A new dietary therapy for adrenoleukodystrophy: biochemical and preliminary clinical results in 36 patients.
A new dietary regimen has been administered for periods ranging from 60 days to 1 1/2 years in 34 patients with various forms of X-linked adrenoleukodystrophy (ALD), as well as in 1 patient with neonatal ALD and 1 patient with infantile Refsum's disease. The diet combines the administration of a glyceryl trioleate oil (GTO) with the dietary restriction of very-long-chain fatty acids (VLFA), particularly hexacosanoic acid (C26:0). Reductions in the levels of plasma C26:0 and other VLFA were achieved in 25 of the 36 patients. Fifteen of these 25 patients were treated for more than 100 days. The mean reduction of the plasma C26:0 level was 53% (range, 22 to 73%) in these 15 patients. While the focus of the study was on biochemical variables, comparison of pre- and post-diet studies of peripheral nerve function showed improvement in 1 patient with adrenomyeloneuropathy (AMN) and 1 heterozygote. In contrast, 2 patients with ALD onset in childhood developed new neurological deficits while on therapy. We conclude that it is possible to lower plasma VLFA levels in ALD patients. A clinical trial is indicated to test whether this approach can alter the neurological progression in patients with AMN or in symptomatic heterozygotes, and to determine whether it can prevent the onset of neurological disability in asymptomatic persons who have the biochemical defect of ALD.


Prosper and Live Long: Productive Life Span Tracks Increasing Overall Life Span Over Historical Time among Privileged Worker Groups.
Life expectancy has increased continuously for at least 150 years, due at least in part to improving life conditions for the majority of the population. A substantial part of this historical increase is due to decreases in early life mortality. In this article, we analyze the longevity of four privileged sets of adults who have avoided childhood mortality and lived a life more similar to the modern middle class. Our analysis is focused on writers and musicians from the 17th through the 21st centuries. We show that their average age at death increased only slightly between 1600 and 1900, but in the 20th century increased at around 2 years/decade. We suggest that this confirms that modern life span extension is driven by delay of death in older life rather than avoidance of premature death. We also show that productive life span, as measured by writing and composition outputs, has increased in parallel with overall life span in these groups. Increase in age of death is confirmed in a group of the minor British aristocracy and in members of the US Congress from 1800 to 2010. We conclude that both life span and productive life span are increasing in the 20th and early 21st century, and that the modern prolongation of life is the extension of productive life and is not the addition of years of disabling illness to the end of life.


Protein kinase D orchestrates the activation of DRAK2 in response to TCR-induced Ca2+ influx and mitochondrial reactive oxygen generation.
DRAK2 is a serine/threonine kinase highly enriched in lymphocytes that raises the threshold for T cell activation and maintains T cell survival following productive activation. T cells lacking DRAK2 are prone to activation under suboptimal conditions and exhibit enhanced calcium responses to AgR stimulation. Despite this, mice lacking DRAK2 are resistant to organ-specific autoimmune diseases due to defective autoreactive T cell survival. DRAK2 kinase activity is induced by AgR signaling, and in this study we show that the induction of DRAK2 activity requires Ca(2+) influx through the Ca(2+) release-activated Ca(2+) channel formed from Orai1 subunits. Blockade of DRAK2 activity with the protein kinase D (PKD) inhibitor Gö6976 or expression of a kinase-dead PKD mutant prevented activation of DRAK2, whereas a constitutively active PKD mutant promoted DRAK2 function. Knockdown of PKD in T cells strongly blocked endogenous DRAK2 activation following TCR ligation, implicating PKD as an essential intermediate in the activation of DRAK2 by Ca(2+) influx. Furthermore, we identify DRAK2 as a novel substrate of PKD, and demonstrate that DRAK2 and PKD physically interact under conditions that activate PKD. Mitochondrial generation of reactive oxygen intermediates was necessary and sufficient for DRAK2 activation in response to Ca(2+) influx. Taken together, DRAK2 and PKD form a novel signaling module that controls calcium homeostasis following T cell activation.


Improvements in glucose tolerance and insulin sensitivity after lifestyle intervention are related to changes in serum fatty acid profile and desaturase activities: the SLIM study.
The aim of this study was to investigate whether lifestyle intervention-induced changes in serum fatty acid profile of cholesteryl esters and estimated desaturase activities are related to improvements in insulin sensitivity in subjects at risk of type 2 diabetes. In the Study on Lifestyle Intervention and Impaired Glucose Tolerance Maastricht (SLIM), 97 men and women with IGT were randomised to a combined diet and exercise programme (47 intervention) or a control group (50 control subjects). At baseline and after 1 year the following assessments were made: an OGTT, an exercise test to determine maximal aerobic capacity, anthropometry, and analysis of the serum fatty acid profile of cholesteryl esters. The lifestyle programme was effective in reducing the intake of total and saturated fat, increasing physical activity, reducing obesity and improving insulin sensitivity and glucose tolerance. Regression analysis of the total population showed that an increase in the C20:4 n-6/C20:3 n-6 ratio (estimated Delta5-desaturase activity) and reductions in the C18:3 n-6/C18:2 n-6 ratio (estimated Delta6-desaturase activity) and the C16:1 n-7/C16:0 ratio (estimated Delta9-desaturase activity or stearoyl-CoA desaturase-1) were significantly associated with a decrease in homeostasis model assessment for insulin resistance. After adjustment for lifestyle changes (change in percentage body fat, aerobic capacity and saturated fat intake), these associations were partly reduced, but remained statistically significant. Lifestyle-induced changes in fatty acid profile of cholesteryl esters and desaturase activities were independently related to changes in insulin sensitivity in subjects at risk of type 2 diabetes.


Identification of the Major Protein Components of Human and Cow Saliva.
Cows produce saliva in very large quantities to lubricate and facilitate food processing. Estimates indicate an amount of 50-150 L per day. Human saliva has previously been found to contain numerous antibacterial components, such as lysozyme, histatins, members of the S-100 family and lactoferrin, to limit pathogen colonization. Cows depend on a complex microbial community in their digestive system for food digestion. Our aim here was to analyze how this would influence the content of their saliva. We therefore sampled saliva from five humans and both nose secretions and saliva from six cows and separated the saliva on SDS-PAGE gradient gels and analyzed the major protein bands with LC-MS/MS. The cow saliva was found to be dominated by a few major proteins only, carbonic anhydrase 6, a pH-stabilizing enzyme and the short palate, lung and nasal epithelium carcinoma-associated protein 2A (SPLUNC2A), also named bovine salivary protein 30 kDa (BSP30) or BPIFA2B. This latter protein has been proposed to play a role in local antibacterial response by binding bacterial lipopolysaccharides (LPSs) and inhibiting bacterial growth but may instead, according to more recent data, primarily have surfactant activity. Numerous peptide fragments of mucin-5B were also detected in different regions of the gel in the MS analysis. Interestingly, no major band on gel was detected representing any of the antibacterial proteins, indicating that cows may produce them at very low levels that do not harm the microbial flora of their digestive system. The nose secretions of the cows primarily contained the odorant protein, a protein thought to be involved in enhancing the sense of smell of the olfactory receptors and the possibility of quickly sensing potential poisonous food components. High levels of secretory IgA were also found in one sample of cow mouth drippings, indicating a strong upregulation during an infection. The human saliva was more complex, containing secretory IgA, amylase, carbonic anhydrase 6, lysozyme, histatins and a number of other less abundant proteins, indicating a major difference to the saliva of cows that show very low levels of antibacterial components, most likely to not harm the microbial flora of the rumen.


Monocarboxylate Transporter 4 (MCT4) Overexpression Is Correlated with Poor Prognosis of Osteosarcoma.
BACKGROUND Monocarboxylate transporter 4 (MCT4) is a critical element for glycolytic metabolism and malignant behaviors in many tumor cells. This study aimed to determine the expression level of MCT4 protein and its prognostic value in osteosarcoma. MATERIAL AND METHODS MCT4 expression was detected via immunohistochemical and Western blot analysis for 100 osteosarcoma patients. The correlation between MCT4 expression and clinical factors among the patients was analyzed using the chi-square test. Overall survival of osteosarcoma patients was estimated by Kaplan-Meier analysis. The prognostic value of MCT4 was evaluated using Cox regression analysis with adjustments for clinicopathological variables. RESULTS MCT4 expression was significantly upregulated in osteosarcoma tissues compared with that in adjacent normal ones, detected via both immunohistochemical and Western blot analyses. High MCT4 expression showed a positive association with distant metastasis (P=0.000) and recurrence (P=0.000) of osteosarcoma. Kaplan-Meier analysis indicated that overall survival of osteosarcoma patients was significantly higher in the low MCT4 expression group than in the high expression group (log-rank test, P<0.001). Multivariate analysis indicated that MCT4 expression and clinical stage, which are tightly related to the prognosis of osteosarcoma, might be independent predictors of osteosarcoma prognosis. CONCLUSIONS High MCT4 expression appears to contribute to osteosarcoma progression and the upregulation of MCT4 may predict poor prognosis among osteosarcoma patients.


Comparative sequence analysis of IS50/Tn5 transposase.
Comparative sequence analysis of IS50 transposase-related protein sequences in conjunction with known structural, biochemical, and genetic data was used to determine domains and residues that play key roles in IS50 transposase function. BLAST and ClustalW analyses have been used to find and analyze six complete protein sequences that are related to the IS50 transposase. The protein sequence identity of these six homologs ranged from 25 to 55% in comparison to the IS50 transposase. Homologous motifs were found associated with each of the three catalytic residues. Residues that play roles in transposase-DNA binding, protein autoregulation, and DNA hairpin formation were also found to be conserved in addition to other residues of unknown function. On the other hand, some homologous sequences did not appear to be competent to encode the inhibitor regulatory protein. The results were also used to compare the IS50 transposase with the more distantly related transposase encoded by IS10.


