Multilevel modeling was a convenient alternative to common regression designs in longitudinal suicide research.
The prospective investigation of repetitive nonfatal suicidal behavior is associated with two methodological problems. Due to the commonly used definitions of nonfatal suicidal behavior, clinical samples usually consist of patients with a considerable between-person variability. Second, repeated nonfatal suicidal episodes of the same subjects are likely to be correlated. We examined three regression techniques to comparatively evaluate their efficiency in addressing the given methodological problems. Repeated episodes of nonfatal suicidal behavior were assessed in two independent patient samples during a 2-year follow-up period. The first regression design modeled repetitive nonfatal suicidal behavior as a summary measure. The second regression model treated repeated episodes of the same subject as independent events. The third regression model represented a hierarchical linear model. The estimated mean effects of the first model were likely to be nonrepresentative for a considerable part of the study subjects. The second regression design overemphasized the impact of the predictor variables. The hierarchical linear model most appropriately accounted for the heterogeneity of the samples and the correlated data structure. The nonhierarchical regression designs did not provide appropriate statistical models for the prospective investigation of repetitive nonfatal suicidal behavior. Multilevel modeling provides a convenient alternative.


Sequence and structure prediction of RNA-dependent RNA polymerase of lily symptomless virus isolated from L. × 'Casablanca'.
The DNA sequence of the RNA-dependent RNA polymerase (RdRp) gene of lily symptomless virus (LSV), a lily-infecting member of the genus Carlavirus, was determined from nine overlapping cDNA fragments of different sizes. The complete sequence of this RdRp gene (HM070294) consisted of 5,847 nucleotides coding for a protein of 220 kDa. It had 97-98% sequence identity with RdRps of other known isolates at both the DNA and the amino acid level. Phylogenetic analysis indicated that this RdRp (designated as RdRp-DL) was closely related to the RdRp of the Korean isolate (AM516059), as well as to the RdRps from Passiflora latent virus (PLV) and Kalanchoe latent virus (KLV) of the genus Carlavirus. Hydrophobic analysis of RdRp-DL revealed a hydrophobic N-terminus and a hydrophilic C-terminus. Helices and Loops were the major secondary structures of RdRp-DL. In addition, RdRp-DL also had three coil structures. Four conserved domains were identified: typoviral methyltransferase, RNA-dependent RNA polymerase, P-loop-containing nucleoside triphosphate hydrolases and carlavirus endopeptidase. A model of the tertiary structure predicted by I-TASSER was obtained for each of these conserved domains. This is the first report of a detailed phylogenetic analysis of LSV RdRp with those of other members of the genus Carlavirus, and the first to predict the domain structures of LSV RdRp.


Duodenal perforation by an inferior vena cava filter in a polyarteritis nodosa sufferer.
Inferior vena cava (IVC) filters are currently used in the management of pulmonary embolism (PE) and lower limb venous thromboembolism (VTE). Despite their widespread use, associated complications including duodenal perforation have been reported. We describe a unique case of duodenal perforation 2 years post IVC filter insertion in a patient with polyarteritis nodosa (steroid dependent) and thrombocytopenia secondary to chronic cyclophosphamide use. IVC filters are commonly employed in the management of VTE. Associated complications have been reported including filter migration, fracture and adjacent organ perforation. There is growing consensus that temporary IVC filters should be retrieved as soon as possible with dedicated IVC filter registries to ensure patients are not lost to follow-up post insertion. Duodenal perforation is a rare complication of IVC filter insertion. This case however illustrates the potentially catastrophic consequences of a relatively common endovascular procedure. Caution should be taken when considering the insertion of IVC filters in patients with longstanding vasculopathies who are on immunosuppressants.


Application of the multiplanar fracture redactor in the treatment of tibial shaft fractures with intramedullary nails.
This prospective study aimed to introduce the application of the multiplanar fracture redactor (MFR) in the treatment of tibial shaft fractures with intramedullary nails (IMNs). From February to June 2018, a total of 18 patients with tibial shaft fractures were recruited. MFR was used to help achieve the reduction of tibial shaft fractures with IMN in all patients. The demographic and fracture characteristics, surgical data, postoperative complications and prognostic indicators of 16 patients were recorded. All operations were performed under closed reduction, excellent radiological and functional outcomes were observed. The average duration of surgery, intraoperative blood loss, intraoperative fluoroscopy times, number of intraoperative assistants, and duration of postoperative hospital stay were 91.2 ± 26.1 min, 95.0 ± 58.3 ml, 19.2 ± 2.3 times, 1 (1-2), and 7.8 ± 2.6 days, respectively. The mean Lysholm Knee Function Score (LKFS), American Orthopaedic Foot and Ankle Society (AOFAS) and visual analogue scale (VAS) scores at one year after surgery were 96.8 ± 2.1, 94.8 ± 2.9, and 1 (0-3), respectively. Wound infection, non-union, malunion or complications associated with MFR were not observed in this study. Thus, MFR was a safe and neater method to achieve and maintain the reduction of tibial shaft fractures with IMN.


Different stressors elicit different responses in the salivary biomarkers cortisol, haptoglobin, and chromogranin A in pigs.
Most commonly, salivary cortisol is used in pig stress assessment, alternative salivary biomarkers are scarcely studied. Here, salivary cortisol and two alternative salivary biomarkers, haptoglobin and chromogranin A were measured in a pig stress study. Treatment pigs (n = 24) were exposed to mixing and feed deprivation, in two trials, and compared to untreated controls (n = 24). Haptoglobin differed for feed deprivation vs control. Other differences were only found within treatment. Treatment pigs had higher salivary cortisol concentrations on the mixing day (P < 0.05). Chromogranin A concentrations were increased on the day of refeeding (P < 0.05). Haptoglobin showed a similar pattern to chromogranin A. Overall correlations between the salivary biomarkers were positive. Cortisol and chromogranin A were moderately correlated (r = 0.49, P < 0.0001), correlations between other markers were weaker. The present results indicate that different types of stressors elicited different physiological stress responses in the pigs, and therefore including various salivary biomarkers in stress evaluation seems useful.


Flow-induced mechanotransduction in skeletal cells.
Human body is subject to many and variegated mechanical stimuli, actuated in different ranges of force, frequency, and duration. The process through which cells "feel" forces and convert them into biochemical cascades is called mechanotransduction. In this review, the effects of fluid shear stress on bone cells will be presented. After an introduction to present the major players in bone system, we describe the mechanoreceptors in bone tissue that can feel and process fluid flow. In the second part of the review, we present an overview of the biological processes and biochemical cascades initiated by fluid shear stress in bone cells.


Assessing the contribution of mobility in the European Union to rubber expansion.
Nearly three-quarters of global natural rubber production is used to produce tyres, supporting mobility around the globe. The projected increase in mobility could contribute to further expansion of rubber plantations and impact tropical ecosystems. We quantified the use of natural rubber in tyres in the European Union (EU), the corresponding land footprint, and explored drivers of tyre use using country-specific transport statistics and trade registers of rubber goods. Five percent of the world's natural rubber is consumed in tyres used in the EU, using up to a quarter of the area under rubber plantations in some producing countries. Car use is responsible for 58% of this consumption, due to car-dependent lifestyles that are associated with economic prosperity and spatial planning paradigms. While the EU's transport policy focuses on reducing dependence on fossil-fuels, cross-cutting policies are needed to address car-dependency and reduce the EU's land footprint in tropical landscapes without compromising progress towards decarbonisation.


Effect of adrenocorticotrophic hormone on muscle acetylcholinesterase and nonspecific esterase.
Acetylcholinesterases in the muscle homogenates of hamsters receiving ACTH intraperitoneally for six weeks were reduced as compared to the activities in the control samples. In polyacrylamide disc gel electrophoresis of the ACTH-treated muscles some acetylcholinesterase bands were absent. These observations may be significant in explaining the ACTH-induced improvement in myasthenia gravis patients and in the pathophysiology of steroid myopathy.


Activation of rabbit platelet phospholipase and thromboxane synthesis by 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (platelet activating factor).
1-O-Hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC), structurally identical with platelet activating factor, is a potent stimulus for rabbit platelet aggregation and serotonin secretion. AGEPC at concentrations between 10(-10) and 10(-8) M induced stimulation of rabbit platelet synthesis of thromboxane B2. The dose vs. response curve for platelet thromboxane B2 synthesis was displaced slightly towards higher stimulus concentrations compared to [3H]serotonin secretion, with half-maximal concentrations of 2.5 . 10(-9) and 8 . 10(-10) M, respectively. Rates of thromboxane B2 synthesis and secretion were similar with a t 1/2 max of 4.0-4.5 s for both processes. AGEPC induced a decrease in platelet [14C]arachidonic acid in both phosphatidylinositol and phosphatidylcholine, although [14C]arachidonic acid turnover in phosphatidylcholine was not observed below 1 . 10(-8) M AGEPC. Concomitantly, this decrease in phospholipid [14C]arachidonic acid was associated with a marked increase of radiolabel in platelet diacylglycerol and phosphatidic acid 15 s after AGEPC addition, suggesting the possibility of a phospholipase C-diacylglycerol lipase mechanism of fatty acid cleavage. As observed previously with secretion and aggregation, removal of the 2-acetyl group from AGEPC abrogated all capacity of this molecule to stimulate platelet phospholipase. This study indicates that AGEPC (or platelet activating factor) activation of rabbit platelet phospholipase occurs in a time-course and concentration range similar to that required for [3H]serotonin secretion.


Poppies as a sleep aid for infants: The "Hypnos" remedy of Cretan folk medicine.
Opium Poppy (Papaver somniferum L.) is considered as one of the earliest medicinal plants known to mankind. Derived from the Greek name "opos" meaning juice, referring to its psychotropic latex, the plant was known and extensively used since Antiquity during religious rituals and for Medical purposes, mainly as hypnotic and pain reliever agent. In Cretan folk medicine it was recommended along with other poppies until the early 20th century to induce children sedation, by the name: "Hypnos" meaning sleep.


One-step detection of aflatoxin-B(1) using scFv-alkaline phosphatase-fusion selected from human phage display antibody library.
A unique human phage display library was used to successfully generate a scFv to the highly carcinogenic toxin aflatoxin B1. Such an antibody has major potential applications in therapy and diagnostics. To further exploit its analytical capacity, the scFv was genetically fused to alkaline phosphatase, thereby generating a novel and highly sensitive self-indicating reagent. The performance of this reagent was further characterized, demonstrating its efficacy. The sensitivity of scFv-AP fusion was three-fold better than that of the scFv form. The ability of this human library to generate antibodies to a small hapten was clearly demonstrated and this is linked to its intrinsic diversity, which exceeds many existing conventional human libraries. Our results indicate that demography may influence the diversity of the repertoire of the library in terms of its capacity to generate antibodies to specific targets. Equally, the approach demonstrated should also be applicable for other haptens and larger antigens.


