Communication: convergence of anharmonic infrared intensities of hydrogen fluoride in traditional and explicitly correlated coupled cluster calculations.
It is shown that the convergence of anharmonic infrared spectral intensities with respect to the basis set size is much enhanced in explicitly correlated calculations as compared to traditional configuration interaction type wave function expansion. Explicitly correlated coupled cluster (CC) calculations using Slater-type geminal correlation factor (CC-F12) yield well-converged dipole derivatives and vibrational intensities for hydrogen fluoride with basis set involving f functions on the heavy atom. Combination of CC-F12 with singles, doubles, and non-iterative triples (CCSD(T)-F12) with small corrections due to quadruple excitations, core-electron correlation, and relativistic effects yields vibrational line positions, dipole moments, and transition dipole matrix elements in good agreement with the best experimental values.


Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: a review of the literature.
Heparin, fondaparinux and vitamin K antagonists (VKAs) are effective for the prevention and treatment of venous thromboembolism. VKAs reduce by almost 60% the rate of cardioembolic complications in patients with atrial fibrillation. The risk for bleeding and the inconvenience for laboratory monitoring, dose adjustment and drug or food interactions are the main limits for VKAs while parenteral administration is the main limit for heparin and fondaparinux. New oral anticoagulants with more predictable anticoagulant response and no need for laboratory monitoring have been shown to be effective for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The pharmacokinetic and pharmacodynamic profile of the new agents differ for mechanisms of action - mainly anti Xa and one antithrombin agent- bioavailability, half life, renal or live clearance. Drug interactions have been described with the new agents and inhibitors or inducers of P-gp or CYP3A4. Overall, in the prevention of venous thromboembolism after major elective orthopaedic surgery dabigatran was shown to be non-inferior, rivaroxaban and apixaban to be superior to enoxaparin. Both, rivaroxaban and dabigatran were shown to be non-inferior to low-molecular weight heparin and VKAs for the treatment of venous thromboembolism. Dabigatran 150mg twice daily reduced the incidence of both ischemic and hemorrhagic stroke in patients with atrial fibrillation respect to warfarin. In these patients rivaroxaban and apixaban reduced the incidence of hemorrhagic stroke with a similar incidence of ischemic stroke. No bleeding concern emerged with the new anticoagulant agents in this indication.


Possible role of human foamy virus in Graves' disease.
Human foamy virus (HFV) is a member of the retroviral family of Spumaretrovirinae. In addition to the three retroviral structural genes, gag, pol and env, HFV also contains regulatory sequences, called bel. Foamy viruses have been previously associated with human thyroid disease, notably DeQuervain's thyroiditis. In indirect immunofluorescence tests we have demonstrated the reactivity of the thyroid glands of 7/7 patients with Graves' disease and antibodies to HFV gag proteins. No reactivity was observed with antibodies to pol, env and bel proteins. Nine thyroids of patients with struma parenchymatosa, 4 with follicular carcinoma and 2 normal thyroids were negative throughout. From the thyroids of 5 patients with Hashimoto's disease, 4 were negative and 1 showed a single small focus of anti-gag antibody reactivity. The uniform immunofluorescent staining was restricted to the basal and lateral intercellular areas between the thyroid epithelial cells. Extension of these studies to the retrobulbar tissue of 1 Graves' disease patient with malignant exophthalmus revealed positive staining with anti-gag antibodies of fibroblasts and fat cells but not eye muscles. Furthermore, we were successful in establishing several T-cell lines derived from the retrobulbar tissue of this patient. They were CD8+ and proliferated, in contrast to peripheral blood cells, upon cocultivation with autologous retroorbital fibroblasts. It remains to be determined whether these observations are of relevance in the pathogenesis of Graves' disease.


Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease.
Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target α-emitters with short half-lives, such as bismuth-213 (²¹³Bi). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)(4)SA fusion protein (FP), followed by a dendrimeric clearing agent and [²¹³Bi]DOTA-biotin. After 90 minutes, tumor uptake for 1F5(scFv)₄SA was 16.5% ± 7.0% injected dose per gram compared with 2.3% ± .9% injected dose per gram for the control FP. Mice treated with anti-CD20 PRIT and 600 μ Ci [²¹³Bi]DOTA-biotin exhibited marked tumor growth delays compared with controls (mean tumor volume .01 ± .02 vs. 203.38 ± 83.03 mm³ after 19 days, respectively). The median survival for the 1F5(scFv)₄SA group was 90 days compared with 23 days for the control FP (P < .0001). Treatment was well tolerated, with no treatment-related mortalities. This study demonstrates the favorable biodistribution profile and excellent therapeutic efficacy attainable with ²¹³Bi-labeled anti-CD20 PRIT.


Evidence for Inhibition of Lysozyme Amyloid Fibrillization by Peptide Fragments from Human Lysozyme: A Combined Spectroscopy, Microscopy, and Docking Study.
Degenerative diseases, such as Alzheimer's and prion diseases, as well as type II diabetes, have a pathogenesis associated with protein misfolding, which routes with amyloid formation. Recent strategies for designing small-molecule and polypeptide antiamyloid inhibitors are mainly based on mature fibril structures containing cross β-sheet structures. In the present study, we have tackled the hypothesis that the rational design of antiamyloid agents that can target native proteins might offer advantageous prospect to design effective therapeutics. Lysozyme amyloid fibrillization was treated with three different peptide fragments derived from lysozyme protein sequence R(107)-R(115). Using low-resolution spectroscopic, high-resolution NMR, and STD NMR-restrained docking methods such as HADDOCK, we have found that these peptide fragments have the capability to affect lysozyme fibril formation. The present study implicates the prospect that these peptides can also be tested against other amyloid-prone proteins to develop novel therapeutic agents.


Identification of adrenoceptors and dopamine receptors mediating vascular responses in the superior mesenteric arterial bed of the rat.
The nature of the adrenoceptors and dopamine receptors mediating vascular responses in the in-situ blood perfused superior mesenteric arterial bed of the rat have been studied. alpha 1-Adrenoceptor agonists produced vasoconstriction but alpha 2-agonists had no significant effect on vascular resistance. The vasoconstrictor effects of noradrenaline were antagonized by low doses of prazosin (26 nmol kg-1 i.v.). Isoprenaline and salbutamol produced vasodilation when the vasculature was preconstricted with arginine vasopressin. The responses to isoprenaline were potently antagonized by propranolol (1.69 mumol kg-1 i.v.) and weakly but significantly reduced by practolol (3.75 mumol kg-1 i.v.) whereas the responses to salbutamol were unaffected by the same dose of practolol. After preconstriction of the vasculature and alpha-adrenoceptor blockade, dopamine and apomorphine produced dilator responses with both compounds producing the same maximal response and apomorphine being 1.8 times more potent than dopamine. The dopamine responses were present after the animals had been pithed and were resistant to spiperone (506 nmol kg-1 i.v.) but were antagonized by cis-alpha-flupenthixol (460 nmol kg-1 i.v.). These results suggest that this vascular bed possesses vasoconstrictor alpha 1- but not alpha 2-adrenoceptors, vasodilator beta 1- and beta 2-adrenoceptors and vasodilator dopamine receptors which appear similar to the D1-type found centrally.


A novel testis-stimulating factor in familial male precocious puberty.
Familial male precocious puberty is a gonadotropin-independent form of precocious puberty that occurs only in males. The cause of the disorder is unknown. To examine the hypothesis that the plasma of boys with familial male precocious puberty contains a novel stimulator of testicular testosterone production, we developed a bioassay using adult male cynomolgus monkeys. We collected plasma from 12 boys with familial male precocious puberty, 7 normal prepubertal boys of similar ages and with similar plasma gonadotropin levels, and 1 boy with hypogonadotropic hypogonadism and infused it into the testicular artery of adult male cynomolgus monkeys that had been pretreated with gonadotropin-releasing-hormone antagonist to inhibit the endogenous secretion of gonadotropins. Testicular venous effluent was collected at 15-minute intervals for 3 or 5 hours for the measurement of testosterone. The mean (+/- SE) peak testosterone response, as compared with base line, was significantly greater in the monkeys infused with plasma from the 12 boys with familial male precocious puberty than in the monkeys infused with plasma from the 7 normal prepubertal boys and the boy with hypogonadotropic hypogonadism (385 +/- 51 vs. 184 +/- 25 percent, P less than 0.005) in the three-hour studies. Plasma from 92 percent of the boys with familial male precocious puberty and 12.5 percent of the normal prepubertal boys stimulated a response greater than 195 percent of base-line values. In the animals studied for five hours after receiving a second dose of antagonist, the mean peak testosterone response, as compared with base line, was significantly greater in the monkeys infused with plasma from three boys with familial male precocious puberty than in the monkeys infused with plasma from three normal prepubertal boys (363 +/- 81 vs. 115 +/- 6 percent, P less than 0.01). The mean area under the testosterone-response curve was significantly larger in the monkeys infused with plasma from the boys with familial male precocious puberty in the five-hour studies (154 +/- 34 vs. -58 +/- 10 percent, P less than 0.005), but not in the three-hour studies. These findings support the presence of a circulating testis-stimulating factor in the plasma of boys with familial male precocious puberty. The production of such a factor would explain the biologic nature of the disorder.


Spontaneous intracranial internal carotid artery dissection: report of 10 patients.
Spontaneous intracranial internal carotid artery (ICA) dissection is an uncommon cause of cerebral infarction, particularly when compared with the dissection of the ICA's cervical portion. Most reports describe extensive strokes with very high mortality rates. To report the clinical and radiological findings of 10 patients with spontaneous intracranial ICA dissection. Ten patients (5 women) were included with ages ranging from 15 to 59 years (mean age, 28 years). Nine patients had a stroke (1 had an associated subarachnoid hemorrhage), whereas 1 patient had only transient ischemic attacks. Severe retro-orbital or temporal headache followed by contralateral hemiparesis was the most common initial clinical symptom. No patient had vascular risk factors or a history of neck or head trauma. Stenosis of the supraclinoid portion of the ICA occurred in 8 patients, with extension to the middle cerebral artery or anterior cerebral artery in 2 patients each. Aneurysm formation in the ipsilateral anterior cerebral artery was seen in 1 patient. Two patients had a total occlusion of the supraclinoid portion of the ICA. All patients did well, with no (n = 3), mild (n = 4), or moderate (n = 3) disability on the Modified Rankin Scale during a 3-month follow-up period. Spontaneous intracranial ICA dissection can cause ischemic stroke with or without subarachnoid hemorrhage and should be considered in the differential diagnosis of intracranial ICA stenosis or occlusion, especially in young patients. Some patients survive with few or moderate deficits.


