Genomic Profiling Reveals Medullary Thyroid Cancer Misdiagnosed as Lung Cancer.
Mutations or other alterations in the RET gene have been implicated in a variety of malignancies - most commonly thyroid, but also chronic myelomonocytic leukemia, acute myeloid leukemia, and lung, breast, pancreatic, and colon cancers. Here we present a case of a gentlemen initially diagnosed with and treated for non-small cell lung adenocarcinoma. Genomic profiling of his tumor specimen revealed a RET point mutation with a known association with medullary thyroid cancer (MTC). Further pathological and molecular diagnostic evaluation confirmed a diagnosis of MTC, leading to a change in treatment from standard chemotherapy for non-small cell lung cancer to targeted therapy against RET and potential implications regarding inherited cancer risk for his offspring. The patient experienced a clinical response to treatment and several months of improved quality of life. This case illustrates the capacity of genomic profiling to uncover molecular drivers of disease and help ensure proper diagnosis and management of cancer.


Improving Sample Distribution Homogeneity in Three-Dimensional Microfluidic Paper-Based Analytical Devices by Rational Device Design.
Paper-based devices are a portable, user-friendly, and affordable technology that is one of the best analytical tools for inexpensive diagnostic devices. Three-dimensional microfluidic paper-based analytical devices (3D-μPADs) are an evolution of single layer devices and they permit effective sample dispersion, individual layer treatment, and multiplex analytical assays. Here, we present the rational design of a wax-printed 3D-μPAD that enables more homogeneous permeation of fluids along the cellulose matrix than other existing designs in the literature. Moreover, we show the importance of the rational design of channels on these devices using glucose oxidase, peroxidase, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) reactions. We present an alternative method for layer stacking using a magnetic apparatus, which facilitates fluidic dispersion and improves the reproducibility of tests performed on 3D-μPADs. We also provide the optimized designs for printing, facilitating further studies using 3D-μPADs.


The stress response and the regulation of inflammatory disease.
The molecular and biochemical bases for interactions between the immune and central nervous systems are described. Immune cytokines not only activate immune function but also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of behaviors that may be adaptive during injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin-releasing hormone (CRH) neurons to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. Corticotropin-releasing hormone not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. The pathophysiologic perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes, such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific central nervous system pathways (for example, the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacologic means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history. These concepts suggest that neuropharmacologic agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune.


Evaluation of the prognostic value of the health assessment form among patients clinically ready for discharge.
The aim of the study was to identify patterns of physical, psychological, and social conditions that may be of prognostic value when it comes to assessing continued care of patients clinically ready for discharge; a related aim was to evaluate instruments used for this identification, especially a Swedish version of the health assessment form. The sample consisted of 53 consecutive patients (mean age 82.8 years, SD = 6.6 years) All patients came from their own homes and were admitted to surgical and orthopaedic departments. Interviews were carried out on the day the patients were assessed as medically ready for discharge, and a second time 1 month later. The health assessment form measured the persons' social and environmental situation, health history, and functional health status, and another instrument measured the persons' sense of coherence. Few significant differences in functional health status were noted between persons who could return to their homes (n = 25) and persons who were referred to institutions after discharge (n = 17). However, the persons being referred to institutions showed less favourable scores within the areas of mood, sense of coherence, and worries about their home accommodation situation. When another sub-group was included (patients who died between the interview occasions; n = 8), significant differences were also noted in the health functions breathing, digestion, elimination, and body movement. Sense of coherence had a significant prognostic value for the continued care after discharge irrespective of whether the deceased patients were included or not.


Phylogeography, genetic structure and population divergence time of cheetahs in Africa and Asia: evidence for long-term geographic isolates.
The cheetah (Acinonyx jubatus) has been described as a species with low levels of genetic variation. This has been suggested to be the consequence of a demographic bottleneck 10 000-12 000 years ago (ya) and also led to the assumption that only small genetic differences exist between the described subspecies. However, analysing mitochondrial DNA and microsatellites in cheetah samples from most of the historic range of the species we found relatively deep phylogeographic breaks between some of the investigated populations, and most of the methods assessed divergence time estimates predating the postulated bottleneck. Mitochondrial DNA monophyly and overall levels of genetic differentiation support the distinctiveness of Northern-East African cheetahs (Acinonyx jubatus soemmeringii). Moreover, combining archaeozoological and contemporary samples, we show that Asiatic cheetahs (Acinonyx jubatus venaticus) are unambiguously separated from African subspecies. Divergence time estimates from mitochondrial and nuclear data place the split between Asiatic and Southern African cheetahs (Acinonyx jubatus jubatus) at 32 000-67 000 ya using an average mammalian microsatellite mutation rate and at 4700-44 000 ya employing human microsatellite mutation rates. Cheetahs are vulnerable to extinction globally and critically endangered in their Asiatic range, where the last 70-110 individuals survive only in Iran. We demonstrate that these extant Iranian cheetahs are an autochthonous monophyletic population and the last representatives of the Asiatic subspecies A. j. venaticus. We advocate that conservation strategies should consider the uncovered independent evolutionary histories of Asiatic and African cheetahs, as well as among some African subspecies. This would facilitate the dual conservation priorities of maintaining locally adapted ecotypes and genetic diversity.


Accounting for institutional change in health economic evaluation: a program to tackle HIV/AIDS and gender violence in Southern Africa.
There has been growing interest in the application of institutionalist perspectives in the health economics literature. This paper investigates the institutionalist notion of social value and its use in economic evaluation with particular reference to a program to address HIV/AIDS and gender violence in Southern Africa (IMAGE). Institutions are the rules that govern the conduct between individuals, groups and organisations. Their social value stems from their capacity to reduce the uncertainty in human interactions thereby both reducing transaction costs and, importantly, enabling the initiation and sustainability of various activities (instrumental value). Furthermore, institutions tend to be formed around certain ethical positions and as a consequence, act in binding future decision making to these positions (intrinsic value). Incorporating such notions of social value within a conventional welfare-based measure of benefit is problematic as institutional development is not necessarily consistent with individual utility. An institutionalist approach allows for these additional domains to be factored into economic evaluation. IMAGE is an intervention to reduce gender violence and HIV through microfinance, health education and community development, and involves significant initial investment in institution-building activities, notably through training activities with program staff and community members. The key to employing an institutionalist approach to the evaluation of IMAGE is in understanding the nature of those actions that can be seen as institution-building and determining: (1) the instrumental value of follow-up activities by appropriate amortisation of transaction costs over an horizon that reflects the economies gained from the intervention; and (2) the intrinsic value of any transformation in the community through a cost-consequences approach informed by an a priori conceptual model. This case study highlights how health sector interventions can effect institutional changes and how these are captured within a theory-based economic evaluation framework.


Two Genome Sequences of Klebsiella pneumoniae Strains with Sequence Type 23 and Capsular Serotype K1.
Here, we report the whole-genome sequences of Klebsiella pneumoniae ED2 and ED23, isolated, respectively, from bacteremic patients with liver abscesses (ED2) and patients with primary liver abscess and metastatic meningitis (ED23). Both strains were of multilocus sequence type 23 with capsule serotype K1.


Alcohol dehydrogenases from Scheffersomyces stipitis involved in the detoxification of aldehyde inhibitors derived from lignocellulosic biomass conversion.
Aldehyde inhibitors such as furfural and 5-hydroxymethylfurfural (HMF) are generated from biomass pretreatment. Scheffersomyces stipitis is able to reduce furfural and HMF to less toxic furanmethanol and furan-2,5-dimethanol; however, the enzymes involved in the reductive reaction still remain unknown. In this study, transcription responses of two known and five putative alcohol dehydrogenase genes from S. stipitis were analyzed under furfural and HMF stress conditions. All the seven alcohol dehydrogenase genes were also cloned and overexpressed for their activity analyses. Our results indicate that transcriptions of SsADH4 and SsADH6 were highly induced under furfural and HMF stress conditions, and the proteins encoded by them exhibited NADH- and/or NADPH-dependent activities for furfural and HMF reduction, respectively. For furfural reduction, NADH-dependent activity was also observed in SsAdh1p and NAD(P)H-dependent activities were also observed in SsAdh5p and SsAdh7p. For HMF reduction, NADPH-dependent activities were also observed in SsAdh5p and SsAdh7p. SsAdh4p displayed the highest NADPH-dependent specific activity and catalytic efficiency for reduction of both furfural and HMF among the seven alcohol dehydrogenases. Enzyme activities of all SsADH proteins were more stable under acidic condition. For most SsADH proteins, the optimum temperature for enzyme activities was 30 °C and more than 50 % enzyme activities remained at 60 °C. Reduction activities of formaldehyde, acetaldehyde, isovaleraldehyde, benzaldehyde, and phenylacetaldehyde were also observed in some SsADH proteins. Our results indicate that multiple alcohol dehydrogenases in S. stipitis are involved in the detoxification of aldehyde inhibitors derived from lignocellulosic biomass conversion.


Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics.
Plasmid-borne colistin resistance mediated by mcr-1 may contribute to the dissemination of pan-resistant Gram-negative bacteria. Here, we show that mcr-1 confers resistance to colistin-induced lysis and bacterial cell death, but provides minimal protection from the ability of colistin to disrupt the Gram-negative outer membrane. Indeed, for colistin-resistant strains of Enterobacteriaceae expressing plasmid-borne mcr-1, clinically relevant concentrations of colistin potentiate the action of antibiotics that, by themselves, are not active against Gram-negative bacteria. The result is that several antibiotics, in combination with colistin, display growth-inhibition at levels below their corresponding clinical breakpoints. Furthermore, colistin and clarithromycin combination therapy displays efficacy against mcr-1-positive Klebsiella pneumoniae in murine thigh and bacteremia infection models at clinically relevant doses. Altogether, these data suggest that the use of colistin in combination with antibiotics that are typically active against Gram-positive bacteria poses a viable therapeutic alternative for highly drug-resistant Gram-negative pathogens expressing mcr-1.


