Calcium-dependent self-association of synaptotagmin I.
Synaptotagmin I, an integral membrane protein of secretory vesicles, appears to have an essential role in calcium-triggered hormone and neurotransmitter release. The large cytoplasmic domain of synaptotagmin I has two C2 domains that are thought to mediate calcium and phospholipid binding. A recombinant protein (p65 1-5) comprised of the cytoplasmic domain was previously shown to aggregate purified chromaffin granules and artificial phospholipid vesicles in a calcium-dependent manner. p65 1-5 may be able to aggregate membrane vesicles by a self-association reaction. This hypothesis led us to investigate the ability of synaptotagmin I protein fragments to multimerize in vitro. We found that p65 1-5, in the absence of membranes, was able to self-associate to form large aggregates in a calcium-dependent manner as shown by light-scattering assays and electron microscopy. In addition, a recombinant protein comprised of only the second half of the cytoplasmic domain, including the second C2 domain, was also able to self-associate and aggregate phospholipid vesicles in a calcium-dependent manner. A recombinant protein comprised of only the first C2 domain was not able to self-associate or aggregate vesicles. These results suggest that synaptotagmin I is able to bind calcium in the absence of membranes and that the second half of the cytoplasmic domain is able to bind calcium and mediate its multimerization in a calcium-dependent manner. The ability of synaptotagmin I protein fragments to multimerize in a calcium-dependent manner in vitro suggests that multimerization may have an important function in vivo.


Geostatistical modelling of malaria indicator survey data to assess the effects of interventions on the geographical distribution of malaria prevalence in children less than 5 years in Uganda.
Malaria burden in Uganda has declined disproportionately among regions despite overall high intervention coverage across all regions. The Uganda Malaria Indicator Survey (MIS) 2014-15 was the second nationally representative survey conducted to provide estimates of malaria prevalence among children less than 5 years, and to track the progress of control interventions in the country. In this present study, 2014-15 MIS data were analysed to assess intervention effects on malaria prevalence in Uganda among children less than 5 years, assess intervention effects at regional level, and estimate geographical distribution of malaria prevalence in the country. Bayesian geostatistical models with spatially varying coefficients were used to determine the effect of interventions on malaria prevalence at national and regional levels. Spike-and-slab variable selection was used to identify the most important predictors and forms. Bayesian kriging was used to predict malaria prevalence at unsampled locations. Indoor Residual Spraying (IRS) and Insecticide Treated Nets (ITN) ownership had a significant but varying protective effect on malaria prevalence. However, no effect was observed for Artemisinin Combination-based Therapies (ACTs). Environmental factors, namely, land cover, rainfall, day and night land surface temperature, and area type were significantly associated with malaria prevalence. Malaria prevalence was higher in rural areas, increased with the child's age, and decreased with higher household socioeconomic status and higher level of mother's education. The highest prevalence of malaria in children less than 5 years was predicted for regions of East Central, North East and West Nile, whereas the lowest was predicted in Kampala and South Western regions, and in the mountainous areas in Mid-Western and Mid-Eastern regions. IRS and ITN ownership are important interventions against malaria prevalence in children less than 5 years in Uganda. The varying effects of the interventions calls for selective implementation of control tools suitable to regional ecological settings. To further reduce malaria burden and sustain malaria control in Uganda, current tools should be supplemented by health system strengthening, and socio-economic development.


[Being an active citizen and the elderly: Old concepts, new approaches. A systematic review and qualitative meta-synthesis].
The politics of active ageing present active citizenship of the elderly as a key challenge for the coming years. Active citizenship has been defined in different ways (as complimentary in most cases), outlining an eclecticism of participatory activities that includes political engagement in a participatory and deliberative manner, as well as community and voluntary action. This term is found in different contexts such as formal politics, work, civil society, and the home. This paper, based on a systematic review, identifies the context in which this concept emerges in relation to older people and people with dementia. It also analyses the different expressions of active citizenship used, and provides key elements to be taken into account in the formulation of policies in a context of accelerated demographic ageing and where dementia is a public health priority. The notion of active citizenship in old age is a step forward from active ageing to a broader concept that integrates the principle of equality between people irrespective of gender, age and the need for support.


Affect regulation and affective experience: individual differences, group differences, and measurement using a Q-sort procedure.
This article describes the development of, and preliminary findings with, the Affect Regulation and Experience Q-Sort (the AREQ), an observer-based assessment of affect regulation and experience. In Study 1, 31 clinicians provided Q-sort descriptions of 90 patients. Factor scores correlated in predicted ways with criteria such as suicide attempts and hospitalizations, as well as with clinicians' ratings of functioning in a variety of domains. Correlations between prototype Q-sorts and actual Q-sort profiles for patients sharing a diagnosis (dysthymia, borderline personality disorder, and narcissistic personality disorder) also provided evidence for convergent and discriminant validity. The data also suggested the importance of distinguishing 2 kinds of negative affect that have very different correlates. Study 2 showed that the AREQ can be applied reliably using an interview that avoids many of the problems of self-report.


Measurements of gaseous mercury exchanges at the sediment-water, water-atmosphere and sediment-atmosphere interfaces of a tidal environment (Arcachon Bay, France).
The elemental mercury evasion from non-impacted natural areas is of significant importance in the global Hg cycle due to their large spatial coverage. Intertidal areas represent a dynamic environment promoting the transformations of Hg species and their subsequent redistribution. A major challenge remains in providing reliable data on Hg species variability and fluxes under typical transient tidal conditions found in such environment. Field experiments were thus carried out to allow the assessment and comparison of the magnitude of the gaseous Hg fluxes at the three interfaces, sediment-water, sediment-atmosphere and water-atmosphere of a mesotidal temperate lagoon (Arcachon Bay, Aquitaine, France) over three distinct seasonal conditions. The fluxes between the sediment-water and the sediment-atmosphere interfaces were directly evaluated with field flux chambers, respectively static or dynamic. Water-atmosphere fluxes were evaluated from ambient concentrations using a gas exchange model. The fluxes at the sediment-water interface ranged from -5.0 to 5.1 ng m(-2) h(-1) and appeared mainly controlled by diffusion. The occurrence of macrophytic covers (i.e.Zostera noltii sp.) enhanced the fluxes under light radiations. The first direct measurements of sediment-atmosphere fluxes are reported here. The exchanges were more intense and variable than the two other interfaces, ranging between -78 and 40 ng m(-2) h(-1) and were mostly driven by the overlying atmospheric Hg concentrations and superficial sediment temperature. The exchanges between the water column and the atmosphere, computed as a function of wind speed and gaseous mercury saturation ranged from 0.4 to 14.5 ng m(-2) h(-1). The flux intensities recorded over the intertidal sediments periodically exposed to the atmosphere were roughly 2 to 3 times higher than the fluxes of the other interfaces. The evasion of elemental mercury from emerged intertidal sediments is probably a significant pathway for Hg evasion in such tidal environments exhibiting background contamination level.


Sudden cardiac arrest during sports activity in middle age.
Sports-associated sudden cardiac arrests (SCAs) occur mostly during middle age. We sought to determine the burden, characteristics, and outcomes of SCA during sports among middle-aged residents of a large US community. Patients with SCA who were 35 to 65 years of age were identified in a large, prospective, population-based study (2002-2013), with systematic and comprehensive assessment of their lifetime medical history. Of the 1247 SCA cases, 63 (5%) occurred during sports activities at a mean age of 51.1±8.8 years, yielding an incidence of 21.7 (95% confidence interval, 8.1-35.4) per 1 million per year. The incidence varied significantly by sex, with a higher incidence among men (relative risk, 18.68; 95% confidence interval, 2.50-139.56) for sports SCAs compared with all other SCAs (relative risk 2.58; 95% confidence interval, 2.12-3.13). Sports SCA was also more likely to be a witnessed event (87% versus 53%; P<0.001) with cardiopulmonary resuscitation (44% versus 25%; P=0.001) and ventricular fibrillation (84% versus 51%; P<0.0001). Survival to hospital discharge was higher for sports-associated SCA (23.2% versus 13.6%; P=0.04). Sports SCA cases presented with known preexisting cardiac disease in 16% and ≥1 cardiovascular risk factors in 56%, and overall, 36% of cases had typical cardiovascular symptoms during the week preceding the SCA. Sports-associated SCA in middle age represents a relatively small proportion of the overall SCA burden, reinforcing the idea of the high-benefit, low-risk nature of sports activity. Especially in light of current population aging trends, our findings emphasize that targeted education could maximize both safety and acceptance of sports activity in the older athlete.


Squamous cell carcinoma of the head and neck in nonsmokers: clinical and biologic characteristics and implications for management.
Squamous cell carcinoma of the head and neck has been strongly linked to chronic tobacco and alcohol abuse. However, we are increasingly recognizing subgroups of patients without traditional risk factors. Recent clinical and molecular investigations suggest that there are distinctive clinical entities, particularly affecting young patients with cancers of the oral tongue and oropharynx. We review data from clinical observations and current biologic inquiries and consider therapeutic implications for these important patient subgroups.


GATA-1 directly regulates p21 gene expression during erythroid differentiation.
Lineage-determination transcription factors coordinate cell differentiation and proliferation by controlling the synthesis of lineage-specific gene products as well as cell cycle regulators. GATA-1 is a master regulator of erythropoiesis. Its role in regulating erythroid-specific genes has been extensively studied, whereas its role in controlling genes that regulate cell proliferation is less understood. Ectopic expression of GATA-1 in erythroleukemia cells releases the block to their differentiation and leads to terminal cell division. An early event in reprogramming the erythroleukemia cells is induction of the cyclin-dependent kinase inhibitor p21. Remarkably, ectopic expression of p21 also induces the erythroleukemia cells to differentiate. We now report that GATA-1 directly regulates transcription of the p21 gene in both erythroleukemia cells and normal erythroid progenitors. Using reporter, electrophoretic mobility shift, and chromatin immunoprecipitation assays, we show that GATA-1 stimulates p21 gene transcription by binding to consensus binding sites in the upstream region of the p21 gene promoter. This activity is also dependent on a binding site for Sp1/KLF-like factors near the transcription start site. Our findings indicate that p21 is a crucial downstream gene target and effector of GATA-1 during red blood cell terminal differentiation.