Weak D and partial D in Slovenian population through serology and genotyping.
Weak D red cell phenotype (formerly D(II)) exhibits weaker serological reaction with anti-D antibodies. Weak D occurs in 0.2% to 1% of whites and is caused by qualitatively altered RhD proteins called partial D or normal, only weakly expressed RhD proteins that are called weak D. Partial D genes are hybrid alleles between RHD an RHCE genes. 23 partial RHD alleles are described. Weak D phenotypes with reduced expression are likely to possess the normal RHD gene, but the latest findings indicate that weak D alleles carry at least one point mutation. The aim of the present work was to answer an important question how to approach partial and weak D identification in diagnostic use and if it is possible to distinguish between partial D and weak D using commercially available anti-D reagents for routine use. We also wanted to evaluate D-screen kit for partial D identification. We compared phenotypes identified by serological testing and genotypes identified by RHD Multiplex PCR and D(VII) specific ASPA PCR. Our results showed that it is not possible to distinguish between partial and weak D using commercially available anti-D reagents for routine use. D-screen proved to be useful for D(VI) and D(VII) identification, whereas for partial D(DFR) identification we must look for another set of monoclonal antibodies or simply use genotyping methods. In 44 samples with not interpretable serological results out of 80 we found all RHD specific exons present and we classified the samples as weak D. Fourteen types of weak D with at least one point mutation were recently proposed. Designing of allele specific PCRs for identification of proposed types of weak D is in progress.


Chemical characterzation of fine particle emissions from the fireplace combustion of woods grown in the Southern United States.
The fireplace combustion of wood is a significant and largely unregulated source of fine particle pollution in the United States. Source apportionment techniques that use particulate organic compounds as tracers have been successful in determining the contribution of wood smoke to ambient fine particle levels in specific areas in California. To apply these techniques to the rest of the United States, the differences in emissions profiles between different wood smoke sources and fuel types should be resolved. To this end, a series of fireplace source tests was conducted on six fuel wood species found in the Southern United States to determine fine particulate emission factors for total mass, ionic and elemental species, elemental and organic carbon, and over 250 individual organic compounds. The wood species tested, chosen for their high abundance and availability in the Southern U.S. region, were yellow poplar, white ash, sweetgum, mockernut hickory, loblolly pine, and slash pine. The differences in the emissions of compounds such as substituted phenols and resin acids help to distinguish between the smoke from hardwood and softwood combustion. Levoglucosan, a cellulose pyrolysis product which may serve as a tracer for wood smoke in general, was quantified in the emissions from all the wood species burned. The furofuran lignan, yangambin, which was emitted in significant quantities from yellow poplar combustion and not detected in any of the other North American wood smokes, is a potential species-specific molecular tracer which may be useful in qualitatively identifying particulate emissions from a specific geographical area where yellow poplar is being burned.


In Silico Bioinformatics Followed by Molecular Validation Using Archival FFPE Tissue Biopsies Identifies a Panel of Transcripts Associated with Severe Asthma and Lung Cancer.
Severe asthma and lung cancer are both heterogeneous pathological diseases affecting the lung tissue. Whilst there are a few studies that suggest an association between asthma and lung cancer, to the best of our knowledge, this is the first study to identify common genes involved in both severe asthma and lung cancer. Publicly available transcriptomic data for 23 epithelial brushings from severe asthmatics and 55 samples of formalin-fixed paraffin-embedded (FFPE) lung cancer tissue at relatively early stages were analyzed by absolute gene set enrichment analysis (GSEA) in comparison to 37 healthy bronchial tissue samples. The key pathways enriched in asthmatic patients included adhesion, extracellular matrix, and epithelial cell proliferation, which contribute to tissue remodeling. In the lung cancer dataset, the main pathways identified were receptor tyrosine kinase signaling, wound healing, and growth factor response, representing the early cancer pathways. Analysis of the enriched genes derived from the pathway analysis identified seven genes expressed in both the asthma and lung cancer sets: BCL3, POSTN, PPARD, STAT1, MYC, CD44, and FOSB. The differential expression of these genes was validated in vitro in the cell lines retrieved from different lung cancer and severe asthma patients using real-time PCR. The effect of the expression of the seven genes identified in the study on the overall survival of lung cancer patients (n = 1925) was assessed using a Kaplan-Meier plot. In vivo validation performed in the archival biopsies obtained from patients diagnosed with both the disease conditions provided interesting insights into the pathogenesis of severe asthma and lung cancer, as indicated by the differential expression pattern of the seven transcripts in the mixed group as compared to the asthmatics and lung cancer samples alone.


In Vitro Reconstitution and Crystallization of Cas9 Endonuclease Bound to a Guide RNA and a DNA Target.
The programmable RNA-guided DNA cleavage activity of the bacterial CRISPR-associated endonuclease Cas9 is the basis of genome editing applications in numerous model organisms and cell types. In a binary complex with a dual crRNA:tracrRNA guide or single-molecule guide RNA, Cas9 targets double-stranded DNAs harboring sequences complementary to a 20-nucleotide segment in the guide RNA. Recent structural studies of the enzyme have uncovered the molecular mechanism of RNA-guided DNA recognition. Here, we provide protocols for electrophoretic mobility shift and fluorescence-detection size exclusion chromatography assays used to probe DNA binding by Cas9 that allowed us to reconstitute and crystallize the enzyme in a ternary complex with a guide RNA and a bona fide target DNA. The procedures can be used for further mechanistic investigations of the Cas9 endonuclease family and are potentially applicable to other multicomponent protein-nucleic acid complexes.


[Low intensity laser irradiation in therapy of elderly patients with occlusive artery diseases].
Shown in the paper is a novel complex approach to the treatment of occlusion affections of arteries by He-Ne and infrared laseropuncture. As many as 80 patients having a history of the above health problem 5 years in duration were kept under medical supervision. Patient age ranged between 50 to 78 years. Laseropuncture was carried out with the aid of the infrared laser stimulator [symbol: see text]-001 (wavelenth 0.89 mm with continuous-wave pulse operation, pulse power 8 W) and 111 He-Ne laser (wavelength 0.63 mm, power density 5 mW/cm2, spot diameter 25 mm). 88.2 percent of patients derived apparent therapeutic benefit, 11.8 percent demonstrating a satisfactory clinical effect.


Phosphorus 31 nuclear magnetic resonance spectroscopy suggests a mitochondrial defect in claudicating skeletal muscle.
Decreased oxygen supply is generally accepted as the primary cause of muscle dysfunction in patients with peripheral arterial occlusive disease (PAOD) and intermittent claudication, although reported morphologic changes in the mitochondria of claudicating muscle suggest that impaired energy utilization may also play a role. With the measurement of the phosphate-rich compounds of muscle energy metabolism (adenosinetriphosphate [ATP], adenosinediphosphate [ADP], and phosphocreatine [PCr]) and pH, phosphorus P 31 magnetic resonance spectroscopy ((31)P MRS) provides a unique, noninvasive method to investigate this hypothesis further. Calf muscle bioenergetics were studied in 12 men with moderate claudication (ankle-brachial index >/=0.5 and </=0.8) and 14 normal control subjects with the use of (31)P MRS and standard treadmill testing. Phosphorus MRS evaluation of the superficial posterior calf muscles was carried out with a 90-second submaximal isometric plantar flexion exercise. This mild exercise was chosen to permit in-magnet testing and to allow study of intrinsic mitochondrial efficiency under conditions of unchallenged blood flow. Phosphocreatine and ADP recovery time constants (t.c.), two very sensitive measures of oxidative mitochondrial function, as well as intracellular pH and ATP production via anaerobic glycolysis were determined during three exercise sessions and the results averaged and compared to known values obtained from a control population. During the (31)P MRS protocol, the end exercise intracellular pH (7.11 +/- 0.01 vs 7.11 +/- 0.01) and ATP production by anaerobic glycolysis (0.13 +/- 0.05 vs 0.14 +/- 0.03 mmol/L per second) were no different in PAOD patients versus control subjects, confirming that the protocol exercise did not significantly reduce oxygen supply. Phosphocreatine and ADP recovery t.c. (137 +/- 41 vs 44 +/- 3 seconds and 60 +/- 10 vs 29 +/- 2 seconds, respectively) were significantly slower than normal (P <.05, t test). There was, however, no correlation between these measures of mitochondrial function and any treadmill parameter (P >.5, Pearson moment correlation). Phosphorus 31 MRS provides the first direct evidence of defective energy metabolism in the mitochondria of claudicating calf muscle. This defect appears to be independent of both arterial flow and the severity of occlusive disease in patients with mild to moderate claudication. Coupled with documented ultrastructural and DNA abnormalities in the mitochondria of claudicating skeletal muscle, these data provide evidence for a secondary cause of muscle dysfunction in intermittent claudication.


Medical management of inflammatory bowel disease in the elderly: balancing safety and efficacy.
The medical management of inflammatory bowel disease (IBD) in the older patient extends beyond luminal disease activity. Factors such as comorbidity, functional status, polypharmacy, and age-related changes in physical reserve and drug metabolism may affect therapeutic decision making. The older patient with IBD is more susceptible to disease-related complications and also to adverse events with therapy, particularly immunosuppression. Appropriate medication selection along with multidisciplinary care, factoring not only disease activity but also these age-related risk factors, may improve therapeutic outcomes and decrease adverse events to therapy.


Scrotal Ultrasonic Features of Congenital Bilateral Absence of Vas Deferens.
This article discusses scrotal ultrasonic features of patients with a congenital bilateral absence of the vas deferens (CBAVD). Thirty-six patients with CBAVD were examined to obtain image characteristics of the bilateral testicle and epididymis by ultrasound. Each patient received a pathological examination of the sperm by percutaneous epididymal biopsy. Scrotal ultrasonic features were as follows: (1) testicular volumes were normal in all the 36 patients; (2) 21% (15/72) of the heads of epididymis, 67% (48/72) of the heads and bodies of epididymis, and 12% (9/72) of the heads, bodies, and tails of epididymis could be shown in the 72 epididymides of the 36 patients; (3) cystic or tubular dilation of the epididymis was obvious in all 72 abnormal epididymides; and (4) bilateral vas deferens could not be found in these patients. Johnsen's grading of sperm in all the 36 patients received a score of 7 or higher (scale of 10, lower numbers denote greater dysfunction). Ultrasonography images of the scrotum revealed characteristics that were commonly present in patients with CBAVD. Therefore, this method is helpful to diagnose CBAVD by identifying the features of epididymis structural abnormalities and cystic or tubular dilation of the epididymis.


