shown that both CD44KO and CD31KO endothelial cells exhibit a reduced VE-cadherin expression correlating with increased survivin expression and YAP nuclear localization, consistent with inactivation of the Hippo pathway, resulting in increased proliferation and decreased apoptosis. These findings support the concept that CD44 mediates several of its effects on endothelia through modulation of adhesion protein expression, which, in addition to its known modulation of junctional integrity, matrix metalloproteinase levels and activation, interactions with cortical membrane proteins, and selected signaling pathways, plays a key role as a critical regulator of vascular function.


Use of Micronized Purified Flavonoid Fraction Together with Rivaroxaban Improves Clinical and Ultrasound Outcomes in Femoropopliteal Venous Thrombosis: Results of a Pilot Clinical Trial.
The aim of this study was to assess the impact of adding long-term micronized purified flavonoid fraction (MPFF) to standard treatment of femoropopliteal deep vein thrombosis (DVT). This pilot, comparative, open-label study with blinded outcome assessor enrolled patients with a first episode of femoropopliteal DVT confirmed by duplex ultrasound scanning (DUS). All participants were randomly allocated to one of two treatment groups: (1) control that received a standard treatment with oral rivaroxaban, and (2) experimental that involved additional treatment with MPFF 1000 mg/day. Both drugs were used for 6 months. Patients were followed for the whole treatment period and underwent DUS every 2 months to determine the degree of recanalization by popliteal (PV), femoral vein (FV), and common femoral vein (CFV) compressibility. Thrombi extension were assessed by the modified Marder score. At the end of the follow-up period, patients were assessed with Villalta and venous clinical severity scales (VCSS). Patients with a Villalta score ≥ 5 were diagnosed with post-thrombotic syndrome (PTS). Sixty patients were randomized to the control or MPFF groups (n = 30 in each group). There were 40 men and 20 women with a mean age ± SD of 56.3 ± 13.4 years. Clinically unprovoked DVT was recognized in 65% of cases and left side localization in 45%. The mean baseline Marder score was 15.0 ± 4.8 and 11.1 ± 4.3 in the experimental and control groups, respectively (p = 0.002). At 6 months, the mean Villalta score in the MPFF group was significantly lower compared with control (2.9 ± 2.7 versus 5.8 ± 3.0; p < 0.0001). PTS was diagnosed in six patients (20%) and 17 patients (57%) in the experimental and control groups respectively (p = 0.007). A significant difference between the groups was also observed for the VCSS value (2.3 ± 1.9 versus 4.9 ± 1.9; p < 0001). After 6 months of treatment the Marder score decreased to 0.8 ± 1.6 and 2.8 ± 3.5 in the experimental and control groups, respectively (p = 0.006). In the MPFF group, there was a greater reduction in the Marder score (p < 0.0001) and more rapid rate of recanalization for the FV (p < 0.0001), with a non-significant trend for the CFV (p = 0.130) and PV (p = 0.204) compared with the control group. Full recanalization of the PV at 6 months was observed in 24 patients (80%) who had received MPFF, and only 17 patients (57%) in the control group (p = 0.095). The addition of MPFF to standard therapy for DVT in the form of oral rivaroxaban can reduce the incidence of PTS at 6 months in patients with proximal DVT and increase the speed of deep vein recanalization. Les Laboratoires Servier funded the article processing fees, editorial assistance, and open access fee for this manuscript.


Algoriphagus lacus sp. nov., isolated from a freshwater lake.
A Gram-stain-negative, non-motile, rod-shaped, oxidase-positive, red-pigmented bacterium, strain N3T, was isolated from Fuxian lake, a freshwater lake in Yunnan Province, PR China. Strain N3T was facultatively anaerobic, heterotrophic and negative for catalase. Optimal growth occurred at 30 °C (range 4-45 °C), pH 7.0-8.0 (range 6.5-9.5) and in the presence of 0-3 % (w/v) NaCl (range 0-3 %). The results of phylogenetic analysis based on 16S rRNA gene sequencing revealed that strain N3T was close to the type strains of Algoriphagus aquaeductus, Algoriphagus shivajiensis and Algoriphagus alkaliphilus with sequence similarities of 97.4, 97.3 and 97.2 % respectively. The G+C content of the genomic DNA was 43.9 mol%. The quinone system contained menaquinone MK-7 as the sole component. The major fatty acids were iso-C15 : 0, summed feature 9 (10-methyl C16 : 0 and/or iso-C17 : 1 ω9c), summed feature 3 (C16 : 1 ω6c and/or C16 : 1 ω 7c) and iso-C16 : 0. Major polar lipids were phosphatidylcholine, phosphatidylethanolamine, an unidentified glycolipid, one unidentified phospholipid, two unidentified aminolipids and four unidentified lipids. On the basis of physiological, chemotaxonomic and molecular properties as well as phylogenetic distinctiveness, strain N3T should be placed into the genus Algoriphagus as a novel species, for which the name Algoriphagus lacus sp. nov. is proposed. The type strain is N3T (=KCTC 62622T=MCCC 1H00308T).


Phosphorylation of alphaB-crystallin in response to various types of stress.
Phosphorylation of alphaB-crystallin, a member of the hsp27 family, in human glioma (U373 MG) cells was stimulated by exposure of the cells to various stimuli, which included heat, arsenite, phorbol 12-myristate 13-acetate (PMA), okadaic acid, H2O2, anisomycin, and high concentrations of NaCl or sorbitol, but not in response to agents that elevated intracellular levels of cyclic AMP. Cells exposed to PMA together with okadaic acid yielded three bands of 32P-labeled alphaB-crystallin when immunoprecipitated samples were subjected to electrophoresis on an isoelectric focusing gel. All of the phosphorylated residues were identified as serine, an indication that three different serine residues can act as sites of phosphorylation in alphaB-crystallin. Structural analysis by mass spectrometry revealed that phosphorylation of alphaB-crystallin occurred at serines 19, 45, and 59. Dithiothreitol and staurosporine selectively inhibited the phosphorylation induced by arsenite and the phorbol ester, respectively. SB202190, an inhibitor of p38 mitogen-activated protein (MAP) kinase, suppressed the phosphorylation induced by arsenite, anisomycin, H2O2, sorbitol, NaCl, and heat shock, but not that induced by PMA and okadaic acid. The PMA-induced phosphorylation was selectively suppressed by an inhibitor of p44 MAP kinase kinase, PD98059. Although PMA and arsenite preferentially stimulated the phosphorylation of Ser-45 and Ser-59, respectively, as determined with antibodies that recognized the respective phosphorylated forms of alphaB-crystallin, all three sites were phosphorylated in response to each stimulus. These results suggest that p38 MAP kinase or p44 MAP kinase might be involved in the signal transduction cascade that leads to the phosphorylation of alphaB-crystallin. The phosphorylation of alphaB-crystallin was also enhanced in the heart and diaphragm when rats were exposed to heat stress (42 degrees C for 20 min).


Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model.
Internal tandem duplications of the juxtamembrane domain of FLT3 (FLT3/ITD) are among the most common mutations in Acute Myeloid Leukemia (AML). Resulting in constitutive activation of the kinase, FLT3/ITD portends a particularly poor prognosis, with reduced overall survival and increased rates of relapse. We previously generated a knock-in mouse, harboring an internal tandem duplication at the endogenous Flt3 locus, which develops a fatal myeloproliferative neoplasm (MPN), but fails to develop acute leukemia, suggesting additional mutations are necessary for transformation. To investigate the potential cooperativity of FLT3/ITD and mutant DNMT3A, we bred a conditional Dnmt3a knockout to a substrain of our Flt3/ITD knock-in mice, and found deletion of Dnmt3a significantly reduced median survival of Flt3ITD/+ mice in a dose dependent manner. As expected, pIpC treated Flt3ITD/+ mice solely developed MPN, while Flt3ITD/+;Dnmt3af/f and Flt3ITD/+;Dnmt3af/+ developed a spectrum of neoplasms, including MPN, T-ALL, and AML. Functionally, FLT3/ITD and DNMT3A deletion cooperate to expand LT-HSCs, which exhibit enhanced self-renewal in serial re-plating assays. These results illustrate that DNMT3A loss cooperates with FLT3/ITD to generate hematopoietic neoplasms, including AML. In combination with FLT3/ITD, homozygous Dnmt3a knock-out results in reduced time to disease onset, LT-HSC expansion, and a higher incidence of T-ALL compared with loss of just one allele. The co-occurrence of FLT3 and DNMT3A mutations in AML, as well as subsets of T-ALL, suggests the Flt3ITD/+;Dnmt3af/f model may serve as a valuable resource for delineating effective therapeutic strategies in two clinically relevant contexts.


