Comparison of spatiotemporal prediction models of daily exposure of individuals to ambient nitrogen dioxide and ozone in Montreal, Canada.
In previous studies investigating the short-term health effects of ambient air pollution the exposure metric that is often used is the daily average across monitors, thus assuming that all individuals have the same daily exposure. Studies that incorporate space-time exposures of individuals are essential to further our understanding of the short-term health effects of ambient air pollution. As part of a longitudinal cohort study of the acute effects of air pollution that incorporated subject-specific information and medical histories of subjects throughout the follow-up, the purpose of this study was to develop and compare different prediction models using data from fixed-site monitors and other monitoring campaigns to estimate daily, spatially-resolved concentrations of ozone (O3) and nitrogen dioxide (NO2) of participants' residences in Montreal, 1991-2002. We used the following methods to predict spatially-resolved daily concentrations of O3 and NO2 for each geographic region in Montreal (defined by three-character postal code areas): (1) assigning concentrations from the nearest monitor; (2) spatial interpolation using inverse-distance weighting; (3) back-extrapolation from a land-use regression model from a dense monitoring survey, and; (4) a combination of a land-use and Bayesian maximum entropy model. We used a variety of indices of agreement to compare estimates of exposure assigned from the different methods, notably scatterplots of pairwise predictions, distribution of differences and computation of the absolute agreement intraclass correlation (ICC). For each pairwise prediction, we also produced maps of the ICCs by these regions indicating the spatial variability in the degree of agreement. We found some substantial differences in agreement across pairs of methods in daily mean predicted concentrations of O3 and NO2. On a given day and postal code area the difference in the concentration assigned could be as high as 131ppb for O3 and 108ppb for NO2. For both pollutants, better agreement was found between predictions from the nearest monitor and the inverse-distance weighting interpolation methods, with ICCs of 0.89 (95% confidence interval (CI): 0.89, 0.89) for O3 and 0.81 (95%CI: 0.80, 0.81) for NO2, respectively. For this pair of methods the maximum difference on a given day and postal code area was 36ppb for O3 and 74ppb for NO2. The back-extrapolation method showed a higher degree of disagreement with the nearest monitor approach, inverse-distance weighting interpolation, and the Bayesian maximum entropy model, which were strongly constrained by the sparse monitoring network. The maps showed that the patterns of agreement differed across the postal code areas and the variability depended on the pair of methods compared and the pollutants. For O3, but not NO2, postal areas showing greater disagreement were mostly located near the city centre and along highways, especially in maps involving the back-extrapolation method. In view of the substantial differences in daily concentrations of O3 and NO2 predicted by the different methods, we suggest that analyses of the health effects from air pollution should make use of multiple exposure assessment methods. Although we cannot make any recommendations as to which is the most valid method, models that make use of higher spatially resolved data, such as from dense exposure surveys or from high spatial resolution satellite data, likely provide the most valid estimates.


Cholera toxin B-subunit gene fusion: structural and functional analysis of the chimeric protein.
A synthetic peptide, encoding amino acid residues 345 to 359 of the glucosyltransferase B enzyme of Streptococcus mutans GS-5, was genetically fused to the N-terminal end of the B-subunit gene of cholera toxin. The protein was overexpressed in Escherichia coli and retained the antigenicity associated with cholera toxin B subunit (CTB) as well as that associated with glucosyltransferase B. The addition of 15 amino acids to the N-terminal end of CTB did not appear to affect the gross structure of the protein significantly. The chimeric protein monomers assembled into a functional oligomer which exhibited only minor conformational differences from native CTB as measured by circular dichroism. The chimera bound to GM1 ganglioside and thus retained the biological activity of CTB. These results demonstrate that genetic fusion of small peptides to the N terminus of CTB has only a minimal effect on the structure and function of the protein. Furthermore, the chimera was shown to be immunogenic when fed to mice. This work has important implications in the construction of CTB chimeras for use as oral vaccines.


Surface Plasmon Coupled Fluorescence-Enhanced Interfacial "Molecular Beacon" To Probe Biorecognition Switching: An Efficient, Versatile, and Facile Signaling Biochip.
Integrating probes and a substrate together, a fluorescence-enhanced interfacial "molecular beacon" (FEIMB) is demonstrated, based on directional surface plasmon coupled emission. Through this simple yet efficient interfacial modulation engineering to create an interfacial quencher (graphene oxide)-enhancer (gold nanofilm) pair, the quenching-to-enhancing region of FEIMB can be actively tuned. Therefore, it provides a spatial match between signal transduction and interface-mediated biorecognition switching. Via combination of strong quenching and efficient plasmonic coupling, a synergistically amplified signal-to-background ratio of >1000-fold has been achieved. FEIMBs have been employed in protein and DNA detection, creating a high-performance and universal chip-based plasmon-mediated fluorescence sensing platform.


IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells.
Chronic lymphocytic leukemia (CLL) displays constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of B-cell receptor (BCR) signaling. Previous studies have shown that an oral PI3K p110δ inhibitor idelalisib exhibits promising activity in CLL. Here, we demonstrate that a dual PI3K p110δ and p110γ inhibitor, IPI-145, antagonizes BCR crosslinking activated prosurvival signals in primary CLL cells. IPI-145 causes direct killing in primary CLL cells in a dose- and time-dependent fashion, but does not generate direct cytotoxicity to normal B cells. However, IPI-145 does reduce the viability of normal T and natural killer cells and decrease activated T-cell production of various inflammatory and antiapoptotic cytokines. Furthermore, IPI-145 overcomes the ibrutinib resistance resulting from treatment-induced BTK C481S mutation. Collectively, these studies provide rationale for ongoing clinical evaluation of IPI-145 as a targeted therapy for CLL and related B-cell lymphoproliferative disorders.


Whether ideal free or not, predatory mites distribute so as to maximize reproduction.
Ideal free distribution (IFD) models predict that animals distribute themselves such that no individual can increase its fitness by moving to another patch. Many empirical tests assume that the interference among animals is independent of density and do not quantify the effects of density on fitness traits. Using two species of predatory mites, we measured oviposition as a function of conspecific density. Subsequently, we used these functions to calculate expected distributions on two connected patches. We performed an experimental test of the distributions of mites on two such connected patches, among which one had a food accessibility rate that was twice as high as on the other. For one of the two species, Iphiseius degenerans, the distribution matched the expected distribution. The distribution also coincided with the ratio of food accessibility. The other species, Neoseiulus cucumeris, distributed itself differently than expected. However, the oviposition rates of both species did not differ significantly from the expected oviposition rates based on experiments on single patches. This suggests that the oviposition rate of N. cucumeris was not negatively affected by the observed distribution, despite the fact that N. cucumeris did not match the predicted distributions. Thus, the distribution of one mite species, I. degenerans, was in agreement with IFD theory, whereas for the other mite species, N. cucumeris, unknown factors may have influenced the distribution of the mites. We conclude that density-dependent fitness traits provide essential information for explaining animal distributions.


The ischemic optic neuropathy decompression trial (IONDT): design and methods.
The objective of the Ischemic Optic Neuropathy Decompression Trial (IONDT) was to investigate the safety and efficacy of optic nerve decompression surgery (ONDS) compared to careful follow-up for nonarteritic ischemic optic neuropathy (NAION) and to observe the natural history of NAION in untreated patients. It was designed as a multicenter, randomized controlled clinical trial. Resource centers included a Chairman's Office, a Coordinating Center, and 25 Clinical Centers at eye centers throughout the United States. The trial's methods were as follows. Eligible patients with visual acuity 20/64 or worse were randomized to ONDS or careful follow-up; eligible patients with visual acuity better than 20/64 made up a natural history cohort and were followed but not randomized to treatment. The primary outcome examined was an increase of three lines or more of visual acuity at 6 months. Additional outcomes were visual acuity at other follow-up times, visual field, quality of life, and morbidity associated with ONDS. Standard quality assurance methodology was used to monitor adherence to protocol. The surgical protocol was monitored by a Surgical Quality Assurance Committee (SQAC). Enrollment began October 8, 1992, and ceased October 20, 1994, because of preliminary findings indicating that surgery was of no benefit and was perhaps harmful. This report describes the design and methods of the trial and the rationale for design elements unique to the IONDT. Specific goals of study design and conduct included achieving an accelerated study start-up and rapidly producing results acceptable to the medical community.


Attentional bias modification is associated with fMRI response toward negative stimuli in individuals with residual depression: a randomized controlled trial
Attentional bias modification (ABM) may lead to more adaptive emotion perception and emotion regulation. Understanding the neural basis of these effects may lead to greater precision for the development of future treatments. Task-related functional MRI (fMRI) after ABM training has not been investigated in depression so far. The main aim of this randomized controlled trial was to explore differences in brain activity after ABM training, in response to emotional stimuli. A total of 134 people with previous depression, who had been treated for depression and had various degrees of residual symptoms, were randomized to 14 days of active ABM or a closely matched placebo training, followed by an fMRI emotion regulation task. The training procedure was a classical dot–probe task with emotional face stimuli. In the active ABM condition, the probes replaced the more positively valenced face of a given pair. As participants implicitly learned to predict the probe location, this would be likely to induce a more positive attentional bias. The placebo condition was identical, except for the contingency of the probe, which appeared equally behind positive and negative stimuli. We compared depression symptoms and subjective ratings of perceived negativity during fMRI between the training groups. We explored brain activation in predefined regions of interest and across the whole brain. We explored activation in areas associated with changes in attentional bias and degree of depression. Compared with the placebo group, the ABM group showed reduced activation in the amygdala and the anterior cingulate cortex when passively viewing negative images. We found no group differences in predefined regions of interest associated with emotion regulation strategies. Response in the temporal cortices was associated with the degree of change in attentional bias and the degree of depressive symptoms in ABM versus placebo. These findings should be replicated in other samples of patients with depression, and in studies using fMRI designs that allow analyses of within-group variability from baseline to follow-up. Attentional bias modification training has an effect on brain function in the circuitry associated with emotional appraisal and the generation of affective states. NCT02931487


Risk factors for antibiotic resistance in Streptococcus pneumoniae.
Streptococcus pneumoniae (the pneumococcus) is the leading vaccine-preventable cause of death in children and adults. The management of pneumococcal infections is complicated by the development of resistance to antimicrobials. Risk factors for increased resistance include young age, isolation from the upper respiratory tract, hospitalisation, residence in an urban area, day care attendance, previous exposure to antibiotics, female gender, exposure to specific serotypes and clones, HIV infection and exposure to a class of drug to which resistance can be easily selected from a susceptible population of organisms. Conjugate pneumococcal vaccine affords protection from resistant strains belonging to vaccine serotypes, but resistance is emerging in non-vaccine types.


