Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study.
A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes. For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 μg/L. We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3-6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis. Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32-55) was lower than in the non-VITT group (57 years; 41-62; p=0·0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2-4) than non-VITT patients (two, 2-3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022). Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate. None.


Activity of trunk muscles during aquatic and terrestrial locomotion in Ambystoma maculatum.
The activity of seven trunk muscles was recorded at two sites along the trunk in adult spotted salamander, Ambystoma maculatum, during swimming and during trotting in water and on land. Several muscles showed patterns of activation that are consistent with the muscles producing a traveling wave of lateral bending during swimming and a standing wave of bending during aquatic and terrestrial trotting: the dorsalis trunci, subvertebralis lateralis and medialis, rectus lateralis and obliquus internus. The interspinalis showed a divergent pattern and was active out of phase with the other muscles suggesting that it functions in vertebral stabilization rather than lateral bending. The obliquus internus and rectus abdominis showed bilateral activity indicating that they counteract sagittal extension of the trunk that is produced when the large dorsal muscles are active to produce lateral bending. Of the muscles examined, only the obliquus internus showed a clear shift in function from lateral bending during swimming to resistance of long-axis torsion during trotting. During terrestrial trotting, muscle recruitment was greater in several muscles than during aquatic trotting, despite similar temporal patterns of muscle activation, suggesting that the trunk is stiffened during terrestrial locomotion against greater gravitational forces whereas the basic functions of the trunk muscles in trotting are conserved across environments.


B-cell chronic lymphocytic leukaemia: a polymorphic family unified by genomic features.
Human cancer is characterised by complex molecular aberrations which result in a wide variety of clinical manifestations. B-cell chronic lymphocytic leukaemia (B-CLL) is particularly diverse, both in terms of molecular changes and clinical course, and consequently our understanding of the pathology of this disease is generally poor. Furthermore, the heterogeneity of this tumour type coupled with the absence of an obvious genetic "hallmark", such as gain of oncogene function or loss of suppressor-gene function, has led many investigators to question whether B-CLL is a single disease entity. In most cases, B-CLL does not show specific reciprocal chromosomal translocations as found in other haemopoietic malignant diseases. The genomic instability of B-CLL results in numerous different types of chromosomal losses and gains, giving rise to unsettled karyotypes among individuals with this disease. Nevertheless, genetic data imply that B-CLL is a single disease characterised by a common gene-expression profile and by the existence of specific subtypes that may have clinical correlates in patients.


Comparison of end-of-life care for people living in home settings versus residential aged care facilities: A nationwide study among Australian general practitioners.
We have little knowledge of differences in end-of-life care between home settings and residential aged care facilities (RACFs) where people spend most of their last year of life. This study aimed to compare end-of-life care between home settings and RACFs from the perspective of Australian general practitioners (GPs). A descriptive study was conducted with 62 GPs from Western Australia, Queensland and Victoria. Participants were asked to provide reports on end-of-life care of decedents in their practice using a validated clinic-based data collection process developed by our team between September 2018 and August 2019. Of the 213 reported expected deaths, 66.2% mainly lived at home in the last year of life. People living at home were more likely to die at a younger age (median 77 vs. 88, p < 0.001), to be male (51.1% vs. 33.3%, p = 0.01) and to die of cancer (53.9% vs. 4.2%, p < 0.001) compared to those in RACFs. There were no significant differences between the two patient groups for seven out of the eight assessed symptoms, except nausea. GPs' perceived roles in caring for patients and levels of their involvement in provision of common palliative care services were comparable between the two groups. The usual accommodation setting was most frequently considered the preferred place of death in both groups. However, more home residents ended up dying in hospital compared to RACF residents. There were significantly higher frequencies of end-of-life discussions (ORs ranged 5.46-9.82 for all topic comparisons) with GPs associated with people living at home versus RACFs. One opportunity for improved care is through promoting greater involvement of GPs in end-of-life discussions with RACF residents and staff. In general, more Australians could potentially remain at home until death if provided with greater access to essential specialist palliative care services and supportive services in home settings.


Humanization and characterization of an anti-ricin neutralization monoclonal antibody.
Ricin is regarded as a high terrorist risk for the public due to its high toxicity and ease of production. Currently, there is no therapeutic or vaccine available against ricin. D9, a murine monoclonal antibody developed previously in our laboratory, can strongly neutralize ricin and is therefore a good candidate for humanization. Humanization of D9 variable regions was achieved by a complementarity-determining region grafting approach. The humanized D9 (hD9) variable regions were further grafted onto human heavy and light chain constant regions to assemble the complete antibody gene. A foot-and-mouth-disease virus-derived 2A self-processing sequence was introduced between heavy and light chain DNA sequences to cleave the recombinant protein into a functional full-length antibody molecule from a single open reading frame driven by a single promoter in an adenoviral vector. After expression in mammalian cells and purification, the hD9 was demonstrated to have equimolar expression of the full-length antibody heavy and light chains. More importantly, the hD9 exhibited high affinity to ricin with K(D) of 1.63 nM, comparable to its parental murine D9 (2.55 nM). In a mouse model, intraperitoneal (i.p.) administration of hD9, at a low dose of 5 µg per mouse, 4 hours after the i.p. challenge with 5×LD50 ricin was found to rescue 100% of the mice. In addition, administered 6 hours post-challenge, hD9 could still rescue 50% of the mice. The hD9 has the potential to be used for prophylactic or therapeutic purposes against ricin poisoning.


Prospective evaluation of fecal calprotectin as a screening biomarker for colorectal neoplasia.
Stool testing is a well established method of screening for colorectal neoplasia. Emerging data suggest that novel biomarkers may offer performance advantages over fecal occult blood. In this large, prospective study, we assessed fecal calprotectin (a leukocyte-derived protein) as a screening biomarker for colorectal neoplasia. Fecal calprotectin was directly compared to fecal hemoglobin (Hb) and colonoscopy as the existing criterion standards for stool screening and structural evaluation, respectively. Subjects included colonoscopy patients with a personal history of colorectal neoplasia, family history of colorectal cancer, or iron deficiency anemia. Stool specimens were collected before purgation, processed appropriately, and quantitatively analyzed for calprotectin (Nycomed Pharma, Oslo, Norway) and for Hb (Mayo Medical Laboratories, Rochester, MN) by masked technicians. Colonoscopies were performed by experienced endoscopists without prior knowledge of the fecal assay results. Among 412 subjects, 97 (24%) subjects had one or more colorectal neoplasms (including three with adenocarcinomas). Fecal calprotectin levels did not differ significantly between subjects with versus subjects without colorectal neoplasms (p = 0.33). Neither tumor number (p = 0.85) nor tumor size (p = 0.86) significantly influenced the observed fecal calprotectin concentrations. Estimates of the sensitivity, specificity, and positive and negative predictive values of fecal calprotectin for any colorectal neoplasms were 37%, 63%, 23%, and 76%, respectively. Comparable performance estimates for fecal Hb were 3%, 97%, 27%, and 77%, respectively. In this cohort of colonoscopy patients at above average risk, fecal calprotectin was a poor screening biomarker for colorectal neoplasia. Further investigation of tumor-derived, rather than blood-based, biomarkers may be a more rewarding approach to stool screening for colorectal neoplasia.


Ewing family of tumours involving the vulva and vagina: report of a series of four cases.
Ewing's sarcoma and peripheral primitive neuroectodermal tumour (pPNET) are now regarded as two morphological ends of a spectrum of neoplasms, characterised by a t(11;22) or other related chromosomal translocation involving the EWS gene on chromosome 22 and referred to as Ewing family of tumours (EFTs). EFTs are extremely rare in the vulva and vagina, a review of the literature revealing only 13 previously reported possible cases, most of which have not had molecular confirmation. In this study, four new cases of EFTs involving the vulva (three cases) or vagina (one case) are reported. The tumours occurred in women aged 19, 20, 30 and 40 years and ranged in size from 3 to 8 cm. Morphologically, all neoplasms had a lobulated architecture and were composed of solid aggregates of cells. In one case, occasional rosettes were formed. In all the tumours, there was diffuse membranous staining with CD99; nuclear positivity with FLI-1 was present in two cases. Three cases were focally positive with the broad-spectrum cytokeratin AE1/3, all were diffusely positive with vimentin and all were desmin negative. In two cases, a t(11;22) (q24;q12) (EWSR1-FLI-1) chromosomal translocation was demonstrated by reverse transcriptase-PCR (one case) and fluorescence in situ hybridisation (FISH) (one case), and in another case a rearrangement of the EWSR1 gene on chromosome 22 was demonstrated by FISH. In the other case, a variety of molecular studies did not reveal a translocation involving the EWS gene but this tumour, on the balance of probability, is still considered to represent a neoplasm in the EFTs. Follow-up in two cases revealed that one patient developed pulmonary metastasis and died and another is alive without disease at 12 months. This report expands the published literature regarding EFTs involving the vulva and vagina and stresses the importance of molecular techniques in firmly establishing the diagnosis, especially when these neoplasms arise at unusual sites.


