The dietary phytochemical chlorophyllin alters E-cadherin and beta-catenin expression in human colon cancer cells.
Chlorophyllin (CHL), an anticarcinogenic and antimutagenic water-soluble derivative of chlorophyll, has been reported to induce apoptosis in human colon cancer cells via a pathway involving cell differentiation. Induction of differentiation markers may be important in limiting cancer-cell invasion and metastasis, and there is much interest in understanding the underlying mechanisms, because this might provide insights for cancer chemotherapy. In the present study, human HCT116 colon-cancer cells were treated with CHL, and the expression levels of E-cadherin and beta-catenin were examined using immunocytochemistry and laser scanning confocal microscopy. E-cadherin was detected almost exclusively at the cell periphery of cancer cells treated with or without CHL, but the expression of E-cadherin in the plasma membrane was markedly elevated in the cells treated with CHL. beta-Catenin also was strongly expressed in the plasma membrane, especially after CHL treatment. No change in the expression of beta-catenin mRNA was detected across a broad range of CHL concentrations (10-500 micromol/L), but there was a concentration-dependent decrease in nuclear beta-catenin protein levels without overt changes in the cytosolic pool of beta-catenin. Our interpretation of these findings is that CHL induces E-cadherin expression, and this facilitates trafficking of beta-catenin away from the nucleus and into the plasma membrane, possibly for destruction via the adherins junction remodeling (Hakai) pathway.


Communal range defence in primates as a public goods dilemma.
Classic socio-ecological theory holds that the occurrence of aggressive range defence is primarily driven by ecological incentives, most notably by the economic defendability of an area or the resources it contains. While this ecological cost-benefit framework has great explanatory power in solitary or pair-living species, comparative work on group-living primates has always found economic defendability to be a necessary, but not sufficient condition to account for the distribution of effective range defence across the taxon. This mismatch between theory and observation has recently been ascribed to a collective action problem among group members in, what is more informatively viewed as, a public goods dilemma: mounting effective defence of a communal range against intrusions by outgroup conspecifics. We here further develop this framework, and report on analyses at three levels of biological organization: across species, across populations within a single lineage and across groups and individuals within a single population. We find that communal range defence in primates very rarely involves collective action sensu stricto and that it is best interpreted as the outcome of opportunistic and strategic individual-level decisions. Whether the public good of a defended communal range is produced by solitary, joint or collective action is thus the outcome of the interplay between the unique characteristics of each individual, local and current socio-ecological conditions, and fundamental life-history traits of the species.


Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan.
There have been few epidemiological studies on gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Japan. We examined the epidemiology of GEP-NETs [pancreatic endocrine tumors (PETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005 using a nationwide stratified random sampling method. A total of 2,845 individuals received treatment for PETs. Prevalence was estimated as 2.23/100,000 with an annual onset incidence of 1.01/100,000. Non-functioning tumor (NF)-PET constituted 47.4%, followed by insulinoma (38.2%) and gastrinoma (7.9%). Distant metastases were reported in 21% patients with NF-PETs and occurred more frequently as tumor size increased (>2 cm). Multiple endocrine neoplasia type 1 (MEN-1) was detected in 10% of PETs but only in 6.1% of NF-PETs. NF-PETs were detected incidentally by physical examination in 24% patients. In 2005, an estimated 4,406 patients received treatment for GI-NETs. Prevalence was estimated as 3.45/100,000, with an annual onset incidence of 2.10/100,000. The locations of GI-NETs varied: foregut, 30.4%; midgut, 9.6%; and hindgut, 60.0%. Distant metastases were observed in 6%. Lymph node metastases occurred more frequently as tumor size increased (>1 cm). The frequency of MEN-1 complications was 1%. Physical examination revealed GI-NETs in 44% patients. The frequency of symptomatic GI-NETs was 3.4%. Interestingly, 77.1% of patients with foregut GI-NETs had type A gastritis. Our results show there are large differences in GEP-NETs between Japan and Western nations, primarily due to differences in the presence of MEN-1 in NF-PETs and the location, symptomatic status, and prevalence of malignancy in GI-NETs.


Low Prevalence of Hip and Knee Arthritis in Active Marathon Runners.
Existing evidence on whether marathon running contributes to hip and knee arthritis is inconclusive. Our aim was to describe hip and knee health in active marathon runners, including the prevalence of pain, arthritis, and arthroplasty, and associated risk factors. A hip and knee health survey was distributed internationally to marathon runners. Active marathoners who completed ≥5 marathons and were currently running a minimum of 10 miles per week were included (n = 675). Questions assessed pain, personal and family history of arthritis, surgical history, running volume, personal record time, and current running status. Multivariable analyses identified risk factors for pain and arthritis. Arthritis prevalence in U.S. marathoners was compared with National Center for Health Statistics prevalence estimates for a matched group of the U.S. Marathoners (n = 675) with a mean age of 48 years (range, 18 to 79 years) ran a mean distance of 36 miles weekly (range, 10 to 150 miles weekly) over a mean time of 19 years (range, 3 to 60 years) and completed a mean of 76 marathons (range, 5 to 1,016 marathons). Hip or knee pain was reported by 47%, and arthritis was reported by 8.9% of marathoners. Arthritis prevalence was 8.8% for the subgroup of U.S. marathoners, significantly lower (p < 0.001) than the prevalence in the matched U.S. population (17.9%) and in subgroups stratified by age, sex, body mass index (BMI), and physical activity level (p < 0.001). Seven marathoners continued to run following hip or knee arthroplasty. Age and family and surgical history were independent risk factors for arthritis. There was no significant risk associated with running duration, intensity, mileage, or the number of marathons completed (p > 0.05). Age, family history, and surgical history independently predicted an increased risk for hip and knee arthritis in active marathoners, although there was no correlation with running history. In our cohort, the arthritis rate of active marathoners was below that of the general U.S. Longitudinal follow-up is needed to determine the effects of marathon running on developing future hip and knee arthritis. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Hypoxemia Within the First 3 Postoperative Days Is Associated With Increased 1-Year Postoperative Mortality After Adjusting for Perioperative Opioids and Other Confounders.
Postoperative hypoxemia (POH) is common and primarily treated with temporary oxygen supplementation. Because the clinical impact of POH is sometimes presumed as minor, efforts to better understand and minimize it have been limited. Here, we hypothesized that, after adjusting for opioids received perioperatively and other confounders, the frequency of POH events (POH%) reported within the first 3 postoperative days (PODs) is associated with increased postoperative 1-year mortality. With prior institutional review board (IRB) approval, the Epic Clarity database was queried for all adult inpatient anesthesia encounters performed at our health system (1 academic and 2 community hospitals) from January 1, 2012 to March 31, 2016. Patients with multiple hospitalizations or subsequent surgeries within the same hospitalization were excluded. We classified patients based on the presence (POH) or not (No-POH) of ≥1 documented peripheral saturation of oxyhemoglobin (SpO2) ≤85% event of any duration occurring between the discharge from the postanesthesia care unit (PACU) until POD 3. Demographics, comorbidities, surgery duration, morphine milligram equivalents (OMME) administered perioperatively, respiratory therapies, intensive care unit (ICU) admission, and hospital length of stay (LOS) were also collected. Logistic regression was used to characterize the association between POH and 1-year postoperative mortality after adjusting for perioperatively administered opioids and other confounding factors. A total of 43,011 patients met study criteria. At least 1 POH event was reported in 10,727 (24.9%) patients. Of these, 7179 (66.9%) had ≥1 hypoxemic event on POD 1, 5340 (49.8%) on POD 2, and 3455 (32.3%) on POD 3. Patients with ≥1 POH event, compared to No-POH patients, were older, had more respiratory and other comorbidities, underwent longer surgeries, received greater opioid doses on the day of surgery and POD 1, and received more continuous pulse oximetry monitoring. POH patients required more frequent postoperative oxygen therapy, noninvasive ventilation (NIV), intubation, and ICU admission. One-year postoperative mortality occurred in 4.4% of patients with ≥1 POH and 3.0% of No-POH patients (P < .001). After adjusting for confounding factors, for every 10% increase in the frequency of SpO2 ≤85% readings, the odds of postoperative 1-year mortality were 1.20 (95% confidence interval [CI], 1.11-1.29; P < .001). Perioperative opioids were not independently associated with increased 1-year mortality. After adjusting for perioperative opioids and other confounders, moderate/severe POH within the first 3 PODs was independently associated with increased 1-year postoperative mortality. Increased efforts should be directed to understand if efforts to detect and reduce POH lead to improved patient outcomes.


In vivo assessment of magnesium status in human body using accelerator-based neutron activation measurement of hands: a pilot study.
Magnesium (Mg) is an element essential for many enzymatic reactions in the human body. Various human and animal studies suggest that changes in Mg status are linked to diseases such as cardiac arrhythmia, coronary heart disease, hypertension, premenstrual syndrome, and diabetes mellitus. Thus, knowledge of Mg levels in the human body is needed. A direct measurement of human blood serum, which contains only 0.3% of the total body Mg, is generally used to infer information about the status of Mg in the body. However, in many clinical situations, Mg stored in large levels, for example in bones, muscles, and soft tissues, needs to be monitored either to evaluate the efficacy of a treatment or to study the progression of diseases associated with the deficiency of total body Mg. This work presents a feasibility study of a noninvasive, in vivo neutron activation analysis (IVNAA) technique using the 26Mg (n, gamma) 27Mg reaction to measure Mg levels in human hands. The technique employs the McMaster University high beam current Tandetron accelerator hand irradiation facility and an array of eight NaI (T1) detectors arranged in a 4 pi geometry for delayed counting of the 0.844 and 1.014 MeV gamma rays emitted when 27Mg decays in the irradiated hand. Mg determination in humans using IVNAA of hands has been demonstrated to be feasible, with effective doses as low as one-quarter of those delivered in chest x rays. The overall experimental uncertainty in the measurements is estimated to be approximately 5% (1 sigma). The results are found to be in the range of the in vitro measurements reported for other cortical bones collected from different sites of the human skeleton, which confirms that this technique mainly provides a measure of the amount of Mg in hand bones. The average concentration of Mg determined in human hands is 10.96 +/- 1.25 (+/- 1 SD) mg Mg/g Ca. The coefficient of variation (11%) observed in this study is comparable with or lower than several studies using in vitro measurements reported in the literature and therefore allows for a quantitative intersubject comparison, even if to a limited extent. The features of the developed technique such as its simplicity, rapidity, accuracy, robustness, noninvasive nature, and very effective use of radiation doses, present the technique as a viable diagnostic tool available for trial in a clinical environment.