Effect of glycyrrhetinic acid on 11 beta-hydroxysteroid dehydrogenase activity in normotensive and hypertensive subjects.
The 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) isoenzymes catalyse the interconversion of cortisol and cortisone. Type 1 11 beta-HSD mainly converts cortisone into active cortisol. Type 2 11 beta-HSD inactivates cortisol in mineralocorticoid target tissues, and its activity can be inhibited by glycyrrhetinic acid (GA). Inactivation of cortisol to cortisone is impaired in a subgroup of patients with primary hypertension. To study where this defect is located, we measured cortisol and cortisone concentrations in arterial plasma, in saliva and across the forearm at baseline and after administration of GA in normotensive and hypertensive subjects. GA (500 mg) or placebo was administered orally to 20 normotensive subjects in a placebo-controlled double-blind fashion. Further, we compared the effect of GA in 20 patients with primary hypertension with that in 20 normotensive subjects. Cortisol and cortisone were measured in plasma from the brachial artery and vein and in saliva. Samples were obtained at 0, 90 and 150 min. Forearm blood flow (FBF) was measured simultaneously. Forearm production of corticosteroid hormones was assessed by multiplying the arteriovenous difference in corticosteroid concentration by FBF. The cortisol/cortisone ratio in arterial plasma remained at baseline levels after placebo (4.9 +/- 1.2; mean +/- S.D.), while after GA the ratio increased similarly in normotensive subjects (12.3 +/- 3.4) and in hypertensive patients (12.2 +/- 3.7). A similar effect of GA on the salivary cortisol/cortisone ratio was found. In both normotensive subjects and hypertensive patients no forearm production of cortisol or cortisone could be demonstrated, either at baseline or after administration of GA. Thus, both before and after GA administration, we did not find any difference in systemic and salivary 11 beta-HSD type 2 activity between subjects with primary hypertension and normotensive controls. Further, both at baseline and after GA administration we were not able to demonstrate net inactivation or re-activation of cortisol and cortisone by the 11 beta-HSD isoenzymes in the forearm in either normotensive or primary hypertensive subjects.


Spatial distance regulates sex-specific feelings to suspected sexual and emotional infidelity.
The present study investigates the hitherto neglected influence of the spatial distance between the jealous person, the partner, and a potential rival as a proximate contextual factor regulating emotion intensity. The study tested four predictions. (1) The jealousy mechanism responds with mild negative feelings at most as long as the partner is close to the jealous person. (2) The negative feelings increase when the partner is far from the jealous person but the rival is close. (3) The most uncomfortable feelings result when the partner and the rival are close together and both far from the jealous person. (4) Based on the evolutionary psychological considerations, men report stronger negative feelings than women when suspecting sexual infidelity. Conversely, women report stronger negative feelings than men when suspecting emotional infidelity. The results confirmed predictions 1 and 4. Reversing predictions 2 and 3, the close rival consistently elicited the most uncomfortable feelings. Implications and limitations of the present study are discussed and suggestions for future research are provided.


Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference.
The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique-Subtype and Stage Inference (SuStaIn)-able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer's disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10-4) or temporal stage (p = 3.96 × 10-5). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.


Dilution of compatibility effects in Simon-type tasks depends on categorical similarity between distractors and diluters.
The presence of a distracting stimulus during performance of the Stroop color-naming task leads to dilution of the Stroop effect. Because the automatic activation of word meaning may interfere with the task-relevant stimulus feature (text color; stimulus-stimulus [S-S] interference) and the response (saying the text color; stimulus-response [S-R] interference), it is unclear which of these types of interference is diluted. We introduce a new dilution paradigm using word- and arrow-based Simon tasks, in which only S-R interference is present. Participants made a left or right response to a central color target. A task-irrelevant location-word (Experiment 1) or arrow (Experiment 2) distractor adjacent to the target produced S-R compatibility effects. An additional neutral word or symbol series (diluter) was sometimes presented on the opposite side of the target from the distractor. The compatibility effect was smaller when the distractor and diluter category domains matched than when they mismatched. This result provides evidence that S-R compatibility effects are susceptible to the presence of diluters that are categorically similar to the distractors.


Retronasal olfactory testing using candies sent by post and for screening purposes: a feasibility study.
The olfactory system is able to detect external odours through the orthonasal- and internal odours through the retronasal route. Flavour perception strongly relies on the sense of smell and this back route. In contrast to orthonasal, retronasal olfactory tests (ROT) are less frequently applied, although testing should be recommended for several reasons. The aim of the present investigation was to propose a suitable form of ROT for home-testing (and postal distribution) and evaluate a retronasal screening test. Initially, 111 participants were tested using a 27-item version of the Candy Smell Test (CST). Fifty-four participants performed retesting, of which 25 subjects did so in a home-setting being supplied with professionally packed "candy-chains". Seven candies were chosen by means of hit rate differences in normosmics and severely hyposmics/anosmics. The 7-CST is designed in a non-forced-choice fashion with same seven flavours to choose from. For the 27-item CST both groups (subjects performing home-testing and those performing retesting at the clinic) showed highly significant test-rest-reliabilities. The 7-CST was capable of discriminating healthy from diseased subjects when being tested in 116 healthy subjects and 47 patients suffering from olfactory dysfunction. The CST is suitable for home-testing and postal distribution. The new 7-item CST can be valuable for rapidly revealing anosmics. These findings help in further standardizing ROT, may encourage rhinologists to more routinely evaluate retronasal olfactory abilities and pave the way for larger epidemiologic studies also in regard to food preferences and nutritional behaviour.


Thyroid cancer of follicular cell origin in inherited tumor syndromes.
Well-differentiated thyroid cancer accounts for 95% of thyroid malignancies. In contrast to medullary thyroid carcinoma, in which about 25% are familial, only 5% of follicular cell-derived thyroid carcinomas are a component of a familial cancer syndrome. The familial follicular cell-derived tumors or nonmedullary thyroid carcinoma encompass a heterogeneous group of diseases, and are classified into 2 distinct groups: syndromic-associated tumors, occurring in syndromes in which nonmedullary thyroid carcinomas are the predominant tumor encountered, and nonsyndromic tumors, those occurring in tumor syndromes in which thyroid involvement is a minor component. The first group, syndromic-associated tumors, includes phosphase and tensin (PTEN)-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis/Gardner syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome. Other syndromes, as McCune Albright syndrome, Peutz-Jeghers syndrome, and Ataxia-teleangiectasia syndrome may be associated with the development of follicular cell-derived tumors, but the link is less established than the above syndromes. The syndromic-associated tumors are the focus of this review. The second group of familial follicular cell-derived tumors syndromes or nonsyndromic tumors, in which nonmedullary thyroid carcinomas are the major findings, include pure familial papillary thyroid carcinoma, with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary thyroid carcinoma with multinodular goiter. This review will discuss the clinical and pathological findings of the patients with familial syndrome-associated tumors: PTEN-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome.


Evaporation dynamics of a sessile droplet on glass surfaces with fluoropolymer coatings: focusing on the final stage of thin droplet evaporation.
The evaporation dynamics of a water droplet with an initial volume of 2 μl from glass surfaces with fluoropolymer coatings are investigated using the shadow technique and an optical microscope. The droplet profile for a contact angle of less than 5° is constructed using an image-analyzing interference technique, and evaporation dynamics are investigated at the final stage. We coated the glass slides with a thin film of a fluoropolymer by the hot-wire chemical vapor deposition method at different deposition modes depending on the deposition pressure and the temperature of the activating wire. The resulting surfaces have different structures affecting the wetting properties. Droplet evaporation from a constant contact radius mode in the early stage of evaporation was found followed by the mode where both contact angle and contact radius simultaneously vary in time (final stage) regardless of wettability of the coated surfaces. We found that depinning occurs at small contact angles of 2.2-4.7° for all samples, which are smaller than the measured receding contact angles. This is explained by imbibition of the liquid into the developed surface of the "soft" coating that leads to formation of thin droplets completely wetting the surface. The final stage, which is little discussed in the literature, is also recorded. We have singled out a substage where the contact line velocity is abruptly increasing for all coated and uncoated surfaces. The critical droplet height corresponding to the transition to this substage is about 2 μm with R/h = 107. The duration of this substage is the same for all coated and uncoated surfaces. Droplets observed at this substage for all the tested surfaces are axisymmetric. The specific evaporation rate clearly demonstrates an abrupt increase at the final substage of the droplet evaporation. The classical R2 law is justified for the complete wetting situation where the droplet is disappearing in an axisymmetric manner.


Structure and dynamics of the mammalian ribosomal pretranslocation complex.
Although the structural core of the ribosome is conserved in all kingdoms of life, eukaryotic ribosomes are significantly larger and more complex than their bacterial counterparts. The extent to which these differences influence the molecular mechanism of translation remains elusive. Multiparticle cryo-electron microscopy and single-molecule FRET investigations of the mammalian pretranslocation complex reveal spontaneous, large-scale conformational changes, including an intersubunit rotation of the ribosomal subunits. Through structurally related processes, tRNA substrates oscillate between classical and at least two distinct hybrid configurations facilitated by localized changes in their L-shaped fold. Hybrid states are favored within the mammalian complex. However, classical tRNA positions can be restored by tRNA binding to the E site or by the eukaryotic-specific antibiotic and translocation inhibitor cycloheximide. These findings reveal critical distinctions in the structural and energetic features of bacterial and mammalian ribosomes, providing a mechanistic basis for divergent translation regulation strategies and species-specific antibiotic action.