Computed tomography angiography as a confirmatory test for the diagnosis of brain death.
OBJECTIVE For a diagnosis of brain death (BD), ancillary testing is performed if patient factors prohibit a complete clinical examination and apnea test. The American Academy of Neurology (AAN) guidelines identify cerebral angiography (CA), cerebral scintigraphy, electroencephalography, and transcranial Doppler ultrasonography as accepted ancillary tests. CA is widely considered the gold standard of these, as it provides the most reliable assessment of intracranial blood flow. CT angiography (CTA) is a noninvasive and widely available study that is also capable of identifying absent or severely diminished intracranial blood flow, but it is not included among the AAN's accepted ancillary tests because of insufficient evidence demonstrating its reliability. The objective of this study was to assess the statistical performance of CTA in diagnosing BD, using clinical criteria alone or clinical criteria plus CA as the gold-standard comparisons. METHODS The authors prospectively enrolled 22 adult patients undergoing workup for BD. All patients had cranial imaging and clinical examination results consistent with BD. In patients who met the AAN clinical criteria for BD, the authors performed CA and CTA so that both tests could be compared with the gold-standard clinical criteria. In cases that required ancillary testing, CA was performed as a confirmatory study, and CTA was then performed to compare against clinical criteria plus CA. Radiographic data were evaluated by an independent neuroradiologist. Test characteristics for CTA were calculated. RESULTS Four patients could not complete the standard BD workup and were excluded from analysis. Of the remaining 18 patients, 16 met AAN criteria for BD, 9 of whom required ancillary testing with CA. Of the 16 patients, 2 who also required CA ancillary testing were found to have persistent intracranial flow and were not declared brain dead at that time. These patients also underwent CTA; the results were concordant with the CA results. Six patients who were diagnosed with BD on the basis of clinical criteria alone also underwent CA, with 100% sensitivity. For all 18 patients included in the study, CTA had a sensitivity of 75%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 33%. CONCLUSIONS Clinical examination with or without CA remains the gold standard in BD testing. Studies assessing the statistical performance of CTA in BD testing should compare CTA to these gold standards. The statistical performance of CTA in BD testing is comparable to several of the nationally accepted ancillary tests. These data add to the growing medical literature supporting the use of CTA as a reliable ancillary test in BD testing.


Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.
Leucine-rich glioma inactivated 1 (LGI1) is a glycoprotein secreted by neurons, the deletion of which leads to autosomal dominant lateral temporal lobe epilepsy. We previously showed that LGI1 deficiency in a mouse model (i.e., knock-out for LGI1 or KO-Lgi1) decreased Kv1.1 channel density at the axon initial segment (AIS) and at presynaptic terminals, thus enhancing both intrinsic excitability and glutamate release. However, it is not known whether normal excitability can be restored in epileptic neurons. Here, we show that the selective expression of LGI1 in KO-Lgi1 neurons from mice of both sexes, using single-cell electroporation, reduces intrinsic excitability and restores both the Kv1.1-mediated D-type current and Kv1.1 channels at the AIS. In addition, we show that the homeostatic-like shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons electroporated with the Lgi1 gene. Furthermore, we reveal a spatial gradient of intrinsic excitability that is centered on the electroporated neuron. We conclude that expression of LGI1 restores normal excitability through functional Kv1 channels at the AIS.SIGNIFICANCE STATEMENT The lack of leucine-rich glioma inactivated 1 (LGI1) protein induces severe epileptic seizures that leads to death. Enhanced intrinsic and synaptic excitation in KO-Lgi1 mice is because of the decrease in Kv1.1 channels in CA3 neurons. However, the conditions to restore normal excitability profile in epileptic neurons remain to be defined. We show here that the expression of LGI1 in KO-Lgi1 neurons in single neurons reduces intrinsic excitability, and restores both the Kv1.1-mediated D-type current and Kv1.1 channels at the axon initial segment (AIS). Furthermore, the homeostatic shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons in which the Lgi1 gene has been rescued. We conclude that LGI1 constitutes a critical factor to restore normal excitability in epileptic neurons.


No exit? Intellectual integrity under the regime of 'evidence' and 'best-practices'.
No exit? Have we arrived at an impasse in the health sciences? Has the regime of 'evidence', coupled with corporate models of accountability and 'best-practices', led to an inexorable decline in innovation, scholarship, and actual health care? Would it be fair to speak of a 'methodological fundamentalism' from which there is no escape? In this article, we make an argument about intellectual integrity and good faith. We take this risk knowing full well that we do so in a hostile political climate in the health sciences, positioning ourselves against those who quietly but assiduously control the very terms by which the public faithfully understands 'integrity' and 'truth'. In doing so, we offer an honest critique of these definitions and of the systemic power that is reproduced and guarded by the gatekeepers of 'Good Science'.


Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy: A Systematic Review and Meta-analysis.
Implantable cardioverter-defibrillators (ICDs) have a role in preventing cardiac arrest in patients at risk for life-threatening ventricular arrhythmias. To compare ICD therapy with conventional care for the primary prevention of death of various causes in adults with ischemic or nonischemic cardiomyopathy. MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, and EMBASE databases, as well as several Web sites, from 1 April 1976 through 31 March 2017. Randomized controlled trials, published in any language, comparing ICD therapy with conventional care and reporting mortality outcomes (all-cause, sudden, any cardiac, or noncardiac) in the primary prevention setting. 2 independent investigators extracted study data and assessed risk of bias. Included were 11 trials involving 8716 patients: 4 (1781 patients) addressed nonischemic cardiomyopathy, 6 (4414 patients) ischemic cardiomyopathy, and 1 (2521 patients) both types of cardiomyopathy. Mean follow-up was 3.2 years. An overall reduction in all-cause mortality, from 28.26% with conventional care to 21.37% with ICD therapy (hazard ratio [HR], 0.81 [95% CI, 0.70 to 0.94]; P = 0.043), was found. The magnitude of reduction was similar in the cohorts with nonischemic (HR, 0.81 [CI, 0.72 to 0.91]) and ischemic (HR, 0.82 [CI, 0.63 to 1.06]) disease, although the latter estimate did not reach statistical significance. The rate of sudden death fell from 12.15% with conventional care to 4.39% with ICD therapy (HR, 0.41 [CI, 0.30 to 0.56]), with a similar magnitude of reduction in patients with ischemic (HR, 0.39 [CI, 0.23 to 0.68]) and those with nonischemic disease (HR, 0.44 [CI, 0.17 to 1.12]). Noncardiac and any cardiac deaths did not differ significantly by treatment. Heterogeneous timing of ICD placement; heterogeneous pharmacologic and resynchronization co-interventions; trials conducted in different eras; adverse events and complications not reviewed. Overall, primary prevention with ICD therapy versus conventional care reduced the incidence of sudden and all-cause death. None.


What stresses men? Predictors of perceived stress in a population-based multi-ethnic cross sectional cohort.
Perceived stress (PS) is a risk factor for a variety of diseases. However, relatively little is known about age- or ethnicity-specific differences in the effect of potential predictors of PS in men. We used a population-based survey of 6,773 White, 1,681 Black, and 617 Hispanic men in Southeastern Pennsylvania to evaluate the relationship of self-reported PS and financial security, health status, social factors, and health behaviors. Interactions across levels of age and ethnicity were tested using logistic regression models adjusted for overall health status, education, and household poverty. High PS decreased significantly with age (p < 0.0001) and varied by ethnicity (p = 0.0001). Exposure to health-related and economic factors were more consistently associated with elevated PS in all ethnicities and ages, while social factors and health behaviors were less strongly or not at all associated with PS in most groups. Significant differences in the relationship of high PS by age and ethnicity were observed among men who are medically uninsured (p = 0.0002), reported missing a meal due to cost (p < 0.0001), or had spent a night in the hospital (p = 0.020). In contrast, not filling a prescription due to cost and diagnosed with a mental health condition were associated with high PS but did not differ by age and ethnicity subgroup. These data suggest that some, but not all, factors associated with high PS differ by age and/or ethnicity. Research, clinical, or public health initiatives that involve social stressors should consider differences by age and ethnicity.


Catch and release patterns for target and bycatch species in the Northeast Atlantic deep-water shrimp fishery: Effect of using a sieve panel and a Nordmøre grid.
The Nordmøre grid and the sieve panel are two of the main devices used to reduce fish bycatch in trawl fisheries targeting shrimp species. However, even when using such devices, some small-sized fish enter the codend of the trawl together with the targeted shrimp. Therefore, bycatch reduction remains a problem in some shrimp fisheries. One such fishery is the Northeast Atlantic deep-water shrimp (Pandalus borealis) fishery where it is mandatory to use a Nordmøre grid. In this study, the bycatch reduction efficiencies and patterns for several fish species using the standard Nordmøre grid and an experimental sieve panel were investigated and compared. The effect of combining these devices was also explored. The bycatch reduction patterns differed significantly between the two devices and a more efficient bycatch reduction was obtained by combining them. However, while the loss of commercial-sized shrimp was only between 0 and 2% for the Nordmøre grid, it was between 37 and 56% for the tested sieve panel, making this completely unacceptable for commercial fishing. Therefore, before a sieve panel can be considered as an option for the fishery, other sieve panel designs that have a significantly lower loss of shrimp catches need to be identified.


Effects of antenatal glucocorticoid therapy on hippocampal histology of preterm infants.
To investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn. Included were consecutive neonates with a gestational age between 24 and 32 weeks, who were born between 1991 to 2009, who had died within 4 days after delivery and underwent brain autopsy. Excluded were neonates with congenital malformations and neonates treated postnatally with glucocorticoids. The brains were routinely fixed, samples of the hippocampus were stained with haematoxylin and eosin and sections were examined for presence or absence of large and small neurons in regions of the hippocampus. Additional staining with GFAP, neurofilament and vimentin was performed to evaluate gliosis and myelination. The proliferation marker Ki67 was used to evaluate neuronal proliferation. Staining with acid fuchsin-thionin was performed to evaluate ischemic damage. The hippocampi of ten neonates who had been treated with antenatal glucocorticoids showed a lower density of large neurons (p = 0.01) and neurons irrespective of size (p = 0.02) as compared to eleven neonates who had not been treated with glucocorticoids. No difference was found in density of small neurons, in myelination, gliosis, proliferation or ischemic damage. We found a significantly lower density of neurons in the hippocampus of neonates after antenatal glucocorticoid treatment. Although the pathophysiological and clinical interpretations of these findings are not clear, they are consistent with those from experiments in mice and rhesus monkeys.


