Adaptive output feedback control of uncertain nonlinear systems using single-hidden-layer neural networks.
We consider adaptive output feedback control of uncertain nonlinear systems, in which both the dynamics and the dimension of the regulated system may be unknown. However, the relative degree of the regulated output is assumed to be known. Given a smooth reference trajectory, the problem is to design a controller that forces the system measurement to track it with bounded errors. The classical approach requires a state observer. Finding a good observer for an uncertain nonlinear system is not an obvious task. We argue that it is sufficient to build an observer for the output tracking error. Ultimate boundedness of the error signals is shown through Lyapunov's direct method. The theoretical results are illustrated in the design of a controller for a fourth-order nonlinear system of relative degree two and a high-bandwidth attitude command system for a model R-50 helicopter.


HLA-A alleles and the risk of cervical squamous cell carcinoma in Japanese women.
We conducted a case-control study to examine the relationship between human leukocyte antigen-A (HLA-A) allele polymorphism and the pathogenesis of cervical neoplasia among Japanese women. A total of 119 patients with invasive cervical squamous cell carcinoma were compared to 119 age- and menopausal status-matched non-cancer controls. Blood samples were taken from all cases and controls and lifestyle information was collected by means of a self-administered questionnaire. The estimated impact of HLA-A alleles on cervical cancer risk was evaluated by unconditional logistic regression models. The frequency of HLA-A(*)0206 among cases was significantly lower than among controls (P = 0.006). There was an inverse association between A(*)0206 and cervical cancer risk (odds ratio [OR] = 0.31, 95% confidence interval [95% CI] = 0.15 to 0.65, P = 0.002), and a positive association for HLA-A(*)2402 (OR = 1.76, 95% CI = 1.00 to 3.09, P = 0.048). After correction for multiple comparisons, A(*)0206 was significantly associated with reduced cervical cancer risk (corrected P = 0.036). Furthermore, the inverse association between A(*)0206 and cervical cancer risk was independent of smoking status (never smoker: OR = 0.37, 95% CI = 0.15 to 0.90; ever smoker: OR = 0.23, 95% CI = 0.06 to 0.89). There was an inverse association between HLA-A(*)0206 and cervical cancer risk among Japanese women, which suggests that HLA-A polymorphism influences cervical cancer risk. Further investigation in other populations is thus warranted.


Complications in Craniovertebral Junction Instrumentation: Hardware Removal Can Be Associated with Long-Lasting Stability. Personal Experience.
The causes of craniovertebral junction (CVJ) instabilities include trauma, rheumatological diseases, tumors, infections, congenital malformations, and degenerative disease processes; these complex pathologies often require CVJ instrumentation. Hardware complications were analyzed in a personal series of 48 treated patients. In light of the analysis of very unusual radiological and clinical findings, the authors tried to better investigate the related mechanisms and to reach possible useful conclusions. In a series of 48 patients who underwent CVJ instrumentation and fusion procedures in our Institution, we describe three cases of hardware failure, due to: (1) infection; (2) radio- and chemotherapy; and (3) incorrect surgical procedure. 1. A stable bone CVJ fusion can occur after instrumentation removal for infection, since this removal can enhance bone fusion mechanisms; 2. Radio- and chemotherapy can cause hardware failure due to interference with local bone metabolism; 3. Although old-fashioned, wiring techniques still deserve consideration, mostly in CVJ re-do surgery after screwing technique failures; nevertheless, although the procedure is simple, safe, and effective, care must be taken in the preparation of the cranial holes in order to avoid sliding complications of the U-shaped rods. CVJ instrumentations provide reasonably good mechanical stabilization with a high rate of bony fusion. Complications, such as dislocation or rupture of the fixation system, screw loosening, dural fistula, neural or vascular damage, and wound infection, are relatively infrequent. Knowledge and prevention of these complications is fundamental to improve surgical results and outcomes.


Administration of radiographic contrast media in high-risk patients.
Patients with a prior history of an anaphylactoid reaction (AR) to radiographic contrast media (RCM) have an increased risk of an AR during subsequent RCM studies. Based on previous studies in high-risk patients using prednisone or diphenhydramine to reduce the incidence of AR, high-risk patients were treated with a combined prednisone and diphenhydramine protocol in an effort to develop an effective, practical approach to this problem. All patients with convincing histories of AR to RCM with an essential need for a repeat RCM study received 50 mg of prednisone orally every 6 hours for 3 doses ending 1 hour before the RCM study, and 50 mg of diphenhydramine intramuscularly 1 hour prior to the procedure. Resuscitation equipment was readily available. One hundred forty-seven repeat procedures using RCM were carried out in 142 high-risk patients. No serious AR occurred. Two patients had generalized urticaria that resolved in 1 hour. The overall reaction rate in these pretreated high-risk patients was 6.8%, suggesting that this prednisone-diphenhydramine program may be the preferred prophylactic regimen when repeat RCM studies are necessary.


Publicly accessible evidence of health-related quality of life benefits associated with cancer drugs approved by the European Medicines Agency between 2009 and 2015.
Health-related quality of life (HRQoL) is one of the most important patient-relevant study end-points for the direct measurement of the benefit of cancer drugs. Therefore, our aim is to detect cancer indications with no published information on HRQoL at the time of European Medicines Agency (EMA) approval and monitor any reported HRQoL evidence updates after at least three years of follow-up. We included all cancer indications that were approved by the EMA between January 2009 and October 2015. Our main sources of information were the EMA website, clinicaltrials.gov and a systematic literature search in PubMed. Information on HRQoL outcomes was extracted alongside evidence on median overall survival. In total, we identified 110 indications, of which more than half (n = 58, 53%) were lacking available information on HRQoL assessments at the time of EMA approval. After a monitoring period of at least three years, 24 updates were identified, resulting in 34 (31%) therapies where information on HRQoL was still not available. For the 76 therapies with reported information on HRQoL, cancer-specific instruments were mostly used (n = 49/76). Regarding cumulative evidence on median overall survival and HRQoL, 33 (n = 33/110, 30%) as well as 15 (n = 15/110, 14%) cancer drugs were lacking information on both study end-points at the time of approval and after monitoring, respectively. Our results demonstrate that there is an urgent need of routine re-evaluation of reimbursed cancer drugs with initially missing information on major outcomes. Standardisation of the typology and quality of HRQoL assessments need to be improved to allow better comparability of results.