Spectral broadening of a partially coherent CW laser beam in single-mode optical fibers.
The nonlinear propagation of a partially coherent continuous-wave laser beam in single-mode optical fibers is investigated both theoretically and experimentally, with a special attention to the zero-dispersion wavelength region where modulation instability is expected. Broadband asymmetric spectral broadening is reported experimentally and found in fairly good agreement with a numerical Schrödinger simulation including a phase-diffusion model for the partially coherent beam. This model shows in addition that the underlying spectral broadening mechanism relies not only on modulation instability but also on the generation of high-order soliton-like pulses and dispersive waves. The coherence degradation which results from these ultrafast phenomena is confirmed by autocorrelation measurement.


Severe conjunctivochalasis in association with classic type Ehlers-Danlos syndrome.
Inferior conjunctivochalasis is common, but is rarely severe enough to require conjunctival excision. This report describes a patient with severe conjunctivochalasis who was subsequently diagnosed with Ehlers Danlos Syndrome, Classic Type. A patient suffering from foreign body sensation, frequent blinking and bilateral inferior conjunctivochalasis was referred and treated by topical ocular lubrication. However, no improvement was observed prompting potential excision of conjunctivochalasis. Following patient consultation and clinical diagnosis including hypermobile joints and skin elasticity, poor wound healing and wide scar morphology, Ehlers-Danlos syndrome was confirmed in the patient. This case highlights the need for direct patient questioning and provides the first reported association between conjunctiovochalasis and Ehlers-Danlos syndrome.


Management of menorrhagia associated with chemotherapy-induced thrombocytopenia in women with hematologic malignancy.
Abnormal uterine bleeding in women with a blood dyscrasia, such as leukemia, or who experience thrombocytopenia secondary to myelosuppressive chemotherapy is a clinical condition associated with significant morbidity. Consequently, effective management is necessary to prevent adverse outcomes. Prevention of menorrhagia, defined as heavy regular menstrual cycles with more than 80 ml of blood loss/cycle or a cycle duration longer than 7 days, in this patient population is the goal of therapy. Gonadotropin-releasing hormone analogs (e.g., leuprolide) are promising therapies that have been shown to decrease vaginal bleeding during periods of thrombocytopenia and to have minimal adverse effects other than those associated with gonadal inhibition. In patients who experience menorrhagia despite preventive therapies, or in patients who have thrombocytopenia and menorrhagia at diagnosis, treatment is indicated. For these women, treatment options may include platelet transfusions, antifibrinolytic therapy (e.g., tranexamic acid), continuous high-dose oral contraceptives, cyclic progestins, or other therapies for more refractory patients such as danazol, desmopressin, and recombinant factor VIIa. Hormonal therapies are often the mainstay of therapy in women with menorrhagia secondary to thrombocytopenia, but data for these agents are sparse. The most robust data for the treatment of menorrhagia are for tranexamic acid. Most women receiving tranexamic acid in randomized trials experienced meaningful reductions in menstrual bleeding, and this translated into improved quality of life; however, these trials were not performed in patients with cancer. Further clinical trials are warranted to evaluate both preventive and therapeutic agents for menorrhagia in premenopausal women with cancer who are receiving myelosuppressive chemotherapy.


A new paradigm to measure probabilistic reasoning and a possible answer to the question why psychosis-prone individuals jump to conclusions.
Jumping to conclusions (JTC) distinguishes patients with schizophrenia from both healthy and psychiatric controls. JTC is typically assessed using the beads task, which, however, faces a number of limitations as to its interpretability and reliability. The present study set out to validate a new paradigm to assess JTC: the box task. We adopted a psychometric psychosis proneness approach and divided a large population sample into participants who scored high versus low on a scale tapping psychosis-like experiences. Participants performed a variant of the original beads task along with a new JTC task, the box task, with or without time pressure. The box task requires participants to infer which of two ball colors will be more prevalent in a matrix of boxes. The box task and the beads task were significantly correlated at a medium effect size, thus demonstrating criterion validity for the box task. As hypothesized, participants who scored high on psychosis-like experiences showed particularly strong JTC and a decreased decision threshold relative to low scorers, especially in the box task version with time pressure; in contrast, group differences in the beads tasks only achieved trend-wise significance. Mediation analyses showed that fewer draws to decisions were predicted by either a lower decision threshold or by higher initial probability estimates for the dominant item. The study establishes the criterion and construct validity of a new JTC task. Its advantages over the traditional beads task are better comprehensibility and usability; multiple parallel versions can be created thus raising reliability. (PsycINFO Database Record


Posttraumatic stress disorder diagnostic criteria and suicidal ideation in a South African Police sample.
Exposure to traumatic events may precipitate suicidal ideation. Once an individual is diagnosed with PTSD, a suicide risk assessment often follows. This study explores how PTSD symptom criteria correlate with suicidal ideation in a sample of police officers. While the psychometric measures of PTSD often mirror the DSM-IV-TR criteria, focusing on exposure, symptom, and duration criteria, suicidal ideation measures often focus on concepts quite different from that. In this report the focus was on investigating how PTSD symptom criteria correlate with the suicidal ideation. A group of South African police officers (N = 217) were assessed by means of the Posttraumatic Diagnostic Scale and a short version of the Adult Suicide Ideation Questionnaire. Linear and hierarchical regressions were used to determine which PTSD symptom criteria best predict suicidal ideation. Hyperarousal was the primary predictor of suicidal ideation (R(2) [adjusted] = 0.249). Intrusive thoughts added only marginally to the model, contributing a further 2.5% to the declared variance. The contributions of the other two symptom types were negligible. In this study hyperarousal correlated significantly with suicidal ideation. It is suggested that practitioners be alert to these symptoms as possible indicators of suicidal ideation. Implications for suicide risk assessment and prevention measures are discussed.


No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using [123I]FP-CIT (DaTSCAN) and SPECT.
Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like receptors. Molecular imaging studies of the relationship between DAT availability/dopamine synthesis capacity and active cigarette smoking have shown conflicting results. Through the collaboration between 13 SPECT centres located in 10 different European countries, a database of FP-CIT-binding in healthy controls was established. We used the database to test the hypothesis that striatal DAT availability is changed in active smokers compared to non-smokers and ex-smokers. A total of 129 healthy volunteers were included. Subjects were divided into three categories according to past and present tobacco smoking: (1) non-smokers (n = 64), (2) ex-smokers (n = 39) and (3) active smokers (n = 26). For imaging of the DAT availability, we used [123I]FP-CIT (DaTSCAN) and single photon emission computed tomography (SPECT). Data were collected in collaboration between 13 SPECT centres located in 10 different European countries. The striatal measure of DAT availability was analyzed in a multiple regression model with age, SPECT centre and smoking as predictor. There was no statistically significant difference in DAT availability between the groups of active smokers, ex-smokers and non-smokers (p = 0.34). Further, we could not demonstrate a significant association between striatal DAT and the number of cigarettes per day or total lifetime cigarette packages in smokers and ex-smokers. Our results do not support the hypothesis that large differences in striatal DAT availability are present in smokers compared to ex-smokers and healthy volunteers with no history of smoking.


Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression.
Myocardial infarction rapidly depletes the endogenous cardiac progenitor cell pool, and the inefficient recruitment of exogenously administered progenitor cells limits the effectiveness of cardiac cell therapy. Recent reports indicate that interactions between the CXC chemokine stromal cell-derived factor 1 and its receptor CXC chemokine receptor 4 (CXCR4) critically mediate the ischemia-induced recruitment of bone marrow-derived circulating stem/progenitor cells, but the expression of CXCR4 in cardiac progenitor cells is very low. Here, we studied the influence of hypoxia on CXCR4 expression in cardiac progenitor cells, on the recruitment of intravenously administered cells to ischemic heart tissue, and on the preservation of heart function in a murine myocardial infarction model. We found that hypoxic preconditioning increased CXCR4 expression in CLK (cardiosphere-derived, Lin(-)c-kit(+) progenitor) cells and markedly augmented CLK cell migration (in vitro) and recruitment (in vivo) to the ischemic myocardium. Four weeks after surgically induced myocardial infarction, infarct size and heart function were significantly better in mice administered hypoxia-preconditioned CLK cells than in mice treated with cells cultured under normoxic conditions. Furthermore, these effects were largely abolished by the addition of a CXCR4 inhibitor, indicating that the benefits of hypoxic preconditioning are mediated by the stromal cell-derived factor 1/CXCR4 axis, and that therapies targeting this axis may enhance cardiac-progenitor cell-based regenerative therapy.


Neural cell adhesion molecule expression and messenger RNA splicing patterns in lung cancer cell lines are correlated with neuroendocrine phenotype and growth morphology.
Diverse histological types of lung cancer express neuroendocrine (NE) markers. We studied the expression and alternative splicing forms of the neural cell adhesion molecule (NCAM) NKH-1, a member of the immunoglobulin superfamily, in 56 lung cancer cell lines representing all histological types. We found a strong correlation between expression of NCAM with both NE phenotype and lack of substrate adhesion in culture. Several cell lines expressed high levels of the leukocyte antigen Leu-7 (HNK-1) but were negative for NCAM antigen and mRNA, indicating that the Leu-7 antigen is distinct from NCAM. All of the NCAM-positive cell lines demonstrate a single 6.2-kilobase mRNA, and analysis of the known 3' alternative splices shows predominant expression of only the membrane form with the small intracytoplasmic domain. We conclude that (a) expression of NCAM is associated with NE phenotype regardless of the histological type of lung cancer; (b) these cell lines share a single form of NCAM; (c) with few exceptions, NCAM expression is associated with cell to cell adhesion and lack of substrate adhesion (growing as floating clusters); and (d) Leu-7 antigen is distinct from NCAM. This form of NCAM may play a functional role in NE differentiation or may be a part of the NE program expressed by these cells.


