Aberrant R-loop-induced replication stress in MED12-mutant uterine fibroids.
Uterine fibroid (UF) driver mutations in Mediator complex subunit 12 (MED12) trigger genomic instability and tumor development through unknown mechanisms. Herein, we show that MED12 mutations trigger aberrant R-loop-induced replication stress, suggesting a possible route to genomic instability and a novel therapeutic vulnerability in this dominant UF subclass. Immunohistochemical analyses of patient-matched tissue samples revealed that MED12 mutation-positive UFs, compared to MED12 mutation-negative UFs and myometrium, exhibited significantly higher levels of R-loops and activated markers of Ataxia Telangiectasia and Rad3-related (ATR) kinase-dependent replication stress signaling in situ. Single molecule DNA fiber analysis revealed that primary cells from MED12 mutation-positive UFs, compared to those from patient-matched MED12 mutation-negative UFs and myometrium, exhibited defects in replication fork dynamics, including reduced fork speeds, increased and decreased numbers of stalled and restarted forks, respectively, and increased asymmetrical bidirectional forks. Notably, these phenotypes were recapitulated and functionally linked in cultured uterine smooth muscle cells following chemical inhibition of Mediator-associated CDK8/19 kinase activity that is known to be disrupted by UF driver mutations in MED12. Thus, Mediator kinase inhibition triggered enhanced R-loop formation and replication stress leading to an S-phase cell cycle delay, phenotypes that were rescued by overexpression of the R-loop resolving enzyme RNaseH. Altogether, these findings reveal MED12-mutant UFs to be uniquely characterized by aberrant R-loop induced replication stress, suggesting a possible basis for genomic instability and new avenues for therapeutic intervention that involve the replication stress phenotype in this dominant UF subtype.


The longevity bottleneck hypothesis: Could dinosaurs have shaped ageing in present-day mammals?
The evolution and biodiversity of ageing have long fascinated scientists and the public alike. While mammals, including long-lived species such as humans, show a marked ageing process, some species of reptiles and amphibians exhibit very slow and even the absence of ageing phenotypes. How can reptiles and other vertebrates age slower than mammals? Herein, I propose that evolving during the rule of the dinosaurs left a lasting legacy in mammals. For over 100 million years when dinosaurs were the dominant predators, mammals were generally small, nocturnal, and short-lived. My hypothesis is that such a long evolutionary pressure on early mammals for rapid reproduction led to the loss or inactivation of genes and pathways associated with long life. I call this the 'longevity bottleneck hypothesis', which is further supported by the absence in mammals of regenerative traits. Although mammals, such as humans, can evolve long lifespans, they do so under constraints dating to the dinosaur era.


Pathology of blast-related brain injury.
Blasts are responsible for about two-thirds of the combat injuries in Operation Iraqi Freedom and Operation Enduring Freedom, which include at least 1,200 traumatic brain injuries. Blasts inflict damage to the brain directly and by causing injuries to other organs, resulting in air emboli, hypoxia, and shock. Direct injuries to the brain result from rapid shifts in air pressure (primary blast injury), from impacts with munitions fragments and other objects propelled by the explosion (secondary blast injury), and from collisions with objects and rapid acceleration of individuals propelled by the explosion (tertiary blast injury). Tertiary injury can occur from a building or other structure collapsing and from an individual being thrown by the blast wind. The pathological consequences of secondary and tertiary blast injuries are very likely to be similar to those of other types of mechanical trauma seen in civilian life. The damage attributable to the specific effects of a blast, however, has received little study, although it has been assumed to include the focal and diffuse lesions characteristic of closed head injuries. Available clinical studies of blast injuries show focal damage similar to that found in other types of closed head injuries but have not determined whether diffuse axonal injury also occurs. In this article, we will try to reach a better understanding of the specific pathology of blast-related brain injury by reviewing the available experimental studies and the autopsy reports of victims of terrorist attacks and military casualties dating back to World War I.


Consensus Paper: Experimental Neurostimulation of the Cerebellum.
The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.


Schizophrenia with good and poor outcome. I: Early clinical features, response to neuroleptics and signs of organic dysfunction.
Seventy-seven patients with diagnosis of schizophrenia (62) or schizoaffective disorder (15) were studied 2-20 years since onset of illness, when in a stable condition. The investigation included clinical assessment, measurement of plasma concentrations of neuroleptics and prolactin, computed tomography brain scan, neuropsychological and neurological examination. Outcome of illness was classified according to the presence of chronic psychiatric symptoms and social impairment, and response to neuroleptics according to the effect of treatment in the most recent psychotic episode. Neither outcome nor response to neuroleptics was related to duration of illness. The groups with good and poor outcome differed in premorbid adjustment, age at onset and symptoms of the initial episode, but not in drug bio-availability or prolactin response. Large cerebral ventricles and cognitive impairment, but not neurological 'soft' signs, were associated with unfavourable outcome. The three measures of organicity were not inter-related. No clinical differences were found between chronic patients with and without signs of organic dysfunction. The findings suggest that schizophrenia with good and unfavourable outcome may be separate sub-types. However, the role of organic factors in the latter group remains unclear.


The effects of platelet-derived growth factor-BB and insulin-like growth factor-1 on epithelial dysplasia.
Growth factors are multi-functional and multi-targeted proteins which play a significant role in wound healing. Platelet-derived growth factor B-chain homodimer (PDGF-BB) and insulin-like growth factor-1 (IGF-1) have demonstrated efficacy for periodontal regeneration in animal models. Although primarily associated with wound healing, PDGF-BB and IGF-1 also facilitate growth of a number of malignant neoplasms. Of particular concern to periodontists is epithelial dysplasia, a necessary precursor to squamous cell carcinoma, the most common oral malignancy. Certain risk factors for oral cancer, such as tobacco, age, and alcohol, are also associated with an increased incidence of periodontal disease. The effects of the combination of PDGF-BB and IGF-1 on epithelial dysplasia have not previously been reported. The purpose of this study was to examine the effects of the combination of PDGF-BB and IGF-1 on epithelial dysplasia induced in the buccal cheek pouch of the Syrian golden hamster. A total of 66 hamsters received 18 applications of 0.5% dimethylbenzanthracene (DMBA), a topical carcinogen, over a 6-week period for the induction of dysplasia. The hamsters were subsequently divided into a baseline and 3 experimental groups (growth factors, saline vehicle, untreated control). Following the final DMBA application (day 0), the baseline group (N = 6) was sacrificed, the growth factor group (N = 21) received a single injection in the cheek pouch containing 4 micrograms of PDGF-BB and 4 micrograms of IGF-1 in saline, the saline group (N = 19) received an injection in the cheek pouch containing the saline vehicle only, and the untreated control group (N = 20) received no injection. Animals in experimental groups were sacrificed on days 3, 6, and 10. The cheek pouches were harvested for histologic and histochemical evaluation. Dysplasia was histologically graded from 0 to 4. Statistical analysis of the histologic data revealed no significant differences either by sacrifice date or by group. Histochemical evaluation, via staining for gamma-glutamyl transpeptidase (GGT), a marker for dysplastic cell colonies, revealed that the density of GGT-positive cells in experimental groups differed significantly from baseline levels. No significant differences were detected between experimental groups. There was poor correlation between the density of GGT-positive cells and the histologic grading of dysplasia. It is concluded that exposure to PDGF-BB and IGF-1 had no demonstrable effect on epithelial dysplasia in this hamster model.


The ground beetle genus Bembidion Latreille in Baltic amber: Review of preserved specimens and first 3D reconstruction of endophallic structures using X-ray microscopy (Coleoptera, Carabidae, Bembidiini).
The ground beetle genus Bembidion is a highly diverse group of small predators with more than 1.200 described extant species. In contrast, only two representatives of Bembidion are known from the amber fossil record and their position within this mega-diverse genus is dubious. Here, we address the taxonomic position of these two extinct Bembidion species (B. succini Giebel, 1856 and B. christelae Ortuño & Arillo, 2010). Based on the insufficient description and the missing type specimen, B. succini, nomen dubium, cannot be assigned to the genus Bembidion and/or to the tribe Bembidiini with certainty. The subgenus Archaeophilochthus Ortuño & Arillo, 2010 was erected for the second extinct species, B. christelae, based on external characters. However, this species seems indistinguishable to members of the earlier described subgenus Philochthemphanes Netolitzky, 1943 which comprises about extant 10 species distributed in East and Southeast Asia. Furthermore, we describe two new species, B. bukejsisp. n. and B. alekseevisp. n., from the Eocene Baltic amber using X-ray microscopy. Based on external and genital morphology including endophallic structures, we erected the monotypic subgenus Eodontium subgen. n. for B. bukejsisp. n., which is probably related to the subgenera Andrewesa Netolitzky, 1931, the Hydrium complex, or the Odontium series sensu Maddison (2012). On the other hand, B. alekseevisp. n. can be assigned to the subgenus Eupetedromus Netolitzky, 1911. The occurrence of representatives of at least two species groups adapted to a temperate climate suggests the presence of at least locally temperate climates in Baltic amber forests.


The impact of Alzheimer's disease susceptibility loci on lateral ventricular surface morphology in older adults.
The enlargement of ventricular volume is a general trend in the elderly, especially in patients with Alzheimer's disease (AD). Multiple susceptibility loci have been reported to have an increased risk for AD and the morphology of brain structures are affected by the variations in the risk loci. Therefore, we hypothesized that genes contributed significantly to the ventricular surface, and the changes of ventricular surface were associated with the impairment of cognitive functions. After the quality controls (QC) and genotyping, a lateral ventricular segmentation method was employed to obtain the surface features of lateral ventricle. We evaluated the influence of 18 selected AD susceptibility loci on both volume and surface morphology across 410 subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI). Correlations were conducted between radial distance (RD) and Montreal Cognitive Assessment (MoCA) subscales. Only the C allele at the rs744373 loci in BIN1 gene significantly accelerated the atrophy of lateral ventricle, including the anterior horn, body, and temporal horn of left lateral ventricle. No significant effect on lateral ventricle was found at other loci. Our results revealed that most regions of the bilateral ventricular surface were significantly negatively correlated with cognitive scores, particularly in delayed recall. Besides, small areas of surface were negatively correlated with language, orientation, and visuospatial scores. Together, our results indicated that the genetic variation affected the localized areas of lateral ventricular surface, and supported that lateral ventricle was an important brain structure associated with cognition in the elderly.


