Assessment of antibacterial and cytotoxic effects of orthodontic stainless steel brackets coated with different phases of titanium oxide: An in-vitro study.
Our objective was to assess the antibacterial and cytotoxic effects of orthodontic stainless steel brackets coated with different phases of photocatalytic titanium oxide. From a total sample of 115 brackets, 68 orthodontic stainless steel brackets were coated with titanium oxide using a radiofrequency magnetron sputtering machine. The coated brackets were then converted into 34 each of the anatase and rutile phases of titanium oxide. These brackets were subdivided into 4 groups for antibacterial study and 3 groups for cytotoxicity study. Brackets for the antibacterial study were assessed against the Streptococcus mutans species using microbiologic tests. Three groups for the cytotoxicity study were assessed using the thiazolyl tetrazolium bromide assay. The antibacterial study showed that both phases were effective, but the rutile phase of photocatalytic titanium oxide had a greater bactericidal effect than did the anatase phase. The cytotoxicity study showed that the rutile phase had a greater decrease in viability of cells compared with the anatase phase. It is recommended that orthodontic brackets be coated with the anatase phase of titanium oxide since they exhibited a significant antibacterial property and were only slightly cytotoxic.


Biomaterials for craniofacial reconstruction.
Biomaterials for reconstruction of bony defects of the skull comprise of osteosynthetic materials applied after osteotomies or traumatic fractures and materials to fill bony defects which result from malformation, trauma or tumor resections. Other applications concern functional augmentations for dental implants or aesthetic augmentations in the facial region. For ostheosynthesis, mini- and microplates made from titanium alloys provide major advantages concerning biocompatibility, stability and individual fitting to the implant bed. The necessity of removing asymptomatic plates and screws after fracture healing is still a controversial issue. Risks and costs of secondary surgery for removal face a low rate of complications (due to corrosion products) when the material remains in situ. Resorbable osteosynthesis systems have similar mechanical stability and are especially useful in the growing skull. The huge variety of biomaterials for the reconstruction of bony defects makes it difficult to decide which material is adequate for which indication and for which site. The optimal biomaterial that meets every requirement (e.g. biocompatibility, stability, intraoperative fitting, product safety, low costs etc.) does not exist. The different material types are (autogenic) bone and many alloplastics such as metals (mainly titanium), ceramics, plastics and composites. Future developments aim to improve physical and biological properties, especially regarding surface interactions. To date, tissue engineered bone is far from routine clinical application.


Treating Women Who Are Pregnant and Parenting for Opioid Use Disorder and the Concurrent Care of Their Infants and Children: Literature Review to Support National Guidance.
The prevalence of opioid use disorder (OUD) during pregnancy is increasing. Practical recommendations will help providers treat pregnant women with OUD and reduce potentially negative health consequences for mother, fetus, and child. This article summarizes the literature review conducted using the RAND/University of California, Los Angeles Appropriateness Method project completed by the US Department of Health and Human Services Substance Abuse and Mental Health Services Administration to obtain current evidence on treatment approaches for pregnant and parenting women with OUD and their infants and children. Three separate search methods were employed to identify peer-reviewed journal articles providing evidence on treatment methods for women with OUD who are pregnant or parenting, and for their children. Identified articles were reviewed for inclusion per study guidelines and relevant information was abstracted and summarized. Of the 1697 articles identified, 75 were included in the literature review. The perinatal use of medication for addiction treatment (MAT, also known as medication-assisted treatment), either methadone or buprenorphine, within comprehensive treatment is the most accepted clinical practice, as withdrawal or detoxification risks relapse and treatment dropout. Medication increases may be needed with advancing pregnancy, and are not associated with more severe neonatal abstinence syndrome (NAS). Switching medication prenatally is usually not recommended as it can destabilize opioid abstinence. Postnatally, breastfeeding is seen as beneficial for the infant for women who are maintained on a stable dose of opioid agonist medication. Less is known about ideal pain management and postpartum dosing regimens. NAS appears generally less severe following prenatal exposure to buprenorphine versus methadone. Frontline NAS medication treatments include protocol-driven methadone and morphine dosing in the context of nonpharmacological supports. Women with OUD can be treated with methadone or buprenorphine during pregnancy. NAS is an expected and manageable condition. Although research has substantially advanced, opportunities to guide future research to improve maternal and infant outcomes are provided.


Physicians' perception about electronic medical record system in Makkah Region, Saudi Arabia.
The study was done to determine the physicians' perception about electronic medical record system (EMRS) in the context of its productivity in order to improve its functionality and advantages. This cross-sectional survey was performed from July to August 2009 with structured questionnaire of 15 closed-ended questions with five points Likert scaling starting from strongly disagree to strongly agree as 1-5, reflecting the perception of physicians about EMRS. The physicians of the Makkah region working in six different hospitals were selected. "Positive" response means if percent of responses were rated 4 or 5 (agree/strongly agree), "neutral" if rated 3, and negative if rated 1 or 2 (strongly disagree/disagree). Descriptive data analysis techniques were used. We selected 317 completed questionnaires. Majority of subjects were from King Fahd Hospital, Jeddah (83, 26.3%), residents (147, 46.4%), male (200,63.1%), expatriates (207, 65%), and age group 36-45 years (133, 42%) were dominant. The stem regarding importance of computers for practicing medicine and EMRS to improve quality of practice was appreciated by majority, that is, 77.7 and 71.2%, respectively. However, "It does not disrupt the workflow" (35.1%) and "EMRS is comfortable while entering the data instead of writing" (34.8%) were appreciated negatively. Consultants (53.9%), male (53.4%), expatriates (56.7%), physicians of King Abdul Aziz Hospital, Ta'if (56.9%), and age group of 46-55 years (53.8%) appreciated EMRS positively. Overall perception of EMRS was found positive by 52.8%. Majority appreciated the EMRS, but specific concerns about its usage easiness and workflow disturbance were opposed by them also.


Effects of nucleosides on glia - neuron interactions open up new vistas in the development of more effective antiepileptic drugs.
One-third of epileptic patients are drug refractory due to the limited efficacy of antiepileptic therapy. Thus, there is an immense need to find more effective, safer and well-tolerated antiepileptic drugs. A great deal of results suggests that adenosine (Ado), guanosine (Guo), inosine (Ino) or uridine (Urd) are endogenous antiepileptogenic modulators. Furthermore, nucleosides and their derivatives may be safe and effective potential drugs in the treatment of epilepsy. Conversely, nucleosidergic modulatory system implying nucleoside levels, metabolism, receptors and transporters may also be involved in seizure pathomechanisms. Application of Ado receptor agonists as well as antagonists, elevation of nucleoside levels (e.g., by nucleoside metabolism inhibitors, and Adoreleasing implants) or utilization of non-Ado nucleosides may also turn to be useful approaches to decrease epileptic activity. However, all drugs exerting their effects on the nucleosidergic modulatory system may affect the fine regulation of glia-neuron interactions that are intimately governed by various nucleosidergic processes. Perturbation of the complex, bidirectional communication between neurons and astrocytes through these nucleosidergic modulatory mechanisms may lead to pathological changes in the central nervous system (CNS) and therefore may cause significant side effects. Thus, a deeper understanding of the nucleosidergic modulatory control over glia-neuron interactions is essential in order to develop more effective and safe nucleoside-based antiepileptic drugs. In this review article we focus on the role of Ado and Urd in glia-neuron interactions, placing emphasis on their implications for the treatment of epilepsy.


Project caring for life--long-term care funding alternative.
The synopsis of The Hawaii Long-Term Care Task Force describes the product of project: "Caring ... For Life" as "the framework for implementation of a long-term care system. Framework will encompass promotion, programs, education, legislation and other initiatives necessary for an effective system. The product will be a combined effort of the private sector and government to bring about changes which will provide a continuum of services to all residents in need of long-term care in the least intensive, most appropriate and affordable setting." The purpose of this concept paper has been to paint the big picture of LTC as it now is and provide, in concept, an alternative picture of what it could be. It is by no means complete but hopefully will serve as an initial effort to be addressed and, if appropriate, be expanded upon or modified. It could also serve as a basis of comparison for other alternatives as they are considered. Long-term care is a complex problem, there are no quick fixes. The solution will require great imagination and the ultimate of our creativity. The product should be flexible and above all, should be able to stand the test of time.


Estimating demand for a new contraceptive method: projections for the introduction of Sayana Press.
To describe a demand estimation exercise conducted in response to an initiative to introduce Sayana Press in Sub-Saharan Africa and South Asia. Secondary data sources were used to develop estimates of the number of Sayana Press units needed for countrywide introductions in 12 countries. To estimate uptake, the number of women who had stated an intention to use injectables was calculated. Two sets of assumptions (one conservative, one more ambitious) were used to assess conversion to actual use. Even with the use of very conservative assumptions, and assuming no method switching, Sayana Press was estimated to have the potential to cumulatively reach 3-6million women by 2016. This projected uptake in a relatively short period and at the very beginning of an adoption curve suggests that Sayana Press has promise for countries looking to expand their list of contraceptive choices.


The dual role of TonB genes in turnerbactin uptake and carbohydrate utilization in the shipworm symbiont Teredinibacter turnerae.
This study highlights diversity in iron acquisition and regulation in bacteria. The mechanisms of iron acquisition and its regulation in Teredinibacter turnerae, as well as its connection to cellulose utilization, a hallmark phenotype of T. turnerae, expand the paradigm of bacterial iron acquisition. Two of the four TonB genes identified in T. turnerae exhibit functional redundancy and play a crucial role in siderophore-mediated iron transport. Unlike typical TonB genes in bacteria, none of the TonB genes in T. turnerae are clearly iron regulated. This unusual regulation could be explained by another important finding in this study, namely, that the two TonB genes involved in iron transport are also essential for cellulose utilization as a carbon source, leading to the expression of TonB genes even under iron-rich conditions.


