Healthcare Costs for the Evaluation, Surgery, and Follow-Up Care of Living Kidney Donors.
The healthcare costs to evaluate, perform surgery, and follow a living kidney donor for the year after donation are poorly described. We obtained information on the healthcare costs of 1099 living kidney donors between April 1, 2004, and March 31, 2014, from Ontario, Canada, using comprehensive healthcare administrative databases. We estimated the cost of 3 periods of the living donation process: the predonation evaluation period (start of evaluation until the day before donation), perioperative period (day of donation until 30-days postdonation), and 1 year of follow-up period (after perioperative period until 1 year postdonation). We analyzed data for donors and healthy matched nondonor controls using regression-based methods to estimate the incremental cost of living donation. Costs are presented from the perspective of the Canadian healthcare payer (2017 CAD $). The incremental healthcare costs (compared with controls) for the evaluation, perioperative, and follow-up periods were CAD $3596 (95% confidence interval [CI], CAD $3350-$3842), CAD $11 694 (95% CI, CAD $11 415-CAD $11 973), and $1011 (95% CI, CAD $793-CAD $1230), respectively, totalling CAD $16 290 (95% CI, CAD $15 814-CAD $16 767). The evaluation cost was higher if the intended recipient started dialysis partway through the donor evaluation (CAD $886; 95% CI, CAD $19, CAD $1752). The perioperative cost varied across transplant centers (P < 0.0001). Although substantial costs of living donor care are related to the nephrectomy procedure, comprehensive assessment of costs must also include the evaluation and follow-up periods. These estimates are informative for planning future work to support and expand living donation and transplantation, and directing efforts to improve the cost efficiency of living donor care.


Insight into the mechanism of antimicrobial conjugated polyelectrolytes: lipid headgroup charge and membrane fluidity effects.
The interactions of antimicrobial cationic conjugated polyelectrolytes (CPEs) with two model membranes, liposomes and lipid monolayers at the air-water interface, have been investigated by fluorescence emission, fluorescence quenching, pressure-area isotherm, and dynamic light scattering measurements. This study continues the evaluation of the antimicrobial mechanism of a cationic poly(phenylene ethynylene) (PPE)-based CPE (polymer 1), which contains a 2,5-thienylene moiety in the repeat unit. To this end, the interactions of polymer 1 with lipids with varying headgroup charge and acyl chain length have been examined. Our results show that the cationic polymer 1 can efficiently associate with and insert into anionic phosphatidylglycerol (PG) membranes. However, polymer 1 does not exhibit any interactions with zwitterionic lipid membranes composed of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) lipids. Polymer 1's selective affinity toward anionic lipids over zwitterionic lipids makes it an attractive antimicrobial agent with low toxicity. The interactions of polymer 1 with lipid membranes of different fluidity were studied by varying the surface pressure of lipid monolayers and by adjusting the temperature of liposomes. We observe that increasing membrane fluidity enhances both the conformational changes of polymer 1 upon associating with lipid membranes and the extent of polymer 1 insertion into lipid monolayers. We also find that the thickness of the lipid bilayers, modulated by acyl chain length, affects the extent of polymer 1 incorporation into the lipid bilayer.


Automated EEG entropy measurements in coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state.
Monitoring the level of consciousness in brain-injured patients with disorders of consciousness is crucial as it provides diagnostic and prognostic information. Behavioral assessment remains the gold standard for assessing consciousness but previous studies have shown a high rate of misdiagnosis. This study aimed to investigate the usefulness of electroencephalography (EEG) entropy measurements in differentiating unconscious (coma or vegetative) from minimally conscious patients. Left fronto-temporal EEG recordings (10-minute resting state epochs) were prospectively obtained in 56 patients and 16 age-matched healthy volunteers. Patients were assessed in the acute (≤1 month post-injury; n=29) or chronic (>1 month post-injury; n=27) stage. The etiology was traumatic in 23 patients. Automated online EEG entropy calculations (providing an arbitrary value ranging from 0 to 91) were compared with behavioral assessments (Coma Recovery Scale-Revised) and outcome. EEG entropy correlated with Coma Recovery Scale total scores (r=0.49). Mean EEG entropy values were higher in minimally conscious (73±19; mean and standard deviation) than in vegetative/unresponsive wakefulness syndrome patients (45±28). Receiver operating characteristic analysis revealed an entropy cut-off value of 52 differentiating acute unconscious from minimally conscious patients (sensitivity 89% and specificity 90%). In chronic patients, entropy measurements offered no reliable diagnostic information. EEG entropy measurements did not allow prediction of outcome. User-independent time-frequency balanced spectral EEG entropy measurements seem to constitute an interesting diagnostic - albeit not prognostic - tool for assessing neural network complexity in disorders of consciousness in the acute setting. Future studies are needed before using this tool in routine clinical practice, and these should seek to improve automated EEG quantification paradigms in order to reduce the remaining false negative and false positive findings.


Complications in spine surgery.
The overall incidence of complications or adverse events in spinal surgery is unknown. Both prospective and retrospective analyses have been performed, but the results have not been critically assessed. Procedures for different regions of the spine (cervical and thoracolumbar) and the incidence of complications for each have been reported but not compared. Authors of previous reports have concentrated on complications in terms of their incidence relevant to healthcare providers: medical versus surgical etiology and the relevance of perioperative complications to perioperative events. Few authors have assessed complication incidence from the patient's perspective. In this report the authors summarize the spine surgery complications literature and address the effect of study design on reported complication incidence. A systematic evidence-based review was completed to identify within the published literature complication rates in spinal surgery. The MEDLINE database was queried using the key words "spine surgery" and "complications." This initial search revealed more than 700 articles, which were further limited through an exclusion process. Each abstract was reviewed and papers were obtained. The authors gathered 105 relevant articles detailing 80 thoracolumbar and 25 cervical studies. Among the 105 articles were 84 retrospective studies and 21 prospective studies. The authors evaluated the study designs and compared cervical, thoracolumbar, prospective, and retrospective studies as well as the durations of follow-up for each study. In the 105 articles reviewed, there were 79,471 patients with 13,067 reported complications for an overall complication incidence of 16.4% per patient. Complications were more common in thoracolumbar (17.8%) than cervical procedures (8.9%; p < 0.0001, OR 2.23). Prospective studies yielded a higher incidence of complications (19.9%) than retrospective studies (16.1%; p < 0.0001, OR 1.3). The complication incidence for prospective thoracolumbar studies (20.4%) was greater than that for retrospective series (17.5%; p < 0.0001). This difference between prospective and retrospective reviews was not found in the cervical studies. The year of study publication did not correlate with the complication incidence, although the duration of follow-up did correlate with the complication incidence (p = 0.001). Retrospective reviews significantly underestimate the overall incidence of complications in spine surgery. This analysis is the first to critically assess differing complication incidences reported in prospective and retrospective cervical and thoracolumbar spine surgery studies.


Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone.
The purpose of this prospective study was to determine the incidence of thyroid dysfunction in cancer patients receiving immunotherapy with interleukin-2 (IL-2) alone, and to assess the relationship of hypothyroidism to clinical response. A cohort of 281 consecutive patients with metastatic melanoma or renal carcinoma were treated with IL-2 alone from July 1, 1989 until June 30, 1993. The majority (n = 216) received high-dose IL-2 and the remainder (n = 65) received low-dose therapy. Thyroid function was measured before, during, and after immunotherapy. Forty-one percent of initially euthyroid patients developed thyroid dysfunction after starting high-dose IL-2-alone therapy. The most common abnormality was hypothyroidism, occurring in 35% of patients, although moderate or severe hypothyroidism requiring thyroid hormone replacement occurred in 9% of patients. Hypothyroidism was related to duration of IL-2 therapy and was not associated with clinical response. Hyperthyroidism developed in 7% of previously euthyroid patients receiving high-dose IL-2. Overall, the incidence of thyroid dysfunction was similar in the high- and low-dose IL-2 regimens. In conclusion, thyroid dysfunction is a common sequela of IL-2 therapy. Thyroid function should be measured routinely in cancer patients receiving IL-2-based treatment. It is recommended that thyroid hormone replacement be given to patients with moderate or severe hypothyroidism.


Behavioral and electrophysiological responses of the banana weevilCosmopolites sordidus to host plant volatiles.
Male and femaleCosmopolites sordidus were attracted to freshly cut banana rhizome and pseudostem in a still-air olfactometer. Females responded similarly to odors from a comparatively resistant and from a susceptible cultivar of banana, when presented as either freshly cut tissue or as Porapak-trapped volatiles. Females were also attracted to rotting banana pseudostem and to volatiles collected from it. Males and females gave similar responses to host tissue in both the behavioral bioassay and to collected volatiles in EAG recordings. Weevils did not respond, either behaviorally or electrophysiologically, to a synthetic mixture of mono- and sesqiterpenes, which made up over 9% of the volatiles collected from pseudostem.


Phase perfection in zinc Blende and Wurtzite III-V nanowires using basic growth parameters.
Controlling the crystallographic phase purity of III-V nanowires is notoriously difficult, yet this is essential for future nanowire devices. Reported methods for controlling nanowire phase require dopant addition, or a restricted choice of nanowire diameter, and only rarely yield a pure phase. Here we demonstrate that phase-perfect nanowires, of arbitrary diameter, can be achieved simply by tailoring basic growth parameters: temperature and V/III ratio. Phase purity is achieved without sacrificing important specifications of diameter and dopant levels. Pure zinc blende nanowires, free of twin defects, were achieved using a low growth temperature coupled with a high V/III ratio. Conversely, a high growth temperature coupled with a low V/III ratio produced pure wurtzite nanowires free of stacking faults. We present a comprehensive nucleation model to explain the formation of these markedly different crystal phases under these growth conditions. Critical to achieving phase purity are changes in surface energy of the nanowire side facets, which in turn are controlled by the basic growth parameters of temperature and V/III ratio. This ability to tune crystal structure between twin-free zinc blende and stacking-fault-free wurtzite not only will enhance the performance of nanowire devices but also opens new possibilities for engineering nanowire devices, without restrictions on nanowire diameters or doping.


