Population and quantitative genetics of regulatory networks.
I evolved boolean regulatory networks in a computer simulation. I varied mutation, recombination, the size of the network, and the number of connections per node. I measured the performance of networks and the heritability and epistasis of genetic effects. Networks of intermediate connectivity performed best. The distinction between metabolic and quantitative genetic additivity explained some of the variation in performance. Metabolic additivity describes the interaction between changes in a single network, whereas quantitative genetic additivity measures the consistency of phenotypic effect caused by gene substitution in randomly chosen members of the population. I analysed metabolic additivity by the distribution of epistatic effects of pairs of mutations in individual networks. I measured quantitative genetic additivity by heritability. Highly connected networks had greater metabolic additivity for perturbations to individual networks, but had lower additivity when measured by the average effect of a gene substitution (heritability). The lower heritability of highly connected nets appeared to reduce the effectiveness of recombination in searching evolutionary space.


Clear cell chondrosarcoma. A report of two cases and review of literature.
Two cases of clear cell chondrosarcoma located in the distal femur and proximal humerus are reported. Both patients were men aged 35 and 51 years. Their initial symptom was a pathologic fracture. Roentgenographically, one patient showed a purely lytic lesion and another lytic with centrally radiodensity. Microscopic examination revealed that the tumor cells have a centrally placed vesicular nucleus surrounded by a clear cytoplasm, with distinct boundaries. Their cytoplasm stained with S-100 protein by the peroxidase-antiperoxidase method. We found 36 reported cases (including the two reported here), and delineated the clinico-pathologic characteristics of the disease.


Digital Clinics and Mobile Technology Implementation for Mental Health Care.
Interest in digital mental health, especially smartphone apps, has expanded in light of limited access to mental health services and the need for remote care during COVID-19. Digital clinics, in which apps are blended into routine care, offer a potential solution to common implementation challenges including low user engagement and lack of clinical integration of apps. While the number of mental health apps available in commercial marketplaces continues to rise, there are few examples of successful implementation of these apps into care settings. We review one example of a digital clinic created within an academic medical center and another within the Department of Veterans Affairs. We then discuss how implementation science can inform new efforts to effectively integrate mental health technologies across diverse use cases. Integrating mental health apps into care settings is feasible but requires careful attention to multiple domains that will influence implementation success, including characteristics of the innovation (e.g., utility and complexity of the app), the recipients of the technology (e.g., patients and clinicians), and context (e.g., healthcare system buy-in, reimbursement, and regulatory policies). Examples of effective facilitation strategies that can be utilized to improve implementation efforts include co-production of technology involving all end users, specialized trainings for staff and patients, creation of new team members to aid in app usage (e.g., digital navigators), and re-design of clinical workflows.


The phylogeography of salmonid proliferative kidney disease in Europe and North America.
Salmonid proliferative kidney disease (PKD) is caused by the myxozoan Tetracapsuloides bryosalmonae. Given the serious and apparently growing impact of PKD on farmed and wild salmonids, we undertook a phylogeographic study to gain insights into the history of genealogical lineages of T. bryosalmonae in Europe and North America, and to determine if the global expansion of rainbow trout farming has spread the disease. Phylogenetic analyses of internal transcribed spacer 1 sequences revealed a clade composed of all North American sequences plus a subset of Italian and French sequences. High genetic diversity in North America and the absence of genotypes diagnostic of the North American clade in the rest of Europe imply that southern Europe was colonized by immigration from North America; however, sequence divergence suggests that this colonization substantially pre-dated fisheries activities. Furthermore, the lack of southern European lineages in the rest of Europe, despite widespread rainbow trout farming, indicates that T. bryosalmonae is not transported through fisheries activities. This result strikingly contrasts with the commonness of fisheries-related introductions of other pathogens and parasites and indicates that fishes may be dead-end hosts. Our results also demonstrate that European strains of T. bryosalmonae infect and induce PKD in rainbow trout introduced to Europe.


Comparative effectiveness of β-lactam versus vancomycin empiric therapy in patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia.
Vancomycin may be inferior to β-lactams for the empiric treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. We compared empiric β-lactams to vancomycin to assess clinical outcomes in patients with MSSA bacteremia. We conducted a retrospective cohort study of adult inpatients with their first episode of MSSA bacteremia at two tertiary care hospitals in Vancouver, Canada, between 2007 and 2014. Exposure was either empiric β-lactam with or without vancomycin or vancomycin monotherapy. All patients received definitive treatment with cloxacillin or cefazolin. The primary outcome was 28-day mortality. Secondary outcomes were 90-day mortality, duration of bacteremia, and hospital length-of-stay. Outcomes were adjusted using multivariable logistic regression. Of 669 patients identified, 255 met inclusion criteria (β-lactam = 131, vancomycin = 124). Overall 28-day mortality was 7.06 % (n = 18). There were more cases of infective endocarditis in the β-lactam than in the vancomycin group [24 (18.3 %) vs 12 (9.7 %), p = 0.05]. Adjusted mortality at 28 days was similar between the two groups (OR 0.85; 95 % CI 0.27-2.67). The duration of bacteremia was longer in the vancomycin group (97.1 vs 70.7 h, p = 0.007). Transition to cloxacillin or cefazolin occurred within a median of 68.3 h in the vancomycin group. Empiric β-lactams was associated with earlier clearance of bacteremia by a median of 1 day compared to vancomycin. Future prospective studies are needed to confirm our findings.


Execution of the meiotic noncoding RNA expression program and the onset of gametogenesis in yeast require the conserved exosome subunit Rrp6.
Budding yeast noncoding RNAs (ncRNAs) are pervasively transcribed during mitosis, and some regulate mitotic protein-coding genes. However, little is known about ncRNA expression during meiotic development. Using high-resolution profiling we identified an extensive meiotic ncRNA expression program interlaced with the protein-coding transcriptome via sense/antisense transcript pairs, bidirectional promoters, and ncRNAs that overlap the regulatory regions of genes. Meiotic unannotated transcripts (MUTs) are mitotic targets of the conserved exosome component Rrp6, which itself is degraded after the onset of meiosis when MUTs and other ncRNAs accumulate in successive waves. Diploid cells lacking Rrp6 fail to initiate premeiotic DNA replication normally and cannot undergo efficient meiotic development. The present study demonstrates a unique function for budding yeast Rrp6 in degrading distinct classes of meiotically induced ncRNAs during vegetative growth and the onset of meiosis and thus points to a critical role of differential ncRNA expression in the execution of a conserved developmental program.


Academic outcomes in childhood-onset systemic lupus erythematosus.
To explore academic outcomes in childhood-onset systemic lupus erythematosus (cSLE) and their relationship to variables such as demographic and socioeconomic status, neurocognitive functioning, behavioral/emotional adjustment, and cSLE disease status. Forty pairs of children diagnosed with cSLE and healthy best friend controls were rated by parents on a standardized scale of school competence. Information about participants' demographic and socioeconomic status was obtained, along with measures of cSLE disease activity and damage. All of the participants received formal neurocognitive testing and were also rated on standardized scales of behavioral/emotional adjustment and executive functioning. Compared to healthy controls, school competence was rated as lower in the cSLE group, although the groups did not differ significantly on indices of cognitive, behavioral, emotional, or executive functioning. School competence ratings were correlated with reading and mathematics achievement test scores in both groups, and with ratings of mental self-regulation in the cSLE group. School competence ratings were correlated with measures of cSLE disease activity and treatment intensity. cSLE is associated with inferior parent-rated academic outcomes compared to those noted in demographically-matched peers, despite similar neurocognitive function. The adverse academic outcomes that distinguish children with cSLE from their demographically-matched peers appear to be mediated by SLE disease activity and treatment.


Jenynsia lineata species complex, revision and new species description (Cyprinodontiformes: Anablepidae).
The Jenynsia lineata species complex comprises J. lineata from Montevideo, Uruguay and Jenynsia multidentata, from coastal basins of Brazil, Uruguay and Argentina up to 1200 m a.s.l. Taxonomic divisions within this group were tested using three different species delimitation methods, which found the two existing names to be synonyms and revealed a new cryptic species. Jenynsia darwini sp. nov. is distinguished from all congeners by having a unique combination of character states, including the shape of the dorsal postcleithrum (three times higher than wide v. less than two times higher than wide) and female colour pattern in the half of the caudal peduncle with rows of chromatophores segmented in unaligned spots (v. aligned spots forming lines). The new species also differs from J. lineata by having 26 nucleotide substitutions in the mitochondrial gene cytochrome c oxidase I (coI). Phylogenetic analysis of the genus based on morphological characters proposed by previous studies corroborates monophyly of the subgenera Plesiojenynsia and Jenynsia, with the new species being allocated to the subgenus Jenynsia as the sister group of J. lineata.


Acupuncture Ameliorates Postoperative Ileus via IL-6-miR-19a-KIT Axis to Protect Interstitial Cells of Cajal.
Acupuncture is a therapy effective in treating postoperative ileus (POI); its underlying mechanisms remain unclear. MicroRNAs (miRNAs) participate in inflammation and injury to the interstitial cells of Cajal (ICCs), both of which are considered to be contributors to POI. C-kit, encoding KIT, a specific marker of ICCs, is predicted to be targeted by miR-19a, an inflammation-related miRNA. Therefore, we investigated a possible link between inflammation, miR-19a, and ICCs in POI, as well as the mechanism by which these factors are affected by acupuncture. The effects of acupuncture on POI were assessed in patients after colorectal resection and in colocolic anastomosis mice. Immunofluorescence staining demonstrated that KIT[Formula: see text]/ano1[Formula: see text] ICCs dramatically decreased around the colonic incision in mice, which was negatively correlated with the pronounced increase in macrophage. However, this decrease was not due to apoptosis. IL-6R was expressed in ICCs, and IL-6 level was significantly increased, as measured by ELISA, in accompaniment with high miR-19a expression. The increase in IL-6 and miR-19a levels was negatively correlated with the decrease in KIT[Formula: see text]/ano1[Formula: see text] ICCs. A luciferase reporter assay demonstrated that miR-19a directly targeted C-kit, indicating that miR-19a caused ICC damage. Interestingly, acupuncture inhibited macrophage activation, IL-6 release, and miR-19a upregulation, while promoting KIT and ano1 restoration in ICCs. High serum miR-19a level in patients after colorectal resection was also reduced by acupuncture. Conclusively, the IL-6 released by macrophages during gastrointestinal surgery upregulated miR-19a, which downregulated KIT in ICCs and finally resulted in POI. Acupuncture can interfere with the "IL-6-miR-19a-KIT" axis, suggesting that it may be a therapeutic mechanism that works against POI.