Self-management interventions to improve skin care for pressure ulcer prevention in people with spinal cord injuries: a systematic review protocol.
Pressure ulcers are a serious, common, lifelong, and costly secondary complication of spinal cord injury (SCI). Community-dwelling people with a SCI can prevent them with appropriate skin care (i.e. pressure relieving activities, skin checks). Adherence to skin care remains suboptimal however, and self-management interventions that focus on improving this have been designed. Little is known on their content, effectiveness, or theoretical basis. The aim of the proposed systematic review is to synthesize the literature on self-management interventions to improve skin care in people with a SCI. Specific objectives are to describe these interventions in relation to their content, effectiveness, theory base, and adherence to reporting guidelines for intervention description. The search strategy will combine an electronic search of nine bibliographic databases (MEDLINE, Embase, PsycInfo, CENTRAL, CINAHL, Rehabdata, CIRRIE, PEDro, ERIC) and two trial registers with a manual search of relevant reference lists. Predefined eligibility criteria will be applied in a two-phase selection process involving title and abstract screening, followed by full-text screening. A data extraction spreadsheet will be applied to included papers. Intervention content will be coded using two taxonomies (behaviour change taxonomy; PRISMS self-management support taxonomy). A validated tool (Theory Coding Scheme) and the Template for Intervention Description and Replication (TIDieR) will be used to examine theoretical basis and assess adherence to reporting guidelines for intervention description. A small number of heterogeneous studies are likely to be included in this review therefore a narrative synthesis is planned. This systematic review will help identify the gaps and priorities to guide future research activities in this area. PROSPERO CRD42016033191.


Gain control of firing rate by shunting inhibition: roles of synaptic noise and dendritic saturation.
Adjusting input-output gain is crucial for information processing by the brain. Gain control of subthreshold depolarization is commonly ascribed to increased membrane conductance caused by shunting inhibition. But contrary to its divisive effect on depolarization, shunting inhibition on its own fails to divisively modulate firing rate, apparently upsetting a critical tenet of neural models that use shunting inhibition to achieve gain control. Using a biophysically realistic neuron model, we show that divisive modulation of firing rate by shunting inhibition requires synaptic noise to smooth the relation between firing rate and somatic depolarization; although necessary, noise alone endows shunting inhibition with only a modest divisive effect on firing rate. In addition to introducing noise, synaptic input is associated with a nonlinear relation between somatic depolarization and excitation because of dendritic saturation; this nonlinearity dramatically enhances divisive modulation of firing rate by shunting inhibition under noisy conditions. Thus, shunting inhibition can act as a mechanism for firing rate gain control, but its modulatory effects (which include both divisive and subtractive components) are fully explained only when both synaptic noise and dendritic saturation are taken into account.


Three-gene PCR and high-resolution melting analysis for differentiating vertebrate species mitochondrial DNA for biodiversity research and complementing forensic surveillance.
Reliable molecular identification of vertebrate species from morphologically unidentifiable tissue is critical for the prosecution of illegally-traded wildlife products, conservation-based biodiversity research, and identification of blood-meal hosts of hematophagous invertebrates. However, forensic identification of vertebrate tissue relies on sequencing of the mitochondrial cytochrome oxidase I (COI) 'barcode' gene, which remains costly for purposes of screening large numbers of unknown samples during routine surveillance. Here, we adapted a rapid, low-cost approach to differentiate 10 domestic and 24 wildlife species that are common in the East African illegal wildlife products trade based on their unique high-resolution melting profiles from COI, cytochrome b, and 16S ribosomal RNA gene PCR products. Using the approach, we identified (i) giraffe among covertly sampled meat from Kenyan butcheries, and (ii) forest elephant mitochondrial sequences among savannah elephant reference samples. This approach is being adopted for high-throughput pre-screening of potential bushmeat samples in East African forensic science pipelines.


PGC-1alpha and PGC-1beta have both similar and distinct effects on myofiber switching toward an oxidative phenotype.
Peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta (PGC-1alpha and PGC-1beta) were overexpressed by adenovirus-mediated gene transfer in cultures of primary rat skeletal muscle cells derived from neonatal myoblasts. Effects on muscle fiber type transition and metabolism were studied from days 5 to 22 of culture. PGC-1alpha and PGC-1beta overexpression caused a three- to fourfold increase in mRNA level, a doubling of enzymatic activity of citrate synthase, a slight increase in short-chain acyl-CoA dehydrogenase mRNA, a doubling of the mRNA level, and a 30-50% increase in enzymatic activity of glyceraldehyde-3-phosphate dehydrogenase. Lactate dehydrogenase or creatine kinase activity was unchanged. PGC-1alpha enhanced glycogen buildup twofold at 5 or 25 mM glucose, whereas PGC-1beta caused a decrease. Both PGC-1alpha and PGC-1beta overexpression caused a faster maturation of myotubes, as seen by mRNA downregulation of the immature embryonal and perinatal myosin heavy-chain (MHC) isoforms. PGC-1alpha or PGC-1beta overexpression enhanced mRNA of the slow oxidative-associated MHC isoform MHCIb and downregulated mRNA levels of the fast glycolytic-associated MHC isoforms MHCIIX and MHCIIB. Only PGC-1beta overexpression caused an increase in mRNA of the intermediary fast oxidative-associated MHC isoform MHCIIA. PGC-1alpha or PGC-1beta overexpression upregulated GLUT4 mRNA and downregulated myocyte enhancer factor 2C transcription factor mRNA; only PGC-1alpha overexpression caused an increase in the mRNA expression of TRB3, a negative regulator of insulin signaling. These results show that both PGC-1alpha and PGC-1beta are involved in the regulation of skeletal muscle fiber transition and metabolism and that they have both overlapping and differing effects.


Parameter importance and uncertainty in predicting runoff pesticide reduction with filter strips.
Vegetative filter strips (VFS) are an environmental management tool used to reduce sediment and pesticide transport from surface runoff. Numerical models of VFS such as the Vegetative Filter Strip Modeling System (VFSMOD-W) are capable of predicting runoff, sediment, and pesticide reduction and can be useful tools to understand the effectiveness of VFS and environmental conditions under which they may be ineffective. However, as part of the modeling process, it is critical to identify input factor importance and quantify uncertainty in predicted runoff, sediment, and pesticide reductions. This research used state-of-the-art global sensitivity and uncertainty analysis tools, a screening method (Morris) and a variance-based method (extended Fourier Analysis Sensitivity Test), to evaluate VFSMOD-W under a range of field scenarios. The three VFS studies analyzed were conducted on silty clay loam and silt loam soils under uniform, sheet flow conditions and included atrazine, chlorpyrifos, cyanazine, metolachlor, pendimethalin, and terbuthylazine data. Saturated hydraulic conductivity was the most important input factor for predicting infiltration and runoff, explaining >75% of the total output variance for studies with smaller hydraulic loading rates ( approximately 100-150 mm equivalent depths) and approximately 50% for the higher loading rate ( approximately 280-mm equivalent depth). Important input factors for predicting sedimentation included hydraulic conductivity, average particle size, and the filter's Manning's roughness coefficient. Input factor importance for pesticide trapping was controlled by infiltration and, therefore, hydraulic conductivity. Global uncertainty analyses suggested a wide range of reductions for runoff (95% confidence intervals of 7-93%), sediment (84-100%), and pesticide (43-100%) . Pesticide trapping probability distributions fell between runoff and sediment reduction distributions as a function of the pesticides' sorption. Seemingly equivalent VFS exhibited unique and complex trapping responses dependent on the hydraulic and sediment loading rates, and therefore, process-based modeling of VFS is required.


Post-Ocular Trauma Corneal Staphyloma in a Child Living in an Underdeveloped Region of Eastern Indonesia.
Ocular trauma occurring in children often leads to visual impairment or blindness when it is not properly managed. This often occurs in underdeveloped regions with difficult access to professional care at local health facilities. We report a case of post-trauma corneal staphyloma in an underdeveloped region of eastern Indonesia to illustrate the importance of proper management of ocular trauma in areas lacking such expertise and where patients have difficulty accessing even basic health care. During a community health outreach in Southwest Sumba, eastern Indonesia in May 2017, a 7-year-old boy presented with white protrusion of the left eye of 3 years' duration following an event of sharp trauma. The patient lived in an inaccessible and impoverished area. Upon contemporary examination, visual acuity of the left eye was 1/300 while that of the right eye was 6/6. Anterior examination revealed corneal staphyloma of the left eye, and its posterior segment could not be evaluated. The patient was transported to an eye care center in Jakarta, receiving a stock prosthesis implant while awaiting a corneal evisceration procedure with dermofat graft. Ocular trauma is one of the most common causes of visual impairment in children. This case illustrates the consequences of inadequate post-trauma management and the importance of prevention of infection.


Pregnancy outcome in eclamptics at the University of Abuja Teaching Hospital, Gwagwalada, Abuja: a 3 year review.
Eclampsia remains one of the major causes of maternal morbidity and mortality especially in the developing countries. In Nigeria, it is the 3 rd commonest cause of maternal mortality. The high maternal morbidity and mortality due to eclampsia in the developing countries has been ascribed to late referral, delay in hospitalization, lack of transport, unbooked status of patients and multiple seizures prior to admission. To review the presentation and management of eclampsia at the University of Teaching Hospital (UATH), the factors associated with it, the maternal and perinatal outcome and make recommendations on how to reduce maternal and perinatal morbidity and mortality from eclampsia. The case notes of all the patients that had eclampsia between 1 st May 2005 and 30 th April 2008 were retrieved and analyzed. The informations sought for include age of the patients, parity, booking status, type of eclampsia and blood pressure at presentation. Other informations include level of proteinuria, anticonvulsants used, mode of delivery, maternal complications and perinatal outcome. There were 4471 total deliveries within the period, out of which 59 had eclampsia, giving an incidence of 13 per 1000 deliveries. There were 5 maternal deaths, giving a case fatality rate of 8.5%. Eclampsia was commonest amongst the age group of 20-24 years (34.8%). Primigravidae constituted 60.9% of the cases. Majority of the patients (89.1 %) were unbooked. Antepartum eclampsia (73.9%) was more than intra-partum (19.6%) and postpartum (2.2%) combined. Thirty two patients had severe hypertension on admission (diastolic BP= 110 mmHg) while 11 (23.9%) had mild hypertension (diastolic BP 90- < 110mmHg). Twenty patients (47.8%) were managed with diazepam alone while 19 patients (41.3%) were managed with magnesium sulphate alone. Five patients were managed with both. Thirty nine (84.8%) were delivered through caesarean section while 5 (10.8%) were delivered vaginally. Maternal complications include 6 cases of acute renal failure and one case of visual impairment. Thirty seven babies were delivered live while 8 stillbirths were recorded. Six babies (13.0%) had very low birth weight, 14 (30.4%) had low birth weight and 16 (34.8%) had normal birth weight. Eclampsia still remains a major cause of maternal morbidity and mortality in Nigeria. More awareness and enabling factors should be created for more women to access antenatal facilities. Information about danger signs of pre-eclampsia/eclampsia should be made available to antenatal clients. Government should be committed to providing emergency obstetric case facilities in our hospitals for effective management of eclampsia.


