Extrapleural pneumonectomy, photodynamic therapy and intensity modulated radiation therapy for the treatment of malignant pleural mesothelioma.
Intensity modulated radiation therapy (IMRT) has recently been proposed for the treatment of malignant pleural mesothelioma (MPM). Here, we describe our experience with a multimodality approach for the treatment of mesothelioma, incorporating extrapleural pneumonectomy, intraoperative photodynamic therapy and postoperative hemithoracic IMRT. From 2004-2007, we treated 11 MPM patients with hemithoracic IMRT, 7 of whom had undergone porfimer sodium-mediated PDT as an intraoperative adjuvant to surgical debulking. The median radiation dose to the planning treatment volume (PTV) ranged from 45.4-54.5 Gy. For the contralateral lung, V20 ranged from 1.4-28.5%, V5 from 42-100% and MLD from 6.8-16.5 Gy. In our series, 1 patient experienced respiratory failure secondary to radiation pneumonitis that did not require mechanical ventilation. Multimodality therapy combining surgery with increased doses of radiation using IMRT, and newer treatment modalities such as PDT , appears safe. Future prospective analysis will be needed to demonstrate efficacy of this approach in the treatment of malignant mesothelioma. Efforts to reduce lung toxicity and improve dose delivery are needed and provide the promise of improved local control and quality of life in a carefully chosen multidisciplinary approach.


Hepatitis B Vaccination in Advanced Chronic Kidney Disease: A Quality Improvement Project at a Veteran Affairs Chronic Kidney Disease Clinic.
Hepatitis B vaccination is recommended in all patients with end-stage kidney disease (ESKD). However, only 50-60% of these patients achieve protective antibody levels if immunized after starting dialysis. Strategies to overcome this low seroconversion rate include a 6-month vaccination schedule starting earlier [chronic kidney disease (CKD) stage 4 and 5] to ensure immunity when patients progress to ESKD. We conducted a quality improvement program to immunize pre-dialysis patients. Patients who were found to have a negative baseline serology with a negative hepatitis B surface antibody level (HBsAb) were offered vaccination on a 6-month schedule (0, 1 and 6 months) with one of two available vaccines within the VA system (Recombivax™ or Engerix™). HBsAb titers were checked 3-4 months later, and titers ≥ 12 mIU/mL were indicative of immunity at VA. Patients who did not seroconvert were offered a repeat schedule of three more doses. We screened 198 patients (187 males and 11 females) with CKD 4 and 5 [glomerular filtration rate (GFR) < 29 mL/min/1.73 m2]. The median age of this cohort was 72 years (range 38-92 years). During the study period of 5 years (2015-2020), 10 patients were excluded since their GFR had improved to more than 30 mL/min/1.73 m2, 24 others had baseline immunity and 2 refused vaccination. The hepatitis B vaccination series was not started on 106 patients. Of the remaining 56, 12 patients progressed to ESKD and started dialysis before completion of the vaccination schedule, 6 expired and 1 did not come to clinic in 2020 due to the pandemic. Of the 37 patients who completed the vaccination schedule, 16 achieved seroconversion with adequate HBsAb titers, 10 did not develop immunity despite a second hepatitis B vaccination series, while 11 did not get a second series. Given the low seroconversion rate, albeit in a small cohort, vaccination should be considered in patients with earlier stages of CKD. Other options include studies on FDA approved vaccines of shorter duration. We plan to increase awareness among nephrologists, patients and nursing staff about the importance of achieving immunity against hepatitis B.


Minimal requirements for the nuclear localization of p27(Kip1), a cyclin-dependent kinase inhibitor.
p27(Kip1) is a cyclin-dependent kinase inhibitor, and its nuclear localization is a prerequisite for it to function as a cell cycle regulator. In the present study, the minimal requirement for the nuclear localization signal (NLS) of p27(Kip1) was determined by analyzing the localization of various mutants of p27(Kip1) tagged with green fluorescent protein (GFP) in HeLa cells and porcine aortic endothelial cells. Wild-type p27(Kip1) exclusively localized into nucleus, while GFP alone localized in both cytosol and nucleus. A comparison of various truncation mutants revealed residues 153-166 to be the minimal region necessary for nuclear localization. However, a fusion of this region to GFP showed cytoplasmic retention in addition to nuclear localization, thus suggesting that some extension flanking this region is required to achieve a full function of NLS. The site-directed mutation of the full-length p27(Kip1) therefore showed that four basic residues (K153, R154, K165, R166), especially R166, play a critical role in the nuclear localization of p27(Kip1).


Significance of karyopherin-{alpha} 2 (KPNA2) expression in esophageal squamous cell carcinoma.
Karyopherin-alpha 2 (KPNA2) is a member of the importin alpha family and has recently been reported to play an important role in tumorigenesis and tumor progression. The aim of the current study was to elucidate the clinicopathological significance of immunohistochemical expression of KPNA2 in esophageal squamous cell carcinoma (ESCC). KPNA2 expression was investigated by immunohistochemistry in 116 surgically resected ESCC, and the association of KPNA2 expression with clinicopathologic features was also examined. Sixty (51.7%) ESCCs demonstrated positive expression of KPNA2. Positive expression of KPNA2 showed a significant association with poor differentiation (p=0.015), tumor depth (p=0.001), lymphatic invasion (p<0.001), venous invasion (p<0.001), and tumor stage (p=0.008). Positive expression of KPNA2 was also significantly associated with Ki-67 labeling index (p=0.039). Univariate analysis revealed that the prognosis of the ESCC patients whose tumors demonstrated positive expression of KPNA2 was significantly poorer than that of those that did not (p=0.009). Multivariate analysis revealed that only tumor depth and the presence of lymph node metastasis, which are strong prognostic factors in ESCC, were independently associated with poor prognosis in this study. KPNA2 expression is associated with poor differentiation, tumor invasiveness, and tumor proliferation in ESCC.


Coronavirus Disease 2019 With Acute Respiratory Distress Syndrome Mimicking Heart Failure Exacerbation: Time to Rethink.
A 67-year-old man with a prior heart failure presented with fever, cough and dyspnea for 4 days. Physical examination showed bilateral rales on the lung exam, yet no lower extremity edema. The combination of symptoms, elevated inflammatory markers, normal baseline pro-B-type natriuretic peptide, PaO2/FiO2 < 300 and positive swab suggested coronavirus disease 2019 (COVID-19) with acute respiratory distress syndrome (ARDS) rather than heart failure exacerbation. We discuss the challenges in management of ARDS in COVID-19 patients that may initially mimic as acute exacerbation of heart failure.


[Intralaboratory monitoring of the quality of sanitary-and-hygienic studies].
The authors shows their experience in organizing a quality system in order to verify the competence of a laboratory and to ensure the validity of study results in the Sanitary Laboratory of the Branch of the Center of Hygiene and Epidemiology in the City of Moscow in the Central Administrative District of Moscow in accordance with the GOST requirements 17025-2006 "General Requirements for the Competence of Testing and Calibration Laboratories".


Heat resistance of salmonellae in concentrated milk.
The heat resistance of Escherichia coli, Salmonella typhimurium, and Salmonella alachua in milk solutions containing 10, 30, 42, and 51% (w/w) skim milk for total solids was determined. Increased milk-solids level effected a significant increase in the heat resistance of each organism. Although E. coli was more heat-resistant than both strains of Salmonella in 10% milk, the situation was reversed in 42 and 51% milk. Prior growth temperature was found to exert a profound effect on the heat resistance of S. typhimurium. Growth of S. typhimurium in 42% milk solids for 24 hr did not greatly enhance the thermal resistance of the organism when heated in a fresh 42% solids concentrate. Application of a partial vaccum during heating greatly diminished the decimal reduction times of S. typhimurium and E. coli and, in addition, virtually eliminated the protective effect of increased solids level.


SRC and MEK Co-inhibition Synergistically Enhances the Anti-tumor Effect in Both Non-small-cell Lung Cancer (NSCLC) and Erlotinib-Resistant NSCLC.
Non-small-cell lung cancer (NSCLC) is the predominant form of lung cancer, and it is regulated by a complex signal transduction network. Single-agent targeted therapy often results in acquired resistance, which leads to treatment failure. In this study, we demonstrated that a combination of the kinase inhibitors trametinib and bosutinib can synergistically suppress the growth of NSCLC by inhibiting both the mitogen-activated protein kinase (MAPK) and proto-oncogene tyrosine-protein kinase (SRC) pathways. The combination was profiled against a panel of 22 NSCLC cell lines, including one erlotinib-resistant cell line, and this combination was found to show synergistic effects against 16 cell lines. NSCLC cell lines (HCC827, HCC827-erlotinib-resistant, and H1650) were treated with trametinib, bosutinib, or a combination of these drugs. The drug combination inhibited colony formation and induced cell apoptosis. A mechanism study showed that the phosphorylation of multiple kinases in the epidermal growth factor receptor (EGFR) signaling pathway in NSCLC was down-regulated. In addition, the combination significantly attenuated tumor growth of HCC827 xenografts with low toxicity. Our findings provide a theoretical basis for further study of the combination of MAPK and SRC pathway inhibitors in NSCLC, especially in the treatment of erlotinib-resistant NSCLC.


Effects of continuous stretching on cell proliferation and collagen synthesis in human burn scars.
Hypertrophic and contracted scars are common complications of deep and partial thickness burns, and the usual way to prevent them is to stretch the burn are actively as well as passively. However, little has been written about the effects of stretching on burn scar tissue at a cellular and molecular level. The stretching usually results in an increased area of skin, and a central question is whether this is caused by stimulation of cell proliferation or decreased cell density, which could lead to impaired quality of the skin. In the present study a new in vitro model was developed and used to study the effects of stretching on the proliferative activity as well as on the synthesis of collagen in human burn scars. Proliferation was measured quantitatively by thymidine incorporation and spatially by immunohistochemistry. The net proliferation in the burn scar was decreased after one day, and significantly decreased after six days of continuous stretching (p = 0.02). However, immunohistochemistry showed increased proliferation in the basal layer of the epidermis while the proliferative activity in the dermal cells was inhibited. Collagen synthesis was decreased after six days of stretching whereas no effect was shown after one day. These findings indicate that static stretching of a human burn scar results in inhibition of proliferation in dermal cells leading to a low cell density in the dermis which, combined with increased collagen synthesis, could lead to reduced biomechanical strength.