A data-driven approach to patient blood management.
Patient blood management (PBM) has become a topic of intense interest; however, implementing a robust PBM system in a large academic hospital can be a challenge. In a joint effort between transfusion medicine and information technology, we have developed three overlapping databases that allow for a comprehensive, semiautomated approach to monitoring up-to-date red blood cell (RBC) usage in our hospital. Data derived from this work have allowed us to target our PBM efforts. Information on transfusions is collected using three databases: daily report, discharge database, and denominator database. The daily report collects data on all transfusions in the past 24 hours. The discharge database integrates transfusion data and diagnostic billing codes. The denominator database allows for rate calculations by tracking all patients with a hemoglobin test ordered. A set of algorithms is applied to automatically audit RBC transfusions. The transfusions that do not fit the algorithms' rules are manually reviewed. Data from audits are compiled into reports and distributed to medical directors. Data are also used to target education efforts. Since our PBM program began, the percentage of appropriate RBC orders increased from an initial 70%-80% to 90%-95%, and the overall RBC transfusions/1000 patient-days has decreased by 67% in targeted areas of the hospital. Our PBM program has shaved approximately 3% from our hospital's blood budget. Our semiautomated auditing system allows us to quickly and comprehensively analyze and track blood usage throughout our hospital. Using this technology, we have seen improvements in our hospital's PBM.


Salivary agglutinin inhibits HIV type 1 infectivity through interaction with viral glycoprotein 120.
Salivary agglutinin (SAG) is a high molecular mass glycoprotein (340 kDa) that plays important roles in innate immunity. SAG has been found to specifically inhibit HIV-1 infectivity and to bind to virus through the envelope protein gp120. Although SAG binds to gp120 of the virus, the exact nature of this binding has not been characterized. Using surface plasmon resonance technology, we have found that SAG interacts with recombinant envelopes derived from diverse HIV-1 isolates with K(D) values ranging from 10(-7) to 10(-10) M, comparable to gp120-sCD4 binding. Furthermore, SAG binding to gp120 is Ca(2+) dependent. sCD4 prebound to gp120 failed to abrogate SAG binding, suggesting a distinct mechanism for SAG inhibition of HIV-1 infectivity. Inhibition by monoclonal antibodies specific for carbohydrates also implicates the involvement of carbohydrates in the interaction between SAG and gp120. These results argue that the anti-HIV-1 activity of SAG is due to carbohydrate-mediated binding to gp120. A demonstration that SAG is related to lung scavenger receptor, gp-340, further suggests the roles of SAG in preventing pathogen invasion at the entry portal and raises its potential as an anti-HIV-1 drug candidate.


A prospective randomized trial comparing intravenous 5-fluorouracil and oral doxifluridine as postoperative adjuvant treatment for advanced rectal cancer.
Postoperative adjuvant chemoradiation treatment after curative resection for rectal cancer was needed to reduce recurrence and improve a survival rate. Intravenous 5-fluorouracil (5-FU) and leucovorin has been a mainstay of chemotherapy, but oral 5-FU derivatives have been shown a comparable antitumor activity. Intravenous 5-FU and oral doxifluridine were compared with respect to therapeutic efficacy, drug toxicity, and quality of life. A total of 166 patients were randomized to receive intravenous 5-FU (450 mg/m2/day) or oral doxifluridine (900 mg/m2/day) in combination with leucovorin (20 mg/m2/day) for depth of invasion, nodal status, metastasis (TNM) stage II and III patients between October 1997 and February 1999. Consecutive daily intravenous infusion for 5 days per every month for a total of 12 cycles (IV arm, n = 74) and oral doxifluridine daily for 3 weeks and 1 week rest for a total of 12 cycles (oral arm, n = 92). Drug toxicity and quality of life were observed. Quality of life was scored according to 22 daily activity items (good, > or =71; fair, < 70; poor, < 52). There was no difference of sex between two groups (IV arm: male/female = 45/29, oral arm: male/female = 59/33). The mean age was 52.3 vs. 59.5, respectively. There was also no difference of TNM stage distribution and type of operation between groups (P>.05). Mean numbers of chemotherapy cycles were 6.5+/-3.7 (IV arm) vs. 7.2+/-4.3 (oral arm), respectively. The rate of recurrence was 9/74 (12.1%) in the IV arm and 6/92 (6.5 %) in the oral arm, respectively (P = .937). Local recurrence was 2/74 (stage III; 2.7%) in the IV arm and 1/92 (stage II; 1.1%) in the oral arm, respectively. Systemic recurrence was 7/74 (stage III; 9.4%) in the IV arm and 5/92 (stage III; 5.4%) in the oral arm, respectively. The most common site of systemic recurrence was the liver. Toxicity profile was as follows: leukopenia (30/74 vs. 17/92) and alopecia (21/74 vs. 13/92) were statistically more common in the IV arm. Diarrhea was more common in the oral arm. Poor quality of life score between two groups was observed at 1 month (23.9% vs. 13%) and 2 months (15.8% vs. 3.7%) after chemotherapy. Good quality of life score was observed at 1 month (19.5% vs. 49%) and 2 months (47% vs. 72%), respectively (P<.05). Oral doxifluridine with leucovorin shows a comparable therapeutic efficacy to intravenous 5-FU regimen with high quality of life as postoperative adjuvant therapy. The oral regimen also can be safely given with appropriate toxicity and tolerability.


Ultrasonic appearance of pyelogenic cysts.
Two cases, one in an adult and one in a child, of ultrasonically demonstrated cystic masses were shown to be pyelogenic cysts on contrast urography. Because of the similar appearance of pyelogenic and simple cysts of the kidney on sonography, contrast urography is important for the differential diagnosis.


Implant Dental Rehabilitation of Fibula-Free Flap Reconstructed Jaws.
The possibility of placing dental fixtures in the reconstructed regions allows us to overcome the problems related to dental rehabilitation with removable prosthesis. The aim of this study was to assess the clinic-radiological outcome in a series of patients who underwent fibula flap jaws reconstruction and rehabilitation with implant-supported prosthesis with a minimum follow-up of 24 months. The study included 10 patients who underwent reconstruction with fibula free flap between 2010 and 2018. Albrektsson criteria were used to define the implant survival. The follow-up evaluation was performed according to a standardized protocol including clinical examination, radiological evaluation (panoramic radiograph) and patient interview. A total of 45 implants were positioned.The time between mandibular reconstruction and implant placement ranged from 13 months to 39 months.The prosthesis used was fixed in 6 cases and supported overdenture in 4 cases.No implant failure was observed.Regarding implant survival no infections were observed in these series. Nine patients out of 10 had no pain and signs of mobility. Seven patients out of 10 had absence of peri-implant radiolucency at the panoramic radiograph.One patient presented with an overgrowth of granulomatous soft tissue around the implant abutments that caused pain. Implant placed in vascularized bone grafts are a safe and reliable opportunity to rehabilitate patients following mandibular resection. The results of this series demonstrate a high survival rate for implants placed in reconstructed mandibles with an improvement of the quality of life.


Impaired Replenishment of Cortico-Striatal Synaptic Glutamate in Huntington's Disease Mouse Model.
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by expansion of CAG repeats in the Huntingtin gene (HTT). Studies suggest cortical to striatal (C-S) projections, which regulate movement and provide cell survival signals to SPNs, are altered in the pre-manifest and early symptomatic stages of HD. But whether and how presynaptic cortical terminals are affected in HD is not well explored. Test size and replenishment of readily releasable pool (RRP), and assess glutamate refill of C-S synapses in HD models. Immunocytochemistry was applied in C-S co-cultures generated from FVB/N (WT: wildtype) mice and YAC128, an HD mouse model expressing human HTT with 128 CAG repeats on the FVB/N background; Whole-cell patch clamp recordings from striatal neurons were performed both in cultures, with or without osmotic stimuli, and in acute brain slices from 6-month-old early symptomatic YAC128 mice and WT following prolonged trains of electrical stimuli in corpus callosum. We found no change in the average size or vesicle replenishment rate of RRP in C-S synapses of YAC128, compared with WT, cultures at day in vitro 21, a time when immunocytochemistry showed comparable neuronal survival between the two genotypes. However, YAC128 C-S synapses showed a slowed rate of recovery of glutamate release in co-cultures as well as in acute brain slices. Mutant HTT expression impairs glutamate refill but not RRP size or replenishment in C-S synapses. This work provides a foundation for examining the contribution of deficits in presynaptic cortical terminals on HD progression.