The correlation of brody high resolution computed tomography scoring system with clinical status and pulmonary function test in patients with cystic fibrosis.
To reduce the mortality and morbidity rates of cystic fibrosis (CF) patients, and to have an effective clinical management, it is important to monitor the progression of the disease. The aim of this study was to evaluate the progression of lung disease in CF patients by means of assessing the correlation of the CT scoring system with clinical status and pulmonary function test at the Pediatric Pulmonary Ward of Masih Daneshvari Hospital in 2008. Pulmonary high resolution computed tomography (HRCT) was performed in 23 CF patients using the Brody's scoring system. Morphologic signs as well as the extent and severity of each sign were scored, and the total score was calculated. The correlation of HRCT scores (total score as well as the score for each parameter) with Shwachman Kuczycki scoring system and pulmonary function test were examined. The study included 9 female and 14 male patients with an age range of 5-23 years (mean: 13.42 years). Bronchiectasis (100%) and peribronchial wall thickening (100%) were the most frequent CT abnormalities. Mucus plugging, air trapping and parenchymal involvements were respectively seen in 95.7%, 91.3% and 47.8% of patients. The overall CT score for all patients was 57.6±24.2 (means±SD). The results of pulmonary function test showed a restrictive pattern; however, in 5.3% of the patients PFT was normal. The overall Shwachman-Kulczycki score was 53.48±13.8. There was a significantly (P=0.015) negative correlation between the total CT score and Shwachman-Kulczycki score; however, there was no significant correlation between total CT score and the results of PFT (P=0.481)CONCLUSION: The Brody's scoring system for high resolution computed tomography seems to be a sensitive and efficient method to evaluate the progression of CF, and can be more reliable when we combine the CT scores with clinical parameters.


Using Language Sample Analysis in Clinical Practice: Measures of Grammatical Accuracy for Identifying Language Impairment in Preschool and School-Aged Children.
This article reviews the existing literature on the diagnostic accuracy of two grammatical accuracy measures for differentiating children with and without language impairment (LI) at preschool and early school age based on language samples. The first measure, the finite verb morphology composite (FVMC), is a narrow grammatical measure that computes children's overall accuracy of four verb tense morphemes. The second measure, percent grammatical utterances (PGU), is a broader grammatical measure that computes children's accuracy in producing grammatical utterances. The extant studies show that FVMC demonstrates acceptable (i.e., 80 to 89% accurate) to good (i.e., 90% accurate or higher) diagnostic accuracy for children between 4;0 (years;months) and 6;11 in conversational or narrative samples. In contrast, PGU yields acceptable to good diagnostic accuracy for children between 3;0 and 8;11 regardless of sample types. Given the diagnostic accuracy shown in the literature, we suggest that FVMC and PGU can be used as one piece of evidence for identifying children with LI in assessment when appropriate. However, FVMC or PGU should not be used as therapy goals directly. Instead, when children are low in FVMC or PGU, we suggest that follow-up analyses should be conducted to determine the verb tense morphemes or grammatical structures that children have difficulty with.


Targeting the Structural Maturation Pathway of HIV-1 Reverse Transcriptase.
Formation of active HIV-1 reverse transcriptase (RT) proceeds via a structural maturation process that involves subdomain rearrangements and formation of an asymmetric p66/p66' homodimer. These studies were undertaken to evaluate whether the information about this maturation process can be used to identify small molecule ligands that retard or interfere with the steps involved. We utilized the isolated polymerase domain, p51, rather than p66, since the initial subdomain rearrangements are largely limited to this domain. Target sites at subdomain interfaces were identified and computational analysis used to obtain an initial set of ligands for screening. Chromatographic evaluations of the p51 homodimer/monomer ratio support the feasibility of this approach. Ligands that bind near the interfaces and a ligand that binds directly to a region of the fingers subdomain involved in subunit interface formation were identified, and the interactions were further characterized by NMR spectroscopy and X-ray crystallography. Although these ligands were found to reduce dimer formation, further efforts will be required to obtain ligands with higher binding affinity. In contrast with previous ligand identification studies performed on the RT heterodimer, subunit interface surfaces are solvent-accessible in the p51 and p66 monomers, making these constructs preferable for identification of ligands that directly interfere with dimerization.


Measuring wrist and hand function: common scales and checklists.
A hand and wrist disorder affects a patient's overall well-being and health-status. One concept serves as the foundation for all further consideration: in order to have confidence in your results when assessing patients with wrist and hand limitations, the clinician and researcher must choose standardised patient-oriented instruments that address the primary aims of the study. In this paper, we assess the quality of reviews published on patient oriented instruments in current use for assessing function of the hand and wrist joint. We highlight features of commonly used scales that improve readers' confidence in the choice and application of these outcome instruments. A literature search (1950-January 2010) was performed using the MESH terms: hand (strength, injuries, joints) and wrist (injuries, joint) combined with outcome and process assessment (questionnaires, outcome assessment, health status indicators, quality of life). Titles and abstracts (n=341) were screened by two reviewers independently. The GRADE approach was used to assess the quality of ten reviews and the inclusion of clinimetric properties were assessed using the COSMIN checklist. We included three systematic reviews rated moderate to high (2 hand injury instrument reviews and 1 wrist fracture outcome review). Recommendations of use and an overview are provided for the disability of the arm, shoulder and hand questionnaire (DASH), QuickDASH, the Michigan hand questionnaire (MHQ), the patient-rated wrist hand evaluation outcome questionnaire (PRWHE) and the carpal tunnel questionnaire (CTQ) scales with established measurement properties. The DASH, a region-specific 30-item questionnaire is the most widely tested instrument in patients with wrist and hand injuries. The MHQ can provide good value to patients with hand injuries. Although, the CTQ is the most sensitive to clinical change, the DASH and MHQ have shown to be sufficiently responsive to outcome studies of carpal tunnel syndrome. The PRWHE has a good construct validity and responsiveness, which is only slightly better than the DASH to assess patients with wrist injuries. As the quality of patient-oriented validation continues to increase then the instruments can be selected more carefully. We will then be able to see that the future orthopaedic care of patients with hand and wrist injuries may also improve.


IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy.
Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression. We performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15. Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers. ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.


A body-packer with a cocaine bag stuck in the stomach.
Management of patients carrying packets of drugs in the digestive tract is a frequent medical problem. We report on a patient who was referred by the police after ingestion of packets of cocaine. After spontaneous elimination of 81 drug packets, the patient had three unremarkable stools. A plain abdominal X-ray disclosed no residual packet but computed tomography (CT) scan showed one in the stomach. As this was not eliminated during the 10 d following ingestion, it was removed through gastrotomy. This case stresses the usefulness of the CT scan to ensure that no residual packet is present before hospital discharge.


ID1 facilitates the growth and metastasis of non-small cell lung cancer in response to nicotinic acetylcholine receptor and epidermal growth factor receptor signaling.
Expression of ID1 (inhibitor of differentiation) has been correlated with the progression of a variety of cancers, but little information is available on its role in non-small cell lung cancer (NSCLC). Here we show that ID1 is induced by nicotinic acetylcholine receptor (nAChR) and epidermal growth factor receptor (EGFR) signaling in a panel of NSCLC cell lines and primary cells from the lung. ID1 induction was Src dependent and mediated through the α7 subunit of nAChR; transfection of K-Ras or EGFR to primary cells induced ID1. ID1 depletion prevented nicotine- and EGF-induced proliferation, migration, and invasion of NSCLC cells and angiogenic tubule formation of human microvascular endothelial cells from lungs (HMEC-Ls). ID1 could induce the expression of mesenchymal markers such as vimentin and fibronectin by downregulating ZBP-89, a zinc finger repressor protein. ID1 levels were elevated in tumors from mice that were exposed to nicotine. Further, human lung tissue microarrays (TMAs) showed elevated levels of ID1 in NSCLC samples, with maximal levels in metastatic lung cancers. Quantitative reverse transcription-PCR (RT-PCR) performed on patient lung tumors showed that ID1 levels were elevated in advanced stages of NSCLC and correlated with elevated expression of vimentin and fibronectin, irrespective of smoking history.


Human Gastrointestinal Metabolism of the Cistanches Herba Water Extract in Vitro: Elucidation of the Metabolic Profile Based on Comprehensive Metabolite Identification in Gastric Juice, Intestinal Juice, Human Intestinal Bacteria, and Intestinal Microsomes.
Cistanches Herba is taken orally as a health food supplement and medicinal plant in Asian countries. It consists of the stems of Cistanche deserticola (CD) and Cistanche tubulosa (CT). The gastrointestinal metabolism of the multiple components contained in Cistanches Herba is crucial for the discovery of bioactive constituents. This study aims to elucidate the comprehensive metabolic profile of the Cistanches Herba water extract by simulating human gastrointestinal metabolism in vitro independently and sequentially using four models: gastric juice, intestinal juice, human intestinal bacteria, and human intestinal microsomes. A total of 35 and 18 metabolites were characterized from CD and CT water extracts, respectively. These metabolites were formed through reduction, methylation, dimethylation, deglycosylation, decaffeoyl, derhamnose, dehydrogenation, and glucuronidation. The difference in metabolites of the Cistanches Herba water extract and single compounds and the difference in metabolites of CD and CT water extracts were caused by the oligosaccharides and polysaccharides in Cistanches Herba.