Dose-response relationships of psilocybin-induced subjective experiences in humans.
Psilocybin is the psychoactive component in Psilocybe mushrooms ('magic mushrooms'). Whether and how the quality of the psilocybin-induced experience might mediate beneficial health outcomes is currently under investigation, for example, in therapeutic applications. However, to date, no meta-analysis has investigated the dose-dependency of subjective experiences across available studies. Establishing dose-response relationships of the subjective experiences induced by psilocybin in healthy study participants and a comparison of patient groups. We applied a linear meta-regression approach, based on the robust variance estimation framework, to obtain linear dose-response relationship estimates on questionnaire ratings after oral psilocybin administration. Data were obtained from the Altered States Database, which contains data extracted from MEDLINE-listed journal articles that used standardized and validated questionnaires: the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire and the Hallucinogen Rating Scale. Psilocybin dose positively correlated with ratings on most factors and scales, mainly those referring to perceptual alterations and positively experienced ego dissolution. Measures referring to challenging experiences exhibited small effects and were barely modulated by dose. Psilocybin intensified almost all characteristics of altered states of consciousness assessed with the given questionnaires. Because subjective experiences are not only determined by dose, but also by individual and environmental factors, the results may only apply to controlled laboratory experiments and not to recreational use. This paper may serve as a general literature citation for the use of psilocybin in experimental and clinical research, to compare expected and observed subjective experiences.


The roles of catenins in the cadherin-mediated cell adhesion: functional analysis of E-cadherin-alpha catenin fusion molecules.
The carboxyl terminus-truncated cadherin (nonfunctional cadherin) has no cell adhesion activity probably because of its failure to associate with cytoplasmic proteins called alpha and beta catenin. To rescue this nonfunctional cadherin as adhesion molecules, we constructed three cDNAs for fusion proteins between nonfunctional E-cadherin and alpha catenin, nE alpha, nE alpha N, and nE alpha C, where the intact, amino-terminal and carboxy-terminal half of alpha catenin, respectively, were directly linked to the nonfunctional E-cadherin, and introduced them into mouse L cells. The subcellular distribution and cell adhesion activity of nE alpha and nE alpha C molecules was similar to those of intact E-cadherin transfectants: they bound to cytoskeletons, were concentrated at cell-cell adhesion sites and showed strong cell adhesion activity. nE alpha N molecules, which also bound to cytoskeletons, showed very poor cell adhesion activity. Taken together, we conclude that in the formation of the cadherin-catenin complex, the mechanical association of alpha catenin, especially its carboxy-terminal half, with E-cadherin is a key step for the cadherin-mediated cell adhesion. Close comparison revealed that the behavior of nE alpha molecules during cytokinesis was quite different from that of intact E-cadherin, and that the intercellular motility, i.e., the cell movement in a confluent sheet, was significantly suppressed in nE alpha transfectants although it was facilitated in E-cadherin transfectants. Considering that nE alpha was not associated with endogenous beta catenin in transfectants, the difference in the nature of cell adhesion between nE alpha and intact E-cadherin transfectants may be explained by the function of beta catenin. The possible functions of beta catenin are discussed with a special reference to its role as a negative regulator for the cadherin-mediated cell adhesion system.


Therapeutic conserved elements (CE) DNA vaccine induces strong T-cell responses against highly conserved viral sequences during simian-human immunodeficiency virus infection.
HIV-specific T-cell responses play a key role in controlling HIV infection, and therapeutic vaccines for HIV that aim to improve viral control will likely need to improve on the T-cell responses induced by infection. However, in the setting of chronic infection, an effective therapeutic vaccine must overcome the enormous viral genetic diversity and the presence of pre-existing T-cell responses that are biased toward immunodominant T-cell epitopes that can readily mutate to evade host immunity and thus potentially provide inferior protection. To address these issues, we investigated a novel, epidermally administered DNA vaccine expressing SIV capsid (p27Gag) homologues of highly conserved elements (CE) of the HIV proteome in macaques experiencing chronic but controlled SHIV infection. We assessed the ability to boost or induce de novo T-cell responses against the conserved but immunologically subdominant CE epitopes. Two groups of animals were immunized with either the CE DNA vaccine or a full-length SIV p57gag DNA vaccine. Prior to vaccination, CE responses were similar in both groups. The full-length p57gag DNA vaccine, which contains the CE, increased overall Gag-specific responses but did not increase CE responses in any animals (0/4). In contrast, the CE DNA vaccine increased CE responses in all (4/4) vaccinated macaques. In SIV infected but unvaccinated macaques, those that developed stronger CE-specific responses during acute infection exhibited lower viral loads. We conclude that CE DNA vaccination can re-direct the immunodominance hierarchy towards CE in the setting of attenuated chronic infection and that induction of these responses by therapeutic vaccination may improve immune control of HIV.


Ancient wolf genome reveals an early divergence of domestic dog ancestors and admixture into high-latitude breeds.
The origin of domestic dogs is poorly understood [1-15], with suggested evidence of dog-like features in fossils that predate the Last Glacial Maximum [6, 9, 10, 14, 16] conflicting with genetic estimates of a more recent divergence between dogs and worldwide wolf populations [13, 15, 17-19]. Here, we present a draft genome sequence from a 35,000-year-old wolf from the Taimyr Peninsula in northern Siberia. We find that this individual belonged to a population that diverged from the common ancestor of present-day wolves and dogs very close in time to the appearance of the domestic dog lineage. We use the directly dated ancient wolf genome to recalibrate the molecular timescale of wolves and dogs and find that the mutation rate is substantially slower than assumed by most previous studies, suggesting that the ancestors of dogs were separated from present-day wolves before the Last Glacial Maximum. We also find evidence of introgression from the archaic Taimyr wolf lineage into present-day dog breeds from northeast Siberia and Greenland, contributing between 1.4% and 27.3% of their ancestry. This demonstrates that the ancestry of present-day dogs is derived from multiple regional wolf populations.


Psychological stress and self-reported functional gastrointestinal disorders.
Functional gastrointestinal disorders (FGID) are common, but despite their relevance in public health care, the etiology of FGID remains essentially unknown. Stress has been suggested as a pathophysiological factor in FGID. The aims of the present study were (a) to determine the prevalence of FGID in a sample of apparently healthy students, and (b) to determine the association of stress and FGID. The prevalence rates of 21 different FGID were assessed using an internet-based design. Subjective experience of chronic stress, individual coping strategies, and dispositional stress reactivity were measured. A total of 668 subjects provided complete data sets (66% women). About 64.2% reported at least one FGID. Symptoms of FGID were significantly predicted by increased levels of perceived chronic stress, dispositional stress reactivity, and use of maladaptive coping strategies. FGID are common in apparently healthy young individuals. The importance of stress-related factors in individuals suffering from FGID indicates that stress-reducing interventions may be beneficial in these patients.


TAP1 down-regulation in primary melanoma lesions: an independent marker of poor prognosis.
Melanoma tumor thickness is a major prognostic factor. Thin lesions, however, may metastasize, and sometimes thick tumors may not. To investigate the role of HLA class I-mediated antigen presentation, we correlated the expression of components of the antigen-processing machinery in primary melanoma lesions with their thickness and with the development of metastases. Seventeen formalin-fixed, paraffin-embedded primary melanomas thinner than 0.76 mm and 21 thicker than 1.50 mm were stained with anti-LMP2, -LMP7, -TAP1, -TAP2, -HLA class I and -beta2-microglobulin monoclonal antibodies. Twenty patients remained tumor-free in the follow-up period (10.5 +/- 1.8 years). Eighteen patients relapsed within a median period of 15.0 months following tumor excision. Expression of all markers in the tested lesions was down-regulated, the frequency ranging from about 40% for LMP and TAP subunits to about 70% for HLA class I antigens. Expression of all markers was not correlated with tumor thickness. Only TAP1 and TAP2 down-regulation was significantly (p = 0.026 and 0.042, respectively) correlated with the development of metastases. This correlation was independent of tumor thickness for TAP1. We suggest that TAP1 and probably TAP2 expression in primary lesions represents an independent prognostic marker in melanoma. Abnormalities in antigen presentation may account for the lack of absolute correlation between tumor thickness and prognosis.


Quantitative description of backbone conformational sampling of unfolded proteins at amino acid resolution from NMR residual dipolar couplings.
An atomic resolution characterization of the structural properties of unfolded proteins that explicitly invokes the highly dynamic nature of the unfolded state will be extremely important for the development of a quantitative understanding of the thermodynamic basis of protein folding and stability. Here we develop a novel approach using residual dipolar couplings (RDCs) from unfolded proteins to determine conformational behavior on an amino acid specific basis. Conformational sampling is described in terms of ensembles of structures selected from a large pool of conformers. We test this approach, using extensive simulation, to determine how well the fitting of RDCs to reduced conformational ensembles containing few copies of the molecule can correctly reproduce the backbone conformational behavior of the protein. Having established approaches that allow accurate mapping of backbone dihedral angle conformational space from RDCs, we apply these methods to obtain an amino acid specific description of ubiquitin denatured in 8 M urea at pH 2.5. Cross-validation of data not employed in the fit verifies that an ensemble size of 200 structures is appropriate to characterize the highly fluctuating backbone. This approach allows us to identify local conformational sampling properties of urea-unfolded ubiquitin, which shows that the backbone sampling of certain types of charged or polar amino acids, in particular threonine, glutamic acid, and arginine, is affected more strongly by urea binding than amino acids with hydrophobic side chains. In general, the approach presented here establishes robust procedures for the study of all denatured and intrinsically disordered states.