Anabolic effects of insulin-like growth factor in combination with insulin-like growth factor binding protein-3 in severely burned adults.
The purpose of this study was to determine the anabolic effects of recombinant human insulin-like growth factor-I (rhIGF-1) complexed with its principal binding protein IGF-1 binding protein-3 (IGFBP-3) in severely burned adults. Ten burned adults were studied consecutively after receiving saline (pretreatment), then rhIGF-1/IGFBP-3 (treatment) for 5 days. Doses were 1, 2, and 4 mg/kg per day. Glucose, electrolytes, hormones, and leg muscle protein metabolism were determined. Nine other studies were performed on similarly injured adults at comparable times to the treatment studies to control for time effects. Serum IGF-1 and IGFBP-3 levels increased with all doses, but no incremental increases were found. Leg protein balance improved with rhIGF-1/IGFBP-3, which was associated with an increase in muscle protein fractional synthetic rate. These effects were independent of time. All patients were euglycemic without electrolyte imbalances. Net protein synthesis in the isolated leg of severely burned adults improved with rhIGF-1/IGFBP-3 without development of glucose abnormalities.


Rape fantasies as a function of exposure to violent sexual stimuli.
Twenty-nine male students, classified on the basis of questionnaire responses as sexually force oriented or non-force oriented, were randomly assigned to exposure to rape or mutually-consenting versions of a slide-audio show. All subjects were then exposed to the same audio description of a rape read by a female. They were later asked to create their own fantasies. Penile tumescence and self-reports of arousal indicated that relatively high levels of sexual arousal were generated by all of the experimental stimuli. No differences in arousal during the exposure phase were found as a function of the manipulation in the content of the slide-audio show. Sexual arousal during the fantasy period, assessed by means of self-reports, indicated that those who had been classified as force oriented created more arousing fantasies after having been exposed to the rape version of the show, whereas those classified as non-force oriented created more arousing fantasies following the mutually-consenting version. Most significantly, those exposed to the rape version, irrespective of their sexual classification, created more violent sexual fantasies than those exposed to the mutually-consenting version. The possible role of such media-elicited fantasies in the development of antisocial attitudes and behavior is considered. Also discussed are ethical issues arising from implementing or failing to implement research in this area.


Compartmentalized Toxoplasma EB1 bundles spindle microtubules to secure accurate chromosome segregation.
Toxoplasma gondii replicates asexually by a unique internal budding process characterized by interwoven closed mitosis and cytokinesis. Although it is known that the centrosome coordinates these processes, the spatiotemporal organization of mitosis remains poorly defined. Here we demonstrate that centrosome positioning around the nucleus may signal spindle assembly: spindle microtubules (MTs) are first assembled when the centrosome moves to the basal side and become extensively acetylated after the duplicated centrosomes reposition to the apical side. We also tracked the spindle MTs using the MT plus end-binding protein TgEB1. Endowed by a C-terminal NLS, TgEB1 resides in the nucleoplasm in interphase and associates with the spindle MTs during mitosis. TgEB1 also associates with the subpellicular MTs at the growing end of daughter buds toward the completion of karyokinesis. Depletion of TgEB1 results in escalated disintegration of kinetochore clustering. Furthermore, we show that TgEB1's MT association in Toxoplasma and in a heterologous system (Xenopus) is based on the same principles. Finally, overexpression of a high-MT-affinity TgEB1 mutant promotes the formation of overstabilized MT bundles, resulting in avulsion of otherwise tightly clustered kinetochores. Overall we conclude that centrosome position controls spindle activity and that TgEB1 is critical for mitotic integrity.


The dynamic volume changes of polymerising polymethyl methacrylate bone cement.
The Swedish hip register found an increased risk of early revision of vacuum-mixed cemented total hip replacements. The influence of cement mixing technique on the dynamic volume change in polymerising PMMA is not well understood and may be relevant to this observation. Applying Archimedes' principle, we have investigated the dynamic volume changes in polymerising cement and determined the influence of mixing technique. All specimens showed an overall volume reduction: hand-mixed 3.4% and vacuum-mixed 6.0%. Regression analysis of sectional porosity and volume reduction showed a highly significant relationship. Hand-mixed porous cement showed a transient volume increase before solidification. However, vacuum-mixed cement showed a progressive volume reduction throughout polymerisation. Transient expansion of porous cement occurs at the critical time of micro-interlock formation, possibly improving fixation. Conversely, progressive volume reduction of vacuum-mixed cement throughout the formation of interlock may damage fixation. Stable fixation of vacuum-mixed cement may depend on additional techniques to offset the altered volumetric behaviour of vacuum-mixed cement.


Effectiveness of a brief behavioural intervention to prevent weight gain over the Christmas holiday period: randomised controlled trial.
To test the effectiveness of a brief behavioural intervention to prevent weight gain over the Christmas holiday period. Two group, double blinded randomised controlled trial. Recruitment from workplaces, social media platforms, and schools pre-Christmas 2016 and 2017 in Birmingham, UK. 272 adults aged 18 years or more with a body mass index of 20 or more: 136 were randomised to a brief behavioural intervention and 136 to a leaflet on healthy living (comparator). Baseline assessments were conducted in November and December with follow-up assessments in January and February (4-8 weeks after baseline). The intervention aimed to increase restraint of eating and drinking through regular self weighing and recording of weight and reflection on weight trajectory; providing information on good weight management strategies over the Christmas period; and pictorial information on the physical activity calorie equivalent (PACE) of regularly consumed festive foods and drinks. The goal was to gain no more than 0.5 kg of baseline weight. The comparator group received a leaflet on healthy living. The primary outcome was weight at follow-up. The primary analysis compared weight at follow-up between the intervention and comparator arms, adjusting for baseline weight and the stratification variable of attendance at a commercial weight loss programme. Secondary outcomes (recorded at follow-up) were: weight gain of 0.5 kg or less, self reported frequency of self weighing (at least twice weekly versus less than twice weekly), percentage body fat, and cognitive restraint of eating, emotional eating, and uncontrolled eating. Mean weight change was -0.13 kg (95% confidence interval -0.4 to 0.15) in the intervention group and 0.37 kg (0.12 to 0.62) in the comparator group. The adjusted mean difference in weight (intervention-comparator) was -0.49 kg (95% confidence interval -0.85 to -0.13, P=0.008). The odds ratio for gaining no more than 0.5 kg was non-significant (1.22, 95% confidence interval 0.74 to 2.00, P=0.44). A brief behavioural intervention involving regular self weighing, weight management advice, and information about the amount of physical activity required to expend the calories in festive foods and drinks prevented weight gain over the Christmas holiday period. ISRCTN Registry ISRCTN15071781.


HBV life cycle and novel drug targets.
With up to 400 million affected people worldwide, chronic hepatitis B virus (HBV) infection is still a major health care problem. During the last decade, several novel therapeutic approaches have been developed and evaluated. In most regions of the world, interferon-α, and nucleos(t)ide analogues (NUCs) are currently approved. Despite major improvements, none of the existing therapies is optimal since viral clearance is rarely achieved. Recently, a better understanding of the HBV life cycle and the development of novel model systems of HBV infection have led to the development of novel antiviral strategies and drug targets. This review will focus on current and potential future drug targets in the HBV life cycle and strategies to modulate the virus-host interaction.


Nanoparticle size and chemical modification play a crucial role in the interaction of nano gold with the brain: extent of accumulation and toxicity.
The blood brain barrier (BBB) is a very selective barrier that protects the brain and the central nervous system (CNS) from the entry of harmful substances and helps regulate the exchange of different molecules and nutrients from and into the brain and the CNS. This selectivity makes delivering therapeutic and diagnostic materials across the BBB very challenging. In this study, different shapes and sizes of gold nanoparticles (GNP) were synthesized and functionalized with five different thiolated ligands to obtain GNP with various surface chemistries. The potential of GNP of different properties to be accumulated into the brain through the BBB and into other organs was investigated in a mouse model using qualitative and quantitative approaches. Gold nanorods (GNR) functionalized with 4-mercaptophenol (Mph) showed the highest penetration ability across the BBB into the brain with no significant deposition in other organs. Interestingly, increasing the size of GNR retarded their delivery into the brain, while enhancing their accumulation in other organs. On the other hand, gold nanospheres (GNS) demonstrated high deposition percentages in the brain and other organs with possible toxic effects. The properties of GNP play a crucial role in their interaction with the BBB and accumulation in the brain and other organs. Thus, GNP can be considered a promising nano-platform for drug delivery into the brain and as a photothermal-inducing agent against brain cancer.


Structure of Halothiobacillus neapolitanus carboxysomes by cryo-electron tomography.
Carboxysomes are polyhedral bodies consisting of a proteinaceous shell filled with ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO). They are found in the cytoplasm of all cyanobacteria and some chemoautotrophic bacteria. Previous studies of Halothiobacillus neapolitanus and Nitrobacter agilis carboxysomes suggest that the structures are either icosahedral or dodecahedral. To determine the protein shell structure more definitively, purified H. neapolitanus carboxysomes were re-examined by cryo-electron tomography and scanning transmission electron microscopy (STEM). Due to the limited tilt angles in the electron microscope, the tomographic reconstructions are distorted. Corrections were made in the 3D orientation searching and averaging of the computationally extracted carboxysomes to minimize the missing data effects. It was found that H. neapolitanus carboxysomes vary widely in size and mass as shown by cryo-electron tomography and STEM mass measurements, respectively. We have aligned and averaged carboxysomes in several size classes from the 3D tomographic reconstruction by methods that are not model-biased. The averages reveal icosahedral symmetry of the shell, but not of the density inside it, for all the size classes.


