[Learning from fungus allergy in atopic dermatitis patients].
It has been recognized that there are considerable variations in their skin reactivity to environmental allergens as well as in immunoreactivities, even in AD patients with similar signs and symptoms. Some AD patients have high serum IgE antibody levels, while others show low levels. There are also differences in the kinds of triggering factors that are related to the development and maintenance of AD, e.g., allergic or non-allergic. Even among AD patients with high titers of serum IgE antibodies, the kinds and number of allergens involved in the exacerbation of AD are different and can change with time. The types of the underlying allergic reactions vary as well, i.e., some show immediate reactions, while others show delayed type hypersensitivity responses to environmental allergens. Thus, even AD patients diagnosed by the established criteria may have remarkably different backgrounds. When we looked over our published data, we noticed that there were differences in levels of IgE RAST and skin reactions between AD with atopic respiratory diseases (ARD) and pure AD without ARD. Levels of IgE RAST against airborne allergens, which come into the body mainly through the respiratory tract, were higher in AD with ARD, while those against allergens such as Candida albicans and Malassezia furfur, which can colonize on the skin, were higher in pure AD. In addition to these Th2-mediated immunological abnormalities, Th1-mediated DTH reaction and lymphocyte proliferation indices against airborne allergens were remarkably low in AD with ARD, whereas those against Candida albicans and Malassezia furfur were relatively preserved, although they were lower than those found in normal subjects. We understand from these findings that routes of allergen entry are important for the outcome of the resultant allergic reactions. This point of view is important answering questions such as how AD develops and how it can be prevented from the insults of each allergen.


Community care for people with chronic conditions: an analysis of nine studies of health and social service utilization in Ontario.
A series of studies conducted in the same region found that programmatic, community-based health and social service interventions have a positive impact on client well-being. These proactive interventions, designed to address the full range of health and social needs, were usually provided at the same--or even lower--costs as uncoordinated, illness-focused care. The results of this series suggest that across-the-board health care reduction, at least in a system of national health insurance, will produce poorer results, at higher cost, for people with chronic conditions living in the community. Policy planners need more research that concentrates on comparisons of outcomes between and within different models of health and social service delivery. The studies should be designed to help them determine who benefits from different service configurations carried out within a range of policy environments at various costs.


Facial emotion perception in patients with epilepsy: A systematic review with meta-analysis.
Facial emotion perception is a fundamental social competency relying on a specialised, yet distributed, neural network. This review aimed to determine whether patients with epilepsy have facial emotion perception accuracy impairments overall, or for a subset of emotions (anger, disgust, happiness, sadness, fear, and surprise), and the relationship to epilepsy type, demographic/treatment variables, and brain organisation. Database searches used PRISMA guidelines with strict inclusion/exclusion criteria. Thirty included studies assessed patients with temporal lobe (TLE; n=709), frontocentral (FCE; n=22), and genetic generalised (GGE; n=48) epilepsy. Large deficits emerged in patients with epilepsy compared to controls (n=746; Hedges' g=0.908-1.076). Patients with TLE were significantly impaired on all emotions except surprise; patients with GGE were significantly impaired in anger, disgust, and fear perception. Meta-regression of patients with TLE revealed younger age at testing was associated with lower accuracy. This review provides evidence for marked global deficits of emotion perception in epilepsy, with differential emotion-specific impairment patterns in patients with TLE and GGE.


Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.
Obesity is a major epidemic, but its causes are still unclear. In this article, we investigate the relation between the intake of high-fructose corn syrup (HFCS) and the development of obesity. We analyzed food consumption patterns by using US Department of Agriculture food consumption tables from 1967 to 2000. The consumption of HFCS increased > 1000% between 1970 and 1990, far exceeding the changes in intake of any other food or food group. HFCS now represents > 40% of caloric sweeteners added to foods and beverages and is the sole caloric sweetener in soft drinks in the United States. Our most conservative estimate of the consumption of HFCS indicates a daily average of 132 kcal for all Americans aged > or = 2 y, and the top 20% of consumers of caloric sweeteners ingest 316 kcal from HFCS/d. The increased use of HFCS in the United States mirrors the rapid increase in obesity. The digestion, absorption, and metabolism of fructose differ from those of glucose. Hepatic metabolism of fructose favors de novo lipogenesis. In addition, unlike glucose, fructose does not stimulate insulin secretion or enhance leptin production. Because insulin and leptin act as key afferent signals in the regulation of food intake and body weight, this suggests that dietary fructose may contribute to increased energy intake and weight gain. Furthermore, calorically sweetened beverages may enhance caloric overconsumption. Thus, the increase in consumption of HFCS has a temporal relation to the epidemic of obesity, and the overconsumption of HFCS in calorically sweetened beverages may play a role in the epidemic of obesity.


[Logopedic intervention in language learning disorderss].
The objective of this study is to analyze, from the conceptual point of view, logopaedic intervention in disorders of acquisition of language. We describe the 'model of intervention at three levels': reinforcing stimulation of language, restructuration of language and substitution of language. We analyze the concepts of 'ambiental intervention', from the naturalist point of view, that of functional exercises and of directed or formal exercises. We study the variables which affect the specificity of logopaedic treatments. As a specific example we describe intervention in auditory perception.


Effect of Molecular Dynamics and Internal Water Contact on the Photophysical Properties of Red pH-Sensitive Proteins.
The pH dependence of the absorption and (time-resolved) fluorescence of two red-shifted fluorescent proteins, mCardinal and mNeptune, was investigated. Decay-associated spectra were measured following fluorescence excitation at 470 nm in PBS buffer with a pH that ranged from 5.5 to 8.0. The fluorescence of both proteins shows two different decay components. mCardinal exhibits an increase in the long-lived fluorescence component with acidification from 1.34 ns at pH 8.0 to 1.62 ns at pH 5.5. An additional fast decay component with 0.64 ns at pH 8.0 up to 1.1 ns at pH 5.5 was found to be blue-shifted compared to the long-lived component. The fluorescence lifetime of mNeptune is insensitive to pH. DAS of mCardinal were simulated assuming a coupled two-level system to describe the 1S state of the chromophore within two different conformations of the protein. MD simulations were conducted to correlate the experimentally observed pH-induced change in the lifetime in mCardinal with its molecular properties. While the chromophores of both protein variants are stabilized by the same number of hydrogen bonds, it was found that the chromophore in mCardinal exhibits more water contacts compared to mNeptune. In mCardinal, interaction between the chromophore and Glu-145 is reduced as compared to mNeptune, but interaction with Thr-147 which is Ser-147 in mNeptune is stronger in mCardinal. Therefore, the dynamics of the excited-state proton transfer (ESPT) might be different in mCardinal and mNeptune. The pH dependency of ESPT is suggested as a key mechanism for pH sensitivity.


Respiratory syncytial virus glycoprotein expression in human and simian cell lines.
Glycoproteins synthesized in both human (HeLa and HEp-2) and simian (Vero and BS-C-1) cell lines following infection with two different strains of respiratory syncytial virus (A2 and Long) were analysed by SDS-PAGE following immunoprecipitation with monoclonal antibodies. Minor virus strain-dependent differences in the large glycoprotein, G, and the fusion protein polypeptides F1 and F2 were observed together with minor cell line-dependent differences in the size of the F2 polypeptide. Major quantities of two glycoproteins, termed Ga (50K) and Gb (45K), were detected in A2 strain-, and to a lesser extent in Long strain-, infected simian cells. These proteins were also present in infected human cells, but in much reduced amounts. Immunoprecipitation with anti-G monoclonal antibodies demonstrated that Ga and Gb shared different epitopes with G.


Case of isolated thoracic aortic aneurysm as a manifestation of undiscovered giant cell arteritis.
A 73-year-old woman was referred to our hospital to investigate dilatation of an aortic arch which had been detected by a chest roentgenogram and severe aortic valve regurgitation detected by echocardiography. On admission, a computed tomography scan of the chest showed a large fusiform ascending aortic aneurysm. She had not shown any symptoms such as headache or polymyalgia rheumatica and had no significant coronary atherosclerosis. She underwent aneurysmectomy and reconstruction of the ascending aorta using cardiopulmonary bypass without aortic valve replacement, and pathological examination of the aneurismal wall revealed giant cell arteritis (GCA). Preoperatively, she did not have any temporal pain, and no signs of inflammation were detected serologically. Postoperatively, aortic valve regurgitation improved and she did well. However, three months after the surgery, she died suddenly due to the rupture or dissection of aorta. In the Japanese population, GCA is reportedly a rare cause of aortic aneurysm. However, retrospective studies show that GCA affects the aorta and that thoracic aortic aneurysm is a possible complication of GCA. In cases of the thoracic aortic aneurysms with unknown etiology, there is a possibility that GCA is the cause of the aortic aneurysm.


The RecA protein as a model molecule for molecular systematic studies of bacteria: comparison of trees of RecAs and 16S rRNAs from the same species.
The evolution of the RecA protein was analyzed using molecular phylogenetic techniques. Phylogenetic trees of all currently available complete RecA proteins were inferred using multiple maximum parsimony and distance matrix methods. Comparison and analysis of the trees reveal that the inferred relationships among these proteins are highly robust. The RecA trees show consistent subdivisions corresponding to many of the major bacterial groups found in trees of other molecules including the alpha, beta, gamma, delta, epsilon proteobacteria, cyanobacteria, high-GC gram-positives, and the Deinococcus-Thermus group. However, there are interesting differences between the RecA trees and these other trees. For example, in all the RecA trees the proteins from gram-positive species are not monophyletic. In addition, the RecAs of the cyanobacteria consistently group with those of the high-GC gram-positives. To evaluate possible causes and implications of these and other differences phylogenetic trees were generated for small-subunit rRNA sequences from the same (or closely related) species as represented in the RecA analysis. The trees of the two molecules using these equivalent species-sets are highly congruent and have similar resolving power for close, medium, and deep branches in the history of bacteria. The implications of the particular similarities and differences between the trees are discussed. Some of the features that make RecA useful for molecular systematics and for studies of protein evolution are also discussed.