Rabbit antithymocyte globulin versus horse antithymocyte globulin for treatment of acquired aplastic anemia: a retrospective analysis.
Studies comparing rabbit antithymocyte globulin (rATG) and horse ATG (hATG) in patients with aplastic anemia (AA) have shown conflicting results. These studies included fewer than 60 subjects in the rATG arm with relatively short follow-up. A total of 169 patients treated with rATG and 62 treated with hATG were included in this retrospective analysis, across 33 centers. Patients were treated with rATG or hATG plus cyclosporine A. Over half were classified, as having severe AA (SAA) or very severe AA (VSAA), and the mean follow-up was 45 months. There was no significant difference detected in cumulative response to treatment or survival between the rATG and hATG groups. The response to treatment was 63 % in the rATG group versus 66 % in the hATG group at 3 months. By 12 months, this pattern had reversed, and 84 % of rATG patients had responded to treatment versus 76 % in the hATG group (n.s.). Early mortality due to infection tended to be higher with rATG compared to hATG (n.s). rATG and hATG would seem to be therapeutically equivalent in SAA and VSAA. However, patients treated with rATG may take longer to respond than those treated with hATG and may also require more active prevention of early infections.


Elbasvir/Grazoprevir Use in Postliver Transplantation Patients on Hemodialysis.
Current national hepatitis C virus (HCV) guidelines do not recommend the use of elbasvir (EBR)/grazoprevir (GZR) in postliver transplantation (LT) patients due to drug-drug interactions with immunosuppression agents. However, recommendations do not address the treatment of HCV in renally impaired post-LT patients. Treatment regimens that are recommended for post-LT patients are not safe in patients with severe renal impairment and patients on dialysis. EBR/GZR is approved for use in patients with renal impairment and patients on dialysis, but not in the post-LT setting. Authors reviewed the electronic medical records of 3 treatment-naive HCV genotype 1a male post-LT patients on hemodialysis who were treated with EBR/GZR with or without ribavirin for 12 or 16 weeks. No patients had serious adverse drug events during treatment and no patients stopped treatment early or died. Providers monitored immunosuppression levels; both patients who were taking tacrolimus required immunosuppression dose adjustments during HCV treatment. No patients experienced organ rejection. All patients achieved sustained virologic response. Current HCV guidelines do not address the treatment options for post-LT patients with severe renal impairment or who are on dialysis, nor do published accounts of use of EBR/GZR in this patient population exist. Clinicians may benefit from exposure to real-world cases of HCV treatment in this historically difficult-to-cure patient population. Providers must address drug-drug interactions with EBR/GZR and monitor for changes in immunosuppression levels to ensure safety with its use in post-LT patients.


A Compassionate Communities Approach in a Grief and Bereavement Support Program: Bridging the Gap in Palliative Care.
Grief and bereavement support is a fundamental component of palliative care, yet there is a gap in practice as not all palliative care services offer it. The compassionate communities (CC) approach aims to build community capacity to address grief as grief support is considered everyone's responsibility. This study describes the characteristics, development, growth and attendees of a grief support program that uses a CC approach to bridge the gap of grief support in palliative care.


Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons.
There has never been a wholesale way of identifying neurons that are monosynaptically connected either to some other cell group or, especially, to a single cell. The best available tools, transsynaptic tracers, are unable to distinguish weak direct connections from strong indirect ones. Furthermore, no tracer has proven potent enough to label any connected neurons whatsoever when starting from a single cell. Here we present a transsynaptic tracer that crosses only one synaptic step, unambiguously identifying cells directly presynaptic to the starting population. Based on rabies virus, it is genetically targetable, allows high-level expression of any gene of interest in the synaptically coupled neurons, and robustly labels connections made to single cells. This technology should enable a far more detailed understanding of neural connectivity than has previously been possible.


Preimplantation genetic testing with HLA matching: from counseling to birth and beyond.
Preimplantation genetic testing-human leukocyte antigen '(PGT-HLA) only' refers to the HLA typing of single or few cells biopsied from in vitro fertilized preimplantation embryos. The aim of the procedure is to establish a pregnancy, in which the fetus is HLA compatible with an affected sibling in need of a hematopoietic stem cell transplantation (HSCT). During PGT-M-HLA, the identification of a HLA-compatible embryo is combined with the detection of mutation(s) underlying immunodeficiencies and hemoglobinopathies. We report a combined retrospective and prospective cohort analysis of PGT-(M-)HLA procedures carried out from 1998 until 2017, with follow-up of transplantations to 2019. During the study period, 234 couples from 22 countries were invited for a multidisciplinary consultation. Two couples were rejected and 70 couples declined (various reasons), leaving 162 couples for which 414 clinical cycles were carried out. Cleavage stage biopsy followed by single-cell multiplex PCR for short tandem repeat-based haplotyping was applied in most cases (98.7%). The diagnostic efficiency was high (94.8%) but only 16.5% of the embryos was genetically suitable for transfer. Fresh and frozen-thawed embryo transfer resulted in 67 clinical pregnancies, 63 deliveries, and 74 live births, of which 60 children were HLA compatible. This yielded a live birth delivery rate of 30.3% per transfer. Information on neonatal characteristics of the matching PGT-(M-)HLA children showed reassuring outcomes. So far, HSCT was carried out successfully for 25 out of 26 cases. In conclusion, our data show that PGT-(M-)HLA is a valuable procedure: the high complexity and limited delivery rate are balanced by the successful HSCT outcome and the positive impact on families.


Recurrent genome duplication events likely contributed to both the ancient and recent rise of ferns.
Ferns, the second largest group of vascular plants, originated ~400 million years ago (Mya). They became dominant in the ancient Earth landscape before the angiosperms and are still important in current ecosystems. Many ferns have exceptionally high chromosome numbers, possibly resulting from whole-genome duplications (WGDs). However, WGDs have not been investigated molecularly across fern diversity. Here we detected and dated fern WGDs using a phylogenomic approach and by calculating synonymous substitution rates (Ks). We also investigated a possible correlation between proposed WGDs and shifts in species diversification rates. We identified 19 WGDs: three ancient events along the fern phylogenetic backbone that are shared by 66%-97% of extant ferns, with additional lineage-specific WGDs for eight orders, providing strong evidence for recurring genome duplications across fern evolutionary history. We also observed similar Ks peak values for more than half of these WGDs, with multiple WGDs occurring close to the Cretaceous (~145-66 Mya). Despite the repeated WGD events, the biodiversity of ferns declined during the Cretaceous, implying that other factors probably contributed to the floristic turnover from ferns to angiosperms. This study provides molecular evidence for recurring WGDs in ferns and offers important clues to the genomic evolutionary history of ferns.


Glucosylceramide Administration as a Vaccination Strategy in Mouse Models of Cryptococcosis.
Cryptococcus neoformans is an opportunistic fungal pathogen and the causative agent of the disease cryptococcosis. Cryptococcosis is initiated as a pulmonary infection and in conditions of immune deficiency disseminates to the blood stream and central nervous system, resulting in life-threatening meningoencephalitis. A number of studies have focused on the development of a vaccine against Cryptococcus, primarily utilizing protein-conjugated components of the Cryptococcus polysaccharide capsule as antigen. However, there is currently no vaccine against Cryptococcus in the clinic. Previous studies have shown that the glycosphingolipid, glucosylceramide (GlcCer), is a virulence factor in C. neoformans and antibodies against this lipid inhibit fungal growth and cell division. In the present study, we have investigated the possibility of using GlcCer as a therapeutic agent against C. neoformans infections in mouse models of cryptococcosis. GlcCer purified from a non-pathogenic fungus, Candida utilis, was administered intraperitoneally, prior to infecting mice with a lethal dose of C. neoformans. GlcCer administration prevented the dissemination of C. neoformans from the lungs to the brain and led to 60% mouse survival. GlcCer administration did not cause hepatic injury and elicited an anti-GlcCer antibody response, which was observed independent of the route of administration and the strains of mouse. Taken together, our results suggest that fungal GlcCer can protect mice against lethal doses of C. neoformans infection and can provide a viable vaccination strategy against Cryptococcus.


Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice.
The mechanisms leading to autoimmune and inflammatory diseases in the CNS have not been elucidated. The environmental triggers of the aberrant presence of CD4+ T cells in the CNS are not known. In this article, we report that abnormal β-catenin expression in T cells drives a fatal neuroinflammatory disease in mice that is characterized by CNS infiltration of T cells, glial activation, and progressive loss of motor function. We show that enhanced β-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin α4β1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of β-catenin in mature naive T cells was sufficient to drive integrin α4β1 expression and CNS migration, whereas pharmacologic inhibition of integrin α4β1 reduced the abnormal T cell presence in the CNS of β-catenin-expressing mice. Together, these results implicate deregulation of the Wnt/β-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders.


A brief account of evolution of assays to study carbohydrate-protein interaction.
Molecular recognition remains one of the most desirable means of cellular communication. Each cell offers a unique surface pattern of biomolecules that makes it very specific about the nature of molecules that interact with the cell. Protein-glycan interaction has been one of the most common forms of cell signaling. Glycans expressed on the cell surface interact with an exogenous protein, and in many cases lead to a physiological response. These carbohydrate-binding proteins, commonly known as lectins, are very specific to the glycan they bind to. An exogenous lectin interacting with an animal cell surface glycan is generally studied using the classical hemagglutination assay. However, this method presents certain challenges that make it imperative to design and develop novel methods that are more specific and efficient in their interaction. In the last decade, a few methods have been developed to analyze more diverse reactions and use a lesser amount of sample. In some cases, the processing of the sample is also reduced. This review discusses how the methods have evolved over the decades and how they have reduced error while becoming more efficient.


A computational model of postprandial adipose tissue lipid metabolism derived using human arteriovenous stable isotope tracer data.
Given the association of disturbances in non-esterified fatty acid (NEFA) metabolism with the development of Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease, computational models of glucose-insulin dynamics have been extended to account for the interplay with NEFA. In this study, we use arteriovenous measurement across the subcutaneous adipose tissue during a mixed meal challenge test to evaluate the performance and underlying assumptions of three existing models of adipose tissue metabolism and construct a new, refined model of adipose tissue metabolism. Our model introduces new terms, explicitly accounting for the conversion of glucose to glyceraldehye-3-phosphate, the postprandial influx of glycerol into the adipose tissue, and several physiologically relevant delays in insulin signalling in order to better describe the measured adipose tissues fluxes. We then applied our refined model to human adipose tissue flux data collected before and after a diet intervention as part of the Yoyo study, to quantify the effects of caloric restriction on postprandial adipose tissue metabolism. Significant increases were observed in the model parameters describing the rate of uptake and release of both glycerol and NEFA. Additionally, decreases in the model's delay in insulin signalling parameters indicates there is an improvement in adipose tissue insulin sensitivity following caloric restriction.


