Interpretation of prospective trials in hypertension: do treatment guidelines accurately reflect current evidence?
To review the findings of prospective controlled trials of antihypertensive treatment and determine whether the evidence they have provided is embodied satisfactorily in current national and international guidelines for hypertension management. Conventional guidelines all advise prompt treatment of moderate-to-severe hypertension and treatment of even mild hypertension in subjects with cardiovascular disease, target organ damage or diabetes, and in the elderly; and treatment of isolated systolic hypertension in the elderly. All acknowledge that evidence for efficacy and safety of treatment is strongest for thiazide diuretics and beta-blockers. Conventional guidelines all emphasize the importance of long-term blood pressure, measured over some months, for treatment decisions. However the blood pressure for routine treatment varies from 160/100 mmHg (British Hypertension Society) to 140/90 mmHg (Joint National Committee V). This dictates very large differences in the number of patients to be treated to prevent a cardiovascular disease event and in the proportion of the population to be treated, yet the reasons for these differences are not explicit. None of the conventional guidelines is entirely satisfactory. The more conservative British Hypertension Society policy may leave untreated some middle-aged men who ought to be treated. The more aggressive Joint National Committee V policy will lead to treatment of some young subjects who have only a remote chance of benefit, at very high cost, and possibly with adverse harm-benefit consequences. RISK-BASED GUIDELINES: Guidelines developed in New Zealand target absolute cardiovascular disease risk in mild hypertension and have the potential to correct this shortcoming of conventional guidelines. However they require further consideration as regards the number needed to treat which is acceptable to well-informed patients, the appropriate estimate of relative cardiovascular disease risk reduction by treatment in mild hypertension, the pattern of treatment which will emerge and their acceptability in ordinary practice. Comparative evaluation will be needed to determine whether the outcome is better with conventional guidelines, which are simple but at the expense of accuracy, or with risk-targeted guidelines, which are more accurate but at the expense of simplicity.


Ultrastructural changes in inherited cardiac calcinosis of DBA/2 mice.
Cardiac dystrophic calcinosis, an inherited condition in DBA/2 mice, produced extensive calcific lesions in the right ventricular myoepicardium of affected mice. The morphogenesis of the cardiac alterations was evaluated by microscopic and ultrastructural studies. The initial event was necrosis and mineralization of subepicardial myocytes. Mineral deposits were seen as dense granular and spicular deposits in mitochondria only, mitochondria and adjacent sarcoplasm, or the entire sarcoplasm in necrotic myocytes. In mature myoepicardial calcific lesions, the remnants of necrotic myocytes were seen as scattered dense masses of mineralized debris with surrounding fibroplasia and occasional macrophages and giant cells. Male weanling DBA/2 mice (n = 135) were fed either a commercial diet adequate in selenium-vitamin E (Se-E) content, or a basal semipurified Se-E-deficient diet with or without silver acetate for 15, 20 or 25 weeks. Cardiac calcinosis severity seemed to increase in mice which developed concurrent Se-E deficiency. Cardiac calcinosis in the DBA/2 mouse is a useful model of cardiac calcification.


Achieving Success of "Accessible India Campaign" Through Universal Design Education in India.
The Prime Minister, "Shri Narendra Modi" of India, launched "Sugamya Bharat Abhiyan" (Accessible India Campaign), on 3rd, December 2015. It is a nationwide flagship campaign for achieving universal accessibility for "Persons with Disabilities" and to create an enabling and barrier free environment, with a focus on three verticals; "Built Environment", "Public Transportation" and "Information and Communication Technologies" [1]. The Accessible India Campaign comprises of the following key components:- (i) Create Mass Awareness; (ii) Capacity Building; (iii) Interventions (Technology solutions, Legal framework, Resource generation); (iv) Leverage corporate sector efforts including CSR resources; (v) Leadership endorsements [1] . In the key components stated above two major components are; 1. Mass Awareness and 2. Capacity Building. To achieve both these components, the need is to develop a knowledge base through which stakeholders associated with built environment development and creation can be brought at one platform and awareness towards universal accessibility can be created among the people at large. Thus this study is an attempt to identify the possibilities to make the "Accessible India Campaign" a success through "Universal Design Education" and to establish and validate the need of universal design in making the "Accessible India Campaign" a success. The study attempts to establish the need of "Universal Design Education' in India. The need of a discipline with which the designers at all levels of design ranging from product, interiors, architecture and planning of built environment can create sustainable, accessible, living environment in India.


The effects of a dynamic tuberal support on ischial buttock load and pattern of blood supply.
Sitting acquired pressure ulcers are places of tissue breakdown that mainly occur under the ischial tuberosities (ITs). Successive durations of pressure relief help the buttock tissue recover from sustained deformation and blood-flow stagnation. A computer-aided simulator chair was developed with two adjustable tuberal support elements (TSE) integrated in a force-sensing seating plane (FSP). This study investigated the redistribution of external buttock load in relation to the pattern (i.e., dynamics) of subtuberal blood supply in sitting with a dynamic tuberal support of 1/60 Hz (80 mm/min). Fifteen healthy male subjects were seated with their ITs on the TSE. The experiment involved periodic TSE adjustment in which buttock interface pressure was measured with the FSP and an external pressure mapping device (PMD). Light-guide tissue spectrophotometry was used for simultaneous noninvasive measurement of oxygenation and perfusion in the skin ( < 2 mm) and subcutaneous ( < 8 mm) tissue under the ITs. TSE adjustment seemed effective to regulate centre of buttock pressure and the forces under the ITs. Differences in measurement with the FSP and PMD have been found due to Hammocking at the seat interface and inaccurate peak pressure readings. Subtuberal blood supply was inversely related to the contact load under the ITs. A rapid inflow of blood in the initial stage of tuberal unloading, followed by a gradual outflow in the rest of the movement cycle indicates that the average blood supply increases when the adjustment frequency increases. Future studies must address the influence of a dynamic tuberal support on the ischial buttock load and pattern of blood supply in impaired individuals.


Which short-term therapy? Matching patient and method.
In recent years, numerous forms of short-term psychotherapy have been developed, without clear guidelines for choosing among them. There are three major approaches in terms of both their techniques and their criteria for patient selection. The "interpretive" method stresses the use of insight produced by a therapist's interpretations, the "existential," the maturational effect of a brief empathic encounter with the therapist, and the "corrective," the behavioral changes resulting from patient management by the therapist. The question facing a short-term therapist is how to choose a particular method for a particular patient. A framework is proposed based on developmental phases of adult life to help therapists match patient and method.


Evaluating the Evidence for Enclothed Cognition: Z-Curve and Meta-Analyses.
Enclothed cognition refers to the systematic influence that clothes can have on the wearer's feelings, thoughts, and behaviors through their symbolic meaning. It has attracted considerable academic and nonacademic interest, with the 2012 article that coined the phrase cited more than 600 times and covered in more than 160 news outlets. However, a recent high-powered replication failed to replicate one of the original effects. To determine whether the larger body of research on enclothed cognition possesses evidential value and replicable effects, we performed z-curve and meta-analyses using 105 effects from 40 studies across 24 articles (N = 3,789). Underscoring the marked improvement of psychological research practices in the mid-2010s, our results raise concerns about the replicability of early enclothed cognition studies but affirm the evidential value for effects published after 2015. These later studies support the core principle of enclothed cognition-what we wear influences how we think, feel, and act.


SMARCB1/INI1 genetic inactivation is responsible for tumorigenic properties of epithelioid sarcoma cell line VAESBJ.
Epithelioid sarcoma is a rare soft tissue neoplasm that usually arises in the distal extremities of young adults. Epithelioid sarcoma presents a high rate of recurrences and metastases and frequently poses diagnostic dilemmas. We previously reported loss of tumor suppressor SMARCB1 protein expression and SMARCB1 gene deletion in the majority of epithelioid sarcoma cases. Unfortunately, no appropriate preclinical models of such genetic alteration in epithelioid sarcoma are available. In the present report, we identified lack of SMARCB1 protein due to a homozygous deletion of exon 1 and upstream regulatory region in epithelioid sarcoma cell line VAESBJ. Restoration of SMARCB1 expression significantly affected VAESBJ cell proliferation, anchorage-independent growth, and cell migration properties, thus supporting the causative role of SMARCB1 loss in epithelioid sarcoma pathogenesis. We investigated the translational relevance of this genetic background in epithelioid sarcoma and showed that SMARCB1 ectopic expression significantly augmented VAESBJ sensitivity to gamma irradiation and acted synergistically with flavopiridol treatment. In VAESBJ, both activated ERBB1/EGFR and HGFR/MET impinged on AKT and ERK phosphorylation. We showed a synergistic effect of combined inhibition of these 2 receptor tyrosine kinases using selective small-molecule inhibitors on cell proliferation. These observations provide definitive support to the role of SMARCB1 inactivation in the pathogenesis of epithelioid sarcoma and disclose novel clues to therapeutic approaches tailored to SMARCB1-negative epithelioid sarcoma.


Human BAG-1/RAP46 protein is generated as four isoforms by alternative translation initiation and overexpressed in cancer cells.
Previously, a Bcl-2-interacting protein, BAG-1, was cloned from mouse cells and was shown to interact with several other proteins and to be important for inhibition of apoptosis. Human BAG-1 (hBAG-1) cDNA, recently isolated by us and two other groups, has been shown to be identical to a hormone receptor-binding protein, RAP46. However, different molecular masses of hBAG-1 protein products were noted by these three groups. Here we demonstrated that hBAG-1 protein was expressed as four isoforms, designated p50, p46, p33 and p29, with apparent molecular masses of 50 kDa, 46 kDa, 33 kDa and 29 kDa, respectively. Deletion, site-directed mutagenesis and in vitro transcription/translation analysis showed that the four protein products of hBAG-1 were expressed by alternative initiation from four different start codons through a leaky scanning mechanism. Furthermore, we demonstrated that the distinct forms of hBAG-1 have different subcellular localizations, suggesting that they may have distinct functions in the cells. Characterization of hBAG-1 RNA and protein also showed that hBAG-1 was overexpressed in human cervical, breast and lung cancer cell lines. Taken together, these data clarify the conflicting observations reported in the literature and suggest that hBAG-1 is expressed as four forms of protein products, which may play a differential role in apoptosis and oncogenesis of human cells.