Insights and challenges in tuberculosis vaccine development.
Tuberculosis kills more people than any other pathogen and the need for a universally effective vaccine has never been greater. An effective vaccine will be a key tool in achieving the targets set by WHO in the End TB Strategy. Tuberculosis vaccine development is difficult and slow. Substantial progress has been made in research and development of tuberculosis vaccines in the past 20 years, and two clinical trial results from 2018 provide reason for optimism. However, many challenges to the successful licensure and deployment of an effective tuberculosis vaccine remain. The development of new tools for vaccine evaluation might facilitate these processes, and continued collaborative working and sustained funding will be essential.


Peroxisome proliferator-activated receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue.
Obesity is associated with infiltration of macrophages into adipose tissue. Adipose macrophages may contribute to an elevated inflammatory status by secreting a variety of proinflammatory mediators, including tumor necrosis factor alpha and interleukin-6 (IL-6). Recent data suggest that during diet-induced obesity the phenotype of adipose-resident macrophages changes from alternatively activated macrophages toward a more classical and pro-inflammatory phenotype. Here, we explore the effect of peroxisome proliferator-activated receptor gamma activation on obesity-induced inflammation in 129SV mice fed a high fat diet for 20 weeks. High fat feeding increased bodyweight gain, adipose tissue mass, and liver triglycerides. Rosiglitazone treatment further increased adipose mass, reduced liver triglycerides, and changed adipose tissue morphology toward smaller adipocytes. Surprisingly, rosiglitazone markedly increased the number of macrophages in adipose tissue, as shown by immunohistochemical analysis and quantification of macrophage marker genes CD68 and F4/80+. In adipose tissue, markers for classically activated macrophages including IL-18 were down-regulated, whereas markers characteristic for alternatively activated macrophages (arginase 1, IL-10) were up-regulated by rosiglitazone. Importantly, conditioned media from rosiglitazone-treated alternatively activated macrophages neutralized the inhibitory effect of macrophages on 3T3-L1 adipocyte differentiation, suggesting that alternatively activated macrophages may be involved in mediating the effects of rosiglitazone on adipose tissue morphology and mass. Our results suggest that short term rosiglitazone treatment increases infiltration of alternatively activated macrophages in adipose tissue. The alternatively activated macrophages might play a role in peroxisome proliferator-activated receptor gamma-dependent expansion and remodeling of adipose tissue.


The organization of the inner nuclear layer of the rabbit retina.
The initial goal of this study was to establish an accounting of the major classes of cells present in the inner nuclear layer (INL) of the rabbit's retina. Series of 80-100 radial sections 1 micron thick were cut from retinal blocks dissected at intervals along the vertical meridian. They were photographed at high magnification in the light microscope. By visualizing the initial segments of processes leaving the somata, we could identify each cell as a bipolar, amacrine, horizontal, or Müller cell. The identifications made by light microscopy were confirmed by electron microscopy of alternating ultrathin sections. On average, bipolar cells made up 41% of the total INL cells, amacrine cells 32%, horizontal cells 1.5%, and Müller cells 24%. These fractions varied relatively little across the retina or among different animals. We next immunolabeled the rod bipolar cells of whole-mounted retinas with antibodies against protein kinase C, using FITC as the visualizing agent. The same retinas were counterstained with a DNA-binding probe that fluoresces at longer wavelengths. Serial optical horizontal sections of the double-labeled wholemounts were made by confocal microscopy. On average, rod bipolars accounted for 10% of the total INL cells. By subtraction, the cone bipolars made up 31% of the total cells. We conclude that cone bipolars substantially outnumber rod bipolars, even in a retina in which rods outnumber cones by more than 20:1. Using the base of reference created here, a similar analysis can be carried out for other subclasses of retinal neuron. Because the analysis does not depend on absolute cell densities or corrections for shrinkage, data acquired by different histochemical techniques may be combined.


Outbreak of adverse reactions associated with contaminated heparin.
In January 2008, the Centers for Disease Control and Prevention began a nationwide investigation of severe adverse reactions that were first detected in a single hemodialysis facility. Preliminary findings suggested that heparin was a possible cause of the reactions. Information on clinical manifestations and on exposure was collected for patients who had signs and symptoms that were consistent with an allergic-type reaction after November 1, 2007. Twenty-one dialysis facilities that reported reactions and 23 facilities that reported no reactions were included in a case-control study to identify facility-level risk factors. Unopened heparin vials from facilities that reported reactions were tested for contaminants. A total of 152 adverse reactions associated with heparin were identified in 113 patients from 13 states from November 19, 2007, through January 31, 2008. The use of heparin manufactured by Baxter Healthcare was the factor most strongly associated with reactions (present in 100.0% of case facilities vs. 4.3% of control facilities, P<0.001). Vials of heparin manufactured by Baxter from facilities that reported reactions contained a contaminant identified as oversulfated chondroitin sulfate (OSCS). Adverse reactions to the OSCS-contaminated heparin were often characterized by hypotension, nausea, and shortness of breath occurring within 30 minutes after administration. Of 130 reactions for which information on the heparin lot was available, 128 (98.5%) occurred in a facility that had OSCS-contaminated heparin on the premises. Of 54 reactions for which the lot number of administered heparin was known, 52 (96.3%) occurred after the administration of OSCS-contaminated heparin. Heparin contaminated with OSCS was epidemiologically linked to adverse reactions in this nationwide outbreak. The reported clinical features of many of the cases further support the conclusion that contamination of heparin with OSCS was the cause of the outbreak.


Head trauma can initiate the onset of adreno-leukodystrophy.
X-linked adreno-leukodystrophy and its adult variant, adrenomyeloneuropathy, are caused by mutations in ABCD1 that encodes a peroxisomal membrane protein of unknown physiological significance. In spite of identical mutations, they can have markedly divergent neurological and neuropathologic characteristics. Adreno-leukodystrophy classically presents in normal boys with mild neuropsychiatric features, which progress to frank neurological signs, the vegetative state and death in approximately three years. Adrenomyeloneuropathy typically affects young men with spastic paraparesis and sensory ataxia that can progress over decades. The neuropathologic correlate for adreno-leukodystrophy is severe inflammatory demyelination of posterior cerebral white matter, while a chronic distal axonopathy of spinal cord and peripheral nerve occurs in adrenomyeloneuropathy. Consequently, both modifier genes and environmental factors have been implicated in their pathogeneses. We report five cases of adreno-leukodystrophy whose onsets were initiated by moderate to severe head trauma, two of whom were conversions from adrenomyeloneuropathy. Their clinical courses were rapidly incapacitating, short (i.e., weeks to a few years) and fatal due to marked cerebral inflammatory demyelination. These cases, in concert with several previous reports, indicate that head trauma is one environmental factor that can have a profoundly deleterious effect on those genetically at risk for, or with milder clinical phenotypes of, this disease. Avoidance of potential head trauma and a rapid response to episodes of moderate to severe head trauma in this patient population seem prudent.


Fibrinolytic therapy for refractory COVID-19 acute respiratory distress syndrome: Scientific rationale and review.
The coronavirus disease 2019 (COVID-19) pandemic has caused respiratory failure and associated mortality in numbers that have overwhelmed global health systems. Thrombotic coagulopathy is present in nearly three quarters of patients with COVID-19 admitted to the intensive care unit, and both the clinical picture and pathologic findings are consistent with microvascular occlusive phenomena being a major contributor to their unique form of respiratory failure. Numerous studies are ongoing focusing on anticytokine therapies, antibiotics, and antiviral agents, but none to date have focused on treating the underlying thrombotic coagulopathy in an effort to improve respiratory failure in COVID-19. There are animal data and a previous human trial demonstrating a survival advantage with fibrinolytic therapy to treat acute respiratory distress syndrome. Here, we review the extant and emerging literature on the relationship between thrombotic coagulopathy and pulmonary failure in the context of COVID-19 and present the scientific rationale for consideration of targeting the coagulation and fibrinolytic systems to improve pulmonary function in these patients.


The magnitude and impact of bullying among school pupils in Muscat, Oman: a cross-sectional study.
Research about bullying among school pupils in the Arab/Muslim population is scarce. This study evaluates the characteristics of bullying and its impact among school pupils in Oman via cross-sectional survey among eighth grade school pupils (n = 1,229) during the academic year 2006-2007. The participants were selected using stratified random selection among 6 administrative divisions of one the governorates in the country. Data were collected using self-completed structured questionnaires. This study found similar percentages of males and females (76%) have experienced one form of bullying, and the majority of the incidents (80%) occurred in the vicinity of the school. In almost half of the cases, the bullying was initiated by a student of the same age or older than the victim. The most common type of bullying encountered in this study was verbal (47.7%), followed by misuse (45.9%), physical (43.9%), and, finally, social isolation/exclusion (22.5%). Although the failure of an academic year was uncommon among victims of bullying, the number of pupils who missed 4-6 and ≥ 7 school days was higher among bullied pupils. If this study will withstand further research, educational initiatives are needed to mitigate the rate of bullying in Oman.