Experimental Models, Induction Protocols, and Measured Parameters in Dry Eye Disease: Focusing on Practical Implications for Experimental Research.
Dry eye disease (DED) is one of the major ophthalmological healthcare challenges worldwide. DED is a multifactorial disease characterized by a loss of homeostasis of the tear film, and its main pathogenesis is chronic ocular surface inflammation related with various cellular and molecular signaling cascades. The animal model is a reliable and effective tool for understanding the various pathological mechanisms and molecular cascades in DED. Considerable experimental research has focused on developing new strategies for the prevention and treatment of DED. Several experimental models of DED have been developed, and different animal species such as rats, mice, rabbits, dogs, and primates have been used for these models. Although the basic mechanisms of DED in animals are nearly identical to those in humans, proper knowledge about the induction of animal models is necessary to obtain better and more reliable results. Various experimental models (in vitro and in vivo DED models) were briefly discussed in this review, along with pathologic features, analytical approaches, and common measurements, which will help investigators to use the appropriate cell lines, animal, methods, and evaluation parameters depending on their study design.


Cardiac allograft vasculopathy: Microvascular arteriolar capillaries ('capioles") and survival.
Cardiac allograft vasculopathy (CAV) is a serious complication of heart transplantation in adults and children. Risk factors include human leukocyte antigen mismatches, number and duration of rejection episodes, type of immunosuppression, antibody-mediated rejection, hypertension, hyperlipidemia, obesity, smoking, diabetes, cytomegalovirus infection, mode of donor brain death, donor age and ischemia/reperfusion injury. Endothelial injury and dysfunction in CAV are characterized by changes in adhesion molecules and up-regulation of major histocompatibility class II antigens followed by endothelial activation of complement C4d. Subsequently, activation of the coagulation cascade leads to deposition of fibrin on endothelium followed by proliferation and migration of vascular smooth muscle cells. The development of a special type of microvessels with phenotypic characteristics of arterial capillaries ("capioles") seems to provide a survival advantage for patients with CAV. Novel therapies of CAV include statins, and heparin-induced extracorporeal low-density lipoprotein apheresis. B beta15-42 which is a fibrin peptide has been shown to improve the graft microvasculature and to reduce ischemia/reperfusion-induced damage. Despite these advances, there is a need to identify and stratify individual CAV risk factors, to develop early biomarkers of CAV, and to better decipher the events that lead to antibody-mediated rejection.


Surgical treatment for recurrent spontaneous pneumothorax during twin pregnancy under video-assisted thoracoscopic surgery (VATS).
Spontaneous pneumothorax during pregnancy is a rare pathological condition. Few cases have been reported previously in the literature. There is no universal guideline for the management of this condition yet. We report a case of recurrent spontaneous pneumothorax during twin pregnancy in a 30-year-old woman. Surgical treatment under video-assisted thoracoscopic surgery (VATS) was successfully performed, without subsequent pneumothorax recurrence.


Effect of Comprehensive Nursing Intervention on the Effect of CT-Guided Intravenous Thrombolysis in Acute Cerebral Infarction.
To investigate the effect of comprehensive nursing intervention on the effect of CT-guided intravenous thrombolytic therapy for acute cerebral infarction. 99 patients with acute cerebral infarction in the internal carotid artery system who were hospitalized in our department from December 2019 to December 2020 with an onset of 3-9 h were selected and randomly divided into two groups. All patients underwent multimode CT examinations and received rt-PA thrombolytic therapy. 52 patients with conventional care were included in the control group, and 47 patients with comprehensive nursing intervention were included in the observation group. The influence characteristics, Barthel score, serum MMP-9 level, and NIHSS score were compared between the two groups. After the comprehensive nursing intervention, the total efficiency, total satisfaction, psychological status, and Barthel score of the observation group were significantly higher than those of the control group (P < 0.05). The serum MMP-9 level and NIHSS score were significantly lower than those of the control group (P < 0.05). The use of comprehensive nursing interventions in the CT-guided intravenous thrombolysis treatment of ACI patients reduced the degree of neurological impairment, improved the therapeutic effect, increased nursing satisfaction, and enabled better control of the condition of patients with cerebral infarction, which is worth promoting research.


Transcriptional activation of hepcidin by the microphthalmia/transcription factor E family.
Hepcidin negatively regulates the circulating iron levels by inhibiting the intestinal absorption of iron as well as iron release from macrophages. Hepcidin activity is largely determined by its expression, which is regulated at the transcriptional level. Hepcidin transcription is induced not only by the iron status-related bone morphogenetic protein (BMP)-2/6, but also by inflammatory cytokines, such as interleukin (IL)-1β and IL-6. The present study reveals that the microphthalmia (MiT)/transcription factor E (TFE) family members are novel regulators of hepcidin transcription. Melanocyte-inducing transcription factor (MITF)-A, a member of the MiT/TFE family, was identified as a positive regulator of hepcidin transcription via stimulus screening for transcription regulators. An E-box (5'-CATGTG-3') spanning nt-645 to nt-640 of the murine hepcidin promoter was identified as an MITF-A-responsive element. Responsiveness to MITF-A on hepcidin transcription decreased when the cells were stimulated with BMP2 or IL-1β. These results suggest a functional interaction between the MITF pathway and BMP- or IL-1β-mediated signaling. TFEB and TFE3, members of the MiT/TFE family, also stimulated hepcidin transcription, but the main region responsible for hepcidin transcription was distinct from that induced by MITF-A. The region spanning nt-581 to nt-526 was involved in TFEB/TFE3-mediated hepcidin transcription. Considering that members of the MiT/TFE family act as regulators of starvation-induced lysosomal biogenesis, hepcidin expression may be controlled by additional pathways apart from those identified so far.


Increasing marketing share through good design.
Adjusting to the pressures of competition, health care executives and trustees are looking for creative ways to position their facilities for future success by using architecture as a marketing tool. The corporate world has for some time used architectural design to achieve marketing goals. This approach is now being used in health. The author cites examples where hospitals have used architecture to reach target customers, successfully support efforts at niche marketing and convey a specific message or image.


Fecal Carriage of Enterobacteriaceae Producing Extended-Spectrum Beta-Lactamases in Hospitalized Patients and Healthy Community Volunteers in Burkina Faso.
Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) have been described worldwide, but few reports focused on Burkina Faso. To assess the prevalence of digestive carriage of such bacteria in the community and in the hospital, 214 fecal samples, 101 from healthy volunteers and 113 from hospitalized patients without digestive pathology, were collected in Bobo Dioulasso, Burkina Faso economic capital, during July and August 2014. Stool samples were screened using ESBL agar plates. Strains were identified by mass spectrometry using the Biotyper MALDI-TOF. ESBL production was confirmed with the double-disc synergy test. Susceptibility was tested using the disk diffusion method on Müller-Hinton agar. The main ESBL genes were detected using multiplex PCR and bidirectional gene sequencing. Escherichia coli phylogenetic groups were identified using a PCR-based method. During the study period, prevalence of subjects with fecal ESBL-PE was 32% (69/214), 22% among healthy volunteers and 42% among inpatients. All but two ESBL, CTX-M-15 and ESBL-PE, were mostly E. coli (78%). Among the 60 ESBL-producing E. coli strains, 26% belonged to phylogenetic group D, 23.3% to group A, 20% to group B1, 6.6% to group B2, and 3.3% to the ST131 clone. Univariate analysis showed that history of hospitalization and previous antibiotic use were risk factors associated with ESBL-PE fecal carriage. In Burkina Faso, the prevalence of both healthy subjects from the community and hospitalized patients with fecal ESBL-PE is alarmingly high. This feature should be taken into consideration by both general practitioners and hospital doctors with regard to empirical treatments of infections, notably urinary tract infections.


BcsKC is an essential protein for the type VI secretion system activity in Burkholderia cenocepacia that forms an outer membrane complex with BcsLB.
The type VI secretion system (T6SS) contributes to the virulence of Burkholderia cenocepacia, an opportunistic pathogen causing serious chronic infections in patients with cystic fibrosis. BcsK(C) is a highly conserved protein among the T6SSs in Gram-negative bacteria. Here, we show that BcsK(C) is required for Hcp secretion and cytoskeletal redistribution in macrophages upon bacterial infection. These two phenotypes are associated with a functional T6SS in B. cenocepacia. Experiments employing a bacterial two-hybrid system and pulldown assays demonstrated that BcsK(C) interacts with BcsL(B), another conserved T6SS component. Internal deletions within BcsK(C) revealed that its N-terminal domain is necessary and sufficient for interaction with BcsL(B). Fractionation experiments showed that BcsK(C) can be in the cytosol or tightly associated with the outer membrane and that BcsK(C) and BcsL(B) form a high molecular weight complex anchored to the outer membrane that requires BcsF(H) (a ClpV homolog) to be assembled. Together, our data show that BcsK(C)/BcsL(B) interaction is essential for the T6SS activity in B. cenocepacia.


Nonlinear Feature Extraction Through Manifold Learning in an Electronic Tongue Classification Task.
A nonlinear feature extraction-based approach using manifold learning algorithms is developed in order to improve the classification accuracy in an electronic tongue sensor array. The developed signal processing methodology is composed of four stages: data unfolding, scaling, feature extraction, and classification. This study aims to compare seven manifold learning algorithms: Isomap, Laplacian Eigenmaps, Locally Linear Embedding (LLE), modified LLE, Hessian LLE, Local Tangent Space Alignment (LTSA), and t-Distributed Stochastic Neighbor Embedding (t-SNE) to find the best classification accuracy in a multifrequency large-amplitude pulse voltammetry electronic tongue. A sensitivity study of the parameters of each manifold learning algorithm is also included. A data set of seven different aqueous matrices is used to validate the proposed data processing methodology. A leave-one-out cross validation was employed in 63 samples. The best accuracy (96.83%) was obtained when the methodology uses Mean-Centered Group Scaling (MCGS) for data normalization, the t-SNE algorithm for feature extraction, and k-nearest neighbors (kNN) as classifier.


Points to consider for designing trials in systemic sclerosis patients with arthritic involvement.
Although musculoskeletal involvement is quite common in SSc (arthritic in particular), there have been few trials and even fewer controlled trials of therapeutic agents in arthritis in SSc. In addition, there have been only three outcome measures that have been validated for use in trials of SSc arthritis: the HAQ Disability Index, the Cochin Hand Function Scale and the Hand Mobility in SSc scale. The purpose of this article is to present evidence-based points to consider for the design of trials in SSc patients with musculoskeletal involvement (joints in particular). In addition, we make an argument for including outcome variables that can be validated within a given trial for use in future trials.