A highactivity ATP translocator in mesophyll chloroplasts of Digitaria sanguinalis, a plant having the C-4 dicarboxylic acid pathway of photosynthesis.
The effect of exogenous adenine nucleotides on CO2 fixation and oxygen evolution was studied with mesophyll protoplast extracts of the C4 plant Digitaria sanguinalis. Exogenous ATP was found to stimulate the rate of pyruvate and pyruvate+oxalacetate induced CO2 fixation, as well as reverse the inhibition of CO2 fixation of carbonyl cyanide m-chlorophenyl hydrazone and several electron transport inhibitors. The ATP-dependent stimulation of CO2 fixation varied from 40 to 70 mumol CO2 fixed/mg chlorophyll per h, suggesting that ATP was crossing the chloroplast membranes at rates of 80-140 mumol/mg chlorophyll per h, since 2 ATP are required for each CO2 fixed. Fixation of CO2 could also be induced in the dark by exogenous ATP, in which case ADP accumulated outside the chloroplasts...


Tumor cell and circulating markers in melanoma: diagnosis, prognosis, and management.
The search is on for biomarkers for use in the diagnosis, staging, prognosis, and management of patients with melanoma. As with many types of cancer, the hematogenous spread of melanoma is a bad prognostic sign, and many groups have attempted to detect circulating melanoma cells in patients with different stages of melanoma. Some studies have used direct extraction of intact tumor cells from the peripheral blood and others the detection of surrogate markers of circulating melanoma cells, such as tyrosinase or MART-1. However, a correlation between the detection of intact melanoma cells in the circulation and prognosis is controversial. Many other biomarkers have also been studied, including lactate dehydrogenase, S100, TA90, and C-reactive protein. Much progress has been made, and preliminary studies have shown promise with many of these markers. Finally, the detection of tumor-specific circulating DNA has shown promise as a prognostic and diagnostic marker of disease in melanoma as well. In this review we examine the most promising biomarkers for use in patients with cutaneous melanoma.


Floral origin modulates the content of a lipid marker in Apis mellifera honey.
The compound DAGE (DiAcyl Glyceryl Ether, 1-stearyl-2,3-dioleoyl glycerol), present in Apis mellifera honey, is a lipidic entomological marker secreted by the salivary glands of worker bees. Its content was determined by NMR, analyzing the organic extracts of a number of Italian honeys of different floral typology. We have found that the DAGE content is related to the botanical origin of honey. This dependence on floral typology was further confirmed by a linear correlation (R2 > 0.83) observed between the content of DAGE and the enzymatic activity of invertase and diastase in honey. Also these enzymes originate from bee salivary secretions and their concentrations in honey are known to depend on the floral source. DAGE content appears to be a sensitive parameter to some forms of honey manipulations, as indicated by the results of artificial bee-feeding experiments. This suggests its possible use as indicator of honey authenticity.


A new patient-focused approach to the treatment of metastatic renal cell carcinoma: establishing customized treatment options.
What's known on the subject? and What does the study add? • Six targeted agents--sorafenib, sunitinib, pazopanib, bevacizumab, temsirolimus and everolimus--have been approved for the treatment of advanced renal cell carcinoma (RCC) based on evidence from large randomized controlled trials (RCTs). However, no head-to-head trials have been conducted to evaluate the relative efficacy of these agents in this setting. • Patient populations included in clinical trials do not accurately reflect the wider population of patients with RCC, as certain subgroups, such as the elderly or those with co-morbidities, are typically under-represented. • The optimum choice of therapy should be based on patient characteristics, nature of disease, and history and aims of therapy; however, there is currently no clear guidance for physicians in this decision-making process. • A patient-focussed schema has been developed that acknowledges nine different patient-, disease-, and treatment-related factors relevant to clinical decision-making, and provides a visual indication of the strength of evidence with which a particular agent can be recommended for use in specific subgroups. • To demonstrate the applicability of this tool, a review of all available evidence (published articles, congress presentations and personal communications) for sorafenib in RCC was conducted by a panel of experts, findings from which showed that sorafenib can be recommended for use in various subgroups of differing age, prognosis, performance status, tumour burden and distribution, treatment history and co-morbidity. • This patient-focussed approach has broad application and can be used to assess other agents and tumour types. Randomized controlled trials (RCTs) show that six targeted agents--sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab and pazopanib--improve outcome in advanced renal cell carcinoma (RCC). The populations enrolled in the pivotal phase III studies differed, and, to date, no head-to-head comparisons allow us to judge relative efficacy and tolerability. Populations recruited to RCTs under-represent certain patient subtypes, notably the elderly and those with comorbidities. Choosing the agent most appropriate in a specific case requires that we take into account the characteristics of the patient, the nature of their disease, and the history and aims of therapy. Data from expanded access programmes and clinical experience may be as relevant as the results of RCTs when making this difficult decision. To show how different sources of data can be integrated, we propose a schema that acknowledges nine patient-, disease-, and treatment-related factors relevant to clinical decision-making and provides an easily understood visual indication of the strength with which a particular agent can be recommended for use in specific subgroups of patients. As an example, we show how this tool shows the suitability of sorafenib in RCC subpopulations of differing age, prognosis, performance status, tumour burden and distribution, treatment history, and comorbidity. This patient-focused approach has broad application to other agents and tumour types.


Hydrogen sulphide-induced hypothermia attenuates stress-related ulceration in rats.
1. Hydrogen sulphide (H(2)S) acts as a gaseous cellular messenger and has recently been reported to induce a suspended animation-like state in mice. The aim of the present study was to investigate the protective role of H(2)S exposure in stress gastric ulcer. 2. In the present study, we used a rat model of water immersion and restraint stress (WRS) to induce the typical stress disease, namely stress gastric ulcer. Rats were treated with WRS for 4 h, with or without pre-exposure to H(2)S (160 p.p.m. H(2)S for 2.5 h). 3. In H(2)S-exposed rats, body temperature was significantly reduced by 2.5C (P < 0.01) and oxygen consumption was reduced by 37.1% (P < 0.01) compared with control rats. Plasma levels of H(2)S were increased by 20.8% (P < 0.01) following pre-exposure. Pre-exposure to H(2)S significantly reduced the gastric ulcer index, from 24 +/- 9 to 9 +/- 2 (P < 0.01), in WRS rats. In addition, WRS increased plasma levels of adrenocorticotropin (ACTH) and corticosterone 4.7- and 4.8-fold, respectively (both P < 0.01). Pre-exposure to H(2)S markedly suppressed plasma ACTH and corticosterone level by 34.4 and 53.2%, respectively (both P < 0.01), and reduced WRS-elevated myeloperoxidase (MPO) activity by 19%. In the present study, WRS increased gastric malondialdehyde and conjugated diene content by 42 and 68%, respectively (both P < 0.01), and H(2)S exposure reduced lipid peroxide production. Finally, H(2)S exposure inhibited the WRS-elevated expression of glucose-regulated protein 78 and caspase 12, markers of endoplasmic reticulum stress. 4. In conclusion, a low concentration of H(2)S may be a new pharmacological tool for induced hypothermia to prevent severe stress-induced diseases and multifarious trauma in the clinical setting.


A neutron scattering study of hydrogen dynamics in coarse-grained and nanostructured ZrCr₂H₃.
The vibrational spectra of hydrogen and parameters of H diffusion in the coarse-grained C15-type system ZrCr(2)H(3) and in nanostructured ZrCr(2)H(3) have been studied by means of inelastic and quasielastic neutron scattering. It is found that the diffusive motion of hydrogen in coarse-grained ZrCr(2)H(3) can be described in terms of at least two jump processes: a fast localized H motion with the jump rate τ(l)( - 1) over the hexagons formed by interstitial Zr(2)Cr(2) sites and a slower process with the rate τ(d)( - 1) associated with H jumps leading to long-range diffusion. While τ(d)( - 1)(T) in the range 250-380 K follows the Arrhenius law with the activation energy of 142 ± 4 meV, the temperature dependence of τ(l)( - 1) deviates from Arrhenius behavior. The nanostructured ZrCr(2)H(3) samples prepared by ball milling consist of C15-type grains and strongly distorted (amorphous-like) regions. H atoms in the strongly distorted regions are found to be immobile on the time scale of our experiments. The microscopic picture of H jump motion in the C15-type grains of the nanostructured samples is similar to that in coarse-grained ZrCr(2)H(3); however, the ball milling leads to a considerable decrease in the jump rate τ(d)( - 1).


Influence of sexual dimorphism and dichromatism on reproductive success in a rare native cactus.
Identifying plant sexual dimorphic traits is critical in advancing our knowledge on plant-pollinator interactions. For example, dimorphism in floral colors, or sexual dichromatism, is a crucial mediator of pollinator choice on foraging decisions. We studied Cylindropuntia wolfii, a model system, with diverse flower colors and a functionally dioecious sexual system. However, evidence suggests that sexual reproduction is limited in this species as it has a low seed set especially in naturally pollinated fruits. Thus, it is critical to this native species' conservation to investigate its relationship with pollinators. Our goals were to: (a) investigate the sexual dimorphism including the sexual dichromatism in the flowers of the cactus, and (b) determine whether sexually dimorphic traits affect the pollinator attraction of both the sexes. We measured several quantitative and qualitative traits and compared them between male and female flowers. Then we recorded the pollinator visitation rate in nature for both sexes and tracked pollinator color preference using fluorescent dyes as pollen analogues. Our study showed that male flowers of C. wolfii are bigger and brighter, and they attract more potential pollinators than females, supporting the hypothesis that sexual dimorphism influences pollinator visitation preference. Fluorescence dichromatism, in which female flowers' anthers fluoresce more than male flower anthers suggest this could be female flowers' strategy to compensate for their dark colors and small size. The results from this study showed that C. wolfii exhibits sexual dichromatism and fluorescence dichromatism, which is a novel finding in plant research.


Measurement of glutathione and glutathione disulfide.
Measurements of glutathione should include quantification of both the reduced and oxidized forms. HPLC-based assays for glutathione and other cellular thiols and disulfides utilize a variety of detection methods, including ultraviolet, fluorescence, and electrochemical methods. This unit provides rapid, sensitive, highly versatile and reproducible HPLC methods for separating and quantifying sulfur-containing amino acids and related derivatives from a variety of biological samples.