[Dynamics of radon decay product activity in saliva following therapeutic radon exposure].
Radon decay product activity was measured in saliva of 10 male patients 20-30 min after a 1-hour radon exposure in the gallery of the Gasteiner Heilstollen (radon activity 36.2 kBq/m(3), radon progeny activity 20.3 kBq/m(3)). In 1 patient showing relatively high activity (75th percentile) measurements were continued until 65 min after exposure. Patients were asked to collect about 2 ml of saliva in the mouth and produce it on a filter. After drying the filter at 300 degrees C, radon progeny activity was measured. Activity (median) at 20-30 min after leaving the treatment area was 4.5 Bq (25th percentile 1 Bq; 75th percentile 21 Bq). In the patient who underwent additional measurements the activity showed a further increase up to 29 Bq (35 min after radon exposure) before it continuously decreased to a very low activity (1-3 Bq) at 65 min after exposure. The results show that a significantly increased radon decay product activity is found in saliva after speleotherapeutic radon exposure. Maximum values were observed 35 min after radon exposure. Radon decay product activity almost disappeared after about 1 h.


Evaluation of neutrophil HDL-C ratio - a new inflammation marker in non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) is a global disease estimated to affect one-third of the world's population. NAFLD is the hepatic manifestation of metabolic syndrome. In recent years, formulations have been made using haematological laboratory parameters, and it has been reported to be associated with inflammation and fibrosis in the liver. In this study, we aimed to evaluate the neutrophil to high-density lipoprotein (HDL) cholesterol (HDL-C) ratio (NHR) in patients diagnosed with NAFLD by ultrasonographic imaging for the first time in the literature. The study was carried out by recruiting men and women between the ages of 18 and 65 years who applied to the check-up outpatient clinic of our hospital. Ultrasonography was used as the diagnostic method for hepatosteatosis in all cases. Venous blood samples were taken from the patients for haematological and biochemical measurements. The study population consisted of 155 patients, 115 of whom were fatty liver patients and 40 were controls. NHR was determined as 99.6 ± 56.8 in those with grade 1 fatty liver, 114.98 ± 39.2 in those with grade 2, 122.9 ± 51.1 in those with grade 3, and 86.17 ± 35.2 in the control group. In the analysis, NHR was statistically significantly higher in grade 2 and 3 fatty liver patients compared with the control group (p = 0.03 and 0.01, respectively). However, there was no statistical difference between grade 1 fatty liver patients and the control group (p = 0.53). We found higher NHR in patients with NAFLD. NHR is a cheap and easy to access parameter. An elevated NHR with FIB-4 in patients with NAFLD may be a marker of liver inflammation or fibrosis.


Combining SELEX screening and rational design to develop light-up fluorophore-RNA aptamer pairs for RNA tagging.
We report here a new small molecule fluorogen and RNA aptamer pair for RNA labeling. The small-molecule fluorogen is designed on the basis of fluorescently quenched sulforhodamine dye. The SELEX (Systematic Evolution of Ligands by EXponential enrichment) procedure and fluorescence screening in E. coli have been applied to discover the aptamer that can specifically activate the fluorogen with micromolar binding affinity. The systematic mutation and truncation study on the aptamer structure determined the minimum binding domain of the aptamer. A series of rationally modified fluorogen analogues have been made to probe the interacting groups of fluorogen with the aptamer. These results led to the design of a much improved fluorogen ASR 7 that displayed a 33-fold increase in the binding affinity for the selected aptamer in comparison to the original ASR 1 and an 88-fold increase in the fluorescence emission after the aptamer binding. This study demonstrates the value of combining in vitro SELEX and E. coli fluorescence screening with rational modifications in discovering and optimizing new fluorogen-RNA aptamer labeling pairs.


Mistakes in ultrasound diagnosis of superficial lymph nodes.
The article discusses basic mistakes that can occur during ultrasound imaging of superficial lymph nodes. Ultrasound is the first imaging method used in the diseases of superficial organs and tissues, including lymph nodes. The causes of mistakes can be either dependent or independent of the performing physician. The first group of mistakes includes inappropriate interpretation of images of anatomical structures, while the latter group includes, among other things, similar ultrasound images of different pathologies. For instance, a lymph node, whether normal or abnormal, may be mimicked by anatomical structures, such as a partially visible, compressed vein. Lymph nodes in lymphomas may be indistinguishable from reactive lymph nodes, even when using Doppler option, as well as morphologically difficult to distinguish from metastases. Metastatic lymph nodes can mimic e.g. nodular, separated postoperative thyroid fragments, a lateral neck cyst, chemodectoma (carotid body tumor) or neuroma. The appearance of lymph nodes in granulomatous diseases, such as tuberculosis or sarcoidosis, can be very similar to that of typical metastatic lymph nodes or lymphomas. Anechoic or hypoechoic areas in a lymph node can represent necrosis or metastatic hemorrhages, but also suppuration in inflamed lymph nodes. Lymph nodes in lymphomas, metastatic and reactive lymph nodes can adopt the classical characteristics of a simple cyst. The overall ultrasound picture along with all criteria for the assessment of a lymph node should be taken into account during ultrasound imaging. It seems that the safest management is to refer patients diagnosed with lymph node abnormalities for ultrasound-guided targeted fine needle aspiration biopsy followed by a total lymph node resection for histopathological examination in the case of suspected lymphoma.


Formation of spherulitic amyloid β aggregate by anionic liposomes.
Alzheimer's disease is the most common form of senile dementia. This neurodegenerative disorder is characterized by an amyloid deposition in senile plaques, composed primarily of fibrils of an aggregated peptide, amyloid β (Aβ). The modeling of a senile plaque formation on a model neuronal membrane under the physiological condition is an attractive issue. In this study, we used anionic liposomes to model the senile plaque formation by Aβ. The growth behavior of amyloid Aβ fibrils was directly observed, revealing that the induction of the spherulitic Aβ aggregates could result from the growth of seeds in the presence of anionic liposomes. The seeds of Aβ fibrils strongly interacted with negatively charged liposome and the subsequent association of the seeds were induced to form the seed cluster with many growth ends, which is advantageous for the formation of spherulitic Aβ aggregates. Therefore, anionic liposomes mediated not only fibril growth but also the aggregation process. These results imply that anionic liposome membranes would affect the aggregate form of Aβ fibrils. The modeling of senile plaque reported here is considered to have great potential for study on the amyloidosis.


Caesarean scar pregnancy.
Caesarean scar pregnancy is one of the rarest forms of ectopic pregnancy. Little is known about its incidence and natural history. With increasing incidence of caesarean section worldwide, more and more cases are diagnosed and reported. Transvaginal ultrasound and colour flow Doppler provides a high diagnostic accuracy with very few false positives. A delay in diagnosis and/or treatment can lead to uterine rupture, major haemorrhage, hysterectomy and serious maternal morbidity. Early diagnosis can offer treatment options of avoiding uterine rupture and haemorrhage, thus preserving the uterus and future fertility. Management plan should be individually tailored. Available data suggest that termination of pregnancy is the treatment of choice in the first trimester soon after the diagnosis. Expectant treatment has a poor prognosis because of risk of rupture. There are no reliable scientific data on the risk of recurrence of the condition in future pregnancy, role of the interval between the previous caesarean delivery and occurrence of caesarean scar pregnancy, and effect of caesarean wound closure technique on caesarean scar pregnancy. In this article, we aim to find the demography, pathophysiology, clinical presentation, most appropriate methods of diagnosis and management, with their implications in clinical practice for this condition.


RNA interference-mediated targeting of human cytomegalovirus immediate-early or early gene products inhibits viral replication with differential effects on cellular functions.
Viral drug toxicity, resistance, and an increasing immunosuppressed population warrant continued research into new avenues for limiting diseases associated with human cytomegalovirus (HCMV). In this study, a small interfering RNA (siRNA), siX3, was designed to target coding sequences within shared exon 3 of UL123 and UL122 transcripts encoding IE1 and IE2 immediate-early proteins of HCMV. Pretreatment of cells with siX3 reduced the levels of viral protein expression, DNA replication, and progeny virus production compared to control siRNA. Two siRNAs against UL54 and overlapping transcripts (UL55-57) were compared to siX3 in HCMV infection and were also found to be effective at inhibiting HCMV replication. Further investigation into the effects of the siRNAs on viral replication showed that pretreatment with each of the siRNAs resulted in an inhibition in the formation of mature replication compartments. The ability of these siRNAs to prevent or reduce certain cytopathic effects associated with HCMV infection was also examined. Infected cells pretreated with siX3, but not siUL54, retained promyelocytic leukemia (PML) protein in cellular PML bodies, an essential component of this host intrinsic antiviral defense. DNA damage response proteins, which are localized in nuclear viral replication compartments, were reduced in the siX3- and siUL54-treated cells. siX3, but not siUL54, prevented DNA damage response signaling early after infection. Therapeutic efficacy was demonstrated by treating cells with siRNAs after HCMV replication had commenced. Together, these findings suggest that siRNAs targeting exon 3 of the major IE genes or the UL54-57 transcripts be further studied for their potential development into anti-HCMV therapeutics.