Enhancement of development of larval Anopheles arabiensis by proximity to flowering maize (Zea mays) in turbid water and when crowded.
To determine whether proximity to flowering maize enhances the development of larval anopheline mosquitoes breeding in turbid water and when crowded, we evaluated the development of larval Anopheles arabiensis under various conditions of turbidity, larval density, and proximity to pollen-shedding maize in simulated breeding puddles in a malaria-endemic site. In naturally formed puddles, water turbidity, as well as larval density, increased as the rainy season progressed. In sites remote from flowering maize, more pupae developed and the resulting adults were larger in relatively clear water than in turbid water, and larval crowding inhibited development. In close proximity to flowering maize, however, larval development was little affected by water turbidity and larval crowding. Larvae of this member of the African An. gambiae complex of mosquitoes develop readily in turbid water and when crowded, provided that their breeding sites are located where maize pollen is abundant.


Advantages of superficial femoral vein grafts for carotid artery reconstruction following carotid artery resection in the treatment of head and neck cancer.
Reconstruction of the carotid artery using the superficial femoral vein (SFV) is very effective due to the ease in harvesting the vessel and its optimal size and length for carotid artery replacement. To evaluate the effectiveness of carotid artery reconstruction using the SFV. Ten patients with malignant tumors involving the carotid artery underwent carotid artery resection followed by reconstruction with the SFV. The SFV between the deep femoral vein and branches to the great saphenous vein and deep femoral vein at the popliteal region was used as a reconstructive vessel. The mean length and diameter of the grafted SFVs were 13.9 cm and 11.2 mm, respectively. The mean time for acquisition of SFV was 18 min. Ultrasonography measurements indicated that the mean lumen diameter of the common carotid artery was 8.37 mm. None of the patients experienced any permanent neurologic complications. The 2-year and 5-year overall survival rates were 60% and 40%, respectively. En bloc resection of the cancer and involved carotid artery followed by reconstruction with the SFV provides effective locoregional control. Our results indicated no postoperative vascular graft thrombosis and no donor site complications.


Hemotoxicity induced by chronic chlorpyrifos exposure in wistar rats: mitigating effect of vitamin C.
The study evaluated the ameliorative effect of vitamin C on chronic chlorpyrifos-induced hematological alterations in Wistar rats. Twenty adult male rats divided into 4 groups of 5 animals each were exposed to the following regimens: group I (S/oil) was administered soya oil (2 mL/kg b.w.), while group II (VC) was given vitamin C (100 mg/kg b.w.); group III was dosed with CPF (10.6 mg/kg b.w.); group IV was pretreated with vitamin C (100 mg/kg) and then exposed to CPF (10.6 mg/kg b.w.), 30 minutes later. The regimens were administered by oral gavage once daily for a period of 17 weeks. Blood samples collected at the end of the study revealed reduction in the levels of pack cell volume, hemoglobin, red blood cells, leukocytes (attributed to neutropenia, lymphopenia, and monocytopenia), and platelets in the CPF group, which were ameliorated in the vitamin C- pretreated group. The elevated values of malonaldehyde, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and neutrophil/lymphocyte ratio in the CPF group were restored in those pretreated with vitamin C. The study has shown that chronic CPF-induced adversity on hematological parameters of Wistar rats was mitigated by pretreatment with vitamin C.


In vitro characterization of aminoglycoside adaptive resistance in Pseudomonas aeruginosa.
Aminoglycoside adaptive resistance was characterized in one reference strain and four clinical isolates of Pseudomonas aeruginosa. Adaptive resistance was initiated with a 2-h gentamicin or tobramycin exposure at the MIC. Each P. aeruginosa strain demonstrated an adaptive-resistance period of between 8 and 12 h when tested with both aminoglycosides. Aminoglycoside adaptive resistance was shown to correlate with a decrease in [3H] gentamicin accumulation and a small (5%) but significant (P < 0.05) reduction in proton motive force. The mean generation time of P. aeruginosa during peak levels of adaptive resistance (i.e., maximum reductions in aminoglycoside killing) was not significantly different from that of control organisms (P < 0.05). No changes in outer membrane protein or lipopolysaccharide sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles were noted when control, adaptively resistant, and postadaptively resistant cells were compared. Cytoplasmic membrane profiles of adaptively resistant cells, however, demonstrated several band changes when compared with control and postadaptively resistant cells. We conclude that the decrease in aminoglycoside accumulation associated with adaptive resistance in P. aeruginosa may be, in part, a function of reductions in proton motive force and/or cytoplasmic membrane protein changes. However, the importance of these changes requires further investigation.


Regionally selective alterations in expression of the alpha(1D) subunit (Ca(v)1.3) of L-type calcium channels in the hippocampus of aged rats.
Calcium currents through the L-type voltage-sensitive calcium channel (L-VSCC) are increased in neurons of area CA1 of the hippocampus in aged rats and rabbits. Furthermore, increases in mRNA for the pore forming subunit alpha(1D) (Ca(v)1.3) have been observed in the hippocampus of aged rats. We have studied the protein expression of the two pore forming subunits, alpha(1C) (Ca(v)1.2) and alpha(1D), of L-VSCCs in the hippocampus of young and aged rats. Here we report selective age-related changes in expression of alpha(1D) in the hippocampus. Specifically, we find that alpha(1D) protein is increased in area CA1 of aged rats while it is decreased in area CA3. Our data suggest that the altered calcium currents seen in aged animals may be due, at least in part, to alterations in the expression of the alpha(1D) subunit of the L-type calcium channel. These findings contribute to our understanding of the mechanisms responsible for changes in calcium homeostasis during aging.


Surface hydration drives rapid water imbibition into strongly hydrophilic nanopores.
The imbibition of liquids into nanopores plays a critical role in numerous applications, and most prior studies focused on imbibition due to capillary flows. Here we report molecular simulations of the imbibition of water into single mica nanopores filled with pressurized gas. We show that, while capillary flow is suppressed by the high gas pressure, water is imbibed into the nanopore through surface hydration in the form of monolayer liquid films. As the imbibition front moves, the water film behind it gradually densifies. Interestingly, the propagation of the imbibition front follows a simple diffusive scaling law. The effective diffusion coefficient of the imbibition front, however, is more than ten times larger than the diffusion coefficient of the water molecules in the water film adsorbed on the pore walls. We clarify the mechanism for the rapid water imbibition observed here.


Deep Learning for Diabetes: A Systematic Review.
Diabetes is a chronic metabolic disorder that affects an estimated 463 million people worldwide. Aiming to improve the treatment of people with diabetes, digital health has been widely adopted in recent years and generated a huge amount of data that could be used for further management of this chronic disease. Taking advantage of this, approaches that use artificial intelligence and specifically deep learning, an emerging type of machine learning, have been widely adopted with promising results. In this paper, we present a comprehensive review of the applications of deep learning within the field of diabetes. We conducted a systematic literature search and identified three main areas that use this approach: diagnosis of diabetes, glucose management, and diagnosis of diabetes-related complications. The search resulted in the selection of 40 original research articles, of which we have summarized the key information about the employed learning models, development process, main outcomes, and baseline methods for performance evaluation. Among the analyzed literature, it is to be noted that various deep learning techniques and frameworks have achieved state-of-the-art performance in many diabetes-related tasks by outperforming conventional machine learning approaches. Meanwhile, we identify some limitations in the current literature, such as a lack of data availability and model interpretability. The rapid developments in deep learning and the increase in available data offer the possibility to meet these challenges in the near future and allow the widespread deployment of this technology in clinical settings.


Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation.
SET domain containing 2 (Setd2), encoding a histone methyltransferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we describe an essential role of Setd2 in maintaining the adult hematopoietic stem cells. Loss of Setd2 results in leukopenia, anemia, and increased platelets accompanied by hypocellularity, erythroid dysplasia, and mild fibrosis in bone marrow. Setd2 knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. Setd2 knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation because of the loss of quiescence, increased apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit from quiescence and commit to differentiation, which lead to hematopoietic stem cell exhaustion. Mechanistically, we attribute an important Setd2 function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes, including Myc Our results reveal a critical role of Setd2 in regulating quiescence and differentiation of hematopoietic stem cells through restricting the NSDs/SEC mediated RNA polymerase II elongation.


Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01.
Information is presented from 555 patients with Dukes B and C rectal cancers treated by curative resection who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-01 between November 1977 and October 1986. Their average time on study was 64.1 months. The patients were randomized to receive no further treatment (184 patients), postoperative adjuvant chemotherapy with 5-fluorouracil, semustine, and vincristine (MOF) (187 patients), or postoperative radiation therapy (184 patients). The chemotherapy group, when compared with the group treated by surgery alone, demonstrated an overall improvement in disease-free survival (P = .006) and in survival (P = .05). Employing the proportional hazards model, a global test was used to determine the presence of treatment interactions. Investigation of stratification variables employed in this study indicated that sex, and to a lesser extent age and Dukes stage, made individual contributions to the disease-free survival and the survival benefit from chemotherapy. When evaluated according to sex, the benefit for chemotherapy at 5 years, both in disease-free survival (29% vs. 47%; P less than .001; relative odds, 2.00) and in survival (37% vs. 60%; P = .001; relative odds, 1.93), was restricted to males. When males were tested for age trend with the use of a logistic regression analysis, chemotherapy was found to be more advantageous in younger patients. When the group receiving post-operative radiation (4,600-4,700 rad in 26-27 fractions; 5,100-5,300 rad maximum at the perineum) was compared to the group treated only by surgery, there was an overall reduction in local-regional recurrence from 25% to 16% (P = .06). No significant benefit in overall disease-free survival (P = .4) or survival (P = .7) from the use of radiation has been demonstrated. The global test for interaction to identify heterogeneity of response to radiation within subsets of patients was not significant. In conclusion, this investigation has demonstrated a benefit from adjuvant chemotherapy (MOF) for the management of rectal cancer. The observed advantage was restricted to males. Postoperative radiation therapy reduced the incidence of local-regional recurrence, but it failed to affect overall disease-free survival and survival.


Recurrent nuclear DNA introgression accompanies chloroplast DNA exchange between two eucalypt species.
Numerous studies within plant genera have found geographically structured sharing of chloroplast (cp) DNA among sympatric species, consistent with introgressive hybridization. Current research is aimed at understanding the extent, direction and significance of nuclear (nr) DNA exchange that accompanies putative cpDNA exchange. Eucalyptus is a complex tree genus for which cpDNA sharing has been established between multiple species. Prior phylogeographic analysis has indicated cpDNA introgression into the widespread forest species Eucalyptus globulus from its rare congener E. cordata. In this study, we use AFLP markers to characterize corresponding nrDNA introgression, on both a broad and fine spatial scale. Using 388 samples we examine (i) the fine-scale spatial structure of cp and nrDNA introgression from E. cordata into E. globulus at a site in natural forest and (ii) broad-scale patterns of AFLP marker introgression at six additional mixed populations. We show that while E. globulus and E. cordata retain strongly differentiated nuclear gene pools overall, leakage of nrDNA occurs at mixed populations, with some AFLP markers being transferred to E. globulus recurrently at different sites. On the fine scale, different AFLP fragments show varying distances of introgression into E. globulus, while introgression of cpDNA is extensive. The frequency of E. cordata markers in E. globulus is correlated with spatial proximity to E. cordata, but departs from expectations based on AFLP marker frequency in E. cordata, indicating that selection may be governing the persistence of introgressed fragments in E. globulus.


Prefrontal cortical dysfunction in depression determined by Wisconsin Card Sorting Test performance.
Neuroimaging studies have demonstrated reduced prefrontal cortical blood flow and metabolism in depression, but the neurobehavioral significance of these observations is not yet established. The Wisconsin Card Sorting Test, a widely used neuropsychological index of prefrontal cortical function, was administered to 79 patients with major depression who had been unmedicated for at least 28 days, to 47 patients with schizophrenia who had never received antipsychotic medication, and to 61 healthy comparison subjects. Depressed patients demonstrated significant deficits on multiple Wisconsin Card Sorting Test measures compared with healthy individuals. These deficits were correlated with the severity of depression and were less severe than those demonstrated by patients with schizophrenia. These results provide neuropsychological evidence for significant prefrontal cortical dysfunction in depression.


Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma.
Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.


Quality of life in eating disorders: a meta-analysis.
Eating disorders (EDs) comprise a variety of symptoms and have a profound impact on everyday life. They are associated with high morbidity and mortality. The objective of this study was to analyse published data on health-related quality of life (HRQoL) in EDs so as to compare the results to general population norm data and to investigate potential differences between ED diagnostic groups. A systematic review of the current literature was conducted using a keyword-based search in PubMed and PsychInfo. The search covered anorexia nervosa (AN), bulimia nervosa (BN), eating disorders not otherwise specified (EDNOS) and binge eating disorder (BED) and used the Medical Outcomes Study Short Form-36 Health Survey (SF-36) as a measure of HRQoL. Of the 102 citations identified, 85 abstracts were reviewed and seven studies were included in the meta-analysis. AN patients were included in five studies (n=227), BN in four studies (n=216), EDNOS in two studies (n=166) and BED in four studies (n=148). We tested for between-study variation and significant differences between the diagnostic groups. The results confirmed a significantly lower level of HRQoL in all EDs compared to a population mean. It was not possible to establish any differences between the diagnostic groups.


Determinants of quality of shared sanitation facilities in informal settlements: case study of Kisumu, Kenya.
Shared facilities are not recognised as improved sanitation due to challenges of maintenance as they easily can be avenues for the spread of diseases. Thus there is need to evaluate the quality of shared facilities, especially in informal settlements, where they are commonly used. A shared facility can be equated to a common good whose management depends on the users. If users do not work collectively towards keeping the facility clean, it is likely that the quality may depreciate due to lack of maintenance. This study examined the quality of shared sanitation facilities and used the common pool resource (CPR) management principles to examine the determinants of shared sanitation quality in the informal settlements of Kisumu, Kenya. Using a multiple case study design, the study employed both quantitative and qualitative methods. In both phases, users of shared sanitation facilities were interviewed, while shared sanitation facilities were inspected. Shared sanitation quality was a score which was the dependent variable in a regression analysis. Interviews during the qualitative stage were aimed at understanding management practices of shared sanitation users. Qualitative data was analysed thematically by following the CPR principles. Shared facilities, most of which were dirty, were shared by an average of eight households, and their quality decreased with an increase in the number of households sharing. The effect of numbers on quality is explained by behaviour reflected in the CPR principles, as it was easier to define boundaries of shared facilities when there were fewer users who cooperated towards improving their shared sanitation facility. Other factors, such as defined management systems, cooperation, collective decision making, and social norms, also played a role in influencing the behaviour of users towards keeping shared facilities clean and functional. Apart from hardware factors, quality of shared sanitation is largely due to group behaviour of users. The CPR principles form a crucial lens through which the dynamics of shared sanitation facilities in informal settlements can be understood. Development and policy efforts should incorporate group behaviour as they determine the quality of shared sanitation facilities.


Reversible induction of TDP-43 granules in cortical neurons after traumatic injury.
Traumatic brain injury (TBI) has been proposed as a risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). To determine whether TBI might trigger or exacerbate ALS-relevant pathology, we delivered a mild stab-wound injury to the motor cortex of three different ALS mouse models expressing mutations in SOD1, TDP-43 or FUS and scrutinized the effects on the formation of phospho-TDP-43 (pTDP-43) cytoplasmic granules. Stab-injury induced the formation of cytoplasmic TDP-43 granules in wt animals, peaking at 3dpi; a much larger response was seen in mutant TDP-43 mice, whose response peaked at 7dpi. The pTDP-43 granules did not colocalize with the stress markers TIAR-1 and FUS but colocalized with FMRP (35%) and with p62 (65%), suggesting their involvement in transport granules and their clearance by autophagy. A similar, albeit smaller effect, was seen in mutant FUS mice. In the SOD1G93A mouse model, neither increase in pTDP-43 granules nor in SOD1 aggregates were detected. In all cases, pTDP-43 granules were cleared and the number of pTDP-43-positive neurons returned to baseline by 40dpi. Neither injury-related neuronal loss nor motor performance or survival was significantly different in transgenic mice receiving injury vs sham mice. Thus, trauma can trigger ALS-related TDP-43 pathology, the extent of which is modulated by ALS-related mutations. However, the pathological findings prove reversible and do not affect disease progression and neuronal vulnerability.


The silent burden of anaemia in Tanzanian children: a community-based study.
To document the prevalence, age-distribution, and risk factors for anaemia in Tanzanian children less than 5 years old, thereby assisting in the development of effective strategies for controlling anaemia. Cluster sampling was used to identify 2417 households at random from four contiguous districts in south-eastern United Republic of Tanzania in mid-1999. Data on various social and medical parameters were collected and analysed. Blood haemoglobin concentrations (Hb) were available for 1979 of the 2131 (93%) children identified and ranged from 1.7 to 18.6 g/dl. Overall, 87% (1722) of children had an Hb <11 g/dl, 39% (775) had an Hb <8 g/dl and 3% (65) had an Hb <5 g/dl. The highest prevalence of anaemia of all three levels was in children aged 6-11 months, of whom 10% (22/226) had an Hb <5 g/dl. However, the prevalence of anaemia was already high in children aged 1-5 months (85% had an Hb <11 g/dl, 42% had an Hb <8 g/dl, and 6% had an Hb <5 g/dl). Anaemia was usually asymptomatic and when symptoms arose they were nonspecific and rarely identified as a serious illness by the care provider. A recent history of treatment with antimalarials and iron was rare. Compliance with vaccinations delivered through the Expanded Programme of Immunization (EPI) was 82% and was not associated with risk of anaemia. Anaemia is extremely common in south-eastern United Republic of Tanzania, even in very young infants. Further implementation of the Integrated Management of Childhood Illness algorithm should improve the case management of anaemia. However, the asymptomatic nature of most episodes of anaemia highlights the need for preventive strategies. The EPI has good coverage of the target population and it may be an appropriate channel for delivering tools for controlling anaemia and malaria.