Prevention of severe pelvic abscess formation following extended radical surgery for locally recurrent rectal cancer.
For treatment of locally recurrent rectal cancer (LRRC), extended radical surgery is sometimes required to obtain a negative margin. Such surgery is often associated with severe postoperative pelvic abscess (PA) formation. The aim of this study was to determine the effects of reconstructive surgery using a large rectus abdominis myocutaneous (RAM) flap and anal preservation surgery on the incidence of severe PA. Between February 1998 and June 2008, 44 patients underwent extended surgery for LRRC. Patients were divided into the pre-2004 group (n = 15) and the post-2004 group (n = 29). To reduce the risk of infections, we modified the surgical approach after 2004 to include a larger volume of RAM flap (modified RAM flap) and implemented anal preservation surgery. The overall incidence of severe PA was significantly lower in the post-2004 group [6 of 29 (21%)] than the pre-2004 group [9 of 15 (60%), P = 0.017]. The incidence of severe PA was lower in the anal preservation group [1 of 12 (8.3%)] compared with those who did not undergo such surgery [14 of 32 (44%), P = 0.035]. Modified RAM flap reduced the incidence of severe PA, albeit insignificantly (pre-2004 group: 57%, post-2004 group: 23%). All three patients who underwent anal preservation and modified RAM flap reconstruction did not develop severe PA. Multiple logistic analysis identified no anal preservation (Odds ratio [OR] = 10.6) and performing of sacrectomy (OR = 20.0) as risk factors for severe PA. Anal preservation surgery is an effective measure against the development of severe PA after radical resection of LRRC.


Measurement of pituitary gland height with MR imaging.
From sagittal magnetic resonance (MR) images with 10 mm slice thickness, the mean vertical height of the pituitary gland in 42 normal patients was found to be 5.4 +/- 0.9 mm. Computed tomographic (CT) scans in the coronal plane showed the same. Measurements of pituitary size in 13 patients with tumors using both CT and MR were also essentially equivalent. The ease, comfort, and accuracy of the MR pituitary measurement supports its use as the examination of choice for measuring pituitary height.


Application of data pooling to longitudinal studies of early post-traumatic stress disorder (PTSD): the International Consortium to Predict PTSD (ICPP) project.
Background: Understanding the development of post-traumatic stress disorder (PTSD) is a precondition for efficient risk assessment and prevention planning. Studies to date have been site and sample specific. Towards developing generalizable models of PTSD development and prediction, the International Consortium to Predict PTSD (ICPP) compiled data from 13 longitudinal, acute-care based PTSD studies performed in six different countries. Objective: The objectives of this study were to describe the ICPP's approach to data pooling and harmonization, and present cross-study descriptive results informing the longitudinal course of PTSD after acute trauma. Methods: Item-level data from 13 longitudinal studies of adult civilian trauma survivors were collected. Constructs (e.g. PTSD, depression), measures (questions or scales), and time variables (days from trauma) were identified and harmonized, and those with inconsistent coding (e.g. education, lifetime trauma exposure) were recoded. Administered in 11 studies, the Clinician Administered PTSD Scale (CAPS) emerged as the main measure of PTSD diagnosis and severity. Results: The pooled data set included 6254 subjects (39.9% female). Studies' average retention rate was 87.0% (range 49.1-93.5%). Participants' baseline assessments took place within 2 months of trauma exposure. Follow-up durations ranged from 188 to 1110 days. Reflecting studies' inclusion criteria, the prevalence of baseline PTSD differed significantly between studies (range 3.1-61.6%), and similar differences were observed in subsequent assessments (4.3-38.2% and 3.8-27.0% for second and third assessments, respectively). Conclusion: Pooling data from independently collected studies requires careful curation of individual data sets for extracting and optimizing informative commonalities. However, it is an important step towards developing robust and generalizable prediction models for PTSD and can exceed findings of single studies. The large differences in prevalence of PTSD longitudinally cautions against using any individual study to infer trauma outcome. The multiplicity of instruments used in individual studies emphasizes the need for common data elements in future studies.


Association Between a Low-Carbohydrate Diet, Glycemic Control, and Quality of Life in Australian Adults Living With Type 1 Diabetes: A Pilot Study.
To examine if there is an association between a low-carbohydrate diet (LCD), glycemic control, and quality of life (QoL) in Australian adults with type 1 diabetes. This single-group, pre-post, mixed methods (quantitative and qualitative) study was conducted in an outpatient tertiary hospital. Eligible participants were those aged ≥18 years, with type 1 diabetes for ≥1 year, and using multiple daily insulin injections. Participants followed a 12-week individualized LCD (<100 g/d). Daily glucose levels were monitored using a continuous glucose monitor. Glycated hemoglobin (HbA1c) and QoL were measured preintervention and postintervention. A post-hoc exploratory regression analysis determined whether changes in carbohydrate intake was associated with changes in HbA1c and QoL. Qualitative data collected postintervention explored participants' perceptions relating to a LCD, glycemic control, and QoL. Participants (n = 22) completed the 12-week LCD intervention. An LCD provided a statistically, significant improvement in HbA1c 0.83% (95% CI 0.32%-1.33%), P = .003 but did not impact QoL: estimated change 1.14 units (95% CI: -5.34 to 7.61); P = .72. The post-hoc exploratory regression analysis showed that participants with poorer baseline glycemic control were more likely to respond to an LCD resulting in significant reductions in HbA1c. Participant perceptions relating to the study variables were mixed. An LCD (<100 g/d) is a potentially effective and safe strategy to improve glycemic control without negatively effecting QoL in Australian adults with type 1 diabetes.


A decision tree built with parameters obtained by computed tomographic pulmonary angiography is useful for predicting adverse outcomes in non-high-risk acute pulmonary embolism patients.
Acute pulmonary embolism (APE) is one of the leading causes of death in cardiovascular disease. The 30-day mortality can still be 1.7-15% in non-high-risk APE patients. Some non-high-risk patients can progress into the high-risk group and even die, which is referred to as an adverse outcome. Promoting the diagnosis and predictive ability of adverse short-term prognosis was still a problem that needed to be solved. Computed tomography pulmonary angiography (CTPA) may be a way to promote the predictive ability. Our aim to develop predictive tools based on parameters obtained by computed tomographic pulmonary angiography (CTPA) in the form of a decision tree for use in non-high-risk acute pulmonary embolism (APE) patients. Adverse outcome was defined within 30 days after admission to the hospital. A decision tree was built to predict adverse outcomes based on discriminating factors screened from cardiac volume and clot characteristics from recursive partitioning analysis and compared with simplified pulmonary embolism severity index (sPESI), Bova scores and risk stratification. The area under the receiver operating characteristic curve (ROC-AUC) was used to confirm the predictive ability. A total of 38 patients with and 303 patients without adverse outcomes were enrolled. Right ventricular/left ventricular (RV/LV) volume ratio, central pulmonary artery (CPA) embolism and right atria/left atria (RA/LA) volume ratio were used as splits in the decision tree to predict adverse outcomes in all patients. The ROC-AUC was 0.858. In CPA embolism patients, a recursive partitioning analysis was performed with cardiac volume and novel clot burden, but only the obstructing area (OA) ratio was included as a discriminating factor to build a second decision tree. The ROC-AUC for the second decision tree was 0.810. The decision trees were superior to those of sPESI, Bova scores and risk stratification, and there were no significant differences between the two decision trees. A decision tree built by CTPA parameters can predict adverse outcomes in non-high-risk APE patients.


Perceptually Motivated Image Features Using Contours.
Dong et al. examined the ability of 51 computational feature sets to estimate human perceptual texture similarity; however, none performed well for this task. While it is well-known that the human visual system is extremely adept at exploiting longer-range aperiodic (and periodic) "contour" characteristics in images, none of the investigated feature sets exploit higher order statistics (HOS) over larger image regions ( > 19×19 pixels). We, therefore, hypothesise that long-range HOS, in the form of contour data, are useful for perceptual texture similarity estimation. We present the results of a psychophysical experiment that shows that contour data are more important, than local image patches, or global second-order data, to human observers for this task. Inspired by this finding, we propose a set of perceptually motivated image features (PMIF) that encode the long-range HOS computed from spatial and angular distributions of contour segments. We use two perceptual texture similarity estimation tasks to compare PMIF against the 51 feature sets referred to above and four commonly used contour representations. This new feature set is also examined in the context of two additional tasks: sketch-based image retrieval and natural scene recognition. The results show that the proposed feature set performs better, or at least comparably to, all the other feature sets. We attribute this promising performance to the fact that the proposed feature set exploits both short-range and long-range HOS.


The revised CONSORT statement for reporting randomized trials: explanation and elaboration.
Overwhelming evidence now indicates that the quality of reporting of randomized, controlled trials (RCTs) is less than optimal. Recent methodologic analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects. Such systematic error is seriously damaging to RCTs, which boast the elimination of systematic error as their primary hallmark. Systematic error in RCTs reflects poor science, and poor science threatens proper ethical standards. A group of scientists and editors developed the CONSORT (Con solidated S tandards o f R eporting T rials) statement to improve the quality of reporting of RCTs. The statement consists of a checklist and flow diagram that authors can use for reporting an RCT. Many leading medical journals and major international editorial groups have adopted the CONSORT statement. The CONSORT statement facilitates critical appraisal and interpretation of RCTs by providing guidance to authors about how to improve the reporting of their trials. This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the CONSORT statement. The meaning and rationale for each checklist item are presented. For most items, at least one published example of good reporting and, where possible, references to relevant empirical studies are provided. Several examples of flow diagrams are included. The CONSORT statement, this explanatory and elaboration document, and the associated Web site ( http://www.consort-statement.org ) should be helpful resources to improve reporting of randomized trials. Throughout the text, terms marked with an asterisk are defined at end of text.


