Immunization of suckling pigs against enteric enterotoxigenic Escherichia coli infection by vaccinating dams with purified pili.
Pregnant swine (gilts) were vaccinated parenterally with a suspension of purified pili from the porcine enterotoxigenic Escherichia coli strain 987 (09:K103::NM). Gilts injected with placebo served as controls. Suckling pigs born to gilts in both groups were challenged intragastrically with virulent strain 987. The percentage of deaths, incidence and duration of diarrhea, numbers of E. coli in the ilea, and E. coli attachment to the villous epithelia were significantly less in suckling pigs of vaccinated gilts than in those of controls. These results are consistent with the hypothesis that pili of some enterotoxigenic E. coli facilitate adhesion to intestinal epithelia. Vaccination of dams with pili appears to be a means of immunizing against diarrheal disease caused by enterotoxigenic E. coli in suckling neonates. This work confirms the role of somatic pili as colonization and virulence factors and provides another example of safe and effective purified pilus vaccines.


Diet and coronary heart disease.
There is a moderately good correlation between dietary saturated fatty acids and coronary heart disease (CHD) when populations in different parts of the world are compared but not within the same cultural community or for individuals. Total energy, essential fatty acids (EFA), dietary fibre, alcohol and salt also contribute to the relationship of diet to CHD. Saturated fatty acids exert their pathogenic role mostly through altering the homoeostasis of lipoprotein metabolism, leading to an increase in cholesterol-rich low-density lipoproteins, and influencing adversely the balance between the accumulation in and clearance of cholesterol esters from the arterial wall. Polyunsaturated fatty acids (PUFA) alter lipoprotein metabolism directly by decreasing synthesis and increasing catabolism and excretion and indirectly by being substitutes for saturated fatty acids, which are therefore consumed in smaller quantities. PUFA have an important additional role, because of their EFA content. A deficiency of the EFA, linoleic and arachidonic acids, relative to the saturated fatty acid intake, can be correlated with CHD mortality. The pathogenic pathways of a relative EFA deficiency leading to CHD are as likely to be related to intravascular coagulation and myocardial metabolism as to lipoprotein metabolism. EFA requirements may not be met in communities having a high intake of saturated fatty acids if there is also a dietary deficiency of antioxidants particularly vitamin E. Two large primary prevention trials of diets enriched with PUFA showed, under institutional circumstances, that it is possible to reduce serum cholesterol by 10-15 per cent. There was in each a reduction in the total incidence of cardiovascular diseases, and the greatest effect was on the incidence of non-fatal myocardial infarction. In both trials there was an increase in non-cardiovascular mortality. The significance of this finding is evaluated in conjunction with a similar finding derived from the only long-term primary prevention trial using a drug. The possibility that gradual depletion of membrane cholesterol over many years might have an adverse effect on the function of ageing cells cannot be dismissed. In communities where there is a high incidence of CHD, the aim should be to reduce plasma cholesterol concentrations to the region of 210 mg/dl. The evidence that it is necessary, practicable or even desirable to reduce plasma cholesterol to lower levels in order to reduce CHD incidence further is not impressive. To achieve this aim by dietary measures there should be a reduction of energy from fats to a level of 35 per cent or below and reduction of the contributions from saturated fats to about 10 per cent. In addition, there is a sound basis for recommending reduction of total energy intake to that actually needed, an increase in dietary cereal fibre and a reduction in alcohol.


Poststroke dementia : clinical features and risk factors.
The goal of the present study was to examine a series of putative risk factors of poststroke dementia (PSD), especially those factors usually associated with cerebrovascular disease and degenerative dementia, in a series of 251 consecutive unselected stroke patients. A standard protocol was prospectively applied at admission and 3 months after stroke; this protocol included clinical, functional, and cognitive assessments, hemogram and serum biochemistry, ECG and CT exams, apolipoprotein E and angiotensin-converting enzyme genotype, and neuropsychological examination. After a neuropsychological examination and an interview with a relative, the following diagnostic criteria were used: the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV for dementia after stroke, DSM-III-R for previous dementia and dementia stage, and Association Internationale pour la Recherche et l'Enseignement en Neurologie (NINDS-AIREN) for vascular dementia. Seventy-five cases (30%) demonstrated dementia at 3-month follow up; 25 of them (10%) had demonstrated dementia before the stroke. Dementia was unrelated to type (ischemic/hemorrhagic) or location of stroke, vascular factors (hypertension, diabetes, ischemic heart disease, or hypercholesterolemia), apolipoprotein E or angiotensin-converting enzyme genotype, and serum homocysteine. Age (odds ratio [OR] 1.1, 95% CI 1.03 to 1.2), previous nephropathy (OR 6.1, 95% CI 1.5 to 24.3), atrial fibrillation (OR 4.4, 95% CI 1. 4 to 13.9), low Canadian Neurological Scale score at discharge (OR 0. 5, 95% CI 0.4 to 0.6), and previous mental decline assessed by the shortened Spanish version of the Informant Questionnaire on Cognitive Decline in the Elderly (SS-IQCODE; OR 1.2, 95% CI 1.1 to 1. 4) were the correlates of dementia in logistic regression analyses. The same risks factors were found when cases with previous dementia and with hemorrhagic stroke were excluded. Dementia is frequent after ischemic or hemorrhagic stroke. Age, nephropathy, atrial fibrillation, previous mental decline, and stroke severity independently contribute to the risk.


Cochlear Implantation in a Patient with Granulomatosis with Polyangiitis.
Granulomatosis with polyangiitis (GPA) otologic manifestations include conductive and sensorineural hearing loss (HL). Vasculitis is assumed to be the primary cause of otologic manifestations. Deaf patients and patients with HL who do not benefit from hearing aids can benefit from cochlear implants (CI). There are currently no specific guidelines for treatment of patients with GPA suited for CI. To assess whether patients who are deaf due to GPA are good candidates for CI and if prior surgical or medical treatment of the inflammation are needed. A case report is presented. A 71-year-old female patient with GPA and bilateral profound HL underwent CI. Prior to CI, preparation consisted of audiological evaluations by an otolaryngologist and a rheumatologist, followed by a course of prednisone and methotrexate for middle ear and nasal inflammations. CI was performed with no complications. The speech reception threshold and the monosyllabic word discrimination score after surgery were 25 dBHL and 75%, respectively. Inflammation due to GPA can be controlled medically with immunosuppressive medications without subtotal petrosectomy, as in chronic suppurative otitis media. Satisfactory audiological results can be expected.


Detection of human papillomavirus-16 in fine-needle aspirates to determine tumor origin in patients with metastatic squamous cell carcinoma of the head and neck.
Patients with head and neck squamous cell carcinoma (HNSCC) often clinically present with metastases to regional lymph nodes. Fine-needle aspiration of neck masses is routinely used to establish the presence of metastatic carcinoma and in turn to initiate a subsequent workup to determine the site of tumor origin. Human papillomavirus (HPV) 16 is an important etiologic agent for HNSCCs that arise from the oropharynx but less so for tumors from non-oropharyngeal sites. HPV16 detection thus provides a strategy for localizing an important subset of HNSCCs, but this approach has not been applied to fine-needle aspiration specimens. We did in situ hybridization for HPV16 on 77 consecutive aspirated neck masses diagnosed as metastatic squamous cell carcinoma. P16 immunohistochemistry was also done because p16 overexpression may serve as a surrogate marker of HPV-associated HNSCC. HPV16 was detected in 13 of the 77 (17%) aspirates. By site of origin, HPV16 was detected in 10 of 19 metastases from the oropharynx but in none of 46 metastases from other sites (53% versus 0%; P < 0.0001). HPV16 was not detected in 2 branchial cleft cysts misdiagnosed as metastatic squamous cell carcinoma, but it was detected in 3 of 10 metastases from occult primary tumors. P16 expression was associated with the presence of HPV16: 12 of 13 HPV16-positive metastases exhibited p16 expression, whereas only 4 of 62 HPV16-negative metastases were p16 positive (92% versus 6%; P < 0.0001). P16 expression also correlated with site of tumor origin: 13 of 19 oropharyngeal metastases were p16 positive, whereas only 1 of 46 non-oropharyngeal metastases was p16 positive (68% versus 2%; P < 0.0001). HPV16 status can be determined in tumor cells aspirated from the necks of patients with metastatic HNSCC. Its presence is a reliable indicator of origin from the oropharynx.


Assessment and control of the bioavailability of nickel in soils.
Nickel, a potentially toxic metal, is present in all soils with an average concentration of 20 to 30 mg/kg, sometimes exceeding 10,000 mg/kg (e.g., ultramafic soils). The ecotoxicological risk of Ni in soils to organisms is controlled by its availability. It is therefore essential to identify an efficient and reliable method for the evaluation of this risk. This paper presents a complete study of the effect of Ni origin, localization, and soil properties on its availability as assessed with the isotopic exchange kinetics (IEK) method and compares plant response to isotopically exchangeable properties of Ni in soils. We performed IEK on 100 soil samples representing a worldwide range of Ni fate, and concentrations showed that pH was the main influencing parameter and that labile Ni (i.e., isotopically exchangeable Ni, Et) could be reasonably well assessed by a single diethylene triamine pentaacetic acid extraction. The identification of the soil mineral phases that bear Ni (bearing phases) in 16 Ni-rich samples selected among the 100 soils showed a strong effect of the mineralogy of the bearing phases on Ni availability (IEK). Plants with different Ni accumulation strategies all took up Ni from the same labile pool of Ni in four contrasting soils, and the amount taken up by hyperaccumulator plants could be anticipated with the IEK parameters, thus confirming the usefulness of isotopic dilution methods for risk assessment.


