Cotinine versus questionnaire: early-life environmental tobacco smoke exposure and incident asthma.
The use of biomarkers has expanded considerably, as an alternative to questionnaire-based metrics of environmental tobacco smoke (ETS); few studies have assessed the affect of such alternative metrics on diverse respiratory outcomes in children, and we aimed to do so. We evaluated various measures of birth-year ETS, in association with multiple respiratory endpoints early years of life, in the novel context of a birth cohort at high risk for asthma. We administered questionnaires to parents, both at the end of pregnancy and at one year of life, and measured cotinine in cord blood (CCot; in 275 children) and in urine (UCot; obtained at 12 months in 365 children), each by radioimmunoassay. Multiple logistic regression was used to assess the association of the various metrics with recurrent wheeze at age 2 and with bronchial hyperresponsiveness (BHR) and asthma at age 7. Self-reported 3rd trimester maternal smoking was associated with significantly increased risk for recurrent wheeze at age 2 (odds ratio 3.5 [95% confidence interval = 1.2,10.7]); the risks associated with CCot and 3rd trimester smoking in any family member were similar (OR 2.9 [1.2,7.0] and 2.6 [1.0,6.5], respectively). No metric of maternal smoking at 12 months appeared to significantly influence the risk of recurrent wheeze at age 2, and no metric of ETS at any time appeared to significantly influence risk of asthma or BHR at age 7. Biomarker- and questionnaire-based assessment of ETS in early life lead to similar estimates of ETS-associated risk of recurrent wheeze and asthma.


Chemoembolization (TACE) of unresectable intrahepatic cholangiocarcinoma with slow-release doxorubicin-eluting beads: preliminary results.
The purpose of this study was to evaluate the safety and efficacy of TACE with microspheres preloaded with doxorubicin in unresectable intrahepatic cholangiocarcinoma (UCH). Twenty patients with UCH were observed; 9 refused, preferring other palliative care or chemotherapy, and 11 agreed to be treated with one or more cycles of DC beads loaded with doxorubicin (100-150 mg) in a TACE procedure between February 2006 and September 2007. A total of 29 individual TACE procedures were performed. Follow-up imaging was performed on all patients before, immediately after, and 4 weeks after each TACE procedure to evaluate the response and need for further treatment. Each patient received i.v hydration, antibiotics, and medications against nausea and pain before TACE. Survival rate was calculated using Kaplan-Meier survival curve. A response rate of 100% followed RECIST criteria was observed. Eight of eleven patients are alive, with a median survival of 13 months. TACE was well tolerated by all patients. One patient developed hepatic abscess requiring antibiotic therapy. No evidence of marrow toxicity has been reported. Only one of nine patients treated with chemotherapy or palliative care is alive (with a median survival of 7 months in this group of patients). In conclusion, we suggest that doxorubicin-eluting beads TACE is a feasible and effective treatment in patients with UCH. Survival seems to be clearly prolonged in the treated group with respect to the palliative group. We consider that doxorubicin-eluting beads TACE of 100-150 mg may be an appropriate palliative therapy for these patients. Further studies are warranted to confirm these interesting preliminary data.


p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy.
Abnormal expression of the cell cycle regulatory proteins p27(Kip1) (p27) and cyclin E may be associated with breast cancer survival and relapse. We studied these markers in a clinical trial setting with patients with breast cancer treated by a uniform drug regimen so that treatment was not associated with variability in outcome. We used tissue microarrays to evaluate the expression of p27 and cyclin E proteins by immunohistochemistry in tumor tissue from 2123 (68%) of 3122 patients with moderate-risk primary breast cancer who were enrolled in Southwest Oncology Group-Intergroup Trial S9313, in which patients were assigned to receive doxorubicin and cyclophosphamide administered concurrently (n = 1595) or sequentially (n = 1527). Disease-free and overall survival were equivalent in the two arms. Expression of the proteins was rated on a scale of 1-7, and the median value was used as the cut point. Log-rank tests and Cox regression analyses were used to assess associations with survival. Overall survival was defined as time to death from all causes; disease-free survival was defined as time to recurrence or death. All P values were from two-sided statistical tests. Lower p27 expression was associated with worse overall survival (unadjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.21 to 1.86) and disease-free survival (unadjusted HR = 1.31, 95% CI = 1.10 to 1.57) than higher p27 expression. Among hormone receptor-positive patients, lower p27 expression was associated with worse overall survival (HR = 1.42, 95% CI = 1.05 to 1.94) and worse disease-free survival (HR = 1.27, 95% CI = 0.99 to 1.63) than higher p27 expression after adjustment for treatment, menopausal status, tumor size, and number of positive lymph nodes. Among these patients, 5-year overall survival associated with higher p27 expression (0.91, 95% CI = 0.89 to 0.93) was similar to that associated with lower p27 expression (0.85, 95% CI = 0.82 to 0.87). No association between p27 expression and survival was found in hormone receptor-negative patients. Cyclin E expression was not statistically significantly associated with overall survival (HR = 1.12, 95% CI = 0.91 to 1.38) or disease-free survival (HR = 1.09, 95% CI = 0.92 to 1.29). Low p27 expression appears to be associated with poor prognosis, especially among patients with steroid receptor-positive tumors.


Alcohol taxation policy in Thailand: implications for other low- to middle-income countries.
Prevention of drinking initiation is a significant challenge in low- and middle-income countries that have a high prevalence of abstainers, including life-time abstainers. This paper aims to encourage a debate on an alternative alcohol taxation approach used currently in Thailand, which aims specifically to prevent drinking initiation in addition to reduce alcohol-attributable harms. Theoretical evaluation, simulation and empirical analysis. The taxation method of Thailand, 'Two-Chosen-One' (2C1) combines specific taxation (as a function of the alcohol content) and ad valorem taxation (as a function of the price), resulting in an effective tax rate that puts a higher tax both on beverages which are preferred by heavy drinkers and on beverages which are preferred by potential alcohol consumption neophytes, compared to either taxation system alone. As a result of these unique properties of the 2C1 taxation system, our simulations indicate that 2C1 taxation leads to a lower overall consumption than ad valorem or specific taxation alone. In addition, it puts a relatively high tax on beverages attractive to young people, the majority of whom are currently abstaining. Currently, the abstention rates in Thailand are higher than expected based on its economic wealth, which could be taken as an indication that the taxation strategy is successful. 'Two-chosen-one' (2C1) taxation has the potential to simultaneously reduce alcohol consumption and prevent drinking initiation among youth; however, additional empirical evidence is needed to assess its effectiveness in terms of the public health impact in low- and middle-income countries.


Neisseria meningitidis serogroups A and W-135: carriage and immunity in Burkina Faso, 2003.
We sought to describe Neisseria meningitidis immunity and its association with pharyngeal carriage in Burkina Faso, where N. meningitidis serogroup W-135 and serogroup A disease are hyperendemic and most of the population received polysaccharide A/C vaccine during 2002. We collected oropharyngeal swab samples from healthy residents of Bobo-Dioulasso (4-14 years old, n=238; 15-29 years old, n=250) monthly during February-June 2003; N. meningitidis isolates were analyzed using polymerase chain reaction and serogrouped using immune sera. Serum samples were collected at the first and last clinic visit and analyzed for anti-A, anti-C, anti-W-135, and anti-Y immunoglobulin G (IgG) concentrations and anti-A and anti-W-135 bactericidal titers. N. meningitidis was carried at least once by 18% of participants; this carriage included strains from serogroups W-135 (5%) and Y and X (both <1%) but not from serogroups A, B, or C. At baseline, the prevalence of putatively protective specific IgG concentrations (> or =2 microg/mL) and bactericidal titers (> or =8) was 85% and 54%, respectively, against serogroup A, and 6% and 22%, respectively, against serogroup W-135. Putatively protective anti-W-135 IgG concentrations and bactericidal titers were of short duration and were not associated with carriage. N. meningitidis serogroup W-135 strains did not induce immunity, despite their circulation. Carriage of serogroup A strains was rare despite the hyperendemic incidence of serogroup A meningitis during 2003 in Bobo-Dioulasso. A vaccine that includes serogroup W-135 antigen and eliminates serogroup A carriage is needed for sub-Saharan Africa.


Perceptual Integration Deficits in Autism Spectrum Disorders Are Associated with Reduced Interhemispheric Gamma-Band Coherence.
The integration of visual details into a holistic percept is essential for object recognition. This integration has been reported as a key deficit in patients with autism spectrum disorders (ASDs). The weak central coherence account posits an altered disposition to integrate features into a coherent whole in ASD. Here, we test the hypothesis that such weak perceptual coherence may be reflected in weak neural coherence across different cortical sites. We recorded magnetoencephalography from 20 adult human participants with ASD and 20 matched controls, who performed a slit-viewing paradigm, in which objects gradually passed behind a vertical or horizontal slit so that only fragments of the object were visible at any given moment. Object recognition thus required perceptual integration over time and, in case of the horizontal slit, also across visual hemifields. ASD participants were selectively impaired in the horizontal slit condition, indicating specific difficulties in long-range synchronization between the hemispheres. Specifically, the ASD group failed to show condition-related enhancement of imaginary coherence between the posterior superior temporal sulci in both hemispheres during horizontal slit-viewing in contrast to controls. Moreover, local synchronization reflected in occipitocerebellar beta-band power was selectively reduced for horizontal compared with vertical slit-viewing in ASD. Furthermore, we found disturbed connectivity between right posterior superior temporal sulcus and left cerebellum. Together, our results suggest that perceptual integration deficits co-occur with specific patterns of abnormal global and local synchronization in ASD. The weak central coherence account proposes a tendency of individuals with autism spectrum disorders (ASDs) to focus on details at the cost of an integrated coherent whole. Here, we provide evidence, at the behavioral and the neural level, that visual integration in object recognition is impaired in ASD, when details had to be integrated across both visual hemifields. We found enhanced interhemispheric gamma-band coherence in typically developed participants when communication between cortical hemispheres was required by the task. Importantly, participants with ASD failed to show this enhanced coherence between bilateral posterior superior temporal sulci. The findings suggest that visual integration is disturbed at the local and global synchronization scale, which might bear implications for object recognition in ASD.