Inhibitory effect of dietary curcumin on skin carcinogenesis in mice.
Laboratory animal model studies have suggested that curcumin may play an important role in inhibiting the process of carcinogenesis. Curcumin, the yellow pigment that is obtained from rhizomes of the plant Curcuma longa Linn (Family Zingiberaceae), is commonly used as a spice and food coloring agent. The present study was designed to investigate the chemopreventive action of dietary curcumin on 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation in male Swiss ablino mice. At 6 weeks of age, groups of animals were fed the standard (modified AIN-76 A) diet or a diet containing 1% curcumin. At 8 weeks of age, all animals, except those in the vehicle (acetone)-treated groups, received 100 microg of DMBA dissolved in 100 microl of acetone in a single application to the skin of the back. From 1 week after DMBA application, tumor promoter (2.5 microg of TPA dissolved in 100 microl of acetone) was applied to the same areas on mouse skin twice a week for 26 weeks. All groups continued on their respective dietary regimen until the termination of the experiment. The results indicate that dietary administration of curcumin significantly inhibited the number of tumors per mouse (P < 0.05) and the tumor volume (P < 0.01). The percentage of tumor-bearing mice tended to be lower in the mice on the curcumin diet than those on the standard diet. There was no difference in growth between mice of the standard and 1% curcumin groups. The results indicate the safety and the anti-carcinogenic effect of curcumin in mice.


Scenting Entertainment: Virtual Reality Storytelling, Theme Park Rides, Gambling, and Video-Gaming.
There has long been interest in both the tonic and phasic release of scent across a wide range of entertainment settings. While the presentation of semantically congruent scent has often been used in order to enhance people's immersion in a particular context, other generally less successful attempts have involved the pulsed presentation of a range of scents tied to specific events/scenes. Scents have even been released in the context of the casino to encourage the guests to linger for longer (and spend more), at least according to the results of one controversial study. In this narrative review, I want to take a closer look at the use of scent in a range of both physical and digital environments, highlighting the successes (as in the case of scented theme park rides) and frequent failures (as, seemingly, in the context of scent-enabled video games). While digitally inducing meaningful olfactory sensations is likely to remain a pipe dream for the foreseeable future, the digital control of scent release/delivery provides some limited opportunities to enhance the multisensory experience of entertainment. That said, it remains uncertain whether the general public will necessarily perceive the benefit, and hence be willing to pay for the privilege.


Repurposing Medications for Hospice/Palliative Care Symptom Control Is No Longer Sufficient: A Manifesto for Change.
The World Health Organization essential medications list for hospice/palliative care reflects that, with the judicious use of currently available medications, the majority of symptoms can be lessened, and some controlled completely. Even with optimal use of current medications, symptom control is still unacceptable for many people. Currently available medications offer great benefit to a minority of patients, some benefit to an additional group, and no benefit or harms to others. In symptom control, development of new drugs is advancing at a glacial pace, contrasting to the rapid advances seen in many other disciplines. Specialists in palliative care should agree on several principles consequently: 1) Access to symptom-control drugs codified in the World Health Organization Essential Medicines list deserves the strongest support from national policies and professional guidelines, especially in resource-challenged countries. 2) The optimal use of currently available symptom-control drugs cannot yield acceptably high rates of net benefits. 3) There is a compelling need to identify patient subgroups that are likely to benefit from available medications and provide rigorous empirical support for indications, dosing, and route of administration for clinical practice. 4) New therapies are needed requiring an accelerated effort to investigate further the pathophysiology, neurobiology, and pharmacogenetics of distressing symptoms, and factors contributing to variations in drug response. This development requires a lengthy lead time. 5) Smarter ways to promote new knowledge into practice are needed as no drug will be suitable for all patients. We need to improve clinical characterization and biomarker technology to bring the best drugs to the right patients every time.


Lats2 is an essential mitotic regulator required for the coordination of cell division.
Tumor suppressor Lats2 is a member of the conserved Dbf2 kinase family. It localizes to the centrosome and has been implicated in regulation of the cell cycle and apoptosis. However, the in vivo function of this kinase remains unclear. Here, we show that complete disruption of the gene encoding Lats2 in mice causes developmental defects in the nervous system and embryonic lethality. Furthermore, mutant cells derived from total LATS2-knock-out embryos exhibit mitotic defects including centrosome fragmentation and cytokinesis defects, followed by nuclear enlargement and multinucleation. We show that the Mob1 family, a regulator of mitotic exit, associates with Lats2 to induce its activation. We also show that the complete LATS2-knock-out cells exhibit an acceleration of exit from mitosis and marked down-regulation of critical mitotic regulators. These results suggest that Lats2 plays an essential mitotic role in coordinating accurate cytokinesis completion, governing the stabilization of other mitotic regulators.


Will like replace like? Linking thermal performance to ecological function across predator and herbivore populations.
The inability of species to adapt to changing climate may cause ecological communities to disassemble and lose ecological functioning. However, theory suggests that communities may be resilient whenever populations within species exhibit variation in thermal plasticity or adaptation whereby thermally tolerant populations replace thermally sensitive ones. But will they maintain the functional roles of the populations being replaced? This study evaluated whether "like replaces like" functionally by measuring how four populations of a grasshopper herbivore and its co-occurring spider predator cope with environmental warming. The study occurred across a latitudinal gradient bounded by southerly, warmer Connecticut and northerly, cooler New Hampshire, USA. The study compared the survival rates, thermal performance, habitat usage, and food chain interactions of each grasshopper and spider population between its home field site (field of origin) and a Connecticut transplant site, and the native Connecticut population. Three grasshopper populations exhibited physiological plasticity by adjusting metabolic rates. The fourth population selected cooler habitat locations. Spider populations did not alter their metabolism and instead selected cooler habitat locations, thereby altering spatial overlap with their prey and food chain interactions. Grasshopper populations that coped physiologically consumed plants in different ratios than the fourth population and the Connecticut population. Hence, "like may not replace like" whenever populations adapt physiologically to warming.


Gay male pornography and the racialisation of desire.
Very few studies have focused on the role pornography plays in influencing and modelling sexual desire on the basis of race and ethnicity. Using sexual script theory as an analytic tool, the purpose of this empirical study was to explore indicators of the racialisation of desire based on a sample of gay male pornography users in Québec (Canada) (n = 974). Because gay male pornography use is widespread, and because it is not simply used for the purposes of education and validation but also influences sexual norms and cultural scripts in a social context where sexual racism seems prevalent, this study offers a new perspective on a timely phenomenon. Based on our findings, the final nested linear regression model demonstrates that higher levels of racialised desire attributed to gay male pornography use were associated with the following: being at least 55 years old; having a yearly income of less than $45,000 CAD; using interracial gay male pornography; not primarily using gender-diverse gay male pornographic content (heterosexual, bisexual, transsexual); having higher levels of perceived pressure to conform; having a higher preference for bareback pornography; and having higher levels of acquired sexual knowledge.


The breeding system of wild red ruffed lemurs (Varecia rubra): a preliminary report.
Captive studies have shown that ruffed lemurs (Varecia) have an unusual suite of reproductive traits combined with extremely high maternal reproductive costs. These traits include the bearing of litters, nesting of altricial young, and absentee parenting. To characterize the breeding system of this enigmatic lemur, reproductive traits must be contextualized in the wild. Here, I provide a preliminary report of mating and infant care in one community of wild red ruffed lemurs (Varecia rubra). Observations span a 15-month period covering two birth seasons and one mating season on the Masoala Peninsula, Madagascar. Factors that are not possible to replicate in captivity are reported, such as mating pattern, natality and mortality rates, the location of nests within the home range, and the structuring of infant care within a natural community. V. rubra at Andranobe have a fission-fusion, multifemale-multimale grouping pattern and a polygamous mating system. They do not mate monogamously or live strictly in family-based groups as suggested by previous workers. During the first 2 months of life, nests and infant stashing localities are situated within each mother's respective core area, and inhabitants of each core area within the communal home range provide care for young. As part of their absentee parenting system, infants are left in concealed, protected, and supportive spots high in the canopy, while mothers travel distantly. This practice is termed 'infant stashing'. Alloparenting appears to be an integral part of V. rubra's overall reproductive strategy in the wild, as it was performed by all age-sex classes. Among the alloparental behaviors observed were infant guarding, co-stashing, infant transport, and allonursing. Alloparenting and absentee parenting may mitigate high maternal reproductive costs. Furthermore, V. rubra may have a breeding system in which genetic partners (i.e., mating partners) do not always correspond to infant care-providers. Combined with recently available information on the behavioral ecology of wild ruffed lemurs, this preliminary report suggests directions for in-depth studies on Varecia's breeding system.


Why are computational neuroscience and systems biology so separate?
Despite similar computational approaches, there is surprisingly little interaction between the computational neuroscience and the systems biology research communities. In this review I reconstruct the history of the two disciplines and show that this may explain why they grew up apart. The separation is a pity, as both fields can learn quite a bit from each other. Several examples are given, covering sociological, software technical, and methodological aspects. Systems biology is a better organized community which is very effective at sharing resources, while computational neuroscience has more experience in multiscale modeling and the analysis of information processing by biological systems. Finally, I speculate about how the relationship between the two fields may evolve in the near future.