Ethics in the work of acting for patients.
A nursing therapeutics requires that nurses literally act for patients, and they do so in three domains: the physical the psychological, and what the author calls the "integrity of the self." Acting for the patient is a matter of inherent ethical significance. Acting for another carries the risk of instrumentality; that is, one person becomes the means to another's end. This can result in a variety of moral problems depending on who determines what the ends will be; the degree to which the ends are agreed on among nurse, patient, significant others, and physicians; and whether nurses are acting for their patients, for themselves, or for institutionalized medicine. A therapeutics exists to do something to and for another, and therefore several knowledges are relevant. While the knowledge of physiology, disease, and interventions is necessary, it is not sufficient, nor perhaps even the most important. Also required for an ethical therapeutics is the knowledge of the social and political place occupied by nurses, self-knowledge, knowledge of the person, and the knowledge of the worthiness of ends to be ends of human life.


The molecular basis of alanine: glyoxylate aminotransferase mistargeting: the most common single cause of primary hyperoxaluria type 1.
The autosomal recessive disease primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver-specific intermediary metabolic enzyme alanine:glyoxylate aminotransferase (AGT). In a third of all Caucasian PH1 patients, disease in caused by an unparalleled intracellular phenomenon in which AGT is mistargeted from one group of intracellular organelles (the peroxisomes) to another (the mitochondria) where it is unable to work properly. The aberrant localisation of AGT in PH1 is caused by the combination of a common Pro 11-->Leu amino acid polymorphism which generates a functionally weak mitochondrial targeting signal (MTS) and a rare Gly170-->Arg mutation which in combination with the Pro11-->Leu polymorphism enhances the functional efficiency of this MTS by slowing AGT folding and dimerization. Elucidation of the molecular basis of AGT mistargeting not only provides an explanation for the mode of action of the most common mutation found in PH1, but also highlights the different structural requirements for protein import into peroxisomes and mitochondria.


Tracing Poly(Vinyl Acetate) Emulsions by Infrared and Raman Spectroscopies: Identification of Spectral Markers.
Vinyl emulsions started to be used by artists in paintings at least since the early 1960s, being now present in several artworks worldwide. However, different vinyl formulations can result in distinct behaviours over time, and if some artworks are currently showing a good condition, others already show damages due to the use of compositions more susceptible to degradation. For this reason, it is fundamental to identify the main components in the vinyl acetate-based (VAc-based) emulsion. This work focuses on the molecular study of VAc-based emulsions by infrared and Raman spectroscopies. It aims at deepening the knowledge on the variability of the composite formulation and on the identification of characteristic bands and spectral profiles (identified as spectral markers) for both polymer and additives. To this end, a broad set of vinyl emulsions was gathered, including reference materials, historical commercial brands in use by Portuguese artists, and commercial brands collected from industrial companies. The entire set includes vinyl homopolymers produced for the purpose of the study and known formulations of vinyl homopolymers and copolymers, with and without plasticisers, according to technical data sheets and previous studies. Furthermore, unknown formulations have been included to validate the usefulness of the identified spectral markers. This set has been studied in the form of solid films deposited in glass slides by infrared spectroscopy in attenuated total reflection mode (ATR-FTIR) and micro-Raman spectroscopy (µ-Raman), both conducted in situ. As conclusions, the combined use of ATR-FTIR and µ-Raman proved to be very useful as different spectral markers were detected by each technique, confirming their complementarity. Besides the clear identification of vinyl acetate-based emulsions by both techniques, it was also possible to suggest spectral markers for the copolymerisation of vinyl acetate with vinyl versatate by µ-Raman, the stabilisation of the emulsion with poly(vinyl alcohol) by ATR-FTIR, and the addition of phthalates or benzoates plasticisers by both ATR-FTIR and µ-Raman.


Diacetyl, acetoin, and acetaldehyde production by mixed-species lactic starter cultures.
Citrate utilization and acetoin, diacetyl, acetaldehyde, and lactic acid production in milk at 21 C by five different mixed-strain starters, containing Streptococcus diacetilactis (D type), Leuconostoc (B type), and S. diacetilactis and Leuconostoc (BD type), were measured. BD and D cultures utilized citrate more rapidly and produced more diacetyl, acetoin, and acetaldehyde than B types. All cultures produced much more acetoin than diacetyl, with the BD and D cultures producing four to five times larger amounts of acetoin than the B cultures. Reduction of diacetyl and acetoin toward the end of the normal incubation period was characteristic of BD and D cultures, whereas a similar reduction of acetaldehyde was characteristic of BD and especially of B cultures. Continued incubation of B cultures beyond 17 h also resulted in reduction of diacetyl and acetoin. Addition of citrate to the milk retarded diacetyl and acetoin reduction. Mn(2+) had no effect on diacetyl production by a BD culture but increased citrate utilization and, as a consequence, caused greater diacetyl destruction in one of the B cultures.


Prepaid entitlements. A new challenge for physician-patient relationships.
The transition from a fee-for-service model to a prepaid health care system creates new challenges for both physicians and patients. Occasionally both can feel trapped in the new setting and must rely on new or different strategies to reach sometimes divergent objectives. This may alter the physician-patient relationship in ways that neither likes. Based on our experience in a large multispecialty academic group practice, we have developed management strategies to mitigate such stresses on both parties. These include review of marketing efforts; education of new patients to foster realistic expectations; a physician-generated, prospective internal policy for dealing with dissatisfied patients and physicians; a strong central administrative physician to serve as a "lightning rod" and counselor; and continuing physician orientation and education to improve judgment and attitudes. These strategies promote the physician's role as expert consultant-educator with the best interests of the patient as the first priority.


Correlates of stunting among children in Ghana.
Stunting, is a linear growth retardation, which results from inadequate intake of food over a long period of time that may be worsened by chronic illness. Over a long period of time, inadequate nutrition or its effects could result in stunting. This paper examines the correlates of stunting among children in Ghana using data from the 2008 Ghana Demographic and Health Survey (GDHS). The paper uses data from the children recode file of the 2008 Demographic and Health Survey (DHS), a nationally representative cross sectional survey conducted in Ghana. A total of 2379 children under five years who had valid anthropometric data were used for the study. Data on the stunting of children were collected by measuring the height of all children under six years of age. A measuring board produced by Shorr Productions was used to obtain the height of the children. Children under 2 years of age were measured lying down on the board while those above 2 years were measured standing. In the DHS data, a z-score is given for the child's height relative to the age. Both bi-variate and multi-variate statistics are used to examine the correlates of stunting. Stunting was common among males than females. Age of child was a significant determinant of stunting with the highest odd of stunting been among children aged 36-47 months. Region was significantly related to stunting. Children from the Eastern Region were more likely to be stunted than children from the Western Region which is the reference group (OR = 1.7 at p < 0.05). Number of children in household was significantly related to stunting. Children in households with 5-8 children were 1.3 times more likely to be stunted compared to those with 1-4 children (p < .05). Mother's age was a significant predictor of stunting with children whose mothers were aged 35-44 years being more likely to be stunted. Culturally appropriate interventions and policies should be put in place to minimise the effects of the distal, proximal and intermediate factors on stunting among under 5 children in Ghana.


Investigation of leakage holes created by four needle types used for closure of canine enterotomies.
The creation of leakage holes in the intestinal wall by four types of swaged-on needles used to close enterotomy incisions in canine cadavers was studied. Twenty-four enterotomies were performed in 10 cm jejunal sections obtained from five dogs following euthanasia. After placement of Doyen intestinal forceps to the ends of each section, a 3 cm antimesenteric incision was performed and closed using 4-0 polydioxanone suture armed in a swaged-on needle in a simple interrupted pattern. One group served as control, with no enterotomies performed. The four groups that we used consisted of six sections each: group CC was closed with a polydioxanone suture armed in a conventional cutting needle, group RC was closed with a reversed cutting needle, group TPP was closed with a taper point plus needle, and group TC was closed with a taper cutting needle. Leak testing was performed by infusion of 13.5 mL methylene blue solution into the intestinal lumen. Significant differences between leakage and non-leakage sections of group CC were detected (P=.027). No statistical differences were detected among other groups. Conventional cutting needles seem to create leaking holes in cadaveric healthy jejunum during needle passage for closing an enterotomy incision.


Heat shock protein derivatives for delivery of antigens to antigen presenting cells.
Delivery of antigens to antigen presenting cells (APCs) is a key issue for developing effective cancer vaccines. Controlling the tissue distribution of antigens can increase antigen-specific immune responses, including the induction of cytotoxic T lymphocytes (CTL). Heat shock protein 70 (Hsp70) forms complexes with a variety of tumor-related antigens via its polypeptide-binding domain. Because Hsp70 is taken up by APCs through recognition by Hsp receptors, such as CD91 and LOX-1, its application to antigen delivery systems has been examined both in experimental and clinical settings. A tissue distribution study revealed that Hsp70 is mainly taken up by the liver, especially by hepatocytes, after intravenous injection in mice. A significant amount of Hsp70 was also delivered to regional lymph nodes when it was injected subcutaneously, supporting the hypothesis that Hsp70 is a natural targeting system for APCs. Model antigens were complexed with or conjugated to Hsp70, resulting in greater antigen-specific immune responses. Cytoplasmic delivery of Hsp70-antigen further increased the efficacy of the Hsp70-based vaccines. These findings indicate that effective cancer therapy can be achieved by developing Hsp70-based anticancer vaccines when their tissue and intracellular distribution is properly controlled.


Bilateral pseudoexfoliation deposits on intraocular lens implants.
We present a rare case of bilateral pseudoexfoliative deposits on both intraocular lens (IOL) implants in an 83-year-old woman with no other associated pathology, 5 years after cataract surgery. Pseudoexfoliation syndrome is the most common cause of secondary open-angle glaucoma worldwide and these deposits are usually found on the natural lens. The fact that pseudoexfoliative deposits have been found on IOL implants implies the need for a thorough examination in pseudophakic patients, for it could be the only sign of secondary glaucoma.


Understanding the positive effects of graphical risk information on comprehension: measuring attention directed to written, tabular, and graphical risk information.
Risk communications are an integral aspect of health education and promotion. However, the commonly used textual risk information is relatively difficult to understand for the average recipient. Consequently, researchers and health promoters have started to focus on so-called decision aids, such as tables and graphs. Although tabular and graphical risk information more effectively communicate risks than textual risk information, the cognitive mechanisms responsible for this enhancement are unclear. This study aimed to examine two possible mechanisms (i.e., cognitive workload and attention). Cognitive workload (mean pupil size and peak pupil dilation) and attention directed to the risk information (viewing time, number of eye fixations, and eye fixation durations) were both measured in a between-subjects experimental design. The results suggest that graphical risk information facilitates comprehension of that information because it attracts and holds attention for a longer period of time than textual risk information. Graphs are thus a valuable asset to risk communication practice for two reasons: first, they tend to attract attention and, second, when attended to, they elicit information extraction with relatively little cognitive effort, and finally result in better comprehension.