The effects of phosphocreatine disodium salts plus blueberry extract supplementation on muscular strength, power, and endurance.
Numerous studies have demonstrated the efficacy of creatine supplementation for improvements in exercise performance. Few studies, however, have examined the effects of phosphocreatine supplementation on exercise performance. Furthermore, while polyphenols have antioxidant and anti-inflammatory properties, little is known regarding the influence of polyphenol supplementation on muscular strength, power, and endurance. Thus, the purpose of the present study was to compare the effects of 28 days of supplementation with phosphocreatine disodium salts plus blueberry extract (PCDSB), creatine monohydrate (CM), and placebo on measures of muscular strength, power, and endurance. Thirty-three men were randomly assigned to consume either PCDSB, CM, or placebo for 28 days. Peak torque (PT), average power (AP), and percent decline for peak torque (PT%) and average power (AP%) were assessed from a fatigue test consisting of 50 maximal, unilateral, isokinetic leg extensions at 180°·s- 1 before and after the 28 days of supplementation. Individual responses were assessed to examine the proportion of subjects that exceeded a minimal important difference (MID). The results demonstrated significant (p < 0.05) improvements in PT for the PCDSB and CM groups from pre- (99.90 ± 22.47 N·m and 99.95 ± 22.50 N·m, respectively) to post-supplementation (119.22 ± 29.87 N·m and 111.97 ± 24.50 N·m, respectively), but no significant (p = 0.112) change for the placebo group. The PCDSB and CM groups also exhibited significant improvements in AP from pre- (140.18 ± 32.08 W and 143.42 ± 33.84 W, respectively) to post-supplementation (170.12 ± 42.68 W and 159.78 ± 31.20 W, respectively), but no significant (p = 0.279) change for the placebo group. A significantly (p < 0.05) greater proportion of subjects in the PCDSB group exceeded the MID for PT compared to the placebo group, but there were no significant (p > 0.05) differences in the proportion of subjects exceeding the MID between the CM and placebo groups or between the CM and PCDSB groups. These findings indicated that for the group mean responses, 28 days of supplementation with both PCDSB and CM resulted in increases in PT and AP. The PCDSB, however, may have an advantage over CM when compared to the placebo group for the proportion of individuals that respond favorably to supplementation with meaningful increases in muscular strength.


Effects unrelated to anti-inflammation of lipid emulsions containing fish oil in parenteral nutrition for adult patients.
Several reviews and meta-analyses on modulated inflammatory and immunologic responses after the administration of omega-3 polyunsaturated fatty acids (PUFAs) in different diseases and conditions have been published. However, omega-3 PUFAs exert several other actions which are not directly related to immunologic or inflammatory responses. The aim of this paper was to review the effects which are not directly related to immunologic and inflammatory responses of intravenous lipid emulsions (IVLEs) containing fish oil (FO) in parenteral nutrition (PN) for adult patients. IVLEs containing FO could have a role in the prevention of alterations in liver enzyme tests (LETs) or PN-associated liver disease (PNALD). Studies using FO doses of ≥ 0.150 mg/kg/day or IVLEs with high FO concentration reported more positive results than those with lower doses. Once PNALD was developed, the use of IVLEs exclusively composed of FO at doses of 0.25-1 g of FO/kg/day for several weeks could attenuate or even eradicate cholestasis and liver alteration. IVLEs containing FO seemed to have faster blood clearance, and this could be beneficial for some patients. Some studies also suggested a possible improvement of respiratory function by the administration of these IVLEs. In general, IVLEs containing FO were safe. Their use did not increase oxidative stress but, in contrast, increased plasma tocopherol content. They did not alter insulin sensitivity or glycemic control, and studies have found no relevant clinical effect on platelet aggregation or hemostasis. In conclusion, the use of IVLEs containing FO in PN may be beneficial with regard to older IVLEs, in addition to the modulation of systemic inflammation response.


miR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4.
Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of miRNAs to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in patients with CRC. We showed that miR-103/107 targeted the known metastasis suppressors death-associated protein kinase (DAPK) and Krüppel-like factor 4 (KLF4) in CRC cells, resulting in increased cell motility and cell-matrix adhesion and decreased cell-cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxia-induced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis effects, which were suppressed by reexpression of DAPK or KLF4. miR-103/107-mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a metastatic site. Clinically, the signature of a miR-103/107 high, DAPK low, and KLF4 low expression profile correlated with the extent of lymph node and distant metastasis in patients with CRC and served as a prognostic marker for metastasis recurrence and poor survival. Our findings therefore indicate that miR-103/107-mediated repression of DAPK and KLF4 promotes metastasis in CRC, and this regulatory circuit may contribute in part to hypoxia-stimulated tumor metastasis. Strategies that disrupt this regulation might be developed to block CRC metastasis.


[Femoral vascular complications after percutaneous coronary interventions].
We aimed to investigate peripheral vascular complications and their relation with treatment and clinical parameters in percutaneous transluminal coronary angioplasty (PTCA) patients. We included into the study 321 patients (aged 57+/-11 years) underwent PTCA between November 2001-August 2002. The age, gender, glycoprotein 2b/3a use, thrombolytic use, intraaortic balloon treatment, transient pacemaker treatment, reintervention history, hypertension, diabetes mellitus, smoking status, family history and the correlations of these parameters with local vascular complications were assessed in all patients. Pseudoaneurysm incidence was significantly correlated with; age [(n=13, 68.0%) p=0.0001, OR 8.38], female gender [(n=12, 63.1%) p<0.015, OR 0.32], reintervention [(n=10, 52.1%) p<0.004, OR 3.6], venous sheath usage [(n=12, 63%) p<0.0001, OR 9.07], thrombolytic treatment [(n=5, 26.3%) p<0.0001, OR 7.9], and intraaortic balloon adjustment [(n=6, 31.5%) p<0.0001, OR 7.2]. No correlation was found between pseudoaneurysm incidence and glycoprotein 2b/3a treatment, smoking, diabetes mellitus, hypertension and family history. The present study showed that patients of female gender, with reintervention, thrombolytic treatment, venous sheath use and intraaortic balloon adjustment are at high risk for serious femoral vascular complications, especially when they are aged. Additionally, glycoprotein 2b/3a agents can be used without increased risk of peripheral vascular complications.


Enhancement of backscattered intensity for a bistatic lidar operating in atmospheric turbulence.
The extended Huygens-Fresnel formulation is used to calculate the enhanced backscattered intensity as a function of the off-axis receiver distance for a bistatic lidar operating in atmospheric turbulence. The result is simple and compact and allows the regime where there is significant enhancement to be readily identified. In addition, the result depends only on the logamplitude covariance, which implies that the enhancement is due to incoherent turbulence perturbation effects.


Predictors of poor outcome in neonates with bacterial sepsis admitted to the University Hospital of the West Indies.
To determine factors that affect outcome in neonates with culture-proven sepsis, the charts of all neonates with culture-proven sepsis admitted to the University Hospital of the West Indies between January 1995 and December 2000 were reviewed retrospectively. Neonates who survived without developing any complications (favourable outcome group) were compared with those who died and/or developed severe complications during the course of treatment (poor outcome group). Chi-square tests were done to determine factors associated with poor outcome; univariate and multivariate logistic regression analyses were also performed. One hundred and thirty-five neonates had culture-proven sepsis, of which 89 (66%) were term infants and 46 (34%) were preterm. Male to female ratio was 1.6:1. One hundred and twenty-six (93%) survived and 9 (7%) died. Case fatality rates were higher for premature infants (15%) than for term infants (2%). Twenty-four (18%) of the neonates with culture proven sepsis had a poor outcome. Gram negative organisms accounted for 19 (70%) of the cases with poor outcome. Prematurity (p < 0.001), very low birthweight (p < 0.001) and female gender (p < 0.05) were factors associated with poor outcome. Strategies aimed at decreasing morbidity and mortality in neonates with sepsis must include measures that will decrease the incidence of prematurity and low birthweight.


Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD.
From approximately one week before normal ovulation resumes, lactating women require protection against pregnancy by a contraceptive that is safe for both infant and mother in a multicenter one-year study, the natural hormone, progesterone, delivered vaginally by a sequence of four contraceptive rings designed for continuous use, was evaluated as a contraceptive for nursing mothers in comparison with the Copper T 380A IUD. Individual rings release in effective average dose of 10 mg day for a 3 month period. Evaluation included measures of lactational performance as well as of contraceptive efficacy and safety to mother and child. Nine participating clinics enrolled 802 ring users and 734 IUD acceptors between postpartum days 29 and 63. Life table analyses were performed with parallel decrements for ring and IUD subjects. Continuation in the study and analysis required that subjects not stop breastfeeding. The ring, with a one-year pregnancy rate of 1.5 per 100, did not differ significantly from the IUD with respect to contraceptive effectiveness (p > 0.05). More than half of the ring subjects were continuing at 6 months post admission and a quarter (23.5 per hundred) were still using the ring and breastfeeding one year after admission. Women with the IUD, however, had higher continuation rates (p < 0.001) at both time points. The largest single decrement for each method was that for weaning. Ring users had more complaints of vaginal problems but had fewer vaginal disorders on examination. At 12 months postpartum, 46 per 100 continuing ring users remained in amenorrhea. Lactation performance and the health and weight gain of the infants were similar among users of either regimen.


CT angiography of the renal arteries and veins: normal anatomy and variants.
Conventional angiography has long been regarded as gold standard imaging modality for evaluation of the renal vasculature. Introduction of multidetector computed tomography (MDCT) angiography had a groundbreaking impact on evaluation of the renal vessels and is gradually replacing conventional angiography as standard imaging. Herein, we review and illustrate the normal and variant anatomy of renal vessels with special emphasis on imaging protocols and reconstruction techniques in MDCT.