Characteristics of child sexual assault within a child advocacy center client population.
This descriptive study summarized data from a child advocacy center to illustrate how such information might be used to profile the scope and character of child sexual abuse (CSA) at the community level. This detailed information is not available from national or state data but is needed to understand the circumstances of the children receiving services and the type of care they may need. Variables included victim demographics, type of sexual abuse and relationship to the perpetrator, and the person to whom the victim was most likely to disclose their sexual assault. A total sample of 841 case reports was reviewed. Chi-square tests were used to determine if there were statistically significant associations between the age groupings, type of abuse, and the perpetrator according to age grouping. Those children most often seen at this child advocacy center were girls (73%); White (67%); and living with their mothers, with both parents, or with parent and stepparent (80%). The incidence of CSA increased for girls across age groups. However, boys aged 6-10 years comprised the greatest percentage of the male sample (56%) who experienced CSA. For all three age groups, over half of the perpetrators were identified as relatives. Most children (85%) experienced high-impact sexual abuse behaviors of fondling, penetration, or some combination thereof. Children most often disclosed CSA to their mothers. Understanding patterns of CSA at the local level provides guidance beyond national and state data to forensic nurses regarding child and family needs within their communities.


Evaluating the Type of Light Transmittance in Mono Crystalline, Poly Crystalline and Sapphire Brackets- An Invitro Spectrofluorometer Study.
Most of the patients seek orthodontic treatment to improve the smile, which improves the facial profile by means of fixed appliances i.e., brackets and wires. The brackets are of different types like stainless steel and ceramic. Ceramic brackets were considered as aesthetic appliance which was divided into mono-crystalline, polycrystalline and sapphire brackets. The light transmittance might influence the degree of curing adhesive material in mono crystalline, polycrystalline and sapphire brackets. The aim of the present study was to evaluate the translucency and intensity of three different aesthetic brackets (mono crystalline, poly crystalline and sapphire ceramic brackets) and to determine their influence on shear bond strength of the brackets. The adhesive remnant index was also measured after debonding of the brackets from the tooth surface. Twenty six samples each of monocrystalline, polycrystalline and sapphire brackets (total 78 ceramic brackets) were used for the study. The bracket samples were subjected to optical fluorescence test using spectrofluorometer to measure the intensity of the brackets. Seventy eight extracted premolar teeth were procured and divided into 3 groups. The brackets were then bonded to the tooth using Transbond XT (3M Unitek) light cure composite material and cured with new light cure unit (Light Emitting Diode) of wood pecker company (400-450nm) for 30 seconds, and these samples were subjected to shear bond strength test with Instron Universal Testing Machine (UNITEK-94100) with a load range between 0 to 100 KN with a maximum cross head speed of 0.5mm/min. ARI (Adhesive Remnant Index) scores were evaluated according to Artun and Bergland scoring system using stereomicroscope at 20x magnification. The light absorption values obtained from spectrofluorometeric study were 3300000-3500000 cps for group 1 (monocrystalline ceramic brackets), 6000000-6500000 cps for Group 2 (polycrystalline ceramic brackets) and 2700000 -3000000 cps for Group 3 (sapphire ceramic brackets) i.e., Group 2 showed the highest light absorption and the least translucency followed by groups 1 and 3. Shear bond strength results were 2.4 mpa, 1.9 mpa and 3.6 mpa for groups 1,2 and 3 respectively. Superior shear bond strength was recorded in group 3 (sapphire ceramic brackets). ARI results showed that group 3 had increased bond between bracket adhesive interfaces when compared to the other 2 groups. From this study, it has been concluded that sapphire ceramic brackets (Group 3) was superior in translucency and shear bond strength followed by monocrystalline and polycrystalline ceramic brackets.


Evidence from automixis with inverted meiosis for the maintenance of sex by loss of complementation.
The adaptive value of sexual reproduction is still debated. A short-term disadvantage of asexual reproduction is loss of heterozygosity, which leads to the unmasking of recessive deleterious mutations. The cost of this loss of complementation is predicted to be higher than the twofold cost of meiosis for most types of asexual reproduction. Automixis with terminal fusion of sister nuclei is especially vulnerable to the effect of loss of complementation. It is found, however, in some taxa including oribatid mites, the most prominent group of ancient asexuals. Here, I show that automixis with terminal fusion is stable if it is associated with inverted meiosis and that this appears to be the case in nature, notably in oribatid mites. The existence of automixis with terminal fusion, and its co-occurrence with inverted meiosis, therefore, is consistent with the hypothesis that loss of complementation is important in the evolution of sexual reproduction.


Age and gender differences in response to neonatal ethanol withdrawal and polyamine challenge in organotypic hippocampal cultures.
Polyamines are synthesized and released in high concentrations during CNS development. These agents can potentiate N-methyl-D-aspartate receptor (NMDAR) function and appear to play an important role in CNS development. Previous work has shown that polyamine release is increased during ethanol withdrawal (EWD). This likely promotes NMDAR overactivity and contributes to neurotoxicity during EWD, however, little is known regarding such effects in early neonatal brain. The present study compared the effects of EWD and polyamine exposure on toxicity in hippocampal slice cultures derived from postnatal day 2 (PND 2) or postnatal day 8 (PND 8) day-old rats. Due to changes in NMDAR subtypes and response to polyamines, we predicted that slices taken from PND 2 pups would be more sensitive to EWD and polyamine challenge. Organotypic hippocampal slice cultures were obtained from neonatal rats either 2 or 8 days of age (PND 2 or PND 8). Five days after explantation, cultures were exposed to ETOH (50 mM- typically subthreshold for EWD induced cell death) for 10 days and then withdrawn from ETOH for 24-hour in the presence of 100 microM of the polyamine spermidine and/or 100 microM ifenprodil, an NMDAR antagonist that blocks the NMDAR that is the most sensitive to polyamine modulation. Cytotoxicity was measured after 24-hour by visualization of propidium iodide (PI) fluorescence. There were clear age and gender-dependent differences in response to EWD and to polyamines. EWD produced significant increases in PI uptake in all subregions (CA1, CA3 and DG) of cultures derived from PND 2 pups, but not PND 8 pups. Exposure of cultures to spermidine for 24-hour also produced significant increases in cytotoxicity in all 3 regions of PND 2 cultures with no gender differences. In contrast, there were both gender and region-specific differences in response to spermidine in cultures from PND 8. While the CA1 region of both sexes displayed increased cytotoxicity following spermidine exposure, only females showed increased cytotoxicity in the CA3 region while the DG appeared relatively insensitive to spermidine. Exposure to spermidine during EWD produced enhanced toxicity in all 3 hippocampal subregions in tissue from both PND 2 and PND 8 rats and this was reduced or prevented by co-exposure to ifenprodil. Of interest, the PND 2 hippocampus was significantly more sensitive than the PND 8 hippocampus to the toxic effects of EWD and to spermidine during EWD in the DG and CA3 regions. Hippocampal slice cultures derived from PND 2 rats were more sensitive to the toxic effects of both EWD and EWD + spermidine exposure than were those derived from PND 8 rats. These findings are similar to recent behavioral data collected from our lab showing greater sensitivity to ETOH's behavioral teratogenic effects when ETOH exposure in vivo occurred during the first postnatal week relative to the second postnatal week. Ifenprodil's ability to block the toxic effects of spermidine during EWD suggests that excess activity of NR2B subunits of the NMDAR contributed to the excitatory and cytotoxic effects of EWD plus spermidine. While no sex differences in toxicity were observed in cultures taken from pups during the first postnatal week, these data do suggest that later in neonatal life (i.e., the second postnatal week), the female hippocampus may be more sensitive to polyamine-induced neurotoxicity than males.