Viral infections as a cause of cancer (review).
In order to promote carcinogenesis multiple factors must be orchestrated. The alteration of the cellular genome after a carcinogenic exposure may result in malignancy if apoptosis is prevented and the immune surveillance fails to eliminate the transformed cell. Infectious agents may exert these properties and transform a host cell. Viruses associated with human cancer are known as 'tumor viruses'. Most of them are capable of integrating into the host genome and have the ability to immortalize the target cell in order to allow their own replication. The infected cell expresses the viral genes, which are able to induce cell growth, proliferation and prevent apoptosis. This review focuses on Epstein-Barr virus, human papilloma virus, hepatitis C virus, hepatitis B virus, human herpes virus 8 and human T-cell leukemia virus, since they have been already established as causative agents of human cancer. An understanding of the viral replication mechanism may provide new targets for the development of specified viral therapy that may have an impact not only on viral infections but in human cancer as well.


Multiple exciton collection in a sensitized photovoltaic system.
Multiple exciton generation, the creation of two electron-hole pairs from one high-energy photon, is well established in bulk semiconductors, but assessments of the efficiency of this effect remain controversial in quantum-confined systems like semiconductor nanocrystals. We used a photoelectrochemical system composed of PbS nanocrystals chemically bound to TiO(2) single crystals to demonstrate the collection of photocurrents with quantum yields greater than one electron per photon. The strong electronic coupling and favorable energy level alignment between PbS nanocrystals and bulk TiO(2) facilitate extraction of multiple excitons more quickly than they recombine, as well as collection of hot electrons from higher quantum dot excited states. Our results have implications for increasing the efficiency of photovoltaic devices by avoiding losses resulting from the thermalization of photogenerated carriers.


Seedling performance covaries with dormancy thresholds: maintaining cryptic seed heteromorphism in a fire-prone system.
The production of morphologically different seeds or fruits by the same individual plant is known as seed heteromorphism. Such variation is expected to be selected for in disturbance-prone environments to allow germination into inherently variable regeneration niches. However, there are few demonstrations that heteromorphic seed characteristics should be favored by selection or how they may be maintained. In fire-prone ecosystems, seed heteromorphism is found in the temperatures needed to break physical dormancy, with seeds responding to high or low temperatures, ensuring emergence under variable fire-regime-related soil heating. Because of the relationship between dormancy-breaking temperature thresholds and fire severity, we hypothesize that different post-fire resource conditions have selected for covarying seedling traits, which contribute to maintenance of such heteromorphism. Seeds with low thresholds emerge into competitive conditions, either after low-severity fire or in vegetation gaps, and are therefore likely to experience selection for seedling characteristics that make them good competitors. On the other hand, high-temperature-threshold seeds would emerge into less competitive environments, indicative of stand-clearing high-severity fires, and would not experience the same selective forces. We identified high and low-threshold seed morphs via dormancy-breaking heat treatments and germination trials for two study species and compared seed mass and other morphological characteristics between morphs. We then grew seedlings from the two different morphs, with and without competition, and measured growth and biomass allocation as indicators of seedling performance. Seedlings from low-threshold seeds of both species performed better than their high-threshold counterparts, growing more quickly under competitive conditions, confirming that different performance can result from this seed characteristic. Seed mass or appearance did not differ between morphs, indicating that dormancy-breaking temperature threshold variation is a form of cryptic heteromorphism. The potential shown for the selective influence of different post-fire environmental conditions on seedling performance provides evidence of a mechanism for the maintenance of heteromorphic variation in dormancy-breaking temperature thresholds.


Two new cryptic and sympatric species of the king crab parasite Briarosaccus (Cirripedia: Rhizocephala) in the North Pacific.
Rhizocephalan barnacles have been reported to parasitize a wide range of king crab species (Lithodidae). So far all these parasites have been assigned to a single species, Briarosaccus callosus Boschma, 1930, which is assumed to have a global distribution. Here we investigate Briarosaccus specimens from three different king crab hosts from the fjord systems of Southeastern Alaska: Lithodes aequispinus Benedict, 1895, Paralithodes camtschaticus (Tilesius, 1815), and Paralithodes platypus (Brandt, 1850). Using molecular markers and by morphological comparison we show that Briarosaccus specimens from these three commercial exploited king crabs are in fact morphologically distinct from B. callosus, and further represent two separate species which we describe. The two new species, Briarosaccus auratum n. sp. and B. regalis n. sp., are cryptic by morphological means and were identified as distinct species by the use of genetic markers (COI and 16S). They occur sympatrically, yet no overlap in king crab hosts occurs, with B. auratum n. sp. only found on L. aequispinus, and B. regalis n. sp. as parasite of the two Paralithodes hosts.


Clinical signs, treatment, and outcome for California sea lions (Zalophus californianus) with Sarcocystis-associated polyphasic rhabdomyositis.
To describe clinical signs, treatment, and outcome for California sea lions (Zalophus californianus) with Sarcocystis-associated polyphasic rhabdomyositis. 38 free-ranging juvenile to adult California sea lions examined at a rehabilitation center in California between September 2015 and December 2017. Medical records at The Marine Mammal Center were reviewed to identify sea lions in which sarcocystosis had been diagnosed. Clinical signs were highly variable and associated with polyphasic rhabdomyositis attributed to Sarcocystis neurona infection. Generalized severe muscle wasting, respiratory compromise, and regurgitation secondary to megaesophagus were the most profound clinical findings. Respiratory compromise and megaesophagus were associated with a poor prognosis. Eight of the 38 sea lions were treated and released to the wild, and 2 subsequently restranded and were euthanized. Two additional animals received no targeted treatment and were released. The remaining 28 animals were either euthanized or died during treatment. Results suggested that unlike other marine mammals, which typically develop encephalitis, California sea lions with sarcocystosis often have polyphasic rhabdomyositis with highly variable clinical signs and that extensive diagnostic testing may be required to confirm the diagnosis. Treatment with an antiprotozoal drug in combination with corticosteroids may resolve clinical disease, but the prognosis is guarded.


Therapeutic efficacy of CXCR3 blockade in an experimental model of severe sepsis.
In our previous studies we demonstrated that CXC chemokine receptor 3 (CXCR3) participates in the regulation of lymphocyte trafficking during cecal ligation and puncture (CLP)-induced sepsis. In this study, we evaluated the effects of treatment with anti-CXCR3 immunoglobulin (IgG) and antibiotics on outcome during septic shock caused by CLP. C57BL/6J mice were treated with neutralizing IgG against CXCR3 plus Primaxin either 24 hours prior to, 2 hours after or 6 hours after CLP. Control mice received nonspecific IgG plus Primaxin in the same regimen. Survival, core body temperature, bacterial clearance and systemic cytokine production were evaluated. Our results show that treatment with anti-CXCR3 IgG plus Primaxin significantly improved survival when administered 24 hours prior to CLP (50% vs. 10%), 2 hours after CLP (55% vs. 10%) or 6 hours after CLP (55% vs. 25%) compared with mice receiving nonspecific IgG plus Primaxin. Treatment with anti-CXCR3 plus Primaxin 24 hours prior to CLP attenuated hypothermia and IL-6 and macrophage inflammatory protein 2 (MIP-2) production but did not alter bacterial clearance. Treatment with anti-CXCR3 IgG and Primaxin 2 hours after CLP did not improve bacterial clearance and systemic cytokine production compared with mice treated with IgG and Primaxin, whereas 6 hours after CLP the bacterial clearance and IL-6 and MIP-2 concentrations, both in plasma and peritoneal lavage fluid, were significantly improved in mice receiving anti-CXCR3 IgG and Primaxin compared with mice that only received nonspecific IgG and Primaxin. The results from this study indicate that neutralization of CXCR3 prior to, 2 hours after or 6 hours after the initiation of CLP-induced septic shock improves survival and attenuates CLP-induced inflammation and physiologic dysfunction.


Epigenetics in Ascending Thoracic Aortic Aneurysm and Dissection.
Thoracic aortic aneurysm (TAA) is an asymptomatic and progressive dilatation of the thoracic aorta. Ascending aortic dissection (AAD) is an acute intraparietal tear, occurring or not on a pre-existing dilatation. AAD is a condition associated with a poor prognosis and a high mortality rate. TAA and AAD share common etiology as monogenic diseases linked to transforming growth factor β signaling pathway, extracellular matrix defect, or smooth muscle cell protein mutations. They feature a complex pathogenesis including loss of smooth muscle cells, altered phenotype, and extracellular matrix degradation in aortic media layer. A better knowledge of the mechanisms responsible for TAA progression and AAD occurrence is needed to improve healthcare, nowadays mainly consisting of aortic open surgery or endovascular replacement. Recent breakthrough discoveries allowed a deeper characterization of the mechanisms of gene regulation. Since alteration in gene expression has been linked to TAA and AAD, it is conceivable that a better knowledge of the causes of this alteration may lead to novel theranostic approaches. In this review article, the authors will focus on epigenetic regulation of gene expression, including the role of histone methylation and acetylation, deoxyribonucleic acid methylation, and noncoding ribonucleic acids in the pathogenesis of TAA and AAD. They will provide a translational perspective, presenting recent data that motivate the evaluation of the potential of epigenetics to diagnose TAA and prevent AAD.