Support supplied by Parkinson's disease specialist nurses to Parkinson's disease patients and their spouses.
The purpose of the study was to identify the role of the Parkinson's disease specialist nurse in providing support both for people with Parkinson's disease (PD) and their spouses. PD is a neurodegenerative disease with symptoms that affect many aspects of daily life. In Sweden, specialised nurses called Parkinson's disease specialist nurses (PD specialist nurses) have been working for over a decade to support PD patients and their families. A qualitative approach was taken using dyad interviews with each PD patient and spouse. The analysis was conducted using conventional qualitative content analysis. The analysis resulted in the identification of one overarching category; competent, professional practice, tailored for the individual. Four categories: professional competence, nursing practice, continuity of contact and emotional support, are distinct but related to each other and show different nuances of the same phenomenon. The work of PD specialist nurses in providing support to PD patients and their relatives should be tailored to individual patients and their families as well as including skilled nursing care to relieve the impact of the disease on daily life.


Adenovirus-mediated expression of antisense urokinase plasminogen activator receptor and antisense cathepsin B inhibits tumor growth, invasion, and angiogenesis in gliomas.
We have shown previously that urokinase plasminogen activator receptor (uPAR) and cathepsin B are overexpressed during glioma progression, particularly at the leading edge of the tumor. In the present study, we simultaneously down-regulated uPAR and cathepsin B in SNB19 glioma cell monolayer or SNB19 spheroids using an adenoviral vector carrying antisense uPAR and antisense cathepsin B and a combination of these genes as determined by Western blot analysis. The Ad-uPAR-Cath B-infected cells revealed a marked reduction in tumor growth and invasiveness as compared with the parental and vector controls. In vitro and in vivo angiogenic assays demonstrated inhibition of capillary-like structure formation and microvessel formation after Ad-uPAR-Cath B infection of SNB19 cells when compared with Ad-cytomegalovirus (CMV)-infected or mock-infected controls. Furthermore, using a near infrared fluorescence probe, in vivo imaging for cathepsin B indicated low/undetectable levels of fluorescence after injection of the Ad-uPAR-Cath B construct into pre-established s.c. tumors as compared with Ad-CMV-treated and untreated tumors. The effect with bicistronic construct (Ad-uPAR-Cath B) was much higher than with single (Ad-uPAR/Ad-Cath B) constructs. These results indicate that the down-regulation of cathepsin B and uPAR plays a significant role in inhibiting tumor growth, invasion, and angiogenesis. Hence, the targeting of these two proteases may be a potential therapy for brain tumors and other cancers.


ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase.
Epidermal growth factor receptor (EGFR) tyrosine kinase is a potential target for anticancer therapy. ZD1839 (Iressa) is a selective inhibitor of EGFR tyrosine kinase. In this study, we investigated the question as to whether the antitumor effect of ZD1839 is partly attributable to antiangiogenic activity and the potential mechanisms involved. Both ZD1839 and SU5416 [a vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor] inhibited the migration of human umbilical vein endothelial cell cocultivated with EGF-stimulated cancer cells. ZD1839 also inhibited EGF-induced migration and the formation of tube-like structures by human microvascular endothelial cells. Moreover, ZD1839 almost completely blocked EGF-induced neovascularization of mice cornea, and SU5416 partially blocked neovascularization. In contrast, ZD1839 did not inhibit VEGF-induced angiogenesis. However, EGF-induced up-regulation of the angiogenic factors, VEGF and IL-8, was almost completely blocked by ZD1839. The antitumor effects of ZD1839 could, therefore, be mediated in part by the inhibition of tumor angiogenesis through direct effects on microvascular endothelial cells that express EGFR and also through reduced production of proangiogenic factors by tumor cells.


Insurability and mitigation of flood losses in private households in Germany.
In Germany, flood insurance is provided by private insurers as a supplement to building or contents insurance. This article presents the results of a survey of insurance companies with regard to eligibility conditions for flood insurance changes after August 2002, when a severe flood caused 1.8 billion euro of insured losses in the Elbe and the Danube catchment areas, and the general role of insurance in flood risk management in Germany. Besides insurance coverage, governmental funding and public donations played an important role in loss compensation after the August 2002 flood. Therefore, this article also analyzes flood loss compensation, risk awareness, and mitigation in insured and uninsured private households. Insured households received loss compensation earlier. They also showed slightly better risk awareness and mitigation strategies. Appropriate incentives should be combined with flood insurance in order to strengthen future private flood loss mitigation. However, there is some evidence that the surveyed insurance companies do little to encourage precautionary measures. To overcome this problem, flood hazards and mitigation strategies should be better communicated to both insurance companies and property owners.


[Celiac disease: evolution in knowledge since its original centennial description up to the present day].
In the recent past, some celiac disease features have been discussed in literature specially related to genetic susceptibility, pathogenesis, clinical presentation and diagnostic criteria. Immunological abnormalities characteristic of celiac disease, such as circulating antibodies and increased numbers of intra-epithelial lymphocytes containing a high percentage of gamma-delta T cells have been demonstrated. Other pictures of clinical presentation besides the classical one deserve attention namely short stature, iron-resistant anaemia, enamel hypoplasia, constipation, neurological manifestation and osteoporosis, among others. Asymptomatic presentation has been recognized since development of serological markers such as anti-gliadin, anti-reticulin and anti-endomysium antibodies. Up to now, small intestinal biopsy is the only decisive diagnostic approach. A Federal law has recently imposed food manufactures to place labels informing the presence of gluten in industrialized foods in Brazil. Lately there has been an increase in celiac disease patients registered in the Brazilian Celiac Association.


Performed Surgical Interventions After the 1999 Marmara Earthquake in Turkey, and Their Importance Regarding Nursing Practices.
Effectively dealing with earthquakes is especially important for the people who live in areas prone to earthquakes such as the country of Turkey. Trauma related to earthquakes has specific relevance to nursing practice. The purpose of this review was to describe the types of surgical interventions after the Marmara earthquake and to evaluate the implications for nursing care. English and Turkish articles about the Marmara earthquake were reviewed between May and July 2013. A total of 7 studies were evaluated. The number of patients admitted to the units, types of injuries, and surgical treatments were recorded, with a total of 2378 patients with earthquake-related injuries. The most commonly traumatized parts of the body were the extremities. Fasciotomy operations were performed on 286 patients and 75 patients underwent extremity amputations. Predetermining surgical problems and interventions may be useful in planning for possible future problems in the case of a disaster.


An assessment of the quality of optical coherence tomography image acquisition.
Optical coherence tomography (OCT) provides excellent image resolution, however OCT optimal acquisition is essential but could be challenging owing to several factors. We sought to assess the quality of OCT pullbacks and identify the causes of suboptimal image acquisition. We evaluated 784 (404 pre-PCI; 380 post-PCI) coronary pullbacks from an anonymized OCT database from our Cardiovascular Imaging Core Laboratory. Imaging of the region-of-interest (ROI-lesion or stented segment plus references) was incomplete in 16.1% pullbacks, caused by pullback starting too proximal (63.7%), inappropriate pullback length (17.1%) and pullback starting too distal (11.4%). The quality of image acquisition was excellent in 36.3% pullbacks; whereas 4% pullbacks were unanalyzable. Pullback quality was most commonly affected by poor blood displacement from inadequate contrast volume (27.4%) or flow (25.6%), followed by artifacts (24.1%). Acquisition mode was 'High-Resolution' (54 mm) in 74.4% and 'Survey' (75 mm) in 25.6% of cases. The 54 mm mode was associated with incomplete ROI imaging (p = 0.020) and inadequate contrast volume (p = 0.035). We observed a substantial frequency of suboptimal image acquisition and identified its causes, most of which can be addressed with minor modifications during the procedure, ultimately improving patient outcomes.


Management of multivessel coronary artery disease.
Optimal management of multivessel disease (MVD) is a complex medical decision with significant prognostic implications. Despite the advent of clinical and angiographic scores to aid with treatment delineation, therapy for MVD must be individualized for each patient and his/her clinical presentation. Particularly among patients with MVD, the selection of coronary revascularization with percutaneous coronary intervention versus coronary artery bypass graft surgery versus guideline-directed medical therapy (GDMT) alone is a prognostically important decision. Several patient factors including clinical presentation, severity of coronary artery disease, presence of left ventricular dysfunction and other comorbidities, and the patient's personal preferences should guide the decision making process. In this review, we discuss the management of MVD with regards to decisions of revascularization versus GDMT alone, mode of revascularization, extent of revascularization (i.e., complete versus incomplete), the strategy of angiography- versus ischemia-guided revascularization, and MVD management in the setting of an acute coronary syndrome.


Community knowledge, health beliefs, practices and experiences related to dengue fever and its association with IgG seropositivity.
Demographic, economic and behavioural factors are central features underpinning the successful management and biological control of dengue. This study aimed to examine these factors and their association with the seroprevalence of this disease. We conducted a cross-sectional telephone survey of households in a 3 km radius of the schools where we had conducted serological tests on the student population in a previous study. Households were surveyed about their socio-demographics, knowledge, practices, and Health Belief Model (HBM) constructs. The results were then associated with the prevalence rate of dengue in the community, as marked by IgG seropositivity of the students who attended school there. A total of 1,400 complete responses were obtained. The community's IgG seropositivity was significantly positively associated with high household monthly income, high-rise residential building type, high surrounding vegetation density, rural locality, high perceived severity and susceptibility, perceived barriers to prevention, knowing that a neighbour has dengue, frequent fogging and a higher level of knowledge about dengue. In the multivariate analyses, three major correlates of the presence of IgG seropositivity in the community: (1) high-rise residential apartment house type or condominium buildings; (2) the main construct of the HBM, perceived severity and susceptibility; and (3) the additional constructs of the HBM, lack of preventive measures from the community level and having a neighbour with dengue as a cue to action. Weak correlations were found between self-practices to prevent dengue and the level of dengue seropositivity in the community, and between HBM constructs and knowledge (r = 0.09). The residential environment factor and the constructs of the HBM are useful and important elements in developing interventions to prevent and control dengue. The study also sheds light on the importance of the need for approaches that ensure the translation of knowledge into practice.