Deciphering the role of fungus in degradation of polypropylene from hospital waste.
Health and environmental consequences are unavoidable when it comes to management of hospital waste (HW) disposables. In order to eradicate the HW, this study isolated a novel fungus SPF21 from a hospital dumping yard to degrade Polypropylene (PP). We measured the attributes of PP inoculated with fungus using mass loss, Fourier trans-form infrared (FTIR), contact angle (CA), and scanning electron microscopy (SEM). The weight of PP exposed to SPF21 was reduced by 25% in 90 days. The SEM images reveal that there are pores all over the sample surface; they alsocaused voids during the biodegradation of PP. FTIR analysis indicates that the spectra of treated mask pieces show the absence of peak at 1746 cm-1 and the appearance of a new peak at 1643 cm-1 . A period of 90-day exposure to the fungal isolate SPF21 reduced the CA of PP by 44.8% when compared to the nonexposed PP samples, suggesting that the surface of PP turned more hydrophilic after exposure. Moreover, our study on PP degradation by the fungus Ascotricha sinuosa SPF21 appears to be promising from the perspective of environmental, health, and economic hazards. Our results indicate that biodegradation greatly facilitates fungus deposition and changes PP film morphology and hydrophilicity.


Fragmentation behavior of metal-coded affinity tag (MeCAT)-labeled peptides.
Quantitative proteomics has become an important method in modern life sciences. Besides protein identification, the aspect of quantification is of rapidly increasing relevance. MeCAT (metal-coded affinity tagging) is able to provide a tool that enables relative as well as absolute quantification. For structural elucidation, knowledge on the fragmentation behavior of MeCAT-modified peptides is highly beneficial. Therefore, the fragmentation behavior of MeCAT-labeled peptides under collision induced dissociation (CID), electron capture dissociation (ECD) and infrared multiphoton dissociation (IRMPD) conditions was studied. Application of CID and ECD allowed a straight-forward sequence elucidation of MeCAT-labeled peptides. During IRMPD all MeCAT-labeled peptides form characteristic fragments resulting from the fragmentational cleavage of the tagging group, thus, providing a screening method for the identification of labeled compounds. Furthermore, occurring side reactions during the labeling process were investigated. By-products were structurally characterized and reaction conditions were optimized in order to prevent the formation of these.


Potentialities and Limits of Some Non-thermal Technologies to Improve Sustainability of Food Processing.
In the whole food production chain, from the farm to the fork, food manufacturing steps have a large environmental impact. Despite significant efforts made to optimize heat recovery or water consumption, conventional food processing remains poorly efficient in terms of energy requirements and waste management. Therefore, in the few last decades, much research has focused on the development of alternative non-thermal technologies. Some of them, such as membrane separation processes, hydrostatic or dynamic high pressure, dense phase or high-pressure carbon dioxide, and pulsed electric fields (PEFs) have been extensively studied for cold pasteurization, concentration, extraction, or food functionalization. However, it is still difficult to evaluate the actual advantages or limits of these innovative processing technologies to replace conventional processes. Thus, the overall aim of this paper is to present an overview of the most relevant studies dealing with the potentialities and limits of these non-thermal technologies to improve sustainability of food processing. After a brief presentation of the physical principles of these technologies, the paper illustrates how these technologies could play a decisive role for sustainable food preservation or valorization of raw materials and by-products.


Neurocognitive performance in drug-dependent males and females with posttraumatic stress disorder symptoms.
Sex differences in neurobiological mechanisms of substance dependence are well documented but studies of sex differences in associated neurocognitive deficits have produced inconsistent results. Posttraumatic stress disorder (PTSD) is comorbid with substance dependence and frequently affects neurocognition. Thus, we investigated the effects of sex and PTSD symptoms on sustained attention and inhibition abilities among 126 female and 297 male substance-dependent individuals (SDIs) using the Immediate Memory Test (IMT). Females with significant PTSD (PTSD+) symptoms demonstrated significantly impaired IMT performance relative to other participants. These results represent progress in efforts to delineate sex-specific risk factors for neurocognitive deficits among SDIs.


A new lymph node ratio-based staging system for rectosigmoid cancer: a retrospective study with external validation.
This study evaluated the clinical value of a new American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) staging prediction model based on lymph node ratio (LNR) in rectosigmoid cancer (RSC). The analysis included 1444 patients with nonmetastatic RSC diagnosed pathologically between 2010 and 2016 who were collected from the National Cancer Institute Surveillance, Epidemiology, and Results database. The AJCC N-stage was redefined according to the LNR cutoff point, and the ability of the new staging system to predict prognosis was compared with that of the AJCC TNM staging system. Data from 739 patients from our hospital were used for external validation. According to the number of examined lymph nodes and LNR, the N stage was divided into five groups (LNR0-5). The 5-year OS of patients divided according to the new T lymph node ratio M (TLNRM) staging into stage I (T1LNR1, T1LNR2), IIA (T1LNR3, T2LNR1, T2LNR2, T2LNR3, T1LNR4, T3LNR1), IIB (T2LNR4), IIC (T3LNR2, T4a LNR1, T1LNR5), IIIA (T3LNR3, T2LNR5, T4b LNR1, T4a LNR2, T3LNR4), IIIB (T3LNR5, T4a LNR3, T4a LNR4, T4b LNR2), and IIIC (T4b LNR3, T4a LNR5, T4b LNR4, T4b LNR5) was significantly different ( P <0.05). Decision curve analysis showed that the net income of the new TLNRM staging system for different decision thresholds was higher than the prediction line of the traditional eighth TNM staging system. The smaller Akaike information criterion and Bayesian information suggested that the new staging system had a higher sensitivity for predicting prognosis than the traditional staging system. TLNRM II and III patients benefited from adjuvant chemotherapy, while adjuvant chemotherapy did not improve the prognosis of TNM II patients. These findings were confirmed by the external validation data. The new TLNRM staging system was superior to the eighth edition AJCC staging system for staging and predicting the prognosis of patients with RSC and may become an effective tool in clinical practice.


Low morbidity profile of spleen mesh wrapping in children.
Spleen mesh wrapping is a valuable and efficacious technique for treating severely traumatized spleens. We report the morbidity of the procedure and describe its management in children. A retrospective survey of children admitted to the Hillel Yaffe Medical Center with a traumatized spleen was carried out. Between 1985 and 2000, we treated 168 children for blunt spleen trauma. The spleen was the only intra-abdominal organ injured in 102 of them. Absorbable mesh wrapping was chosen for 20 children (age range 1 - 15 years), with grade III/IV lesions that would otherwise probably have required splenectomy. Hemostasis was achieved in all 20 children. All children survived with intact spleens as suggested by the absence of long-term infectious complications and by normal hematological, US and scintigraphy studies. Anti-pneumococcal vaccination was not required. Complications were diagnosed in 12 cases, the most common being prolonged fever. Perisplenic fluid, oozing, and left pleural effusion were also present. Only one intrasplenic pseudoaneurysm occurred and this resolved spontaneously. There was one splenic abscess which was successfully treated by transmesh transcutaneous computerized tomography-guided drainage. No complications were detected at the 1 year follow-up. Absorbable mesh wrapping is safe and effective for treating grade III/IV spleen ruptures in children. Complications are mostly minor, and resolve spontaneously. Major complications are rare and can usually be managed nonsurgically.


Drug biotransformation in microsomes from the fetal stumptailed macaque, Macaca arctoides: hepatic N-demethylation.
The kinetics of the N-demethylation of benzphetamine, ethylmorphine, meperidine, and methadone have been studied in microsomes isolated from livers of the fetal stumptailed macaque (Macaca arctoides) during the last third of gestation. The apparent KM for each substrate did not change during this time period. Values were similar to those from livers of adult African green monkeys. The Vmax for each substrate, when expressed per mg of microsomal protein, did not change during the last third of gestation. N-demethylase activity (Vmax) per g of liver increased during the last third of gestation, as did the content of microsomal protein, cytochrome P-450 concentration, and liver weight. The amount of cytochrome P-450 per g of liver was greater in whole homogenates of the left physiological lobe than in those of the right physiological lobe of fetal liver obtained near term; no differences occurred in whole homogenates of the separate lobes of adult liver. This observation suggests that a differential capacity for drug (and possibly steroid) metabolism may exist between the two physiological lobes of fetal liver.


A case report of ten-month-neglected anterior shoulder dislocation managed by open reduction combined with Latarjet procedure.
Neglected shoulder dislocation is a rare case and may be accompanied by pathological changes in bony and soft tissue structure. Therefore, it requires extensive surgical procedure. Until now, there is no standard treatment protocol to overcome this case and it is still a challenging case. We presented a 27-year-old male patient with deformity on his left shoulder. The patient has suffered a ten-month-neglected anterior shoulder dislocation with a Hill-Sachs lesion. The treatment was open reduction combined with Latarjet procedure. Evaluation of treatment was performed three months after surgery. Management of a neglected shoulder dislocation, especially with significant bony defects, is challenging and cannot be managed with standard surgical technique because of severe soft-tissue contracture and imbalance as well as bone deficiency. Chronic locked anterior shoulder dislocation is a difficult condition for both patient and clinician. In addition to that, the treatment results can be unsatisfactory. Latarjet procedure has been shown to be effective for the treatment of recurrent anterior shoulder dislocation with a large glenoid osseous defect which might justify the application of this procedure for the treatment of neglected anterior shoulder dislocation. Open reduction combined with Latarjet procedure performed for treatment of neglected anterior shoulder dislocation was found to have a high rate of successful in preventing further dislocation of the shoulder joint although the high risk of osteoarthritis of the shoulder joint can still persist.


Effect of Some Sulfhydryl-containing Substances on the Toxicity of an Organic Mercurial Compound.
The acute toxicity of an organic mercurial as studied on the mouse, intact anesthetized cat and dog, and the heart-lung preparation of the dog can be readily counteracted by sulfhydryl-containing compounds such as glutathione, cysteine, and 2,3-dimercapto-propanol. Equimolar doses of 2,3-dimercapto-propanol are about five times as active as cysteine or glutathione.


Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis.
The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis In this study, we found that >64 mg/liter of static benzylpenicillin concentrations killed 1.16 to 1.43 log10 CFU/ml below starting inoculum of extracellular and intracellular M. tuberculosis over 7 days. When we added the β-lactamase inhibitor avibactam, benzylpenicillin maximal kill (Emax) of extracellular log-phase-growth M. tuberculosis was 6.80 ± 0.45 log10 CFU/ml at a 50% effective concentration (EC50) of 15.11 ± 2.31 mg/liter, while for intracellular M. tuberculosis it was 2.42 ± 0.14 log10 CFU/ml at an EC50 of 6.70 ± 0.56 mg/liter. The median penicillin (plus avibactam) MIC against South African clinical M. tuberculosis strains (80% either multidrug or extensively drug resistant) was 2 mg/liter. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow-fiber model of tuberculosis (HFS-TB). The percent time above the MIC was linked to effect, with an optimal exposure of ≥65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase-growth M. tuberculosis was 1.44 log10 CFU/ml/day, while 3.28 log10 CFU/ml of intracellular M. tuberculosis was killed over 3 weeks. In an 8-week HFS-TB study of nonreplicating persistent M. tuberculosis, penicillin-avibactam alone and the drug combination of isoniazid, rifampin, and pyrazinamide both killed >7.0 log10 CFU/ml. Monte Carlo simulations of 10,000 preterm infants with disseminated disease identified an optimal dose of 10,000 U/kg (of body weight)/h, while for pregnant women or nonpregnant adults with pulmonary tuberculosis the optimal dose was 25,000 U/kg/h, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.


Overlap between the neural correlates of cued recall and source memory: evidence for a generic recollection network?
Recall of a studied item and retrieval of its encoding context (source memory) both depend on recollection of qualitative information about the study episode. This study investigated whether recall and source memory engage overlapping neural regions. Participants (n = 18) studied a series of words, which were presented either to the left or right of fixation. fMRI data were collected during a subsequent test phase in which three-letter word-stems were presented, two thirds of which could be completed by a study item. Instructions were to use each stem as a cue to recall a studied word and, when recall was successful, to indicate the word's study location. When recall failed, the stem was to be completed with the first word to come to mind. Relative to stems for which recall failed, word-stems eliciting successful recall were associated with enhanced activity in a variety of cortical regions, including bilateral parietal, posterior midline, and parahippocampal cortex. Activity in these regions was enhanced when recall was accompanied by successful rather than unsuccessful source retrieval. It is proposed that the regions form part of a "recollection network" in which activity is graded according to the amount of information retrieved about a study episode.


Can selective ligands for glutamate binding proteins be rationally designed?
A major neurotransmitter, L-Glutamate must be stored, transported and received, and these processes are mediated by proteins that bind this simple yet essential amino acid. Detailed evidence continues to emerge on the structure of Glu binding proteins, which includes both receptors and transporters. It appears that receptors and transporters bind to Glu in different conformations, which may present a pharmacological opportunity. This review will compare and contrast information available on Glu Receptors (AMPA, NMDA, KA and mGlu), excitatory amino acid transporters (EAATs), the system Xc- transporter (XCT) and the vesicular Glutamate transporter (GVT). The cross-reactivity of ligands which have been previously used to characterize the glutamate binding proteins with system Xc- raises some fundamental interpretational issues regarding the mechanisms through which these analogues produce CNS damage. Although at one time it was thought that unraveling selectivity among glutamate binding proteins was an intractable problem, recently the NMDA antagonist (memantine) has been approved for general medical practice for treatment of Alzheimer's disease. Two other agents are in advanced clinical trials: an Ampakine for potential improvement of cognitive disorders, and a selective mGlu agonist for treatment of anxiety. The prospects for unraveling cross-reactivity will be weighed in light of a critical comparison of the glutamate binding protein targets.


Band Gap of Pb(Fe0.5Nb0.5)O3 Thin Films Prepared by Pulsed Laser Deposition.
Ferroelectric materials have gained high interest for photovoltaic applications due to their open-circuit voltage not being limited to the band gap of the material. In the past, different lead-based ferroelectric perovskite thin films such as Pb(Zr,Ti)O3 (Pb,La)(Zr,Ti)O3 and PbTiO3 were investigated with respect to their photovoltaic efficiency. Nevertheless, due to their high band gaps they only absorb photons in the UV spectral range. The well-known ferroelectric PbFe0.5Nb0.5O3 (PFN), which is in a structure similar to the other three, has not been considered as a possible candidate until now. We found that the band gap of PFN is around 2.75 eV and that the conductivity can be increased from 23 S/µm to 35 S/µm during illumination. The relatively low band gap value makes PFN a promising candidate as an absorber material.


5-aza-2'-deoxycytidine-induced genome rearrangements are mediated by DNMT1.
Observations that genome-wide DNA hypomethylation induces genome instability and tumors in animals caution against the indiscriminate use of demethylating agents, such as 5-aza-2'-deoxycytidine (5-Aza-dC). Using primary mouse embryonic fibroblasts harboring a lacZ mutational reporter construct that allows the quantification and characterization of a wide range of mutational events, we found that, in addition to demethylation, treatment with 5-Aza-dC induces γ-H2AX expression, a marker for DNA breaks, and both point mutations and genome rearrangements. To gain insight into the source of these mutations, we first tested the hypothesis that the mutagenic effect of 5-Aza-dC may be directly mediated through the DNA methyltransferase 1 (DNMT1) covalently trapped in 5-Aza-dC-substituted DNA. Knockdown of DNMT1 resulted in increased resistance to the cytostatic effects of 5-Aza-dC, delayed onset of γ-H2AX expression and a significant reduction in the frequency of genome rearrangements. There was no effect on the 5-Aza-dC-induced point mutations. An alternative mechanism for 5-Aza-dC-induced demethylation and genome rearrangements via activation-induced cytidine deaminase (AID) followed by base excision repair (BER) was found not to be involved. That is, 5-Aza-dC treatment did not significantly induce AID expression and inhibition of BER did not reduce the frequency of genome rearrangements. Thus, our results indicate that the formation of DNMT1 adducts is the prevalent mechanism of 5-Aza-dC-induced genome rearrangements, although hypomethylation per se may still contribute. As the therapeutic effects of 5-Aza-dC greatly depend on the presence of DNMT1, the expression level of DNA methyltransferases in tumors may serve as a prognostic factor for the efficacy of 5-Aza-dC treatment.


Subgrain-controlled grain growth in the laser-melted 316 L promoting strength at high temperatures.
Stainless steel 316 L prepared by laser melting consisted of a hierarchical austenitic microstructure with micrometre-sized (10-25 µm) grains containing fine 1 µm subgrains with a cellular structure. At high-temperature thermal treatments (greater than or equal to 1100°C), merging and growth of the 1 µm subgrains into bigger subgrains restricted the rapid grain growth and microstructure coarsening. Partial phase transformation of austenite to ferrite at temperatures greater than or equal to 1100°C, in combination with gradual and steady growth of subgrains inside the micrometre-sized grains and nucleation of the sigma phase, has promoted the tensile strength of stainless steel 316 L to 300 MPa at 1100°C compared with that of conventionally made 316 L counterparts (approx. 40 MPa). The grain growth mechanism of the laser-melted microstructure can change the application criteria for 316 L and expand the application fields for 316 L.


Detailed secondary structure models of invertebrate 7SK RNAs.
The 7SK RNA is a small nuclear RNA that is involved in the regulation of Pol-II transcription. It is very well conserved in vertebrates, but shows extensive variations in both sequence and structure across invertebrates. A systematic homology search extended the collection of 7SK genes in both Arthropods and Lophotrochozoa making use of the large number of recently published invertebrate genomes. The extended data set made it possible to infer complete consensus structures for invertebrate 7SK RNAs. These show that not only the well-conserved 5'- and 3'- domains but all the interior Stem A domain is universally conserved. In contrast, Stem B region exhibits substantial structural variation and does not adhere to a common structural model beyond phylum level.


Fibroblast-Activation Protein PET and Histopathology in a Single-Center Database of 324 Patients and 21 Tumor Entities.
We present an overview of our prospective fibroblast-activation protein inhibitor (FAPI) registry study across a 3-y period, with head-to-head comparison of tumor uptake in 68Ga-FAPI and 18F-FDG PET, as well as FAP immunohistochemistry. Methods: This is an interim analysis of the ongoing 68Ga-FAPI PET prospective observational trial at our department. Patients who underwent clinical imaging with 68Ga-FAPI PET between October 2018 and October 2021 were included. Tracer uptake was quantified by SUVmax for tumor lesions and by SUVmean for normal organs. PET tumor volume (40% isocontour) and tumor-to-background ratios were calculated. Correlation between SUVmax and FAP staining in tissue samples was analyzed. Results: In total, 324 patients with 21 different tumor entities underwent 68Ga-FAPI imaging; 237 patients additionally received 18F-FDG PET. The most common tumor entities were sarcoma (131/324, 40%), pancreatic cancer (67/324, 21%), and primary tumors of the brain (22/324, 7%). The mean primary tumor SUVmax was significantly higher for 68Ga-FAPI than 18F-FDG among pancreatic cancer (13.2 vs. 6.1, P < 0.001) and sarcoma (14.3 vs. 9.4, P < 0.001), and the same was true for mean SUVmax in metastatic lesions of pancreatic cancer (9.4 vs. 5.5, P < 0.001). Mean primary tumor maximum tumor-to-background ratio was significantly higher for 68Ga-FAPI than 18F-FDG across several tumor entities, most prominently pancreatic cancer (14.7 vs. 3.0, P < 0.001) and sarcoma (17.3 vs. 4.7, P < 0.001). Compared with 18F-FDG, 68Ga-FAPI showed superior detection for locoregional disease in sarcoma (52 vs. 48 total regions detected) and for distant metastatic disease in both sarcoma (137 vs. 131) and pancreatic cancer (65 vs. 57), respectively. Among 61 histopathology samples, there was a positive correlation between 68Ga-FAPI SUVmax and overall FAP immunohistochemistry score (r = 0.352, P = 0.005). Conclusion: 68Ga-FAPI demonstrates higher absolute uptake in pancreatic cancer and sarcoma, as well as higher tumor-to-background uptake along with improved tumor detection for pancreatic cancer, sarcoma, and other tumor entities when compared with 18F-FDG. 68Ga-FAPI is a new tool for tumor staging with theranostic potential.