Medical journals: old, not senescent. A tribute to Revista Médica de Chile on its 135th anniversary.
Medical journals, like the Revista Médica de Chile, are the product of a long history of printing, literary styles, and scientific inquiry. They would not have developed without the craft of paper making, the invention of movable type, the need to communicate ideas and observations in a timely and digestible format, and the growth of "natural philosophy" during the European Renaissance and Enlightenment. The proliferation of scientific and medical periodical literature during Europe's industrialization in the nineteenth and twentieth centuries followed the emergence of medical science and care as a separate discipline and the creation of common and worldwide professional expectations and credentials. Medical journals continue to evolve with the advent of digital paperless publishing. Prognostication remains uncertain but it seems to me unlikely that printed paper, so called "hard copy, "journals will become extinct any time soon.


Metabolite Fruit Profile Is Altered in Response to Source-Sink Imbalance and Can Be Used as an Early Predictor of Fruit Quality in Nectarine.
Peaches and nectarines [Prunus persica (L.) Batsch] are among the most exported fresh fruit from Chile to the Northern Hemisphere. Fruit acceptance by final consumers is defined by quality parameters such as the size, weight, taste, aroma, color, and juiciness of the fruit. In peaches and nectarines, the balance between soluble sugars present in the mesocarp and the predominant organic acids determines the taste. Biomass production and metabolite accumulation by fruits occur during the different developmental stages and depend on photosynthesis and carbon export by source leaves. Carbon supply to fruit can be potentiated through the field practice of thinning (removal of flowers and young fruit), leading to a change in the source-sink balance favoring fruit development. Thinning leads to fruit with increased size, but it is not known how this practice could influence fruit quality in terms of individual metabolite composition. In this work, we analyzed soluble metabolite profiles of nectarine fruit cv "Magique" at different developmental stages and from trees subjected to different thinning treatments. Mesocarp metabolites were analyzed throughout fruit development until harvest during two consecutive harvest seasons. Major polar compounds such as soluble sugars, amino acids, organic acids, and some secondary metabolites were measured by quantitative 1H-NMR profiling in the first season and GC-MS profiling in the second season. In addition, harvest and ripening quality parameters such as fruit weight, firmness, and acidity were determined. Our results indicated that thinning (i.e., source-sink imbalance) mainly affects fruit metabolic composition at early developmental stages. Metabolomic data revealed that sugar, organic acid, and phenylpropanoid pathway intermediates at early stages of development can be used to segregate fruits impacted by the change in source-sink balance. In conclusion, we suggest that the metabolite profile at early stages of development could be a metabolic predictor of final fruit quality in nectarines.


Microscopic mechanism of DNA damage searching by hOGG1.
The DNA backbone is often considered a track that allows long-range sliding of DNA repair enzymes in their search for rare damage sites in DNA. A proposed exemplar of DNA sliding is human 8-oxoguanine ((o)G) DNA glycosylase 1 (hOGG1), which repairs mutagenic (o)G lesions in DNA. Here we use our high-resolution molecular clock method to show that macroscopic 1D DNA sliding of hOGG1 occurs by microscopic 2D and 3D steps that masquerade as sliding in resolution-limited single-molecule images. Strand sliding was limited to distances shorter than seven phosphate linkages because attaching a covalent chemical road block to a single DNA phosphate located between two closely spaced damage sites had little effect on transfers. The microscopic parameters describing the DNA search of hOGG1 were derived from numerical simulations constrained by the experimental data. These findings support a general mechanism where DNA glycosylases use highly dynamic multidimensional diffusion paths to scan DNA.


Alcohol intake and bone metabolism in elderly women.
Published reports on the effect of alcohol consumption on bone mineral density (BMD) are inconsistent. The objective of this study was to examine the relation between alcohol intake and BMD, calcitropic hormones, calcium absorption, and other biochemical indexes of bone and mineral metabolism in elderly women. The results presented are derived from baseline observations of 489 elderly women (aged 65-77 y) recruited for an osteoporosis study. The nondrinking group comprised 297 women and the drinking group comprised 148 women. Furthermore, the effect of different alcohol intakes (</=28.6, >28.6 to </=57.2, >57.2 to </=142.9, and >142.9 g/wk) was studied. Women who consumed alcohol had significantly higher spine (10%), total body (4.5%), and midradius (6%) BMD than did nondrinkers. An alcohol intake >28.6 g/wk was associated with higher BMD; maximum effect was seen with an intake of >28.6 to </=57.2 g/wk (16%, 12%, and 14% increase in spine, total body, and midradius BMD, respectively). There was a marked reduction in bone remodeling markers, serum osteocalcin, and the ratio of urinary cross-linked N:-telopeptides of type 1 collagen to creatinine with alcohol consumption, suggesting that increased BMD with alcohol consumption could be due to reduced bone remodeling. Further, serum parathyroid hormone concentrations were significantly lower in alcohol drinkers than in nondrinkers and could be one of the causes of decreased bone resorption. Moderate alcohol intake was associated with higher BMD in postmenopausal elderly women. The protective effect of alcohol may have been a result of lower bone remodeling due to reduced parathyroid hormone concentrations or factors such as increased estrogen concentrations.


Source identification and apportionment of halogenated compounds observed at a remote site in East Asia.
The sources of halogenated compounds in East Asia associated with stratospheric ozone depletion and climate change are relatively poorly understood. High-precision in situ measurements of 18 halogenated compounds and carbonyl sulfide (COS) made at Gosan, Jeju Island, Korea, from November 2007 to December 2011 were analyzed by a positive matrix factorization (PMF). Seven major industrial sources were identified from the enhanced concentrations of halogenated compounds observed at Gosan and corresponding concentration-based source contributions were also suggested: primary aluminum production explaining 37% of total concentration enhancements, solvent usage of which source apportionment is 25%, fugitive emissions from HCFC/HFC production with 11%, refrigerant replacements (9%), semiconductor/electronics industry (9%), foam blowing agents (6%), and fumigation (3%). Statistical trajectory analysis was applied to specify the potential emission regions for seven sources using back trajectories. Primary aluminum production, solvent usage and fugitive emission sources were mainly contributed by China. Semiconductor/electronics sources were dominantly located in Korea. Refrigerant replacement, fumigation and foam blowing agent sources were spread throughout East Asian countries. The specified potential source regions are consistent with country-based consumptions and emission patterns, verifying the PMF analysis results. The industry-based emission sources of halogenated compounds identified in this study help improve our understanding of the East Asian countries' industrial contributions to halogenated compound emissions.


RSL genes are sufficient for rhizoid system development in early diverging land plants.
Land plants are anchored to their substratum from which essential inorganic nutrients are taken up. These functions are carried out by a system of rhizoids in early diverging groups of land plants, such as mosses, liverworts and hornworts. Physcomitrella patens RHD SIX-LIKE1 (PpRSL1) and PpRSL2 transcription factors are necessary for rhizoid development in mosses. Similar proteins, AtRHD6 and AtRSL1, control the development of root hairs in Arabidopsis thaliana. Auxin positively regulates root hair development independently of AtRHD6 and AtRSL1 in A. thaliana but the regulatory interactions between auxin and PpRSL1 and PpRSL2 are unknown. We show here that co-expression of PpRSL1 and PpRSL2 is sufficient for the development of the rhizoid system in the moss P. patens; constitutive expression of PpRSL1 and PpRSL2 converts developing leafy shoot axes (gametophores) into rhizoids. During wild-type development, PpRSL1 and PpRSL2 are expressed in the specialized cells that develop rhizoids, indicating that cell-specific expression of PpRSL1 and PpRSL2 is sufficient to promote rhizoid differentiation during wild-type P. patens development. In contrast to A. thaliana, auxin promotes rhizoid development by positively regulating PpRSL1 and PpRSL2 activity in P. patens. This indicates that even though the same genes control the development of root hairs and rhizoids, the regulation of this transcriptional network by auxin is different in these two species. This suggests that auxin might have controlled the development of the first land plant soil anchoring systems that evolved 465 million years ago by regulating the expression of RSL genes and that this regulatory network has changed since mosses and angiosperms last shared a common ancestor.


Treatment of ligneous conjunctivitis with amniotic membrane transplantation and topical cyclosporine.
Ligneous conjunctivitis (LC) is a rare form of bilateral chronic recurrent disease in which thick membranes form on the palpebral conjunctiva and other mucosal sites. We report the clinical features and describe the management of two cases. Case 1 was an 8-month-old patient with bilateral membranous conjunctivitis. Case 2 was a 5-year-old patient with unilateral membranous conjunctivitis, esotropia, mechanical ptosis and complicated cataract, and had been treated with a number of medications. Histological investigation of the membrane in both cases showed LC. Treatments with amniotic membrane transplantation and institution of topical cyclosporine have shown good response. There has been complete resolution of the membranes with no recurrence at the end of 40- and 28-month follow-ups, respectively. No treatment related side effects were seen. Thus, it appears that amniotic membrane transplantation and topical cyclosporine are effective alternatives for the treatment of LC.


NAL-NL2 empirical adjustments.
NAL-NL1, the first procedure from the National Acoustic Laboratories (NAL) for prescribing nonlinear gain, was a purely theoretically derived formula aimed at maximizing speech intelligibility for any input level of speech while keeping the overall loudness of speech at or below normal loudness. The formula was obtained through an optimization process in which speech intelligibility and loudness were predicted from selected models. Using updated models and applying some revisions to the derivation process, a theoretically derived NAL-NL2 formula was obtained in a similar way. Further adjustments, directed by empirical data collected in studies using NAL-NL1 as the baseline response, have been made to the theoretically derived formula. Specifically, empirical data have demonstrated that (a) female hearing aid users prefer lower overall gain than male users; (b) new hearing aid users with more than a mild hearing loss prefer increasingly less gain with increasing degree of hearing loss than experienced hearing aid users, and require up to 2 years to adapt to gain levels selected by experienced hearing aid users; (c) unilaterally and bilaterally fitted hearing aid users prefer overall gain levels that vary less than estimated by the bilateral correction factor; (d) adults prefer lower overall gain than children; and (e) people with severe/profound hearing loss prefer lower compression ratios than predicted when fitted with fast-acting compression. The literature and data leading to these conclusions are summarized and discussed in this article, and the procedure for implementing the adjustments to the theoretically derived NAL-NL2 formula is described.