Epileptiform EEG during sevoflurane mask induction: effect of delaying the onset of hyperventilation.
Hyperventilation during sevoflurane-N2O-O2 mask induction in adults is associated with a hyperdynamic circulatory response and epileptiform electroencephalogram (EEG). We tested the hypothesis that delaying onset of hyperventilation will prevent severe (periodic) epileptiform EEG and hyperdynamic response. Thirty patients were randomized to receive either delayed (group D, n=15) or immediate (group I, n=15) onset of hyperventilation during sevoflurane (8% in N2O 50%) mask inhalation induction with single-breath method for unconsciousness. Fifteen patients were allowed to breathe spontaneously for 2 min after loss of consciousness and controlled hyperventilation (ETCO2 <4%) was started thereafter. In 15 patients controlled hyperventilation was started immediately after loss of consciousness. EEG was recorded, and mean arterial pressure (MAP) and heart rate (HR) registered. Epileptiform EEG patterns were seen in 13 patients in group I and in 9 patients in group D (n.s.). Periodic epileptiform discharges (PED) tended to occur more often in group I (P=0.07). Heart rate and MAP were higher in group I than in group D from 2 min to 3 min (P < 0.05), and both HR and MAP rose significantly from the baseline in group I. In group D, HR but not MAP rose significantly from baseline. Regardless of its timing, hyperventilation at a high sevoflurane concentration produced severe epileptiform EEG with a hyperdynamic response. PED tended to occur more often with immediate onset of hyperventilation.


Sulfitobacter undariae sp. nov., isolated from a brown algae reservoir.
A Gram-stain-negative, aerobic, non-spore-forming, non-flagellated and coccoid, ovoid or rod-shaped bacterial strain, W-BA2(T), was isolated from a brown algae reservoir in Wando of South Korea. Strain W-BA2(T) grew optimally at 25 °C, at pH 7.0-8.0 and in the presence of approximately 2.0-3.0% (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain W-BA2(T) fell within the clade comprising the type strains of species of the genus Sulfitobacter , clustering coherently with the type strains of Sulfitobacter donghicola and Sulfitobacter guttiformis showing sequence similarity values of 98.0-98.1%. Sequence similarities to the type strains of the other species of the genus Sulfitobacter were 96.0-97.4%. Strain W-BA2(T) contained Q-10 as the predominant ubiquinone and C18 : 1ω7c as the major fatty acid. The major polar lipids of strain W-BA2(T) were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminolipid and one unidentified lipid. The DNA G+C content of strain W-BA2(T) was 55.0 mol% and its DNA-DNA relatedness values with the type strains of Sulfitobacter donghicola , Sulfitobacter guttiformis and Sulfitobacter mediterraneus were 16-23%. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain W-BA2(T) is separated from other species of the genus Sulfitobacter . On the basis of the data presented, strain W-BA2(T) is considered to represent a novel species of the genus Sulfitobacter, for which the name Sulfitobacter undariae sp. nov. is proposed. The type strain is W-BA2(T) ( = KCTC 42200(T) = NBRC 110523(T)).


Detecting the optic disc boundary in digital fundus images using morphological, edge detection, and feature extraction techniques.
Optic disc (OD) detection is an important step in developing systems for automated diagnosis of various serious ophthalmic pathologies. This paper presents a new template-based methodology for segmenting the OD from digital retinal images. This methodology uses morphological and edge detection techniques followed by the Circular Hough Transform to obtain a circular OD boundary approximation. It requires a pixel located within the OD as initial information. For this purpose, a location methodology based on a voting-type algorithm is also proposed. The algorithms were evaluated on the 1200 images of the publicly available MESSIDOR database. The location procedure succeeded in 99% of cases, taking an average computational time of 1.67 s. with a standard deviation of 0.14 s. On the other hand, the segmentation algorithm rendered an average common area overlapping between automated segmentations and true OD regions of 86%. The average computational time was 5.69 s with a standard deviation of 0.54 s. Moreover, a discussion on advantages and disadvantages of the models more generally used for OD segmentation is also presented in this paper.


Long-Term Pancreatic Functional Impairment after Surgery for Neuroendocrine Neoplasms.
Radical surgery represents the only curative treatment for pancreatic neuroendocrine neoplasms (PanNEN). The aim of this study was to evaluate the postoperative onset of diabetes mellitus (DM) and/or pancreatic exocrine insufficiency (PEI) in surgically treated PanNEN. Consecutive PanNEN patients, without preoperative DM, who underwent partial pancreatic resection, were included. After a median follow-up of 72 months, overall 68/276 patients (24%) developed DM. Patients who developed DM were significantly older (p = 0.002) and they had a higher body mass index (BMI) (p < 0.0001) than those who did not; they were more frequently male (p = 0.017) and with nonfunctioning neoplasms (p = 0.019). BMI > 25 Kg/m2 was the only independent predictor of DM (p = 0.001). Overall, 118/276 patients (43%) developed a PEI, which was significantly more frequent after pancreaticoduodenectomy (p < 0.0001) and in patients with T3-T4 tumors (p = 0.001). Pancreaticoduodenectomy was the only independent predictor of PEI (p < 0.0001). Overall, 54 patients (20%) developed disease progression. Patients with and without DM had similar progression free survival (PFS), whereas patients without PEI had better five-year-PFS (p = 0.002), although this association was not confirmed in multivariate analysis. The risk of DM and PEI after surgery for PanNEN is relatively high but it does not affect PFS. BMI and pancreatic head resection are independent predictors of DM and PEI, respectively.


Antipyrine and aminopyrine permeability of individually perfused frog capillaries.
The mechanisms of transport of water and solutes across both hydrophilic and lipophilic pathways in the capillary wall were investigated. Paired measurements of the osmotic reflection and solute permeability coefficients of a lipid soluble solute (antipyrine MW 188 or aminopyrine 231) and a hydrophilic solute (glucose 180) were made on individually perfused capillaries of frog mesentery at temperatures between 5 and 25 degrees C. Below 15 degrees C, the lipophilic pathway accounts for less than 10% of the flux of antipyrine across the capillary wall, whereas at 25 degrees C the lipophilic pathway accounts of 50% of the flux. These results conform to the hypothesis that water and both hydrophilic and lipophilic solutes share an extracellular pathway, but water and lipids cross the cell by entirely separate routes. Both the activation energy for antipyrine and aminopyrine diffusion in the lipophilic pathway (25.9 kcal/mol) and the estimated cell membrane-water partition coefficients of the solutes are similar to values found for mammalian erythrocytes. Lateral diffusion in the cell membranes would account for the lipophilic pathway permeability just as well as diffusion across the cell membranes.


[Effect of adrenaline on the ATPase activity of rat liver plasma membranes].
In vivo and in vitro adrenaline affected dissimilarly the activity of Na+, K+-, HCO3- and Mg2+-ATPases from plasmatic membranes of rat liver tissue. Inhibition of Na+, K+-ATPase and stimulation of Mg2+-ATPase activities were observed within 1, 24 and 48 hrs after subcutaneous administration of the hormone at a dose of 0.3 and 1.0 1.0 mg/kg of body weight; at the same time, HCO3- -ATPase activity was inhibited by adrenaline at a dose of 1.0 mg/kg and stimulated--at a dose of 0.3 mg/kg. After in vitro incubation of the plasmatic membranes with 5.45 10(-6)--10(-4) M of the hormone the activities of HCO3- - and Na+, K+-ATPases were inhibited but Mg2+-ATPase activity was not altered. The data obtained suggest that the ATPases, responsible for the active membrane transport of K+, Na+ and HCO3-, are highly sensitive to adrenaline.


Athermal echelle grating filter in silicon-on-insulator using a temperature-synchronized input.
Athermal design of integrated photonic devices can reduce the need for active temperature stabilization and consequently the energy required to operate photonic integrated circuits. For silicon photonic filters such as AWGs which employ wire or ridge waveguides, temperature insensitivity can be achieved using cladding materials with negative thermo-optic coefficients. On the other hand, in echelle grating filters the inteference takes place in the slab free-propagation region, and therefore the modal overlap with the cladding is small, rendering this method ineffective. In this work we present an approach to design an athermal echelle grating filter exploiting a temperature-synchronized Mach-Zehnder interferometer as input. This reduces the spectral shift over a temperature range of 20 K to less than ±45 pm compared to the 1.6 nm shift for the same echelle grating with a conventional waveguide input. Furthermore, the proposed design relies exclusively on a standard fabrication process for silicon-on-insulator photonic devices and exhibits a good tolerance to fabrication uncertainties.


Artificial intelligence as a medical device in radiology: ethical and regulatory issues in Europe and the United States.
Worldwide interest in artificial intelligence (AI) applications is growing rapidly. In medicine, devices based on machine/deep learning have proliferated, especially for image analysis, presaging new significant challenges for the utility of AI in healthcare. This inevitably raises numerous legal and ethical questions. In this paper we analyse the state of AI regulation in the context of medical device development, and strategies to make AI applications safe and useful in the future. We analyse the legal framework regulating medical devices and data protection in Europe and in the United States, assessing developments that are currently taking place. The European Union (EU) is reforming these fields with new legislation (General Data Protection Regulation [GDPR], Cybersecurity Directive, Medical Devices Regulation, In Vitro Diagnostic Medical Device Regulation). This reform is gradual, but it has now made its first impact, with the GDPR and the Cybersecurity Directive having taken effect in May, 2018. As regards the United States (U.S.), the regulatory scene is predominantly controlled by the Food and Drug Administration. This paper considers issues of accountability, both legal and ethical. The processes of medical device decision-making are largely unpredictable, therefore holding the creators accountable for it clearly raises concerns. There is a lot that can be done in order to regulate AI applications. If this is done properly and timely, the potentiality of AI based technology, in radiology as well as in other fields, will be invaluable. TEACHING POINTS: • AI applications are medical devices supporting detection/diagnosis, work-flow, cost-effectiveness. • Regulations for safety, privacy protection, and ethical use of sensitive information are needed. • EU and U.S. have different approaches for approving and regulating new medical devices. • EU laws consider cyberattacks, incidents (notification and minimisation), and service continuity. • U.S. laws ask for opt-in data processing and use as well as for clear consumer consent.