Mucin-mediated mucosal retention via end-terminal modified Pluronic F127-based hydrogel to increase drug accumulation in the lungs.
Noninvasive lung drug delivery is critical for treating respiratory diseases. Pluronic-based copolymers have been used as multifunctional materials for medical and biological applications. However, the Pluronic F127-based hydrogel is rapidly degraded, adversely affecting the mechanical stability for prolonged drug release. Therefore, this study designed two thermosensitive copolymers by modifying the Pluronic F127 terminal groups with carboxyl (ADF127) or amine groups (EDF127) to improve the viscosity and storage modulus of drug formulations. β-alanine and ethylenediamine were conjugated at the terminal of Pluronic F127 using a two-step acetylation process, and the final copolymers were characterized using 1H nuclear magnetic resonance (1H NMR) and Fourier-transform infrared spectra. According to the 1H NMR spectra, Pluronic F127 was functionalized to form ADF127 and EDF127 with 85 % and 71 % functionalization degrees, respectively. Rheological studies revealed that the ADF127 (15 wt%) and EDF127 (15 wt%) viscosities increased from 1480 Pa.s (Pluronic F127) to 1700 Pa.s and 1800 Pa.s, respectively. Furthermore, the elastic modulus of ADF127 and EDF127 increased, compared with that of native Pluronic F127 with the addition of 5 % mucin, particularly for ADF127, thereby signifying the stronger adhesive nature of ADF127 and EDF127 with mucin. Additionally, ADF127 and EDF127 exhibited a decreased gelation temperature, decreasing from 33 °C (Pluronic F127 at 15 wt%) to 24 °C. Notably, the in vitro ADF127 and EDF127 drug release was prolonged (95 %; 48 h) by the hydrogel encapsulation of the liposome-Bdph combined with mucin, and the intermolecular hydrogen bonding between the mucin and the hydrogel increased the retention time and stiffness of the hydrogels. Furthermore, ADF127 and EDF127 incubated with NIH-3T3 cells exhibited biocompatibility within 2 mg/mL, compared with Pluronic F127. The nasal administration method was used to examine the biodistribution of the modified hydrogel carrying liposomes or exosomes with fluorescence using the IVIS system. Drug accumulation in the lungs decreased in the following order: ADF127 > EDF127 > liposomes or exosomes alone. These results indicated that the carboxyl group-modified Pluronic F127 enabled well-distributed drug accumulation in the lungs, which is beneficial for intranasal administration routes in treating diseases such as lung fibrosis.


Development and 10-year history of a biosimilar: the example of Binocrit®.
Patent expirations for several biological products have prompted the development of alternative versions, termed 'biosimilars', which have comparable quality, safety and efficacy to a licensed biological medicine (also referred to as the 'reference' medicine). The first biosimilars developed in oncology were the supportive-care agents filgrastim and epoetin. Binocrit® (HX575) is a biosimilar version of epoetin alfa, indicated in the oncology setting for the treatment of chemotherapy-induced anemia (CIA). The process for development and approval of Binocrit® as a biosimilar included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program comprising phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory phase III study to confirm therapeutic effectiveness in CIA. Since its approval, Binocrit® has been extensively used and studied in real-world clinical practice. The accumulated data confirm that Binocrit® is an effective and well-tolerated option for the treatment of CIA in patients with cancer.


The role of antibodies in tuberculosis diagnosis, prophylaxis and therapy: a review from the ESGMYC study group.
Tuberculosis (TB) is still responsible for the deaths of >1 million people yearly worldwide, and therefore its correct diagnosis is one of the key components of any TB eradication programme. However, current TB diagnostic tests have many limitations, and improved diagnostic accuracy is urgently needed. To improve the diagnostic performance of traditional serology, a combination of different Mycobacterium tuberculosis (MTB) antigens and different antibody isotypes has been suggested, with some showing promising performance for the diagnosis of active TB. Given the incomplete protection conferred by bacille Calmette-Guérin (BCG) vaccination against adult pulmonary TB, efforts to discover novel TB vaccines are ongoing. Efficacy studies from advanced TB vaccines designed to stimulate cell-mediated immunity failed to show protection, suggesting that they may not be sufficient and warranting the need for other types of immunity. The role of antibodies as tools for TB therapy, TB diagnosis and TB vaccine design is discussed. Finally, we propose that the inclusion of antibody-based TB vaccines in current clinical trials may be advisable to improve protection.


Lack of Association of a Functional Polymorphism in the Serotonin Receptor Gene With Body Mass Index and Depressive Symptoms in a Large Meta-Analysis of Population Based Studies.
The serotonin receptor 5-HTR2C is thought to be involved in the function of multiple brain structures. Consequently, the HTR2C gene has been studied extensively with respect to its association with a variety of phenotypes. One coding variant in the HTR2C gene, Cys23Ser (rs6318), has been associated with depressive symptoms. and adiposity; however, these findings have been inconsistent. The reasons for this mixed picture may be due to low statistical power or due to other factors such as failure to account for possible interacting environmental factors, such as psychosocial stress. Further, the literature around this polymorphism is marked by limited inclusion of persons of African ancestry. The present study sought to overcome these limitations and definitively determine the relationship of this polymorphism with depressive and obesity phenotypes in a large sample meta-analysis. Thus, we harmonized individual level data from 10 studies including the Women's Health Initiative, CARDIA, ARIC, Framingham Offspring, and the Jackson Heart Study, resulting in a sample of 27,161 individuals (10,457 Black women, 2,819 Black men, 7,419 White women, and 6,466 White men). We conducted a random effects meta-analysis using individual level data to examine whether the Cys23Ser variant-either directly, or conditionally depending on the level of psychosocial stress-was associated with depressive symptoms and body mass index (BMI). We found that psychosocial stress was associated with both depression and BMI, but that Cys23Ser was not directly associated with, nor did it modify the associations of psychosocial stress with depression or BMI. Thus, in the largest study of this polymorphism, we have determined that rs6318 is not associated with depression, or BMI.


The molecular through ecological genetics of abnormal abdomen in Drosophila mercatorum. V. Female phenotypic expression on natural genetic backgrounds and in natural environments.
The abnormal abdomen (aa) syndrome in Drosophila mercatorum depends on the presence of R1 inserts in a third or more of the X-linked 28S rDNA genes and the absence of selective underreplication of inserted repeats in polytene tissues that is controlled by an X-linked locus (ur) half a map unit from the rDNA complex. This syndrome affects both life history and morphology in the laboratory. Because abnormal morphologies are rarely encountered in nature, the purpose of this study is to see if the female life history traits are still affected under more natural genetic backgrounds and environmental conditions. Two outbred stocks were extracted from the natural population living near Kamuela, Hawaii: KaaX that has only X chromosomes with uraa alleles, and K+X that has only ur+ alleles. These two stocks have nonoverlapping distributions of insert proportions, indicating strong disequilibrium between the ur locus and the rDNA complex. The KaaX stock had almost no morphological penetrance of uraa, indicating that genetic background is important. KaaX expressed longer female egg-to-adult developmental times, increased early adult female fecundity, and decreased female adult longevity compared with K+X. By bagging natural rots of the cactus Opuntia megacantha near Kamuela, Hawaii, it was shown that egg-to-adult developmental time is slowed down by 0.92 days in females bearing uraa alleles in nature, with no detectable slowdown in uraa males. The bagged rot data also indicate that females bearing uraa alleles have a strong fecundity advantage in nature under some ecological conditions but not others.


Campylobacteriosis Outbreak Associated with Contaminated Municipal Water Supply - Nebraska, 2017.
In March 2017, the Nebraska Department of Health and Human Services (NDHHS) and the Southwest Nebraska Public Health Department were notified of an apparent cluster of Campylobacter jejuni infections in city A and initiated an investigation. Overall, 39 cases were investigated, including six confirmed and 33 probable. Untreated, unboiled city A tap water (i.e., well water) was the only exposure significantly associated with illness (odds ratio [OR] = 7.84; 95% confidence interval [CI] = 1.69-36.36). City A is served by four untreated wells and an interconnected distribution system. Onsite investigations identified that a center pivot irrigation system intended to pump livestock wastewater from a nearby concentrated animal feeding operation onto adjacent farmland had malfunctioned, allowing excessive runoff to collect in a road ditch near two wells that supplied water to the city. These wells were promptly removed from service, after which no subsequent cases occurred. This coordinated response rapidly identified an important risk to city A's municipal water supply and provided the evidence needed to decommission the affected wells, with plans to build a new well to safely serve this community.


[Nutritional utilization of cottonseed flour, compared to soya flour, by growing rats with protein malnutrition].
The aim of this study was to compare the nutritional value of three diets with rats submitted to protein malnutrition. After one month on a low protein diet (2% casein), the rats were refed with corn-soya-milk (60%/30%/5%, W/W/W) and rice-cotton-milk (60%/30%/5%) diets. This produced a higher growth rate than either the corn-cotton milk (60%/30%/5%) diets or a control diet containing 20% casein. The caloric intake/100 g body weight was about the same with the four rehabilitation diets. The highest apparent nitrogen digestive utilization coefficients (C. U. D.) values were obtained with the control diet, lower values with the rice-cotton-milk diet, then the corn-cotton-milk diet and lowest with the corn-soya-milk diet. Results of lipid C. U. D. were in the same order. The highest nitrogen balances were obtained with the control diet, then the corn-soya-milk diet, the rice-cotton-milk diet and lowest values with the corn-cotton-milk diet. Our data prove that the cotton flour mixed with rice may perfectly replace soya flour associated with corn in a nutritional rehabilitation diet.


Sympatho-adrenal morphogenesis regulated by the dorsal aorta.
The autonomic nervous system, composed of sympathetic- and para-sympathetic neurons, plays essential roles in a variety of physiological functions including homeostasis and responses to external stimuli. We here present an overview of recent findings concerning how the sympathetic nervous system is formed during the early development, paying particular attention to the morphogenesis of those tissues derived from migrating neural crest cells. Neural crest cells, originally multipotent, are progressively specified to sympathetic ganglia neurons and adrenomedullary cells during their migration through the body. Importantly, the dorsal aorta, the first-forming blood vessel, acts as a signaling center for their migration and differentiation. BMP signals emanating from the dorsal aorta are essential for establishing environmental cues that directly act on the migrating cells. The mechanisms underlying these early neuro-vascular interactions provide insights into understanding diseases caused by malfunctions and malformations of the autonomic nervous system.