Pediatric residents' ability to perform a lumbar puncture: evaluation of an educational intervention.
To assess the baseline ability of pediatric residents to successfully perform a lumbar puncture (LP) and to evaluate the impact of an educational intervention on this skill in both a simulated and clinical environment. An experimental group of first-year residents and a control group of second-year residents were enrolled in a prospective nonrandomized intervention study. Knowledge and skill at performing LPs were assessed using a written and a simulated LP test. The experimental group was tested at the start of their residency and then received the educational intervention. They were retested 6 months later. The control group did not receive the educational intervention and were tested at the start of their second year. The outcomes of clinical LPs performed by the 2 groups were also recorded. The experimental group showed significant improvement on both the written and the simulated LP test after the educational intervention. When compared with the control group, they performed the simulated LP significantly better as measured by the number of correctly performed steps. Both groups performed a low number of clinical LPs. After an educational intervention, pediatric first-year residents performed a simulated LP better than a group of second-year residents who had greater clinical LP experience. The low number of clinical LPs performed limits our ability to determine the educational intervention's impact in the clinical setting and reinforces the concern that recent changes to pediatric residencies may negatively impact residents' procedural experience.


Method for integrating the absorption cross sections of spheres over wavelength or diameter.
The absorption cross sections of spherical particles and droplets must be integrated over frequency or droplet size or both for various applications. Morphology-dependent resonances (MDRs) of the spheres can make evaluation of such integrals difficult because the MDRs can contribute significantly to the integrals even when their linewidths are extremely narrow, especially when the absorption is weak. A method of evaluating these integrals by use of Lorentzian approximations near MDRs is described. Calculated frequency-integrated absorption cross sections illustrate how the method obtains accurate cross sections with far fewer integration points than a method that uses equally spaced points. The method reported here suggests a way to integrate over frequency in more-complicated scattering and emission problems and should also be useful for integrating scattering and absorption by other shapes, e.g., spheroids and cylinders, for which the MDR positions and linewidths can be calculated.


Application of the homogenization approximation to rough one-dimensional photonic crystals.
As previously reported [Opt. Lett. 29, 2791 (2004)], one-dimensional photonic crystals exhibit a decrease in their normal reflectivity if their interfaces are not flat. We show that the homogenization approximation accurately predicts this diminished optical response by comparing results with finite-difference time-domain (FDTD) simulations applied to the same roughened structures. Within the parameter range tested (rms roughness < 20% and rms wavelengths < 100% of the photonic crystal periodicity), the homogenization approximation accurately reproduces the reflectivities obtained by the FDTD simulations, which are much more computationally expensive.


Using a mobile health application to reduce alcohol consumption: a mixed-methods evaluation of the drinkaware track & calculate units application.
Smartphone applications ("apps") offer promise as tools to help people monitor and reduce their alcohol consumption. To date, few evaluations of alcohol reduction apps exist, with even fewer considering apps already available to the public. The aim of this study was to evaluate an existing publically available app, designed by Drinkaware, a UK-based alcohol awareness charity. We adopted a mixed-methods design, analysing routinely collected app usage data to explore user characteristics and patterns of usage. Following this, in-depth interviews were conducted with a sub-sample of app users to examine perceptions of acceptability, usability and perceived effectiveness, as well as to provide recommendations on how to improve the app. One hundred nineteen thousand seven hundred thirteen people downloaded and entered data into the app over a 13-month period. High attrition was observed after 1 week. Users who engaged with the app tended to be "high risk" drinkers and to report being motivated "to reduce drinking" at the point of first download. In those who consistently engaged with the app over time, self-reported alcohol consumption levels reduced, with most change occurring in the first week of usage. Our qualitative findings indicate satisfaction with the usability of the app, but mixed feedback was given regarding individual features. Users expressed conflicting views concerning the type of feedback and notifications that the app currently provides. A common preference was expressed for more personalised content. The Drinkaware app is a useful tool to support behaviour change in individuals who are already motivated and committed to reducing their alcohol consumption. The Drinkaware app would benefit from greater personalisation and tailoring to promote longer term use. This evaluation provides insight into the usability and acceptability of various app features and contains a number of recommendations for improving user satisfaction and the potential effectiveness of apps designed to encourage reductions in alcohol consumption.


Improved Production of Highly Active and Pure Human Creatine Kinase MB.
Human creatine kinase MB (hCKMB) is one of the most preferred biomarkers used for the diagnosis of acute coronary syndrome due to its high sensitivity and specificity. The increasing need for highly purified and biologically active hCKMB in the field of diagnostics makes its production valuable. Currently, the production of hCKMB is mainly achieved in methylotrophic yeast, Pichia pastoris, because the production in Escherichia coli is challenging and generally yields an inactive enzyme with a low quantity. With the aim of finding the best way for the high-yield production of active hCKMB in E. coli, an efficient strategy was developed using a construct allowing tandem expression of each subunit with 2 different tags. The strategy allowed the efficient expression and separate characterization of each subunit and 1-step purification of the heterodimeric protein into homogeneity. The heterodimeric protein displayed more than 11-fold greater specific activity than the commercially available one. The production strategy described in this study shows a clear advantage over the currently used ones and can be made available not only for laboratory scale production but also for commercial production. Our study is also a well-suited example for the studies in which novel protein expression strategies are needed to achieve greater yields with higher purities.


Recognition of Endogenous Nucleic Acids by the Innate Immune System.
Recognition of DNA and RNA by endosomal and cytosolic sensors constitutes a central element in the detection of microbial invaders by the innate immune system. However, the capacity of these sensors to discriminate between microbial and endogenous nucleic acids is limited. Over the past few years, evidence has accumulated to suggest that endogenous DNA or RNA species can engage nucleic-acid-sensing pattern-recognition receptors that can trigger or sustain detrimental pathology. Here, we review principles of how the activation of innate sensors by host nucleic acids is prevented in the steady state and discuss four important determinants of whether a nucleic-acid-driven innate response is mounted. These include structural features of the ligand being sensed, the subcellular location and quantity of pathogen-derived or endogenous nucleic acids, and the regulation of sensor-activation thresholds. Furthermore, we emphasize disease mechanisms initiated by failure to discriminate self from non-self in nucleic acid detection.


Identification and characterization of fusolisin, the Fusobacterium nucleatum autotransporter serine protease.
Fusobacterium nucleatum is an oral anaerobe associated with periodontal disease, adverse pregnancy outcomes and colorectal carcinoma. A serine endopeptidase of 61-65 kDa capable of damaging host tissue and of inactivating immune effectors was detected previously in F. nucleatum. Here we describe the identification of this serine protease, named fusolisin, in three oral F. nucleatum sub-species. Gel zymogram revealed fusobacterial proteolytic activity with molecular masses ranging from 55-101 kDa. All of the detected proteases were inhibited by the serine protease inhibitor PMSF. analysis revealed that all of the detected proteases are encoded by genes encoding an open reading frame (ORF) with a calculated mass of approximately 115 kDa. Bioinformatics analysis of the identified ORFs demonstrated that they consist of three domains characteristic of autotransporters of the type Va secretion system. Our results suggest that the F. nucleatum fusolisins are derived from a precursor of approximately 115 kDa. After crossing the cytoplasmic membrane and cleavage of the leader sequence, the C-terminal autotransporter domain of the remaining 96-113 kDa protein is embedded in the outer membrane and delivers the N-terminal S8 serine protease passenger domain to the outer cell surface. In most strains the N-terminal catalytic 55-65 kDa domain self cleaves and liberates itself from the autotransporter domain after its transfer across the outer cell membrane. In F. nucleatum ATCC 25586 this autocatalytic activity is less efficient resulting in a full length membrane-anchored serine protease. The mature serine protease was found to cleave after Thr, Gly, Ala and Leu residues at the P1 position. Growth of F. nucleatum in complex medium was inhibited when serine protease inhibitors were used. Additional experiments are needed to determine whether fusolisin might be used as a target for controlling fusobacterial infections.


Tau-Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer's Disease.
Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationship - manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region-based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology. Cortical thickness (N) and 18 F-Flortaucipir SUVR (T) were computed in 104 gray matter regions from a cohort of cognitively-impaired, amyloid-positive (A+) individuals. Region-specific residuals from a robust linear fit between SUVR and cortical thickness were computed as a surrogate for T-N mismatch. A summary T-N mismatch metric defined using residuals were correlated with demographic and imaging-based modulatory factors, and to partition the cohort into data-driven subgroups. The summary T-N mismatch metric correlated with underlying factors such as age and burden of white matter hyperintensity lesions. Data-driven subgroups based on clustering of residuals appear to represent different biologically relevant phenotypes, with groups showing distinct spatial patterns of higher or lower atrophy than expected. These data support the notion that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may help identify possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials. ANN NEUROL 2021;90:751-762.