Gene expression signatures in conjunctival fornix aspirates of patients with dry eye disease associated with Meibomian gland dysfunction. A proof-of-concept study.
Meibomian gland dysfunction (MGD) is one of the most common conditions in ophthalmic practice and the most frequent cause of evaporative dry eye disease (DED). However, the immune mechanisms leading to this pathology are not fully understood and the diagnostic tests available are limited. Here, we used the nCounter technology to analyze immune gene expression in DED-MGD that can be used for developing diagnostic signatures for DED. Conjunctival cell samples were obtained by aspiration from patients with DED-MGD (n = 27) and asymptomatic controls (n = 22). RNA was purified, converted to cDNA, preamplified and analyzed using the Gene Expression Human Immune V2 panel (NanoString), which includes 579 target and 15 housekeeping genes. A machine learning (ML) algorithm was applied to design a signature associated with DED-MGD. Forty-five immune genes were found upregulated in DED-MGD vs. controls, involved in eight signaling pathways, IFN I/II, MHC class I/II, immunometabolism, B cell receptor, T Cell receptor, and T helper-17 (Th-17) differentiation. Additionally, statistically significant correlations were found between 31 genes and clinical characteristics of the disease such as lid margin or tear osmolarity (Pearson's r < 0.05). ML analysis using a recursive feature elimination (RFE) algorithm selected a 4-gene mRNA signature that discriminated DED-MGD from control samples with an area under the ROC curve (AUC ROC) of 0.86 and an accuracy of 77.5%. Multiplexed mRNA analysis of conjunctival cells can be used to analyze immune gene expression patterns in patients with DED-MGD and to generate diagnostic signatures.


Estimation of test error rates, disease prevalence and relative risk from misclassified data: a review.
We review methods for the analysis of categorical clinical and epidemiological data, in which the observations are subject to misclassification. Under certain conditions, it is possible to estimate error parameters such as sensitivity, specificity, relative risk, or predictive value, even though no definitive classification (gold standard) is available. The parameter estimates are obtained by modelling the data, using maximum likelihood, with or without some constraints. The models recognize that the true classification of an individual is unknown, and so are sometimes referred to as "latent class" models. The latent class approach provides a unified framework for various methods found in a dispersed literature, characterising each by the number of populations or subgroups in the data, and the number of observations made on each individual; the statistical degrees of freedom are implied by the sampling design. Data sets with less than three replicate observations per individual necessarily require constraints for parameter estimation to be possible. Data sets with three or more replicates lead directly to estimates of the misclassification rates, subject to some simple assumptions. Some more complex problems are also discussed, including data where the response variable has more than two levels, sequential and irregular designs and the effects of assumption violations.


Incidence of clinical malaria in pregnant women exposed to intense perennial transmission.
The interaction between pregnancy and malaria attacks was investigated from 1990 to 1994 among women in the village of Dielmo, a holoendemic area in Senegal where malaria transmission is intense and perennial. Clinical and parasitological data collected during the daily follow-up of 48 pregnancies among 31 women were compared with those collected from the same women using the same methods during the year which preceded or followed their pregnancy. The parasite prevalence, mean and maximum parasite density in Plasmodium falciparum infections were significantly higher during pregnancy. The incidence rate of malaria attacks was, on average, 4.2 times higher during pregnancy than during the control period. Although most pregnancies were not associated with a malaria attack and the incidence of malaria attacks decreased as the number of previous pregnancies increased, a significant increase in risk of malaria attacks among multigravidae was noted until the fifth pregnancy.


Using functional magnetic resonance imaging and electroencephalography to detect consciousness after severe brain injury.
In recent years, rapid technological developments in the field of neuroimaging have provided new methods for revealing thoughts, actions, and intentions based solely on the pattern of activity that is observed in the brain. In specialized centres, these methods are now being employed routinely in the assessment of patients diagnosed with so-called "disorders of consciousness," mapping patterns of residual function and dysfunction and helping to reduce diagnostic errors between related conditions such as the vegetative and minimally conscious states. Both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) have now been shown to be effective tools for detecting covert awareness in behaviorally nonresponsive patients when standard clinical approaches have been unable to provide that information. Indeed, in some patients, communication with the outside world via simple "yes" and "no" questions has been achieved, even in cases where no possibility for behavioral interaction exists. These studies have profound implications for clinical care, diagnosis, prognosis and medical-legal decision making relating to the prolongation, or otherwise, of life after severe brain injury. Moreover, the results suggest an urgent need for a re-evaluation of the existing diagnostic guidelines for behaviorally nonresponsive patients to include information derived from functional neuroimaging.


Three-dimensional ultrasound with surface rendering for the study of fetal small parts.
The purpose of this article is to report that the use of three-dimensional (3D) ultrasound with surface rendering offers advantage in fetal small parts evaluation. Compared with two-dimensional (2D) ultrasonography, three-dimensional ultrasonography provides a better spatial vision of the surface and anatomic boundary of different embryonal and fetal organs and structures. Visualization of an embryo or fetus in all space planes with surface rendering allows a more detailed evaluation of external fetal structures that could easily be missed with 2D ultrasonography. The advent of 3D ultrasound has dramatically improved clinical prenatal diagnosis of small parts anomalies. We anticipate that 3D ultrasonography will be used more widely in obstetrics.


A comprehensive repertoire of tRNA-derived fragments in prostate cancer.
Prostate cancer (PCa) is the most common cancer among men in developed countries. Although its genetic background is thoroughly investigated, rather little is known about the role of small non-coding RNAs (sncRNA) in this disease. tRNA-derived fragments (tRFs) represent a new class of sncRNAs, which are present in a broad range of species and have been reported to play a role in several cellular processes. Here, we analyzed the expression of tRFs in fresh frozen patient samples derived from normal adjacent prostate and different stages of PCa by RNA-sequencing. We identified 598 unique tRFs, many of which are deregulated in cancer samples when compared to normal adjacent tissue. Most of the identified tRFs are derived from the 5'- and 3'-ends of mature cytosolic tRNAs, but we also found tRFs produced from other parts of tRNAs, including pre-tRNA trailers and leaders, as well as tRFs from mitochondrial tRNAs. The 5'-derived tRFs comprise the most abundant class of tRFs in general and represent the major class among upregulated tRFs. The 3'-derived tRFs types are dominant among downregulated tRFs in PCa. We validated the expression of three tRFs using qPCR. The ratio of tRFs derived from tRNALysCTT and tRNAPheGAA emerged as a good indicator of progression-free survival and a candidate prognostic marker. This study provides a systematic catalogue of tRFs and their dysregulation in PCa and can serve as the basis for further research on the biomarker potential and functional roles of tRFs in this disease.


Unraveling the Intricacies of Autophagy and Mitophagy: Implications in Cancer Biology.
Autophagy is an essential lysosome-mediated degradation pathway that maintains cellular homeostasis and viability in response to various intra- and extracellular stresses. Mitophagy is a type of autophagy that is involved in the intricate removal of dysfunctional mitochondria during conditions of metabolic stress. In this review, we describe the multifaceted roles of autophagy and mitophagy in normal physiology and the field of cancer biology. Autophagy and mitophagy exhibit dual context-dependent roles in cancer development, acting as tumor suppressors and promoters. We also discuss the important role of autophagy and mitophagy within the cancer microenvironment and how autophagy and mitophagy influence tumor host-cell interactions to overcome metabolic deficiencies and sustain the activity of cancer-associated fibroblasts (CAFs) in a stromal environment. Finally, we explore the dynamic interplay between autophagy and the immune response in tumors, indicating their potential as immunomodulatory targets in cancer therapy. As the field of autophagy and mitophagy continues to evolve, this comprehensive review provides insights into their important roles in cancer and cancer microenvironment.


Fluoxetine exposure during pregnancy and lactation: Effects on acute stress response and behavior in the novelty-suppressed feeding are age and gender-dependent in rats.
Fluoxetine (FLX) is commonly used to treat anxiety and depressive disorders in pregnant women. Since FLX crosses the placenta and is excreted in milk, maternal treatment with this antidepressant may expose the fetus and neonate to increased levels of serotonin (5-HT). Long-term behavioral abnormalities have been reported in rodents exposed to higher levels of 5-HT during neurodevelopment. In this study we evaluated if maternal exposure to FLX during pregnancy and lactation would result in behavioral and/or stress response disruption in adolescent and adult rats. Our results indicate that exposure to FLX influenced restraint stress-induced Fos expression in the amygdala in a gender and age-specific manner. In male animals, a decreased expression was observed in the basolateral amygdala at adolescence and adulthood; whereas at adulthood, a decrease was also observed in the medial amygdala. A lack of FLX exposure effect was observed in females and also in the paraventricular nucleus of both genders. Regarding the behavioral evaluation, FLX exposure did not induce anhedonia in the sucrose preference test but decreased the latency to feed of both male and female adolescent rats evaluated in the novelty-suppressed feeding test. In conclusion, FLX exposure during pregnancy and lactation decreases acute amygdalar stress response to a psychological stressor in males (adolescents and adults) as well as influences the behavior of adolescents (males and females) in a model that evaluates anxiety and/or depressive-like behavior. Even though FLX seems to be a developmental neurotoxicant, the translation of these findings to human safe assessment remains to be determined since it is recognized that not treating a pregnant or lactating woman may also impact negatively the development of the descendants.


Late emergence of macular sparing in a stroke patient: Clinical Case Report.
Occlusive cerebrovascular disease is the most common cause of homonymous hemianopia (HH) with macular sparing. A 61-year-old man came to our ophthalmology clinic complaining of right-side hemianopia. Ophthalmic examination, visual field (VF) examination, and brain magnetic resonance imaging (MRI) were performed. He had right HH without macular sparing on the initial VF test. And brain MRI 6 days after the visual symptoms began revealed a left occipital infarction. Thirty-seven days after the onset, his follow-up 24-2 VF examination showed HH with bilateral macular sparing, which was not apparent in the initial VF examination. About 4 months after the stroke, his central 10-2 VF examination also showed HH with bilateral macular sparing. We report a case of HH with a dramatic improvement in central vision several days after an occipital infarction. To our knowledge, this is the first case to show macular sparing developing after several days.