Clinical correlates of quality of life in systemic sclerosis measured with the World Health Organization Disability Assessment Schedule II.
To identify the clinical characteristics of systemic sclerosis (SSc) that best correlate with the health-related quality of life (HRQOL) of patients with SSc, using the World Health Organization Disability Assessment Schedule II (WHODAS II) as the measure of HRQOL. A cross-sectional, multicenter study of 337 patients from the Canadian Scleroderma Research Group Registry was conducted. Patients were assessed through detailed clinical histories, medical examination, and the WHODAS II. Hierarchical multiple linear regression was used to assess the relationship between selected clinical variables and HRQOL. The mean WHODAS II score was 23.7 (range 0-100), with the greatest impairments seen in the subscales measuring life activities, mobility, and participation in society. In multivariate analysis, significant predictors of the WHODAS II were skin scores, shortness of breath, number of gastrointestinal problems, fatigue, pain, and depression. The final model explained 61% of the variance in the WHODAS II scores. The clinical characteristics identified in this study as significant correlates of HRQOL in SSc should each be targets of intervention in order to improve the HRQOL of patients with this disease.


Investigating the form-function interface in African apes: Relationships between principal moments of area and positional behaviors in femoral and humeral diaphyses.
Investigations of cross-sectional geometry in nonhuman primate limb bones typically attribute shape ratios to qualitative behavioral characterizations, e.g., leaper, slow climber, brachiator, or terrestrial vs. arboreal quadruped. Quantitative positional behavioral data, however, have yet to be used in a rigorous evaluation of such shape-behavior connections. African apes represent an ideal population for such an investigation because their relatedness minimizes phylogenetic inertia, they exhibit diverse behavioral repertoires, and their locomotor behaviors are known from multiple studies. Cross-sectional data from femoral and humeral diaphyses were collected for 222 wild-shot specimens, encompassing Pan paniscus and all commonly recognized African ape subspecies. Digital representations of diaphyseal cross sections were acquired via computed tomography at three locations per diaphysis. Locomotor behaviors were pooled broadly into arboreal and terrestrial categories, then partitioned into quadrupedal walking, quadrumanous climbing, scrambling, and suspensory categories. Sex-specific taxonomic differences in ratios of principal moments of area (PMA) were statistically significant more often in the femoral diaphysis than the humeral diaphysis. While it appears difficult to relate a measure of shape (e.g., PMA ratio) to individual locomotor modes, general locomotor differences (e.g., percentage arboreal vs. terrestrial locomotion) are discerned more easily. As percentage of arboreal locomotion for a group increases, average cross sections appear more circular. Associations between PMA ratio and specific locomotor behaviors are less straightforward. Individual behaviors that integrate eccentric limb positions (e.g., arboreal scrambling) may not engender more circular cross sections than behaviors that incorporate repetitive sagittal movements (e.g., quadrupedal walking) in a straightforward manner.


Racial Disparities in Extremity Soft-Tissue Sarcoma Outcomes: A Nationwide Analysis.
Racial disparities in access and survival have been reported in a variety of cancers. These issues, however, have yet to be explored in detail in patients with soft-tissue sarcomas (STS). The purpose of this paper was to investigate the independent role of race with respect to survival outcomes in STS. A total of 7601 patients were evaluated in this study. A SEER registry query for patients over 20 years old with extremity STS diagnosed between 2004 and 2009 (n=7225) was performed. Survival outcomes were analyzed after patients were stratified by race. Multivariable survival models were used to identify independent predictors of sarcoma-specific death. The Wilcoxon rank-sum test was used to compare continuous variables. Statistical significance was maintained at P<0.05. This study showed that African American patients were more likely to die of their STS. They were younger at presentation (P=0.001), had larger tumors (P<0.001), had less surgery (P=0.002), received radiotherapy less frequently (P=0.024), had higher family income (P<0.001), and were less likely to be married (P<0.001). African American race by itself was not an independent predictor of death. African Americans encounter death due to STS at a much larger proportion and faster rate than their respective white counterparts. African Americans frequently present with a larger size tumor, do not undergo surgical resection, or receive radiation therapy as frequently as compared with their white peers. Barriers to timely and appropriate care should be further investigated in this group of at-risk patients.


Associations of Prenatal Per- and Polyfluoroalkyl Substance (PFAS) Exposures with Offspring Adiposity and Body Composition at 16-20 Years of Age: Project Viva.
Findings on the associations between prenatal PFAS exposures and offspring adiposity are inconsistent. Whether such associations may extend to adolescence is especially understudied. We investigated associations of prenatal PFAS exposures with offspring adiposity and body composition at 16-20 years of age. We studied 545 mother-child pairs in the prospective prebirth cohort Project Viva (Boston, Massachusetts). We measured six PFAS (PFOA, PFOS, PFNA, PFHxS, EtFOSAA, and MeFOSAA) in maternal early pregnancy (median age=9.6wk, range: 5.7-19.6 wk) plasma samples. At the late adolescence visit (median age=17.4 y, range: 15.9-20.0 y), we obtained anthropometric measures and assessed body composition using bioelectrical impedance analysis and dual-energy X-ray absorptiometry. We examined associations of individual PFAS with obesity [i.e., age- and sex-specific body mass index (BMI) ≥95th percentile] and adiposity and body composition using multivariable Poisson and linear regression models, respectively. We assessed PFAS mixture effects using Bayesian kernel machine regression (BKMR) and quantile g-computation. We used fractional-polynomial models to assess BMI trajectories (at 3-20 years of age) by prenatal PFAS levels. Thirteen percent (n=73) of the children had obesity in late adolescence. After multivariable adjustment, higher prenatal PFAS concentrations were associated with higher obesity risk [e.g., 1.59 (95% CI: 1.19, 2.12), 1.24 (95% CI: 0.98, 1.57), and 1.49 (95% CI: 1.11, 1.99) times the obesity risk per doubling of PFOS, PFOA, and PFNA, respectively]. BKMR showed an interaction between PFOA and PFOS, where the positive association between PFOS and obesity was stronger when PFOA levels were lower. Each quartile increment of the PFAS mixture was associated with 1.52 (95% CI: 1.03, 2.25) times the obesity risk and 0.52 (95% CI: -0.02, 1.06) kg/m2 higher BMI. Children with higher prenatal PFOS, EtFOSAA, and MeFOSAA concentrations had higher rates of BMI increase starting from 9-11 years of age. Prenatal PFAS exposures may have obesogenic effects into late adolescence. https://doi.org/10.1289/EHP12597.


From awareness to action: an urgent call to reduce mortality and improve outcomes in eating disorders.
High mortality rates and poor outcomes from eating disorders, especially anorexia nervosa, are largely preventable and require urgent action. A national strategy to address this should include prevention; early detection; timely access to integrated physical and psychological treatments; safe management of emergencies; suicide prevention; and investment in training, services and research.


Naloxegol versus Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Patients.
Constipation impacts 58% to 83% of critically ill patients and is associated with increased time on mechanical ventilation, delirium, and increased length of stay (LOS) in the intensive care unit (ICU). The purpose of this study was to evaluate the efficacy of enteral naloxegol (NGL) versus subcutaneous methylnaltrexone (MNTX) for the management of opioid-induced constipation (OIC) in critically ill patients. A retrospective analysis was conducted on adult patients admitted to the ICU who received a parenteral opioid infusion for at least 4 hours and experienced no bowel movement (BM) within the 48-hour period preceding the administration of NGL or MNTX. The primary outcome was time to first BM from the start of NGL or MNTX therapy. Secondary outcomes included number of BMs 72 hours following NGL or MNTX administration, ICU LOS, and cost-effectiveness. After exclusion criteria were applied, 110 and 51 patients were included in the NGL and MNTX groups, respectively. With a 10% noninferiority margin, NGL was noninferior to MNTX (Wald statistic = 1.67; P = 0.047). Median time to first BM was 23.7 hours for NGL and 18.3 hours for MNTX patients. Median LOS was 14 days (NGL) and 12 days (MNTX), and the average number of BMs in 72 hours was 3.9 for NGL and 3.8 for MNTX. Using wholesale acquisition cost (WAC), the cost per BM for NGL and MNTX was $21.74 and $170.00, respectively. This study determined that NGL and MNTX had similar time to BM. NGL appears to be a safe and effective alternative with cost-saving potential in treating OIC in critically ill patients.