AP-1 (Fos-Jun) regulation by IP-1: effect of signal transduction pathways and cell growth.
Transcription factor AP-1 is constituted by the various products of the fos and jun proto-oncogene family members, which associate as dimers to bind with variable efficiency to 12-O-tetradecanoyl phorbol 13-acetate (TPA)-responsive promoter elements (TREs). We have recently shown that DNA binding of AP-1 is regulated by an inhibitory protein, IP-1, whose activity is modulated by phosphorylation. Here it is shown that although AP-1 has a very high affinity for its recognition sequence, its binding to the TRE can be quickly inhibited by the addition of IP-1. IP-1 is more active on AP-1 complexes formed during a shorter period of time. IP-1 activity is blocked by stimulation of the protein kinase C (PKC) signal transduction pathway, achieved by treating HeLa cells with phorbol esters or with a diacylglycerol analog. We observed an increase in AP-1-DNA binding after treatment of the cells with either the calcium ionophore A-23187 or dibutyryl cAMP; this could be ascribed to inhibition of IP-1 activity. A decreased IP-1 activity also correlates with the increase in AP-1-DNA binding after stimulating cells with serum. This suggests that IP-1 is an important target of the various signal transduction pathways. No effect on AP-1 and IP-1 was detected in cells transformed by Ki-ras or v-raf; nor could an effect of inhibition of protein synthesis be observed. We also analysed IP-1 regulation upon differentiation of P19 embryonal carcinoma cells by retinoic acid. We conclude that IP-1 regulation has a pivotal role in the final modulation of Fos-Jun by signal transduction pathways.


Hypoxia-inducible factor 1 in lower limb ischemia.
In the Western world, peripheral vascular disease (PVD) has a high prevalence and is associated with high morbidity and mortality. More patients are presenting with critical limb ischemia (CLI), the end stage of PVD, because of an increased life expectancy owing to improved medical care. In a large percentage of these patients, lower limb amputation is still required, despite current advances in surgery and interventional radiology. Studies of ischemic skeletal muscles disclosed evidence of endogenous angiogenesis and adaptive skeletal muscle metabolic changes in response to hypoxia. Many of the genes responsible for these responses are regulated by hypoxia-inducible factor (HIF)-1. HIF-1, consisting of HIF-1alpha and HIF-1beta subunits, is a major transcription factor that functions as a master regulator of oxygen homeostasis that plays essential roles in cellular and systemic pathophysiology. HIF-1alpha expression and HIF-1 transcriptional activity increase exponentially as cellular oxygen concentration is decreased. More than 60 target genes that are transactivated by HIF-1 have been identified. Many of the target genes, such as vascular endothelial growth factor, have been studied extensively, especially in tumors. However, only recently that interest in HIF-1 is growing in relation to ischemic diseases. Most of the studies concentrated mainly on the angiogenic property of HIF-1. In contrast, there is a lack of information on the role of HIF-1 in skeletal muscle metabolic adaptive changes as the end-organ in PVD. This review aims to summarize our current understanding of HIF-1 roles and the therapeutic potential in PVD.


Prevalence of sexually transmitted infections among men who have sex with men in Zagreb, Croatia.
We used respondent-driven sampling among men who have sex with men (MSM) in Zagreb, Croatia in 2006 to investigate the prevalence of HIV, other sexually transmitted infections and sexual behaviours. We recruited 360 MSM. HIV infection was diagnosed in 4.5%. The seroprevalence of antibodies to viral pathogens was: herpes simplex virus type-2, 9.4%; hepatitis A, 14.2%; hepatitis C, 3.0%. Eighty percent of participants were susceptible to HBV infection (HBs antigen negative, and no antibodies to HBs and HBc antigen). Syphilis seroprevalence was 10.6%. Prevalence of Chlamydia and gonorrhoea was 9.0%, and 13.2%, respectively. Results indicate the need for interventions to diagnose, treat and prevent sexually transmitted infections among this population.


Mitochondrial DNA D-loop haplogroup contributions to the genetic diversity of East European domestic chickens from Russia.
To elucidate geographical and historical aspects of chicken dispersal across Eastern Europe, we analysed the complete mitochondrial DNA D-loop sequence of 86 representatives from chicken breeds traditionally raised in the territory of the East European Plain (Orloff, Pavlov, Russian White, Yurlov Crower, Uzbek Game and Naked Neck). From the 1231-1232 bp D-loop sequence, 35 variable sites that defined 22 haplotypes were identified in modern chicken. All populations, except Uzbek Game, exhibited high values of haplotype and nucleotide diversity suggesting a wide variation in maternal diversity. Inclusion of mtDNA sequences from other European and Asian countries revealed representatives from this study belonging to haplogroups A, E1 and C1. We also assessed fossil chicken material dated to the 9th-18th century from archaeological sites in Northern and Eastern Europe. Three haplotypes found in the fossil specimens belonged to haplogroup E1, while one sample dated to the 18th century was assigned to the C1 haplogroup. This is the first report of the occurrence of the C1 haplogroup in European chicken populations prior to the 20th century based on the fossil material. These results provide evidence for a relatively recent introduction of all haplotypes other than E1 into the East European chicken gene pool with the significant impact of the C1 haplogroup mainly distributed in Southern China.


Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel.
An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with ≥10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DLI strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT.


CUTICULAR DRUSEN: Risk of Geographic Atrophy and Macular Neovascularization.
Cuticular drusen (CD) have been associated with manifestations of age-related macular degeneration such as atrophy and neovascularization in the macula. In this study, eyes with CD were followed and investigated for the estimated 5-year risk of progression to sequelae of age-related macular degeneration such as geographic atrophy (GA) and macular neovascularization (MNV). A consecutive series of patients with CD were followed for the development of GA and MNV. Whenever possible, they were also studied retrospectively. The patients with CD were categorized into three phenotypic groups. Phenotype 1: eyes had concentrated, densely populated CD in the macular and paramacular area, Phenotype 2: eyes showed scattered CD in the posterior fundus, and Phenotype 3: involved eyes with CD mixed with large drusen (>200 µm). The 5-year incidence of progression was then estimated using a Kaplan-Meier estimator. A total of 63 eyes from 38 patients (35 women with a mean age at presentation of 58.9 ± 14.2 years) were studied and followed for a mean of 40 ± 18 months. Thirteen patients had single eyes with GA (84.5%; 11/13) or MNV (15.5%; 2/13) in one eye at presentation and were subsequently excluded. Geographic atrophy developed in 19.0% (12/63) of eyes and MNV in 4.8% (3/63) of eyes. The cumulative estimated 5-year risk of GA and MNV was 28.4% and 8.7%, respectively. The estimated 5-year incidence of MNV or GA was 12.6%, 50.0%, and 51.6% in Phenotype 1, Phenotype 2, and Phenotype 3, respectively (P = 0.0015, log-rank test). No difference in risk was found in the development of GA or MNV (P = 0.11) between the subgroup of patients presenting with GA or MNV in their fellow eye and those with both eyes included. When patients with CD are followed longitudinally, there was a significant risk of progression to GA or MNV for Phenotype 2 and Phenotype 3. Patients with CD are commonly first diagnosed in the fifth decade of life, and there is a female predominance. Clinicians should use multimodal imaging to detect and be aware of the risk of progression to manifestations of GA and MNV. These risks of GA and MNV suggest that patients with CD may be part of the overall spectrum of age-related macular degeneration.


Maternal transmission of immunity to Eimeria maxima: enzyme-linked immunosorbent assay analysis of protective antibodies induced by infection.
Vaccination of broiler chickens against Eimeria infection is problematic because of the need to ensure that birds are protected from the time of hatching. We have therefore investigated the feasibility of protecting hatchling broilers via maternal transfer of protective antibodies from hens to their offspring. Oral infection of broiler breeder hens with 20,000 sporulated Eimeria maxima oocysts caused production of antibodies which were passed into the egg yolk and subsequently to hatchlings. The level of specific antibodies in the yolks to unsporulated oocysts, sporulated oocysts, merozoites, and gametocytes was assessed by enzyme-linked immunosorbent assays. The levels in yolks of antibodies to all developmental stages peaked 3 to 4 weeks after infection of the hens. Groups of 10 hatchlings were challenged at 3 days of age by oral infection with 100 sporulated E. maxima oocysts. In the first experiment, the mean 4-day (days 6 to 9 post-infection) total number of oocysts excreted in the feces of chicks from eggs collected 3 weeks after infection of the hens was (0.6 +/- 0.4) x 10(6) (mean +/- standard error) compared with (9.9 +/- 1.4) x 10(6) for the progeny of uninfected hens, which represents a greater than 90% reduction. However, oocyst excretion by chicks from eggs collected 7 or 8 weeks after infection of the hens was only 47 or 68% lower than control values, reflecting declining levels of protective antibodies. In a second experiment, in which the hens were somewhat older and pretreated by intramuscular injection of saline in the emulsifying agent, Arlacel A, the period for which protective antibodies were transferred to hatchlings was prolonged. Thus, oocyst excretion by challenged hatchlings from eggs collected for an 8-week period after infection of the hens was more than 90% lower than oocyst excretion by control chicks, and even hatchlings of eggs collected 19 weeks after infection of the hens showed a 60% reduction in oocyst output. In both experiments, the levels of immunoglobulin G (IgG) antibodies to all developmental stages in yolks or hatchling sera were very strongly correlated with maternally derived immunity to E. maxima. In contrast, parasite-specific IgM or IgA was not detectable, either in egg yolk or egg white. These results demonstrate the ability of IgG antibodies to protect against E. maxima in poultry, thus raising the possibility of using protective maternally derived IgG antibodies to identify potentially protective parasite antigens and indicating the feasibility of using maternal immunization as a means for parasite control.


Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation.
Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3+ T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3+ T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3+ T cell dose cutoff of 14 × 107 cells/kg identified MSD/low CD3+ (n = 223) and MSD/high CD3+ (n = 1214), and a dose of 15 × 107 cells/kg identified MUD/low CD3+ (n = 197) and MUD/high CD3+ (n = 1102). On univariate analysis, the MSD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3+ group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3+ group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3+ T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4+ T cells, CD8+ T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3+ T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4+ and CD8+ T cell doses were not possible given our small sample size.