Isoform composition of connexin channels determines selectivity among second messengers and uncharged molecules.
Intercellular connexin channels (gap junction channels) have long been thought to mediate molecular signaling between cells, but the nature of the signaling has been unclear. This study shows that connexin channels from native tissue have selective permeabilities, partially based on pore diameter, that discriminate among cytoplasmic second messenger molecules. Permeability was assessed by measurement of selective loss/retention of tracers from liposomes containing reconstituted connexin channels. The tracers employed were tritiated cyclic nucleotides and a series of oligomaltosaccharides derivatized with a small uncharged fluorescent moiety. The data define different size cut-off limits for permeability through homomeric connexin-32 channels and through heteromeric connexin-32/connexin-26 channels. Connexin-26 contributes to a narrowed pore. Both cAMP and cGMP were permeable through the homomeric connexin-32 channels. cAMP was permeable through only a fraction of the heteromeric channels. Surprisingly, cGMP was permeable through a substantially greater fraction of the heteromeric channels than was cAMP. The data suggest that isoform stoichiometry and/or arrangement within a connexin channel determines whether cyclic nucleotides can permeate, and which ones. This is the first evidence for connexin-specific selectivity among biological signaling molecules.


Expression of the tumor suppressor Krüppel-like factor 4 as a prognostic predictor for colon cancer.
The zinc finger transcription factor Krüppel-like factor 4 (KLF4) regulates numerous physiologic processes, including proliferation, differentiation, and development. Studies also showed that KLF4 is involved in tumorigenesis and somatic cell reprogramming. Here, we aimed to assess whether KLF4 is a prognostic indicator for colon cancer. Levels of KLF4 were measured by immunohistochemical analysis of a tissue microarray containing 367 independent colon cancer sections. Univariate data analysis was done in addition to construction of multivariate models with several clinicopathologic factors to evaluate KLF4 as an independent predictor of survival and cancer recurrence (disease-free survival). Colon cancer tissues had significantly overall lower KLF4 levels compared with noncancer tissues (P < 0.0001). Using logistic regression, a trend was noted for decreased odds of KLF4 expression in higher stages of tumors. In univariate and multivariate analyses, KLF4 was a significant predictor of survival and recurrence. KLF4 expression is significantly downregulated in colon cancer, and loss of KLF4 is an independent predictor of survival and recurrence. These findings suggest that KLF4 may serve as a prognostic biomarker for colon cancer.


Influence of Upper Airway Surgery on Voice and Speech Recognition.
Upper airway surgery comprises a set of techniques that modify the anatomy of the vocal tract, including tonsillectomy and septoplasty. The objective of this work is to study the changes in acoustic parameters and the effects on the identification or verification of the speaker through the speech produced after the vocal tract surgeries, comparing them with a control group. A prospective study was performed between January 2019 and June 2019 including. The final study sample consisted of 84 patients who met the inclusion criteria. Of these, 31 underwent septoplasty, 26 tonsillectomy patients, and 27 controls. Demographic data and GRBAS evaluation were statistically evaluated. Tests were taken before surgery, 2 weeks after surgery and 3 months later. Furthermore, to establish the equal error rate, the recording of patients' voices was made with a succeeding acoustic analysis and programmed identification of the speaker through machine learning systems. A significant variance was observed in GRBAS, after surgery. Regarding acoustic parameters, a greater change was observed in the fundamental frequency at 2 weeks after surgery in the tonsillectomy group. Formants (F1-F3) and antiformants (AntiF1-AntiF3) changed in septoplasty group, not in tonsillectomy and control group at 3 months. When studying the impact of voice changes on the verification of the speaker through the speech, it was observed that there was a greater error in recognition in the tonsillectomy group at 2 weeks, coinciding with the results obtained in the rest of the parameters studied. Results suggest that upper airway surgery produces modifications in the vocal tract affecting GRBAS, acoustic parameters, including formants and antiformants, producing an effect on verification of the speaker through the speech.


High-Performance Self-Cascade Pyrite Nanozymes for Apoptosis-Ferroptosis Synergistic Tumor Therapy.
As next-generation artificial enzymes, nanozymes have shown great promise for tumor catalytic therapy. In particular, their peroxidase-like activity has been employed to catalyze hydrogen peroxide (H2O2) to produce highly toxic hydroxyl radicals (•OH) to kill tumor cells. However, limited by the low affinity between nanozymes with H2O2 and the low level of H2O2 in the tumor microenvironment, peroxidase nanozymes usually produced insufficient •OH to kill tumor cells for therapeutic purposes. Herein, we present a pyrite peroxidase nanozyme with ultrahigh H2O2 affinity, resulting in a 4144- and 3086-fold increase of catalytic activity compared with that of classical Fe3O4 nanozyme and natural horseradish peroxidase, respectively. We found that the pyrite nanozyme also possesses intrinsic glutathione oxidase-like activity, which catalyzes the oxidation of reduced glutathione accompanied by H2O2 generation. Thus, the dual-activity pyrite nanozyme constitutes a self-cascade platform to generate abundant •OH and deplete reduced glutathione, which induces apoptosis as well as ferroptosis of tumor cells. Consequently, it killed apoptosis-resistant tumor cells harboring KRAS mutation by inducing ferroptosis. The pyrite nanozyme also exhibited favorable tumor-specific cytotoxicity and biodegradability to ensure its biosafety. These results indicate that the high-performance pyrite nanozyme is an effective therapeutic reagent and may aid the development of nanozyme-based tumor catalytic therapy.


Secondary and tertiary transmission of vaccinia virus from US military service member.
During February and March 2010, the New York State Department of Health investigated secondary and tertiary vaccinia contact transmission from a military vaccinee to 4 close contacts. Identification of these cases underscores the need for strict adherence to postvaccination infection control guidance to avoid transmission of the live virus.


Core human mitochondrial transcription apparatus is a regulated two-component system in vitro.
The core human mitochondrial transcription apparatus is currently regarded as an obligate three-component system comprising the bacteriophage T7-related mitochondrial RNA polymerase, the rRNA methyltransferase-related transcription factor, h-mtTFB2, and the high mobility group box transcription/DNA-packaging factor, h-mtTFA/TFAM. Using a faithful recombinant human mitochondrial transcription system from Escherichia coli, we demonstrate that specific initiation from the mtDNA promoters, LSP and HSP1, only requires mitochondrial RNA polymerase and h-mtTFB2 in vitro. When h-mtTFA is added to these basal components, LSP exhibits a much lower threshold for activation and a larger amplitude response than HSP1. In addition, when LSP and HSP1 are together on the same transcription template, h-mtTFA-independent transcription from HSP1 and h-mtTFA-dependent transcription from both promoters is enhanced and a higher concentration of h-mtTFA is required to stimulate HSP1. Promoter competition experiments revealed that, in addition to LSP competing transcription components away from HSP1, additional cis-acting signals are involved in these aspects of promoter regulation. Based on these results, we speculate that the human mitochondrial transcription system may have evolved to differentially regulate transcription initiation and transcription-primed mtDNA replication in response to the amount of h-mtTFA associated with nucleoids, which could begin to explain the heterogeneity of nucleoid structure and activity in vivo. Furthermore, this study sheds new light on the evolution of mitochondrial transcription components by showing that the human system is a regulated two-component system in vitro, and thus more akin to that of budding yeast than thought previously.


[Surgeries on major vessels in removal of different tumors].
Experience in diagnosis and surgical treatment of 49 patients with tumors of different localization close to their major with main vessels is analyzed. Two variants of tumor - vessel interrelation were seen, patients with iatrogenic vascular lesions were included into a separate group. In 9 patients (group 1) only extravasal compression by the tumor was seen. Most of these tumors were benign. In 15 patients (group 2) reconstructive vascular surgeries were performed because of close interrelation with the tumor or tumor spread into the vessel. Most of these tumors were malignant. Iatrogenic lesions of arteries during surgeries were in 25 patients (group 3). It is demonstrated that duplex sonography permits to diagnose affection of vessels by tumors without invasive procedures. All the patients underwent vascular reconstruction simultaneously with tumor removing. Sceletization of vessels with their decompression was the surgery of choice in benign tumors. In malignant tumors it is recommended to remove the tumor with affected segment of vessel and repair of blood flow. Ligation of vessel may be justified in some cases.