Toxicity measurement of orthopedic implant alloy degradation products using a bioluminescent bacterial assay.
The toxicity of aqueous metal solutions representative of ionic degradation products from orthopedic implant alloys was determined using a bacterial bioluminescence assay, Microtox. The toxicity of forms of the individual elements released from ASTM F75 Co-Cr-Mo (Co-Cr-Mo), F138 316L stainless steel (316L), and F136 Ti-6Al-4V (Ti-6Al-4V) was first determined, and a mathematical model was developed to predict the toxicity of mixtures of these ions. Aqueous metal solutions were then mixed according to the proportions of the ions found in these alloys, and their toxicity was measured with Microtox. Mixture behavior was classified as synergistic, antagonistic, or additive by comparing measured toxicity to predicted toxicity. Since relating these tests to actual implant corrosion processes can be confounded by selective leaching, the predicted and measured toxicity of aqueous metal solutions mixed according to proportions representative of selective leaching were next determined, and the mixture behaviors were classified as before. The most toxic individual alloying elements were found to be hexavalent Cr, Ni, and Co, in that order: a finding in accord with prior biocompatibility research. Co-Cr-Mo was found to be the most toxic alloy mixture of both those combined according to alloy composition and those combined to reflect selective leaching. The Ti-6Al-4V mixtures were found to behave synergistically, while the Co-Cr-Mo and 316L mixtures behaved antagonistically. By providing insight into degradation product toxicity and elemental interaction, these experiments demonstrate the utility of employing bioluminescent bacterial assays to investigate biocompatibility of implant materials. Further studies to more closely simulate in vivo conditions, though, are required to fully gauge their potential in this regard.


Prostaglandin E2-dependent enhancement of tissue inhibitors of metalloproteinases-1 production limits dendritic cell migration through extracellular matrix.
Dendritic cell (DC) migration is crucial for the initiation of immune responses. The balance between metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) has been shown to modulate DC migration. PGE2, which is overproduced in a wide variety of human malignancies, has been implicated in MMP and TIMP regulation in various cells, including monocytes. In the present study, we hypothesized that tumor-derived PGE2 would affect DC migratory capacity through the extracellular matrix (ECM) by altering MMP and TIMP balance. Treatment of monocyte-derived immature DC with exogenous PGE2 induced TIMP-1 secretion but not MMP-9 production and was correlated with reduced DC migration through ECM. Because recombinant TIMP-1 replicated PGE2 inhibition of DC migration while anti-TIMP-1 neutralizing Ab reversed it, we conclude that PGE2-mediated induction of TIMP-1 was responsible for the reduced migration of PGE2-treated DC. Similarly, DC cultured for 48 h in supernatants from cyclooxygenase-2 overexpressing lung cancer cells that secrete high levels of PGE2, exhibited decreased migration through ECM. Finally, analysis of E prostanoid receptor expression and their selective inhibition revealed that the enhanced TIMP-1 secretion in PGE2-treated DC was mediated predominantly by the E prostanoid receptor 2. These findings indicate that PGE2-dependent enhancement of TIMP-1 production causes reduced migration of DC through ECM.


Lead contamination of small cetaceans in European waters--the use of stable isotopes for identifying the sources of lead exposure.
Lead concentrations and isotopic composition have been measured in bone and teeth of small cetaceans belonging to three species (Delphinus delphis, Phocoena phocoena and Stenella coeruleoalba), to evaluate the toxicological risk and to determine sources of lead in the European waters. Lead concentrations, far lower than threshold value inducing toxic effects in human, were higher in teeth than in bones, but highly correlated between the two tissues (r=0.92, p<0.001). Large variations of 206Pb/207Pb values in bone tissue showed that cetaceans must be submitted to various atmospheric influences. No geographical differences appeared which is consistent with studies on their distribution indicating seasonal movements between Brittany waters and the Bay of Biscay. The negative correlation between 206Pb/207Pb ratios and age of the individuals reflected the decrease in the production of alkyl lead in Europe, i.e., the increasing use of unleaded gasoline.


Legacy of Polio-Use of India's Social Mobilization Network for Strengthening of the Universal Immunization Program in India.
The Social Mobilization Network (SMNet) has been lauded as one of the most successsful community engagement strategies in public health for its role in polio elimination in India. The UNICEF-managed SMNet was created as a strategy to eradicate polio by engaging >7000 frontline social mobilizers to advocate for vaccination in some of the most underserved, marginalized, and at-risk communities in India. This network focused initially on generating demand for polio vaccination but later expanded its messaging to promote routine immunization and other health and sanitation interventions related to maternal and children's health. As an impact of the network's interventions, in collaboration with other eradication efforts, these high-risk pockets witnessed an increase in full routine immunization coverage. The experience of the SMNet offers lessons for health-system strengthening for social mobilization and promoting positive health behaviors for other priority health programs like the Universal Immunization Program.


Kinetics of early HIV-1 gene expression in infected H9 cells assessed by PCR.
The time course of viral gene expression in H9 cells acutely infected with HIV-1 was analysed by the polymerase chain reaction (PCR). Virus-specific sequences were first detected in genomic DNA of H9 cells 1-2 h after infection. RNA for the regulatory genes such as the tat and nef appeared 2-3 h post-infection and RNA for the gag and env at 3 h. The results demonstrate that viral DNA synthesis occurs rapidly after infection of target cells followed by synthesis of viral RNA. Cell-associated reverse transcriptase activity increased after 24 h, while culture supernatant enzyme activity increased later, between 1-5 days. The delay in virus release after rapid integration and transcriptional activity suggests the involvement of additional factors, perhaps both cellular and viral, that control the formation and budding of mature virions.


Thyroid function is associated with non-alcoholic fatty liver disease in euthyroid subjects.
This study was designed to test the hypothesis that normal thyroid function is associated with non-alcoholic fatty liver disease (NAFLD) in euthyroid general subjects. A total of 739 euthyroid subjects were enrolled in this cross-sectional study. Using ultrasound, a diagnosis of NAFLD was made in subjects without a history of excessive alcohol consumption or liver diseases. Fasting serum samples were collected for determining thyroid function [thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels] and other biochemical parameters. Among the enrolled subjects, 196 (26.5%) satisfied the diagnostic criteria for NAFLD. Subjects with NAFLD had significantly higher TSH levels and lower FT4 levels than those without NAFLD (p < 0.01 for both). NAFLD prevalence increased gradually with increasing quartiles of TSH levels and decreasing quartiles of FT4 levels. After adjustment for gender and age, TSH levels were found to correlate positively with body mass index (BMI), waist circumference (WC), and LDL-cholesterol levels (p < 0.05 for all) and negatively with HDL-cholesterol levels (p < 0.01). FT4 levels correlated negatively with both BMI and WC (p < 0.05 for both). Multiple logistic regression analysis showed that TSH and FT4 levels were independent risk factors for NAFLD [odds ratio (OR): 2.21, 95% confidence interval (CI): 1.21-4.02, p = 0.01, for TSH levels; OR: 0.39, 95% CI: 0.17-0.87, p = 0.02, for FT4 levels]. Our findings suggest that serum FT4 and TSH levels, even those within the reference range, are associated with NAFLD in the general population, independent of known metabolic risk factors.


Taphonomic patterns mimic biologic structures: diagenetic Liesegang rings in Mesozoic coleoids and coprolites.
Because of physiology of coleoids, their fossils preserve soft-tissue-remains more often than other cephalopods. Sometimes, the phosphatized soft-tissues, particularly parts of the muscular mantle, display dark circular patterns. Here, we showcase that these patterns, here documented for fossil coleoids from the Jurassic of Germany and the Cretaceous of Lebanon, superficially resemble chromatophores (which enable living coleoids to alter their coloration). We examined and chemically analyzed the circular structures in these specimens, describe them, and discuss their genesis. Based on their structure and color, we visually differentiate between three types of circles. By comparison with similar structures, we suggest that these structures are not biogenic but Liesegang rings, which formed due to reaction-diffusion processes very soon after death.


Protein Aggregation of NPAS3, Implicated in Mental Illness, Is Not Limited to the V304I Mutation.
An emerging phenomenon in our understanding of the pathophysiology of mental illness is the idea that specific proteins may form insoluble aggregates in the brains of patients, in partial analogy to similar proteinopathies in neurodegenerative diseases. Several proteins have now been detected as forming such aggregates in the brains of patients, including DISC1, dysbindin-1 and TRIOBP-1. Recently, neuronal PAS domain protein 3 (NPAS3), a known genetic risk factor for schizophrenia, was implicated through a V304I point mutation in a family with major mental illness. Investigation of the mutation revealed that it may lead to aggregation of NPAS3. Here we investigated NPAS3 aggregation in insular cortex samples from 40 individuals, by purifying the insoluble fraction of these samples and testing them by Western blotting. Strikingly, full-length NPAS3 was found in the insoluble fraction of 70% of these samples, implying that aggregation is far more widely spread than can be accounted for by this rare mutation. We investigated the possible mechanism of aggregation further in neuroblastoma cells, finding that oxidative stress plays a larger role than the V304I mutation. Finally, we tested to see if NPAS3 aggregation could also be seen in blood serum, as a more accessible tissue than the human brain for future diagnosis. While no indication of NPAS3 aggregation was seen in the serum, soluble NPAS3 was detected, and was more prevalent in patients with schizophrenia than in those with major depressive disorder or controls. Aggregation of NPAS3 therefore appears to be a widespread and multifactorial phenomenon. Further research is now needed to determine whether it is specifically enhanced in schizophrenia or other mental illnesses.


An unstructured protein with destructive potential: TPPP/p25 in neurodegeneration.
TPPP/p25 is a recently discovered, unstructured protein involved in brain function. It is found predominantly in oligodendrocytes in normal brain but is enriched in neuronal and glial inclusions of Parkinson's disease and other synucleinopathies. Its physiological function seems to be the dynamic stabilization of microtubular ultrastructures, as well as the projections of mature oligodendrocytes and ciliary structures. We reappraise the earlier belief that TPPP/p25 is a brain-specific protein. We have identified and cloned two shorter (N-terminal-free) homologs of TPPP/p25 that behave differently from each other and from TPPP/p25. Two unique cell models have been established and used to study the effect of the unstructured protein on the energy metabolism and the formation of pathological aggregates. Our data suggest that the intracellular level of TPPP/p25 influences the cell differentiation, proliferation and the formation of protein aggregates, and consequently, the etiology of central nervous system diseases.