The effect of electrical stimulation of the pudendal nerve on sciatic nerve blood flow in animals.
To investigate the mechanism of the clinical effect of electroacupuncture of the pudendal nerve on the lumbar and lower limb symptoms caused by lumbar spinal canal stenosis, we studied changes in sciatic nerve blood flow during electrical stimulation of the pudendal nerve in the rat. METHODS Using rats (n=5), efferent electrical stimulation to the pudendal nerve was performed and sciatic nerve blood flow was measured with laser Doppler flowmetry. Simultaneously, changes in the blood pressure and cardiac rate were measured. Furthermore, the effect of atropine on these responses to the stimulation was also studied. Electrical stimulation of the pudendal nerve significantly increased blood flow in the sciatic nerve transiently without increasing heart rate and systemic blood pressure. The significant increase in the sciatic nerve blood flow disappeared after administration of atropine. Electrical stimulation of the pudendal nerve causes a transient and significant increase in sciatic nerve blood flow. This response is eliminated or attenuated by administration of atropine, indicating that it occurs mainly via cholinergic nerves.


Current Practices in Treating Cardiomyopathy and Heart Failure in Duchenne Muscular Dystrophy (DMD): Understanding Care Practices in Order to Optimize DMD Heart Failure Through ACTION.
Cardiac disease has emerged as a leading cause of mortality in Duchenne muscular dystrophy in the current era. This survey sought to identify the diagnostic and therapeutic approach to DMD among pediatric cardiologists in Advanced Cardiac Therapies Improving Outcomes Network. Pediatric cardiology providers within ACTION (a multi-center pediatric heart failure learning network) were surveyed regarding their approaches to cardiac care in DMD. Thirty-one providers from 23 centers responded. Cardiac MRI and Holter monitoring are routinely obtained, but the frequency of use and indications for ordering these tests varied widely. Angiotensin converting enzyme inhibitor and aldosterone antagonist are generally initiated prior to onset of systolic dysfunction, while the indications for initiating beta-blocker therapy vary more widely. Seventeen (55%) providers report their center has placed an implantable cardioverter defibrillator in at least 1 DMD patient, while 11 providers (35%) would not place an ICD for primary prevention in a DMD patient. Twenty-three providers (74%) would consider placement of a ventricular assist device (VAD) as destination therapy (n = 23, 74%) and three providers (10%) would consider a VAD only as bridge to transplant. Five providers (16%) would not consider VAD at their institution. Cardiac diagnostic and therapeutic approaches vary among ACTION centers, with notable variation present regarding the use of advanced therapies (ICD and VAD). The network is currently working to harmonize medical practices and optimize clinical care in an era of rapidly evolving outcomes and cardiac/skeletal muscle therapies.


Shape matters: plasmonic nanoparticle shape enhances interaction with dielectric substrate.
Numerical analyses of the ultraviolet and visible plasmonic spectra measured from hemispherical gallium nanostructures on dielectric substrates reveal that resonance frequencies are quite sensitive to illumination angle and polarization in a way that depends on nanostructure size, shape, and substrate. Large, polarization-dependent splittings arise from the broken symmetry of hemispherical gallium nanoparticles on sapphire substrates, inducing strong interactions with the substrate that depend sensitively on the angle of illumination and the nanoparticle diameter.


Evidence-based approach to treatment of febrile neutropenia in hematologic malignancies.
Applying the principles of evidence-based medicine to febrile neutropenia (FN) results in a more limited set of practices than expected. Hundreds of studies over the last 4 decades have produced evidence to support the following: (1) risk stratification allows the identification of a subset of patients who may be safely managed as outpatients given the right health care environment; (2) antibacterial prophylaxis for high-risk patients who remain neutropenic for ≥7 days prevents infections and decreases mortality; (3) the empirical management of febrile neutropenia with a single antipseudomonal beta-lactam results in the same outcome and less toxicity than combination therapy using aminoglycosides; (4) vancomycin should not be used routinely empirically either as part of the initial regimen or for persistent fever, but rather should be added when a pathogen that requires its use is isolated; (5) empirical antifungal therapy should be added after 4 days of persistent fever in patients at high risk for invasive fungal infection (IFI); the details of the characterization as high risk and the choice of agent remain debatable; and (6) preemptive antifungal therapy in which the initiation of antifungals is postponed and triggered by the presence, in addition to fever, of other clinical findings, computed tomography (CT) results, and serological tests for fungal infection is an acceptable strategy in a subset of patients. Many practical management questions remain unaddressed.


Seven years' experience with antilymphoblast globulin for renal transplantation from cadaver donors.
Antibody of the IgGab type can be isolated from horses immunized with cultured human lymphoblasts plus complete Freund's adjuvant. The essential steps for the production of a safe, potent anti-human lymphoblast globulin (ALG) are: A) the use of early bleedings after immunization to reduce the titer of antibodies which react with red blood cells and platelets; B) careful absorption with human red blood cell stroma and platelets; C) stabilization with non-crystalline silica dioxide; D) chromatography through QAE sephadex to remove pyrogens, microaggregates and possible inhibitors of ALG activity; E) careful safety testing in animals for toxicity and pyrogenicity; and F) testing in vitro for sterility. Such a purified horse ALG (IgGab) can be administered safely intravenously to patients to supplement a standardized immunosuppressive regimen incorporating azathioprine and prednisone. Under these circumstances, allergic reactions are very rare, antibodies to horse IgG do not develop, skin tests to horse IgG remain negative, and immune elimination of circulating horse IgG from the human circulation cannot be demonstrated. The overall results of ALG patient survival and transplant function after 184 consecutive first cadaver transplants at the University of Minnesota demonstrate a statistically significant improvement in both parameters accompanying increases in ALG dose while rigidly utilizing standardized doses of azathioprine and prednisone. There is a significant reduction in the number of grafts lost to rejection; significant reduction in the number of rejection episodes; significant delay in the onset of rejection episodes; but there is no increase in septic loss of patients or kidneys. These efforts could be seen in the gross data or when subgroups controlling for patient age, tissue typing were analyzed. Excluding patients at high risk did not alter the results. The beneficial effects of ALG were particularly striking in good matches. In the highest doses, ALG may be dangerous for older patients with poor matches who develop an increased incidence of septic loss of kidney and/or life. Thus, ALG appears to be a useful adjunct in the early management of cadaver transplants by reducing the incidence and frequency of rejection episodes. The dose should probably be reduced in the older patients who receive kidneys from badly mismatched donors. One cannot conclude from this study that ALG manufactured in other centers by this or other techniques, will accomplish the same results since the multiplicity of factors involved in the success and failure of transplants must be controlled so that the influence of intravening variables in the assessment of ALG effectiveness can be assessed.


Infrared Resonance Tuning of Nanoslit Antennas with Phase-Change Materials.
Phase-change materials (PCMs) have been established as prime candidates for nonvolatile resonance tuning of nanophotonic components based on a large optical contrast between their amorphous and crystalline states. Recently, the plasmonic PCM In3SbTe2 was introduced, which can be switched from an amorphous dielectric state to a crystalline metallic one over the entire infrared spectral range. While locally switching the PCM around metallic nanorod antennas has already been demonstrated, similar tuning of inverse antenna structures (nanoslits) has not yet been investigated. Here, we demonstrate optical resonance tuning of nanoslit antennas with dielectric and plasmonic PCMs. We compare two geometries with fundamentally different resonance tuning mechanisms: tuning the resonance of aluminum slit antennas by change of the refractive index (dielectric PCM Ge3Sb2Te6), and creating slit-like volumes of amorphous In3SbTe2 and modifying the slit geometry directly (plasmonic PCM In3SbTe2). While the tuning range with the plasmonic PCM is about 3.4 μm and only limited by fabrication, the resonances with the dielectric PCM feature a three times larger quality factor compared to resonances obtained with the plasmonic PCM.


Nerve fiber conduction velocity distributions: studies of normal and diabetic human nerves.
We have assessed the clinical applicability of a previously described new method for analyzing the distribution of conduction velocities (DCV) in peripheral nerve. Surface-recorded median sensorimotor compound action potentials (CAPs) were found to contain contributions from classes of fibers conducting between 25 and 80 m/sec in the elbow-to-axilla segment. Test-retest correlation coefficients ranged from 0.91 to 0.98. Increasing stimulus intensity recruited additional fiber activity into the CAP with relative preferential activation of faster-conducting fibers at lower stimulus levels. Changes in limb temperature altered the conduction velocity of all fiber classes 4% per degree Celsius. A comparison of fiber diameter distribution and DCVs in a normal sural nerve gave a correlation of 0.70 over the range of 7 to 12 mu. Diabetic patients with minimal or no clinical polyneuropathy showed varying degrees of DCV shift toward the slower conduction velocities, sometimes even in the face of normal conventional nerve conduction studies. These findings indicate that the DCV may be considered the electrophysiological counterpart--not equivalent--of the fiber diameter distribution, with the capacity to distinguish subtle differences in conduction properties of normal and diseased human nerves.