[Prognostic indices of the normalization of left ventricular function in chronic aortic insufficiency following valve replacement].
The aim of this study of 31 patients was to identify M mode echocardiographic parameters predictive of normalisation of left ventricular function after valvular replacement for chronic aortic incompetence in order to determine the optimal time for surgery. Only patients with chronic, pure aortic incompetence (ventriculo-aortic pressure gradient less than or equal to 30 mmHG) were considered. At the time of investigation 4 patients were in functional Class I, 6 in Class II, 10 in Class III and 11 in Class IV (NYHA). M mode echocardiography was performed on an Echovideorex or an Irex System II echocardiograph. The following measurements were made and corrected for body surface area according to the recommendations of the American Society of Echocardiography; end systolic and end diastolic dimensions (mm), fractional shortening (%), end systolic and end diastolic wall thickness (mm), diastolic radius to wall thickness ratio, short axis myocardial surface area (cme), wall stress, end systolic stress (mmHg). The study comprised pre and postoperative studies with an interval of 22.7 +/- 12.5 months (range 5 to 46 months); the data obtained was compared with a control group of 10 normal subjects. The results showed that preoperative fractional shortening less than 28% was associated with an increased risk of persistent postoperative left ventricular dysfunction.


Receptor tyrosine phosphatase sigma (RPTPσ) regulates, p250GAP, a novel substrate that attenuates Rac signaling.
Cumulative evidence supports an important role for RPTPsigma in the development of the nervous system and nerve regeneration. However, the signaling mechanisms regulated by RPTPsigma remain largely unknown and the identification of RPTPsigma substrate(s) and binding partners is essential to understanding its mechanisms of action. We employed a modified yeast-two-hybrid approach, the yeast substrate-trapping system, to identify new substrates and interacting partners of RPTPsigma. The binding proteins RPTPdelta, Liprinalpha4, p130Cas and Trio were found to interact with RPTPsigma in the yeast system independently of tyrosine phosphorylation. Importantly, using the trapping mutant of RPTPsigma we identified p250GAP as a novel substrate and RPTPsigma displayed its phosphatase specificity toward p250GAP in vitro. In the mammalian expression system, the trapping mutant of RPTPsigma recognized p250GAP as its physiological substrate in the presence of active Fyn, suggesting that the interaction of the two proteins is primarily dependent on tyrosine phosphorylation. Furthermore, p250GAP activity increased in the presence of RPTPsigma leading to attenuated Rac activity. Overexpression of p250GAP and RPTPsigma inhibited axonal outgrowth in differentiated PC12 cells. Cumulative evidence implicates that RPTPsigma modulates the actin cytoskeleton by regulating Rac GTPase activity through p250GAP. Taken together, our results demonstrate for the first time that RPTPsigma modulates Rac dependent activity through regulating a novel substrate, p250GAP.


[Possibilities of intracapsular implantation of intraocular lenses in eye injuries].
The authors analyze the results of 63 surgeries for implantation of intraocular lenses, V. N. Alexeyev's design, in patients with traumatic cataracts and other injuries after perforating and contusion injuries. The results evidence a high efficacy of intracapsular implantation. Vision acuity with correction has improved in 36 eyes to make up 0.5 and more diopters. In the rest cases (27 eyes) vision acuity with correction has made up 0.1-0.4. The implantation was simple and the course of the postoperative period smooth in the patients with membranous and semiresolved cataracts, with primary and secondary glaucoma, and implantation into the posterior chamber.


Internet-delivered aftercare following multimodal rehabilitation program for chronic pain: a qualitative feasibility study.
Methods for delivering aftercare to help chronic pain patients to continue practice self-management skills after rehabilitation are needed. Internet-delivered cognitive behavioral therapy (ICBT) has the potential to partly fill this gap given its accessibility and emphasis on self-care. Methods for engaging and motivating patients to persist throughout the full length of treatment are needed. The aim of this study was to describe how chronic pain patients work in an ICBT program, through their descriptions of what is important when they initiate behavior change in aftercare and their descriptions of what is important for ongoing practice of self-management skills in aftercare. Following a multimodal rehabilitation program, 29 chronic pain patients participated in a 20-week-long Internet-delivered aftercare program (ACP) based on acceptance-based cognitive behavioral therapy. Latent content analysis was made on 138 chapters of diary-like texts written by participants in aftercare. Attitudes regarding pain and body changed during ACP, as did attitudes toward self and the future for some participants. How participants practiced self-management skills was influenced by how they expressed motivation behind treatment goals. Whether they practiced acceptance strategies influenced their continuous self-management practice. Defusion techniques seemed to be helpful in the process of goal setting. Mindfulness strategies seemed to be helpful when setbacks occurred. Self-motivating goals are described as important both to initiate and in the ongoing practice of self-management skills. Experiencing a helpful effect of acceptance strategies seems to encourage participants to handle obstacles in new ways and to persist throughout treatment. Research on whether tailored therapist guidance might be helpful in stating self-motivating goals and contribute to ongoing practice of self-management skills is needed.


Flexible elastomer molds in burn scar control.
Burn scar hypertrophies and contractures have responded well to pressure techniques with pressure gradient burn garments except over soft tissue areas and concave body areas such as the axilla, hand, clavicle, neck, and face. Although these areas represent only 20 percent of the body area, when scarred from burns they pose perplexing functional and esthetic problems. Rigid splints and face masks have been used but their rigidity makes them uncomfortable for long-term wear. Silastic Medical Elastomer molds have proved highly successful in these areas when worn under pressure garments. They are flexible and of definite shape. The elastomer molds fill the concave gapping so that consistent definitive pressure can be maintained and scar hypertrophies prevented.


Poly(epsilon-caprolactone) and poly (L-lactic-co-glycolic acid) degradable polymer sponges attenuate astrocyte response and lesion growth in acute traumatic brain injury.
This study evaluated the response of rat brain to 2 degradable polymers (poly (L-lactic-co-glycolic acid) (PLGA), and poly(epsilon-caprolactone) (PCL)), two common materials in tissue engineering. PLGA has been extensively studied in the brain for controlled drug release as injectable microspheres and is generally accepted as biocompatible in that capacity. Biocompatibility in other forms and for different functions in the brain has not been widely studied. PCL was chosen as an alternative to PLGA for its slower degradation and less-acidic pH upon degradation. Porous scaffolds were made from both polymers and implanted into rat cerebral cortex for 1 and 4 weeks. Morphology, defect size, activation of microglia (OX-42) and astrocytes (glial fibrillary acidic protein (GFAP)), infiltration of activated macrophages (major histocompatibility complex (MHC)-II), and ingrowth of neurons (beta-tubulin type III (Tuj-1)) and progenitor cells (nestin) were analyzed using hematoxylin and eosin staining and immunofluorescence. PCL induced a lower inflammatory response than PLGA, as demonstrated by lower MHC-II and GFAP expression and greater ingrowth. Both polymers alleviated astrocytic activation and prevented enlargement of the defect. Tuj-1-, nestin-, and GFAP-positive cells were observed growing on both polymers at the peripheries of the sponge implants, demonstrating their permissiveness to neural ingrowth. These findings suggest that both polymers attenuate secondary death and scarring and that PCL might have advantages over PLGA.


Evaluation of acrosome on Papanicolaou-stained sperm and its relationship to the in vitro fertilizing capacity of human spermatozoa.
Papanicolaou-stained sperm smears from 1150 ejaculates evaluated from infertility clinic patients and 166 ejaculates in an in vitro fertilization program were studied for the presence of acrosomal abnormalities. Morphologically, a normal acrosome was defined as a sperm having a ratio of 1:1 to 2:1 between the acrosome and postacrosomal part in an oval or round, uniformly shaped head. Acrosomal abnormality was identified in at least a few of the spermatozoa in all the ejaculates (range 8-98%) and appeared to be closely related to normal sperm morphology (r = 0.85). A significantly higher (p less than 0.01) correlation (r = 0.31) was noted between the presence of normal acrosome and in vitro fertilizing capacity of spermatozoa as compared to other standard semen characteristics. Acrosome can be identified on Papanicolaou-stained smears, and since it appears to be related to fertility it may be beneficial to evaluate the acrosome morphologically during routine semen analysis.


Evaluation of adult celiac disease from a tertiary reference center: a retrospective analysis.
It has been observed that celiac disease (CD) is not restricted to a single type characterized by diarrhea but also has atypical, asymptomatic (silent), and latent forms. The prevalence of this autoimmune disease, which affects approximately 1% of the world, is estimated to be around 3%, including atypical and asymptomatic cases. In our study, we aimed to evaluate adult celiac patients. Between December 2008-2015, patients diagnosed with CD over the age of 18 years old were included in the study. Patients' symptoms at admission, frequency and type of anemia, transaminase levels, and celiac antibody positivity, and autoimmune diseases diagnosed at follow up were evaluated retrospectively. Of 195 patients, 151 (77.4%) were female. The mean age of the patients was 35.73 ± 12.19 years (range, 18-71 years). A hundred patients (51.3%) had gastrointestinal symptoms. At the time of admission, 118 patients (60.5%) had anemia, and 52 (26.7%) had hypertransaminasemia. During the mean follow-up period of 58 months (36-120 months), 84 (43.1%) of the patients presented at least one autoimmune disease, and this rate was 96.6% in individuals diagnosed above the age of 50 years. In adult CD, resistant anemia, dyspepsia, and hypertransaminasemia are very common findings at the time of diagnosis, and the association with other autoimmune diseases, especially Hashimoto's thyroiditis, is high.