Impact of artificial diets on the biological and chemical properties of red palm weevil, Rhynchophorus Ferrugineus Olivier (Coleoptera:Curculionidae).
One of the most common palm pests is the red palm weevil, Rhynchophorus ferrugineus Olivier. Five artificial diets were evaluated to rear RPW, and to facilitate its behavioral and biological studies. The developmental of R. ferruginus was studied on the tested artificial diets based on primarily composed of sugarcane stem pieces (1st diet; control), sweet pumpkin (2nd diet), ground sugarcane + sweet pumpkin (3rd diet), sweet potato (4th diet) and ground sugarcane + sweet potato (5th diet) under rearing room (28 ± 1 °C and 75 ± 5 RH%) at Faculty of Agriculture in Benha district. The biological aspects, pre-oviposition, oviposition, larval & pupal durations, the longevity of male and female adults and the generation period of R. ferrugineus have all been estimated. Moreover, the impact of these artificial diets on the quantities of total proteins, carbohydrates and lipids were determined in the full-grown larvae. Obtained results showed that the insect manifested the shortest larval and pupal periods and the longest longevity for males and females when rearing of R. ferruginus took place on an artificial diet based on sweet potato as a successful and economical for mass rearing of the red palm weevil under laboratory conditions. Larvae fed on diet 4 (sweet potato) was exhibited the shortest duration (114.80 days), while 1st diet (Sugarcane stem pieces) was recorded the longest period (125.00 ± days). Similarly for pupation and both male and female longevity, the shortest periods resulted from larvae feeding on 4th diet (14.65, 49.40 and 48.0 days, respectively). Contrariwise, the longest pupal period was reported with 5th diet (15.70 days). The highest of eggs hatchability % (96.53%) resulted from the rearing nof R. ferruginus larvae on the 4th diet. Chemical analyses of the full-grown larva were indicated that the highest contents of total carbohydrates (45.57 µg/g), lipids (28.46 µg/g) and proteins (20.01µg/g) were obtained in case of larvae reared on 1st and 4th diets, respectively. Consequently, the development of R. ferruginus stages was slightly lower on both 1st and 4th artificial diets. So that, both of them were a successful and economic artificial diet for RPW development under laboratory conditions. Therefore, this study added valuable alternative ingredients to prepare more practical and economical feeding substrate for weevil rearing to help for proposal of its management and conservation in palm plantations.


Elevated tissue Cr levels, increased plasma oxidative markers, and global hypomethylation of blood DNA in male Sprague-Dawley rats exposed to potassium dichromate in drinking water.
Hexavalent chromium [Cr (VI)] is prevalent in ground water in some areas, but evidence on the toxic effects of Cr (VI) via ingestion through drinking water remains insufficient. The aims of our study were to investigate the toxic effects of Cr (VI) through oral water ingestion on oxidative stress and DNA methylation. Thirty-two Sprague-Dawley rats were randomly divided into four groups, and exposed to porassium dichromate (K2 Cr2 O7 ; 0, 30, 100, and 300 mg/L) in drinking water for 4 weeks. Mean body weight gain, mean water consumption, clinical chemistry determinations, and oxidative stress levels in plasma were measured. Global DNA methylation changes and DNA methylation status at the promoter of p16 gene were also detected. After 4 weeks, mild anemic effects and increased plasma malondialdehyde (MDA) levels occurred in rats exposed to 100 mg/L or 300 mg/L of Cr (VI). Plasma glutathione peroxidase (GSH-Px) activity decreased in all exposed groups. Global DNA methylation levels were reduced in 100 mg/L and 300 mg/L exposure groups. However, DNA methylation status at the promoter of P16 gene remained unchanged in all K2 Cr2 O7- treated groups. The correlation analysis indicated that increased MDA levels were closely correlated to global DNA hypomethylation. Our results indicated that oral ingestion of Cr (VI) through drinking water caused not only oxidative stress in plasma, but also global DNA hypomethylation in blood cells from male rats, and a good correlation was found between increased MDA levels and reduced global DNA methylation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1080-1090, 2016.


A novel type of colistin resistance genes selected from random sequence space.
Antibiotic resistance is a rapidly increasing medical problem that severely limits the success of antibiotic treatments, and the identification of resistance determinants is key for surveillance and control of resistance dissemination. Horizontal transfer is the dominant mechanism for spread of resistance genes between bacteria but little is known about the original emergence of resistance genes. Here, we examined experimentally if random sequences can generate novel antibiotic resistance determinants de novo. By utilizing highly diverse expression libraries encoding random sequences to select for open reading frames that confer resistance to the last-resort antibiotic colistin in Escherichia coli, six de novo colistin resistance conferring peptides (Dcr) were identified. The peptides act via direct interactions with the sensor kinase PmrB (also termed BasS in E. coli), causing an activation of the PmrAB two-component system (TCS), modification of the lipid A domain of lipopolysaccharide and subsequent colistin resistance. This kinase-activation was extended to other TCS by generation of chimeric sensor kinases. Our results demonstrate that peptides with novel activities mediated via specific peptide-protein interactions in the transmembrane domain of a sensory transducer can be selected de novo, suggesting that the origination of such peptides from non-coding regions is conceivable. In addition, we identified a novel class of resistance determinants for a key antibiotic that is used as a last resort treatment for several significant pathogens. The high-level resistance provided at low expression levels, absence of significant growth defects and the functionality of Dcr peptides across different genera suggest that this class of peptides could potentially evolve as bona fide resistance determinants in natura.


Co-evolution of departmental research collaboration and scholarly outcomes.
Understanding scientific collaboration networks can assist research centres to develop strategies to maximize productivity, and help diagnose the causes of low system productivity. The purpose of this study was to use social network analysis to better understand how research collaboration within a productive department impacts scholarly productivity individually and departmentally. Over a 13-year period, departmental faculty completed an annual survey describing their research collaborations and scholarly productivity. Data were analyzed using social network analysis. Quadratic assignment procedure regression assessed the predictive value that an individual's measures of centrality within the network and effective size of their own network (egonet) had each year in predicting each scholarly outcome. Simulation Investigation for Empirical Network Analysis software assessed the co-evolution of the collaborative network and scholarship. While no consistent patterns for individual's presentations were seen, individual's publications were associated with betweenness and eigenvector centrality, and effective egonet size. Grant submissions were associated with degree and eigenvector centrality, as well as effective egonet size. Departmentally, network dynamics depended upon the scholarship of those around you, but none of the forms of scholarship depended upon network characteristics. Of the three forms of scholarship, network dynamics depended primarily on publications in others. Although individual scholarship was dependent upon individual centrality and effective egonet size, research collaboration within the department depended upon reciprocity, transitivity and scholarly productivity of its constituent investigators. Scholarly dynamics, at a departmental level, did not depend upon network characteristics.


Characterization of the mouse ClC-K1/Barttin chloride channel.
Several Cl(-) channels have been described in the native renal tubule, but their correspondence with ClC-K1 and ClC-K2 channels (orthologs of human ClC-Ka and ClC-Kb), which play a major role in transcellular Cl(-) absorption in the kidney, has yet to be established. This is partly because investigation of heterologous expression has involved rat or human ClC-K models, whereas characterization of the native renal tubule has been done in mice. Here, we investigate the electrophysiological properties of mouse ClC-K1 channels heterologously expressed in Xenopus laevis oocytes and in HEK293 cells with or without their accessory Barttin subunit. Current amplitudes and plasma membrane insertion of mouse ClC-K1 were enhanced by Barttin. External basic pH or elevated calcium stimulated currents followed the anion permeability sequence Cl(-)>Br(-)>NO3(-)>I(-). Single-channel recordings revealed a unit conductance of ~40pS. Channel activity in cell-attached patches increased with membrane depolarization (voltage for half-maximal activation: ~-65mV). Insertion of the V166E mutation, which introduces a glutamate in mouse ClC-K1, which is crucial for channel gating, reduced the unit conductance to ~20pS. This mutation shifted the depolarizing voltage for half-maximal channel activation to ~+25mV. The unit conductance and voltage dependence of wild-type and V166E ClC-K1 were not affected by Barttin. Owing to their strikingly similar properties, we propose that the ClC-K1/Barttin complex is the molecular substrate of a chloride channel previously detected in the mouse thick ascending limb (Paulais et al., J Membr. Biol, 1990, 113:253-260).


Are "goods for guns" good for the community? An update of a community gun buyback program.
Gun violence remains a leading cause of death in the United States. Community gun buyback programs provide an opportunity to dispose of extraneous firearms. The purpose of this study was to understand the demographics, motivation, child access to firearms, and household mental illness of buyback participants in hopes of improving the program's effectiveness. A 2015 Injury Free Coalition for Kids gun buyback program which collaborated with local police departments was studied. We administered a 23-item questionnaire survey to gun buyback participants assessing demographic characteristics, motivation for relinquishing firearms, child firearm accessibility, and mental illness/domestic violence history. A total of 186 individuals from Central/Western Massachusetts turned in 339 weapons. Participants received between US $25 and US $75 in gift cards dependent on what type of gun was turned in, with an average cost of $41/gun. A total of 109 (59%) participants completed the survey. Respondents were mostly white (99%), men (90%) and first-time participants in the program (85.2%). Among survey respondents, 54% turned in firearms "for safety reasons." Respondents reported no longer needing/wanting their weapons (47%) and approximately one in eight participants were concerned the firearm(s) were accessible to children. Most respondents (87%) felt the program encouraged neighborhood awareness of firearm safety. Three of every five participants reported that guns still remained in their homes; additionally, 21% where children could potentially access them and 14% with a history of mental illness/suicide/domestic violence in the home. Gun buybacks can provide a low-cost means of removing unwanted firearms from the community. Most participants felt their homes were safer after turning in the firearm(s). In homes still possessing guns, emphasis on secure gun storage should continue, increasing the safety of children and families. The results of this survey also provided new insights into the association between mental illness/suicide and gun ownership. Epidemiological, level III.


Morphological and Functional Imaging for Detecting and Assessing the Resectability of Neuroendocrine Liver Metastases.
This review evaluates the diagnostic efficacy of different morphological and functional imaging modalities (ultrasound [US], computed tomography [CT], magnetic resonance [MR] imaging, scintigraphy, and positron emission tomography [PET]) in detecting neuroendocrine liver metastases (NELM), assessing vascular and biliary involvement, and the presence of extrahepatic disease. MR imaging is superior for depicting NELM compared to US, CT, and somatostatin receptor scintigraphy. Diffusion-weighted MR imaging is more sensitive for detecting NELM than both T2-weighted and dynamic gadolinium-enhanced MR sequences, and should be systematically performed. Similarly, gadoxetic acid-enhanced MR imaging is more sensitive for detecting liver metastases than conventional extracellular gadolinium chelate-enhanced MR sequences. Its role in detecting NELM remains investigational but appears promising. Somatostatin receptor-targeted PET/CT is a highly effective approach in assessing the resectability of well-differentiated NELM due to very high specificity (and high sensitivity) and its ability to detect small volume extrahepatic disease; this molecular imaging modality is becoming increasingly available in and outside Europe after the recent approval of 6868-DOTATATE in the US. In addition, the information from multiphase, contrast-enhanced CT with 3D reconstruction - obtained concurrently with the information on somatostatin receptor expression of the metastases - is very helpful in planning the extent and type of resection of NELM.