Comparative genomics of Spiraeoideae-infecting Erwinia amylovora strains provides novel insight to genetic diversity and identifies the genetic basis of a low-virulence strain.
Erwinia amylovora is the causal agent of fire blight, one of the most devastating diseases of apple and pear. Erwinia amylovora is thought to have originated in North America and has now spread to at least 50 countries worldwide. An understanding of the diversity of the pathogen population and the transmission to different geographical regions is important for the future mitigation of this disease. In this research, we performed an expanded comparative genomic study of the Spiraeoideae-infecting (SI) E. amylovora population in North America and Europe. We discovered that, although still highly homogeneous, the genetic diversity of 30 E. amylovora genomes examined was about 30 times higher than previously determined. These isolates belong to four distinct clades, three of which display geographical clustering and one of which contains strains from various geographical locations ('Widely Prevalent' clade). Furthermore, we revealed that strains from the Widely Prevalent clade displayed a higher level of recombination with strains from a clade strictly from the eastern USA, which suggests that the Widely Prevalent clade probably originated from the eastern USA before it spread to other locations. Finally, we detected variations in virulence in the SI E. amylovora strains on immature pear, and identified the genetic basis of one of the low-virulence strains as being caused by a single nucleotide polymorphism in hfq, a gene encoding an important virulence regulator. Our results provide insights into the population structure, distribution and evolution of SI E. amylovora in North America and Europe.


Utility of nocturnal home oximetry for case finding in patients with suspected sleep apnea hypopnea syndrome.
To evaluate prospectively the validity of home oximetry for case finding in patients clinically suspected of having the sleep apnea hypopnea syndrome (SAHS). Blinded comparison of home oximetry and polysomnographic nocturnal recordings. Sleep clinic of a tertiary referral center. A total of 240 outpatients referred because of reported sleep disturbances or daytime hypersomnia compatible with the diagnosis of SAHS. All participants had nocturnal home oximetry followed by a conventional polysomnographic study. The two recordings were interpreted blindly. Home oximetry test results were classified as abnormal (suspicion of sleep-related breathing abnormalities) in the presence of repetitive, short-duration arterial oxyhemoglobin saturation. (SaO2) fluctuations without any absolute or relative decrease in the SaO2 threshold. The diagnosis of SAHS was confirmed when the apnea-plus-hypopnea index was greater than 10. Based on the results of the polysomnographic sleep study, 110 patients had SAHS (apnea-plus-hypopnea index, 38.1 +/- 2.5/h; mean +/- SE). Home oximetry test results were interpreted as abnormal in 176 patients (this included 108 patients with SAHS and 68 without SAHS) and were read as normal in 62 patients without SAHS and in 2 with SAHS. Home oximetry testing had a sensitivity of 108/110 or 98.2% (95% Cl, 93.6% to 99.8%); a specificity of 62/130 or 47.7% (Cl, 38.8% to 56.6%); a positive predictive value of 108/176 or 61.4%; and a negative predictive value of 62/64 or 96.9%. A negative home oximetry test result is helpful in ruling out the diagnosis of SAHS in patients clinically suspected of having this syndrome, because a negative test result reduced the probability from 54.1% to 3.1% in our patients. However, a positive oximetry test increased the probability from 46% to 61.4% in our group of patients.


Current status of glycemic control of patients with diabetes in Korea: the fifth Korea national health and nutrition examination survey.
The Korea National Health and Nutrition Examination Survey (KNHANES) III (2005) reported that 22.9% of individuals with diabetes have a glycated hemoglobin (HbA1c) <6.5% and that 43.5% have an HbA1c <7%. We investigated the levels of glycemic control and the factors associated with glycemic control using data from the KNHANES V (2010 to 2012). Subjects with diabetes diagnosed by a physician or those taking antidiabetic medications were classified as individuals with known diabetes. Of 1,498 subjects aged ≥30 years with diabetes, we excluded 157 individuals who were missing HbA1c data. A total of 1,341 subjects were included in the final analysis. The prevalence of known diabetes was 7.7% (n=1,498, estimated to be 2.32 million people). The proportions of well-controlled diabetes meeting a HbA1c goal of <6.5% and <7% were 27% and 45.6%, respectively. HbA1c increased as the duration of diabetes increased. HbA1c in subjects with a duration of diabetes ≤5 years was lower than in subjects with a duration >5 years. HbA1c in the group taking only oral hypoglycemic agents (OHAs) was significantly lower than that in the group administered only insulin or OHA and insulin in combination. In logistic regression analysis, a longer duration of diabetes, insulin use and the absence of chronic renal failure were associated with HbA1c levels >6.5%. The level of adequate glycemic control was similar to but slightly improved compared with previous levels. The glycemic control of long-standing diabetes patients is more difficult even though they receive insulin treatment.


Mithramycin represses basal and cigarette smoke-induced expression of ABCG2 and inhibits stem cell signaling in lung and esophageal cancer cells.
Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell-related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies.


Polarization-insensitive arrayed-waveguide grating wavelength multiplexer on silicon.
A wavelength-division multiplexer with no polarization dependence is demonstrated. It is based on an arrayed-waveguide grating fabricated with silica-based optical waveguides on a silicon substrate. The polarization dependence that is due to the birefringence of the waveguide is eliminated by inserting a quartz lambda/2 plate in the middle of the arrayed waveguide. Moreover the grating is designed to operate in the 115th order for high wavelength resolution. The polarization insensitivity and the high resolution lead to the successful multiplexing of 13 wavelength channels with 1-nm spacing. A passband width of 0.3 nm and a cross-talk level of -30 dB are achieved.


The reliability of alcohol abusers' self-reports of drinking and life events that occurred in the distant past.
This study investigated the test-retest reliability of 69 alcohol abusers' current reports about their past (approximately 8 years prior to interview) drinking behavior and life events. Drinking behavior was assessed by the Lifetime Drinking History (LDH) questionnaire and life events were assessed using the Recent Life Changes Questionnaire (RLCQ). Reliability coefficients for LDH variables were generally moderate to high (r = .52 to .81). Using empirical criteria, the diagnostic power of the two LDH interviews to classify correctly subjects as either having had or not having had a drinking problem was quite high. The reliability coefficient for the RLCQ was r = .85 and 91.7% of the identified events were reported in both interviews. Similarly high test-retest reliabilities and individual event agreement rates were obtained for the six homogeneous subscales of the RLCQ. Subjects were also asked why they had given inconsistent answers to life events questions in the two interviews. Inconsistencies often resulted from errors in the temporal placement of events or from misunderstanding items, rather than from failure to recall an event; this suggests that some sources of error in recalling life events can be reduced. It is concluded that alcohol abusers' reports of drinking and life events occurring many years prior to the date of interview are generally reliable. This finding is consistent with previous studies showing high test-retest reliabilities for reports of recent drinking and related events.


Realization of high performance silicon nanowire based solar cells with large size.
We report the realization of high performance silicon nanowire (SiNW) based solar cells with a conversion efficiency of 17.11% and a large size of 125 × 125 mm(2). The key factor for success lies in an efficient approach of dielectric passivation to greatly enhance the electrical properties while keeping the advantage of excellent light trapping of the SiNW structure. The suppression of carrier recombination has been demonstrated through the combination of the SiO2/SiNx stack, which exhibits a good passivation effect on heavily doped SiNWs via reducing both the Shockley-Read-Hall recombination and near surface Auger recombination. We have examined in detail the effects of different passivations and SiNW lengths on the effective minority carrier lifetime, reflectance and carrier recombination characteristics, as well as cell performance. The proposed passivation techniques can be easily adapted to conventional industrial manufacturing processes, providing a potential prospect of SiNW based solar cells in mass production.


Biomechanical evaluation of a coracoclavicular and acromioclacicular ligament reconstruction technique utilizing a single continuous intramedullary free tendon graft.
Reconstruction of only the coracoclavicular (CC) ligaments may restore superior-inferior (S-I) but not anterior-posterior (A-P) stability of the acromioclavicular (AC) joint. Concomitant reconstruction of both the AC and CC ligaments may more reliably restore intact biomechanical characteristics of the AC joint. Ten matched pairs of shoulders were utilized. Five specimens underwent CC ligament reconstruction while an equal number underwent combined AC and CC ligament reconstruction utilizing an intramedullary tendon graft. Each of the reconstructions was compared with the intact contralateral control. Translational and load to failure characteristics were compared between groups. No difference was found in S-I translation between intact specimens and CC-only reconstructions (P = .20) nor between intact specimens and AC/CC reconstructions (P = .33) at 10 Newton (N) loads. Significant differences were noted in A-P translation between intact specimens and CC-only reconstructions (P < .001) but no difference in A-P translation between intact specimens and AC/CC reconstructions (P = .34). The A-P and S-I translational biomechanical characteristics of the AC joint were restored using the new technique described. Reconstruction of the CC ligaments only (versus AC/CC combined) led to significantly increased translational motion in the A-P plane as compared to intact control specimens.


Clinical outcomes and survival in pediatric patients initiating chronic dialysis: a report of the NAPRTCS registry.
The 2011 annual report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) registry comprises data on 6482 dialysis patients over the past 20 years of the registry. The study compared clinical parameters and patient survival in the first 10 years of the registry (1992-2001) with the last decade of the registry (2002-2011). There was a significant increase in hemodialysis as the initiating dialysis modality in the most recent cohort (42% vs. 36%, p < 0.001). Patients in the later cohort were less likely to have a hemoglobin <10 g/dl [odds ratio (OR) 0.68; confidence interval (CI) 0.58-0.81; p < 0.001] and height z-score <2 standard deviations (SD) below average (OR 0.68, CI 0.59-0.78, p < 0.0001). They were also more likely to have a parathyroid hormone (PTH) level two times above the upper limits of normal (OR 1.39, CI 1.21-1.60, p < 0.0001). Although hypertension was common regardless of era, patients in the 2002-2011 group were less likely to have blood pressure >90th percentile (OR 1.39, CI 1.21-1.60, p < 0.0001), and a significant improvement in survival at 36 months after dialysis initiation was observed in the 2002-2011 cohort compared with the 1992-2001 cohort (95% vs. 90%, respectively). Cardiopulmonary causes were the most common cause of death in both cohorts. Young age, growth deficit, and black race were poor predictors of survival. The survival of pediatric patients on chronic dialysis has improved over two decades of dialysis registry data, specifically for children <1year.