Synthesis and properties of unsymmetrical azatrioxa[8]circulenes.
Insights to the subtle reactivity patterns of hydroxy-substituted carbazoles allows the precise synthesis of unsymmetrical azatrioxa[8]circulenes by the reaction of N-benzyl-2,7-di-tert-butyl-3,6-dihydroxycarbazole with two different 1,4-benzoquinones in the presence of an oxidant (chloranil) and a Lewis acid (BF3OEt2). The unique synthetic control obtained originates from the selectivity obtained upon reacting N-benzyl-2,7-di-tert-butyl-3,6-dihydroxycarbazole with an electron-rich benzoquinone to give first the C-C bond formation and then subsequently the dibenzofuran formation with high regioselectivity. Herein the first synthesis of unsymmetrical antiaromatic azatrioxa[8]circulenes and the full characterization using NMR spectroscopy, optical spectroscopy, electrochemistry, computational techniques and single crystal X-ray crystallography is reported. The controlled stepwise condensation of N-benzyl-2,7-di-tert-butyl-3,6-dihydroxycarbazole with two different 1,4-benzoquinones gives selectively the unsymmetrical azatrioxa[8]circulenes.


The Value of Motion: Patient-Reported Outcome Measures Are Correlated With Range of Motion in Total Ankle Replacement.
The proposed benefit of total ankle replacement (TAR) over ankle fusion is preserved ankle motion, thus we hypothesized that an increase in range of motion (ROM) is positively correlated with validated patient-reported outcome measures (PROMs) in individuals receiving TAR. Patients undergoing TAR at a single academic medical center between 2007 and 2013 were evaluated in this study. In addition to a minimum of 2-year follow-up, complete preoperative and postoperative outcome measures for the Foot and Ankle Disability Index (FADI), Short Musculoskeletal Function Assessment (SMFA) Bother and Function Indices, Visual Analog Scale (VAS), and 36-Item Short Form Health Survey (SF-36) were requisite for inclusion. Standardized weightbearing maximum dorsiflexion and plantarflexion sagittal radiographs were obtained and previously described ankle and foot measurements were performed to determine ankle ROM. Eighty-eight patients met inclusion criteria (33 INBONE, 18 Salto-Talaris, 37 STAR). Mean time to final ROM radiographs was 43.8 months (range 24-89 months). All aforementioned PROMs improved between preoperative evaluation and most recent follow-up ( P < .01). Final ankle ROM was significantly correlated with postoperative FADI, SF-36 Mental Component Summary (MCS), SMFA Bother and Function Indices, and VAS. Additionally, dorsiflexion was positively associated with FADI, SF-36 MCS, and SMFA Function ( P < .05) but plantarflexion had no such influence on outcomes. No differences were identified with subset stratification by prosthesis type, fixed versus mobile-bearing design or etiology. In this TAR cohort with prospectively collected outcomes data, radiographic sagittal plane ankle motion was positively correlated with multiple PROMs. Disease-specific and generic health-related quality of life PROMs demonstrated improvement postoperatively in all domains when evaluating final total range of motion. Patients who undergo TAR for end-stage osteoarthritis with improvement in ROM demonstrate a direct correlation with improved patient-centric metrics and outcome scores. Level III: Retrospective comparative study.


AT-RvD1 combined with DEX is highly effective in treating TNF-α-mediated disruption of the salivary gland epithelium.
Sjögren's syndrome (SS) is an autoimmune disorder characterized by chronic inflammation and destruction of salivary and lacrimal glands leading to dry mouth and dry eyes, respectively. Currently, the etiology of SS is unknown and the current therapies have no permanent benefit; therefore, new approaches are necessary to effectively treat this condition. Resolvins are highly potent endogenous lipid mediators that are synthesized during the resolution of inflammation to restore tissue homeostasis. Previous studies indicate that the resolvin family member, RvD1, binds to the ALX/FPR2 receptor to block inflammatory signals caused by tumor necrosis factor-alpha (TNF-α) in the salivary epithelium. More recently, the corticosteroid, dexamethasone (DEX), was shown to be effective in reducing salivary gland inflammation. However, DEX, as with other corticosteroids, elicits adverse secondary effects that could be ameliorated when used in smaller doses. Therefore, we investigated whether the more stable aspirin-triggered (AT) epimer, AT-RvD1, combined with reduced doses of DEX is effective in treating TNF-α-mediated disruption of polarized rat parotid gland (Par-C10) epithelial cell clusters. Our results indicate that AT-RvD1 and DEX individually reduced TNF-α-mediated alteration in the salivary epithelium (i.e, maintained cell cluster formation, increased lumen size, reduced apoptosis, and preserved cell survival signaling responses) as compared to untreated cells. Furthermore, AT-RvD1 combined with a reduced dose of DEX produced stronger responses (i.e., robust salivary cell cluster formation, larger lumen sizes, further reduced apoptosis, and sustained survival signaling responses) as compared to those observed with individual treatments. These studies demonstrate that AT-RvD1 combined with DEX is highly effective in treating TNF-α-mediated disruption of salivary gland epithelium.


High-throughput transcriptomics reveals common and strain-specific responses of human macrophages to infection with Mycobacterium abscessus Smooth and Rough variants.
Mycobacterium abscessus (MAB) is an emerging pathogen causing pulmonary infections in those with inflammatory lung disorders, such as Cystic Fibrosis (CF), and is associated with the highest fatality rate among rapidly growing mycobacteria (RGM). Phenotypically, MAB manifests as either a Smooth (MAB-S) or a Rough (MAB-R) morphotype, which differ in their levels of cell wall glycopeptidolipids (GPLs) and in their pathogenicity in vivo. As one of the primary immune cells encountered by MAB, we sought to examine the early transcriptional events within macrophages, following infection with both MAB-S or MAB-R. We sampled the transcriptomes (mRNA and miRNA) of THP-1-derived macrophages infected with both MAB-R and MAB-S at 1, 4 and 24 h post-infection (hpi) using RNA-seq. A core set of 606 genes showed consistent expression profiles in response to both morphotypes, corresponding to the early transcriptional response to MAB. The core response is type I Interferon (IFN)-driven, involving the NF-κB and MAPK signaling pathways with concomitant pro-inflammatory cytokine production, and network analysis identified STAT1, EGR1, and SRC as key hub and bottleneck genes. MAB-S elicited a more robust transcriptional response at both the mRNA and miRNA levels, which was reflected in higher cytokine levels in culture supernatants. The transcriptional profiles of macrophages infected with both morphotypes were highly correlated, however, and a direct comparison identified few genes to distinguish them. Most of the induced miRNAs have previously been associated with mycobacterial infection and overall miRNA expression patterns were similarly highly correlated between the morphotypes. The report here details the first whole transcriptome analysis of the early macrophage response to MAB infection. The overall picture at the early stages of macrophage infection is similar to that of other mycobacteria, reflected in a core type I IFN and pro-inflammatory cytokine response. Large-scale transcriptional differences in the host response to the different MAB morphotypes are not evident in the early stages of infection, however the subset of genes with distinct expression profiles suggest potentially interesting differences in internal trafficking of MAB within macrophages.


Treading a tightrope: Professional perspectives on balancing the rights of patient's and relative's under the Mental Health Act in England.
Involuntary detention is used internationally to detain and treat people who are deemed to have a mental disorder. In England and Wales, approved mental health professionals (AMHPs) co-ordinate Mental Health Act assessments which allow for patients to be detained. AMHPs have legal duties to identify, inform and consult with a patient's nearest relative (NR), who are, in turn, given powers to initiate or challenge detention. Our study takes an original approach through examining how AMHPs interpret their duties towards nearest relatives. We adopted a two-stage design, which involved an online questionnaire with 55 AMHPs and focus group discussions with 33 AMHPs. The research was conducted in England between 2017 and 2018. Our questionnaire found that a high proportion of AMHPs reported that they had spoken to NRs for background information when assessing patients under the Mental Health Act. However, AMHPs were less likely to ask patients about their views of involving the NR prior to assessment. Focus group findings showed that AMHPs saw the NR role as offering an important 'safeguard' on the basis that NRs could provide information about the patient and advocate on their behalf. AMHPs identified practical difficulties in balancing their legal obligation towards NRs and patients; particularly where issues of potential abuse were raised or where patients had identified that they did not want NR involvement. While AMHPs stated that they sought to prioritise patient wishes regarding confidentiality, their accounts identified that patient consent about information sharing was sometimes implied rather than sought explicitly. Our findings reinforce conclusions by the recent Independent Review of the MHA, which states that current NR provisions are 'outdated, variable and insufficient'. We identify that current practice could be improved using advanced choice documents and outline implications for AMHP practice.


Expression of the gene cluster associated with the Escherichia coli pilus adhesin K99.
The biogenesis of the pilus adhesin K99 is dependent on the expression of eight contiguous genes, fanA to fanH. Transposon mutants were prepared by using TnlacZ and TnphoA, and selected transposon mutants were used to measure expression of each K99 gene. Expression of the K99 genes is likely controlled at the transcription level, since in general, there were no differences between the results obtained with the two transposons. fanC was the most highly expressed, and fanD was expressed at very low levels. The expression of TnlacZ fusions in fanA and fanB fusions was high. Deletion of fanA, fanB, and part of fanC abolished the expression of fanD but had no effect on the distal genes fanE to fanH. To locate the DNA regions required for expression of fanE to fanH, deletion mutations were prepared and the effects on expression of fanE to fanH were determined. The deletion of a segment between fanD and fanE abolished fanE and fanF expression but did not affect fanG and fanH. The deletion of a portion of fanF (approximately 1 kb proximal to fanG) abolished the expression of fanG and fanH. These results indicate the presence of regulatory elements proximal to fanE and to fanG. Putative promoters were identified in these regions by DNA homology and by primer extension. A stem-loop structure that may act as a transcriptional attenuator of fanF was also found at the beginning of fanF. These data confirm our previous model of K99 transcriptional organization.