Collagenase Clostridium Histolyticum in the Treatment of Urologic Disease: Current and Future Impact.
Peyronie's disease (PD) is a connective tissue disorder resulting in the abnormal accumulation of type I to III collagen, fibrin, and disorganized elastic fibers in the tunica albuginea of the penis. Many medical and non-pharmacologic modalities have been used in the treatment of PD; however, these approaches have proved largely ineffective, with surgery being the only definitive treatment. Intralesional injection of collagenase Clostridium histolyticum (CCH) has recently become the gold standard for minimally invasive treatment of PD, and studies have suggested the role of CCH could expand to the treatment of other urologic conditions such as urethral stricture disease. To provide an update on available data on the use of CCH in the treatment of PD and other urologic conditions. Comprehensive review of recent clinical trials and in vivo studies that examined the safety and efficacy of CCH in urologic disease. Assessing the efficacy of CCH in the management of PD as determined by improvement in the severity of penile fibrosis, curvature deformity, and pain. Several well-designed clinical trials have demonstrated the efficacy and tolerability of CCH in the treatment of PD. CCH has demonstrated significant decreases in penile curvature and plaque consistency and improvements in patient satisfaction. Treatment durability and long-term adverse effects are still being assessed; however, outcomes of PD management with CCH continue to replicate the results obtained during the IMPRESS clinical trials. Preliminary studies support the premise that CCH can modify disease progression in patients with acute-phase PD. Furthermore, one in vivo study showed that CCH also could be applied to urethral stricture disease without serious adverse complications. CCH continues to be the mainstay for non-surgical management of stable-phase PD. However, its role in the treatment of acute-phase PD, PD with ventral plaques, and urethral stricture disease could expand in the coming years. Gabrielson AT, Spitz JT, Hellstrom WJG. Collagenase Clostridium Histolyticum in the Treatment of Urologic Disease: Current and Future Impact. Sex Med Rev 2018;6:143-156.


Hepatocyte-stimulating factor, beta 2 interferon, and interleukin-1 enhance expression of the rat alpha 1-acid glycoprotein gene via a distal upstream regulatory region.
The rat alpha 1-acid glycoprotein (AGP) gene is transcriptionally regulated by dexamethasone, interleukin 1 (IL-1), hepatocyte-stimulating factor, and beta 2 interferon. The steroid and peptide hormones stimulate expression of the AGP gene synergistically as well as independently. The regulatory sequence responsible for dexamethasone-stimulated expression has been localized previously to a region that is 120 to 64 base pairs (bp) upstream of the transcription start site (H. Baumann and L. E. Maquat, Mol. Cell. Biol. 6:2551-2561, 1986). To identify the regulatory sequence that is responsive to the peptide hormones, different lengths of the AGP gene 5'-flanking DNA were linked to the chloramphenicol acetyltransferase gene and then assayed for hormone-inducible chloramphenicol acetyltransferase gene expression in transiently transfected HepG2 cells. We demonstrate that an enhancer region that is responsive to IL-1, hepatocyte-stimulating factor, and beta 2 interferon lies within a 142-bp sequence located 5,300 to 5,150 bp upstream of the transcription start site. This distal regulatory region can confer hormone inducibility to a heterologous promoter; exert its affect in either orientation; and function, to a lesser degree, in nonhepatic but IL-1-responsive cells.


Covalent Linkage of BODIPY-Photosensitizers to Anderson-Type Polyoxometalates Using CLICK Chemistry.
The covalent attachment of molecular photosensitizers (PS) to polyoxometalates (POMs) opens new pathways to PS-POM dyads for light-driven charge-transfer and charge-storage. Here, we report a synthetic route for the covalent linkage of BODIPY-dyes to Anderson-type polyoxomolybdates by using CLICK chemistry (i. e. copper-catalyzed azide-alkyne cycloaddition, CuAAC). Photophysical properties of the dyad were investigated by combined experimental and theoretical methods and highlight the role of both sub-components for the charge-separation properties. The study demonstrates how CLICK chemistry can be used for the versatile linkage of organic functional units to molecular metal oxide clusters.


Lanthanum, Gallium and their Impact on Oxidative Stress.
The role metals play in living organisms is well established and subject to extensive research. Some of them participate in electron-exchange reactions. Such reactions cause generation of free radicals that can adversely impact biological systems, as a result of oxidative stress. The impact of 'non-biological' metals on oxidative stress is also a worthy pursuit due to the crucial role they play in modern civilization. Lanthanides (Ln) are widely used in modern technology. As a result, human exposure to them is increasing. They have a number of established medical applications and are being extensively researched for their potential antiviral, anticancer and anti-inflammatory properties. The present review focuses on lanthanum (La) and its impact on oxidative stress. Another metal, widely used in modern high-tech is gallium (Ga). In some respects, it shows certain similarities to La, therefore it is a subject of the present review as well. Both metals exhibit ionic mimicry which allows them to specifically target malignant cells, initiating apoptosis that makes their simple salts and coordination complexes promising candidates for future anticancer agents.


Identification of core competencies for primary care of allergy patients using a modified Delphi technique.
The majority of allergy patients who seek medical advice are seen in primary care. In-service training of professionals in general practice is needed in order to increase knowledge among primary care clinicians about allergy. Therefore it is important to establish a consensus about what primary care professionals should be able to do, and what the public can expect. We sought to identify core competencies for good practice amongst primary care providers with respect to diagnosis and therapy of allergic diseases and to outline learning objectives for a postgraduate training programme in this field. The study involved three rounds, involving a total of 43 expert panelists. In the first round, a panel was asked to indicate competencies (knowledge, diagnostics, therapy and communication) necessary for primary care providers. The second and third rounds were answered by primary care physicians (26) and nurses (10). A Likert scale 1-4 was applied in the second round and two choices ("agree"/"disagree") in the third round, with a criterion of 75% being adopted. The second round included 80 competencies and the third 50. The third round selected a consensus of 46 competencies defining nine learning outcomes for in-service medical training. The competencies in the field of allergy recommended in this study may serve as a reference of what can be expected from primary care providers.


Postoperative handover: problems, pitfalls, and prevention of error.
To identify the information transfer and communication problems in postoperative handover and to develop and validate a novel protocol for standardizing this communication. Effective clinical handover ensures continuity of patient care. Patient handovers within surgical units are largely informal. A thorough understanding of the problem is vital to develop standardized protocols. A qualitative semistructured interview study was conducted with 18 healthcare professionals to uncover the problems with postoperative handover and to identify solutions, including components of a postoperative handover protocol. Interviews were recorded, transcribed verbatim, and submitted to emergent theme analysis. Multiple blind coders were used to ensure triangulation and reliability of the coding process. A Delphi method was used to elicit consensus from a group of 50 surgical professionals so as to validate the handover protocol. Many of the information transfer and communication failures at the postoperative phase are deemed to be due to an incomplete handover. All the interviewed healthcare professionals agreed that postoperative handover should be structured in the form of a standardized protocol so as to prevent omissions of any critical information. Based on this, 28 items were submitted to the Delphi process. Of these, 21 items had a mean importance score greater than 4.0 and were included in the final postoperative handover proforma under the following headings: patient-specific information, surgical information, and anesthetic information. The present study identified that the postoperative handover is informal, unstructured and inconsistent with often incomplete information transfer. Based on end-user input, a handover protocol was successfully developed and validated. Use of this may facilitate standardization of this critical activity and thereby improve the quality of patient care.


Testing genotypic variation of an invasive plant species in response to soil disturbance and herbivory.
Herbivores, competitors, and predators can inhibit biological invasions ("biotic resistance" sensu Elton 1959), while disturbance typically promotes biological invasions. Although biotic resistance and disturbance are often considered separately in the invasion literature, these two forces may be linked. One mechanism by which disturbance may facilitate biological invasions is by decreasing the effectiveness of biotic resistance. The effects of both disturbance and biotic resistance may vary across invading genotypes, and genetic variation in the invasive propagule pool may increase the likelihood that some genotypes can overcome biotic resistance or take greater advantage of disturbance. We conducted an experimental field trial in which we manipulated soil disturbance (thatch removal and loosening soil) and the presence of insect herbivores and examined their effects on the invasion success of 44 Medicago polymorpha genotypes. As expected, insecticide reduced leaf damage and increased Medicago fecundity, suggesting that insect herbivores in this system provide some biotic resistance. Soil disturbance increased Medicago fecundity, but did not alter the effectiveness of biotic resistance by insect herbivores. We found significant genetic variation in Medicago in response to disturbance, but not in response to insect herbivores. These results suggest that the ability of Medicago to invade particular habitats depends on the amount of insect herbivory, the history of disturbance in the habitat, and how the specific genotypes in the invader pool respond to these factors.


Anaphylaxis to L-asparaginase during treatment for acute lymphoblastic leukemia in children--evidence of a complement-mediated mechanism.
L-Asparaginase (l-Asp) is widely used as an effective drug against childhood and adult acute lymphoblastic leukemia (ALL). However, it is immunogenic in humans and may lead to hypersensitivity reactions. The immunological basis of these reactions is not clear. Since the presence of l-Asp specific IgG-antibodies seems to correlate better with clinical reactions than IgE-antibodies and IgG-antibodies are known to be able to fix and activate the complement system, we speculated that the mechanism of anaphylaxis may be complement- rather than IgE-mediated. We analyzed 24 children with ALL (age 2-15 yr) for changes in the complement system during l-Asp infusions. Chemotherapy was administered according to the CoALL 82 protocol which is derived from the CoALL 80 protocol recently published. The formation of specific antibodies of IgM and IgG classes against l-Asp was monitored by a solid phase ELISA. The immunological responsiveness of individual patients varied over a wide range but both types of antibodies were induced. Anaphylactic reactions were observed on eight occasions in eight children. The infusions in the remaining 16 patients were tolerated without clinical reactions. Significant activation of complement was demonstrated in seven of eight reaction occasions and in none of the occasions without reactions. The most important complement activation parameter monitored was the C3 split product C3d measured in EDTA-plasma. We conclude that anaphylaxis to l-Asp in patients with ALL can be explained in most instances on the basis of complement activation induced by the formation of immune complexes of l-Asp and specific antibodies of IgM and IgG classes.