Fungal Diversity and Enzyme Activity Associated with the Macroalgae, Agarum clathratum.
Agarum clathratum, a brown macroalgae species, has recently become a serious environmental problem on the coasts of Korea. In an effort to solve this problem, fungal diversity associated with decaying A. clathratum was investigated and related β-glucosidase and endoglucanase activities were described. A total of 233 fungal strains were isolated from A. clathratum at 15 sites and identified 89 species based on morphology and a multigene analysis using the internal transcribed spacer region (ITS) and protein-coding genes including actin (act), β-tubulin (benA), calmodulin (CaM), and translation elongation factor (tef1). Acremonium, Corollospora, and Penicillium were the dominant genera, and Acremonium fuci and Corollospora gracilis were the dominant species. Fifty-one species exhibited cellulase activity, with A. fuci, Alfaria terrestris, Hypoxylon perforatum, P. madriti, and Pleosporales sp. Five showing the highest enzyme activities. Further enzyme quantification confirmed that these species had higher cellulase activity than P. crysogenum, a fungal species described in previous studies. This study lays the groundwork for bioremediation using fungi to remove decaying seaweed from populated areas and provides important background for potential industrial applications of environmentally friendly processes.


Fluorescent labeling of proteins.
Many single-molecule experimental techniques exploit fluorescence as a tool to investigate conformational dynamics and molecular interactions or track the movement of proteins in order to gain insight into their biological functions. A prerequisite to these experimental approaches is to graft one or more fluorophores on the protein of interest with the desired photophysical properties. Here, we present detailed procedures for the current most efficient methods used to covalently attach fluorophores to proteins. Alternative direct and indirect labeling strategies are also described.


Predicting with confidence the efficiency of new dyes in dye sensitized solar cells.
We ask whether it is possible to predict the efficiency of a new dye in dye sensitized solar cells (DSSCs) on the basis of the known performance of existing dyes in the same type of device. We evaluate a number of computable predictors of the efficiency for a large set of dyes whose experimental efficiency is known. We have then used statistical regression methods to establish the relation between the predictors and the efficiency. Our predictions are associated with a rigorously determined confidence level. For a new dye of the same family we are able to predict the probability that its efficiency in a DSSC is larger than a certain threshold. This method is useful for accelerating the discovery of new dyes and establishing more rigorously the existence of specific correlations between structure and properties. Within the properties considered we find that the dye efficiency correlates more strongly with its oxidation potential and reorganization energy.


Clinical decision rules to rule out subarachnoid hemorrhage for acute headache.
Three clinical decision rules were previously derived to identify patients with headache requiring investigations to rule out subarachnoid hemorrhage. To assess the accuracy, reliability, acceptability, and potential refinement (ie, to improve sensitivity or specificity) of these rules in a new cohort of patients with headache. Multicenter cohort study conducted at 10 university-affiliated Canadian tertiary care emergency departments from April 2006 to July 2010. Enrolled patients were 2131 adults with a headache peaking within 1 hour and no neurologic deficits. Physicians completed data forms after assessing eligible patients prior to investigations. Subarachnoid hemorrhage, defined as (1) subarachnoid blood on computed tomography scan; (2) xanthochromia in cerebrospinal fluid; or (3) red blood cells in the final tube of cerebrospinal fluid, with positive angiography findings. Of the 2131 enrolled patients, 132 (6.2%) had subarachnoid hemorrhage. The decision rule including any of age 40 years or older, neck pain or stiffness, witnessed loss of consciousness, or onset during exertion had 98.5% (95% CI, 94.6%-99.6%) sensitivity and 27.5% (95% CI, 25.6%-29.5%) specificity for subarachnoid hemorrhage. Adding "thunderclap headache" (ie, instantly peaking pain) and "limited neck flexion on examination" resulted in the Ottawa SAH Rule, with 100% (95% CI, 97.2%-100.0%) sensitivity and 15.3% (95% CI, 13.8%-16.9%) specificity. Among patients presenting to the emergency department with acute nontraumatic headache that reached maximal intensity within 1 hour and who had normal neurologic examination findings, the Ottawa SAH Rule was highly sensitive for identifying subarachnoid hemorrhage. These findings apply only to patients with these specific clinical characteristics and require additional evaluation in implementation studies before the rule is applied in routine clinical care.


Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells.
T-cell recovery following myeloablative preparatory regimens and cord blood transplantation in adult patients gen erally occurs between 1 and 3 years following allogeneic bone marrow transplantation. T-cell reconstitution may involve thymic education of donor-derived precursors or peripheral expansion of mature T-cells transferred in the graft. We measured quantitative and qualitative immunologic reconstitution, T-cell receptor spectratyping, and T-cell receptor excision circle (TREC) levels in adult recipients of umbilical cord blood transplants following a novel nonmyeloablative regimen. These results were compared to previously published results of similar patients receiving a myeloablative regimen and cord blood stem cells. With small numbers of patients treated so far, T-cells (CD3+) reached normal levels in adults 6 to 12 months following nonmyeloablative transplantation compared with 24 months in adults receiving a myeloablative regimen. At 12 months after transplantation, the numbers of phenotypically naive (CD45RA) T-cells were higher in those receiving the nonmyeloablative regimen. The T-cell repertoire in cord blood recipients treated with a nonmyeloablative regimen was markedly more diverse and robust compared with the repertoire in those receiving the myeloablative regimen at similar time points. TRECs (which are generated within the thymus and identify new thymic emigrants and those that have not divided) were detected 12 months after transplantation in the nonmyeloablative recipients, whereas TRECs were not detected in adults until 18 to 24 months in those receiving myeloablative regimens. Thus, in adults receiving a nonmyeloablative preparatory regimen, the quantitative and qualitative recovery of T-cells occurs through rapid peripheral expansion. The ability of patients receiving a nonmyeloablative regimen to recover within a few months suggests that the peripheral niches in which T-cells can proliferate are preserved in these patients compared to those receiving ablative regimens. Moreover, the presence of TREC-positive cells within 1 year suggests that thymic recovery is likewise accelerated in non myeloablative compared to myeloablative regimens.


Immediate outcomes of eptifibatide therapy during intracoronary stent implantation.
The objective of the present study was to assess the major immediate outcomes of eptifibatide therapy during intracoronary stent implantation. In an interventional study, patients undergoing percutaneous coronary intervention (PCI) were randomized into either the eptifibatide (n = 100) or the control (n = 107) group. In each group, demographic and clinical characteristics such as cardiac death, stent thrombosis (ST), myocardial infarction (MI), rates of target lesion and vessel revascularization, cerebral vascular accident (CVA), and emergency coronary artery bypass grafting (CABG) were recorded. The overall rates of major adverse events such as mortality, Stent thrombosis (ST), Myocardial Infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), CVA, and emergency CABG within 24 h after stent implantation were low and comparable between the two groups; P > 0.05 considered significant for all comparisons. There were no statistical differences between the clinical outcomes of groups administered with single-dose intracoronary eptifibatide and control groups among patients undergoing PCI during stent implantation.


Ceruloplasmin is a novel adipokine which is overexpressed in adipose tissue of obese subjects and in obesity-associated cancer cells.
Obesity confers an increased risk of developing specific cancer forms. Although the mechanisms are unclear, increased fat cell secretion of specific proteins (adipokines) may promote/facilitate development of malignant tumors in obesity via cross-talk between adipose tissue(s) and the tissues prone to develop cancer among obese. We searched for novel adipokines that were overexpressed in adipose tissue of obese subjects as well as in tumor cells derived from cancers commonly associated with obesity. For this purpose expression data from human adipose tissue of obese and non-obese as well as from a large panel of human cancer cell lines and corresponding primary cells and tissues were explored. We found expression of ceruloplasmin to be the most enriched in obesity-associated cancer cells. This gene was also significantly up-regulated in adipose tissue of obese subjects. Ceruloplasmin is the body's main copper carrier and is involved in angiogenesis. We demonstrate that ceruloplasmin is a novel adipokine, which is produced and secreted at increased rates in obesity. In the obese state, adipose tissue contributed markedly (up to 22%) to the total circulating protein level. In summary, we have through bioinformatic screening identified ceruloplasmin as a novel adipokine with increased expression in adipose tissue of obese subjects as well as in cells from obesity-associated cancers. Whether there is a causal relationship between adipose overexpression of ceruloplasmin and cancer development in obesity cannot be answered by these cross-sectional comparisons.


Detection of glucocorticoid receptors on Friend erythroleukemia cells.
The inhibition of dimethyl sulfoxide-induced differentiation of Friend erythroleukemia cells by steroids led us to examine these cells for the presence of glucocorticoid receptors. Direct assessement of dexamethasone binding revealed high-affinity dexamethasone receptors on the untreated cells. The specific binding of [3H]dexamethasone was dose dependent. At a concentration of 10(-8) M, almost all binding sites were occupied. The mean number of binding sites per cell in two separate experiments was 8045 and 7191, respectively, and the Kd varied between 3.38 and 3.49 x 10(-9) M. Dimethyl sulfoxide treatment led to a decrease in the number of dexamethasone binding sites on the cells induced to differentiate. After 5 days of treatment, the mean number of sites per cell was reduced to 1216 and 896 in two experiments, with a Kd of 5 x 10(-9) M. Dexamethasone treatment resulted in a moderate decrease in the efficiency of colony formation within 72 hr after the cells were plated in methylcellulose. The mechanism of this inhibitory effect is unknown. However, it was also dose dependent and could be abrogated by appropriate concentrations of progesterone or 11-deoxycortisone. These results suggest that the steroid effects on growth and differentiation of the erythroleukemia cells may be mediated via glucocorticoid receptors.


Rapid Review of Social Contact Patterns During the COVID-19 Pandemic.
Physical distancing measures aim to reduce person-to-person contact, a key driver of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. In response to unprecedented restrictions on human contact during the coronavirus disease 2019 (COVID-19) pandemic, studies measured social contact patterns under the implementation of physical distancing measures. This rapid review synthesizes empirical data on the changing social contact patterns during the COVID-19 pandemic. We conducted a systematic review using PubMed, Medline, Embase, and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We descriptively compared the distribution of contacts observed during the pandemic to pre-COVID data across countries to explore changes in contact patterns during physical distancing measures. We identified 12 studies reporting social contact patterns during the COVID-19 pandemic. Eight studies were conducted in European countries and eleven collected data during the initial mitigation period in the spring of 2020 marked by government-declared lockdowns. Some studies collected additional data after relaxation of initial mitigation. Most study settings reported a mean of between 2 and 5 contacts per person per day, a substantial reduction compared to pre-COVID rates, which ranged from 7 to 26 contacts per day. This reduction was pronounced for contacts outside of the home. Consequently, levels of assortative mixing by age substantially declined. After relaxation of initial mitigation, mean contact rates increased but did not return to pre-COVID levels. Increases in contacts post-relaxation were driven by working-age adults. Information on changes in contact patterns during physical distancing measures can guide more realistic representations of contact patterns in mathematical models for SARS-CoV-2 transmission.