Aortic dissection in patients with Marfan syndrome based on the IRAD data.
Between January 1996 and May 2017, the International Registry on Acute Aortic Dissections has collected information on a total of 6,424 consecutive patients with acute aortic dissection, including 258 individuals with a diagnosis of Marfan syndrome. Patients with Marfan syndrome presented at a significantly younger age compared to patients without Marfan syndrome (38.2±13.2 vs. 63.0±14.0 years; P<0.001) and in general had fewer comorbidities, although they more frequently had a known aortic aneurysm and history of prior cardiac surgery. We noted significantly larger diameters of the aortic annulus and root in the Marfan syndrome cohort, but no larger diameters more distally. The in-hospital mortality in type A dissection was not significantly different in patients with or without Marfan syndrome, despite the differences in age and comorbidities and the lower incidence of aortic rupture in the Marfan syndrome cohort. In contrast, the in-hospital mortality of Marfan syndrome patients with type B dissection appears to be lower than that of patients without Marfan syndrome. The Marfan syndrome cohort that was treated with open surgery for type B dissection seemed to do especially well, with a 0% mortality rate (n=27). Follow-up data for type A and B dissections combined show an estimated five-year survival rate of 80.1% and an estimated reintervention rate of 55.3% in patients with Marfan syndrome. Such a high rate of reinterventions highlights the need for careful surveillance and treatment for patients with Marfan syndrome surviving the acute phase of aortic dissection.


Idiopathic ventricular arrhythmias originating from the aortic root prevalence, electrocardiographic and electrophysiologic characteristics, and results of radiofrequency catheter ablation.
This study investigated the prevalence and electrocardiographic and electrophysiologic characteristics of aortic root ventricular arrhythmias (VAs). Idiopathic VAs originating from the ostium of the left ventricle may be ablated at the base of the aortic cusps. We studied 265 patients with idiopathic VAs with an inferior QRS-axis morphology. The successful ablation site was within (or below) the aortic cusps in 44 patients (16.6%). The site of the origin was the left coronary cusp (LCC) in 24 (54.5%), the right coronary cusp (RCC) in 14 (31.8%), the noncoronary cusp (NCC) in 1 (2.3%), and at the junction between the LCC and RCC (L-RCC) in 5 (11.4%) cases. The maximum amplitude of the R-wave in the inferior leads was significantly greater with an LCC than with an RCC origin (p < 0.05). The ratio of the R-wave amplitude in leads II and III was significantly greater with an LCC than with an RCC origin (p < 0.01) and was significantly smaller in the NCC than in the other sites (p < 0.0001). The ventricular deflection in the His bundle electrogram was significantly later relative to the surface QRS with an LCC or L-RCC origin than with an RCC or NCC origin (p < 0.0001). The ratio of the atrial-to-ventricular deflection amplitude was significantly greater in the NCC than in the other sites (p < 0.0001). No other factors predicted the site of origin. Idiopathic VAs are more common in the LCC than in the RCC and rarely arise from the NCC. The electrocardiogram is useful for differentiating the site of origin.


Network structure of anticipatory pleasure and risk features: Evidence from a large college sample.
Investigating the relationship between anticipatory pleasure deficits and risk features of mental disorders not only theoretically benefits the understanding of anhedonia, but could also facilitate early detection and intervention of mental disorders. Using network analysis, the present study examined the pattern of relationship between anticipatory pleasure and risk features of schizophrenia spectrum, depressive, anxiety, autism spectrum, and obsessive-compulsive disorders in a large sample of college students (n = 2152). It was found that interpersonal features of schizotypal personality traits and poor social skills of autistic traits showed strong correlation with low social anticipatory pleasure. Depressive symptoms severity was weakly associated with reduced abstract anticipatory pleasure, while obsessive-compulsive traits were weakly associated with high contextual anticipatory pleasure. No significant correlation was found between anxiety symptoms severity and anticipatory pleasure. Social anticipatory pleasure had the highest strength centrality among all anticipatory pleasure components, while interpersonal features of schizotypal personality traits had the highest strength centrality in the whole network. Our findings suggest that impaired anticipatory pleasure, especially social anticipatory pleasure, is a particular feature of schizotypal personality traits and autistic traits. Our findings may have implications for intervention in that the social component may be a target to improve anhedonia in individuals with schizotypal and autistic traits, while interpersonal features may be a key treatment target given that it was central to the relationship between anticipatory pleasure and risk features.


Ubiquitylation of the COMPASS component Swd2 links H2B ubiquitylation to H3K4 trimethylation.
Mono-ubiquitylation of histone H2B correlates with transcriptional activation and is required for di- and trimethylation at Lys 4 on the histone H3 tail (H3K4) by the SET1/COMPASS methyltransferase complex through a poorly characterized trans-tail pathway. Here we show that mono-ubiquitylation of histone H2B promotes ubiquitylation at Lys 68 and Lys 69 of Swd2, the essential component of SET1/COMPASS in Saccharomyces cerevisiae. We found that Rad6/Bre1 ubiquitylation enzymes responsible for H2B ubiquitylation also participate directly in Swd2 modification. Preventing Swd2 or H2B ubiquitylation did not affect Set1 stability, interaction of Swd2 with Set1 or the ability of Swd2 to interact with chromatin. However, we found that mutation of Lys 68 and Lys 69 of Swd2 markedly reduced trimethylation, and to a lesser extent dimethylation, of H3K4 at the 5'-end of transcribing genes without affecting monomethylation. This effect results from the ability of Swd2 ubiquitylation to control recruitment of Spp1, a COMPASS subunit necessary for trimethylation. Our results further indicate that Swd2 is a major H3-binding component of COMPASS. Swd2 thus represents a key factor that mediates crosstalk between H2B ubiquitylation and H3K4 trimethylation on chromatin.


Myth-Busting? Confronting Six Common Perceptions about Unconditional Cash Transfers as a Poverty Reduction Strategy in Africa.
This paper summarizes evidence on six perceptions associated with cash transfer programming, using eight rigorous evaluations conducted on large-scale government unconditional cash transfers in sub-Saharan Africa under the Transfer Project. Specifically, it investigates if transfers: 1) induce higher spending on alcohol or tobacco; 2) are fully consumed (rather than invested); 3) create dependency (reduce participation in productive activities); 4) increase fertility; 5) lead to negative community-level economic impacts (including price distortion and inflation); and 6) are fiscally unsustainable. The paper presents evidence refuting each claim, leading to the conclusion that these perceptions-insofar as they are utilized in policy debates-undercut potential improvements in well-being and livelihood strengthening among the poor, which these programs can bring about in sub-Saharan Africa, and globally. It concludes by underscoring outstanding research gaps and policy implications for the continued expansion of unconditional cash transfers in the region and beyond.


The association between hip morphology parameters and nineteen-year risk of end-stage osteoarthritis of the hip: a nested case-control study.
Subtle deformities of the hip joint are implicated in the etiology of osteoarthritis (OA) of the hip. Parameters that quantify these deformities may aid understanding of these associations. We undertook this study to examine relationships between such parameters and the 19-year risk of total hip arthroplasty (THA) for end-stage OA. A new software program designed for measuring morphologic parameters around the hip was developed and validated in a reliability study. THA was the outcome measure for end-stage OA. A nested case-control study was used with individuals from a cohort of 1,003 women who were recruited at year 1 in 1989 and followed up to year 20 (the Chingford Study). All hips with THA by year 20 and 243 randomly selected control hips were studied. Pelvis radiographs obtained at year 2 were analyzed for variations in hip morphology. Measurements were compared between the THA case group and the control group. Patients with THA had a higher prevalence of cam deformity than did their respective controls (median alpha angle 62.4° versus 45.8° [P = 0.001]; mean modified triangular index height 28.5 mm versus 26.9 mm [P = 0.001]) as well as a higher prevalence of acetabular dysplasia (mean lateral center edge angle 29.5° versus 34.3° [P = 0.001]; median extrusion index 0.25 versus 0.185 [P = 0.009]). Logistic regression analyses clustering by subject and adjusting for radiographic hip OA at year 2 showed that these morphologic parameters were still significantly associated with THA by year 20. The alpha angle and lateral center edge angle predicted the risk of THA independently when included in the same model. This investigation describes measurements that predict the risk of THA for end-stage OA by year 20, independently of the presence of radiographic hip OA at year 2. These measurements can be made on an anteroposterior pelvis radiograph, which is an inexpensive and commonly used clinical method of investigation.


The role of race in thyroid cancer: systematic review.
The incidence of thyroid cancer is increasing. There is conflicting evidence as to why. However, studies suggest that it is not an apparent increase resulting from enhanced diagnostic practices, but a true increase with more affected patients. This study aimed to assess racial variation in thyroid cancer. A narrative systematic review of the literature was conducted. Eight retrospective cohort studies were identified, comprising 611 777 adult patients. Variations exist between racial groups, which are also dependent on gender; white patients have a slightly higher male population when compared to their counterparts. Black and white patients have a higher proportion of follicular cancer. Hispanics were younger at the age of diagnosis. Outcomes are greatly affected by socioeconomic status. This study identified many gaps in the way that these types of data are presented. A more concise manner of reporting, with individual-level risk factors, is recommended.


Impaired function of Fanconi anemia type C-deficient macrophages.
FA is a genetic disorder characterized by BM failure, developmental defects, and cancer predisposition. Previous studies suggest that FA patients exhibit alterations in immunologic function. However, it is unclear whether the defects are immune cell-autonomous or secondary to leukopenia from evolving BM failure. Given the central role that macrophages have in the innate immune response, inflammation resolution, and antigen presentation for acquired immunity, we examined whether macrophages from Fancc-/- mice exhibit impaired function. Peritoneal inflammation induced by LPS or sodium periodate resulted in reduced monocyte/macrophage recruitment in Fancc-/- mice compared with WT controls. Fancc-/- mice also had decreased inflammatory monocytes mobilized into the peripheral blood after LPS treatment compared with controls. Furthermore, Fancc-/- peritoneal macrophages displayed cell-autonomous defects in function, including impaired adhesion to FN or endothelial cells, reduced chemoattractant-mediated migration, and decreased phagocytosis. Moreover, dysregulated F-actin rearrangement was detected in Fancc-/- macrophages after adhesion to FN, which was consistent with an observed reduction in RhoA-GTP levels. Importantly, these data suggest that impaired cytoskeletal rearrangements in Fancc-/- macrophages may be the common mechanism responsible for cell-autonomous defects detected in vitro, as well as altered monocyte/macrophage trafficking in vivo.