Adjunctive therapies to reduce thrombotic events in patients with a history of myocardial infarction: role of vorapaxar.
Acute myocardial infarction (AMI) is generally attributed to coronary atherothrombotic disease. Platelet activation is essential for thrombus formation and is thus an important target for pharmacological intervention to prevent and treat AMI. Despite contemporary treatment with dual antiplatelet therapy, including acetylsalicylic acid and adenosine diphosphate receptor antagonists, patients with prior AMI remain at increased risk of future thrombotic events. This has stimulated the search for more potent antithrombotic agents. Among these is the oral protease-activated receptor-1 antagonist vorapaxar, which represents a new oral antiplatelet agent to reduce thrombotic risk in patients with atherothrombotic disease. The TRACER and the TRA 2°P-TIMI 50 trials concluded that vorapaxar in addition to standard therapy reduced ischemic adverse cardiac events. A remarkable benefit was observed in patients with stable atherosclerotic disease, particularly those with a previous history of AMI. Although favorable effects were seen in reduction of adverse cardiac events, this was associated with excess major and intracranial bleeding, particularly in patients at high risk of bleeding and those with a history of stroke or transient ischemic attack. Currently, the lack of a reliable individualized risk stratification tool to assess patients for thrombotic and bleeding tendencies in order to identify those who might gain most net clinical benefit has led to limited use of vorapaxar in clinical practice. Vorapaxar may find a niche as an adjunct to standard care in patients at high risk of thrombotic events and who are at low risk of bleeding.


Investigating the ability of non-invasive measures of cardiac output to detect a reduction in blood volume resulting from venesection in spontaneously breathing subjects.
Monitoring cardiac output (CO) in shocked patients provides key etiological information and can be used to guide fluid resuscitation to improve patient outcomes. Previously this relied on invasive monitoring, restricting its use in the Emergency Department (ED) setting. The development of non-invasive devices (such as LiDCOrapidv2 with CNAP™ and USCOM 1A), and ultrasound based measurements (Transthoracic echocardiography, inferior vena cava collapsibility index (IVCCI), carotid artery blood flow (CABF) and carotid artery corrected flow time (FTc)) enables stroke volume (SV) and CO to be measured non-invasively in the ED. We investigated the ability of these techniques to detect a change in CO resulting from a 500 ml reduction in circulating blood volume (CBV) following venesection in spontaneously breathing subjects. Additionally, we investigated if using incentive spirometry to standardise inspiratory effort improved the accuracy of IVC based measurements in spontaneously breathing subjects. We recorded blood pressure, heart rate, IVCCI, CABF, FTc, transthoracic echocardiographic (TTE) SV and CO, USCOM 1A SV and CO, LIDCOrapidv2 SV, CO, Stroke volume variation (SVV) and pulse pressure variation (PPV) in 40 subjects immediately before and after venesection. The Log-Odds and coefficient of variation of the difference between pre- and post-venesection values for each technique were used to compare their ability to consistently detect CO changes resulting from a reduction in CBV resulting from venesection. TTE consistently detected a reduction in CO associated with venesection with an average decrease in measured CO of 0.86 L/min (95% CI 0.61 to 1.12) across subjects. None of the other investigated techniques changed in a consistent manner following venesection. The use of incentive spirometry improved the consistency with which IVC ultrasound was able to detect a reduction in CBV. In a population of spontaneously breathing patients, TTE is able to consistency detect a reduction in CO associated with venesection.


Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis, and staging.
Cutaneous squamous cell carcinoma (cSCC), a malignant proliferation of cutaneous epithelium, represents 20% to 50% of skin cancers. Although the majority of cSCCs are successfully eradicated by surgical excision, a subset of cSCC possesses features associated with a higher likelihood of recurrence, metastasis, and death. The proper identification of these aggressive cSCCs can guide additional work-up and management. In the first article in this continuing medical education series, we discuss the incidence, recurrence rates, mortality rates, and risk factors associated with cSCC and review the staging systems used to stratify patients into high- and low-risk groups. The second article in this series reviews the treatment options for cSCC, with focused attention on the management of high-stage tumors.


Kallikrein messenger RNA in rat arteries and veins.
Glandular kallikrein (EC 188.8.131.52) belongs to a subgroup of serine proteases coded by a multigene family. A kininogenase resembling glandular kallikrein has been identified in vascular tissue; however, it is not clear whether it is synthesized by vascular tissue or taken up from plasma. To determine the potential for kallikrein synthesis in vascular tissues, we tested whether messenger RNA (mRNA) for glandular kallikrein is present in rat arteries and veins. Poly(A+) RNA was isolated from pools of arteries or veins (n = 3, 30 rats each). Poly(A+) RNA from the kidney and liver was used as a positive and negative control, respectively. As a probe, we used rat pancreatic kallikrein 32P-labeled complementary DNA, which recognizes mRNA of the entire rat kallikrein family. Slot-blot analysis indicated that kallikrein mRNA was present in mRNA from the arteries, veins, and kidney but not from the liver. Poly(A+) RNA from arteries and veins contained approximately 1% as much kallikrein mRNA as that from the kidney. To confirm the slot-blot results and determine whether the mRNA for true glandular kallikrein was present in vascular tissue, we employed a polymerase chain reaction assay, first using primers specific for the entire kallikrein family (which amplify a 430-bp fragment) and then using primers specific for true glandular kallikrein mRNA (which amplify a 370-bp fragment). After the polymerase chain reaction assay, both arteries and veins showed fragments of these sizes when tested with rat kallikrein complementary DNA probe, thus confirming the presence of glandular kallikrein mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)


Physical activity and cardiovascular health.
To provide physicians and the general public with a responsible assessment of the relationship between physical activity and cardiovascular health. A non-Federal, nonadvocate, 13-member panel representing the fields of cardiology, psychology, exercise physiology, nutrition, pediatrics, public health, and epidemiology. In addition, 27 experts in cardiology, psychology, epidemiology, exercise physiology, geriatrics, nutrition, pediatrics, public health, and sports medicine presented data to the panel and a conference audience of 600. The literature was searched through Medline and an extensive bibliography of references was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. The panel, answering predefined questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. All Americans should engage in regular physical activity at a level appropriate to their capacity, needs, and interest. Children and adults alike should set a goal of accumulating at least 30 minutes of moderate-intensity physical activity on most, and preferably, all days of the week. Most Americans have little or no physical activity in their daily lives, and accumulating evidence indicates that physical inactivity is a major risk factor for cardiovascular disease. However, moderate levels of physical activity confer significant health benefits. Even those who currently meet these daily standards may derive additional health and fitness benefits by becoming more physically active or including more vigorous activity. For those with known cardiovascular disease, cardiac rehabilitation programs that combine physical activity with reduction in other risk factors should be more widely used.


Menstrual cycle effects on sympathetic neural responses to upright tilt.
Young women are more susceptible to orthostatic intolerance than men, though the sex-specific pathophysiology remains unknown. As blood pressure (BP) is regulated through the baroreflex mechanism, we tested the hypothesis that baroreflex control of muscle sympathetic nerve activity (MSNA) during orthostasis is impaired in women and can be affected by the menstrual cycle. MSNA and haemodynamics were measured supine and during a graded upright tilt (30 deg for 6 min, 60 deg for 45 min or till presyncope) in 11 young men and 11 women during the early follicular (EFP) and mid-luteal phase (MLP) of the menstrual cycle. Sympathetic baroreflex sensitivity was quantified using the slope of the linear correlation between total activity and diastolic BP during spontaneous breathing. Baroreflex function was further assessed during a Valsalva manoeuvre (VM). Although MSNA burst frequency responses during tilting were similar between sexes and menstrual phases, increases in total activity were lower in women during EFP than MLP (P = 0.030), while total peripheral resistance and plasma noradrenaline were not similarly lower; upright total activity tended to be lower in women during EFP than men (P = 0.102). Sympathetic baroreflex sensitivity did not differ between sexes (P = 0.676) supine (-281 +/- 46 (S.E.M.) units beat(-1) mmHg(-1) in men vs -252 +/- 52 in EFP and -272 +/- 40 in MLP in women), at 30 deg tilt (-648 +/- 129 vs -611 +/- 79 and -487 +/- 94), and at 60 deg tilt (-792 +/- 135 vs -831 +/- 92 and -814 +/- 142); this sensitivity was not affected by the menstrual cycle (P = 0.747). Similar sympathetic baroreflex sensitivity between sexes and phases was also observed during the VM. Cardiovagal baroreflex sensitivity assessed during decreasing BP (i.e. early phase II of the VM) was comparable between sexes, but it was greater in men than women during increasing BP (i.e. phase IV); the menstrual cycle had no influences on cardiovagal baroreflex sensitivity. We conclude that the menstrual cycle affects sympathetic neural responses but not sympathetic baroreflex sensitivity during orthostasis, though upright vasomotor sympathetic activity is not clearly different between men and women. Not only sympathetic but also cardiovagal baroreflex sensitivity is similar between sexes and menstrual phases during a hypotensive stimulus. However, cardiovagal baroreflex-mediated bradycardia during a hypertensive stimulus is different between sexes but not affected by the menstrual cycle. Thus, other factors rather than sympathetic baroreflex control mechanisms contribute to sex differences in orthostatic tolerance in young humans.


Neonatal teratomas.
Teratomas are composed of multiple tissues foreign to the organ or site in which they arise. Their origin is postulated by 3 theories one of which is the origin from totipotent primodial germ cells. Anatomically, teratomas are divided into gonadal or extragonadal lesions and histologically they are classified as mature or immature tumors. Teratomas are mainy isolated lesions and may occur anywhere in the body. In the neonatal age group most of these tumors are benign and occur mainly in the sacrococcygeal area followed by the anterior mediastinum. Diagnosis is usually established prenatally and may require intervention in compromised fetuses. Postnatal imaging with ultrasound, CT scan or MRI provides useful information for surgical intervention. Complete surgical excision is the treatment of choice for neonatal teratomas. Alpha feto protein is the tumor marker of choice and is particularly useful for assessing the presence of residual or recurrent disease.