Deployed Assessment and Management of mTBI Casualties.
The wars in Afghanistan and Iraq have placed a spotlight on screening, evaluation, and treatment of mild traumatic brain injury, otherwise known as concussion. The author presents a mass casualty case in which a Ranger company medical section assessed and managed 30 Servicemembers (SM) diagnosed with concussion. Through the process of treating these Servicemembers, a consolidated checklist was created based on existing Department of Defense, United States Special Operations Command (USSOCOM), and United States Army Special Operations Command (USASOC) guidelines. During this and subsequent clinical encounters, utilization of this checklist resulted in efficient identification of concussed personnel, appropriate treatment, and documentation.


Formation of unreduced megaspores (diplospory) in apomictic dandelions (Taraxacum officinale, s.l.) is controlled by a sex-specific dominant locus.
In apomictic dandelions, Taraxacum officinale, unreduced megaspores are formed via a modified meiotic division (diplospory). The genetic basis of diplospory was investigated in a triploid (3x = 24) mapping population of 61 individuals that segregated approximately 1:1 for diplospory and meiotic reduction. This population was created by crossing a sexual diploid (2x = 16) with a tetraploid diplosporous pollen donor (4x = 32) that was derived from a triploid apomict. Six different inheritance models for diplospory were tested. The segregation ratio and the tight association with specific alleles at the microsatellite loci MSTA53 and MSTA78 strongly suggest that diplospory is controlled by a dominant allele D on a locus, which we have named DIPLOSPOROUS (DIP). Diplosporous plants have a simplex genotype, Ddd or Dddd. MSTA53 and MSTA78 were weakly linked to the 18S-25S rDNA locus. The D-linked allele of MSTA78 was absent in a hypotriploid (2n = 3x - 1) that also lacked one of the satellite chromosomes. Together these results suggest that DIP is located on the satellite chromosome. DIP is female specific, as unreduced gametes are not formed during male meiosis. Furthermore, DIP does not affect parthenogenesis, implying that several independently segregating genes control apomixis in dandelions.


A spatial national health facility database for public health sector planning in Kenya in 2008.
Efforts to tackle the enormous burden of ill-health in low-income countries are hampered by weak health information infrastructures that do not support appropriate planning and resource allocation. For health information systems to function well, a reliable inventory of health service providers is critical. The spatial referencing of service providers to allow their representation in a geographic information system is vital if the full planning potential of such data is to be realized. A disparate series of contemporary lists of health service providers were used to update a public health facility database of Kenya last compiled in 2003. These new lists were derived primarily through the national distribution of antimalarial and antiretroviral commodities since 2006. A combination of methods, including global positioning systems, was used to map service providers. These spatially-referenced data were combined with high-resolution population maps to analyze disparity in geographic access to public health care. The updated 2008 database contained 5,334 public health facilities (67% ministry of health; 28% mission and nongovernmental organizations; 2% local authorities; and 3% employers and other ministries). This represented an overall increase of 1,862 facilities compared to 2003. Most of the additional facilities belonged to the ministry of health (79%) and the majority were dispensaries (91%). 93% of the health facilities were spatially referenced, 38% using global positioning systems compared to 21% in 2003. 89% of the population was within 5 km Euclidean distance to a public health facility in 2008 compared to 71% in 2003. Over 80% of the population outside 5 km of public health service providers was in the sparsely settled pastoralist areas of the country. We have shown that, with concerted effort, a relatively complete inventory of mapped health services is possible with enormous potential for improving planning. Expansion in public health care in Kenya has resulted in significant increases in geographic access although several areas of the country need further improvements. This information is key to future planning and with this paper we have released the digital spatial database in the public domain to assist the Kenyan Government and its partners in the health sector.


Firing up the front line.
For many organizations, achieving competitive advantage means eliciting superior performance from employees on the front line--the burger flippers, hotel room cleaners, and baggage handlers whose work has an enormous effect on customers. That's no easy task. Front line workers are paid low wages, have scant hope of advancement, and--not surprisingly--often care little about the company's performance. But then how do some companies succeed in engaging the emotional energy of rank-and-file workers? A team of researchers at McKinsey & Company and the Conference Board recently explored that question and discovered that one highly effective route is demonstrated by the U.S. Marine Corps. The Marines' approach to motivation follows the "mission, values, and pride" path, which researchers say is practical and relevant for the business world. More specifically, the authors say the Marines follow five practices: they over-invest in cultivating core value; prepare every person to lead, including front line supervisors; learn when to create teams and when to create single-leader work groups; attend to all employees, not just the top half; and encourage self-discipline as a way of building pride. The authors admit there are critical differences between the Marines and most businesses. But using vivid examples from companies such as KFC and Marriott International, the authors illustrate how the Marines' approach can be translated for corporate use. Sometimes, the authors maintain, minor changes in a company's standard operating procedure can have a powerful effect on front line pride and can result in substantial payoffs in company performance.


Incidence and etiology of chronic pulmonary infections in patients with idiopathic pulmonary fibrosis.
The incidence and etiologies of chronic pulmonary infection (CPI) in patients with idiopathic pulmonary fibrosis (IPF) have been poorly investigated. We conducted a retrospective study of 659 patients with IPF to assess the incidence, etiologies, and risk factors of CPI development. CPI was defined if the etiology of infection was diagnosed one or more months after the onset of symptoms or upon the appearance of new shadows on pulmonary radiological images. At IPF diagnosis, 36 (5.5%) patients had CPI, and 46 (7.0%) patients without CPI at IPF diagnosis developed CPI over a median follow-up period of 6.1 years. The incidence density of CPI development was 18.90 cases per 1000 person-years. Detected organisms from these 46 patients were Mycobacterium avium complex in 20 patients, other nontuberculous mycobacteria in 4, M. tuberculosis in 7, Aspergillus spp. in 22, and Nocardia sp. in one. In a multivariate Cox regression hazard model, PaO2 <70 Torr and KL-6 ≥2000 U/mL were associated with CPI development. Nontuberculous mycobacteria, M. tuberculosis, and Aspergillus and Nocardia spp. were the four most frequent etiologies of CPI in patients with IPF. During follow-up of IPF, clinicians should pay attention to the development of CPI, especially in patients with PaO2 <70 Torr or KL-6 ≥2000 U/mL.


Biomarkers of milk fat and the risk of myocardial infarction in men and women: a prospective, matched case-control study.
High intakes of saturated fat have been associated with cardiovascular disease, and milk fat is rich in saturated fat. The objective of this study was to investigate the association between the serum milk fat biomarkers pentadecanoic acid (15:0), heptadecanoic acid (17:0), and their sum (15:0+17:0) and a first myocardial infarction (MI). The study design was a prospective case-control study nested within a large population-based cohort in Sweden. Included in the study were 444 cases (307 men) and 556 controls (308 men) matched on sex, age, date of examination, and geographic region. Clinical, anthropometric, biomarker fatty acid, physical activity, and dietary data were collected. The odds of a first MI were investigated by using conditional logistic regression. In women, proportions of milk fat biomarkers in plasma phospholipids were significantly higher (P < 0.05) in controls than in cases and were, in general, negatively, albeit weakly, correlated with risk factors for metabolic syndrome. The crude standardized odds ratios of becoming an MI case were 0.74 (95% CI: 0.58, 0.94) in women and 0.91 (95% CI: 0.77, 1.1) in men. After multivariable adjustment for confounders, the inverse association remained in both sexes and was significant in women. In agreement with biomarker data, quartiles of reported intake of cheese (men and women) and fermented milk products (men) were inversely related to a first MI (P for trend < 0.05 for all). Milk fat biomarkers were associated with a lower risk of developing a first MI, especially in women. This was partly confirmed in analysis of fermented milk and cheese intake. Components of metabolic syndrome were observed as potential intermediates for the risk relations.


Regulation of insulin-like growth factor-binding protein-3 ternary complex in feline diabetes mellitus.
The 140 kDa ternary complex of insulin-like growth factor-binding protein-3 (IGFBP-3), IGFs and an acid-labile subunit (ALS) has previously been shown to be decreased in diabetes mellitus in humans and rats. We have studied IGF-I levels and ternary complex formation in normal and diabetic cats. Total IGF-I concentrations, measured by RIA using des(1-3)-IGF-I as tracer were (+/-s.e.m.) 54+/-13 nmol/l in eight normal and 227+/-57 nmol/l in eight diabetic cats (P<0.01). The size-distribution of IGFBPs in the cat circulation was determined by incubation with (125)I-IGF-II and Superose 12 chromatography. In normal animals 26+/-2% of the (125)I-IGF-II were in a 140 kDa form compared with 48+/-5% in diabetic cats (P<0.01). When samples from normal and diabetic animals were co-incubated 52+/-3% were at 140 kDa. A similar shift was seen when normal cat and normal human serum were co-incubated. A 2-fold increase in the 140 kDa form in diabetic cats was confirmed first by size-fractionating samples and then performing a ligand-binding assay with (125)I-IGF-I or -II and charcoal separation. SDS-PAGE and Western ligand blotting demonstrated a 45 kDa doublet (presumably IGFBP-3) and 30-35 kDa forms. There were no apparent differences between normal and diabetic profiles on SDS-PAGE, suggesting that a proportion of IGFBP-3 which circulates 'free' in normal cats forms a ternary complex in the diabetic circulation. We conclude that (i) in contrast to humans and rats, ALS is the limiting factor for ternary complex formation in normal cats, (ii) ALS concentrations increase in feline diabetes mellitus and, by promoting ternary complex formation, this leads to an increase in total IGF-I concentrations, and (iii) total IGF-I concentrations may not be reliable in the diagnosis of acromegaly in diabetic cats.