A kinetic study on the hydrolytic activity of mitochondrial ATPase (F0-F1 complex) from pig heart.
A kinetic study of mitochondrial ATPase (F0-F1 complex) from pig heart reported in this paper shows that when it was incubated with free Mg2+ (0-2mM), the hydrolytic activity of the ATPase was competitively activated by the Mg2+ and revealed no cooperativity. In the case of incubation with free ATP the hydrolytic activity was competitively inhibited and revealed positive cooperativity. These results are quite different from those of free F1 as obtained by Gautheron and coworkers (1). This indicates that either Mg2+ or ATP produces different effects on F1 when it is in different states, i.e., free state and membrane bound state. This may be considered to mean that the conformation of F1 in membrane bound state, which is influenced by F0 and membrane lipids is different from that of F1 in free state, thus exhibiting different catalytic site cooperativity between subunits, which is the fundamental feature of the mechanism of the enzyme action.


Respiratory movement patterns during vocalizations at 7 and 11 months of age.
The present investigation was designed to study the modulation of abdomen and rib cage movements during vocalization over a period of development associated with rapid decreases in the compliance of the chest wall. Rib cage and abdominal kinematics were recorded during spontaneous vocalizations in 7- and 11-month old infants. Principal component analysis was used to represent each infant's abdomen and rib cage traces as the weighted sum of a small number of principal component (PC) waveforms. The fundamental periods of infants' PC waveforms in the 11-month group were significantly shorter than those in the 7-month group. In addition, the variance contributed by PCs describing unidirectional patterns of respiratory movement decreased in the 11-month group, whereas the variances contributed by PCs describing modulated patterns of movement increased. Lastly, the extent to which abdomen and rib cage movements predicted the duration of corresponding vocalizations also increased significantly in the 11-month group compared with the 7-month group. The findings of the present study were consistent with the hypothesis that decreases in the compliance of the chest wall result in more rapid modulation of chest wall movements and greater control of those movements by the developing neuromuscular system.


Enterococcal PrgA Extends Far Outside the Cell and Provides Surface Exclusion to Protect against Unwanted Conjugation.
Horizontal gene transfer between Gram-positive bacteria leads to a rapid spread of virulence factors and antibiotic resistance. This transfer is often facilitated via type 4 secretion systems (T4SS), which frequently are encoded on conjugative plasmids. However, donor cells that already contain a particular conjugative plasmid resist acquisition of a second copy of said plasmid. They utilize different mechanisms, including surface exclusion for this purpose. Enterococcus faecalis PrgA, encoded by the conjugative plasmid pCF10, is a surface protein that has been implicated to play a role in both virulence and surface exclusion, but the mechanism by which this is achieved has not been fully explained. Here, we report the structure of full-length PrgA, which shows that PrgA protrudes far out from the cell wall (approximately 40 nm), where it presents a protease domain. In vivo experiments show that PrgA provides a physical barrier to cellular adhesion, thereby reducing cellular aggregation. This function of PrgA contributes to surface exclusion, reducing the uptake of its cognate plasmid by approximately one order of magnitude. Using variants of PrgA with mutations in the catalytic site we show that the surface exclusion effect is dependent on the activity of the protease domain of PrgA. In silico analysis suggests that PrgA can interact with another enterococcal adhesin, PrgB, and that these two proteins have co-evolved. PrgB is a strong virulence factor, and PrgA is involved in post-translational processing of PrgB. Finally, competition mating experiments show that PrgA provides a significant fitness advantage to plasmid-carrying cells.


Alloy Partitioning Effect on Strength and Toughness of κ-Carbide Strengthened Steels.
Alloy partitioning during heat treatment in a lightweight precipitation hardened steel was investigated using transmission electron microscopy and atom probe tomography. The mechanical properties are discussed as a function of the effect of solution treatment temperature and aging time, giving rise to variations in chemical modulation. A wrought lightweight steel alloy with a nominal composition of Fe-30Mn-9Al-1Si-1C-0.5Mo (wt. %) was solution-treated between 1173-1273 K and aged at 773 K. Lower solution treatment temperatures retained a finer grain size and accelerated age hardening response that also produced an improved work hardening behavior with a tensile strength of -1460 MPa at 0.4 true strain. Atom probe tomography indicated these conditions also had reduced modulation in the Si and Al content due to the reduced aging time preventing silicon from diffusing out of the κ-carbide into the austenite. This work provides the framework for heat-treating lightweight, age hardenable steels with high strength and improved energy absorption.


Abscisic Acid accumulation in spinach leaf slices in the presence of penetrating and nonpenetrating solutes.
Abscisic acid (ABA) accumulated in detached, wilted leaves of spinach (Spinacia oleracea L. cv Savoy Hybrid 612) and reached a maximum level within 3 to 4 hours. The increase in ABA over that found in detached turgid leaves was approximately 10-fold. The effects of water stress could be mimicked by the use of thin slices of spinach leaves incubated in the presence of 0.6 molar mannitol, a compound which causes plasmolysis (loss of turgor). About equal amounts of ABA were found both in the leaf slices and in detached leaves, whereas 2 to 4 times more ABA accumulated in the medium than in the slices. When spinach leaf slices were incubated with ethylene glycol, a compound which rapidly penetrates the cell membrane causing a decrease in the osmotic potential of the tissue and only transient loss of turgor, no ABA accumulated. Ethylene glycol was not inhibitory with respect to ABA accumulation. Spinach leaf slices incubated in both ethylene glycol and mannitol had ABA levels similar to those found when slices were incubated with mannitol alone. Increases similar to those found with mannitol also occurred when Aquacide III, a highly purified form of polyethylene glycol, was used. Aquacide III causes cytorrhysis, a situation similar to that found in wilted leaves. Thus, it appears that loss of turgor is essential for ABA accumulation.When spinach leaf slices were incubated with solutes which are supposed to disturb membrane integrity (KHSO(3), 2-propanol, or KCl) no increase in ABA was observed. These data indicate that, with respect to the accumulation of ABA, mannitol caused a physical stress (loss of turgor) rather than a chemical stress (membrane damage).


Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus placebo.
Knee osteoarthritis (OA) is prevalent and associated with both pain and functional disability. Current treatments aim to alleviate mild to moderate symptoms by various methods. Topical capsaicin (0.075% and 0.05%) has been evaluated for the treatment of the painful joints. A burning sensation was the most common side effect at these strengths. Therefore, the authors aimed to evaluate the efficacy of 0.0125% capsaicin gel (Capsika gel) compared to a placebo (the vehicle gel) in patients with symptomatic OA knee. This was a cross-over; double blinded, randomized, controlled trial of 100 patients with mild to moderate knee OA. All of the patients received either capsaicin gel or placebo gel applied to the affected knee, three times daily for 4 weeks with one week washout period after which the treatment switched to either capsaicin gel or placebo gel for the next 4 weeks. A blinded examiner used the visual analog scale (VAS) and WOMAC score to do weekly assessments. Subjects averaged 61 years of age (range, 44 to 82). During the enrollment phase, only female farmers presented. Mean body weight and height was 62.97 +/- 10.25 kg and 1.54 +/- 0.053 m, respectively The respective baseline VAS and WOMAC score was 6.40 +/- 1.64 and 51.65 +/- 13.3. The severity of OA, according to the KL criteria was: 83 patients with grade 2 and 16 with grade 3. The respective mean difference of VAS and total WOMAC score in the capsaicin group vs. the placebo group was statistically significant (p < 0.05). The mean difference of the WOMAC pain, stiffness and functional subscales in the capsaicin vs. the placebo group was also significant (p < 0.05). The only adverse event reported was a burning sensation. During the 4-week treatment with capsaicin, approximately 67% of patients had a burning sensation but none withdrew for this reason. 0.0125% capsaicin gel was an effective treatment in mildly to moderately painful OA knees. The burning sensation reported by patients in the capsaicin group was less disturbing than in previous studies and none of the present patients withdrew for this reason.


Maternal Emotional States in Relation to Offspring Weight and Health-Related Quality of Life: Tehran Lipid and Glucose Study.
Maternal characteristics have been known to be associated with parenting practices, which could eventually influence their child's weight and health-related quality of life (HRQoL). This study aimed to assess the direct and indirect associations of maternal emotional states (depression, anxiety, and stress) with body mass index (BMI) and HRQoL in their children. This study was conducted within the framework of the Tehran lipid and glucose study (TLGS). Participants were the children (n = 231) enrolled in TLGS during 2014 - 2016, who had complete data on maternal emotional states. The body weight and height of children were measured using the standard protocol, and BMI Z-score was determined using Anthroplus. Also, HRQoL in children and emotional states in mothers were assessed using the Iranian version of the pediatric quality of life inventory (PedsQLTM4.0) and the depression, anxiety, and stress scale (DASS-21), respectively. Structural equations modeling (SEM) was used to assess the direct and indirect relations of maternal emotional states with children's BMI Z-score and HRQoL. Mean age, BMI Z-score, and HRQoL total score in children were 13.8 ± 3.1 years, 0.74 ± 1.5, and 84.7 ± 11.3, respectively. In the mothers, median DASS-21 scores (interquartile ranges) in the three scales of depression, anxiety, and stress were 4 (0 - 10), 6 (2 - 12), and 14 (8 - 20), respectively. Maternal level of education was significantly associated with the DASS-21 score (β = -0.23, 95% CI: -0.37,-0.07). Maternal DASS-21 score was significantly associated with BMI Z-score only in girls (β = 0.25, 95% CI: 0.06, 0.53). Significant determinants of HRQoL in boys were the child's age (β = -0.21, 95% CI: -0.40, -0.01) and maternal education (β = -0.24, 95%CI: -0.44, -0.02) and emotional state (β = -0.24, 95% CI: -0.44, -0.03). The child's age (β = -0.33, 95% CI: -0.53, -0.10) and maternal emotional state (β = -0.31, 95% CI: -0.54, -0.08) were significantly associated with HRQoL in girls. The maternal emotional state is an important determinant of HRQoL in children, regardless of their weight status. Further research is recommended to examine the current hypothesized model in rural and suburban populations, taking into consideration more influential factors.