Non-specific bronchial hyper-reactivity in workers exposed to toluene di-isocyanate, diphenyl methane di-isocyanate and colophony.
Non-specific bronchial reactivity to histamine has been measured before specific occupational bronchial tests in the following groups: 51 workers exposed to toluene di-isocyanate (TDI); 40 workers exposed to diphenylmethane diisocyanate (MDI); 45 electronics workers exposed to colophony fumes and 13 unexposed controls. Finally 38 electronics workers had repeated measurements after moving their place of work. The results showed that histamine reactivity was an important, but not obligatory, factor in the development of occupational asthma, and that it appeared to be the result rather than the cause of occupational asthma, as it returned towards normal in workers removed from exposure. TDI and MDI were shown to be acting as specific causes of occupational asthma rather than nonspecific irritants at concentrations up to 0.02 ppm. There was evidence that some irritant reactions to colophony were occurring at exposure levels encountered at work, but that the majority of workers with colophony asthma were having specific reactions to the colophony fume.


Invasions but not extinctions change phylogenetic diversity of angiosperm assemblage on southeastern Pacific Oceanic islands.
We assessed changes in phylogenetic diversity of angiosperm flora on six oceanic islands located in the southeastern Pacific Ocean, by comparing flora from two periods: the pre-European colonization of islands and current times. We hypothesize that, in the time between these periods, extinction of local plant species and addition of exotic plants modified phylogenetic-α-diversity at different levels (deeper and terminal phylogeny) and increased phylo-β-diversity among islands. Based on floristic studies, we assembled a phylogenetic tree from occurrence data that includes 921 species, of which 165 and 756 were native or exotic in origin, respectively. Then, we studied change in the phylo-α-diversity and phylo-β-diversity (1 -Phylosor) by comparing pre-European and current times. Despite extinction of 18 native angiosperm species, an increase in species richness and phylo-α-diversity was observed for all islands studied, attributed to introduction of exotic plants (between 6 to 477 species per island). We did not observe significant variation of mean phylogenetic distance (MPD), a measure of the 'deeper' phylogenetic diversity of assemblages (e.g., orders, families), suggesting that neither extinctions nor introductions altered phylogenetic structure of the angiosperms of these islands. In regard to phylo-β-diversity, we detected temporal turnover (variation in phylogenetic composition) between periods to flora (0.38 ± 0.11). However, when analyses were performed only considering native plants, we did not observe significant temporal turnover between periods (0.07 ± 0.06). These results indicate that introduction of exotic angiosperms has contributed more notably than extinctions to the configuration of plant assemblages and phylogenetic diversity on the studied islands. Because phylogenetic diversity is closely related to functional diversity (species trait variations and roles performed by organisms), our results suggests that the introduction of exotic plants to these islands could have detrimental impacts for ecosystem functions and ecosystem services that islands provide (e.g. productivity).


[Accuracy of different body mass index reference values to predict body fat in adolescents].
This study evaluates the accuracy of cutoff points in the body mass index (BMI) for identifying adolescents with overweight, compared to the percentage of body fat, estimated by electric bioimpediance, in a probabilistic sample of 610 adolescents from 12 to 19 years of age (222 boys and 388 girls) enrolled in public schools in Niterói, Rio de Janeiro, Brazil. ROC was used to evaluate the sensitivity and specificity of BMI cutoffs from one Brazilian, two North American, and one international reference. The cutoff points in the study sample were lower than the other references, with 76% to 95% sensitivity and 75% to 95% specificity. The Brazilian cutoff points were also more sensitive (53% to 100%) as compared to the other references (40% to 86%). The international parameter showed better sensitivity for older adolescents, and the Northern American references for younger adolescents. BMI was a good proxy for adiposity, but cutoff points from other population references should be used with caution, since they can lead to classification errors in adolescents with overweight.


Is immediate reconstruction of the mandible with nonvascularized bone graft following resection of benign pathology a viable treatment option?
The purpose of this study was to address the following clinical question: Is immediate reconstruction of the mandible with a nonvascularized bone graft after resection of benign pathology a viable treatment option? Another purpose was to determine whether any variables affect the success of this treatment approach. The authors implemented a retrospective cohort study from a sample of patients diagnosed with a benign tumor of the mandible who were treated with segmental resection and primary reconstruction with an autogenous nonvascularized bone graft. The predictor variables were age, gender, lesion size, and diagnosis, and the outcome variable was graft success determined by re-establishment of mandibular continuity with sufficient bone for implant placement. The χ(2) test was used for statistical analysis of the categorical data and P values less than .05 were considered statistically significant. Twenty patients with benign mandibular tumors were treated with transoral resection and immediate reconstruction with nonvascularized bone grafts. The mean age was 28.3 years (range, 9 to 63 yr) and 55% (11 of 20) were men. The most common lesion type was ameloblastoma (13 of 20) and all patients underwent reconstruction with autogenous anterior iliac crest bone grafting. Ninety percent of patients (18 of 20) had successful reconstruction. Ten patients underwent successful implant placement and restoration. Using careful patient selection, treatment of benign pathology with transoral resection and immediate reconstruction with a nonvascularized bone graft from the anterior iliac crest can be successful. In addition, the total treatment time from implant restoration to return to preoperative function is minimized. Therefore, this method of treatment is a viable treatment option and an alternative to delayed reconstruction or reconstruction with vascularized bone flaps.


Uterus transplant: evidence and ethics.
Absolute uterine infertility affects millions of women in the United States and more throughout the world. For instance, each year in the United States about 5,000 hysterectomies are performed in women under the age of 24. In total, nearly 9 million women of reproductive age have had a hysterectomy. Based on fecundity rates, thousands of these women may be candidates for uterus transplantation. An ongoing study enrolling some of these potential recipients onto a uterus transplant "waiting list" has revealed that most of these women have Rokitansky syndrome, hysterectomy secondary to endometriosis, cervical cancer, or compelling personal accounts justifying their candidacy. Fertility restoration by uterus transplantation was derived from fertility preservation research, including the development of the radical trachelectomy, oxygenation and perfusion of the in situ uterus, and work with organ donor networks. A decade of modern animal research set the foundation for this human work. Ongoing experiments include stable, long-term large animal allografts for investigating immunosuppression regimens and other transplantation details. Each of the animal models has contributed to the current knowledge base. Recently, nonhuman primates have been used to further investigate the possibility of human uterus transplantation. Nonhuman primate anatomy is analogous to that of humans with notable exceptions. The first human uterus transplant surgery took place in 2000, but it did not result in a pregnancy. However, taken in total, the magnitude of the intervening work from multiple groups throughout the world has made uterus transplantation a topic for discussion. It may also soon be a reality.


Genetic counselor implicit bias and its effects on cognitive and affective exchanges in racially discordant simulations.
Previous studies have linked clinicians' implicit racial bias with less patient-centered communication between healthcare providers and patients in a variety of healthcare contexts. The current study extends this research by exploring the influence of implicit racial bias in genetic counselors' (GCs') facilitation of simulated clients' cognitive and emotional processing during genetic counseling sessions. We conducted a secondary analysis of a nationally representative sample of genetic counseling sessions of White and ethnic and/or racial minority (Black and Latinx) simulated clients with a subset of 60 GCs who had completed a Race Implicit Association Test (IAT). Linguistic Inquiry Word Count (LIWC) was applied to session transcripts to identify word use by the simulated client consistent with emotional and cognitive processing. The Roter Interaction Analysis System (RIAS) was used to link GC statements consistent with facilitation of emotional and cognitive processing, as used in previous studies. Multiple linear regression analyses were performed to relate LIWC and RIAS variables to GC IAT scores, client race/ethnicity, and statistical interaction between GC IAT scores and client race/ethnicity. GCs used more cognitive facilitation strategies with ethnic and/or racial minority than with White clients (p = .04). There were no statistically significant associations between GCs' pro-White implicit bias and GCs' facilitation of cognitive and emotional processing or clients' use of positive, negative, or cognitive process words. While implicit bias may affect some communication processes, our analysis did not show a relationship between GC IAT score and how GCs help clients process emotional or cognitive information conveyed during a session. It is also possible that the LIWC measure of cognitive and emotional processing is not a sensitive enough measure to capture an implicit bias effect if indeed one is present.


Degenerative Spondylolisthesis Is Related to Multiparity and Hysterectomies in Older Women.
A case-control study. To determine whether parity and abdominal surgeries are associated with degenerative spondylolisthesis (DS). DS is considered to be a major cause of low back pain (LBP) in the older population, with greater prevalence of DS among women. Because LBP and impaired abdominal muscle function are common during pregnancy and post-partum, parity-related abdominal muscle deficiency, resulting in poor spinal mechanics, could be a factor in the development of DS in women. Indeed a relationship between the number of pregnancies and DS was reported in one study. A total of 322 women between the ages of 40 and 80 (149 with DS and 173 controls) filled out a questionnaire providing information about their demographics, the number of full-term pregnancies, the number and types of abdominal surgeries (including cesarean section and hysterectomies), and age at menopause among other items. A binary logistic regression was used as a multivariate model to identify the variables associated with DS. Along with age and body mass index as covariates, the number of full-term pregnancies and the hysterectomy were significant predictors of DS. Other abdominal surgeries, cesarean section, or the number of years postmenopause were not significant predictors of DS in this regression model after adjusting for all other significant variables. Each full-term pregnancy seems to be associated with the 22% increase in odds of developing DS. Hysterectomy nearly doubles the odds of DS as compared to women who did not have hysterectomy. 4.


Stimulated emission depletion microscopy resolves individual nitrogen vacancy centers in diamond nanocrystals.
Nitrogen-vacancy (NV) color centers in nanodiamonds are highly promising for bioimaging and sensing. However, resolving individual NV centers within nanodiamond particles and the controlled addressing and readout of their spin state has remained a major challenge. Spatially stochastic super-resolution techniques cannot provide this capability in principle, whereas coordinate-controlled super-resolution imaging methods, like stimulated emission depletion (STED) microscopy, have been predicted to fail in nanodiamonds. Here we show that, contrary to these predictions, STED can resolve single NV centers in 40-250 nm sized nanodiamonds with a resolution of ≈10 nm. Even multiple adjacent NVs located in single nanodiamonds can be imaged individually down to relative distances of ≈15 nm. Far-field optical super-resolution of NVs inside nanodiamonds is highly relevant for bioimaging applications of these fluorescent nanolabels. The targeted addressing and readout of individual NV(-) spins inside nanodiamonds by STED should also be of high significance for quantum sensing and information applications.