Low-lying electronic states and Cl-loss photodissociation of the C2H3Cl+ ion studied using multiconfiguration second-order perturbation theory.
We studied the 1(2)A' '(X2A' '), 1(2)A' (A2A'), 2(2)A' ' (B2A' '), and 2(2)A' (C2A') states of the C2H3Cl+ ion using the complete active space self-consistent field (CASSCF) and multiconfiguration second-order perturbation theory (CASPT2) methods. For the four ionic states, we calculated the equilibrium geometries, adiabatic (T0) and vertical (Tv) excitation energies, and relative energies (Tv') at the geometry of the molecule at the CASPT2 level and the Cl-loss dissociation potential energy curves (PECs) at the CASPT2//CASSCF level. The computed oscillator strength f value for the X2A' ' <-- A2A' transition is very small, which is in line with the experimental fact that the A state has a long lifetime. The CASPT2 geometry and T0 value for the A2A' state are in good agreement with experiment. The CASPT2 Tv' values for the A2A', B2A' ', and C2A' states are in good agreement with experiment. The Cl-loss PEC calculations predict that the X2A' ', A2A', and C2A' states correlate to C2H3+ (XA1) and the BA' ' state to C2H3+ (1A' ') (the B2A' ' and C2A' PECs cross at R(C-Cl) approximately 2.24 A). Our calculations indicate that at 357 nm the X2A' ' state can undergo a transition to B2A' ' followed by a predissociation of B2A' ' by the repulsive C2A' state (via the B/C crossing), leading to C2H3+ (X1A1), and therefore confirm the experimentally proposed pathway for the photodissociation of X2A' ' at 357 nm. Our CASPT2 D0 calculations support the experimental fact that the X state does not undergo dissociation in the visible spectral region and imply that a direct dissociation of the A state to C2H3+ (X1A1) is energetically feasible.


A Randomized, Double-Blind Noninferiority Study to Evaluate the Efficacy of the Cabozantinib Tablet at 60 mg Per Day Compared with the Cabozantinib Capsule at 140 mg Per Day in Patients with Progressive, Metastatic Medullary Thyroid Cancer.
Background: Cabozantinib inhibits pathways involved in medullary thyroid cancer (MTC). Cabozantinib is approved as 140 mg/day in capsules for MTC and 60 mg/day in tablets for other solid tumors. This study compared the two doses in progressive metastatic MTC. Methods: In this Phase 4, randomized, double-blind noninferiority (NI) trial (NCT01896479), patients with progressive metastatic MTC were randomized 1:1 to cabozantinib 60 mg/day tablet or 140 mg/day capsules. The primary end point was progression-free survival (PFS) by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. NI would be concluded if the upper 95% confidence interval [CI] for the PFS hazard ratio (HR) was less than the NI margin, 1.58. The secondary end point was objective response rate (ORR) by BIRC per RECIST v1.1; additional end points included safety and pharmacokinetics. Results: At data cutoff (July 15, 2020), 247 patients were randomized to the 60 mg/day tablet arm (n = 123) and the 140 mg/day capsules arm (n = 124). NI was not met (median PFS 11.0 months vs. 13.9 months in the 60 and 140 mg/day arms [HR 1.24; CI 0.90-1.70; p = 0.19]). The ORR was 33% in both arms. Generally, adverse event (AE) incidence was lower in the 60 mg/day arm (Grade 3/4, 63% vs. 72%), as were dose reductions (69% vs. 81%) and treatment discontinuations due to AEs (23% vs. 36%). Initially, cabozantinib plasma concentrations were higher in the 140 mg/day arm but became similar between arms at later time points. Conclusions: PFS NI of the cabozantinib 60 mg/day tablet vs. 140 mg/day capsules was not met. The 60 mg/day tablet had the same ORR and lower rates of AEs. Clinical Trial Registry: ClinicalTrials.gov NCT01896479.


Expression of EPHRIN-A1, SCINDERIN and MHC class I molecules in head and neck cancers and relationship with the prognostic value of intratumoral CD8+ T cells.
Our group has previously shown that EPHRIN-A1 and SCINDERIN expression by tumor cells rendered them resistant to cytotoxic T lymphocyte-mediated lysis. Whereas the prognostic value of EPHRIN-A1 expression in cancer has already been studied, the role of SCINDERIN presence remains to be established. In the present work, we investigated the prognosis value of EPHRIN-A1 and SCINDERIN expression in head and neck carcinomas. In addition, we monitored the HLA-class I expression by tumor cells and the presence of tumor-infiltrating CD8+ T cells to evaluate a putative correlation between these factors and the survival prognosis by themselves or related to EPHRIN-A1 and SCINDERIN expression. Tumor tissue sections of 83 patients with head and neck cancer were assessed by immunohistochemistry for the expression of EPHRIN-A1, SCINDERIN, HLA class I molecules and the presence of CD8+ T cells. No significant prognosis value could be attributed to these factors independently, despite a tendency of association between EPHRIN-A1 and a worse clinical outcome. No prognostic value could be observed when CD8+ T cell tumor infiltration was analyzed combined with EPHRIN-A1, SCINDERIN or HLA class I expression. These results highlight that molecules involved in cancer cell resistance to cytotoxic T lymphocytes by themselves are not a sufficient criteria for prognosis determination in cancer patients. Other intrinsic or tumor microenvironmental features should be considered in prognostic evaluation.


Attentional Bias and Training in Individuals With High Dental Anxiety.
Dental anxiety is common and associated with negative outcomes. According to information-processing models, anxiety is maintained by maladaptive patterns of processing threatening information. Furthermore, attention training interventions can reduce anxiety in one session. Fifty-three individuals with high levels of dental anxiety completed a Posner reaction-time task. Participants were randomized to attention training or control using a dot-probe task, and then attentional bias was remeasured using another Posner task. Participants then completed a script-driven imaginal exposure task. Results indicated that individuals high in dental anxiety exhibit threat-relevant attentional bias. There was mixed evidence about the efficacy of attention training. On the one hand, training did not eliminate attentional bias and training condition did not predict distress during the imagery task. On the other hand, cue dependency scores in the control group were higher for dental than neutral cues, but did not differ in the training group. In addition, cue dependency scores for both dental and neutral cues predicted subjective anxiety in anticipation of the imagery task. The mixed results of training are considered in terms of the possibility that it enhanced attentional control, rather than reducing bias.


Novel insect leaf-mining after the end-Cretaceous extinction and the demise of cretaceous leaf miners, Great Plains, USA.
Plant and associated insect-damage diversity in the western U.S.A. decreased significantly at the Cretaceous-Paleogene (K-Pg) boundary and remained low until the late Paleocene. However, the Mexican Hat locality (ca. 65 Ma) in southeastern Montana, with a typical, low-diversity flora, uniquely exhibits high damage diversity on nearly all its host plants, when compared to all known local and regional early Paleocene sites. The same plant species show minimal damage elsewhere during the early Paleocene. We asked whether the high insect damage diversity at Mexican Hat was more likely related to the survival of Cretaceous insects from refugia or to an influx of novel Paleocene taxa. We compared damage on 1073 leaf fossils from Mexican Hat to over 9000 terminal Cretaceous leaf fossils from the Hell Creek Formation of nearby southwestern North Dakota and to over 9000 Paleocene leaf fossils from the Fort Union Formation in North Dakota, Montana, and Wyoming. We described the entire insect-feeding ichnofauna at Mexican Hat and focused our analysis on leaf mines because they are typically host-specialized and preserve a number of diagnostic morphological characters. Nine mine damage types attributable to three of the four orders of leaf-mining insects are found at Mexican Hat, six of them so far unique to the site. We found no evidence linking any of the diverse Hell Creek mines with those found at Mexican Hat, nor for the survival of any Cretaceous leaf miners over the K-Pg boundary regionally, even on well-sampled, surviving plant families. Overall, our results strongly relate the high damage diversity on the depauperate Mexican Hat flora to an influx of novel insect herbivores during the early Paleocene, possibly caused by a transient warming event and range expansion, and indicate drastic extinction rather than survivorship of Cretaceous insect taxa from refugia.


Effects of administration of testosterone, dihydrotestosterone, oestrogen and fadrozole, an aromatase inhibitor, on sex skin colour in intact male rhesus macaques.
For defining the mechanism of control of sex skin colour in male rhesus macaques (Macaca mulatta) by hormones, a spectrocolorimeter was used to monitor skin redness after administration of testosterone, dihydrotestosterone (a non-aromatizable androgen), oestradiol or fadrozole (an aromatase inhibitor that blocks the conversion of testosterone to oestrogen). Skin blood flow was measured by laser doppler. Eight 9-14 kg, 5-9 year old intact male rhesus macaques were given hormone, fadrozole or vehicle treatments in a cross-over experimental design. Baseline blood flow and colour measurements were taken in four paired tattoo defined areas on the back and legs of each animal (one pair in non-sex skin, three pairs in sex skin). Colour and blood flow measurements were taken 3-4 days after the first dose and, thereafter, once a week for 3-6 weeks. Measurements taken after treatments were compared with baseline and intra-animal comparisons were made between treatment and vehicle for each animal. In all animals after administration of 4 mg testosterone kg-1 (long-acting), redness in the sex skin areas increased (P = 0.032) by day 3 and returned to baseline values by day 7. Administration of 1 mg oestradiol kg-1 day-1 for 4 days caused increased redness in all animals (P = 0.007) similar in magnitude to that caused by testosterone. Administration of 0.1 mg dihydrotestosterone kg-1 day-1 for 4 days resulted in a nonsignificant decrease in redness (P = 0.09) on days 3-7. Treatment with fadrozole (0.25-0.5 mg kg-1 day-1) for 3 weeks caused sex skin to become significantly less red during treatment (P = 0.014). There was no significant change in redness in non-sex skin areas during any treatment. Sex skin blood flow increased in animals treated with testosterone, correlating with increased redness (R = 0.906), while blood flow in non-sex skin was unchanged. Increased redness after treatment with testosterone and oestrogen, no change in redness with treatment with dihydrotestosterone and a decrease in redness after treatment with fadrozole support the conclusion that oestrogen controls sex skin redness, and testosterone acts indirectly through conversion to oestrogen to cause increased sex skin redness in male rhesus macaques.


Policy on infant formula industry funding, support or sponsorship of articles submitted for publication.
Despite current scientific evidence that artificial feeding is a harmful practice, unquestioned acceptance of breastfeeding as the normal or "default" method of infant feeding remains elusive in the industrialised world. Throughout the developing world the profound consequences of the aggressive marketing strategies of the infant formula industry since the end of the Second World War is well known. A key objective of the International Breastfeeding Journal is to promote breastfeeding through addressing issues that encourage breastfeeding initiation, duration and effective management. Informing this aim is the recognition of artificial feeding as a harmful practice that places infant health at risk. From this perspective it would be unethical for this journal to accept for publication any manuscript that has received funding, sponsorship or any other means of support from infant formula manufacturers. This stance is consistent with the journal's aim of supporting, protecting and promoting breastfeeding. It will also contribute to the promotion of a breastfeeding culture.