The integrin alpha(v)beta(3) and CD44 regulate the actions of osteopontin on osteoclast motility.
In the studies reported here we demonstrate that osteopontin is secreted from the basolateral surfaces of osteoclasts where it binds to the avb3-integrin, suggesting that it may be an autocrine factor. Osteopontin stimulation of osteoclasts produced changes in cell shape by causing disruption of peripheral podosome structures and formation of actin filaments at the leading edge of the migrating osteoclasts. The latter was part of the assumption of a motile phenotype prior to cells reforming peripheral ring type podosome containing clear zones. It is well established in our laboratory as well as in others that osteopontin stimulated osteoclast motility and bone resorption. The effect of osteopontin was mimicked by RGD containing peptides and blocked by a avb3 antibody, demonstrating that signals generated by integrin ligation contributed to the actions of osteopontin. In addition, the migratory effects of osteopontin on osteoclasts were also mediated through CD44 receptors since blocking antibodies to CD44 blocked stimulation of motility. Our data strongly suggest that osteopontin is an osteoclast autocrine motility factor binding to avb3 and CD44 during stimulation of osteoclast migration.


Active Videogaming Compared to Unstructured, Outdoor Play in Young Children: Percent Time in Moderate- to Vigorous-Intensity Physical Activity and Estimated Energy Expenditure.
The majority of children do not achieve recommended amounts of moderate- to vigorous-intensity physical activity (MVPA). Active videogames (AVGs) may be a source of MVPA for young children. Thus, the purpose of this study was to compare, in children 5-8 years of age, percentage of time engaged in MVPA, assessed via accelerometry and direct observation (DO), and estimated energy expenditure (EE), assessed via accelerometry, while playing AVG and unstructured, outdoor play (OP). Sixteen normal-weight young children (6.4±0.8 years old, 62.5 percent male, 81.3 percent white, standardized body mass index=-0.18±0.66) completed two 15-minute sessions of AVG and OP. For AVG, participants played "River Rush" (Xbox(®) 360 Kinect(®); Microsoft Corp., Redmond, WA), and OP was conducted in an outdoor playground. Three Actical (Philips Respironics Co. Inc., Bend, OR) accelerometers (hip and left and right wrists) measured percentage MVPA and estimated EE. DO was conducted using the Children's Activity Rating Scale, from which percentage MVPA was coded. Repeated-measures analysis of variance controlling for condition differences in humidity and condition order found greater percentage MVPA in AVG condition with the accelerometer located on the hip (AVG=74.6±31.1 percent versus OP=67.5±31.1 percent; P<0.05, d=0.23) and with DO (AVG=23.8±12.4 percent versus OP=13.2±13.0 percent; P<0.05, d=0.83). These findings suggest that AVGs may be a source of MVPA for young children.


[Epidemic of methicillin-resistant Staphylococcus aureus due to the transfer of 2 Dutch burn patients from a hospital outside of the Netherlands; who suffers the consequences?].
Two burns patients who were transferred to the Central Military Hospital Utrecht from a foreign hospital, were found to be colonised with MRSA. During their 5-week hospitalisation, 21 healthcare workers and one patient became colonised with the same MRSA strain, despite isolation precautions. The department was closed for 29 days; 96 admissions were cancelled and 1411 screening cultures for MRSA were performed. Colonised healthcare workers were temporarily unable to work and additional costs were incurred for disposables and cleaning procedures. The resultant bill for this outbreak was approximately [symbol: see text] 122,500. MRSA outbreaks occur in hospitals with some degree of regularity, but the strong dispersal during this epidemic was exceptional. The transfer of possible MRSA-colonised patients from hospitals outside of the Netherlands sometimes faces opposition due to the considerable demands it makes on a hospital's personnel, organisation and finances. If this were to be compensated, then the currently successful Dutch MRSA policy could be coupled with a willingness to accept patients from hospitals outside of the Netherlands.


Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: a subanalysis of data from the randomized phase III GeparSepto trial.
The neoadjuvant phase III GeparSepto study showed that substituting nab-paclitaxel for standard solvent-based paclitaxel significantly improved the pathologic complete response (pCR) rate achieved with a sequential neoadjuvant chemotherapy regimen of paclitaxel, epirubicin, and cyclophosphamide for high-risk primary breast cancer. Recent trials demonstrated that in HER2+ breast cancer pCR can be increased by using pertuzumab in addition to trastuzumab and chemotherapy. The present analysis focuses on efficacy and safety data from the subset of patients with HER2+ tumors from the GeparSepto trial (n = 396) in comparison to the HER2- cohort. Patients with histologically confirmed breast cancer (n = 1206) received four cycles of weekly paclitaxel [either solvent-based (Pac) or nab-paclitaxel (nab-Pac), according to randomization] followed by 4 cycles of epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 q3w, with concurrent trastuzumab and pertuzumab q3w for those with HER2+ tumors. The primary endpoint was pCR defined as ypT0 ypN0. Higher rates of pCR were achieved in HER2+ than in HER2- tumors (57.8% versus 22.0%, P < 0.0001), with the highest rate in the HER2+/HR- cohort (71.0%; 66.7% Pac, 74.6% nab-Pac). In HER2+/HR+ tumors, the pCR rate was 52.9% (49.7% Pac, 56.4% nab-Pac). Grade ≥3 toxic effects were significantly more common in HER2+ than in HER2- patients, with grade 3-4 diarrhea in 7.6% versus 0.9% (P < 0.001) and febrile neutropenia in 6.3% versus 3.3% (P = 0.023) of patients. Left ventricular ejection fraction decreases from baseline were uncommon, with 2.0% versus 0.4% of patients showing decreases to <50% along with a ≥10% decrease from baseline. In HER2+ early breast cancer, a dual HER2-targeted combination of pertuzumab and trastuzumab, together with taxane-epirubicin-cyclophosphamide neoadjuvant chemotherapy, achieved high rates of pCR.


A case of unknown origin subarachnoid hemorrhage immediately following drainage for chronic subdural hematoma.
A 56-year-old man treated with anticoagulants complained of a gradually worsening headache. A left chronic subdural hematoma (CSH) was shown by head computed tomographic (CT) scans and the operation, one burr hole surgery under local anesthesia, itself was performed uneventfully. However, immediately after we began draining the hematoma at the patient's bedside, the patient complained of a sudden headache. CT scans showed a subarachnoid hemorrhage (SAH). Cerebral angiography was immediately performed, but the source of hemorrhage could not be found. The next day, a CT scan showed that most of the SAH had disappeared. To our knowledge, there are no previous reports of SAH of unknown origin following surgery for CSH. The likely mechanism for the occurrence of the SAH, in addition to a coagulopathy due to anticoagulant therapy, could include the possibility that the drainage of the hematoma produced a movement of the hemisphere along with hyperperfusion that resulted in the rupture of a weak subarachnoid vessel, such as a perforating artery.


Diagnostic Yield of Rescreening Adults for Pulmonary Arteriovenous Malformations.
To determine the yield of rescreening adult hereditary hemorrhagic telangiectasia (HHT) patients with initial negative screening CT for pulmonary arteriovenous malformations (PAVMs). Patients with a definite diagnosis of HHT were identified in the University of Toronto, Université de Montréal, and Mayo Clinic HHT databases. Inclusion criteria were: (i) definite diagnosis of HHT; (ii) initial negative PAVM screening based on bubble echocardiography and/or chest CT; and (iii) minimum 2-year imaging follow-up. A positive rescreen was defined as a newly detected PAVM on follow-up CT. Frequency of new PAVMs was calculated at 3 ± 1 years, 5 ± 1 years, 7-9 years, and ≥10 years. The primary endpoint was the rate of new PAVMs at 5 ± 1 years. One hundred seventy-two patients (mean age, 49.6 ± 16.7 years; 59% female) were followed for a median of 7 years. Nine patients (5.2%) had newly detected PAVMs. At the 3-, 5-, 7-, and ≥10-year time points, the cumulative rate of newly detected PAVMs was 1.8% (3/166), 5.0% (7/140), 8.8% (8/91), and 13.8% (9/65), respectively. Median feeding artery diameter was 1.3 mm. One patient had a feeding artery larger than 3 mm discovered after 6 years and was treated with embolization. The overall rate of newly detected PAVMs was 0.7%/patient-year. There is a definite but low rate of newly detected PAVMs in HHT patients with initial negative screening studies. No new treatable PAVMs were identified at the 5-year mark, although 1 treatable case was identified after 6 years. These findings suggest that a longer screening interval may be warranted.


Sugar uptake by cotton tissues: leaf disc versus cultured roots.
The tissue accumulation of sucrose, glucose, and fructose has been studied in cultured cotton (Gossypium hirsutum L.) roots and leaf discs. Sucrose uptake by both tissues from high apoplastic concentrations was independent of pH but has a slightly acidic pH optimum from low concentrations. Like other higher plant tissues, cotton root cells accumulate sucrose via a ;saturable,' inhibitor-sensitive mechanism and a linear, inhibitor-resistant mechanism. The linear mechanism of sucrose uptake is not as pronounced in leaf disc data as it is in root data. Further, sucrose uptake by cotton leaf discs is more resistant than uptake by root cells to pH alterations, inhibitors, and monosaccharides in the uptake medium. The saturable phase of sucrose influx into cotton root is eliminated by glucose, fructose, and high pH. Sucrose influx into both tissues is not altered by osmotica up to 200 milliOsmolar. Sucrose accumulated by both tissues is rapidly converted to other chemical forms, especially in root tissue where only approximately 50% remains as neutral sugars 1 hour following the start of radiolable exposure. Although the entry of radiolabeled sucrose is faster in abraded leaf discs, they give the same response patterns to pH, inhibitors, and monosaccharide as do unabraded discs.The sucrose accumulation kinetics of cotton roots and leaf discs differ. These differences may be related to the physiological roles (source versus sink) of the two tissues in the intact plant.


Alternating ROMP copolymers containing charge-transfer units.
Alternating copolymers derived from the ring-opening metathesis polymerization (ROMP) of functionalized cyclobutene esters (CBE) and cyclohexenes (CH) are described. The copolymer poly(CBE-alt-CH)n contains alternating side-chains based on dialcoxynaphthalene (DAN) and pyromellitc dianhydride (PDI). Characterization by UV-Vis spectroscopy showed that the copolymers exhibit an increase in charge-transfer intensity in comparison to previously reported alternating copolymers. The bulky side-chains inhibit backbiting during the polymerization and allow for enhanced control over the polymerization in comparison to copolymers functionalized with linear alkyl groups.