Defined subunit arrangement and rab interactions are required for functionality of the HOPS tethering complex.
Within the endomembrane system of eukaryotic cells, multisubunit tethering complexes together with their corresponding Rab-GTPases coordinate vesicle tethering and fusion. Here, we present evidence that two homologous hexameric tethering complexes, the endosomal CORVET (Class C core vacuole/endosome transport) and the vacuolar HOPS (homotypic vacuole fusion and protein sorting) complex, have similar subunit topologies. Both complexes contain two Rab-binding proteins at one end, and the Sec1/Munc18-like Vps33 at the opposite side, suggesting a model on membrane bridging via Rab-GTP and SNARE binding. In agreement, HOPS activity can be reconstituted using purified subcomplexes containing the Rab and Vps33 module, but requires all six subunits for activity. At the center of HOPS and CORVET, the class C proteins Vps11 and Vps18 connect the two parts, and Vps11 binds both HOPS Vps39 and CORVET Vps3 via the same binding site. As HOPS Vps39 is also found at endosomes, our data thus suggest that these tethering complexes follow defined but distinct assembly pathways, and may undergo transition by simple subunit interchange.


Serum visfatin in Asian women with polycystic ovary syndrome.
To determine serum visfatin levels in Asian polycystic ovary syndrome (PCOS) women and its correlations with various parameters. Case-control study. University hospital. Eighty women were enrolled in this study. Of these, 40 women were PCOS and 40 age-matched subjects with regular menstrual cycles were controls. Seventy-five gram oral glucose tolerance tests were performed in all women. Fasting venous blood samples for serum visfatin, insulin and androgen levels were obtained both from the PCOS and the control women. Serum concentrations of visfatin, fasting insulin (FI), fasting glucose, 2-h post-load glucose (2hPG), homeostasis model assessment insulin resistance, homeostasis model assessment beta cell function, total testosterone, free testosterone, androstenedione and dehydroepiandrosterone sulfate were measured in both groups. Women with PCOS had significantly higher serum visfatin levels than the healthy controls [100.39 +/- 41.90 vs. 45.09 +/- 28.24 mg/ml, p < 0.01]. PCOS women also had significantly higher concentrations of all androgens (p < 0.01). Insulin resistance seemed to be greater in the PCOS than the control groups, but did not reach a statistically significant level. In the PCOS group, serum visfatin levels were positively correlated with 2hPG, and systolic blood pressure and diastolic blood pressure. Serum visfatin levels were negatively associated with FI (r = -0.80, p = 0.03) and positively associated with systolic and diastolic blood pressure (r = 0.77, p = 0.04, r = 0.79, p = 0.03, respectively) in the sub-group of PCOS women with abnormal glucose tolerance (AGT). Asian PCOS women had significantly higher serum visfatin levels than age-matched healthy controls. Their levels were significantly correlated with 2hPG and blood pressure in PCOS women, and with FI and blood pressure in PCOS women with AGT.


Inhibition of host PARP1 contributes to the anti-inflammatory and antitubercular activity of pyrazinamide.
The antibiotic pyrazinamide (PZA) is a cornerstone of tuberculosis (TB) therapy that shortens treatment durations by several months despite being only weakly bactericidal. Intriguingly, PZA is also an anti-inflammatory molecule shown to specifically reduce inflammatory cytokine signaling and lesion activity in TB patients. However, the target and clinical importance of PZA's host-directed activity during TB therapy remain unclear. Here, we identify the host enzyme Poly(ADP-ribose) Polymerase 1 (PARP1), a pro-inflammatory master regulator strongly activated in TB, as a functionally relevant host target of PZA. We show that PZA inhibits PARP1 enzymatic activity in macrophages and in mice where it reverses TB-induced PARP1 activity in lungs to uninfected levels. Utilizing a PZA-resistant mutant, we demonstrate that PZA's immune-modulatory effects are PARP1-dependent but independent of its bactericidal activity. Importantly, PZA's bactericidal efficacy is impaired in PARP1-deficient mice, suggesting that immune modulation may be an integral component of PZA's antitubercular activity. In addition, adjunctive PARP1 inhibition dramatically reduces inflammation and lesion size in mice and may be a means to reduce lung damage and shorten TB treatment duration. Together, these findings provide insight into PZA's mechanism of action and the therapeutic potential of PARP1 inhibition in the treatment of TB.


Rejection of capillary wall background light in an on-column confocal fluorescence detector.
Minimization of the background arising from the capillary wall is of extreme importance in laser induced fluorescence on-column detection for capillary electrophoresis. A sensitive confocal fluorescence detection scheme is described. The intense capillary wall background light was effectively rejected by an adjustable precision slit in a confocal configuration. Rhodamine 640 was used as a standard fluorophore. Detection linearity was demonstrated over four orders of magnitude of concentration and the concentration detection limit was 3.38 x 10(-11) M.


The role of gastric acid in preventing foodborne disease and how bacteria overcome acid conditions.
The secretion of hydrochloric acid by the stomach plays an important role in protecting the body against pathogens ingested with food or water. A gastric fluid pH of 1 to 2 is deleterious to many microbial pathogens; however, the neutralization of gastric acid by antacids or the inhibition of acid secretion by various drugs may increase the risk of food- or waterborne illnesses. Peptic ulcer disease is often treated by decreasing or eliminating gastric acid secretion, and such treatment blocks the protective antibacterial action of gastric fluid. The majority of peptic ulcer disease cases originate from Helicobacter pylori infections. Treatment of H. pylori-induced peptic ulcers with antibiotics reduces the need for drugs that inhibit gastric acid secretion and thereby diminishes the risk of food- and waterborne illness for peptic ulcer disease patients. Many bacterial pathogens, such as Escherichia coli, Salmonella Typhimurium, and H. pylori, can circumvent the acid conditions of the stomach by developing adaptive mechanisms that allow these bacteria to survive in acid environments. As a consequence, these bacteria can survive acidic stomach conditions and pass into the intestinal tract, where they can induce gastroenteritis.


Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy.
To identify the upstream signals of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy (TLE), we evaluated by immunohistochemistry and confocal microscopy brain tissues of 13 TLE patients and 5 control patients regarding expression of chemokines and cell-cycle proteins. The chemokine RANTES (CCR5) and other CC-chemokines and apoptotic markers (caspase-3, -8, -9) were expressed in lateral temporal cortical and hippocampal neurons of TLE patients, but not in neurons of control cases. The chemokine RANTES is usually found in cytoplasmic and extracellular locations. However, in TLE neurons, RANTES was displayed in an unusual location, the neuronal nuclei. In addition, the cell-cycle regulatory transcription factor E2F1 was found in an abnormal location in neuronal cytoplasm. The pro-inflammatory enzyme cyclooxygenase-2 and cytokine interleukin-1β were expressed both in neurons of patients suffering from temporal lobe epilepsy and from cerebral trauma. The vessels showed fibrin leakage, perivascular macrophages and expression of IL-6 on endothelial cells. In conclusion, the cytoplasmic effects of E2F1 and nuclear effects of RANTES might have novel roles in neuronal apoptosis of TLE neurons and indicate a need to develop new medical and/or surgical neuroprotective strategies against apoptotic signaling by these molecules. Both RANTES and E2F1 signaling are upstream from caspase activation, thus the antagonists of RANTES and/or E2F1 blockade might be neuroprotective for patients with medically intractable temporal lobe epilepsy. The results have implications for the development of new medical and surgical therapies based on inhibition of chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy.


The acute effect of position of immobilization on capital femoral epiphyseal blood flow. A quantitative study using the hydrogen washout technique.
Quantitative studies of femoral head blood flow by the hydrogen washout technique with the hips in various positions of immobilization were determined. Immobilization in flexion consistently resulted in the highest rate of femoral head blood flow. A position of relaxed abduction seemed to slightly, but significantly, decrease the rate of blood flow. The position of forced frog-leg abduction and forced internal rotation obliterated or drastically reduced circulation in the femoral head. We think that the ischemia of forced acute immobilization is secondary to compression of the immature cartilaginous femoral head. These experimental data further indicate the importance of the selected position of immobilization in the treatment of congenital dislocated hips as a cause of iatrogenic avascular necrosis.


Antidoping program: an important factor in the promotion and protection of the integrity of sport and athlete's health.
Using performance-enhancing drugs concerns not only elite Olympic and Paralympic Games' athletes but also amateur athletes, who are making increasing use of substances and/or methods. Furthermore, a new frontier reached by the doping is the use of genes. World Anti-Doping Agency expressly prohibited the participation in competitive sports by the athlete in case of taking banned substances to treat disease in the event that the above assumption implies an excessive improvement of performance. This study aims to analyze and show the doping control as an essential part of the antidoping program to promote and protect the integrity of sport and athlete's health. Testing is carried out in accordance with the World Anti-Doping Code (WADC) and several international standards (ISs). The ISs were developed for laboratories, testing, the prohibited list, and for therapeutic use exemptions. It seems that the 2009 version of the WADC obliges all the healthcare professionals not to assist athletes engaged in doping behaviours; they can be removed from working with athletes. Many people do not know doping's dangerous effects on health. It is necessary, therefore, to implement the knowledge on this issue through public and sports institutions information and awareness campaigns. For this reason, local institutions and the National Olympic Committee shall give tools, in particular economic, to carry out the work of education, training, and control.


Practices and attitudes of providers towards continuity of care with patients using prescription contraceptives.
The aim of this study was to explore provider practices and attitudes towards routine follow-up counselling after prescription of contraceptives. An anonymous 16-item survey was pilot-tested and sent to providers of the Internal Medicine, Family Medicine, Pediatrics, and OBGYN departments of Thomas Jefferson University Hospitals (TJUH), an urban academic medical centre in Philadelphia, PA, USA. Frequency and descriptive statistics were used to analyse quantitative data while a framework analysis approach was applied to open-ended questions. Fifty percent of providers said they typically follow up with patients regarding a newly prescribed contraceptive. Only 15.3% said they do for an existing prescription. Eighty-three percent reported that it is important though only 30% believed follow-up guidelines were clear. Ultimately, there is a gap between providers' interest in delivering follow-up care and established direction on how to do so.Impact StatementWhat is already known on the subject? Prescription contraceptive adherence is suboptimal. However, it is known that proactive follow-up has positive effects on prescription contraceptive adherence.What do the results of the study add? Most respondents believe that patients take their prescription contraception as prescribed. In light of this finding, providers are less likely to follow up with an existing prescription contraceptive. Interestingly, most respondents do believe that follow-up is important for patients using prescribed contraception but endorse that guidelines about follow-up are neither established nor clear.What are the implications of these findings for clinical practice and/or further research? Patient adherence to prescription contraceptives can be improved through optimised routine patient follow-up after initial prescription. This must be done in ways that minimise burdens to both patients and providers. Providers could benefit from clear guidelines regarding best practices. Future research is needed to understand how providers can best support patients on their contraceptive journey.