Fungal Signature of Moisture Damage in Buildings: Identification by Targeted and Untargeted Approaches with Mycobiome Data.
Identifying microbial indicators of damp and moldy buildings remains a challenge at the intersection of microbiology, building science, and public health. Sixty homes in New York City were assessed for moisture-related damage, and three types of dust samples were collected for microbiological analysis. We applied four approaches for detecting fungal signatures of moisture damage in these buildings. Two novel targeted approaches selected specific taxa, identified by a priori hypotheses, from the broad mycobiome as detected with amplicon sequencing. We investigated whether (i) hydrophilic fungi (i.e., requiring high moisture) or (ii) fungi previously reported as indicating damp homes would be more abundant in water-damaged rooms/homes than in nondamaged rooms/homes. Two untargeted approaches compared water-damaged to non-water-damaged homes for (i) differences between indoor and outdoor fungal populations or (ii) differences in the presence or relative abundance of particular fungal taxa. Strong relationships with damage indicators were found for some targeted fungal groups in some sampling types, although not always in the hypothesized direction. For example, for vacuum samples, hydrophilic fungi had significantly higher relative abundance in water-damaged homes, but mesophilic fungi, unexpectedly, had significantly lower relative abundance in homes with visible mold. Untargeted approaches identified no microbial community metrics correlated with water damage variables but did identify specific taxa with at least weak positive links to water-damaged homes. These results, although showing a complex relationship between moisture damage and microbial communities, suggest that targeting particular fungi offers a potential route toward identifying a fungal signature of moisture damage in buildings.IMPORTANCE Living or working in damp or moldy buildings increases the risk of many adverse health effects, including asthma and other respiratory diseases. To date, however, the particular environmental exposure(s) from water-damaged buildings that causes the health effects have not been identified. Likewise, a consistent quantitative measurement that would indicate whether a building is water damaged or poses a health risk to occupants has not been found. In this work, we tried to develop analytical tools that would find a microbial signal of moisture damage amid the noisy background of microorganisms in buildings. The most successful approach taken here focused on particular groups of fungi-those considered likely to grow in damp indoor environments-and their associations with observed moisture damage. With further replication and refinement, this hypothesis-based strategy may be effective in finding still-elusive relationships between building damage and microbiomes.


Gonadotropin-releasing hormone receptor levels and cell context affect tumor cell responses to agonist in vitro and in vivo.
Activation of gonadotropin-releasing hormone (GnRH) receptors inhibits proliferation of transformed cells derived from reproductive tissues and in transfected cell lines. Hence, GnRH receptors represent a therapeutic target for direct action of GnRH analogues on certain proliferating cells. However, more cell biological data are required to develop this particular application of GnRH analogues. Therefore, we compared the effects of GnRH receptor activation in transfected HEK293 cells (HEK293([SCL60])) with transfected human ovarian cancer cell lines SKOV3 and EFO21, human hepatoblastoma HepG2 cells, and rat neuroblastoma B35 cells. Marked differences in receptor levels, magnitude of inositol phosphate generation, and dynamics of inositol phosphate turnover occurred in the different cells. Activation of GnRH receptors, expressed at high or moderate levels, inhibited the growth of HEK293([SCL60]) and B35 cells, respectively. Western blotting detected markers of apoptosis [cleaved poly(ADP-ribose) polymerase, caspase-9] in HEK293([SCL60]) and B35 following treatment with 100 nmol/L d-Trp(6)-GnRH-I. Cell growth inhibition was partially or completely rescued with inhibitor Q-VD-OPh or Ro32-0432. Low levels of GnRH receptor expression in transfected SKOV3, EFO21, or HepG2 activated intracellular signaling but did not induce apoptosis or significantly affect cell proliferation. Tumor xenografts prepared from HEK293([SCL60]) regressed during treatment with d-Trp(6)-GnRH-I and growth of xenografts derived from transfected B35 was slowed. SKOV3 xenografts were not growth inhibited. Therefore, differences in levels of GnRH receptor and signaling differentially affect the apoptotic machinery within cell lines and contribute to the cell type-specific effects of GnRH on growth. Further studies should exploit the growth-inhibitory potential of GnRH receptor activation in abnormal cells in diseased human tissues.


The distribution of leprosy in Zambia.
The distribution of leprosy in Zambia is analysed on a district basis. High density areas are identified and it is suggested that genetic (tribal) factors may be relevant. It is shown that the treatment of leprosy patients has moved away from largely church-related institutions to Government Rural Health Centres. In spite of the urban drift, leprosy remains essentially a rural problem in Zambia. Differences in provincial prevalence rates for leprosy in Zambia have been recorded in previous Annual Reports of the Ministry of Health. However, an analysis of prevalence rates at a District level appears not to have been undertaken previously. It was felt this would prove of interest and be of value both for future planning of leprosy services and research.