D 600 block of L-type Ca2+ channel in vascular smooth muscle cells: comparison with permanently charged derivative, D 890.
It has been reported that D 600 blocks the high-threshold Ca2+ channel (L-type) from the outside in isolated vascular and ileal smooth muscle cells of the rabbit (Y. Ohya, K. Terada, K. Kitamura, and H. Kuriyama. Pfluegers Arch. 408: 80-82, 1987). We have reinvestigated this hypothesis by comparing the effects of external and internal applications of D 600 and the permanently charged quaternary derivative D 890 on the whole cell Ca2+ current (Ica) recorded in vascular smooth muscle cells isolated from the rabbit portal vein. At low frequencies of stimulation (0.05 Hz), externally applied D 600 inhibited Ica in a dose-dependent fashion, with a complete block occurring at 10(-4) M. D 600 was approximately 1,000 times more potent than D 890 for causing inhibition of Ica using this protocol. During a train of stimulations at 0.5 Hz, D 600 (10(-6) M) produced a minor additional frequency-dependent block of Ica, as shown in other preparations. During superfusion with D 890 (10(-4) M), a similar protocol produced little if any decline in the amplitude of Ica. No evidence of block could be detected during intracellular dialysis of D 600 (10(-4) M). At the same concentration, intracellular application of D 890 produced a slow block of Ica. To test whether D 600 could be effectively dialysed using a patch micropipette, similar experiments were performed in cardiac ventricular myocytes. In this preparation, intracellular dialysis of D 600 induced a rapid inhibition of the Ica.(ABSTRACT TRUNCATED AT 250 WORDS)


Microbial α-L-Rhamnosidases of Glycosyl Hydrolase Families GH78 and GH106 Have Broad Substrate Specificities toward α-L-Rhamnosyl- and α-L-Mannosyl-Linkages.
α-L-Rhamnosidases (α-L-Rha-ases, EC 188.8.131.52) are glycosyl hydrolases (GHs) that hydrolyze a terminal α-linked L-rhamnose residue from a wide spectrum of substrates such as heteropolysaccharides, glycosylated proteins, and natural flavonoids. As a result, they are considered catalysts of interest for various biotechnological applications. α-L-rhamnose (6-deoxy-L-mannose) is structurally similar to the rare sugar α-L-mannose. Here we have examined whether microbial α-L-Rha-ases possess α-L-mannosidase activity by synthesizing the substrate 4-nitrophenyl α-L-mannopyranoside. Four α-L-Rha-ases from GH78 and GH106 families were expressed and purified from Escherichia coli cells. All four enzymes exhibited both α-L-rhamnosyl-hydrolyzing activity and weak α-L-mannosyl-hydrolyzing activity. SpRhaM, a GH106 family α-L-Rha-ase from Sphingomonas paucimobilis FP2001, was found to have relatively higher α-L-mannosidase activity as compared with three GH78 α-L-Rha-ases. The α-L-mannosidase activity of SpRhaM showed pH dependence, with highest activity observed at pH 7.0. In summary, we have shown that α-L-Rha-ases also have α-L-mannosidase activity. Our findings will be useful in the identification and structural determination of α-L-mannose-containing polysaccharides from natural sources for use in the pharmaceutical and food industries.


Modulation of in vitro splicing of the upstream intron by modifying an intra-exon sequence which is deleted from the dystrophin gene in dystrophin Kobe.
Molecular analysis of dystrophin Kobe showed that exon 19 of the dystrophin gene bearing 52-bp deletion was skipped during splicing, although the known consensus sequences at the 5' and 3' splice sites of exon 19 were maintained (Matsuo, M., T. Masumura, H. Nishio, T. Nakajima, Y. Kitoh, T. Takumi, J. Koga, and H. Nakamura. 1991. J. Clin. Invest. 87:2127-2131). These data suggest that the deleted sequence of exon 19 may function as a cis-acting element for exact splicing for the upstream and downstream introns. To investigate this potential role of exon 19, an in vitro splicing system using artificial dystrophin mRNA precursors (pre-mRNAs) was established. Pre-mRNA containing exon 18, truncated intron 18, and exon 19 was spliced precisely in vitro, whereas splicing of intron 18 was almost completely abolished when the wild-type exon 19 was replaced by the dystrophin Kobe exon 19. Splicing of intron 18 was not fully reactivated when dystrophin Kobe exon 19 was restored to nearly normal length by inserting other sequences into the deleted site. These results suggest that the presence of the exon 19 sequence which is lost in dystrophin Kobe is more critical for splicing of intron 18 than the length of the exon 19 sequence. Characteristically, the efficiency of splicing of this intron seemed to correlate with the presence of polypurine tracks within the downstream exon 19. Moreover, an antisense 31-mer 2'-O-methyl ribonucleotide complementary to the 5' half of the deleted sequence in dystrophin Kobe exon 19 inhibited splicing of wild-type pre-mRNA in a dose- and time-dependent manner. This first in vitro evidence that dystrophin pre-mRNA splicing can be modulated by an antisense oligonucleotide raises the possibility of a new therapeutic approach for Duchenne muscular dystrophy.


Temporal profile of angiogenesis and expression of related genes in the brain after ischemia.
Angiogenesis is an intricately regulated phenomenon. Its mechanisms in the ischemic brain have not been clearly elucidated. The authors investigated expression of angiogenesis-related genes using a complementary DNA (cDNA) array method as well as Western blotting and immunohistochemistry, and compared these studies with a temporal profile of angiogenesis in mouse brains after ischemia. The number of vessels significantly increased 3 days after injury, and proliferating endothelial cells increased as early as 1 day. This means that angiogenesis occurs immediately after the injury. Ninety-six genes implicated in angiogenesis were investigated with a cDNA array study. It was found that 42, 29, and 13 genes were increased at 1 hour, 1 day, and 21 days, respectively. Most of the well-known angiogenic factors increased as early as 1 hour. Vessel-stabilizing factors such as thrombospondins also increased. At 1 day, however, thrombospondins decreased to lower levels than in the control, indicating a shift from vascular protection to angiogenesis. At 21 days, many genes were decreased, but some involved in tissue repair were newly increased. Western blotting and immunohistochemistry showed findings compatible with the cDNA array study. Many molecules act in an orchestrated fashion in the brain after ischemia and should be taken into account for therapeutic angiogenesis for stroke.


Barriers to physical activity in patients with intermittent claudication.
The main barriers reported by the patients with claudication are related to claudication symptoms. However, it remains unclear whether these barriers are associated with physical activity levels in these patients. The aim of this study was to analyze the barriers to and the factors associated with physical activity (PA) in intermittent claudication (IC) patients. The sample included 150 IC Brazilian patients and mean age 64 ± 9 years old. Sociodemographic factors, comorbid conditions and cardiovascular risk factors, personal and environmental barriers to PA, and walking capacity (claudication onset distance-COD and peak walking distance-PWD) were obtained. PA was assessed using a pedometer over seven consecutive days. Patients performed 6,041 ± 3,166 steps/day. The most prevalent personal and environmental barriers to PAs were exercise-induced pain and the presence of obstacles that aggravate the leg pain. Multiple linear regression showed that level of PA was inversely associated with age (β = -81.13; p < 0.001), lack of green areas (β = -1363.54; p < 0.001), and positively associated with PWD (β = 3.07; p < 0.001). Older IC patients who live in neighborhoods that lack green areas to walk in, and who have poor walking capacity present lower levels of PA.


Ondansetron absorption in adults: effect of dosage form, food, and antacids.
Ondansetron is a competitive serotonin 5-HT3 receptor blocker that has proved useful in the prevention of emesis due to cisplatin and other cancer chemotherapeutic agents. In a randomized, open-label, crossover study in 24 healthy male subjects, the relative bioavailability of a single 8-mg tablet was compared with that of an 8-mg solution using the two one-sided t-tests. The tablet and solution formulations were bioequivalent, as confirmed by similarities in mean Cmax (26.3 vs 27.7 ng/mL), Tmax (1.79 vs 1.70 h), and AUC (166.0 vs 167.3 ng.h/mL) values. In another randomized, open-label, crossover study in 12 healthy male subjects, the bioavailability of an 8-mg ondansetron tablet administered 5 min after a standard meal was slightly but significantly greater than in fasted subjects, as indicated by comparative mean AUC values [201.4 ng.h/mL (fed) vs 172.5 ng.h/mL (fasted)]. Coadministration of a magnesium hydroxide/aluminum hydroxide antacid did not affect the bioavailability of the ondansetron tablet.


Echocardiographic characteristics of premature infants with patient ductus arteriosus.
As part of a multicenter collaborative study, M-mode echocardiograms were obtained shortly after birth on 3,559 premature infants with birth weight less than or equal to 1,750 g. Of these infants, 1,496 did not develop a cardiac murmur or other signs of a "hemodynamically significant" patent ductus arteriosus (PDA). Echocardiographic parameters from this "normal" group were compared with results obtained from 415 infants in whom PDA was diagnosed on the basis of clinical findings alone, irrespective of the echocardiogram (PDA group). The best discrimination between the two groups, when considering a single parameter, was provided by a left atrial to aortic root ratio (LA/AO) of 1.40, a left ventricular to aortic root ratio (LV/AO) of 2.10, or a left ventricular systolic time interval ratio (LPEP/LVET) of 0.27. Multivariate analysis demonstrated that better separation between the two groups occurred when the left atrial to aortic root ratio and the left ventricular systolic time interval ratio were considered jointly. Because of a large degree of overlap of all echocardiographic variables between the normal group and the group with PDA, the echocardiogram alone was not a good indicator of PDA. However, when used in conjunction with a priori estimates of the probability of PDA (based, for example, on birth weight and degree of respiratory disease), use of echocardiographic data was found to improve the detection of hemodynamically significant patent ductus arteriosus in premature infants.


Legacies of invertebrate exclusion and tree secondary metabolites control fungal communities in dead wood.
During decomposition of organic matter, microbial communities may follow different successional trajectories depending on the initial environment and colonizers. The timing and order of the species arrival (assembly history) can lead to divergent communities through priority effects. We explored how assembly history and resource quality affected fungal communities and decay rate of decomposing wood, 1.5 and 4.5 years after tree felling. Additionally, we investigated the effect of invertebrate exclusion during the first two summers. We measured initial resource quality of bark and wood of aspen (Populus tremula) logs and surveyed the fungal communities by DNA metabarcoding at different times during succession. We found that gradients in fungal community composition were related to resource quality and we discuss how this may reflect different fungal life history strategies. As with previous studies, the initial amount of bark tannins was negatively correlated with wood decomposition rate over 4.5 years. The initial fungal community explained variation in community composition after 1.5, but not 4.5, years of succession. Although the assembly history of initial colonizers may cause alternative trajectories in successional communities, our results indicate that the communities may converge with the arrival of secondary colonizers. We also identified a strong legacy of invertebrate exclusion on fungal communities, even after 4.5 years of succession, thereby adding crucial knowledge on the importance of invertebrates in affecting fungal community development. By measuring and manipulating aspects of assembly history and resource quality that have rarely been studied, we expand our understanding of the complexity of fungal community dynamics.