A graphical approach to characterize sub-daily flow regimes and evaluate its alterations due to hydropeaking.
Most flow regime characterizations focus on long time scale flow patterns, which are not precise enough to capture key components of short-term flow fluctuations. Recent proposed methods describing sub-daily flow fluctuations are focused on limited components of the flow regime being unable to fully represent it, or on the identification of peaking events based on subjectively defined thresholds, being unsuitable for evaluations of short-term flow regime alterations through comparisons between regulated and free-flowing rivers. This study aims to launch an innovative approach based on the visual display of quantitative information to address the challenge of the short-term hydrologic characterization and evaluation of alteration resulting from hydropeaking. We propose a graphical method to represent a discrete set of ecologically relevant indices that characterize and evaluate the alteration of sub-daily flow regimes. The frequency of occurrence of classified values of a descriptive hydrological variable is represented in a map-like graph where longitude, latitude and altitude represent the Julian day, the value of the variable and the frequency of occurrence, respectively. Subsequently, we tested the method on several rivers, both free-flowing and subjected to hydropower production. The advantages of our approach compared to other analytical methods are: (i) it displays a great amount of information without oversimplification; (ii) it takes into account changes in the intensity, timing and frequency of the sub-daily flows, without needing a priori defined thresholds to identify hydropeaking events; and (iii) it supports the Water Framework Directive goal. Specifically, results from applications of our graphical method agree with Sauterleute and Charmasson (2014) analytical method.


Variable genetic element typing: a quick method for epidemiological subtyping of Legionella pneumophila.
A total of 57 isolates of Legionella pneumophila were randomly selected from the German National Legionella strain collection and typed by monoclonal antibody subgrouping, seven-gene locus sequence-based typing (SBT) scheme and a newly developed variable element typing (VET) system based on the presence or absence of ten variable genetic elements. These elements were detected while screening a genomic library of strain Corby, as well as being taken from published data for PAI-1 (pathogenicity island) from strain Philadelphia. Specific primers were designed and used in gel-based polymerase chain reaction (PCR) assays. PCR amplification of the mip gene served as a control. The end-point was the presence/absence of a PCR product on an ethidium bromide-strained gel. In the present study, the index of discrimination was somewhat lower than that of the SBT (0.87 versus 0.97). Nevertheless, the results obtained showed as a 'proof of principle' that this simple and quick typing assay might be useful for the epidemiological characterisation of L. pneumophila strains.


Metacognitive Monitoring of Executive Control Engagement During Childhood.
Emerging executive control supports greater autonomy and increasingly adaptive behavior during childhood. The present study addressed whether children's greater monitoring of how they engage control drives executive control development. Gaze position was recorded while twenty-five 6-year-olds and twenty-eight 10-year-olds performed a self-paced task-switching paradigm in which they could proactively prepare for the next task for as long as they wanted before completing it. Gaze trajectories and performance showed that younger children were less well prepared than older children when they triggered the target, even though they could have taken longer to fully prepare. With age, children better monitor how they engage control, highlighting the contribution of metacognitive processes to executive control development.


Dual role of IL-12 in early and late stages of murine collagen type II arthritis.
IL-12 can promote Th1 responses, and early administration of IL-12 during immunization was shown to enhance expression of autoimmune collagen-induced arthritis (CIA). We now studied the impact of IL-12 at the stage of disease expression and during established CIA in DBA-1 mice. Accelerated onset and enhanced severity were provoked when i.p. injections of 100 ng of murine IL-12 (mIL-12) were given around the time of arthritis onset. Moreover, the onset of CIA could be ameliorated with anti-mIL-12 Abs, indicating that IL-12 is a pivotal mediator in the expression of CIA. In addition, the effect of anti-mIL-12 treatment was analyzed in established CIA. Continued treatment did not suppress established arthritis. Instead, these mice showed an impressive exacerbation of arthritis shortly after cessation of anti-mIL-12 treatment, indicative of impairment of endogenous control. Exaggerated disease was characterized by massive granulocyte influx and enhanced expression of IL-1 beta and TNF-alpha mRNA in the synovial tissue. Subsequently, we treated established collagen arthritis with recombinant mIL-12 for 7 days. Profound suppression of the arthritis score was noted, including reduced influx of cells and diminished cartilage damage. Tenfold enhanced levels of IL-10 were detected in sera of mIL-12-treated mice, and up-regulated mRNA levels of IL-10, IFN-gamma, and IL-12 were measured in synovial tissue. Finally, the anti-inflammatory effect of IL-12 on CIA could be reversed by coadministration of anti-IL-10 Abs. This study indicates that IL-12 has a stimulatory role in early arthritis expression, whereas it has a suppressive role in the established phase of collagen arthritis.


CD4+ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-beta.
Nylon wool adherent, CD4+ T cells from the spleens of rats that have recovered from experimental autoimmune encephalomyelitis (EAE) inhibit the in vitro production of IFN-gamma, but not IL-2, by effector cells of EAE when cocultured in the presence of myelin basic protein Ag. When anti-transforming growth factor-beta (TGF-beta) antibodies are added to the co-cultures, IFN-gamma production is restored to normal levels. Irrelevant control antibodies have no effect. The same pattern of response was obtained with cells incubated in serum-free medium. In other experiments, purified TGF-beta was added to cultures of effector cells in the presence of antigen. TGF-beta inhibited the production of IFN-gamma by these cells in a dose-dependent manner, but had no apparent inhibitory effect on IL-2 production. Finally, supernatants from cultures containing effector cells and CD4+ suppressor cells plus Ag contained measurable amounts of TGF-beta, whereas supernatants from cultures of effector cells plus Ag contained no measurable amounts of TGF-beta. These results suggest that CD4+ Ts cells of EAE regulate effector cells of EAE through a mechanism that involves the secretion of TGF-beta and that the inhibitory function of this cytokine can be reversed with neutralizing antibodies directed against TGF-beta.


Phytoscreening for chlorinated solvents using rapid in vitro SPME sampling: application to urban plume in Verl, Germany.
Rapid detection and delineation of contaminants in urban settings is critically important in protecting human health. Cores from trees growing above a plume of contaminated groundwater in Verl, Germany, were collected in 1 day, with subsequent analysis and plume mapping completed over several days. Solid-phase microextraction (SPME) analysis was applied to detect tetrachloroethene (PCE) and trichloroethene (TCE) to below nanogram/liter levels in the transpiration stream of the trees. The tree core concentrations showed a clear areal correlation to the distribution of PCE and TCE in the groundwater. Concentrations in tree cores were lower than the underlying groundwater, as anticipated; however, the tree core water retained the PCE:TCE signature of the underlying groundwater in the urban, populated area. The PCE:TCE ratio can indicate areas of differing degradation activity. Therefore, the phytoscreening analysis was capable not only of mapping the spatial distribution of groundwater contamination but also of delineating zones of potentially differing contaminant sources and degradation. The simplicity of tree coring and the ability to collect a large number of samples in a day with minimal disruption or property damage in the urban setting demonstrates that phytoscreening can be a powerful tool for gaining reconnaissance-level information on groundwater contaminated by chlorinated solvents. The use of SPME decreases the detection level considerably and increases the sensitivity of phytoscreening as an assessment, monitoring, and phytoforensic tool. With rapid, inexpensive, and noninvasive methods of detecting and delineating contaminants underlying homes, as in this case, human health can be better protected through screening of broader areas and with far faster response times.


Neurobiological correlates of apathy in Alzheimer's disease and mild cognitive impairment: a critical review.
In Alzheimer's disease (AD) and mild cognitive impairment (MCI), apathy was associated with faster clinical deterioration. Studies involving neurobiological correlates such as neuroimaging and biomarkers have presented distinct results. This work aimed to analyze neurobiological correlates of apathy in AD and MCI based on evidence from the literature involving brain neuroimaging and classical AD biomarkers. This review comprised studies published from 1996 to June 2013 from the Pubmed database. The studies were divided into Part I (neuroimaging) and Part II (chemical biomarkers). The analysis included the identification of brain regions involved and assessments of apathy and cognition. We found 68 publications: 33 fulfilled the inclusion criteria; 35 were case reports or were not clear about the measurements of apathy and were excluded. From the 33 eligible studies, 26 were classified into part I, and 7 studies were included in part II. We created specific criteria to appropriately classify the quality level of each publication. Prefrontal regions and the anterior cingulate were the leading brain areas associated with apathy in AD and MCI. Other regions, including cortical and subcortical structures, have also been implicated in this syndrome. Abnormalities in frontal regions (associated with impairments in planning and decision making) and anterior cingulate (related to emotional blunting and loss of motivation) were the crucial structures associated with apathy in AD and MCI.


Cationic bovine serum albumin based self-assembled nanoparticles as siRNA delivery vector for treating lung metastatic cancer.
It is generally believed that intravenous application of cationic vectors is limited by the binding of abundant negatively charged serum components, which may cause rapid clearance of the therapeutic agent from the blood stream. However, previous studies show that systemic delivery of cationic gene vectors mediates specific and efficient transfection within the lung, mainly as a result of interaction of the vectors with serum proteins. Based on these findings, a novel and charge-density-controllable siRNA delivery system is developed to treat lung metastatic cancer by using cationic bovine serum albumin (CBSA) as the gene vector. By surface modification of BSA, CBSA with different isoelectric points (pI) is synthesized and the optimal cationization degree of CBSA is determined by considering the siRNA binding and delivery ability, as well as toxicity. The CBSA can form stable nanosized particles with siRNA and protect siRNA from degradation. CBSA also shows excellent abilities to intracellularly deliver siRNA and mediate significant accumulation in the lung. When Bcl2-specific siRNA is introduced to this system, CBSA/siRNA nanoparticles exhibit an efficient gene-silencing effect that induces notable cancer cell apoptosis and subsequently inhibits the tumor growth in a B16 lung metastasis model. These results indicate that CBSA-based self-assembled nanoparticles can be a promising strategy for a siRNA delivery system for lung targeting and metastatic cancer therapy.


Accelerated Compressed Sensing Based CT Image Reconstruction.
In X-ray computed tomography (CT) an important objective is to reduce the radiation dose without significantly degrading the image quality. Compressed sensing (CS) enables the radiation dose to be reduced by producing diagnostic images from a limited number of projections. However, conventional CS-based algorithms are computationally intensive and time-consuming. We propose a new algorithm that accelerates the CS-based reconstruction by using a fast pseudopolar Fourier based Radon transform and rebinning the diverging fan beams to parallel beams. The reconstruction process is analyzed using a maximum-a-posterior approach, which is transformed into a weighted CS problem. The weights involved in the proposed model are calculated based on the statistical characteristics of the reconstruction process, which is formulated in terms of the measurement noise and rebinning interpolation error. Therefore, the proposed method not only accelerates the reconstruction, but also removes the rebinning and interpolation errors. Simulation results are shown for phantoms and a patient. For example, a 512 × 512 Shepp-Logan phantom when reconstructed from 128 rebinned projections using a conventional CS method had 10% error, whereas with the proposed method the reconstruction error was less than 1%. Moreover, computation times of less than 30 sec were obtained using a standard desktop computer without numerical optimization.