Variability in training Experience during orthopaedic surgery post-graduate year-1.
This article was migrated. The article was marked as recommended. Background: Recently, the orthopaedic surgery PGY-1 curriculum was redesigned to maximize time spent on orthopaedic surgery rotations. Additionally, surgical skills modules were introduced to standardize curricula for orthopaedic interns in the United States. Objective: The purpose of this study is to determine the implementation of the curriculum guidelines were implemented on a national level. Methods: An anonymous survey with 14 multiple choice questions was electronically distributed to program directors (PDs) for all ACGME-accredited orthopaedic surgery residency programs in the US (n=163) in January 2017. Seventy-nine of the 162 PDs (49%) completed the survey in its entirety. Results: The most common non-orthopaedic rotations included: general surgery trauma (67/79=85%), surgical/medical intensive care unit (60/79=76%), plastic and burn surgery (56/79=71%), musculoskeletal radiology (44/79=56%), and vascular surgery (40/79=51%). Seventy-two of 162 residency programs (91%) have a formal surgical skills curriculum for first-year residents, separate from intern boot camp. A variety of training modalities were utilized to teach the interns, most commonly saw bones for fracture fixation (68/79=86%) and cadaveric specimens for surgical approaches (63.79=80%). Conclusions: While all PGY-1 orthopaedic residents are now required to spend six months on orthopaedic rotations, the remaining six months are variable. These non-orthopaedic rotations are likely determined by the PD and available services at the trainee's institution. This variability has granted PDs the opportunity to individualize the intern experience by maximizing each institution's assets and designing their own surgical skill curriculum to train their interns using the resources available.


Extension of the renormalized coupled-cluster methods exploiting left eigenstates of the similarity-transformed hamiltonian to open-shell systems: a benchmark study.
The recently formulated completely renormalized coupled-cluster method with singles, doubles, and noniterative triples, exploiting the biorthogonal form of the method of moments of coupled-cluster equations (Piecuch, P.; Włoch, M. J. Chem. Phys. 2005, 123, 224105; Piecuch, P.; Włoch, M.; Gour, J. R.; Kinal, A. Chem. Phys. Lett. 2006, 418, 467), termed CR-CC(2,3), is extended to open-shell systems. Test calculations for bond breaking in the OH radical and the F2+ ion and singlet-triplet gaps in the CH2, HHeH, and (HFH)- biradical systems indicate that the CR-CC(2,3) approach employing the restricted open-shell Hartree--Fock (ROHF) reference is significantly more accurate than the widely used CCSD(T) method and other noniterative triples coupled-cluster approximations without making the calculations substantially more expensive. A few molecular examples, including the activation energies of the C2H4 + H --> C2H5 forward and reverse reactions and the triplet states of the CH2 and H2Si2O2 biradicals, are used to show that the dependence of the ROHF-based CR-CC(2,3) energies on the method of canonicalization of the ROHF orbitals is, for all practical purposes, negligible.


Wax ester production in nitrogen-rich conditions by metabolically engineered Acinetobacter baylyi ADP1.
Metabolic engineering can be used as a powerful tool to redirect cell resources towards product synthesis, also in conditions that are not optimal for the production. An example of synthesis strongly dependent on external conditions is the production of storage lipids, which typically requires a high carbon/nitrogen ratio. This requirement also limits the use of abundant nitrogen-rich materials, such as industrial protein by-products, as substrates for lipid production. Acinetobacter baylyi ADP1 is known for its ability to produce industrially interesting storage lipids, namely wax esters (WEs). Here, we engineered A. baylyi ADP1 by deleting the gene aceA encoding for isocitrate lyase and overexpressing fatty acyl-CoA reductase Acr1 in the wax ester production pathway to allow redirection of carbon towards WEs. This strategy led to 3-fold improvement in yield (0.075 g/g glucose) and 3.15-fold improvement in titer (1.82 g/L) and productivity (0.038 g/L/h) by a simple one-stage batch cultivation with glucose as carbon source. The engineered strain accumulated up to 27% WEs of cell dry weight. The titer and cellular WE content are the highest reported to date among microbes. We further showed that the engineering strategy alleviated the inherent requirement for high carbon/nitrogen ratio and demonstrated the production of wax esters using nitrogen-rich substrates including casamino acids, yeast extract, and baker's yeast hydrolysate, which support biomass production but not WE production in wild-type cells. The study demonstrates the power of metabolic engineering in overcoming natural limitations in the production of storage lipids.


Supercritical fluid extracts of rosemary leaves exhibit potent anti-inflammation and anti-tumor effects.
Supercritical fluid SF-CO2 treatment of Rosemarinus officinalis L. fresh leaves under optimum conditions (80 degrees C at 5,000 psi) yielded 5.3% of extract supercritical fluid extraction (SFE)-80, in which five major active principles were identified by liquid chromatography/mass spectrometry (LC/MS), viz., rosmarinic acid, carnosol, 12-methoxycarnosic acid, carnosic acid, and methyl carnosate. Total phenolic content was 155.8 mg/ gallic acid equivalent (GAE)/g in SFE-80, which showed 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging of 81.86% at 0.01 mg/ml. When treated in RAW 264.7, apparent dose-dependent NO inhibition occurred at dosages of 1.56 to 6.25 microg/ml, and more drastically at 12.5 and 25 microg/ml. At 0.5 to 5.0 microg/ml, SFE-80 exhibited dose-dependent viability suppression and significant tumor necrosis factor alpha (TNF-alpha) production in Hep 3B, whereas no effect was found in Chang liver cells. Furthermore, no effect was observed in RAW 264.7 at dosages of 3.13 to 25 microg/ml, indicating that SFE-80 exhibited a noncytotoxic character. Conclusively, rosemary can be considered an herbal anti-inflammatory and anti-tumor agent.


Biosynthesis and secretion of procollagenase by rabbit synovial fibroblasts. Inhibition of procollagenase secretion by monensin and evidence for glycosylation of procollagenase.
Monolayer cultures of rabbit synovial fibroblasts stimulated with phorbol myristate acetate to produce large amounts of collagenase (EC 22.214.171.124) were used to study the biosynthesis and secretion of this enzyme. [3H]Leucine was added to cell cultures for pulse-chase and continuous-labelling experiments. The labelled procollagenase synthesized was identified by immunoprecipitation followed by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and fluorography. The amounts of intracellular and extracellular proenzyme were quantified by measuring radioactivity incorporated into the proteins. procollagenase was synthesized as doublet proteins of Mr 57 000 and Mr 61 000. Immunoprecipitable proenzyme proteins were first detected in culture medium 35 min after [3H]leucine was added to the cells. Monensin treatment of the cells inhibited procollagenase secretion and led to intracellular accumulation of the proenzyme. Cells treated with tunicamycin produced only the 57 000-Mr form, indicating that in rabbit synovial cells the 61 000-Mr form was post-translationally modified by addition of oligosaccharides to asparagine residues. The ratios of glycosylated to unglycosylated forms in cell lysates and in culture medium were 0.22:1 and 0.07:1 respectively.


Characterization of a novel class of antimalarials and its applicability to plasmodial target identification.
Candidate drugs related to the lead compound propafenone are highly effective inhibitors of P. falciparum growth with 50% inhibitory concentrations (IC(50)s) in the sub-micromolar range. The parental compound propafenone is a cardiac sodium channel blocker which is in clinical use for the treatment of ventricular arrhythmia. An in house library of more than 400 compounds with systematically varied structures is available for 2D and 3D quantitative structure activity relationship studies. In a first step selected compounds were evaluated for their antimalarial activity using the histidine-rich protein 2 drug sensitivity assay. Propafenone analogues contain an inherently photoactive aryl-carbonyl substructure, which allows their use in photolabeling studies. Labelling efficiency is increased for compounds in which the phenylpropiophenone core structure is replaced by a benzophenone substructure. However, the phenylpropiophenone substructure represents part of the pharmacophore of the compounds. Benzophenone-type analogues show IC(50) values that are higher than their congeneric phenylpropiophenones. Nevertheless, one of the photoligands shows an IC(50) value in the low micro-molar range. Use of this photoligand is thus expected to allow identification of candidate targets by mass spectrometry following two dimensional separation of the plasmodial proteome. The Malaria Genome Project has advanced our understanding of parasite biology and development of novel drugs can mount on data made available by the recently completed sequencing effort of P. falciparum. The lead compound propafenone is a registered drug and this compound class might therefore have a major potential as an antimalarial drug, either alone, or in combination with conventional antimalarials.


[Effect of ruthenium red on the induction by Ca2+ ions of the beta- and gamma states of comuton regulation of mitochondrial respiration and oxidative phosphorylation].
Preincubation of liver mitochondria (Mch) with Ca2+ ions at inorganic phosphate concentration less than I mM in the presence of liver cell soluble phase (CSP) induced rotenone-independent tissue-specific uncoupling of oxidative phosphorylation (beta state of comuton regulation) and rotenone-stimulated tissue-specific uncoupling (gamma state of comuton regulation). The reduction in K+ ion concentration in the incubation medium entirely inhibited the induction of beta state. Tissue-specific stimulation of the rat liver Mch respiration in substrate-containing medium was increased after rotenone addition. Ruthenium red was added to the medium before and after the end of Mch preincubation with Ca2+ in the presence of CSP. The results suggest that limited Ca2+ transport in Mch is necessary for the induction of beta and gamma states of comuton regulation. Ca2+ ejected from Mch also participates in the induction of beta state of comuton regulation. Comuton receptor on the mitochondrial membrane surface is devoid of glyco- and mucoprotein components bound by ruthenium red.