Validation of a new piezoelectric device for noninvasive measurement of central aortic systolic blood pressure.
The objective of this study was to compare the aortic piezoelectric device for noninvasive measurement of central aortic systolic blood pressure (cSBP) with the SphygmoCor. A total of 85 participants from both sexes, aged 18-80 years, were stratified into three age groups (<30, 30-60, >60 years), with an equal number of healthy volunteers and hypertensive patients. We performed three cSBP measurements with each device, in an alternate manner, using the Bland-Altman method to determine the level of agreement. The standard of the Association for the Advancement of Medical Instrumentation for brachial blood pressure evaluation was used for the comparison. The mean cSBPs were 109.3±12.05 and 109.0±12.2 mmHg with the SphygmoCor and the Aortic device, respectively, showing a strong correlation (r=0.98, P<0.001). A mean difference of 0.35±2.43 mmHg (95% confidence interval: 0.17-0.87, P=NS) was obtained with the Bland-Altman method. The 95% limits of agreement was -4.4 to +5.1 mmHg. Complying with the Association for the Advancement of Medical Instrumentation criteria, cSBP measurements obtained with the Aortic and the SphygmoCor devices are equivalent.


Development of a mobile mindfulness smartphone app for post-traumatic stress disorder and alcohol use problems for veterans: Beta test results and study protocol for a pilot randomized controlled trial.
Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are highly prevalent, and co-occurring among post-9/11 veterans. Mobile health (mHealth) applications, specifically those focused on mindfulness-based techniques, may be an effective avenue to intervene with veterans who cannot or will not seek care at traditional in-person settings. Thus, to address areas of improvement in mHealth for veterans, we developed Mind Guide and prepared it for testing in a pilot randomized controlled trial (RCT) with veterans. We have completed phase 1 (treatment development) and Phase 2 (beta test) of our mobile mHealth app, Mind Guide. In this paper we describe the methods for Phase 1 as well as results for our beta test (n = 16; inclusion criteria included screen for PTSD, AUD, a post-9/11 veteran, and not currently receiving treatment) for Mind Guide as well as outline procedures for our pilot RCT of Mind Guide (Phase 3). The PTSD Checklist, self-reported alcohol use, the Perceived Stress Scale, Penn Alcohol Craving Scale, and the Emotion Regulation Questionnaire were used. Results of our beta test of Mind Guide show promising past 30 day effects on PTSD (d = -1.12), frequency of alcohol use (d = -0.54), and alcohol problems (d = -0.44), and related mechanisms of craving (d = -0.53), perceived stress (d = -0.88), and emotion regulation (d = -1.22). Our initial beta-test of Mind Guide shows promise for reducing PTSD and alcohol related problems among veterans. Recruitment is ongoing for our pilot RCT in which 200 veterans will be recruited and followed up for 3 months. gov Identifier: NCT04769986.


Density functional theory and Hartree-Fock studies: geometry, vibrational frequencies and electronic properties of Anderson-type heteropolyanion, [XM6O24]n- (X=TeVI, IVII and M=Mo, W) and [SbVW6O24]7-.
The geometry, IR and Raman spectra and electronic properties of Anderson-type heteropolyanions with main-group high oxidation state heteroatom, [Te(VI)Mo(6)O(24)](6-), [I(VII)Mo(6)O(24)](5-), [Sb(V)W(6)O(24)](7-), [Te(VI)W(6)O(24)](6-) and [I(VII)W(6)O(24)](5-) have been investigated using Hartree-Fock (HF) and density functional theory (DFT) methods. HF method has good results in geometry parameters but poorer than DFT method in the results of vibrational frequencies. Also we have investigated the effect of LanL2DZ augmented in the vibrational frequencies. With attention to relative charge and size of the cavity occupied by XO(6) subunit in these anions, we suggest that the general formula [XO(6)(n-)@M(6)O(18)] to describe electronic properties of these anions.


Inequalities in the benefits of national health insurance on financial protection from out-of-pocket payments and access to health services: cross-sectional evidence from Ghana.
A central pillar of universal health coverage (UHC) is to achieve financial protection from catastrophic health expenditure. There are concerns, however, that national health insurance programmes with premiums may not benefit impoverished groups. In 2003, Ghana became the first sub-Saharan African country to introduce a National Health Insurance Scheme (NHIS) with progressively structured premium charges. In this study, we test the impact of being insured on utilization and financial risk protection compared with no enrolment, using the 2012-13 Ghana Living Standards Survey (n = 72 372). Consistent with previous studies, we observed that participating in health insurance significantly decreased the probability of unmet medical needs by 15 percentage points (p.p.) and that of incurring catastrophic out-of-pocket (OOP) health payments by 7 p.p. relative to no enrolment in the NHIS. Households living outside a 1-h radius to the nearest hospital had lower reductions in financial risk from excess OOP medical spending relative to households living closer (-5 p.p. vs -9 p.p.). We also find evidence that in Ghana, the scheme was highly pro-poor. Once insured, the poorest 40% of households experienced significantly larger improvements in medical utilization (18 p.p. vs. 8 p.p.) and substantively larger reductions in catastrophic OOP health expenditure (-10 p.p. vs. -6 p.p.) compared with that of the richest households. However, health insurance did not benefit vulnerable persons equally from financial risk. Once insured, poor, low-educated and self-employed households living far from hospitals had significantly lower reductions in catastrophic OOP medical spending compared with their counterparts living closer. Taken together, we show that enrolment in the NHIS is associated with improved financial protection but less so among geographically remote vulnerable groups. Efforts to boost not just insurance uptake but also health service delivery may be needed as a supplement for insurance schemes to accelerate progress towards UHC.


Onyiuke Grading Scale: A clinical classification system for the diagnosis and management of Bertolotti syndrome.
Lumbosacral transitional vertebrae (LSTV) is a common anatomic variant of the spine, characterized by the formation of a pseudoarticulation between the transverse process of the lumbar vertebrae and sacrum or ilium. LSTVs have been implicated as a potential source of low back pain - dubbed Bertolotti syndrome. Traditionally, LSTVs have only been subdivided into types I-IV based on the Castellvi radiographic classification system. Solely identifying the type of LSTV radiographically provides no clinical relevance to the treatment of Bertolotti syndrome. Here, we seek to analyze such patients and identify a clinical grading scale and diagnostic-therapeutic algorithm to optimize care for patients with this congenital anomaly. Patients presenting with back pain between 2011 and 2018 attributable to a lumbosacral transitional vertebra were identified retrospectively. Data was collected from these patients' charts regarding demographic information, clinical presentation, diagnostic imaging, treatment and outcomes. Based on evaluation of these cases and review of the literature, a diagnostic-therapeutic algorithm is proposed. Based on our experiences evaluating and treating these patients and review of the existing literature, we propose a clinical classification system for Bertolotti syndrome: we proposed a 4-grade scale for patients with Bertolotti syndrome based upon location, severity, and characteristics of pain experienced due to LSTVs. Based on our experience with the cases illustrated here, we recommend managing patients with LSTV based on our diagnostic-therapeutic algorithm. Moving forward, a larger prospective study with a larger patient cohort is needed to further validate the treatment paradigm.


Methods for Differentiating hiPSCs into Vascular Smooth Muscle Cells.
Despite numerous efforts to generate vascular tissues that recapitulate the physiological characteristics of native vessels, vascular cell source remains one of the principal challenges in the construction of tissue-engineered vascular grafts (TEVGs). Human pluripotent stem cells, therefore, represent an indispensable source to supply a large production of vascular smooth muscle cells (VSMCs) for cell-based therapy. In particular, human induced pluripotent stem cells (hiPSCs) generated from the same individual have opened up new avenues of achieving patient specificity through the derivation of autologous and immunocompatible VSMCs. This book chapter will detail three representative methods of differentiating hiPSCs into VSMCs that are structurally and functionally mature for TEVG engineering. Luo et al. reported an embryoid body (EB)-based approach to generate a robust, large-scale production of mature, functional hiPSC-derived VSMCs as a cell replacement for vascular tissue engineering. EB formation has an advantage of resembling early embryonic development and allowing cellular interactions in three dimensions. Cheung et al. established a system to produce embryological origin-specific hiPSC-derived VSMCs from the neuroectoderm, lateral plate mesoderm, and paraxial mesoderm lineages in a chemically defined manner. This allows site-specific vascular disease modeling. Moreover, Eoh et al. followed Wanjare et al.'s method to construct hiPSC-derived VSMCs using monolayer cultures of extracellular matrix proteins, with the addition of a pulsatile flow for the secretion of mature, organized elastic fibers. The generation of TEVGs, powered by the unlimited supply of hiPSC-derived VSMCs, has begun a new era in cellular therapy for vascular bypass and defective vessel segment replacement, aimed at addressing millions of cases of cardiovascular diseases across the globe.


Imaging of primary testicular lymphoma with unusual intraabdominal spread along the spermatic cord and gonadal vein.
Primary testicular lymphoma (PTL) is a rare Testicular neoplasm found in elderly patients. Imaging features in PTL presenting with contiguous involvement of spermatic cord and extension along gonadal vein have been rarely detailed before. We describe a case of a 50-year-old male who presented with complaints of scrotal swelling and abdominal discomfort. Imaging, which included Ultrasonography and contrast-enhanced computed tomography of chest-abdomen, showed features of aggressive-looking bilateral testicular mass lesions with the distinctive feature of contiguous spread along the spermatic cord and gonadal vein till retroperitoneum and disseminated chest and abdominal metastases. The distinctive feature of contiguous extension along the spermatic cord and gonadal vein can help suggest a diagnosis of PTL on imaging.


Brain structural plasticity in visual and sensorimotor areas of airline pilots: A voxel-based morphometric study.
Airline pilot is a highly specialized profession that requires to response quickly and accurately in the presence of a wide variety of visual information. Although functional imaging studies have employed virtual simulation to identify brain areas that underlie various flying-related tasks, little is known about the specific patterns of structural plasticity in the airline pilot's brain. In this study, we examined differences of gray matter and white matter volumes between 42 airline pilots and 39 non-pilots by using voxel-based morphometry, and further assessed the association between magnitude of structural alterations and flight time in the pilots. We found significantly increased white matter volume in the cuneus area in the pilot group compared to the non-pilot group (p < 0.05, FWE corrected). Using a relaxed threshold, it was also observed that the pilots had increased gray matter volume in the lingual gyrus, inferior frontal gyrus, supramarginal gyrus, cuneus, and postcentral gyrus, and increased white matter volume in the postcentral area (p < 0.001, uncorrected). Moreover, the pilots' flight time was positively correlated with gray matter volume in the postcentral gyrus and white matter volume in the cuneus area (p < 0.001, uncorrected). The morphological changes in specific visual and sensorimotor areas may provide airline pilots with neural efficiency in the visuo-motor processing related to flight.