Susceptibility to smoking and determinants among medical students: A representative nationwide study in China.
The rationale behind why the majority of medical students are non-smokers, but some initiate smoking after becoming physicians is not fully understood in China. Exploring factors that may increase susceptibility to smoking initiation among medical students is an essential first step in assessing preventative actions. Participants were 11954 students, who were identified through a multistage survey sampling process that included 50 universities in China. Subsequent analysis focused on 8916 non-smokers among medical students. Both unadjusted and adjusted logistic methods were considered in the data analyses. The prevalence of susceptibility to smoking was 23.0%. Multivariate logistic regression analyses found that exposure to secondhand smoke (SHS) in domestic places (OR= 1.63) and in public places (OR=1.78), cigarette advertising (OR=1.91) and promotional activities on campus (OR=1.90) were positively associated with susceptibility to smoking. In contrast, positive attitudes toward tobacco control on the part of health professionals, HPs, (OR=0.52) were negatively associated with susceptibility to smoking. Those who received information about the dangers of smoking (OR=0.75) and did not agree that light cigarettes are less harmful to health (OR=0.79) were less susceptible to smoke. Caring about exposure to secondhand smoke (OR=0.68 care, and OR=0.33 very) and advising family members to stop smoking (OR=0.81) were negatively associated with susceptibility to smoking. These findings underscore the importance of tobacco control training and establishing smoke-free campuses for reducing susceptibility to smoking among medical students.


Distress in Neuro-Oncology Patients and Its Implications for Communication.
Psychoemotional distress affects patients with cancer, including patients with a diagnosis of a malignant brain tumor. Empathy, professional expertise, and conversational skills are required to ensure successful communication with patients. The purpose of this study was to assess whether knowing the communication needs of patients would be helpful to neuro-oncologists before meeting with them. Patients in our neuro-oncology center were asked to complete the National Comprehensive Cancer Network Distress Thermometer (DT) and a study-specific questionnaire on patients' expectations for communication with the treating physician. The questions targeted issues such as attention/caring and awareness of their disease and prognosis. Importance ratings were compared between patients, with high vs. low distress scores to analyze the impact of distress on the patient's needs in physician-patient communication. A total of 81 patients completed the DT and questionnaire. One third (n = 27) had IDH wild-type astrocytoma, and 42 patients (51.9%) were undergoing therapy for primary or recurrent disease. Mean distress was 4.88 (standard deviation ± 2.64) in the whole cohort, and 56.8% of patients had a high distress score (≥ 5 on a 10-point scale). All issues were assessed as important or very important for communication by the majority of patients, and importance ratings increased in patients with high distress levels for most items. Mean importance ratings correlated significantly with distress scores (p < .001). Distress was increased in neuro-oncology patients. Patients with higher distress levels considered issues of both attention/caring and medical information about the disease as more important than patients with lower distress levels. Using distress assessment may help physicians and advanced practitioners to tailor the contents of their discussion for successful communication with patients.


Generation of reactive oxygen species from conventional laboratory media.
We previously reported that superoxide anion was generated from glucose-peptone-meat extract medium. We found that superoxide anion was generated from other conventional laboratory media, Nutrient Broth, Tryptic Soy Broth, and Mueller Hinton Broth as well as glucose-peptone-meat extract medium. The glucose-peptone-meat extract medium consisting of 1% glucose, 0.5% peptone, 0.5% meat extract, and 0.3% NaCl showed the highest superoxide anion generation among the media tested. The meat extract and peptone, which are natural nutrient sources in the medium, showed an increase in absorbance intensity by WST-1 formazan products upon reaction with superoxide anion. The specific type of reactive oxygen species was measured by SOD-inhibitable reduction of cytochrome c and WST-1 (for superoxide anion), Fluoro H(2)O(2) kit (for hydrogen peroxide), hydroxyphenyl fluorescein (for hydroxyl radical), and Singlet Oxygen Sensor Green (for singlet oxygen). The generation of hydroxyl radical was also evaluated by ESR-spin trapping method. We detected superoxide anion, hydrogen peroxide, and hydroxyl radical but not singlet oxygen. These results suggest that the superoxide anion spontaneously generated from glucose-peptone-meat extract medium is finally converted to hydroxyl radical.


Low-frequency flexural wave based microparticle manipulation.
Manipulation of microparticles and bio-samples is a critical task in many research and clinical settings. Recently, acoustic based methods have garnered significant attention due to their relatively simple designs, and biocompatible and precise manipulation of small objects. Herein, we introduce a flexural wave based acoustofluidic manipulation platform that utilizes low-frequency (4-6 kHz) commercial buzzers to achieve dynamic particle concentration and translation in an open fluid well. The device has two primary modes of functionality, wherein particles can be concentrated in pressure nodes that are present on the bottom surface of the device, or particles can be trapped and manipulated in streaming vortices within the fluid domain; both of these functions result from flexural mode vibrations that travel from the transducers throughout the device. Throughout our research, we numerically and experimentally explored the wave patterns generated within the device, investigated the particle concentration phenomenon, and utilized a phase difference between the two transducers to achieve precision movement of fluid vortices and the entrapped particle clusters. With its simple, low-cost nature and open fluidic chamber design, this platform can be useful in many biological, biochemical, and biomedical applications, such as tumor spheroid generation and culture, as well as the manipulation of embryos.


Short leg length, a marker of early childhood deprivation, is associated with metabolic disorders underlying type 2 diabetes: the PROMISE cohort study.
Short leg length, a marker of early childhood deprivation, has been used in studies of the association of early life conditions with adult chronic disease risk. The objective of this study was to determine the cross-sectional associations of leg length with measures of insulin sensitivity and β-cell function. Subjects (n = 462) at risk for type 2 diabetes were recruited into the PROspective Metabolism and ISlet cell Evaluation (PROMISE) longitudinal cohort. Leg length was calculated from sitting and standing height at the 3-year clinical examination. Glucose tolerance status was determined using an oral glucose tolerance test. Insulin sensitivity was assessed using homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda insulin sensitivity index (ISI), while the insulinogenic index over HOMA-IR (IGI/IR) and the insulin secretion sensitivity index 2 (ISSI-2) determined β-cell function. Multiple linear regression analysis was conducted, adjusting for covariates including age, sex, ethnicity, family history of diabetes, waist, and weight. Leg length and leg-to-height ratio were significantly associated with HOMA-IR (β = -0.037, β = -10.49, respectively; P < 0.0001), ISI (β = 0.035, β = 8.83, respectively; P < 0.0001), IGI/IR (β = 0.021, P < 0.05; β = 7.60, P < 0.01, respectively), and ISSI-2 (β = 0.01, P < 0.03; β = 3.34, P < 0.01, respectively) after adjustment for covariates. The association of shorter leg length with lower insulin sensitivity was most evident for those with high waist circumferences. Shorter legs were independently associated with lower insulin sensitivity and β-cell function, suggesting that early childhood deprivation may increase the risk of developing diabetes.


Calcium and phosphate: a duet of ions playing for bone health.
The acquisition and maintenance of bone mass and strength are influenced by environmental factors, including physical activity and nutrition. Among micronutrients, calcium (Ca) and inorganic (i) phosphate (P) are the two main constituents of hydroxyapatite, the bone mineral that strengthens the mechanical resistance of the organic matrix. Bone contains about 99% and 80% of the body's entire supply of Ca and P, respectively. The Ca/P mass ratio in bone is 2.2, which is similar to that measured in human milk. The initial step of Ca-Pi crystal nucleation takes place within matrix vesicles that bud from the plasma membrane of osteogenic cells and migrate into the extracellular skeletal compartment. They are endowed with a transport system that accumulates Pi inside the matrix vesicles, followed by the influx of Ca ions. This process leads to the formation of hydroxyapatite crystal and its subsequent association with the organic matrix collagen fibrils. In addition to this structural role, both Ca and Pi positively influence the activity of bone-forming and bone-resorbing cells. Pi plays a role in the maturation of osteocytes, the most abundant cells in bone. Osteocytes are implicated in bone mineralization and systemic Pi homeostasis. They produce fibroblast growth factor-23, a hormonal regulator of renal Pi reabsorption and 1,25-dihydroxy vitamin D production. This relationship is in keeping with the concept proposed several decades ago of a bone-kidney link in Pi homeostasis. In contrast to their tight association in bone formation and resorption, Ca and Pi renal reabsorption processes are independent from each other, driven by distinct molecular machineries. The distinct renal control is related to the different extraskeletal functions that Ca and Pi play in cellular metabolism. At both the renal and the intestinal levels, interactions of Ca and Pi have been documented that have important implications in the acquisition and maintenance of bone health, as well as in osteoporosis management. In the kidney, increased Pi intake enhances Ca reabsorption and Ca balance. During growth and adulthood, administration of Ca-Pi in a ratio close to that of dairy products leads to positive effects on bone health. In contrast, when separately ingested as pharmaceutical salt supplements, thus inducing large differences between Ca and Pi concentrations in the intestinal lumen, they might have adverse effects on bone health. In osteoporotic patients treated with anabolic agents, a Ca-Pi supplement appears to be preferable to carbonate or citrate Ca salt. In conclusion, Ca and Pi constitute a key duo for appropriate bone mineral acquisition and maintenance throughout life. Outside the skeleton, their essential but distinct physiological functions are controlled by specific transporters and hormonal systems that also serve to secure the appropriate supply of Ca and Pi for bone health. Key teaching points: Bone contains about 99% and 80% of the body's supply of Ca and P, respectively, as hydroxyapatite and has a Ca/P mass ratio of about 2.2, close to that measured in human milk. The first step of Ca-Pi crystal nucleation takes place within matrix vesicles that bud from the plasma membrane of osteogenic cells. In addition to their structural role, both Ca and Pi influence bone-forming and bone-resorbing cells. There is a bone-kidney link in Pi homeostasis in which fibroblast growth factor-23, a molecule produced by osteocytes, appears to play a pivotal role. In contrast to their tight association during bone formation and resorption, both intestinal and renal Ca and Pi processes are independent of each other. Observational and interventional studies suggest that Ca-Pi salt or dairy products can exert positive effects on bone acquisition and maintenance.