Cross-sectional analysis of specific complementary and alternative medicine (CAM) use by racial/ethnic group and menopausal status: the Study of Women's Health Across the Nation (SWAN).
To examine the relationships of race/ethnicity, menopausal status, health characteristics, and symptoms with use of 21 types of complementary and alternative medicine (CAM) in midlife women. Cross-sectional, multiple logistic regression analyses of 2,118 women completing the sixth annual visit in the Study of Women's Health Across the Nation, a multisite, multiethnic, longitudinal study. More than half of women used some type of CAM. Use of most types of CAM differed significantly by race/ethnicity, except the use of ginkgo biloba and glucosamine. Significantly more African Americans at most sites and Chinese women used ginseng. Use of most types of CAM did not differ significantly by menopausal status or vasomotor symptoms, except the use of soy supplements, which was significantly greater among women who reported vasomotor symptoms. Women reporting somatic symptoms were significantly more likely to use glucosamine. Women reporting psychological symptoms were significantly more likely to use ginkgo biloba and soy supplements. The number of comorbidities, moderate or high socioeconomic status, number of healthy behaviors, symptom sensitivity, age, and dietary genistein intake were significantly positively associated with use of several types of CAM. The use of most types of CAM is not related to menopausal status or symptom reporting but to sociodemographic factors, comorbidities, and health behaviors. Given the large proportion of midlife women who use CAM and the potential for interactions with prescribed medications, healthcare practitioners should inquire about CAM use and be aware of which factors influence the use of different types of CAM.


Model-Averaged [Formula: see text] Regularization using Markov Chain Monte Carlo Model Composition.
Bayesian Model Averaging (BMA) is an effective technique for addressing model uncertainty in variable selection problems. However, current BMA approaches have computational difficulty dealing with data in which there are many more measurements (variables) than samples. This paper presents a method for combining [Formula: see text] regularization and Markov chain Monte Carlo model composition techniques for BMA. By treating the [Formula: see text] regularization path as a model space, we propose a method to resolve the model uncertainty issues arising in model averaging from solution path point selection. We show that this method is computationally and empirically effective for regression and classification in high-dimensional datasets. We apply our technique in simulations, as well as to some applications that arise in genomics.


Complete nucleotide sequence of the human corticotropin-beta-lipotropin precursor gene.
The nucleotide sequence of an 8658-base-pair human genomic DNA segment containing the entire corticotropin-beta-lipotropin precursor gene has been determined, and some sequence features of the gene and its flanking regions have been analysed. The gene is composed of 7665 base pairs including two introns of 3708 and 2886 base pairs. Comparison of the 5'-flanking sequences of the human, bovine and mouse corticotropin-beta-lipotropin precursor genes reveals the presence of a highly conserved region, which contains sequences of 14-15 base pairs homologous with sequences located upstream of the mRNA start site of other glucocorticoid-regulated genes.


Optimizing patient referral and center capacity in the management of chronic hepatitis C: Lessons from the Italian experience.
In 2017 the Italian Drug Agency (Agenzia Italiana del Farmaco, AIFA) revised the criteria for access to therapy for patients with chronic hepatitis C as part of a three-year plan to eradicate HCV. We conducted a Delphi study to determine strategies to identify and treat patients with HCV and to develop through a shared pathway, a model to manage patient referral and optimize prescription center capacity with the overall aim of increasing access to therapy. The process took place in two phases - Phase I (January 2017), before the criteria for treatment of HCV were revised and Phase II (May 2017) when AIFA developed a framework for the eradication of HCV infection in Italy. Two questionnaires were devised with Q1 administered in Phase I and Q2 in Phase II. Q1 was sent to 823 hepatitis specialists working in 235 Italian HCV centers authorized to prescribe direct-acting antiviral drugs (DAAs). Overall, 167 centers (71%) participated with a good geographical representativeness (North 69%, Centre 74%; South and islands 70%). 548 prescribers (68.8%) provided responses to Q1 and 443 (80%) specialists who responded to Q1 completed Q2. Over 70% considered that to meet the new therapy targets local/regional networks need to be consolidated and reinforced with GPs providing the 'missing link' in current regional networks. Adherence to therapy was considered important by 75% of clinicians with reduction in follow-up intervals/length considered important by 65% - to free up staff/resources to manage increasing numbers of new patients. About 80% of respondents stated that medical personnel were principally involved in follow-up with follow-up having a significant impact on center capacity. Enhancing patient referral, the need for an increased role of GPs, increasing center capacity in particular medical personnel in outpatient centers and greater liaison between Hub centers and healthcare professionals currently managing high-risk groups as yet untreated, were factors that need to be streamlined in order to meet treatment targets for eradication of HCV.


SARS-CoV-2 vaccine booster in solid organ transplant recipients previously immunised with inactivated versus mRNA vaccines: A prospective cohort study.
Solid-organ transplant (SOT) recipients have worse COVID-19 outcomes than general population and effective immunisation in these patients is essential but more difficult to reach. We aimed to determine the immunogenicity of an mRNA SARS-CoV-2 vaccine booster in SOT recipients previously immunised with either inactivated or homologous SARS-CoV-2 mRNA vaccine. Prospective cohort study of SOT recipients under medical care at Red de Salud UC-CHRISTUS, Chile, previously vaccinated with either CoronaVac or BNT162b2. All participants received a BNT162b2 vaccine booster. The primary study end point was anti-SARS-CoV-2 total IgG antibodies (TAb) seropositivity at 8-12 weeks (56-84 days) post booster. Secondary end points included neutralising antibodies (NAb) and specific T-cell responses. A total of 140 (50% kidney, 38% liver, 6% heart) SOT recipients (mean age 54 [13.6] years; 64 [46%] women) were included. Of them, 62 had homologous (three doses of BNT162b2) and 78 heterologous vaccine schedules (two doses of CoronaVac followed by BNT162b2 booster). Boosters were received at a median of 21.3 weeks after primary vaccination. The proportion achieving TAb seropositivity (82.3% vs 65.4%, P = 0.035) and NAb positivity (77.4% vs 55.1%, P = 0.007) were higher for the homologous versus the heterologous group. On the other hand, the number of IFN-γ and IL-2 secreting SARS-CoV-2-specific T-cells did not differ significantly between groups. This cohort study shows that homologous mRNA vaccine priming plus boosting in SOT recipients, reaches a significantly higher humoral immune response than inactivated SARS-CoV-2 vaccine priming followed by heterologous mRNA booster. School of Medicine, UC-Chile and ANID.ClinicalTrials.gov ID: NCT05124509.


[Sike activity of low-threshold stretch receptors in the lungs of cats under dynamic conditions].
The disharge frequency at the end of inspiration was by 13--19% higher and during expiration--by 18--20% lower than at the corresponding lung volume under static conditions. The influence of dynamic factor on impulse activity of low-threshold pulmonary stretch receptors was relatively weak ("volume receptors"). Afferent output from pulmonary stretch receptors during inspiration is 8 times as great as at the expiratory phase. During inspiratory efforts after tracheal occlusion the afferent output was 2 times, and during expiratory phase--1.5 times as great as the afferent output during expiration before the occlusion. The dynamic lowering of discharge frequency in fibers o pulmonary stretch receptors aid to the shortening of expiratory phase.


[3-year results of the combined treatment of stage I and II lymphogranulomatosis patients].
The authors present the results of the combined treatment (radiotherapy combined with 6 cycles of polychemotherapy using either the COPP or CVPP scheme) of 120 patients according to 4 programs differing in the volume of irradiation and intervals, between the cycles of polychemotherapy. The results of the study were compared to those of radiotherapy (irradiation of unilateral diaphragmatic and splenic lymph nodes) of 277 patients with Hodgkin's disease, Stages I--II. The combined treatment was shown to yield in better rates of a recurrence-free course of the disease and in slightly increased 3-year survival rates. It was shown that with identical drug therapy (6 cycles of polychemotherapy) the results of treatment in the groups of patients with different volumes of irradiation (irradiation of the clinically detectable foci of lesion only or of all the lymph nodes over the diaphragm and spleen) are rather similar. The results obtained indicate the advantages of the combined method of treatment of patients with Hodgkin's disease, Stages I--II. A reduced volume of irradiation seems possible in some cases.


Effects of gingival retraction materials on gingival blood flow.
The effects of 2 chemical retraction agents on gingival blood flow and systemic blood pressure in subjects with healthy gingiva were investigated. Thirty volunteer dental students were selected for the study and randomly divided into 2 groups. Aluminium chloride-impregnated cord (right side) and nonimpregnated cord (left side) were placed in the gingival sulcus of group 1. Epinephrine-impregnated cord (right side) and nonimpregnated cord (left side) were placed in group 2. Blood flow in the retracted marginal gingiva was measured by laser Doppler flowmetry, and the systemic blood pressures of subjects were recorded before and after the retraction procedure. A statistically significant decrease in blood flow was observed in group 2, but there was no significant change in gingival blood flow in group 1. A decrease in diastolic blood pressure of the subjects in group 2 was also observed. However, there was no significant change in blood pressure of the subjects in group 1. Gingival retraction affects gingival blood flow temporarily. Epinephrine-impregnated cords can be used safely in patients who have healthy gingiva, if patient stress and gingival trauma are avoided during cord placement.


The novel insulinotropic mechanism of pimobendan: direct enhancement of the exocytotic process of insulin secretory granules by increased Ca2+ sensitivity in beta-cells.
Pimobendan is a new class of inotropic drug that augments Ca2+ sensitivity and inhibits phosphodiesterase (PDE) activity in cardiomyocytes. To examine the insulinotropic effect of pimobendan in pancreatic beta-cells, which have an intracellular signaling mechanism similar to that of cardiomyocytes, we measured insulin release from rat isolated islets of Langerhans. Pimobendan augmented glucose-induced insulin release in a dose-dependent manner, but did not increase cAMP content in pancreatic islets, indicating that the PDE inhibitory effects may not be important in beta-cells. This agent increased the intracellular Ca2+ concentration ([Ca2+]i) in the presence of 30 mM K+, 16.7 mM glucose, and 200 microM diazoxide, but failed to enhance the 30 mM K+-evoked [Ca2+]i rise in the presence of 3.3 mM glucose. Insulin release evoked by 30 mM K+ in 3.3 mM glucose was augmented. Then, the direct effects of pimobendan on the Ca2+-sensitive exocytotic apparatus were examined using electrically permeabilized islets in which [Ca2+]i can be manipulated. Pimobendan (50 microM) significantly augmented insulin release at 0.32 microM Ca2+, and a lower threshold for Ca2+-induced insulin release was apparent in pimobendan-treated islets. Moreover, 1 microM KN93 (Ca2+/calmodulin-dependent protein kinase II inhibitor) significantly suppressed this augmentation. Pimobendan, therefore, enhances insulin release by directly sensitizing the intracellular Ca2+-sensitive exocytotic mechanism distal to the [Ca2+]i rise. In addition, Ca2+/calmodulin-dependent protein kinase II activation may at least in part be involved in this Ca2+ sensitization for exocytosis of insulin secretory granules.