OccuPeak: ChIP-Seq peak calling based on internal background modelling.
ChIP-seq has become a major tool for the genome-wide identification of transcription factor binding or histone modification sites. Most peak-calling algorithms require input control datasets to model the occurrence of background reads to account for local sequencing and GC bias. However, the GC-content of reads in Input-seq datasets deviates significantly from that in ChIP-seq datasets. Moreover, we observed that a commonly used peak calling program performed equally well when the use of a simulated uniform background set was compared to an Input-seq dataset. This contradicts the assumption that input control datasets are necessary to fatefully reflect the background read distribution. Because the GC-content of the abundant single reads in ChIP-seq datasets is similar to those of randomly sampled regions we designed a peak-calling algorithm with a background model based on overlapping single reads. The application, OccuPeak, uses the abundant low frequency tags present in each ChIP-seq dataset to model the background, thereby avoiding the need for additional datasets. Analysis of the performance of OccuPeak showed robust model parameters. Its measure of peak significance, the excess ratio, is only dependent on the tag density of a peak and the global noise levels. Compared to the commonly used peak-calling applications MACS and CisGenome, OccuPeak had the highest sensitivity in an enhancer identification benchmark test, and performed similar in an overlap tests of transcription factor occupation with DNase I hypersensitive sites and H3K27ac sites. Moreover, peaks called by OccuPeak were significantly enriched with cardiac disease-associated SNPs. OccuPeak runs as a standalone application and does not require extensive tweaking of parameters, making its use straightforward and user friendly. http://occupeak.hfrc.nl.


Chronic hepatitis: a retrospective study in 34 dogs.
The aims of this study were to characterize the histological changes observed in 34 accessioned cases of canine chronic hepatitis and to correlate these changes with the clinical pathological data. Cases of chronic hepatitis were subdivided into 6 categories: chronic active hepatitis (10/34), chronic persistent hepatitis (7/32), chronic cholestatic hepatitis (6/34), fibrosing hepatitis with cirrhosis (3/34), chronic cholangiohepatitis (3/34), and miscellaneous secondary hepatitis (5/34). Iron accumulation was a consistent finding in all livers examined. Although all cases of chronic hepatitis had elevated liver enzymes, no correlation was detected between biochemical parameters and the severity of morphologic changes. Similarly, no correlation was detected between rhodanine staining for copper and morphologic or biochemical indicators of cholestasis. However, presence of copper correlated well with reticulo-fibrosis (r = 0.8) and bile duct hyperplasia, suggesting that changes in the hemodynamics of the hepatic acini due to fibrosis could influence storage of copper.


Naturally occurring enzyme activity variation in Drosophila melanogaster. I. Sources of variation for 23 enzymes.
The genetic component of variation of enzyme activity levels in Drosophila melanogaster was investigated by using 48 second- and 48 third-chromosome isogenic substitution lines derived from natural populations. The results confirm those of our earlier experiments with the same lines and extend them to a number of additional enzymes. All 23 enzymes show a significant genetic component to the variation in one or both sets of lines and only a small part of this variation is accounted for by variation among the lines in the amount of tissue per fly. The magnitude of line effects is, in most cases, considerably larger than the magnitude of environmental and measurement error effects, and the line effects are approximately continuous in distribution. Variation in the geographic origin and karyotype of the chromosomes generally does not contribute to the line component of variation, but allozymes provide an important source of variation for a few of the enzymes. Many of the enzymes show evidence for variation of activity modifiers that are not linked to the structural locus of the enzyme.


Residential summer camp: a new venue for nutrition education and physical activity promotion.
Millions of children attend residential summer camps each year. However, few studies have examined the potential of camps for obesity prevention efforts. Research in the domain of positive youth development has shown that camp programs as short as one week have both short- and long-term positive effects on self-esteem, self-efficacy and other youth outcomes. The objective of the present study was to highlight the potential of resident camps as promising venues for the promotion of healthy eating and physical activity behaviors in the children who attend. Data for this study came from the American Camp Association 2007 Emerging Issues Survey. This survey assessed camp professionals' perspectives on a diverse array of issues, including the healthy eating and physical activity of children. Data analysis focused on responses from 247 camp professionals whose camps offered resident camp programs. Descriptive and Chi-square statistics were calculated. Ninety-two percent of camp professionals reported that the healthy eating and physical activity of campers was an "important" or "very important" issue for camps. The majority of camps reported offering vegetarian options, healthy snacks and salad bars, and allergen-free options. Additionally, 86% of camp professionals indicated that they had implemented one or more strategies to address concerns related to the unhealthy eating behaviors of children, with top strategies including increasing the availability of fruits and vegetables, increasing the availability of healthy drink options, and improving the nutritional quality of menus. Fewer camp professionals (50%) indicated they had implemented strategies to increase children's physical activity levels, but many professionals indicated that their camp programs were inherently active and additional strategies to promote physical activity were not necessary. Associations were found between camp affiliation and food options available to campers. The majority of camp professionals believe the healthy eating and physical activity of children are important issues for camps and have implemented strategies to address these issues. An important question for future research is to examine whether these strategies are effective in promoting healthy eating and physical activity behaviors in children, as well as ways that camp programs could be improved.


The Effect of Medicaid on Dental Care of Poor Adults: Evidence from the Oregon Health Insurance Experiment.
To evaluate the effect of Medicaid coverage on dental care outcomes, a major health concern for low-income populations. Primary and secondary data on health care use and outcomes for participants in Oregon's 2008 Medicaid lottery. We used the lottery's random selection to gauge the causal effects of Medicaid on dental care needs, medication, and emergency department visits for dental care. Data were collected for lottery participants over 2 years, including mail surveys (N = 23,777) and in-person questionnaires (N = 12,229). Emergency department (ED) records were matched to lottery participants in Portland (N = 24,646). Medicaid coverage significantly reduced the share of respondents who reported needing dental care (-9.8 percentage points, p < .001) or having unmet dental care needs (-13.5 percentage points, p < 0.001). Medicaid doubled the share visiting the ED for dental care (+2.6 percentage points, p = .003) and the use of anti-infective medications often prescribed for dental care, but it had no detectable effect on uncovered dental care or out-of-pocket spending. Expansion of Medicaid covering emergency dental care substantially reduced unmet need for dental care, increasing ED dental visits and medication use, while not changing patient use of uncovered dental services.


Early environmental exposure and the development of lupus.
Systemic lupus erythematosus (SLE) is a complex trait with evidence of polygenic inheritance influenced by environmental factors. However, the precise underlying causes of SLE remain unclear. A number of environmental exposures have been associated with lupus or related autoimmune phenomena. Evidence suggests that some environmental exposures need to be present many years before the onset of SLE. Both SLE and rheumatoid arthritis (RA) can occur in very young children and this supports the possibility that important environmental factors must be present during or before this time. In addition, the immune pathology, including autoantibody production, in adult lupus may begin years before clinical disease. There is also evidence that the developing immune system demonstrates developmental plasticity and can be permanently altered or 'programmed' by the early environment. We describe how early life environmental influences including infectious exposure may lead to autoantibody production in later life thus beginning the journey that leads to autoimmune diseases such as lupus in susceptible individuals.


Demographics, epidemiology and the impact of vaccination campaigns in a measles-free world - Can elimination be maintained?
All six WHO regions currently have goals for measles elimination by 2020. Measles vaccination is delivered via routine immunization programmes, which in most sub-Saharan African countries reach children around 9months of age, and supplementary immunization activities (SIAs), which target a wider age range at multi-annual intervals. In the absence of endemic measles circulation, the proportion of individuals susceptible to measles will gradually increase through accumulation of new unvaccinated individuals in each birth cohort, increasing the risk of an epidemic. The impact of SIAs and the financial investment they require, depend on coverage and target age range. We evaluated the impact of target population age range for periodic SIAs, evaluating outcomes for two different levels of coverage, using a demographic and epidemiological model adapted to reflect populations in 4 sub-Saharan African countries. We found that a single SIA can maintain elimination over short time-scales, even with low routine coverage. However, maintaining elimination for more than a few years is difficult, even with large (high coverage/wide age range) recurrent SIAs, due to the build-up of susceptible individuals. Across the demographic and vaccination contexts investigated, expanding SIAs to target individuals over 10years did not significantly reduce outbreak risk. Elimination was not maintained in the contexts we evaluated without a second opportunity for vaccination. In the absence of an expanded routine program, SIAs provide a powerful option for providing this second dose. We show that a single high coverage SIA can deliver most key benefits in terms of maintaining elimination, with follow-up campaigns potentially requiring smaller investments. This makes post-campaign evaluation of coverage increasingly relevant to correctly assess future outbreak risk.


Risk of fatal and near-fatal asthma in relation to inhaled corticosteroid use.
To examine the relationship between patterns of use of inhaled beclomethasone dipropionate and the risk of fatal and near-fatal asthma. Nested case-control analysis of a historical cohort; a further analysis. The 12,301 residents of Saskatchewan aged 5 to 54 years who were dispensed 10 or more asthma drugs from 1978 to 1987. The 129 persons who experienced asthma death (n = 44) and near-death (n = 85) and their 655 controls matched as to age and date of entry into the cohort, with the additional matching criteria of at least one hospitalization for asthma in the prior 2 years, region of residence, and having received social assistance. Life-threatening attacks of asthma defined as death due to asthma or the occurrence of hypercarbia, intubation, and mechanical ventilation during an acute attack of asthma. After accounting for the risk associated with use of other medications and adjustment for markers of risk of adverse events related to asthma, subjects who had been dispensed, on average, one or more metered-dose inhalers of beclomethasone per month over a 1-year period had a significantly lower risk of fatal and near-fatal asthma (odds ratio, 0.1; 95% confidence interval, 0.02 to 0.6). These data support recent guidelines from several countries that recommend the use of inhaled corticosteroids in moderate and severe asthma.