How do I measure physical activity in my patients? Questionnaires and objective methods.
How do healthcare providers know if their patients are getting enough physical activity to promote good health and to reduce their risks of chronic diseases and injury? The first step is to identify the patient's current level of physical activity using questionnaires and/or motion sensors. Questionnaires assess activity levels by having patients answer a set of questions about the types and amounts of activity performed at some time in the past. Motion sensors assess physical activity by patients wearing a small monitoring device that records their body movement as it occurs. If a provider is interested in determining a patient's caloric energy expenditure, he/she can apply statistical regression models to the questionnaire and motion sensor data to estimate kilocalories. If more precise measures of energy expenditure are desired, a provider can use the isotopic doubly labelled water method to estimate kilocalories; however, this method is costly and is impractical in non-research clinical settings.


Mandibular adenomatoid odontogenic tumor: Radiographic and pathologic correlation.
Adenomatoid odontogenic tumor (AOT) is a rare tumor of epithelial origin comprising 3% of all the odontogenic tumors. It is a benign, painless, noninvasive, and slow-growing lesion, with a relative frequency of 2.2-13% and often misdiagnosed as an odontogenic cyst on clinical examination. AOT affects young individuals with a female predominance, occurs mainly in the second decade, and usually surrounds the crown of unerupted teeth. This lesion is most commonly located in the anterior maxilla and rarely in the mandible. It is usually associated with an impacted canine. AOT frequently resembles lesions like dentigerous cyst or ameloblastoma. AOT has three variants, follicular, extrafollicular, and peripheral. The intraoral periapical radiograph is the best radiograph to show radiopacities in AOT as discrete foci having a flocculent pattern within radiolucency even with minimal calcified deposits. These calcified deposits are seen in approximately 78% of the lesions. Herewith, we present the report of four unusual cases of AOT located in the mandible, with an emphasis on radiographic findings and on pathologic correlation, and on reviewing the existing literature on this tumor.


Evidence of a hyperkinetic state in children with elevated blood pressure.
Left ventricular hypertrophy (LVH) and elevated left ventricular mass index (LVMI) are important predictors of cardiovascular morbidity and mortality in adults. Children with hypertension and pre-hypertension demonstrate LVH and greater LVMI compared to normotensive children. The impact of blood pressure (BP) on early changes in left ventricular properties provides an opportunity to understand and identify cardiovascular risk early in childhood. The aim of this study was to assess left ventricular structural and functional properties in a sample of children across a wide range of BP values. Children aged 11-14-years were divided into BP groups: hypertensives (HTN; ≥95th percentile; n = 21) and normotensives (NTN; <90th percentile; n = 85) based on BP measures taken at two time points. Resting supine heart rate (HR), cardiac output (CO) and total peripheral resistance (TPR) were collected along with left ventricular structural and functional properties using ultrasound sonography. LVMI and TPR were not different between groups. CO, HR and left ventricular end-diastolic and end-systolic volumes were elevated in the HTN group. Furthermore, HR and body mass index were found to be independent predictors of BP group status in children. These findings show that children with elevated BP are characterized by high HR and CO and normal TPR. Also, the results identify HR as a predictor of BP group status in early childhood.


"Until the trial is complete you can't really say whether it helped you or not, can you?": exploring cancer patients' perceptions of taking part in a trial of acupressure wristbands.
Nested qualitative studies within clinical trials provide data on patients' experiences of receiving trial interventions and can inform and improve trial designs. The present study explored patients' experiences of participating in a randomised controlled trial of acupressure wristbands for chemotherapy related nausea. A randomised three-group sham-controlled trial was carried out to evaluate the effectiveness of acupressure wristbands in the management of chemotherapy-related nausea. A convenience sample of 26 patients volunteered to participate in a qualitative study to explore their experiences of using acupressure wristbands, and taking part in the clinical trial. Participants were recruited from each of the three UK geographical sites from which the trial was conducted: Manchester, Liverpool and Plymouth. In-depth semi-structured interviews were conducted with the participants in their own homes or other location convenient for participating patients. Interviews were audio-taped, transcribed verbatim and analysed using Framework methodology. The main motivational factors influencing participants to take part in the trial were a desire to 'give something back' and limit their own experience of nausea. Participants were largely satisfied with the organisation and running of the acupressure wristband trial. Many participants experienced positive outcomes as a result of taking part in the trial. Lapses in memory, or poor health as a result of their chemotherapy treatment, led to some participants failing to complete trial paperwork on designated days. Two sham wristband participants reported wearing the bands inappropriately resulting in pressure being applied to the acupoint. Almost all of the participants interviewed had only experienced mild nausea or vomiting during the trial. Participants were pragmatic on the extent to which the wristbands were responsible for this lack of nausea and vomiting during the trial. However, many participants, including some patients receiving sham acupressure, believed the wristbands to have had a positive impact on their nausea and vomiting; there was a perception that the wristbands were, at least in part, responsible for the lack of nausea and vomiting they had experienced. Participants perceive acupressure wristbands as reducing the level of nausea and vomiting experienced during chemotherapy treatment. Reports that some participants wore wristbands inappropriately, and/or delayed completion of trial paperwork could represent confounding variables and have implications for the trial results, and the design of clinical trials within the field of cancer.


Transitions between blocked and zonal flows in a rotating annulus with topography
The mid-latitude atmosphere is dominated by westerly, nearly zonal flow. Occasionally, this flow is deflected poleward by blocking anticyclones that persist for 10 days or longer. Experiments in a rotating annulus used radial pumping to generate a zonal jet under the action of the Coriolis force. In the presence of two symmetric ridges at the bottom of the annulus, the resulting flows were nearly zonal at high forcing or blocked at low forcing. Intermittent switching between blocked and zonal patterns occurs because of the jet's interaction with the topography. These results shed further light on previous atmospheric observations and numerical simulations.


AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.
Efficient control of energy metabolic homeostasis, enhanced stress resistance, and qualified cellular housekeeping are the hallmarks of improved healthspan and extended lifespan. AMPK signaling is involved in the regulation of all these characteristics via an integrated signaling network. Many studies with lower organisms have revealed that increased AMPK activity can extend the lifespan. Experiments in mammals have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling which augment the quality of cellular housekeeping. Moreover, AMPK-induced stimulation of FoxO/DAF-16, Nrf2/SKN-1, and SIRT1 signaling pathways improves cellular stress resistance. Furthermore, inhibition of NF-κB signaling by AMPK suppresses inflammatory responses. Emerging studies indicate that the responsiveness of AMPK signaling clearly declines with aging. The loss of sensitivity of AMPK activation to cellular stress impairs metabolic regulation, increases oxidative stress and reduces autophagic clearance. These age-related changes activate innate immunity defence, triggering a low-grade inflammation and metabolic disorders. We will review in detail the signaling pathways of this integrated network through which AMPK controls energy metabolism, autophagic degradation and stress resistance and ultimately the aging process.


Desmoglein 3: a help or a hindrance in cancer progression?
Desmoglein 3 is one of seven desmosomal cadherins that mediate cell-cell adhesion in desmosomes. Desmosomes are the intercellular junctional complexes that anchor the intermediate filaments of adjacent cells and confer strong cell adhesion thus are essential in the maintenance of tissue architecture and structural integrity. Like adherens junctions, desmosomes function as tumour suppressors and are down regulated in the process of epithelial-mesenchymal transition and in tumour cell invasion and metastasis. However, recently several studies have shown that various desmosomal components, including desmoglein 3, are up-regulated in cancer with increased levels of expression correlating with the clinical stage of malignancy, implicating their potentiality to serve as a diagnostic and prognostic marker. Furthermore, in vitro studies have demonstrated that overexpression of desmoglein 3 in cancer cell lines activates several signal pathways that have an impact on cell morphology, adhesion and locomotion. These additional signalling roles of desmoglein 3 may not be associated to its adhesive function in desmosomes but rather function outside of the junctions, acting as a key regulator in the control of actin based cellular processes. This review will discuss recent advances which support the role of desmoglein 3 in cancer progression.


Eyes on crowding: crowding is preserved when responding by eye and similarly affects identity and position accuracy.
Peripheral vision guides recognition and selection of targets for eye movements. Crowding—a decline in recognition performance that occurs when a potential target is surrounded by other, similar, objects—influences peripheral object recognition. A recent model study suggests that crowding may be due to increased uncertainty about both the identity and the location of peripheral target objects, but very few studies have assessed these properties in tandem. Eye tracking can integrally provide information on both the perceived identity and the position of a target and therefore could become an important approach in crowding studies. However, recent reports suggest that around the moment of saccade preparation crowding may be significantly modified. If these effects were to generalize to regular crowding tasks, it would complicate the interpretation of results obtained with eye tracking and the comparison to results obtained using manual responses. For this reason, we first assessed whether the manner by which participants responded—manually or by eye—affected their performance. We found that neither recognition performance nor response time was affected by the response type. Hence, we conclude that crowding magnitude was preserved when observers responded by eye. In our main experiment, observers made eye movements to the location of a tilted Gabor target while we varied flanker tilt to manipulate target-flanker similarity. The results indicate that this similarly affected the accuracy of peripheral recognition and saccadic target localization. Our results inform about the importance of both location and identity uncertainty in crowding.


Leishmania donovani amastigotes impair gamma interferon-induced STAT1alpha nuclear translocation by blocking the interaction between STAT1alpha and importin-alpha5.
The protozoan parasite Leishmania donovani, the etiological agent of visceral leishmaniasis, is renowned for its capacity to sabotage macrophage functions and signaling pathways stimulated by activators such as gamma interferon (IFN-gamma). Our knowledge of the strategies utilized by L. donovani to impair macrophage responsiveness to IFN-gamma remains fragmentary. In the present study, we investigated the impact of an infection by the amastigote stage of L. donovani on IFN-gamma responses and signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in mouse bone marrow-derived macrophages. The levels of IFN-gamma-induced expression of major histocompatibility complex class II and inducible nitric oxide synthase (iNOS) were strongly reduced in L. donovani amastigote-infected macrophages. As the expression of those genes is mediated by the transcription factors STAT1alpha and IFN regulatory factor 1 (IRF-1), we investigated their activation in amastigote-infected macrophages treated with IFN-gamma. We found that whereas STAT1alpha protein levels and the levels of phosphorylation on Tyr701 and Ser727 were normal, IRF-1 expression was inhibited in infected macrophages. This inhibition of IRF-1 expression correlated with a defective nuclear translocation of STAT1alpha, and further analyses revealed that the IFN-gamma-induced STAT1alpha association with the nuclear transport adaptor importin-alpha5 was compromised in L. donovani amastigote-infected macrophages. Taken together, our results provide evidence for a novel mechanism used by L. donovani amastigotes to interfere with IFN-gamma-activated macrophage functions and provide a better understanding of the strategies deployed by this parasite to ensure its intracellular survival.


Derealisation following head injury: a case report.
Depersonalisation and derealisation which are often present together, occur in a number of functional and organic conditions. However, their occurrence in the post-concussional syndrome has been previously described in only one case. A case is presented in which derealisation was the only presentation following a minor closed head injury. The possible aetiology is discussed.