Pulmonary and cerebral lipiodol embolism after transcatheter arterial chemoembolization [corrected] in hepatocellular carcinoma.
Pulmonary and cerebral lipiodol embolism after transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma is rare. To our knowledge, only 7 cases have been reported in the literature. We present a case of pulmonary and cerebral lipiodol embolism, and analyzed retrospectively the imaging and clinical data of the patient and conclude the most probable mechanism of pulmonary and cerebral lipiodol embolism, which is different from that of the cases reported previously.


Aging of bone marrow mesenchymal stromal/stem cells: Implications on autologous regenerative medicine.
With their proliferation, differentiation into specific cell types, and secretion properties, mesenchymal stromal/stem cells (MSC) are very interesting tools to be used in regenerative medicine. Bone marrow (BM) was the first MSC source characterized. In the frame of autologous MSC therapy, it is important to detect donor's parameters affecting MSC potency. Age of the donors appears as one parameter that could greatly affect MSC properties. Moreover, in vitro cell expansion is needed to obtain the number of cells necessary for clinical developments. It will lead to in vitro cell aging that could modify cell properties. This review recapitulates several studies evaluating the effect of in vitro and in vivo MSC aging on cell properties.


[Effect of nitroprusside, nitroglycerin, propranolol and mannitol on the size of a myocardial infarct].
Effects of nitroprusside, nitroglycerin, propranolol and mannitol on the size of infarcted and peri-infarction areas were examined in 276 patients with acute left-ventricular anterior myocardial infarction. The study involved an assessment of electrocardiograms from 35 precordial leads, and the measurement of central venous blood pressure, hemodynamic parameters, serum enzymes, acid-base state and, in some patients, the pressure inside the pulmonary artery, right and left cavities of the heart and the aorta, left-ventricular kinetocardiography, etc. All the drugs examined were shown to have a favourable effect on the size of the peri-infarction area and reduce the extent of myocardial infarction. Indications for each of the drugs have been worked out on a differential basis. A detailed analysis of ECG patterns from multiple chest leads under the action of nitroprusside, nitroglycerin, propranolol and mannitol is presented.


Neurosurgical management and postoperative whole-brain radiotherapy for colorectal cancer patients with symptomatic brain metastases.
New systemic treatments for advanced colorectal cancer have conferred a survival advantage, allowing patients to reach a median survival of almost 2 years. Due to this remarkable life extension, the incidence of brain metastases, though still low, is progressively increasing over time. There is little reported data on the optimal strategy to manage brain lesions from colorectal cancer. To explore the role of an aggressive approach to colorectal cancer brain metastases, we retrospectively collected and analyzed data from 30 patients who underwent neurosurgical resection + whole-brain radiotherapy between March 1998 and December 2006. Univariate (logrank) and multivariate (Cox's model) analyses were used to identify prognostic factors. Median age at the time of surgery was 66 years, median ECOG PS was 1, most patients (87%) had concomitant lung and/or liver metastases. Median number of previous chemotherapies was two, with half of the patients being exposed both to oxaliplatin and irinotecan. A median of 27 Gy of radiotherapy were administered to 16 patients after resection. At the time of the analysis, 29 out of 30 patients had died, with a median survival time after brain metastasectomy of 167 days (8-682). Only one patient died within a month from surgery. Median survival was significantly longer in patients who received postsurgical radiotherapy (7.6 vs. 4.7 months, P = 0.014). Neurosurgical management of symptomatic brain metastases from colorectal cancer is feasible, relatively safe, and offers a chance of prolonged survival. Patients who received radiotherapy after resection experienced a better outcome.


Adrenergic and possible nonadrenergic sources of adenosine 5'-triphosphate release from nerve varicosities isolated from ileal myenteric plexus.
Pretreatment of guinea pigs with 6-hydroxydopamine in vivo for 24 h (250 mg/kg i.p.) reduced the norepinephrine and tyrosine hydroxylase contents of varicosities isolated from ileal myenteric plexus by 91 and 89%, respectively, indicating extensive destruction of noradrenergic varicosities. Destruction appeared to be restricted to noradrenergic varicosities because 5-hydroxytryptamine contents were unaffected. In vivo 6-hydroxydopamine treatment reduced the K+- and veratridine-evoked release of ATP from myenteric varicosities by 56 and 63%, respectively, indicating that much, but not all, of the evoked release of ATP probably originated from noradrenergic varicosities. Pretreatment of guinea pigs with 5 mg/kg of reserpine i.p. depleted norepinephrine contents of isolated varicosities by 90% but did not significantly reduce K+- or veratridine-evoked release of ATP, suggesting that the exocytotic release process was unaffected by reserpine. Selective destruction of serotonergic varicosities by treatment of guinea pigs with 50 mg/kg of desmethylimipramine i.p. followed by 40 mg/kg of 5,7-dihydroxytryptamine s.c. failed to diminish K+- or veratridine-evoked release of ATP from myenteric varicosities, indicating that the nonadrenergic release of ATP did not arise from serotonergic varicosities.


Occurrence of primary aromatic amines and nicotine in sediments collected from the United States.
Despite extensive use of primary aromatic amines (AAs) in consumer products, little is known about their occurrence in the environment. In this study, we investigated the occurrence of 14 AAs and nicotine in 75 sediment samples collected from seven estuarine and freshwater ecosystems in the Unites States. Additionally, risk quotients (RQs) were calculated to assess potential risks of these chemicals to aquatic organisms. Of the 14 AAs analyzed, seven of them were found in sediments. The sum concentrations of seven AAs in sediments were in the range of 10.2 to 1810 ng/g, dry wt (mean: 388 ng/g). Aniline was the most abundant compound, accounting for, on average, 53 % of the total concentrations. Nicotine was found in sediments at a concentration range of <LOQ to 1340 ng/g, dry wt (mean: 119 ng/g). Among the seven sampling locations studied, AAs and nicotine concentrations were the highest in sediment from Altavista wastewater lagoon in Virginia (AV, mean: 1700 ng/g) followed in descending order by Chicago Sanitary and Ship Canal (CSSC, mean: 807 ng/g), Indiana Harbor and Ship Canal (IHSC, mean: 698 ng/g) and New Bedford Harbor (NBH, mean: 482 ng/g). Sediments from the upper Mississippi River (MISS, mean: 63.4 ng/g) and Tittabawassee River (TBR, mean: 52.3 ng/g) contained the lowest concentrations. The RQ values for AAs in sediment ranged from 0 to 733 and that for nicotine ranged from 0 to 2060. Among AAs, the highest RQ value was found for 4-chloroaniline. Nicotine exhibited notable RQ values, which suggested risk from this chemical to aquatic organisms. This is the first study to report the occurrence of AAs in sediments and our results suggest the need for further investigations on the sources and ecological impacts of these chemicals in aquatic ecosystems.


Protective effects of epigallocatechin-3-gallate counteracting the chronic hypobaric hypoxia-induced myocardial injury in plain-grown rats at high altitude.
Exposure to hypobaric hypoxia (HH) environment causes stress to the body, especially the oxygen-consuming organs. Chronic HH conditions have adverse effects on the myocardium. Thus, we conducted this experiment and aim to evaluate such adverse effects and explore the therapeutic role of epigallocatechin-3-gallate (EGCG) in rats' heart under chronic HH conditions. For that purpose, we transported rats from plain to a real HH environment at high altitude for establishing the HH model. At high altitude, animals were treated with EGCG while the salidroside was used as the positive control. General physiological data were collected, and routine blood test results were analyzed. Cardiac magnetic resonance (CMR) was examined to assess the structural and functional changes of the heart. Serum levels of cardiac enzymes and pro-inflammatory cytokines were examined. Oxidative markers in the left ventricle (LV) were detected. Additionally, ultrastructural and histopathological changes and apoptosis of the LV were assessed. Furthermore, the antioxidant stress-relevant proteins nuclear factor E2-related factor 2 (Nrf2) and the heme oxygenase-1 (HO-1) were detected. The experiment revealed that EGCG treatment decreased HH-induced elevation of cardiac enzymes and relieved mitochondrial damage of the LV. Notably, EGCG treatment significantly alleviated oxidative stress in the LV and inflammatory response in the blood. Western blot confirmed that EGCG significantly upregulated Nrf2 and HO-1. Therefore, EGCG may be considered a promising natural compound for treating the HH-induced myocardial injuries.