Reducing fracture risk with calcium and vitamin D.
Studies of vitamin D and calcium for fracture prevention have produced inconsistent results, as a result of different vitamin D status and calcium intake at baseline, different doses and poor to adequate compliance. This study tries to define the types of patients, both at risk of osteoporosis and with established disease, who may benefit from calcium and vitamin D supplementation. The importance of adequate compliance in these individuals is also discussed. Calcium and vitamin D therapy has been recommended for older persons, either frail and institutionalized or independent, with key risk factors including decreased bone mineral density (BMD), osteoporotic fractures, increased bone remodelling as a result of secondary hyperparathyroidism and increased propensity to falls. In addition, treatment of osteoporosis with a bisphosphonate was less effective in patients with vitamin D deficiency. Calcium and vitamin D supplementation is a key component of prevention and treatment of osteoporosis unless calcium intake and vitamin D status are optimal. For primary disease prevention, supplementation should be targeted to those with dietary insufficiencies. Several serum 25-hydroxyvitamin D (25(OH)D) cut-offs have been proposed to define vitamin D insufficiency (as opposed to adequate vitamin D status), ranging from 30 to 100 nmol/l. Based on the relationship between serum 25(OH)D, BMD, bone turnover, lower extremity function and falls, we suggest that 50 nmol/l is the appropriate serum 25(OH)D threshold to define vitamin D insufficiency. Supplementation should therefore generally aim to increase 25(OH)D levels within the 50-75 nmol/l range. This level can be achieved with a dose of 800 IU/day vitamin D, the dose that was used in successful fracture prevention studies to date; a randomized clinical trial assessing whether higher vitamin D doses achieve a greater reduction of fracture incidence would be of considerable interest. As calcium balance is not only affected by vitamin D status but also by calcium intake, recommendations for adequate calcium intake should also be met. The findings of community-based clinical trials with vitamin D and calcium supplementation in which compliance was moderate or less have often been negative, whereas studies in institutionalized patients in whom medication administration was supervised ensuring adequate compliance demonstrated significant benefits.


spe-10 encodes a DHHC-CRD zinc-finger membrane protein required for endoplasmic reticulum/Golgi membrane morphogenesis during Caenorhabditis elegans spermatogenesis.
C. elegans spermatogenesis employs lysosome-related fibrous body-membranous organelles (FB-MOs) for transport of many cellular components. Previous work showed that spe-10 mutants contain FB-MOs that prematurely disassemble, resulting in defective transport of FB components into developing spermatids. Consequently, spe-10 spermatids are smaller than wild type and contain defective FB-MO derivatives. In this article, we show that spe-10 encodes a four-pass integral membrane protein that has a DHHC-CRD zinc-finger motif. The DHHC-CRD motif is found in a large, diverse family of proteins that have been implicated in palmitoyl transfer during protein lipidation. Seven spe-10 mutants were analyzed, including missense, nonsense, and deletion mutants. An antiserum to SPE-10 showed significant colocalization with a known marker for the FB-MOs during wild-type spermatogenesis. In contrast, the spe-10(ok1149) deletion mutant lacked detectable SPE-10 staining; this mutant lacks a spe-10 promoter and most coding sequence. The spe-10(eb64) missense mutation, which changes a conserved residue within the DHHC-CRD domain in all homologues, behaves as a null mutant. These results suggest that wild-type SPE-10 is required for the MO to properly deliver the FB to the C. elegans spermatid and the DHHC-CRD domain is essential for this function.


Intraligamentary anesthesia: benefits and limitations.
Intraligamentary anesthesia was described in France early in the 20th century as a novel and effective method of dental local anesthesia, but the method did not become established because of the inadequacy of dental instruments available at the time. Today, the use of a state-of-the-art armamentarium and the administration of well-proven anesthetic agents with intraligamentary anesthesia reduce the experience of typical unwanted effects, that is, sensation of elongation, pressure pain, precontact after the end of the analgesia, and reversible tissue changes. Dosing lever and dosing wheel syringes in combination with system-adapted injection needles enable the operator to feel the back-pressure and inject the anesthetic smoothly into the periodontal ligament. The results of most recent studies show that periodontal ligament injections do not generate unwanted effects when sensible instruments are used, proven anesthetics are administered, and the anesthesia method is practiced lege artis and mastered safely by the operator. This article discusses the advantages and technique of intraligamentary anesthesia and presents results from recent studies in the literature.


Effect of polyhedron deformation on the 5d energy level of Ce3+ in lanthanide aluminum perovskites.
The crystal-field levels of Ce3+ in a series of lanthanide aluminum perovskites have been investigated with reference to polyhedron deformation. For each compound, the corresponding ideal cuboctahedron is derived through a least-square procedure. The virtual energy levels of Ce3+ in these ideal polyhedrons are then obtained considering both crystal-field splitting and spin-orbit coupling. From comparison to real levels, we have a clear understanding of how polyhedron deformation affects the energy levels of Ce3+ in the perovskites.


Recurrence and Familial Inheritance of Intronic NIPBL Pathogenic Variant Associated With Mild CdLS.
Splicing pathogenic variants account for a notable fraction of NIPBL alterations underlying Cornelia de Lange syndrome but are likely underrepresented, due to overlooking of non-canonical intronic variants by traditional and contemporary sequencing methods. We describe five subjects, belonging to three families, displaying a mild Cornelia de Lange syndrome phenotype who carry the NIPBL pathogenic variant c.5329-15A>G, affecting the IVS27 branch site, yet reported in a single case. By RNA analysis we evidenced two alternative transcripts: the exon 28 in frame skipped transcript, described in the published case and an out-of-frame transcript retaining 14 nucleotides of IVS27 3'end. Even if both aberrant transcripts are at negligible levels, their presence justifies the CdLS phenotype shared by our patients consisting of borderline-mild cognitive impairment and slight but typical facial dysmorphisms. Transmission of the pathogenic variant from pauci-symptomatic mother to her siblings emphasizes the need of molecular diagnosis extended to deep intronic regions in patients with subtle but recognizable CdLS phenotype.


Hygroma of the elbow in dogs.
Two serious complications-infection and skin ulceration-have been associated with the treatment of elbow hygromas in large and giant breed dogs. Infection in 3 dogs followed the injection of a corticosteroid preparation into the cavity of the hygroma. Skin ulceration developed in 6 dogs following excision of the hygroma and wound breakdown. These skin ulcers were eventually closed by a simple reconstructive procedure. It is recommended that hygromas should not be treated by aspiration and injection of corticosteroid preparations, or by excision. A simple drainage procedure was used successfully in the treatment of 18 hygromas.


Systematic Review of Intracochlear Measurements and Effect on Postoperative Auditory Outcomes after Cochlear Implant Surgery.
Quality and adequacy of the electrode neuron interface (ENI) is postulated to be a determining factor in affecting auditory outcomes after cochlear implantation. This study aims to review radiological parameters affecting ENI, including angular insertion (AngI), wrapping factor (WF), scalar translocation (ScaT), and electrode-modiolar distance (EMD) and their effect on auditory outcomes. PubMed, MEDLINE, Embase, Scopus, OpenGrey, and Google Scholar from inception to 01 September 2022. Inclusion criteria were (i) all humans with any cochlear implant (CI); (ii) postoperative cross-sectional imaging with electrode position factors of AngI, ScaT, EMD, and/or WF; and (iii) associated auditory outcomes. Search was restricted to English-language literature. Two independent reviewers performed title and abstract screening, data extraction, and ROBINS-I risk of bias assessment. Formal statistical analysis not performed due to data heterogeneity. PROSPERO (CRD42022359198). Thirty-one studies (n = 2,887 patients, 3,091 electrodes) underwent qualitative synthesis. Higher AngI (n = 1921 patients) demonstrated positive correlation in 11 studies, no correlation in eight studies, and negative correlation in four studies. ScaT (n = 2,115 patients) demonstrated negative correlation in 12 studies, none in six studies, and one unclear correlation. Larger EMD (n = 240 patients) showed negative correlation in two studies, no correlation in one, and unclear correlation in one study. Smaller WF (n = 369 patients) demonstrated no correlation in three studies and positive correlation in one study. Our study finds variable reported relationship between AngI and auditory outcomes. CI electrodes with a ScaT or larger EMD are more likely to exhibit poorer outcomes, and WF does not correlate with outcomes.


Simvastatin restores pulmonary endothelial function in the setting of pulmonary over-circulation.
Statin therapy is a cornerstone in the treatment of systemic vascular diseases. However, statins have failed to translate as therapeutics for pulmonary vascular disease. Early pulmonary vascular disease in the setting of congenital heart disease (CHD) is characterized by endothelial dysfunction, which precedes the more advanced stages of vascular remodeling. These features make CHD an ideal cohort in which to re-evaluate the potential pulmonary vascular benefits of statins, with a focus on endothelial biology. However, it is critical that the full gamut of the pleiotropic effects of statins in the endothelium are uncovered. The purpose of this investigation was to evaluate the therapeutic potential of simvastatin for children with CHD and pulmonary over-circulation, and examine mechanisms of simvastatin action on the endothelium. Our data demonstrate that daily simvastatin treatment preserves endothelial function in our shunt lamb model of pulmonary over-circulation. Further, using pulmonary arterial endothelial cells (PAECs) isolated from Shunt and control lambs, we identified a new mechanism of statin action mediated by increased expression of the endogenous Akt1 inhibitor, C-terminal modifying protein (CTMP). Increases in CTMP were able to decrease the Akt1-mediated mitochondrial redistribution of endothelial nitric oxide synthase (eNOS) which correlated with increased enzymatic coupling, identified by increases in NO generation and decreases in NOS-derived superoxide. Together our data identify a new mechanism by which simvastatin enhances NO signaling in the pulmonary endothelium and identify CTMP as a potential therapeutic target to prevent the endothelial dysfunction that occurs in children born with CHD resulting in pulmonary over-circulation.


Temperature and water stress affect plant-pollinator interactions in Borago officinalis (Boraginaceae).
Climate change alters the abiotic constraints faced by plants, including increasing temperature and water stress. These changes may affect flower development and production of flower rewards, thus altering plant-pollinator interactions. Here, we investigated the consequences of increased temperature and water stress on plant growth, floral biology, flower-reward production, and insect visitation of a widespread bee-visited species, Borago officinalis. Plants were grown for 5 weeks under three temperature regimes (21, 24, and 27°C) and two watering regimes (well-watered and water-stressed). Plant growth was more affected by temperature rise than water stress, and the reproductive growth was affected by both stresses. Vegetative traits were stimulated at 24°C, but impaired at 27°C. Flower development was mainly affected by water stress, which decreased flower number (15 ± 2 flowers/plant in well-watered plants vs. 8 ± 1 flowers/plant under water stress). Flowers had a reduced corolla surface under temperature rise and water stress (3.8 ± 0.5 cm2 in well-watered plants at 21°C vs. 2.2 ± 0.1 cm2 in water-stressed plants at 27°C). Both constraints reduced flower-reward production. Nectar sugar content decreased from 3.9 ± 0.3 mg/flower in the well-watered plants at 21°C to 1.3 ± 0.4 mg/flower in the water-stressed plants at 27°C. Total pollen quantity was not affected, but pollen viability decreased from 79 ± 4% in the well-watered plants at 21°C to 25 ± 9% in the water-stressed plants at 27°C. Flowers in the well-watered plants at 21°C received at least twice as many bumblebee visits compared with the other treatments. In conclusion, floral modifications induced by abiotic stresses related to climate change affect insect behavior and alter plant-pollinator interactions.