Refractive errors in an urban population in Southern India: the Andhra Pradesh Eye Disease Study.
To assess the prevalence, distribution, and demographic associations of refractive error in an urban population in southern India. Two thousand five hundred twenty-two subjects of all ages, representative of the Hyderabad population, were examined in the population-based Andhra Pradesh Eye Disease Study. Objective and subjective refraction was attempted on subjects >15 years of age with presenting distance and/or near visual acuity worse than 20/20 in either eye. Refraction under cycloplegia was attempted on all subjects < or =15 years of age. Spherical equivalent >0.50 D in the worse eye was considered as refractive error. Data on objective refraction under cycloplegia were analyzed for subjects < or =15 years and on subjective refraction were analyzed for subjects >15 years of age. Data on refractive error were available for 2,321 (92.0%) subjects. In subjects < or =15 years of age, age-gender-adjusted prevalence of myopia was 4.44% (95% confidence interval [CI], 2.14%-6.75%), which was higher in those 10 to 15 years of age (odds ratio, 2.75; 95% CI, 1.25-6.02), of hyperopia 59.37% (95% CI, 44.65%-74.09%), and of astigmatism 6.93% (95% CI, 4.90%-8.97%). In subjects >15 years of age, age-gender-adjusted prevalence of myopia was 19.39% (95% CI, 16.54%-22.24%), of hyperopia 9.83% (95% CI, 6.21%-13.45%), and of astigmatism 12.94% (95% CI, 10.80%-15.07%). With multivariate analysis, myopia was significantly higher in subjects with Lens Opacity Classification System HI nuclear cataract grade > or =3.5 (odds ratio, 9.10; 95% CI, 5.15-16.09), and in subjects with education of class 11 or higher (odds ratio, 1.80; 95% CI, 1.18-2.74); hyperopia was significantly higher in subjects > or =30 years of age compared with those 16 to 29 years of age (odds ratio, 37.26; 95% CI, 11.84-117.19), in females (odds ratio, 1.86; 95% CI, 1.33-2.61), and in subjects belonging to middle and upper socioeconomic strata (odds ratio, 2.10; 95% CI, 1.09-4.03); and astigmatism was significantly higher in subjects > or =40 years of age (odds ratio, 3.00; 95% CI, 2.23- 4.03) and in those with education of college level or higher (odds ratio, 1.73; 95% CI, 1.07-2.81). These population-based data on distribution and demographic associations of refractive error could enable planning of eye-care services to reduce visual impairment caused by refractive error. If these data are extrapolated to the 255 million urban population of India, among those >15 years of age an estimated 30 million people would have myopia, 15.2 million hyperopia, and 4.1 million astigmatism not concurrent with myopia or hyperopia; in addition, based on refraction under cycloplegia, 4.4 million children would have myopia and 2.5 million astigmatism not concurrent with myopia or hyperopia.


FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL).
On July 24, 2006, the U.S. Food and Drug Administration granted approval to pegaspargase (Oncaspar; Enzon Pharmaceuticals, Inc., Bridgewater, NJ; hereafter, O) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multiagent chemotherapy regimen. O was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase. The trial supporting this new indication was an open label, randomized, multicenter clinical trial that enrolled 118 children (age, 1-9 years) with previously untreated, standard risk ALL. Patients received either native Escherichia coli asparaginase (Elspar; Merck, Whitehouse Station, NJ; hereafter, E) or O along with multiagent chemotherapy during remission induction and delayed intensification (DI) phases of treatment. O, at a dose of 2,500 IU/m(2), was administered i.m. on day 3 of the 4-week induction phase and on day 3 of each of two 8-week DI phases. E, at a dose of 6,000 IU/m(2), was administered i.m. three times weekly for nine doses during induction and for six doses during each DI phase. This study allowed direct comparison of O and E for asparagine depletion, asparaginase activity, and development of asparaginase antibodies. An unplanned comparison of event-free survival (EFS) was conducted to rule out a deleterious O efficacy effect. Following induction and DI treatment there was complete (</=1 microM) or moderate (1-10 microM) depletion of serum asparagine levels in the large majority of samples tested over the 4-week period in both O-treated and E-treated subjects. Similarly, depletion of cerebrospinal fluid asparagine levels during induction was similar between O-treated and E-treated subjects. The number of days asparaginase activity exceeded >0.03 IU/ml in O-treated subjects was greater than the number of days in E-treated subjects during both the induction and DI phases of treatment. There was no correlation, however, between asparaginase activity and serum asparagine levels, making the former determination less clinically relevant. Using the protocol-prespecified threshold for a positive result of >2.5 times the control, 7 of 56 (12%) O subjects tested at any time during the study demonstrated antiasparaginase antibodies and 16 of 57 (28%) E subjects tested at any time during the study had antiasparaginase antibodies. In both study arms EFS was in the range of 80% at 3 years. The most serious, sometimes fatal, O toxicities were anaphylaxis, other serious allergic reactions, thrombosis (including sagittal sinus thrombosis), pancreatitis, glucose intolerance, and coagulopathy. The most common adverse events were allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Disclosure of potential conflicts of interest is found at the end of this article.


RNA-Seq Data Analysis: From Raw Data Quality Control to Differential Expression Analysis.
As a revolutionary technology for life sciences, RNA-seq has many applications and the computation pipeline has also many variations. Here, we describe a protocol to perform RNA-seq data analysis where the aim is to identify differentially expressed genes in comparisons of two conditions. The protocol follows the recently published RNA-seq data analysis best practice and applies quality checkpoints throughout the analysis to ensure reliable data interpretation. It is written to help new RNA-seq users to understand the basic steps necessary to analyze an RNA-seq dataset properly. An extension of the protocol has been implemented as automated workflows in the R package ezRun, available also in the data analysis framework SUSHI, for reliable, repeatable, and easily interpretable analysis results.


Pretreatment of hepatetctomized rats with Coleus forskohlii did not interfere with the course of hepatic hyperplasia.
Coleus forskohlii Briq., a medicinal plant originally from India, has been indicated against heart disease, expiratory disorders, convulsions, and hepatic changes, among others. In view of the broad pharmacological potential of the plant and the scarce information about its effects, the objective of the present study was to investigate the effect of its use for pretreatment of partially hepatectomized rats. The animals were divided into two experimental groups: Control (CG) receiving physiological saline for 10 days before partial hepatetctomy, and Treated (TG) receiving 40 mg Coleus forskohlii/kg/day for 10 days before partial hepatectomy. The treatments were performed by gastric gavage. After the surgical procedure, treatment was continued according to the following groups: CG 24 h, CG 48 h, TG 24 h, and TG 48 hs, and liver tissue and intracardiac blood samples were obtained for histological and biochemical analysis, respectively. No significant differences were observed in mitotic or apoptotic index or in the concentrations of the enzymes AST, ALT and alkaline phosphatase, and no areas of fibrosis were detected. Treatment with Coleus forskohlii did not interfere with the course of hepatic hyperplasia.


Invited commentary: dietary pattern analysis.
The analytic approaches used in nutritional epidemiology for dietary pattern analyses share common characteristics with those of genetic epidemiology. In this issue of the Journal, Gorst-Rasmussen et al. (Am J Epidemiol. 2011;173(10):1097-1104) discuss one such approach. Application of methods used in genetic pattern analyses to nutritional epidemiology could prove valuable but raises important issues that need to be considered because dietary and genetic studies often address different types of questions in analyzing interrelated variables. These different aims require statistical methods that assume different characteristics of the underlying patterns. The authors briefly describe such differences to facilitate interpretation and applications of previous and future pattern studies.


Predictors and outcomes of variability in subjective alcohol intoxication among college students: an event-level analysis across 4 years.
Individual differences in subjective alcohol intoxication, as measured by laboratory-based alcohol challenge, have been identified as a phenotypic risk factor for alcohol use disorders. Further, recent evidence indicates that subjective alcohol response is also associated with event-level physiological consequences among college students, including blackouts and hangovers. The current investigation tested predictors of and outcomes associated with subjective intoxication in the natural drinking environment. In a preliminary laboratory alcohol-challenge study (n = 53), we developed a brief measure of subjective alcohol intoxication for use in event-level research. Participating students in the principal study (n = 1,867; 63% women; 54% Caucasian) completed 30 days of Web-based self-monitoring in each of the 4 college years. In the principal study, generalized estimating equation analyses revealed that both lighter drinking and a family history of alcohol problems predicted greater subjective intoxication after accounting for estimated blood alcohol concentration (eBAC). Moreover, greater subjective intoxication during a given drinking episode was associated with negative alcohol-related consequences, illicit drug use, and unsafe sex, and at higher eBACs, was associated with aggression, sex, and property crime. Students who on average experienced greater subjective intoxication were also more likely to experience negative consequences and engage in illicit drug use, sex, unsafe sex, and aggression. These findings suggest that both within-person variability and between-person individual differences in subjective intoxication may be risk factors for adverse drinking outcomes at the event level. Intervention efforts aimed at reducing problems associated with collegiate drinking may benefit from consideration both of who experiences greater subjective intoxication and of the situations in which they are more likely to do so.


TRIM5α self-assembly and compartmentalization of the HIV-1 viral capsid.
The tripartite-motif protein, TRIM5α, is an innate immune sensor that potently restricts retrovirus infection by binding to human immunodeficiency virus capsids. Higher-ordered oligomerization of this protein forms hexagonally patterned structures that wrap around the viral capsid, despite an anomalously low affinity for the capsid protein (CA). Several studies suggest TRIM5α oligomerizes into a lattice with a symmetry and spacing that matches the underlying capsid, to compensate for the weak affinity, yet little is known about how these lattices form. Using a combination of computational simulations and electron cryo-tomography imaging, we reveal the dynamical mechanisms by which these lattices self-assemble. Constrained diffusion allows the lattice to reorganize, whereas defects form on highly curved capsid surfaces to alleviate strain and lattice symmetry mismatches. Statistical analysis localizes the TRIM5α binding interface at or near the CypA binding loop of CA. These simulations elucidate the molecular-scale mechanisms of viral capsid cellular compartmentalization by TRIM5α.


Effects of acupuncture on monoamine neurotransmitters in raphe nuclei in obese rats.
Effects of acupuncture on the levels of neurotransmitters in the raphe nuclei were investigated in obese rats. It was found that the levels of tryptophan (Trp) and 5-hydroxyindoleacetic acid (5-HIAA) were increased, and 5-hydroxytryptamine (5-HT) level and 5-HT/5-HIAA ratio decreased in the raphe nuclei of the obese group as compared with the normal group; and that acupuncture could produce weight reduction, increase the 5-HT level and 5-HT/5-HIAA ratio, and decrease the contents of Trp and 5-HIAA, but did not change the levels of dopamine (DA) and noradrenaline (NA). It is indicated that benign regulative action of acupuncture on 5-HT and its metabolism in the raphe nuclei is possibly one of the factors for reducing weight by acupuncture.