COVID-19 in Workplace Settings: Lessons Learned for Occupational Medicine in the UK.
This paper addresses lessons learned from the COVID-19 pandemic from a UK Occupational Medicine perspective to permit comparison with other national accounts. In spite of good prior research and statute, the necessary resources to protect workers' health were seriously lacking when the pandemic struck. Weak public health guidance, which did not recognise dominant airborne transmission, was applied to workplaces, leaving workers and others unprotected, especially in respect to Respiratory Protective Equipment (RPE). The Health and Safety Executive (HSE) as regulator was lacking, for example, in not producing guidance to protect HealthCare Workers (HCW) who were amongst the most at risk. The UK COVID-19 Public Inquiry should address shortcomings such as these, but recommendations must be accompanied by robust means to ensure appropriate implementation. These should range from substantial measures to improve indoor air quality, to a permanent pandemic management organization with adequate resources. The enforcing authority has to be obliged to publish more specific workplace guidance than the public health authorities. Occupational medicine as a discipline needs to be better prepared, and hence to assert its responsibility towards high standards of workers' health protection. Future research has to include investigating the best means of mitigation against airborne infection and the management of post-acute covid sequelae.


Lysosome-damage-induced scattering changes coincide with release of cytochrome c.
Light scattering measurements made at visible wavelengths have the ability to quantify subcellular morphology. Apoptosis, or programmed cell death, is associated with distinct morphological signatures such as mitochondrial swelling and nuclear condensation as well as characteristic biochemical signaling pathways, many of which are initiated by the release of cytochrome c from the mitochondria into the cytosol. In this Letter, we examine the time course of mitochondrial morphology changes as reported by light scattering and the subcellular location of cytochrome c measured by immunofluorescence microscopy in response to intracellular cell death signaling induced by photodynamic damage to lysosomes. We report that within this system, release of cytochrome c from the mitochondria into the cytosol occurs approximately simultaneously with mitochondrial-morphology-induced light scattering changes, providing further evidence that light scattering has the potential to play an important role in future studies of cell death biology.


Mechanisms mediating renal sympathetic activation to leptin in obesity.
Leptin plays a critical role in the control of energy homeostasis. The sympathetic cardiovascular actions of leptin have emerged as a potential link between obesity and hypertension. We previously demonstrated that in mice, modest obesity induced by 10 wk of a high-fat diet is associated with preservation of leptin ability to increase renal sympathetic nerve activity (SNA) despite the resistance to the metabolic effects of leptin. Here, we examined whether selective leptin resistance exists in mice with late-stage diet-induced obesity (DIO) produced by 20 wk of a high-fat diet. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular injection of leptin was significantly attenuated in the DIO mice. Regional SNA responses to intravenous leptin were also attenuated in DIO mice. In contrast, intracerebroventricularly administered leptin caused contrasting effects on regional SNA in DIO mice. Renal SNA response to intracerebroventricular leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated. Intact renal SNA response to leptin combined with the increased cerebrospinal fluid leptin levels in DIO mice represents a potential mechanism for the adverse cardiovascular consequences of obesity. Lastly, we examined the role of phosphoinositol-3 kinase (PI3K) and melanocortin receptors (MCR) in mediating the preserved renal SNA response to leptin in obesity. Presence of PI3K inhibitor (LY294002) or MC3/4R antagonist (SHU9119) significantly attenuated the renal SNA response to leptin in DIO and agouti obese mice. Our results demonstrate the importance of PI3K and melanocortin receptors in the transduction of leptin-induced renal sympathetic activation in obesity.


The search for assisted reproduction: profile of patients seen in the fertility outpatient clinic of a public hospital.
To analyze the epidemiological profile of patients treated at the Fertility Outpatient Clinic of a tertiary public hospital in Juiz de Fora. This cross-sectional study analyzed the medical records of 448 patients who sought fertility treatment at a tertiary public hospital. The data collected from the medical records were used to assess the main causes of infertility, find the most frequently performed procedures, and the cases eligible to therapeutic or prophylactic intervention. Of the 448 patients included in the study, 385 (86%) sought fertility consultation, 49 (10%) came in for repeated miscarriages, and 14 (3%) for other reasons. Of the 438 infertile patients, 280 (63.9%) had primary and 158 (36.1%) had secondary infertility. The top-three conditions of the 295 patients with established diagnoses were chronic anovulation (n=98; 33%); tubal factor infertility (n=86; 29%); and male factor infertility (n=59; 20%). Improving care in reproductive health requires a more profound comprehension of the epidemiological profile of patients seeking treatment. There are alternative cost-effective means to contain the development of infertility. Additional expenditure in public healthcare is needed to accommodate the growing number of individuals seeking fertility treatment in Brazil.


Refining the mouse chromosomal location of Cdm, the major gene associated with susceptibility to cadmium-induced testicular necrosis.
Cadmium (Cd++) is a widespread environmental pollutant and classifed as an IARC 'Category I' human carcinogen. Cd++ can also cause severe renal toxicity and may be involved clinically in cardiovascular disease and osteoporosis. Genetic differences in sensitivity to cadmium toxicity have been noted in humans, whereas, among inbred mouse strains, unequivocal genetic data exist. Resistance to cadmium-induced testicular damage was reported in 1973 to be associated with a single major recessive gene, named Cdm, which has now been localized to mouse chromosome (Chr) 3. Using polymorphic microsatellite markers and semiquantitative histological parameters, we have corroborated the original 1973 data concerning mendelian inheritance and have further refined the region containing the Cdm gene from more than 24 cM to 0.64 cM (estimated 40-80 genes). We phenotyped 26 recombinant inbred lines generated from C57BL/6J (B6, resistant) and DBA/2J (D2, sensitive) inbred mice, and determined that the Cdm gene maps between microsatellite markers D3Mit110 and D3Mit255. Although toxicity to numerous heavy metals is well known, virtually no molecular mechanisms have yet been uncovered either in humans or laboratory animals. Identification and characterization of the mouse Cdm gene should enhance our understanding of heavy metal toxicity by identifying and characterizing, for the first time, a major mammalian gene responsible for susceptibility to diseases caused by heavy metal toxicity.


Clinical effectiveness of a one-step self-etch adhesive in non-carious cervical lesions at 2 years.
A 2-year randomized, controlled prospective study evaluated the clinical effectiveness of a one-step self-etch adhesive and a "gold-standard" three-step etch-and-rinse adhesive in non-carious Class-V lesions. The null hypothesis tested was that the one-step self-etch adhesive does perform clinically equally well as the three-step etch-and-rinse adhesive. A total of 161 lesions in 26 patients were restored with Clearfil AP-X (Kuraray). The restorations were bonded either with the "all-in-one" adhesive Clearfil S3 Bond (Kuraray) or with the three-step etch-and-rinse adhesive Optibond FL (Kerr). The restorations were evaluated at baseline and after 6 months, 1 and 2 years, regarding their retention, marginal adapation, marginal discoloration, caries occurrence, preservation of tooth vitality and post-operative sensivity. Retention loss, severe marginal defects and/or discoloration that needed intervention (repair or replacement) and the occurrence of caries were considered as clinical failures. The recall rate at 2 years was 93.8%. Only one Clearfil S3 Bond restoration was lost at the 2-year recall. All other restorations were clinically acceptable. The number of restorations with defect-free margins decreased severely during the 2-year study period (to 6.7% and 25.3% for Clearfil S3 Bond and Optibond FL, respectively). The Clearfil S3 Bond restorations presented significantly more small marginal defects at the enamel side than the Optibond FL restorations (Clearfil S3 Bond: 93.3%; Optibond FL: 73.3%; p = 0.000). Superficial marginal discoloration increased in both groups (to 53.3% and 36% for Clearfil S3 Bond and Optibond FL, respectively) and was also more pronounced in the Clearfil S3 Bond group (p = 0.007). After 2 years, the simplified one-step self-etch adhesive Clearfil S3 Bond and the three-step etch-and-rinse adhesive Optibond FL were clinically equally successful, even though both adhesives were characterized by progressive degradation in marginal integrity. Clearfil S3 Bond exhibited more small enamel marginal defects and superficial marginal discolorations.


Early Archean serpentine mud volcanoes at Isua, Greenland, as a niche for early life.
The Isua Supracrustal Belt, Greenland, of Early Archean age (3.81-3.70 Ga) represents the oldest crustal segment on Earth. Its complex lithology comprises an ophiolite-like unit and volcanic rocks reminiscent of boninites, which tie Isua supracrustals to an island arc environment. We here present zinc (Zn) isotope compositions measured on serpentinites and other rocks from the Isua supracrustal sequence and on serpentinites from modern ophiolites, midocean ridges, and the Mariana forearc. In stark contrast to modern midocean ridge and ophiolite serpentinites, Zn in Isua and Mariana serpentinites is markedly depleted in heavy isotopes with respect to the igneous average. Based on recent results of Zn isotope fractionation between coexisting species in solution, the Isua serpentinites were permeated by carbonate-rich, high-pH hydrothermal solutions at medium temperature (100-300 °C). Zinc isotopes therefore stand out as a pH meter for fossil hydrothermal solutions. The geochemical features of the Isua fluids resemble the interstitial fluids sampled in the mud volcano serpentinites of the Mariana forearc. The reduced character and the high pH inferred for these fluids make Archean serpentine mud volcanoes a particularly favorable setting for the early stabilization of amino acids.


Mechanism of phosphaturia elicited by administration of phosphonoformate in vivo.
We examined whether phosphonoformate (PFA) can cause phosphaturia through its direct action on brush-border membrane (BBM) in vivo. Infusion of PFA or of parathyroid hormone (PTH) to thyroparathyroidectomized rats caused a marked increase in fractional excretion of phosphate without changes in excretion of Na+ or of GFR. The PFA-induced phosphaturia was not accompanied by an increase in urinary adenosine-3',5'-cyclic monophosphate (cAMP); moreover, PFA added in vitro did not influence the PTH-sensitive adenylate cyclase and cAMP-phosphodiesterase in proximal convoluted tubules. In BBM vesicles (BBMV) from rats with PFA-elicited phosphaturia, neither the rate of Na+-Pi symport nor Na+-dependent binding of [14C]PFA on BBMV was changed, whereas in BBMV from PTH-infused rats the Vmax of Na+-Pi symport decreased. PFA is almost completely ultrafiltrable; no metabolic transformation of PFA was detected after [14C]PFA exposure to rat renal cortical slices, homogenate, or to blood. We conclude that PFA causes phosphaturia by direct inhibition of Na+-Pi symport across BBM in proximal tubules, acting from the luminal side. Thus PFA (foscarnet) has a unique direct mechanism of phosphaturic effect, via its action on Pi reabsorption in proximal tubules in vivo.