Effect of a short message service (SMS) intervention on adherence to a physiotherapist-prescribed home exercise program for people with knee osteoarthritis and obesity: protocol for the ADHERE randomised controlled trial.
Knee osteoarthritis (OA) is a highly prevalent condition. People with knee OA often have other co-morbidities such as obesity. Exercise is advocated in all clinical guidelines for the management of knee OA. It is often undertaken as a home-based program, initially prescribed by a physiotherapist or other qualified health care provider. However, adherence to home-based exercise is often poor, limiting its ability to meaningfully change clinical symptoms of pain and/or physical function. While the efficacy of short message services (SMS) to promote adherence to a range of health behaviours has been demonstrated, its ability to promote home exercise adherence in people with knee OA has not been specifically evaluated. Hence, this trial is investigating whether the addition of an SMS intervention to support adherence to prescribed home-based exercise is more effective than no SMS on self-reported measures of exercise adherence. We are conducting a two-arm parallel-design, assessor-and participant-blinded randomised controlled trial (ADHERE) in people with knee OA and obesity. The trial is enrolling participants exiting from another randomised controlled trial, the TARGET trial, where participants are prescribed a 12-week home-based exercise program (either weight bearing functional exercise or non-weight bearing quadriceps strengthening exercise) for their knee by a physiotherapist and seen five times over the 12 weeks for monitoring and supervision. Following completion of outcome measures for the TARGET trial, participants are immediately enrolled into the ADHERE trial. Participants are asked to continue their prescribed home exercise program unsupervised three times a week for 24-weeks and are randomly allocated to receive a behaviour change theory-informed SMS intervention to support home exercise adherence or to have no SMS intervention. Outcomes are measured at baseline and 24-weeks. Primary outcomes are self-reported adherence measures. Secondary outcomes include self-reported measures of knee pain, physical function, quality-of-life, physical activity, self-efficacy, kinesiophobia, pain catastrophising, participant-perceived global change and an additional adherence measure. Findings will provide new information into the potential of SMS to improve longer-term exercise adherence and ultimately enhance exercise outcomes in knee OA. Prospectively registered with the Australian New Zealand Clinical Trials Registry. Reference: ACTR N12617001243303 Date/version: August 2019/two.


[The toxicity and biological effects of organophosphorus epoxides].
In the series of glycidylic ethers of alkylophosphoric and methylphosphoric acids three types of compounds have been identified: those possessing anticholinesterase, narcotic, and antineoplastic activity. Monoglycidylic ethers of diethyl- and diisopropylphosphoric acids and diglycidylic ether of ethylphosphoric acid caused intoxication of animals with the cholinergic excitation syndrome, and in vitro in a concentration of 1 mmol/liter strongly inhibited cholinesterase, stimulated the motor activity of an intestinal segment, but did not demonstrate cytotoxic activity in relation to NK/Ly strain tumor cells. Monoglycidylic ethers of di-n-propyl-, di-iso-butyl, and di-n-butyl-phosphoric acids as well as diglycidylic ethers of n-butyl- and iso-amylphosphoric acids caused a "hypnotic state" in the animals, suppressed the motor activity of an isolated intestinal segment, considerably increased the number of diffusely stained by Aĭzenman's [correction of Aisenmanns'] method cells of ascitic NK/Ly tumor in vitro, but poorly inhibited the growth of this tumor in chemotherapeutic experiments. Diglycidylic ethers of methyl-, n-propyl-, iso-butylphosphoric, and methylphosphonic acids caused poisoning of the type of intoxication by alkylating agents, weakly influenced cholinesterase activity, did not change the character of contractions of the intestinal segment. In vitro they caused a strong cytotoxic effect, but delayed the growth of the NK/Ly tumor treated animals by 84-100%. The possibility of the phosphororganic epoxides under study taking part in the reactions of alkylation and phosphorylation is suggested.


Head and neck cancers in France: an analysis of the hospital medical information system (PMSI) database.
With 16,005 new cases and 5,406 related deaths in 2005, France is particularly concerned by Head and Neck (H&N) cancers. In addition to tobacco and alcohol, Human Papillomavirus (HPV) has been reported as a risk factor for H&N cancers. The literature on the burden of these cancers in Europe is scarce. This study was performed to assess the medical and economical burden of hospitalisations for H&N cancers in France. The French national hospital database (PMSI), in which admissions to public and private hospitals are recorded, was retrospectively analysed to assess the annual number of patients hospitalised for H&N cancers and associated hospital costs from the healthcare payer perspective. ICD-10 codes (16 codes classified as oral cavity, oropharynx, pharynx, salivary glands and larynx) were used to extract admissions for these cancers. Hospital stays, chemotherapy and radiotherapy sessions were extracted to assess patients' management. Costs of admissions were obtained from French official tariffs. In 2007, there were 36 268 patients hospitalised for H&N cancers, of whom 81% were men, corresponding to 60 200 hospital stays and 287 846 sessions of chemo- or radio-therapy. Oropharynx cancer was the most frequent (28% of patients), followed by oral cavity cancer (25% of patients). The peak of frequency was observed in the 55-59 years age group. Patients were mainly treated in medicine (48%) and surgery (23%) units. Mean annual cost per patient ranged from €2,764 to €7,673 leading to a total hospital cost of €323 millions in 2007 (including hospitalization and expensive drugs). With 26% of H&N cancers attributable to HPV infections, 9 430 patients were hospitalized due to HPV-related H&N cancers, representing €138 million in 2007. Even without taking into account the rehabilitation costs, the hospital burden of H&N cancers is considerable.


Changing epidemiology of candidaemia in Australia.
Knowledge of contemporary epidemiology of candidaemia is essential. We aimed to identify changes since 2004 in incidence, species epidemiology and antifungal susceptibilities of Candida spp. causing candidaemia in Australia. These data were collected from nationwide active laboratory-based surveillance for candidaemia over 1 year (within 2014-2015). Isolate identification was by MALDI-TOF MS supplemented by DNA sequencing. Antifungal susceptibility testing was performed using Sensititre YeastOne™. A total of 527 candidaemia episodes (yielding 548 isolates) were evaluable. The mean annual incidence was 2.41/105 population. The median patient age was 63 years (56% of cases occurred in males). Of 498 isolates with confirmed species identity, Candida albicans was the most common (44.4%) followed by Candida glabrata complex (26.7%) and Candida parapsilosis complex (16.5%). Uncommon Candida species comprised 25 (5%) isolates. Overall, C. albicans (>99%) and C. parapsilosis (98.8%) were fluconazole susceptible. However, 16.7% (4 of 24) of Candida tropicalis were fluconazole- and voriconazole-resistant and were non-WT to posaconazole. Of C. glabrata isolates, 6.8% were resistant/non-WT to azoles; only one isolate was classed as resistant to caspofungin (MIC of 0.5 mg/L) by CLSI criteria, but was micafungin and anidulafungin susceptible. There was no azole/echinocandin co-resistance. We report an almost 1.7-fold proportional increase in C. glabrata candidaemia (26.7% versus 16% in 2004) in Australia. Antifungal resistance was generally uncommon, but azole resistance (16.7% of isolates) amongst C. tropicalis may be emerging.


Molecular dissection of cardiac repolarization by in vivo Kv4.3 gene transfer.
Heart failure leads to marked suppression of the Ca(2+)-independent transient outward current (I(to1)), but it is not clear whether I(to1) downregulation suffices to explain the concomitant action potential prolongation. To investigate the role of I(to1) in cardiac repolarization while circumventing culture-related action potential alterations, we injected adenovirus vectors in vivo to overexpress or to suppress I(to1) in guinea pigs and rats, respectively. Myocytes were isolated 72 hours after intramyocardial injection and stimulation of the ecdysone-inducible vectors with intraperitoneal injection of an ecdysone analog. Kv4.3-infected guinea pig myocytes exhibited robust transient outward currents. Increasing density of I(to1) progressively depressed the plateau potential in Kv4. 3-infected guinea pig myocytes and abbreviated action potential duration (APD). In vivo infection with a dominant-negative Kv4. 3-W362F construct suppressed peak I(to1) in rat ventriculocytes, elevated the plateau height, significantly prolonged the APD, and resulted in a prolongation by about 30% of the QT interval in surface electrocardiogram recordings. These results indicate that I(to1) plays a crucial role in setting the plateau potential and overall APD, supporting a causative role for suppression of this current in the electrophysiological alterations of heart failure. The electrocardiographic findings indicate that somatic gene transfer can be used to create gene-specific animal models of the long QT syndrome.


[Principles of antihypertensive therapy in metabolic syndrome].
Clinical features of arterial hypertension in patients with metabolic syndrome are described with reference to antihypertensive therapy and the choice of adequate drugs for the purpose. Characteristics of the most frequently used preparations are presented along with algorithms for their application depending on clinical condition. Advantages of combined antihypertensive therapy in metabolic syndrome are substantiated, their most efficacious combinations are recommended.


Sleep and Food Choice in a Dutch Student Population.
The increased risk of obesity among short sleepers is most likely explained by increased energy intake. However, food intake could not only be altered quantitavely but also qualitatively. Therefore, we performed a correlational analysis on self-reported food intake and sleep in 51 students from Maastricht and surroundings. Students that slept longer had a lower caloric intake: ρ = -0.378, p = 0.006, the amount of calories consumed per minute awake remaining relatively stable. However, sleep duration did not correlate with intake of percentage fat, saturated fat, carbohydrates or protein. Average energy intake during the reported breakfasts, lunches, dinners or snacks separately did also not correlate with total sleep time. It seems that shorter sleep correlates with absolute caloric intake, but not with the intake of specific dietary components.


Cardiovascular responses in anticipation of changes in posture and locomotion.
Measurements were made in 29 adult baboons that were housed in social groups, allowing the occurrence of the full range of species-specific behavioral interactions. The cardiovascular variables measured included blood pressure, heart rate, renal blood flow, lower limb blood flow, and occasionally mesenteric blood flow. The data were telemetered from backpacks worn by the animals and were recorded in analogue form on a polygraph, digitally on a computer and were also recorded on the audio channels of videotape being made of the behavior and social interactions of the baboons. The video and the computer recordings were synchronized by a timing system that made it possible to relate the cardiovascular responses to the behavioral responses. A numerically based behavioral code was developed that allowed the categorization of the totality of the behavior, including postural and locomotor changes. Comparisons between baseline cardiovascular values and those occurring 1 s before the initiation of a movement or posture change gave no evidence of anticipatory cardiovascular responses unless the movement was associated with behavior that included emotional content. Hypothalamic perifornical lesions reduced or eliminated these anticipatory changes.