Clustering by well-being in workplace social networks: Homophily and social contagion.
Social interaction among employees is crucial at both an organizational and individual level. Demonstrating the value of recent methodological advances, 2 studies conducted in 2 workplaces and 2 countries sought to answer the following questions: (a) Do coworkers interact more with coworkers who have similar well-being? and, if yes, (b) what are the processes by which such affiliation occurs? Affiliation was assessed via 2 methodologies: a commonly used self-report measure (i.e., mutual nominations by coworkers) complemented by a behavioral measure (i.e., sociometric badges that track physical proximity and social interaction). We found that individuals who share similar levels of well-being (e.g., positive affect, life satisfaction, need satisfaction, and job satisfaction) were more likely to socialize with one another. Furthermore, time-lagged analyses suggested that clustering in need satisfaction arises from mutual attraction (homophily), whereas clustering in job satisfaction and organizational prosocial behavior results from emotional contagion. These results suggest ways in which organizations can physically and socially improve their workplace. (PsycINFO Database Record


Understanding the Multidimensional Effects of Resident Duty Hours Restrictions: A Thematic Analysis of Published Viewpoints in Surgery.
Individuals representing various surgical disciplines have expressed concerns with the impact of resident duty hours (RDH) restrictions on resident education and patient outcomes. This thematic review of published viewpoints aimed to describe the effects of these restrictions in surgery. The authors conducted a qualitative systematic review of non-research-based literature published between 2003 and 2015. Articles were included if they focused on the RDH restrictions in surgery and resident wellness, health promotion, resident safety, resident education and/or training, patient safety, medical errors, and/or heterogeneity regarding training or disciplines. A thematic analysis approach guided data extraction. Contextual data were abstracted from the included articles to aid in framing the identified themes. Of 1,482 identified articles, 214 were included in the review. Most were from authors in the United States (144; 67%) and focused on the 80-hour workweek (164; 77%). The emerging themes were organized into three overarching categories: (1) impact of the RDH restrictions, (2) surgery has its own unique culture, and (3) strategies going forward. Published opinions suggested that RDH restrictions alone are insufficient to achieve the desired outcomes and that careful consideration of the surgical training model is needed to maintain the integrity of educational outcomes. Opinions from the surgical community highlight the complexity of issues surrounding the RDH restrictions and suggest that recent changes are not achieving all the desired outcomes and have resulted in unintended outcomes. From the perceptions of the various stakeholders in surgical education studied, areas for new policies were identified.


Communicating with older people with dementia.
Being able to communicate with older people with dementia requires a high level of competence in assessment of specific and individual communication challenges and needs of the person. One of the most effective means of assessment and skills development is the use of reminiscence interventions, memory books or life-story work. There is considerable evidence that communication skills can be developed and enhanced through education and skills training. This article aims to invite and encourage readers to reflect on their present knowledgeand skills in communicating with older people with dementia.


Expected frequencies of codon use as a function of mutation rates and codon fitnesses.
A method is shown to determine the expected pattern of codon use for any given set of mutation rates between nucleotides and any set of fitnesses for the codons. If it is assumed that mutations to stop codons are lethal then those codons which can mutate in one step to a stop codon tend to be used less frequently. This tendency is however, a very small one and is not likely to be observable within a single gene. Nor is it necessarily a general tendency. For example, the leucine pretermination codons may be used preferentially when mutations to proline are deleterious. It is shown that different mutation rates (eg: transitions occurring more frequently than transversions) may have as large an effect on codon usage as would strong selection for particular codons. For the model presented, an increase in the rate of transitions strongly decreases the expected frequency of UGG and CRR codons. Other codes are moderately affected by such a change in the mutation rates. Many other models can be examined using this method.


Sub-chronic rolipram treatment leads to a persistent improvement in long-term object memory in rats.
In the present study the effects of sub-chronic rolipram treatment in an object recognition task in 3-month-old male rats were investigated. Rats remember which object they have explored in a previous trial (T1) when they are tested 1 h later (T2). However, when tested 24 h later, they do not remember which object was presented to them in the first trial. Drug treatments may improve discrimination performance after 24 h, i.e., improve memory for the familiar object. Rats were sub-chronically treated with 0.5 mg/kg rolipram (p.o.) for five consecutive days and tested with a 24 h delay between T1 and T2. Memory performance in the object recognition task was assessed before, during and after sub-chronic treatment. In addition, we investigated whether the timing of the final dose, i.e., 24, 1, or 6 h before training, had an effect on memory performance. During sub-chronic treatment, i.e., after 2-3 days of rolipram treatment, moderate effects on memory performance were observed. Regardless of when the final administration was given, sub-chronic rolipram treatment improved long-term memory performance. Since plasma and brain rolipram levels were undetectable at 24 h before the test, and acute treatment with rolipram 24 h before training had no effects, the observed memory enhancement cannot be attributed to acute rolipram effects. The long-term memory enhancing effects of rolipram might be explained by long-lasting neuronal changes by the chronic treatment due to recurring activation of the cAMP/PKA/CREB pathway leading to CREB phosphorylation.


Accuracy of self-reported versus measured weight over adolescence and young adulthood: findings from the national longitudinal study of adolescent health, 1996-2008.
Many studies rely on self-reports to capture population trends and trajectories in weight gain over adulthood, but the validity of self-reports is often considered a limitation. The purpose of this work was to examine long-term trajectories of self-reporting bias in a national sample of American youth. With 3 waves of data from the National Longitudinal Study of Adolescent Health (1996-2008), we used growth curve models to examine self-reporting bias in trajectories of weight gain across adolescence and early adulthood (ages 13-32 years). We investigated whether self-reporting bias is constant over time, or whether adolescents become more accurate in reporting their weight as they move into young adulthood, and we examined differences in self-reporting bias by sex, race/ethnicity, and attained education. Adolescent girls underreported their weight by 0.86 kg on average, and this rate of underreporting increased over early adulthood. In contrast, we found no evidence that boys underreported their weight either in adolescence or over the early adult years. For young men, self-reports of weight were unbiased estimates of measured weight among all racial/ethnic and educational subpopulations over adolescence and early adulthood.


Care for young victims of assault in public emergency services in 2011: Sex differences.
This article aims to describe the characteristics of assaults among youth victims of violence treated in Public Emergency Departments, according to sex. This is a descriptive study using data from the Brazilian Violence and Accidents Surveillance System based on a multicenter survey conducted by the Ministry of Health in 71 public emergency departments, located in 24 state capitals and the Federal District in 2011. Male subjects predominated among the victims (75.1%) and also among aggressors (83.1% and 69.7% of cases of violence against male and female victims, respectively). Among female victims, episodes of violence were more frequent at home (43.6%). The perpetrator was a stranger in 49.7% and 26.8% of cases among male and female victims, respectively, while the perpetrator was a partner or ex-partner in 3.9% and 31.5% cases, respectively (p < 0.001). Greater severity of injuries among men was consistent with the higher proportion of deaths in the first 24 hours (2.1%) compared to women (0.2%) (p < 0.001). The violence profile among youth victims treated in Public Emergency Departments was substantially different according to the sex of the victims. The results highlight the need to implement intersectoral policies, in line with the Brazilian Youth Statute.


Are changing semen parameters a universal phenomenon?
The semen characteristics of 100 fertile indigenous blacks were studied. The mean semen volume was 2.6 ml, sperm density 55 million/ml, motility 61% and well-formed sperm 71%. These figures are comparable to those of similar recent studies in Caucasians but differ significantly from earlier studies. Our data seem to support recent observations that there has been a decline in the sperm density of fertile males in the past 3 decades and that the earlier standards of sperm concentration may be too high for the present.


Iron and Iron Oxide Nanoparticles Synthesized Using Green Tea Extract: Improved Ecotoxicological Profile and Ability to Degrade Malachite Green.
In recent years, iron-based nanoparticles (FeNPs) have been successfully used in environmental remediation and water treatment. This study examined ecotoxicity of two FeNPs produced by green tea extract (smGT, GTFe) and their ability to degrade malachite green (MG). Their physicochemical properties were assessed using transmission electron microscopy, X-ray powder diffraction, dynamic light scattering, and transmission Mössbauer spectroscopy. Using a battery of ecotoxicological bioassays, we determined toxicity for nine different organisms, including bacteria, cyanobacterium, algae, plants, and crustaceans. GTFe, amorphous complex of Fe(II, III) ions and polyphenols from green tea extract, proved low capacity to degrade MG and was toxic to all tested organisms. Superparamagnetic iron oxide NPs (smGT) derived from GTFe, showed no toxic effect on most of the tested organisms up to a concentration of 1g/L, except for algae and cyanobacterium and removed 93 % MG at concentration 125 mg Fe/L after 60 minutes. The procedure described in this paper generates new superparamagnetic iron oxide NPs from existing and toxic GTFe, which are nontoxic and has degradative potential for organic compounds. These findings suggest low ecotoxicological risks and suitability of this green-synthesized FeNPs for environmental remediation purposes.


Molecular and clinical correlates in iron overload associated with mutations in ferroportin.
Mutations in ferroportin (Fpn) result in iron overload. We correlate the behavior of three Fpn mutants in vitro with patients' phenotypes. Patients with Fpn mutations A77D or N174I showed macrophage iron loading. In cultured cells, FpnA77D did not reach the cell surface and cells did not export iron. Fpn mutant N174I showed plasma membrane and intracellular localization, and did not transport iron. Fpn mutation G80S was targeted to the cell surface and was transport competent, however patients showed macrophage iron. We suggest that FpnG80S represents a class of Fpn mutants whose behavior in vitro does not explain the patients' phenotype.


Case report. Failure of metronidazole in amebic liver abscess.
A 51-year-old man was treated with open surgical drainage and metronidazole for an amebic liver abscess. During therapy and while the original abscess was resolving, a second, noncontiguous amebic liver abscess developed. This second abscess eventually responded to emetine, chloroquine, and diodohydroxyquin therapy without surgical drainage. This unique case serves to document that new abscess may develop in the course of metronidazole therapy and illustrates the value of serial hepatoscanning in such patients.


Phase 3 Trial of Concizumab in Hemophilia with Inhibitors.
Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).


Principles of British health visiting.
In an international context, it is sometimes helpful to consider how concepts are understood in different countries, and to explore some different roles. Such knowledge rarely transfers directly from one country or place to another, but to hear about developments from elsewhere can spark ideas and thinking that may be helpful for local developments. This paper gives some brief background about how the health visiting profession developed in Great Britain, and then explains the values and principles that underpin its practice today. Some parallels are drawn with the health situation in modern Brazil.