Codon reading patterns in Drosophila melanogaster mitochondria based on their tRNA sequences: a unique wobble rule in animal mitochondria.
Mitochondrial (mt) tRNA(Trp), tRNA(Ile), tRNA(Met), tRNA(Ser)GCU, tRNA(Asn)and tRNA(Lys)were purified from Drosophila melanogaster (fruit fly) and their nucleotide sequences were determined. tRNA(Lys)corresponding to both AAA and AAG lysine codons was found to contain the anticodon CUU, C34 at the wobble position being unmodified. tRNA(Met)corresponding to both AUA and AUG methionine codons was found to contain 5-formylcytidine (f(5)C) at the wobble position, although the extent of modification is partial. These results suggest that both C and f(5)C as the wobble bases at the anticodon first position (position 34) can recognize A at the codon third position (position 3) in the fruit fly mt translation system. tRNA(Ser)GCU corresponding to AGU, AGC and AGA serine codons was found to contain unmodified G at the anticodon wobble position, suggesting the utilization of an unconventional G34-A3 base pair during translation. When these tRNA anticodon sequences are compared with those of other animal counterparts, it is concluded that either unmodified C or G at the wobble position can recognize A at the codon third position and that modification from A to t(6)A at position 37, 3'-adjacent to the anticodon, seems to be important for tRNA possessing C34 to recognize A3 in the mRNA in the fruit fly mt translation system.


Developmental regulation of the gibberellin biosynthetic gene GA1 in Arabidopsis thaliana.
The GA1 gene of Arabidopsis thaliana encodes ent-kaurene synthase A (KSA), which catalyzes the first committed step in the biosynthetic pathway of the plant hormone gibberellin (GA). Its location in the GA biosynthetic pathway has led to speculation that KSA regulation is one of the controlling steps. However, because KSA activity is so low that it is only measurable in Arabidopsis siliques, GA1 promoter-GUS reporter gene fusions and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) were used to examine the expression pattern of GA1. The results from this study indicate that GA1 gene expression is highly regulated during growth and development, and it is restricted to specific cell types at the sites of expression. GA1 promoter activity is highest in rapidly growing tissues, e.g. shoot apicas, root tips, developing flowers and seeds. It is also active in the vascular tissue of some non-growing organs, such as expanded leaves, suggesting that these leaves may be a site of GA synthesis for transport to other organs. It was also found that the first one or two introns in the GA1 gene are required for proper expression. Because of the high degree of regulation, GA1 may act as a gatekeeper, controlling the flow of metabolites into the GA biosynthetic pathway, while the levels of specific bioactive GAs are controlled by other downstream steps.


PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid.
Retinoic acid stimulates alpha-secretase processing of amyloid precursor protein (APP) and decreases beta-secretase cleavage that leads to amyloid-beta formation. Here, we investigated the effect of retinoic acid on the two putative alpha-secretases, the disintegrin metalloproteinases ADAM10 and TACE, and the beta-site cleaving enzyme BACE1, in human neuroblastoma SH-SY5Y cells. Western blot analysis showed that exposure to retinoic acid resulted in significantly increased levels of ADAM10 and TACE, suggesting that regulation of alpha-secretases causes the effects on APP processing. The presence of the phosphatidylinositol 3-kinase inhibitor LY 294002 selectively reduced the effect on ADAM10 protein levels but not on ADAM10 mRNA levels as determined by RT-PCR. On the other hand, the effect on TACE was shown to be dependent on protein kinase C, since it was completely blocked in the presence of the inhibitor bisindolylmaleimide XI. Our data indicate that different signalling pathways are involved in retinoic acid-induced up-regulation of the secretases.


Increased risk for atherosclerosis estimated by pulse wave velocity in hypothyroidism and its reversal with appropriate thyroxine treatment.
Pulse wave velocity (PWV) is known to represent arterial stiffness and is established as a marker for cardiovascular risk and a prognostic factor for mortality in the case of chronic renal failure or hypertension. The application of an automated apparatus for measuring brachial-ankle pulse wave velocity (baPWV) has made PWV measurement non-invasive, easier to screen for cardiovascular risk and as a result, baPWV measurements have become widely applied in clinical practice in recent years. We assessed the baPWV in 7 flank hypothyroidism patients and 28 subclinical hypothyroidism patients. In comparison with age matched healthy controls, 3 hypothyroid patients had advanced values and by replacement therapy, all 7 subjects showed improvement in their baPWV values (1531.2 +/- 242.7 to 1330.2 +/- 208.6 cm/s, p<0.05). In 28 subclinical hypothyroid subjects, 71% also had accelerated baPWV values for their age. Ten subjects (36% of all) had neither hypertension, hyperlipidemia, diabetes nor were taking any medication, and yet 8 patients out of 10 showed advanced baPWV values compared to age matched mean values. The baPWV was not correlated to TSH or total cholesterol levels, and was associated with only age and blood pressure (p = 0.01, <0.001, respectively), which are widely demonstrated as the characteristics for baPWV. In two subclinical hypothyroid subjects, who were normotensive and had no dyslipidemia, thyroxine treatment was performed and the baPWV decreased with unchanged blood pressure and total cholesterol levels. We concluded that the arterial wall stiffness tends to be increased in both overt and subclinical hypothyroid patients, and an appropriate treatment could reverse the abnormalities. It is possible that the initiation of adequate treatment in subclinical hypothyroidism may reduce the cardiovascular risk.


'Outsourced' patients and their companions: stories from forced medical travellers.
In this paper, I describe the experience of 'outsourced' patients who are sent by their governments or insurers through contractual arrangements to a hospital in another country for treatment. I present case studies of nine patients and their accompanying families from the Gulf Cooperation Council (GCC) who were interviewed in a Thai hospital as part of a broader study of medical travel from patients' perspectives. The health systems of the GCC suffer shortages in infrastructure, human resources and management skills, and as a consequence patients with particular needs, especially in neurology, orthopaedics and oncology may be sent overseas for treatment. Patients experience long stays overseas producing a considerable burden to their families supporting them. Such patients complicate notions of medical travel but their status also contrasts markedly from stereotypes held about Gulf patients within Thailand. Despite their appreciation of government sponsoring, for many patients the experience of care in Thailand underscored perceived inadequacies of their home health systems and governments. For some, outsourcing represented a betrayal of the obligations of their states to its citizens.


Fusarium species isolated from Pennisetum clandestinum collected during outbreaks of kikuyu poisoning in cattle in South Africa.
Kikuyu poisoning occurs sporadically in South Africa. It is of major economic importance, as valuable dairy cows are often poisoned by it, and once affected, the mortality rate is high. Pennisetum clandestinum samples were collected during eight outbreaks of kikuyu poisoning in cattle in the Eastern Cape Province of South Africa from 2008 to 2010. The kikuyu grass samples were submitted specifically for the isolation and molecular identification of Fusarium species, as it was recently suggested that mycotoxins synthesised by Fusarium torulosum could be the cause of this intoxication. Ninety-four Fusarium isolates were retrieved from the grass samples, of which 72 were members of the Fusarium incarnatum/Fusarium equiseti species complex based on morphology and phylogenetic analyses of the translation elongation factor 1α sequence data. The South African isolates from kikuyu identified as members of the F. incarnatum/F. equiseti species complex grouped together in six separate clades. The other isolates were Fusarium culmorum (n = 3), Fusarium redolens (n = 4) and Fusarium oxysporum (n = 15). Although F. torulosum could not be isolated from P. clandestinum collected during kikuyu poisoning outbreaks in South Africa, the mycotoxicosis theory is still highly plausible.