[A suspected case of acute respiratory failure caused by ritodrine hydrochloride].
A 36-year-old woman was admitted to the obstetric department because of possible premature labor of twins at 35 weeks. She had been treated by ritodrine hydrochloride, a tocolytic agent, for 1 week, and delivered healthy twins by cesarean operation. After the operation, she suddenly complained of dyspnea with associated hypoxemia and was admitted to our hospital. She presented with hypoxemia and was given a diagnosis of pulmonary edema. She was given a diuretic with ventilator therapy, and improved rapidly. However, an echocardiogram showed continuing left ventricular systolic dysfunction after 3 months. From these results, this case was suspected to be pulmonary edema due to ritodrin after myocardial failure, including peripartum cardiomyopathy.


High frequency of porcine norovirus infection in finisher units of Brazilian pig-production systems.
Norovirus (NoV) is a member of the Caliciviridae family and is considered an emerging human enteric pathogen. NoVs are detected in farm animals such as cattle, sheep and pigs. Porcine NoV (PoNoV) is widespread worldwide, but frequency of infection is often low. This study aimed to investigate the natural PoNoV infection from adult animals of an important Brazilian pig-production region. Faecal samples (n = 112) of asymptomatic pigs aged 9 to 24 weeks old were collected from 16 grower-to-finish herds located in Paraná state, Brazilian Southern region, and evaluated for PoNoV presence. A reverse transcription-polymerase chain reaction (RT-PCR) assay was performed using specific primers that target a conserved region of the virus capsid gene (VP1). PoNoV was detected in 58 (51.8%) of the 112 faecal samples and in 14 (87.5%) of the 16 herds evaluated. Six of the obtained amplicons were submitted to phylogenetic genotyping analysis. The higher nucleotide (86.5-97.4%) and amino acid (100%) similarities of the sequences in this study were with the representative strains of the porcine NoV genogroup II genotype 11 (PoNoV GII-11). These results reveal that PoNoV infection is endemic in one of the most important pork production areas of Brazil and that the PoNoV GII-11 is prevalent in this region.


Long Noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 Promotes the Osteoblast Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Targeting the microRNA-96/Osterix Axis.
To investigate whether and how the long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) sponges microRNA-96 (miR-96) to achieve the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). Protein levels were detected by Western blot. Mineralized bone matrix formation was studied by alizarin red staining. Metastasis-associated lung adenocarcinoma transcript 1, miR-96, and osteogenesis-related Messenger RNA expression was assessed by Quantitative Real-time Polymerase Chain Reaction (qRT-PCR). The interactions between miR-96 and osterix (Osx), MALAT1, and miR-96 were determined by luciferase reporter assay. The expression of MALAT1 was upregulated whereas that of miR-96 was downregulated in osteogenic hBMSCs. In addition, the expression of MALAT1 significantly decreased whereas that of miR-96 increased in the hBMSCs of osteoporosis (OP) patients. qRT-PCR and alizarin red staining assays showed that MALAT1 silencing or miR-96 overexpression inhibits hBMSC osteogenic differentiation and vice versa. overexpression of miR-96 reversed the promotive effect of MALAT1 on the osteogenic differentiation of hBMSCs. Dual luciferase report assay verified that miR-96 is a regulatory target of MALAT1 and that Osx is a gene target of miR-96. Taken together, the results demonstrate that MALAT1 promotes the osteogenic differentiation of hBMSCs by regulating the miR-96/Osx axis. Our study provides novel mechanistic insights into the critical role of lncRNA MALAT1 as a microRNA sponge in OP patients and sheds new light on lncRNA-directed diagnostics and therapeutics in OP.


Treatment effects of gabapentin for primary insomnia.
The prevalence of insomnia is very high in our society. Although pharmacological treatment of insomnia is available, most hypnotics have been shown to alter sleep architecture and have many adverse effects. Gabapentin was originally designed for antiepileptic therapy; however, some studies reported that its use increases slow-wave sleep in healthy volunteers or patients. Our goal was to evaluate the benefits of gabapentin in the treatment of primary insomnia in patients. Eighteen patients with primary insomnia participated in the study. They received gabapentin treatment for at least 4 weeks. All patients received polysomnography, a biochemical blood test, and neuropsychological tests before and after the treatment period. All measures were analyzed with Student t test to examine the treatment effects of gabapentin, except that the measures of heart rate variability were analyzed with analysis of variance. Polysomnographic study revealed increased sleep efficiency and slow-wave sleep, decreased wake after sleep onset, and spontaneous arousal index after gabapentin treatment. The biochemical blood test revealed decreased prolactin levels in the morning after treatment. Electroencephalographic power spectral analysis showed increased delta-2 and theta power in sleep stage 1 and decreased sigma activity power in sleep stages N2 and N3 after gabapentin treatment. Heart rate variability analyses also showed a significant increase in normalized high frequency percentage in sleep stages N2 and N3 and low frequency-high frequency ratio in sleep stage N2 after treatment. In addition, neuropsychological tests revealed the elevation of visual motor processing speed after gabapentin treatment. Gabapentin enhances slow-wave sleep in patients with primary insomnia. It also improves sleep quality by elevating sleep efficiency and decreasing spontaneous arousal. The results suggest that gabapentin may be beneficial in the treatment of primary insomnia.


Autoimmune Diseases of Digestive Organs-A Multidisciplinary Challenge: A Focus on Hepatopancreatobiliary Manifestation.
It is well known that some pathological conditions, especially of autoimmune etiology, are associated with the HLA (human leukocyte antigen) phenotype. Among these diseases, we include celiac disease, inflammatory bowel disease, autoimmune enteropathy, autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cholangitis. Immunoglobulin G4-related diseases (IgG4-related diseases) constitute a second group of autoimmune gastrointestinal, hepatobiliary and pancreatic illnesses. IgG4-related diseases are systemic and rare autoimmune illnesses. They often are connected with chronic inflammation and fibrotic reaction that can occur in any organ of the body. The most typical feature of these diseases is a mononuclear infiltrate with IgG4-positive plasma cells and self-sustaining inflammatory response. In this review, we focus especially upon the hepatopancreatobiliary system, autoimmune pancreatitis and IgG4-related sclerosing cholangitis. The cooperation of the gastroenterologist, radiologist, surgeon and histopathologist is crucial for establishing correct diagnoses and appropriate treatment, especially in IgG4 hepatopancreatobiliary diseases.


DAC-less PAM-4 generation in the O-band using a silicon Mach-Zehnder modulator.
We demonstrate 20-Gb/s 4-level pulse amplitude modulation (PAM-4) signal generation using a silicon Mach-Zehnder modulator (MZM) in the O-band. The modulator is driven by two independent binary streams, and the PAM-4 signal is thus generated directly on the chip, avoiding the use of power-hungry digital-to-analog converters (DACs). With optimized amplitude levels of the binary signals applied to the two arms of the MZM, a pre-forward error correction (FEC) bit-error rate (BER) as low as 7.6 × 10-7 is obtained. In comparison with a commercially available LiNbO3 modulator, the penalty is only 2 dB at the KP4 FEC threshold of 2.2 × 10-4.


Neuron-Specific FMRP Roles in Experience-Dependent Remodeling of Olfactory Brain Innervation during an Early-Life Critical Period.
Critical periods are developmental windows during which neural circuits effectively adapt to the new sensory environment. Animal models of fragile X syndrome (FXS), a common monogenic autism spectrum disorder (ASD), exhibit profound impairments of sensory experience-driven critical periods. However, it is not known whether the causative fragile X mental retardation protein (FMRP) acts uniformly across neurons, or instead manifests neuron-specific functions. Here, we use the genetically-tractable Drosophila brain antennal lobe (AL) olfactory circuit of both sexes to investigate neuron-specific FMRP roles in the odorant experience-dependent remodeling of the olfactory sensory neuron (OSN) innervation during an early-life critical period. We find targeted OSN class-specific FMRP RNAi impairs innervation remodeling within AL synaptic glomeruli, whereas global dfmr1 null mutants display relatively normal odorant-driven refinement. We find both OSN cell autonomous and cell non-autonomous FMRP functions mediate odorant experience-dependent remodeling, with AL circuit FMRP imbalance causing defects in overall glomerulus innervation refinement. We find OSN class-specific FMRP levels bidirectionally regulate critical period remodeling, with odorant experience selectively controlling OSN synaptic terminals in AL glomeruli. We find OSN class-specific FMRP loss impairs critical period remodeling by disrupting responses to lateral modulation from other odorant-responsive OSNs mediating overall AL gain control. We find that silencing glutamatergic AL interneurons reduces OSN remodeling, while conversely, interfering with the OSN class-specific GABAA signaling enhances remodeling. These findings reveal control of OSN synaptic remodeling by FMRP with neuron-specific circuit functions, and indicate how neural circuitry can compensate for global FMRP loss to reinstate normal critical period brain circuit remodeling.SIGNIFICANCE STATEMENT Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder (ASD), manifests severe neurodevelopmental delays. Likewise, FXS disease models display disrupted neurodevelopmental critical periods. In the well-mapped Drosophila olfactory circuit model, perturbing the causative fragile X mental retardation protein (FMRP) within a single olfactory sensory neuron (OSN) class impairs odorant-dependent remodeling during an early-life critical period. Importantly, this impairment requires activation of other OSNs, and the olfactory circuit can compensate when FMRP is removed from all OSNs. Understanding the neuron-specific FMRP requirements within a developing neural circuit, as well as the FMRP loss compensation mechanisms, should help us engineer FXS treatments. This work suggests FXS treatments could use homeostatic mechanisms to alleviate circuit-level deficits.


Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets.
In patients with asthma or chronic obstructive pulmonary disease, rhinovirus (RV) infections can provoke acute worsening of disease, and limited treatment options exist. Viral replication in the host cell induces significant remodeling of intracellular membranes, but few studies have explored this mechanistically or as a therapeutic opportunity. We performed unbiased lipidomic analysis on human bronchial epithelial cells infected over a 6 h period with the RV-A1b strain of RV to determine changes in 493 distinct lipid species. Through pathway and network analysis, we identified temporal changes in the apparent activities of a number of lipid metabolizing and signaling enzymes. In particular, analysis highlighted FA synthesis and ceramide metabolism as potential anti-rhinoviral targets. To validate the importance of these enzymes in viral replication, we explored the effects of commercially available enzyme inhibitors upon RV-A1b infection and replication. Ceranib-1, D609, and C75 were the most potent inhibitors, which confirmed that FAS and ceramidase are potential inhibitory targets in rhinoviral infections. More broadly, this study demonstrates the potential of lipidomics and pathway analysis to identify novel targets to treat human disorders.