Ranking the Meso Level Critical Factors of Electronic Medical Records Adoption Using Fuzzy Topsis Method.
As Electronic Medical Records (EMRs) have a great possibility for rising physician's performance in their daily work which improves quality, safety and efficiency in healthcare, they are implemented throughout the world (Boonstra and Broekhuis, 2010). In physician practices the rate of EMRs adoption has been slow and restricted (around 25%) according to Endsley, Baker, Kershner, and Curtin (2005) in spite of the cost savings through lower administrative costs and medical errors related with EMRs systems. The core objective of this research is to identify, categorize, and analyse meso-level factors introduced by Lau et al, 2012, perceived by physicians to the adoption of EMRs in order to give more knowledge in primary care setting. Finding was extracted through questionnaire which distributed to 350 physicians in primary cares in Malaysia to assess their perception towards EMRs adoption. The findings showed that Physicians had positive perception towards some features related to technology adoption success and emphasized EMRs had helpful impact in their office. The fuzzy TOPSIS physician EMRs adoption model in meso-level developed and its factors and sub-factors discussed in this study which provide making sense of EMRs adoption. The related factors based on meso-level perspective prioritized and ranked by using the fuzzy TOPSIS. The purpose of ranking using these approaches is to inspect which factors are more imperative in EMRs adoption among primary care physicians. The result of performing fuzzy TOPSIS is as a novelty method to identify the critical factors which assist healthcare organizations to inspire their users in accepting of new technology.


[Regulation of germline stem cells: the niche expands in Drosophila].
Our fascination for stem cells originates from their ability to divide asymmetrically in order to self-renew and produce daughter cells which can differentiate and replenish tissues. Stem cells could thus represent an unlimited source of differentiated cells that could be used to repair malformed, damaged or ageing tissues. Understanding how their behaviour is regulated is then of paramount medical interest. Specific microenvironments surrounding the stem cells, termed "niches", were proposed to play a major role in the balance between self-renewal and differentiation. However, it is only recently, in the case of the stem cells producing the germline (GSGs) in Drosophila, that the cells and signals creating a niche were identified for the first time. Here, we review how this niche has been defined at the cellular and functional levels in vivo, thanks to the powerful genetic tools available in Drosophila. Such studies have revealed adhesive interactions, cell-cycle modifications and intercellular signals that control the GSC behavior. Extracellular signals from the niche activate the BMP or JAK-STAT pathways in the GSCs and are necessary for their maintenance. Strikingly, both signaling pathways are also sufficient to convert differentiated germ cells into functional GSCs, demonstrating in vivo that a niche has the capacity to regenerate stem cells from differentiated cells. Rapid progresses have further identified direct links between these signaling pathways and the transcriptional regulation of the GSCs, providing a simple paradigm for stem cells regulation. Many of these features and signals are conserved in stem cells niches from Drosophila to mammals. We can thus hope that research on the GSCs in Drosophila will benefit therapeutic approaches to human degenerative diseases.


Intestinal necrosis and perforation after renal transplantation.
An acute intestinal disorder occurred in seven patients soon after renal transplantation. The disorder was characterized initially by massive abdominal distention with progression to multiple bowel perforations in three patients and extensive bowel necrosis in two. Surgical manipulation did not appear to be the cause since the transplants were performed retroperitoneally in the iliac fossa. Ischemia also was not a factor since the mesenteric vessels were patent with no evidence of thrombus formation or vasculitis. The cause appeared to be related to immunosuppressive agents, in particular, high doses of corticosteroids. The disease process appeared to be reversible if immunosuppression was discontinued early, as occurred in two patients.


[Comorbidity of diabetes mellitus and eating disorders. A comparison of psychological features of eating disordered and non-eating disordered patients with diabetes mellitus].
As part of a multicentre study on the comorbidity of diabetes mellitus and eating disorders, the following paper compares the psychological features of diabetic patients with and without an eating disorder. In a sample of 663 diabetic patients (type 1: n = 341 type 2: n = 322), eating disorder related variables, self-esteem, body acceptance and emotional distress, especially depression in diabetic patients with and without an eating disorder, were compared. A possible relationship to diabetic control was investigated. Type 2 diabetics revealed more pronounced psychopathology in comparison to type 1 diabetics. According to our assumption, diabetic patients with an eating disorder and diabetic patients who deliberately reduced insulin in order to loose weight (insulin purging) revealed a much more severe psychopathology compared to diabetics without an eating disorder. The type of diabetes was of no importance. With the exception of the variable body and figure satisfaction in the sample of type 1 diabetes and the variable self-acceptance in the sample of type 2 diabetes, no relationship to diabetic control could be found.


BAC contig from a 3-cM region of mouse chromosome 11 surrounding Brca1.
Even with the completion of a draft version of the human genome sequence only a fraction of the genes identified from this sequence have known functions. Chromosomal engineering in mouse cells, in concert with gene replacement assays to prove the functional significance of a given genomic region or gene, represents a rapid and productive means for understanding the role of a given set of genes. Both techniques rely heavily on detailed maps of chromosomal regions, initially to understand the scope of the regions being modified and finally to provide the cloned resources necessary to allow both finished sequencing and large insert complementation. This report describes the creation of a BAC clone contig on mouse chromosome 11 in a region showing conservation of synteny with sequences on human chromosome 17. We have created a detailed map of an approximately 3-cM region containing at least 33 genes through the use of multiple BAC mapping strategies, including chromosome walking and multiplex oligonucleotide hybridization and gap filling. The region described is one of the targets of a large effort to create a series of mice with regional deletions on mouse chromosome 11 (33-80 cM) that can subsequently be subjected to further mutagenesis.


Cost-effectiveness analysis of postoperative surveillance protocols following radical surgery for colorectal cancer.
Up to 30-50% of patients who undergo radical surgery for colorectal cancer (CRC) develop tumor relapse. The aim of this study was to assess various surveillance protocols utilized in a tertiary referral hospital in Northern Italy. Data concerning 373 consecutive patients who underwent radical surgery for CRC between 1990 and 2006 and whose data had been entered into a prospective database were considered eligible for this study. The overall costs and the percentages of recurrence following the various surveillance protocols were calculated. One hundred two (27.35%) of the patients suffered a recurrence after a mean of 17.6 (95% CI 13.9-21.1) months. The combination of physical examination, colonoscopy, thorax-abdominal computed tomography (CT) scan, and serum carcinoembryonic antigen (CEA) dosage was found to be the most cost/effective one to monitor stages I and II colon cancer; while physical examination, rigid sigmoidoscopy, thorax-abdominal CT scan, and serum CEA dosage were found to be the most cost/effective surveillance to monitor stages III and IV of colon cancer and rectal cancer. Adherence to follow-up guidelines and early detection are vital factors affecting the curability of relapsed cancer in CRC patients who undergo surgery. The first five years after surgery was found to be the most risky period for recurrence. Cost/effectiveness analysis indicate that follow-up protocols should be tailored to the risk of recurrence with the aim of identifying relapse when the disease is at an asymptomatic, presumably more curable stage.


Fluoroscopy-guided implantation of subacromial "biodegradable spacer" using local anesthesia in patients with irreparable rotator cuff tear.
Treatment of massive rotator cuff tears can be challenging, especially when tears are considered irreparable or, when repaired, at significant risk of retear. A surgical technique is described using a biodegradable subacromial balloon-shaped spacer (InSpace; Ortho-Space, Caesarea, Israel) that, when implanted between the humeral head and acromion, permits smooth, frictionless gliding, supporting shoulder biomechanics. The specific insertion technique described herein is a simple procedure that can be performed in a day-care or outpatient setting with patients under local anesthesia, thus providing a treatment option for patients with multiple comorbidities complicating or contraindicating surgery, such as reverse arthroplasty under general anesthesia.


Oral fibroblasts rescue osteogenic differentiation of mesenchymal stem cells after exposure to Zoledronic acid in a paracrine effect.
Background: Medication-related osteonecrosis of the jaw is a serious complication that develops in oncologic patients treated with Zoledronic acid. Although used for over 30 years, the influence of Zoledronic acid on bone has been thoroughly investigated, mainly on osteoclasts. While decreasing osteoclast differentiation and function, for many years it was thought that Zoledronic acid increased osteoblast differentiation, thus increasing bone volume. Moreover, despite the influence of soft tissue on the bone healing process, the impact of zoledronic acid on the interaction between soft tissue and bone was not investigated. Aim: Our goal was to investigate the influence of Zoledronic Acid and soft tissue cells on osteogenic differentiation of mesenchymal stem cells (MSCs). Materials and methods: Osteogenic differentiation of MSCs was examined after exposure to Zoledronic Acid. To determine the influence of soft tissue cells on MSCs' osteogenic differentiation, conditioned media from keratinocytes and oral fibroblasts were added to osteogenic medium supplemented with Zoledronic Acid. Proteomic composition of keratinocytes' and fibroblasts' conditioned media were analyzed. Results: Zoledronic Acid decreased osteogenic differentiation of MSCs by seven-fold. The osteogenic differentiation of MSCs was restored by the supplementation of fibroblasts' conditioned medium to osteogenic medium, despite Zoledronic acid treatment. Five osteogenic proteins involved in the TGFβ pathway were exclusively identified in fibroblasts' conditioned medium, suggesting their role in the rescue effect. Conclusion: Oral fibroblasts secrete proteins that enable osteogenic differentiation of MSCs in the presence of Zoledronic Acid.


Are We Using the Best Tumor Size Cut-points for Renal Cell Carcinoma Staging?
To compare the predictive ability for oncologic outcomes among current tumor size cut-points and clinically relevant alternatives to determine which are optimal. Patients who underwent radical or partial nephrectomy between 1970 and 2010 for T1-2Nx/N0M0 renal cell carcinoma (RCC) were identified. Associations between tumor size and progression-free survival (PFS) and cancer-specific survival (CSS) were evaluated using Kaplan-Meier analyses and Cox models. Predictive ability was assessed using c-indexes. The cohort included 3304 patients with a median age of 63 years (interquartile range 53, 70). Median follow-up among survivors was 9.9 years (interquartile range 6.9, 14.3). There were 536 patients who progressed and 354 who died from RCC. For RCC tumors ≤3.0 cm, 10-year PFS and CSS rates were 93%-95% and 97%-99%, respectively. For tumors >3.0-4.0 cm, PFS and CSS began to decline (91% and 95%, respectively), with further gradual declines in PFS and CSS with increasing tumor size. Plots of hazard ratios for progression and RCC death as a function of tumor size did not reveal major inflection points. Differences in discrimination based on various combinations of tumor-size cut-points for progression or RCC death were small, with c-indexes ranging between 0.691-0.704 and 0.734-0.750, respectively. RCC tumors ≤3.0 cm in size are associated with favorable outcomes. Thereafter, risks of progression and RCC death increase gradually with tumor size, with no compelling biological reason to endorse a given cut-point over another.