Therapeutic effect of quercetin in collagen-induced arthritis.
Quercetin, a bioactive flavonoid with anti-inflammatory, immunosuppressive, and protective properties, is a potential agent for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) is the most commonly used animal model for studying the pathogenesis of RA. This study analysed the therapeutic role of quercetin in collagen-induced arthritis in C57BL/6 mice. The animals were allocated into five groups that were subjected to the following treatments: negative (untreated) control, positive control (arthritis-induced), arthritis+methotrexate, arthritis+quercetin, and arthritis+methotrexate+quercetin. Assessments of weight, oedema, joint damage, and cytokine production were used to determine the therapeutic effect of quercetin. This study demonstrated for the first time the anti-inflammatory and protective effects of quercetin in vivo in CIA. The results also showed that the concurrent administration of quercetin and methotrexate did not offer greater protection than the administration of a single agent. The use of quercetin as a monotherapeutic agent resulted in the lowest degree of joint inflammation and the highest protection. The reduced severity of the disease in animals treated with quercetin was associated with decreased levels of TNF-α, IL-1β, IL-17, and MCP-1. In conclusion, this study determined that quercetin, which was non-toxic, produced better results than methotrexate for the protection of joints from arthritic inflammation in mice. Quercetin may be an alternative treatment for RA because it modulates the main pathogenic pathways of RA.


Innovative public-private partnerships to maximize the delivery of anti-malarial medicines: lessons learned from the ASAQ Winthrop experience.
This case study describes how a public-private partnership initiated to develop a new anti-malarial combination, ASAQ Winthrop, has evolved over time to address issues posed by its effective deployment in the field. In 2002, DNDi created the FACT project to develop two fixed-dose combinations, artesunate-amodiaquine and artesunate-mefloquine, to meet the WHO anti-malarial treatment recommendations and international regulatory agencies approval standards. In 2002, Sanofi-Aventis had started a development programme for a fixed-dose combination of artesunate and amodiaquine, to replace its co-blister combination. DNDi and Sanofi-Aventis joined forces in 2004, with the objective of developing within the shortest possible time frame a non-patented, affordable and easy to use fixed-dose combination of artesunate and amodiaquine adapted to the needs of patients, in particular, those of children. The partners developed Coarsucam®/Artesunate Amodiaquine Winthrop® ("ASAQ Winthrop") which was prequalified by the WHO in 2008. Additional partnerships have since been established by DNDi and Sanofi-Aventis to ensure: 1) the adoption of this new medicine by malaria-endemic countries, 2) its appropriate usage through a broad range of information tools, and 3) the monitoring of its safety and efficacy in the field through an innovative Risk Management Plan. The partnership between DNDi and Sanofi-Aventis has enabled the development and pre-qualification of ASAQ Winthrop in a short timeframe. As a result of the multiple collaborations established by the two partners, as of late 2010, ASAQ Winthrop was registered in 30 sub-Saharan African countries and in India, with over 80 million treatments distributed in 21 countries. To date, 10 clinical studies, involving 3432 patients with ASAQ Winthrop were completed to document efficacy and safety issues identified in the Risk Management Plan. The speed at which ASAQ Winthrop was adopted in the field shows that this drug fits the needs of patients and health authorities. It also demonstrates the power of partnerships that combine different sets of strengths and skills, and that evolve to include additional actors to meet new global health challenges for poverty-related diseases.


Metabolic responses of shrimp Palaemonetes sinensis to isopod Tachaea chinensis parasitization.
Tachaea chinensis, a parasitic isopod, negatively affects the production of several commercially important shrimp species in China. The mechanism of parasite-host interaction cannot be accurately described by transcriptomic and proteomic approaches individually. Here, comparative metabolite profiling was used to achieve a broad coverage of primary metabolite changes in Chinese grass shrimp Palaemonetes sinensis following T. chinensis parasitization. In total, 66 metabolites were significantly differentially accumulated between the control and infected groups; of these, 19 were upregulated and 47 were downregulated after T. chinensis infection. Moreover, the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that 10 pathways were significantly enriched. The protein digestion and absorption pathways were highly enriched, followed by the mineral absorption, aminoacyl-tRNA biosynthesis, biosynthesis of amino acids, and metabolic metabolism pathways. Parasitization by T. chinensis enhanced the glycolytic pathway and tricarboxylic acid (TCA) cycle in P. sinensis, thereby releasing more energy for swimming, foraging, and evading predation. Glucogenic amino acids such as alanine, histidine, glutamine, and proline were consumed to generate glutamate and enhance the TCA cycle. Nucleotide-related metabolic pathways were downregulated, possibly because T. chinensis can secrete molecules to degrade nucleotides and inhibit hemostasis and inflammatory responses. These results suggest that the isopod parasite can increase the host's metabolic burden by enhancing the host's TCA cycle and secreting molecules to degrade host proteins, thereby enabling the parasite to feed on the host and inhibit an inflammatory response. The results will be a valuable contribution to understanding the metabolic responses of crustaceans to isopod parasitism.


Hypoxia-induced lncRNA-AC020978 promotes proliferation and glycolytic metabolism of non-small cell lung cancer by regulating PKM2/HIF-1α axis.
Rationale: Non-small cell lung cancer (NSCLC) is a deadly disease with a hallmark of aberrant metabolism. The mechanism of glycolysis associated lncRNA underlying the aggressive behaviors of NSCLC is poorly understood. Methods: The expression level of AC020978 in NSCLC was measured by quantitative real-time PCR and fluorescence in situ hybridization (FISH) assay. The biological role of AC020978 in cell proliferation and aerobic glycolysis was determined by functional experiments in vitro and in vivo. The transcription of AC020978 was assessed by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assay. RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP) assays were used to identify the interaction protein with AC020978. Western blotting, in situ proximity ligation assay (PLA), and co-immunoprecipitation (co-IP) were performed to reveal the potential mechanism of AC020978. Results: The present study indicated that AC020978 was upregulated in NSCLC, significantly correlated with advanced TNM stage and poor clinical outcomes, representing as an independent prognostic predictor. Functional assays revealed AC020978's role in promoting cell growth and metabolic reprogramming. Moreover, AC020978 was an upregulated lncRNA under glucose starvation as well as hypoxia conditions, and directly transactivated by HIF-1α. Mechanistic investigations identified that AC020978 directly interacted with Pyruvate kinase isozymes M2 (PKM2) and enhanced PKM2 protein stability. Besides, this study uncovered that AC020978 could promote the nuclear translocation of PKM2 and regulate PKM2-enhanced HIF-1α transcription activity. Conclusions: Together, these data provided evidence that AC020978 conferred an aggressive phenotype to NSCLC and was a poor prognosticator. Targeting AC020978 might be an effective therapeutic strategy for NSCLC.


Overexpression of the activated form of the AtAREB1 gene (AtAREB1ΔQT) improves soybean responses to water deficit.
Abscisic acid-responsive element binding protein (AREB1) is a basic domain/leucine zipper transcription factor that binds to the abscisic acid (ABA)-responsive element motif in the promoter region of ABA-inducible genes. Because AREB1 is not sufficient to direct the expression of downstream genes under non-stress conditions, an activated form of AREB1 (AREB1ΔQT) was created. Several reports claim that plants overexpressing AREB1 or AREB1ΔQT show improved drought tolerance. In our studies, soybean plants overexpressing AREB1ΔQT were characterized molecularly, and the phenotype and drought response of three lines were accessed under greenhouse conditions. Under conditions of water deficit, the transformed plants presented a higher survival rate (100%) than those of their isoline, cultivar BR 16 (40%). Moreover, the transformed plants displayed better water use efficiency and had a higher number of leaves than their isoline. Because the transgenic plants had higher stomatal conductance than its isoline under well-watered conditions, it was suggested that the enhanced drought response of AREB1ΔQT soybean plants might not be associated with altered transpiration rates mediated by ABA-dependent stomatal closure. However, it is possible that the smaller leaf area of the transgenic plants reduced their transpiration and water use, causing delayed stress onset. The difference in the degree of wilting and percentage of survival between the 35S-AREB1ΔQT and wildtype plants may also be related to the regulation of genes that protect against dehydration because metabolic impairment of photosynthesis, deduced by an increasing internal CO2 concentration, was not observed in the transgenic plants.


Impaired neurovascular coupling in the APPxPS1 mouse model of Alzheimer's disease.
The tight coupling between neuronal activity and the local increase of blood flow termed neurovascular coupling is essential for normal brain function. This mechanism of regulation is compromised in Alzheimer's Disease (AD). In order to determine whether a purely vascular dysfunction or a neuronal alteration of blood vessels diameter control could be responsible for the impaired neurovascular coupling observed in AD, blood vessels reactivity in response to different pharmacological stimulations was examined in double transgenic APPxPS1 mice model of AD. Blood vessels movements were monitored using infrared videomicroscopy ex vivo, in cortical slices of 8 month-old APPxPS1 and wild type (WT) mice. We quantified vasomotor responses induced either by direct blood vessel stimulation with a thromboxane A2 analogue, the U46619 (9,11-dideoxy-11a,9a-epoxymethanoprostaglandin F2α) or via the stimulation of interneurons with the nicotinic acetylcholine receptor (nAChRs) agonist DMPP (1,1-Dimethyl-4- phenylpiperazinium iodide). Using both types of stimulation, no significant differences were detected for the amplitude of blood vessel diameter changes between the transgenic APPxPS1 mice model of AD and WT mice, although the kinetics of recovery were slower in APPxPS1 mice. We find that activation of neocortical interneurons with DMPP induced both vasodilation via Nitric Oxide (NO) release and constriction via Neuropeptide Y (NPY) release. However, we observed a smaller proportion of reactive blood vessels following a neuronal activation in transgenic mice compared with WT mice. Altogether, these results suggest that in this mouse model of AD, deficiency in the cortical neurovascular coupling essentially results from a neuronal rather than a vascular dysfunction.


Murine models of paroxysmal nocturnal hemoglobinuria.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder characterized by chronic intravascular hemolysis, cytopenia, and an increased tendency to thrombosis. All patients with PNH studied so far have a somatic mutation of phosphatidyl inositol glycan complementation group A (PIG-A), an X-linked gene involved initially in the biosynthesis of the glycosyl phosphatidylinositol (GPI) molecule, which serves as an anchor for many cell surface proteins. The mutation occurs in a hematopoietic stem cell, and consequently, all cells derived from the mutated stem cell are devoid of GPI-linked proteins. The absence of GPI-linked proteins explains some clinical symptoms of the disease but not the mechanism that allows the expansion of the mutated clone. By using targeted disruption of the PIG-A gene in mouse embryonic stem cells, some mice models of PNH have been generated. These animals have a discrete proportion of blood cells devoid of GPI-linked proteins, and although not anemic, they have evidence of hemolysis. The clinical course of these animals is benign, and there are no signs of a substantial expansion of the PNH clone, as observed in human patients. The fact that these animals do not develop the disease strongly supports the notion that a mutation of PIG-A is not sufficient per se to cause PNH and that another factor, namely, bone marrow failure, is necessary to allow proliferation and expansion of the PNH clone.