An Indoor Navigation App using Computer Vision and Sign Recognition.
Indoor navigation is a major challenge for people with visual impairments, who often lack access to visual cues such as informational signs, landmarks and structural features that people with normal vision rely on for wayfinding. Building on our recent work on a computer vision-based localization approach that runs in real time on a smartphone, we describe an accessible wayfinding iOS app we have created that provides turn-by-turn directions to a desired destination. The localization approach combines dead reckoning obtained using visual-inertial odometry (VIO) with information about the user's location in the environment from informational sign detections and map constraints. We explain how we estimate the user's distance from Exit signs appearing in the image, describe new improvements in the sign detection and range estimation algorithms, and outline our algorithm for determining appropriate turn-by-turn directions.


A warm heart and a clear head. The contingent effects of weather on mood and cognition.
Prior studies on the association between weather and psychological changes have produced mixed results. In part, this inconsistency may be because weather's psychological effects are moderated by two important factors: the season and time spent outside. In two correlational studies and an experiment manipulating participants' time outdoors (total N = 605), pleasant weather (higher temperature or barometric pressure) was related to higher mood, better memory, and "broadened" cognitive style during the spring as time spent outside increased. The same relationships between mood and weather were not observed during other times of year, and indeed hotter weather was associated with lower mood in the summer. These results are consistent with findings on seasonal affective disorder, and suggest that pleasant weather improves mood and broadens cognition in the spring because people have been deprived of such weather during the winter.


Wound complications after inguinal lymph node dissection for melanoma: is ACS NSQIP adequate?
In the treatment of melanoma, inguinal lymph node dissection (ILND) is the standard of care for palpable or biopsy-proven lymph node metastases. Wound complications occur frequently after ILND. In the current study, the multicenter American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) was utilized to examine the frequency and predictors of wound complications after ILND. Patients with cutaneous melanoma who underwent superficial and superficial with deep ILND from 2005-2010 were selected from the ACS NSQIP database. Standard ACS NSQIP 30-day outcome variables for wound occurrences-superficial surgical site infection (SSI), deep SSI, organ space SSI, and disruption-were defined as wound complications. Of 281 total patients, only 14 % of patients had wound complications, a rate much lower than those reported in previous single institution studies. In a multivariable model, superficial with deep ILND, obesity, and diabetes were significantly associated with wound complications. There was no difference in the rate of reoperation in patients with and without wound complications. ACS NSQIP appears to markedly underreport the actual incidence of wound complications after ILND. This may reflect the program's narrow definition of wound occurrences, which does not include seroma, hematoma, lymph leak, and skin necrosis. Future iterations of the ACS NSQIP for Oncology and procedure-specific modules should expand the definition of wound occurrences to incorporate these clinically relevant complications.


Syncope: etiology, management, and when to refer.
An abnormality of blood pressure control is by far the most likely cause of syncope in children; however, syncope in children may be due to primary cardiac dysrhythmias, particularly in the presence of structural heart disease. An appropriate work-up should include an ECG with a 60-second rhythm strip at first presentation. Tilt testing can usually wait until after a second occurrence on non-pharmacologic therapy. Patients who require more than a history and ECG by the algorithm in the Figure should probably be referred to a cardiologist familiar with the evaluation of syncope. The common form of neurally mediated syncope is also probably related to both breath-holding spells in toddlers, and to many of the cases of chronic fatigue syndrome.


The growing feather as a dermal test site: Comparison of leukocyte profiles during the response to Mycobacterium butyricum in growing feathers, wattles, and wing webs.
Using the response to Mycobacterium butyricum as the test-immune response, the main goal of this study was to demonstrate the suitability of the growing feather (GF) as a dermal test site and window into in vivo cellular/tissue responses (US-Patent 8,216,551). Using M. butyricum immunized chickens, the specific objectives were to: 1) compare the leukocyte infiltration response to intra-dermally injected M. butyricum in GF, wattles, and wing webs; 2) use GF as the test site to monitor leukocyte response profiles to recall antigen in the same individuals; and 3) gain new knowledge regarding the local response to M. butyricum in chickens. For objective 1, chickens were euthanized for tissue collection at 4 to 6, 24, 48, and 72 h after intra-dermal antigen injection. Leukocyte infiltration profiles were determined using immunochemical and conventional histology. Data from this study established the similarities between the cellular response in GF, wattles, and wing webs and uncovered many advantages of working with GF. For objective 2, antigen was injected into multiple GF per individual. GF were collected before and at 0.25, 1, 2, 3, and 7 d post injection and processed for cell population analysis by flow cytometry. Advantages of the approach used in objective 2 included a technically easier, more comprehensive, and more objective leukocyte profile analysis; same-day data acquisition; and, most importantly, easy, minimally invasive sample collection from the same individual throughout the study. Both studies contributed new knowledge regarding the local cutaneous response to M. butyricum in M. butyricum immunized chickens and confirmed the cell-mediated nature of the immune response to M. butyricum (e.g., elevated levels [P < 0.05] of T cells [CD4+ and CD8+], macrophages and MHC class II+-cells on days one to 3 post injection in M. butyricum- compared to PBS-injected tissues). The use of GF as an "in vivo test tube" to monitor local innate and adaptive immune activities will find direct application in vaccine development, as well as in the assessment and optimization of immune system development and function in poultry.


Attraction Effects in Honorific Agreement in Korean.
Previous studies have suggested that sentence processing is mediated by content-addressable direct retrieval processes (McElree, 2000; McElree et al., 2003). However, the memory retrieval processes may differ as a function of the type of dependency. For example, while many studies have reported facilitatory intrusion effects associated with a structurally illicit antecedent during the processing of subject-verb number or person agreement and negative polarity items (Pearlmutter et al., 1999; Xiang et al., 2009; Dillon et al., 2013), studies investigating reflexives have not found consistent evidence of intrusion effects (Parker et al., 2015; Sturt and Kwon, 2015; cf. Nicol and Swinney, 1989; Sturt, 2003). Similarly, the memory retrieval processes could be also sensitive to cross-linguistic differences (cf. Lago et al., 2015). We report one self-paced reading experiment and one eye-tracking experiment that examine the processing of subject-verb honorific agreement, a dependency that is different from those that have been studied to date, in Korean, a typologically different language from those previously studied. The overall results suggest that the retrieval processes underlying the processing of subject-verb honorific agreement in Korean are susceptible to facilitatory intrusion effects from a structurally illicit but feature-matching subject, with a pattern that is similar to subject-verb agreement in English. In addition, the attraction effect was not limited to the ungrammatical sentences but was also found in grammatical sentences. The clear attraction effect in the grammatical sentences suggest that the attraction effect does not solely arise as the result of an error-driven process (cf. Wagers et al., 2009), but is likely also to result from general mechanisms of retrieval processes of activating of potential items in memory (Vasishth et al., 2008).


Is there a universal need for positive self-regard?
It is assumed that people seek positive self-regard; that is, they are motivated to possess, enhance, and maintain positive self-views. The cross-cultural generalizability of such motivations was addressed by examining Japanese culture. Anthropological, sociological, and psychological analyses revealed that many elements of Japanese culture are incongruent with such motivations. Moreover, the empirical literature provides scant evidence for a need for positive self-regard among Japanese and indicates that a self-critical focus is more characteristic of Japanese. It is argued that the need for self-regard must be culturally variant because the constructions of self and regard themselves differ across cultures. The need for positive self-regard, as it is currently conceptualized, is not a universal, but rather is rooted in significant aspects of North American culture. Conventional interpretations of positive self-regard are too narrow to encompass the Japanese experience.


A feasibility study in the development of biological markers for ovarian cancer.
As a primary feasibility study for the selection of biomarkers for more extended clinical evaluation, 17 potential biomarker candidates were measured in the body fluids of patients with ovarian carcinoma. For comparative purposes, patients were staged and separated into three groups: those considered completely free of disease, those with residual but minimal tumor, and those with advanced disease. Individual markers included plasma carcinoembryonic antigen, serum human chorionic gonadotrophin, urinary beta-aminoisobutyric acid, serum UDP-galactosyltransferase, and urinary hydroxyproline. Structurally related groups of biomarkers included six modified nucleosides and three polyamines analyzed in urine, and three serum protein-bound neutral carbohydrates. The respective chromatographic methods developed for these latter biochemical materials enabled all the individual compounds in each group to be quantitated simultaneously in one analytical run. The general frequency and degree of elevation for the total number of biomarkers was directly proportional to increasing tumor burden with specific exceptions, human chorionic gonadotropin and beta-aminoisobutyric acid. Galactosyltransferase was the most frequently elevated in the limited disease categories. Several of the biomarkers were elevated in the majority of patients with advanced disease and appeared potentially superior to carcinoembryonic antigen or human chorionic gonadotrophin.


Position Information Encoded by Population Activity in Hierarchical Visual Areas.
Neurons in high-level visual areas respond to more complex visual features with broader receptive fields (RFs) compared to those in low-level visual areas. Thus, high-level visual areas are generally considered to carry less information regarding the position of seen objects in the visual field. However, larger RFs may not imply loss of position information at the population level. Here, we evaluated how accurately the position of a seen object could be predicted (decoded) from activity patterns in each of six representative visual areas with different RF sizes [V1-V4, lateral occipital complex (LOC), and fusiform face area (FFA)]. We collected functional magnetic resonance imaging (fMRI) responses while human subjects viewed a ball randomly moving in a two-dimensional field. To estimate population RF sizes of individual fMRI voxels, RF models were fitted for individual voxels in each brain area. The voxels in higher visual areas showed larger estimated RFs than those in lower visual areas. Then, the ball's position in a separate session was predicted by maximum likelihood estimation using the RF models of individual voxels. We also tested a model-free multivoxel regression (support vector regression, SVR) to predict the position. We found that regardless of the difference in RF size, all visual areas showed similar prediction accuracies, especially on the horizontal dimension. Higher areas showed slightly lower accuracies on the vertical dimension, which appears to be attributed to the narrower spatial distributions of the RF centers. The results suggest that much position information is preserved in population activity through the hierarchical visual pathway regardless of RF sizes and is potentially available in later processing for recognition and behavior.