Moral responsibility: a relational way of being.
This article reports a study exploring the meaning of the complex phenomenon of moral responsibility in nursing practice. Each of three focus groups with a total of 14 student nurses were conducted twice to gather their views on moral responsibility in nursing practice. The data were analysed by qualitative thematic content analysis. Moral responsibility was interpreted as a relational way of being, which involved guidance by one's inner compass composed of ideals, values and knowledge that translate into a striving to do good. It was concluded that, if student nurses are to continue striving to do good in a way that respects themselves and other people, it is important that they do not feel forced to compromise their values. Instead they should be given space and encouragement in their endeavours to do good in a relational way that advances nursing as a moral practice.


Earliest known human burial in Africa.
The origin and evolution of hominin mortuary practices are topics of intense interest and debate1-3. Human burials dated to the Middle Stone Age (MSA) are exceedingly rare in Africa and unknown in East Africa1-6. Here we describe the partial skeleton of a roughly 2.5- to 3.0-year-old child dating to 78.3 ± 4.1 thousand years ago, which was recovered in the MSA layers of Panga ya Saidi (PYS), a cave site in the tropical upland coast of Kenya7,8. Recent excavations have revealed a pit feature containing a child in a flexed position. Geochemical, granulometric and micromorphological analyses of the burial pit content and encasing archaeological layers indicate that the pit was deliberately excavated. Taphonomical evidence, such as the strict articulation or good anatomical association of the skeletal elements and histological evidence of putrefaction, support the in-place decomposition of the fresh body. The presence of little or no displacement of the unstable joints during decomposition points to an interment in a filled space (grave earth), making the PYS finding the oldest known human burial in Africa. The morphological assessment of the partial skeleton is consistent with its assignment to Homo sapiens, although the preservation of some primitive features in the dentition supports increasing evidence for non-gradual assembly of modern traits during the emergence of our species. The PYS burial sheds light on how MSA populations interacted with the dead.


How have mathematical models contributed to understanding the transmission and control of SARS-CoV-2 in healthcare settings? A systematic search and review.
Since the onset of the COVID-19 pandemic, mathematical models have been widely used to inform public health recommendations regarding COVID-19 control in healthcare settings. The objective of this study was to systematically review SARS-CoV-2 transmission models in healthcare settings, and to summarize their contributions to understanding nosocomial COVID-19. A systematic search and review of published articles indexed in PubMed was carried out. Modelling studies describing dynamic inter-individual transmission of SARS-CoV-2 in healthcare settings, published by mid-February 2022 were included. Models have mostly focused on acute-care and long-term-care facilities in high-income countries. Models have quantified outbreak risk, showing great variation across settings and pandemic periods. Regarding surveillance, routine testing rather than symptom-based was highlighted as essential for COVID-19 prevention due to high rates of silent transmission. Surveillance impacts depended critically on testing frequency, diagnostic sensitivity, and turn-around time. Healthcare re-organization also proved to have large epidemiological impacts: beyond obvious benefits of isolating cases and limiting inter-individual contact, more complex strategies (staggered staff scheduling, immune-based cohorting) reduced infection risk. Finally, vaccination impact, while highly effective for limiting COVID-19 burden, varied substantially depending on assumed mechanistic impacts on infection acquisition, symptom onset and transmission. Modelling results form an extensive evidence base that may inform control strategies for future waves of SARS-CoV-2 and other viral respiratory pathogens. We propose new avenues for future models of healthcare-associated outbreaks, with the aim of enhancing their efficiency and contributions to decision-making.


Prevention and diagnosis of venous thromboembolism in critically ill patients: a Canadian survey.
Venous thromboembolism (VTE) confers considerable morbidity and mortality in hospitalized patients, although few studies have focused on the critically ill population. The objective of this study was to understand current approaches to the prevention and diagnosis of deep venous thrombosis (DVT) and pulmonary embolism (PE) among patients in the intensive care unit (ICU). Mailed self-administered survey of ICU Directors in Canadian university affiliated hospitals. Of 29 ICU Directors approached, 29 (100%) participated, representing 44 ICUs and 681 ICU beds across Canada. VTE prophylaxis is primarily determined by individual ICU clinicians (20/29, 69.0%) or with a hematology consultation for challenging patients (9/29, 31.0%). Decisions are usually made on a case-by-case basis (18/29, 62.1%) rather than by preprinted orders (5/29, 17.2%), institutional policies (6/29, 20.7%) or formal practice guidelines (2/29, 6.9%). Unfractionated heparin is the predominant VTE prophylactic strategy (29/29, 100.0%) whereas low molecular weight heparin is used less often, primarily for trauma and orthopedic patients. Use of pneumatic compression devices and thromboembolic stockings is variable. Systematic screening for DVT with lower limb ultrasound once or twice weekly was reported by some ICU Directors (7/29, 24.1%) for specific populations. Ultrasound is the most common diagnostic test for DVT; the reference standard of venography is rarely used. Spiral computed tomography chest scans and ventilation-perfusion scans are used more often than pulmonary angiograms for the diagnosis of PE. ICU Directors recommend further studies in the critically ill population to determine the test properties and risk:benefit ratio of VTE investigations, and the most cost-effective methods of prophylaxis in medical-surgical ICU patients. Unfractionated subcutaneous heparin is the predominant VTE prophylaxis strategy for critically ill patients, although low molecular weight heparin is prescribed for trauma and orthopedic patients. DVT is most often diagnosed by lower limb ultrasound; however, several different tests are used to diagnose PE. Fundamental research in critically ill patients is needed to help make practice evidence-based.


Non-orthogonal tool/flange and robot/world calibration.
For many robot-assisted medical applications, it is necessary to accurately compute the relation between the robot's coordinate system and the coordinate system of a localisation or tracking device. Today, this is typically carried out using hand-eye calibration methods like those proposed by Tsai/Lenz or Daniilidis. We present a new method for simultaneous tool/flange and robot/world calibration by estimating a solution to the matrix equation AX = YB. It is computed using a least-squares approach. Because real robots and localisation are all afflicted by errors, our approach allows for non-orthogonal matrices, partially compensating for imperfect calibration of the robot or localisation device. We also introduce a new method where full robot/world and partial tool/flange calibration is possible by using localisation devices providing less than six degrees of freedom (DOFs). The methods are evaluated on simulation data and on real-world measurements from optical and magnetical tracking devices, volumetric ultrasound providing 3-DOF data, and a surface laser scanning device. We compare our methods with two classical approaches: the method by Tsai/Lenz and the method by Daniilidis. In all experiments, the new algorithms outperform the classical methods in terms of translational accuracy by up to 80% and perform similarly in terms of rotational accuracy. Additionally, the methods are shown to be stable: the number of calibration stations used has far less influence on calibration quality than for the classical methods. Our work shows that the new method can be used for estimating the relationship between the robot's and the localisation device's coordinate systems. The new method can also be used for deficient systems providing only 3-DOF data, and it can be employed in real-time scenarios because of its speed.


Relationship between Daytime Sleepiness and Health Utility in Patients after Cardiac Surgery: A Preliminary Study.
Background Daytime sleepiness can be assessed by the Epworth Sleepiness Scale (ESS), which is widely used in the field of sleep medicine as a subjective measure of a patient's sleepiness. Also, health utility assessed by the mean Short-Form Six-Dimension (SF-6D) score, one of several preference-based utility measures, is an important measure in health care. We aimed to examine age-related differences in daytime sleepiness and health utility and their relationship in patients 5 months after cardiac surgery. Methods; This cross-sectional study assessed 51 consecutive cardiac surgery patients who were divided into a middle-aged (<65 years, n = 29) and older-age group (≥65 years, n = 22). The mean ESS and SF-6D utility scores were measured at 5 months after cardiac surgery and compared. In addition, the relationship between ESS and SF-6D utility scores were assessed. Results; There were no significant differences between the middle-aged and older-aged groups in either the mean ESS (5.14 ± 2.96 vs. 4.05 ± 3.23, p = 0.22) or SF-6D utility (0.72 ± 0.14 vs. 0.71 ± 0.10, p = 0.76) scores. However, there was a negative correlation between both values in all of the patients after cardiac surgery (r = -0.41, p = 0.003). Conclusions; Although there were no age-related differences in the ESS and SF-6D utility values between the two groups, there was a negative correlation between these values in all patients at 5 months after cardiac surgery. This suggested that sleepiness is associated with decreased utility scores in patients at 5 months after cardiac surgery.


External kinetics of the kettlebell snatch in amateur lifters.
Kettlebell lifting has gained increased popularity as both a form of resistance training and as a sport, despite the paucity of literature validating its use as a training tool. Kettlebell sport requires participants to complete the kettlebell snatch continuously over prolonged periods of time. Kettlebell sport and weightlifting involve similar exercises, however, their traditional uses suggest they are better suited to training different fitness qualities. This study examined the three-dimensional ground reaction force (GRF) and force applied to the kettlebell over a 6 min kettlebell snatch set in 12 kettlebell-trained males. During this set, VICON was used to record the kettlebell trajectory with nine infrared cameras while the GRF of each leg was recorded with a separate AMTI force plate. Over the course of the set, an average of 13.9 ± 3.3 repetitions per minute were performed with a 24 kg kettlebell. Significance was evaluated with a two-way ANOVA and paired t-tests, whilst Cohen's F (ESF) and Cohen's D (ESD) were used to determine the magnitude. The applied force at the point of maximum acceleration was 814 ± 75 N and 885 ± 86 N for the downwards and upwards phases, respectively. The absolute peak resultant bilateral GRF was 1,746 ± 217 N and 1,768 ± 242 N for the downwards and upwards phases, respectively. Bilateral GRF of the first and last 14 repetitions was found to be similar, however there was a significant difference in the peak applied force (F (1.11) = 7.42, p = 0.02, ESF = 0.45). Unilateral GRF was found have a significant difference for the absolute anterior-posterior (F (1.11) = 885.15, p < 0.0001, ESF = 7) and medio-lateral force vectors (F (1.11) = 5.31, p = 0.042, ESF = 0.67). Over the course of a single repetition there were significant differences in the GRF and applied force at multiple points of the kettlebells trajectory. The kettlebell snatch loads each leg differently throughout a repetition and performing the kettlebell snatch for 6 min will result in a reduction in peak applied force.