Therapeutic potential of a gamma-secretase inhibitor for hearing restoration in a guinea pig model with noise-induced hearing loss.
Notch signaling plays a crucial role in the fate determination of cochlear progenitor cells, hair cells, and supporting cells in the developing cochlea. Recent studies have demonstrated the temporal activation of Notch signaling in damaged mature cochleae, and have demonstrated the induction of new hair cells by pharmacologically inhibiting Notch signaling. The present study aimed to illustrate the feasibility of pharmacologically inhibiting Notch signaling by using a gamma-secretase inhibitor for treating sensorineural hearing loss. The effect of the sustained local delivery of MDL28170, a gamma-secretase inhibitor, on hearing and hair cell induction was tested in a guinea pig model with noise-induced hearing loss. MDL28170 was directly delivered into the cochlear fluids via a micro-osmotic pump. Drug application was initiated 7 days after noise exposure. Measurements of auditory brainstem responses revealed better hearing in the MDL28170-treated animals than in the vehicle controls. Histological analysis demonstrated a higher number of outer hair cells in the MDL28170-treated cochleae than the vehicle-treated cochleae. These findings strongly suggest that local sustained delivery of a gamma-secretase inhibitor into the cochlea could be a novel strategy for treating acute hearing loss that is refractory to conventional treatment.


Long-term Inflammation Transforms Intestinal Epithelial Cells of Colonic Organoids.
Patients with ulcerative colitis [UC] are at an increased risk of developing colitis-associated cancer [CAC], suggesting that continuous inflammation in the colon promotes the transformation of colonic epithelial cells. However, the mechanisms underlying cell transformation in UC remain unknown. We therefore aimed to investigate the effect of long-term inflammation on intestinal epithelial cells [IECs] using organoid culture. IECs were isolated from mouse colon, and were cultured according to a method for a three-dimensional [3D] organoid culture. To mimic chronic inflammation, a mixture of cytokines and bacterial components were added to the medium for over a year. Cell signal intensity was assessed by 3D immunofluorescence. Cell transformation was assessed by microarray with gene set enrichment analysis. Stimulation with cytokines resulted in a significant induction of target genes for the nuclear factor [NF]-κB pathway in colonic organoids. Following 60 weeks of continuous stimulation, cell differentiation was suppressed. Continuous stimulation also resulted in significant amplification of NF-κB signalling. Amplified NF-κB signalling by long-term stimulation remained in colonic organoids even 11 weeks after the removal of all cytokines. Some genes were specifically upregulated only in colonic organoids after the removal all cytokines following long-term stimulation. Colonic organoids stimulated with cytokines for a prolonged period were established as in vitro model to assess long-term epithelial responses to inflammatory cytokines. Chronic inflammation led to sustained NF-κB signalling activation in colonic organoids, resulting in cell transformation that might be related to the carcinogenesis of CAC in UC.


Best Practices for Derivation and Application of Thresholds for Metals Using Bioavailability-Based Approaches.
The primary goal of the present study is to provide a broad view of best practices for evaluating bioavailability models for metals for use in the protection of aquatic life. We describe the state of the science regarding 1) the evaluation and selection of ecotoxicity data, 2) the selection of bioavailability models for use in normalization, and 3) subsequent application of bioavailability models. Although many examples of normalization steps exist worldwide, a scheme is proposed to evaluate and select a model that takes account of its representativeness (water chemistry and taxonomic coverage of the ecotoxicity data set) and validation performance. Important considerations for a suitable model are the quantity of inputs needed, accuracy, and ease of use, all of which are needed to set protective values for aquatic life and to use these values to evaluate potential risks to organisms in receiving waters. Although the end results of different model application approaches may be broadly similar, the differences in these application frameworks ultimately come down to a series of trade-offs between who needs to collect the data and use the bioavailability model, the different requirements of spatial scales involved (e.g., regional vs site-specific values), and model predictiveness and protectiveness. Ultimately, understanding the limits and consequences of these trade-offs allows for selection of the most appropriate model and application framework to best provide the intended levels of aquatic life protection. Environ Toxicol Chem 2019;39:118-130. © 2019 SETAC.


Prevention of lens epithelial cell growth in vitro using mibefradil-containing PLGA micro particles.
The prevention of the posterior capsule opacification is still unsolved. To interfere with proliferating cells the T-type calcium channel antagonist Mibefradil was immobilized in poly-lactic-co-glycolic-acid micro particles which were fixed at a capsular tension ring and tested in a human organ culture model as well as in human lens cells HLE-B3 in vitro. It is feasible to get a release significantly affecting cell viability and growth evaluated by MTT test and cell cycle analysis. In addition, Bionas(®) sensor chips were used for time-dependent adhesion experiments in living lens cells. Interestingly, the concentration of Mibefradil which inhibited subconfluent cells is not effective in confluent cells. This is an important feature for the protection of the intact tissue in the eye.