Strategies for the prevention of psychiatric disorder in primary care in south London.
To compare the potential impact of high risk and population based approaches to the prevention of psychiatric disorder, using a representative sample of general practice attenders as the target population. This was a prospective cohort study. A health centre in south London. Three hundred and seven consecutive attenders aged 16-65, recruited at randomly selected general practice surgeries. A linear association was found between the number of different types of socioeconomic adversity reported at recruitment (T1) and the prevalence of psychiatric disorder one year later (T2). The population attributable fraction (PAF) for socioeconomic adversity at T1 was 37.4%. In theory, social interventions for high risk individuals at T1 would reduce the prevalence of psychiatric disorder at T2 by 9% at most, compared with a reduction of 18% if just one item of socioeconomic adversity were eliminated among those with any socioeconomic risk factors. Social interventions targeted at individuals at highest risk of the most common mental disorders are likely to be extremely limited in their capacity to reduce the prevalence of these conditions. A population based risk reduction strategy, modified according to individual risk, represents a potentially feasible and effective alternative.


Quality of life trajectories after diagnosis of gynecologic cancer: a theoretically based approach.
The course of quality of life after diagnosis of gynecologic cancer is not well understood. We aimed to identify subgroups of gynecologic cancer patients with distinct trajectories of quality of life outcomes in the 18-month period after diagnosis. We also aimed to determine whether these subgroups could be distinguished by predictors derived from Social-Cognitive Processing Theory. Gynecologic cancer patients randomized to usual care as part of a psychological intervention trial (NCT01951807) reported on depressed mood, quality of life, and physical impairment soon after diagnosis and at five additional assessments ending 18 months after baseline. Clinical, demographic, and psychosocial predictors were assessed at baseline, and additional clinical factors were assessed between 6 and 18 months after baseline. A two-group growth mixture model provided the best and most interpretable fit to the data for all three outcomes. One class revealed subclinical and improving scores for mood, quality of life, and physical function across 18 months. A second class represented approximately 12 % of patients with persisting depression, diminished quality of life, and greater physical disability. Membership of this high-risk subgroup was associated with holding back concerns, more intrusive thoughts, and use of pain medications at the baseline assessment (ps < .05). Trajectories of quality of life outcomes were identified in the 18-month period after diagnosis of gynecologic cancer. Potentially modifiable psychosocial risk factors were identified that can have implications for preventing quality of life disruptions and treating impaired quality of life in future research.


Two hyperplastic esophagogastric polyps in a child with neurofibromatosis type 1 (NF-1).
Hyperplastic esophagogastric polyps usually occur in the distal esophagus or gastroesophageal junction and have been associated with damage to the esophageal mucosa. Histologically these polyps show hyperplastic gastric foveolar and/or squamous epithelium with inflamed stroma. Reports of esophagogastric polyps in the pediatric population are rare. Most of these reports only describe chronic inflammation within the lamina propria of the polyp, with only rare reports specifying the presence of epithelial hyperplasia. There have been 2 previous cases of hyperplastic esophagogastric polyps occurring in the context of neurofibromatosis type 1 (NF-1) in a single article. Here we report a 3rd case of hyperplastic esophagogastric polyps occurring in an 11-year-old male with NF-1. This case is unique in that there were 2 polyps in the same patient and in that the polyps showed hyperplastic gastric peptic glands in addition to foveolar-type and focal squamous epithelium. The case is discussed and literature reviewed.


Genetic differences between the wild and hatchery-produced populations of Korean short barbeled grunter (Hapalogenys nitens) determined with microsatellite markers.
Short barbeled grunter, Hapalogenys nitens, is an economically important fishery resource. In Korea, this fish is in the early stage of domestication, and it has been regarded as the candidate marine fish species for prospective aquaculture diversification. This study presents a preliminary investigation of the future viability of sustainable fry production from short barbeled grunter. We used 12 polymorphic nuclear microsatellite DNA loci to analyze the possible genetic variability between the wild and hatchery-produced populations of short barbeled grunter from Korea and identified 91 alleles. Compared to the wild population, significant genetic changes including reduced genetic diversity (average allele number: 7.42 vs 3.75; average expected heterozygosity: 0.713 vs 0.598, Wilcoxon signed-rank test; P < 0.05) and differentiation [overall fixation index (FST) = 0.088, P < 0.01] occurred in the hatchery-produced population, as indicated by the observation of allele richness, unique allele, heterozygosity, FST, and results of molecular analysis of variance. These findings indicate that genetic drift may have promoted the differentiation between these 2 populations, which may have negative effects on sustainable fry production. Therefore, genetic variations of the wild and hatchery-produced populations should be monitored and subjected to control inbreeding through a commercial breeding program. The information presented by this paper would provide a useful genetic basis for future sustainable culturing planning and management of H. nitens.


Contribution of Underlying Connective Tissue Cells to Taste Buds in Mouse Tongue and Soft Palate.
Taste buds, the sensory organs for taste, have been described as arising solely from the surrounding epithelium, which is in distinction from other sensory receptors that are known to originate from neural precursors, i.e., neural ectoderm that includes neural crest (NC). Our previous study suggested a potential contribution of NC derived cells to early immature fungiform taste buds in late embryonic (E18.5) and young postnatal (P1-10) mice. In the present study we demonstrated the contribution of the underlying connective tissue (CT) to mature taste buds in mouse tongue and soft palate. Three independent mouse models were used for fate mapping of NC and NC derived connective tissue cells: (1) P0-Cre/R26-tdTomato (RFP) to label NC, NC derived Schwann cells and derivatives; (2) Dermo1-Cre/RFP to label mesenchymal cells and derivatives; and (3) Vimentin-CreER/mGFP to label Vimentin-expressing CT cells and derivatives upon tamoxifen treatment. Both P0-Cre/RFP and Dermo1-Cre/RFP labeled cells were abundant in mature taste buds in lingual taste papillae and soft palate, but not in the surrounding epithelial cells. Concurrently, labeled cells were extensively distributed in the underlying CT. RFP signals were seen in the majority of taste buds and all three types (I, II, III) of differentiated taste bud cells, with the neuronal-like type III cells labeled at a greater proportion. Further, Vimentin-CreER labeled cells were found in the taste buds of 3-month-old mice whereas Vimentin immunoreactivity was only seen in the CT. Taken together, our data demonstrate a previously unrecognized origin of taste bud cells from the underlying CT, a conceptually new finding in our knowledge of taste bud cell derivation, i.e., from both the surrounding epithelium and the underlying CT that is primarily derived from NC.


Event-Based Near-Eye Gaze Tracking Beyond 10,000 Hz.
The cameras in modern gaze-tracking systems suffer from fundamental bandwidth and power limitations, constraining data acquisition speed to 300 Hz realistically. This obstructs the use of mobile eye trackers to perform, e.g., low latency predictive rendering, or to study quick and subtle eye motions like microsaccades using head-mounted devices in the wild. Here, we propose a hybrid frame-event-based near-eye gaze tracking system offering update rates beyond 10,000 Hz with an accuracy that matches that of high-end desktop-mounted commercial trackers when evaluated in the same conditions. Our system, previewed in Figure 1, builds on emerging event cameras that simultaneously acquire regularly sampled frames and adaptively sampled events. We develop an online 2D pupil fitting method that updates a parametric model every one or few events. Moreover, we propose a polynomial regressor for estimating the point of gaze from the parametric pupil model in real time. Using the first event-based gaze dataset, we demonstrate that our system achieves accuracies of 0.45°-1.75° for fields of view from 45° to 98°. With this technology, we hope to enable a new generation of ultra-low-latency gaze-contingent rendering and display techniques for virtual and augmented reality.


Quality indicators of fresh frozen plasma and platelet utilization.
To determine the normative rates of expiration and wastage for units of fresh frozen plasma (FFP) and platelets (PLTs) in hospital communities throughout the United States, and to examine hospital blood bank practices associated with more desirable (lower) rates. In 3 separate studies, participants in the College of American Pathologists Q-Probes laboratory quality improvement program collected data retrospectively on the numbers of units of FFP and PLTs that expired (outdated) prior to being used and that were wasted due to mishandling. Participants also completed questionnaires describing their hospitals' and blood banks' laboratory and transfusion practices. One thousand six hundred thirty-nine public and private institutions, more than 80% of which were known to be located in the United States. Quality indicators of FFP and PLT utilization: the rates of expiration and wastage of units of FFP and PLTs. Participants submitted data on 8 981 796 units of FFP and PLTs. In all 3 studies, aggregate combined FFP and PLT expiration rates ranged from 5.8% to 6.4% and aggregate combined FFP and PLT wastage rates ranged from 2.0% to 2.5%. Among the top-performing 10% of participants (90th percentile and above), FFP and PLT expiration rates were 0.6% or lower and FFP and PLT wastage rates were 0.5% or lower. Among the bottom-performing 10% of participants (10th percentile and below), expiration rates were 13.8% or higher and wastage rates were 6.8% or higher. We were unable to associate selected hospital characteristics or blood bank practices with lower rates of FFP and PLT utilization. The rates of FFP and PLT expiration and wastage vary greatly among hospitals in the United States. Hospital blood bank personnel are capable of achieving FFP and PLT expiration and wastage rates below 1%.


A study evaluating the safety and efficacy of the VelaSmooth system in the treatment of cellulite.
Most cellulite treatments are limited in their effectiveness. A combination of radiofrequency energy, infrared light and mechanical manipulation of the skin and fat merits further examination. Subjects were treated with a device combining these energies to evaluate its safety and efficacy. Sixteen subjects with cellulite were treated twice weekly for 6 weeks with the VelaSmooth system. One thigh was treated while the other served as a control. Treatment efficacy was measured through circumferential measurements of both thighs and by having the investigator and an independent evaluator grade visual improvement during follow-up visits. Five patients provided blood specimens for assessment of lipid and hormone levels and liver function. Two subjects provided three biopsies each in order to monitor the level of estrogen and progesterone receptors. The overall thigh circumference decreased in 71.87% of the treated legs. The mean decrease was 0.44 cm of the lower thigh and 0.53 cm of the upper thigh. There was significant visual improvement in cellulite and skin texture. At the final follow-up visit, 50% of subjects had greater than 25% improvement (good be very good). This study showed positive results. Future studies employing higher energy levels and additional treatments will likely augment the results of the present study.