Training trajectories by continuous recurrent multilayer networks.
This paper addresses the problem of training trajectories by means of continuous recurrent neural networks whose feedforward parts are multilayer perceptrons. Such networks can approximate a general nonlinear dynamic system with arbitrary accuracy. The learning process is transformed into an optimal control framework where the weights are the controls to be determined. A training algorithm based upon a variational formulation of Pontryagin's maximum principle is proposed for such networks. Computer examples demonstrating the efficiency of the given approach are also presented.


[Applications of molecular imaging in vulnerable atherosclerotic plaque].
Atherosclerosis plaque is the underline cause of ischemic stroke and acute coronary syndrome. In this article, the applications of molecular imaging in vulnerable plaque are reviewed.


Non-cell-autonomous control of vascular stem cell fate by a CLE peptide/receptor system.
Land plants evolved a long-distance transport system of water and nutrients composed of the xylem and phloem, both of which are generated from the procambium- and cambium-comprising vascular stem cells. However, little is known about the molecular mechanism of cell communication governing xylem-phloem patterning. Here, we show that a dodecapeptide (HEVHypSGHypNPISN; Hyp, 4-hydroxyproline), TDIF (tracheary element differentiation inhibitory factor), is secreted from the phloem and suppresses the differentiation of vascular stem cells into xylem cells through a leucine-rich repeat receptor-like kinase (LRR-RLK). TDIF binds in vitro specifically to the LRR-RLK, designated TDR (putative TDIF receptor), whose expression is restricted to procambial cells. However, the combined analysis of TDIF with a specific antibody and the expression profiles of the promoters of two genes encoding TDIF revealed that TDIF is synthesized mainly in, and secreted from, the phloem and its neighboring cells. The observation that TDIF is capable of promoting proliferation of procambial cells while suppressing xylem differentiation suggests that this small peptide functions as a phloem-derived, non-cell-autonomous signal that controls stem cell fate in the procambium. Our results indicate that we have discovered a cell communication system governing phloem-xylem cross-talk.


Dental students' beliefs about culture in patient care: self-reported knowledge and importance.
In order to decrease the well-documented disparities in oral health and oral health care, the next generation of dentists must be prepared to serve a diverse patient population. This article describes dental students' self-reported knowledge of culture and importance of using culturally sensitive dental practices. Three consecutive graduating classes (n=111) were surveyed anonymously in their sophomore years. Students indicated their self-rated knowledge of oral health and oral health care for their own culture and the cultures of patients they are likely to see in dental practice. Students also rated their perceived importance of culturally sensitive dental practice. Overall, students reported low knowledge of the cultures of the patients they will see in practice. Few students could identify any cultural group that they knew well. However, students as a group indicated that using culturally sensitive practices in dentistry is important. Students who could identify at least one cultural group they knew well perceived cultural sensitivity in dental practice as more important than students who could not. These results suggest that students need cross-cultural training and believe that such training is important. The results also suggest that a specific curriculum that increases knowledge of other cultures may have the potential to ultimately increase the use of culturally sensitive practices.


Enhanced directional excitation and emission of single emitters by a nano-optical Yagi-Uda antenna.
We demonstrate by 3D numerical calculations that the interaction of a single quantum emitter with the electromagnetic field is both enhanced and directed by a nano-optical Yagi-Uda antenna. The single emitter is coupled in the near field to the resonant plasmon mode of the feed element, enhancing both excitation and emission rates. The angular emission of the coupled system is highly directed and determined by the antenna mode. Arbitrary control over the main direction of emission is obtained, regardless of the orientation of the emitter. The directivity is even more increased by the presence of a dielectric substrate, making such antennas a promising candidate for compact easy-to-address planar sensors.


Sexual harassment issues in home care: what employers should do about it.
Recent court decisions and public scandals have brought sexual harassment to the forefront of workplace issues. Home care employers may face legal liability if they do not establish firm guidelines prohibiting sexual harassment and train employees to recognize and avoid this problem.


Purification, biochemical characterization of a lectin from marine sponge Ircinia strobilina and its effect on the inhibition of bacterial biofilms.
A new lectin from marine sponge Ircinia strobilina, denominated IsL, was isolated by combination of affinity chromatography in Guar gum matrix followed by size exclusion chromatography. IsL was able to agglutinate native and enzymatically treated rabbit erythrocytes, being inhibited by galactosides, such as α-methyl-D-galactopyranoside, β-methyl-D-galactopyranoside and α-lactose. IsL hemagglutinating activity was stable at neutral to alkaline pH, however the lectin loses its activity at 40° C. The molecular mass determinated by mass spectrometry was 13.655 ± 5 Da. Approximately 40% of the primary structure of IsL was determined by mass spectrometry, but no similarity was observed with any protein. The secondary structure of IsL consists of 28% α-helix, 26% β-sheet, and 46% random region, as determined by dichroism circular. IsL was a calcium-dependent lectin, but no significant variations were observed by circular dichroism when IsL was incubated in presence of calcium and EDTA. IsL was not toxic against Artemia nauplii and did not have antimicrobial activity against bacterial cells. However, the IsL was able to significantly inhibit the biofilm formation of Staphylococcus aureus and Staphylococcus epidermidis.


Shedding light on emotional perception: Interaction of brightness and semantic content in extrastriate visual cortex.
The rapid extraction of affective cues from the visual environment is crucial for flexible behavior. Previous studies have reported emotion-dependent amplitude modulations of two event-related potential (ERP) components - the N1 and EPN - reflecting sensory gain control mechanisms in extrastriate visual areas. However, it is unclear whether both components are selective electrophysiological markers of attentional orienting toward emotional material or are also influenced by physical features of the visual stimuli. To address this question, electrical brain activity was recorded from seventeen male participants while viewing original and bright versions of neutral and erotic pictures. Bright neutral scenes were rated as more pleasant compared to their original counterpart, whereas erotic scenes were judged more positively when presented in their original version. Classical and mass univariate ERP analysis showed larger N1 amplitude for original relative to bright erotic pictures, with no differences for original and bright neutral scenes. Conversely, the EPN was only modulated by picture content and not by brightness, substantiating the idea that this component is a unique electrophysiological marker of attention allocation toward emotional material. Complementary topographic analysis revealed the early selective expression of a centro-parietal positivity following the presentation of original erotic scenes only, reflecting the recruitment of neural networks associated with sustained attention and facilitated memory encoding for motivationally relevant material. Overall, these results indicate that neural networks subtending the extraction of emotional information are differentially recruited depending on low-level perceptual features, which ultimately influence affective evaluations.


Effects of flunixin meglumine in dogs following experimentally induced endotoxemia.
Twelve dogs were randomly divided into three groups. Group 1 dogs were given Escherichia coli endotoxin and then treated with flunixin meglumine. Group 2 dogs were given endotoxin as group 1, but untreated. Group 3 dogs were given flunixin meglumine alone. The dogs were monitored clinically and urine and serum samples were collected at regular intervals for 72 hours. All surviving dogs were humanely killed after 72 hours and examined for gross and histologic lesions. Group 1 dogs all survived 72 hours, but showed prerenal azotemia, hepatocellular damage, hemorrhagic enteritis, and numerous gastric ulcerations. Three of the four dogs in group 2 died before 72 hours. Group 2 dogs showed many of the same chemical and hemodynamic changes as group 1. They had severe hemorrhage into the intestinal lumen; however, there were no gastric ulcerations. Group 3 dogs all survived and showed little physical or hematologic change. The study suggested the following: 1) flunixin meglumine was an effective drug in ameliorating the fatal effects of canine endotoxemia, 2) the effects of endotoxin in combination with flunixin meglumine, at 1.1 mg/kg body weight, caused gastric ulcerations, and 3) in normal dogs flunixin meglumine at 1.1 mg/kg body weight did not cause severe side effects or gross lesions.


Consanguinity and primary immunodeficiencies.
Primary immunodeficiencies (PIDs) are a heterogeneous group of genetic disorders caused by defects in the immune system that predispose patients to infections, autoimmune diseases, lymphoproliferation and malignancies. Most PIDs are inherited in an autosomal recessive pattern; therefore, they are more common in areas with high rates of consanguineous marriage. Reports about PIDs from these areas have demonstrated a peculiar prevalence of more severe forms of diseases compared to other regions, and patients born to consanguineous parents have increased rates of morbidity and mortality compared to other patients. Individuals at high risk of having a child with a PID who wish to have a healthy child have limited options, these include prenatal diagnosis and pre-implantation genetic diagnosis. However, these options require a collaborative team of specialists and may not always be implemented due to geographic, religious, financial or social factors. The recent introduction of newborn-screening programs for a number of T and B lymphocyte deficiencies will facilitate early diagnosis and therapeutic interventions, which may include hematopoietic stem cell transplantation and intravenous immunoglobulin treatment. There is a need for the implementation of strategies to increase public awareness of the health risks associated with consanguineous marriage. It should be stressed that genetic counseling should be an important component of the care of patients with PIDs as well as their families.


Lactobacillus plantarum attenuates anxiety-related behavior and protects against stress-induced dysbiosis in adult zebrafish.
The consumption of probiotics has become increasingly popular as a means to try to improve health and well-being. Not only are probiotics considered beneficial to digestive health, but increasing evidence suggests direct and indirect interactions between gut microbiota (GM) and the central nervous system (CNS). Here, adult zebrafish were supplemented with Lactobacillus plantarum to determine the effects of probiotic treatment on structural and functional changes of the GM, as well as host neurological and behavioral changes. L. plantarum administration altered the β-diversity of the GM while leaving the major core architecture intact. These minor structural changes were accompanied by significant enrichment of several predicted metabolic pathways. In addition to GM modifications, L. plantarum treatment also significantly reduced anxiety-related behavior and altered GABAergic and serotonergic signaling in the brain. Lastly, L. plantarum supplementation provided protection against stress-induced dysbiosis of the GM. These results underscore the influence commensal microbes have on physiological function in the host, and demonstrate bidirectional communication between the GM and the host.


Optimized atomic statistical potentials: assessment of protein interfaces and loops.
Statistical potentials have been widely used for modeling whole proteins and their parts (e.g. sidechains and loops) as well as interactions between proteins, nucleic acids and small molecules. Here, we formulate the statistical potentials entirely within a statistical framework, avoiding questionable statistical mechanical assumptions and approximations, including a definition of the reference state. We derive a general Bayesian framework for inferring statistically optimized atomic potentials (SOAP) in which the reference state is replaced with data-driven 'recovery' functions. Moreover, we restrain the relative orientation between two covalent bonds instead of a simple distance between two atoms, in an effort to capture orientation-dependent interactions such as hydrogen bonds. To demonstrate this general approach, we computed statistical potentials for protein-protein docking (SOAP-PP) and loop modeling (SOAP-Loop). For docking, a near-native model is within the top 10 scoring models in 40% of the PatchDock benchmark cases, compared with 23 and 27% for the state-of-the-art ZDOCK and FireDock scoring functions, respectively. Similarly, for modeling 12-residue loops in the PLOP benchmark, the average main-chain root mean square deviation of the best scored conformations by SOAP-Loop is 1.5 Å, close to the average root mean square deviation of the best sampled conformations (1.2 Å) and significantly better than that selected by Rosetta (2.1 Å), DFIRE (2.3 Å), DOPE (2.5 Å) and PLOP scoring functions (3.0 Å). Our Bayesian framework may also result in more accurate statistical potentials for additional modeling applications, thus affording better leverage of the experimentally determined protein structures. SOAP-PP and SOAP-Loop are available as part of MODELLER (http://salilab.org/modeller).


Spatial dynamics of lyme disease: a review.
Lyme disease (LD), the most frequently reported vector-borne disease in the United States, requires that humans, infected vector ticks, and infected hosts all occur in close spatial proximity. Understanding the spatial dynamics of LD requires an understanding of the spatial determinants of each of these organisms. We review the literature on spatial patterns and environmental correlates of human cases of LD and the vector ticks, Ixodes scapularis in the northeastern and midwestern United States and Ixodes pacificus in the western United States. The results of this review highlight a need for a more standardized and comprehensive approach to studying the spatial dynamics of the LD system. Specifically, we found that the only environmental variable consistently associated with increased LD risk and incidence was the presence of forests. However, the reasons why some forests are associated with higher risk and incidence than others are still poorly understood. We suspect that the discordance among studies is due, in part, to the rapid developments in both conceptual and technological aspects of spatial ecology hastening the obsolescence of earlier approaches. Significant progress in identifying the determinants of spatial variation in LD risk and incidence requires that: (1) existing knowledge of the biology of the individual components of each LD system is utilized in the development of spatial models; (2) spatial data are collected over longer periods of time; (3) data collection and analysis among regions are more standardized; and (4) the effect of the same environmental variables is tested at multiple spatial scales.


Effects of a context shift and multiple context extinction on reactivity to alcohol cues.
Cue exposure treatment (CET) attempts to reduce the influence of conditioned substance cues on addictive behavior via extinction, but has received only modest empirical support in clinical trials. This may be because extinction learning appears to be context dependent and a change in context may result in a return of conditioned responding (i.e., renewal), although this has received only limited empirical examination. The current study used a 4-session laboratory analogue of CET to examine whether a change in context following 3 sessions of alcohol cue exposure with response prevention would result in renewal of conditioned responding. In addition, this study examined whether conducting extinction in multiple contexts would attenuate renewal of conditioned responding. In one-way between-subjects design, 73 heavy drinkers (71% men) were randomized to 3 conditions: (a) single context extinction (extinction to alcohol cues in the same context for 3 sessions followed by a context shift at the fourth session), (b) multiple context extinction (extinction to alcohol cues in different contexts each day for all 4 sessions), and (c) pseudoextinction control condition (exposure to neutral cues in the same context for 3 sessions followed by exposure to alcohol cues at the fourth session). The results revealed the predicted cue reactivity and extinction effects, but the hypotheses that a context shift would generate renewed cue reactivity and that multiple contexts would enhance extinction were not supported. Methodological aspects of the study and the need for parametric data on the context dependency of extinction to alcohol cues are discussed.


Severe bilateral papilledema after sigmoid sinus constriction surgery: a case report.
Papilledema is a common sign of various diseases in the eye. It could result from any conditions of increased intracranial pressure (ICP). Underlying the etiology of papilledema and appropriate treatment in time is essential. We present a case of severe bilateral papilledema after sigmoid sinus constriction surgery. A 25-year-old female presented with a 1-month history of bilateral blurred vision, headache, and vomiting. The patient had a history of right-side sigmoid sinus constriction surgery for pulsatile tinnitus (PT) one month before in another hospital. Fundus examination showed severe bilateral papilledema. Lumbar puncture showed an elevated cerebrospinal fluid (CSF) opening pressure of 29 cm H2O. Neuroimaging examination demonstrated the right sigmoid sinus filling defect as changes after surgery. We referred the patient to the initial surgeon, who repaired the sigmoid sinus on the right side by removing the implanted gelatin sponge, as diuretic treatment could not be effective. Intracranial hypertension symptoms and signs improved soon after eliminating sigmoid sinus stenosis. Neuroimaging showed resolved right sigmoid sinus stenosis after the second surgery. CSF opening pressure was 14.5 cm H2O at the 1-month follow-up. Fundus examination showed entirely resolved papilledema. Three years of follow-up showed no recurrence. This is the first clinical report of intracranial hypertension associated with sigmoid sinus constriction surgery. Although rare, rapid detection and adequate etiology management could lead to a good prognosis. It highlights the need for ophthalmologists to be aware of the diagnostic approach to papilledema and enhance cooperation with multidisciplinary departments. The most likely cause of the intracranial hypertension was dominant sinus surgical constriction by mechanical external compression, as confirmed by the complete clinical remission following the second operation to remove the implanted gelatin sponge. Thus, this case also highlights the importance of selecting the appropriate therapeutic option for PT. Surgical sinus constriction should no longer be considered a viable option for PT treatment.


Oil sands development contributes elements toxic at low concentrations to the Athabasca River and its tributaries.
We show that the oil sands industry releases the 13 elements considered priority pollutants (PPE) under the US Environmental Protection Agency's Clean Water Act, via air and water, to the Athabasca River and its watershed. In the 2008 snowpack, all PPE except selenium were greater near oil sands developments than at more remote sites. Bitumen upgraders and local oil sands development were sources of airborne emissions. Concentrations of mercury, nickel, and thallium in winter and all 13 PPE in summer were greater in tributaries with watersheds more disturbed by development than in less disturbed watersheds. In the Athabasca River during summer, concentrations of all PPE were greater near developed areas than upstream of development. At sites downstream of development and within the Athabasca Delta, concentrations of all PPE except beryllium and selenium remained greater than upstream of development. Concentrations of some PPE at one location in Lake Athabasca near Fort Chipewyan were also greater than concentration in the Athabasca River upstream of development. Canada's or Alberta's guidelines for the protection of aquatic life were exceeded for seven PPE-cadmium, copper, lead, mercury, nickel, silver, and zinc-in melted snow and/or water collected near or downstream of development.


Tip-Oriented Closed Rhinoplasty Built on Septocolumellar Suture and a New Caudal Septal Graft Technique.
A beautiful and appealing nose receives the greatest contribution from the nasal tip subunit, which should be regarded as the primary center of attention during a rhinoplasty procedure. In achieving the desired shape and position of the nasal tip during closed rhinoplasty, the septocolumellar suture functions as the major determinant together with the caudal portion of the septal cartilage, which has a significant influence on the versatility of the septocolumellar suture. The purpose of this study was to present the analysis of the indications, the technical steps, and the advantages of caudal septal graft and septocolumellar suture utilization in closed rhinoplasty. The septocolumellar suture with or without the caudal septal graft combination procedure has been performed in 2286 patients via a closed rhinoplasty approach. Intraoperatively, the septal cartilage at hand was thoroughly evaluated and one of the 5 types of caudal septal grafts was used when necessary. After the establishment of a strong and straight septal cartilage with sufficient height and length, 4 different septocolumellar sutures in a specific order were used to modify the relationship between the lower lateral cartilages and the nasal septum. Of the 2286 cases, 1837 (80.3%) were primary and 449 (19.7%) secondary rhinoplasties, which have been followed up for 9 to 48 months. The caudal septal graft was combined to the septocolumellar suture in 621 (27.1%) patients. Of the caudal septal grafts, 69.7% were used for primary rhinoplasty cases, and 30.3% for secondary rhinoplasties. At the 18th month postoperatively, tip projection was found to be satisfactory for 98% of the patients. The septocolumellar suture combined with caudal septal graft in closed rhinoplasty substantially facilitates the achievement of a cosmetically and functionally pleasing end result, bringing the solution for a wide array of problems such as short nose, supratip deformity, nasolabial angle change, or columellar bowing. Nevertheless, the technique has a steep learning curve; therefore, a meticulous preoperative evaluation should be exerted, a precise surgical planning should be prosecuted, and an excessive reduction of the nasal tip or exaggerated columellar retraction should be avoided.


Age verification using random forests on facial 3D landmarks.
Three-dimensional facial images are becoming more and more widespread. As such images provide more information about facial morphology than 2D imagery, they show great promise for use in future forensic applications, including age estimation and verification. This paper proposes an approach using random forests, a machine learning method, to develop and test models for classification of legal age thresholds (15 years and 18 years) using 3D facial landmarks. Our approach was developed on a set of 3D facial scans from 394 Czech individuals (194 males and 200 females) aged between 10 and 25 years. The dataset was retrieved from a sizable database of Central European faces - The FIDENTIS 3D Face Database. Three main types of input variables were processed using random forests: I) shape (size-invariant) coordinates of 3D landmarks, II) size and shape coordinates of 3D landmarks, and III) inter-landmark distances, angles and indices. The performance rates for the combinations of variables and age threshold were expressed in terms of sensitivity and specificity. The overall accuracy rates varied from 71.4%-91.5% (when the male and female samples were pooled). In general, higher accuracy was achieved for the age limit of 18 years than for 15 years. Whereas size-variant variables showed a better performance rate for the age limit of 15 years, the size-invariant variables (i.e., shape variables) were better for classifying individuals under 18 years. The verification models grounded on traditional variables (distances, angles, indices) yielded consistently higher performance rates on females than on males, whereas the inverse trend was observed for the models built on 3D coordinates. The results indicate that age verification based on 3D facial data with processing by the random forests method has high potential for further forensic or biometric applications.


Trends in European computational neuroscience.
Understanding the complex structure and function of the central nervous system requires the integration of many scientific disciplines and descriptive levels, and the development and application of adequate research tools. The fast growing field of computational neuroscience plays an important role within this integrative effort. In Europe, an active community is emerging that investigates structure-function relationships in the nervous system at subcellular, cellular, network, and behavioural levels. An increasing number of courses and conferences are offering opportunities for development and exchange of ideas between scientists interested in computational neuroscience. Thus, it is timely to present a spectrum of European activities in this field and to foster the communication between scientists across disciplines towards joint efforts.


An essential role of the yeast pheromone-induced Ca2+ signal is to activate calcineurin.
Previous studies showed that, in wild-type (MATa) cells, alpha-factor causes an essential rise in cytosolic Ca2+. We show that calcineurin, the Ca2+/calmodulin-dependent protein phosphatase, is one target of this Ca2+ signal. Calcineurin mutants lose viability when incubated with mating pheromone, and overproduction of constitutively active (Ca(2+)-independent) calcineurin improves the viability of wild-type cells exposed to pheromone in Ca(2+)-deficient medium. Thus, one essential consequence of the pheromone-induced rise in cytosolic Ca2+ is activation of calcineurin. Although calcineurin inhibits intracellular Ca2+ sequestration in yeast cells, neither increased extracellular Ca2+ nor defects in vacuolar Ca2+ transport bypasses the requirement for calcineurin during the pheromone response. These observations suggest that the essential function of calcineurin in the pheromone response may be distinct from its modulation of intracellular Ca2+ levels. Mutants that do not undergo pheromone-induced cell cycle arrest (fus3, far1) show decreased dependence on calcineurin during treatment with pheromone. Thus, calcineurin is essential in yeast cells during prolonged exposure to pheromone and especially under conditions of pheromone-induced growth arrest. Ultrastructural examination of pheromone-treated cells indicates that vacuolar morphology is abnormal in calcineurin-deficient cells, suggesting that calcineurin may be required for maintenance of proper vacuolar structure or function during the pheromone response.


Spinal cord stimulation as a treatment option for complex regional pain syndrome: a narrative review.
Objectives: This review aims to analyze the last years' experience of applying spinal cord stimulation (SCS) in complex regional pain syndrome (CRPS) patients with persistent or refractory chronic pain. Methods: This is a narrative review which was executed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was carried out through the following databases: PUBMED and Cochrane Library. Also, a search for trials in the metaRegister of controlled trials (www.clinicaltrials.gov) was performed. Results: SCS provides pain reduction and improves sensory, vasomotor and sudomotor symptoms. It can reduce opioid using, offering better life quality for the patients. Conclusions: SCS found to be an excellent therapeutic alternative for patients with CRPS. It offers immediate pain relief and allows patients to regain functionality and have a better quality of life.


Population structure of the wild soybean (Glycine soja) in China: implications from microsatellite analyses.
Wild soybean (Glycine soja), a native species of East Asia, is the closest wild relative of the cultivated soybean (G. max) and supplies valuable genetic resources for cultivar breeding. Analyses of the genetic variation and population structure of wild soybean are fundamental for effective conservation studies and utilization of this valuable genetic resource. In this study, 40 wild soybean populations from China were genotyped with 20 microsatellites to investigate the natural population structure and genetic diversity. These results were integrated with previous microsatellite analyses for 231 representative individuals from East Asia to investigate the genetic relationships of wild soybeans from China. Analysis of molecular variance (AMOVA) revealed that 43·92 % of the molecular variance occurred within populations, although relatively low genetic diversity was detected for natural wild soybean populations. Most of the populations exhibited significant effects of a genetic bottleneck. Principal co-ordinate analysis, construction of a Neighbor-Joining tree and Bayesian clustering indicated two main genotypic clusters of wild soybean from China. The wild soybean populations, which are distributed in north-east and south China, separated by the Huang-Huai Valley, displayed similar genotypes, whereas those populations from the Huang-Huai Valley were different. The previously unknown population structure of the natural populations of wild soybean distributed throughout China was determined. Two evolutionarily significant units were defined and further analysed by combining genetic diversity and structure analyses from Chinese populations with representative samples from Eastern Asia. The study suggests that during the glacial period there may have been an expansion route between south-east and north-east China, via the temperate forests in the East China Sea Land Bridge, which resulted in similar genotypes of wild soybean populations from these regions. Genetic diversity and bottleneck analysis supports that both extensive collection of germplasm resources and habitat management strategies should be undertaken for effective conservation studies of these important wild soybean resources.


Effect of Nosodes on Lettuce, Parasitized or Not by Meloidogyne enterolobii.
Nosodes are homeopathic preparations (HPs) obtained from tissues or substances associated with the targeted disease or from culture of the pathogenic agent. Nosodes are thought to modulate host resistance, easing symptoms or promoting cure. A few studies have been published about control of plant-parasitic nematodes with HPs, but none with nosodes. Conceptually, nosodes prepared from nematode infective stages might interact with the plant's pathogen-recognition system and initiate or modulate plant resistance to nematodes. Our goal was to investigate whether nosodes prepared from second-stage juveniles (J2) of Meloidogyne enterolobii can affect the moderate resistance already existing in the lettuce cultivar 'Elisa'. Nosodes at the Hahnemannian concentrations (cH) 6, 18, 30 and 42 were applied on lettuce plants through irrigation, with a constant daily dosage. The nosode treatment started at the seedling stage, before nematode inoculation with 3,000 eggs + J2 per plant. A series of absolute and relative controls, and 10 replicates per treatment, were employed. At harvest, variables related to plant growth and nematode reproduction were assessed. The nosode at 6, 18, and 30cH reduced (p <0.05) the nematode reproduction factor and root density. The nosode effect was cH-dependent since nematode reproduction was favored by treatment with 42cH. The nosode also affected (p <0.05) lettuce roots, which presented higher or lower fresh weight and volume depending on the cH applied and the condition-parasitized or not. Nosodes obtained from Meloidogyne J2 may affect plant parasitism by nematodes, possibly by interfering with plant resistance. The nature-positive or negative-and intensity of the nosode effect depends on the cH applied to the plants. Further studies are necessary to identify which cH values are more effective in reducing nematode reproduction without causing negative side effects on plant growth.


Risks and rewards of school-based mentoring relationships: A reanalysis of the student mentoring program evaluation.
In the United States, school-based mentoring programs are a large and widely funded form of mentoring. Despite widespread support, meta-analyses indicate that the effects of school-based mentoring programs are small. One hypothesis for these results is that school-based mentors are not able to develop a sufficiently high-quality relationship with mentees to produce the hypothesized positive effects. This study presents a reanalysis of a large randomized controlled trial of school-based mentoring and examines the estimated effect of mentoring as a function of mentee-reported relationship quality using a novel statistical approach. Although we found that average effect sizes were near zero and consistent with researchers' original findings, our findings also indicate that low relationship quality is associated with some harmful effects, particularly on misconduct, and that as relationship quality improves, so do effects. However, we found that this association decelerates and resulted in small, positive effects for some outcomes. These results suggest that that poor relationship quality may produce harmful effects and a strong relationship may not be sufficient to produce moderate, positive academic and behavioral outcomes in a school-based mentoring context. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Expression analysis of the SG-SSPN complex in smooth muscle and endothelial cells of human umbilical cord vessels.
Recently, participation of the sarcoglycan (SG)-sarcospan (SSPN) complex in the development of cardiomyopathy in patients with limb-girdle muscular dystrophy has been shown, and presence of the complex in smooth muscle may be important for the contraction/dilation process of vessels. However, there are few studies determining the SG-SSPN complex in vascular smooth muscle and endothelial cells of vessels. In this study, we analyzed by reverse transcriptase-polymerase chain reaction and immunofluorescence the expression of different components of the complex in vein/artery smooth muscle and endothelial cells of the human umbilical cord. By RNA analysis, we observed expression of alpha-, beta-, gamma-, delta-, epsilon-SG, and SSPN in smooth muscle cells. In endothelial cells, RNA expression was restricted to beta-, delta-, epsilon-SG, and SSPN. At protein level, we observed in smooth muscle the presence of beta-, delta-, epsilon-SG, and SSPN. In endothelial cells, immunostaining only evidenced the presence of epsilon-SG and SSPN. However, colocalization of SGs and SSPN with dystrophin and utrophin was noted. These results, interestingly, suggest that the SG-SSPN complex may either form with dystrophin or utrophin in smooth muscle cells, and with utrophin in endothelial cells. Additionally, we also observed in some smooth muscle regions the colocalization of the SG-SSPN complex with caveolin, with colocalization being more pronounced between epsilon-SG-SSPN and caveolin in endothelial cells.


The role of prefrontal lobes in psychonervous memory in vertebrates.
The memory phenomena are classified into image memory, emotional memory and conditioned reflex memory. It is assumed that prefrontal area is critically involved in the image memory, and in particular, in short-term image memory. On the other hand, both emotional and conditianed reflex memory do not depend on the prefrontal area but they are controlled by other parts of the neocortex and by paleocortex. The intimate nature of both short-term and long-term memory is discussed.