Changes in intracellular potassium and thiol levels in Escherichia coli K12 under various stresses.
The levels of intracellular K+ and thiols were measured synchronously in E. coli cells under starvation stress and osmotic upshock,alkaline shift and cytoplasm acidification. The level of nonprotein thiols increased in response to osmotic upshock and alkaline shift but decreased under cytoplasm acidification. A positive correlation between the changes in the K+ pool and the level of nonprotein thiols was found under osmotic shock and alkaline shift. Inverse correlation between these parameters was observed after the acidification of cytoplasm. It is supposed that there is a tight relationship between the levels of K+, nonprotein thiols and intracellular pH.


PA suppresses antitumor immunity of T cells by disturbing mitochondrial activity through Akt/mTOR-mediated Ca2+ flux.
Deciphering the mechanisms behind how T cells become exhausted and regulatory T cells (Tregs) differentiate in a tumor microenvironment (TME) will significantly benefit cancer immunotherapy. A common metabolic alteration feature in TME is lipid accumulation, associated with T cell exhaustion and Treg differentiation. However, the regulatory role of free fatty acids (FFA) on T cell antitumor immunity has yet to be clearly illustrated. Our study observed that palmitic acid (PA), the most abundant saturated FFA in mouse plasma, enhanced T cell exhaustion and Tregs population in TME and increased tumor growth. In contrast, oleic acid (OA), a monounsaturated FFA, rescued PA-induced T cell exhaustion, decreased Treg population, and ameliorated T cell antitumor immunity in an obese mouse model. Mechanistically, mitochondrial metabolic activity is critical in maintaining T cell function, which PA attenuated. PA-induced T cell exhaustion and Treg formation depended on CD36 and Akt/mTOR-mediated calcium signaling. The study described a new mechanism of PA-induced downregulation of antitumor immunity of T cells and the therapeutic potential behind its restoration by targeting PA.


Characterisation of an inverted X chromosome (p11.2q21.3) associated with mental retardation using FISH.
We report on a patient with a pericentric inversion of the X chromosome, 46,Y,inv(X) (p11.2q21.3), who was referred for cytogenetic analysis because of mild mental retardation, short stature, prepubescent macro-orchidism, and submucous cleft palate. The same chromosomal abnormality was found in the proband's mother. The inverted X chromosome was late replicating in all the mother's lymphocytes studied, indicative of a likely unbalanced inversion. We show, by fluorescence in situ hybridisation (FISH) using a panel of ordered yeast artificial chromosome (YAC) clones, that the Xp breakpoint is localised in Xp11.23 between DXS146 and DXS255 and that the Xq breakpoint is assigned to the X-Y homologous region in Xq21.3. YACs crossing the Xp and Xq breakpoints have been identified. One of these two breakpoints could be linked to the mental retardation in this patient as many non-specific mental retardation (MRX) loci have previously been located in the pericentromeric region of the X chromosome. Morever, the elucidation at the molecular level of this rearrangement will also indicate if cleft palate or prepubescent macro-orchidism, or both, in this boy are related to one of the two X breakpoints.


Relation between mRNA expression level of multidrug resistance 1/ABCB1 in blood cells and required level of tacrolimus in pediatric living-donor liver transplantation.
It has been difficult to set an individualized therapeutic window of tacrolimus after organ transplantation, because of wide interindividual variation of responsiveness to immunosuppressive therapy. In this study, we examined the significance of multidrug resistance 1 (MDR1) in the peripheral blood cells by comparing the trough concentration of tacrolimus with the occurrence of acute cellular rejection (ACR) in retrospectively collected pediatric living-donor liver transplant patients, who were enrolled after obtaining written informed consent. No significant difference in the intraindividual variation in MDR1 mRNA expression in the peripheral blood cells was observed between postoperative days 3 and 7. The average trough concentration of tacrolimus during the 15-day postoperative period was significantly higher in the event-free patients than in those who experienced ACR (21 of 44 cases), and they had higher levels of blood MDR1 mRNA. In addition, the average trough concentration of tacrolimus significantly correlated with the logarithmically transformed MDR1 mRNA data from the blood cells in patients of both the event-free (r = 0.5406; P = 0.0077) and ACR (r = 0.4772; P = 0.0284). The cellular accumulation of [(14)C]tacrolimus in the peripheral blood mononuclear cells was 2-fold higher in mdr1a/1b-knockout mice than in wild-type mice (P = 0.0182). These results suggest that MDR1 in blood cells decreases the leukocytic concentration of tacrolimus, and it could be a useful marker to establish an individualized target concentration of tacrolimus to prevent ACR in pediatric patients after liver transplantation.


Autoradiographic localization of serum retinol-binding protein receptors on the pigment epithelium of dystrophic rat retinas.
The density and distribution of the retinal pigment epithelium membrane receptor for serum retinol-binding protein (RBP) was compared in young rats (28 days postnatal) and adult rats (7.5 months postnatal) afflicted with retinal dystrophy. Following an intravascular injection of 125I-labeled RBP (125I-RBP) complexed with prealbumin, the binding of 125I-RBP was analyzed by quantitative autoradiographic methods. As the course of the disease progressed, the pigment epithelium of the dystrophic retina underwent regional modification. Some areas remained unchanged, whereas others were grossly altered by vascular infiltration or by attenuation due to reduction in cell number. The basal infoldings of the pigment epithelium in young and adult rats exhibited nearly identical binding densities for 125I-RBP when unmodified cells were compared. In areas of severe disruption, the blood-retinal barrier was compromised, and the labeled protein diffused readily into the the neural retina. The results imply that the RBP receptors persist on the surface of unmodified pigment epithelial cells in adult dystrophic retinas in spite of the decrease in demand for retinol that accompanies the loss of photoreceptors.


[Pancreatitis, genes and islet cells auto transplant; updates and new horizons].
Pancreatitis is an inflammation of the pancreas that can progress from an acute presentation to an acute recurring presentation and eventually to chronic pancreatitis, which is characterized by irreversible morphological changes and scarring of the pancreas. The entity known as hereditary pancreatitis has been recognized in the literature for years and certainly the discovery of the PRSS1 gene in 1996 marked the beginning of a new era of genetic discoveries associated with the disease. Since then, multiple genes have been described as the causing agents of pancreatitis or disease modifiers, some of the most important ones being the PRSS1, SPINK1, CFTR, CASR, CTRC, CLDN2, and CPA1. The patient selection process for genetic testing should be guided by the current experts' recommendations and should meet specific corresponding criteria. Once the diagnosis has been made, treatment should be tailored to each patient's particular needs. Certainly, the advent of the total pancreatectomy with auto islet cell transplantation, which has the main goal to improve the pain caused by the chronic pancreatitis and simultaneously reduce the severity of the pancreatectomy induced diabetes, is an attractive alternative in the treatment and management of patient with a diagnosis of hereditary pancreatitis. However, strict criteria and an interdisciplinary management are essential since this surgery is irreversible and carries lifetime health consequences that all patients must be aware of and the medical team must be able to early recognize these and treat accordingly. However, there are many potential areas in this field for more, better and forefront research to be developed aiming for a better understanding of the disease process and for the development of a cure.


Glycoalkaloids selectively permeabilize cholesterol containing biomembranes.
The effects of the glycoalkaloids alpha-solanine, alpha-chaconine and alpha-tomatine on different cell types were studied in order to investigate the membrane action of these compounds. Hemolysis of erythrocytes was compared to 6-carboxyfluorescein leakage from both ghosts and erythrocyte lipid vesicles, whereas leakage of enzymes from mitochondria and the apical and baso-lateral side of Caco-2 cells was determined. Furthermore, the effects of glycoalkaloids on the gap-junctional communication between Caco-2 cells was studied. From these experiments, it was found that glycoalkaloids specifically induced membrane disruptive effects of cholesterol containing membranes as was previously reported in model membrane studies. In addition, alpha-chaconine was found to selectively decrease gap-junctional intercellular communication. Furthermore, the glycoalkaloids were more potent in permeabilizing the outer membrane of mitochondria compared to digitonin at the low concentrations used.


All-mail voting in Colorado increases turnout and reduces turnout inequality.
The COVID-19 crisis has generated interest in all-mail voting (AMV) as a potential policy solution for avoiding in-person elections. However, the quality of AMV implementation has varied greatly across states, leading to mixed results in previous research. We exploit the understudied 2014 implementation of AMV in Colorado to estimate the effect on turnout for all registered voters, along with age, racial, education, income and wealth, and occupational subgroups. Using large voter file data and a difference-in-differences design within individuals, we find a positive overall turnout effect of approximately 8 percentage points-translating into an additional 900,000 ballots being cast between 2014 and 2018. Effects are significantly larger among lower-propensity voting groups, such as young people, blue-collar workers, voters with less educational attainment, and voters of color. The results suggest that researchers and policymakers should look to Colorado's AMV approach as an effective model for boosting aggregate turnout and reducing voting disparities across subgroups.


Delayed opportunistic infections in hematopoietic stem cell transplantation patients: a surmountable challenge.
Changes in the transplantation procedure and the implementation of effective supportive care strategies have decreased the incidence of infectious complications early after conditioning therapy for allogeneic hematopoietic stem cell transplantation (HCT) and have extended the duration of risks later. Therefore, the types of infections that cause significant morbidity and the timing of risks have changed. These late infections are caused by all types of organisms, bacterial, viral, and fungal, but risks are predictable and surmountable with the use of tailored prevention strategies. Specifically, recent studies document prolonged risks for bacterial infections in the setting of GVHD, especially those caused by encapsulated organisms and those secondary to impaired Ab responses. Both prophylaxis and vaccination strategies can be used as a means to prevent infections, which typically manifest in the respiratory tract. Multiple viruses cause infection later after HCT, including several herpesviruses (eg, CMV and varicella zoster virus) and other respiratory viruses such as influenza and adenovirus. These infections can cause severe disease with diagnostic challenges, but prevention strategies using enhanced monitoring and/or prophylaxis may be effective. Finally, fungi also cause disease late after HCT, especially filamentous fungi (eg, Aspergillus species and Mucormycoses) and Pneumocystis jiroveci; prophylactic strategies may be used successfully to prevent invasive infection. Late infections and methods to prevent them are reviewed herein.