What are the Key Characteristics of a 'Good' Psychotherapy? Calling for Ethical Patient Involvement.
The evidence-based practice movement clearly defines the relevant components of a good treatment. In the present article, we elaborate on how the active involvement of patients within psychotherapy can and should be increased in order to respect ethical considerations. Our arguments complement the requirements of evidence-based practice, and are independent of the actual psychotherapeutic treatment approach being used. Theoretical and ethical analysis. In order to respect patient autonomy, psychotherapy needs to be transparent and honest when it comes to disclosing the relevant factors for promoting therapeutic change. It has been argued that ethical informed consent needs to include empirically supported patient information. In this paper we go one step further: we outline that fully respecting ethical considerations in psychotherapeutic treatment necessarily calls for acknowledging and strengthening the active role of patients in the course of psychotherapy. Accordingly, patients need not only to be informed openly and transparently about the planned treatment, the treatment rationale, and the expected prognosis of improvement in the course of psychotherapy, but they also need to be actively involved in the decision-making process and during the entire process of psychotherapeutic treatment. Our arguments support the tendency that can be observed in health care in recent years towards more active patient involvement across different health-care domains, but also in clinical research. This article offers an ethical perspective on the question what defines a 'good psychotherapy', which, hopefully, will help to leave behind some of the ongoing psychotherapy debates and move the field forward.


PPAR activation induces M1 macrophage polarization via cPLA₂-COX-2 inhibition, activating ROS production against Leishmania mexicana.
Defence against Leishmania depends upon Th1 inflammatory response and, a major problem in susceptible models, is the turnoff of the leishmanicidal activity of macrophages with IL-10, IL-4, and COX-2 upregulation, as well as immunosuppressive PGE2, all together inhibiting the respiratory burst. Peroxisome proliferator-activated receptors (PPAR) activation is responsible for macrophages polarization on Leishmania susceptible models where microbicide functions are deactivated. In this paper, we demonstrated that, at least for L. mexicana, PPAR activation, mainly PPAR γ , induced macrophage activation through their polarization towards M1 profile with the increase of microbicide activity against intracellular pathogen L. mexicana. PPAR activation induced IL-10 downregulation, whereas the production of proinflammatory cytokines such as TNF- α , IL-1 β , and IL-6 remained high. Moreover, PPAR agonists treatment induced the deactivation of cPLA2-COX-2-prostaglandins pathway together with an increase in TLR4 expression, all of whose criteria meet the M1 macrophage profile. Finally, parasite burden, in treated macrophages, was lower than that in infected nontreated macrophages, most probably associated with the increase of respiratory burst in these treated cells. Based on the above data, we conclude that PPAR agonists used in this work induces M1 macrophages polarization via inhibition of cPLA2 and the increase of aggressive microbicidal activity via reactive oxygen species (ROS) production.


Computer-aided classification of malignancy in astrocytomas. I. The value of nuclear parameters obtained by automated black and white image analysis.
Ninety-three selected cases of astrocytomas including glioblastomas (astrocytomas grades 1-4) were evaluated by means of Feulgen-stained microscopic slides for nuclear parameters obtained by automated black and white image analysis (ABWIA). The goal was to determine to what extent nuclear features evaluated by ABWIA were applicable as classifiers for the computer-aided numerical classification of malignancy in astrocytomas. Before the automated evaluation, all tumours had been subjectively graded according to the Mayo Clinic grading rules as delineated by Ringertz. Twenty-three nuclear parameters were evaluated and tested for their classification impact. With a model of five parameters (number of nuclei per area, mean of the convex form factor, extinction sum, extinction variation, and full-width-half-maximum of the extinction distribution) the highest reclassification rate of 75% correctly reclassified cases was obtained. Although this is a good result for a classification using only nuclear parameters, it is too poor for practical application. Thus, nuclear parameters evaluated by ABWIA alone are insufficient for numerical classification models assessing the malignant expression of astrocytomas.


Collagen Type III and VI Turnover in Response to Long-Term Immobilization.
Muscle mass and function are perturbed by immobilization and remobilization. When muscle mass changes, the quality and quantity of the extracellular matrix protein, particularly the collagens, change with it. In this study, we investigated the temporal profile of three peptide biomarkers derived from turnover of collagen type III and type VI in a long-term immobilization and remobilization study. We also compared individual biomarker levels with Lean body Mass (LBM) and changes therein, hypothesizing that these biomarkers would be biomarkers of the remodeling processes associated with immobilization and/or remobilization. In the Berlin bed rest study, 20 young men were recruited and randomly assigned to 8-week's strict bed rest with or without resistive vibration exercise countermeasure. We measured three neo-epitope ELISA kits in the serum samples of this study: Pro-C3, measured the synthesis of collagen type III; Pro-C6, measured the synthesis of collagen type VI; and C6M measured the degradation of collagen type VI induced by MMP-2 and MMP-9 cleavage. Pro-C3 and Pro-C6 biomarkers are up-regulated with both immobilization and remobilization, whereas C6M is hardly affected at all. We found that Pro-C3 and C6M levels are related to LBM at baseline and that high levels of Pro-C6 are associated with smaller changes in muscle mass during both immobilization and remobilization. The Pro-C3 and-C6 biomarkers change likely reflect remodeling changes in response to unloading or reloading, whereas C6M does not appear to respond to unloading. Pro-C3 and C6M levels correlate with LBM at baseline, while Pro-C6 is related to the anabolic and catabolic responses to unloading and reloading.


The meaning of adherence when behavioral risk patterns vary: obscured use- and method-effectiveness in HIV-prevention trials.
Recently promising trials of innovative biomedical approaches to prevent HIV transmission have been reported. Participants' non-adherence to the prevention methods complicates the analyses and interpretation of trial results. The influence of variable sexual behaviors within and between participants of trials further obscures matters. Current methodological and statistical approaches in HIV-prevention studies, as well as ongoing debates on contradictory trial results, may fail to accurately address these topics. Through developing a cumulative probability model of infection within HIV prevention trials, we demonstrate how adherence and sexual behavior patterns impact the overall estimate of effectiveness, the effectiveness of prevention methods as a function of adherence, and conclusions about methods' true effectiveness. Applying the model to summary-level data from the CAPRISA trial, we observe markedly different values for the true method effectiveness of the microbicide, and show that if the gel would have been tested among women with slightly different sexual behavior patterns, conclusions might well have been that the gel is not effective. Relative risk and adherence analyses in HIV prevention trials overlook the complex interplay between adherence and sexual behavior patterns. Consequently, they may not provide accurate estimates of use- and method-effectiveness. Moreover, trial conclusions are contingent upon the predominant sexual behavior pattern of participants and cannot be directly generalized to other contexts. We recommend researchers to (re)examine their data and use the cumulative probability model to estimate the true method effectiveness, which might contribute to resolving current questions about contradictory trial results. Moreover, we suggest taking into account the issues raised in the design of future trials and in population models estimating the impact of large-scale dissemination of prevention methods. Comprehension of the topics described will help readers to better interpret (apparently contradictory) trial outcomes.


Impact of chemical structure of flavanol monomers and condensed tannins on in vitro anthelmintic activity against bovine nematodes.
Plants containing condensed tannins (CT) may have potential to control gastrointestinal nematodes (GIN) of cattle. The aim was to investigate the anthelmintic activities of four flavan-3-ols, two galloyl derivatives and 14 purified CT fractions, and to define which structural features of CT determine the anti-parasitic effects against the main cattle nematodes. We used in vitro tests targeting L1 larvae (feeding inhibition assay) and adults (motility assay) of Ostertagia ostertagi and Cooperia oncophora. In the larval feeding inhibition assay, O. ostertagi L1 were significantly more susceptible to all CT fractions than C. oncophora L1. The mean degree of polymerization of CT (i.e. average size) was the most important structural parameter: large CT reduced larval feeding more than small CT. The flavan-3-ols of prodelphinidin (PD)-type tannins had a stronger negative influence on parasite activity than the stereochemistry, i.e. cis- vs trans-configurations, or the presence of a gallate group. In contrast, for C. oncophora high reductions in the motility of larvae and adult worms were strongly related with a higher percentage of PDs within the CT fractions while there was no effect of size. Overall, the size and the percentage of PDs within CT seemed to be the most important parameters that influence anti-parasitic activity.


Effects of implant drill wear, irrigation, and drill materials on heat generation in osteotomy sites.
This study evaluated the effects of drill wear on bone temperature during osteotomy preparation with 3 types of drills and compared heat production between drills. The drills used in this study were titanium nitride-coated metal, tungsten carbide carbon-coated metal, and zirconia ceramic drills. An osteotomy 11 mm in depth was formed in bovine scapular bone following the manufacturer's recommended drill sequences. Drilling was performed without irrigation and repeated 20 times; temperature was measured every 5 times. Next, 200 rounds of drilling during irrigation were performed for each drill, with temperature change monitored until round 200. Analysis of variance statistics were used for analyses of the measured data. Drilling without irrigation showed significant thermal increase at all time points compared to drilling with irrigation (P < .001). No significant difference was found between drill materials. Under irrigation, the frequency of previous drilling had minimal effects on thermal change. The repeated-measures analysis of variance revealed major thermal change at the initial time point (P < .0001), and the multiple comparison tests revealed a significant difference in temperature between the initial drills that had been used 50 or fewer times and those that had been used more than 50 times, irrespective of the drill material. The results of this study indicate that the initial drill should be changed in osteotomy preparation with irrigation after they have been used 50 times. Irrigation may be a more critical factor for the control of temperature elevation than is the drill material.