The accuracy of transrectal ultrasound-guided biopsy for decision making in prostate cancer.
The most important surgical complications of renal transplantation are stenosis and obstruction of anastomosis of the ureter to the bladder. Hence, routine use of ureteral stents to prevent such complications seems logical; however, the optimal time to remove the ureteral stent is still controversial. The purpose of this study was to compare the benefits and complications of the early or delayed ureteral stent removal post-transplantation. All patients who underwent kidney transplantation in Modarres Hospital from May 2011 through March 2012 were recruited. The patients were allocated to three groups. Ureteral stent removed 10, 20, and 30 days after transplantation in groups one, two, and three, respectively. A total of 91 patients had undergone renal transplantation in our center. Ureteral stent was removed at 10, 20, and 30 days after surgery. Urologic complications among the three groups included hydronephrosis, urinoma, and collection around the graft; there was no statistically significant difference among study groups with regard to frequency of complications. We can remove the ureteral stent at shorter interval after renal transplantation with no increased risk of urologic complications.


Induction of adenocarcinoma from hamster pancreatic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro.
Our previous studies in the hamster pancreatic cancer model have indicated that pancreatic ductal adenocarcinomas derive not only from ductal/ductular cells but also from islets. To verify the presence of carcinogen-responsive cells within islets, we tested the effect of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) on recently established continuous hamster pancreatic islet culture. Isolated pure pancreatic islets of hamsters were treated in vitro with BOP at a concentration of 0.25 mM three times a week for 19 weeks. Each treatment week was designed as a stage. The growth of these cells, designated KL5B, was compared with untreated cultured islets, designated KL5N. As in our previous study, between 14 and 21 days of culture, exocrine and intermediary cells developed within both KL5N and KL5B islets, which were then replaced by undifferentiated cells. No differences were found in the growth patterns of KL5N and KL5B until stage 4, when KL5B cells showed accelerated cell growth and cell pleomorphism, which increased gradually at later stages of treatment. Anchorage-independent and in vivo growth did not appear until stage 19. Mutation of c-Ki-ras at codon 12 (GGT-->GAT) was detected in KL5B cells but not in KL5N cells. In vivo KL5B cells formed anaplastic invasive cancer with areas of glandular formation, overexpressed TGF-alpha and EGFR, expressed cytokeratin, vimentin, laminin and alpha-1 antitrypsin and reacted strongly with L-phytohemagglutinin and tomato lectin. Some cells within islets are responsive to the carcinogenic effects of BOP. Whether these cells represent islet cell precursors (stem cells) or malignant transdifferentiated islet cells remains to be seen.


Toward fluorescence nanoscopy.
For more than a century, the resolution of focusing light microscopy has been limited by diffraction to 180 nm in the focal plane and to 500 nm along the optic axis. Recently, microscopes have been reported that provide three- to sevenfold improved axial resolution in live cells. Moreover, a family of concepts has emerged that overcomes the diffraction barrier altogether. Its first exponent, stimulated emission depletion microscopy, has so far displayed a resolution down to 28 nm. Relying on saturated optical transitions, these concepts are limited only by the attainable saturation level. As strong saturation should be feasible at low light intensities, nanoscale imaging with focused light may be closer than ever.


Information needs of patients with incurable cancer.
The aims of this study were to describe to what extent cancer patients with incurable cancer report to have been informed about disease-related topics and how they evaluate the quality of the information giving. One hundred and twenty-eight patients participated in our study within 2 months after having had a diagnosis of incurable cancer. They filled out a questionnaire and were interviewed personally. We assessed the level of information, information needs and demographic factors, and we registered the type and duration of the cancer, cancer therapy, other types of received care and contacts with health care professionals. Furthermore, we assessed patients' appreciation of the information giving by their health care professionals. The majority of the patients said to have been informed about treatment options, side effects of their treatment, physical symptoms, where to get help, helpful devices, and diet, whereas less than half of the patients were informed about psychosocial care, euthanasia, and complementary care. Of all patients, 39% felt a need for additional information about topics such as physical symptoms, diet, euthanasia, and alternative or complementary care, whereas 19% would have appreciated extra written information. Most patients (78-88%) were satisfied with the information giving by the clinical specialist, oncology nurses, and non-specialised nurses, but only 63% evaluated the information giving by general practitioners as good. We conclude that most patients feel sufficiently informed about important disease-specific issues and are satisfied with the information giving by health care professionals. Nevertheless, a considerable number of patients appreciate additional information.


Mutations in the retinoblastoma protein-binding LXCXE motif of rubella virus putative replicase affect virus replication.
The rubella virus (RV)-encoded protein NSP90, which contains the retinoblastoma protein (Rb)-binding motif LXCXE, interacts with Rb and RV replication is reduced in cells lacking Rb. Whether the LXCXE motif of RV NSP90 itself is essential for Rb binding and virus replication is not known. Therefore, in the present study, the functional role of this motif was investigated by site-directed mutagenesis in a plasmid from which infectious RV RNA can be produced. Three critical mutations in the motif, two substitutions at the conserved cysteine residue (C --> G and C --> R) and a deletion of the entire motif, were created. A cell-free translated NSP90 C terminus polypeptide containing the deletion did not bind to Rb and a polypeptide carrying the C --> R substitution had barely detectable binding affinity for Rb. Rb binding by the C --> G mutant was reduced significantly compared to that of wild-type protein. Correlating with the binding results, mutant viruses containing the LXRXE and LXGXE motifs had a reduction in replication to < 0.5% and 47% of the wild-type, respectively, while deletion of the motif was found to be lethal. By the first serial passage, replication of the LXRXE-carrying virus had increased from < 0.5% to 2% of the wild-type. Sequencing of the genome of this virus revealed a nucleotide change that altered the motif from LXRXE to LXSXE, which is a known Rb-binding motif in two protein phosphatase subunits. Thus, our results clearly demonstrate that the LXCXE motif is required for efficient RV replication.


New distribution records of Amblyomma americanum (L.) (Acari: Ixodidae) in New York State.
Amblyomma americanum, commonly called the lone star tick, has been widely-distributed in the southeastern United States for many years. Distribution of this species apparently did not extend to New York State until the 1970s, after which the northern distribution in New York was limited to Long Island (Suffolk and Nassau counties), where it has become locally abundant. Since then, there has been just one published record from New York State, in Westchester County, just north of New York City. From 1988 to 1996, through the Tick Identification Service of the New York State Department of Health, 244 specimens of A. americanum were documented from mammalian hosts in 46 of the 62 New York State counties. These records extend the distribution of A. americanum to several more northern and western New York State counties. With a demonstrated expansion of geographic distribution, continued surveillance of A. americanum is of great public health importance. Besides being a severe pest where abundant, this species is a probable vector of human monocytic ehrlichiosis (HME), and a suspected vector of Borrelia lonestari, the etiologic agent of a Lyme disease-like illness.


Somatic mitochondrial mutations in melanoma resection specimens.
As epidemiological data suggest ultraviolet (UV) radiation to be the major environmental factor for the development of melanoma, we screened this malignancy for UV-specific C right curved arrow T and CC right curved arrow TT DNA mutations as described in squamous and basal cell carcinomas of the skin. Mitochondrial (mt) DNA was addressed which is known to be highly more susceptible for mutations than nuclear DNA. In the mt genome we chose part of the non-coding displacement-loop (D-loop) containing two hypermutable (C)n tracts especially prone for C right curved arrow T and CC right curved arrow TT changes. A total of 69 melanoma resection specimens was investigated by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) electrophoresis, followed by DNA cloning and sequencing. We detected alterations of the mt D-loop fragment in 4/34 (12%) melanoma primary tumours and in 7/35 (20%) cutaneous and subcutaneous metastases which was no statistically higher proportion upon Fisher's exact test (p=0.17). Among these 11 positive cases, 9 exhibited alterations in the (C)n microsatellite sequences indicating microsatellite instability (MSI) of mtDNA (C)n tracts. Besides 7 insertions and 2 deletions of nucleotides, 11 mutations occurred including only 4 UV-specific C right curved arrow T mutations in a nodular melanoma of the skin and in two subcutaneous metastases. CC right curved arrow TT mutations were not detected in any tissue sample. As (C)n tract alterations occurred in 2/9 primary melanomas with subsequent metastasis, whereas all 20 non-metastasizing cutaneous melanomas were not affected, these somatic changes may reflect genomic imbalance during tumour progression and may be useful for the assessment of patients' prognosis.


Does Body Mass Index Cause a Clinical Difference in Simultaneous Bilateral and Unilateral Knee Arthroplasty?
This study aims to investigate clinical and functional factors in patients undergoing unilateral and simultaneous bilateral total knee arthroplasty (TKA) who were classified into subgroups of nonobese, obese, and morbidly obese, and to determine perioperative and postoperative complications. We conducted an evaluation of 489 nonobese, obese, and morbidly obese patients who underwent TKA due to primary knee osteoarthritis between January 2006 and December 2013. The arthroplasties were performed by three different surgeons. Patients who underwent unilateral (group 1) or simultaneous bilateral (group 2) TKAs were divided into subgroups in accordance with BMI levels, that is, (a) nonobese (BMI < 30 kg/m2), (b) obese (BMI = 30-34.9 kg/m2), and (c) morbidly obese (BMI ≥35 kg/m2). Clinical and functional assessments were performed using Knee Society Scores (KSSs), the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC), and range of motion (ROM) values. Perioperative and early postoperative complications were assessed. The mean follow-up period was 46.65 months (minimum: 24 months; maximum: 84 months). There were no significant differences between the patients undergoing unilateral or simultaneous bilateral TKA procedures regarding postoperative ROM, WOMAC indices, and KSSs (p > 0.05), except for morbidly obese patients. Most intraoperative and early postoperative complications occurred in the morbidly obese group, especially in those undergoing simultaneous bilateral TKA procedures (p < 0.001). Unilateral and simultaneous bilateral TKA procedures showed no differences regarding ROM, clinical scores, and perioperative and early postoperative complications in nonobese and obese patients. A moderate increase was detected in complication rates in the unilateral TKA morbidly obese patients (group 1c); however, morbidly obese patients constituted the major risk group in simultaneous bilateral TKA patients (group 2c) regarding clinical scores (lower WOMAC scores and KSSs) and the development of complications.


Faecal volatile organic compounds analysis using field asymmetric ion mobility spectrometry: non-invasive diagnostics in paediatric inflammatory bowel disease.
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), remains challenging to diagnose. Diagnostic work-up carries a high burden, especially in paediatric patients, due to invasive endoscopic procedures. IBD is associated with alterations in intestinal microbiota composition. Faecal volatile organic compounds (VOCs) reflect gut microbiota composition. The aim of this study was to assess the diagnostic accuracy of faecal VOC profiling as a non-invasive diagnostic biomarker for paediatric IBD. In this diagnostic accuracy study performed in two tertiary centres in the Netherlands, faecal VOC profiles of 36 de novo, treatment-naïve paediatric IBD patients (23 CD, 13 UC), and 24 healthy, matched controls were measured by field asymmetric ion mobility spectrometry (Owlstone Ltd, Lonestar®, UK). Faecal VOC profiles of de novo paediatric IBD patients could be differentiated from healthy controls (AUC ± 95% CI, p-value, sensitivity, specificity; 0.76 ± 0.14, p < 0.001, 79%, 78%). This discrimination from controls was observed in both CD (0.90 ± 0.10, p < 0.0001, 83%, 83%) and UC (0.74 ± 0.19, p = 0.02, 77%, 75%). VOC profiles from UC could not be discriminated from CD (0.67 ± 0.19, p = 0.0996, 65%, 62%). Field asymmetric ion mobility spectrometry allowed for discrimination between faecal VOC profiles of de novo paediatric IBD patients and healthy controls, confirming the potential of faecal VOC analysis as a non-invasive diagnostic biomarker for paediatric IBD. This method may serve as a complementary, non-invasive technique in the diagnosis of IBD, possibly limiting the number of endoscopies needed in children suspected for IBD.


[Effect of D,L-dopa on the content of protein antigens in rat brain structures].
Cross immunoelectrophoresis was used to study the effect of administering the noradrenaline precursor D,L-DOPA on the content of water-soluble antigens in the hypothalamus, cerebellum and frontal cortex of rats. The content of 3 out of the 10 antigens under study significantly increased in the hypothalamus and that of 2 in the cerebellum after intraperitoneal injection of D,L-DOPA. The content of these antigens was greater in the structures with a high noradrenaline level.


Reverse engineering of biochar.
This study underpins quantitative relationships that account for the combined effects that starting biomass and peak pyrolysis temperature have on physico-chemical properties of biochar. Meta-data was assembled from published data of diverse biochar samples (n=102) to (i) obtain networks of intercorrelated properties and (ii) derive models that predict biochar properties. Assembled correlation networks provide a qualitative overview of the combinations of biochar properties likely to occur in a sample. Generalized Linear Models are constructed to account for situations of varying complexity, including: dependence of biochar properties on single or multiple predictor variables, where dependence on multiple variables can have additive and/or interactive effects; non-linear relation between the response and predictors; and non-Gaussian data distributions. The web-tool Biochar Engineering implements the derived models to maximize their utility and distribution. Provided examples illustrate the practical use of the networks, models and web-tool to engineer biochars with prescribed properties desirable for hypothetical scenarios.


The global development of community psychology as reflected in the American Journal of Community Psychology.
This commentary presents a virtual special issue on the global growth of community psychology (CP), particularly, but not exclusively, as reflected in the American Journal of Community Psychology (AJCP). CP exists in at least 50 countries all over the world, in many of those for over 25 years. Yet, aside from several early Israeli articles, AJCP rarely published work from or about countries outside the US and Canada until the early 2000s, when the number of international articles began to rise sharply. The focus of CP developed differently in different continents. CP in Australia and New Zealand initially followed North America's emphasis on improving social service systems, but has since focused more on environmental and indigenous cultural and decolonial issues that are as salient in those countries as in North America, but have drawn much more attention. CP came later to most of Asia, where it also tended to follow the North American path, but starting in Japan, India, and Hong Kong and now in China and elsewhere, it is establishing its own way. The other two global hotspots for CP for over 40 years have been Europe and Latin America. The level and focus of CP in Europe varies in each country, with some focused on applied developmental psychology and/or community services and others advancing critical and liberation psychology. CP in Latin America evolved from social psychology, but like CP in Sub-Saharan Africa, is also more explicitly political due to a history of political oppression, social activism, and the limitations of individualistic psychology to focus on social change, overcoming poverty, and interventions by (not just for) community members. Despite those differences, CP literature over the past 23 years suggests an increasingly common interest in social justice, multinational collaborations, and decoloniality. There is still a need for more truly (bidirectional) cross-cultural, comparative work for mutual learning, sharing of ideas, methods, and intervention practices, and for CP to develop in countries and communities throughout the globe where it could have the greatest impact.


High amounts of broccoli in pasta-like products: nutritional evaluation and sensory acceptability.
Pasta and noodles were enriched with concentrations of broccoli powder (BP) up to 30% (v/v). To ensure the benefits from the broccoli nutrients, their leakage during cooking should be prevented. Such leakage is determined by the microstructure. In a previous study we have shown that the microstructure can change dramatically in such broccoli-enriched products. In this article we investigated the amount of nutrients retained within the product. As a representative of nutrients we have chosen glucosinolates (GLs). Therefore, we have investigated the concentration of these phytochemicals in dried and cooked pasta and noodles. We have found that glucosinolates present in the pasta and noodles increase linearly with the volume fraction of BP up to 20%. At 30% BP the retained amount of GLs was equal to that of 20% BP and did not increase further. Therefore incorporation of 30% BP does not lead to additional health benefits over incorporation of 20% BP. We conclude that the nutritional function of our pasta-like products can be improved by enrichment up to 20% broccoli. This value is much higher than that found in common commercial products (which is a few percent). In this article we also briefly address the sensory acceptability of such products. Up to 20% broccoli the products turned out to remain acceptable. Combining this with our results on texture analysis we conclude that the GLs release, sensory acceptability and textural properties are related via the microstructure.


Quantum efficiency and capture cross section of first and second excitonic transitions of single-walled carbon nanotubes measured through photoconductivity.
Comparing photoconductivity measurements, using p-n diodes formed along individual single-walled carbon nanotubes (SWNT), with modeling results, allows determination of the quantum efficiency, optical capture cross section, and oscillator strength of the first (E11) and second (E22) excitonic transitions of SWNTs. This is in the infrared region of the spectrum, where little experimental work on SWNT optical absorption has been reported to date. We estimate quantum efficiency (η) ~1-5% and provide a correlation of η, capture cross section, and oscillator strength for E11 and E22 with nanotube diameter. This study uses the spectral weight of the exciton resonances as the determining parameter in optical measurements.


[Synthesis and dual antagonistic activity against thromboxane A2 and leukotriene D4 of benzenesulfonamide derivatives].
In order to find dual antagonists against both thromboxane A2 (TXA2) and leukotriene D4 (LTD4) receptors for a new antiasthmatic agent, various benzenesulfonamide derivatives were synthesized and evaluated for those pharmacological effects. TXA2 and LTD4 antagonistic activities in vitro were evaluated by the inhibitory effects on LTD4-induced and U-46619-induced contraction of guinea-pig trachea. Furthermore, TXA2 and LTD4 antagonistic activities in vivo were evaluated by the inhibitory effects on LTD4-induced and U-46619-induced bronchoconstriction of guinea-pig after oral administration of test compounds. It was found that 4-[5-[1-(4-chlorobenzenesulfonamido)-5-methylhexyl]-2-thi eny l]butyric acid and 4-[5-[1-(4-fluorobenzenesulfonamido)-5-methyl-hexyl]-2-thienyl]but yric acid possess good anti-LTD4 and anti-TXA2 activities by oral administration.


Altered mRNA Expression of Genes Involved in Endocannabinoid Signalling in Squamous Cell Carcinoma of the Oral Tongue.
Little is known about the endocannabinoid (eCB) system in squamous cell carcinoma of the oral tongue (SCCOT). Here we have investigated, at the mRNA level, expression of genes coding for the components of the eCB system in tumour and non-malignant samples from SCCOT patients. Expression of NAPEPLD and PLA2G4E, coding for eCB anabolic enzymes, was higher in the tumour tissue than in non-malignant tissue. Among genes coding for eCB catabolic enzymes, expression of MGLL was lower in tumour tissue while PTGS2 was increased. It is concluded that the eCB system may be dysfunctional in SCCOT.


The role of conserved Cys residues in Brassica rapa auxin amidohydrolase: Cys139 is crucial for the enzyme activity and Cys320 regulates enzyme stability.
Brassica rapa auxin amidohydrolase (BrILL2) participates in the homeostasis of the plant hormones auxins by hydrolyzing the amino acid conjugates of auxins, thereby releasing the free active form of hormones. Herein, the potential role of the two conserved Cys residues of BrILL2 (at sequence positions 139 and 320) has been investigated by using interdisciplinary approaches and methods of molecular biology, biochemistry, biophysics and molecular modelling. The obtained results show that both Cys residues participate in the regulation of enzyme activity. Cys320 located in the satellite domain of the enzyme is mainly responsible for protein stability and regulation of enzyme activity through polymer formation, as has been revealed by enzyme kinetics and differential scanning calorimetry analysis of the BrILL2 wild type and mutants C320S and C139S. Cys139 positioned in the active site of the catalytic domain is involved in the coordination of one Mn(2+) ion of the bimetal center and is crucial for the enzymatic activity. Although the point mutation Cys139 to Ser causes the loss of enzyme activity, it does not affect the metal binding to the BrILL2 enzyme, as has been shown by isothermal titration calorimetry, circular dichroism spectropolarimetry and differential scanning calorimetry data. MD simulations (200 ns) revealed a different active site architecture of the BrILL2C139S mutant in comparison to the wild type enzyme. Additional possible reasons for the inactivity of the BrILL2C139S mutant have been discussed based on MD simulations and MM-PBSA free energy calculations of BrILL2 enzyme complexes (wt and C139S mutant) with IPA-Ala as a substrate.