Fluctuations in butyrate-producing bacteria in ulcerative colitis patients of North India.
To study the interplay between butyrate concentration and butyrate-producing bacteria in fecal samples of ulcerative colitis (UC) patients vs control individuals. Fecal samples were collected from 14 control individuals (hemorrhoid patients only) and 26 UC patients (severe: n = 12, moderate: n = 6, remission: n = 8), recruited by the gastroenterologist at the Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India. Disease activity in UC patients was determined by clinical colitis activity index. We employed fluorescent in situ hybridization in combination with flow cytometry to enumerate the clostridium cluster population targeted by 16S rRNA gene probe. Major butyrate-producing species within this cluster were quantified to see if any change existed in control vs UC patients with different disease activity. This observed change was further validated by quantitative polymerase chain reaction. In addition to this, we carried out gas chromatography to evaluate the changes in concentration of major short chain fatty acids (SCFAs), namely acetate, n-butyrate, iso-butyrate, in the above samples. Student t test and Graph pad prism-6 were used to compare the data statistically. There was a significant decrease of Clostridium coccoides (control, 25.69% ± 1.62% vs severe, 9.8% ± 2.4%, P = 0.0001) and Clostridium leptum clusters (control, 13.74% ± 1.05% vs severe, 6.2% ± 1.8%, P = 0.0001) in fecal samples of UC patients. Furthermore, we demonstrated that some butyrate-producing members of the clostridial cluster, like Fecalibacterium prausnitzii (control, 11.66% ± 1.55% vs severe, 6.01% ± 1.6%, P = 0.0001) and Roseburia intestinalis (control, 14.48% ± 1.52% vs severe, 9% ± 1.83%, P = 0.02) were differentially present in patients with different disease activity. In addition, we also demonstrated decreased concentrations of fecal SCFAs, especially of n-butyrate (control, 24.32 ± 1.86 mmol/μL vs severe, 12.74 ± 2.75 mmol/μL, P = 0.003), iso-butyrate (control, 1.70 ± 0.41 mmol/μL vs severe, 0.68 ± 0.24 mmol/μL, P = 0.0441) and acetate (control, 39.51 ± 1.76 mmol/μL vs severe, 32.12 ± 2.95 mmol/μL, P = 0.047), in the fecal samples of UC patients. The observed decrease of predominant butyrate producers of clostridial clusters correlated with the reduced SCFA levels in active UC patients. This was further confirmed by the restoration in the population of some butyrate producers with simultaneous increase in the level of SCFA in remission samples. Our observations indicate that decreases in members of the clostridial cluster resulting in reduced butyrate levels contribute to the etiology of UC.


Identification of the gene encoding the alpha1,3-mannosyltransferase (ALG3) in Arabidopsis and characterization of downstream n-glycan processing.
Glycosyltransferases are involved in the biosynthesis of lipid-linked N-glycans. Here, we identify and characterize a mannosyltransferase gene from Arabidopsis thaliana, which is the functional homolog of the ALG3 (Dol-P-Man:Man5GlcNAc2-PP-Dol alpha1,3-mannosyl transferase) gene in yeast. The At ALG3 protein can complement a Deltaalg3 yeast mutant and is localized to the endoplasmic reticulum in yeast and in plants. A homozygous T-DNA insertion mutant, alg3-2, was identified in Arabidopsis with residual levels of wild-type ALG3, derived from incidental splicing of the 11th intron carrying the T-DNAs. N-glycan analysis of alg3-2 and alg3-2 in the complex-glycan-less mutant background, which lacks N-acetylglucosaminyl-transferase I activity, reveals that when ALG3 activity is strongly reduced, almost all N-glycans transferred to proteins are aberrant, indicating that the Arabidopsis oligosaccharide transferase complex is remarkably substrate tolerant. In alg3-2 plants, the aberrant glycans on glycoproteins are recognized by endogenous mannosidase I and N-acetylglucosaminyltransferase I and efficiently processed into complex-type glycans. Although no high-mannose-type glycoproteins are detected in alg3-2 plants, these plants do not show a growth phenotype under normal growth conditions. However, the glycosylation abnormalities result in activation of marker genes diagnostic of the unfolded protein response.


Laparoscopic prosthetic reinforcement of hiatal herniorrhaphy.
Primary repair of a large hiatal hernia is associated with a published recurrence rate of up to 10%; anecdotal rates even higher than this have been reported to the authors. The use of prosthetic material in the repair of other abdominal wall defects has often produced better results than primary repair. We wanted to compare laparoscopic primary repair of large hiatus hernias with laparoscopic primary repair reinforced with prosthetic. Thirty-one patients with symptomatic gastroesophageal reflux and a hiatal defect 8 cm or greater were randomized to Nissen fundoplication with posterior cruroplasty (n = 16) or Nissen cruroplasty, and onlay of polytetrafluoroethylene (PTFE) mesh (n = 15). All patients underwent preoperative esophagogastroduodenoscopy (EGD) and barium esophagography. After posterior cruroplasty with interrupted nonabsorbable suture, the mesh reinforcement group had an onlay of PTFE placed around the hiatus. A radial slit with 3 cm 'keyhole' (to accommodate the esophagus) was cut into the PTFE. The prosthetic was stapled to the diaphragm, and the two leaves of the slit were stapled to each other. All patients underwent EGD at 3 months and all had esophagrams every 6 months postoperatively. Follow-up ranged from 12 to 36 months. Length of hospital stay was equal in both groups (2 days). The average cost to the patient with PTFE was USD 1,050 higher than to the patient with primary repair. There were 2 complications (1 pneumonia, 1 urinary retention) in the PTFE group, and 1 complication (pneumothorax) in the primary repair group. There were 3 recurrences (18.8%) in the primary group (p = 0.08, chi(2) test). The use of PFTE reinforcement for primary repair of large hiatal hernias may result in a lower rate of recurrent herniation compared to primary repair alone.


Association Between Preoperative Obstructive Sleep Apnea and Preoperative Positive Airway Pressure With Postoperative Intensive Care Unit Delirium.
Obstructive sleep apnea has been associated with postoperative delirium, which predisposes patients to major adverse outcomes. Positive airway pressure may be an effective intervention to reduce delirium in this population. To determine if preoperative obstructive sleep apnea is associated with postoperative incident delirium in the intensive care unit and if preoperative positive airway pressure adherence modifies the association. A retrospective single-center cohort study was conducted at a US tertiary hospital from November 1, 2012, to August 31, 2016, among 7792 patients admitted to an intensive care unit who underwent routine Confusion Assessment Method for the intensive care unit after major surgery. Patients were adults who had undergone a complete preoperative anesthesia assessment, received general anesthesia, underwent at least 1 delirium assessment, were not delirious preoperatively, and had a preoperative intensive care unit stay of less than 6 days. Statistical analysis was conducted from August 20, 2019, to January 11, 2020. Self-reported obstructive sleep apnea, billing diagnosis of obstructive sleep apnea, or STOP-BANG (Snoring, Tiredness, Observed Apnea, Blood Pressure, Body Mass Index, Age, Neck Circumference and Gender) questionnaire score greater than 4, as well as self-reported use of preoperative positive airway pressure. Delirium within 7 days of surgery. A total of 7792 patients (4562 men; mean [SD] age, 59.2 [15.3] years) met inclusion criteria. Diagnosed or likely obstructive sleep apnea occurred in 2044 patients (26%), and delirium occurred in 3637 patients (47%). The proportion of patients with incident delirium was lower among those with obstructive sleep apnea than those without (897 of 2044 [44%] vs 2740 of 5748 [48%]; unadjusted risk difference, -0.04; 99% credible interval [CrI], -0.07 to -0.00). Positive airway pressure adherence had minimal association with delirium (risk difference, -0.00; 99% CrI, -0.09 to 0.09). Doubly robust confounder adjustment eliminated the association between obstructive sleep apnea and delirium (risk difference, -0.01; 99% CrI, -0.04 to 0.03) and did not change that of preoperative positive airway pressure adherence (risk difference, -0.00, 99% CrI, -0.07 to 0.07). The results were consistent across multiple sensitivity analyses. After risk adjustment, this study found no association between obstructive sleep apnea and postoperative delirium in the context of usual care in the intensive care unit, with 99% CrIs excluding clinically meaningful associations. With limited precision, no association was found between positive airway pressure adherence and delirium. Selection bias and measurement error limit the validity and generalizability of these observational associations; however, they suggest that interventions targeting sleep apnea and positive airway pressure are unlikely to have a meaningful association with postoperative intensive care unit delirium.


Augmented expression and secretion of adipose-derived pigment epithelium-derived factor does not alter local angiogenesis or contribute to the development of systemic metabolic derangements.
Impaired coupling of adipose tissue expansion and vascularization is proposed to lead to adipocyte hypoxia and inflammation, which in turn contributes to systemic metabolic derangements. Pigment epithelium-derived factor (PEDF) is a powerful antiangiogenic factor that is secreted by adipocytes, elevated in obesity, and implicated in the development of insulin resistance. We explored the angiogenic and metabolic role of adipose-derived PEDF through in vivo studies of mice with overexpression of PEDF in adipocytes (PEDF-aP2). PEDF expression in white adipocytes and PEDF secretion from adipose tissue was increased in transgenic mice, but circulating levels of PEDF were not increased. Overexpression of PEDF did not alter vascularization, the partial pressure of O2, cellular hypoxia, or gene expression of inflammatory markers in adipose tissue. Energy expenditure and metabolic substrate utilization, body mass, and adiposity were not altered in PEDF-aP2 mice. Whole body glycemic control was normal as assessed by glucose and insulin tolerance tests, and adipocyte-specific glucose uptake was unaffected by PEDF overexpression. Adipocyte lipolysis was increased in PEDF-aP2 mice and associated with increased adipose triglyceride lipase and decreased perilipin 1 expression. Experiments conducted in mice rendered obese by high-fat feeding showed no differences between PEDF-aP2 and wild-type mice for body mass, adiposity, whole body energy expenditure, glucose tolerance, or adipose tissue oxygenation. Together, these data indicate that adipocyte-generated PEDF enhances lipolysis but question the role of PEDF as a major antiangiogenic or proinflammatory mediator in adipose tissue in vivo.