Impact of regional analgesia techniques on the long-term clinical outcomes following thoracic surgery.
Continuous monitoring of clinical outcomes after thoracotomy is very important to improve medical services and to reduce complications. The use of regional analgesia techniques for thoracotomy offers several advantages in the perioperative period including effective pain control, reduced opioid consumption and associated side effects, enhanced recovery, and improved patient satisfaction. Postthoracotomy complications, such as chronic postthoracotomy pain syndrome, postthoracotomy ipsilateral shoulder pain, pulmonary complications, recurrence, and unplanned admission to the intensive care unit are frequent and may be associated with poor outcomes and mortality. The role of regional techniques to reduce the incidence of these complications is questionable. This narrative review aims to investigate the impact of regional analgesia on the long-term clinical outcomes after thoracotomy.


Relaxation as a cognitive task.
In the present experiment the instruction to relax was given to awake highly (Highs) and non hypnotizable subjects (Lows), while their heart rate, respirogram and skin resistance were recorded together with electroencephalogram, electroculogram and corrugator electromiogram. At the beginning of the experiment, Highs exhibited no significant difference in heart rate (HR), respiratory frequency (RF) and heart rate variability (HRV) with respect to Lows, but showed a higher EEG alpha and theta1 power. During the session, both groups decreased their heart rate, but changes were significant only in Lows, which increased significantly also the parasympathetic component of their HRV (high frequency, HF). In both groups, EEG showed alpha, beta2 and theta2 power decrements; theta1 activity decreased only in Lows, while gamma power increased in Highs and decreased in Lows. Results suggest that Highs and Lows used different cognitive strategies in the elaboration of the relaxation request and that Highs performed the task through a higher integrative activity.


Contributing factors to the plasma albumin level at diagnosis of hematological malignancy.
Many factors contribute to the plasma albumin (PA) level. We aimed to quantify different factors' relative contribution to the PA level when diagnosing hematological malignancy (HM). The study was a population-based registry study including patients with HM in a Danish region. We applied multivariate linear regression analyses with C-reactive protein (CRP), WHO performance score (WHO-PS), age, sex, comorbidity, and HM type as exposures and the PA level on the day of the HM diagnosis (DX) as the outcome. The relative contribution of each exposure was determined as a percentage of the models' coefficient of determination (R2). In total, 2528 patients with HM had PA measured on DX. In the model comprising all exposures, CRP contributed with 65.8% to the R2 of 0.389 whereas 3 variables (CRP, WHO-PS, HM type) together contributed with 96.1%. When CRP was excluded from the model, R2 declined to 0.215 and the WHO-PS contributed with 96%. Other models, including separate analyses for each HM type, corroborated these results, except in myeloma patients where WHO-PS contributed with 61.1% to the R2 of 0.234. The inflammation biomarker CRP was the main predictor of the PA level on DX. The WHO-PS also contributed to the PA level on DX whereas the remaining factors (HM type, age, sex, and comorbidity) were of much less importance.


Direct Streptococcus pneumoniae real-time PCR serotyping from pediatric parapneumonic effusions.
To determine the serotypes of Streptococcus pneumoniae responsible for pneumonia complicated by parapneumonic effusion in children, we performed real-time PCR based pneumococcal "serotyping" directly on parapneumonic fluid samples. Specimens were collected at two children's hospitals in Ontario, Canada from 2009 to 2011. Samples in which S. pneumoniae was detected by PCR were tested with serotype-specific 5'exonuclease PCR assays for the 13 serotypes contained in the 13-serotype pneumococcal vaccine. Thirty-five S. pneumoniae PCR-positive pleural samples were studied. Pneumococcal serotyping PCR assays were positive for 34 of 35 (97%). Serotype 3 was detected most frequently, in 19/35 (54%), followed by serotype 19A in 9/35 (26%), serotype 7 F/A in 4/35 (11%), serotype 1 in 1/35 (3%), and serotype 6A also in 1/35 (3%). PCR testing demonstrated that the vast majority (97%) of S. pneumoniae parapneumonic effusions were caused by serotypes present in the 13-serotype vaccine that were not present in the original 7 serotype vaccine. This suggests that use of the 13-serotype vaccine could potentially prevent many S. pneumoniae pneumonias complicated by parapneumonic effusion in our region, provided serotype replacement does not occur.


Association between bone turnover rate and bone microarchitecture in men: the STRAMBO study.
Few data concern the relationship between bone turnover and microarchitecture in men. We investigated the association between levels of biochemical markers of bone turnover (BTM) and bone microarchitecture in 1149 men aged 19 to 85 years. Bone microarchitecture was assessed by high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Bone formation was assessed by serum osteocalcin, bone alkaline phosphatase, and N-terminal extension propeptide of type I collagen. Bone resorption was assessed by serum C-terminal telopeptide of type I collagen and urinary excretion of total deoxypyridinoline. BTM levels were high in young men and decreased until age 50 years. Urinary deoxypyridinoline (DPD) increased after age 70 years, whereas other BTMs remained stable. Before 50 years of age, only cortical volumetric bone mineral density (D(cort)) correlated negatively with BTM levels. Between 50 and 70 years of age, D(cort) and some microarchitectural parameters correlated significantly with BTM at the radius and tibia. After 70 years of age, higher BTM levels were associated with lower cortical thickness and D(cort) at both the skeletal sites. At the distal radius, men in the highest BTM quartile had lower trabecular density, number (Tb.N), and thickness (Tb.Th) and more heterogeneous trabecular distribution compared with men in the lower quartiles. At the distal tibia, higher BTM levels were associated with lower Tb.N and Tb.Th in the central but not subendocortical area. Thus, in men, bone microarchitecture depends weakly on the current bone turnover rate until age 70. Thereafter, bone turnover seems to be a significant determinant of bone microarchitecture.


Density-dependent predation influences the evolution and behavior of masquerading prey.
Predation is a fundamental process in the interaction between species, and exerts strong selection pressure. Hence, anti-predatory traits have been intensively studied. Although it has long been speculated that individuals of some species gain protection from predators by sometimes almost-uncanny resemblances to uninteresting objects in the local environment (such as twigs or stones), demonstration of antipredatory benefits to such "masquerade" have only very recently been demonstrated, and the fundamental workings of this defensive strategy remain unclear. Here we use laboratory experiments with avian predators and twig-mimicking caterpillars as masqueraders to investigate (i) the evolutionary dynamics of masquerade; and (ii) the behavioral adaptations associated with masquerade. We show that the benefit of masquerade declines as the local density of masqueraders relative to their models (twigs, in our system) increases. This occurs through two separate mechanisms: increasing model density both decreased predators' motivation to search for masqueraders, and made masqueraders more difficult to detect. We further demonstrated that masquerading organisms have evolved complex microhabitat selection strategies that allow them to best exploit the density-dependent properties of masquerade. Our results strongly suggest the existence of opportunity costs associated with masquerade. Careful evaluation of such costs will be vital to the development of a fuller understanding of both the distribution of masquerade across taxa and ecosystems, and the evolution of the life history strategies of masquerading prey.


Vein patterning by tissue-specific auxin transport.
Unlike in animals, in plants, vein patterning does not rely on direct cell-cell interaction and cell migration; instead, it depends on the transport of the plant hormone auxin, which in turn depends on the activity of the PIN-FORMED1 (PIN1) auxin transporter. The current hypotheses of vein patterning by auxin transport propose that, in the epidermis of the developing leaf, PIN1-mediated auxin transport converges to peaks of auxin level. From those convergence points of epidermal PIN1 polarity, auxin would be transported in the inner tissues where it would give rise to major veins. Here, we have tested predictions of this hypothesis and have found them unsupported: epidermal PIN1 expression is neither required nor sufficient for auxin transport-dependent vein patterning, whereas inner-tissue PIN1 expression turns out to be both required and sufficient for auxin transport-dependent vein patterning. Our results refute all vein patterning hypotheses based on auxin transport from the epidermis and suggest alternatives for future tests.


[Occupational safety of cleaning personnel in Palestinian district hospitals].
This study examined occupational safety among cleaning workers in Palestinian hospitals and its relation with the medical waste management in these hospitals. The level of occupational safety was below standard requirements, as protective equipment and clothes are not available for most workers. Over 40% of workers had been pricked with needles while handling medical waste. There was no clear policy for vaccination of workers against infectious diseases and no medical examination for workers before or during employment. Only 37.2% were trained in handling medical waste and 23.2% were working 15 hours per day or more; 55.8% had spent 1 year or less in their work.


The reliability and validity of the Chinese version of the Dysfunctional Attitudes Scale Form A (DAS-A) in a community sample.
This study investigated the reliability and validity of the DAS-A in a sample of 308 Chinese adults in Hong Kong. The reliability of the DAS-A and its relevant sub-scales was measured using internal consistency (Cronbach's alpha) and Guttman split-half reliability. Principal components analysis was performed to assess construct validity. Discriminant validity of the DAS-A was performed by examining whether the DAS-A could discriminate between the depressed and the non-depressed subjects in this study. The split-half reliability of the DAS-A was found to be r = 0.87; Cronbach's alpha was 0.945; and item-total correlations ranged between 0.36 and 0.75. Factor analysis revealed three factors that were similar to those that were found in other studies: Performance Evaluation, Need for Approval, and Anaclitic Self-Esteem. Discriminant validity suggested that the DAS-A discriminated successfully between the non-depressed and the depressed groups. Nevertheless, some differences were noticed in the relative strength of the factors and in the distribution of the scale items into the three factors. It was hoped that with this type of cross-cultural information, the universality of the constructs of the DAS-A could be reliably demonstrated.