Body condition and wind support initiate the shift of migratory direction and timing of nocturnal departure in a songbird.
1. An innate migration strategy guides birds through space and time. Environmental variation further modulates individual behaviour within a genetically determined frame. In particular, ecological barriers could influence departure direction and its timing. A shift in the migratory direction in response to an ecological barrier could reveal how birds adjust their individual trajectories to environmental cues and body condition. 2. Northern wheatears of the Greenland/Iceland subspecies Oenanthe oenanthe leucorhoa arrive in Western Europe en route from their West African winter range. They then undergo an endogenously controlled shift in migratory direction from north to north-west to cross a large ecological barrier, the North Atlantic. We radiotracked these songbirds departing from Helgoland, a small island in the North Sea, over an unprecedented range of their journey. 3. Here, we show that both birds' body condition and the wind conditions that they encountered influenced the departure direction significantly. Jointly high fuel loads and favourable wind conditions enabled migrants to cross large stretches of sea. Birds in good condition departed early in the night heading to the sea towards their breeding areas, while birds with low fuel loads and/or flying in poor weather conditions departed in directions leading towards nearby mainland areas during the entire night. These areas could be reached even after setting off late at night. 4. Behavioural adjustment of migratory patterns is a critical adaptation for crossing ecological barriers. The observed variation in departure direction and time in relation to fuel load and wind revealed that these birds have an innate ability to respond by jointly incorporating internal information (body condition) and external information (wind support).


A multicentre study to improve clinical interpretation of proteinase-3 and myeloperoxidase anti-neutrophil cytoplasmic antibodies.
The objective of this multicentre study was to improve the clinical interpretation of PR3- and MPO-ANCAs as an adjunct for the diagnosis of ANCA-associated vasculitis (AAV) by defining thresholds and test result intervals based on predefined specificities and by calculating test result interval-specific likelihood ratios (LRs). Eight different PR3- and MPO-ANCA immunoassays from seven companies were evaluated using 251 diagnostic samples from AAV patients and 924 diseased controls. Thresholds for antibody levels were determined based on predefined specificities (95, 97.5, 99 and 100%) and used to delimit test result intervals. Test result interval-specific LRs were determined. For all assays, the LR for AAV increased with increasing antibody level. For all but one immunoassay, high antibodies levels (associated with LR >55) were found in a substantial fraction (>65%) of patients. The area under the curve (AUC) of receiver operating characteristics analysis of a diagnostic approach in which positive results were confirmed by IIF or another immunoassay was not substantially higher than the AUC of performing immunoassay only. The highest AUC was found when immunoassay was combined with another immunoassay or with IIF. To diagnose AAV based on PR3- and MPO-ANCA, it is useful to define thresholds for antibody levels and to assign test result interval-specific LRs. Higher antibody levels are associated with a higher likelihood for disease. Such information improves clinical interpretation.


Non-invasive continuous respiratory monitoring using temperature-based sensors.
Respiratory rate (RR) is a key vital sign that has been traditionally employed in the clinical assessment of patients and in the prevention of respiratory compromise. Despite its relevance, current practice for monitoring RR in non-intubated patients strongly relies on visual counting, which delivers an intermittent and error-prone assessment of the respiratory status. Here, we present a novel non-invasive respiratory monitor that continuously measures the RR in human subjects. The respiratory activity of the user is inferred by sensing the thermal transfer between the breathing airflow and a temperature sensor placed between the nose and the mouth. The performance of the respiratory monitor is assessed through respiratory experiments performed on healthy subjects. Under spontaneous breathing, the mean RR difference between our respiratory monitor and visual counting was 0.4 breaths per minute (BPM), with a 95% confidence interval equal to [- 0.5, 1.3] BPM. The robustness of the respiratory sensor to the position is assessed by studying the signal-to-noise ratio in different locations on the upper lip, displaying a markedly better performance than traditional thermal sensors used for respiratory airflow measurements.


Neurological manifestations of Ehlers-Danlos syndrome(s): A review.
The term "Ehlers-Danlos syndrome" (EDS) groups together an increasing number of heritable connective tissue disorders mainly featuring joint hypermobility and related complications, dermal dysplasia with abnormal skin texture and repair, and variable range of the hollow organ and vascular dysfunctions. Although the nervous system is not considered a primary target of the underlying molecular defect, recently, increasing attention has been posed on neurological manifestations of EDSs, such as musculoskeletal pain, fatigue, headache, muscle weakness and paresthesias. Here, a comprehensive overview of neurological findings of these conditions is presented primarily intended for the clinical neurologist. Features are organized under various subheadings, including pain, fatigue, headache, stroke and cerebrovascular disease, brain and spine structural anomalies, epilepsy, muscular findings, neuropathy and developmental features. The emerging picture defines a wide spectrum of neurological manifestations that are unexpectedly common and potentially disabling. Their evaluation and correct interpretation by the clinical neurologist is crucial for avoiding superfluous investigations, wrong therapies, and inappropriate referral. A set of basic tools for patient's recognition is offered for raising awareness among neurologists on this underdiagnosed group of hereditary disorders.


Dental alterations associated with X-linked hypophosphatemic rickets.
The X-linked hypophosphatemic rickets is a rare metabolic disorder characterized by low serum phosphate levels caused by a decreased renal tubular reabsorption of inorganic phosphates. The initial complaints are a delay in the development of walking caused by deformity of the legs. Oral findings include poorly mineralized dentin, enlarged pulp chambers and root canals, and periradicular abscesses in caries-free teeth. We present three patients from the same family with X-linked hypophosphatemic rickets showing bone and dental alterations.


Time-dependent regulation of perineuronal nets in the cerebellar cortex during abstinence of cocaine-self administration.
The probability of structural remodeling in brain circuits may be modulated by molecules of perineuronal nets (PNNs) that restrict neuronal plasticity to stabilize circuits. Animal research demonstrates that addictive drugs can remodel PNNs in different brain regions, including the cerebellum. This study aimed to investigate the effects of short versus extended access to cocaine self-administration on PNN expression around Golgi interneurons in the cerebellar cortex after different periods of abstinence. After 1 week of training (2 h/day), Sprague-Dawley rats self-administered cocaine daily for 20 days under short (ShA) or extended (LgA) access. PNN expression in the cerebellum was assessed after 1 day, 7 days, and 28 days of forced abstinence. PNNs were immunolabeled using Wisteria floribunda agglutinin (WFA) and captured by confocal microscopy. WFA intensity increased in PNN-bearing Golgi neurons over the abstinence period and a higher proportion of more intense PNNs were formed throughout the first month of abstinence. After the first 24 h of cocaine abstinence, however, we found a reduction in WFA intensity in the cerebellar cortex of rats with ShA to cocaine as compared to naïve animals. When comparing with naïve rats, LgA rats showed consistent PNN upregulation at 28 days of cocaine abstinence. Our results suggest that cocaine self-administration produces modifications in PNN that enhance conditions for synaptic plasticity in the cerebellar cortex. These modifications are revealed shortly after the cessation of drug intake but PNNs become more intense during protracted abstinence in the LgA group, pointing to the stabilization of drug-induced synaptic changes. These findings indicate that extended access to cocaine self-administration dynamically regulates conditions for plasticity in the cerebellum during abstinence.


Ambulatory endovascular surgery: cost advantage and factors influencing its safe performance.
To perform a retrospective analysis of chronic limb ischemia and determine whether endovascular surgery can be performed safely and cost effectively on an ambulatory basis. Among 42 patients undergoing endovascular interventions for lower limb ischemia over a 12-month period ending October 1997, 32 (18 men, mean age 68 years, range 44 to 89) were treated solely by endovascular interventions. These patients were grouped according to time inhospital: 20 (63%) patients had endovascular procedures performed on an ambulatory basis, 7 (22%) were hospitalized for > 24 hours, and 5 (16%) required an overnight stay. The angioplasty procedures, which included placement of 21 stents, were performed in the abdominal aorta (n = 1) and the common iliac (n = 9), external iliac (n =7), superficial femoral (n = 11), popliteal (n = 5), tibioperoneal (n = 7), and subclavian (n = 1) arteries. Hospital charges were compared for the 3 groups. Other than the presence of coronary artery disease, there were no significant differences in demographics or risk factors among the 3 groups. Angioplasty was technically successful in all patients, and there were no procedural complications. Patients with tissue loss required hospitalization more frequently compared to those with claudication. Significantly more patients who were hospitalized had epidural anesthesia as opposed to local when compared to the ambulatory group, 43% versus 5%, respectively (p = 0.04). Excluding professional fees, mean total hospital cost differed significantly between the ambulatory group and the group of patients with a hospital stay > 24 hours ($8227 versus $40,383, respectively; p = 0.03) and between the 2 hospitalized groups ($9476 for overnight stay versus $40,383 for > 24-hour stay, p = 0.03). Peripheral endovascular interventions can be performed safely on an ambulatory basis resulting in decreased hospital cost. Patients who receive epidural anesthesia, require concomitant open vascular reconstruction, present with tissue loss, or have unstable medical conditions are more likely to require hospitalization.