[Current data about fungi prevalence in various ontocenoses in women during procreation period].
The aim of study was to analyse fungi prevalence in three ontocenoses (vagina, oral cavity and anus) in women during procreation period, which should be helpful in developing prophylactic programmes for pregnant womem, newborns and infants infected with fungi. In 716 examined women (age 20-45 years), 1411 samples of appropriate biological materials were taken and inoculated in the fluid Sabouraud medium and then axenic fungi strains were isolated in Sabouraud agar. High fungi prevalence in three ontocenoses of examined women was noted. Mean percentage for ontocenosis was: 39% +/- 1.8% for vagina, 42.18% +/- 1.8% for oral cavity and 25.03 +/- 1.6% for anus. These data indicate the necessity for further examinations of multifocal fungal infection in women during procreation period.


Do female patients with metabolic syndrome have masked left ventricular dysfunction?
Metabolic syndrome (MS) is a condition, which is recognized as raising the risk of cardiovascular disease. The aim of our study is to estimate the left ventricular functions by atrioventricular plane displacement (AVPD), myocardial performance index (MPI) and conventional methods in patients with MS who were diagnosed according to NCEP (ATP III) criteria. Fifty-three female patients with MS (mean age 53.1+/-6.9 years) and 30 healthy female subjects (mean age 52.8+/-6.3 years, p>0.05) underwent complete echocardiographic assessment. All of the subjects had no heart and pulmonary diseases. The systolic mitral AVPD was recorded at 4 sites (septal, lateral, anterior, and posterior) by M-mode echocardiography and left ventricle ejection fraction (LVEF) was calculated from the AVPD-mean (EF-AVPD). The LVEF was also established by biplane Simpson's (EF-2D) and Teichholz's methods (EF-T). Left ventricular MPI was calculated as (isovolumic contraction time + isovolumic relaxation time) / aortic ejection time by Doppler echocardiography. Patients with MS showed mild left ventricular diastolic dysfunction (DD) in comparison to healthy subjects. The EF-2D and EF-T in patients with MS and healthy subjects were not different significantly and were within normal limits. Patients with MS showed LV global dysfunctions compared to healthy subjects (MPI: 0.56+/-0.12 and 0.46+/-0.11 respectively, p<0.01). Both the septal, anterior, lateral and posterior part of the atrioventricular plane values and also AVPD-mean during systole were statistically lower in patients with MS (12.85+/-1.76 mm) as compared with controls (14.65+/-2.19 mm, p<0.05). The EF-AVPD in patients with MS was statistically lower (65.58+/-11.95%) as compared with healthy subjects (74.45+/-11.07%, p<0.01). Female patients with MS had both left ventricular DD and a global dysfunction with an increased MPI. The EF-2D and EF-T were not different significantly between patients and controls, but patients with MS had a relatively reduced EF-AVPD. The AVPD method may indicate a systolic dysfunction with a relatively lower AVPD-mean and relatively lower EF-AVPD. The presence of global dysfunction in patients with MS may lead to heart failure.


Useful predictive factors of common bile duct stones prior to laparoscopic cholecystectomy for gallstones.
The aim of this study was to determine useful predictive factors of common bile duct stones (CBDs) as diagnosed by endoscopic retrograde cholangiopancreatography (ERCP) in patients who underwent laparoscopic cholecystectomy (LC) for gallstones. A total of 510 patients underwent ERCP prior to LC. Also reviewed in each were clinical data, laboratory data, and ultrasonographic findings. Data were evaluated by uni- and multivariate analysis to determine which of the useful predictive factors thus far reported might be in the concurrence of CBDs. Univariate analysis identified jaundice, pancreatitis, ALT, total bilirubin, alkaline phosphatase, amylase, and CBD dilatation at ultrasonography as predictors. Multivariate analysis subsequently identified alkaline phosphatase (p<0.0001), total bilirubin (p=0.0008), amylase (p=0.0009), and CBD dilatation at ultrasonography (p=0.0012) as independent predictive factors of CBDs. The estimates for the detection of CBDs, when the indication of ERCP is determined on the basis of the four predictive factors, were found to be as follows: sensitivity 97.6%, positive predictive value 78.6%, and positive accuracy 95.3%. It is advisable to ascertain by preoperative ERCP whether there might be any CBDs in patients about to undergo an LC for treatment of cholelithiasis insofar as the patient has one or more of these factors. It is concluded that an LC may be performed by omitting the prior ERCP, conversely, on patients devoid of all of these factors.


Preparation and Use of a Monoclonal Antibodyagainst Luffin b.
Luffin b is one of the most toxic single chain plant ribosome inactivating proteins. It has been successfully used to prepare an immunotoxin against human melanoma cells. Two strains of hybridomas (1E5 and 2E1) were screened out using cell fusion technique which steadily secreted monoclonal antibodies against luffin b. These antibodies specifically reacted with luffin b. The affinity constants of 1E5 and 2E1 monoclonal antibodies were determined to be 1.1x10(9) mol(-1).L and 7.5x10(8) mol(-)1.L, by RIA,respectively. An immunoaffinity gel composed with the 1E5 monoclonal antibody and Sepharose 4B was prepared. The luffin b was successfully purified by one step immunoaffinity chromatography from the crude extract of Luffa cylindrica seeds. An immunoconjugate 1E5-HRP was also prepared and it was successfully used in Western blotting for detection of recombinant luffin b from E.coli total proteins.


Understanding Curli Amyloid-Protein Aggregation by Hydrogen-Deuterium Exchange and Mass Spectrometry.
Bacteria within Curli biofilms are protected from environmental pressures (e.g., disinfectants, antibiotics), and this is responsible for intractable infections. Understanding aggregation of the major protein component of Curli, CsgA, may uncover disease-associated amyloidogenesis mechanisms. Here, we report the application of pulsed hydrogen-deuterium exchange and mass spectrometry (HDX-MS) to study CsgA aggregation, thereby obtaining region-specific information. By following time-dependent peptide signal depletion, presumably a result of insoluble fibril formation, we acquired sigmoidal profiles that are specific for regions (region-specific) of the protein. These signal-depletion profiles not only provide an alternative aggregation measurement, but also give insight on soluble species in the aggregation. The HDX data present as bimodal isotopic distributions, one representing a highly disordered species whereas the other a well-structured one. Although the extents of deuterium uptake of the two species remain the same with time, the relative abundance of the lower mass, less-exchanged species increases in a region-specific manner. The same region-specific aggregation properties also pertain to different aggregation conditions. Although CsgA is an intrinsically disordered protein, within the fibril it is thought to consist of five imperfect β-strand repeating units (labeled R1-R5). We found that the exterior repeating units R1 and R5 have higher aggregation propensities than do the interior units R2, R3, and R4. We also employed TEM to obtain complementary information of the well-structured species. The results provide insight on aggregation and a new approach for further application of HDX-MS to unravel aggregation mechanisms of amyloid proteins.


The Impact of Smartphone Apps Designed to Reduce Food Waste on Improving Healthy Eating, Financial Expenses and Personal Food Waste: Crossover Pilot Intervention Trial Studying Students' User Experiences.
Global sustainability and individual health need coordinated attention. While individuals are recommended a healthy diet to reduce the burden of noncommunicable diseases, global attention to natural resource conservation is also needed. The latter specifically means effective measures to reduce food waste. This pilot study evaluates the experiences of students and effect from using smartphone apps designed to reduce food waste on personal healthy eating, financial expenses, and food waste. A total of 6 students from different study programs (mean age 24.7, SD 2.9) were recruited to evaluate 2 different apps designed to reduce food waste and to register food consumption, food waste, and financial food expenses before and after the app trials. The apps evaluated were the commercially available TotalCtrl Home and Too-Good-To-Go. Results were analyzed by mixed methods, comprising statistical analyses for quantifiable data and thematic analyses for qualitative data. The apps were used separately in random order, each for 1 month. Primary outcome was user expectations to and experiences from the use of the apps, which were obtained by semistructured interviews. Secondary outcomes were changes in food waste volume, financial food expenses, and healthy eating. While information on food waste and food expenses was obtained by weighing food waste and registering food costs for 2 weeks before and after app trials, scores for consuming healthy diets were calculated from registered food records by scoring criteria matched to national recommendations for healthy eating. Awareness on food waste increased after app trials, but experiences with apps pointed toward several potential for technical and content improvements. The students reported that there were too many manual operations in the apps to induce permanent use (TotalCtrl Home), that services seemed more concerned about the producers' interests than the individual's needs (Too-Good-To-Go), and that they missed a composite app that included functions to promote healthy eating and overview of budget and expenses as well as of food waste (both apps). Use of apps designed to reduce food waste and personal costs and to improve healthy eating did not result in any measurable effects, that is, no change in food waste (mean change 0.81, SD 1.5 kg; P=.13), healthy eating (mean change -0.24, SD 0.43; P=.24), or personal food expenses (mean change 47.5 NOK or US $4.8, SD 416.9 NOK or US $42.5; P=.39). Apps may aid in increased awareness of food waste at the producer and consumer levels. Large-scale studies with longer duration are needed to see if apps may induce measurable changes in food waste, healthy eating, and financial expenses.


Preparation and Material Application of Amylose-Polymer Inclusion Complexes by Enzymatic Polymerization Approach.
This review presents our researches on the preparation and material application of inclusion complexes that comprises an amylose host and polymeric guests through phosphorylase-catalyzed enzymatic polymerization. Amylose is a well-known polysaccharide and forms inclusion complexes with various hydrophobic small molecules. Pure amylose is produced by enzymatic polymerization by using α-d-glucose 1-phosphate as a monomer and maltooligosaccharide as a primer catalyzed by phosphorylase. We determined that a propagating chain of amylose during enzymatic polymerization wraps around hydrophobic polymers present in the reaction system to form inclusion complexes. We termed this polymerization "vine-twining polymerization" because it is similar to the way vines of a plant grow around a rod. Hierarchical structured amylosic materials, such as hydrogels and films, were fabricated by inclusion complexation through vine-twining polymerization by using copolymers covalently grafted with hydrophobic guest polymers. The enzymatically produced amyloses induced complexation with the guest polymers in the intermolecular graft copolymers, which acted as cross-linking points to form supramolecular hydrogels. By including a film-formable main-chain in the graft copolymer, a supramolecular film was obtained through hydrogelation. Supramolecular polymeric materials were successfully fabricated through vine-twining polymerization by using primer-guest conjugates. The products of vine-twining polymerization form polymeric continuums of inclusion complexes, where the enzymatically produced amylose chains elongate from the conjugates included in the guest segments of the other conjugates.