[Stability of iodinated contrast media in UV-laser irradiation and toxicity of the photoproducts].
In XeCl-Excimer laser angioplasty, unintended and possibly harmful interaction of the UV-laser light and the contrast media may occur due to the high concentration of contrast medium proximal to the occlusion or subtotal stenosis. One ml of three nonionic monomeric contrast agents (iopromide, iomeprol, iopamidol), one nonionic dimeric (jotrolane), and one ionic monomeric (amidotrizoate) X-ray contrast agent were irradiated with a XeCl excimer laser (lambda = 308 nm, pulse duration 120 ns, 50 Hz) using a 9 French multifiber catheter (12 sectors). Up to 20,000 pulses (106 J) were applied. Using high performance liquid chromatography the amount of liberated iodide as well as the fraction of unchanged contrast media were measured. Cytotoxicity of the photoproducts was tested in a colony formation assay of human skin fibroblasts. The contrast agents were irradiated with 2000 pulses/ml (5.3 mJ/pulse; 10.6 J) and then added to the cell cultures for a period of three hours in a concentration of 10%. Excimer laser irradiation induced iodide liberation of up to 3.3 mg iodide/ml. Up to 19% of the contrast agents changed their original molecular structure. Incubation of irradiated contrast agents resulted in a significantly decreased potential for colony formation (p values ranging from 0.0044 to 0.0102) with significantly higher toxicity of amidotrizoate and iomeprol in comparison to iopromide, iotrolan, and iopamidol. Due to the cytotoxic photoproducts and the high level of liberated iodide, it is recommended to flush the artery with physiological saline solution before applying a pulsed excimer laser in human arterial obstructions in order to reduce the contrast agent concentration at the site of irradiation.


CFTR: domains, structure, and function.
Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) (Collins, 1992). Over 500 naturally occurring mutations have been identified in CF gene which are located in all of the domains of the protein (Kerem et al., 1990; Mercier et al., 1993; Ghanem et al., 1994; Fanen et al., 1992; Ferec et al., 1992; Cutting et al., 1990). Early studies by several investigators characterized CFTR as a chloride channel (Anderson et al.; 1991b,c; Bear et al., 1991). The complex secondary structure of the protein suggested that CFTR might possess other functions in addition to being a chloride channel. Studies have established that the CFTR functions not only as a chloride channel but is indeed a regulator of sodium channels (Stutts et al., 1995), outwardly rectifying chloride channels (ORCC) (Gray et al., 1989; Garber et al., 1992; Egan et al., 1992; Hwang et al., 1989; Schwiebert et al., 1995) and also the transport of ATP (Schwiebert et al., 1995; Reisin et al., 1994). This mini-review deals with the studies which elucidate the functions of the various domains of CFTR, namely the transmembrane domains, TMD1 and TMD2, the two cytoplasmic nucleotide binding domains, NBD1 and NBD2, and the regulatory, R, domain.


Targeted Discovery of Cryptic Metabolites with Antiproliferative Activity.
Microorganisms have provided a rich source of therapeutically valuable natural products. Recent advances in whole genome sequencing and bioinformatics have revealed immense untapped potential for new natural products in the form of silent or "cryptic" biosynthetic genes. We herein conducted high-throughput elicitor screening (HiTES) in conjunction with cytotoxicity assays against selected cancer cell lines with the goal of uncovering otherwise undetectable cryptic metabolites with antiproliferative activity. Application to Streptomyces clavuligerus facilitated identification of clavamates A and B, two bioactive metabolites with unusual structural features, as well as facile activation of a gene cluster coding for tunicamycin, which exhibited strong growth-inhibitory activity. The elicitor we identified was pleiotropic, additionally leading to the discovery of a modified, bicyclic pentapeptide natural product. Our results highlight the utility of this approach in identifying new molecules with antiproliferative activity from even overexploited microbial strains.


Effects of the charge-transfer reorganization energy on the open-circuit voltage in small-molecular bilayer organic photovoltaic devices: comparison of the influence of deposition rates of the donor.
The theoretical maximum of open-circuit voltage (VOC) of organic photovoltaic (OPV) devices has yet to be determined, and its origin remains debated. Here, we demonstrate that VOC of small-molecule OPV devices can be improved by controlling the deposition rate of a donor without changing the interfacial energy gap at the donor/acceptor interface. The measurement of external quantum efficiency and electroluminescence spectra facilitates the observation of the existence of charge transfer (CT) states. A simplified approach by reusing the reciprocity relationship for obtaining the properties of the CT states is proposed without introducing complex techniques. We compare experimental and fitting results and propose that reorganization energy is the primary factor in determining VOC instead of either the CT energy or electronic coupling term in bilayer OPV devices. Atomic force microscopy images indicate a weak molecular aggregation when a higher deposition rate is used. The results of temperature-dependent measurements suggest the importance of molecular stacking for the CT properties.


Decision-Making with D-Dimer in the Diagnosis of Pulmonary Embolism.
The measurement of D-dimer can provide useful information to aid in the diagnosis of patients with suspected venous thromboembolism. D-dimer measurement in conjunction with adequate estimation of pretest probability can facilitate the safe discharge of patients with suspected pulmonary embolism and limit unnecessary investigation or anticoagulation. We review clinical decision-making strategies in the diagnosis of pulmonary embolism and propose means to minimize diagnostic error that might arise from knowledge of the D-dimer result prior to clinical assessment.


Trypanosoma cruzi: biological characterization of a isolate from an endemic area and its susceptibility to conventional drugs.
We describe some biological and molecular characteristics of a Trypanosoma cruzi isolate derived from a Triatomine captured in Nicaragua. PCR based typification showed that this isolate, named Nicaragua, belonged to the lineage Tc I. Nicaragua infected culture cells were treated with allopurinol, showing different behavior according to the cellular compartment, being cardiomyocyte primary cultures more resistant to this drug. The course of the infection in a mice experimental model and its susceptibility to benznidazole and allopurinol was analyzed. In benznidazole treatment, mice reverted the high lethal effect of parasites during the acute infection, however, a few parasites were detected in the heart of 88% of mice 1 year post-infection. Since T. cruzi is a heterogeneous species population it is important to study and characterize different parasites actually circulating in humans in endemic areas. In this work we show that T. cruzi Nicaragua isolate, is sensitive to early benznidazole treatment.


Logistic regression analysis of populations of electrophysiological models to assess proarrythmic risk.
Population-based computational approaches have been developed in recent years and helped to gain insight into arrhythmia mechanisms, and intra- and inter-patient variability (e.g., in drug responses). Here, we illustrate the use of multivariable logistic regression to analyze the factors that enhance or reduce the susceptibility to cellular arrhythmogenic events. As an example, we generate 1000 model variants by randomly modifying ionic conductances and maximal rates of ion transports in our atrial myocyte model and simulate an arrhythmia-provoking protocol that enhances early afterdepolarization (EAD) proclivity. We then treat EAD occurrence as a categorical, yes or no variable, and perform logistic regression to relate perturbations in model parameters to the presence/absence of EADs. We find that EAD formation is sensitive to the conductance of the voltage-gated Na+, the acetylcholine-sensitive and ultra-rapid K+ channels, and the Na+/Ca2+ exchange current, which matches our mechanistic understanding of the process and preliminary sensitivity analysis. The described technique: •allows investigating the factors underlying dichotomous outcomes, and is therefore a useful tool improve our understanding of arrhythmic risk;•is valid for analyzing both deterministic and stochastic models, and various phenomena (e.g., delayed afterdepolarizations and Ca2+ sparks);•is computationally more efficient than one-at-a-time parameter sensitivity analysis.


Ethnomedicine and ethnobotany of fright, a Caribbean culture-bound psychiatric syndrome.
"Fright" is an English-speaking Caribbean idiom for an illness, or ethnomedical syndrome, of persistent distress. A parallel ethnopsychiatric idiom exists in the French Antilles as sésisma. Fright is distinct from susto among Hispanics, though both develop in the wake of traumatic events. West Indian ethnophysiology (ethnoanatomy) theorizes that an overload of stressful emotions (fear, panic, anguish or worry) causes a cold humoral state in which blood coagulates causing prolonged distress and increased risks of other humorally cold illnesses. Qualitative data on local explanatory models and treatment of fright were collected using participant-observation, informal key informant interviews and a village health survey. Ethnobotanical and epidemiological data come from freelist (or "free-list") tasks, analyzed for salience, with nearly all adults (N = 112) of an eastern village in Dominica, and a village survey on medicinal plant recognition and use (N = 106). Along with prayer and exercise, three herbs are salient fright treatments: Gossypium barbadense L., Lippia micromera Schauer, and, Plectranthus [Coleus] amboinicus [Loureiro] Sprengel. The survey indicated that 27% of village adults had medicated themselves for fright. Logistic regression of fright suffering onto demographic variables of age, education, gender, parental status and wealth measured in consumer goods found age to be the only significant predictor of having had fright. The probability of having (and medicating for) fright thus increases with every year. While sufferers are often uncomfortable recalling personal fright experiences, reporting use of medicinal plants is less problematic. Inquiry on fright medical ethnobotany (or phytotherapies) serves as a proxy measurement for fright occurrence. Cross-cultural and ethnopharmacology literature on the medicinal plants suggests probable efficacy in accord with Dominican ethnomedical notions of fright. Further, the cultural salience and beliefs about these medicines may give these medications extra psychoneuroimmune (i.e. mind-body) benefits, or placebo-like effects, for this stress-related folk illness.


Oligomeric proanthocyanidins inhibit apoptosis of chondrocytes induced by interleukin-1β.
Oligomeric proanthocyanidin (OPC) is a water-soluble plant polyphenolic compound known for its cytoprotective effects in various tissue types. However, its effect on chondrocytes has not been well characterized. The present study aimed to investigate the effect of OPC on interleukin‑1β (IL‑1β)‑induced apoptosis in chondrocytes, and to determine the mechanisms underlying the protective effects of OPC. Knee articular chondrocytes obtained from 6‑week‑old SPF Kunming mice were cultured and serially passaged. First‑generation chondrocytes were selected for subsequent experiments following toluidine blue staining. Subsequent to IL‑1β and OPC administration, an MTT assay was performed to examine the viability rate of chondrocytes, and the optimal drug concentration was determined. The fluorescence dye 2',7'-dichlorofluorescein diacetate was used to determine the intracellular content of reactive oxygen species (ROS). Mitochondrial membrane potential (MMP) was measured using a 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC‑1) assay. The apoptosis rate of chondrocytes was assessed using an Annexin V‑FITC/PI assay and ultrastructural changes were observed under an electron microscope. The results demonstrated that OPC increased the survival rate of chondrocytes against IL‑1β‑induced apoptosis. The most significant protective effect of OPC was observed at the concentration of 0.050 mg/ml. OPC reversed the increased ROS content and MMP levels, and inhibited IL‑1β‑induced apoptosis in chondrocytes. In addition, OPC was revealed to protect the ultrastructural integrity of chondrocytes. Taken together, the results of the present study suggest that OPC protects chondrocytes against IL‑1β‑induced damage by decreasing ROS content and MMP levels.


Fast Regulation of GABAAR Diffusion Dynamics by Nogo-A Signaling.
Precisely controlling the excitatory and inhibitory balance is crucial for the stability and information-processing ability of neuronal networks. However, the molecular mechanisms maintaining this balance during ongoing sensory experiences are largely unclear. We show that Nogo-A signaling reciprocally regulates excitatory and inhibitory transmission. Loss of function for Nogo-A signaling through S1PR2 rapidly increases GABAAR diffusion, thereby decreasing their number at synaptic sites and the amplitude of GABAergic mIPSCs at CA3 hippocampal neurons. This increase in GABAAR diffusion rate is correlated with an increase in Ca2+ influx and requires the calcineurin-mediated dephosphorylation of the γ2 subunit at serine 327. These results suggest that Nogo-A signaling rapidly strengthens inhibitory GABAergic transmission by restricting the diffusion dynamics of GABAARs. Together with the observation that Nogo-A signaling regulates excitatory transmission in an opposite manner, these results suggest a crucial role for Nogo-A signaling in modulating the excitation and inhibition balance to restrict synaptic plasticity.


Macroglossia. An unusual presentation of pemphigus vulgaris.
A 19-year-old woman presented with macroglossia of five months' duration and without bullae or erosions. A biopsy revealed a picture consistent with pemphigus vulgaris. The patient subsequently developed typical oral erosions. Her tongue enlargement and oral ulcerations improved dramatically with topical and systemic steroid therapy. Pemphigus vulgaris should be considered in the differential diagnosis of macroglossia.


The kinetics of slow-binding and slow, tight-binding inhibition: the effects of substrate depletion.
Inhibitors with dissociation constants in the micromolar to nanomolar range are important, but hard to characterize kinetically, especially when the substrate concentration in the assay is less than Km. When inhibition increases during the course of the assay (slow-binding inhibition) the concentration of substrate may decrease appreciably. Methods that take substrate depletion into account are described for analysing experiments in which the initial substrate concentration is below Km. Fitting progress curves gives the rate constants for the second (slow) step in a two-step mechanism. An approximate value for the overall dissociation constant may be determined from measurements of rates when the reaction is treated as a first-order process. When the concentrations of inhibitor and enzyme are comparable numerical methods are required. Procedures, suitable for implementation on a microcomputer, for the solution of the differential equations and the fitting of progress curves are described.


Critical role of Bcr1-dependent adhesins in C. albicans biofilm formation in vitro and in vivo.
The fungal pathogen Candida albicans is frequently associated with catheter-based infections because of its ability to form resilient biofilms. Prior studies have shown that the transcription factor Bcr1 governs biofilm formation in an in vitro catheter model. However, the mechanistic role of the Bcr1 pathway and its relationship to biofilm formation in vivo are unknown. Our studies of biofilm formation in vitro indicate that the surface protein Als3, a known adhesin, is a key target under Bcr1 control. We show that an als3/als3 mutant is biofilm-defective in vitro, and that ALS3 overexpression rescues the biofilm defect of the bcr1/bcr1 mutant. We extend these findings with an in vivo venous catheter model. The bcr1/bcr1 mutant is unable to populate the catheter surface, though its virulence suggests that it has no growth defect in vivo. ALS3 overexpression rescues the bcr1/bcr1 biofilm defect in vivo, thus arguing that Als3 is a pivotal Bcr1 target in this setting. Surprisingly, the als3/als3 mutant forms a biofilm in vivo, and we suggest that additional Bcr1 targets compensate for the Als3 defect in vivo. Indeed, overexpression of Bcr1 targets ALS1, ECE1, and HWP1 partially restores biofilm formation in a bcr1/bcr1 mutant background in vitro, though these genes are not required for biofilm formation in vitro. Our findings demonstrate that the Bcr1 pathway functions in vivo to promote biofilm formation, and that Als3-mediated adherence is a fundamental property under Bcr1 control. Known adhesins Als1 and Hwp1 also contribute to biofilm formation, as does the novel protein Ece1.


CD4+ T cell hyporesponsiveness after repeated exposure to Schistosoma mansoni larvae is dependent upon interleukin-10.
The effect that multiple percutaneous exposures to Schistosoma larvae has on the development of early CD4+ lymphocyte reactivity is unclear, yet it is important in the context of humans living in areas where schistosomiasis is endemic. In a murine model of multiple infections, we show that exposure of mice to repeated doses (4×) of Schistosoma mansoni cercariae, compared to a single dose (1×), results in CD4+ T cell hyporesponsiveness within the skin-draining lymph nodes (sdLN), manifested as reduced CD4+ cell proliferation and cytokine production. FoxP3+ CD4+ regulatory T cells were present in similar numbers in the sdLN of 4× and 1× mice and thus are unlikely to have a role in effecting hyporesponsiveness. Moreover, anergy of the CD4+ cell population from 4× mice was slight, as proliferation was only partly circumvented through the in vitro addition of exogenous interleukin-2 (IL-2), and the in vivo blockade of the regulatory molecule PD1 had a minimal effect on restoring responsiveness. In contrast, IL-10 was observed to be critical in mediating hyporesponsiveness, as CD4+ cells from the sdLN of 4× mice deficient for IL-10 were readily able to proliferate, unlike those from 4× wild-type cohorts. CD4+ cells from the sdLN of 4× mice exhibited higher levels of apoptosis and cell death, but in the absence of IL-10, there was significantly less cell death. Combined, our data show that IL-10 is a key factor in the development of CD4+ T cell hyporesponsiveness after repeated parasite exposure involving CD4+ cell apoptosis.


Parcellating an individual subject's cortical and subcortical brain structures using snowball sampling of resting-state correlations.
We describe methods for parcellating an individual subject's cortical and subcortical brain structures using resting-state functional correlations (RSFCs). Inspired by approaches from social network analysis, we first describe the application of snowball sampling on RSFC data (RSFC-Snowballing) to identify the centers of cortical areas, subdivisions of subcortical nuclei, and the cerebellum. RSFC-Snowballing parcellation is then compared with parcellation derived from identifying locations where RSFC maps exhibit abrupt transitions (RSFC-Boundary Mapping). RSFC-Snowballing and RSFC-Boundary Mapping largely complement one another, but also provide unique parcellation information; together, the methods identify independent entities with distinct functional correlations across many cortical and subcortical locations in the brain. RSFC parcellation is relatively reliable within a subject scanned across multiple days, and while the locations of many area centers and boundaries appear to exhibit considerable overlap across subjects, there is also cross-subject variability-reinforcing the motivation to parcellate brains at the level of individuals. Finally, examination of a large meta-analysis of task-evoked functional magnetic resonance imaging data reveals that area centers defined by task-evoked activity exhibit correspondence with area centers defined by RSFC-Snowballing. This observation provides important evidence for the ability of RSFC to parcellate broad expanses of an individual's brain into functionally meaningful units.


Skin cancer risk in people living with HIV: a call for action.
A diagnosis of HIV poses secondary medical risks to patients, ranging from infections to neoplastic conditions. Regarding skin cancer, these risks extend beyond the well known association with Kaposi sarcoma and include Merkel cell carcinoma, squamous cell carcinoma, and high-risk melanomas. Despite evidence of these risks, knowledge and awareness remain low, among care providers for people living with HIV, individual patients, and even some specialists in dermatology. Crucially, medical organisations do not adequately address this concern, as there is an absence of treatment guidelines for the screening and management of skin cancer for people living with HIV. To continue providing high-quality care for this population, the increased risk of multiple high-risk skin cancers needs to be appropriately recognised by both providers and patients. Accordingly, we call for renewed emphasis on patient education and implementation of improved organisational guidelines for skin cancer screening protocols.


Comparing the quality of antidepressant pharmacotherapy in the Department of Veterans Affairs and the private sector.
Comparing quality of care between large health care systems is important for health systems management. This study compared measures of the quality of pharmacotherapy for patients with major depression across a sample of patients from the Department of Veterans Affairs (VA) and the private sector. In this observational study, all patients who were given a new prescription for an antidepressant and a diagnosis of major depression in the VA during fiscal year 2000 were identified by using administrative data (N=27,713). In the private sector, a similar sample of patients were identified by using Medstat's MarketScan database (N=4,852). For both groups, measures of the quality of antidepressant pharmacotherapy were constructed. These measures were compared across the two groups by using logistic regression models. Controls for age, gender, comorbid disorders, and initial antidepressant drug prescribed were included in some models. Although the populations had different demographic and clinical characteristics, differences in the quality measures between the two systems were few, with the VA slightly outperforming the private sector in the prescription of antidepressants during the acute phase of treatment, the first 84 days (84.7 compared with 81 percent) and during the maintenance phase of treatment, the first 181 days (53.9 compared with 50.9 percent). Patient characteristics that were associated with quality measures included being older, being female, and having a comorbid diagnosis of substance use disorder, bipolar disorder, or anxiety or adjustment disorder. Both systems had relatively high rates of adherence to pharmacotherapy guidelines. Even though the populations in the two systems were different, adjusting the analyses for clinical characteristics did little to change the measured differences between the two systems.


Safety of Routine Pedicle Division during Delayed Breast Augmentation following Free Flap Breast Reconstruction.
Autologous free flap breast reconstruction is a common reconstructive procedure, with the ability to produce a natural breast shape and a long history of success. Despite its benefits, there are special situations in which patients lack sufficient donor-site tissue to achieve adequate breast size and projection. With this study, the authors describe their institutional experience of delayed implant augmentation after autologous breast reconstruction with a particular focus on pedicle division as a technique to improve aesthetic results. A retrospective chart review of patients that underwent free flap autologous breast reconstruction with delayed implant augmentation was conducted over a 13-year period. Flaps were divided into a control group without pedicle division and a divided pedicle group. Groups were compared in terms of demographics, clinical and surgical characteristics, implant details, and postoperative implant and flap complications. No significant differences in terms of age, body mass index, comorbidities, radiation therapy, or surgical indications were noted. The most common reason for delayed implant augmentation after autologous breast reconstruction was change in breast size and breast asymmetry. In terms of implant and flap complications, we found no significant differences between the control and divided pedicle groups after delayed implant augmentation. From the authors' institutional experience, pedicle division in delayed breast augmentation with implants after free flap breast reconstruction can be safety performed in selected cases. This technique can be a powerful tool for plastic surgeons to improve the final aesthetic appearance of the reconstructed breast. Therapeutic, III.


Novel application of plasma treatment for pharmaceutical and biomedical engineering.
The nature of plasma-induced surface radicals formed on a variety of organic polymers has been studied by electron spin resonance (ESR), making it possible to provide a sound basis for future experimental design of polymer surface processing using plasma treatment. On the basis of the findings from such studies, several novel bio-applications in the field of drug- and biomedical- engineering have been developed. Applications for drug engineering include the preparation of reservoir-type drug delivery system (DDS) of sustained- and delayed-release, and floating drug delivery system (FDDS) possessing gastric retention capabilities, followed by preparation of "Patient-Tailored DDS". Furthermore, the preparation of composite powders applicable to matrix-type DDS was developed by making a mechanical application to the surface radical-containing polymer powders with drug powders. In applications for biomedical engineering, the novel method to introduce the durable surface hydrophilicity and lubricity on hydrophobic biomedical polymers was developed by plasma-assisted immobilization of carboxyl group-containing polymer on the polymer substrate. The surfaces thus prepared were further used for the covalent immobilization of oligo-nucleotides (DNA) onto the polymer surfaces applicable to constructing DNA diagnosis system, and also plasma-assisted preparation of functionalized chemo-embolic agent of vinyl alcohol-sodium acrylate copolymer (PVA- PAANa).


Activation of PKC inhibits NaF-induced inositol phospholipid turnover in rat insulinoma cells.
An investigation was done to elucidate the regulatory role of protein kinase C (PKC) in insulin release and also the effects of PKC activation on NaF-induced inositol phospholipid (PI) turnover in and insulin release from rat insulinoma cells (RINr). NaF stimulated insulin secretion in association with an increase in [3H]inositol phosphate formation in RINr cells. Furthermore, NaF induced a rapid decrease in 32P-labeling of phosphatidylinositol-4,5-diphosphate (PIP2) with a concomitant increase of [32P]phosphatidic acid in prelabeled cells. In contrast, NaF had no effect on cyclic AMP production. Although phorbol 12,13-dibutyrate (PDBu) also stimulated insulin release, on concomitant administration of NaF and PDBu, insulin secretion was clearly less than that expected on the basis of an additive action. Moreover, PDBu significantly inhibited NaF-enhanced PI turnover. However, this inhibition was abolished after downregulating PKC by pretreating RINr cells with PDBu. Thus NaF-induced insulin release from RINr cells appears to involve enhancement of PI turnover. Moreover, because NaF is known to activate guanine nucleotide binding proteins (G proteins) directly, PKC activation appears to induce a mechanism that inhibits stimulus-secretion coupling at a level between G protein and phospholipase C-induced PIP2 hydrolysis.


Identification of novel polymorphisms and two distinct haplotype structures in dog leukocyte antigen class I genes: DLA-88, DLA-12 and DLA-64.
The current information on the polymorphism variation and haplotype structure of the domestic dog leukocyte antigen (DLA) genes is limited in comparison to other experimental animals. In this paper, to better elucidate the degree and types of polymorphisms and genetic differences for DLA-88, DLA-12 and DLA-64, we genotyped four families of 38 beagles and another 404 unrelated dogs representing 49 breeds by RT-PCR based Sanger sequencing. We also sequenced and analyzed the genomic organization of the DLA-88 and DLA-12 gene segments to better define these two-gene DLA haplotypes more precisely. We identified 45 alleles for DLA-88, 15 for DLA-12 and six for DLA-64, of which 20, 14 and six, respectively, were newly described alleles. Therefore, this study shows that the DLA-12 and DLA-64 loci are far more polymorphic than previously reported. Phylogenetic analysis strongly supported that the DLA-88, DLA-12 and DLA-64 alleles were independently generated after the original divergence of the DLA-79 alleles. Two distinct DLA-88 and DLA-12 haplotype structures, tentatively named DLA-88-DLA-12 and DLA-88-DLA-88L, were identified, and the novel haplotype DLA-88-DLA-88L contributed to 32.7% of the unrelated dogs. Quantitative real-time PCR analysis showed that the gene expression levels of DLA-88L and DLA-88 were similar, and that the gene expression level of DLA-12 was significantly lower. In addition, haplotype frequency estimations using frequently occurring alleles revealed 45 different DLA-class I haplotypes (88-88L/12-64) overall, and 22 different DLA-class I haplotypes in homozygous dogs for 18 breeds and mongrels.


Behavioral health providers' beliefs about health information exchange: a statewide survey.
To assess behavioral health providers' beliefs about the benefits and barriers of health information exchange (HIE). Survey of a total of 2010 behavioral health providers in a Midwestern state (33% response rate), with questions based on previously reported open-ended beliefs elicitation interviews. Factor analysis resulted in four groupings: beliefs that HIE would improve care and communication, add cost and time burdens, present access and vulnerability concerns, and impact workflow and control (positively and negatively). A regression model including all four factors parsimoniously predicted attitudes toward HIE. Providers clustered into two groups based on their beliefs: a majority (67%) were positive about the impact of HIE, and the remainder (33%) were negative. There were some professional/demographic differences between the two clusters of providers. Most behavioral health providers are supportive of HIE; however, their adoption and use of it may continue to lag behind that of medical providers due to perceived cost and time burdens and concerns about access to and vulnerability of information.


Diet and calcium stones.
To review the current literature on the dietary modification of urinary risk factors as a means of reducing the likelihood of recurrent stone formation and to develop practical dietary recommendations that might be useful to this end. MEDLINE was searched for English-language articles published from 1983 to 1990. Additional references were selected from the bibliographies of identified articles. Nonrandomized trials and retrospective reviews were included because of a paucity of randomized controlled trials. Information on the dietary intake of calcium, oxalate, protein, sodium and fibre and on alcohol and fluid intake was used to develop practical guidelines on dietary modification. Dietary modification plays an important role in the reduction of urinary risk factors in patients with calcium stone disease of the urinary tract. As an initial form of prevention attention should be directed toward moderating the intake of calcium, oxalate, protein, sodium and alcohol and increasing the intake of fibre and water. Future research should include an assessment of the long-term reduction of dietary and urinary risk factors and the rates of recurrence of calcium stones.


Child-, Family-, and Community-Level Facilitators for Promoting Oral Health Practices among Indigenous Children.
Despite the preventive nature of oral diseases and their significance for general wellbeing, poor oral health is highly prevalent and has unfavourable ramifications for children around the world. Indigenous children in Australia experience disproportionate rates of early childhood caries compared to their non-Indigenous counterparts. Therefore, this paper aims to collate parental experiences and generate an understanding of facilitators for Indigenous childhood oral health. This project aggregated stories from parents of Indigenous children across South Australia who were participants in an early childhood caries-prevention trial. This paper explores facilitators for establishing oral health and nutrition behaviours for Indigenous children under the age of three through reflexive thematic analysis. Fisher-Owens' conceptual model for influences on children's oral health is utilised as a framework for thematic findings. Child-level facilitators include oral hygiene routines and regular water consumption. Family-level facilitators include familial ties, importance of knowledge, and positive oral health beliefs. Community-level facilitators include generational teaching, helpful community resources, and holistic health care. Recommendations from findings include the following: exploration of Indigenous health workers and elder participation in oral health initiatives; inclusion of Indigenous community representatives in mainstream oral health discussions; and incorporation of child-level, family-level, and community-level facilitators to increase support for efficacious oral health programs.


Colchicine treatment can improve outcomes of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis.
Currently, there is no widely acceptable and proven effective treatment for coronavirus disease 2019 (COVID-19). Colchicine has been shown to offer a benefit in reducing the inflammation in several inflammatory diseases. This study aims to analyze the efficacy of colchicine administration and outcomes of COVID-19. We systematically searched the PubMed and Europe PMC database using specific keywords related to our aims until January 29, 2021. All articles published on COVID-19 and colchicine treatment were retrieved. The quality of the study was assessed using the Newcastle-Ottawa Scale (NOS) tool for observational studies and Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) for clinical trial studies. Statistical analysis was done using Review Manager 5.4 software. A total of eight studies with 5778 COVID-19 patients were included in this meta-analysis. This meta-analysis showed that the administration of colchicine was associated with improvement of outcomes of COVID-19 [OR 0.43 (95% CI 0.34-0.55), p < 0.00001, I2 = 0%, fixed-effect modelling] and its subgroup which comprised of reduction from severe COVID-19 [OR 0.44 (95% CI 0.31-0.63), p < 0.00001, I2 = 0%, fixed-effect modelling] and reduction of mortality rate from COVID-19 [OR 0.43 (95% CI 0.32-0.58), p < 0.00001, I2 = 0%, fixed-effect modelling]. Our study suggests the routine use of colchicine for treatment modalities of COVID-19 patients. More randomized clinical trial studies are still needed to confirm the results from this study.


Altenusin, a Nonsteroidal Microbial Metabolite, Attenuates Nonalcoholic Fatty Liver Disease by Activating the Farnesoid X Receptor.
Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The incidence of NAFLD has increased steadily due to its close association with the global epidemic of obesity and type 2 diabetes. However, there is no effective pharmacological therapy approved for NAFLD. Farnesoid X receptor (FXR), a member of the nuclear receptor subfamily, plays important roles in maintaining the homeostasis of bile acids, glucose, and lipids. FXR agonists have shown promise for the treatment of NAFLD. In this study, we report altenusin (2076A), a natural nonsteroidal fungal metabolite, as a novel selective agonist of FXR with an EC50 value of 3.2 ± 0.2 μM. Administration of 2076A protected mice from high-fat diet (HFD)-induced obesity by reducing the body weight and fat mass by 22.9% and 50.0%, respectively. Administration of 2076A also decreased the blood glucose level from 178.3 ± 12.4 mg/dl to 116.2 ± 4.1 mg/dl and the serum insulin level from 1.4 ± 0.6 ng/dl to 0.4 ± 0.1 ng/dl. Moreover, 2076A treatment nearly reversed HFD-induced hepatic lipid droplet accumulation and macrovesicular steatosis. These metabolic effects were abolished in FXR knockout mice. Mechanistically, the metabolic benefits of 2076A might have been accounted for by the increased insulin sensitivity and suppression of genes that are involved in hepatic gluconeogenesis and lipogenesis. In summary, we have uncovered a new class of nonsteroidal FXR agonist that shows promise in treating NAFLD and the associated metabolic syndrome.


Conformation of a double-membrane-spanning fragment of a G protein-coupled receptor: effects of hydrophobic environment and pH.
Overcoming the problems associated with the expression, purification and in vitro handling of membrane proteins requires an understanding of the factors governing the folding and stability of such proteins in detergent solutions. As a sequel to our earlier report (Biochim. Biophys. Acta 1747(2005), 133-140), we describe an improved purification procedure and a detailed structural analysis of a fragment of the mu-opioid receptor ('TM2-3') that comprises the second and third transmembrane segments and the extracellular loop that connects them. Circular dichroism (CD) spectroscopy of TM2-3 in 2,2,2-trifluoroethanol gave a helical content similar to that predicted by published homology models, while spectra acquired in several detergents showed significantly lower helical contents. This indicates that this part of the mu-opioid receptor has an intrinsic propensity to be highly helical in membrane-like environments, but that in detergent solutions, this helical structure is not fully formed. Proteolysis of TM2-3 with trypsin showed that the helical portions of TM2 and TM3 are both shorter than their predicted lengths, indicating that helix-helix interactions in the full-length receptor are apparently important for stabilizing their conformation. Lengthening the alkyl chain of the detergent led to a small but significant increase in the helicity of TM2-3, suggesting that hydrophobic mismatch could play an important role in the stabilization of transmembrane helices by detergents. Protonation of aspartic acid residues in detergent-solubilized TM2-3 also caused a significant increase in helicity. Our results thus suggest that detergent alkyl chain-length and pH may influence membrane protein stability by modulating the stability of individual transmembrane segments.


Systemic complement activation and acute lung injury.
Experimental studies of rats have provided significant evidence that intravascular complement activation after i.v. injection of cobra venom factor (CVF) or thermal injury of skin can result in acute lung injury. This has been determined by morphological changes in lung and increases in lung vascular permeability. Systemic complement activation is associated with an early appearance of C5-derived chemotactic activity in the circulation coincident with the development of transient neutropenia, followed by extensive granulocytosis and sequestration of neutrophils in lung interstitial capillaries. The acute pulmonary injury depends on availability of complement and neutrophils. Depletion of either complement or blood neutrophils before CVF injection or thermal injury will prevent development of lung injury. Interventional studies with catalase, scavengers of hydroxyl radical OH., and iron chelators have revealed that the acute pulmonary injury is related to production of oxygen-derived free radicals by activated neutrophils. OH. appears to be the key mediator involved in the acute lung microvascular injury.


Critical roles of hydrophobicity and orientation of side chains for inactivation of sarcoplasmic reticulum Ca2+-ATPase with thapsigargin and thapsigargin analogs.
Thapsigargin (Tg), a specific inhibitor of sarco/endoplasmic Ca(2+)-ATPases (SERCA), binds with high affinity to the E2 conformation of these ATPases. SERCA inhibition leads to elevated calcium levels in the cytoplasm, which in turn induces apoptosis. We present x-ray crystallographic and intrinsic fluorescence data to show how Tg and chemical analogs of the compound with modified or removed side chains bind to isolated SERCA 1a membranes. This occurs by uptake via the membrane lipid followed by insertion into a resident intramembranous binding site with few adaptative changes. Our binding data indicate that a balanced hydrophobicity and accurate positioning of the side chains, provided by the central guaianolide ring structure, defines a pharmacophore of Tg that governs both high affinity and access to the protein-binding site. Tg analogs substituted with long linkers at O-8 extend from the binding site between transmembrane segments to the putative N-terminal Ca(2+) entry pathway. The long chain analogs provide a rational basis for the localization of the linker, the presence of which is necessary for enabling prostate-specific antigen to cleave peptide-conjugated prodrugs targeting SERCA of cancer cells (Denmeade, S. R., Jakobsen, C. M., Janssen, S., Khan, S. R., Garrett, E. S., Lilja, H., Christensen, S. B., and Isaacs, J. T. (2003) J. Natl. Cancer Inst. 95, 990-1000). Our study demonstrates the usefulness of a simple in vitro system to test and direct development toward the formulation of new Tg derivatives with improved properties for SERCA targeting. Finally, we propose that the Tg binding pocket may be a regulatory site that, for example, is sensitive to cholesterol.


The ANNIGMA-wrapper approach to fast feature selection for neural nets.
This paper presents a novel feature selection approach for backpropagation neural networks (NNs). Previously, a feature selection technique known as the wrapper model was shown effective for decision trees induction. However, it is prohibitively expensive when applied to real-world neural net training characterized by large volumes of data and many feature choices. Our approach incorporates a weight analysis-based heuristic called artificial neural net input gain measurement approximation (ANNIGMA) to direct the search in the wrapper model and allows effective feature selection feasible for neural net applications. Experimental results on standard datasets show that this approach can efficiently reduce the number of features while maintaining or even improving the accuracy. We also report two successful applications of our approach in the helicopter maintenance applications.


Theories and measures of elder abuse.
Elder abuse is a pervasive phenomenon around the world with devastating effects on the victims. Although it is not a new phenomenon, interest in examining elder abuse is relatively new. This paper aims to provide an overview of the aetiological theories and measures of elder abuse. The paper briefly reviews theories to explain causes of elder abuse and then discusses the most commonly used measures of elder abuse. Based on the reviewed theories, it can be concluded that elder abuse is a multifactorial problem that may affect elderly people from different backgrounds and involve a wide variety of potential perpetrators, including caregivers, adult children, and partners. The review of existing measurement instruments notes that many different screening and assessment instruments have been developed to identify elders who are at risk for or are victims of abuse. However, there is a real need for more measurements of elder abuse, as the current instruments are limited in scope.


Comparison of the two major classes of assembly algorithms: overlap-layout-consensus and de-bruijn-graph.
Since the completion of the cucumber and panda genome projects using Illumina sequencing in 2009, the global scientific community has had to pay much more attention to this new cost-effective approach to generate the draft sequence of large genomes. To allow new users to more easily understand the assembly algorithms and the optimum software packages for their projects, we make a detailed comparison of the two major classes of assembly algorithms: overlap-layout-consensus and de-bruijn-graph, from how they match the Lander-Waterman model, to the required sequencing depth and reads length. We also discuss the computational efficiency of each class of algorithm, the influence of repeats and heterozygosity and points of note in the subsequent scaffold linkage and gap closure steps. We hope this review can help further promote the application of second-generation de novo sequencing, as well as aid the future development of assembly algorithms.


Single and multiple dose pharmacokinetics of acetaminophen (paracetamol) in polymedicated very old patients with rheumatic pain.
To determine whether multiple dosing of acetaminophen would result in drug accumulation in polymedicated elderly patients with rheumatic pain. Twelve inpatients (11 women), aged 89 +/- 4 years, weight 59 +/- 10 kg, receiving 3 to 8 concomitant medications, entered the study. Their creatinine clearance according to the Cockroft-Gault formula was 42 +/- 12 ml/min. The pharmacokinetics of 1 g acetaminophen was evaluated after the first dose (D1) and after the last dose (D7) during a 3 times daily regimen of 1 g for 5 consecutive days. The plasma pharmacokinetic profile of acetaminophen did not change significantly at D7 compared to D1. No significant within-patient differences were observed, especially with respect to plasma elimination half-life (2.74 +/- 0.48 and 2.77 +/- 0.32 hours, respectively), area under the concentration-time curve (82.5 +/- 21.1 and 90.1 +/- 15.2 microg x h/ml, respectively), and apparent oral clearance (3.68 +/- 0.85 and 3.28 +/- 0.52 ml/min/kg, respectively). No drug accumulation occurred during multiple dosing with acetaminophen in these very old subjects. On the basis of pharmacokinetic data alone, a dose regimen of acetaminophen 1 g tid seems to be appropriate in such patients.


Meibum Color and Free Fatty Acid Composition in Patients With Meibomian Gland Dysfunction.
We measured the components of meibum in patients with meibomian gland dysfunction (MGD) and control subjects and then examined the relation between meibum composition and clinical parameters. Thirty-eight patients with MGD (13 men and 25 women; mean age ± SD, 66.9 ± 15.0 years) and 20 control subjects (8 men and 12 women; 64.5 ± 6.7 years) were enrolled. Ocular symptom score, keratoconjunctival staining score, tear film breakup time, and Schirmer's test value were determined. Lid margin abnormalities and meibomian gland morphology were assessed for upper and lower eyelids, and meibum properties were evaluated at temporal, central, and nasal sites of each lid. Free fatty acid (FFA) composition of meibum was analyzed by liquid chromatography-Fourier transform mass spectrometry. Upper meibum color score was significantly correlated with epiphora and sticky sensation in MGD patients. Meibum grade, color, or viscosity did not differ significantly among the sites evaluated. A total of 103 species of FFA--including very long chain (such as C36 and C37) and odd-numbered chain (such as C17, C19, and C21) FFAs--were detected in meibum. Free fatty acid composition differed between clear and colored (cloudy or yellow) meibum, with unsaturated FFAs tending to be more abundant in colored meibum. Free fatty acid composition of human meibum correlates with meibum color as determined with a slit-lamp microscope. This finding may provide insight into the pathogenesis of MGD.