Bystander CPR and Long-Term Survival in Older Adults With Out-of-Hospital Cardiac Arrest.
Most studies on bystander cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) have focused on in-hospital or short-term survival. The purpose of this study was to examine the association between bystander CPR and long-term survival outcomes for OHCA. Within the Cardiac Arrest Registry to Enhance Survival, we identified 152,653 patients with OHCA ≥65 years of age or older. Using multivariable hierarchical logistic regression, we first examined the association between bystander CPR and in-hospital survival. Then, among those surviving to discharge and linked to Medicare files, we evaluated the association between bystander CPR and long-term mortality over 5 years using multivariable Cox regression. Overall, 58,464 (38.3%) received bystander CPR. Patients receiving bystander CPR were more likely to have an OHCA that was witnessed, in a public location, and with an initial shockable rhythm. Bystander CPR was associated with a 24% higher likelihood of surviving to hospital discharge (10.2% vs 5.5%; adjusted relative risk: 1.24 [95% CI: 1.19-1.29]; P < 0.001), and this survival benefit was similar (interaction P = 0.24) for those who were 65 to 74, 75 to 84, and ≥85 years of age. Among patients surviving to hospital discharge (median follow-up of 31 months), bystander CPR was additionally associated with lower long-term mortality vs those without bystander CPR (adjusted hazard ratio: 0.78 [95% CI: 0.73-0.84]; P < 0.001), and this benefit was also consistent across age groups (interaction P = 0.13). In older adults with OHCA, bystander CPR was associated with higher rates of in-hospital survival. This survival benefit was not attenuated by competing mortality risks but increased in magnitude after hospital discharge.


Phonon transport across crystal-phase interfaces and twin boundaries in semiconducting nanowires.
We combine state-of-the-art Green's-function methods and nonequilibrium molecular dynamics calculations to study phonon transport across the unconventional interfaces that make up crystal-phase and twinning superlattices in nanowires. We focus on two of their most paradigmatic building blocks: cubic (diamond/zinc blende) and hexagonal (lonsdaleite/wurtzite) polytypes of the same group-IV or III-V material. Specifically, we consider InP, GaP and Si, and both the twin boundaries between rotated cubic segments and the crystal-phase boundaries between different phases. We reveal the atomic-scale mechanisms that give rise to phonon scattering in these interfaces, quantify their thermal boundary resistance and illustrate the failure of common phenomenological models in predicting those features. In particular, we show that twin boundaries have a small but finite interface thermal resistance that can only be understood in terms of a fully atomistic picture.


Oxytocin and prolactin suppress cortisol responses to acute stress in both lactating and non-lactating sheep.
Cortisol response to stress appears to differ between lactating and non-lactating animals. Lactating (14 d post partum) and non-lactating sheep were fitted with probes so that drugs and hormones could be infused directly into the posterior pituitary and paraventricular nucleus of the hypothalamus. The animals were also fitted with instruments to allow monitoring of heart rate, body temperature and blood cortisol levels. Their reactions to a source of acute stress (a barking dog) were then followed, with or without drug and hormone manipulation. Results in both lactating and non-lactating animals indicated shortcomings in the use of cortisol as a stress indicator. Infusing prolactin and oxytocin into either the posterior pituitary or the paraventricular nucleus of the hypothalamus suppressed cortisol responsiveness to stress in both lactating and non-lactating animals (the latter to a greater extent). In the absence of drugs, lactating animals had a slightly higher basal level of cortisol and a lower cortisol response to stress than their non-lactating counterparts. Despite suppression of cortisol responses, with or without drugs, other indicators of stress still changed with the presence of a barking dog, suggesting the complexity of control involved in stress responses.


Temporal regulation of viral and cellular gene expression during human T-lymphotropic virus type I-mediated lymphocyte immortalization.
An autocrine mechanism of proliferation may play a significant role in the leukemogenesis of adult T-cell leukemia, a mature T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-I). To further delineate the role of HTLV-I and the interleukin 2 (IL2) system in the transformation process, human primary lymphocytes were infected by cocultivation with lethally X-irradiated MT2 cells in the presence or absence of human rIL2; the polymerase chain amplification reaction was used to examine quantitatively the expression of HTLV-I, IL2, and IL2R alpha mRNAs during early and late proliferation phases that displayed polyclonal (days 7 to 49) and oligoclonal (days 100 to 150) proviral integration, respectively. IL2 mRNA and IL2 activity were transiently expressed during the polyclonal phase but were undetectable at later time points. IL2R alpha mRNA expression remained at a constitutively high level throughout the examined time course. Viral transcripts were detectable at each time point. Expression of the tax-rex mRNA was inversely related to IL2 mRNA levels; it was low early in the polyclonal phase but increased 30-fold with the development of oligoclonality. In addition, paraformaldehyde-fixed HTLV-I-producing cells activated peripheral blood lymphocytes. These data suggest that HTLV-I activates human T lymphocytes. However, IL2 expression is transient, indicating a limited involvement of an IL2 autocrine growth loop in the transformation process. Lastly, another viral determinant, in addition to the trans activator tax, may be important in HTLV-I-induced T-cell proliferation.


[Confocal laser scanning microscopy].
Reflectance confocal microscopy (RCM) allows the in vivo evaluation of melanocytic and nonmelanocytic skin tumours with high sensitivity and specificity. RCM represents an optical imaging technique, which enables us to examine the skin at high resolution. Today, RCM represents not only an interesting tool for dermatologic research but has also been introduced as a diagnostic tool in every day clinical practice. As such, RCM is applied for improvement of skin cancer diagnosis adjunct to clinical and dermatoscopic examination. In combination with dermatoscopy RCM has shown an increased specificity with similar sensitivity. In this regard RCM helps to decrease the rate of unnecessary biopsies of benign lesions. Despite its use in dermatooncology RCM may also be used for diagnosis and monitoring of inflammatory diseases. Future developments include technical improvements, teledermatology solutions and the application of ex vivo RCM in Moh's micrographic surgery.


Genealogy-based methods for inference of historical recombination and gene flow and their application in Saccharomyces cerevisiae.
Genetic exchange between isolated populations, or introgression between species, serves as a key source of novel genetic material on which natural selection can act. While detecting historical gene flow from DNA sequence data is of much interest, many existing methods can be limited by requirements for deep population genomic sampling. In this paper, we develop a scalable genealogy-based method to detect candidate signatures of gene flow into a given population when the source of the alleles is unknown. Our method does not require sequenced samples from the source population, provided that the alleles have not reached fixation in the sampled recipient population. The method utilizes recent advances in algorithms for the efficient reconstruction of ancestral recombination graphs, which encode genealogical histories of DNA sequence data at each site, and is capable of detecting the signatures of gene flow whose footprints are of length up to single genes. Further, we employ a theoretical framework based on coalescent theory to test for statistical significance of certain recombination patterns consistent with gene flow from divergent sources. Implementing these methods for application to whole-genome sequences of environmental yeast isolates, we illustrate the power of our approach to highlight loci with unusual recombination histories. By developing innovative theory and methods to analyze signatures of gene flow from population sequence data, our work establishes a foundation for the continued study of introgression and its evolutionary relevance.


Bone marrow transplantation with interleukin-2-activated bone marrow followed by interleukin-2 therapy for acute myeloid leukemia in mice.
We have investigated approaches to induce graft-versus-leukemia (GVL) effect in autologous bone marrow transplantation (ABMT) without graft-versus-host disease to improve survival and cure in leukemia. The present study shows that bone marrow transplantation (BMT) using syngeneic bone marrow activated with interleukin-2 (ABM) for 24 hours in vitro, followed by interleukin-2 (IL-2) therapy, was superior to BMT with fresh, syngeneic bone marrow (FBM) in terms of survival and cure in mice with acute myeloid leukemia (P less than .001) and led to normal hematopoietic reconstitution. Addition of IL-2 therapy after BMT with FBM did not improve the results over BMT with FBM alone (P = .98). These results suggest that the GVL effect of ABMT can be enhanced by using ABM for BMT followed by IL-2 therapy without compromising engraftment.


New York's statistical model accurately predicts mortality risk for veterans who obtain private sector CABG.
To determine whether patients' use of the Veterans Health Administration health care system (VHA) is an independent risk factor for mortality following coronary artery bypass grafting (CABG) in the private sector in New York. VHA administrative and New York Department of Health Cardiac Surgery Reporting System (CSRS) databases for surgeries performed in 1999 and 2000. Prospective cohort study comparing observed, expected, and risk-adjusted mortality rates following private sector CABG for 2,326 male New York State residents aged 45 years and older who used the VHA (VHA users) and 21,607 who did not (non-VHA users). We linked VHA administrative databases to New York's CSRS to identify VHA users who obtained CABG in the private sector in New York in 1999 and 2000. Using CSRS risk factors and previously validated risk-adjustment model, we compared patient characteristics and expected and risk-adjusted mortality rates of VHA users to non-VHA users. Compared with non-VHA users, patients undergoing private sector CABG who had used the VHA were older, had more severe cardiac disease, and were more likely to have the following comorbidities associated with increased risk of mortality: diabetes, chronic obstructive pulmonary disease, cerebrovascular disease, peripheral vascular disease, and history of stroke (p<.001 for all); a calcified aorta (p=.009); and a high creatinine level (p=.003). Observed (2.28 versus 1.80 percent) and expected (2.48 versus 1.78 percent) mortality rates were higher for VHA users than for non-VHA users. The risk-adjusted mortality rate for VHA users (1.70 percent; 95 percent confidence interval [CI]: 1.27-2.22) was not statistically different than that for the non-VHA users (1.87 percent; 95 percent CI: 1.69-2.06). Use of the VHA was not an independent risk factor for mortality in the risk-adjustment model. Although VHA users had a greater illness burden, use of the VHA was not found to be an independent risk factor for mortality following private sector CABG in New York. The New York Department of Health risk adjustment model adequately applies to veterans who obtain CABG in the private sector in New York.