Facilitators and Barriers to Care Coordination in Patient-centered Medical Homes (PCMHs) from Coordinators' Perspectives.
Care coordinators are increasingly featured in patient-centered medical home (PCMH) projects, yet little research examines how coordinators themselves define and experience their role. This is the first study describing experiences of care coordinators across the US from their own perspectives. This qualitative study used a 5-month private, online discussion forum to gather data from 25 care coordinators from PCMH practices representing diversity in practice size, setting, and type. Participants answered questions and interacted with one another, creating an online social learning collaborative while allowing for data collection for research. Coordinators identified barriers and facilitators in their work at the organization/system level, the interpersonal level, and the individual level. Some factors emerged as both barriers and facilitators, including the functionality of clinical information technology; the availability of community resources; interactions with clinicians and other health care facilities; interactions with patients; and self-care practices for mental health and wellness. Colocation and full integration into practices were other key facilitators, whereas excessive case loads and data management responsibilities were felt to be important barriers. While all the barriers and facilitators were important to performing coordinators' roles, relationship building materialized as key to effective care coordination, whether with clinicians, patients, or outside organizations. We discuss implications for practice and provide suggestions for further research.


A trial of a comprehensive nursing rehabilitation program for nursing home residents post-hospitalization.
This pilot study examined the feasibility of implementing a comprehensive nursing rehabilitation program (CNRP) designed to promote the physical functioning of moderately frail nursing home residents post-hospitalization. The 4-week to 8-week CNRP incorporated three interventions: the Capacity Intervention (improving strength and balance), Performance Intervention (fostering daily mobility and activity), and Facilitating Intervention (providing education, support, and stress management). A longitudinal design was used with a convenience sample of 24 moderately frail residents. The CNRP was found to be not practical as designed because the intervention occurred too close to hospital discharge, and many prospective participants did not "feel up" to participating in a voluntary nursing rehabilitation program in addition to other prescribed rehabilitation. Regardless, participants were found to be able to perform the exercises safely and the CNRP was easily implemented in nursing homes. Testing the efficacy of the CNRP with nursing home residents is recommended after the initial post-hospitalization period.


Orbital quantum magnetism in spin dynamics of strongly interacting magnetic lanthanide atoms.
Laser-cooled lanthanide atoms are ideal candidates with which to study strong and unconventional quantum magnetism with exotic phases. Here, we use state-of-the-art closed-coupling simulations to model quantum magnetism for pairs of ultracold spin-6 erbium lanthanide atoms placed in a deep optical lattice. In contrast to the widely used single-channel Hubbard model description of atoms and molecules in an optical lattice, we focus on the single-site multichannel spin evolution due to spin-dependent contact, anisotropic van der Waals, and dipolar forces. This has allowed us to identify the leading mechanism, orbital anisotropy, that governs molecular spin dynamics among erbium atoms. The large magnetic moment and combined orbital angular momentum of the 4f -shell electrons are responsible for these strong anisotropic interactions and unconventional quantum magnetism. Multichannel simulations of magnetic Cr atoms under similar trapping conditions show that their spin evolution is controlled by spin-dependent contact interactions that are distinct in nature from the orbital anisotropy in Er. The role of an external magnetic field and the aspect ratio of the lattice site on spin dynamics is also investigated.


Clinical neurophysiology of visual and auditory processing in dyslexia: a review.
Neurophysiological studies on children and adults with dyslexia provide a deeper understanding of how visual and auditory processing in dyslexia might relate to reading deficits. The goal of this review is to provide an overview of research findings in the last two decades on motion related and contrast sensitivity visual evoked potentials and on auditory event related potentials to basic tone and speech sound processing in dyslexia. These results are particularly relevant for three important theories about causality in dyslexia: the magnocellular deficit hypothesis, the temporal processing deficit hypothesis and the phonological deficit hypothesis. Support for magnocellular deficits in dyslexia are primarily provided from evidence for altered visual evoked potentials to rapidly moving stimuli presented at low contrasts. Consistently ERP findings revealed altered neurophysiological processes in individuals with dyslexia to speech stimuli, but evidence for deficits processing certain general acoustic information relevant for speech perception, such as frequency changes and temporal patterns, are also apparent.


Dual-stimuli responsive injectable microgel/solid drug nanoparticle nanocomposites for release of poorly soluble drugs.
An in situ forming implant (ISFI) for drug delivery combines the potential to improve therapeutic adherence for patients with simple administration by injection. Herein, we describe the preparation of an injectable nanocomposite ISFI composed of thermoresponsive poly(N-isopropylacrylamide) based microgels and solid drug nanoparticles. Monodisperse poly(N-isopropylacrylamide) or poly(N-isopropylacrylamide-co-allylamine) microgels were prepared by precipitation polymerisation with mean diameters of approximately 550 nm at 25 °C. Concentrated dispersions of these microgels displayed dual-stimuli responsive behaviour, forming shape persistent bulk aggregates in the presence of both salt (at physiological ionic strength) and at body temperature (above the lower critical solution temperature of the polymer). These dual-stimuli responsive microgels could be injected into an agarose gel tissue mimic leading to rapid aggregation of the particles to form a drug depot. Additionally, the microgel particles aggregated in the presence of other payload nanoparticles (such as dye-containing polystyrene nanoparticles or lopinavir solid drug nanoparticles) to form nanocomposites with high entrapment efficiency of the payload. The resulting microgel and solid drug nanoparticle nanocomposites displayed sustained drug release for at least 120 days, with the rate of release tuned by blending microgels of poly(N-isopropylacrylamide) with poly(N-isopropylacrylamide-co-allylamine) microgels. Cytotoxicity studies revealed that the microgels were not toxic to MDCK-II cells even at high concentrations. Collectively, these results demonstrate a novel, easily injectable, nanocomposite ISFI that provides long-term sustained release for poorly water-soluble drugs without a burst release.


Health research in the Western Cape province, South Africa: lessons and challenges.
Health research can play a critical role in strengthening health systems.However, little monitoring of health research is conducted in African countries to identify whether research contributes to addressing local health priorities.Aim/Setting: To review the profile of research on the health service platform in the Western Cape province of South Africa which was approved by the health authorities over the period January 2011 to December 2012. Databases held by both the Provincial and City of Cape Town health departments were reviewed. Descriptions of research institution, location of research, topic and funding size and source were analysed. Of the health research approved in the province, 56% of projects were located on the District Health Services platform and 70% were based in the Cape Metropolitan area. For projects reporting budgetary information, the total funding was US $29.2 million. The primary focus of research was on HIV and tuberculosis (TB), whilst relatively few studies addressed nutrition, mental health or injury and there was little health systems research. Research funding was dominated by very large grants from foreign funders for HIV and/or TB research. South African government sources comprised less than 8% of all health research funding. There is a partial mismatch of donor funding to local health priorities. Greater focus on neglected areas such as mental health, trauma, nutrition and non-communicable disease, as well as greater investment in health systems research, is needed. Unless governments increase funding for research and a culture of research translation is achieved, health research will have limited impact on both local and national priorities.


GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood.
Lymphocytes egress from lymphoid organs in response to sphingosine-1-phosphate (S1P); minutes later they migrate from blood into tissue against the S1P gradient. The mechanisms facilitating cell movement against the gradient have not been defined. Here, we show that heterotrimeric guanine nucleotide-binding protein-coupled receptor kinase-2 (GRK2) functions in down-regulation of S1P receptor-1 (S1PR1) on blood-exposed lymphocytes. T and B cell movement from blood into lymph nodes is reduced in the absence of GRK2 but is restored in S1P-deficient mice. In the spleen, B cell movement between the blood-rich marginal zone and follicles is disrupted by GRK2 deficiency and by mutation of an S1PR1 desensitization motif. Moreover, delivery of systemic antigen into follicles is impaired. Thus, GRK2-dependent S1PR1 desensitization allows lymphocytes to escape circulatory fluids and migrate into lymphoid tissues.


Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.
To delineate the clinical characteristics of patients with coronavirus disease 2019 (covid-19) who died. Retrospective case series. Tongji Hospital in Wuhan, China. Among a cohort of 799 patients, 113 who died and 161 who recovered with a diagnosis of covid-19 were analysed. Data were collected until 28 February 2020. Clinical characteristics and laboratory findings were obtained from electronic medical records with data collection forms. The median age of deceased patients (68 years) was significantly older than recovered patients (51 years). Male sex was more predominant in deceased patients (83; 73%) than in recovered patients (88; 55%). Chronic hypertension and other cardiovascular comorbidities were more frequent among deceased patients (54 (48%) and 16 (14%)) than recovered patients (39 (24%) and 7 (4%)). Dyspnoea, chest tightness, and disorder of consciousness were more common in deceased patients (70 (62%), 55 (49%), and 25 (22%)) than in recovered patients (50 (31%), 48 (30%), and 1 (1%)). The median time from disease onset to death in deceased patients was 16 (interquartile range 12.0-20.0) days. Leukocytosis was present in 56 (50%) patients who died and 6 (4%) who recovered, and lymphopenia was present in 103 (91%) and 76 (47%) respectively. Concentrations of alanine aminotransferase, aspartate aminotransferase, creatinine, creatine kinase, lactate dehydrogenase, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer were markedly higher in deceased patients than in recovered patients. Common complications observed more frequently in deceased patients included acute respiratory distress syndrome (113; 100%), type I respiratory failure (18/35; 51%), sepsis (113; 100%), acute cardiac injury (72/94; 77%), heart failure (41/83; 49%), alkalosis (14/35; 40%), hyperkalaemia (42; 37%), acute kidney injury (28; 25%), and hypoxic encephalopathy (23; 20%). Patients with cardiovascular comorbidity were more likely to develop cardiac complications. Regardless of history of cardiovascular disease, acute cardiac injury and heart failure were more common in deceased patients. Severe acute respiratory syndrome coronavirus 2 infection can cause both pulmonary and systemic inflammation, leading to multi-organ dysfunction in patients at high risk. Acute respiratory distress syndrome and respiratory failure, sepsis, acute cardiac injury, and heart failure were the most common critical complications during exacerbation of covid-19.