Toluene's effects on activity and extracellular dopamine in the mouse are altered by GABAA antagonism.
The abuse of inhalants like toluene continues to be widespread around the world, especially among children and teenagers. Despite its frequency of misuse, the dynamics between dopamine (DA) and gamma-aminobutyric acid (GABA) in response to toluene exposure remains unclear. To further decipher toluene's actions, we used a dynamic exposure system in combination with microdialysis to examine in vivo the effects of acutely inhaled toluene on DA release within the mouse caudate putamen (CPu). Results show that toluene inhalation produced increases in DA levels and locomotor activity. In mice that were pretreated with the GABAA antagonist, bicuculline, there was no change in the locomotor response during toluene but activity was potentiated following toluene exposure. Bicuculline pretreatment increased extracellular DA levels during toluene exposure, suggesting that DA and GABA-releasing neuron interaction may play a role in the rewarding properties of toluene.


[The importance of the Musculus canalis ani for continence and anorectal diseases (author's transl)].
The functional morphology of the M. canalis ani is described. Hitherto this muscle has not been studied in detail. The M. canalis ani is located inside of the M. sphincter ani internus and reaches through the spatium submucosum et subcutaneum of the analcanal. This muscle is part of a described "organ of continence". Its importance in the course of anorectal disease is shown.


Successful defibrotide treatment of a patient with veno-occlusive disease after living-donor liver transplantation: A case report.
Veno-occlusive disease (VOD) is characterized by painful hepatomegaly, ascites, weight gain, and jaundice with nonthrombotic, fibrous obliteration of the centrilobular hepatic veins. VOD after liver transplantation is a rare complication, with an incidence of approximately 2%; however, it can be life-threatening in severe cases. The precise etiology and mechanism of VOD after liver transplantation remains unclear. Acute cellular rejection, antibody-mediated rejection, and treatment with tacrolimus or azathioprine may be associated with the development of VOD after liver transplantation. Additionally, the optimal treatment of VOD after liver transplantation has not yet been established and focuses on supportive care. Defibrotide is an anti-ischemic and antithrombotic drug with no systemic anticoagulant effects. Moreover, only a few reports have investigated the use of defibrotide for VOD after liver transplantation, which has shown promising results. A 39-year-old woman with primary biliary cholangitis underwent living-donor liver transplantation at our center. She experienced right upper quadrant pain with increased ascites, pleural effusion, and weight gain on postoperative day 14. Imaging and pathological tests showed no evidence of rejection or vessel complications. VOD was diagnosed clinically based on the findings of weight gain, ascites, jaundice, and pathological biopsy. Defibrotid, 25 mg/kg/day, was administered intravenously for 21 days. She showed complete clinical resolution of the VOD. Herein, we report a case of successful defibrotide treatment of VOD after living-donor liver transplantation.


Risk factor targeting for vaccine prioritization during the COVID-19 pandemic.
A key public health question during any disease outbreak when limited vaccine is available is who should be prioritized for early vaccination. Most vaccine prioritization analyses only consider variation in risk of infection and death by a single risk factor, such as age. We provide a more granular approach with stratification by demographics, risk factors, and location. We use this approach to compare the impact of different COVID-19 vaccine prioritization strategies on COVID-19 cases, deaths and disability-adjusted life years (DALYs) over the first 6 months of vaccine rollout, using California as a case example. We estimate the proportion of cases, deaths and DALYs averted relative to no vaccination for strategies prioritizing vaccination by a single risk factor and by multiple risk factors (e.g. age, location). When targeting by a single risk factor, we find that age-based targeting averts the most deaths (62% for 5 million individuals vaccinated) and DALYs (38%) and targeting essential workers averts the least deaths (31%) and DALYs (24%) over the first 6 months of rollout. However, targeting by two or more risk factors simultaneously averts up to 40% more DALYs. Our findings highlight the potential value of multiple-risk-factor targeting of vaccination against COVID-19 and other infectious diseases, but must be balanced with feasibility for policy.


Balance abilities of junior ice hockey players.
Postural control is required during various fast-paced and offensive ice hockey actions, and therefore seems to be an important component in ice hockey performance. Data were collected from two ice hockey teams with differing performance levels. The higher-performance team consisted of 26 players (with ages of 16.3±0.9 y, heights of 178.26±6.71 cm, and weights of 74.3±9.6 kg). The lower-performance team consisted of 19 players (with ages of 16.2±1.8 y, heights of 176.11±9.81 cm, and weights of 68.7±13.9 kg). Each participant performed six unilateral stances under static conditions on a balance pad placed on a force platform and five bilateral stances under dynamic conditions using a wobble board placed on the force platform. The higher-level players performed better in the unilateral static stance task in both the anterior-posterior direction and the medial-lateral direction (with a P value of P<0.001), and total velocity (P=0.001). The higher-level players also performed better in both the anterior-posterior and medial-lateral directions, and total velocity (with P value of P<0.001), in the bilateral dynamic stance task and therefore performed significantly better than the lower-level players. Hockey players who possess a highly developed postural control strategy have a superior ability to compensate for unexpected postural disturbances and collisions, and thus possess a strong competitive advantage. Therefore, testing the balance abilities of hockey players under static and dynamic conditions may be useful for evaluating their competitive performance levels.


Allergic airborne contact dermatitis from essential oils used in aromatherapy.
Contact allergy to various essential oils used in aromatherapy was demonstrated on patch testing in a 53-year-old patient suffering from relapsing eczema resistant to therapy on various uncovered parts of the skin, in particular the scalp, neck and hands. Sensitization was due to previous exposure to lavender, jasmine and rosewood. Laurel, eucalyptus and pomerance also produced positive tests, although there was no hint of previous exposure. A diagnosis of allergic airborne contact dermatitis was thus established. On topical and systemic glucocorticoid treatment (peroral methylprednisolone at an initial dose of 60 mg/day) the skin lesions eventually resolved. Due to persistence of the volatile essential oils in the patient's home after a year-long use of aroma lamps, complete renewal of the interior of the patient's flat was considered essential. Due to changing self-medication habits, with increasing orientation to 'natural' modes of treatment, increasing numbers of such sensitizations might be on the horizon.


MiRNA 24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogels for corneal epithelial healing.
The damage of corneal epithelium may lead to the formation of irreversible corneal opacities and even blindness. The migration rate of corneal epithelial cells directly affects corneal repair. Here, we explored ocu-microRNA 24-3p (miRNA 24-3p) that can promote rabbit corneal epithelial cells migration and cornea repair. Exosomes, an excellent transport carrier, were exacted from adipose derived mesenchymal stem cells for loading with miRNA 24-3p to prepare miRNA 24-3p-rich exosomes (Exos-miRNA 24-3p). It can accelerate corneal epithelial migration in vitro and in vivo. For application in cornea alkali burns, we further modified hyaluronic acid with di(ethylene glycol) monomethyl ether methacrylate (DEGMA) to obtain a thermosensitive hydrogel, also reported a thermosensitive DEGMA-modified hyaluronic acid hydrogel (THH) for the controlled release of Exos-miRNA 24-3p. It formed a highly uniform and clear thin layer on the ocular surface to resist clearance from blinking and extended the drug-ocular-epithelium contact time. The use of THH-3/Exos-miRNA 24-3p for 28 days after alkali burn injury accelerated corneal epithelial defect healing and epithelial maturation. It also reduced corneal stromal fibrosis and macrophage activation. MiRNA 24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogel as a multilevel delivery strategy has a potential use for cell-free therapy of corneal epithelial regeneration.


[Primary reconstructive operations in open injuries of the hand and fingers].
The experience with 1613 plastic operations is described. The use of skin plastic reconstruction resulted in the healing of the wound by first intention in 80,7% of cases.


Iatrogenic rupture of the left gastric artery during percutaneous endoscopic gastrostomy.
Gastric arterial rupture is a rare but serious and potentially fatal complication of percutaneous endoscopic gastrostomy (PEG). We report a case in which insertion of a needle during PEG caused iatrogenic rupture of the left gastric artery.


High risks adverse events associated with trastuzumab emtansine and trastuzumab deruxtecan for the treatment of HER2-positive/mutated malignancies: a pharmacovigilance study based on the FAERS database.
T-DM1 and T-DXd are two promising antibody-drug conjugates for treating advanced HER2-positive breast cancer and HER2-mutated lung cancer. Understanding the differences in the adverse events (AEs) profile of both drugs may help clinicians make an appropriate treatment decision. All data obtained from the FDA Adverse Event Reporting System (FAERS) database from Q1 2004 to Q3 2022 underwent disproportionality analysis and Bayesian analysis to detect and assess the AE signals of T-DM1 and T-DXd for comparison. A total of 2,113 and 1,269 AE reports associated with T-DM1 and T-Dxd, respectively, were retrieved from FAERS database, in which, respondents were mostly elderly women. Their statistical differences (p < 0.001), poses high incidence of thrombocytopenia, including cardiotoxicity (p < 0.05) for T-DM1, while myelosuppression, interstitial lung disease (ILD), and pneumonitis for T-DXd. Splenomegaly, nodular regenerative hyperplasia, hepatic cirrhosis, portal hypertension, neuropathy peripheral, and spider nevus, are particular to T-DM1. Similarly, febrile neutropenia, pneumocystis jirovecii pneumonia, neutrophil count decreased, and KL-6 increased, are unique to T-DXd. T-DXd is more likely to induce ILD/pneumonia and myelosuppression than T-DM1, whereas T-DM1 has higher risk of hepatotoxicity, cardiotoxicity, and thrombocytopenia than T-DXd. T-DM1-related hepatotoxicity may need redefinition. Clinicians may need to balance the benefits and risks of antibody-drug conjugates treatment for certain patients.


Detecting Lipoproteins Sneaking Out of the Lipopolysaccharide Leaflet.
The envelope of Gram-negative bacteria is an essential compartment which is in direct contact with the environment; the envelope maintains cellular integrity and functions as a permeability barrier protecting the cell from toxic compounds. The outer layer of the envelope is an asymmetric membrane whose external leaflet is mainly composed of lipopolysaccharide molecules. Recently, there has been growing evidence that lipoproteins (i.e., soluble proteins anchored to a membrane by a lipid moiety) decorate the lipopolysaccharide leaflet in the model bacterium Escherichia coli, challenging the current paradigm that lipoproteins remain in the periplasm in this organism. However, assessing the surface exposure of lipoproteins is challenging. Here, we describe an optimized and reproducible dotblot protocol to assess the presence of lipoproteins at the surface of E. coli and other bacterial models. We added all necessary controls to reduce the possibility of artifacts giving rise to false-positive results. We selected the stress sensor RcsF as a model lipoprotein to illustrate the method, which can be used for any other lipoprotein.