Comparison of amoxicillin and clavulanic acid (augmentin) for the treatment of nonbullous impetigo.
We undertook a prospective double-blind controlled study to compare the efficacy of a drug that usually has no antistaphylococcal activity (amoxicillin trihydrate) with the efficacy of the same drug with an addition of a beta-lactamase inhibitor (amoxicillin plus clavulanic acid [Augmentin]) in the treatment of nonbullous impetigo. Fifty-one culture-positive patients, aged 6 months to 9 years, were included, 26 in the amoxicillin group and 25 in the Augmentin group. The study groups were clinically and bacteriologically comparable at the start of the study. Staphylococcus aureus was isolated from all patients and beta-hemolytic streptococcus from 14 (29%). All staphylococci were sensitive to Augmentin but resistant to amoxicillin. Forty-nine patients completed the study. The clinical response was significantly better among the Augmentin recipients (marked improvement in 71% and 95% of patients after 2 and 5 days, respectively; no new lesions during the treatment course) than among the amoxicillin recipients (marked improvement in 44% and 68% of patients after 2 and 5 days, respectively; new lesions appeared in 20% of patients). Recurrence within 3 weeks occurred in 12 (26%) of 49 patients, and no difference was observed between the two groups. We conclude that S aureus is common in nonbullous impetigo, and that at least in some cases it plays an important role in the course of the disease that can be altered by specific therapy.


Prolonged fasting and the effects on biomarkers of inflammation and on adipokines in healthy lean men.
Obesity and insulin resistance are associated with low-grade systemic inflammation, which is related to increased concentrations of plasma FFAs, glucose, or insulin. Prolonged fasting induces insulin resistance due to elevated plasma FFAs, but is not accompanied by hyperinsulinemia or hyperglycemia. This makes it possible to study effects of physiologically increased FFA concentrations on inflammatory markers, when insulin and glucose concentrations are not increased. In random order, 10 healthy young lean men (mean BMI: 22.8 kg/m2) were fasted or fed in energy balance for 60 h with a 2-week wash-out period. Subjects stayed in a respiration chamber during the 60-h periods. Blood samples were taken after 12, 36, and 60 h. Then, a hyperinsulinemic-euglycemic clamp was performed.Fasting decreased insulin sensitivity by 45% and increased FFA concentrations 5-fold. Fasting did not change concentrations of the inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-8, or of hs-CRP. Effects on vascular endothelial growth factor (VEGF)--which may positively relate to insulin resistance, and on chemerin and leptin--adipokines related to obesity, and obesity-related pathologies, were also studied. At t=60 h, VEGF concentrations were significantly increased during the fasted period (p<0.05). At the same time point, chemerin (p<0.01) and leptin (p<0.01) were significantly decreased after fasting. For leptin, this decrease was also significant after 36 h (p<0.01). Adiponectin levels remained unchanged. In healthy young lean men, fasting-induced increases in FFAs leading to insulin resistance do not cause changes in concentrations of the inflammatory cytokines. VEGF concentrations increased and those of chemerin decreased.


Hydration of fat-free body in protein-depleted patients.
It is widely believed that increased hydration of the fat-free body accompanies most major disease processes as a result of contraction of the body cell mass and expansion of the extracellular fluid. Measurements of total body water (TBW) and total body nitrogen in 68 normal volunteers and 95 surgical ward patients presenting for intravenous nutrition have been used to derive ratios of TBW to fat-free mass (TBW:FFM) and protein indices (PI), where PI is defined as the ratio of measured total body protein to predicted TBP. Mean values of PI were 1.009 +/- 0.116 (SD) and 0.783 +/- 0.152 in the normal and patient groups, respectively, corresponding to mean TBW:FFM ratios of 0.719 +/- 0.016 and 0.741 +/- 0.029. However, 48 patients had normal TBW:FFM despite having lost 15% of body protein. A theoretical model of body composition changes in catabolic illness is presented, which is in accord with the patient data, demonstrating that TBW:FFM does not necessarily increase in catabolic illness and that the ratio masks underlying shifts in body fluid compartments.


Aggregating resistant Staphylococcus aureus induces hypocoagulability, hyperfibrinolysis, phagocytosis, and neutrophil, monocyte, and lymphocyte binding in canine whole blood.
Staphylococcus aureus is an opportunistic pathogen with the ability to form mobile planktonic aggregates during growth, in vitro. The in vivo pathophysiologic effects of S aureus aggregates on host responses are unknown. Knowledge of these could aid in combating infections. This study aimed to investigate the effect of increasing concentrations of two different aggregating S aureus strains on the hemostatic and inflammatory host responses in canine whole blood. The hypothesis was that aggregating bacteria would induce pronounced hemostatic and inflammatory responses. Citrate-stabilized whole blood from 10 healthy dogs was incubated with two strains of aggregating S aureus at three different concentrations. Each sample was analyzed using tissue factor-thromboelastography (TF-TEG) and the formed clot was investigated with electron microscopy. The plasma activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen, and D-dimer tests were measured. Bacteria-leukocyte binding was evaluated with flow cytometry, and neutrophil phagocytosis was assessed using light and transmission electron microscopy. The highest concentration of bacteria resulted in a significantly shortened TF-TEG initiation time, decreased alpha, maximum amplitude, global strength, and increased lysis. In addition, significantly shortened PT, decreased fibrinogen, and increased D-dimers were demonstrated at the highest concentration of bacteria. Lower concentrations of bacteria showed no differences in TF-TEG when compared with controls. The findings were similar for both S aureus strains. Increased concentration-dependent binding of bacteria and leukocytes and neutrophil bacterial phagocytosis was observed. Two strains of S aureus induced alterations of clot formation in concentrations where bacterial aggregates were formed. A concentration-dependent cellular inflammatory response was observed.


Integrating gestational diabetes and type 2 diabetes care into primary health care: Lessons from prevention of mother-to-child transmission of HIV in South Africa - A mixed methods study.
Implementation of the programmes for the Prevention of Mother to Child Transmission (PMTCT) of Human Immunodeficiency Virus (HIV) into antenatal care over the last three decades could inform implementation of interventions for other health challenges such as gestational diabetes mellitus (GDM). This study assessed PMTCT outcomes, and how GDM screening, care, and type 2 diabetes (T2DM) prevention were integrated into PMTCT in Western Cape (WC), South Africa. A convergent mixed methods and triangulation design were used. Content and thematic analysis of PMTCT-related policy documents and of 30 semi-structured interviews with HIV/PMTCT experts, health care workers and women under PMTC diagnosed with GDM complement quantitative longitudinal analysis of PMTCT implementation indicators across the WC for 2012-2017. Provincial PMTCT and Post Natal Care (PNC) documents emphasized the importance of PMTCT, but GDM screening and T2DM prevention were not covered. Data on women with both HIV and GDM were not available and GDM screening was not integrated into PMTCT. Women who attended HIV counselling and testing annually increased at 17.8% (95% CI: 12.9% - 22.0%), while women who delivered under PMTCT increased at 3.1% (95% CI: 0.6% - 5.9%) annually in the WC. All 30 respondents favour integrating GDM screening and T2DM prevention initiatives into PMTCT. PMTCT programmes have not yet integrated GDM care. However, Western Cape PMTCT integration experience suggests that antenatal GDM screening and post-partum initiatives for preventing or delaying T2DM can be successfully integrated into PMTCT and primary care.


Integrated Molecular Optomechanics with Hybrid Dielectric-Metallic Resonators.
Molecular optomechanics describes surface-enhanced Raman scattering using the formalism of cavity optomechanics as a parametric coupling of the molecule's vibrational modes to the plasmonic resonance. Most of the predicted applications require intense electric field hotspots but spectrally narrow resonances, out of reach of standard plasmonic resonances. The Fano lineshapes resulting from the hybridization of dielectric-plasmonic resonators with a broad-band plasmon and narrow-band cavity mode allow reaching strong Raman enhancement with high-Q resonances, paving the way for sideband resolved molecular optomechanics. We extend the molecular optomechanics formalism to describe hybrid dielectric-plasmonic resonators with multiple optical resonances and with both free-space and waveguide addressing. We demonstrate how the Raman enhancement depends on the complex response functions of the hybrid system, and we retrieve the expression of Raman enhancement as a product of pump enhancement and the local density of states. The model allows prediction of the Raman emission ratio into different output ports and enables demonstrating a fully integrated high-Q Raman resonator exploiting multiple cavity modes coupled to the same waveguide.


Predictors of weight loss in children with attention deficit hyperactivity disorder treated with stimulant medication.
A retrospective study was undertaken to examine predictors of weight loss in children with attention deficit hyperactivity disorder (ADHD) treated with stimulant medication. Children diagnosed with ADHD and treated with methylphenidate hydrochloride (MPH) or dextroamphetamine sulfate (DEX) for at least 5 months were identified by retrospective chart review. Analyses were performed on 32 children (29 boys) treated with MPH and 28 children (25 boys) treated with DEX. Variables examined included pretreatment weight, pretreatment body mass index (BMI), duration of treatment, total daily dose, and weight-adjusted dose. The MPH-treated group was initially seen at a mean age (+/- standard deviation) of 7.5 years (+/- 2.1). Mean duration of follow-up was 11.2 months (+/- 3.8). Mean total daily dose was 25.5 mg (+/- 8.2) and mean weight-adjusted dose was 1.0 mg/kg/day (+/- .5). Mean change in weight as expressed in z scores was -0.4 SD (+/- .7). The DEX-treated group was initially seen at a mean age of 9.3 years (+/- 2.7). Mean duration of follow-up was 10.8 months (+/- 4.1). Mean total daily dose was 14.9 mg (+/- 8.2) and mean weight-adjusted dose was .5 mg/kg/day (+/- .3). Mean change in weight was -0.6 SD (+/- .6). Although the MPH group was younger than the DEX group, there were no between-group differences in weight or height either before treatment or at follow-up when adjusted for age and gender. Using linear regression analysis, significant correlations were found between pretreatment weight and change in weight for both the MPH-treated group (r = .63) and the DEX-treated group (r = .47). Stepwise multiple-regression analysis indicated that pretreatment age, weight-adjusted dose, and duration of follow-up did not significantly contribute to the variance in change of weight for either the MPH- or DEX-treated groups. To adjust for height, changes in BMI were also analyzed. For both medication groups, no differences were found between the heavier (BMI > or = 50%) and thinner (BMI < 50%) children in duration of follow-up, total daily dose, or weight-adjusted dose. When the medication groups were combined, a greater proportion of heavier children experienced a decrease relative to their predicted BMI compared with thinner children (80% vs 52%). Comparisons of mean BMI slopes revealed that the heavier group experienced an absolute decrease in their BMI (-.139) in contrast to the thinner group (+.014) (t = 2.70). Pretreatment weight, adjusted for age, gender, and height, is a significant predictor of weight loss in children with ADHD treated with either MPH or DEX. In contrast, pretreatment age, duration of treatment, and weight-adjusted dose were not found to be significant predictors.