The Medicare Electronic Health Record Incentive Program: provider performance on core and menu measures.
To measure performance by eligible health care providers on CMS's meaningful use measures. Medicare Electronic Health Record Incentive Program Eligible Professionals Public Use File (PUF), which contains data on meaningful use attestations by 237,267 eligible providers through May 31, 2013. Cross-sectional analysis of the 15 core and 10 menu measures pertaining to use of EHR functions reported in the PUF. Providers in the dataset performed strongly on all core measures, with the most frequent response for each of the 15 measures being 90-100 percent compliance, even when the threshold for a particular measure was lower (e.g., 30 percent). PCPs had higher scores than specialists for computerized order entry, maintaining an active medication list, and documenting vital signs, while specialists had higher scores for maintaining a problem list, recording patient demographics and smoking status, and for providing patients with an after-visit summary. In fact, 90.2 percent of eligible providers claimed at least one exclusion, and half claimed two or more. Providers are successfully attesting to CMS's requirements, and often exceeding the thresholds required by CMS; however, some troubling patterns in exclusions are present. CMS should raise program requirements in future years.


The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials.
Pragmatic trials compare the effects of different decisions in usual clinical practice. To develop and evaluate methods to implement simple pragmatic trials using routinely collected electronic health records (EHRs) and recruiting patients at the point of care; to identify the barriers and facilitators for general practitioners (GPs) and patients and the experiences of trial participants. Two exemplar randomised trials (Retropro and eLung) with qualitative evaluations. Four hundred and fifty-nine English and Scottish general practices contributing EHRs to a research database, of which 17 participated in the trials. Retropro aimed to recruit 300 patients with hypercholesterolaemia and high cardiovascular risk and eLung aimed to recruit 150 patients with a chronic obstructive pulmonary disease exacerbation. Retropro randomised between simvastatin and atorvastatin and eLung between immediate antibiotics and deferred or non-use. eLung recruited during an unscheduled consultation using EHR flagging. Successful trial completion with implementation of information technology (IT) system for flagging and data processing and documentation of operational and scientific experiences. EHR research database. The governance approval process took over 3 years. A total of 58.8% of the practices (n = 270) expressed interest in participating. The number of interested practices dropped substantially with each stage of the governance process. In Retropro, 6.5% of the practices (n = 30) were eventually approved and 3.7% (n = 17) recruited patients; in eLung, these numbers were 6.8% (n = 31) and 1.3% (n = 6) respectively. Retropro successfully completed recruitment (301 patients) whereas eLung recruited 31 patients. Retropro recruited 20.6% of all statin starters in recruiting practices and 1.1% in the EHR database; the comparable numbers for eLung were 32.3% and 0.9% respectively. The IT system allowed for complex eligibility criteria with central on and off control of recruitment and flagging at a practice. Good Clinical Practice guidelines, governance and consent procedures were found to have substantially affected the intended simple nature of the trials. One qualitative study of 13 clinicians found that clinicians were generally positive about the principle of computerised trial recruitment (flagging during consultation). However, trials which did not include patients with acute illness were favoured. The second qualitative process evaluation interviewed 27 GPs about their actual experiences, including declining, recruiting and non-recruiting GPs. Opportunistic patient recruitment during a routine GP consultation was found to be the most controversial element. The actual experiences of recruiting patients during unscheduled consultation were generally more positive than the hypothetical views of GPs. Several of the recruiting GPs reported the process took 5 minutes and was straightforward and feasible on most occasions. Almost all GPs expressed their strong support for the use of EHRs for trials. Ten eLung participants were interviewed, all of whom considered it acceptable to be recruited during a consultation and to use EHRs for trials. EHR point-of-care trials are feasible, although the recruitment of clinicians is a major challenge owing to the complexity of trial approvals. These trials will provide substantial evidence on clinical effectiveness only if trial interventions and participating clinicians and patients are typical of usual clinical care and trials are simple to initiate and conduct. Recommendations for research include the development of evidence and implementation of risk proportionality in trial governance and conduct. Current Controlled Trials ISRCTN33113202 and ISRCTN72035428. This project was funded by the NIHR Health Technology Assessment programme and the Wellcome Trust and will be published in full in Health Technology Assessment; Vol. 18, No. 43. See the NIHR Journals Library website for further project information.


Cortical constriction during abscission involves helices of ESCRT-III-dependent filaments.
After partitioning of cytoplasmic contents by cleavage furrow ingression, animal cells remain connected by an intercellular bridge, which subsequently splits by abscission. Here, we examined intermediate stages of abscission in human cells by using live imaging, three-dimensional structured illumination microscopy, and electron tomography. We identified helices of 17-nanometer-diameter filaments, which narrowed the cortex of the intercellular bridge to a single stalk. The endosomal sorting complex required for transport (ESCRT)-III co-localized with constriction zones and was required for assembly of 17-nanometer-diameter filaments. Simultaneous spastin-mediated removal of underlying microtubules enabled full constriction at the abscission site. The identification of contractile filament helices at the intercellular bridge has broad implications for the understanding of cell division and of ESCRT-III-mediated fission of large membrane structures.


Fast growth phenotype of E. coli K-12 from adaptive laboratory evolution does not require intracellular flux rewiring.
Adaptive laboratory evolution (ALE) is a widely-used method for improving the fitness of microorganisms in selected environmental conditions. It has been applied previously to Escherichia coli K-12 MG1655 during aerobic exponential growth on glucose minimal media, a frequently used model organism and growth condition, to probe the limits of E. coli growth rate and gain insights into fast growth phenotypes. Previous studies have described up to 1.6-fold increases in growth rate following ALE, and have identified key causal genetic mutations and changes in transcriptional patterns. Here, we report for the first time intracellular metabolic fluxes for six such adaptively evolved strains, as determined by high-resolution 13C-metabolic flux analysis. Interestingly, we found that intracellular metabolic pathway usage changed very little following adaptive evolution. Instead, at the level of central carbon metabolism the faster growth was facilitated by proportional increases in glucose uptake and all intracellular rates. Of the six evolved strains studied here, only one strain showed a small degree of flux rewiring, and this was also the strain with unique genetic mutations. A comparison of fluxes with two other wild-type (unevolved) E. coli strains, BW25113 and BL21, showed that inter-strain differences are greater than differences between the parental and evolved strains. Principal component analysis highlighted that nearly all flux differences (95%) between the nine strains were captured by only two principal components. The distance between measured and flux balance analysis predicted fluxes was also investigated. It suggested a relatively wide range of similar stoichiometric optima, which opens new questions about the path-dependency of adaptive evolution.


Gene and MicroRNA Expression Are Predictive of Tumor Response in Rectal Adenocarcinoma Patients Treated With Preoperative Chemoradiotherapy.
Preoperative chemoradiotherapy (pCRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). However, tumor response to pCRT is not uniform, and there are no effective predictive methods. This study investigated whether specific gene and miRNA expression are associated with tumor response to pCRT. Tissue biopsies were obtained from patients before pCRT and resection. Gene and miRNA expression were analyzed using a one-color microarray technique that compares signatures between responders (R) and non-responders (NR), as measured based on tumor regression grade. Two groups composed of 38 "exploration cohort" and 21 "validation cohort" LARC patients were considered for a total of 32 NR and 27 R patients. In the first cohort, using SAM Two Class analysis, 256 genes and 29 miRNAs that were differentially expressed between the NR and R patients were identified. The anti-correlation analysis showed that the same 8 miRNA interacted with different networks of transcripts. The miR-630 appeared only with the NR patients and was anti-correlated with a single transcript: RAB5B. After PAM, the following eight transcripts were strong predictors of tumor response: TMEM188, ITGA2, NRG, TRAM1, BCL2L13, MYO1B, KLF7, and GTSE1. Using this gene set, an unsupervised cluster analysis was applied to the validation cohort and correctly assigned the patients to the NR or R group with 85.7% accuracy, 90% sensitivity, and 82% specificity. All three parameters reached 100% when both cohorts were considered together. In conclusion, gene and miRNA expression profiles may be helpful for predicting response to pCRT in LARC patients. J. Cell. Physiol. 232: 426-435, 2017. © 2016 Wiley Periodicals, Inc.


An update of the HLA genomic region, locus information and disease associations: 2004.
The human major histocompatibility (MHC) genomic region at chromosomal position 6p21 encodes the six classical transplantation HLA genes and many other genes that have important roles in the regulation of the immune system as well as in some fundamental cellular processes. This small segment of the human genome has been associated with more than 100 diseases, including common diseases--such as diabetes, rheumatoid arthritis, psoriasis, asthma and various autoimmune disorders. The MHC 3.6 Mb genomic sequence was first reported in 1999 with the annotation of 224 gene loci. The locus and allelic information of the MHC continue to be updated by identifying newly mapped expressed genes and pseudogenes based on comparative genomics, SNP analysis and cDNA projects. Since 1999, new innovations in bioinformatics and gene-specific functional databases and studies on the MHC genes have resulted in numerous changes to gene names and better ways to update and link the MHC gene symbols, names and sequences together with function, variation and disease associations. In this study, we present a brief overview of the MHC genomic structure and the recent information that we have gathered on the MHC gene loci via LocusLink at the National Centre for Biological Information (http://www.ncbi.nih.gov/.) and the MHC genes' association with various diseases taken from publications and records in public databases, such as the Online Mendelian Inheritance in Man and the Genetic Association Database.