NCCN Colorectal Cancer Practice Guidelines. The National Comprehensive Cancer Network.
In summary, the committee believes that a multidisciplinary approach is necessary for the management of the patient with colorectal cancer. The committee endorses the concept that treatment of patients on a clinical trial has priority over standard or accepted therapy. The recommended surgical procedure for managing resectable colon cancer is an en bloc resection; laparoscopic surgery should be done only in the context of a clinical trial. For patients with stage III disease, 5-FU-based adjuvant chemotherapy is recommended. A patient who has metastatic disease in the liver or lung should be considered for surgical resection if he or she is a candidate for surgery and if surgery can extend survival. The committee advocates a conservative post-treatment surveillance program for colon and rectal cancer patients. A determination of CEA should be done only if CEA was elevated at baseline and decreased following primary resection. Abdominal and pelvic CT scans should be utilized only when there are clinical indications of possible recurrence. Patients whose disease progresses during 5-FU-based therapy should be considered for treatment with irinotecan or encouraged to participate in a phase I or II clinical trial.


The 10 kb Drosophila virilis 28S rDNA intervening sequence is flanked by a direct repeat of 14 base pairs of coding sequence.
Most repeat units of rDNA in Drosophila virilis are interrupted in the 28S rRNA coding region by an intervening sequence about 10 kb in length; uninterrupted repeats have a length of about 11 kb. We have sequenced the coding/intervening sequence junctions and flanking regions in two independent clones of interrupted rDNA, and the corresponding 28S rRNA coding region in a clone of uninterrupted rDNA. The intervening sequence is terminated at both ends by a direct repeat of a fourteen nucleotide sequence that is present once in the corresponding region of an intact gene. This is a phenomenon associated with transposable elements in other eukaryotes and in prokaryotes, and the Drosophila rDNA intervening sequence is discussed in this context. We have compared more than 200 nucleotides of the D. virilis 28S rRNA gene with sequences of homologous regions of rDNA in Tetrahymena pigmentosa (Wild and Sommer, 1980) and Xenopus laevis (Gourse and Gerbi, 1980): There is 93% sequence homology among the diverse species, so that the rDNA region in question (about two-thirds of the way into the 28S rRNA coding sequence) has been very highly conserved in eukaryote evolution. The intervening sequence in T. pigmentosa is at a site 79 nucleotides upstream from the insertion site of the Drosophila intervening sequence.


Chemical Genetics of AGC-kinases Reveals Shared Targets of Ypk1, Protein Kinase A and Sch9.
Protein phosphorylation cascades play a central role in the regulation of cell growth and protein kinases PKA, Sch9 and Ypk1 take center stage in regulating this process in S. cerevisiae To understand how these kinases co-ordinately regulate cellular functions we compared the phospho-proteome of exponentially growing cells without and with acute chemical inhibition of PKA, Sch9 and Ypk1. Sites hypo-phosphorylated upon PKA and Sch9 inhibition were preferentially located in RRxS/T-motifs suggesting that many are directly phosphorylated by these enzymes. Interestingly, when inhibiting Ypk1 we not only detected several hypo-phosphorylated sites in the previously reported RxRxxS/T-, but also in an RRxS/T-motif. Validation experiments revealed that neutral trehalase Nth1, a known PKA target, is additionally phosphorylated and activated downstream of Ypk1. Signaling through Ypk1 is therefore more closely related to PKA- and Sch9-signaling than previously appreciated and may perform functions previously only attributed to the latter kinases.


Cell-Targeted Metal-Phenolic Nanoalgaecide in Hydroponic Cultivation to Enhance Food Sustainability.
The growing global population necessitates substantial increases in food production. Hydroponic cultivation systems afford a critical alternative for food sustainability and enable stable annual production regardless of the climatic and geographical variations. However, the overgrowth of harmful algal blooms significantly threatens the crop yield by competing with nutrition in the solution and producing contaminants. The conventional practice of algaecides fails to control algal proliferation due to the limited efficiency and food safety concerns. Nanopesticides can deliver active ingredients responsively to suppress crop diseases and offer solutions to current practical challenges and difficulties. Inspired by prospects of nanotechnology for agricultural applications, we have utilized natural polyphenols and copper ions (Cu2+ ions) to develop self-assembled nanoalgaecides referred to as CuBes. The nanoalgaecide attached to algal cells via phenolic surface interactions, enabling localized Cu2+ ion release. This cell-targeted delivery suppressed Chlorella vulgaris for over 30 days (99% inhibition). Transcriptomics revealed that the nanoalgaecide disrupted algal metabolism by downregulating photosynthesis and chlorophyll pathways. In a solar-illuminated plant factory, the nanoalgaecide showed higher algal inhibition and lettuce biosafety versus the commercial Kocide 3000. Notably, the use of nanoalgaecide can enhance the nutrient value of lettuces, which meets the daily supply of Cu for adults. By integrating smart nanotechnology design with selective delivery mechanisms, this metal-phenolic nanoalgaecide provides a nanoenabled solution for controlling harmful algal blooms in hydroponics to advance food production.


Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).
Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.


Coordination between digit forces and positions: interactions between anticipatory and feedback control.
Humans adjust digit forces to compensate for trial-to-trial variability in digit placement during object manipulation, but the underlying control mechanisms remain to be determined. We hypothesized that such digit position/force coordination was achieved by both visually guided feed-forward planning and haptic-based feedback control. The question arises about the time course of the interaction between these two mechanisms. This was tested with a task in which subjects generated torque (± 70 N·mm) on a virtual object to control a cursor moving to target positions to catch a falling ball, using a virtual reality environment and haptic devices. The width of the virtual object was varied between large (L) and small (S). These object widths result in significantly different horizontal digit relative positions and require different digit forces to exert the same task torque. After training, subjects were tested with random sequences of L and S widths with or without visual information about object width. We found that visual cues allowed subjects to plan manipulation forces before contact. In contrast, when visual cues were not available to predict digit positions, subjects implemented a "default" digit force plan that was corrected after digit contact to eventually accomplish the task. The time course of digit forces revealed that force development was delayed in the absence of visual cues. Specifically, the appropriate digit force adjustments were made 250-300 ms after initial object contact. This result supports our hypothesis and further reveals that haptic feedback alone is sufficient to implement digit force-position coordination.


Invasive Fungal Infections in Children with Leukemia: Clinical Features and Prognosis
The incidence of invasive fungal infections (IFIs) has increased due to intensive chemotherapy in childhood leukemia. The aim of this study was to evaluate the incidence, risk factors, causative pathogens, and impact on survival of IFIs among pediatric leukemia patients. The hospital records of 307 children with acute lymphoblastic leukemia (ALL, n=238), acute myeloid leukemia (AML, n=51), and relapsed leukemia (n=18) between January 2010 and December 2015 were retrospectively evaluated. A total of 1213 febrile neutropenia episodes were recorded and 127 (10.4%) of them were related to an IFI. Of 307 children, 121 (39.4%) developed IFIs. The mean age was significantly older in the IFI group compared to children without IFIs (p<0.001). IFIs were defined as possible, probable, and proven in 73.2%, 11.9%, and 14.9% of the attacks, respectively. Invasive aspergillosis (81.9%) was the most frequent infection, followed by invasive candidiasis (13.4%) and rare fungal diseases (4.8%). The majority of IFI attacks in both ALL and AML occurred during the induction phase. In total, the death rate was 24% and the IFI-related mortality rate was 18%. The mortality rate among children with IFIs was found to be significantly higher than that of children without IFIs (p<0.001). Overall and event-free survival rates at 5 years were also found to be significantly lower in the IFI group (p<0.001). Relapse (odds ratio: 8.49) was the most effective risk factor for mortality, followed by developing an IFI episode (odds ratio: 3.2) and AML (odds ratio: 2.33) according to multivariate regression analysis. Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode Conclusion: Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode