A review of the dragon millipede genus Desmoxytes Chamberlin, 1923 in China, with descriptions of four new species (Diplopoda, Polydesmida, Paradoxosomatidae).
Four new species of Desmoxytes are described from southern China: Desmoxyteslingulata sp. n., Desmoxytesparvula sp. n., and Desmoxytesnodulosa sp. n., from Guangxi Zhuang Autonomous Region, and Desmoxytesgetuhensis sp. n. from Guizhou Province. In addition, new records of Desmoxytesscutigeroides Golovatch, Geoffroy & Mauriès, 2010 and Desmoxytesscolopendroides Golovatch, Geoffroy & Mauriès, 2010 are provided, with a modified key to Desmoxytes species currently known to occur in China. Two of the new species, Desmoxytesnodulosa sp. n. and Desmoxytesgetuhensis sp. n., seem to be troglobites.


Quantum Dot-Based Molecularly Imprinted Polymers on Three-Dimensional Origami Paper Microfluidic Chip for Fluorescence Detection of Phycocyanin.
In this work, we developed a novel strategy using fluorescent quantum dots (QDs) combined with molecularly imprinted polymers (MIPs) on three-dimensional (3D) origami paper-based microfluidic devices for specific recognition and sensitive detection of phycocyanin. This method can realize the liquid phase of QDs@MIPs being transferred to the solid-phase paper base and achieve easy portability for the analysis. Under optimal conditions, we successfully demonstrated the proposed paper@QDs@MIPs 3D microfluidic chip for the sensitive and selective detection of phycocyanin protein target in a simple and robust manner. Our results revealed that the method exhibited a dynamic response to phycocyanin in the range of 10-50 mg/L with a limit of detection of 2 mg/L. Importantly, this device could provide quantitative information very conveniently and show great potential to be further extended to the detection of other proteins or biomarkers for environmental and food safety research.


Mineral Trioxide Aggregate Apexogenesis: A Systematic Review.
To evaluate the clinical and radiographic outcomes of apexogenesis with mineral trioxide aggregate (MTA) against other pulpotomy agents in carious/traumatized immature permanent teeth. A web-based search for possibly relevant scientific papers in the English language between January 2013 and August 2022 was undertaken in the databases such as PubMed, Scopus, Cochrane Library, and EMBASE. Only randomized clinical trials that compared MTA against other pulpotomy medicaments conducted in vital immature permanent dentition with open apex, having a sample size of not less than 20 with at least 6 months follow-up, reporting clinical or radiographic outcomes were included in the current review. Case studies, case series, animal studies, in vitro studies, non-clinical/clinical trials on mature/necrotic permanent or primary dentition, systematic reviews, and letters to the editor were excluded. A total of 236 articles were retrieved from the databases during the search procedure. Two independent investigators conducted a full-text review of 83 studies following a screening of titles and abstracts. Eventually, seven studies were considered for the review. The Cochrane bias assessment tool was used to evaluate the quality of included studies. Five of the selected studies were assigned a low evidence level, whereas two were rated a high evidence level. The present review indicated that the diverse pulpotomy agents had comparable clinical outcomes with MTA for apexogenesis in traumatized or carious immature permanent teeth. However, there is a lack of substantial information to draw firm conclusions about the benefits of one material over another.


Applications of thiyl radical cyclizations for the synthesis of thiosugars.
The use of intramolecular thiyl radical cyclizations for the synthesis of thiosugars has been investigated, and a new free-radical-based methodology for the synthesis of biologically important thiosugars has been developed. The methodology is mild and proceeds via either 6-endo or 5-exo cyclization to furnish the thiosugar ring. This represents the first examples of thiyl radical cyclization being applied to the synthesis of thiosugars.


Florid Bacillus cereus Infection of the Placenta Associated With Intrauterine Fetal Demise.
Bacillus cereus is a gram-positive, rod-shaped bacterium that is commonly implicated in foodborne illness but has also become increasingly recognized as a source of serious non-gastrointestinal infections, including sepsis, meningitis, and pneumonia. Non-gastrointestinal B. cereus infections have been identified in children, especially in neonates; however, there are no previously described cases of fetal demise associated with B. cereus placental infection. We present a case of acute chorioamnionitis-related intrauterine fetal demise of twin A at 17 weeks gestation, noted two days after selective termination of twin B. Histological examination revealed numerous gram-positive bacilli in placental tissue, as well as fetal vasculature, in the setting of severe acute necrotizing chorioamnionitis and subchorionitis, intervillous abscesses, acute villitis, and peripheral acute funisitis. Cultures of maternal blood and placental tissue both yielded growth of B. cereus. This case underscores the importance of B. cereus as a human pathogen, and specifically demonstrates its potential as an agent of severe intraamniotic and placental infection with poor outcomes for the fetus.


Hes1 is upregulated by ischemic postconditioning and contributes to cardioprotection.
The expression of Hes1 is increased following myocardial infarct and other ischemic cardiomyopathies, but the role of Hes1 in cardioprotection provided by ischemic postconditioning (IPost) remains unclear. In this study, we used gain and loss of function approaches to investigate the role of Hes1 in cardioprotection during IPost. Primary cardiac myocytes exposed to ischemia reperfusion injury (IRI) and IPost were used as the experimental model. The results showed that Hes1 expression was increased during myocardial IPost, and Hes1 promoted the viability while inhibited the apoptosis of cardiomyocytes. Moreover, Hes1 inhibited the opening of mitochondrial permeability transition pore (mPTP) and the generation of reactive oxygen species in primary cardiac myocytes exposed to IRI. Mechanistically, we found that Hes1-mediated cardioprotection was related to the downregulation of phosphatase and tensin homolog and the activation of phosphatidylinositol 3-kinase/Akt and signal transducer and activator of transcription 3 signalling. These data demonstrate that Hes1 is upregulated and mediates cardioprotection provided by IPost and suggest that Hes1 is a potential new target for the treatment of ischemic cardiomyopathy.


Comparison of mammary serum antigen (MSA) with beta 2-microglobulin (beta 2M) and carcinoembryonic antigen (CEA) assays in patients with breast cancer.
Serum levels of mammary serum antigen (MSA), beta 2-microglobulin (beta 2M) and carcinoembryonic antigen (CEA) were evaluated in 186 subjects to assess their use in the diagnosis and monitoring of breast cancer, either singly or in combination. Raised MSA levels (greater than 300 I.U.) were detected in 79% of patients with Stage I/II breast cancer, compared with 25% for beta 2M (greater than 2000 micrograms/l) and 12% for CEA (greater than 5 ng/ml) levels respectively. Of 53 patients with Stage III/IV breast cancer, 98% (MSA), 55% (beta 2M) and 64% (CEA) had raised levels. In 25 patients followed over 3-9 months, the changes in MSA levels correlated with the clinical course of the disease in 23/25 (92%), compared with 7/25 (28%) using beta 2M, and 9/25 (36%) using CEA assays. The overall sensitivity, specificity and accuracy in detecting breast cancer were 88%, 95% and 99% for MSA; 39%, 90% and 96% for beta 2M; and 38%, 95% and 98% for CEA, respectively. MSA and beta 2M assays in combination enhanced the sensitivity in the detection of breast cancer (93%) especially early breast cancer, while maintaining specificity (90%). MSA seems to be superior to beta 2M or CEA as a tumour marker in breast cancer and its levels seem to correlate with tumour burden. While it appears that beta 2M or CEA measurements used alone are of little value in the current management of breast cancer, beta 2M may be a helpful adjunct to enhance the sensitivity of MSA assay especially in early breast cancer.


Caulophyine A, a Rare Azapyrene Alkaloid from the Roots of Caulophyllum robustum.
A novel alkaloid caulophyine A (1) was isolated from the roots of Caulophyllum robustum Maxim., along with six known alkaloids 2-7. The structure of 1 was elucidated by extensive NMR and high resolution-time-of-flight (HR-TOF)-MS analyses, it is a rare nitrogen containing polycyclic aromatic hydrocarbon. The in vitro bioassays revealed that 2 presented remarkable cytotoxicity against A549 with an IC50 value of 3.83 µM in comparison with the positive control etoposide (IC50 = 11.63 µM). Compounds 1 and 2 also displayed weak Acetylcholinesterase (AChE) inhibitory activity with IC50 values of 123.03 and 80.74 µM respectively.


Objective age of acquisition norms for a set of 286 words in Russian: relationships with other psycholinguistic variables.
Normative data on the objective age of acquisition (AoA) for 286 Russian words are presented in this article. In addition, correlations between the objective AoA and subjective ratings, name agreement, picture name agreement, imageability, familiarity, word frequency, and word length are provided, as are correlations between the objective AoA and two measures of exemplar dominance (exemplar generation frequency and the number of times an exemplar was named first). The correlations between the aforementioned variables are generally consistent with the correlations reported in other normative studies. The objective AoA data are highly correlated with the subjective AoA ratings, whereas the correlations between the objective AoA and other psycholinguistic variables are moderate. The correlations between the objective AoA of Russian words and similar data for other languages are moderately high. The complete word norms may be downloaded from supplementary material.


Changes in P2Y1 nucleotide receptor activity during the development of rat salivary glands.
Experiments that used dispersed salivary gland cells from 1-day-old rats indicated the presence of the P2Y nucleotide receptor subtype, P2Y1, based on the agonist potency profile for mobilization of intracellular free Ca2+ [2-methylthio-ATP > ADP > adenosine 5'-O-(2-thiodiphosphate) > ATP, with UTP ineffective] and sequence analysis of reverse transcription-polymerase chain reaction (RT-PCR) products obtained with P2Y1 receptor-specific primers. P2Y1 receptor activity appears to be developmentally regulated, since Ca2+ mobilization in response to the P2Y1-selective agonist, 2-methylthio-ATP, decreased as animal age increased, with the maximal response of 129 +/- 23 nM obtained in 1-day-old animals, decreasing to 30 +/- 3 nM in 4-wk-old animals. However, the abundance of P2Y1 receptor mRNA, assessed by semiquantitative RT-PCR, did not change over this time period, suggesting that receptor activity is regulated by some mechanism other than changes in steady-state levels of P2Y1 receptor mRNA. These findings indicate that functional P2Y1 nucleotide receptors are expressed in immature salivary glands and that receptor activity decreases as the glands mature, suggesting that P2Y1 receptors may have an important role during salivary gland development.


Social cognition: the key factor predicting social outcome in people with schizophrenia?
Impairments in different cognitive abilities have been found to be correlated with reduced real-world functioning in people with schizophrenia. A number of other features of the illness, such as depression and negative symptoms, contribute to the overall prediction of these outcomes. Impairment in social cognition is of particular interest as a mediating influence between cognition and social outcomes. Social cognition is a set of cognitive processes applied to the recognition, understanding, accurate processing, and effective use of social cues in real-world situations. In schizophrenia research, social cognition comprises the following domains: emotion perception, theory of mind (ToM), and attributional style. While substantial research has indicated that these abilities are clearly related to social outcomes, research has been slowed by problems in the measurement of these abilities. In this article, I will describe these abilities, discuss how they are currently measured, and how research could improve the current measurement of these abilities to make them more clinically useful.


Catheter-related infections associated with home parenteral nutrition and predictive factors for the need for catheter removal in their treatment.
The inpatient and outpatient records were reviewed for 527 patients, including 138 children, who were discharged on home total parenteral nutrition and followed by the University of California, Los Angeles, home total parenteral nutrition service for a minimum of 1 week between April 1973 and October 1991. The total follow-up time was 1154 patient years; the median follow-up time was 206 days (range 7 to 6344 days). Thirty-six patients were followed for more than 10 years (median 12.7 years). Three hundred fifteen adults (but only four children) were never infected. A total of 427 catheter-related infections occurred, giving an overall infection rate of 0.37 per patient year (0.51 per patient year in children and 0.28 per patient year in patients followed for more than 10 years). Seventy percent of the infections overall were sepsis (0.26 per patient year); of those, 17% were exit site (0.06 per patient year), and 2% were tunnel (0.01 per patient year) infections. In children, 67% of the infections were sepsis (0.37 per patient year) and 24% were exit site (0.13 per patient year). Fifty-four different organisms were responsible, and 12% of the infections were polymicrobial in origin. Sixty percent of sepsis in all patients was caused by Gram-negative organisms (44% of the catheters were removed). Forty-three percent of sepsis in children was caused by Gram-negative organisms. Twenty-six percent of sepsis in all patients was caused by Gram-positive organisms (40% of the catheters were removed). Thirty-six percent of sepsis in children was caused by Gram-positive organisms.(ABSTRACT TRUNCATED AT 250 WORDS)


Anatomical study of the fabella, fabellar complex and its clinical implications.
The fabella has been mainly studied using imaging methods but there are less research reports on the gross anatomical studies. We performed this anatomical study of the fabella and its surrounding structures with functional implications using 150 heads of the gastrocnemius muscles of 75 knees from 39 Japanese cadavers. This study is the direct representation of the human fabella and its functional implications. We observed 99 fabellae (66.0%) including 44 complete bony fabellae (29.3%). Of these bony fabellae, 43 (97.7%) were located in the lateral head of the gastrocnemius muscle with its surrounding structures and were positioned only on the lateral condyle of the femur. Moreover, the cartilage and bony fabellae, especially on the lateral side, contributed to the fabella complex with its surrounding muscles and ligaments and formed small articular cavity by cooperating with the femoral condyle. Although the human fabella is considered as appearing in the fabella complex with ageing and it possibly induces clinical symptoms, the fabella may play an important role as a stabilizer between the fabella complex and the femoral condyle.


Cystourethropexy to correct refractory urinary incontinence due to urethral sphincter mechanism incompetence. Preliminary results in ten bitches.
Cystourethropexy was performed in 10 bitches with refractory urinary incontinence due to urethral sphincter mechanism incompetence. All animals had an abnormally shaped vesicourethral junction. The bladder neck was located in the pelvic canal in nine dogs (pelvic bladder). Surgery alone restored urinary continence in two cases and markedly improved incontinence in two cases. Surgery combined with medical therapy (phenylpropanolamine, 1.5 mg/kg orally once or twice a day, using a sustained-action preparation) restored urinary continence in four cases and markedly improved continence in one case. Surgery, with medical therapy, was completely ineffective in one case. No major complications were encountered in any dogs. In four cases, histopathologic evaluation of the dorsal bladder wall and neck revealed the presence of a single, perinuclear, clear vacuole in the cytoplasm of smooth muscle fibers. Electron microscopic examination showed that the vacuoles represented a dilatation of normal membrane organelles. Such abnormalities have the potential to alter the smooth muscle motility. This study indicates that cystourethropexy alone restored urinary continence only temporarily in the majority of the patients. The significance and frequency of the histopathologic findings requires further investigation.


Adjunctive agents to antipsychotics in schizophrenia: a systematic umbrella review and recommendations for amino acids, hormonal therapies and anti-inflammatory drugs.
This umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and World Federation of Societies of Biological Psychiatry (WFSBP)-grading recommendations, 63 randomised control trials (RCTs) (of which 4219 unique participants have completed the RCTs) and 29 meta-analyses were analysed. Provisional recommendations (WFSBP-grade 1) could be made for two molecules in augmentation to antipsychotics: (1) N-acetyl-cysteine (NAC, 1200-3600 mg/day, for >12 consecutive weeks) in improving negative symptoms, general psychopathology (positive and negative syndrome scale for schizophrenia (PANSS) general psychopathology factor (G)-G subscale), with the RCTs with the longer duration showing the most robust findings; (2) polyunsaturated fatty acids (3000 mg/day of eicosapentaenoic acid, for >12 weeks) in improving general psychopathology. Weaker recommendations (ie, WFSBP-grade 2) could be drawn for sarcosine (2 g/day) and minocycline (200-300 mg/day) for improving negative symptoms in chronic schizophrenia (not early schizophrenia), and NAC for improving positive symptoms and cognition. Weak recommendations are not ready for clinical practice. There is provisional evidence that oestrogens and raloxifene are effective in some patients, but further research is needed to determine their benefit/risk ratio. The results of this umbrella review should be interpreted with caution as the number of RCTs included in the meta-analyses was generally small and the effect sizes were weak or medium. For NAC, two RCTs with low risk of bias have provided conflicting results and the WFSBP-grade recommendation included also the results of meta-analyses. These drugs could be provisionally prescribed for patients for whom no other treatments have been effective, but they should be discontinued if they prove ineffective.


Study: Atezolizumab Improves Survival in SCLC.
Combining the PD-L1 inhibitor atezolizumab with platinum-based chemotherapy improves overall survival among patients with extensive-stage small cell lung cancer relative to chemotherapy alone. These findings could lead to a new first-line treatment option for patients with the disease.


Treatment of posterior fossa tumors in children.
The most common posterior fossa tumors in children are medulloblastoma, astrocytoma and ependymoma. Atypical rhabdoid teratoid tumors and brain stem gliomas are relatively rare. As the posterior fossa is a limited space, the tumors presenting in this region cause symptoms early on and require prompt treatment to avoid potential morbidity and mortality. Early detection and diagnosis of these tumors and prompt neurosurgical consultation is crucial in the optimum management of pediatric infratentorial brain tumors. Surgery is the mainstay of treatment, as it provides biopsy and decompression of the tumor. Adjuvant therapy is required in the majority of cases. Recent advances in the field of radiation biology and pharmacology have improved dose and delivery techniques of chemoradiation therapy. In the current era, advances in translational research and molecular genetics have assumed a major role in the pursuit of achieving a 'cure' for these potentially malignant tumors.


Long-term continuous ambulatory peritoneal dialysis in diabetics.
Of 147 diabetic patients with end-stage renal disease who were treated in our CAPD program between 1978 and 1991, 6 men and 1 woman (5 had type II and 2 type I diabetes) with a mean age of 54 (range 21-70) years have been on CAPD for more than five years (mean: 76 mos, range: 65-109 mos) and on peritoneal dialysis (IPD+CAPD) for an average of 85 (range: 67-118) mos. They had a variety of comorbid conditions at the start of CAPD: Retinopathy (5/7), blindness (3/7), hypertension (5/7), peripheral neuropathy (7/7), peripheral vascular disease (3/7), congestive heart failure (3/7), myocardial infarction (1/7), ischemic heart disease (2/7). Two were smokers and five over the age of 65. Peritonitis rate was 1 episode/11.4 pt mos, exit-site infection 1/76.4 pt mos and average hospitalization rate 32.8 days/patient/year. Hypertension was well-controlled with discontinuation of all medications; after initiation of CAPD two of them remained without medications throughout the study but in the rest, medications had to be restarted. As assessed by HbA1c, blood glucose control improved with IP administration of insulin. Residual renal function progressively decreased. None of them developed severe hyperparathyroidism. Peripheral neuropathy remained stable in four and deteriorated in two. Total protein, albumin, cholesterol and triglycerides decreased during the last two years indicating a degree of malnutrition. Our experience with these seven patients suggests that diabetic patients, even the aged and those with many comorbid conditions and complications, can survive for long periods on CAPD.


Lactose, oligosaccharide and monosaccharide content of milk from mothers delivering preterm newborns over the first month of lactation.
Monosaccharide, lactose and oligosaccharide content of milk from mothers delivering prematurely (PT milk) was studied to evaluate whether changes occur during lactation, as observed in milk from mothers delivering at term (T milk). To study a homogeneous population, women having the most common phenotype (secretory both Lewis and A, B, or H phenotype) were selected. Milk samples from 26 mothers who delivered between the 27th and 35th week of gestation were collected at the 4th, 10th, and 30th post-partum days. Monosaccharides, lactose and oligosaccharides were measured by high-pressure liquid chromatography. Lactose concentration increased significantly (p < 0.05) from 52.81 +/- 8.2 g/L on day 4 to 69.24 +/- 9.36 g/L on day 30. During the same period of time oligosaccharide content decreased significantly (p < 0.05) from 25.61 +/- 5.19 g/L to 15.83 +/- 6.05 g/L. Monosaccharides did not show statistically significant variations. Our results indicate that PT milk contains in addition to lactose, a substantial amount of oligosaccharides and a lower percentage of monosaccharides. Compared to T milk, in the colostral phase PT milk presents significantly lower lactose concentration (p < 0.0001); on the contrary its oligosaccharide content is significantly higher (p < 0.0001). The physiological role of human milk carbohydrates in view of the peculiar needs of the preterm newborn is also discussed.


Biosynthesized gold and silver nanoparticles by aqueous fruit extract of Chaenomeles sinensis and screening of their biomedical activities.
The design of mild and non-toxic synthesis of metallic nanoparticles is a topical subject in the nanotechnology field. The objective of this present study is to screen the bioactivity of biosynthesized nanoparticles by aqueous fruit extract of Chaenomeles sinensis. The reducing and stabilizing ability of C. sinensis to fabricate gold (Cs-AuNps) and silver (Cs-AgNps) nanoparticles was confirmed by UV-visible (UV-Vis) spectroscopy at 562 nm and 477 nm, respectively. The field-emission transmission electron microscopy (FE-TEM) and X-ray diffraction analysis (XRD) verify the nano-scale morphology and crystallinity of Cs-AuNps (20-40 nm) and Cs-AgNps (5-20 nm). Furthermore, we evaluated the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging capacity, antimicrobial activity against Staphylococcus aureus and Escherichia coli and cytotoxicity against breast cancer cells. The results showed that Cs-AuNps (IC50: 725.93 μg/mL) displayed superior inhibitory activities on DPPH than Cs-AuNps. The biosynthesized Cs-AuNps successfully inhibited the growth of pathogenic bacteria S. aureus (ATCC 6538) and E. coli (BL21). The cytotoxic effect of Cs-AuNps and Cs-AgNps was evaluated in murine macrophage (RAW264.7) and human breast cancer cell lines (MCF7) by MTT assay. Thus, the present study explores the biomedical applications of gold and silver nanoparticles synthesized by C. sinensis.


Diagnosis of progressive multifocal leukoencephalopathy by brain biopsy with biotin labeled DNA:DNA in situ hybridization.
DNA:DNA in situ hybridization using a cloned JC virus (JCV) DNA probe labeled with biotin confirmed the presence of JCV DNA in formalin-fixed, paraffin-embedded brain biopsies from four cases of progressive multifocal leukoencephalopathy (PML). Only small pieces of tissue were available in each case. Detection of the JC DNA:DNA hybrids was carried out by affinity cytochemistry. JCV DNA was identified predominantly in the nuclei of interfascicular oligodendrocytes in demyelinated areas of the biopsies. JC virus was isolated from one case, and the diagnosis of PML was substantiated in all cases by electron microscopic identification or immunocytochemical labeling of JC viral antigen. In situ hybridization using a biotin labeled JCV DNA probe is a specific, sensitive and convenient method for confirming the diagnosis of PML in suspected cases evaluated by brain biopsy.


Neuropsychologic impairment and MRI abnormalities associated with chronic solvent abuse.
Individuals chronically abusing organic solvents have been reported in the medical literature for almost four decades to have a variety of neurological abnormalities. Most have been single case reports or studies in small numbers of individuals. The purpose of this study was to evaluate the neurologic and neuropsychologic effects of chronic solvent abuse in a larger group of individuals and compare the results to a control group of other drug abusers. Attempts to estimate a dose-response relationship between solvent abuse and either neuropsychological tests or magnetic resonance imaging (MRI) abnormalities were also undertaken. A sample of 55 solvent abusers was compared to a sample of 61 users of other drugs, especially cocaine and alcohol, on a battery of cognitive and neuropsychological tests. Fifty of the solvent abusers and 51 members of the comparison sample also underwent MRI of the brain. Comparisons were made by means of multivariate analysis of variance and covariance. Compared to the general population, both groups performed poorly, scoring below the mean on most neuropsychological measures. Solvent abusers performed more poorly than the comparison sample on measures of working memory and executive cognitive functions. Both groups showed evidence of abnormal MRI findings, but a greater percentage of the solvent abuse group showed such abnormalities. No clear dose-response relationship was seen between solvent abuse and abnormalities on neuropsychological tests, but a strong dose-response relationship was seen in the presence of MRI abnormalities. The findings in this study document widespread cognitive impairment, which could not be attributed to the effects of solvents entirely. These findings expand upon previous data regarding neurological abnormalities in solvent abusers, by demonstrating a dose-response relationship with MRI abnormalities. An unexpected finding was the high prevalence of neuropsychological impairment and MRI abnormalities among the comparison group. The results of this study has implications regarding low-level solvent exposure, as in the occupational setting, suggesting that MRI may be a more useful tool to sort out the presence of neurological abnormalities rather than neuropsychological tests. Since no dose-response relationship was seen between solvent abuse and neuropsychological testing, reliance upon these tests in assessing neurological injury from solvents is a highly dubious practice.


EFFECTIVENESS OF SELECTION IN REDUCING THE GENETIC LOAD IN POPULATIONS OF PEROMYSCUS POLIONOTUS DURING GENERATIONS OF INBREEDING.
It has been hypothesized that natural selection reduces the "genetic load" of deleterious alleles from populations that inbreed during bottlenecks, thereby ameliorating impacts of future inbreeding. We tested the efficiency with which natural selection purges deleterious alleles from three subspecies of Peromyscus polionotus during 10 generations of laboratory inbreeding by monitoring pairing success, litter size, viability, and growth in 3604 litters produced from 3058 pairs. In P. p. subgriseus, there was no reduction across generations in inbreeding depression in any of the fitness components. Strongly deleterious recessive alleles may have been removed previously during episodes of local inbreeding in the wild, and the residual genetic load in this population was not further reduced by selection in the lab. In P. p. rhoadsi, four of seven fitness components did show a reduction of the genetic load with continued inbreeding. The average reduction in the genetic load was as expected if inbreeding depression in this population is caused by highly deleterious recessive alleles that are efficiently removed by selection. For P. p. leucocephalus a population that experiences periodic bottlenecks in the wild, the effect of further inbreeding in the laboratory was to exacerbate rather than reduce the genetic load. Recessive deleterious alleles may have been removed from this population during repeated bottlenecks in the wild; the population may be close to a threshold level of heterozygosity below which fitness declines rapidly. Thus, the effects of selection on inbreeding depression varied substantially among populations, perhaps due to different histories of inbreeding and selection.


Vascular cognitive impairment in diabetes mellitus: are prevention and treatment effective?
Vascular dementia is caused by progressive atherosclerosis leading to multiple small strokes and subsequent brain damage. Approximately 10%-20% of all cases of dementia are attributed to vascular dementia. The 5-year survival rate is 39% for patients with vascular dementia compared with 75% for age-matched controls. It is a growing public health concern because of the lack of effective curative treatment options and rising global prevalence. Duration of diabetes mellitus of 10 years or longer, onset of diabetes before age 65, treatment with insulin and oral antidiabetic medications, and presence of diabetes complications have an impact on the incidence of vascular dementia. On the other hand, patients who suffered stroke either had or are later diagnosed with diabetes (16%-24%). Treatment of vascular dementia in diabetes patients rests on a two-pronged approach: modification of the underlying disease and prevention and treatment of dementia symptoms.


A "Turn-On" Fluorescence Copper Biosensor Based on DNA Cleavage-Dependent Graphene Oxide-dsDNA-CdTe Quantum Dots Complex.
A novel "turn-on" fluorescent copper biosensor is developed successfully based on the graphene oxide (GO)-dsDNA-CdTe quantum dots (QDs) complex via chemical crosslink method. The optical and structure properties of GO-dsDNA-CdTe QDs complex are studied by fluorescence (FL) spectra and transmission electron microscopy (TEM) in detail. It is demonstrated that the fluorescence quenching of CdTe QDs is a process of fluorescence resonance energy transfer (FRET) due to the essential surface and quenching properties of two-dimensional GO. Copper ions induce the catalytic reaction of DNA chain and irreversibly break at the cleavage site, which will cause the G-quadruplex formation, moreover further result in the CdTe QDs separated from GO and restored its fluorescence. Therefore, a significant recovery effect on the fluorescence of the GO-dsDNA-CdTe QDs complex is observed in the presence of copper ions. The fluorescence responses are concentration-dependent and can be well described by a linear equation. Compared with other metal ions, the sensor performs good selectivity for copper ions.


Cu,Zn Superoxide Dismutase Genes in Tribolium castaneum: Evolution, Molecular Characterisation, and Gene Expression during Immune Priming.
The production of reactive oxygen species (ROS) is a normal consequence of the aerobic cell metabolism. Despite their high and potentially detrimental reactivity with various biomolecules, the endogenous production of ROS is a vital part of physiological, immunological, and molecular processes that contribute to fitness. The role of ROS in host-parasite interactions is frequently defined by their contribution to innate immunity as effectors, promoting parasite death during infections. In vertebrates, ROS and antioxidant system enzymes, such as superoxide dismutase (SOD) are also involved in acquired immune memory, where they are responsible for T-cell signalling, activation, proliferation, and viability. Based on recent findings, ROS are now also assumed to play a role in immune priming, i.e., a form of memory in invertebrates. In this study, the potential involvement of Cu,Zn SODs in immunity of the red flour beetle Tribolium castaneum is described for the first time, applying an approach that combines an in silico gene characterisation with an in vivo immune priming experiment using the Gram-positive entomopathogen Bacillus thuringiensis. We identified an unusually high number of three different transcripts for extracellular SOD and found that priming leads to a fine-tuned modulation of SOD expression, highlighting the potential of physiological co-adaptations for immune phenotypes.


Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins.
Ceramides are known to play a major regulatory role in apoptosis by inducing cytochrome c release from mitochondria. We have previously reported that C(2)- and C(16)-ceramide, but not dihydroceramide, form large channels in planar membranes (Siskind, L. J., and Colombini, M. (2001) J. Biol. Chem. 275, 38640-38644). Here we show that ceramides do not trigger a cytochrome c secretion or release mechanism, but simply raise the permeability of the mitochondrial outer membrane, via ceramide channel formation, to include small proteins. Exogenously added reduced cytochrome c was able to freely permeate the mitochondrial outer membrane with entry to and exit from the intermembrane space facilitated by ceramides in a dose- and time-dependent manner. The permeability pathways were eliminated upon removal of C(2)-ceramide by bovine serum albumin, thus ruling out a detergent-like effect of C(2)-ceramide on membranes. Ceramide channels were not specific to cytochrome c, as ceramides induced release of adenylate kinase, but not fumerase from isolated mitochondria, showing some specificity of these channels for the outer mitochondrial membrane. SDS-PAGE results show that ceramides allow release of intermembrane space proteins with a molecular weight cut-off of about 60,000. These results indicate that the ceramide-induced membrane permeability increases in isolated mitochondria are via ceramide channel formation and not a release mechanism, as the channels that allow cytochrome c to freely permeate are reversible, and are not specific to cytochrome c.


Complex calcaneal defect reconstruction with osteotomized free fibula-flexor hallucis longus osteomuscular flap.
Complex calcaneal defects represent a reconstructive challenge since calcaneous plays a key role in standing and gait. We report the case of a 35-year-old patient with a complex calcaneal defect due to chronic osteomyelitis after a high energy Gustillo type IIIB calcaneal fracture that was reconstructed with a free fibula-flexor hallucis longus osteomuscular flap. The fibula was osteotomized into two segments, which were used to reconstruct the bone defect, and the muscular component of the flap was used for coverage of the reconstructed calcaneal skeleton. Fifteen days later permanent skin coverage was ensured with a local random pattern rhomboid skin flap. Early and late postoperative periods were uneventful. Bone maturation was radiographically evident at a follow up of 12 weeks, and complete bone incorporation at 3 years. Full weight bearing was possible at 6 months postop. Final follow up, at 3 years postop, verified a very good functional and aesthetic outcome.


Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα.
Covalent protein kinase inhibitors exploit currently noncatalytic cysteines in the adenosine 5'-triphosphate (ATP)-binding site via electrophiles directly appended to a reversible-inhibitor scaffold. Here, we delineate a path to target solvent-exposed cysteines at a distance >10 Å from an ATP-site-directed core module and produce potent covalent phosphoinositide 3-kinase α (PI3Kα) inhibitors. First, reactive warheads are used to reach out to Cys862 on PI3Kα, and second, enones are replaced with druglike warheads while linkers are optimized. The systematic investigation of intrinsic warhead reactivity (kchem), rate of covalent bond formation and proximity (kinact and reaction space volume Vr), and integration of structure data, kinetic and structural modeling, led to the guided identification of high-quality, covalent chemical probes. A novel stochastic approach provided direct access to the calculation of overall reaction rates as a function of kchem, kinact, Ki, and Vr, which was validated with compounds with varied linker lengths. X-ray crystallography, protein mass spectrometry (MS), and NanoBRET assays confirmed covalent bond formation of the acrylamide warhead and Cys862. In rat liver microsomes, compounds 19 and 22 outperformed the rapidly metabolized CNX-1351, the only known PI3Kα irreversible inhibitor. Washout experiments in cancer cell lines with mutated, constitutively activated PI3Kα showed a long-lasting inhibition of PI3Kα. In SKOV3 cells, compounds 19 and 22 revealed PI3Kβ-dependent signaling, which was sensitive to TGX221. Compounds 19 and 22 thus qualify as specific chemical probes to explore PI3Kα-selective signaling branches. The proposed approach is generally suited to develop covalent tools targeting distal, unexplored Cys residues in biologically active enzymes.


[Polygraphy in hospitalized children under 3 months].
Apnea and apparently lethal events have great etiological diversity thus complementary tests may help diagnosis. The aim of this study was to describe the results of polygraph studies of children under 3 months hospitalized with suspected apnea. Retrospective case series. Children under 3 months with suspected apnea were considered and in whom a polygraphy (PG) was performed during hospitalization. General data, the apnea/hypopnea index (AHI), index of central. apnea, obstructive apnea index, average and minimum saturation were recorded. Desaturation index (ID) below 80% higher 1 per hour, one or more events of desaturation below 80% for more than 20 seconds or an AHI greater than or equal 1 were considered as criteria of sleep disorder breathing (SLB). Descriptive analysis was performed and the associations between AHI and saturation parameters were determined. 51 patients, 32 males, entered the study. 15,6% had altered PG. In 5 of them coexisted more than one diagnostic criterion. Iin 15,6% of the patients was observed an IAH greater 1, in 7.8% a desaturation index below 80% and in 11,8% a desaturation index under 80% for 20 seconds greater than 1. The AHI was associated with the parameters of saturation. Most of the patients had normal PG and among patients with a suggestive SLB a pattern of respiratory immaturity prevailed, which is characteristic of this age.


What Are Clinically Relevant Levels of Cellular and Biomolecular Analytes?
The ultimate goal of developing sensors for biomolecular analytes is to offer new tools for the analysis of clinical specimens for biomarkers of disease. It is thus important to understand the types of samples that are routinely used in the clinic for specific indications, and what the typical levels of relevant analytes are in these specimens. This Sensor Issues article summarizes information concerning levels of target molecules and cells that are of interest for the development of new diagnostics for infectious disease and cancer. Having this information in hand helps better define the "needle-in-a-haystack" challenge associated with developing robust sensors with the needed levels of sensitivity and specificity.


Dairy management practices associated with incidence rate of clinical mastitis in low somatic cell score herds in France.
An epidemiological prospective study was carried out in French dairy herds with Holstein, Montbéliarde, or Normande cows and with low herd somatic cell scores. The objective was to identify dairy management practices associated with herd incidence rate of clinical mastitis. The studied herds were selected on a national basis, clinical cases were recorded through a standardized system, and a stable dairy management system existed. In the surveyed herds, mean milk yield was 7420 kg/cow per yr and mean milk somatic cell score was 2.04 (132,000 cells/mL). Overdispersion Poisson models were performed to investigate risk factors for mastitis incidence rate. From the final model, the herds with the following characteristics had lower incidence rates of clinical mastitis: 1) culling of cows with more than 3 cases of clinical mastitis within a lactation; 2) more than 2 person-years assigned to dairy herd management; 3) balanced concentrate in the cow basal diet. Moreover, herds with the following characteristics had higher incidence rates of clinical mastitis: 1) milking cows loose-housed in a straw yard; 2) no mastitis therapy performed when a single clot was observed in the milk; 3) clusters rinsed using water or soapy water after milking a cow with high somatic cell count; 4) 305-d milk yield >7435 kg; 5) herd located in the South region; 6) herd located in the North region; 7) cows with at least 1 nonfunctional quarter; and 8) premilking holding area with a slippery surface. The underlying mechanisms of some highlighted risk factors, such as milk production level and dietary management practices, should be investigated more thoroughly through international collaboration.


Colony stimulating factor 1 is required for mammary gland development during pregnancy.
The study of colony stimulating factor 1 (CSF-1), a homodimeric serum growth factor that regulates mononuclear phagocytes and is involved in maternal-fetal interactions during pregnancy, was dramatically enhanced by the observation that the recessive mutation osteopetrosis, op, is an inactivating mutation in the CSF-1-encoding gene. Homozygous mutant (op/op) mice completely lack CSF-1, are osteopetrotic consequent to a deficiency in osteoclasts, have severely reduced numbers of macrophages, and have reduced fertility evident at the pre- and postimplantation stages of pregnancy. We show here that op/op females have a lactational defect, and consequently, although some are able to produce offspring, few nurture any pups and none feeds a full litter. This lactational defect is due to incomplete mammary gland ductal growth during pregnancy, a precocious development of the lobulo-alveolar system, and despite expression of milk proteins, a failure to switch to a lactational state. These data show that CSF-1 has a role in the development of the mammary gland during pregnancy.


An efficient MRF embedded level set method for image segmentation.
This paper presents a fast and robust level set method for image segmentation. To enhance the robustness against noise, we embed a Markov random field (MRF) energy function to the conventional level set energy function. This MRF energy function builds the correlation of a pixel with its neighbors and encourages them to fall into the same region. To obtain a fast implementation of the MRF embedded level set model, we explore algebraic multigrid (AMG) and sparse field method (SFM) to increase the time step and decrease the computation domain, respectively. Both AMG and SFM can be conducted in a parallel fashion, which facilitates the processing of our method for big image databases. By comparing the proposed fast and robust level set method with the standard level set method and its popular variants on noisy synthetic images, synthetic aperture radar (SAR) images, medical images, and natural images, we comprehensively demonstrate the new method is robust against various kinds of noises. In particular, the new level set method can segment an image of size 500 × 500 within 3 s on MATLAB R2010b installed in a computer with 3.30-GHz CPU and 4-GB memory.


Glycan-Functionalized Microgels for Scavenging and Specific Binding of Lectins.
Lectins are proteins with a well-defined carbohydrate recognition domain. Many microbial proteins such as bacterial toxins possess lectin or lectin-like binding domains to interact with cell membranes that are decorated with glycan recognition motifs. We report a straightforward way to prepare monodisperse and biocompatible polyethylene glycol microgels, which carry glycan motifs for specific binding to lectins. The sugar-functionalized colloids exhibit a wide mesh size and a highly accessible volume. The microgels are prepared via drop-based microfluidics combined with radical polymerization. GSII and ECL are used as model lectins that bind specifically to the corresponding carbohydrates, namely, GlcNAc and LacNAc. LacNAc microgels bind ECL with a high capacity and high affinity (Kd ≈ 0.5 to 1 μM), suggesting multivalent binding of the lectin to the LacNAc-decorated flexible microgel network. Glycan-functionalized microgels present a useful tool for lectin scavenging in biomedical applications.


Latin American Cancer Research Coalition. Community primary care/academic partnership model for cancer control.
The Latin American Cancer Research Coalition (LACRC) was funded by NCI as a Special Populations Network to 1) provide training to clinic staff in cancer control and foster development of Latino faculty training, 2) conduct a needs assessment with the community clinics, 3) enhance the ability of the clinics to promote healthy lifestyles, 4) collaborate on research projects to improve use of early detection, and 5) explore partnerships to increase access to culturally competent cancer care. The LACRC developed a model for cancer control focused on community-based clinics as the focal point for in-reach and community outreach targeted to Latinos to reduce cancer disparities. This framework was designed to link the community to local hospitals and academic centers, build capacity, and promote diffusion of innovations directly into delivery systems. Eight research projects submitted by junior investigator/clinic teams have been funded by NCI. These research projects range from recruiting for clinical trials to prevention to survivorship. The LACRC has trained 6 cancer control coordinators from partner sites and educated 59 undergraduate minority student interns in aspects of cancer control research. Central to LACRC's success to date has been the creation and maintenance of an infrastructure of trusting relationships, especially those developed between clinician/investigators and individuals within the greater Latino community. Community clinics can be effective agents for cancer control among Latinos. Latinos are likely to participate in research conducted by culturally representative teams of researchers using culturally appropriate recruiting strategies. Cancer 2006. (c) 2006 American Cancer Society.


Pyrazolopyrimidines in 'all-natural' products for erectile dysfunction treatment: the unreliable quality of dietary supplements.
A herbal food supplement advertised as a potency pill was screened for the presence of PDE5 inhibitors. The resulting signals were characterised by UV, LC-MS in ESI-negative mode, and NMR spectroscopy using 1D and 2D experiments. Several substances were identified, bearing the basic chemical structure of sildenafil, but were not supposed to exhibit PDE5 inhibition. These compounds may be process-related impurities or by-products of different reaction steps in the synthesis of PDE5 analogues. As they were found to be present in different capsules at different concentrations, this is an example of the unreliable quality of dietary supplements.


Serum Proteome Alterations in Human Cystathionine β-Synthase Deficiency and Ischemic Stroke Subtypes.
Ischemic stroke induces brain injury via thrombotic or embolic mechanisms involving large or small vessels. Cystathionine β-synthase deficiency (CBS), an inborn error of metabolism, is associated with vascular thromboembolism, the major cause of morbidity and mortality in affected patients. Because thromboembolism involves the brain vasculature in these patients, we hypothesize that CBS deficiency and ischemic stroke have similar molecular phenotypes. We used label-free mass spectrometry for quantification of changes in serum proteomes in CBS-deficient patients (n = 10) and gender/age-matched unaffected controls (n = 14), as well as in patients with cardioembolic (n = 17), large-vessel (n = 26), or lacunar (n = 25) ischemic stroke subtype. In CBS-deficient patients, 40 differentially expressed serum proteins were identified, of which 18 were associated with elevated homocysteine (Hcy) and 22 were Hcy-independent. We also identified Hcy-independent differentially expressed serum proteins in ischemic stroke patients, some of which were unique to a specific subtype: 10 of 32 for cardioembolic vs. large-vessel, six of 33 for cardioembolic vs. lacunar, and six of 23 for large-vessel vs. lacunar. There were significant overlaps between proteins affected by CBS deficiency and ischemic stroke, particularly the cardioembolic subtype, similar to protein overlaps between ischemic stroke subtypes. Top molecular pathways affected by CBS deficiency and ischemic stroke subtypes included acute phase response signaling and coagulation system. Similar molecular networks centering on NFκB were affected by CBS deficiency and stroke subtypes. These findings suggest common mechanisms involved in the pathologies of CBS deficiency and ischemic stroke subtypes.


Impact of diet composition and temperature-humidity index on water and dry matter intake of high-yielding dairy cows.
The temperature-humidity index (THI) is widely used to characterize heat stress in dairy cattle. Diet composition is known to induce variation in metabolic-associated heat production. However, the relationships between THI and diet are poorly characterized with regard to performance and intake behaviour. Therefore, the objectives were to evaluate the impact of THI on water intake (WI), dry matter intake (DMI) and the frequency of drinking and feeding bouts in lactating dairy cows offered four dietary treatments: each contained 20% grass silage and additionally (i) 20% maize silage, 60% concentrate (M-HC); (ii) 60% maize silage, 20% concentrate (M-LC); (iii) 20% pressed beet pulp silage, 60% concentrate (BPS-HC); or (iv) 60% pressed beet pulp silage, 20% concentrate (BPS-LC) (DM basis). Individual WI and DMI were recorded from April to July 2013. Furthermore, dietary effects on milk production and reticular pH were estimated. Milk yield was lowest for M-LC, while energy-corrected milk was similar for all diets. Milk fat percentage was higher and milk protein amount lower for cows offered both LC diets. Reticular pH below 6.3, 6.0 and 5.8 lasted longest for BPS-LC. WI was higher for HC diets. However, the frequency of drinking bouts was not influenced by the ration. Lower DMI occurred for BPS-LC compared to M-LC. Frequency of feeding bouts was significantly higher for LC diets. THI was significantly related to WI, DMI as well as drinking and feeding bouts. Per increasing THI, WI increased slightly more for LC diets and DMI decreased more for HC diets. Frequency of drinking bouts increased slightly higher for BPS rations per rising THI, while the decrease in feeding bouts was highest for M-HC. In conclusion, TMR composition and moderate heat stress impacted WI and DMI of dairy cows, while both dietary energy density and ruminal filling might intensify the THI impact.


JNJ-26481585 primes rhabdomyosarcoma cells for chemotherapeutics by engaging the mitochondrial pathway of apoptosis.
Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma in childhood with a poor prognosis, highlighting the need for new treatment strategies. Here we identify a synergistic interaction of the second-generation histone deacetylase inhibitor (HDACI) JNJ-26481585 and common chemotherapeutic drugs (i.e. Doxorubicin, Etoposide, Vincristine, Cyclophosphamide and Actinomycin D) to trigger apoptosis in RMS cells. Importantly, JNJ-26481585/Doxorubicin cotreatment also significantly suppresses long-term clonogenic survival of RMS cells and tumor growth in vivo in a preclinical RMS model. Mechanistically, JNJ-26481585/Doxorubicin cotreatment causes upregulation of the BH3-only proteins Bim and Noxa as well as downregulation of the antiapoptotic proteins Mcl-1 and Bcl-xL. These changes in the ratio of pro- and antiapoptotic Bcl-2 proteins contribute to JNJ-26481585/Doxorubicin-mediated apoptosis, since knockdown of Bim or Noxa significantly inhibits cell death. Also, JNJ-26481585 and Doxorubicin cooperate to stimulate activation of Bax and Bak, which is required for JNJ-26481585/Doxorubicin-induced apoptosis, since silencing of Bax or Bak protects against apoptosis. Consistently, overexpression of Bcl-2 significantly reduces JNJ-26481585/Doxorubicin-mediated apoptosis. JNJ-26481585/Doxorubicin cotreatment leads to caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) rescues cells from apoptosis. In conclusion, the second-generation HDACI JNJ-26481585 cooperates with chemotherapeutics to engage mitochondrial apoptosis in RMS cells, demonstrating that JNJ-26481585 represents a promising strategy for chemosensitization of RMS.


A study on epidermal proliferation ability in cholesteatoma.
With the objective of estimating proliferation ability of epidermis of middle ear cholesteatoma, the difference in proliferating cell nuclear antigen (PCNA) staining between the skin of the bone region of the external ear canal (control skin) and cholesteatoma epidermis and the effects on PCNA staining of subepidermal inflammatory cell infiltration of cholesteatoma were immunohistochemically studied using an antibody against PCNA. Transforming growth factor-alpha (TGF-alpha) is known to promote epidermal proliferation based on autocrine mechanism. But it is not clear that cholesteatoma epidermis is actually in the state of hyperproliferation under the effect of this growth factor. To estimate the effect of TGF-alpha on epidermal proliferation ability, the authors compared the location of PCNA and TGF-alpha in the same specimen. Unlike the control skin, not only epidermal basal cell layer and suprabasal cell layer, but also more superior layers were found to have high levels of PCNA staining in the epidermis of cholesteatoma. However, in the same cholesteatoma epidermal tissue, the PCNA staining was varied and the difference was ascribable to subepidermal cell inflammation. It appeared that the proliferation ability was high in regions where subepidermal inflammatory cell infiltration was severe. These differences in microenvironment are inferred to greatly affect proliferation ability of cholesteatoma epidermis.


Enhanced bandwidth, high gain, low noise transimpedance amplifier for asynchronous optical sampling systems.
The methodology to correctly identify the high-bandwidth devices that are able to deliver the lowest noise voltage-amplification from receiving terahertz antenna or photodiode current sources is detailed. We further show that to achieve the lowest noise levels, amplifier input capacitance must be minimized requiring the amplifier and detection circuitry to be carefully integrated. We validate a useful technique to minimize feedback parasitic capacitance and demonstrate a transimpedance amplifier (TIA) with a peak gain of 100 MΩ, 0.5 MHz bandwidth, and a signal power to noise power ratio (SNR) of 23 dB for a 5 nA peak-current input and outline the steps required to increase this to 50 dB. Employing this TIA on a 1550 nm fiber-based terahertz asynchronous optical sampling system realizes a 700 mV, 26 dB SNR, single-scan signal from the 8 nA peak/peak antenna source and removes the requirement for an additional data acquisition trigger signal. Real time, subsecond terahertz data collection is possible at a SNR of 30 dB averaging over 16 scans.


Diagnostic pitfalls in postinterventional intraarterial magnetic resonance angiography after recanalization of femoropopliteal arterial occlusions.
Magnetic resonance (MR)-guided vascular interventions are of increasing interest, and, with the use of contrast-enhanced techniques, intraarterial contrast-enhanced MR angiography (ia-ce-MRA) competes with intraarterial digital subtraction angiography (ia-DSA) for the diagnostic evaluation of the infrainguinal vessel tree. To assess the diagnostic value of ia-ce-MRA and high-resolution T1-weighted (hr-T1w) imaging compared to the gold-standard ia-DSA for residual stenosis and local dissections after femoropopliteal recanalization in patients with peripheral arterial occlusive disease (PAOD). Eight patients with PAOD and short vessel occlusion of their femoropopliteal arteries underwent recanalization and balloon positioning under DSA. Patients were transferred to a short-bore MR scanner. Percutaneous transluminal angioplasty (PTA) was accomplished under MR fluoroscopy. Pre- and postinterventional ia-ce three-dimensional (3D) gradient-echo MRA with gadopentate dimeglumine was performed using the intraarterial introducer sheath. Maximum intensity projections (MIP) and multiplanar reconstructions (MPR) were calculated from the data set. High-resolution T1w images of the angioplasty region before and after dilatation were acquired. Control ia-DSA images were obtained. The postinterventional angioplasty results for stenosis grading were comparable in ia-MRA and ia-DSA. Only two of five local dissections in ia-DSA were visualized with the ia-ce-MRA runs including MIPs and MPRs. To clearly depict dissection, hr-T1w images were needed. Grading of stenotic lesions with ia-ce-MRA after PTA is comparable to ia-DSA. Intraarterial ce-MRA with calculated MIPs and MPRs is only partially sufficient to visualize local dissections after PTA. High-resolution T1w images are required for precise diagnosis of dissections in magnetic resonance tomography.


[Adolescent and youth access to primary health care services in a city in the state of Bahia, Brazil].
The study sought to analyze the association between adolescents and young adults' access to primary health care services and Family Health Strategy (FHS) services. It is a cross-sectional study based on a household survey of 812 individuals aged between 15 and 24 years in Camaçari, Bahia State, Brazil, through cluster sampling. Demographic, socioeconomic, health and health service variables were used to describe the population according to primary health care area. The association between primary health care coverage area and access to its services, access barriers and participation in educational activities were estimated through prevalence ratios (PR) using multilevel logistic regression models in the R software. Access to primary health care services was reported by 89.5% of individuals, with no statistically significant differences between this type of access and primary health care coverage area. However, among individuals who reside in areas covered by FHS, there was greater access to harm reduction and health promotion actions (PR = 3.0; 95%CI: 1.68-5.34), but also lower probability of being seen by a health worker on the same day the appointment was scheduled (PR = 0.60; 95%CI: 0.48-0.74) and lower availability of public transportation (RP = 0.59; 95%CI: 0.39-0.90). Study results point to a high prevalence of access to primary health care services among adolescents and young adults. Though we did not observe a difference in access between areas with FHS coverage, young people's greater participation in prevention and health promotion activities reinforces this strategy's importance within Brazilian Unified National Health System (SUS).


Poly Implant Prothèse (PIP) incidence of rupture: a retrospective MR analysis in 64 patients.
The purpose of this retrospective study was to describe the magnetic resonance imaging (MRI) features of Poly Implant Prothèse (PIP) hydrogel implants in a group of 64 patients and to assess the incidence of rupture, compared to other clinical trials. In this double-center study, we retrospectively reviewed the data sets of 64 consecutive patients (mean age, 43±9 years, age range, 27-65 years), who underwent breast MRI examinations, between January 2008 and October 2013, with suspected implant rupture on the basis of clinical assessment or after conventional imaging examination (either mammography or ultrasound). All patients had undergone breast operation with bilateral textured cohesive gel PIP implant insertion for aesthetic reasons. The mean time after operation was 8 years (range, 6-14 years). No patients reported history of direct trauma to their implants. At the time of clinical examination, 41 patients were asymptomatic, 16 complained of breast tenderness and 7 had clinical evidence of rupture. Normal findings were observed in 15 patients. In 26 patients there were signs of mild collapse, with associated not significant peri-capsular fluid collections and no evidence of implant rupture; in 23 patients there was suggestion of implant rupture, according to breast MRI leading to an indication for surgery. In particular, 14 patients showed intra-capsular rupture, with associated evidence of the linguine sign in all cases; the keyhole sign and the droplet signs were observed in 6 cases. In 9 patients there was evidence of extra-capsular rupture, with presence of axillary collections (siliconomas) in 7 cases and peri-prosthetic and mediastinal cavity siliconomas, in 5 cases. The results of this double center retrospective study, confirm the higher incidence (36%) of prosthesis rupture observed with the PIP implants, compared to other breast implants.


Implementation of a Generalized Vestibular Rehabilitation Approach.
Vestibular dysfunction is common in military populations as the result of traumatic brain injury, blast exposure, and/or repetitive acoustic insult. Vestibular rehabilitation (VR) has been proven to be an effective approach in the treatment of vestibular dysfunction. VR consists of a series of exercises prescribed on the basis of individual patient needs by a vestibular trained physical therapist (PT). A generalized approach to VR in a military setting could help widen the system capacity to take care of patients with vestibular symptoms, shorten waiting times for patients without impacting the burden on PTs. The rehabilitation team at the Warrior Recovery Center on Fort Carson, Colorado, developed a generalized approach in which a series of exercises were administered to individuals with vestibular dysfunction. The implementation of this approach was evaluated for quality improvement purposes and is presented below. We utilized a combined observational/survey approach to evaluate the patients' tolerance to a variety of exercises provocative of dizziness symptoms, their overall satisfaction with the intervention, the appropriateness of the allocated resources, and the providers' confidence with the treatment and its administration. Research staff members were present as observers in all therapy sessions during the 3-month implementation period and administered surveys to patients and clinical staff at pre-established time points. Descriptive analysis was performed to summarize observations and responses to surveys. Linear regression was utilized to evaluate if a reduction in the number of patient:provider interactions occurred over the course of the implementation period. A total of 25 therapy sessions took place during the implementation period. Each visit lasted an average of 56 minutes with 6 minutes allocated for set up, 45 minutes for intervention and 5 minutes for cleanup. The mean number of patients per session was 3 (Max 6, Min 1) with one staff member running the intervention 56% of the time and two staff members running the intervention 44% of the time. Exercise tolerance was at 99% and the need for one-on-one interactions between providers and patients was easily attained at a 3:1 patient:provider rate. Survey assessment demonstrated 100% patient satisfaction with the program and 100% provider confidence with treatment delivery. Generalized Vestibular Rehabilitation Treatment (GVRT) was successfully implemented at the Warrior Recovery Center at Fort Carson, Colorado. The individual exercises used during the interventions were challenging to patients yet well tolerated. Resource allocation was appropriate in terms of personnel, time, and equipment. Both the clinical staff and the patients felt comfortable with the therapy and subjectively found it to be effective. The project provided valuable information to clinical staff, administrators, and the organization.


Pharmacogenomic association study on the role of drug metabolizing, drug transporters and drug target gene polymorphisms in drug-resistant epilepsy in a north Indian population.
In epilepsy, in spite of the best possible medications and treatment protocols, approximately one-third of the patients do not respond adequately to anti-epileptic drugs. Such interindividual variations in drug response are believed to result from genetic variations in candidate genes belonging to multiple pathways. In the present pharmacogenetic analysis, a total of 402 epilepsy patients were enrolled. Of them, 128 were diagnosed as multiple drug-resistant epilepsy and 274 patients were diagnosed as having drug-responsive epilepsy. We selected a total of 10 candidate gene polymorphisms belonging to three major classes, namely drug transporters, drug metabolizers and drug targets. These genetic polymorphism included CYP2C9 c.430C>T (*2 variant), CYP2C9 c.1075 A>C (*3 variant), ABCB1 c.3435C>T, ABCB1c.1236C>T, ABCB1c.2677G>T/A, SCN1A c.3184 A> G, SCN2A c.56G>A (p.R19K), GABRA1c.IVS11 + 15 A>G and GABRG2 c.588C>T. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods, and each genotype was confirmed via direct DNA sequencing. The relationship between various genetic polymorphisms and responsiveness was examined using binary logistic regression by SPSS statistical analysis software. CYP2C9 c.1075 A>C polymorphism showed a marginal significant difference between drug resistance and drug-responsive patients for the AC genotype (Odds ratio [OR] = 0.57, 95% confidence interval [CI] = 0.32-1.00; P = 0.05). In drug transporter, ABCB1c.2677G>T/A polymorphism, allele A was associated with drug-resistant phenotype in epilepsy patients (P = 0.03, OR = 0.31, 95% CI = 0.10-0.93). Similarly, the variant allele frequency of SCN2A c.56 G>A single nucleotide polymorphism was significantly higher in drug-resistant patients (P = 0.03; OR = 1.62, 95% CI = 1.03, 2.56). We also observed a significant difference at the genotype as well as allele frequencies of GABRA1c.IVS11 + 15 A > G polymorphism in drug-resistant patients for homozygous GG genotype (P = 0.03, OR = 1.84, 95% CI = 1.05-3.23) and G allele (P = 0.02, OR = 1.43, 95% CI = 1.05-1.95). Our results showed that pharmacogenetic variants have important roles in epilepsy at different levels. It may be noted that multi-factorial diseases like epilepsy are also regulated by various other factors that may also be considered in the future.


Imaging in patients with cardiovascular implantable electronic devices - Part 2: Imaging after device implantation.
Cardiac implantable electronic devices (CIED) improve quality of life and prolong survival, but there are additional considerations for cardiovascular imaging after implantation - both for standard indications and for diagnosing and guiding management of device-related complications. This clinical consensus statement (Part 2) from the European Association of Cardiovascular Imaging, in collaboration with the European Heart Rhythm Association, provides comprehensive, up-to-date and evidence-based guidance to cardiologists, cardiac imagers and pacing specialists regarding the use of imaging in patients after implantation of conventional pacemakers, cardioverter defibrillators and resynchronization therapy devices. The document summarizes the existing evidence regarding the role and optimal use of various cardiac imaging modalities in patients with suspected CIED-related complications and also discusses CRT optimization, the safety of magnetic resonance imaging in CIED carriers, and describes the role of chest radiography in assessing CIED type, position, and complications. The role of imaging before and during CIED implantation is discussed in a companion document (Part 1).


Clinical accompaniments of the burst-suppression EEG pattern.
A burst-suppression pattern on the EEG following anoxic insult is usually associated with a poor prognosis. Myoclonic jerks may accompany the electrographic burst. On rare occasions oral, ocular, or appendicular movements can be associated with bursts of EEG activity recorded following cerebral anoxic insult. At times these movements may cause confusion about the patient's state of consciousness or the purposefulness of the movements; they may mimic volitional movements in response to external stimuli. To better describe the variety of movements that may accompany bursts of EEG activity in comatose patients, we review 12 cases where movements occurred in association with the electrographic bursts.


Mannitol and dextran increase cochlear blood flow in normotensive and spontaneously hypertensive rats.
Pharmacologic treatments for otopathologies of possible vascular origin are aimed at enhancing vascular transport and are intended to increase cochlear blood flow (CBF). In the current study, normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs) were given intravascular infusions of mannitol (20%), dextran 70 (6%), or control saline. In general, the results clearly indicate that both osmotic agents effectively increase CBF, as measured by laser Doppler flowmetry. However, the mechanism of action of these agents is less clear.


Alcohol consumption, alcoholics anonymous membership, and homicide mortality rates in Ontario 1968 to 1991.
Research has shown a strong link between alcohol use and a variety of problems, including violence. Parker and colleagues have presented a selective disinhibition theory for the link between alcohol use and homicide (and other violence) that posits a causal relationship that is also influenced by other situational and contextual factors. This model is particularly well suited for aggregate-level investigations. In this study, we examine the impact of alcohol factors, including consumption measures and Alcoholics Anonymous (AA) membership rates, on homicide mortality rates in Ontario, and test predictions derived from the selective disinhibition model. Time series analyses with ARIMA modeling were applied to total, male, and female homicide rates in Ontario between 1968 and 1991. The analyses performed included total alcohol consumption, spirits consumption, beer consumption, and wine consumption. Missing AA membership data were interpolated with cubic splines. For the total population and males, homicide rates were significantly and positively related to total alcohol consumption and to the consumption of beer and spirits. They were also negatively related to AA membership rates in the analyses involving spirits and wine and positively related to unemployment rates in the analyses involving beer, wine, and total alcohol. Among females, none of the measures were significant predictors of homicide mortality rates. These data provide important support for the selective disinhibition model and confirm important relationships between per capita consumption measures and homicide mortality rates, especially among males, seen in other studies. Additionally, the results for AA membership rates are consistent with the hypothesis that AA membership and treatment for misuse of alcohol can exert beneficial effects observable at the population level.


In vivo notch signaling blockade induces abnormal spermatogenesis in the mouse.
In a previous study we identified active Notch signaling in key cellular events occurring at adult spermatogenesis. In this study, we evaluated the function of Notch signaling in spermatogenesis through the effects of in vivo Notch blockade. Adult CD1 male mice were either submitted to a long term DAPT (?-secretase inhibitor) or vehicle treatment. Treatment duration was designed to attain one half the time (25 days) or the time (43 days) required to accomplish a complete cycle of spermatogenesis. Blockade of Notch signaling was depicted from decreased transcription of Notch effector genes. Notch signaling blockade disrupted the expression patterns of Notch components in the testis, induced male germ cell fate aberrations, and significantly increased germ cell apoptosis, mainly in the last stages of the spermatogenic cycle, and epididymis spermatozoa morphological defects. These effects were more pronounced following the 43 day than the 25 day DAPT treatment schedule. These results indicate a relevant regulatory role of Notch signaling in mammalian spermatogenesis.


Caridean prawn (Crustacea, Decapoda) with description of a new species and an invasive crayfish from Yuelu mountain national park, Hunan, China.
Yuelu mountain national park (5A scenic area) is a rare urban mountain scenic area. The major impacts from human activity are growing, such as largely unplanned tourist activity, urbanization, and accelerated the others responsible for environmental changes. It is unavoidable to have great pressure and influence on the diversity of fauna on the scenic area. In order to better understand the diversity of the decapod fauna in the Yuelu mountain national park, an intensive field survey has been carried out. A total of five species was collected, three species of atyid shrimps, Neocaridina palmata (Shen, 1948), N. yueluensis, new species, and Paracaridina longispina (Guo He, 1992), one species of palaemonid prawn, Macrobrachium nipponense (De Haan,1849), and an invasive crayfish, Procambarus clarkii (Girard, 1852). N. yueluensis is distiguished from congeners by the shorter rostrum, the stout carpus of first pereiopod and the stout chela of second pereiopod, not sexual dimorphism of the third and fourth pereiopods, the long appendix interna and arising from the inner border of appendix masculina, and the narrower scaphocerite.


Quality of life, satisfaction with life, and functional mobility of young adults with arthrogryposis after leaving pediatric care.
The aim of this study was to describe satisfaction and quality of life (QOL) of young adults with arthrogryposis after leaving pediatric care. Twenty-three adults with arthrogryposis multiplex congenital (AMC) followed at a single pediatric orthopedic hospital (average age 23.6 years; range 18-36 years; 9 males, 14 females) completed questionnaires related to demographics, mobility, and activities of daily living. The Patient Reported Outcomes Measure Information System and Satisfaction with Life Scale were utilized to evaluate QOL and life satisfaction. Eighty-three percent reported general health as good/excellent, 30% lived independently, 69% were ambulatory in the community, and 57% were employed. QOL scores for physical function were lower, but other QOL scores were consistent with the general U.S. population. Average pain intensity was mild at 2.6 out of 10, with pain frequently reported in the legs and feet. Fifty-six percent were satisfied to extremely satisfied with life. Five individuals who were dissatisfied with life also reported lower physical function, higher anxiety, depression and fatigue, and pain in multiple joints. Although most young adults with AMC presented with mild pain and limitations in physical function; overall, they reported good QOL. Findings from the current study will help clinicians anticipate the needs of individuals with AMC as they transition from pediatric to adult care.


Parasagittal organization of the rat cerebellar cortex: direct comparison of Purkinje cell compartments and the organization of the spinocerebellar projection.
Retrograde and anterograde transport of tracers, electrophysiological recording, somatotopic mapping, and histochemical and immunological techniques have all revealed a parasagittal parcellation of the cerebellar cortex, including its efferent and many of its afferent connections. In order to establish whether the different compartments share a common organizational plan, a systematic comparative analysis of the patterns of parasagittal zonation in the cerebellar cortex of the rat has been undertaken, by using the parasagittal compartmentation of zebrin I+ and zebrin I- Purkinje cells as revealed by monoclonal antibody Q113 as a reference frame. The distribution of mossy fiber terminals originating from the lower thoracic-higher lumbar spinal cord was compared to the distribution of zebrin I bands. Three-dimensional reconstructions from alternate frontal sections processed either for the anterograde transport of tracer or for zebrin I immunoreactivity reveal that the limits of the spinocerebellar terminal fields in the granular layer correlate well with the boundaries of some, but not all, zebrin I compartments in the molecular layer above. This leads to a subdivision of the zebrin I compartments into spinal receiving and spinal nonreceiving portions. In lobules II and VIII, the spinocerebellar terminal fields assume different positions relative to the zebrin I compartments in the ventral compared to the dorsal faces. Thus, each longitudinal compartment may be further divided transversely into subzones, each receiving a specific combination of mossy fiber afferents. The further subdivision of zebrin I compartments by mossy fiber terminal fields increases the resolution of the topography to such a point that anatomical compartment widths become compatible with the width of the microzones and the patches identified by electrophysiological methods.


[Dance therapy in laryngectomy patients: our experience].
This study describes the first contact of laringectomized people with dance in the Group of Support to Ostomized-Laringectomized Patients. This study aimed at searching for elements about the therapeutic and educative importance of dance to them. The technique utilized was group dynamics with the participation of twenty patients. Music and body movements were resources employed for the development of therapy through dance. Results showed a good involvement of the patients in the dynamics though verbal and non-verbal language as well as a decrease in stress.


Differential V gene expression detected in the immune response to Streptococcus pneumoniae capsular polysaccharide between elderly and young adults.
Streptococcus pneumoniae is one of the major causative agents of respiratory infections in the elderly population. The 23-valent pneumococcal polysaccharide vaccine is recommended for use in this age group. However, research has indicated that the protective efficacy of the vaccine declines with age. Although similar levels of antibody induction are seen in both young and elderly adults, following immunization with this vaccine, recent studies have indicated that the elderly possess antibodies with lower opsonophagocytic activity and avidity than young adults. We investigated whether a shift in V(H) gene usage may be responsible for this observation. To this end we utilized anti-idiotypic determinants to detect V(H)1 and V(H)3 gene usage by antibodies to pneumococcal capsular polysaccharides in both young and elderly subjects by enzyme-linked immunosorbent assay (ELISA). We found no significant difference in V(H)3 idiotypic expression in antibody responses to capsular polysaccharide from serotype 14 (PPS14). In response to PPS14 a significant higher level of V(H)1 idiotypic expressing antibodies was detected in the elderly as compared with young adults. V(H)1 idiotypic expression in response to capsular polysaccharide from serotype 4 (PPS4) was identical in young and elderly individuals. V(H)3 idiotypic expression in the elderly response to PPS4 was significantly lower than that seen in young individuals. These patterns of idiotypic expression are discussed in relation to recent studies of functional activity of pneumococcal reactive antibodies from young and aged humans.


Transforming care at the bedside: implementation and spread model for single-hospital and multihospital systems.
Institute of Medicine reports provide evidence of the failings of the healthcare system in the United States and a vision of the required transformation. The Institute for Healthcare Improvement and the Robert Wood Johnson Foundation created the Transforming Care at the Bedside initiative in 2003 to develop and validate a process for transforming care in hospital medical-surgical units. The authors describe Transforming Care at the Bedside as implemented by one of Institute for Healthcare Improvement/Robert Wood Johnson's initial pilot hospitals, including promising outcomes and a model for spreading the initiative.


Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells.
Thymidylate synthase (TS) overexpression is a key determinant of 5-fluorouracil (5-FU) resistance in human cancer cells. TS is also acutely up-regulated with 5-FU treatment, and, thus, novel strategies targeting TS down-regulation seem to be promising in terms of modulating 5-FU resistance. Here, we report that histone deacetylase inhibitors can reverse 5-FU resistance by down-regulating TS. By using cDNA microarrays and validation experiments, we found that trichostatin A reduced the expression of both TS mRNA and TS protein. Cotreatment with trichostatin A and cycloheximide restored TS mRNA expression, suggesting that TS mRNA is repressed through new protein synthesis. On the other hand, TS protein expression was significantly reduced by lower doses of trichostatin A (50 nmol/L). Mechanistically, TS protein was found to interact with heat shock protein (Hsp) complex, and trichostatin A treatment induced chaperonic Hsp90 acetylation and subsequently enhanced Hsp70 binding to TS, which led to the proteasomal degradation of TS protein. Of note, combined treatment with low-dose trichostatin A and 5-FU enhanced 5-FU-mediated cytotoxicity in 5-FU-resistant cancer cells in accordance with TS protein down-regulation. We conclude that a combinatorial approach using histone deacetylase inhibitors may be useful at overcoming 5-FU resistance.


Bisphenol A-induced DNA damages promote to lymphoma progression in human lymphoblastoid cells through aberrant CTNNB1 signaling pathway.
Lymphoma is a group of blood cancers that develop from the immune system, and one of the main risk factors is associated with exposure to environmental chemicals. Bisphenol A (BPA) is a common chemical used in the manufacture of materials in polycarbonate and epoxy plastic products and can interfere with the immune system. BPA is considered to possibly induce lymphoma development by affecting the immune system, but its potential mechanisms have not been well established. This study performed a gene-network analysis of microarray data sets in human lymphoma tissues as well as in human cells with BPA exposure to explore module genes and construct the potential pathway for lymphomagenesis in response to BPA. This study provided evidence that BPA exposure resulted in disrupted cell cycle and DNA damage by activating CTNNB1, the initiator of the aberrant constructed CTNNB1-NFKB1-AR-IGF1-TWIST1 pathway, which may potentially lead to lymphomagenesis.


Crystalline bacterial cell surface layers.
Crystalline arrays of proteinaceous subunits forming surface layers (S-layers) are one of the most commonly observed prokaryotic cell envelope structures. They are ubiquitous amongst Gram-positive and Gram-negative archeaobacteria and eubacteria and, if present, account for the major protein species produced by the cells. S-layers can provide organisms with a selection advantage by providing various functions including protective coats, molecular sieves, ion traps and structures involved in cell surface interactions. S-layers were identified as contributing to virulence when present as a structural component of pathogens. In Gram-negative archaeobacteria they are involved in determining cell shape and cell division. The crystalline arrays reveal a broad-application potential in biotechnology, vaccine development and molecular nanotechnology.


Ocular autonomic nerve function in proliferative diabetic retinopathy.
Ocular autonomic nerve function was assessed in 28 diabetic patients with proliferative retinopathy (PDR) and 61 age- and sex-matched control subjects, by measurement of the pupil cycle time and determination of autonomic denervation hypersensitivity of the iris. Sustained pupil cycle time was absent in 88.5 per cent of PDR compared with 9.8 per cent of control subjects (p less than 0.001). Pupil constriction in response to 2.5 per cent methacholine--indicative of parasympathetic denervation hypersensitivity--was significantly increased in PDR (p less than 0.001), whilst pupil dilation in response to 0.5 per cent phenylephrine--indicative of sympathetic denervation hypersensitivity--was also significantly higher in PDR (p less than 0.001). Pupil reflexes were abnormal in 88.5 per cent of diabetics with proliferative retinopathy, with established autonomic denervation hypersensitivity in 57 per cent of patients.