Differential apoptotic signaling in primary glial cells infected with herpes simplex virus 1.
Microglial cells and astrocytes are glial cell types that perform distinct functions and generate innate immune responses to counter invading pathogens. Herpes simplex virus 1 (HSV-1) is a neurotropic virus that is capable of causing severe, necrotizing encephalitis. HSV-1 infects both of these glial cell types. Microglial cells undergo an abortive infection, yet respond to viral infection by inducing a burst of proinflammatory cytokine and chemokine production. Following this cytokine burst, they rapidly succumb to cell death. In contrast, astrocytes do permit productive viral replication, but do not generate these same innate immune mediators. Although apoptosis has been implicated in a number of acute and chronic neurological disorders, little is known about apoptosis during viral encephalitis. In the present study, the authors investigated the effect of HSV-1 infection on cell survival and studied the mechanisms of cell-death in virus-infected, primary murine glial cells. The authors report that although apoptosis occurred rapidly in microglia, it was delayed during productive infection of astrocytes. Furthermore, microarray studies revealed significant variations in the expression of apoptotic genes between these two types of glial cells, indicating crucial differences in signaling pathways. Intrinsic as well as extrinsic pathways of apoptosis were found to be activated in both glial cell types. Specifically, genes involved in the tumor necrosis factor (TNF) signaling pathway were predominantly up-regulated in microglia, whereas genes of the Fas pathway were induced during HSV infection of astrocytes.


Hidden Relationships between N-Glycosylation and Disulfide Bonds in Individual Proteins.
N-Glycosylation (NG) and disulfide bonds (DBs) are two prevalent co/post-translational modifications (PTMs) that are often conserved and coexist in membrane and secreted proteins involved in a large number of diseases. Both in the past and in recent times, the enzymes and chaperones regulating these PTMs have been constantly discovered to directly interact with each other or colocalize in the ER. However, beyond a few model proteins, how such cooperation affects N-glycan modification and disulfide bonding at selective sites in individual proteins is largely unknown. Here, we reviewed the literature to discover the current status in understanding the relationships between NG and DBs in individual proteins. Our results showed that more than 2700 human proteins carry both PTMs, and fewer than 2% of them have been investigated in the associations between NG and DBs. We summarized both these proteins with the reported relationships in the two PTMs and the tools used to discover the relationships. We hope that, by exposing this largely understudied field, more investigations can be encouraged to unveil the hidden relationships of NG and DBs in the majority of membranes and secreted proteins for pathophysiological understanding and biotherapeutic development.


Smooth muscle cells and myofibroblasts use distinct transcriptional mechanisms for smooth muscle alpha-actin expression.
There has been considerable controversy regarding the lineage relationship between smooth muscle cells (SMCs) and myofibroblasts, because they express a number of common cell-selective markers including smooth muscle (SM) alpha-actin. We have shown previously that MCAT elements within the SM alpha-actin promoter confer differential activity in cultured SMCs versus myofibroblasts. In the present study, to determine the role of MCAT elements in vivo, we generated transgenic mice harboring an SM alpha-actin promoter-enhancer-LacZ reporter gene containing MCAT element mutations and compared transgene expression patterns with wild-type SM alpha-actin promoter-enhancer-LacZ transgenic mice. Results showed no differences in LacZ expression patterns in adult SMC-containing tissues. However, of interest, mutations of MCAT elements selectively abolished transgene expression in myofibroblasts within granulation tissue of skin wounds. In addition, mutations of MCAT elements caused a delay in the induction of transgene expression in SMCs, as well as loss of expression in cardiac and skeletal muscles during embryogenesis. Results of small interfering RNA-induced knockdown experiments showed that RTEF-1 regulated SM alpha-actin transcription in myofibroblasts, but not in differentiated SMCs. Moreover, quantitative chromatin immunoprecipitation assays revealed that RTEF-1 bound to the MCAT element-containing region within the SM alpha-actin promoter in myofibroblasts, whereas transcriptional enhancer factor (TEF)-1 was bound to the same region in differentiated SMCs. These results provide novel evidence that, although both SMCs and myofibroblasts express SM alpha-actin, they use distinct transcriptional control mechanisms for regulating its expression. Results also indicate that the MCAT element-mutated SM alpha-actin promoter-enhancer is a useful tool to direct gene expression selectively in differentiated SMCs.


Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population.
In current clinical practice, genetic testing to detect Lynch syndrome mutations ideally begins with diagnostic testing of an individual affected with cancer before offering predictive testing to at-risk relatives. An alternative strategy that warrants exploration involves screening unaffected individuals via demographic and family histories, and offering genetic testing to those individuals whose risks for carrying a mutation exceed a selected threshold. Whether this approach would improve health outcomes in a manner that is cost-effective relative to current standards of care has yet to be demonstrated. To do so, we developed a simulation framework that integrated models of colorectal and endometrial cancers with a 5-generation family history model to predict health and economic outcomes of 20 primary screening strategies (at a wide range of compliance levels) aimed at detecting individuals with mismatch repair gene mutations and their at-risk relatives. These strategies were characterized by (i) different screening ages for starting risk assessment and (ii) different risk thresholds above which to implement genetic testing. For each strategy, 100,000 simulated individuals, representative of the U.S. population, were followed from the age of 20, and the outcomes were compared with current practice. Findings indicated that risk assessment starting at ages 25, 30, or 35, followed by genetic testing of those with mutation risks exceeding 5%, reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%, respectively. For a population of 100,000 individuals containing 392 mutation carriers, this strategy increased quality-adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY. The cost-effectiveness of screening for mismatch repair gene mutations is comparable to that of accepted cancer screening activities in the general population such as colorectal cancer screening, cervical cancer screening, and breast cancer screening. These results suggest that primary screening of individuals for mismatch repair gene mutations, starting with risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost-effective manner relative to current practice.


Human Nudel and NudE as regulators of cytoplasmic dynein in poleward protein transport along the mitotic spindle.
Emerging evidence supports the idea that a signaling pathway containing orthologs of at least mammalian NudE and Nudel, Lis1, and cytoplasmic dynein is conserved for eukaryotic nuclear migration. In mammals, this pathway has profound impact on neuronal migration during development of the central nervous system. Lis1 and dynein are also involved in other cellular functions, such as mitosis. Here we show that Nudel also participates in a subset of dynein function in M phase. Nudel was specifically phosphorylated in M phase in its serine/threonine phosphorylation motifs, probably by Cdc2 and also Erk1 and -2. A fraction of Nudel bound to centrosomes strongly in interphase and localized to mitotic spindles in early M phase. By using mutants incapable of or simulating phosphorylation, we confirmed that phosphorylation of Nudel regulated the cell-cycle-dependent distribution, possibly by increasing its dissociation rate at the microtubule-organizing center. Moreover, phosphorylated Nudel or the phosphorylation-mimicking mutant bound Lis1 more efficiently. We further demonstrated that a Nudel mutant incapable of binding to Lis1 impaired the poleward movement of dynein and hence the dynein-mediated transport of kinetochore proteins to spindle poles along microtubules, a process contributing to inactivation of the spindle checkpoint in mitosis. These results point to the importance of Nudel-Lis1 interaction for the dynein activity in M phase and to a possible role of Nudel phosphorylation as facilitating such interaction. In addition, comparative studies suggest that NudE is also functionally related to its paralog, Nudel.


Compound A398, a novel podophyllotoxin analogue: cytotoxicity and induction of apoptosis in human leukemia cells.
Despite advances in oncology research, cancer is one of the leading causes of death worldwide. Thus, there is a demand for the development of more selective and effective antitumor agents. This study showed that A398, a novel podophyllotoxin analogue, was cytotoxic to the HT-29, MCF-7, MOLT-4 and HL-60 tumor cell lines, being less active in human peripheral blood mononuclear cells and normal cell lines FGH and IEC-6. Tests using the HepG2 lineage indicated that its metabolites do not contribute to its cytotoxicity. In the HL-60 cells, A398 induced apoptosis in a time and concentration-dependent manner, promoting mitochondrial depolarization, inhibition of Bcl-2, phosphatidylserine exposure, activation of caspases -8, -9 and -3, and DNA fragmentation. The production of reactive oxygen species does not seem to be a crucial event for the apoptotic process. Pretreatment with specific inhibitors of kinases ERK1/2, JNK and p38 resulted in an increased percentage of death induced by A398. These results indicate that the compound induced apoptosis through activation of intrinsic and extrinsic death pathways with the mechanism involving the inhibition of the MAPKs and Bcl-2. Taken together, our findings suggest that A398 has an anticancer potential, proving itself to be a candidate for preclinical studies.


Severity of whooping cough in England before and after the decline in pertussis immunisation.
Since the decline of pertussis immunisation, hospital admission and death rates from whooping cough have fallen unexpectedly. Although this might be taken to indicate that the disease is becoming less severe, a comparison of admissions and deaths in England and Wales before and after the decline in immunisation suggests that several factors other than disease severity--a shift in the social class distribution of the disease, an increase in the proportion of milder cases notified, and improved care--were responsible for this. The severity of attacks and the complication rates in children admitted to hospital were virtually unchanged. Very young infants, those from disadvantaged families, and children with chronic illness were at greatest risk.