Modeling the response of passive samplers to varying ambient fluid concentrations of organic contaminants.
Passive samplers are an important and versatile adjunct to active sampling methods for air and water. The underlying theory is increasingly mature but is often based on the assumption of constant concentrations with time in the ambient fluid. This theoretical work details the passive sampler response to possible environmental situations in which ambient concentrations vary linearly with time, decrease exponentially with time, constitute a pulsed event, or oscillate regularly with time. The modeled shape of sampler response curve with time is characteristic and can be used to determine how fluid concentrations have changed with time. The sampler elimination rate constant is shown to be crucial in governing sampler response. Thus, by using performance reference compounds and under certain conditions, information from the sampler response can in theory be used to derive specific details of the temporal variation of the contaminant in the ambient fluid. For example, data captured by a passive sampler can be used to characterize a contamination pulse. This extends the versatility of passive samplers.


Physical activity and survival after diagnosis of invasive breast cancer.
Previous studies suggest that increased physical activity may lower the risk of breast cancer incidence, but less is known about whether levels of physical activity after breast cancer diagnosis can influence survival. We prospectively examined the relation between postdiagnosis recreational physical activity and risk of breast cancer death in women who had a previous invasive breast cancer diagnosed between 1988 and 2001 (at ages 20-79 years). All women completed a questionnaire on recent postdiagnosis physical activity and other lifestyle factors. Among 4,482 women without history of recurrence at the time of completing the questionnaire, 109 died from breast cancer within 6 years of enrollment. Physical activity was expressed as metabolic equivalent task-hours per week (MET-h/wk); hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression. After adjusting for age at diagnosis, stage of disease, state of residence, interval between diagnosis and physical activity assessment, body mass index, menopausal status, hormone therapy use, energy intake, education, family history of breast cancer, and treatment modality compared with women expending <2.8 MET-h/wk in physical activity, women who engaged in greater levels of activity had a significantly lower risk of dying from breast cancer (HR, 0.65; 95% CI, 0.39-1.08 for 2.8-7.9 MET-h/wk; HR, 0.59; 95% CI, 0.35-1.01 for 8.0-20.9 MET-h/wk; and HR, 0.51; 95% CI, 0.29-0.89 for > or =21.0 MET-h/wk; P for trend = 0.05). Results were similar for overall survival (HR, 0.44; 95% CI, 0.32-0.60 for > or =21.0 versus <2.8 MET-h/wk; P for trend <0.001) and were similar regardless of a woman's age, stage of disease, and body mass index. This study provides support for reduced overall mortality and mortality from breast cancer among women who engage in physical activity after breast cancer diagnosis.


The latent collagenase and gelatinase of human polymorphonuclear neutrophil leucocytes.
Two metallo-proteinases of human neutrophil leucocytes, collagenase and gelatinase, were studied. Collagenase specifically cleaved native collagen into the TCA and TCB fragments, whereas gelatinase degraded denatured collagen, i.e. gelatin, and the TCA fragments produced by collagenase. On subcellular fractionation by zonal sedimentation, collagenase was found to be localized in the specific granules, separate from gelatinase, which was recovered in smaller subcellular organelles known as C-particles. Neither enzyme was present in the azurophil granules, which contain the two major serine proteinases of neutrophils, elastase and cathepsin G. Collagenase and gelatinase were separated by gel filtration from extracts of partially purified granules. Both enzymes were found to occur in latent forms and were activated either by trypsin or by 4-aminophenylmercuric acetate. Gelatinase was also activated by cathepsin G, which, however, destroyed collagenase. Both enzymes were destroyed by neutrophil elastase. Activation resulted in a decrease by 25 000 in the apparent mol. wt. of both latent metallo-proteinases.


CT in the Evaluation of Acute Injuries of the Anterior Eye Segment.
Slit-lamp ophthalmologic examination and ocular B-scan sonography of the globe are frequently constrained by technical limitations in the setting of traumatic orbital injury. The main purpose of this study was to evaluate the diagnostic performance of CT in acute anterior segment ocular injuries as an adjunctive diagnostic modality. We retrospectively identified 122 patients who presented to the emergency department from April 2011 through April 2016 with recent direct trauma to the anterior segment of the eye. Deidentified multiplanar thin-slice CT images were reviewed by two subspecialty board-certified neuroradiologists for the presence of anterior segment rupture and hyphema, as well as lens, ciliary body, and lacrimal gland injury. The CT findings were compared to slit-lamp, B-scan ultrasound, or operative data as the reference standard. The neuroradiologists' CT evaluation showed high sensitivity of 87.2% (95% CI, 74.3-95.2%) and specificity of 97.3% (95% CI, 90.7-99.7%) in diagnosing anterior globe rupture with high interrater agreement (κ = 0.876; 95% CI, 0.787-0.965). Detection of lens dislocation and anterior hyphema showed a sensitivity and specificity of 88.0% and 90.7% and 77.4% and 88.4%, respectively. A shallow anterior chamber was detectable with a sensitivity of 89.2% and specificity of 87.1%. This critically important sign predicted anterior globe rupture in 39 of 47 patients (odds ratio, 68.25; p < 0.0001). Subtle ocular findings are readily detectable at CT and can provide valuable information to the ophthalmologist concerning acute trauma to the ocular anterior segment.


Echinacea purpurea (L.) Moench treatment of monocytes promotes tonic interferon signaling, increased innate immunity gene expression and DNA repeat hypermethylated silencing of endogenous retroviral sequences.
Herbal remedies of Echinacea purpurea tinctures are widely used today to reduce common cold respiratory tract infections. Transcriptome, epigenome and kinome profiling allowed a systems biology level characterisation of genomewide immunomodulatory effects of a standardized Echinacea purpurea (L.) Moench extract in THP1 monocytes. Gene expression and DNA methylation analysis revealed that Echinaforce® treatment triggers antiviral innate immunity pathways, involving tonic IFN signaling, activation of pattern recognition receptors, chemotaxis and immunometabolism. Furthermore, phosphopeptide based kinome activity profiling and pharmacological inhibitor experiments with filgotinib confirm a key role for Janus Kinase (JAK)-1 dependent gene expression changes in innate immune signaling. Finally, Echinaforce® treatment induces DNA hypermethylation at intergenic CpG, long/short interspersed nuclear DNA repeat elements (LINE, SINE) or long termininal DNA repeats (LTR). This changes transcription of flanking endogenous retroviral sequences (HERVs), involved in an evolutionary conserved (epi) genomic protective response against viral infections. Altogether, our results suggest that Echinaforce® phytochemicals strengthen antiviral innate immunity through tonic IFN regulation of pattern recognition and chemokine gene expression and DNA repeat hypermethylated silencing of HERVs in monocytes. These results suggest that immunomodulation by Echinaforce® treatment holds promise to reduce symptoms and duration of infection episodes of common cold corona viruses (CoV), Severe Acute Respiratory Syndrome (SARS)-CoV, and new occurring strains such as SARS-CoV-2, with strongly impaired interferon (IFN) response and weak innate antiviral defense.


Outcomes Using Grafts from Donors after Cardiac Death.
Previous reports suggest that donation after cardiac death (DCD) liver grafts have increased primary nonfunction (PNF) and cholangiopathy thought to be due to the graft warm ischemia before cold flushing. In this single-center, retrospective study, 866 adult liver transplantations were performed at our institution from January 2005 to August 2014. Forty-nine (5.7%) patients received DCD donor grafts. The 49 DCD graft recipients were compared with all recipients of donation after brain death donor (DBD) grafts and to a donor and recipient age- and size-matched cohort. The DCD donors were younger (age 28, range 8 to 60 years) than non-DCD (age 44.3, range 9 to 80 years) (p < 0.0001), with similar recipient age. The mean laboratory Model for End-Stage Liver Disease (MELD) was lower in DCD recipients (18.7 vs 22.2, p = 0.03). Mean cold and warm ischemia times were similar. Median ICU and hospital stay were 2 days and 7.5 days in both groups (p = 0.37). Median follow-ups were 4.0 and 3.4 years, respectively. Long-term outcomes were similar between groups, with similar 1-, 3- and 5-year patient and graft survivals (p = 0.59). Four (8.5%) recipients developed ischemic cholangiopathy (IC) at 2, 3, 6, and 8 months. Primary nonfunction and hepatic artery thrombosis did not occur in any patient in the DCD group. Acute kidney injury was more common with DCD grafts (16.3% of DCD recipients required dialysis vs 4.1% of DBD recipients, p = 0.01). An increased donor age (>40 years) was shown to increase the risk of IC (p = 0.006). Careful selection of DCD donors can provide suitable donors, with results of liver transplantation comparable to those with standard brain dead donors.


Hydrolysis and rearrangement of phthalamic acid derivatives and assessment of their potential as prodrug forms for amines.
Although it is well-known that N-substituted phthalamic acid derivatives are readily hydrolyzed in acidic aqueous solution due to intramolecular catalysis by the neighbouring carboxy group, sparse information is available on the degradation behaviour in neutral solutions. A recent publication [5] has claimed that N-(3-bromopropyl)phthalamic acid is very easily hydrolyzed in mildly alkaline solutions by an intramolecular catalytic effect of the ionized carboxy group. In this study, the degradation behaviour of N-(2-bromoethyl)phthalamic acid (I), N-(3-bromopropyl)phthalamic acid (II) and various other N-alkyl and N-aryl substituted phthalamic acid derivatives were examined with the primary aim of assessing their degradation rate at physiological pH. Whereas the compounds I and II were indeed found to be easily degraded in neutral aqueous solutions, the degradation was not due to hydrolysis of the amide bond as previously claimed but rather to an intramolecular displacement reaction of the bromo group by the amide moiety, as evidenced by HPLC analysis of the rection products. The other phthalamic acid derivatives studies showed a very high stability in neutral and alkaline solution. It is concluded that phthalamic acid derivatives are too stable chemically and enzymatically to be considered as prodrug forms for primary or secondary amines.