3-(Phenylamino)alanine, a novel aniline-derived amino acid associated with the eosinophilia-myalgia syndrome: a link to the toxic oil syndrome?
The eosinophilia-myalgia syndrome (EMS) is an inflammatory disease that occurred in epidemic proportions in the United States during 1989. Cases of EMS were also reported in Europe and elsewhere. Clinically, EMS resembles the Spanish toxic oil syndrome. EMS has been associated with ingestion of manufactured L-tryptophan and, more specifically, with lots of tryptophan that contained the trace contaminant 1,1'-ethylidenebis(tryptophan) (EBT). Another trace contaminant ("peak UV-5") has been reported, but the strength of its association with EMS has not been demonstrated. Herein we report independently that peak UV-5 is 3-(phenylamino)alanine (PAA). Patients with EMS ingested significantly greater amounts of both PAA and EBT than did control tryptophan users. PAA is chemically similar to 3-phenylamino-1,2-propanediol, an aniline derivative isolated from samples of oil that were consumed by persons in whom the toxic oil syndrome developed. The discovery of an aniline-derived contaminant in tryptophan raises the possibility that EMS and toxic oil syndrome may have a common etiologic trigger.


Anthropogenic noise affects behavior across sensory modalities.
Many species are currently experiencing anthropogenically driven environmental changes. Among these changes, increasing noise levels are specifically a problem for species using acoustic signals (i.e., species relying on signals that use the same sensory modality as anthropogenic noise). Yet many species use other sensory modalities, such as visual and olfactory signals, to communicate. However, we have only little understanding of whether changes in the acoustic environment affect species that use sensory modalities other than acoustic signals. We studied the impact of anthropogenic noise on the common cuttlefish Sepia officinalis, which uses highly complex visual signals. We showed that cuttlefish adjusted their visual displays by changing their color more frequently during a playback of anthropogenic noise, compared with before and after the playback. Our results provide experimental evidence that anthropogenic noise has a marked effect on the behavior of species that are not reliant on acoustic communication. Thus, interference in one sensory channel, in this case the acoustic one, affects signaling in other sensory channels. By considering sensory channels in isolation, we risk overlooking the broader implications of environmental changes for the behavior of animals.


Cocaine and sudden "natural" death.
The cardiovascular effects of cocaine may culminate in clinical episodes of angina pectoris, myocardial infarction, arrhythmias, and intracranial hemorrhage. To clarify whether or not cocaine causes fatalities by these mechanisms, we studied 24 cases of sudden, apparently natural deaths as a result of coronary arteriosclerosis (15 cases), hypertensive cardiovascular disease (4 cases), and intracranial hemorrhage (5 cases) associated with cocaine use. In 11 cases, cocaine was found in the blood (average concentration: 0.57 mg/L, range: 0.05 to 1.45 mg/L), whereas in the remainder, cocaine or its major metabolite was found in the urine or other tissues. In the majority of decedents, autopsy disclosed the existence of severe natural disease which could have been exacerbated by the administration of stimulant drugs, including cocaine. These data, and a review of the current medical literature, indicate that cocaine may precipitate the sudden death of an individual with undiagnosed cardiovascular disease. A contributory role of cocaine should be considered in any apparently natural death occurring in a population where cocaine abuse is prevalent.


Single rod-shaped cell fluctuations from stochastic surface and volume growth rates.
Growing rod-shaped bacterial cells need to modulate the production rates of different surface and bulk components. Population data show that the balance between these rates is central for cell physiology and affects cell shape, but we still know little about these processes in single cells. We study a minimal stochastic model where single cells grow by two fluctuating volume-specific surface and volume growth rates, solving for the steady-state distributions and the correlation functions of the main geometric features. Our predictions allow us to address the detectability of different scenarios for the intrinsic coupling between the allocation of resources to surface and bulk growth.


Substrates for Paraoxonase.
Paraoxonase (PON) is a family of calcium-dependent hydrolases, which is related to many diseases. Elucidation of PON physiological roles, active center and all applications in medical fields are dependent on its substrates. The reports about PON substrates scattered in a long span of period are collected to afford clue for drug design, diagnosis of PON status and other academic purposes. PON substrates from 133 references are classified and compared. Structurally, PON substrates are generally classified as organic phosphorous esters, lactones and arylesters. Some phosphoramidates, organophosphorous obidoximes, aryl carboxylic acid amides and special fatty alcohol esters as PON substrates are also included. The electron nature, steric hindrance and hydrophilicity of substrate substituents affecting the PON catalytic ability, binding ability and specificities are discussed. Drugs, prodrugs and naturally endogenous molecules in life processes activated or inactivate by PON are reviewed. Interestingly, some organophosphate and lactone substrates are preferably hydrolyzed by one of the PON1R192Q allozymes, and such a substrate is generally essential for differentiating the three PON1192R phenotypes by using a dual-substrate method. Intricately, some chiral substrates are hydrolyzed by PON stereoselectively. As more substrates are synthesized and characterized, more facts about PON structure and catalytic properties (including PON active center and catalytic mechanism) will be revealed, and therefore the use of PON as a drug target or as an accurate disease marker will be achieved.


Clinical Informatics Approaches to Facilitate Cancer Data Sharing.
Despite growing enthusiasm surrounding the utility of clinical informatics to improve cancer outcomes, data availability remains a persistent bottleneck to progress. Difficulty combining data with protected health information often limits our ability to aggregate larger more representative datasets for analysis. With the rise of machine learning techniques that require increasing amounts of clinical data, these barriers have magnified. Here, we review recent efforts within clinical informatics to address issues related to safely sharing cancer data. We carried out a narrative review of clinical informatics studies related to sharing protected health data within cancer studies published from 2018-2022, with a focus on domains such as decentralized analytics, homomorphic encryption, and common data models. Clinical informatics studies that investigated cancer data sharing were identified. A particular focus of the search yielded studies on decentralized analytics, homomorphic encryption, and common data models. Decentralized analytics has been prototyped across genomic, imaging, and clinical data with the most advances in diagnostic image analysis. Homomorphic encryption was most often employed on genomic data and less on imaging and clinical data. Common data models primarily involve clinical data from the electronic health record. Although all methods have robust research, there are limited studies showing wide scale implementation. Decentralized analytics, homomorphic encryption, and common data models represent promising solutions to improve cancer data sharing. Promising results thus far have been limited to smaller settings. Future studies should be focused on evaluating the scalability and efficacy of these methods across clinical settings of varying resources and expertise.


Acupuncture for the treatment of hiccups following stroke: a systematic review and meta-analysis.
To assess the effectiveness and safety of acupuncture for hiccups following stroke. Medline, Embase, CENTRAL, CINAHL, and four Chinese medical databases were searched from their inception to 1 June 2015. The dataset included randomised controlled trials (RCTs) with no language restrictions that compared acupuncture as an adjunct to medical treatment (effectiveness) or acupuncture versus medical treatment (comparative effectiveness) in stroke patients with hiccups. The Cochrane risk of bias tool was used to assess the methodological quality of the trials. Out of 436 potentially relevant studies, five met the inclusion criteria. When acupuncture was compared with other interventions (as sole or adjunctive treatment), meta-analysis revealed a significant difference in favour of cessation of hiccups within a specified time period (CHWST) following intervention when used as an adjunct (risk ratio (RR) 1.59, 95% CI 1.16 to 2.19, I2=0%), but not when used alone (RR 1.40, 95% CI 0.79 to 2.47, I2=65%, ie, high heterogeneity). No safety information was reported in these studies. Our systematic review and meta-analysis suggests that acupuncture may be an effective treatment for patients suffering from hiccups following stroke when used as an adjunct to medical treatment. However, due to the limited number of RCTs and poor methodology quality, we cannot reach a definitive conclusion, hence further large, rigorously designed trials are needed.


Biological Activity of Humulus Lupulus (L.) Essential Oil and Its Main Components Against Sitophilus granarius (L.).
Besides its use in the brewing industry, hop cones appear as a powerful source of biologically active compounds, already checked for their putative anticancer, antimicrobial, and other bioactivities. Conversely, hop use in pest control remains to date under-investigated. Therefore, the biological activity of hop essential oil (EO) and its main constituents was investigated here against Sitophilus granarius. Adult contact toxicity was found 24 h after treatment with hop EO (LD50/LD90 13.30/40.23 µg/adult), and its three most abundant components, α-humulene, β-myrcene, and β-caryophyllene (LD50/LD90 41.87/73.51, 75.91/126.05, and 138.51/241.27 µg/adult, respectively); negligible variations at 48 h, except for α-humulene (LD50/LD90 26.83/49.49 µg/adult), were found. The fumigant toxicity of the EO and terpenes was also checked: in the absence of wheat grains, β-myrcene showed the highest inhalation toxicity (LC50/LC90 72.78/116.92 mg/L air), whereas α-humulene, β-caryophyllene, and the EO induced similar values (LC50/LC90 about 130/200 mg/L air); with the exception for EO, the wheat presence increased (30-50%) LC50/LC90 values. Moreover, EO and terpenes were perceived by insect antennae and elicited repellent activity. Only β-caryophyllene showed an anticholinesterase effect, this suggesting that different mechanisms of action should be responsible for hop EO toxicity. Therefore, hop EO appears suitable for developing control means against this pest.