Determination of a protein structure by iodination: the structure of iodinated acetylxylan esterase.
Enzymatic and non-enzymatic iodination of the amino acid tyrosine is a well known phenomenon. The iodination technique has been widely used for labeling proteins. Using high-resolution X-ray crystallographic techniques, the chemical and three-dimensional structures of iodotyrosines formed by non-enzymatic incorporation of I atoms into tyrosine residues of a crystalline protein are described. Acetylxylan esterase (AXE II; 207 amino-acid residues) from Penicillium purpurogenum has substrate specificities towards acetate esters of D-xylopyranose residues in xylan and belongs to a new class of alpha/beta hydrolases. The crystals of the enzyme are highly ordered, tightly packed and diffract to better than sub-angström resolution at 85 K. The iodination technique has been utilized to prepare an isomorphous derivative of the AXE II crystal. The structure of the enzyme determined at 1.10 A resolution exclusively by normal and anomalous scattering from I atoms, along with the structure of the iodinated complex at 1.80 A resolution, demonstrate the formation of covalent bonds between I atoms and C atoms at ortho positions to the hydroxyl groups of two tyrosyl moieties, yielding iodotyrosines.


Obstructive Sleep Apnea and Risk of COVID-19 Infection, Hospitalization and Respiratory Failure.
To study the relationship between OSA and risk of COVID-19 infection and disease severity, identified by the need for hospitalization and progression to respiratory failure. We queried the electronic medical record system for an integrated health system of 10 hospitals in the Chicago metropolitan area to identify cases of COVID-19. Comorbidities and outcomes were ascertained by ICD-10-CM coding and medical record data. We evaluated the risk for COVID-19 diagnosis, hospitalization, and respiratory failure associated with OSA by univariate tests and logistic regression, adjusting for diabetes, hypertension, and BMI to account for potential confounding in the association between OSA, COVID-19 hospitalization, and progression to respiratory failure. We identified 9405 COVID-19 infections, among which 3185 (34%) were hospitalized and 1779 (19%) were diagnosed with respiratory failure. OSA was more prevalent among patients requiring hospitalization than those who did not (15.3% versus 3.4%, p < 0.0001; OR 5.20, 95% CI (4.43, 6.12)), and among those who progressed to respiratory failure (19.4% versus 4.5%, p < 0.0001; OR 5.16, 95% CI (4.41, 6.03)). After adjustment for diabetes, hypertension, and BMI, OSA was associated with increased risk for hospitalization (OR 1.65; 95% CI (1.36, 2.02)) and respiratory failure (OR 1.98; 95% CI (1.65, 2.37)). Patients with OSA experienced approximately 8-fold greater risk for COVID-19 infection compared to a similar age population receiving care in a large, racially, and socioeconomically diverse healthcare system. Among patients with COVID-19 infection, OSA was associated with increased risk of hospitalization and approximately double the risk of developing respiratory failure.


A single FPGA-based portable ultrasound imaging system for point-of-care applications.
We present a cost-effective portable ultrasound system based on a single field-programmable gate array (FPGA) for point-of-care applications. In the portable ultrasound system developed, all the ultrasound signal and image processing modules, including an effective 32-channel receive beamformer with pseudo-dynamic focusing, are embedded in an FPGA chip. For overall system control, a mobile processor running Linux at 667 MHz is used. The scan-converted ultrasound image data from the FPGA are directly transferred to the system controller via external direct memory access without a video processing unit. The potable ultrasound system developed can provide real-time B-mode imaging with a maximum frame rate of 30, and it has a battery life of approximately 1.5 h. These results indicate that the single FPGA-based portable ultrasound system developed is able to meet the processing requirements in medical ultrasound imaging while providing improved flexibility for adapting to emerging POC applications.


Dissociative electron attachment to HGaF4 Lewis-Brønsted superacid.
The consequences of an excess electron attachment to HGaF4 (HF/GaF3) superacid are investigated on the basis of theoretical calculations employing ab initio methods. It is found that the dipole potential of HGaF4 plays an important role in the initial formation of a dipole-bound anionic state. Due to the kinetic instability of that initially formed anion, a fragmentation reaction occurs promptly and leads to (GaF4)- and H as the final products. The energy profile of this process, its rate, and mechanism are presented and discussed.


Fasciola hepatica-Derived Molecules as Regulators of the Host Immune Response.
Helminths (worms) are one of the most successful organisms in nature given their ability to infect millions of humans and animals worldwide. Their success can be attributed to their ability to modulate the host immune response for their own benefit by releasing excretory-secretory (ES) products. Accordingly, ES products have been lauded as a potential source of immunomodulators/biotherapeutics for an array of inflammatory diseases. However, there is a significant lack of knowledge regarding the specific interactions between these products and cells of the immune response. Many different compounds have been identified within the helminth "secretome," including antioxidants, proteases, mucin-like peptides, as well as helminth defense molecules (HDMs), each with unique influences on the host inflammatory response. HDMs are a conserved group of proteins initially discovered in the secretome of the liver fluke, Fasciola hepatica. HDMs interact with cell membranes without cytotoxic effects and do not exert antimicrobial activity, suggesting that these peptides evolved specifically for immunomodulatory purposes. A peptide generated from the HDM sequence, termed FhHDM-1, has shown extensive anti-inflammatory abilities in clinically relevant models of diseases such as diabetes, multiple sclerosis, asthma, and acute lung injury, offering hope for the development of a new class of therapeutics. In this review, the current knowledge of host immunomodulation by a range of F. hepatica ES products, particularly FhHDM-1, will be discussed. Immune regulators, including HDMs, have been identified from other helminths and will also be outlined to broaden our understanding of the variety of effects these potent molecules exert on immune cells.


Role of interferon homeostasis in the pathogenesis of bronchial asthma in children.
Interferon homeostasis was studied in children with bronchial asthma (BA) at different stages of the disease. The control group consisted of 10 children with no predisposition to atopic reaction. Children with BA showed a disfunction of interferon homeostasis, with a significant decline in the leukocyte ability to produce IFN-alpha and IFN-gamma. The concentration of blood serum IFN-gamma was reduced at all stages of BA, with a more significant decrease during BA attacks than during the remission period. IFN-gamma synthesis disturbances in BA children were stable and resistant to therapeutic treatment by recombinant IFN-alpha2b (Viferon). Viferon normalized the production of IFN-alpha, and the effect remained unchanged during a half-year examination period. Thus, Viferon appears promising as part of a complex therapy for children with BA at remission stages and frequent respiratory infections.


In vivo optical frequency domain imaging of human retina and choroid.
Optical frequency domain imaging (OFDI) using swept laser sources is an emerging second-generation method for optical coherence tomography (OCT). Despite the widespread use of conventional OCT for retinal disease diagnostics, until now imaging the posterior eye segment with OFDI has not been possible. Here we report the development of a highperformance swept laser at 1050 nm and an ophthalmic OFDI system that offers an A-line rate of 18.8 kHz, sensitivity of >92 dB over a depth range of 2.4 mm with an optical exposure level of 550 muW, and deep penetration into the choroid. Using these new technologies, we demonstrate comprehensive human retina, optic disc, and choroid imaging in vivo. This advance enables us to view choroidal vasculature in vivo without intravenous injection of fluorescent dyes and may provide a useful tool for evaluating choroidal as well as retinal diseases.


Hg(II) adsorption by bacteria: a surface complexation model and its application to shallow acidic lakes and wetlands in Kejimkujik National Park, Nova Scotia, Canada.
The fate and environmental threat posed by mercury in aquatic systems is controlled, in part, bythe transport of Hg(II) from oxic to anoxic zones in lakes and its subsequent transformation to organic mercury. The transport of Hg(II) in aquatic systems can be affected by its partitioning between the dissolved and particulate phases. In this study, batch experiments were performed to quantify Hg(II) adsorption to Bacillus subtilis as bacteria-to-metal ratio, pH, chloride concentration, growth phase, and reaction time were independently varied. The laboratory data were well described by a surface complexation model (SCM) considering the adsorption of neutral Hg(II) hydroxide and chloride complexes by specific functional groups on the bacterial surface. To evaluate its applicability to complex aquatic systems, the SCM was used to predict the distributions of Hg(II) in 36 shallow acidic lakes and wetlands in Kejimkujik National Park, Nova Scotia, Canada. The lab-derived SCM provided a statistically accurate (r2 = 0.615, P < 0.01) fit to the field data when it was expanded to consider Hg(II) complexation by dissolved organic matter. Inclusion of Hg(II)-mineral adsorption reactions did not improve the fit of the model. The quality of fit provided by the expanded SCM suggested that the major assumptions implicit in applying a lab-derived model to the field were justifiable. Our study has demonstrated that SCMs are powerful tools for dynamic prediction of the sorption of environmental contaminants to biocolloids at the regional scale.


Anaphylaxis in chopped guinea pig lung. III. Effect of carbon monoxide, cyanide, salicylaldoxime, and ionic strength.
The anaphylactic release of histamine from perfused, chopped guinea pig lung is very sensitive to changes in the NaCl concentration of the containing medium, and it is ionic strength rather than particle concentration which is critical. Consequently, in studies with inhibitors care must be taken to avoid inadvertently increasing ionic strength and thereby misinterpreting the cause of the inhibition. Since immune hemolysis exhibits a similar sensitivity to changes in the NaCl concentration of the suspending medium, salicylaldoxime and phlorizin, which prevent the participation of the third component of complement in immune hemolysis, were investigated for their effect on the anaphylactic reaction. Salicylaldoxime is a potent inhibitor of in vitro anaphylaxis in guinea pig lung, but phlorizin is only a weak inhibitor. Potassium cyanide, 1 mM, inhibits the anaphylactic release of histamine most effectively if the duration of contact between the tissue and the cyanide prior to antigen addition is minimal; preincubation of the tissue with cyanide prior to antigen addition results in progressive diminution of inhibition even when there is only minimal loss of cyanide from the containing medium. The anaphylactic release of histamine from perfused whole lungs or suspensions of blood-free chopped lung is not prevented by the cytochrome oxidase inhibitor, carbon monoxide. In addition, 2-heptyl 4 hydroxyquinoline N oxide and malonic acid, which inhibit aerobic metabolism at different sites, do not prevent the reaction. These studies and those with cyanide indicate that the anaphylactic release of histamine in guinea pig lung is not dependent on cytochrome-mediated aerobic metabolism.