Alpha-amanitin-resistant transcription units in trypanosomes: a comparison of promoter sequences for a VSG gene expression site and for the ribosomal RNA genes.
Transcription of the predominant surface antigen genes in Trypanosoma brucei is unusual in its resistance to the RNA polymerase inhibitor alpha-amanitin, a property typical for rDNA transcription in eukaryotes. Transcription of most other protein-coding genes in trypanosomes is sensitive to alpha-amanitin. To investigate whether RNA polymerase I, the polymerase that transcribes rRNA genes, can give rise to functional mRNAs in trypanosomes, we have fused the putative promoter of the T.brucei rRNA genes to the chloramphenicol acetyl transferase (CAT) gene and determined CAT activity after transient expression of chimeric constructs in procyclic trypanosomes. We show here that the rRNA promoter yields the same high CAT activity as the promoters for the two predominant surface antigen genes of trypanosomes, the Variant-specific Surface Glycoprotein (VSG) gene of bloodstream trypanosomes and the procyclin gene of insect-form trypanosomes, both of which are also transcribed by an alpha-amanitin-insensitive RNA polymerase. RNA polymerase I of trypanosomes seems therefore able to synthesize pre-mRNAs that are effectively processed into translatable mRNAs. Dissection of the promoter segments showed the minimal elements for a VSG gene expression site promoter to be confined to a segment of -60 to +77 bp, overlapping the most 5' putative transcription start sites as determined in vivo by RNase protection experiments. For the ribosomal promoter region a segment of -258 to +200 bp relative to the putative transcription start site was sufficient for maximal CAT activity. There is a precise requirement for specific nucleotides at the rRNA transcription start site. We detect no homology between the sequences required for promoter function of the three alpha-amanitin-resistant transcription units, rRNA, VSG and procyclin (parp) genes. This suggests that the sequence-specific recognition of these promoters either occurs by common factors detecting sequence homologies that escape us, or by separate factors that bind to different DNA sequences but interact with a common alpha-amanitin-resistant RNA polymerase.


Metalloporphyrin-modified semiconductors for solar fuel production.
We report a direct one-step method to chemically graft metalloporphyrins to a visible-light-absorbing gallium phosphide semiconductor with the aim of constructing an integrated photocathode for light activating chemical transformations that include capturing, converting, and storing solar energy as fuels. Structural characterization of the hybrid assemblies is achieved using surface-sensitive spectroscopic methods, and functional performance for photoinduced hydrogen production is demonstrated via three-electrode electrochemical testing combined with photoproduct analysis using gas chromatography. Measurements of the total per geometric area porphyrin surface loadings using a cobalt-porphyrin based assembly indicate a turnover frequency ≥3.9 H2 molecules per site per second, representing the highest reported to date for a molecular-catalyst-modified semiconductor photoelectrode operating at the H+/H2 equilibrium potential under 1-sun illumination.


Risk factors for rapid-onset cervical cancer.
The current study was designed to elucidate risk factors associated with the development of cervical cancer during the course of routine Papanicolaou smear screening (rapid-onset cervical cancer). Four hundred eighty-three women diagnosed with invasive cervical cancer, representing 73% of all such tumors diagnosed in Connecticut between 1985 and 1990, were studied. Papanicolaou smear screening and risk factor information was obtained by questionnaire and physician record review. Results from human papillomavirus deoxyribonucleic acid testing by polymerase chain reaction of tumor samples were available for 278 study participants. Prediagnostic Papanicolaou smear slides were reviewed for 67% of cases with a screening history. Screening history information, slide review, and questionnaire data were used to classify women as having rapid-onset cervical cancer (n = 43), possible rapid-onset cervical cancer (n = 111), or normal-onset cervical cancer (n = 329). Compared with normal-onset cases, rapid-onset cases tended to be younger (P =.001) and were more likely to be white (P =.002), diagnosed with adenocarcinomas or adenosquamous carcinomas (P =.001), and diagnosed with early-stage disease (P =.001). Cases diagnosed as possible rapid-onset disease tended to have a profile that was intermediate to that observed for rapid-onset and normal-onset cases. Human papillomavirus deoxyribonucleic acid was detected in 75.2% of cases tested. Compared with women who tested positive for human papillomavirus type 16 or other, those positive for human papillomavirus type 18 had a relative risk for rapid-onset disease of 1.6 (95% confidence interval 0.52-4.9). No significant association was observed between type 18 and possible rapid-onset disease when possible rapid-onset cases were compared with women diagnosed with normal-onset cervical cancer (relative risk 0.67, 95% confidence interval 0.29-1.6). Oral contraceptive use, cigarette smoking, number of pregnancies, and a maternal history of cervical cancer were not significantly associated with rapid-onset disease. Results from this study suggest that the risk factors associated with the development of rapid-onset cervical cancer are similar to those for normal-onset disease.


TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.
The activation and fusion of macrophages and of osteoclasts require the adaptor molecule DNAX-activating protein of 12 kD (DAP12), which contains immunoreceptor tyrosine-based activation motifs (ITAMs). TREM2 (triggering receptor expressed on myeloid cells-2) is the main DAP12-associated receptor in osteoclasts and, similar to DAP12 deficiency, loss of TREM2 in humans leads to Nasu-Hakola disease, which is characterized by bone cysts and dementia. Furthermore, in vitro experiments have shown that deficiency in DAP12 or TREM2 leads to impaired osteoclast development and the formation of mononuclear osteoclasts. Here, we demonstrate that the ligation of TREM2 activated phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase 1 (ERK1) and ERK2, and the guanine nucleotide exchange factor Vav3; induced the mobilization of intracellular calcium (Ca(2+)) and the reorganization of actin; and prevented apoptosis. The signaling adaptor molecule DAP10 played a key role in the TREM2- and DAP12-dependent recruitment of PI3K to the signaling complex. Src homology 2 (SH2) domain-containing inositol phosphatase-1 (SHIP1) inhibited TREM2- and DAP12-induced signaling by binding to DAP12 in an SH2 domain-dependent manner and preventing the recruitment of PI3K to DAP12. These results demonstrate a previously uncharacterized interaction of SHIP1 with DAP12 that functionally limits TREM2- and DAP12-dependent signaling and identify a mechanism through which SHIP1 regulates key ITAM-containing receptors by directly blocking the binding and activation of PI3K.


What makes a doctor a scholar: a systematic review and content analysis of outcome frameworks.
Many national outcome frameworks (OF) call for a sound scholarship education and scholarly behaviour of physicians. Educators however are known to interpret the scholar role in markedly different ways and at least one major initiative to unify several national outcome frameworks failed to agree on a common definition of the scholar role. Both circumstances currently limit the development of educational and assessment strategies specific for the scholar role. Given increasing physician mobility together with the global perspective inherent in a doctor's role as a scholar, we were interested in what different OFs define as the scholar role and attempted to identify communalities and differences between them. We conducted a systematic review for OF in medical education in PubMed and google. After in- and exclusion processes, we extracted all content listed under the scholar role (if present) and categorized it based on Boyer's established model of scholarship. Next, we extracted all content related to scholarship from OFs not explicitly defining a scholar role and used it to validate the categories resulting from step one. From 1816 search results, we identified 13 eligible OFs, seven of which explicitly specified a scholar role. The outcomes only partly map onto Boyer's definition of scholarship: Discovery, Integration, Application, and Teaching. We adapted and validated a model extending this definition to contain Common Basics (partly overlapping with Integration and Teaching), Clinical Application (specifying Application), Research (Discovery and partly Integration), Teaching and Education (partly overlapping with Teaching) and Lifelong Learning (no equivalent in Boyer's model). Whereas almost all OFs cover Common Basics, Clinical Application, and Lifelong Learning, fewer and less specific outcomes relate to Research or Teaching. The need to adapt existing models of scholarship may result from the changing demands directed at medical scholars. The considerable differences identified between OFs may explain why educators have difficulties defining the scholar role and why the role is rarely assessed. We may have missed OFs due to our in- and exclusion criteria but the results provide a solid basis on which to build a common understanding of what makes a doctor a scholar.


Prevalence of restless legs syndrome in blood donors.
Iron deficiency anemia has been linked to restless legs syndrome (RLS) and regular blood donation may lead to iron deficiency. It has been reported that blood donations may be associated with RLS. A recent study from Sweden found that 25% of the women donors were affected by RLS. However, this type of study has not been replicated in the United States. We conducted a study in our blood donation unit between September and October 2008. To identify those with RLS, we used the RLS diagnostic index questionnaire by Benes et al. The proportion of blood donors with RLS was estimated and the number of blood donations and hemoglobin levels were compared according to RLS status. One hundred and fifty one patients were interviewed; 7 patients who donated only platelets were excluded, leaving 144 patients for analysis. There were 13 (9.0%, 95% confidence interval [CI]: 4.9-14.9%) patients with RLS. Of these, 7 (4.9%, 95% CI: 2.0-9.8%) had possible RLS and 6 (4.2%, 95% CI: 1.5-8.9%) had major or clinically relevant RLS. There was no dramatic association between RLS and number of blood donations or hemoglobin level (all P >or= 0.21). In our sample of blood donors in the United States, the prevalence of major RLS was 4%. We could not demonstrate an association between RLS and the frequency of blood donation or hemoglobin level in our relatively small sample; a larger sample is needed to better identify any associations.


Effect of buffer species on the unfolding and the aggregation of humanized IgG.
The aggregation propensity of humanized antibody after heat treatment is evaluated in the presence of six buffer species. The comparison under equivalent pH showed high aggregation propensity on phosphate and citrate buffer. In contrast, 2-(N-Morpholino) ethane sulfonate (MES), 3-(N-Morpholino) propane sulfonate (MOPS), acetate and imidazole buffer showed lower aggregation propensity than the above two buffers. Meanwhile, unfolding temperature evaluated by differential scanning calorimetry measurement was not altered among these buffer species. The light scattering analysis suggested that heat-denatured intermediate was aggregated slightly on MES and acetate buffer. Therefore, it was found that the different aggregation propensity among buffer species was caused from the aggregation propensity of heat-denatured intermediate rather than the unfolding temperature. Furthermore, it was revealed that the aggregation dependency on buffer species is accounted for by the specific molecular interaction between buffer and IgG, rather than the ionic strength. On the contrary, on the analyses of unfolding and aggregation propensity by molecular dissection of IgG into Fab and Fc fragments, aggregation propensity of Fc fragment on MES, acetate and phosphate buffer was almost the same as whole IgG. From the above results, it was suggested that the specific interaction between buffer molecule and Fc domain of IgG was involved in the aggregation propensity of heat-denatured IgG.