Building a Bridge between Chemotherapy and Immunotherapy in Malignant Pleural Mesothelioma: Investigating the Effect of Chemotherapy on Immune Checkpoint Expression.
In light of the promising results of immune checkpoint blockade (ICPB) in malignant pleural mesothelioma (MPM), we investigated the effect of different chemotherapeutic agents on the expression of immune checkpoints (ICPs) in order to rationally design a good treatment schedule for their combination with ICP blocking antibodies. Cisplatin, oxaliplatin and pemetrexed are interesting chemotherapeutic agents to combine with immunotherapy given their immunomodulatory capacities. We looked into cisplatin and pemetrexed because their combination is used as first-line treatment of MPM. Additionally, the effect of the immunogenic chemotherapeutic agent, oxaliplatin, was also studied. Three different MPM cell lines were used for representation of both epithelioid and sarcomatoid subtypes. The desired inhibitory concentrations of the chemotherapeutic agents were determined with the SRB-assay. Allogeneic co-cultures of MPM cells with healthy donor peripheral blood mononuclear cells (PBMC) were set up to assess the effect of these chemotherapeutic agents on the expression of ICPs (PD-1, LAG-3, TIM-3) and their ligands (PD-L1, PD-L2, galectin-9). Cisplatin might be a promising treatment to combine with ICP blocking antibodies since our MPM cell lines were most susceptible to this stand-alone treatment. We found that the expression of ICPs and their ligands on both MPM cells and PBMC was mostly downregulated or unaltered when treated with chemotherapeutic agents, though no clear trend could be determined.


A new methodical approach in neuroscience: assessing inter-personal brain coupling using functional near-infrared imaging (fNIRI) hyperscanning.
Since the first demonstration of how to simultaneously measure brain activity using functional magnetic resonance imaging (fMRI) on two subjects about 10 years ago, a new paradigm in neuroscience is emerging: measuring brain activity from two or more people simultaneously, termed "hyperscanning". The hyperscanning approach has the potential to reveal inter-personal brain mechanisms underlying interaction-mediated brain-to-brain coupling. These mechanisms are engaged during real social interactions, and cannot be captured using single-subject recordings. In particular, functional near-infrared imaging (fNIRI) hyperscanning is a promising new method, offering a cost-effective, easy to apply and reliable technology to measure inter-personal interactions in a natural context. In this short review we report on fNIRI hyperscanning studies published so far and summarize opportunities and challenges for future studies.


A Modern Approach to Dyslipidemia.
Lipid disorders involving derangements in serum cholesterol, triglycerides, or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and overall health. Recent advances in knowledge, recommendations, and treatment options have necessitated an updated approach to these disorders. Older classification schemes have outlived their usefulness, yielding to an approach based on the primary lipid disturbance identified on a routine lipid panel as a practical starting point. Although monogenic dyslipidemias exist and are important to identify, most individuals with lipid disorders have polygenic predisposition, often in the context of secondary factors such as obesity and type 2 diabetes. With regard to cardiovascular disease, elevated low-density lipoprotein cholesterol is essentially causal, and clinical practice guidelines worldwide have recommended treatment thresholds and targets for this variable. Furthermore, recent studies have established elevated triglycerides as a cardiovascular risk factor, whereas depressed high-density lipoprotein cholesterol now appears less contributory than was previously believed. An updated approach to diagnosis and risk assessment may include measurement of secondary lipid variables such as apolipoprotein B and lipoprotein(a), together with selective use of genetic testing to diagnose rare monogenic dyslipidemias such as familial hypercholesterolemia or familial chylomicronemia syndrome. The ongoing development of new agents-especially antisense RNA and monoclonal antibodies-targeting dyslipidemias will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms.


Infectious pericarditis: an experience spanning a decade.
Although recent literature suggests a changing spectrum for infectious pericarditis (IP), this view has not been proven. In this report, we aim to review the features of IP in cases from a large tertiary centre. A retrospective review of our institution's database was conducted to identify cases with IP between January 1994 and December 2004. All pericardial biopsy tissue results from the same period were also reviewed. One hundred and thirty-eight cases were identified, of which 14 cases were identified by pathology. The mean age was 53 +/- 18 years, and 74% were men. The most frequently identified causative organisms were Propionibacterium acnes (P. acnes), staphylococci and streptococci. A common predisposing factor was an immune-compromised state, followed by cardiac surgery. Fifty-five patients were treated with antibiotics (medical group) while 63 cases (surgical group) underwent surgical drainage (pericardial window) and/or pericardiectomy. In comparison to the medical group, the surgical group was more critically ill and immunocompromised (40% versus 24%, respectively). There were 52 late deaths during follow-up. Mortality in the medical group was 67% while in the surgical group it was 24% (P < 0.0001). In contradistinction to the literature reports, the most prevalent organism for IP was P. acnes. Patients managed aggressively with both antibiotics and surgery, demonstrated lower mortality rates. Therefore, clinicians should maintain a high index of suspicion for IP so that timely and appropriate mortality-reducing strategies can be offered.


Neuraminidase inhibition by chemically sulphated glycopeptides.
Chemically sulphated glycopeptides (derived from pig duodenal mucosa) inhibited Clostridium perfringens neuraminidase (EC 184.108.40.206) activity in a pH-dependent manner. Analysis of inhibition kinetics data indicated that, although the enzyme inhibition could not be categorized into any of the classical types of inhibition, it could be interpreted as a function of the size and shape of the substrates used. The enzyme activity was inhibited by 86% and 40% when tested with bovine submaxillary-gland mucin (mol. wt. 4 x 10(5)-40 x 10(5) and N-acetylneuraminyl-lactose (mol. wt. 633) as substrates respectively. Presence of sulphated glycopeptide did not affect the binding of N-acetylneuraminic acid (mol. wt. 309), a competitive inhibitor of Vibrio cholerae neuraminidase, to the enzyme active site. The enzyme inhibition was thus considered to be due to steric hindrance as a consequence of the non-specific interactions between the enzyme molecule and polyanionic sulphated glycopeptide affecting the differential accessibility of the substrate molecules to the enzyme active site. The enzyme-inhibitor interaction could be suppressed by rapid and many-fold dilution of the reaction mixture, by concurrent addition of the inactive enzyme or by partial removal of the sulphate esters from the sulphated glycopeptide molecule by the action of Helix pomatia arylsulphatase (EC 188.8.131.52).


Charge transfer excitations from exact and approximate ensemble Kohn-Sham theory.
By studying the lowest excitations of an exactly solvable one-dimensional soft-Coulomb molecular model, we show that components of Kohn-Sham ensembles can be used to describe charge transfer processes. Furthermore, we compute the approximate excitation energies obtained by using the exact ensemble densities in the recently formulated ensemble Hartree-exchange theory [T. Gould and S. Pittalis, Phys. Rev. Lett. 119, 243001 (2017)]. Remarkably, our results show that triplet excitations are accurately reproduced across a dissociation curve in all cases tested, even in systems where ground state energies are poor due to strong static correlations. Singlet excitations exhibit larger deviations from exact results but are still reproduced semi-quantitatively.


Global forest loss disproportionately erodes biodiversity in intact landscapes.
Global biodiversity loss is a critical environmental crisis, yet the lack of spatial data on biodiversity threats has hindered conservation strategies. Theory predicts that abrupt biodiversity declines are most likely to occur when habitat availability is reduced to very low levels in the landscape (10-30%). Alternatively, recent evidence indicates that biodiversity is best conserved by minimizing human intrusion into intact and relatively unfragmented landscapes. Here we use recently available forest loss data to test deforestation effects on International Union for Conservation of Nature Red List categories of extinction risk for 19,432 vertebrate species worldwide. As expected, deforestation substantially increased the odds of a species being listed as threatened, undergoing recent upgrading to a higher threat category and exhibiting declining populations. More importantly, we show that these risks were disproportionately high in relatively intact landscapes; even minimal deforestation has had severe consequences for vertebrate biodiversity. We found little support for the alternative hypothesis that forest loss is most detrimental in already fragmented landscapes. Spatial analysis revealed high-risk hot spots in Borneo, the central Amazon and the Congo Basin. In these regions, our model predicts that 121-219 species will become threatened under current rates of forest loss over the next 30 years. Given that only 17.9% of these high-risk areas are formally protected and only 8.9% have strict protection, new large-scale conservation efforts to protect intact forests are necessary to slow deforestation rates and to avert a new wave of global extinctions.


Resilience training with soldiers during basic combat training: randomisation by platoon.
Resilience Training has the potential to mitigate mental health symptoms when provided during initial military training. The present study examined the impact of Resilience Training on US soldier well-being and attitudes during Basic Combat Training. Platoons were randomly assigned to Resilience Training or Military History provided during the first few days of Basic Combat Training. Surveys were conducted at baseline, post-intervention, and 3, 6, and 9 weeks. The sample resulted in a total of 1,939 soldiers who completed at least the baseline and one follow-up survey. There were no significant differences between conditions in terms of depression symptoms, anxiety symptoms, or sleep problems. However, while anxiety decreased in both conditions, the rate of decrease was faster in the Resilience Training condition. In contrast, Resilience Training had a slower rate of increase in group cohesion over time than the Military History condition. In addition, Resilience Training was associated with greater confidence in helping others and received more positive ratings than Military History. Findings demonstrate that the brief Resilience Training studied here may have some utility in supporting mental health and peer support but may not benefit unit climate.