Spontaneous coronary artery dissection and acute myocardial infarction during pregnancy.
Spontaneous coronary artery dissection is a rare cause of infarction in the general population, but a common cause of myocardial infarction during pregnancy, and even nowadays carries a high risk of mortality. We describe the case of a 31-year-old primigravida who presented during the 34th week of pregnancy with the chief complaint of chest pain and was found to suffer from myocardial infarction. She was otherwise healthy and had no known risk factors for coronary artery disease. The patient was treated conservatively with nitrates, aspirin, heparin and beta-blockers, eventually sustained a large myocardial infarction and, after an initial period of instability, remained asymptomatic. A week later she delivered 3 healthy babies. A coronary angiogram performed 3 months after the initial event revealed an extensive obstructive dissection of the circumflex coronary artery. The decision whether to pursue percutaneous coronary intervention, surgical revascularisation or appropriate medical therapy, is based on clinical presentation, the extent of the dissection, and the amount of ischaemic myocardium at risk. Cardiologists must be aware of this rare entity during pregnancy or postpartum, since early diagnosis and treatment are crucial for the survival of the mother and the foetus.


Spatial and activity-dependent catecholamine release in rat adrenal medulla under native neuronal stimulation.
Neuroendocrine chromaffin cells of the adrenal medulla in rat receive excitatory synaptic input through anterior and posterior divisions of the sympathetic splanchnic nerve. Upon synaptic stimulation, the adrenal medulla releases the catecholamines, epinephrine, and norepinephrine into the suprarenal vein for circulation throughout the body. Under sympathetic tone, catecholamine release is modest. However, upon activation of the sympathoadrenal stress reflex, and increased splanchnic firing, adrenal catecholamine output increases dramatically. Moreover, specific stressors can preferentially increase release of either epinephrine (i.e., hypoglycemia) or norepinephrine (i.e., cold stress). The mechanism for this stressor-dependent segregated release of catecholamine species is not yet fully understood. We tested the hypothesis that stimulation of either division of the splanchnic selects for epinephrine over norepinephrine release. We introduce an ex vivo rat preparation that maintains native splanchnic innervation of the adrenal gland and we document experimental advantages and limitations of this preparation. We utilize fast scanning cyclic voltammetry to detect release of both epinephrine and norepinephrine from the adrenal medulla, and report that epinephrine and norepinephrine release are regulated spatially and in a frequency-dependent manner. We provide data to show that epinephrine is secreted preferentially from the periphery of the medulla and exhibits a higher threshold and steeper stimulus-secretion function than norepinephrine. Elevated stimulation of the whole nerve specifically enhances epinephrine release from the peripheral medulla. Our data further show that elimination of either division from stimulation greatly attenuated epinephrine release under elevated stimulation, while either division alone can largely support norepinephrine release.


[Pulmonary carcinoma associated with bullous emphysema].
Malignant complication of pulmonary bullous disease is rare but not negligible. Its importance lies in the young age when it appears. Eighty-nine cases in the literature, including four of our own cases, are included in this review. Etiopathogenic theories are discussed along with clinical, radiological, pathological, diagnostic, prognostic, and treatment characteristics. Smoking is a primary factor in this process, and quitting is key in terms of prevention. Surgical methods are usually necessary to perform the diagnosis, but that does not exclude the use of other techniques-particularly, fine-needle aspiration biopsy under radiological control-whose role should be validated. The prognosis is bad if there is no commitment to prevention. Even though the value of serial radiological controls is unknown, such controls may help in the early detection of neoplastic degeneration in bullous disease. The nature of the problem in handling these cases therapeutically is determined by the severity of bullous dystrophy: therefore, surgery should be considered on an individual basis.


Use of the gas exchange threshold to noninvasively determine the lactate threshold in patients with cystic fibrosis.
The anaerobic threshold (AT) is a submaximal index related to endurance exercise performance, which is usually determined by the measurement of blood lactate concentration during an incremental exercise test (lactate threshold [LT]). The LT, and thus the AT, can also be detected noninvasively in normal subjects by means of the gas exchange threshold (GET). This study was undertaken to validate the use of GET in patients with cystic fibrosis (CF) with a wide range of disease severity, and to assess the reproducibility of this index. In patients with CF (FEV(1) range, 23 to 118% of predicted) and control subjects, gas exchange was measured breath by breath during the incremental exercise tests to allow determination of the GET. Arterialized-venous blood was sampled for determination of the LT. The GET and LT were determined in a blinded manner. The mean differences (GET - LT) for control subjects (n = 18) and patients with CF (n = 23) were - 40 mL/min and + 10 mL/min, respectively, neither being significantly different from zero. The limits of agreement were +/- 550 mL/min and +/- 410 mL/min, respectively. The mean test-retest differences in GET for control subjects (n = 14) and patients with CF (n = 12) were - 50 mL/min and 0 mL/min, respectively, neither being significantly different from zero; the respective limits of reproducibility were +/- 450 mL/min and +/- 350 mL/min. This study demonstrates that in patients with CF, the GET can be used to obtain an unbiased estimate of the LT, and that the GET is reproducible.


[Music and health--what kind of music is helpful for whom? What music not?].
It is well known that music not only may improve quality of life (QoL) but also have different effects on heart rate (HR) and its variability (HRV). Music emphasis and rhythmic phrases are tracked consistently by physiological variables. Autonomic responses are synchronized with music, which might therefore convey emotions through autonomic arousal during crescendos or rhythmic phrases. A greater modulation of HR, HRV and modulations in cardiac autonomic nerve activity was revealed with a greater effect for music performance than music perception. Reactions to music are considered subjective, but studies suggested that cardiorespiratory variables are influenced under different circumstances. It has been shown that relaxing music decreases significantly the level of anxiety in a preoperative setting to a greater extent than orally administered midazolam (p < 0,001). Higher effectiveness and absence of apparent adverse effects make preoperative relaxing music a useful alternative to midazolam for premedication. In addition, there is sufficient practical evidence of stress reduction to suggest that a proposed regimen of listening to music while resting in bed after open heart surgery. Music intervention should be offered as an integral part of the multimodal regime administered to the patients that have undergone cardiovascular surgery. It is a supportive source that increases relaxation. Music is also effective in under conditions and music can be utilized as an effective intervention for patients with depressive symptoms, geriatrics and in pain, intensive care or palliative medicine. However, careful selected music that incorporates a patient's own preferences may offer an effective method to reduce anxiety and to improve quality of life. The most benefit on health is visible in classic music, meditation music whereas heavy metal music or technosounds are even ineffective or dangerous and will lead to stress and/or life threatening arrhythmias. There are many composers most effectively to improve QoL, particularly Bach, Mozart and Italian composers are "ideal".


Optimization of continuous wave nuclear magnetic resonance to determine in situ volume fractions and individual flow rates in two component mixtures.
In this paper, the optimization of continuous wave nuclear magnetic resonance in two component flowing mixtures to determine the in situ volume fractions and the individual component flow rates is described from both an analytical and an experimental point of view. A simple and accurate measuring system is discussed and the analytical and experimental results are compared for oil-water mixes. The use of a relatively long polarizing magnet prior to the highly homogeneous detector magnet has been shown to improve the flow-rate range considerably and makes feasible a relatively inexpensive, accurate, and genuine two-phase or two component flow meter. By measuring the optimum value of H(1), or the rf level required to produce that optimum value, and by simultaneously measuring the magnitude of the signal at that time, both the in situ volume fraction and the flow rate can be determined. This is provided that there is no chemical reaction between the two components and that they travel at the same average velocity. The system may be also used for monitoring changes in constituency of a single substance since the optimum value of H(1) depends upon this constituency.


Induction of anaesthesia with propofol ('Diprivan') or thiopentone and interactions with suxamethonium, atracurium and vecuronium.
A randomized study involving 60 healthy patients was performed to examine the induction characteristics and the possible interactions between propofol 2.5 mg/kg or thiopentone 4 mg/kg and three neuromuscular blocking agents, suxamethonium, atracurium and vecuronium. The time of onset to maximum blockade, the degree of blockade and the duration of blockade were measured using the electromyogram. The response to each muscle relaxant was not significantly different after induction of anaesthesia by propofol or thiopentone. A decrease in arterial blood pressure which occurred after both induction agents was greater after propofol than after thiopentone P less than 0.05. There was no significant difference in the increase in heart rate which occurred after the injection of either propofol or thiopentone.


Simultaneous determination of cypermethrin and fenvalerate residues in tomato by gas chromatography and their applications to kinetic studies after field treatment.
In this study simultaneous determination of cypermethrin and fenvalerate residues in tomato fruit (Lycopesicon esculentum) grown in Khartoum, Sudan, was carried out using gas chromatography with electron capture detector (GC-ECD). The method was linear in the ranges of 0.075-0.009 and 0.75-0.037 mg/mL for cypermethrin and fenvalerate, respectively. The limits of detection and quantification were found to be 0.003 and 0.01 mg/mL and 0.014, 0. 047 mg/mL for cypermethrin and fenvalerate, respectively. The recoveries of cypermethrin and fenvalerate spiked in tomato were 97 ± 7.5 and 99.5 ± 1.8%, respectively. The kinetic study of the degradation of both pesticides was performed and the ultimate evaluation of the kinetic data revealed a first-order kinetics with respect to the tomato fruit; an explanation was put forward to account for the results.


Some Novel Cobalt Diphenylphosphine Complexes: Synthesis, Characterization, and Behavior in the Polymerization of 1,3-Butadiene.
Some novel cobalt diphenylphosphine complexes were synthesized by reacting cobalt(II) chloride with (2-methoxyethyl)diphenylphosphine, (2-methoxyphenyl)diphenylphosphine, and 2-(1,1-dimethylpropyl)-6-(diphenylphosphino)pyridine. Single crystals suitable for X-ray diffraction studies were obtained for the first two complexes, and their crystal structure was determined. The novel compounds were then used in association with methylaluminoxane (MAO) for the polymerization of 1,3-butadiene, and their behavior was compared with that exhibited in the polymerization of the same monomer by the systems CoCl2(PnPrPh2)2/MAO and CoCl2(PPh3)2/MAO. Some significant differences were observed depending on the MAO/Co ratio used, and a plausible interpretation for such a different behavior is proposed.