Optimization of antibody-conjugated magnetic nanoparticles for target preconcentration and immunoassays.
Biosensors based on antibody recognition have a wide range of monitoring applications that apply to clinical, environmental, homeland security, and food problems. In an effort to improve the limit of detection of the Naval Research Laboratory (NRL) Array Biosensor, magnetic nanoparticles (MNPs) were designed and tested using a fluorescence-based array biosensor. The MNPs were coated with the fluorescently labeled protein, AlexaFluor647-chicken IgG (Alexa647-chick IgG). Antibody-labeled MNPs (Alexa647-chick-MNPs) were used to preconcentrate the target via magnetic separation and as the tracer to demonstrate binding to slides modified with anti-chicken IgG as a capture agent. A full optimization study of the antibody-modified MNPs and their use in the biosensor was performed. This investigation looked at the Alexa647-chick-MNP composition, MNP surface modifications, target preconcentration conditions, and the effect that magnetic extraction has on the Alexa647-chick-MNP binding with the array surface. The results demonstrate the impact of magnetic extraction using the MNPs labeled with fluorescent proteins both for target preconcentration and for subsequent integration into immunoassays performed under flow conditions for enhanced signal generation.


Complications of herpes zoster in children.
Herpes zoster (HZ) may cause complications; however, information regarding complications of HZ in children is relatively sparse. We reviewed cases of HZ in children retrospectively and investigated the risk factors contributing to the development of complications. A retrospective observational study was conducted at a tertiary care children's hospital in Japan. Children receiving a diagnosis of HZ between January 2010 and October 2016 were identified from electronic medical records. In this study, the following diseases were recognized as complications of HZ: bacterial skin infection, facial paralysis, meningitis, uveitis and keratitis, postherpetic neuralgia, acute retinal necrosis, pneumonia, and otitis interna. Details regarding clinical information of HZ patients with complications were described. We found 138 cases with HZ. Among these, 58 (42%) occurred in immunocompetent children and 80 cases (58%) occurred in immunocompromised children. Complications were observed in 10 cases of immunocompromised children and in eight cases of immunocompetent children. Although secondary bacterial skin infection was the most common complication (n = 6, 33.3%), severe complications such as facial paralysis (n = 3, 16.7%), meningitis (n = 2, 11.1%), uveitis and keratitis (n= 2, 11.1%), acute retinal necrosis (n = 1, 5.6%), pneumonia (n = 1, 5.6%), and otitis interna (n = 1, 5.6%) were observed. Patients with complications tended to have a rash on the head or neck, compared with those without complications (n = 9, 50% vs n = 18, 15%; P = 0.001). Severe HZ complications may occur in immunocompetent children. Development of a rash on the head or neck might be a risk factor for complications.


Development of a Vietnamese version of the Revised Hasegawa's Dementia scale.
As the aging population grows worldwide, the problem of age-related health is becoming an important public health concern. Dementia is a devastating disease that places a significant physical, emotional, and financial burden on patients, their caregivers, and society. It is predicted to increase in developing countries. The Revised Hasegawa's Dementia Scale (HDS-R) has been used in many Asian countries to measure cognitive function. However, there is still no Vietnamese version of the HDS-R. Therefore, this paper describes the development of the HDS-R scale and manual in Vietnamese language. Two Vietnamese researchers translated the HDS-R from English to Vietnamese. To confirm the accuracy of the translation, two other Vietnamese researchers conducted a back-translation. Another pair of Vietnamese researchers compared the back-translated English version to the original one. All six researchers discussed the inconsistencies between English HDS-R scale and manual and derived the most suitable version for the Vietnamese context. In Questions 4 and Question 7, we changed the words from "cherry blossom" and "train" to "daisy flower" and "bicycle" for the first option, and from "plum blossom" to "rose" for the second option. We also changed the expressions in some places in the manual to fit the Vietnamese language. Future studies are needed to validate this version to be able to access cognitive function in both clinical and public healthcare settings.


Temperature rise required for production of minimal lesions in the Macaca mulatta retina.
Fundus temperatures of the rhesus monkey were measured with argon laser (488 nm) irradiations that produced minimal, ophthalmoscopically visible lesions five minutes after exposure. Measurements were made with 10- to 20-mu tip diameter, copper-nickel thermocouples. Preliminary data included measurements at eight paramacular sites and seven macular sites. The threshold temperature rise was 17 to 26 degrees C for a ten-second exposure at these sites. Decreasing the exposure duration to 20 msec increased the threshold temperature rise range to the interval between 30 and 40 degrees C. The temperature measurements in the eye were compared to a computer solution of the heat conduction equation.


Simultaneous measurement of epinephrine-induced platelet aggregation in 14 plasma samples.
A method is described for the simultaneous measurement of epinephrine-induced platelet aggregation in 14 different plasma samples in 15 min. It is based upon discontinuous registration of platelet aggregation and computer evaluation of the data. The samples are placed in holders mounted over magnetic stirring bars in a 37 degrees C water bath and the extinction is measured by removing the samples one after the other, placing them in a Braun Universal Aggregometer and returning them to their holders in the water bath. The time required to reach 37% of maximal aggregation was chosen as the evaluation criterion. It sufficed for the determination of aggregation sensitivity. This method for the first time permits measurement of a complete titration curve rapidly and under identical conditions and can be used to show the influence of a wide range of aggregation inducers and the concurrent effects of inducers plus various blocking agents. A correlation between aggregation sensitivity and alpha 2-receptor binding capacity in platelets, measured by competitive radioactive binding, was established in samples from 10 healthy volunteers. One group exhibited high aggregation sensitivity coupled with high alpha 2-binding capacity and the other showed low sensitivity with low binding capacity.


MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 5: Carbon-substituted analogues at the C-2 position.
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with carbon-linked substituents, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Palladium-catalyzed cross-coupling methods were applied for the incorporation of aliphatic and aromatic substituents.


Solitary fibrous tumour of the prostate identified on needle biopsy.
The clinical and radical prostatectomy features of a case of solitary fibrous tumour (SFT) of the prostate identified on needle biopsy are presented. The main differential diagnoses are discussed. SFTs involving the prostate are relatively uncommon, with only isolated cases reported in the literature. Owing to their relative rarity and lack of long-term follow-up, the clinical behaviour of prostatic SFTs is difficult to predict. Complete resection of the tumour is currently the single main prognostic factor.


Analytical method for the sensitive determination of major di-(2-propylheptyl)-phthalate metabolites in human urine.
Di-(2-propylheptyl)-phthalate (DPHP) is a specific phthalic acid ester of isomeric C10 alcohols. It is classified as high molecular weight phthalate and marketed as plasticizer for polyvinyl chloride (PVC). The increase of its production volume and its wide field of application suggest a possible background exposure of the human population as found for other phthalates, making suitable analytical methods necessary. The aim of the presented analytical report is the sensitive and selective determination of the three major DPHP metabolites mono-2-(propyl-6-hydroxy-heptyl)-phthalate (OH-MPHP), mono-2-(propyl-6-oxoheptyl)-phthalate (oxo-MPHP) and mono-2-(propyl-6-carboxy-hexyl)-phthalate (cx-MPHxP) in human urine. Most of the published analytical methods for phthalate metabolites use high pressure liquid chromatography tandem mass spectrometry (HPLC-MS/MS). The methods presented here allow a comparison of chromatographic separation between HPLC-MS/MS and gas chromatography high resolution mass spectrometry (GC-HRMS), which is useful to distinguish between DPHP and DIDP. The enhanced detection limits range between 0.05-0.1μg/L for GC-HRMS and 0.1-0.2μg/L for HPLC-MS/MS.


Hypertensive APOL1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers.
Hypertension (HTN) disproportionately affects African Americans (AAs), who respond better to thiazide diuretics than other antihypertensives. Variants of the APOL1 gene found in AAs are associated with a higher rate of kidney disease and play a complex role in cardiovascular disease. AA subjects from four HTN trials (n = 961) (GERA1, GERA2, PEAR1, and PEAR2) were evaluated for blood pressure (BP) response based on APOL1 genotype after 4-9 weeks of monotherapy with thiazides, beta blockers, or candesartan. APOL1 G1 and G2 variants were determined by direct sequencing or imputation. Baseline systolic BP (SBP) and diastolic BP (DBP) levels did not differ based on APOL1 genotype. Subjects with 1-2 APOL1 risk alleles had a greater SBP response to candesartan (-12.2 +/- 1.2 vs -7.5 +/- 1.8 mmHg, p = 0.03; GERA2), and a greater decline in albuminuria with candesartan (-8.3 +/- 3.1 vs +3.7 +/- 4.3 mg/day, p = 0.02). APOL1 genotype did not associate with BP response to thiazides or beta blockers. GWAS was performed to determine associations with BP response to candesartan depending on APOL1 genotype. While no SNPs reached genome wide significance, SNP rs10113352, intronic in CSMD1, predicted greater office SBP response to candesartan (p = 3.7 x 10-7) in those with 1-2 risk alleles, while SNP rs286856, intronic in DPP6, predicted greater office SBP response (p = 3.2 x 10-7) in those with 0 risk alleles. Hypertensive AAs without overt kidney disease who carry 1 or more APOL1 risk variants have a greater BP and albuminuria reduction in response to candesartan therapy. BP response to thiazides or beta blockers did not differ by APOL1 genotype. Future studies confirming this initial finding in an independent cohort are required.


Impact of comorbidity on survival by tumour location: Breast, colorectal and lung cancer (2000-2014).
To assess the impact of comorbidity, measured by the Charlson Comorbidity Index (CCI), on survival in breast, colorectal and lung cancer. We identified 3455 breast cancer, 3336 colorectal cancer and 2654 lung cancer patients through the Hospital del Mar cancer registry. The prevalence of comorbidities according to the CCI was calculated. Kaplan-Meier curves and the log-rank test were used to compare survival curves for each cancer location. Cox regression was used to calculate survival hazard ratios and 1-, 3- and 5-year mortality rate ratios adjusted by age, sex, CCI, place of first consultation, stage, treatment and period of diagnosis. The overall unadjusted 5-year follow-up survival proportion was 82.6% for breast cancer, 55.7% for colorectal cancer, and 16.3% for lung cancer. Overall survival was associated with CCI≥3 in breast cancer (HR: 2.33 95%CI: 1.76-3.08), colorectal cancer (HR: 1.39; 95%CI: 1.13-1.70) and lung cancer (HR: 1.22; 95%CI: 1.06-1.40). In breast cancer, the higher the CCI, the higher the adjusted mortality rate ratio and differences were greater in 5-year than in 1-year follow-up survival. Comorbidity is a significant predictor of overall survival in cancer patients; however, it has a stronger impact on survival in breast cancer than in colorectal and lung cancer.


Purification of a glucagon releasing factor from the rat hypothalamus.
The purification of a peptide from the rat hypothalamus which is capable of stimulating the release of glucagon from the endocrine pancreas and therefore named glucagon releasing factor (GlRF), is described. Compositional analysis of the product obtained using well established techniques for peptide isolation revealed that GlRF appeared to consist of 30-31 amino acids. The significance of GlRF in the physiological regulation of glucagon secretion is yet to be determined but the existence of this very potent factor supports the concept of a hypothalamic-pancreatic neurohormonal link.


Quantifying the value of AMPA membership services.
The purpose of this study was to quantify the value of current and future Air Medical Physician Association (AMPA) membership services. Three-hundred-ninety-eight AMPA members were contacted by e-mail to participate in ranking AMPA membership services by a perceived numeric value (10 = highest to 1 = lowest), using a web-based survey. One-hundred-eighteen AMPA members completed the survey. The percentage of respondents having attended the conference and their AMPA-related Conference ranked-value scores were as follows: Air Medical Transport Conference (AMTC), 43%, 9.6 +/- 1.9; AirMed International Conference, 9%, 7.8 +/- 4.2; AMTC Pre-conference, 65%, 7.6 +/- 2.5; Critical Care Transport Medicine Conference (CCTMC), 47%, 6.6 +/- 2.6; CCTMC Pre-conference, 37%, 6.6 +/- 2.6; the Association of Air Medical Services (AAMS) Mid-Year Conference, 6%, 6.4 +/- 4.9; and General Membership meeting, 63%, 5.6 +/- 2.4. Current AMPA Benefit/Service ranked-value scores were as follows: textbook, 8.4 +/- 1.8; voice for physicians, 8.0 +/- 2.3; position papers, 7.9 +/- 1.8; Air Medical Journal subscription, 7.8 +/- 2.1; networking with others, 7.7 +/- 2.4; newsletter, 7.3 +/- 1.9; means to enhance professional credibility, 7.1 +/- 2.5; web site, 7.0 +/- 2.1; voice on Commission on Accreditation of Medical Transport Systems (CAMTS), 7.0 +/- 2.7; continuing medical education (CME) credits, 6.6 +/- 3.0; conference discounts, 6.4 +/- 2.9; and curriculum vitae builder, 4.9 +/- 2.9. Future AMPA Benefits/Services ranked-value scores were as follows: evidence-based guidelines, 8.6 +/- 1.7; transport database, 7.7 +/- 2.1; malpractice repository, 7.6 +/- 2.2; DVD lectures, 7.4 +/- 2.0; medical director certification, 7.2 +/- 2.9; lobbying, 7.1 +/- 2.4; photo library, 6.4 +/- 2.3; salary and benefits surveys, 6.4 +/- 2.6; speaker's bureau, 6.2 +/- 2.4; and consulting service list, 6.2 +/- 2.4. This AMPA survey was useful in prioritizing membership services.


Carvedilol attenuates 6-hydroxydopamine-induced cell death in PC12 cells: involvement of Akt and Nrf2/ARE pathways.
Oxidative stress is closely related to the pathogenesis of neurodegenerative disorders such as Parkinson's disease. Carvedilol, a nonselective β-adrenergic receptor blocker with pleiotropic activity has been shown to exert neuroprotective effect due to its antioxidant property. However, the neuroprotective mechanism of carvedilol is still not fully uncovered. The phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway plays key role in cell survival and the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is the major cellular defense mechanism against oxidative stress. Here we investigated the effects of carvedilol on 6-hydroxydopamine (6-OHDA)-induced cell death as well as the Akt and Nrf2/ARE pathways in PC12 cells. We found that carvedilol significantly increased cell viability and decreased reactive oxygen species in PC12 cells exposed to 6-OHDA. Furthermore, carvedilol activated the Akt and Nrf2/ARE pathways in a concentration-dependent manner, and increased the protein levels of heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1(NQO-1), two downstream factors of the Nrf2/ARE pathway. In summary, our results indicate that carvedilol protects PC12 cells against 6-OHDA-induced neurotoxicity possibly through activating the Akt and Nrf2/ARE signaling pathways.


Early and late complications among 15 victims exposed to indoor fire and smoke inhalation.
To evaluate early and late complications among victims exposed to indoor fire and smoke inhalation. An observational, descriptive and prospective longitudinal study of 15 victims of smoke inhalation admitted to the intensive care unit. Although without significant burns, 13 of the victims were unconscious, with airway injury, abnormal temperature and hypokalaemia, and underwent mechanical ventilation. Initial carbon monoxide concentration averaged 20.4+/-8.3%, dropping to 3.9+/-3.3% 4h later. On the 1st day, two victims recovered and were transferred, and another two died. Creatine kinase levels (2594+/-2455 U/l) correlated with duration of intensive care. Of the remaining 11 patients, 10 had early pneumonia. Steroid treatment was initiated for four patients receiving prolonged mechanical ventilation, because of persistent fever and dry cough without evidence of infection. Mortality and systemic involvement were related to burn of the upper airway and contact with combustion products. Initial creatine kinase levels emerged as a prognostic marker of injury severity. Bronchoscopy was useful in grading airway injury and obtaining bronchoalveolar culture. Corticosteroids were effective, after the acute phase, in treating non-infectious pulmonary complications.


Stimulatory effect of polyethylene glycol (PEG) on gene expression in mouse liver following hydrodynamics-based transfection.
Rapid intravenous injection of a large volume of plasmid DNA (pDNA), i.e. a transfection procedure based on hydrodynamics, is known to be an efficient and liver-specific method of in vivo gene delivery. However, the gene expression is transient. We investigated the effect of addition of polyethylene glycol (PEG) to a solution of naked pDNA (luciferase) on the expression of the gene in mouse liver following transfection by the hydrodynamics-based technique. In addition, the mechanism leading to the enhancement of the gene expression was studied. The addition of 1% (w/v) PEG2000 to the pDNA solution enhanced the resulting gene expression in the liver. Increasing the PEG2000 concentration to more than 1 and up to 10% (w/v) rather diminished the gene expression level. By contrast, increasing the molecular weight of PEG to over 2000 up to 10 000 did not affect the level of gene expression. Histopathological and serum-chemistry examinations indicated that hydrostatic or osmotic pressure increased tissue and hepatocellular damage in a PEG-concentration-dependent manner, and resulted in a decrease in gene expression. Quantitative evaluation showed that the enhanced gene expression resulted from stabilization of the pDNA introduced into the hepatocytes and an enhancement of the transport of intact pDNA to the nucleus. For most gene therapy applications and gene function studies, sustained expression of the introduced gene(s) is necessary. This simple method to achieve enhanced gene expression in liver may have a great potential for a wide variety of laboratory studies in molecular and cellular biology as well as possibly for future clinical applications in humans.


[Lung Ultrasound in Neonatology to diagnose a Pneumothorax (part two): A Guideline].
Lung ultrasound is a fast and reliable diagnostic tool in the detection of a neonatal pneumothorax. This tutorial provides basic information for understanding and detecting the generated artefacts, such as A-lines, B-lines, and the lung point. Essential knowledge of these artefacts allows for rule-in and rule-out criteria of a pneumothorax diagnosis. Lung ultrasound could help to reduce the use of radiation in neonatology in the future.


Optimal use of transmedullary support screws and fibular management in distal tibial fracture nailing based on a new biomechanical classification.
Based on a novel simple frontal view classification, a comprehensive concept for systematic management of intramedullary fixation of distal tibial fractures is introduced. Even the usage of thin (unreamed) nails allows for anatomic reduction and stable fixation if applied in combination with transmedullary support (TMS) screws. Our classification system guides the placement of the TMS screw (medial or lateral) and suggests whether to fix the fibula or not. The fixation concept of the classification was applied to 67 distal tibial fracture cases. Patients were followed up until nail removal after at least 12 months. All fractures united. Besides 5 cases of slight external malrotation (<5 degrees) no axial malunion was found. Two infections were encountered, but both were treated effectively by exchange nailing, antibiotic therapy until wound healing and C-reactive protein normalization. Final functional assessment according to Olerud/Molander Score was 85 pts (100 pts. possible, range 50-100 pts). The stability we achieved even with single screw interlocking was high due to anatomic reduction with interfragmental compression in the lowest fracture line. In cases of fracture extension into the ankle joint, interfragmental compression screws were applied before nail insertion. In more comminuted fracture types additional screws are advisable. The frontal view classification has proven to be a reliable guideline for effective intramedullary fracture fixation by minimally invasive means, allowing for optimized soft tissue protection.


Acute leukemia following a previous malignancy: do acute lymphoid leukemia and acute myeloid leukemia have common risk factors?
Within the framework of the GIMEMA Study Group, the characteristics of acute lymphoid leukemia and acute myeloid leukemia occurring in patients who have suffered a previous malignancy were studied. Assessment was also made of the clinical course, laboratory features and overall outcome of these conditions. A four-year, multi-center retrospective study was conducted to evaluate the effect of treatment for previous hematological malignancy on the development of secondary leukemia. The study collected in the GIMEMA Archive of Adult Acute Leukemia 3934 new cases of acute leukemia (2964 AML, 901 ALL, 60 acute biphenotypic leukemia). Among these cases, data were evaluated from patients with a personal history of a previous malignancy, and included inquiring into demographic data, history of neoplastic diseases in the 1st degree relatives, type and treatment of the previous malignancy, latency until the development of a secondary acute leukemia diagnosis, laboratory features, treatment and outcome at the onset of secondary acute leukemia. Approximately 200 (5.1%) patients presented a previous malignancy. Twenty-one were affected by ALL and 179 by AML. The proportion of patients with secondary AML was higher than that of patients with secondary ALL (179/2964 vs 21/901, O.R. 2.69-95% C.I. 1.66-4.39, P<0.001). The median latency, from the onset of the previous malignancy to the development of secondary ALL was 27 months and to the development of secondary AML was 52 months (P<0.05). Furthermore, of patients who previously received chemotherapy more developed a second AML (66/127 sAML vs 5/21 sALL; O.R. 3.46-95% C.I. 1.10-11.56, P<0.01). In most cases, chemotherapy treatment for a previous malignancy can play a role in the development of secondary AML. In almost all cases of secondary ALL, the role of previous drugs does not appear to be relevant. On the basis of our analysis, performed systematically for the first time on a large adult series of acute leukemia, we conclude that in these patients a biological predisposition to cancer may be suspected.