Mechanochemical Signaling Directs Cell-Shape Change.
For specialized cell function, as well as active cell behaviors such as division, migration, and tissue development, cells must undergo dynamic changes in shape. To complete these processes, cells integrate chemical and mechanical signals to direct force production. This mechanochemical integration allows for the rapid production and adaptation of leading-edge machinery in migrating cells, the invasion of one cell into another during cell-cell fusion, and the force-feedback loops that ensure robust cytokinesis. A quantitative understanding of cell mechanics coupled with protein dynamics has allowed us to account for furrow ingression during cytokinesis, a model cell-shape-change process. At the core of cell-shape changes is the ability of the cell's machinery to sense mechanical forces and tune the force-generating machinery as needed. Force-sensitive cytoskeletal proteins, including myosin II motors and actin cross-linkers such as α-actinin and filamin, accumulate in response to internally generated and externally imposed mechanical stresses, endowing the cell with the ability to discern and respond to mechanical cues. The physical theory behind how these proteins display mechanosensitive accumulation has allowed us to predict paralog-specific behaviors of different cross-linking proteins and identify a zone of optimal actin-binding affinity that allows for mechanical stress-induced protein accumulation. These molecular mechanisms coupled with the mechanical feedback systems ensure robust shape changes, but if they go awry, they are poised to promote disease states such as cancer cell metastasis and loss of tissue integrity.


New Data on Dinosaurs of the Crimean Peninsula.
Reexamination of the holotype of Riabininohadros weberae from the Upper Cretaceous (upper Maastrichtian) of the Crimean Peninsula (Besh-Kosh) allowed determination of previously unknown elements of the femur, astragalus, and calcaneus. This taxon shows a set of primitive characters observed in iguanodontids and basal ornithischians and is referred to as Styracosterna indet. The second dinosaur specimen from Crimea (Aleshino) is a fragmentary skeleton, including cervical and dorsal vertebrae. It possibly belongs to advanced iguanodontids or primitive hadrosauroids. Thus, in the Maastrichtian of the Crimean Peninsula, at least two dinosaur species coexisted.


Transplanted human cones incorporate into the retina and function in a murine cone degeneration model.
Once human photoreceptors die, they do not regenerate, thus, photoreceptor transplantation has emerged as a potential treatment approach for blinding diseases. Improvements in transplant organization, donor cell maturation, and synaptic connectivity to the host will be critical in advancing this technology for use in clinical practice. Unlike the unstructured grafts of prior cell-suspension transplantations into end-stage degeneration models, we describe the extensive incorporation of induced pluripotent stem cell (iPSC) retinal organoid-derived human photoreceptors into mice with cone dysfunction. This incorporative phenotype was validated in both cone-only as well as pan-photoreceptor transplantations. Rather than forming a glial barrier, Müller cells extended throughout the graft, even forming a series of adherens junctions between mouse and human cells, reminiscent of an outer limiting membrane. Donor-host interaction appeared to promote polarization as well as the development of morphological features critical for light detection, namely the formation of inner and well-stacked outer segments oriented toward the retinal pigment epithelium. Putative synapse formation and graft function were evident at both structural and electrophysiological levels. Overall, these results show that human photoreceptors interacted readily with a partially degenerated retina. Moreover, incorporation into the host retina appeared to be beneficial to graft maturation, polarization, and function.


Total electrification of large-scale nanophotonic arrays by frictional charges.
Localized surface plasmon resonance (LSPR) of metallic nanostructures is a unique phenomenon that controls the light in sub-wavelength volumes and enhances the light-matter interactions. Traditionally, the excitation and measurement of LSPR require bulky external light sources, and efforts to scale down to nano-plasmonic devices have predominantly relied on the system's miniaturization and associated accessories. Addressing this, here we show the generation and detection of LSPR wavelength (λLSPR) shifts in large-area nanostructured Au surfaces using frictional charges generated by triboelectric surfaces. We observe a complex interplay of the localized surface plasmons with frictional charges via concurrent spectroscopic and triboelectric measurements undertaken for the detection of bioconjugation in the streptavidin-biotin complex. When subjected to multivariate principal component analysis, a strong correlation between the triboelectric peak-to-peak voltage output response and the λLSPR shift is observed. Furthermore, we reveal a landscape of the interfacial events involved in the electrical generation/detection of the LSPR by using theoretical models and surface characterization. The demonstrated concept of electrification of plasmon resonance thus provides the underlying basis for the subsequent development of self-powered nano-plasmonic sensors and opens new horizons for advanced nanophotonic applications.


Parental mate choice manipulation tactics: exploring prevalence, sex and personality effects.
Parents and children are genetically related but not genetically identical, which means that their genetic interests overlap but also diverge. In the area of mating, this translates into children making mate choices that are not in the best interest of their parents. Parents may then resort to manipulation in order to influence their children's mating decisions in a way that best promotes the former's interests. This paper attempts to identify the structure of manipulation tactics that parents employ on their daughters and sons, as well as on their daughters' and sons' mates, and also to estimate their prevalence. On the basis of the structure of the derived tactics, four hypotheses are tested: Mothers are more willing than fathers to use manipulation tactics; parents are willing to use more manipulation on their daughters than on their sons; the personality of parents predicts the use of tactics on their children and on their children's mates; and the personality of children and of children's mates predicts the use of tactics on them. Evidence from two independent studies provides support for the first three hypotheses, but mixed support for the fourth hypothesis. The implications of these findings are further discussed.


Demographic, Clinical, and Co-Morbidity Characteristics of COVID-19 Patients: A Retrospective Cohort from a Tertiary Hospital in Kenya.
The first documented case of COVID-19 in Kenya was recorded March of 2020. Co-morbidities including hypertension and diabetes have been associated with increased morbidity, hospitalization, and mortality among COVID-19 patients. This retrospective study describes the clinical characteristics, disease severity, and outcomes among the patient population at a tertiary hospital in Kenya. This was a retrospective descriptive study of COVID-19 patients who were admitted between March 2020 and December 2020 at the Aga Khan University Hospital in Nairobi, Kenya. Data collected include patient demographic and baseline characteristics. Differences between patients who were known to have diabetes and hypertension during admission were compared for statistical significance. Difference between those who survived and those who died were also compared for statistical significance. A total of 913 records of patients were studied with a mean age of 51.2 years (SD = 16.7), 66.5% were male and 80.8% were of African origin. History of diabetes, hypertension, and HIV status were at 27.3%, 33.1%, and 2.3%, respectively. At presentation, 33.1% (302/913) of patients had known hypertension by history, and following admission, this proportion increased to 37.7% (344/913). At presentation, 27.3% (249/913) of patients had known diabetes. During hospital stay, 20.8% (190) more patients were found to have diabetes, raising the overall percent to 48.1% (439/913). When comparing diabetes and hypertension at baseline versus at the end of admission, diabetes increased by 20.8% (p < 0.001) and hypertension by 4.6% (p = 0.049). HIV co-infection was 2.3%, and no patient had tuberculosis. This study showed a high incidence of co-morbidities in patients infected with COVID-19. Diabetes was most common, followed by hypertension. All patients admitted with COVID-19 infection should routinely be tested for diabetes with HbA1c and have regular blood pressure monitoring in order to diagnose occult diabetes and hypertension. Adverse outcomes were found in patients with these co-morbidities and should be monitored and treated appropriately.


Incidence of injury in adult elite women's football: a systematic review and meta-analysis.
To estimate the incidence of injury in adult elite women's football and to characterise the nature and anatomical location of injuries. Systematic review and meta-analysis. Combinations of the key terms were entered into the following electronic databases (PubMed, SPORTDiscus, Science Direct and Discover) from inception to May 2021. (1) Used a prospective cohort design; (2) captured data on elite adult women players; (3) reported injury incidence by anatomical site; (4) captured data of at least one season or national team tournament; (5) included a definition of injury; and (6) written in English. The search identified 1378 records. Twelve studies published between 1991 and 2018 were included in our review and sampled 129 teams. In domestic club football, injury incidence rate was estimated to be 5.7/1000 hours (total), 19.5/1000 hours (match) and 3.1/1000 hours (training). In tournament, football match incidence was estimated to be 55.7/1000 hours. The knee (22.8%; 368/1822) was the most common site of injury in domestic club football. The ankle (23.7%, 105/443) was the most common site of injury in tournament football. Ligament sprains were the most common type of injury (27.8%), followed by muscle strains (19.1%). Severn studies (58%) had a high risk of bias associated with exposure definition and measurement and considerable heterogeneity exists between the included studies (I2=49.7%-95%). Ligament sprains occur more frequently in adult elite women football players. We advise caution in interpretating point estimates of the incidence of injury due to high statistical heterogeneity. Standardising injury reporting and the accurate recording of match and training exposure will overcome such limitations. CRD42019130407.su.


Incidence of atopy in rheumatic disease.
The incidence of hay fever, positive skin tests to grass pollen and specific IgG and IgE antibodies to a pollen allergen was found to be the same in a group of 40 patients with juvenile chronic arthritis as that expected in a normal population. The geometric mean total serum IgE of this group was also normal. In sera from patients with adult rheumatoid arthritis the incidence of IgG an IgE antibodies to pollen appeared to be low and the geometric mean total IgE was also low.


Cellular mechanisms of potassium transport in plants.
Potassium (K(+)) is the most abundant ion in the plant cell and is required for a wide array of functions, ranging from the maintenance of electrical potential gradients across cell membranes, to the generation of turgor, to the activation of numerous enzymes. The majority of these functions depend more or less directly upon the activities and regulation of membrane-bound K(+) transport proteins, operating over a wide range of K(+) concentrations. Here, we review the physiological aspects of potassium transport systems in the plasma membrane, re-examining fundamental problems in the field such as the distinctions between high- and low-affinity transport systems, the interactions between K(+) and other ions such as NH(4)(+) and Na(+), the regulation of cellular K(+) pools, the generation of electrical potentials and the problems involved in measurement of unidirectional K(+) fluxes. We place these discussions in the context of recent discoveries in the molecular biology of K(+) acquisition and produce an overview of gene families encoding K(+) transporters.