An assessment of community pharmacists' attitudes towards professional practice in the Republic of Moldova.
Pharmacy in Moldova is undergoing a period of transition. The professional practice is adjusting to a market-oriented economy from the previous Soviet system. The pharmaceutical sector has been liberalised giving rise to a significant increase in the number of community pharmacies. This has led to some adverse effects on the profession of pharmacy with pharmacists having considerable difficulties fulfilling their professional aspirations and possibly losing confidence in further developing their professional role. To assess community pharmacists' attitudes towards their professional practice and to determine their perceived competence in various pharmaceutical activities. A questionnaire which addressed managerial activities, dispensing activities, pharmaceutical care activities, inter-professional relationships, public health and competence was mailed to 600 community pharmacists who were asked to score the importance and perceived competence for each activity on a scale ranging from 0-5. In the case of pharmaceutical care activities, pharmacists were asked to score their degree of agreement or disagreement as to whether it is the responsibility of the pharmacist to engage in specific pharmaceutical care activities. A total of 370 valid questionnaires were returned giving a response rate of 61.7%. Managerial and dispensing activities were scored the highest both in terms of perceived importance and competence. The more innovative pharmaceutical care activities scored relatively low. Overall scores relating to the importance of pharmacists engaging in public health activities appear to be the lowest of the entire questionnaire. Younger pharmacists between the ages of 22-30 obtained significantly higher scores with regards to the perceived pharmacist's responsibility in engaging in various pharmaceutical care activities. Respondents who practiced in an accredited pharmacy scored higher in the majority of questions. Pharmacists in Moldova appear to be deeply rooted in the traditional approach to the practice of pharmacy pertaining mainly to distributive practice model and are somewhat distant from the other models of practice such as pharmaceutical care, drug information and self-care.


Alzheimer and Lewy body pathology or Creutzfeldt-Jakob disease.
The objective of this work is to describe the neuropathological findings of a patient clinically presenting with rapidly progressive nonspecific neurological symptoms suggestive of Creutzfeldt-Jakob disease. Methods used were clinical description with laboratory analyses, repeated electroencephalogram, cerebral computed tomography, magnetic resonance imaging studies and details on neuropathological work-up. Neuropathological examination excluded Creutzfeldt-Jakob disease. By contrast other neurodegenerative changes combining Alzheimer-type pathology and Lewy body pathology were detected as the most likely substrate of neurological symptoms. Dementia with Lewy bodies should be included in the differential diagnosis in individuals presenting with rapidly progressive dementia.


Internet Interventions for Adults with Anxiety and Mood Disorders: A Narrative Umbrella Review of Recent Meta-Analyses.
Internet-delivered cognitive behaviour therapy (ICBT) has existed for 20 years and there are now several controlled trials for a range of problems. In this paper, we focused on recent meta-analytic reviews of the literature and found moderate to large effects reported for panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, and major depression. In total, we reviewed 9 recent meta-analytic reviews out of a total of 618 meta-analytic reviews identified using our search terms. In these selected reviews, 166 studies were included, including overlap in reviews on similar conditions. We also covered a recent review on transdiagnostic treatments and 2 reviews on face-to-face v. internet treatment. The growing number of meta-analytic reviews of studies now suggests that ICBT works and can be as effective as face-to-face therapy.


The nitrogen concentration effect on Ce doped SiOxNy emission: towards optimized Ce3+ for LED applications.
Ce-Doped SiOxNy films are deposited by magnetron reactive sputtering from a CeO2 target under a nitrogen reactive gas atmosphere. Visible photoluminescence measurements regarding the nitrogen gas flow reveal a large emission band centered at 450 nm for a sample deposited under a 2 sccm flow. Special attention is paid to the origin of such an emission at high nitrogen concentration. Different emitting centers are suggested in Ce doped SiOxNy films (e.g. band tails, CeO2, Ce clusters, Ce3+ ions), with different activation scenarios to explain the luminescence. X-ray photoelectron spectroscopy (XPS) reveals the exclusive presence of Ce3+ ions whatever the nitrogen or Ce concentrations, while transmission electron microscopy (TEM) shows no clusters or silicates upon high temperature annealing. With the help of photoluminescence excitation spectroscopy (PLE), a wide excitation range from 250 nm up to 400 nm is revealed and various excitations of Ce3+ ions are proposed involving direct or indirect mechanisms. Nitrogen concentration plays an important role in Ce3+ emission by modifying Ce surroundings, reducing the Si phase volume in SiOxNy and causing a nephelauxetic effect. Taking into account the optimized nitrogen growth parameters, the Ce concentration is analyzed as a new parameter. Under UV excitation, a strong emission is visible to the naked eye with high Ce3+ concentration (6 at%). No saturation of the photoluminescence intensity is observed, confirming again the lack of Ce cluster or silicate phase formation due to the nitrogen presence.


Using BD Vacutainer CD4 Stabilization Tubes for Absolute Cluster of Differentiation Type 4 Cell Count Measurement on BD FacsCount and Partec Cyflow Cytometers: A Method Comparison Study from Zimbabwe.
Blood collected in conventional EDTA tubes requires laboratory analysis within 48 hours to provide valid CD4 cell count results. This restricts access to HIV care for patients from rural areas in resource-constraint settings due to sample transportation problems. Stabilization Tubes with extended storage duration have been developed but not yet evaluated comprehensively. To investigate stability of absolute CD4 cell count measurement of samples in BD Vacutainer CD4 Stabilization Tubes over the course of 30 days. This was a laboratory-based method comparison study conducted at a rural district hospital in Beitbridge, Zimbabwe. Whole peripheral blood from 88 HIV positive adults was drawn into BD Vacutainer CD4 Stabilization Tubes and re-tested 1, 2, 3, 5, 7, 14 and 30 days after collection on BD FacsCount and Partec Cyflow cytometers in parallel. Absolute CD4 cell levels were compared to results from paired samples in EDTA tubes analysed on BD FacsCount at the day of sample collection (references methodology). Bland-Altman analysis based on ratios of the median CD4 counts was used, with acceptable variation ranges for Limits of Agreements of +/-20%. Differences in ratios of the medians remained below 10% until day 21 on BD FacsCount and until day 5 on Partec Cyflow. Variations of Limits of Agreement were beyond 20% after day 1 on both cytometers. Specimen quality decreased steadily after day 5, with only 68% and 40% of samples yielding results on BD FacsCount and Partec Cyflow at day 21, respectively. We do not recommend the use of BD Vacutainer CD4 Stabilization Tubes for absolute CD4 cell count measurement on BD FacsCount or Partec Cyflow due to large variation of results and decay of specimen quality. Alternative technologies for enhanced CD4 testing in settings with limited laboratory and sample transportation capacity still need to be developed.


Immunohistochemical study of microphthalmia transcription factor and tyrosinase in angiomyolipoma of the kidney, renal cell carcinoma, and renal and retroperitoneal sarcomas: comparative evaluation with traditional diagnostic markers.
Angiomyolipoma has a unique immunophenotype with co-expression of muscle-specific actin and melanocytic markers such as HMB-45 and Melan-A. The most recently developed melanocytic markers, microphthalmia transcription factor and tyrosinase, have not been studied in the diagnosis of angiomyolipoma. We tested 29 renal angiomyolipomas (21 classic histology, 4 epithelioid variants, 2 lipomatous variants, and 2 leiomyomatous variants) with an immunohistochemical panel, including microphthalmia transcription factor, tyrosinase, HMB-45, Melan-A, and muscle-specific actin. Results were compared with 15 renal cell carcinomas (9 conventional types, 6 with sarcomatoid change), 2 leiomyosarcomas, 5 liposarcomas, and 1 unclassified high-grade sarcoma. Microphthalmia transcription factor expression was seen in 22 of 29 angiomyolipomas, one renal cell carcinoma, and one well-differentiated liposarcoma (that is, 2 of 23 non-angiomyolipomas; sensitivity 75%, specificity 91%). Tyrosinase expression was seen in 4 of 29 angiomyolipomas and 0 of 23 non-angiomyolipomas (sensitivity 14%, specificity 100%). HMB-45 was positive in 24 of 29 angiomyolipomas and 0 of 23 non-angiomyolipomas (sensitivity 83%, specificity 100%). Melan-A was expressed by 25 of 29 angiomyolipomas and 0 of 23 non-angiomyolipomas (sensitivity 86%, specificity 100%). Muscle-specific actin was expressed by 29 of 29 angiomyolipomas and 2 of 23 non-angiomyolipomas (both leiomyosarcomas; sensitivity 100%, specificity 91% [100% excluding leiomyosarcomas]). Microphthalmia transcription factor showed the most widespread staining in angiomyolipoma (50% of cases staining more than half of the tumor cells) followed by Melan-A (24% of cases staining more than 50%). Only three cases showed positivity for all four melanocytic markers, while in one case each only microphthalmia transcription factor and Melan-A were positive. We conclude that microphthalmia transcription factor, but not tyrosinase immunostaining, has a sensitivity and specificity that rivals those of the established markers, HMB-45 and Melan-A, in the diagnosis of angiomyolipoma. Our data supports the use of a panel in difficult cases that includes antibodies to microphthalmia transcription factor, either Melan-A or HMB-45, and muscle-specific actin to provide the best mix of high sensitivity, high specificity, nuclear and cytoplasmic immunolocalization, and widespread staining of cells within a given tumor.