Transient hydropic signs in the donor fetus after fetoscopic laser coagulation in severe twin-twin transfusion syndrome: incidence and clinical relevance.
To evaluate the incidence, characteristics, and impact on perinatal outcome of the development of hydropic signs in the donor fetus after laser coagulation for severe twin-twin transfusion syndrome in the second trimester. Forty cases of second-trimester severe twin-twin transfusion underwent fetoscopic laser coagulation of placental anastomoses and were followed up with serial ultrasound up to 14 days after therapy. Ultrasound scans were performed just before, and on days 1, 3, 5 and 14 after therapy, and fetuses were monitored for the presence of hydropic signs (skin edema, pleural effusion, ascites and pericardial effusion). Response to therapy and perinatal outcome in terms of neonatal survival were recorded for all cases. Four recipients (10%) and three donors (7.5%) died over the first 72 h after therapy. During the study period, two recipients (5.5%) developed frank hydrops fetalis, and eventually died in utero. Ten donors (27.0%) developed one or more hydropic signs. In nine (90%), signs were mild or moderate and transient (mean, 3.2 days), while in one case hydrops worsened and the fetus eventually died. No donors with transient hydrops died in utero, and two died postnatally due to extreme prematurity. Gestational age at procedure and deepest amniotic fluid vertical pocket were similar between hydropic and non-hydropic donors. Discrepancy in estimated fetal weight at procedure was significantly lower in donors developing hydrops (9.6 (SD, 6.4) vs. 17.8 (14.4)%,P = 0.018). In pregnancies with hydropic donors, gestational age at delivery (33.1 (3.4) vs. 29.7 (3.5) weeks,P = 0.015) and birth weight for recipient (2392 (423) vs. 1631 (576) g, P < 0.001) and donor (1908 (774) vs. 1281 (583) g,P = 0.021) were significantly higher. The development of transient hydrops had no influence on neonatal survival at 28 days nor on the rate of clinical resolution of intertwin transfusion. Transient hydropic signs may develop in a proportion of donor fetuses after laser coagulation for severe twin-twin transfusion syndrome. This phenomenon is normally not associated with a poor prognosis, and possibly indicates an hemodynamic adaptation response following interruption of the transfusion process.


Prevalence of obstructive airways disease in the disadvantaged elderly of Chicago.
The prevalence of obstructive airways disease in the disadvantaged elderly population is underestimated. Consequently, asthma may be suboptimally managed in this population leading to poorer symptom control and quality of life in this group. The objective of this study was to estimate the prevalence of obstructive airways disease (OAD) in a disadvantaged elderly population. A cross-sectional study was conducted in which we interviewed older adults at centers subsidized by the Chicago Department on Aging. Participants were individuals who agreed to complete a five-page questionnaire about their health. Three hundred eighty individuals agreed to fill out a questionnaire about their health. The mean and median age was 74 years. There were 38 (10%) individuals with self-report of doctor-diagnosed asthma, 40 (11%) individuals with doctor-diagnosed chronic bronchitis, and 14 (4%) individuals with doctor-diagnosed emphysema. They had these diagnoses for a mean of 10.4 years (range, 0-50 years). Thirty-three (9%) individuals who did not have doctor-diagnosed disease had wheezing or whistling when they breathed and shortness of breath or cough with exercise. Of those 125 individuals with doctor-diagnosed disease or symptoms suggestive of OAD, only 22 (18%) individuals took their prescribed medications on a regular basis. Symptoms of OAD appear to be common in the disadvantaged elderly in Chicago. Based on these results, 92 (24%) individuals had doctor-diagnosed asthma, chronic bronchitis, and/or emphysema. The majority did not take their medications regularly. Another 33 (9%) individuals had symptoms compatible with OAD that had not been diagnosed or treated.


DNA hydroxymethylation differences underlie phenotypic divergence of somatic growth in Nile tilapia reared in common garden.
Phenotypic plasticity of metabolism and growth are essential for adaptation to new environmental conditions, such as those experienced during domestication. Epigenetic regulation plays a key role in this process but the underlying mechanisms are poorly understood, especially in the case of hydroxymethylation. Using reduced representation 5-hydroxymethylcytosine profiling, we compared the liver hydroxymethylomes in full-sib Nile tilapia with distinct growth rates (3.8-fold difference) and demonstrated that DNA hydroxymethylation is strongly associated with phenotypic divergence of somatic growth during the early stages of domestication. The 2677 differentially hydroxymethylated cytosines between fast- and slow-growing fish were enriched within gene bodies (79%), indicating a pertinent role in transcriptional regulation. Moreover, they were found in genes involved in biological processes related to skeletal system and muscle structure development, and there was a positive association between somatic growth and 5hmC levels in genes coding for growth factors, kinases and receptors linked to myogenesis. Single nucleotide polymorphism analysis revealed no genetic differentiation between fast- and slow-growing fish. In addition to unveiling a new link between DNA hydroxymethylation and epigenetic regulation of growth in fish during the initial stages of domestication, this study suggests that epimarkers may be applied in selective breeding programmes for superior phenotypes.


Promoter prediction on a genomic scale--the Adh experience.
We describe our statistical system for promoter recognition in genomic DNA with which we took part in the Genome Annotation Assessment Project (GASP1). We applied two versions of the system: the first uses a region-based approach toward transcription start site identification, namely, interpolated Markov chains; the second was a hybrid approach combining regions and signals within a stochastic segment model. We compare the results of both versions with each other and examine how well the application on a genomic scale compares with the results we previously obtained on smaller data sets.


Predictors of late clinical outcome following orthopedic injuries after multiple trauma.
The long-term clinical status of surviving patients with multiple injuries has not been well described. The aim of this study was to evaluate whether certain injury patterns predispose a patient to a poor clinical outcome 10 or more years after multiple injuries. Patients who were treated at a level I trauma center at least 10 years before participation in this study were reinvited for a follow-up physical examination. Clinical outcome included the assessment of pain, gait, and various outcome scores (Short-Form [SF]-12, Lysholm, Merle D'Aubigne) were also used to measure outcome. Binary logistic regression was used to test predictors of physical and psychosocial outcomes 10 years or longer after trauma. Differences between the types of injury and outcomes were assessed using Mann-Whitney and Kruskal Wallis tests. Of 1,034, 637 patients (62%) participated in this study. Predictors of poor physical and psychosocial functioning using a clinical outcome score at 10 or more years follow-up included lower extremity amputation (odds ratio = 15.08; 95% confidence interval = 1.87-121.61) and a higher Abbreviated Injury Scale (AIS) spine score (SF-12 Mental subscale [odds ratio = 0.78; 95% confidence interval = 0.64-0.96]). Other factors associated with worse outcome scores were presence of two or more articular injuries, lower extremity injuries, and a combination of shaft and articular injuries. If patients survived, traumatic lower extremity amputation and a high initial maximum AIS (MAIS) spine score was the only predictive parameter for an increased odds of adverse clinical outcomes late after trauma. Injuries associated with these outcomes should be the focus of attention regarding injury prevention and priority in care.