Functional and genetic analysis of annexin VI.
This study is concerned with the determination of the function of the 68kDa calcium-binding protein, annexin VI. Studies on the structure and regulation of the gene include a detailed analysis of annexin VI expressed heterologously in human A431 carcinoma cells. We have recently discovered that annexin VI is subject to a novel growth dependent post-translational modification. Interestingly, the protein exerts a negative effect on A431 cells. This effect was manifested as a partial reversal of the transformed phenotype. We are currently exploring the hypothesis that the post-translational modification of annexin VI is required for sub-cellular targeting, and that correct localisation within the cell is essential for function.


Cholinesterase activity in the rat superior cervical ganglion: effect of denervation and axotomy.
Cholinesterase activity and its various forms in the superior cervical ganglion of the rat were studied after denervation, axotomy and double section. The response of this activity to various inhibitors was also studied. The specific activity of cholinesterase activity was 323 +/- 25 nmol/mg protein/min in homogenates of normal ganglia and the total enzyme activity was 78 +/- 5 nmol/ganglion/min. Axotomy produced approximately a 40% decrease in total activity in ganglia at 3 days compared to contralateral ganglia. Activity in the contralateral ganglia was also decreased by about 30% compared to normal ganglia. Decentralization alone for 3 days did not affect the specific or total cholinesterase activity. However, decentralization followed by axotomy 3 days later resulted in a greater loss in activity compared to axotomy and a significant change in the forms of cholinesterase. After chromatography on Sepharose 6B-100 columns, 3 forms (a, c, d) of cholinesterase activity could be separated from homogenates of single ganglia. The 3 forms had estimated molecular weights of 1,934,000, 129,000 and 59,000 daltons, respectively. A fourth form (b) presented as a shoulder and had an estimated molecular weight of 404,000 daltons. Decentralization or axotomy decreased forms a and d. A reduction in the proportion of form c was also observed in the axotomized ganglion. Decentralization followed by axomoty resulted in large decreases in forms a, b and c and complete loss of form d. Assay of the separated forms in the presence of the specific inhibitor of acetylcholinesterase, BW284C-51, indicated that the majority of the enzyme recovered after chromatography is acetylcholinesterase.


Effects of prostaglandins E2 and I2 on human lymphocyte transformation in the presence and absence of inhibitors of prostaglandin biosynthesis.
1 The reactivity of human peripheral blood mononuclear cells to phytohaemagglutinin ([3H]-thymidine incorporation) was enhanced in indomethacin- and eicosatetraynoic acid-treated cells compared with untreated cells, from normal volunteers. This suggests that endogenously synthesized prostaglandins have an inhibitory effect during cell preparation and/or culture. 2 Prostaglandin E2 inhibited [3H]-thymidine incorporation induced by suboptimal phytohaemagglutinin concentrations and had a more potent effect on indomethacin-treated cells than on untreated cells. 3 Prostaglandin I2 also exhibited an inhibitory effect and, under defined conditions, was more potent than prostaglandin E2 or than prostacyclin which had been allowed to decay at pH 7.4 and 37 degrees C. 4 These results indicate that, in attempting to define altered lymphocyte reactivity in disease states, the involvement of prostaglandins should be considered both during cell preparation and culture.


Preparation and evaluation of lactose-modified monoliths for the adsorption and decontamination of plant toxins and lectins.
A series of sugar-modified porous silica monoliths with different sugar ligands (β-lactoside, β-N-acetyllactosaminide, β-d-galactoside, β-d-N-acetylgalactosaminide and β-d-glucoside) and linkers were prepared and evaluated using plant toxins and lectins including ricin and a Ricinus communis agglutinin (RCA(120)). Among these sugar monoliths, a lactose monolith carrying a triethylene glycol spacer adsorbed ricin and RCA(120) with the highest efficiency. The monolith showed no binding with albumin, globulin, and lectins from Jack beans, Osage orange, Amur maackia and wheat germ. All these data support the utility of the lactose-modified monolith as a tool for adsorption and decontamination of plant toxins.


Ultrastructural and morphometric investigations into the arterial wall of the genetically hypertensive rat.
A number of injurious agents, including "load-failure" of hemodynamic or metabolic origin, constitute "risk factors"for the wall of a blood vessel. We are here concerned with arterial hypertension, which is a primary risk factor for the production of atherosclerotic change. The SHR (spontaneously hypertensive rat) has been included among the more extensive series of experiments conducted by our research team (STAUBESAND et al.) as a particular model for the investigation of metabolic and hemodynamic "load-failure". The aims of the present contribution are to describe the morphological changes in the diseased vessel wall and to support these findings morphometrically.


Rapid detection of laboratory cross-contamination with Mycobacterium tuberculosis using multispacer sequence typing.
The ability to culture Mycobacterium tuberculosis from clinical specimens serves as the gold standard for the diagnosis of tuberculosis. However, a number of false-positive diagnoses may be due to cross-contamination of such specimens. We herein investigate such episode of cross-contamination by using a technique known as multispacer sequence typing (MST). This technique was applied to six M. tuberculosis isolates prepared within the same laboratory over a two-week period of time. MST analysis indicated a unique and common sequence profile between a strain isolated from a patient with proven pulmonary tuberculosis and a strain isolated from a patient diagnosed with lung carcinoma. Using this approach, we were able to provide a clear demonstration of laboratory cross-contamination within just four working days. Further epidemiological investigations revealed that the two isolates were processed for culture on the same day. The application of MST has been demonstrated to serve as a rapid and efficient method to investigate cases of possible cross-contamination with M. tuberculosis.


Roles of Bak and Sirt3 in Paraquat-Induced Cochlear Hair Cell Damage.
Paraquat, a superoxide generator, can damage the cochlea causing an ototoxic hearing loss. The purpose of the study was to determine if deletion of Bak, a pro-apoptotic gene, would reduce paraquat ototoxicity or if deletion of Sirt3, which delays age-related hearing loss under caloric restriction, would increase paraquat ototoxicity. We tested these two hypotheses by treating postnatal day 3 cochlear cultures from Bak±, Bak-/-, Sirt3±, Sirt3-/-, and WT mice with paraquat and compared the results to a standard rat model of paraquat ototoxicity. Paraquat damaged nerve fibers and dose-dependently destroyed rat outer hair cells (OHCs) and inner hair cells (IHCs). Rat hair cell loss began in the base of the cochlea with a 10 μM dose and as the dose increased from 50 to 500 μM, the hair cell loss increased near the base of the cochlea and spread toward the apex of the cochlea. Rat OHC losses were consistently greater than IHC losses. Unexpectedly, in all mouse genotypes, paraquat-induced hair cell lesions were maximal near the apex of the cochlea and minimal near the base. This unusual damage gradient is opposite to that seen in paraquat-treated rats and in mice and rats treated with other ototoxic drugs. However, paraquat always induced greater OHC loss than IHC loss in all mouse strains. Contrary to our hypothesis, Bak deficient mice were more vulnerable to paraquat ototoxicity than WT mice (Bak-/- > Bak± > WT), suggesting that Bak plays a protective role against hair cell stress. Also, contrary to expectation, Sirt3-deficient mice did not differ significantly from WT mice, possibly due to the fact that Sirt3 was not experimentally upregulated in Sirt3-expressing mice prior to paraquat treatment. Our results show for the first time a gradient of ototoxic damage in mice that is greater in the apex than the base of the cochlea.


The tolerance to saline-alkaline stress was dependent on the roots in wheat.
Saline-alkaline stress is one of the most serious global problems affecting agriculture, causing enormous economic and yield losses in agricultural production. Wheat, one of the most important crops worldwide, is often subjected to saline-alkaline stress. In this study, two wheat cultivars with different saline-alkaline tolerance, XC-12 (non-tolerance) and XC-45 (tolerance), were used to investigate the influence of saline-alkaline stress on photosynthesis and nitrogen (N) metabolism through hydroponic experiment with aim of elucidating the mechanism of resistance to salt-alkali. These results showed that saline-alkaline stress significantly reduced biomass accumulation, chlorophyll content, photosynthetic ability and N absorption but increased N utilization efficiency. There was no significant difference in photosynthesis between XC-12 and XC-45 under saline-alkaline stress. In addition, XC-45 had lower ratio of Na+/K+ in leaves and Na+-K+ selection rate and higher N absorption ability than XC-12, thereby improving physiological metabolism. Moreover, the roots exhibited greater growth performance in response to saline-alkaline stress as a result of increasing glutamine synthetase activity in roots, thus promoting N metabolism in roots. By coordinating the synergistic effect of increasing soluble protein in root, XC-45 exhibited greater tolerance to saline-alkaline stress. All data pinpoint that the root physiological function was more responsible for resistance to saline-alkaline stress in wheat.


Clinical impact of HLA class I expression in rectal cancer.
To determine the clinical impact of human leukocyte antigen (HLA) class I expression in irradiated and non-irradiated rectal carcinomas. Tumor samples in tissue micro array format were collected from 1,135 patients. HLA class I expression was assessed after immunohistochemical staining with two antibodies (HCA2 and HC10). Tumors were split into two groups: (1) tumors with >50% of tumor cells expressing HLA class I (high) and (2) tumors with < or =50% of tumor cells expressing HLA class I (low). No difference in distribution or prognosis of HLA class I expression was found between irradiated and non-irradiated patients. Patients with low expression of HLA class I (15% of all patients) showed an independent significantly worse prognosis with regard to overall survival and disease-free survival. HLA class I expression had no effect on cancer-specific survival or recurrence-free survival. Down-regulation of HLA class I in rectal cancer is associated with poor prognosis. In contrast to our results, previous reports on HLA class I expression in colorectal cancer described a large population of patients with HLA class I negative tumors, having a good prognosis. This difference might be explained by the fact that a large proportion of HLA negative colon tumors are microsatellite instable (MSI). MSI tumors are associated with a better prognosis than microsatellite stable (MSS). As rectal tumors are mainly MSS, our results suggest that it is both, oncogenic pathway and HLA class I expression, that dictates patient's prognosis in colorectal cancer. Therefore, to prevent confounding in future prognostic analysis on the impact of HLA expression in colorectal tumors, separate analysis of MSI and MSS tumors should be performed.