Mechanisms of asymmetric stem cell division.
Stem cells self-renew but also give rise to daughter cells that are committed to lineage-specific differentiation. To achieve this remarkable task, they can undergo an intrinsically asymmetric cell division whereby they segregate cell fate determinants into only one of the two daughter cells. Alternatively, they can orient their division plane so that only one of the two daughter cells maintains contact with the niche and stem cell identity. These distinct pathways have been elucidated mostly in Drosophila. Although the molecules involved are highly conserved in vertebrates, the way they act is tissue specific and sometimes very different from invertebrates.


The Nanos3-3'UTR is required for germ cell specific NANOS3 expression in mouse embryos.
The regulation of gene expression via a 3' untranslated region (UTR) plays essential roles in the discrimination of the germ cell lineage from somatic cells during embryogenesis. This is fundamental to the continuation of a species. Mouse NANOS3 is an essential protein required for the germ cell maintenance and is specifically expressed in these cells. However, the regulatory mechanisms that restrict the expression of this gene in the germ cells is largely unknown at present. In our current study, we show that differences in the stability of Nanos3 mRNA between germ cells and somatic cells is brought about in a 3'UTR-dependent manner in mouse embryos. Although Nanos3 is transcribed in both cell lineages, it is efficiently translated only in the germ lineage. We also find that the translational suppression of NANOS3 in somatic cells is caused by a 3'UTR-mediated mRNA destabilizing mechanism. Surprisingly, even when under the control of the CAG promoter which induces strong ubiquitous transcription in both germ cells and somatic cells, the addition of the Nanos3-3'UTR sequence to the coding region of exogenous gene was effective in restricting protein expression in germ cells. Our current study thus suggests that Nanos3-3'UTR has an essential role in translational control in the mouse embryo.


Molecular dissection of the tissue transglutaminase autoantibody response in celiac disease.
Celiac disease (CD) is an intestinal malabsorption characterized by intolerance to cereal proteins accompanied by immunological responses to dietary gliadins and tissue transglutaminase, an autoantigen located in the endomysium. Tissue transglutaminase belongs to the family of enzymes that catalyze protein cross-linking reactions and is constitutively expressed in many tissues as well as being activated during apoptosis. The role of gliadins in eliciting the immune response in CD and how transglutaminase is linked to the primary reaction are still unclear. In this work, we report the production and analysis of six phage Ab libraries from the peripheral and intestinal lymphocytes of three CD patients. We were able to isolate Abs to transglutaminase from all intestinal lymphocytes libraries but not from those obtained from peripheral lymphocytes. This is in contrast to Abs against gliadin, which could be obtained from all libraries, indicating that the humoral response against transglutaminase occurs at the local level, whereas that against gliadin occurs both peripherally and centrally. Abs from all three patients recognized the same transglutaminase epitopes with a bias toward the use of the V(H)5 Ab variable region family. The possible role of these anti-transglutaminase Abs in the onset of CD and associated autoimmune pathologies is discussed.


Unmet Palliative Care Needs Among Patients With End-Stage Kidney Disease: A National Registry Study About the Last Week of Life.
End-stage kidney disease (ESKD) is characterized by high physical and psychological burden, and therefore, more knowledge about the palliative care provided close to death is needed. To describe symptom prevalence, relief, and management during the last week of life, as well as end-of-life communication, in patients with ESKD. This study was based on data from the Swedish Register of Palliative Care. Patients aged 18 or older who died from a chronic kidney disease, with or without dialysis treatment (International Classification of Diseases, Tenth Revision, Sweden; N18.5 or N18.9), during 2011 and 2012 were selected. About 472 patients were included. Of six predefined symptoms, pain was the most prevalent (69%), followed by respiratory secretion (46%), anxiety (41%), confusion (30%), shortness of breath (22%), and nausea (17%). Of patients with pain and/or anxiety, 32% and 44%, respectively, were only partly relieved or not relieved at all. Of patients with the other symptoms, a majority (55%-84%) were partly relieved or not relieved at all. End-of-life discussions were reported in 41% of patients and 71% of families. A minority died in specialized palliative care: 8% in hospice/inpatient palliative care and 5% in palliative home care. Of all patients, 19% died alone. Bereavement support was offered to 38% of families. Even if death is expected, most patients dying with ESKD had unmet palliative care needs regarding symptom management, advance care planning, and bereavement support.


Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells.
Cardiosphere-derived cells (CDCs) are an attractive cell type for tissue regeneration, and autologous CDCs are being tested clinically. However, autologous therapy necessitates patient-specific tissue harvesting and cell processing, with delays to therapy and possible variations in cell potency. The use of allogeneic CDCs, if safe and effective, would obviate such limitations. We compared syngeneic and allogeneic CDC transplantation in rats from immunologically-mismatched inbred strains. In vitro, CDCs expressed major histocompatibility complex class I but not class II antigens or B7 costimulatory molecules. In mixed-lymphocyte cocultures, allogeneic CDCs elicited negligible lymphocyte proliferation and inflammatory cytokine secretion. In vivo, syngeneic and allogeneic CDCs survived at similar levels in the infarcted rat heart 1 week after delivery, but few syngeneic (and even fewer allogeneic) CDCs remained at 3 weeks. Allogeneic CDCs induced a transient, mild, local immune reaction in the heart, without histologically evident rejection or systemic immunogenicity. Improvements in cardiac structure and function, sustained for 6 months, were comparable with syngeneic and allogeneic CDCs. Allogeneic CDCs stimulated endogenous regenerative mechanisms (cardiomyocyte cycling, recruitment of c-kit(+) cells, angiogenesis) and increased myocardial vascular endothelial growth factor, insulin-like growth factor-1, and hepatocyte growth factor equally with syngeneic CDCs. Allogeneic CDC transplantation without immunosuppression is safe, promotes cardiac regeneration, and improves heart function in a rat myocardial infarction model, mainly through stimulation of endogenous repair mechanisms. The indirect mechanism of action rationalizes the persistence of benefit despite the evanescence of transplanted cell survival. This work motivates the testing of allogeneic human CDCs as a potential off-the-shelf product for cellular cardiomyoplasty.


[False acute abdomen in clinical practice].
Some situations in which endocrinological diseases and their complications (diabetic ketoacidosis, acute adrenal failure, pheochromocytoma, thyrotoxicosis, thyrotoxic crisis, hyperparathyroidism crisis) give the picture of false acute abdomen are analyzed.


Experiences of families with children and adolescents after completing a cancer treatment: support for the nursing care.
The survival of children and adolescents with cancer has increased in recent years. Researchers and professionals in the health area have prioritized studies on the delayed effects of the treatment and quality of life of the survivors. This study aims to understand how parents and other family members of children and adolescents with cancer, experience the completion of the treatment. This descriptive and exploratory study adopted a qualitative methodological approach. A total of ten families whose children had completed the cancer treatment and were in follow-up in a hospital-school were selected for the study. The data were organized in two thematic axes: the memory % what was experienced and the present % what is being experienced. The study evidenced the participants' vitality to survive the treatment and fragility to live after it. The results allowed identifying aspects that need intervention, aiming at the improvement of quality of life of children, adolescents and the whole family after the end of the treatment.


Pathologic changes in lambs with Ostertagia circumcincta infections associated with decreased infectivity of Haemonchus contortus.
Two experiments were done to examine the severity and type of abomasal lesions induced by moderate infections of Ostertagia circumcincta in young lambs and to examine the differences in pathologic changes in lambs with monospecific and combined infections of O circumcincta and Haemonchus contortus. Observations included descriptions of gross and microscopic changes in the abomasums, as well as quantitative analysis of the thickness of the mucosa, numbers of mucus-containing cells, and inflammatory cell accumulations. Seemingly, the changes in the abomasal mucosa of lambs inoculated with O circumcincta were mild and included dilated glands, focal accumulations of lymphocytes, and significant (P less than 0.05) numerical increases of mucus-containing cells, eosinophils, and globule leukocytes, and increase of mucosal thickness when compared with those in noninoculated controls. These differences were less pronounced in lambs given anthelmintic treatment to remove O circumcincta. When H contortus infections were superimposed upon O circumcincta infection, the changes were essentially the same as those described for O circumcincta plus a small, but significant (P less than 0.05), numerical increase of globule leukocytes. Abomasal mucosa of lambs inoculated only with H contortus was more roughened and hyperemic than that of lambs with combined infections, but contained few dilated glands and globule leukocytes. Our conclusions were that moderate infection with O circumcincta did not cause severe or permanent damage to the abomasal mucosa and that such infection decreased the severity of the gross lesions produced by H contortus.


New assessment based on the use of principal factor analysis to investigate corn silage quality from nutritional traits, fermentation end products and mycotoxins.
A survey on 68 dairy farms was carried out to evaluate the ensiling procedures adopted to store corn silage. Samples from core, lateral and apical zones of the feed-out face of silos were analysed. A principal factor analysis (PFA) was carried out on the entire database (196 silage samples and 36 variables) and 11 principal factor components (PCs) were retained and interpreted. Ensiling procedures influenced the area exposed to risk of air penetration. Cores had higher dry matter, starch and lactic acid content or lower pH, fibre, propionate and butyrate concentrations than peripheral samples (P < 0.05). The highest (P < 0.05) mycophenolic acid and roquefortina C concentrations were detected in lateral samples. Chemical and digestibility variables loaded on two PCs; four PCs were characterized by end-products associated with clostridia, heterolactic, homolactic and aerobic fermentations; two PCs were associated with mycotoxins, whereas three PCs explained ensiling procedures. The main quality traits of corn silages differed throughout the entire silo face. Minimization of the area exposed to risk of air penetration represents the best strategy to preserve the nutritional value and safety of corn silages. PFA allowed a clusterization of original variables into 11 PCs, appearing able to discriminate well and poorly preserved corn silages.