Duplicate maize Wrinkled1 transcription factors activate target genes involved in seed oil biosynthesis.
WRINKLED1 (WRI1), a key regulator of seed oil biosynthesis in Arabidopsis (Arabidopsis thaliana), was duplicated during the genome amplification of the cereal ancestor genome 90 million years ago. Both maize (Zea mays) coorthologs ZmWri1a and ZmWri1b show a strong transcriptional induction during the early filling stage of the embryo and complement the reduced fatty acid content of Arabidopsis wri1-4 seeds, suggesting conservation of molecular function. Overexpression of ZmWri1a not only increases the fatty acid content of the mature maize grain but also the content of certain amino acids, of several compounds involved in amino acid biosynthesis, and of two intermediates of the tricarboxylic acid cycle. Transcriptomic experiments identified 18 putative target genes of this transcription factor, 12 of which contain in their upstream regions an AW box, the cis-element bound by AtWRI1. In addition to functions related to late glycolysis and fatty acid biosynthesis in plastids, the target genes also have functions related to coenzyme A biosynthesis in mitochondria and the production of glycerol backbones for triacylglycerol biosynthesis in the cytoplasm. Interestingly, the higher seed oil content in ZmWri1a overexpression lines is not accompanied by a reduction in starch, thus opening possibilities for the use of the transgenic maize lines in breeding programs.


Using well-plate microfluidic devices to conduct shear-based thrombosis assays.
Shear stress plays a critical role in regulating platelet adhesion and thrombus formation at the site of vascular injury. As such, platelets are often examined in vitro under controlled shear flow conditions for their hemostatic and thrombotic functions. Common shear-based platelet analyses include the evaluation of genetic mutants, inhibitory or experimental compounds, matrix substrates, and the effects of different physiological and pathological shear forces. There are several laboratory instruments widely used for studying shear flow, including cone and plate viscometers and parallel plate perfusion chambers. These technologies vary widely in the types of samples, substrates, blood volumes, and throughput that are involved. Here, we describe a microfluidic system for platelet analysis under shear flow. We used the devices to study thrombus formation on collagen I and von Willebrand factor. The system was also used to investigate dose response to the antiplatelet compound, Abciximab, under shear flow conditions with an emphasis on maximizing the number of data points per single patient sample. The presented method confers multiple advantages over conventional approaches. These include the ability to assess up to 24 conditions simultaneously in real time, maintain identical physical conditions across experiments, and use extremely low donor volumes.


Absorbable Implant to Treat Nasal Valve Collapse.
Objective To evaluate the safety and effectiveness of an absorbable implant for lateral cartilage support in subjects with nasal valve collapse (NVC) with 12 months follow-up. Methods Thirty subjects with Nasal Obstruction Symptom Evaluation (NOSE) score ≥ 55 and isolated NVC were treated; 14 cases were performed in an operating suite under general anesthesia and 16 cases were performed in a clinic-based setting under local anesthesia. The implant, a polylactic acid copolymer, was placed with a delivery tool within the nasal wall to provide lateral cartilage support. Subjects were followed up through 12 months postprocedure. Results Fifty-six implants were placed in 30 subjects. The mean preoperative NOSE score was 76.7 ± 14.8, with a range of 55 to 100. At 12 months, the mean score was 35.2 ± 29.2, reflecting an average within-patient reduction of -40.9 ± 31.2 points. The majority (76%) of the subjects were responders defined as having at least one NOSE class improvement or a NOSE score reduction of at least 20%. There were no adverse changes in cosmetic appearance at 12 months postprocedure. Three implants in three subjects required retrieval within 30 days postprocedure and resulted in no clinical sequelae. Conclusion This study demonstrates safety and effectiveness of an absorbable implant for lateral cartilage support in subjects with NVC at 12 months postprocedure.


Taxonomic and functional diversity of Streptomyces in a forest soil.
In this work we report the isolation and the characterization of 79 Streptomyces isolates from a French forest soil. The 16S rRNA gene phylogeny indicated that a great diversity of Streptomyces was present in this soil, with at least nine different and potentially new species. Growth plate assays showed that most Streptomyces lineages exhibit cellulolytic and hemicellulolytic capacities and potentially participate in wood decomposition. Molecular screening for a specific hydrogenase also indicated a widespread potential for atmospheric H2 uptake. Co-culture experiments with representative strains showed antagonistic effects between Streptomyces of the same population and between Streptomyces and various fungi. Interestingly, in certain conditions, growth promotion of some fungi also occurred. We conclude that in forest soil, Streptomyces populations exhibit many important functions involved in different biogeochemical cycles and also influence the structure of soil microbial communities.


Methylation of specific cytosine residues enhances simian virus 40 T-antigen binding to origin region DNA.
Specific binding of simian virus 40 large T antigen to origin region DNA requires the interaction of T antigen with multiples of a consensus recognition pentanucleotide sequence (5'-G[T]-A[G]-G-G-C-3'). To assess the interaction of T antigen with cytosine residues in the recognition sequences, bacterial methylases were used to methylate simian virus 40 form I DNA in vitro at specific cytosine residues. Methylation of a subset of the cytosine residues in the pentanucleotide sequences resulted in enhanced binding of T antigen to origin region DNA. Enhanced binding to the methylated pentanucleotides indicates that the methyl groups introduced on this subset of pentanucleotide cytosine residues could not have sterically interfered with the interaction of T antigen with the recognition sequences. This lack of steric interference suggests that T antigen does not make close contact in the major groove with these particular cytosine residues during normal binding.


Effect of Repetitive Transcranial Magnetic Stimulation on Pain Management: A Systematic Narrative Review.
Recently, clinicians have been using repetitive transcranial magnetic stimulation (rTMS) for treating various pain conditions. This systematic narrative review aimed to examine the use and efficacy of rTMS for controlling various pain conditions. A PubMed search was conducted for articles that were published until June 7, 2019 and used rTMS for pain alleviation. The key search phrase for identifying potentially relevant articles was (repetitive transcranial magnetic stimulation AND pain). The following inclusion criteria were applied for article selection: (1) patients with pain, (2) rTMS was applied for pain management, and (3) follow-up evaluations were performed after rTMS stimulation to assess the reduction in pain. Review articles were excluded. Overall, 1,030 potentially relevant articles were identified. After reading the titles and abstracts and assessing eligibility based on the full-text articles, 106 publications were finally included in our analysis. Overall, our findings suggested that rTMS is beneficial for treating neuropathic pain of various origins, such as central pain, pain from peripheral nerve disorders, fibromyalgia, and migraine. Although data on the use of rTMS for orofacial pain, including trigeminal neuralgia, phantom pain, low back pain, myofascial pain syndrome, pelvic pain, and complex regional pain syndrome, were promising, there was insufficient evidence to determine the efficacy of rTMS for treating these conditions. Therefore, further studies are needed to validate the effects of rTMS on pain relief in these conditions. Overall, this review will help guide clinicians in making informed decisions regarding whether rTMS is an appropriate option for managing various pain conditions.


Hypoxia-induced thrombocytopenia in mice.
In mice hypoxic hypoxia (0.5 atm.) results in a severe and persistent thrombocytopenia with a rapid decline in the platelet count between the fifth and ninth days of hypoxia, after which platelet counts level off at about half their normal value. The thrombocytopenia is not due to the associated polycythemia, splenomegaly, or increased blood volume. There is no significant change in platelet counts of mice made polycythemic by daily injections of 6 units of erythropoietin. Fifteen days of hyperbaria (3 atm.) has no effect on the platelet count of otherwise normal mice. Since there is only a slight decline in platelet count during the first 5 days of hypoxia, the persistent thrombocytopenia appears to be due to either a decreased rate of production of platelets or a structural or metabolic defect in platelets produced under conditions of hypoxia.


A wavelet-based spatially adaptive method for mammographic contrast enhancement.
A method aimed at minimizing image noise while optimizing contrast of image features is presented. The method is generic and it is based on local modification of multiscale gradient magnitude values provided by the redundant dyadic wavelet transform. Denoising is accomplished by a spatially adaptive thresholding strategy, taking into account local signal and noise standard deviation. Noise standard deviation is estimated from the background of the mammogram. Contrast enhancement is accomplished by applying a local linear mapping operator on denoised wavelet magnitude values. The operator normalizes local gradient magnitude maxima to the global maximum of the first scale magnitude subimage. Coefficient mapping is controlled by a local gain limit parameter. The processed image is derived by reconstruction from the modified wavelet coefficients. The method is demonstrated with a simulated image with added Gaussian noise, while an initial quantitative performance evaluation using 22 images from the DDSM database was performed. Enhancement was applied globally to each mammogram, using the same local gain limit value. Quantitative contrast and noise metrics were used to evaluate the quality of processed image regions containing verified lesions. Results suggest that the method offers significantly improved performance over conventional and previously reported global wavelet contrast enhancement methods. The average contrast improvement, noise amplification and contrast-to-noise ratio improvement indices were measured as 9.04, 4.86 and 3.04, respectively. In addition, in a pilot preference study, the proposed method demonstrated the highest ranking, among the methods compared. The method was implemented in C++ and integrated into a medical image visualization tool.