Acetate templating on digital images is more accurate than computer-based templating for total hip arthroplasty.
Templating is an important aspect of preoperative planning for total hip arthroplasty and can help determine the size and positioning of the prosthesis. Historically, templating has been performed using acetate templates over printed radiographs. As a result of the increasing use of digital imaging, surgeons now either obtain additional printed radiographs solely for templating purposes or use specialized digital templating software, both of which carry additional cost. The purposes of this study was to compare acetate templating of digitally calibrated images on an LCD monitor to digital templating in terms of (1) accuracy; (2) reproducibility; and (3) time efficiency. Acetate onlay templating was performed directly over digital radiographs on an LCD monitor and was compared with digital templating. Five separate observers participated in this study templating on 52 total hip arthroplasties. For the acetate templating, the digital images were magnified to the scaled reference on the templates provided by the manufacturer (ratio 1.2:1) before templating using a 25-mm marker as a reference. Both the acetate and digital templating results were then compared with the actual implanted components to determine accuracy. Interobserver and intraobserver variability was determined by an intraclass correlation coefficient. Observers recorded time to complete templating from the time of complete upload of patients' imaging onto the system to completion of templating. Both acetate and digital templates demonstrated moderate accuracy in predicting within one size of the eventual implanted acetabular cup (77% [199 of 260]; 70% [181 of 260], respectively; p = 0.050; 95% confidence interval [CI], 0.058-0.32), whereas acetate templating was better at predicting the femoral stem compared to digital templating (75% [195 of 260]; 60% [155 of 260], respectively; p < 0.001; 95% CI, 0.084-0.32). Acetate templating showed moderate to substantial interobserver agreement (cup intraclass correlation coefficient [ICC] = 0.55; 95% CI, 0.14-0.86; femoral ICC = 0.75; 95% CI, 0.39-0.95) and both methods showed almost perfect intraobserver agreement in reproducibility (acetate cup ICC = 0.82; 95% CI, 0.66-0.97; acetate femoral ICC = 0.86; 95% CI, 0.74-0.97; digital cup ICC = 0.82; 95% CI, 0.68-0.97; digital femoral ICC = 0.88; 95% CI, 0.77-1.0). Acetate templating could be performed more quickly (acetate mean 119 seconds; range, 37-220 seconds versus 154 seconds; range, 73-343 seconds; p < 0.001). Acetate onlay templating on digitally calibrated images can be a reliable substitute for digital templating using specialized software. It is quicker to perform and much less expensive. Hospitals and practices need not purchase expensive software, particularly at lower volume centers. Level III, diagnostic study.


Effectiveness of acupuncture for smoking cessation in a Chinese population.
An observational study was conducted to evaluate the effectiveness of acupuncture for smoking cessation, and determine predictors for successful quitters. Smokers received at least 6 sessions of body acupuncture provided by Chinese medicine practitioners and initiated self-administered auricular acupuncture. We determined self-report 26-week and 52-week quit rates by intention-to-treat analysis and examined predictors for successful quitting by univariate and multivariate analyses. A total of 1002 smokers were recruited; 26-week and 52-week quit rates were 16.8% and 15.8%, respectively. Male sex, older age, lower nicotine dependence level, and number of body acupuncture and counseling sessions received were associated with successful quitting. A multiple logistic regression model showed that sex, nicotine dependence level, and number of body acupuncture sessions received were predictors for successful quitting. Body and auricular acupuncture is effective in smoking cessation and should be considered as an alternative to help smokers in quitting, especially for those whose past attempts using conventional methods were in vain.


Systems modelling of the EGFR-PYK2-c-Met interaction network predicts and prioritizes synergistic drug combinations for triple-negative breast cancer.
Prediction of drug combinations that effectively target cancer cells is a critical challenge for cancer therapy, in particular for triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype with no effective targeted treatment. As signalling pathway networks critically control cancer cell behaviour, analysis of signalling network activity and crosstalk can help predict potent drug combinations and rational stratification of patients, thus bringing therapeutic and prognostic values. We have previously showed that the non-receptor tyrosine kinase PYK2 is a downstream effector of EGFR and c-Met and demonstrated their crosstalk signalling in basal-like TNBC. Here we applied a systems modelling approach and developed a mechanistic model of the integrated EGFR-PYK2-c-Met signalling network to identify and prioritize potent drug combinations for TNBC. Model predictions validated by experimental data revealed that among six potential combinations of drug pairs targeting the central nodes of the network, including EGFR, c-Met, PYK2 and STAT3, co-targeting of EGFR and PYK2 and to a lesser extent of EGFR and c-Met yielded strongest synergistic effect. Importantly, the synergy in co-targeting EGFR and PYK2 was linked to switch-like cell proliferation-associated responses. Moreover, simulations of patient-specific models using public gene expression data of TNBC patients led to predictive stratification of patients into subgroups displaying distinct susceptibility to specific drug combinations. These results suggest that mechanistic systems modelling is a powerful approach for the rational design, prediction and prioritization of potent combination therapies for individual patients, thus providing a concrete step towards personalized treatment for TNBC and other tumour types.


[Proteasomes: their role in cellular processes].
The presented review concerns the structure functional analysis of proteasomes and the participation of ubiquitin proteasome system in the basic cellular processes. 26S proteasomes is a key enzyme of the ubiquitin-dependent pathway of protein degradation in cells. This protein particle is composed of 20S catalytic core and associated regulatory complexes. In addition to several types of peptidase activities, eukaryotic proteasomes also have endoribonuclease, protein-chaperone and DNA-helicase activities. The ubiquitin proteasome system controls the levels of most regulatory proteins in a cell and, thus, is absolutely necessary element for cell life. Proteasomal population in a cell is structurally and functionally heterogeneous. These particles are subjected to multistep regulation, particularly, by set of posttranslation modifications. In this review, we also consider the current knowledge on the involvement of proteasomes in controlling the cell cycle, transcription, apoptosis, differentiation, DNA repair and immune response.


Inherited polyneuropathy in Leonberger dogs: a mixed or intermediate form of Charcot-Marie-Tooth disease?
A spontaneous distal, symmetrical polyneuropathy in related Leonberger dogs with onset between 1 to 9 years of age was characterized clinically, electrophysiologically, histologically, and morphometrically. Exercise intolerance and weakness was associated with a high-steppage pelvic-limb gait, a loss or change in the pitch of the bark, and dyspnea. Neurological examination revealed marked atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexes, and weak or absent movement of the laryngeal and pharyngeal muscles. Electrophysiological evaluation was consistent with denervation and was characterized by loss or marked attenuation of compound muscle action potentials and slowed motor nerve conduction velocity. Muscle biopsy specimens showed neurogenic atrophy. Chronic nerve fiber loss associated with decreased myelinated fiber density and a shift of the axonal size-frequency distribution toward smaller fibers was the predominant finding in peripheral nerve specimens. Pedigree analysis of a large multigenerational family, including nine sibships with at least one affected individual, suggested X-linked inheritance. Mutational and linkage analysis of this family may aid in identification of the chromosomal loci and gene responsible for this inherited axonal neuropathy. Further characterization of this inherited axonal neuropathy may establish the Leonberger dog as a spontaneous animal model of inherited axonal neuropathy and possibly lead to the discovery of a new gene or genes associated with axonal variants.


Risk factors for bullying among children with autism spectrum disorders.
Although children with disabilities have been found to be at an increased risk of bullying, there are limited studies investigating predictors of bullying involvement in children with autism spectrum disorders. The current study presents findings from 1221 parents of children diagnosed with autism spectrum disorder who were selected from a national web-based registry. Parents completed a survey dedicated to the school and bullying experiences of their child, and multivariate logistic regression analyses were conducted to identify child and school risk factors for involvement as victim, bully, or bully-victim. Additional analyses examined the risk of bullying involvement based on the amount of time spent in general education classrooms. Children diagnosed with Asperger's disorder, attending a public school or a school with a general education population, were at the greatest risk of being victimized in the past month. Children with comorbid conditions and a high level of autistic traits were the most likely to be victims, bullies, and bully-victims. Finally, children in full inclusion classrooms were more likely to be victimized than those who spend the majority of their time in special education settings. Future research studies should be invested in finding appropriate supports for children with autism spectrum disorder placed in inclusive settings.


The cost of selective attention in category learning: developmental differences between adults and infants.
Selective attention plays an important role in category learning. However, immaturities of top-down attentional control during infancy coupled with successful category learning suggest that early category learning is achieved without attending selectively. Research presented here examines this possibility by focusing on category learning in infants (6-8months old) and adults. Participants were trained on a novel visual category. Halfway through the experiment, unbeknownst to participants, the to-be-learned category switched to another category, where previously relevant features became irrelevant and previously irrelevant features became relevant. If participants attend selectively to the relevant features of the first category, they should incur a cost of selective attention immediately after the unknown category switch. Results revealed that adults demonstrated a cost, as evidenced by a decrease in accuracy and response time on test trials as well as a decrease in visual attention to newly relevant features. In contrast, infants did not demonstrate a similar cost of selective attention as adults despite evidence of learning both to-be-learned categories. Findings are discussed as supporting multiple systems of category learning and as suggesting that learning mechanisms engaged by adults may be different from those engaged by infants.


Facile Fabrication of Multilayer Stretchable Electronics via a Two-mode Mechanical Cutting Process.
A time- and cost-effective fabrication methodology via a two-mode mechanical cutting process for multilayer stretchable electronics has been developed without using the conventional photolithography-based processes. A commercially available vinyl cutter is used for defining complex patterns on designated material layers by adjusting the applied force and the depth of the cutting blade. Two distinct modes of mechanical cutting can be achieved and employed to establish the basic fabrication procedures for common features in stretchable electronics, such as the metal interconnects, contact pads, and openings by the "tunnel cut" mode, and the flexible overall structure by the "through cut" mode. Three robust and resilient stretchable systems have been demonstrated, including a water-resistant, omnidirectionally stretchable supercapacitor array, a stretchable mesh applicable in sweat extraction and sensing, and a skin-mountable human breathing monitoring patch. Results show excellent electronic performances of these devices made of multilayer functional materials after repetitive large deformations.