Anemia and the Need for Intravenous Iron Infusion after Roux-en-Y Gastric Bypass.
The frequency of anemia, iron deficiency, and the long-term need for IV iron following Roux-en-y gastric bypass (RYGB) surgery has not been well characterized. Three-hundred and nineteen out of 904 consecutive subjects who underwent RYGB at Penn State Hershey Medical Center from 1999 to 2006 met the inclusion criteria for a preoperative complete blood count (CBC) and at least one CBC >6 months following surgery. Cumulative incidence of anemia 7 years post procedure was 58%. Menstruation status and presence of preoperative anemia were predictive of anemia by univariate analysis and multivariable Cox regression (P = 0.0014 and 0.044, respectively). Twenty-seven subjects, primarily premenopausal women, representing 8.5% of the cohort and 22% of the 122 anemic subjects, needed intravenous (IV) iron a mean of 51 months postoperatively for anemia unresponsive or refractory to oral iron. The risk for development of anemia necessitating IV iron therapy following RYGB is highest in menstruating women and continues to increase for many years, even in post-menopausal women. Well-designed prospective studies are needed to identify the incidence of iron deficiency anemia and the patient populations at increased risk for requiring IV iron replacement after RYGB surgery.


Insights into mechanism of pyrido[2,3-d]pyrimidines as DYRK1A inhibitors based on molecular dynamic simulations.
DYRK1A is characterized by the early development and regulation of neuronal proliferation, and its over expression gives rise to neurological abnormalities. As the promising DYRK1A inhibitors, the binding mechanism between DYRK1A and pyrido[2,3-d]pyrimidines derivatives at molecular level are still veiled. In this article, it was achieved to get the structural insights into pyrido[2,3-d]pyrimidines derivatives as DYRK1A inhibitors by means of comprehensive computational approaches involving molecular docking, molecular dynamics simulation, free energy calculation, and energy decomposition analysis. The calculated energy values were highly consistent with the experimental activities. Based on the individual energy terms analysis, the van der Waals interaction was the major leading force in the DYRK1A-ligand interaction. Lys188 was the important residue that formed the hydrogen bond, which improved the inhibitory activity. Furthermore, four novel inhibitors with higher predicted activity were designed based on the obtained findings and confirmed by molecular simulations. Our study is expected to provide significant drug design strategy for the development of more promising DYRK1A inhibitors. Proteins 2016; 84:1108-1123. © 2016 Wiley Periodicals, Inc.


To compare PubMed Clinical Queries and UpToDate in teaching information mastery to clinical residents: a crossover randomized controlled trial.
To compare PubMed Clinical Queries and UpToDate regarding the amount and speed of information retrieval and users' satisfaction. A cross-over randomized trial was conducted in February 2009 in Tehran University of Medical Sciences that included 44 year-one or two residents who participated in an information mastery workshop. A one-hour lecture on the principles of information mastery was organized followed by self learning slide shows before using each database. Subsequently, participants were randomly assigned to answer 2 clinical scenarios using either UpToDate or PubMed Clinical Queries then crossed to use the other database to answer 2 different clinical scenarios. The proportion of relevantly answered clinical scenarios, time to answer retrieval, and users' satisfaction were measured in each database. Based on intention-to-treat analysis, participants retrieved the answer of 67 (76%) questions using UpToDate and 38 (43%) questions using PubMed Clinical Queries (P<0.001). The median time to answer retrieval was 17 min (95% CI: 16 to 18) using UpToDate compared to 29 min (95% CI: 26 to 32) using PubMed Clinical Queries (P<0.001). The satisfaction with the accuracy of retrieved answers, interaction with UpToDate and also overall satisfaction were higher among UpToDate users compared to PubMed Clinical Queries users (P<0.001). For first time users, using UpToDate compared to Pubmed Clinical Queries can lead to not only a higher proportion of relevant answer retrieval within a shorter time, but also a higher users' satisfaction. So, addition of tutoring pre-appraised sources such as UpToDate to the information mastery curricula seems to be highly efficient.


Active specific immunotherapy in patients with melanoma. A clinical trial with mouse antiidiotypic monoclonal antibodies elicited with syngeneic anti-high-molecular-weight-melanoma-associated antigen monoclonal antibodies.
In two clinical trials the mouse antiidiotypic monoclonal antibody (MAb) MF11-30, which bears the internal image of human high-molecular-weight-melanoma-associated antigen (HMW-MAA) was administered by subcutaneous route without adjuvants to patients with stage IV malignant melanoma on day 0, 7, and 28. Additional injections were administered if anti-antiidiotypic antibodies were not found or their titer decreased. In the first phase I trial with 16 patients the initial dose was 0.5 mg per injection and escalated to 4 mg per injection. Neither toxicity nor allergic reactions were observed despite the development of anti-mouse Ig antibodies. Minor responses were observed in three patients. In a second clinical trial MAb MF11-30 was administered to 21 patients at a dose of 2 mg per injection, since this dose had been shown in the initial study to be effective in inducing anti-antiidiotypic antibodies. Two patients were inevaluable; in the remaining 19 patients, the average duration of treatment was 34 wk. In this trial as well, neither toxicity nor allergic reactions were observed. 17 of the 19 immunized patients increased the levels of anti-mouse Ig antibodies and 16 developed antibodies that inhibit the binding of antiidiotypic MAb MF11-30 to the immunizing anti-HMW-MAA MAb 225.28. One patient increased the level of anti-HMW-MAA antibodies. One patient achieved a complete remission with disappearance of multiple abdominal lymph nodes for a duration of 95 wk. Minor responses were observed in three patients. These results suggest that mouse antiidiotypic MAb that bear the internal image of HMW-MAA may be useful reagents to implement active specific immunotherapy in patients with melanoma.


Usp28 counteracts Fbw7 in intestinal homeostasis and cancer.
The stability of several oncoproteins, including c-Myc, is regulated by ubiquitin-dependent degradation mediated by the SCF(Fbw7) ubiquitin ligase. This activity is antagonized by the deubiquitinase Usp28, which is highly expressed in murine and human intestinal cancers. Usp28 was previously shown to interact with its substrates via a "piggyback" interaction with Fbw7, which suggested that Fbw7 is required for Usp28 activity. Unexpectedly, we found that genetic deletion of Usp28 rescued the lethality of Fbw7-deficient primary fibroblasts. Moreover, Usp28 inactivation in the intestine (Usp28(ΔIEC)) ameliorated the hyperproliferation and the impaired goblet and Paneth cell differentiation observed in Fbw7(ΔIEC) mice. The aggressive intestinal tumor formation of APC(Min/+); Fbw7(ΔIEC) mice was restrained when Usp28 was inactivated concomitantly. In both fibroblasts and intestinal cells, Usp28 deficiency corrected the accumulation of SCF(Fbw7) substrate proteins, including NICD1, c-Jun, and c-Myc. These findings suggested that Usp28 function does not depend on the presence of Fbw7, but instead independently recognizes and deubiquitylates the same substrates as SCF(Fbw7). Fbw7 binds to a phosphorylated motif termed the phosphodegron and we found that Usp28 also interacted with this same motif, but only when it is unphosphorylated, offering a mechanistic explanation for identical substrate selection by Fbw7 and Usp28. Our results indicate an unusually direct antagonism between an E3 ligase and a deubiquitinase, Fbw7 and Usp28, in modulating intestinal homeostasis and cancer.


Surgical procedures and outcomes among children with sickle cell disease.
Although children with sickle cell disease often undergo surgery, there are limited current epidemiological data for this pediatric population. We performed a database analysis to estimate population characteristics, surgical procedures, and perioperative outcomes in this population. We queried the Nationwide Inpatient Sample Database from 2000 to 2010 for discharges pertaining to patients <18 years of age having a diagnosis of sickle cell disease who underwent 1 or more surgical procedures during that admission. We abstracted surgical procedures using the Clinical Classifications Software procedure codes and the ICD-9-CM procedure codes. We described characteristics of patients undergoing the 6 most common procedures. During 2000 to 2010, 3.6 % (SE 0.12) of individual hospital discharges were of children with sickle cell disease who had undergone surgical procedures. The most frequent surgical procedures were cholecystectomy (1.47% [0.08]), tonsillectomy/adenoidectomy (0.81% [0.06]), splenectomy (0.62% [0.06]), repair of umbilical hernia (0.19% [0.02]), and appendectomy (0.17% [0.02]). Acute chest syndrome was recorded among 3.08% (0.60) of patients undergoing elective surgery. The incidence of stroke was 0.20% (0.11); death was reported in <11 patients (<0.20%). Surgical procedures such as cholecystectomy, tonsillectomy, splenectomy, hernia repair, and appendectomy account for a small but significant proportion of hospital admissions in children with sickle cell disease. Acute chest syndrome is among the most common complications of elective surgery, while stroke and death are rare.


Radiation and Internal Loss Engineering of High-Stress Silicon Nitride Nanobeams.
High-stress Si3N4 nanoresonators have become an attractive choice for electro- and optomechanical devices. Membrane resonators can achieve quality factor (Q)-frequency (f) products exceeding 1013 Hz, enabling (in principle) quantum coherent operation at room temperature. String-like beam resonators possess smaller Q × f products; however, on account of their significantly lower mass and mode density, they remain a canonical choice for precision force, mass, and charge sensing, and have recently enabled Heisenberg-limited position measurements at cryogenic temperatures. Here we explore two techniques to enhance the Q of a nanomechanical beam. The techniques relate to two main loss mechanisms: internal loss, which dominates for high aspect ratios and f ≲ 100 MHz, and radiation loss, which dominates for low aspect ratios and f ≳ 100 MHz. First, we show that by embedding a nanobeam in a 1D phononic crystal (PnC), it is possible to localize its flexural motion and shield it against radiation loss. Using this method, we realize f > 100 MHz modes with Q ≈ 104, consistent with internal loss and contrasting sharply with unshielded beams of similar dimensions. We then study the Q × f product of high-order modes of millimeter-long nanobeams. Taking advantage of the mode-shape dependence of stress-induced "loss dilution", we realize a f ≈ 4 MHz mode with Q × f ≈ 9 × 1012 Hz. Our results complement recent work on PnC-based "soft-clamping" of nanomembranes, in which mode localization is used to enhance loss dilution. Combining these strategies should enable ultra-low-mass nanobeam oscillators that operate deep in the quantum coherent regime at room temperature.