Directing Charge Transfer in Quantum Dot Assemblies.
The optical and electronic properties of semiconductor quantum dots (QDs) make them attractive candidates for applications in photovoltaics, spintronics, photocatalysis, and optoelectronics. Understanding how to control the flow of charge in QD assemblies is essential for realizing novel applications. This Account explores some unique characteristics of charge transport in QD dyads, triads, and their assemblies. The emerging features of these assemblies that provide new opportunities to manipulate charge flow at the nanoscale are (1) cascading energy landscapes and band offsets to inhibit charge recombination, (2) electrostatic fields that direct charge flow through QD-QD and QD-conjugated polymer junctions, and (3) QD chirality and chiral imprinting that promotes vectorial electron and spin selective transport. Charge flow kinetics is determined by a combination of familiar electron transfer parameters (reaction free energy, reorganization energy, and electronic coupling), donor and acceptor electronic densities of states, and internal electric fields. Electron transfer and electronic structure theory, combined with kinetic modeling, place the measured kinetics of QD electron transfer donor-acceptor assemblies into a unified conceptual context. The experimental transfer rates measured in these systems depend upon structure and the internal electric fields that are present in the assemblies. A negatively charged donor and positively charged acceptor, for example, facilitates (inhibits) electron (hole) transfer, while an electric field of opposite orientation (reversal of charges) inhibits (promotes) electron (hole) transfer. These and other emerging rules that govern charge flow in NP assemblies provide a strategy to design the directionality and yield of interfacial charge transport. Chirality at the nanoscale can induce spin selective charge transport, providing new ways to direct charge (and spin) flow in QD assemblies. Magnetoresistance and magnetic conductive probe atomic force microscopy experiments show spin selective electron transport for chirally imprinted QD assemblies. Photoinduced electron transfer from achiral donor-QDs to chiral acceptor-QDs depends on the electron spin and chiroptical properties of the acceptor-QDs. These assemblies show transport characteristics that correlate with features of the QDs' circular dichroism spectra, presenting intriguing challenges to theory, and indicating that spectroscopic signatures may assist in the design and diagnosis of functional molecular assemblies. Theoretical and experimental studies of charge transport in well-defined QD assemblies are establishing design principles for vectorial charge transport and are also refining questions surrounding the mechanism and control of these processes. These intensified efforts are forging links between fundamental discoveries regarding mechanism and practical applications for these novel assembled nanostructures.


Hemodynamic, pulmonary vascular, and myocardial abnormalities secondary to pharmacologic constriction of the fetal ductus arteriosus. A possible mechanism for persistent pulmonary hypertension and transient tricuspid insufficiency in the newborn infant.
The prostaglandin synthetase inhibitor indomethacin was given orally or intravenously to pregnant ewes. This resulted in a significant rise in the fetal pulmonary-to-systemic arterial mean blood pressure difference across the ductus arteriosus, presumably secondary to constriction of the ductus arteriosus. In five experiments the pressure difference could be promptly but temporarily reversed by the administration of prostaglandin E1 (PGE1) into the fetal inferior vena cava. Fetal lungs from study and control animals were fixed by perfusion at measured pulmonary arterial mean blood pressure, and fifth-generation resistance vessels were studied. The medial width/external diameter ratio was significantly increased in the study vs the control lungs due to increased smooth muscle and decreased external diameter. In addition, study fetuses had acute degenerative myocardial changes in the tricuspid valve papillary muscles, the right ventricular free wall and the interventricular septum. Similar changes were not seen in control fetuses. Indomethacin administration during pregnancy causes constriction of the fetal ductus arteriosus, fetal pulmonary arterial hypertension, and right ventricular damage. If severe, this may cause rapid fetal death. If less severe, in the newborn infant, this mechanism may be one cause of persistent pulmonary hypertension due to vasoconstriction and increased pulmonary arterial smooth muscle and/or tricuspid insufficiency due to papillary muscle infarction.


IL-10 enhances expression of the IL-2 receptor alpha chain on T cells.
Interleukin-10 (IL-10) has various immunomodulatory actions depending on the target cell type. Some of these effects have been shown to be owing to its ability to down-regulate surface expression of markers, for example HLA-DR on macrophages and CD25 (IL-2 receptor alpha chain) on B cells. In this report we show that preincubation of IL-10 for 24 hr up-regulates expression of the activation marker CD25, but not HLA-DR on cloned T cells of various phenotypes such as CD4+, CD8+, CD4- CD8- alpha beta and gamma delta T-cell receptor (TCR)-expressing cells. This up-regulation of CD25 was accompanied by an increase in the T cells IL-2-dependent proliferative response in 63% of the CD4+ clones and 100% of the CD8+, CD4-, CD8- alpha beta and gamma delta TCR+ clones analysed. IL-10 was also shown to be at least partly responsible for the up-regulation of CD25 on mitogen-activated peripheral blood mononuclear cells, suggesting that IL-10 has this CD25 modulatory effect within a more physiological environment. Our data suggest that IL-10 can have a multitude of effects on human T cells, and should not be considered exclusively as an immunoinhibitory cytokine.


[Comparison of bioactive aldehydes modifying action on human albumin].
Protein's postsynthetic modifications are a cause and a consequence of many diseases. Endogenous aldehydes are one of the main factors of these modifications formation. The human albumin's modification under some aldehydes influence in in vitro experiment has been investigated. Human albumin (20 mM) was incubated with following aldehydes: ribose, glyoxal, methylglyoxal and formaldehyde (20 mM each) and their combinations in 0.1 M Na-phosphate buffer (pH 7.4) with 0.02% sodium azide at 37 degrees C in the dark for up to 30 days. We have determined the fluorescent properties of the samples, the content of protein's carbonyl groups and the redistribution of protein's molecular weight. The following ratings of aldehydes from the lowest to the highest effect have been obtained. Fluorescent albumin adducts formation: formaldehyde, methylglyoxal, ribose, glyoxal; carbonylation of the protein: ribose, formaldehyde, glyoxal, methylglyoxal; polymerization of albumin--the formation of intermolecular crosslinks: ribose, methylglyoxal, glyoxal, formaldehyde. The results indicate that these aldehydes have different capability for protein's modifications. For example, formaldehyde, having the lowest ability to form fluorescent adducts, shows the highest ability to form protein's intermolecular crosslinks. Therefore, methods and parameters in order to evaluate the protein postsynthetic modification intensity have to be chosen correctly according to carbonyl stress peculiarity in order to evaluate the protein's postsynthetic modification intensity.


Evaluation of cytokines as Th1/Th2 markers in pathogenesis of children with Crimean-Congo hemorrhagic fever.
Cytokine networks play a key role in the pathogenesis of the disease in Crimean-Congo Hemorrhagic Fever (CCHF) patients. Therefore, our aim was to study the effects of cytokine levels on the pathogenesis and severity of the disease in children with CCHF. Fifty-two patients diagnosed with CCHF and 34 healthy controls (HC) were included in the study. The patients with CCHF were divided into two groups (severe and non-severe). The levels of the Interleukin-10 (IL-10), IL-12, IL-6, Endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) were measured in all groups. IL-12 levels did not show any difference between the CCHF and HC groups and among the severe, non-severe and HC groups. IL-10 and ET-1 levels were significantly higher in the severe group when compared to the non-severe group and the HC group. Moreover, IL-10 and ET-1 levels were significantly higher in the non-severe group when compared to the HC group. In terms of IL-6 and TNF-α levels, there was no difference between the severe and non-severe groups while the said levels were significantly higher in the severe group when compared to the HC group. The results of the present study showing significantly higher IL-10 and ET-1 levels in the severe group suggest that Th2-mediated humoral immunity is more effective in the pathogenesis and severity of CCHF in children.


Norwegian reference values for the Short-Form Health Survey 36: development over time.
Reference values for patient-reported outcome measures are useful for interpretation of results from clinical trials. The study aims were to collect Norwegian SF-36 reference values and compare with data from 1996 to 2002. In 2015, SF-36 was sent by mail to a representative sample of the population (N = 6165). Time trends and associations between background variables and SF-36 scale scores were compared by linear regression models. The 2015 response rate was 36% (N = 2118) versus 67% (N = 2323) in 1996 and 56% (N = 5241) in 2002. Only 5% of the youngest (18-29 years) and 27% of the oldest (>70 years) responded in 2015. Age and educational level were significantly higher in 2015 relative to 1996/2002 (p < .001). The oldest age group in 2015 reported better scores on five of eight scales (p < 0.01), the exceptions being bodily pain, vitality, and mental health compared to 1996/2002 (NS). Overall, the SF-36 scores were relatively stable across surveys, controlled for background variables. In general, the most pronounced changes in 2015 were better scores on the role limitations emotional scale (7.4 points, p < .001) and lower scores on the bodily pain scale (4.6 points, p < .001) than in the 1996/2002 survey. The low response rate in 2015 suggests that the results, especially among the youngest, should be interpreted with caution. The high response rate among the oldest indicates good representativity for those >70 years. Despite societal changes in Norway the past two decades, HRQoL has remained relatively stable.