Rhodopsin expression level affects rod outer segment morphology and photoresponse kinetics.
The retinal rod outer segment is a sensory cilium that is specialized for the conversion of light into an electrical signal. Within the cilium, up to several thousand membranous disks contain as many as a billion copies of rhodopsin for efficient photon capture. Disks are continually turned over, requiring the daily synthesis of a prodigious amount of rhodopsin. To promote axial diffusion in the aqueous cytoplasm, the disks have one or more incisures. Across vertebrates, the range of disk diameters spans an order of magnitude, and the number and length of the incisures vary considerably, but the mechanisms controlling disk architecture are not well understood. The finding that transgenic mice overexpressing rhodopsin have enlarged disks lacking an incisure prompted us to test whether lowered rhodopsin levels constrain disk assembly. The structure and function of rods from hemizygous rhodopsin knockout (R+/-) mice with decreased rhodopsin expression were analyzed by transmission electron microscopy and single cell recording. R+/- rods were structurally altered in three ways: disk shape changed from circular to elliptical, disk surface area decreased, and the single incisure lengthened to divide the disk into two sections. Photocurrent responses to flashes recovered more rapidly than normal. A spatially resolved model of phototransduction indicated that changes in the packing densities of rhodopsin and other transduction proteins were responsible. The decrease in aqueous outer segment volume and the lengthened incisure had only minor effects on photon response amplitude and kinetics. Rhodopsin availability limits disk assembly and outer segment girth in normal rods. The incisure may buffer the supply of structural proteins needed to form larger disks. Decreased rhodopsin level accelerated photoresponse kinetics by increasing the rates of molecular collisions on the membrane. Faster responses, together with fewer rhodopsins, combine to lower overall sensitivity of R+/- rods to light.


A window-DEA based efficiency evaluation of the public hospital sector in Greece during the 5-year economic crisis.
The main objective of this study was to apply the non-parametric method of Data Envelopment Analysis (DEA) to measure the efficiency of Greek NHS hospitals between 2009-2013. Hospitals were divided into four separate groups with common characteristics which allowed comparisons to be carried out in the context of increased homogeneity. The window-DEA method was chosen since it leads to increased discrimination on the results especially when applied to small samples and it enables year-by-year comparisons of the results. Three inputs -hospital beds, physicians and other health professionals- and three outputs-hospitalized cases, surgeries and outpatient visits- were chosen as production variables in an input-oriented 2-year window DEA model for the assessment of technical and scale efficiency as well as for the identification of returns to scale. The Malmquist productivity index together with its components (i.e. pure technical efficiency change, scale efficiency change and technological scale) were also calculated in order to analyze the sources of productivity change between the first and last year of the study period. In the context of window analysis, the study identified the individual efficiency trends together with "all-windows" best and worst performers and revealed that a high level of technical and scale efficiency was maintained over the entire 5-year period. Similarly, the relevant findings of Malmquist productivity index analysis showed that both scale and pure technical efficiency were improved in 2013 whilst technological change was found to be in favor of the two groups with the largest hospitals.


Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review.
The central nervous system (CNS) can be a sanctuary site for cancer cells, because the blood-brain barrier impedes penetration of most chemotherapeutic agents. The authors hypothesized that, with improved survival from childhood metastatic neuroblastoma (NB), the incidence of CNS (intraparenchymal and leptomeningeal) spread may increase. They undertook this study to assess the frequency of CNS NB, to analyze risk factors and treatment options, and to review the literature. The authors retrospectively analyzed all patients with metastatic NB who were treated on protocols N4, N5, N6, and N7 from 1980 to 1999 at Memorial Sloan-Kettering Cancer Center (MSKCC), during which time there was an increase in the overall survival rate. Two hundred fifty-one patients with Stage 4 NB (Group 251) were studied, of which 127 (Group 127) were newly diagnosed patients who were treated initially at MSKCC. None had CNS NB at the time of diagnosis. Eleven patients developed documented CNS disease; 8 of these 11 recurrences were isolated in the CNS. For Group 127, the overall incidence rate of CNS NB was 6.3%, with an increase in incidence from N4-N5 to N6-N7 of from 1.7% to 11.7%. Seven patients had isolated CNS disease recurrences. Only lumbar punctures (LP) performed near the time of diagnosis in patients with known bone marrow involvement were associated with subsequent development of CNS disease. For the entire group of 251 patients, lumbar puncture at the time of diagnosis and elevated serum lactic dehydrogenase levels were prognostic. Among the larger series reported in the literature, CNS involvement from metastatic lesions was rare at the time of diagnosis and remained an uncommon complication. The incidence of CNS NB may be increasing. Because it is the sole site of disease recurrence in 64% of patients, the CNS may represent a sanctuary site for NB. CNS NB is associated with diagnostic lumbar punctures in patients with known bone marrow disease, raising the possibility that circulating or epidural microscopic tumor cells may seed the craniospinal axis.


Patients at Risk for Aortic Rupture Often Exposed to Fluoroquinolones during Hospitalization.
Several studies have indicated that fluoroquinolone use may be associated with an increased risk of aortic aneurysm or dissection (AAD). Because patients with AAD or Marfan syndrome are at increased risk for aortic rupture, we performed a retrospective cohort study to determine the prevalence of systemic fluoroquinolone exposure and predictors of fluoroquinolone use in these patients. Data were obtained from the advisory board billing and administrative database, which contained information on 22 million adult hospitalizations in the United States for the study period (2009 to 2015). International Classification of Diseases (9/10) and Current Procedural Terminology codes were used to identify patients who had AAD or Marfan syndrome or underwent aortic repair. We identified 136,789 admissions for AAD, which involved 99,818 unique patients, 20% of whom received fluoroquinolone during a hospital admission. Of the 7,045 patients with dissection, 18% were exposed to fluoroquinolone. Of the 27,876 AAD patients who underwent aortic repair, 19% received fluoroquinolone during a hospitalization before the repair. In the AAD patients, having a diagnosis of pneumonia or urinary tract infection increased the likelihood of receiving fluoroquinolone during admission by 46% and 40%, respectively (P < 0.001). Additionally, we identified 2,871 admissions for Marfan syndrome, which involved 1,872 patients, 14% of whom received fluoroquinolone during an admission. In these patients, pneumonia and urinary tract infections also increased the risk of fluoroquinolone exposure. If the deleterious effects of fluoroquinolone on aortic integrity are substantiated, reducing fluoroquinolone use in hospitalized patients with aortic disorders will become an urgent safety issue for antibiotic stewardship programs.


Nucleoside-Modified mRNA-Based Influenza Vaccines Circumvent Problems Associated with H3N2 Vaccine Strain Egg Adaptation.
Most human influenza vaccine antigens are produced in fertilized chicken eggs. Recent H3N2 egg-based vaccine antigens have limited effectiveness, partially due to egg-adaptive substitutions that alter the antigenicity of the hemagglutinin (HA) protein. The nucleoside-modified mRNA encapsulated in lipid nanoparticles (mRNA-LNP) vaccine platform is a promising alternative for egg-based influenza vaccines because mRNA-LNP-derived antigens are not subject to adaptive pressures that arise during the production of antigens in chicken eggs. Here, we compared H3N2-specific antibody responses in mice vaccinated with either 3c.2A H3-encoding mRNA-LNP or a conventional egg-based Fluzone vaccine (which included an egg-adapted 3c.2A antigen) supplemented with an MF59-like adjuvant. We tested mRNA-LNP encoding wild-type and egg-adapted H3 antigens. We found that mRNA-LNP encoding wild-type H3 elicited antibodies that neutralized the wild-type 3c.2A H3N2 virus more effectively than antibodies elicited by mRNA-LNP encoding egg-adapted H3 or the egg-based Fluzone vaccine. mRNA-LNP expressing either wild-type or egg-adapted H3 protected mice against infection with the wild-type 3c2.A H3N2, whereas the egg-based Fluzone vaccine did not. We found that both mRNA-LNP vaccines elicited high levels of group 2 HA stalk-reactive antibodies, which likely contributed to protection in vivo. Our studies indicate that nucleoside-modified mRNA-LNP-based vaccines can circumvent problems associated with egg adaptations with recent 3c2.A H3N2 viruses. IMPORTANCE This study shows that the nucleoside-modified mRNA-LNP vaccine platform is a promising alternative for egg-based influenza vaccines. We show that mRNA-LNP vaccines expressing H3 antigens elicit high levels of antibodies in mice and protect against H3N2 influenza virus infection.


Recommendations for the Prescription of Opioids at Discharge After Abdominopelvic Surgery: A Systematic Review.
The prescription of opioids at discharge after abdominopelvic surgery is variable and often excessive. A lack of guidance for abdominopelvic surgeons may explain the suboptimal nature of current prescribing practices. To systematically review existing recommendations on the prescription of opioids at discharge, the appropriate disposal of opioids, and the prevention of chronic postsurgical opioid use after abdominopelvic surgery. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. From January 2010 to December 2018, a search of MEDLINE, PsycINFO, HealthSTAR, Embase, and the difficult to locate and unpublished (ie, gray) literature was performed using a peer-reviewed strategy with variations of the terms opioid, surgery, and guideline to identify English-language documents that contained recommendations published by professional societies or health care institutions. The quality of clinical practice guidelines was assessed using the Appraisal of Guidelines Research and Evaluation II (AGREE II) tool. A descriptive synthesis of results was performed. Of 5530 citations screened, 41 full-text documents were included in the systematic review. Fifteen clinical practice guidelines were identified. AGREE II domain scores varied substantially. Identified among the 41 included documents were 98 recommended interventions for the prescription of opioids at discharge, 8 interventions for the disposal of opioids, and 8 interventions for the prevention of chronic postsurgical opioid use. Only 13 of 114 interventions (11.4%) were supported by an assessment of strength or level of evidence, and the amount of opioid recommended after specific abdominopelvic surgical procedures varied widely between guidance documents, even for the same procedure. Current guidance for the prescription of opioids at discharge after abdominopelvic surgery is heterogeneous and rarely supported by evidence. More research is needed on this topic to guide the development of future recommendations.