Study on nutritional monitoring of Persian malnourished school students: A check on reproducibility and validity of questionnaire.
To develop a nutritional screening tool and examine its reliability and validity in elementary school children with malnutrition based on PRECEDE-PROCEED model, in Shiraz, Iran. A questionnaire was designed and its reproducibility was analysed via test-retest design among students with malnutrition. The students were in the fourth to sixth grades. Validity was assessed using face validity, content validity, construct validity, item difficulty and item discrimination. Reliability was measured by Cronbach's alpha (internal consistency), the intra-class correlation coefficient (ICC) and κ statistics (test-retest reliability). A total of 165 primary school students (mean age of 11.21 ± 1.08 years, 65.5% females) participated in the study. The PRECEDE-PROCEED theoretical model for health education was adapted for this questionnaire. The questionnaire was divided into four main sections: predisposing, reinforcing, enabling factors and behaviour. Coefficient α reliability estimate was above 0.9 for most scales. The ICCs for different scales of the questionnaire were within the range of 0.402-0.800. Values for κ ranged from 0.412 to 0.785 for most scales. The results showed reasonable validity, excellent reliability and moderate to substantial reproducibility for all scales of the questionnaire except two questions for κ statistics. The present study is of great importance, as there are no psychometrically evaluated tools (based on health behaviour models) with accepted validity and reliability for the evaluation of such factors in children with malnutrition. The questionnaire developed in the present study can be used to assess the effect of intervention among primary school students with malnutrition.


Optical control of the refractive index of a single atom.
We experimentally demonstrate the elementary case of electromagnetically induced transparency with a single atom inside an optical cavity probed by a weak field. We observe the modification of the dispersive and absorptive properties of the atom by changing the frequency of a control light field. Moreover, a strong cooling effect has been observed at two-photon resonance, increasing the storage time of our atoms twenty-fold to about 16 seconds. Our result points towards all-optical switching with single photons.


Patient-Reported Satisfaction With the Fixed Combination Calcipotriene/Betamethasone Dipropionate Foam for Plaque Psoriasis.
Psoriasis is a chronic, immune-mediated inflammatory disease characterized by localized scaling and plaques associated with itching and pain. In some cases, topical therapies are effective to treat mild to moderate psoriasis. Topical agents can be used concomitantly with other treatments for moderate and severe or treatment-resistant psoriasis. Patient adherence to medication regimens remains a major challenge in therapy, especially with topical agents, for which adherence can be affected by the amount of time needed for application, the treatment formulation, cost, and cosmetic characteristics. This study was conducted to obtain feedback from patients clinically diagnosed with psoriasis regarding their satisfaction following once-daily topical application of the fixed combination calcipotriene (Cal) 0.005% and betamethasone dipropionate (BD) 0.064% foam for 15 days. Patients completed a 13-question online survey. In this community-based setting of patients with mild to severe psoriasis, patients were satisfied with Cal/BD foam after 15 days of use; 94% were satisfied or highly satisfied with symptom relief. Most of the patients (88%) were satisfied with how Cal/BD foam felt on their skin. After 15 days of use, 94% of patients would recommend Cal/BD foam to other patients with psoriasis, with 73% being very likely to do so. These findings may have important implications for optimizing medical decision-making, treatment adherence, and health outcomes in clinical practice. The cosmetic acceptability of the fixed combination Cal/BD foam formulation and patient satisfaction may make Cal/BD aerosol foam a more acceptable topical treatment than other currently available vehicles for patients with plaque psoriasis. J Drugs Dermatol. 2018;17(8):880-884.


Antibody responses in melanoma patients immunized with an anti-idiotype antibody mimicking disialoganglioside GD2.
We initiated a clinical trial for patients with advanced malignant melanoma treated with an anti-idiotype antibody that mimics the disialoganglioside GD2. We report the clinical and immune responses of the first 12 patients entered into this trial. Patients received 1-, 2-, 4-, or 8-mg doses of the anti-idiotype antibody mixed with 100 microg of QS-21 adjuvant every other week, four times, and then monthly. Twelve patients have been on trial for 2-23 months, and all of them have generated immune responses. Patients were removed from the study if they demonstrated disease progression. Hyperimmune sera from all 12 patients revealed an anti-anti-idiotypic Ab3 response, as demonstrated by the inhibition of Ab2 binding to Ab1 by patients' immune sera. To further test the anti-anti-idiotypic response, patients' Ab3 antibodies were affinity purified on Sepharose 4B columns containing adsorbed immunizing anti-idiotype immunoglobulin. Purified Ab3 of all patients studied inhibited binding of Ab1 to a GD2-positive cell line. Purified Ab3 also inhibited binding of Ab1 to purified GD2, in a manner comparable to equal quantities of purified Ab1. The patient Ab3 was truly an Ab1' because it specifically bound to purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody was predominantly IgG, with only minimal IgM. The predominant IgG subclass was IgG1, with approximately equal quantities of IgG2, IgG3, and IgG4. These Ab3 antibodies reacted specifically with tumor cells expressing GD2 by immune flow cytometry and immunoperoxidase assays. Five patients' Ab3 antibodies studied for antibody-dependent cellular cytotoxicity were positive. One patient had a complete clinical response, with resolution of soft tissue disease, and six patients had stable disease, ranging from 9 to 23 months, and are being continued on vaccine therapy. Toxicity consisted of local reaction at the site of the injection, including induration and pain that generally resolved within a few days. Mild fever and chills were observed in 75% of the patients but rarely required acetaminophen. There was no additional toxicity, including abdominal pain that was previously seen with infusion of murine monoclonal anti-GD2 antibody. Current trials include patients with stage III melanoma and small cell lung cancer. Future trials will attempt to enhance the antitumor response by the addition of interleukin 2, granulocyte macrophage colony-stimulating factor, and other cytokines, together with the 1A7 vaccine.


Effect of Attachment Type on Implant Strain in Maxillary Implant Overdentures: Comparison of Ball, Locator, and Magnet Attachments. Part 1. Overdenture with Palate.
Implant overdentures with attachments have been used in clinical practice and the effect of attachments on implant strain has been frequently reported. However, most studies have focused on mandibular overdentures; there are few reports on maxillary overdentures. The purpose of this study was to examine the influence of attachment type on implant strain in maxillary overdentures under various implant configurations. A maxillary edentulous model with implants and experimental overdentures were fabricated. Four strain gauges were attached to each implant, positioned in anterior, premolar, and molar areas. Three types of unsplinted attachments-ball, locator, and magnet-were set on the implants under various implant configurations. A vertical occlusal load of 98 N was applied through the mandibular complete denture, and implant strain was compared using the Kruskal-Wallis test. Ball attachments caused the greatest amount of strain, while magnet attachments caused the least amount under all conditions. For all attachments, two anterior implants caused significantly more strain than four implants (P < .05). No significant difference was observed between subtypes in four-implant configurations except when using locator attachments. When using unsplinted attachments for maxillary implant overdentures, magnet attachments are recommended to reduce implant stress. Using only two implants, especially two anterior implants, is not recommended regardless of attachment type.


The interaction of phospholipase A2 with a phospholipid bilayer: coarse-grained molecular dynamics simulations.
A number of membrane-active enzymes act in a complex environment formed by the interface between a lipid bilayer and bulk water. Although x-ray diffraction studies yield structures of isolated enzyme molecules, a detailed characterization of their interactions with the interface requires a measure of how deeply such a membrane-associated protein penetrates into a lipid bilayer. Here, we apply coarse-grained (CG) molecular dynamics (MD) simulations to probe the interaction of porcine pancreatic phospholipase A2 (PLA2) with a lipid bilayer containing palmitoyl-oleoyl-phosphatidyl choline and palmitoyl-oleoyl-phosphatidyl glycerol molecules. We also used a configuration from a CG-MD trajectory to initiate two atomistic (AT) MD simulations. The results of the CG and AT simulations are evaluated by comparison with available experimental data. The membrane-binding surface of PLA2 consists of a patch of hydrophobic residues surrounded by polar and basic residues. We show this proposed footprint interacts preferentially with the anionic headgroups of the palmitoyl-oleoyl-phosphatidyl glycerol molecules. Thus, both electrostatic and hydrophobic interactions determine the location of PLA2 relative to the bilayer. From a general perspective, this study demonstrates that CG-MD simulations may be used to reveal the orientation and location of a membrane-surface-bound protein relative to a lipid bilayer, which may subsequently be refined by AT-MD simulations to probe more detailed interactions.


Bean alpha-amylase inhibitor 1 in transgenic peas (Pisum sativum) provides complete protection from pea weevil (Bruchus pisorum) under field conditions.
Two alpha-amylase inhibitors, called alphaAI-1 and alphaAI-2, that share 78% amino acid sequence identity and have a differential specificity toward mammalian and insect alpha-amylases are present in different accessions of the common bean (Phaseolus vulgaris). Using greenhouse-grown transgenic peas (Pisum sativum), we have shown previously that expression of alphaAI-1 in pea seeds can provide complete protection against the pea weevil (Bruchus pisorum). Here, we report that alphaAI-1 also protects peas from the weevil under field conditions. The high degree of protection is explained by our finding that alphaAI-1 inhibits pea bruchid alpha-amylase by 80% over a broad pH range (pH 4.5-6.5). alphaAI-2, on the other hand, is a much less effective inhibitor of pea bruchid alpha-amylase, inhibiting the enzyme by only 40%, and only in the pH 4.0-4.5 range. Nevertheless, this inhibitor was still partially effective in protecting field-grown transgenic peas against pea weevils. The primary effect of alphaAI-2 appeared to be a delay in the maturation of the larvae. This contrasts with the effect of alphaAI-1, which results in larval mortality at the first or second instar. These results are discussed in relationship to the use of amylase inhibitors with different specificities to bring about protection of crops from their insect pests or to decrease insect pest populations below the economic injury level.