A novel preoperative scoring system for predicting endometrial cancer in patients with complex atypical endometrial hyperplasia and accuracy of frozen section pathological examination in this context: a multicenter study.
To estimate the accuracy of frozen pathological analysis in patients preoperatively diagnosed with endometrial atypical complex hyperplasia (ACH) and to develop a model predicting the probability of the presence of endometrial carcinoma in ACH. Patients (n = 128) who underwent total hysterectomies because of diagnoses of ACH were evaluated at four tertiary centers. Diagnoses made using frozen sections and permanent sections were in good agreement (ĸ = 0.61, p < 0.0001). A useful scoring system combining weighted risk factors derived from a regression model is as follows: (2 × age ≥50 years) + (3 × BMI ≥30) + (2 × menopausal status) + (2 × diabetes comorbidity) + (3 × endometrial thickness >12 mm). The AUC of this score was 0.793, and the score afforded 80.9% sensitivity, 70.3% specificity, a 75.3% positive predictive value, and a 76.4% negative predictive value, when a score of 5 was used as a cutoff. Patients with ACH should be evaluated by gynecological oncologists and intraoperative frozen section analysis should be performed by pathologists specializing in the evaluation of gynecological malignancies, because ACH is closely associated with endometrial cancer (EC). Our novel preoperative scoring system may aid in the detection of patients at increased risk of EC and thus guide general gynecologists.


Differential effects of chronic dehydration on protein synthesis in neurons of the rat hypothalamus.
The rate of methionine incorporation was measured in individual hypothalamic nuclei by a quantitative autoradiographic technique: the L-[35S]methionine method. Physiological stimulation of the hypothalamo-neurohypophysial system by two days of water deprivation, a stress that increased the plasma total neurophysins concentration 4-5-fold, resulted in a 70-80% increase in overall protein synthesis in the supraoptic nucleus and in the magnocellular subdivisions of the paraventricular nucleus. The same stimulus had no effect on protein synthesis rate of the suprachiasmatic nucleus and of the other representative cerebral structures examined. This differential effect on protein synthesis was also observed within the paraventricular nucleus.


Clines in quantitative traits: the role of migration patterns and selection scenarios.
The existence, uniqueness, and shape of clines in a quantitative trait under selection toward a spatially varying optimum is studied. The focus is on deterministic diploid two-locus n-deme models subject to various migration patterns and selection scenarios. Migration patterns may exhibit isolation by distance, as in the stepping-stone model, or random dispersal, as in the island model. The phenotypic optimum may change abruptly in a single environmental step, more gradually, or not at all. Symmetry assumptions are imposed on phenotypic optima and migration rates. We study clines in the mean, variance, and linkage disequilibrium (LD). Clines result from polymorphic equilibria. The possible equilibrium configurations are determined as functions of the migration rate. Whereas for weak migration, many polymorphic equilibria may be simultaneously stable, their number decreases with increasing migration rate. Also for intermediate migration rates polymorphic equilibria are in general not unique, however, for loci of equal effects the corresponding clines in the mean, variance, and LD are unique. For sufficiently strong migration, no polymorphism is maintained. Both migration pattern and selection scenario exert strong influence on the existence and shape of clines. The results for discrete demes are compared with those from models in which space varies continuously and dispersal is modeled by diffusion. Comparisons with previous studies, which investigated clines under neutrality or under linkage equilibrium, are performed. If there is no long-distance migration, the environment does not change abruptly, and linkage is not very tight, populations are almost everywhere close to linkage equilibrium.


Effects of Reallocating Time Spent in Different Physical Activity Intensities on Sarcopenia Risk in Older Adults: An Isotemporal Substitution Analysis.
The role of daily time spent sedentary and in different intensities of physical activity (PA) for the maintenance of muscle health currently remains unclear. Therefore, we investigated the impact of reallocating time spent in different PA intensities on sarcopenia risk in older adults, while considering PA type (muscle strengthening activities, MSA) and protein intake. In a sample of 235 community-dwelling older adults (65-70 years), a sarcopenia risk score (SRS) was created based on muscle mass assessed by bioimpedance, together with handgrip strength and performance on the five times sit-to-stand (5-STS) test assessed by standardized procedures. Time spent in light-intensity PA (LPA), moderate-to-vigorous PA (MVPA), and being sedentary was assessed by accelerometry, and PA type (MSA) by self-report. Linear regression models based on isotemporal substitution were employed. Reallocating sedentary time to at least LPA was significantly (p < 0.05) related to a lower SRS, which remained evident after adjustment by PA type (MSA) and protein intake. Similarly, reallocating time in LPA by MVPA was related to a significantly (p < 0.05) lower SRS. Our results emphasize the importance of displacing sedentary behaviours for more active pursuits, where PA of even light intensities may alleviate age-related deteriorations of muscle health in older adults.


Effects of lamotrigine on cognition and behavior compared to carbamazepine as monotherapy for children with partial epilepsy.
To compare the cognitive and behavioral effects of lamotrigine (LTG) to carbamazepine (CBZ) as monotherapy for pediatric epilepsy. A multicenter, randomized, open-label, parallel-group clinical trial was conducted in children with partial-onset seizures. LTG or CBZ was prescribed as monotherapy for previously untreated children and titrated over 8 weeks, followed by maintenance for 24 weeks. Outcome measures were change in cognition and behavior in a combined analysis of standardized measures from screening to the end of the maintenance phase, as well as antiepileptic efficacy and tolerability. A total of 67 children completed the study, including 32 of 43 (74.4%) treated with LTG and 35 of 41 (85.4%) treated with CBZ. Seizure-free outcomes did not differ between the intent-to-treat populations (53.5% LTG, 56.1% CBZ; p=0.81). There were no statistically significant differences in the intelligence of the two groups after treatment. Externalizing behavior problems improved in the CBZ group (p<0.05). However, there were no significant differences between the two groups in terms of externalizing behavior. The parents' report on the Conner scale showed an improvement in the CBZ group compared to the LTG group (p<0.05). LTG and CBZ showed similar efficacy and cognitive effects in treating childhood partial epilepsy. However, CBZ showed more benefits in improving externalizing behaviors.


β-Glucan protects against chronic nicotine-induced oxidative damage in rat kidney and bladder.
In this study, we investigated the protective effect of β-glucan against nicotine induced oxidative damage in urinary bladder and kidney tissues. Wistar albino rats were injected i.p. with nicotine hydrogen bitartarate (0.6mg/kg daily for 21 days) or saline. β-Glucan (50mg/kg, p.o.) was administered alone or with nicotine injections for 21 days. After decapitation, the urinary bladder and kidney tissues were taken for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity. Tissue samples were also examined histologically. In serum samples MDA, GSH, BUN, creatinine, TNF-α levels and LDH activity were analyzed. Chronic nicotine administration caused a significant decrease in GSH levels and increases in MDA levels and MPO activity in kidney and bladder tissues, suggesting oxidative organ damage, which was also histologically verified. Furthermore, β-glucan restored the reduced GSH levels, while it significantly decreased MDA levels and MPO activity. Renal function tests, LDH and TNF-α levels, which were increased significantly due to nicotine administration, were decreased with β-glucan treatment. The present data suggest that β-glucan supplementation effectively counteracts the chronic nicotine toxicity and attenuates oxidative damage of bladder and kidney tissues possibly by its antioxidant effects.


The Ongoing Unmet Needs in Chronic Lymphocytic Leukemia: TP53 Disruption, Richter, and Beyond.
Despite recent success in regard to targeted therapies in chronic lymphocytic leukemia (CLL), patients with TP53 disruption (including deletion and/or mutation) continue to have poor outcomes compared with other patients with CLL. In this article, a review of common TP53 mutations in CLL, and recent trials using novel targeted agents in CLL patients with TP53 disruption, is provided with the goal of emphasizing the need to continuously focus on this area of research. In addition, limited but available data on double refractory CLL to BTK inhibitor and BCL-2 inhibitor, and on Richter syndrome, are reviewed.


Targeting MICA/B with cytotoxic therapeutic antibodies leads to tumor control [version 2; peer review: 2 approved].
MICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention. We have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules. The anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro. However, it showed insufficient efficiency against solid tumors in vivo, which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice. These data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy.


Reassessment of 14CO2 compartmentation and of [14C]formate oxidation in rat liver.
Our previous report (Marsolais, C., Huot, S., David, F., Garneau, M., and Brunengraber, H. (1987) J. Biol. Chem. 262, 2604-2607) had concluded that a fraction of [14C]formate oxidation in liver occurs in the mitochondrion. This conclusion was based on the labeling patterns of urea and acetoacetate labeled via 14CO2 generated from [14C]formate and other [14C]substrates. We reassessed our interpretation in experiments conducted in (i) perifused mitochondria and (ii) isolated livers perfused with buffer containing [14C]formate, [14C]gluconolactone, 14CO2, or NaH13CO3, in the absence and presence of acetazolamide, an inhibitor of carbonic anhydrase. Our data show that the cytosolic pools of bicarbonate and CO2 are not in isotopic equilibrium when 14CO2 is generated in the cytosol or is supplied as NaH14CO3. We retract our earlier suggestion of a mitochondrial site of [14C]formate oxidation.


Substrate-biased activity-based probes identify proteases that cleave receptor CDCP1.
CUB domain-containing protein 1 (CDCP1) is an oncogenic orphan transmembrane receptor and a promising target for the detection and treatment of cancer. Extracellular proteolysis of CDCP1 by poorly defined mechanisms induces pro-metastatic signaling. We describe a new approach for the rapid identification of proteases responsible for key proteolytic events using a substrate-biased activity-based probe (sbABP) that incorporates a substrate cleavage motif grafted onto a peptidyl diphenyl phosphonate warhead for specific target protease capture, isolation and identification. Using a CDCP1-biased probe, we identify urokinase (uPA) as the master regulator of CDCP1 proteolysis, which acts both by directly cleaving CDCP1 and by activating CDCP1-cleaving plasmin. We show that coexpression of uPA and CDCP1 is strongly predictive of poor disease outcome across multiple cancers and demonstrate that uPA-mediated CDCP1 proteolysis promotes metastasis in disease-relevant preclinical in vivo models. These results highlight CDCP1 cleavage as a potential target to disrupt cancer and establish sbABP technology as a new approach to identify disease-relevant proteases.