A Methodology for Individual-Specific Modeling of Rat Optic Nerve Head Biomechanics in Glaucoma.
Glaucoma is the leading cause of irreversible blindness and involves the death of retinal ganglion cells (RGCs). Although biomechanics likely contributes to axonal injury within the optic nerve head (ONH), leading to RGC death, the pathways by which this occurs are not well understood. While rat models of glaucoma are well-suited for mechanistic studies, the anatomy of the rat ONH is different from the human, and the resulting differences in biomechanics have not been characterized. The aim of this study is to describe a methodology for building individual-specific finite element (FE) models of rat ONHs. This method was used to build three rat ONH FE models and compute the biomechanical environment within these ONHs. Initial results show that rat ONH strains are larger and more asymmetric than those seen in human ONH modeling studies. This method provides a framework for building additional models of normotensive and glaucomatous rat ONHs. Comparing model strain patterns with patterns of cellular response seen in studies using rat glaucoma models will help us to learn more about the link between biomechanics and glaucomatous cell death, which in turn may drive the development of novel therapies for glaucoma.


The crystal structure of Pyrococcus abyssi tRNA (uracil-54, C5)-methyltransferase provides insights into its tRNA specificity.
The 5-methyluridine is invariably found at position 54 in the TPsiC loop of tRNAs of most organisms. In Pyrococcus abyssi, its formation is catalyzed by the S-adenosyl-l-methionine-dependent tRNA (uracil-54, C5)-methyltransferase ((Pab)TrmU54), an enzyme that emerged through an ancient horizontal transfer of an RNA (uracil, C5)-methyltransferase-like gene from bacteria to archaea. The crystal structure of (Pab)TrmU54 in complex with S-adenosyl-l-homocysteine at 1.9 A resolution shows the protein organized into three domains like Escherichia coli RumA, which catalyzes the same reaction at position 1939 of 23S rRNA. A positively charged groove at the interface between the three domains probably locates part of the tRNA-binding site of (Pab)TrmU54. We show that a mini-tRNA lacking both the D and anticodon stem-loops is recognized by (Pab)TrmU54. These results were used to model yeast tRNA(Asp) in the (Pab)TrmU54 structure to get further insights into the different RNA specificities of RumA and (Pab)TrmU54. Interestingly, the presence of two flexible loops in the central domain, unique to (Pab)TrmU54, may explain the different substrate selectivities of both enzymes. We also predict that a large TPsiC loop conformational change has to occur for the flipping of the target uridine into the (Pab)TrmU54 active site during catalysis.


Effects of Unfiltered Coffee and Bioactive Coffee Compounds on the Development of Metabolic Syndrome Components in a High-Fat-/High-Fructose-Fed Rat Model.
The literature is inconsistent as to how coffee affects metabolic syndrome (MetS), and which bioactive compounds are responsible for its metabolic effects. This study aimed to evaluate the effects of unfiltered coffee on diet-induced MetS and investigate whether or not phenolic acids and trigonelline are the main bioactive compounds in coffee. Twenty-four male Sprague‒Dawley rats were fed a high-fat (35% W/W) diet plus 20% W/W fructose in drinking water for 14 weeks, and were randomized into three groups: control, coffee, or nutraceuticals (5-O-caffeoylquinic acid, caffeic acid, and trigonelline). Coffee or nutraceuticals were provided in drinking water at a dosage equal to 4 cups/day in a human. Compared to the controls, total food intake (p = 0.023) and mean body weight at endpoint (p = 0.016) and estimated average plasma glucose (p = 0.041) were lower only in the coffee group. Surrogate measures of insulin resistance including the overall fasting insulin (p = 0.010), endpoint HOMA-IR (p = 0.022), and oral glucose tolerance (p = 0.029) were improved in the coffee group. Circulating triglyceride levels were lower (p = 0.010), and histopathological and quantitative (p = 0.010) measurements indicated lower grades of liver steatosis compared to controls after long-term coffee consumption. In conclusion, a combination of phenolic acids and trigonelline was not as effective as coffee per se in improving the components of the MetS. This points to the role of other coffee chemicals and a potential synergism between compounds.


Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline.
The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GC>TT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline.


"Talking About Chance": The Presentation of Risk Information During Genetic Counseling for Breast and Ovarian Cancer.
Using observations, questionnaires, and interviews, this study describes the formats used to present risk information during genetic counseling for breast and ovarian cancer. Counselees' preferences for different types of qualitative and quantitative presentation formats are also discussed. The data indicate that there is considerable variation in the presentation of risk information both within and between consultations. The counselees were positive about the way the counselors had described their risk. Seventy-three percent of the sample expressed a preference for risk to be described using quantitative formats, and there was little difference in the number who stated a preference for percentages, proportions, or population comparisons. Comparing preferred formats with those used in the consultations indicated that in over 40% of cases, risk information was not presented in the counselees' preferred quantitative format. This descriptive study raises questions about the presentation of risk information which warrant further research.


Matching initial torque with different stimulation parameters influences skeletal muscle fatigue.
A fundamental barrier to using electrical stimulation in the clinical setting is an inability to maintain torque production secondary to muscle fatigue. Electrical stimulation parameters are manipulated to influence muscle torque production, and they may also influence fatigability during repetitive stimulation. Our purpose was to determine the response of the quadriceps femoris to three different fatigue protocols using the same initial torque obtained by altering stimulator parameter settings. Participants underwent fatigue protocols in which either pulse frequency (lowHz), pulse duration (lowPD), or voltage (lowV) was manipulated to obtain an initial torque that equaled 25% of maximum voluntary isometric contraction. Muscle soreness was reported on a visual analog scale 48 h after each fatigue test. The lowHz protocol resulted in the least fatigue (25% +/- 14%); the lowPD (50% +/- 13%) and lowV (48% +/- 14%) protocols had similar levels of fatigue. The lowHz protocol resulted in significantly less muscle soreness than the higher frequency protocols. Stimulation protocols that use a lower frequency coupled with long pulse durations and high voltages result in lesser amounts of muscle fatigue and perceived soreness. The identification of optimal stimulation patterns to maximize muscle performance will reduce the effect of muscle fatigue and potentially improve clinical efficacy.


PALEOCLIMATE: An Appealing Snowball Earth That's Still Hard to Swallow.
The startling claim that Earth has frozen over from pole to pole for millions of years at a time, a hypothesis widely known as the "snowball Earth" scenario, has intrigued many earth scientists but as yet convinced few. But the theory, which would explain some previously inexplicable observations from the Neoproterozoic era 600 million to 700 million years ago, is gaining adherents. Last year, for example, most researchers agreed that one part of the sweeping hypothesis--the claim that glaciers once flowed into ice-covered tropical seas--is correct, even though this idea had been rebuffed for more than 30 years.


Differential induction and suppression of potato 3-hydroxy-3-methylglutaryl coenzyme A reductase genes in response to Phytophthora infestans and to its elicitor arachidonic acid.
Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is essential for the biosynthesis of sesquiterpenoid phytoalexins and steroid derivatives in Solanaceous plants following stresses imposed by wounding and pathogen infection. To better understand this complex step in stress-responsive isoprenoid synthesis, we isolated three classes of cDNAS encoding HMGR (hmg1, hmg2, and hmg3) from a potato tuber library using a probe derived from an Arabidopsis HMGR cDNA. The potato cDNAs had extensive homology in portions of the protein coding regions but had low homology in the 3' untranslated regions. RNA gel blot analyses using gene-specific probes showed that hmg1 was strongly induced in tuber tissue by wounding, but the wound induction was strongly suppressed by treatment of the tissue with the fungal elicitor arachidonic acid or by inoculation with an incompatible or compatible race of the fungal pathogen Phytophtora infestans. The hmg2 and hmg3 mRNAs also accumulated in response to wounding, but in contrast to hmg1, these mRNAs were strongly enhanced by arachidonic acid or inoculation. Inoculation with a compatible race of P. infestans resulted in similar patterns in HMGR gene expression of hmg2 and hmg3 except that the magnitude and rate of the changes in mRNA levels were reduced relative to the incompatible interaction. The differential regulation of members of the HMGR gene family may explain in part the previously reported changes in HMGR enzyme activities following wounding and elicitor treatment. The suppression of hmg1 and the enhancement of hmg2 and hmg3 transcript levels following elicitor treatment or inoculation with the incompatible race parallel the suppression in steroid and stimulation of sesquiterpenoid accumulations observed in earlier investigations. The results are discussed in relation to the hypothesis that there are discrete organizational channels for sterol and sesquiterpene biosynthesis in potato and other Solanaceous species.


Large scale MALDI-TOF MS based taxa identification to identify novel pigment producers in a marine bacterial culture collection.
A challenge in the rational exploitation of microbial culture collections is to avoid superfluous testing of replicas. MALDI-TOF MS has been shown to be an efficient dereplication tool as it can be used to discriminate between bacterial isolates at the species level. A bacterial culture collection of more than 10,000 heterotrophic marine bacterial isolates from sea-water surface layers of the Norwegian Trondheimsfjord and neighbouring coastal areas has been established. A sub-collection of pigmented isolates was earlier screened for novel carotenoids with UVA-Blue light absorbing properties. This was a comprehensive analytical task and it was observed that a significant number of extracts with identical pigment profile were recovered. Hence, this study was undertaken to explore the use of MALDI-TOF MS as a dereplication tool to quickly characterize the bacterial collection. Furthermore, LC-DAD-MS analysis of pigment profiles was performed to check if pigment profile diversity was maintained among isolates kept after the potential MALDI-TOF MS selection step. Four hundred isolates comprising both pigmented and non-pigmented isolates were used for this study. The resulting MALDI-TOF MS dendrogram clearly identified a diversity of different taxa and these were supported by the pigment profile clustering, thus linking the pigment production as species-specific properties. Although one exception was found, it can be concluded that MALDI-TOF MS dereplication is a promising pre-screening tool for more efficient screening of microbial culture collection containing pigments with potential novel properties.