Meta-analysis of Drosophila circadian microarray studies identifies a novel set of rhythmically expressed genes.
Five independent groups have reported microarray studies that identify dozens of rhythmically expressed genes in the fruit fly Drosophila melanogaster. Limited overlap among the lists of discovered genes makes it difficult to determine which, if any, exhibit truly rhythmic patterns of expression. We reanalyzed data from all five reports and found two sources for the observed discrepancies, the use of different expression pattern detection algorithms and underlying variation among the datasets. To improve upon the methods originally employed, we developed a new analysis that involves compilation of all existing data, application of identical transformation and standardization procedures followed by ANOVA-based statistical prescreening, and three separate classes of post hoc analysis: cross-correlation to various cycling waveforms, autocorrelation, and a previously described fast Fourier transform-based technique. Permutation-based statistical tests were used to derive significance measures for all post hoc tests. We find application of our method, most significantly the ANOVA prescreening procedure, significantly reduces the false discovery rate relative to that observed among the results of the original five reports while maintaining desirable statistical power. We identify a set of 81 cycling transcripts previously found in one or more of the original reports as well as a novel set of 133 transcripts not found in any of the original studies. We introduce a novel analysis method that compensates for variability observed among the original five Drosophila circadian array reports. Based on the statistical fidelity of our meta-analysis results, and the results of our initial validation experiments (quantitative RT-PCR), we predict many of our newly found genes to be bona fide cyclers, and suggest that they may lead to new insights into the pathways through which clock mechanisms regulate behavioral rhythms.


Microbial transformation of distinct exogenous substrates into analogous composition of recalcitrant dissolved organic matter.
Oceanic dissolved organic matter (DOM) comprises a complex molecular mixture which is typically refractory and homogenous in the deep layers of the ocean. Though the refractory nature of deep-sea DOM is increasingly attributed to microbial metabolism, it remains unexplored whether ubiquitous microbial metabolism of distinct carbon substrates could lead to similar molecular composition of refractory DOM. Here, we conducted microbial incubation experiments using four typically bioavailable substrates (L-alanine, trehalose, sediment DOM extract, and diatom lysate) to investigate how exogenous substrates are transformed by a natural microbial assemblage. The results showed that although each-substrate-amendment induced different changes in the initial microbial assemblage and the amended substrates were almost depleted after 90 days of dark incubation, the bacterial community compositions became similar in all incubations on day 90. Correspondingly, revealed by ultra-high resolution mass spectrometry, molecular composition of DOM in all incubations became compositionally consistent with recalcitrant DOM and similar toward that of DOM from the deep-sea. These results indicate that while the composition of natural microbial communities can shift with substrate exposures, long-term microbial transformation of distinct substrates can ultimately lead to a similar refractory DOM composition. These findings provide an explanation for the homogeneous and refractory features of deep-sea DOM.


[Robotic Surgery for Urologic Malignancy - Prostate, Kidney and Bladder].
Robotic-assisted surgery has been wide-spreading rapidly as a technique to develop laparoscopic surgery by innovative technological improvement such as high magnifided 3D-image and multi-degree freedom of forceps, leading to safety enhancement and better functional recovery. Robotic surgery in the urological field made it possible to highly fine operation in a narrow field, such as pelvic cavity or retroperitoneal space. Better outcomes were recognized especially in perioperative complications and postoperative QOL recovery than other procedures like open or laparoscopic. According to these results, radical prostatectomy, partial nephrectomy and radical cystectomy were approved for health insurance coverage in 2012, 2016 and 2018, respectively. Robotic-assistance has definitely brought a paradigm shift in urologic surgery. The application to more and more a variety of procedure and the improvement of treatment outcomes are expected in the future.


Cancer cells and normal cells differ in their requirements for Thoc1.
The evolutionarily conserved TREX (Transcription/Export) complex physically couples transcription, messenger ribonucleoprotein particle biogenesis, RNA processing, and RNA export for a subset of genes. HPR1 encodes an essential component of the S. cerevisiae TREX complex. HPR1 loss compromises transcriptional elongation, nuclear RNA export, and genome stability. Yet, HPR1 is not required for yeast viability. Thoc1 is the recently discovered human functional orthologue of HPR1. Thoc1 is expressed at higher levels in breast cancer than in normal epithelia, and expression levels correlate with tumor size and metastatic potential. Depletion of Thoc1 protein (pThoc1) in human cancer cell lines compromises cell proliferation. It is currently unclear whether Thoc1 is essential for all mammalian cells or whether cancer cells may differ from normal cells in their dependence on Thoc1. To address this issue, we have compared the requirements for Thoc1 in the proliferation and survival of isogenic normal and oncogene-transformed cells. Neoplastic cells rapidly lose viability via apoptotic cell death on depletion of pThoc1. Induction of apoptotic cell death is coincident with increased DNA damage as indicated by the appearance of phosphorylated histone H2AX. In contrast, the viability of normal cells is largely unaffected by pThoc1 loss. Normal cells lacking Thoc1 cannot be transformed by forced expression of E1A and Ha-ras, suggesting that Thoc1 may be important for neoplastic transformation. In sum, our data are consistent with the hypothesis that cancer cells require higher levels of pThoc1 for survival than normal cells. If true, pThoc1 may provide a novel molecular target for cancer therapy.


Mucinous tubular and spindle cell carcinoma of the kidney with sarcomatoid differentiation.
We report a unique case of mucinous tubular and spindle cell carcinoma (MTSC) of the kidney with extensive sarcomatoid differentiation, multiple metastases, and a rapidly fatal clinical course. The patient presented with back pain and a pathologic L1 fracture. Diagnostic imaging revealed a large retroperitoneal mass arising from the left kidney and compressing the spinal cord. Radiotherapy and surgery were performed, but the patient died from disease progression three weeks postoperatively. MTSC is a recently recognized entity that is considered to be a low-grade carcinoma with a favorable prognosis. Our case demonstrates that although MTSC is usually a low-grade carcinoma, sarcomatoid differentiation may occur and lead to a fatal course, as in all other types of renal cell carcinomas. Adequate sampling and the exclusion of sarcomatoid differentiation in the spindle cell component are necessary for proper management and prognostication. To our knowledge, this is the first reported case of MTSC with sarcomatoid differentiation and a fatal outcome.


[Adenocarcinoma of the lung with metastases to the pituitary and both adrenal glands].
A case of lung adenocarcinoma with metastases in both adrenals and pituitary gland in 52-year old patient is presented. Adrenal glands metastases were diagnosed on a base of CT scans. Pituitary metastases caused gradual loss of vision. MR imaging showed a lesion in the sella and suprasellar areas and suggested meningioma. Right frontal craniotomy with the partial removal of the tumor was performed. Three days later the patient died. Histopathological results of the pituitary masses revealed adenocarcinoma.


Prognostic Impact of Pre- and Post-operative P-CRP Levels in Pancreatic Cancer Patients.
C-reactive protein (CRP) levels reflect ongoing inflammation and/or tissue damage, and studies suggest that platelets play a role in tumor invasion and metastasis. P-CRP is defined as the multiplied product of serum CRP and platelet levels. Here the prognostic value of pre- and post-operative P-CRP levels in pancreatic cancer (PC) patients was assessed. This retrospective study used data from 107 consecutive PC patients who had undergone either pancreaticoduodenectomy or distal pancreatectomy. Clinicopathological parameters and pre/post-operative laboratory data derived from patient records were used for analyses. P-CRP was defined as the product of peripheral thrombocyte count (/uL) × serum CRP level (mg/dL) divided by 104; the optimal P-CRP cut-off value was defined using receiver operating characteristic curves. PC patients were classified as either P-CRPLow (< 1.782; n = 49) or P-CRPHigh (≥ 1.782; n = 58), based on the cut-off value of 1.782. Univariate analysis revealed that performance status, clinical stage, pathological T and N stages, P-CRP, and carbohydrate antigen 19-9 (CA19-9) significantly affected overall survival (OS). Multivariate analysis revealed that independent risk factors for OS were pathological N stage, P-CRP, and CA19-9. Additionally, 103 PC patients for whom postoperative data were available were classified into four groups (P-CRPLow-Down, P-CRPLow-Up, P-CRPHigh-Down and P-CRPHigh-Up), based on preoperative P-CRP and postoperative trend of P-CRP, and we found that prognosis, in terms of OS, was significantly different among these groups (P = 0.012). Pre- and post-operative P-CRP values are a potential predictor of prognosis in PC patients.


Review article: oral ulcers and its relevance to systemic disorders.
Oral ulceration is a common problem, and is sometimes a marker of gastroenterological disease. Patients with signs or symptoms of oral ulcers are sometimes referred to gastroenterology clinics, however, in most instances the ulcers does not reflect gastrointestinal disease. Indeed, a spectrum of disorders other than those of the gut can give rise to oral mucosal ulcers ranging from minor local trauma to significant local disease such as malignancy or systemic illness. This present article reviews aspects of the aetiology, diagnosis and management of common ulcerative disorders of the oral mucosa.


Management of hypertension: considerations involving cardiovascular risk reduction.
Obvious, but often forgotten, is the premise that blood pressure reduction in the patient with hypertension is a surrogate for our real goal, which is reduction in the risks consequent to hypertension. This surrogate, a convenience for regulatory agencies, has therapeutic implications. As the array of antihypertensive agents available has grown, along with information from clinical trials and insights into underlying mechanisms, it has become reasonable to examine that premise. The overall success of antihypertensive therapy has been undeniable, but has not influenced the advance of atherosclerosis, primarily coronary events. Multiple observations suggest that metabolic disarray consequent to the use of antihypertensive agents, especially thiazides and beta-blockers, may have contributed to this scenario. Electrolyte abnormalities predispose to malignant arrhythmias and sudden death during myocardial infarction. Left ventricular hypertrophy, a major risk factor for coronary events, arrhythmias, and heart failure, responds selectively to antihypertensive agents. Similarly, the progression of renal injury in the hypertensive patient may be sensitive to the agents employed. Obesity and hypertension coexist frequently; moreover, evidence is growing that atherogenic abnormalities common in the obese patient, such as insulin resistance, not only occur frequently in the nonobese patient, but are also sensitive to the antihypertensive agent selected. Although predictions are risky, it seems safe to predict that the next chapter in antihypertensive therapy will examine whether we need to go beyond blood pressure reduction in selecting such therapy.


Coffee consumption and the risk of breast cancer.
On the basis of clinical observations that some women with fibrocystic breast disease experienced resolution of the disease on eliminating methylxanthines from their diet, it has been suggested that coffee intake might be related to breast carcinogenesis. The relationship between coffee (mostly expresso and mocha), decaffeinated coffee and tea intake and breast cancer risk was therefore considered, combining data from two case-control studies, conducted in Italy between 1983 and 1994. Cases were 5,984 women, below age 75, with histologically confirmed breast cancer, and controls were 5,504 women admitted to hospital for a wide spectrum of acute, non-neoplastic, non-hormone-related diseases. The odds ratios (ORs) were estimated from multiple logistic regression equations including terms for study/centre, age, education, body mass index, smoking status, total alcohol intake, age at menarche and menopause, parity and age at first birth, use of oral contraceptives, use of hormone replacement therapy, history of benign breast disease and family history of breast cancer. No relationship was observed between coffee intake and the risk of breast cancer. The multivariate ORs were 1.17 (1.03-1.33), 1.17 (1.04-1.33), 1.21 (1.06-1.37) and 0.96 (0.83-1.11) for women drinking < 2, 2, > 2 to < 4 and > or = 4 cups/day compared to non-drinkers. Decaffeinated coffee was consumed only by 6-7% of cases and controls and the corresponding OR was 0.84 (0.72-0.98). Tea consumption was also low and not associated with the risk of breast cancer (OR 0.94, 95% CI 0.85-1.03). No significant heterogeneity was found for coffee intake across strata of age at diagnosis, education, body mass index, smoking status, total alcohol intake, age at menarche and menopause, parity, age at first birth, ever use of oral contraceptives, hormone replacement therapy, history of benign breast disease and family history of breast cancer. Thus, this study, based on a large data set, allows us to exclude the hypothesis that coffee intake is related to breast cancer risk in this Italian population.


Image recovery using partitioned-separable paraboloidal surrogate coordinate ascent algorithms.
Iterative coordinate ascent algorithms have been shown to be useful for image recovery, but are poorly suited to parallel computing due to their sequential nature. This paper presents a new fast converging parallelizable algorithm for image recovery that can be applied to a very broad class of objective functions. This method is based on paraboloidal surrogate functions and a concavity technique. The paraboloidal surrogates simplify the optimization problem. The idea of the concavity technique is to partition pixels into subsets that can be updated in parallel to reduce the computation time. For fast convergence, pixels within each subset are updated sequentially using a coordinate ascent algorithm. The proposed algorithm is guaranteed to monotonically increase the objective function and intrinsically accommodates nonnegativity constraints. A global convergence proof is summarized. Simulation results show that the proposed algorithm requires less elapsed time for convergence than iterative coordinate ascent algorithms. With four parallel processors, the proposed algorithm yields a speedup factor of 3.77 relative to single processor coordinate ascent algorithms for a three-dimensional (3-D) confocal image restoration problem.


Pharmacokinetic assessment of a fast-release orodispersible tramadol tablet compared to a conventional tramadol capsule.
The purpose of this clinical trial was to compare the pharmacokinetics of a recently developed fast-release orodispersible tramadol tablet (CAS 27203-92-5, Zamadol Melt) to that of a conventional tramadol capsule. This new formulation, once placed into the mouth, disintegrates rapidly in contact with the saliva. Therefore, when the saliva is swallowed, the drug reaches the gastrointestinal tract. In an open, randomised, two-period, crossover study performed in 20 healthy volunteers, the orodispersible tramadol tablet and a conventional tramadol capsule were administered. Even although the galenics of both products are far different, statistical analysis of pharmacokinetic parameters allows concluding bioequivalence, not only for the parent molecule (tramadol), but also for its active metabolite O-desmethyl tramadol. This orally dispersible formulation, being bioequivalent to the standard capsules so far used, has the practical advantage that it can be taken without liquids. This facilitates an early treatment of emergent pain, irrespective of the place or situation where it may arise.


Frontrunners in novel pharmacotherapy of COPD.
The mainstay of current drug therapy is long-acting bronchodilators; several longer acting inhaled beta(2)-agonists and muscarinic antagonists (and combinations) are now in development. No treatments reduce the progression or suppress the inflammation of COPD. With better understanding of the inflammatory and destructive process, several new targets have been identified. Several mediator antagonists tested in COPD have been disappointing, but of CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment may be more promising. Broad spectrum anti-inflammatory drugs may be more effective, and include inhibitors of PDE4, p38 MAPK and NF-kappaB, but side effects will be a major limitation so that inhaled delivery will be necessary. Perhaps the most promising approach is reversal corticosteroid resistance through increasing HDAC2 activity. This may be achieved by theophylline-like drugs, more effective antioxidants and non-antibiotic macrolides.


Plant retromer, localized to the prevacuolar compartment and microvesicles in Arabidopsis, may interact with vacuolar sorting receptors.
Receptors for acid hydrolases destined for the lytic compartment in yeast and mammalian cells are retrieved from intermediate, endosomal organelles with the help of a pentameric protein complex called the retromer. We cloned the Arabidopsis thaliana homologs of the three yeast proteins (Vps35, Vps29, and Vps26) constituting the larger subunit of retromer and prepared antisera against them. With these antibodies, we demonstrated the presence of a retromer-like protein complex in salt extracts prepared from Arabidopsis microsomes. This complex is associated with membranes that coequilibrate with prevacuolar compartment markers and with high-density sedimenting membranes. Immunogold negative staining identified these membranes as 90-nm-diameter coated microvesicles. Confocal laser scanning immunofluorescence studies performed on tobacco (Nicotiana tabacum) BY-2 cells revealed high degrees of colabeling between all three retromer antisera and the prevacuolar compartment (PVC) markers PEP12 and vacuolar sorting receptor VSR(At-1). The presence of plant retromer at the surface of multivesicular bodies was also demonstrated by immunogold labeling of sections obtained from high-pressure frozen/freeze-substituted specimens. Treatment of BY-2 cells with wortmannin led to swelling of the PVC and a separation of the VPS35 and VSR signals. Preliminary data suggesting that retromer interacts with the cytosolic domain of a VSR were obtained by immunoprecipitation experiments performed on detergent-solubilized microsomes with Vps35 antibodies.


Force classification during robotic interventions through simulation-trained neural networks.
Intravitreal injection is among the most frequent treatment strategies for chronic ophthalmic diseases. The last decade has seen a serious increase in the number of intravitreal injections, and with it, adverse effects and drawbacks. To tackle these problems, medical assistive devices for robotized injections have been suggested and are projected to enhance delivery mechanisms for a new generation of pharmacological solutions. In this paper, we present a method aimed at improving the safety characteristics of upcoming robotic systems. Our vision-based method uses a combination of 2D OCT data, numerical simulation and machine learning to classify the range of the force applied by an injection needle on the sclera. We design a neural network to classify force ranges from optical coherence tomography (OCT) images of the sclera directly. To avoid the need for large real data sets, the network is trained on images of simulated deformed sclera. This simulation is based on a finite element method, and the model is parameterized using a Bayesian filter applied to observations of the deformation in OCT images. We validate our approach on real OCT data collected on five ex vivo porcine eyes using a robotically guided needle. The thorough parameterization of the simulations leads to a very good agreement between the virtually generated samples used to train the network and the real OCT acquisitions. Results show that the applied force range on real data can be predicted with 93% accuracy. Through a simulation-trained neural network, our approach estimates the force range applied by a robotically guided needle on the sclera based solely on a single OCT slice of the deformed sclera. Being real-time, this solution can be integrated in the control loop of the system, permitting the prompt withdrawal of the needle for safety reasons.


Autism-related traits and suicide risk among active duty U.S. military service members.
Suicide rates within the U.S. military are elevated. The interpersonal theory of suicide, supported within military samples, suggests that social disconnectedness confers risk for suicide. Autism spectrum disorder (ASD) is characterized by symptoms-difficulties in social communication/interaction (SCI) and restricted and repetitive behaviors (RRBs)-that contribute to social disconnectedness. To our knowledge, no study has examined ASD-related traits and suicide risk among active duty U.S. military service members. Participants included 292 active duty U.S. military service members (M [SD] age = 28.67 [7.40] years, 68.5% male, 78.1% White). The Autism Spectrum Quotient, Repetitive Behaviours Questionnaire-2 for Adults, Self-Injurious Thoughts and Behaviors Interview-Short Form, and Interpersonal Needs Questionnaire assessed for SCI difficulties, RRBs, suicidal symptoms, and interpersonal theory of suicide constructs (i.e., perceived burdensomeness, thwarted belongingness), respectively. Elevated levels of SCI difficulties and RRBs were associated with increased odds of reporting suicidal thoughts and behaviors occurring since joining the military, controlling for the number of years of service and suicidal symptoms occurring prior to joining the military. Perceived burdensomeness and thwarted belongingness statistically accounted for the relationship between ASD-related traits and suicidal ideation occurring since joining the military; a rival mediator, emotion dysregulation, was not a significant mediator. Among active duty U.S. military service members, greater ASD-related traits were associated with an increased likelihood of reporting suicidal thoughts and behaviors occurring since joining the military. Clinical efforts targeting perceived burdensomeness and thwarted belongingness might reduce suicide risk among military service members with elevated ASD-related traits. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Epithelial cell contributions to intestinal immunity.
The epithelial surfaces of the mammalian intestine interface directly with the external environment and thus continuously encounter pathogenic bacteria, fungi, viruses, and parasites. The intestinal epithelium is also closely associated with complex communities of symbiotic microorganisms. Intestinal epithelial cells are thus faced with the unique challenge of directly interacting with enormous numbers of microbes that include both pathogens and symbionts. As a result, gut epithelia have evolved an array of strategies that contribute to host immunity. This chapter considers the various mechanisms used by epithelial cells to limit microbial invasion of host tissues, shape the composition of indigenous microbial communities, and coordinate the adaptive immune response to microorganisms. Study of intestinal epithelial cells has contributed fundamental insights into intestinal immune homeostasis and has revealed how impaired epithelial cell function can contribute to inflammatory disease.


Predictors of caregiver distress among palliative home care clients in Ontario: evidence based on the interRAI Palliative Care.
This study examines predictors of caregiver distress among community-based palliative care clients. Analyses are based upon interRAI Palliative Care (interRAI PC) assessment data from palliative home care programs in three regions in Ontario, Canada. The study sample involved all community-based palliative care clients in Ontario who were assessed with the interRAI PC as part of normal clinical practice during pilot implementation of the instrument between 2007 and 2009 (N = 3,929). The assessments were performed by trained case managers and were used as the basis for determining service needs to be addressed through services contracted from provider agencies. The main study outcome of interest was the presence of one or more indicators of caregiver distress: helper(s) unable to continue caring activities; primary informal helper expresses feelings of distress, anger, or depression; family or close friends report feeling overwhelmed by person's illness. Caregiver distress was evident among about 22% of palliative home care clients. Multivariate analyses identified included clinical instability (Changes in Health, End Stage disease, Signs and Symptoms [CHESS] scale), depressive symptoms, cognitive impairment, and positive outlook as significant client-level predictors. Significant caregiver characteristics included hours of informal care. Three service use/provider variables were significant predictors of caregiver distress: the specific home care agency, hospitalizations in the last 90 days, and nursing visits. Caregiver distress affects approximately one in five palliative care clients in the community. This may lead to a number of adverse outcomes for the caregiver and client. The experience of distress is affected by client, caregiver, and agency characteristics that are readily identified by the interRAI PC assessment instrument. The present results point to the need for a care planning protocol that may be used on a targeted basis for clients experiencing or at elevated risk of caregiver distress.


[Pathological anatomy of pneumonia in Mycoplasma pneumoniae infection in children].
A total of 43 section observations on acute respiratory viral diseases in children aged between 13 days to 13 years are described. Using the direct and indirect fluorescent antibody test in 11 observations M. pneumoniae antigen was detected; in 4 observations this antigen was represented as monoantigen, and in 7 observations--in association with viruses of influenza, parainfluenza and adenovirus. The characteristic features of mycoplasma pneumoniae were noted; very high blood filling of vessels of all calibres with the involvement of the system of microcirculation of the lungs, with phenomana of pronounced dilatation of the capillary net and with a tendency to thrombo-formation; diffuse lesions (dystrophic and inflammatory changes) of large and small bronchi and bronchioles; plasmocellular reaction in interstitia of the lungs, perbronchial follicles and bifurcated lymphatic nodes; the presence of M. pneumoniae antigen in histological sections of the lungs. The author thinks it advisable to discard the term "M. pneumoniae-pneumonia" and replace it by "M. pneumoniae-infection" with predominent localization of the process in the lungs.


Ulnar dysmelia.
Eleven patients with hypoplasia and partial or complete aplasia of the ulna (examples of a complex spectrum of postaxial forearm and hand abnormalities) were reviewed. Three types of ulnar deformity were observed: (1) hypoplasia, (2) partial aplasia (ossification of the proximal part of the ulna present at birth); and (3) total aplasia (ossification not development). The roentgenographically "absent" segment of the ulna may be a large fibrocartilaginous anlage attached distally to the distal radial epiphysis or the ulnar side of the carpus, or both. The tethering effect of this band may cause ulnar deviation of the wrist (and hand) and dislocation of th badial head in utero as well as progression of these deformities after birth. Resection of the distal end of the fibrocartilaginous anlage during the first to second year of life is recommended, since the results of this procedure suggest that it reduces the angular growth deformities. It is also suggested that if the one-bone-forearm operation is indicated, it should be deferred until a later age, since complications may be less likely to occur then than at the time that the anlage is resected.


Predictive value of the school-leaving grade and prognosis of different admission groups for academic performance and continuity in the medical course - a longitudinal study.
The school-leaving GPA and the time since completion of secondary education are the major criteria for admission to German medical schools. However, the predictive value of the school-leaving grade and the admission delay have not been thoroughly examined since the amendment of the Medical Licensing Regulations and the introduction of reformed curricula in 2002. Detailed information on the prognosis of the different admission groups is also missing. To examine the predictive values of the school-leaving grade and the age at enrolment for academic performance and continuity throughout the reformed medical course. The study includes the central admission groups "GPA-best" and "delayed admission" as well as the primary and secondary local admission groups of three consecutive cohorts. The relationship between the criteria academic performance and continuity and the predictors school-leaving GPA, enrolment age, and admission group affiliation were examined up to the beginning of the final clerkship year. The academic performance and the prolongation of the pre-clinical part of undergraduate training were significantly related to the school-leaving GPA. Conversely, the dropout rate was related to age at enrolment. The students of the GPA-best group and the primary local admission group performed best and had the lowest dropout rates. The students of the delayed admission group and secondary local admission group performed significantly worse. More than 20% of these students dropped out within the pre-clinical course, half of them due to poor academic performance. However, the academic performance of all of the admission groups was highly variable and only about 35% of the students of each group reached the final clerkship year within the regular time. The school-leaving grade and age appear to have different prognostic implications for academic performance and continuity. Both factors have consequences for the delayed admission group. The academic prognosis of the secondary local admission group is as problematic as that of the delayed admission group. Additional admission instruments would be necessary, in order to recognise potentially able applicants independently of their school-leaving grade and to avoid the secondary admission procedure.


The Elimination of Neglected Tropical Diseases: A Case Study Exemplifying How Foreign Assistance Funding Can Be Catalytic in Reducing the Burden of Major Global Health Conditions.
In 2006, following direct advocacy and published rationale, the US Agency for International Development (USAID) established a neglected tropical diseases (NTDs) program to support the scale-up of integrated platforms to target the elimination and control of 5 NTDs-lymphatic filariasis, trachoma, onchocerciasis, schistosomiasis, and soil-transmitted helminthiasis. By 2017, more than 2.3 billion NTD treatments had been delivered to at-risk populations in 25 countries, leveraging $19 billion in donated drugs-approximately $26 dollars in donated medicine per $1 spent by USAID. As a result, most of the supported countries are on track to achieve their elimination goals (for lymphatic filariasis and trachoma) by 2020 or 2021 and their control goals soon thereafter. Though "small" when compared to other global health initiatives, this investment proved to be catalytic, and indeed highlights how foreign assistance funding can be transformative, in reducing the burden of major global health conditions such as NTDs.


Relationships between accident investigations, risk analysis, and safety management.
Several different approaches to achieve safety are in common use, and examples are accident investigations (AI), risk analysis (RA), and safety management systems (SMS). The meaning of these concepts and their practical applications vary quite a lot, which might cause confusion. A summary of definitions is presented. A general comparison is made of application areas and methodology. A proposal is made how to indicate parameters of variation. At one end of the scale there are organisations, which are highly organised in respect to safety. At the other end are small companies with informal safety routines. Although the three concepts differ in a number of respects, there are many links between them which is illustrated in a model. A number of relations have been described mainly concerned with more advanced organisations. Behind the practical safety work, there are varying sets of more or less explicit explanations and theories on safety and accident causation. Depending on the theory applied, the relations between approaches can be more or less clear and essential.


Water precautions in children with tympanostomy tubes.
To compare the effectiveness of antibiotic ear drops (suspension of polymyxin B sulfate, neomycin sulfate, and hydrocortisone [Pediotic]), prefabricated ear molds, or no precautions in decreasing the incidence of posttympanostomy water-related otorrhea. Five-year prospective controlled study. University referral center. Five hundred thirty-three pediatric patients who were undergoing tympanostomy tube placement (including those who were undergoing tonsillectomy, adenoidectomy, or both) were self-selected into four groups. The use of antibiotic ear drops that contained polymyxin B, neomycin, and hydrocortisone and the use of prefabricated ear molds. Group 1 comprised patients who were not given any water precautions with swimming regardless of the depth or type of water; group 2 comprised patients in whom antibiotic ear drops were applied after all forms of swimming; group 3 comprised patients who used ear molds with all forms of swimming (all children were advised against diving and swimming more than 180 cm below the surface, and parents were cautioned to avoid the entrance of soapy water into their child's ears during bathing); and group 4 comprised patients who were selected not to swim at all (they served as a control group). No statistically significant difference was observed in the incidence of posttympanostomy swimming-related otorrhea among the three swimming groups (11%, 14%, and 20% of children in groups 1, 2, and 3, respectively, reported swimming-related otorrhea [P=.26, df-2, chi-square=2.66]). Children who did not swim at all (group 4) did not differ significantly in their overall incidence of otorrhea (59%) from the three swimming groups combined (68%) during the follow-up period (P=.11, df=1, chi-square=2.54). Young children with tympanostomy tubes who surface swim and do not dive receive no additional benefit from the taking of water precautions in the form of earplugs or antibiotic ear drops.


Health impact assessment (HIA) of political proposals at the local level: successful introduction, but what has happened 15 years later?
Health impact assessments (HIAs) were first introduced in Sweden in the mid-to-late 1990s, with the aim of placing health issues on the political agenda and helping to reduce health inequalities. In the early 2000s, HIAs entered a second phase and the Swedish Parliament adopted a national public health policy. A national survey conducted in 2001 showed that 10/289 municipalities had begun to use HIA and 55/289 had decided to use HIA or had initiated an adoption process. In a 2013 follow-up study based on a strategic sample of municipalities, 9/36 municipalities reported using HIA and/or similar tools. Corresponding figures for the 21 Swedish regions were 10 regions in 2001 and four in 2013. HIA and similar tools (sustainability analyses, child impact assessments, and others) were applied to the same extent as HIA. Fifteen years after implementation began, HIA is still being used. Regions show a clear decrease in the use of HIA. There are several explanations for this development. One is the political context, and other explanations are shifts in which actors are responsible for HIA and for public health at the local/regional levels.


Oxidized High-Density Lipoprotein Induces Endothelial Fibrosis Promoting Hyperpermeability, Hypotension, and Increased Mortality.
During systemic inflammation, reactive oxygen species (ROS) are generated in the bloodstream, producing large amounts of oxidized HDL (oxHDL). OxHDL loses the vascular protective features of native HDL, acquiring detrimental actions. Systemic inflammation promotes endothelial fibrosis, characterized by adhesion protein downregulation and fibrotic-specific gene upregulation, disrupting endothelial monolayer integrity. Severe systemic inflammatory conditions, as found in critically ill patients in the intensive care unit (ICU), exhibit endothelial hyperpermeability, hypotension, and organ hypoperfusion, promoting organ dysfunction and increased mortality. Because endothelial fibrosis disturbs the endothelium, it is proposed that it is the cellular and molecular origin of endothelial hyperpermeability and the subsequent deleterious consequences. However, whether oxHDL is involved in this process is unknown. The aim of this study was to investigate the fibrotic effect of oxHDL on the endothelium, to elucidate the underlying molecular and cellular mechanism, and to determine its effects on vascular permeability, blood pressure, and mortality. The results showed that oxHDL induces endothelial fibrosis through the LOX-1/NOX-2/ROS/NF-κB pathway, TGF-β secretion, and ALK-5/Smad activation. OxHDL-treated rats showed endothelial hyperpermeability, hypotension, and an enhanced risk of death and mortality, which was prevented using an ALK-5 inhibitor and antioxidant diet consumption. Additionally, the ICU patients showed fibrotic endothelial cells, and the resuscitation fluid volume administered correlated with the plasma oxHDL levels associated with an elevated risk of death and mortality. We conclude that oxHDL generates endothelial fibrosis, impacting blood pressure regulation and survival.


Fitting models for the joint action of two drugs using SAS.
Combinations of drugs are increasingly being used for a wide variety of diseases and conditions. A pre-clinical study may allow the investigation of the response at a large number of dose combinations. In determining the response to a drug combination, interest may lie in seeking evidence of 'synergism', in which the joint action is greater than the actions of the individual drugs, or of 'antagonism', in which it is less. Two well-known response surface models representing no interaction are Loewe additivity and Bliss independence, and Loewe or Bliss synergism or antagonism is defined relative to these. We illustrate an approach to fitting these models for the case in which the marginal single drug dose-response relationships are represented by four-parameter logistic curves with common upper and lower limits, and where the response variable is normally distributed with a common variance about the dose-response curve. When the dose-response curves are not parallel, the relative potency of the two drugs varies according to the magnitude of the desired effect and the models for Loewe additivity and synergism/antagonism cannot be explicitly expressed. We present an iterative approach to fitting these models without the assumption of parallel dose-response curves. A goodness-of-fit test based on residuals is also described. Implementation using the SAS NLIN procedure is illustrated using data from a pre-clinical study.


Enhanced extractability of articular cartilage protoglycans in osteoarthrosis.
Tissue contents of small, easily extracted, proteoglycans, relatively poor in keratan sulphate, were compared in normal and osteoarthrotic cartilage. Although the amounts of small proteoglycans were similar in each tissue, as were the collagen contents, some proteoglycans in the diseased cartilage were much more readily extracted than those in the normal tissue.


Eye tracking research to answer questions about augmentative and alternative communication assessment and intervention.
Recently, eye tracking technologies (i.e., technologies that automatically track the point of an individual's gaze while that person views or interacts with a visual image) have become available for research purposes. Based on the sampling of the orientation of the individual's eyes, researchers can quantify which locations within the visual image were fixated (viewed), for how long, and how many times. These automated eye tracking research technologies open up a wealth of avenues for investigating how individuals with developmental or acquired communication disabilities may respond to aided augmentative and alternative communication (AAC) systems. In this paper, we introduce basic terminology and explore some of the special challenges of conducting eye tracking research with populations with disabilities who might use AAC, including challenges of inferring attention from the presence of fixation and challenges related to calibration that may result from participant characteristics, behavioral idiosyncracies, and/or the number of calibration points. We also examine how the technology can be applied to ask well-structured experimental questions that have direct clinical relevance, with a focus on the unique contributions that eye tracking research can provide by (a) allowing evaluation of skills in individuals who are difficult to assess via traditional methods, and (b) facilitating access to information on underlying visual cognitive processes that is not accessible via traditional behavioral measures.


Challenges to the diagnosis, evaluation, treatment, and management of clustered cardiometabolic risk factors.
A panel was convened on January 10, 2007, to discuss the challenges to the diagnosis, evaluation, treatment, and management of clustered cardiometabolic risk factors. George Bakris, MD, Professor of Medicine, University of Chicago, Chicago, IL, moderated the panel. Vivian Fonseca, MD, Tulane University Health Science Center, New Orleans, LA, and JoAnne Foody, MD, Harvard School of Medicine, Boston, MA, participated in the discussion. This expert panel discussion was supported by and each author received an honorarium from Merck & Co, Inc, and Sanofi-Aventis for time and effort spent participating in the discussion and reviewing the transcript for important intellectual content before publication. The authors maintained full control of the discussion and the resulting content of this article.


Substantiation as a multitier process: the results of a NIS-3 analysis.
Previous studies on child maltreatment reporting have focused mainly on one level of substantiation. This article analyzes factors influencing the multitiered substantiation process. The 1993 Third National Incidence Study (NIS-3) data of substantiated and non-substantiated reported incidents (N=7,263) of maltreatment were analyzed. Substantiation was classified into three categories: unfounded, indicated, and founded. Independent variables included demographic characteristics, case-processing variables, and maltreatment characteristics. Bivariate and multiple logistic regression (MLR) analyses were calculated to determine whether demographic and case processing variables predicted unfounded or founded/indicated dispositions. Second-level analysis examined demographic, case processing, and maltreatment characteristics as predictors of founded or indicated status. These results showed that 60.2% of CPS investigations conducted were evaluated as unfounded, about 22% were categorized as founded, and 17% were classified as indicated. In the MLR analysis for the first level of substantiation, case processing variables were highly significant predictors of founded/indicated status. In the second-level substantiation MLR model, cases in the mid-range income level (dollars 15,000-29,999) had a lower probability (adjusted OR = .58, p = .02) of being founded than those of less than dollars 15,000, and reports involving Hispanic children (OR = 3.04, p = .05) were more likely than the "all other" race-ethnic social classification to have been substantiated as founded. This analysis of NIS-3 data suggests that a three-tiered rather than a two-tiered system is a more accurate representation of the CPS substantiation process. Further analysis of substantiation patterns is required to provide a basis for developing more effective investigation systems.


Herbaspirillum frisingense sp. nov., a new nitrogen-fixing bacterial species that occurs in C4-fibre plants.
The enrichment of nitrogen-fixing bacteria from the C4-fibre plants, Spartina pectinata, Miscanthus sinensis, Miscanthus sacchariflorus and Pennisetum purpureum, with nitrogen-free semi-solid media led to the isolation of Herbaspirillum-like strains among other diazotrophic bacteria. On the basis of physiological properties, phylogenetic analysis comparing 16S rDNA sequences and DNA-DNA hybridization experiments of chromosomal DNA the new isolates could be grouped together in a new species with the proposed name Herbaspirillum frisingense sp. nov. Morphological characteristics, such as cell size and shape, colony appearance, motility and flagellation are largely identical to the known species Herbaspirillum rubrisubalbicans and Herbaspirillum seropedicae. On the basis of utilization of adipate (-), N-acetyl-D-glucosamine (+), meso-erythritol (-), L-rhamnose (-) and meso-inositol (-) Herbaspirillum frisingense sp. nov. can be distinguished from other known Herbaspirillum spp. Nitrogen-fixing capability was examined by PCR amplification of the nifD gene and an acetylene reduction assay, and was found with all isolates tested. 16S rDNA sequence similarity to the other Herbaspirillum spp. is 98.5-99.1%. In genomic DNA-DNA hybridization experiments Herbaspirillum frisingense sp. nov. forms a homogeneous group with 70-100+/-10% similarity, clearly distinct from Herbaspirillum seropedicae and Herbaspirillum rubrisubalbicans with 1-34% similarity. 16S rRNA-targeted oligonucleotide probes, specific for the whole genus Herbaspirillum and for three Herbaspirillum species were designed and are suitable for fluorescence in situ hybridization. The DNA G+C content of Herbaspirillum frisingense sp. nov. is 63+/-2 mol%, in agreement with the values of 61-65% for the genus. PCR fingerprinting exhibits a consistent pattern for groups of strains isolated from the same plant, suggesting a low genomic diversity among bacteria inhabiting C4-gramineous plant tissues. Low genetic DNA diversity seems to be common between probable endophytic bacterial isolates of the same taxon. The type strain of Herbaspirillum frisingense sp. nov. is GSF30T (= DSM 13128T).


G protein-coupled estrogen receptor 1 (GPER1)/GPR30 increases ERK1/2 activity through PDZ motif-dependent and -independent mechanisms.
G protein-coupled receptor 30 (GPR30), also called G protein-coupled estrogen receptor 1 (GPER1), is thought to play important roles in breast cancer and cardiometabolic regulation, but many questions remain about ligand activation, effector coupling, and subcellular localization. We showed recently that GPR30 interacts through the C-terminal type I PDZ motif with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, which anchor the receptor in the plasma membrane and mediate an apparently constitutive decrease in cAMP production independently of Gi/o Here, we show that GPR30 also constitutively increases ERK1/2 activity. Removing the receptor PDZ motif or knocking down specifically AKAP5 inhibited the increase, showing that this increase also requires the PDZ interaction. However, the increase was inhibited by pertussis toxin as well as by wortmannin but not by AG1478, indicating that Gi/o and phosphoinositide 3-kinase (PI3K) mediate the increase independently of epidermal growth factor receptor transactivation. FK506 and okadaic acid also inhibited the increase, implying that a protein phosphatase is involved. The proposed GPR30 agonist G-1 also increased ERK1/2 activity, but this increase was only observed at a level of receptor expression below that required for the constitutive increase. Furthermore, deleting the PDZ motif did not inhibit the G-1-stimulated increase. Based on these results, we propose that GPR30 increases ERK1/2 activity via two Gi/o-mediated mechanisms, a PDZ-dependent, apparently constitutive mechanism and a PDZ-independent G-1-stimulated mechanism.


Distress and DNA repair in human lymphocytes.
This research assessed differences in DNA repair in lymphocytes from high- and low-distressed individuals. A median split on Minnesota Multiphasic Personality Inventory (MMPI) Scale 2 divided 28 newly admitted nonpsychotic psychiatric inpatients into high- and low-distress subgroups. The high-distress subgroup had significantly poorer DNA repair in lymphocytes exposed to X-irradiation than low-distress subjects. We also found that lymphocytes obtained from this psychiatric sample had significantly poorer DNA repair than lymphocytes from nonpsychiatric control subjects when compared 5 hr after X-irradiation. A high level of distress therefore appears to be associated with significant dysfunctional differences at the molecular level which may have important implications for health. These data provide evidence for a direct pathway through which distress could influence the incidence of cancer.


[Dietary intake and macrovascular disease in a Japanese-Brazilian population: a cross-sectional study].
To describe the food intake of Japanese-Brazilians with and without macrovascular disease (MVD). MVD was defined, for 1,165 Japanese-Brazilians, by scores attributed to the health historical, electrocardiogram and ankle-brachial index values. The usual dietary intake was determined using a food frequency questionnaire. The MVD prevalence was of 3.2%, being similar among genders. Statistically higher frequencies of individuals with MVD were observed among those of first generation, with age > 60 years, tobacco user, with hypertension, hypertriglyceridemia and diabetes. Subjects with MVD were older, with smaller hip circumference, and higher systolic blood pressure levels, triglycerides and glycemia concentration; they informed higher consumption of iron source food and smaller of grains fibers. Statistically significant difference was found to saturated fat (crude analysis: second tercile versus first tercile). Programs of nutritional education should be stimulated in this group with high prevalence of non-communicable chronic diseases.


K0.78Na0.22MoO2AsO4.
The title compound, potassium sodium dioxidomolybden-um(VI) arsenate, K0.78Na0.22MoO2AsO4, was synthesized by a solid-state reaction route. The structure is built up from corner-sharing MoO6 octa-hedra and AsO4 tetra-hedra, creating infinite [MoAsO8]∞ chains running along the b-axis direction. As, Mo and all but one O atom are on special positions (4c) with m symmetry and K (occupancy 0.78) is on a position (4a) of -1 in the tunnels. The possible motion of the alkali cations has been investigated by means of the bond-valance sum (BVS) model. The simulation shows that the Na(+) motion appears to be easier mainly along the b-axis direction. Structural relationships between the different compounds of the AMoO2AsO4 (A = Ag, Li, Na, K, Rb) series and MXO8 (M = V; X = P, As) chains are discussed.


Predicting the ideal serum creatinine of kidney transplant recipients by a simple formula based on the balance between metabolic demands of recipients and renal mass supply from donors.
Serum creatinine (Scr) is the most frequently used test to estimate graft function after kidney transplantation. Our previous study demonstrated that the independent predictors of recipient posttransplantation Scr included the ratio of graft weight to recipient body weight, the ratio of graft weight to recipient body surface area (BSA), and the ratio of graft weight to recipient body mass index (BMI). A prospective analysis about the impact of the balance between metabolic demands and renal supply on posttransplantation Scr of recipients was previously reported. We plotted the scatter graph using the X-axis as the independent predictors of Scr by linear regression and the Y-axis as the recipient Scr. To generate the predictive formula of Scr, we calculated a fit of the line of plotted cases using a linear regression method with 2 regression lines for prediction of the upper and lower 95% confidence intervals. Each line was converted into a predictive formula: Scr = -0.0033* (Graft weight(g)/Recipient BSA(m2))+1.75. Under 95% confidence, the Scr ranges from -0.0033* (Graft weight(g)/Recipient BSA(m2))+1.07 to -0.0033* (Graft weight(g)/Recipient BSA (m2))+2.44. Scr = -0.1049* (Graft weight(g)/Recipient body weight(kg))+1.72, which ranges from -0.1049* (Graft weight(g)/Recipient body weight(kg))+1.06 to -0.1049* (Graft weight(g)/Recipient body weight(kg))+2.37. Scr = -0.0158* (Graft weight(g)/Recipient BMI(kg/m2))+1.56, which ranges from -0.0158* (Graft weight(g)/Recipient BMI(kg/m2))+0.75 to -0.0158* (Graft weight(g)/Recipient BMI(kg/m2))+2.26. Prediction of posttransplantation Scr may be achieved by measuring graft weight as well as recipient weight and height. When recipient Scr is significantly higher than that predicted by the formula, a clinician should suspect an underlying graft injury.


Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects.
Understanding the complexity of cancer and of the underlying regulatory networks provides a new paradigm that tackles cancer development and treatment through a system biology approach, contemporarily acting on various intersecting pathways. Cancer cell metabolism is an old pathogenetic issue that has recently gained new interest as target for therapeutic approaches. More than 70 years ago, Warburg discovered that malignant cells generally have altered metabolism with high rates of glucose uptake and increased glycolysis, even under aerobic condition. Observational studies have provided evidence that impaired metabolism, obesity, hyperglycemia and hyperinsulinemia may have a role in cancer development, progression and prognosis, and actually diabetic and obese patients have increased cancer risk. On the other hand, caloric restriction has been shown to prolong life span and reduce cancer incidence in several animal models, having an impact on different metabolic pathways. Metformin, an antidiabetic drug widely used for over 40 years, mimics caloric restriction acting on cell metabolism at multiple levels, reducing all energy-consuming processes in the cells, including cell proliferation. By overviewing molecular mechanisms of action, epidemiological evidences, experimental data in tumor models and early clinical study results, this review provides information supporting the promising use of metformin in cancer prevention and treatment.


[Effect of phosphorylating myosin light chains and ionic strength on actin-myosin interaction in a relaxed skeletal muscle fiber].
The effect of LC-2 phosphorylation and ionic strength on actin-myosin interaction in relaxed skeletal muscle fibers have been studied using polarization fluorimetry. F-actin was chemically modified by the fluorescent dye, rhodamine-phalloidin, and the mode of myosin-actin interaction was estimated by a polarized fluorescence technique based on changes in the dye orientation (phi E) and thin filament flexibility (sin 2 theta). Phosphorylation of LC-2 at relaxation in low ionic strength induced typical for the force production ("strong" binding) state changes in the polarized fluorescence of F-actin (decreasing of phi E and increasing of sin 2 theta). In contrast, phosphorylation in high ionic strength induced changes similar to those typical for the nonforce production ("weak" binding) state (phi E did not change, while sin 2 theta decreased). It is suggested that phosphorylation of LC-2 at approximately physiological ionic strength may provide fiber relaxation by switching some of the cross-bridges to the nonforce production state at the initial stage of relaxation.


A parallel framework for the FE-based simulation of knee joint motion.
We present an object-oriented framework for the finite-element (FE)-based simulation of the human knee joint motion. The FE model of the knee joint is acquired from the patients in vivo by using magnetic resonance imaging. The MRI images are converted into a three-dimensional model and finally an all-hexahedral mesh for the FE analysis is generated. The simulation environment uses nonlinear finite-element analysis (FEA) and is capable of handling contact of the model to handle the complex rolling/sliding motion of the knee joint. The software strictly follows object-oriented concepts of software engineering in order to guarantee maximum extensibility and maintainability. The final goal of this work-in-progress is the creation of a computer-based biomechanical model of the knee joint which can be used in a variety of applications, ranging from prosthesis design and treatment planning (e.g., optimal reconstruction of ruptured ligaments) over surgical simulation to impact computations in crashworthiness simulations.


Water usage for energy production and supply in China: Decoupled from industrial growth?
The energy industry, one of the largest water consumers in the socioeconomic system, has been constrained by water scarcity in some areas worldwide. Therefore, decoupling water usage from the energy system is a pressing issue for ensuring energy security and maintaining environmental sustainability. This study applied an input-output analysis and the Tapio decoupling index, which may be considered the first attempt to investigate the decoupling degree between water usage, i.e., the direct water withdrawal for energy production (WWEP) from a production-based perspective and the water footprint for energy supply (WFES) from a consumption-based perspective, and industrial growth for five major energy sectors in China from 2002 to 2015. We found that WWEP was roughly three times higher than WFES for the whole energy industry, and both values underwent a considerable decrease during the study period. Production and supply of electricity and heat (PSEH) contributed most to the total WWEP and WFES, and was mainly responsible for the overall decline. Moreover, WFES exceeded WWEP in Processing of petroleum, coking, and processing of nuclear fuel (PPC) and Production and supply of gas (PSG), whose WEFS values accounted for 36.3% and 12.2%, respectively, of the total WFES in 2015. In terms of the decoupling status, only PSEH achieved strong decoupling in both WWEP and WFES, while PPC and PSG presented a better decoupling performance for WWEP than that for WFES. In contrast, Mining and washing of coal and Extraction of petroleum and natural gas performed relatively worse from both perspectives. These results can help provide a foundation and support for effective water conservation policies from both energy production and energy consumption perspectives.


Trichoscopy in alopecias: diagnosis simplified.
Trichoscopy is the term coined for dermoscopic imaging of the scalp and hair. This novel diagnostic technique, both simple and non-invasive, can be used as a handy bed side tool for diagnosing common hair and scalp disorders. Trichoscopic observations can be broadly grouped as hair signs, vascular patterns, pigment patterns and interfollicular patterns. In this article, we have briefly described the trichoscopic findings in the common categories of cicatricial and non-cicatricial alopecias such as androgenetic alopecia, alopecia areata, telogen effluvium, tinea capitis, trichotillomania, lichen planopilaris, discoid lupus erythematosus and hair shaft disorders. Besides diagnosing alopecia, it has the potential for obviating unnecessary biopsies and when a biopsy is still needed it is helpful in choosing an ideal biopsy site. Moreover, trichoscopy is a valuable tool for evaluating the treatment response photographically at each follow-up. The last statement here is deleted as asked.


Evaluating An Automated Compounding Workflow Software for Safety and Efficiency: Implementation Study.
The forms of automation available to the oncology pharmacy range from compounding robotic solutions through to combination workflow software, which can scale-up to cover the entire workflow from prescribing to administration. A solution that offers entire workflow management for oncology is desirable because (in terms of cytotoxic delivery of a regimen to a patient) the chain that starts with prescription and the assay of the patient's laboratory results and ends with administration has multiple potential safety gaps and choke points. The aim of this study was to show how incremental change to a core compounding workflow software solution has helped an organization meet goals of improved patient safety; increasing the number of oncology treatments; improving documentation; and improving communication between oncologists, pharmacists, and nurses. We also aimed to illustrate how using this technology flow beyond the pharmacy has extended medication safety to the patient's bedside through the deployment of a connected solution for confirming and documenting right patient-right medication transactions. A compounding workflow software solution was introduced for both preparation and documentation, with pharmacist verification of the order, gravimetric checks, and step-by-step on-screen instructions displayed in the work area for the technician. The software supported the technician during compounding by proposing the required drug vial size, diluents, and consumables. Out-of-tolerance concentrations were auto-alerted via an integrated gravimetric scale. A patient-medication label was created. Integration was undertaken between a prescribing module and the compounding module to reduce the risk of transcription errors. The deployment of wireless-connected handheld barcode scanners was then made to allow nurses to use the patient-medication label on each compounded product and to scan patient identification bands to ensure right patient-right prescription. Despite an increase in compounding, with a growth of 12% per annum and no increase in pharmacy headcount, we doubled our output to 14,000 medications per annum through the application of the compounding solution. The use of a handheld barcode scanning device for nurses reduced the time for medication administration from ≈6 minutes per item to 41 seconds, with a mean average saving of 5 minutes and 19 seconds per item. When calculated against our throughput of 14,000 items per annum (current production rate via pharmacy), this gives a saving of 3 hours and 24 minutes of nursing time per day, equivalent to 0.425 full-time nurses per annum. The addition of prescribing, compounding, and administration software solutions to our oncology medication chain has increased detection and decreased the risk of error at each stage of the process. The double-checks that the system has built in by virtue of its own systems and through the flow of control of drugs and dosages from physician to pharmacist to nurse allow it to integrate fully with our human systems of risk management.


Signals in limb development: STOP, GO, STAY and POSITION.
Cell-to-cell interactions in early limb development are considered within the framework of the extracellular signals STOP, GO, STAY and POSITION, a classification which emphasises that the signals are elective rather than instructive, and that complexity arises from cells' response. Patterning in the limb is analysed in terms of signals that specify positional values along the anteroposterior axes, and retinoic acid is thought to be a positional morphogen. There is however, evidence for patterning which does not depend on a positional signal. In the early bud the mesenchyme gives POSITION signals to the apical ridge, which in turn provides a STAY signal to the mesenchyme in the progress zone. Non-ridge ectoderm produces a STOP signal with respect to cartilage differentiation. The pattern of cartilage differentiation is specified well before cartilage condensation. Growth factors affect both cartilage and muscle differentiation in culture. Pigment patterns result from feather germs providing STOP or GO signals to the melanoblasts which enter all feather germs. The pathways for the cell-to-cell signals are not known but may involve gap junctions.


Divergent metabolome and proteome suggest functional independence of dual phloem transport systems in cucurbits.
Cucurbitaceous plants (cucurbits) have long been preferred models for studying phloem physiology. However, these species are unusual in that they possess two different phloem systems, one within the main vascular bundles [fascicular phloem (FP)] and another peripheral to the vascular bundles and scattered through stem and petiole cortex tissues [extrafascicular phloem (EFP)]. We have revisited the assumption that the sap released after shoot incision originates from the FP, and also investigated the long-standing question of why the sugar content of this sap is ~30-fold less than predicted for requirements of photosynthate delivery. Video microscopy and phloem labeling experiments unexpectedly reveal that FP very quickly becomes blocked upon cutting, whereas the extrafascicular phloem bleeds for extended periods. Thus, all cucurbit phloem sap studies to date have reported metabolite, protein, and RNA composition and transport in the relatively minor extrafascicular sieve tubes. Using tissue dissection and direct sampling of sieve tube contents, we show that FP in fact does contain up to 1 M sugars, in contrast to low-millimolar levels in the EFP. Moreover, major phloem proteins in sieve tubes of FP differ from those that predominate in the extrafascicular sap, and include several previously uncharacterized proteins with little or no homology to databases. The overall compositional differences of the two phloem systems strongly indicate functional isolation. On this basis, we propose that the fascicular phloem is largely responsible for sugar transport, whereas the extrafascicular phloem may function in signaling, defense, and transport of other metabolites.


Clopidogrel treatment before percutaneous coronary intervention reduces adverse cardiac events.
Platelet inhibition during percutaneous coronary intervention (PCI) generally reduces adverse cardiac events. There are very few data on the combination of aspirin and the platelet adenosine diphosphate-receptor inhibitor clopidogrel given before the intervention. In a non-randomized comparison, a total of 706 consecutive patients received clopidogrel 375 mg in addition to aspirin on the day before PCI. The control group consisted of 724 consecutive PCI patients receiving only aspirin pre-treatment. The two groups were well balanced regarding baseline characteristics. Pre-treatment with clopidogrel reduced the in-hospital composite of death, myocardial infarction or urgent revascularization by 41% compared to the control (8.2% versus 4.8%, respectively; p = 0.010). This was due to a decreased incidence of myocardial infarction (7.2% versus 4.4%; p = 0.024) and percutaneous reintervention (1.2% versus 0.3%; p = 0.039). There was no difference in femoral complications between the groups. For every patient in the clopidogrel group, there was a cost reduction of SEK 447 ($40 United States currency). Clopidogrel treatment in addition to aspirin before PCI was associated with a reduction of in-hospital adverse cardiac events. It was also safe and cost-saving.


Urinary excretion of prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha during volume expansion in patients with glomerulonephritis.
Thirteen patients with active IgA glomerulonephritis (IgA GN), ten patients with a history of Henoch-Schönlein glomerulonephritis (HS GN) and nine healthy controls were studied during hydropenia (HP) and 3% volume expansion (VE) with isotonic saline. Clearance of inulin and para-aminohippurate, urinary excretion of Na, immunoreactive prostaglandin F2 alpha (PGF2 alpha) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were determined. The patients with a history of HS GN had normal blood pressure and renal function. As in the controls, the urinary excretion of PGF 2 alpha decreased and the excretion of 6-keto-PGF1 alpha increased during VE. In the patients with IgA GN the glomerular filtration rate (GFR) was normal, markedly reduced and supernormal. Five patients had hypertension and an increased NA excretion in relation to the GFR during VE. As a group, the patients with IgA GN increased their urinary excretion of 6-keto-PGF1 alpha during VE, while the excretion of PGF2 alpha did not change. In relation to the GFR, the urinary excretion of PGF2 alpha and 6-keto-PGF1 alpha was markedly increased in two patients with low GFR, which implies that these substances play a role in advanced renal disease. VE had little effect on PG excretion in these patients. In the hypertensive patients the urinary excretion of PGF2 alpha and 6-keto-PGF1 alpha was the same as in those with normal blood pressure. PGs are therefore not likely to mediate the increased natriuretic response to VE in hypertension.


Treatment of patients with severe hypertension by inhibition of angiotensin-converting enzyme.
1. The results of the administration of the nona-peptide inhibitor (SQ 20,881) of the enzymatic conversion of angiotensin I into angiotensin II in twelve severe hypertensive patients are presented. 2. Administration of the compound was associated with a fall in blood pressure in ten of twelve patients. 3. Four patients had a normal plasma renin activity (PRA) with a range of 1.6-3.7 ng h-1 ml-1 and eight patients had a high PRA with a range of 5.0-74 ng h-1 ml-1. Two of the patients with normal PRA had no fall in blood pressure despite receiving 2 mg/kg of the compound. Two patients with normal PRA, however, did respond, thus indicating that a high PRA is not necessary for a response to the inhibitor compound. 4. It was found that haemodialysis or diuresis with frusemide enhanced the blood pressure response to the compound. 5. The presence of a measured low total blood volume was found to be associated with an exaggerated fall in blood pressure to a small dose of compound (0.125 mg/kg) in one patient.


CD8alpha dendritic cells and immune protection from experimental allergic encephalomyelitis.
Dendritic cells (DC) represent a phenotypically heterogeneous population endowed with two important biological functions, immunity and tolerance. Here we report that the injection of splenic CD8alpha(+) DC, derived from rats with experimental allergic encephalomyelitis (EAE), delayed the onset and suppressed the severity of EAE in Lewis rats. This was accompanied by the lack of magnetic resonance imaging (MRI) lesions in the brain and spinal cord and by reduced numbers of inflammatory cells within the central nervous system. Injection of CD8(alpha+) DC inhibited T cell proliferation that may relate to increased interferon (IFN)-gamma and nitric oxide production. Although CD8(+)CD28(-) suppressor T cells, apoptotic cells and co-stimulatory molecules were not altered, CD4(+) T cells expressing interleukin (IL)-10 were augmented in rats receiving CD8alpha(+) DC compared to rats receiving total DC or medium. These results demonstrate that rat splenic CD8alpha(+) DC could provide a cellular basis for a novel, individualized immunotherapy using autologous DC as a complement to conventional therapy in diseases with an autoimmune background such as multiple sclerosis.


[Chronic care model: an evidence-based approach to caring for people with chronic disease].
The Chronic Care Model (CCM) is an organizational approach to caring for people with chronic disease in a primary care setting. The system creates practical, supportive, evidence-based interactions between an informed, activated patient and a prepared, proactive practice team. The CCM identifies essential elements of a health care system that encourage high-quality chronic disease care: the community; the health system; self-management support; delivery system design; decision support, and clinical information systems.


Glucose-induced decomposition of layer-by-layer films composed of phenylboronic acid-bearing poly(allylamine) and poly(vinyl alcohol) under physiological conditions.
Multilayer thin films prepared via layer-by-layer (LbL) deposition of phenylboronic acid-bearing poly(allylamine hydrochloride) (PBA-PAH) and poly(vinyl alcohol) (PVA) were combined with glucose oxidase (GOx) to develop LbL films that can be decomposed in response to glucose. LbL deposition of PBA-PAH and PVA on a GOx-modified quartz slide afforded GOx/(PBA-PAH/PVA)n films, in which PBA-PAH and PVA layers were connected to each other through boronate ester bonds, while GOx was immobilized electrostatically. The GOx/(PBA-PAH/PVA)n films were stable in glucose-free solutions under physiological conditions. In contrast, films decomposed in the presence of glucose, depending on the concentration of glucose and solution pH. The GOx/(PBA-PAH/PVA)10 film decomposed almost completely in 60 min in the presence of 10 mM glucose at pH 7.4, while it took 120 min in 0.1 mM glucose solution. Film decomposition was accelerated at pH 5.0-7.4, whereas it was suppressed in acidic and basic media (pH 3.0 and 9.0, respectively) due to the lower catalytic activity of GOx. Glucose-induced decomposition of the film can be rationalized based on the scission of the carbon-boron bonds of PBA in the film by hydrogen peroxide (H2O2), which is produced through a GOx-catalyzed oxidation reaction of glucose.


How right should the customer be?
If your salespeople aren't sure who their boss is--the district manager? the regional manager? the customer?--it could be a sign that your company's sales force controls are working at cross-purposes and that your sales function is in trouble. Sales force controls are the policies and practices that govern the way you train, supervise, motivate, and evaluate your sales staff. They include the types of compensation you offer your people and the criteria your sales managers use to evaluate the reps' performance. These controls let salespeople know which trade-offs the company would prefer them to make when the inevitable conflicts arise between what they want to do (spend lots of time and money to get a sale) and what they actually can do (use limited resources and still get the sale). When sales force controls aren't aligned--when, say, the system simultaneously encourages reps to be entrepreneurial but also to file detailed call reports and check in frequently with their bosses--individuals become discouraged and unproductive, and they eventually leave the company. The authors' research suggests there are significant differences between the control systems of companies that encourage salespeople to put the customer first-outcome control (OC) systems--and those that encourage reps to put their managers first--behavior control (BC) systems. In this article, they list the characteristics of OC and BC systems, describe the potential fallout from conflicts within these systems, and explain how you can tell which control system is appropriate for your firm. In most cases, the right choice will be a consistent system somewhere in the middle of the OC-BC continuum.


Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function.
Early stages of viral infections are associated with local recruitment and activation of dendritic cells (DC) and NK cells. Although activated DC and NK cells are known to support each other's functions, it is less clear whether their local interaction in infected tissues can modulate the subsequent ability of migrating DC to induce T cell responses in draining lymph nodes. In this study, we report that NK cells are capable of inducing stable type 1-polarized "effector/memory" DC (DC1) that act as carriers of NK cell-derived helper signals for the development of type 1 immune responses. NK cell-induced DC1 show a strongly elevated ability to produce IL-12p70 after subsequent CD40 ligand stimulation. NK-induced DC1 prime naive CD4+ Th cells for high levels of IFN-gamma, but low IL-4 production, and demonstrate a strongly enhanced ability to induce Ag-specific CD8+ T cell responses. Resting NK cells display stringent activation requirements to perform this novel, DC-mediated, "helper" function. Although their interaction with K562 cells results in effective target cell killing, the induction of DC1 requires a second NK cell-activating signal. Such costimulatory signal can be provided by type I IFNs, common mediators of antiviral responses. Therefore, in addition to their cytolytic function, NK cells also have immunoregulatory activity, induced under more stringent conditions. The currently demonstrated helper activity of NK cells may support the development of Th1- and CTL-dominated type 1 immunity against intracellular pathogens and may have implications for cancer immunotherapy.


Chlorine and sulfur determination in water using indirect laser-induced breakdown spectroscopy.
The detection sensitivity of chlorine (Cl) and sulfur (S) elements is poor using direct laser-induced breakdown spectroscopy (LIBS) because of the high ionization energy of Cl and S. Therefore, a new technique, namely indirect laser-induced breakdown spectroscopy (ID-LIBS), was proposed to improve the detection sensitivity of Cl and S elements. The method detected Cl in water by indirectly detecting the excess silver (Ag) after the precipitation reaction of Ag and chloride. Similarly, the method indirectly detected S in water by detecting the excess barium (Ba) after the precipitation reaction of Ba and sulfate, due to Ag and Ba with low ionization energy and easy excitation. The lines of Ag I 546.5 nm and Ba I 553.5 nm were detected. The R2 values of 0.999 and 0.997 were obtained for Cl and S, respectively. The limit of quantitation (LoQ) was 2 mg/L for Cl and 5 mg/L for S. The detection sensitivity was improved by about three orders of magnitude compared to using Cl I 822.17 nm and S I 921.28 nm. The results showed that the technique of indirect LIBS can achieve the sensitive detection of Cl and S in water indicating that the technique has tremendous potential for element analysis of water.


Polymorphisms in the XRCC1 gene are associated with treatment response to platinum chemotherapy in advanced non-small cell lung cancer patients based on meta-analysis.
X-ray repair cross complementing group 1(XRCC1) polymorphisms have been implicated in interindividual variability of efficacy of platinum chemotherapy for treating non-small cell lung cancer (NSCLC); however, results of different studies have been inconsistent. We conducted a meta-analysis to investigate the association between polymorphisms in the XRCC1 gene and response rate of platinum chemotherapy in advanced NSCLC patients. Searches were performed on MEDLINE, PubMed, EMBASE, Chinese Biological Medicine Database, China National Knowledge Infrastructure, and Wangfang Data, covering all relevant studies published up to August 1, 2012. Statistical analyses were performed using the Revman 5.0 and STATA 10.0 software. Two polymorphisms, Arg399Gln (G>A) and Arg194Trp (C>T), were investigated in 19 studies, involving 2152 advanced NSCLC patients. For XRCC1 Arg399Gln, patients carrying two G alleles had a significantly increased response rate of platinum chemotherapy, when compared with those carrying the A allele [odds ratio (OR) = 2.05, 95% confidence interval CI = 1.62-2.60 for GG vs GA+AA]. Similarly, the AA carriers had a 54% decreased response rate compared with the G allele carriers (OR = 0.46, 95%CI = 0.30-0.70 for AA vs GA+GG). For XRCC1 Arg194Trp, patients carrying two C alleles had a 62% decreased response rate compared with those carrying either one or two variant T alleles (OR = 0.38, 95%CI = 0.30-0.48 for CC vs CT+TT). However, although TT carriers had a better response rate compared with the C allele carriers, the difference was not significant (OR = 1.27, 95%CI = 0.92-1.77 for TT vs CC+CT). Based on this meta-analysis, we conclude that XRCC1 polymorphisms are associated with treatment response to platinum chemotherapy in advanced NSCLC patients.


Teriflunomide Preserves Neuronal Activity and Protects Mitochondria in Brain Slices Exposed to Oxidative Stress.
Teriflunomide (TFN) limits relapses in relapsing-remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria.


UV Radiation and Visible Light Induce hsp70 Gene Expression in the Antarctic Psychrophilic Ciliate Euplotes focardii.
The psychrophilic ciliate Euplotes focardii inhabits the shallow marine coastal sediments of Antarctica, where, over millions of years of evolution, it has reached a strict molecular adaptation to such a constant-temperature environment (about -2 °C). This long evolution at sub-zero temperatures has made E. focardii unable to respond to heat stress with the activation of its heat shock protein (hsp) 70 genes. These genes can, however, be expressed in response to other stresses, like the oxidative one, thus indicating that the molecular adaptation has exclusively altered the heat stress signaling pathways, while it has preserved hsp70 gene activation in response to other environmental stressors. Since radiative stress has proved to be affine to oxidative stress in several organisms, we investigated the capability of UV radiation to induce hsp70 transcription. E. focardii cell cultures were exposed to several different irradiation regimes, ranging from visible only to a mixture of visible, UV-A and UV-B. The irradiation values of each spectral band have been set to be comparable with those recorded in a typical Antarctic spring. Using Northern blot analysis, we measured the expression level of hsp70 immediately after irradiation (0-h-labeled samples), 1 h, and 2 h from the end of the irradiation. Surprisingly, our results showed that besides UV radiation, the visible light was also able to induce hsp70 expression in E. focardii. Moreover, spectrophotometric measurements have revealed no detectable endogenous pigments in E. focardii, making it difficult to propose a possible explanation for the visible light induction of its hsp70 genes. Further research is needed to conclusively clarify this point.


8q23-q24 duplication--further delineation of a rare chromosomal abnormality.
Presented here is a young girl with a rare interstitial duplication of 8q23.3-q24.21. At birth, unusual facial features led to karyotype analysis with a finding of increased material in 8q. Specific determination of where the extra material came from required comparative genomic hybridization (CGH). The affected girl has dysmorphic facial features including hypertelorism, a wide nasal bridge, retrognathia, hyperopic astigmatism, hirsutism, and developmental delay. The area duplicated includes at least 47 genes including TRPS1 and EXT1. Her features will be described and compared to two similar cases.