Preoperative computed tomography findings predict surgical resectability of thymoma.
The aim of the study was to identify preoperative computed tomography (CT) imaging characteristics that correlated with surgical resectability. We retrospectively reviewed the CT scans of 133 patients who underwent surgical resection for thymoma at our institution between July 21, 1997, and September 22, 2010. Imaging characteristics recorded included tumor size, attenuation, contact of mediastinal vessels, tumor morphology, infiltration of surrounding fat, changes in the adjacent lung parenchyma, lymphadenopathy, and pleural involvement. The study group included 66 men and 67 women, aged 23-88 years (mean 58.8 years). Eighty patients (60.2%) were Masaoka stage I or II and 53 (39.8%) were Masaoka stage III or IV. Twenty-three patients (17.3%) had an incomplete surgical resection. Of these, 15 patients had microscopic residual disease (11.2%) and eight had gross residual disease (6.0%). The preoperative CT characteristics that correlated with an incomplete surgical resection included a lobulated tumor contour (p = 0.016), greater than or equal 50% abutment of the circumference of an adjacent vessel (p < 0.001), thoracic lymphadenopathy (p = 0.029), adjacent lung changes (p = 0.005) and pleural nodularity (p = 0.001). Tumor size was larger in the incompletely versus completely resected groups, with mean values of 9.7 and 6.9 cm (p value 0.013). On multivariate analysis, only degree of abutment of adjacent vessels and pleural nodularity were independent predictors of incomplete resection. Preoperative CT findings can predict the likelihood of successful surgical resection and could help to identify patients who might benefit from neoadjuvant chemotherapy.


Widespread cytoplasmic mRNA transport in yeast: identification of 22 bud-localized transcripts using DNA microarray analysis.
Cytoplasmic mRNA localization provides a means of generating cell asymmetry and segregating protein activity. Previous studies have identified two mRNAs that localize to the bud tips of the yeast Saccharomyces cerevisiae. To identify additional localized mRNAs, we immunoprecipitated the RNA transport components She2p, She3p, and Myo4p and performed DNA microarray analysis of their associated RNAs. A secondary screen, using a GFP-tagged RNA reporter assay, identified 22 mRNAs that are localized to bud tips. These messages encode a wide variety of proteins, including several involved in stress responses and cell wall maintenance. Many of these proteins are asymmetrically localized to buds. However, asymmetric localization also occurs in the absence of RNA transport, suggesting the existence of redundant protein localization mechanisms. In contrast to findings in metazoans, the untranslated regions are dispensable for mRNA localization in yeast. This study reveals an unanticipated widespread use of RNA transport in budding yeast.


Developmental and tissue specific changes of ubiquitin forms in Drosophila melanogaster.
In most Eukaryotes, ubiquitin either exists as free monoubiquitin or as a molecule that is covalently linked to other proteins. These two forms cycle between each other and due to the concerted antagonistic activity of ubiquitylating and deubiquitylating enzymes, an intracellular ubiquitin equilibrium is maintained that is essential for normal biological function. However, measuring the level and ratio of these forms of ubiquitin has been difficult and time consuming. In this paper, we have adapted a simple immunoblotting technique to monitor ubiquitin content and equilibrium dynamics in different developmental stages and tissues of Drosophila. Our data show that the level of total ubiquitin is distinct in different developmental stages, lowest at the larval-pupal transition and in three days old adult males, and highest in first instar larvae. Interestingly, the ratio of free mono-ubiquitin remains within 30-50% range of the total throughout larval development, but peaks to 70-80% at the larval-pupal and the pupal-adult transitions. It stays within the 70-80% range in adults. In developmentally and physiologically active tissues, the ratio of free ubiquitin is similarly high, most likely reflecting a high demand for ubiquitin availability. We also used this method to demonstrate the disruption of the finely tuned ubiquitin equilibrium by the abolition of proteasome function or the housekeeping deubiquitylase, Usp5. Our data support the notion that the ubiquitin equilibrium is regulated by tissue- and developmental stage-specific mechanisms.


Adult weight loss diets: metabolic effects and outcomes.
The global prevalence of overweight and obesity as a public health concern is well established and reflects the overall lack of success in our ability to achieve and maintain a healthy body weight. Being overweight and obese is associated with numerous comorbidities and is a risk factor for several of the leading causes of death, including cardiovascular disease, diabetes mellitus, and many types of cancer. The foundation of treatment has been diet and exercise. There are >1,000 published weight loss diets, with more appearing in the lay literature and the media on a regular basis. The sheer number of existing diet regimens would suggest that no one diet has been universally successful at inducing and maintaining weight loss. Many of these dietary programs are based on sound scientific evidence and follow contemporary principles of weight loss. Others simply eliminate 1 or more of the essential food groups or recommend consumption of 1 type of food at the expense of other foods with little to no supporting evidence. The focus of this review is on weight loss diets, specifically those with the most supporting scientific evidence and those that are most likely to succeed in achievement and maintenance of desirable body weight. The effects of weight loss diets on energy expenditure, body weight, body composition, and metabolic parameters will be evaluated. Ultimately, the best diet is the one the patient will follow and incorporate into his or her daily life for lifelong maintenance of a healthy body weight.


AgriSeqDB: an online RNA-Seq database for functional studies of agriculturally relevant plant species.
The genome-wide expression profile of genes in different tissues/cell types and developmental stages is a vital component of many functional genomic studies. Transcriptome data obtained by RNA-sequencing (RNA-Seq) is often deposited in public databases that are made available via data portals. Data visualization is one of the first steps in assessment and hypothesis generation. However, these databases do not typically include visualization tools and establishing one is not trivial for users who are not computational experts. This, as well as the various formats in which data is commonly deposited, makes the processes of data access, sharing and utility more difficult. Our goal was to provide a simple and user-friendly repository that meets these needs for data-sets from major agricultural crops. AgriSeqDB ( https://expression.latrobe.edu.au/agriseqdb ) is a database for viewing, analysing and interpreting developmental and tissue/cell-specific transcriptome data from several species, including major agricultural crops such as wheat, rice, maize, barley and tomato. The disparate manner in which public transcriptome data is often warehoused and the challenge of visualizing raw data are both major hurdles to data reuse. The popular eFP browser does an excellent job of presenting transcriptome data in an easily interpretable view, but previous implementation has been mostly on a case-by-case basis. Here we present an integrated visualisation database of transcriptome data-sets from six species that did not previously have public-facing visualisations. We combine the eFP browser, for gene-by-gene investigation, with the Degust browser, which enables visualisation of all transcripts across multiple samples. The two visualisation interfaces launch from the same point, enabling users to easily switch between analysis modes. The tools allow users, even those without bioinformatics expertise, to mine into data-sets and understand the behaviour of transcripts of interest across samples and time. We have also incorporated an additional graphic download option to simplify incorporation into presentations or publications. Powered by eFP and Degust browsers, AgriSeqDB is a quick and easy-to-use platform for data analysis and visualization in five crops and Arabidopsis. Furthermore, it provides a tool that makes it easy for researchers to share their data-sets, promoting research collaborations and data-set reuse.


Indications and outcomes of strabismus repair in visually mature patients.
To identify and examine the indications, outcomes and potential risks of strabismus surgery in visually mature patients. Case series. University-based referral practice in Edmonton. A total of 222 patients (115 females and 107 males) aged 9 to 69 (mean 29) years who underwent strabismus surgery for various types of strabismus (as grouped by original diagnosis). All patients were followed for at least 6 weeks postoperatively. Previous surgery and deviation in prism dioptres (delta) (distance and near), sensory status (measured by the Titmus stereotest at near) and the presence of symptoms (diplopia, abnormal head posture or asthenopia), recorded preoperatively, 6 weeks postoperatively and at the last postoperative visit. The patients were followed for an average of 14 months postoperatively. At the last postoperative visit 187 patients (84%) were aligned to within 15 delta of orthotropia. Overall, 116 patients (52%) demonstrated some degree of stereopsis postoperatively, compared with 78 (35%) preoperatively. A total of 116 patients (52%) had symptoms preoperatively, including diplopia, abnormal head posture or asthenopia; 88 (76%) of the 116 had complete resolution of their symptoms. Six patients (4%) without diplopia preoperatively were found to have this symptom postoperatively. The findings suggest that most visually mature patients under-going strabismus surgery can expect functional benefits, including improvement of alignment, preservation and occasionally restoration of sensory fusion, and elimination of diplopia, abnormal head posture and asthenopia.


Effect of choices of boundary conditions on the numerical efficiency of direct solutions of finite difference frequency domain systems with perfectly matched layers.
Direct solvers are a common method for solving finite difference frequency domain (FDFD) systems that arise in numerical solutions of Maxwell's equations. In a direct solver, one factorizes the system matrix. Since the system matrix is typically very sparse, the fill-in of these factors is the single most important computational consideration in terms of time complexity and memory requirements. As a result, it is of great interest to determine ways in which this fill-in can be systematically reduced. In this paper, we show that in the context of commonly used perfectly matched boundary layer methods, the choice of boundary condition behind the perfectly matched boundary layer can be exploited to reduce fill-in incurred during the factorization, leading to significant gains of up to 40% in the efficiency of the factorization procedure. We illustrate our findings by solving linear systems and eigenvalue problems associated with the FDFD method.


Endocrine abnormalities in lithium toxicity.
Lithium toxicity can manifest as a variety of biochemical -abnormalities. This case report describes a patient -presenting to the emergency department with neuropsychiatric -symptoms on a background of bipolar disorder, for which she was prescribed lithium for 26 years previously. Cases of lithium toxicity are rare but can be severe and this case report -demonstrates to clinicians that they must be thorough in investigating patients with lithium toxicity, as there are many potential abnormalities that can manifest concurrently.


Rethinking the focusing effect in decision-making.
According to Legrenzi et al. [Cognition 49 (1993) 37], in making a choice people consider only the alternatives explicitly represented in their mental model of the decision situation. Their idea has found empirical support in the "focusing effect": Individuals focus on the alternatives explicitly stated in the problem context, and do not take into account other possibilities. In their original study, Legrenzi and colleagues considered only one factor to account for the explicit representation of an alternative--i.e., its explicit verbal formulation in the decision problem. Recent theories of relevance and information gain can help articulate their original idea, suggesting that individuals explicitly represent relevant alternatives, whether or not they are explicitly formulated in the decision problem. In three experiments we first replicated Legrenzi et al.'s original experiment, and then showed that the explicit verbal mention of an alternative is neither sufficient nor necessary to focus on it. The results suggest that individuals are able to consider relevant alternatives, even when they are not made explicit in the verbal formulation of a decision problem.