Efficacy of hypochlorous acid scavengers in the prevention of protein carbonyl formation.
We observed that protein (bovine serum albumin) carbonyl content increases upon hypochlorite oxidation, and this increase is inhibited in a concentration-dependent manner in the presence of hypochlorite scavengers. Based on this observation, we tested whether some known hypochlorite scavengers (lipoic acid, cysteine, and glutathione) and some other antioxidants (uric acid, ascorbic acid, alpha-tocopherol, and probucol) could prevent protein carbonyl formation. N-acetylcysteine, dihydrolipoic acid, cysteine, and glutathione (reduced form, GSH), which otherwise could not be tested in a previously reported 5-thio-2-nitrobenzoic acid test system, were successfully evaluated in our assay. The hypochlorite scavenging capacity of different compounds, compared by determining the IC50 (concentration which produces 50% inhibition), showed that the compounds tested have the following potency: dihydrolipoic acid > GSH, N-acetylcysteine > cysteine > S-methyl glutathione > lipoic acid, ascorbic acid > cystine, GSSG, and uric acid. No scavenging ability was observed for either alpha-tocopherol or probucol.


Joint Estimation of Treatment and Placebo Effects in Clinical Trials with Longitudinal Blinding Assessments.
In some therapeutic areas, treatment evaluation is frequently complicated by a possible placebo effect (i.e., the psychobiological effect of a patient's knowledge or belief of being treated). When a substantial placebo effect is likely to exist, it is important to distinguish the treatment and placebo effects in quantifying the clinical benefit of a new treatment. These causal effects can be formally defined in a joint causal model that includes treatment (e.g., new versus placebo) and treatmentality (i.e., a patient's belief or mentality about which treatment she or he has received) as separate exposures. Information about the treatmentality exposure can be obtained from blinding assessments, which are increasingly common in clinical trials where blinding success is in question. Assuming that treatmentality has a lagged effect and is measured at multiple time points, this article is concerned with joint evaluation of treatment and placebo effects in clinical trials with longitudinal follow-up, possibly with monotone missing data. We describe and discuss several methods adapted from the longitudinal causal inference literature, apply them to a weight loss study, and compare them in simulation experiments that mimic the weight loss study.


Laminin-5γ-2 (LAMC2) is highly expressed in anaplastic thyroid carcinoma and is associated with tumor progression, migration, and invasion by modulating signaling of EGFR.
Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy having no effective treatment. Laminin subunit-γ-2 (LAMC2) is an epithelial basement membrane protein involved in cell migration and tumor invasion and might represent an ideal target for the development of novel therapeutic approaches for ATC. The objective of the investigation was to study the role of LAMC2 in ATC tumorigenesis. LAMC2 expression was evaluated by RT-PCR, Western blotting, and immunohistochemistry in tumor specimens, adjacent noncancerous tissues, and cell lines. The short hairpin RNA (shRNA) approach was used to investigate the effect of LAMC2 knockdown on the tumorigenesis of ATC. LAMC2 was highly expressed in ATC samples and cell lines compared with normal thyroid tissues. Silencing LAMC2 by shRNA in ATC cells moderately inhibited cell growth in liquid culture and dramatically decreased growth in soft agar and in xenografts growing in immunodeficient mice. Silencing LAMC2 caused cell cycle arrest and significantly suppressed the migration, invasion, and wound healing of ATC cells. Rescue experiments by overexpressing LAMC2 in LAMC2 knockdown cells reversed the inhibitory effects as shown by increased cell proliferation and colony formation. Microarray data demonstrated that LAMC2 shRNA significantly altered the expression of genes associated with migration, invasion, proliferation, and survival. Immunoprecipitation studies showed that LAMC2 bound to epidermal growth factor receptor (EGFR) in the ATC cells. Silencing LAMC2 partially blocked epidermal growth factor-mediated activation of EGFR and its downstream pathway. Interestingly, cetuximab (an EGFR blocking antibody) or EGFR small interfering RNA additively enhanced the antiproliferative activity of the LAMC2 knockdown ATC cells compared with the control cells. To our knowledge, this is the first report investigating the effect of LAMC2 on cell growth, cell cycle, migration, invasion, and EGFR signaling in ATC cells, suggesting that LAMC2 may be a potential therapeutic target for the treatment of ATC.


Transforming growth factor beta 2 inhibits interleukin 1 beta- and tumour necrosis factor alpha-induction of nitric oxide synthase in rat renal mesangial cells.
Treatment of mesangial cells with interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha (TNF alpha) has been shown to induce nitric oxide (NO) synthase with subsequent autocrine stimulation of soluble guanylate cyclase (Pfeilschifter and Schwarzenbach, 1990, FEBS Lett. 273, 185-187). Here we report that transforming growth factor beta 2 (TGF beta 2) dose-dependently inhibits IL-1 beta- and TNF alpha-stimulated cGMP formation in mesangial cells. Half-maximal inhibition is observed at concentrations of 0.4 and 0.06 ng/ml of TGF beta 2, respectively. Maximum inhibition of cGMP formation over a 24 h period requires the presence of TGF beta 2 during the first 4 h of induction. In addition, the inhibitory effect of TGF beta 2 on cytokine-induced cGMP formation is not affected by the potent cyclo-oxygenase inhibitor indomethacin, thus excluding prostaglandins as mediators.


Preliminary Exploration of Obesity-Related Eating Behaviour Patterns in a Sample of Saudi Preschoolers Aged 2-6 Years through the Children's Eating Behaviour Questionnaire.
The Children's Eating Behaviour Questionnaire (CEBQ) is used with parents to determine the characteristics of eating behaviour of their children and, consequently, children's propensity to become obese. It has been successfully used mainly in Western countries, but not in Saudi Arabia. In this pilot study, we explored the use of the Saudi version of the CEBQ for preschool children aged 2-6 years in Saudi Arabia, and assessed the associations between eating behaviours and children's age, gender and relative weight and parental weight. Parents of 200 Saudi preschool children in Riyadh completed the Saudi version of the CEBQ. Factor analyses on all CEBQ items were performed and differences between genders and age groups were examined. Correlations between children's BMI z-scores and eating behaviours were analysed using linear regression. The factor analysis revealed an eight-factor solution similar to the theoretical factor structure, with good internal reliability and acceptable correlations between subscales. Boys scored higher than girls on food responsiveness; no difference between age groups was found. Positive associations between BMI z-scores and 'food approach' subscales, food responsiveness, enjoyment of food and emotional overeating were found, while 'food avoidant' subscales, satiety responsiveness and slowness in eating had inverse relationships with BMI z-scores. Maternal BMI had a positive association with BMI z-scores and food responsiveness. The CEBQ is a valid psychometric tool that can be reliably used to assess eating behaviour characteristics in Saudi preschool children.


A novel X-linked disorder with developmental delay and autistic features.
Genomic duplications that lead to autism and other human diseases are interesting pathological lesions since the underlying mechanism almost certainly involves dosage sensitive genes. We aim to understand a novel genomic disorder with profound phenotypic consequences, most notably global developmental delay, autism, psychosis, and anorexia nervosa. We evaluated the affected individuals, all maternally related, using childhood autism rating scale (CARS) and Vineland Adaptive scales, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) brain, electroencephalography (EEG), electromyography (EMG), muscle biopsy, high-resolution molecular karyotype arrays, Giemsa banding (G-banding) and fluorescent in situ hybridization (FISH) experiments, mitochondrial DNA (mtDNA) sequencing, X-chromosome inactivation study, global gene expression analysis on Epstein-Barr virus (EBV)-transformed lymphoblasts, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). We have identified a novel Xq12-q13.3 duplication in an extended family. Clinically normal mothers were completely skewed in favor of the normal chromosome X. Global transcriptional profiling of affected individuals and controls revealed significant alterations of genes and pathways in a pattern consistent with previous microarray studies of autism spectrum disorder patients. Moreover, expression analysis revealed copy number-dependent increased messenger RNA (mRNA) levels in affected patients compared to control individuals. A subset of differentially expressed genes was validated using qRT-PCR. Xq12-q13.3 duplication is a novel global developmental delay and autism-predisposing chromosomal aberration; pathogenesis of which may be mediated by increased dosage of genes contained in the duplication, including NLGN3, OPHN1, AR, EFNB1, TAF1, GJB1, and MED12.


Administrative challenges in a collaborative baccalaureate program.
The collaboration between Vancouver General Hospital and the University of British Columbia in offering the four-year baccalaureate nursing program is unique, as it is the first of its kind in Canada. This paper describes the administrative challenges that occurred at VGH as a result of this collaboration. These challenges arose as a result of altered roles and responsibilities, as well as changes in organizational structure and function. Nurse administrators, who are involved in educational collaborations, may find that they are facing similar challenges.


Macroscopic, flexible, high-performance graphene ribbons.
Tailoring the structure and properties of graphene fibers is an important step toward practical applications. Here, we report macroscopic, long graphene ribbons formed by combining electrostatic interaction and shear stress during the wet-spinning process. The graphene ribbons are flexible and can be woven into complex structures, and the ribbon morphology can be tailored by controlling the orientation of wrinkles to obtain elasticity within a modest strain. We demonstrate several potential applications of pure or Pt-graphene hybrid ribbons as elastic strain sensors, counter electrodes for dye-sensitized fiber solar cells with cell efficiencies reaching 4.69% under standard illumination and 6.41% with a back reflector, and woven fabric supercapacitor electrodes. Our method can directly fabricate meter-long graphene ribbons with controlled structure and high performance as both energy conversion and energy storage materials.


Implementing a bioterrorism response plan in your pharmacy.
Pharmacies and other types of health care facilities need emergency response plans. Pharmacists need to stay current on biologic and other agents that can be used as agents of mass destruction and their clinical management. Local plans should incorporate federal resources that can be used in emergencies, but the time required for these resources to be organized, delivered, and distributed needs to be considered. Pharmacists are urged to assist with inventories of available health care facilities, supplies, and medications. Planning needs to be coordinated with local emergency preparedness officials.


[Regulation of the intensity of delayed-type hypersensitivity to sheep erythrocytes by the K-region of the major histocompatibility complex in mice].
The injection of 6 x 10(9) sheep red blood cells (SRBC) to mice suppressed the delayed type hypersensitivity (DTH) in situ and activated spleen T cells which prevent sensitization of syngeneic recipients. Similar effect was obtained when suppressor cells induced in F1 hybrids were transferred to parental mice. Suppression was also reached in allogeneic strain combination if suppressor cells of donors and recipients shared the major histocompatibility complex (MHC). Studied performed with recombinant and mutant strains revealed that the prerequisite for interaction of DTH suppressors and effectors was the identity of K-region of MHC. Passive transfer of DTH to SRBC was also possible if donors and recipients were identical in K-region of MHC. It is believed that interaction between DTH suppressors and effectors is restricted by a region of MHC whose product takes part in antigen representation.