Effects of tryptophan depletion on selective serotonin reuptake inhibitor-remitted patients with obsessive compulsive disorder.
Serotonergic antidepressants are first-line medication therapies for obsessive-compulsive disorder, however it is not known if synaptic serotonin availability is important for selective serotonin reuptake inhibitor efficacy. The present study tested the hypothesis that temporary reduction in central serotonin transmission, through acute tryptophan depletion, would result in an increase in anxiety in selective serotonin reuptake inhibitor-remitted obsessive-compulsive disorder patients. Eight patients (four males) with obsessive-compulsive disorder who showed sustained clinical improvement with selective serotonin reuptake inhibitor treatment underwent acute tryptophan depletion in a randomized, double-blind, placebo-controlled, within-subjects design, over two days one week apart. Five hours after consumption of the depleting/sham drink the participants performed a personalized obsessive-compulsive disorder symptom exposure task. Psychological responses were measured using the Spielberger State Anxiety Inventory, Yale-Brown Obsessive Compulsive Scale and Visual Analogue Scales. Free plasma tryptophan to large neutral amino acid ratio decreased by 93% on the depletion day and decreased by 1% on the sham day, as anticipated. Psychological rating scores as measured by Visual Analogue Scale showed a significant decrease in perceived control and increase in interfering thoughts at the time of provocation on the depletion day but not on the sham day. A measure of convergent validity, namely Visual Analogue Scale Similar to past, was significantly higher at the time of provocation on both the depletion and sham days. Both the depletion and time of provocation scores for Visual Analogue Scale Anxiety, Spielberger State Anxiety Inventory, Yale-Brown Obsessive Compulsive Scale and blood pressure were not significant. Acute tryptophan depletion caused a significant decrease in perceived control and increase in interfering thoughts at the time of provocation. Acute tryptophan depletion had no effect on the Spielberger State Anxiety Inventory or Visual Analogue Scale Anxiety measures, which suggests that the mechanism of action of selective serotonin reuptake inhibitors may be different to that seen in panic, social anxiety and post-traumatic stress disorder. Successful selective serotonin reuptake inhibitor treatment of obsessive-compulsive disorder may involve the ability of serotonin to switch habitual responding to goal-directed behaviour.


[The peculiarities of diagnosis and treatment of chronic venous insufficiency and venous forms of lower extremity dysplasia].
The authors present the modern viewpoint concerning the problem of chronic venous insufficiency in the cases of venous forms of dysplasia. The treatment of patients with of venous forms of dysplasia should be based on the principles of interdisciplinary approach, which stipulates both the careful diagnosis on the basis of mainly non-invasive methods and integration of surgical and conservative treatment methods. Today such treatment should be combined and conducted within the multi-purpose highly specialized institution. Only the combination of all treatment methods will allow achieving the best functional and esthetic results. In the cases when indications are absent and conduction of surgical or any other treatment method is impossible it is necessary control the venous anomaly (dynamical follow-up, compression as a basic variant of conservative therapy). It will allow minimizing the unfavorable influence on vital functions and improving the patient's life quality.


[Reversibility or irreversibility of pulmonary function changes after cardiac surgery on insufficient or stenotic cardiac valves (author's transl)].
In 69 patients with mitral- or aortic valves disease lung function tests were made preoperatively and 2 to 4 years after cardiac surgery. We wanted to demonstrate the extent and the improvement of restriction, obstruction and disturbed diffusing capacity of the separate diseases with different severities. We found correlations between the clinical grade of the disease and the changes in lung function. In particular grade III of the mitral stenosis showed severe restriction, obstruction and disturbed diffusing capacity. Patients with mitral insufficiency III had changes of mild degree, aortic diseases were without disturbed lung function. All detected changes of lung function were irreversible and could not be influenced by postoperative hemodynamic improvements.


Excitation mapping of whispering gallery modes in silica microcavities.
We report the direct observation of the electromagnetic-field distribution of whispering gallery modes in silica microcavities (spheres and toroids). It is revealed by their excitation efficiency with a tapered fiber coupler swept along the meridian. The originality of this method lies in the use of the coupler itself for the near-field mapping, eliminating the need of additional tools used in previous work. This method is successfully applied to microspheres and microtoroids.


Leukocyte screening using the ELT-800/WS.
In order to provide performance standards for instruments utilizing automated cell differentiation, a study was undertaken using the NCCLS Standard H20-T. The ELT-800/WS using light scattering technology was compared with a manual reference method. These were compared using normal values developed in the study for determination of sensitivity of the method, utilizing arbitration where necessary. Statistical analyses were performed including ANOVA, imprecision, sample size efficiency, and clinical sensitivity. Whereas the two methods (manual and automated) are quite different technologically, the mean differences are not significantly different for clinical purposes. The automated method is very precise. The normal values developed for the ELT 800/WS are comparable not only to the manual values developed by NCCLS but also to earlier values used for reference in the laboratory. In studies to identify or to classify samples as either normal or distributionally or morphologically abnormal, a false abnormal rate of 6.3% and a morphologically false abnormal rate of 8.7% were found. When the specific types are considered, in only two instances (3.2%) did the test method fail to show an operator alert with an abnormal specimen. The performance of the ELT-800/WS seems to be as accurate and as sensitive as the reference manual method and is satisfactory for clinical decision-making.