Disparities in access to surgery for glioblastoma multiforme at high-volume Commission on Cancer-accredited hospitals in the United States.
Although it has been shown that surgery for glioblastoma (GBM) at high-volume facilities (HVFs) may be associated with better postoperative outcomes, the use of such hospitals may not be equally distributed. The authors aimed to evaluate racial and socioeconomic differences in access to surgery for GBM at high-volume Commission on Cancer (CoC)-accredited hospitals. The National Cancer Database was queried for patients with GBM that was newly diagnosed between 2004 and 2015. Patients who received no surgical intervention or those who received surgical intervention at a site other than the reporting facility were excluded. Annual surgical case volume was calculated for each hospital, with volume ≥ 90th percentile defined as an HVF. Multivariable logistic regression was performed to identify patient-level predictors for undergoing surgery at an HVF. Furthermore, multiple subgroup analyses were performed to determine the adjusted odds ratio of the likelihood of undergoing surgery at an HVF in 2016 as compared to 2004 for each patient subpopulation (by age, race, sex, educational group, etc.). A total of 51,859 patients were included, with 10.7% (n = 5562) undergoing surgery at an HVF. On multivariable analysis, Hispanic White patients (OR 0.58, 95% CI 0.49-0.69, p < 0.001) were found to have significantly lower odds of undergoing surgery at an HVF (reference = non-Hispanic White). In addition, patients from a rural residential location (OR 0.55, 95% CI 0.41-0.72, p < 0.001; reference = metropolitan); patients with nonprivate insurance status (Medicare [OR 0.78, 95% CI 0.71-0.86, p < 0.001], Medicaid [OR 0.68, 95% CI 0.60-0.78, p < 0001], other government insurance [OR 0.68, 95% CI 0.52-0.86, p = 0.002], or who were uninsured [OR 0.61, 95% CI 0.51-0.72, p < 0.001]); and lower-income patients ($50,354-$63,332 [OR 0.68, 95% CI 0.63-0.74, p < 0.001], $40,227-$50,353 [OR 0.84, 95% CI 0.76-0.92, p < 0.001]; reference = ≥ $63,333) were also found to be significantly associated with a lower likelihood of surgery at an HVF. Subgroup analyses revealed that elderly patients (age ≥ 65 years), both male and female patients and non-Hispanic White patients, and those with private insurance, Medicare, metropolitan residential location, median zip code-level household income in the first and second quartiles, and educational attainment in the first and third quartiles had increased odds of undergoing surgery at an HVF in 2016 compared to 2004 (all p ≤ 0.05). On the other hand, patients with other governmental insurance, patients with a rural residence, and those from a non-White racial category did not show a significant difference in odds of surgery at an HVF over time (all p > 0.05). The present analysis from the National Cancer Database revealed significant disparities in access to surgery at an HVF for GBM within the United States. Furthermore, there was evidence that these racial and socioeconomic disparities may have widened between 2004 and 2016. The findings should assist health policy makers in the development of strategies for improving access to HVFs for racially and socioeconomically disadvantaged populations.


The concentration-dependence of macromolecular parameters.
Theories concerning the concentration-dependence of sedimentation and diffusion coefficients for macro-molecules in dilute solution are compared and discussed, together with their experimental basis. An attempt has been made to clarify an important uncertainty still present in the literature as to whether sedimentation coefficients should be corrected for solvent or solution density. It is pointed out that the two processes yield the same extrapolation limit but different concentration-dependencies, which have, however, been related. A general expression is derived thermodynamically for the concentration-dependence of diffusion that includes the coefficient of the concentration term involved in sedimentation (on the basis of sedimentation coefficients corrected from solution density). For rigid spherical particles the expression is shown to be exactly equivalent to one given by Batchelor [(1976) J. Fluid Mech. 74, 1-29], which was derived on the basis of sedimentation coefficients corrected from solvent density. Finally, we discuss the concentration-dependence of apparent weight-average relative molecular masses ('molecular weights') (from, e.g., sedimentation equilibrium) and note an important omission in some earlier representations.


Increase in ascorbate-glutathione metabolism as local and precocious systemic responses induced by cadmium in durum wheat plants.
Durum wheat plants (Triticum durum cv Creso) were grown in the presence of cadmium (0-40 microM) and analysed after 3 and 7 d for their growth, oxidative stress markers, phytochelatins, and enzymes and metabolites of the ascorbate (ASC)-glutathione (GSH) cycle. Cd exposure produced a dose-dependent inhibition of growth in both roots and leaves. Lipid peroxidation, protein oxidation and the decrease in the ascorbate redox state indicate the presence of oxidative stress in the roots, where H2O2 overproduction and phytochelatin synthesis also occurred. The activity of the ASC-GSH cycle enzymes significantly increased in roots. Consistently, a dose-dependent accumulation of Cd was evident in these organs. On the other hand, no oxidative stress symptoms or phytochelatin synthesis occurred in the leaves; where, at least during the time of our analysis, the levels of Cd remained irrelevant. In spite of this, enzymes of the ASC-GSH cycle significantly increased their activity in the leaves. When ASC biosynthesis was enhanced, by feeding plants with its last precursor, L-galactono-gamma-lactone (GL), Cd uptake was not affected. On the other hand, the oxidative stress induced in the roots by the heavy metal was alleviated. GL treatment also inhibited the Cd-dependent phytochelatin biosynthesis. These results suggest that different strategies can successfully cope with heavy metal toxicity. The changes that occurred in the ASC-GSH cycle enzymes of the leaves also suggest that the whole plant improved its antioxidant defense, even in those parts which had not yet been reached by Cd. This precocious increase in the enzymes of the ASC-GSH cycle further highlight the tight regulation and the relevance of this cycle in the defense against heavy metals.


Planning for agricultural return flow allocation: application of info-gap decision theory and a nonlinear CVaR-based optimization model.
A new methodology is proposed for sizing the required infrastructures for water and waste load allocation in river systems receiving return flow from agricultural networks. A nonlinear optimization model with a constraint based on conditional value at risk (CVaR) is developed to provide water and waste load allocation policies. The CVaR-based constraint limits the probabilistic losses due to existing uncertainties in available surface water. The deep uncertainties of return flow simulation model parameters, which have significant impacts on the simulated quantity and quality of agricultural return flows, are handled by using the info-gap theory. Total dissolved solid (TDS) is selected as water quality indicator and diverting a fraction of return flows to evaporation ponds is considered to control the TDS load of agricultural waste load dischargers. Quantity and TDS load of agricultural return flows over a 1-year cultivation period are simulated by using a calibrated SWAP agro-hydrological model. The results of many runs of SWAP model for different combinations of important uncertain parameters in their ranges of variations provide some response (impact) matrixes which are used in optimization model. The applicability of the proposed methodology is illustrated by applying it to the PayePol region in the Karkheh River catchment, southwest Iran. The selected strategy for water and waste load allocation in the study area is expected to provide total annual benefit of 48.64 million US dollars, while 7.84 million m3 of total return flow should be diverted to evaporation ponds. The results support the effectiveness of the methodology in incorporating existing deep uncertainties associated with agricultural water and waste load allocation problems.


The quest for a tumor suppressor gene phenotype.
Our current definitions of the tumor suppressor gene (TSG) have been guided by the identification of the prototypical gene, RB1, a TSG that is implicated in the development of both the inherited and sporadic forms of retinoblastoma. The hallmark feature of this TSG is loss of function in tumoral cells, which can be restored by reintroduction of a normally functioning protein with concomitant reversion of tumorigenicity. Key to this discovery was that loss of function is often achieved by deletion of a normal copy of the TSG and retention of a mutated allele, which was either inherited or acquired. Suppression of tumorigenicity and the loss-of-function concept of TSGs was also demonstrated in early studies where normal cellular growth was achieved when tumorigenic cells were fused with normal cells. Thus loss of genetic content and restoration of gene function has guided studies aimed at the discovery of novel TSGs. Here we review the successes of TSG discovery using three approaches that are based on the genetic analysis of inherited predisposition to cancer, tumors that display chromosome loss, and tumorigenic cells that display a suppression of tumorigenicity as a result of transfer of normal chromosomes. Based on a review of the literature we conclude that the discovery of TSGs has been highly successful in the genetic analysis of inherited predisposition to cancer with a dominant mode of inheritance. In contrast, the latter two approaches have yielded a paucity of TSGs that exhibit features similar to the prototypical RB1 in that they are rarely inactivated by somatic mutations in tumors displaying LOH, although decreased gene expression is observed. Nevertheless, some of these genes have been shown to suppress tumorigenicity when normal function is restored in tumorigenic cells consistent with the loss-of-function concept. These observations continue to challenge our current definition of TSG.


Reconstruction of Pediatric Scalp Avulsion Injuries After Dog Bites.
Dog bite injuries are common and the head and neck is most frequently involved in pediatric patients. In severe cases, the combination of crushing, tearing, and puncturing can result in scalp avulsion. Currently, microsurgical replantation of the avulsed scalp remains the gold standard but may not always be possible. The authors present their treatment algorithm with 2 patient examples. In Patient 1, the scalp was deemed unsuitable for replantation due to extensive soft tissue injury; in Patient 2, the scalp was not available on presentation. Both patients underwent debridement and early wound coverage followed by multistage secondary revision through serial tissue expansion and excision. At 3-years follow-up, both patients have achieved satisfactory aesthetic outcomes following the initial loss of 70% and 40% of hair-bearing scalp. There were no infective complications or wound dehiscence and the areas of scar alopecia are much improved with preservation of the hairline. Pediatric scalp avulsion injuries resulting from dog bites are uncommon and involve a unique injury mechanism. Coupled with the diminutive size of vessels in this patient population, replantation may be precluded altogether. A delayed and staged approach to reconstruction can restore a hair-bearing scalp for satisfactory outcomes.


Subcutaneous formulation of belimumab in treatment of systemic lupus erythematosus: a critical review with focus on safety and satisfaction.
Belimumab is a novel add-on therapy that has been approved for patients with active and antibody-mediated systemic lupus erythematosus. It is a monoclonal antibody that decreases the activation of B-cells and consequently decreases antibodies' production. Recently, the US Food and Drug Administration approved subcutaneous belimumab for patients who have received training on using it. Subcutaneous belimumab can be administered using either a prefilled syringe or an auto-injector device. Weekly subcutaneous belimumab seems to be as effective as monthly intravenous belimumab with a similar safety margin. In this article, we reviewed the literature on subcutaneous belimumab focusing on safety and patients' experiences and satisfaction. Overall, subcutaneous belimumab appears to be preferred over intravenous belimumab for a number of reasons. However, more studies are still required to prove these findings.