Primary lymphoma of the brain.
In this study, clinical and histopathological features of primary lymphomas of the brain have been described in eight patients. The primary nature of lymphoma in these patients was confirmed by extensive clinical as well as radiological investigations and supported by a detailed histopathological examination. Computerised tomography (CT) scan showed multiple intra-cerebral lesion in two patients and in six patients the lesion was solitary. Although primary lymphoma of the brain carries poor prognosis, it is essential that these tumours should be accurately diagnosed as well as should be distinguished from secondary tumours.


Agent-based models of inflammation in translational systems biology: A decade later.
Agent-based modeling is a rule-based, discrete-event, and spatially explicit computational modeling method that employs computational objects that instantiate the rules and interactions among the individual components ("agents") of system. Agent-based modeling is well suited to translating into a computational model the knowledge generated from basic science research, particularly with respect to translating across scales the mechanisms of cellular behavior into aggregated cell population dynamics manifesting at the tissue and organ level. This capacity has made agent-based modeling an integral method in translational systems biology (TSB), an approach that uses multiscale dynamic computational modeling to explicitly represent disease processes in a clinically relevant fashion. The initial work in the early 2000s using agent-based models (ABMs) in TSB focused on examining acute inflammation and its intersection with wound healing; the decade since has seen vast growth in both the application of agent-based modeling to a wide array of disease processes as well as methodological advancements in the use and analysis of ABM. This report presents an update on an earlier review of ABMs in TSB and presents examples of exciting progress in the modeling of various organs and diseases that involve inflammation. This review also describes developments that integrate the use of ABMs with cutting-edge technologies such as high-performance computing, machine learning, and artificial intelligence, with a view toward the future integration of these methodologies. This article is categorized under: Translational, Genomic, and Systems Medicine > Translational Medicine Models of Systems Properties and Processes > Mechanistic Models Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Models of Systems Properties and Processes > Organismal Models.


Scalp ulcer as first sign of cholangiocarcinoma.
Metastases from distant primary tumors are rarely the first indicators of cancer. However, cutaneous metastases are not uncommon in cases of internal malignancy. This article describes the case of a 65-year-old man with cutaneous metastasis of cholangiocarcinoma who presented with a scalp ulcer as the only initial sign. This is only the third reported case of cholangiocarcinoma with distant cutaneous metastasis.


Health Sector Reform in the Kurdistan Region - Iraq: Financing Reform, Primary Care, and Patient Safety.
In 2010, the Kurdistan Regional Government asked the RAND Corporation to help guide reform of the health care system in the Kurdistan Region of Iraq. The overarching goal of reform was to help establish a health system that would provide high-quality services efficiently to everyone to prevent, treat, and manage physical and mental illnesses and injuries. This article summarizes the second phase of RAND's work, when researchers analyzed three distinct but intertwined health policy issue areas: development of financing policy, implementation of early primary care recommendations, and evaluation of quality and patient safety. For health financing, the researchers reviewed the relevant literature, explored the issue in discussions with key stakeholders, developed and assessed various policy options, and developed plans or approaches to overcome barriers and achieve stated policy objectives. In the area of primary care, they developed and helped to implement a new management information system. In the area of quality and patient safety, they reviewed relevant literature, discussed issues and options with health leaders, and recommended an approach toward incremental implementation.


A Conserved Structural Motif Mediates Retrograde Trafficking of Shiga Toxin Types 1 and 2.
Shiga toxin-producing Escherichia coli (STEC) produce two types of Shiga toxin (STx): STx1 and STx2. The toxin A-subunits block protein synthesis, while the B-subunits mediate retrograde trafficking. STEC infections do not have definitive treatments, and there is growing interest in generating toxin transport inhibitors for therapy. However, a comprehensive understanding of the mechanisms of toxin trafficking is essential for drug development. While STx2 is more toxic in vivo, prior studies focused on STx1 B-subunit (STx1B) trafficking. Here, we show that, compared with STx1B, trafficking of the B-subunit of STx2 (STx2B) to the Golgi occurs with slower kinetics. Despite this difference, similar to STx1B, endosome-to-Golgi transport of STx2B does not involve transit through degradative late endosomes and is dependent on dynamin II, epsinR, retromer and syntaxin5. Importantly, additional experiments show that a surface-exposed loop in STx2B (β4-β5 loop) is required for its endosome-to-Golgi trafficking. We previously demonstrated that residues in the corresponding β4-β5 loop of STx1B are required for interaction with GPP130, the STx1B-specific endosomal receptor, and for endosome-to-Golgi transport. Overall, STx1B and STx2B share a common pathway and use a similar structural motif to traffic to the Golgi, suggesting that the underlying mechanisms of endosomal sorting may be evolutionarily conserved.


Intermediate uveitis in a child with phosphatase and tensin homolog gene mutation and Bannayan-Riley-Ruvalcaba syndrome.
Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a congenital disorder characterised by macrocephaly, multiple hamartomas, lipomas, and pigmented macules of the glans penis. Intermediate uveitis is characterised by chronic inflammatory cells aggregates on the pars plana (snowbanks) and within the vitreous cavity (snowballs). We describe what we believe to be the first case of intermediate uveitis associated with BRRS. Early examination under anaesthesia should be considered in the management of young children diagnosed with this syndrome in order to provide appropriate ocular evaluation, treatment and follow-up. Further research is needed to establish a better understanding of the ophthalmic manifestations of this syndrome.


Toll-like receptor 9 mediates paraquat-induced acute lung injury: an in vitro and in vivo study.
This study aimed to investigate the role of Toll-like receptor 9 in paraquat-induced acute lung injury (ALI). For in vivo study,C57BL mice were randomly assigned into the vehicle control group, paraquat group, paraquat + TLR9 antagonist (ODN2088) group, and TLR9 antagonist (ODN2088) group (n=36 per group). After paraquat 30mg/kg ip for 2, 24 and 48h, serum samples and lung tissues were collected to evaluate ALI and TLR9 signaling by lung injury score, protein levels of TLR9, MyD88, p-IRAK4, p-p65, and serum TNF-α and IL-1β levels. As for in vitro research A549 cells were randomly divided into the control group, paraquat group, paraquat + TLR9 siRNA group, and TLR9 siRNA group. After paraquat treatment for 24h, the cells and supernatant were collected to measureTLR9, TNF-α, IL-1 mRNA expression, and detect activation of NF-κB, caspase-3. In vivo, the lung injury score, the TLR9, MyD88, p-IRAK4 and p-p65 protein levels, and cytokines TNF-α and IL-1β levels in paraquat group were significantly higher than that in the control group;TLR9 blocker ODN2088 pretreatment attenuated lung injury, inhibited MyD88 and NF-κB activation, and reduced TNF-α and IL-1β in serum. In vitro result shows that the gene silencing of TLR9 reduced the mRNA expression of TLR9, TNF-α and IL-1, inhibited NF-κB and caspase-3 activation, attenuated cell apoptosis. TLR9 mediates paraquat-induced ALI, antagonizing TLR9 or silencing TLR9gene may attenuate paraquat-induced ALI.


Concentration of prothrombin fragment 1 + 2 (f1 + 2) in patients with liver cirrhosis and chronic hepatitis C infection.
The aim of this study was to assess the serum concentration of F1 + 2 in patients with liver cirrhosis developed during HCV infection and in patients with chronic hepatitis C infection. The study group consisted of 52 patients hospitalised at the Department of Infectious Diseases of Medical University of Lublin, Poland. Among them, 18 patients (8 men and 10 women), aged 19-59 years, had a stable liver cirrhosis and 34 patients (21 men and 13 women), aged 20-41 years, were diagnosed with chronic hepatitis C infection. The control group consisted of 25 healthy individuals (13 men and 12 women), aged 19-60 years. The serum concentration of F1 + 2 was determined by the immunoenzymatic assay Enzygnost F1 + 2 micro. There were no statistically significant differences observed in serum concentration of F1 + 2, both in patients with stable cirrhosis and with CHC, compared to controls. However, in 16.7% of patients with cirrhosis and in 35.3% of patients with CHC elevated serum levels of F1 + 2 were observed.


Molecular imaging: The latest generation of contrast agents and tissue characterization techniques.
Molecular Imaging technologies will have a profound impact on both basic research and clinical imaging in the near future. As the field covers many different specialties and scientific disciplines it is not possible to review all in a single article. In the current article we will turn our attention to those modalities that are either currently in use or in development for the medical imaging clinic.


Effect of lithotripter focal width on stone comminution in shock wave lithotripsy.
Using a reflector insert, the original HM-3 lithotripter field at 20 kV was altered significantly with the peak positive pressure (p(+)) in the focal plane increased from 49 to 87 MPa while the -6 dB focal width decreased concomitantly from 11 to 4 mm. Using the original reflector, p(+) of 33 MPa with a -6 dB focal width of 18 mm were measured in a pre-focal plane 15-mm proximal to the lithotripter focus. However, the acoustic pulse energy delivered to a 28-mm diameter area around the lithotripter axis was comparable ( approximately 120 mJ). For all three exposure conditions, similar stone comminution ( approximately 70%) was produced in a mesh holder of 15 mm after 250 shocks. In contrast, stone comminution produced by the modified reflector either in a 15-mm finger cot (45%) or in a 30-mm membrane holder (14%) was significantly reduced from the corresponding values (56% and 26%) produced by the original reflector (no statistically significant differences were observed between the focal and pre-focal planes). These observations suggest that a low-pressure/broad focal width lithotripter field will produce better stone comminution than its counterpart with high-pressure/narrow focal width under clinically relevant in vitro comminution conditions.


Accessing Low-Valent Inorganic Cations by Using an Extremely Bulky N-Heterocyclic Carbene.
The extremely bulky N-heterocyclic carbene (NHC), ITr (ITr=[(HCNCPh3 )2 C:]) featuring sterically shielding umbrella-shaped trityl (CPh3 ) substituents was prepared. This NHC features the highest percent buried volume (%Vbur ) to date, and was used to form a thermally stable quasi one-coordinate thallium(I) cation [ITr-Tl]+ . This TlI adduct and the corresponding lithium complex [ITr⋅Li(OEt2 )]+ are versatile "all-in-one" transmetalation/ligation reagents for preparing low-coordinate inorganic species inaccessible by pre-existing routes.