Chemical characterization of interspecific hybrids between Allium cepa L. and Allium kermesinum Rchb.
Interspecific hybridization between wild and cultivated species of the genus Allium has been performed to generate plant material possessing biochemical properties of both parental plants. These cross-breeding experiments should lead to Allium plants with higher amounts of valuable constituents. The chemical characterization of interspecific hybrids between A. cepa and A. kermesinum is described on the basis of their sulfur-containing constituents and secondary metabolites. In addition, the hybrid character has been proven by random amplified polymorphic DNA (RAPD) analysis of the progenies obtained from the crosses. It has been shown that the distribution of the cysteine sulfoxides as well as the volatile secondary metabolites in the hybrids is not uniform. The profiles are mainly determined by the paternal wild species A. kermesinum. It has been ascertained that the gas chromatography profiles of the hybrids show increasing amounts of unsymmetrical substituted oligosulfides, which are known to be physiologically active substances. On the basis of statistical calculations, three different types of hybrids can be separated. The chemical analysis of cysteine sulfoxides and volatile sulfur-containing substances is shown to be a useful tool for breeding purposes as it allows an effective selection with regard to optimal distribution and amount of valuable constituents.


Analysis of translating mitoribosome reveals functional characteristics of translation in mitochondria of fungi.
Mitoribosomes are specialized protein synthesis machineries in mitochondria. However, how mRNA binds to its dedicated channel, and tRNA moves as the mitoribosomal subunit rotate with respect to each other is not understood. We report models of the translating fungal mitoribosome with mRNA, tRNA and nascent polypeptide, as well as an assembly intermediate. Nicotinamide adenine dinucleotide (NAD) is found in the central protuberance of the large subunit, and the ATPase inhibitory factor 1 (IF1) in the small subunit. The models of the active mitoribosome explain how mRNA binds through a dedicated protein platform on the small subunit, tRNA is translocated with the help of the protein mL108, bridging it with L1 stalk on the large subunit, and nascent polypeptide paths through a newly shaped exit tunnel involving a series of structural rearrangements. An assembly intermediate is modeled with the maturation factor Atp25, providing insight into the biogenesis of the mitoribosomal large subunit and translation regulation.


FORECAST - A cloud-based personalized intelligent virtual coaching platform for the well-being of cancer patients.
Well-being of cancer patients and survivors is a challenge worldwide, considering the often chronic nature of the disease. Today, a large number of initiatives, products and services are available that aim to provide strategies to face the challenge of well-being in cancer patients; nevertheless the proposed solutions are often non-sustainable, costly, unavailable to those in need, and less well-received by patients. These challenges were considered in designing FORECAST, a cloud-based personalized intelligent virtual coaching platform for improving the well-being of cancer patients. Personalized coaching for cancer patients focuses on physical, mental, and emotional concerns, which FORECAST is able to identify. Cancer patients can benefit from coaching that addresses their emotional problems, helps them focus on their goals, and supports them in coping with their disease-related stressors. Personalized coaching in FORECAST offers support, encouragement, motivation, confidence, and hope and is a valuable tool for the wellbeing of a patient.


Ectopic activation of the miR-200c-EpCAM axis enhances antitumor T cell responses in models of adoptive cell therapy.
Adoptive T cell therapy (ACT) is a promising strategy for treating cancer, but it often fails because of cell intrinsic regulatory programs that limit the degree or duration of T cell function. In this study, we found that ectopic expression of microRNA-200c (miR-200c) markedly enhanced the antitumor activity of CD8+ cytotoxic T lymphocytes (CTLs) during ACT in multiple mouse models. CTLs transduced with miR-200c exhibited reduced apoptosis during engraftment and enhanced in vivo persistence, accompanied by up-regulation of the transcriptional regulator T cell factor 1 (TCF1) and the inflammatory cytokine tumor necrosis factor (TNF). miR-200c elicited these changes by suppressing the transcription factor Zeb1 and thereby inducing genes characteristic of epithelial cells. Overexpression of one of these genes, Epcam, was sufficient to augment therapeutic T cell responses against both solid and liquid tumors. These results identify the miR-200c–EpCAM axis as an avenue for improving ACT and demonstrate that select genetic perturbations can produce phenotypically distinct T cells with advantageous therapeutic properties.


Spatial quenching of a molecular charge-transfer process in a quantum fluid: the Csx-C60 reaction in superfluid helium nanodroplets.
A recent experimental study [Renzler et al., J. Chem. Phys., 2016, 145, 181101] on superfluid helium nanodroplets reported different reactivities for Cs atoms and Cs2 dimers with C60 fullerenes inside helium droplets. Alkali metal atoms and clusters are heliophobic, therefore typically residing on the droplet surface, while fullerenes are fully immersed into the droplet. In this theoretical study, which combines standard methods of computational chemistry with orbital-free helium density functional theory, we show that the experimental findings can be interpreted in the light of a quenched electron-transfer reaction between the fullerene and the alkali dopant, which is additionally hindered by a reaction barrier stemming from the necessary extrusion of helium upon approach of the two reactants.


Structural Insights into Endobiotic Reactivation by Human Gut Microbiome-Encoded Sulfatases.
Phase II drug metabolism inactivates xenobiotics and endobiotics through the addition of either a glucuronic acid or sulfate moiety prior to excretion, often via the gastrointestinal tract. While the human gut microbial β-glucuronidase enzymes that reactivate glucuronide conjugates in the intestines are becoming well characterized and even controlled by targeted inhibitors, the sulfatases encoded by the human gut microbiome have not been comprehensively examined. Gut microbial sulfatases are poised to reactivate xenobiotics and endobiotics, which are then capable of undergoing enterohepatic recirculation or exerting local effects on the gut epithelium. Here, using protein structure-guided methods, we identify 728 distinct microbiome-encoded sulfatase proteins from the 4.8 million unique proteins present in the Human Microbiome Project Stool Sample database and 1766 gut microbial sulfatases from the 9.9 million sequences in the Integrated Gene Catalogue. We purify a representative set of these sulfatases, elucidate crystal structures, and pinpoint unique structural motifs essential to endobiotic sulfate processing. Gut microbial sulfatases differentially process sulfated forms of the neurotransmitters serotonin and dopamine, and the hormones melatonin, estrone, dehydroepiandrosterone, and thyroxine in a manner dependent both on variabilities in active site architecture and on markedly distinct oligomeric states. Taken together, these data provide initial insights into the structural and functional diversity of gut microbial sulfatases, providing a path toward defining the roles these enzymes play in health and disease.


Reducing toxic reactive carbonyl species in e-cigarette emissions: testing a harm-reduction strategy based on dicarbonyl trapping.
Reducing the concentration of reactive carbonyl species (RCS) in e-cigarette emissions represents a major goal to control their potentially harmful effects. Here, we adopted a novel strategy of trapping carbonyls present in e-cigarette emissions by adding polyphenols in e-liquid formulations. Our work showed that the addition of gallic acid, hydroxytyrosol and epigallocatechin gallate reduced the levels of carbonyls formed in the aerosols of vaped e-cigarettes, including formaldehyde, methylglyoxal and glyoxal. Liquid chromatography mass spectrometry analysis highlighted the formation of covalent adducts between aromatic rings and dicarbonyls in both e-liquids and vaped samples, suggesting that dicarbonyls were formed in the e-liquids as degradation products of propylene glycol and glycerol before vaping. Short-term cytotoxic analysis on two lung cellular models showed that dicarbonyl-polyphenol adducts are not cytotoxic, even though carbonyl trapping did not improve cell viability. Our work sheds lights on the ability of polyphenols to trap RCS in high carbonyl e-cigarette emissions, suggesting their potential value in commercial e-liquid formulations.


Selective Neck Dissection (IIa, III): A Rational Replacement for Extended Supraomohyoid Neck Dissection in Patients with N0 Supraglottic and Glottic Squamous Cell Carcinoma.
To evaluate the effectiveness of selective neck dissection of sublevel IIa and level III in cases of glottis and supraglottic laryngeal carcinoma in the absence of lymph node metastasis and to show if there is value in dissecting the sublevel IIb or level IV in these cases. Twenty-five patients with N0 glottic or supraglottic cancer were subjected to unilateral or bilateral selective neck dissection according to the site and the extent of the tumor, and the specimens were histopathologically examined for metastasis. Twenty-five patients (23 males and 2 females) with mean age of 55.72 years were included in the study. Lymph node metastasis to sublevel IIa and level III was found in 6/25 (24%) cases with glottic or supraglottic carcinoma, while to sublevel IIb and level IV was found in 1/25 (4%) with P-value of 0.05, which is statistically significant. Selective neck dissection of level IIb is not required in cases of the supraglottic laryngeal cancer. Dissection of sublevel IIa and level III takes less time and is effective. Dissection of level IV is not needed in the case of supraglottic cancer.


Causal inference in infectious diseases.
Since the 1970s, Rubin has promoted a model for causal inference based on the potential outcomes if individuals received each of the treatments under study. Commonly, the assumption is made that the outcome in one individual is independent of the treatment assignment and outcome in other individuals. In infectious diseases, however, whether one person become infected is quite often dependent on the infection outcome in other individuals, a situation known as dependent happenings. Here, we review the model proposed by Rubin for the example of infectious disease. Consequences of the violation of the stability assumption include the need for an expanded representation of outcomes, and the existence of different kinds of effects, such as direct and indirect effects. Effects of interest include changes in susceptibility as well as changes in infectiousness. We define the transmission probability formally as an average causal parameter of effect in a population by conditioning on exposure to infection. Unconditional indirect and total effects are difficult to define formally using this model for causal inference. The assignment mechanism can influence the sampling mechanism when it determines who is exposed to infection, raising problems that require further inquiry. We conclude by contrasting the role of differential exposure to infection in direct and indirect effects.