TOM1 family conservation within the plant kingdom for tobacco mosaic virus accumulation.
The susceptibility factor TOBAMOVIRUS MULTIPLICATION 1 (TOM1) is required for efficient multiplication of tobacco mosaic virus (TMV). Although some phylogenetic and functional analyses of the TOM1 family members have been conducted, a comprehensive analysis of the TOM1 homologues based on phylogeny from the most ancient to the youngest representatives within the plant kingdom, analysis of support for tobamovirus accumulation and interaction with other host and viral proteins has not been reported. In this study, using Nicotiana benthamiana and TMV as a model system, we functionally characterized the TOM1 homologues from N. benthamiana and other plant species from different plant lineages. We modified a multiplex genome editing tool and generated a sextuple mutant in which TMV multiplication was dramatically inhibited. We showed that TOM1 homologues from N. benthamiana exhibited variable capacities to support TMV multiplication. Evolutionary analysis revealed that the TOM1 family is restricted to the plant kingdom and probably originated in the Chlorophyta division, suggesting an ancient origin of the TOM1 family. We found that the TOM1 family acquired the ability to promote TMV multiplication after the divergence of moss and spikemoss. Moreover, the capacity of TOM1 orthologues from different plant species to promote TMV multiplication and the interactions between TOM1 and TOM2A and between TOM1 and TMV-encoded replication proteins are highly conserved, suggesting a conserved nature of the TOM2A-TOM1-TMV Hel module in promoting TMV multiplication. Our study not only revealed a conserved nature of a gene module to promote tobamovirus multiplication, but also provides a valuable strategy for TMV-resistant crop development.


Transactivation of the human p53 tumor suppressor gene by c-Myc/Max contributes to elevated mutant p53 expression in some tumors.
Elevated levels of mutant forms of the p53 tumor suppressor are a hallmark of many transformed cells. Multiple mechanisms such as increased stability of the protein and increased transcription of the gene can account for elevated p53 expression. Recent findings indicate that c-Myc/Max heterodimers can bind to an essential CA(C/T)GTG-containing site in the p53 promoter and elevate its expression. We have addressed the possibility that elevated mutant p53 expression is due to deregulated c-Myc expression. Here we demonstrate that the human p53 promoter is transactivated by high c-Myc expression and repressed by high Max expression. In examining the relative levels of c-Myc and p53 in human Burkitt's lymphomas and other B-lymphoid lines, we found that there is a correlation between the levels of c-Myc protein and p53 mRNA expression. In particular, cells that express very low levels of c-Myc protein also express low levels of p53 mRNA, while cells that express high levels of c-Myc tend to express high levels of p53 mRNA. To determine whether the p53 gene can be a target for c-Myc in vivo, we assayed the effects of antisense c-myc RNA on the levels of endogenous p53 mRNA. The results indicate that the presence of antisense c-myc RNA leads to a reduction in the levels of c-Myc protein, p53 mRNA, and expression from the p53 promoter. Taken together, our findings support a direct role for c-Myc in elevating expression of the mutant p53 gene in some tumors.


Are rural family physicians comfortable performing cesarean sections?
Provision of obstetric care in the United States requires the capacity to perform cesarean sections. It is unknown who actually performs these procedures in rural hospitals and whether nonobstetricians feel comfortable performing cesarean sections. We conducted a telephone survey of the 41 rural hospitals in Washington State, asking about the obstetric services offered and the composition and obstetrical practices of physician staff. A supplementary questionnaire was sent to the 112 family physicians providing obstetric services in the subset of hospitals with 50 or fewer beds, asking whether they performed cesarean sections. Eighty-six responded, for a response rate of 75%. Thirty-one (75%) of the rural hospitals provide obstetric services; of the 31 hospitals, 19 (61%) had no obstetricians on staff. In these hospitals the majority of physicians on staff both practice obstetrics and perform cesarean sections. Family physicians performed the majority of cesarean sections in all but the eight largest rural hospitals; even in these large hospitals (mean annual deliveries, 785), family physicians performed 28% of the cesarean sections. Most family physicians who performed cesarean sections felt very comfortable performing these operations. There was a strong association between the number of cesarean sections performed in formal residency training settings and the family physician's comfort level. Cesarean sections remain an important service in those rural hospitals providing obstetric services. Most Washington State rural hospitals depend on family physicians for this operative intervention. Physicians' comfort in doing cesarean sections appears to be closely related to prior formal training during residency. This relationship suggests that training programs preparing future rural physicians need to ensure adequate training in this area for their residents.


CRISPR/Cas9-mediated knock-in of an optimized TetO repeat for live cell imaging of endogenous loci.
Nuclear organization has an important role in determining genome function; however, it is not clear how spatiotemporal organization of the genome relates to functionality. To elucidate this relationship, a method for tracking any locus of interest is desirable. Recently clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) or transcription activator-like effectors were adapted for imaging endogenous loci; however, they are mostly limited to visualization of repetitive regions. Here, we report an efficient and scalable method named SHACKTeR (Short Homology and CRISPR/Cas9-mediated Knock-in of a TetO Repeat) for live cell imaging of specific chromosomal regions without the need for a pre-existing repetitive sequence. SHACKTeR requires only two modifications to the genome: CRISPR/Cas9-mediated knock-in of an optimized TetO repeat and its visualization by TetR-EGFP expression. Our simplified knock-in protocol, utilizing short homology arms integrated by polymerase chain reaction, was successful at labeling 10 different loci in HCT116 cells. We also showed the feasibility of knock-in into lamina-associated, heterochromatin regions, demonstrating that these regions prefer non-homologous end joining for knock-in. Using SHACKTeR, we were able to observe DNA replication at a specific locus by long-term live cell imaging. We anticipate the general applicability and scalability of our method will enhance causative analyses between gene function and compartmentalization in a high-throughput manner.


Adverse events of herbal food supplements for body weight reduction: systematic review.
Herbal weight-loss supplements are marketed with claims of effectiveness. Our earlier systematic review identified data from double-blind, randomized controlled trials for a number of herbal supplements. The aim of this systematic review was to assess all clinical evidence of adverse events of herbal food supplements for body weight reduction for which effectiveness data from rigorous clinical trials exist. We assessed Ephedra sinica, Garcinia cambogia, Paullinia cupana, guar gum, Plantago psyllium, Ilex paraguariensis and Pausinystalia yohimbe. Literature searches were conducted on Medline, Embase, Amed and The Cochrane Library. Data were also requested from the spontaneous reporting scheme of the World Health Organization. We hand-searched relevant medical journals and our own files. There were no restrictions regarding the language of publication. The results show that adverse events including hepatic injury and death have been reported with the use of some herbal food supplements. For herbal ephedra and ephedrine-containing food supplements an increased risk of psychiatric, autonomic or gastrointestinal adverse events and heart palpitations has been reported. In conclusion, adverse events are reported for a number of herbal food supplements, which are used for reducing body weight. Although the quality of the data does not justify definitive attribution of causality in most cases, the reported risks are sufficient to shift the risk-benefit balance against the use of most of the reviewed herbal weight-loss supplements. Exceptions are Garcinia cambogia and yerba mate, which merit further investigation.


The economics of fuel management: wildfire, invasive plants, and the dynamics of sagebrush rangelands in the western United States.
In this article we develop a simulation model to evaluate the economic efficiency of fuel treatments and apply it to two sagebrush ecosystems in the Great Basin of the western United States: the Wyoming Sagebrush Steppe and Mountain Big Sagebrush ecosystems. These ecosystems face the two most prominent concerns in sagebrush ecosystems relative to wildfire: annual grass invasion and native conifer expansion. Our model simulates long-run wildfire suppression costs with and without fuel treatments explicitly incorporating ecological dynamics, stochastic wildfire, uncertain fuel treatment success, and ecological thresholds. Our results indicate that, on the basis of wildfire suppression costs savings, fuel treatment is economically efficient only when the two ecosystems are in relatively good ecological health. We also investigate how shorter wildfire-return intervals, improved treatment success rates, and uncertainty about the location of thresholds between ecological states influence the economic efficiency of fuel treatments.


Clinical significance of human immunodeficiency virus type 1 replication fitness.
The relative fitness of a variant, according to population genetics theory, is that variant's relative contribution to successive generations. Most drug-resistant human immunodeficiency virus type 1 (HIV-1) variants have reduced replication fitness, but at least some of these deficits can be compensated for by the accumulation of second-site mutations. HIV-1 replication fitness also appears to influence the likelihood of a drug-resistant mutant emerging during treatment failure and is postulated to influence clinical outcomes. A variety of assays are available to measure HIV-1 replication fitness in cell culture; however, there is no agreement regarding which assays best correlate with clinical outcomes. A major limitation is that there is no high-throughput assay that incorporates an internal reference strain as a control and utilizes intact virus isolates. Some retrospective studies have demonstrated statistically significant correlations between HIV-1 replication fitness and clinical outcomes in some patient populations. However, different studies disagree as to which clinical outcomes are most closely associated with fitness. This may be in part due to assay design, sample size limitations, and differences in patient populations. In addition, the strength of the correlations between fitness and clinical outcomes is modest, suggesting that, at present, it would be difficult to utilize these assays for clinical management.


Cryptic non-canonical splice site activation is part of the mechanism that abolishes multimer organization in the c.2269_2270del von Willebrand factor.
We report a new pathogenic mechanism in von Willebrand disease involving the use of a non-canonical splicing site. The proband, carrying the homozygous c.2269_2270del mutation previously classified as a type 3 mutation, showed severely reduced plasma and platelet von Willebrand factor antigen levels and functions, and no factor VIII binding capacity. A particular von Willebrand factor multimer pattern emerged in plasma, characterized by the presence of only two oligomers: the dimer and an unusually large band, with no intermediate components. There were von Willebrand factor multimers in platelets, but each band ran more slowly than the normal counterpart. No anti-von Willebrand factor antibodies were detectable. The proband was classified as having severe type 1 von Willebrand disease. Seeking the relationship between phenotype and genotype, we found the c.2269_2270del mutation associated with three different RNA: r.2269_2270del (RNAI), giving a truncated von Willebrand factor protein; r.[2269_2270del;2282_2288del] (RNAII), resulting from activation of a cryptic "AG" splicing site; and r.[2269_2270del;2281_2282insAG] (RNAIII), where the wild-type "AG" acceptor of exon 18 was retained due to the non-canonical 2279-2280 "CG" acceptor splicing site being used. The aberrant RNAII and RNAIII caused the alteration of the furin cleavage and binding sites, respectively, both resulting in a von Willebrand factor protein characterized by the persistence of von Willebrand factor propeptide, as confirmed by western blot analysis of the recombinant mutated von Willebrand factor molecules produced in vitro Taken together, these findings explain the residual von Willebrand factor synthesis, slower-running multimers, and absent factor VIII binding capacity. The apparently pure gene null mutation c.2269_2270del profoundly alters von Willebrand factor gene splicing, inducing a complex RNA expression pattern.