Paternal chromosome segregation during the first mitotic division determines Wolbachia-induced cytoplasmic incompatibility phenotype.
The most common Wolbachia-induced phenotype in insects is cytoplasmic incompatibility (CI), which occurs when sperm from infected males fertilize eggs from uninfected females. CI produces distinct phenotypes in three closely related haplo-diploid species of the genus Nasonia: mortality in N. longicornis and N. giraulti, and conversion to male development in N. vitripennis. We demonstrate that the majority of CI-induced mortality occurs during embryogenesis and that the pattern of paternal chromosome segregation during the first mitosis is a good predictor of CI phenotype. In N. giraulti and N. longicornis, the paternal chromosomes mis-segregate, producing abnormal nuclei connected by chromatin bridges. Consequently, these embryos arrest development with very few and abnormal nuclei. In contrast, the paternal genome in N. vitripennis is either not segregated or mis-segregates to one of the two daughter nuclei. Consequently, these embryos continue development utilizing the maternally derived haploid nuclei, resulting in male offspring. The latter class is the first documented example of asymmetric mitotic segregation of abnormal chromosomes. We conclude that in haplo-diploids, CI-induced embryonic lethality occurs only when abnormal paternal genome segregation affects both products of the first mitotic division. This is the first study to associate differences in types of CI with specific cytological defects.


Naturally occurring carboxypeptidase A6 mutations: effect on enzyme function and association with epilepsy.
Carboxypeptidase A6 (CPA6) is a member of the A/B subfamily of M14 metallocarboxypeptidases that is expressed in brain and many other tissues during development. Recently, two mutations in human CPA6 were associated with febrile seizures and/or temporal lobe epilepsy. In this study we screened for additional CPA6 mutations in patients with febrile seizures and focal epilepsy, which encompasses the temporal lobe epilepsy subtype. Mutations found from this analysis as well as CPA6 mutations reported in databases of single nucleotide polymorphisms were further screened by analysis of the modeled proCPA6 protein structure and the functional role of the mutated amino acid. The point mutations predicted to affect activity and/or protein folding were tested by expression of the mutant in HEK293 cells and analysis of the resulting CPA6 protein. Common polymorphisms in CPA6 were also included in this analysis. Several mutations resulted in reduced enzyme activity or CPA6 protein levels in the extracellular matrix. The mutants with reduced extracellular CPA6 protein levels showed normal levels of 50-kDa proCPA6 in the cell, and this could be converted into 37-kDa CPA6 by trypsin, suggesting that protein folding was not greatly affected by the mutations. Interestingly, three of the mutations that reduced extracellular CPA6 protein levels were found in patients with epilepsy. Taken together, these results provide further evidence for the involvement of CPA6 mutations in human epilepsy and reveal additional rare mutations that inactivate CPA6 and could, therefore, also be associated with epileptic phenotypes.


Establishment and characterization of a sustained delayed-type hypersensitivity model with arthritic manifestations in C57BL/6J mice.
Rheumatoid arthritis (RA) is a chronic progressive, inflammatory and destructive autoimmune disease, characterised by synovial joint inflammation and bone erosion. To better understand the pathophysiology and underlying immune mechanisms of RA various models of arthritis have been developed in different inbred strains of mice. Establishment of arthritis models with components of adaptive immunity in the C57BL/6J strain of mice has been difficult, and since most genetically modified mice are commonly bred on this background, there is a need to explore new ways of obtaining robust models of arthritis in this strain. This study was undertaken to establish and characterise a novel murine model of arthritis, the delayed-type hypersensitivity (DTH)-arthritis model, and evaluate whether disease can be treated with compounds currently used in the treatment of RA. DTH-arthritis was induced by eliciting a classical DTH reaction in one paw with methylated bovine serum albumin (mBSA), with the modification that a cocktail of type II collagen monoclonal antibodies was administered between the immunisation and challenge steps. Involved cell subsets and inflammatory mediators were analysed, and tissue sections evaluated histopathologically. Disease was treated prophylactically and therapeutically with compounds used in the treatment of RA. We demonstrate that DTH-arthritis could be induced in C57BL/6 mice with paw swelling lasting for at least 28 days and that disease induction was dependent on CD4+ cells. We show that macrophages and neutrophils were heavily involved in the observed pathology and that a clear profile of inflammatory mediators associated with these cell subsets was induced locally. In addition, inflammatory markers were observed systemically. Furthermore, we demonstrate that disease could be both prevented and treated. Our findings indicate that DTH-arthritis shares features with both collagen-induced arthritis (CIA) and human RA. DTH-arthritis is dependent on CD4+ cells for induction and can be successfully treated with TNFα-blocking biologics and dexamethasone. On the basis of our findings we believe that the DTH-arthritis model could hold potential in the preclinical screening of novel drugs targeting RA. The model is highly reproducible and has a high incidence rate with synchronised onset and progression, which strengthens its potential.


Managing fisheries for maximum nutrient yield.
Wild-caught fish are a bioavailable source of nutritious food that, if managed strategically, could enhance diet quality for billions of people. However, optimising nutrient production from the sea has not been a priority, hindering development of nutrition-sensitive policies. With fisheries management increasingly effective at rebuilding stocks and regulating sustainable fishing, we can now begin to integrate nutritional outcomes within existing management frameworks. Here, we develop a conceptual foundation for managing fisheries for multispecies Maximum Nutrient Yield (mMNY). We empirically test our approach using size-based models of North Sea and Baltic Sea fisheries and show that mMNY is predicted by the relative contribution of nutritious species to total catch and their vulnerability to fishing, leading to trade-offs between catch and specific nutrients. Simulated nutrient yield curves suggest that vitamin D, which is deficient in Northern European diets, was underfished at fishing levels that returned maximum catch weights. Analysis of global catch data shows there is scope for nutrient yields from most of the world's marine fisheries to be enhanced through nutrient-sensitive fisheries management. With nutrient composition data now widely available, we expect our mMNY framework to motivate development of nutrient-based reference points in specific contexts, such as data-limited fisheries. Managing for mMNY alongside policies that promote access to fish could help close nutrient gaps for coastal populations, maximising the contribution of wild-caught fish to global food and nutrition security.


Experimentally induced clinical Cystoisospora canis coccidiosis in dogs with prior natural patent Cystoisospora ohioensis-like or C. canis infections.
Diarrhea caused by intestinal coccidia (Cystoisospora species) is a common problem in pet dogs and in dogs in animal shelters. Cystoisospora canis has the largest oocysts of the 4 named species of coccidia infecting dogs. The present study examined an isolate of C. canis obtained from a dog from São Paulo, SP, Brazil. Oocysts sporulated within 2 days at room temperature, and 20 sporulated oocysts were measured at 37.6 by 28.6 μm (range 35-42 by 26-31 μm). Most sporulated oocysts contained 2 sporocysts, each with 4 sporozoites, although a few (<1%) were Caryospora-like and contained 1 sporocyst with 8 sporozoites. Two experiments using a total of 11 female 6-wk-old beagles were conducted to determine the pathogenicity of oral infection with 5 × 10(4) sporulated oocysts of this isolate of C. canis. Five of the 11 dogs had natural infections with Cystoisospora ohioensis-like (n = 4) or C. canis (n = 1) species prior to the predicted patent period of 9-10 days. Ten of the dogs developed diarrhea with occasional blood, and 3 dogs were affected to the extent that clinical treatment for coccidiosis using sulfadimethoxine was recommended. Dog CRU had a natural C. canis infection and did not develop clinical disease after oral infection with C. canis oocysts. This dog had a prepatent period of 9 days and a patent period of 3 days, corresponding to experimental infection with the new isolate of C. canis. It excreted fewer C. canis oocysts than did the other dogs. The 4 dogs with natural C. ohioensis-like infection all developed clinical disease, and 1 required treatment. The prepatent period was 9-10 days, and the patent period was 10-11 days in these dogs. All 6 dogs not naturally infected with Cystoisospora developed clinical disease, and 2 required treatment. The prepatent period was 9-10 days, and the patent period was 8-12 days. The present study confirms that C. canis is a primary pathogen for young dogs. It demonstrates that prior infection with C. canis but not C. ohioensis-like coccidia confers some resistance to clinical disases and a decrease in oocyst production in dogs challenged with C. canis.


A urinary metabolite of phenanthrene as a biomarker of polycyclic aromatic hydrocarbon metabolic activation in workers exposed to residual oil fly ash.
Residual oil fly ash is a chemically complex combustion product containing a significant component of potentially carcinogenic transition metals and polycyclic aromatic hydrocarbons (PAH). Various biomarkers of PAH exposure have been investigated previously, most notably 1-hydroxypyrene (1-OHP), in urine. In this study, we assessed the utility of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (trans, anti-PheT), a metabolite of phenanthrene, to detect occupational PAH exposure. Urine samples collected across the workweek were analyzed for 1-OHP and trans, anti-PheT in boilermakers (n = 20) exposed to residual oil fly ash. Median baseline urinary trans, anti-PheT concentrations were 0.50 microg/g creatinine in current tobacco smokers and 0.39 microg/g creatinine in nonsmokers. Median baseline urinary 1-OHP concentrations in smokers and nonsmokers were 0.31 and 0.13 microg/g creatinine, respectively. To study further the effect of smoking exposure on the urinary PAH markers, urinary cotinine was used. Although urinary trans, anti-PheT and 1-OHP concentrations were correlated (Spearman r = 0.63; P < 0.001) for all subjects, the regression coefficient between log-transformed trans, anti-PheT and log 1-OHP was statistically significant only for subjects with low levels of urinary cotinine or for nonsmokers. Each 1-unit increase in log 1-OHP was associated with a 0.77-unit increase (95% confidence interval, 0.45-1.09) in log trans, anti-PheT in subjects with low levels of urinary cotinine (P < 0.001). In these subjects, dichotomized occupational exposure status was a significant predictor of log trans, anti-PheT (P = 0.02) but not of log 1-OHP (P = 0.2). In conclusion, we found that urinary trans, anti-PheT was detected in levels comparable with 1-OHP in occupationally exposed workers, particularly nonsmokers. This study shows that urinary trans, anti-PheT may be an effective biomarker of uptake and metabolic activation of PAHs.


Role of heart rate as a marker and mediator of poor outcome for patients with heart failure.
Tachycardia has been associated with worse outcomes for patients with heart failure and is also thought to have a direct adverse impact on the myocardium. This report highlights the current evidence for heart rate as both a risk factor and mediator for poor outcome for patients with heart failure. We summarize the large number of studies evaluating heart rate in patients with systolic dysfunction and newer studies that examine patients with preserved systolic function. The effect on outcomes in heart failure of medications known to slow the heart rate such as β-blockers and the more recently developed drug ivabradine are discussed. The data clearly show that a high heart rate is a marker of increased mortality. There is also a strong suggestion that a higher heart rate directly worsens outcome and that this can be mitigated by heart rate-reducing medications.


Involvement of oviduct in sperm capacitation and oocyte development in pigs.
An overview is presented on the structure and function of the pig oviduct in relation to sperm capacitation and oocyte development in vivo. In pigs, a functional sperm reservoir is established in the uterotubal junction-isthmus when sperm deposition occurs before ovulation. Capacitation is assumed to occur in this location, and spermatozoa progress towards the ampullary-isthmic junction at about the time of ovulation as a consequence of capacitation and hyperactivation. Preliminary data from our laboratory on viable spermatozoa retrieved from the sperm reservoir and the ampullary-isthmic junction of mated sows at pre- and periovulation oestrus showed that the largest subpopulation (60-90%) was of uncapacitated spermatozoa (using merocyanine-540), whereas 6-37% of the gated cells were capacitated spermatozoa. Incubation in a capacitation-inducing medium (bicarbonate-containing modified Brackett-Oliphant medium; mBO) for < 30 min effected capacitation readily, more markedly in ampullary-isthmic junction samples than in samples from the uterotubal junction, thereby indicating that uncapacitated spermatozoa responded to the addition of the effector bicarbonate at concentrations similar to those recorded in the periovulatory ampullary-isthmic junction in vivo. Addition of preovulatory isthmic oviductal fluid and hyaluronan under a similar incubation regimen maintained tubal sperm viability without obvious induction of capacitation. This finding indicates that, before ovulation, the intraluminal fluid of the sperm reservoir might delay sperm capacitation, perhaps because of its hyaluronan content. Evidence is presented that the sperm population in the oviduct undergoes capacitation under particular conditions in the upper tubal compartments. The diverse response of spermatozoa to capacitation stimuli helps to ensure full rates of fertilization in vivo. Data are also provided on the importance of final zona pellucida maturation in the pig oviduct to warrant proper zona pellucida reaction after sperm penetration, which would address in part the abnormal occurrence of polyspermy in in vitro fertilization of pigs.


Angioedema due to acquired C1-inhibitor deficiency: spectrum and treatment with C1-inhibitor concentrate.
Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is a serious condition that may result in life-threatening asphyxiation due to laryngeal edema. It is associated with malignant B-cell lymphoma and other disorders. The purpose of this study was to describe the characteristics and associated disorders of patients with AAE-C1-INH and assess the efficacy of plasma-derived C1-INH concentrate (pdC1-INH) in the treatment of AAE-C1-INH. Forty-four patients with AAE-C1-INH from the Angioedema Outpatient Service of Mainz were assessed for associated disorders. In 32 of these patients, the duration of swelling attacks was measured before and after treatment with pdC1-INH (Berinert® (CSL Behring, Marburg, Germany)). The time between injection and complete resolution of symptoms and treatment effectiveness was provided by the patients. The following underlying disorders were present: monoclonal gammopathy of undetermined significance (47.7%), non-Hodgkin lymphoma (27.3%), anti-C1-INH autoantibodies alone (11.4%), and other conditions (4.5%). In 9.1% patients, no associated disorder could be found. AAE-C1-INH led to the detection of lymphoma in 75% of patients with the malignancy. Treatment with pdC1-INH shortened attacks by an average (SD) 54.4 (± 32.8) hours (P < 0.0001). The earlier the attack was treated, the shorter the time between injection and resolution of symptoms (P = 0.0149). A total of 3553 (97.7%) of the 3636 attacks were effectively treated with pdC1-INH as assessed by the patient. The mean (SD) dose per-attack was 787 (± 442) U. pdC1-INH was effective in 1246 (93.8%) of 1329 attacks in 8 patients with anti-C1-INH autoantibodies and in 344 (99.4%) of 346 attacks in 6 patients without autoantibodies. The average (SD) dose per effectively treated attack was 1238.4 (± 578.2) U in patients with anti-C1-INH autoantibodies and 510.2 (± 69.1) U in patients without autoantibodies. pdC1-INH is highly effective in treating AAE-C1-INH patients and is also effective in the vast majority of attacks in patients with anti-C1-INH autoantibodies. It is fast-acting and reduces attack duration.


Limitations of the complement-fixation test for distinguishing naturally acquired from vaccine-induced yellow fever infection in flavivirus-hyperendemic areas.
On the basis of previous studies, it has long been stated that 17D yellow fever (YF) vaccine generally does not induce complement-fixing (CF) antibodies, and that the presence of CF antibodies could be used in epidemiological studies to distinguish individuals infected with wild YF virus from vaccinated persons. In January 1979, seroepidemiological investigations were conducted during a YF epidemic in The Gambia, West Africa. Since a mass vaccination campaign was also in progress, it was important to confirm that the CF test could be used for serodiagnosis and determination of the incidence of natural YF infections. The serological responses of 58 individuals who received 17D YF vaccine were studied. The vaccinees fell into three gorups: 1) those with prevaccination YF neutralizing (N) antibodies; 2) immunological virgins without prevaccination YF-N antibody or hemagglutination-inhibiting (HI) antibodies to heterologous flaviviruses (Zika, West Nile, dengue 1, Uganda S, Spondweni, or Ntaya; and 3) those without prevaccination YF-N antibodies but with heterologous flaviviral HI antibodies. Vaccination of persons without prior flaviviral immunological experience resulted in monotypic YF HI and/or N antibody seroconversions, but no CF antibody response. The presence of prevaccination YF N antibodies blocked serological response to the vaccine in a high proportion of the cases; however, 24% of vaccinees in this group had a marked rise in log2 YF CF antibody titer (mean increase of 3.9). Thirteen (46%) of 28 persons without prevaccination YF N, but with heterologous flaviviral HI antibodies demonstrated YF CF antibody seroconversion or increase in titer following vaccination; in this group the mean increase in log2/ YF CF antibody titer was 2.1. The CF antibody response was generally broadly cross-reactive; but in a few individuals, the YF CF antibody response was homotypic. Nine different patterns of HI and CF homologous and heterologous antibody responses were defined and are discussed. The practical significance of these studies is that they demonstrate that in a high percentage of persons with prior flavivirus exposure, anamnestic serological responses to YF vaccine result in CF antibodies similar to those induced by natural YF virus infection. In Africa and tropical America, where the background of flaviviral immunity is high, it is imperative that seroepidemiologic investigations during or after YF outbreaks be conducted prior to vaccination.


Decentral gene expression analysis: analytical validation of the Endopredict genomic multianalyte breast cancer prognosis test.
EndoPredict (EP) is a clinically validated multianalyte gene expression test to predict distant metastasis in ER-positive, HER2-negative breast cancer treated with endocrine therapy alone. The test is based on the combined analysis of 12 genes in formalin-fixed, paraffin-embedded (FFPE) tissue by reverse transcription-quantitative real-time PCR (RT-qPCR). Recently, it was shown that EP is feasible for reliable decentralized assessment of gene expression. The aim of this study was the analytical validation of the performance characteristics of the assay and its verification in a molecular-pathological routine laboratory. Gene expression values to calculate the EP score were assayed by one-step RT-qPCR using RNA from FFPE tumor tissue. Limit of blank, limit of detection, linear range, and PCR efficiency were assessed for each of the 12 PCR assays using serial samples dilutions. Different breast cancer samples were used to evaluate RNA input range, precision and inter-laboratory variability. PCR assays were linear up to Cq values between 35.1 and 37.2. Amplification efficiencies ranged from 75% to 101%. The RNA input range without considerable change of the EP score was between 0.16 and 18.5 ng/μl. Analysis of precision (variation of day, day time, instrument, operator, reagent lots) resulted in a total noise (standard deviation) of 0.16 EP score units on a scale from 0 to 15. The major part of the total noise (SD 0.14) was caused by the replicate-to-replicate noise of the PCR assays (repeatability) and was not associated with different operating conditions (reproducibility). Performance characteristics established in the manufacturer's laboratory were verified in a routine molecular pathology laboratory. Comparison of 10 tumor samples analyzed in two different laboratories showed a Pearson coefficient of 0.995 and a mean deviation of 0.15 score units. The EP test showed reproducible performance characteristics with good precision and negligible laboratory-to-laboratory variation. This study provides further evidence that the EP test is suitable for decentralized testing in specialized molecular pathological laboratories instead of a reference laboratory. This is a unique feature and a technical advance in comparison with existing RNA-based prognostic multigene expression tests.


Acceptance of homosexuality through education? Investigating the role of education, family background and individual characteristics in the United Kingdom.
Higher educated people tend to be more accepting of homosexuality than lower educated people. This has inspired claims that education leads to a higher acceptance of homosexuality. Alternatively, the association between education and acceptance of homosexuality could be confounded by (un)observed family background and stable individual characteristics. This study investigated the association between education and acceptance of homosexuality and the role of potential confounders in a unique longitudinal sample of British siblings. Multilevel and fixed effects analyses show that both perspectives apply. A large part of the association between education and acceptance of homosexuality could be attributed to family background and observed individual characteristics (one third), as well as unobserved individual characteristics (an additional third), but the positive association remains. Findings are discussed in light of existing explanations regarding the effect of education on the acceptance of homosexuality.