The roles of nucleic acid editing in adaptation of zoonotic viruses to humans.
Following spillover, viruses must adapt to new selection pressures exerted by antiviral responses in their new hosts. In mammals, cellular defense mechanisms often include viral nucleic acid editing pathways mediated through protein families apolipoprotein-B mRNA-editing complex (APOBEC) and Adenosine Deaminase Acting on ribonucleic acid (ADAR). APOBECs induce C→U transitions in viral genomes; the APOBEC locus is highly polymorphic with variable numbers of APOBEC3 paralogs and target preferences in humans and other mammals. APOBEC3 paralogs have shaped the evolutionary history of human immunodeficiency virus, with compelling bioinformatic evidence also for its mutagenic impact on monkeypox virus and severe acute respiratory syndrome coronavirus 2. ADAR-1 induces adenose-to-inosine (A→I) substitutions in double-stranded ribonucleic acid (RNA); its role in virus adaptation is less clear, as are epigenetic modifications to viral genomes, such as methylation. Nucleic acid editing restricts evolutionary space in which viruses can explore and may restrict viral-host range.


Using Simulation in Global Health: Considerations for Design and Implementation.
Providers and educators increasingly participate in global health work during their careers. Simulation can play an important role in both preparing learners for work in resource-limited settings and training providers in these countries. However, little guidance exists for educators interested in creating and implementing scenarios for these settings. We discuss several key considerations unique to global health simulation ranging from addressing common cultural differences surrounding healthcare and varied regional approaches to disease identification and management to understanding precisely what resources exist in the setting and what strategies can be used to provide care when the expected resources are not available. We also discuss specific strategies for considering sustainability and for facilitating scenarios in these settings. We developed our recommendations on the basis of existing literature and our own work designing and implementing simulation curricula in resource-limited countries and preparing providers for work in these settings.


Molecular determinants for sodium-dependent activation of G protein-gated K+ channels.
G protein-gated inwardly rectifying K+ channels (GIRKs) are activated by a direct interaction with Gbetagamma subunits and also by raised internal [Na+]. Both processes require the presence of phosphatidylinositol bisphosphate (PIP2). Here we show that the proximal C-terminal region of GIRK2 mediates the Na+-dependent activation of both the GIRK2 homomeric channels and the GIRK1/GIRK2 heteromeric channels. Within this region, GIRK2 has an aspartate at position 226, whereas GIRK1 has an asparagine at the equivalent position (217). A single point mutation, D226N, in GIRK2, abolished the Na+-dependent activation of both the homomeric and heteromeric channels. Neutralizing a nearby negative charge, E234S had no effect. The reverse mutation in GIRK1, N217D, was sufficient to restore Na+-dependent activation to the GIRK1N217D/GIRK2D226N heteromeric channels. The D226N mutation did not alter either the single channel properties or the ability of these channels to be activated via the m2-muscarinic receptor. PIP2 dramatically increased the open probability of GIRK1/GIRK2 channels in the absence of Na+ or Gbetagamma but did not preclude further activation by Na+, suggesting that Na+ is not acting simply to promote PIP2 binding to GIRKs. We conclude that aspartate 226 in GIRK2 plays a crucial role in Na+-dependent gating of GIRK1/GIRK2 channels.


Burkitt's lymphoma presenting with lactic acidosis and hypoglycemia - a case presentation.
We present what appears to be the first reported case of lactic acidosis and hypoglycemia in an adult patient with Burkitt's lymphoma. Lactic acidosis and hypoglycemia are rare complications of non-Hodgkin's lymphoma (NHL) with only 26 and 8 previous reports, respectively. Two prior cases of Burkitt's lymphoma-induced lactic acidosis have been reported (one child, one adult), both in the absence of hypoglycemia. A 74-year-old man presented with right upper extremity swelling, pleural effusion and axillary lymphadenopathy. Thoracentesis and bone marrow studies revealed Burkitt's lymphoma. On the second day of his hospitalization he developed severe lactic acidosis (pH 7.29, lactate 15.8 mmol/L) and hypoglycemia (27 - 60 mg/dl) resistant to glucose infusions. Serum insulin, proinsulin and C-peptide levels were normal and insulin antibodies were negative. Insulin-like growth factors I and II were low, while thyroid and cortisol studies were normal. The patient's mental status became altered, care was withdrawn and the patient expired. An autopsy revealed significant tumor burden that appeared to spare the liver. An extensive review of the literature demonstrates that NHL-induced lactic acidosis is associated with a mortality rate of 73% at 1 month and 92% overall with the clinical course closely linked to the chemotherapeutic response of the tumor. Furthermore, in contrast to our patient, 90% of previously reported cases were associated with liver involvement.


Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia.
Children who survive acute lymphoblastic leukemia are at risk for leukemia-related or treatment-related complications, which can adversely affect survival and socioeconomic status. We determined the long-term survival and the rates of health insurance coverage, marriage, and employment among patients who had attained at least 10 years of event-free survival. A total of 856 eligible patients were treated between 1962 and 1992 in 13 consecutive clinical trials. Survival rates, the cumulative risk of a second neoplasm, and selected indicators of socioeconomic status were analyzed for the entire group and for patients who did or did not receive cranial or craniospinal radiation therapy during initial treatment. Fifty-six patients had major adverse events, including 8 deaths during remission, 4 relapses, and 44 second neoplasms (41 of them radiation-related); most of the second neoplasms were benign or of a low grade of malignant potential. The risk of a second neoplasm was significantly higher in the 597 patients who received radiation therapy (irradiated group) than in the 259 patients who did not receive radiation therapy (nonirradiated group) (P=0.04; estimated cumulative risk [+/-SE] at 20 years, 20.9+/-3.9 percent vs. 0.95+/-0.9 percent). The death rate for the irradiated group slightly exceeded the expected rate in the general U.S. population (standardized mortality ratio, 1.90; 95 percent confidence interval, 1.12 to 3.00), whereas that for the nonirradiated group did not differ from the population norm (standardized mortality ratio, 1.75; 95 percent confidence interval, 0.34 to 5.00). The rates of health insurance coverage, marriage, and employment in the nonirradiated group were similar to the age- and sex-adjusted national averages. Despite having health insurance rates similar to those in the general population, men and women in the irradiated group had higher-than-average unemployment rates (15.1 percent vs. 5.4 percent and 35.4 percent vs. 5.2 percent, respectively), and women in the irradiated group were less likely to be married (35.2 percent vs. 48.8 percent). Children with acute lymphoblastic leukemia who did not receive radiation therapy and who have attained 10 or more years of event-free survival can expect a normal long-term survival. Irradiation is associated with the development of second neoplasms, a slight excess in mortality, and an increased unemployment rate.


Taxonomy of the extrasolar planet.
When a star is described as a spectral class G2V, we know that the star is similar to our Sun. We know its approximate mass, temperature, age, and size. When working with an extrasolar planet database, it is very useful to have a taxonomy scale (classification) such as, for example, the Harvard classification for stars. The taxonomy has to be easily interpreted and present the most relevant information about extrasolar planets. I propose an extrasolar planet taxonomy scale with four parameters. The first parameter concerns the mass of an extrasolar planet in the form of units of the mass of other known planets, where M represents the mass of Mercury, E that of Earth, N Neptune, and J Jupiter. The second parameter is the planet's distance from its parent star (semimajor axis) described in a logarithm with base 10. The third parameter is the mean Dyson temperature of the extrasolar planet, for which I established four main temperature classes: F represents the Freezing class, W the Water class, G the Gaseous class, and R the Roasters class. I devised one additional class, however: P, the Pulsar class, which concerns extrasolar planets orbiting pulsar stars. The fourth parameter is eccentricity. If the attributes of the surface of the extrasolar planet are known, we are able to establish this additional parameter where t represents a terrestrial planet, g a gaseous planet, and i an ice planet. According to this taxonomy scale, for example, Earth is 1E0W0t, Neptune is 1N1.5F0i, and extrasolar planet 55 Cnc e is 9E-1.8R1.


The Effect of Cataract on Color Vision Measurement with the Low-Vision Cambridge Colour Test: Providing an Adjustment Factor for Clinical Trials.
To quantify the effect of cataract on color vision as measured by the low-vision Cambridge Colour Test (lvCCT; Cambridge Research Systems) and to understand whether different types and severities of cataract have different effects on color vision. Cohort study. Patients aged 18 to 95 undergoing routine cataract surgery at the Oxford Eye Hospital. The lvCCT was performed to measure color sensitivity in both eyes both before and after surgery. The crystalline lens was examined and graded according to the Lens Opacities Classification System III to determine the type and severity of cataract. Measures of repeatability were performed for the data to explore test-retest bias using Bland-Altman analysis. The Wilcoxon signed-rank test was performed to assess the effect of cataract on color vision by comparing control and surgical test measurements. Three multiple linear regressions were performed to relate cataract grading or severity to color vision measurements. Color discrimination along each of the protan, deutan, and tritan confusion lines. The Wilcoxon signed-rank test showed a statistically significant difference in both the protan (P = 0.024) and tritan (P = 0.020) axes on comparison of control and surgical test measurements. As severity of cataract increased, color vision sensitivity was affected more greatly, and nuclear sclerotic cataract showed the most profound effect on color vision sensitivity in the lvCCT; however, the linear regression models showed that these observations did not reach statistical significance. Cataract surgery has a statistically significant effect on color vision in both the protan and tritan axes. The effects of specific subtypes of cataract and different severities could not be elucidated because of the high prevalence of patients with mixed cataract. The lvCCT color sensitivity measurements are used regularly as outcome measures in clinical gene therapy trials involving vitreoretinal surgery, and vitrectomy accelerates cataract formation. Therefore, it is important to quantify the effect of cataract on color vision measurements so that it may be taken into account when used as an outcome measure in clinical trials. We were unable to derive a precise correction factor for cataract on color vision measurements.