The Nutraceutic Silybin Counteracts Excess Lipid Accumulation and Ongoing Oxidative Stress in an In Vitro Model of Non-Alcoholic Fatty Liver Disease Progression.
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality. Oxidative stress and release of pro-inflammatory cytokines, such as tumor necrosis factor α (TNFα), are major consequences of hepatic lipid overload, which can contribute to progression of NAFLD to non-alcoholic steatohepatitis (NASH). Also, mitochondria are involved in the NAFLD pathogenesis for their role in hepatic lipid metabolism. Definitive treatments for NAFLD/NASH are lacking so far. Silybin, the extract of the milk thistle seeds, has previously shown beneficial effects in NAFLD. Sequential exposure of hepatocytes to high concentrations of fatty acids (FAs) and TNFα resulted in fat overload and oxidative stress, which mimic in vitro the progression of NAFLD from simple steatosis (SS) to steatohepatitis (SH). The exposure to 50 µM silybin for 24 h reduced fat accumulation in the model of NAFLD progression. The in vitro progression of NAFLD from SS to SH resulted in reduced hepatocyte viability, increased apoptosis and oxidative stress, reduction in lipid droplet size, and up-regulation of IκB kinase β-interacting protein and adipose triglyceride lipase expressions. The direct action of silybin on SS or SH cells and the underlying mechanisms were assessed. Beneficial action of silybin was sustained by changes in expression/activity of peroxisome proliferator-activated receptors and enzymes for FA oxidation. Moreover, silybin counteracted the FA-induced mitochondrial damage by acting on complementary pathways: (i) increased the mitochondrial size and improved the mitochondrial cristae organization; (ii) stimulated mitochondrial FA oxidation; (iii) reduced basal and maximal respiration and ATP production in SH cells; (iv) stimulated ATP production in SS cells; and (v) rescued the FA-induced apoptotic signals and oxidative stress in SH cells. We provide new insights about the direct protective effects of the nutraceutic silybin on hepatocytes mimicking in vitro NAFLD progression.


On the impact of masking and blocking hypotheses for measuring the efficacy of new tuberculosis vaccines.
Over the past 60 years, the Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used worldwide to prevent tuberculosis (TB). However, BCG has shown a very variable efficacy in different trials, offering a wide range of protection in adults against pulmonary TB. One of the most accepted hypotheses to explain these inconsistencies points to the existence of a pre-existing immune response to antigens that are common to environmental sources of mycobacterial antigens and Mycobacterium tuberculosis. Specifically, two different mechanisms have been hypothesized to explain this phenomenon: the masking and the blocking effects. According to masking hypothesis, previous sensitization confers some level of protection against TB that masks vaccine's effects. In turn, the blocking hypothesis postulates that previous immune response prevents vaccine taking of a new TB vaccine. In this work we introduce a series of models to discriminate between masking and blocking mechanisms and address their relative likelihood. We apply our methodology to the data reported by BCG-REVAC clinical trials, which were specifically designed for studying BCG efficacy variability. Our results yield estimates that are consistent with high levels of blocking (41% in Manaus -95% CI [14-68]- and 96% in Salvador -95% CI [52-100]-). Moreover, we also show that masking does not play any relevant role in modifying vaccine's efficacy either alone or in addition to blocking. The quantification of these effects around a plausible model constitutes a relevant step towards impact evaluation of novel anti-tuberculosis vaccines, which are susceptible of being affected by similar effects, especially if applied on individuals previously exposed to mycobacterial antigens.


Prebiotic carbohydrates modify the mucosa associated microflora of the human large bowel.
The mucosa associated flora of the large intestine is important in determining mucosal function although what controls its composition is unknown. This study has determined the effect of the prebiotic carbohydrates oligofructose and inulin on the mucosal flora. An in vitro chemostat model of both planktonic and surface associated bacteria was used followed by an intervention study in 29 subjects undergoing colonoscopy. Fourteen subjects, recruited from colonoscopy waiting lists, supplemented their diet for two weeks with a mix of 7.5 g of oligofructose and 7.5 g inulin. Fifteen subjects were recruited at the time of colonoscopy and given no supplement. Multiple endoscopic biopsies were taken from the caecum, transverse and descending colon, and rectum. The mucosal flora was characterised by culture and to species level by cellular fatty acid profiles. Cell proliferation was assessed by immunohistochemical staining for minichromosome maintenance protein 2, Ki67, and proliferating cell nuclear antigen. In vitro prebiotics increased surface counts of bifidobacteria from 6.6 to 7.3 log(10) colony forming units (CFU) per slide (p<0.0006) with no significant changes in planktonic bacteria. In the feeding study, prebiotics increased mucosal bifidobacteria (log CFU/g mucosa (SEM)) in both the proximal (control 5.3 (0.4) v prebiotic 6.3 (0.3)) (p = 0.059) and distal (control 5.2 (0.3) v prebiotic 6.4 (0.3)) colon (p = 0.01). Lactobacilli were also increased (3.0 (0.1) v 3.7 (0.2) (p = 0.02) in the proximal and 3.1 (0.1) v 3.6 (0.2) (p = 0.04) in the distal colon, respectively). There were significantly more eubacteria in fed subjects but no changes in total anaerobes clostridia, bacteroides, or coliforms, nor in proliferation indices. Prebiotic carbohydrates can change the composition of the mucosa associated flora significantly.


Sex differences in the oxygen uptake kinetic response to heavy-intensity exercise in prepubertal children.
It has been demonstrated that there are no sex differences in the oxygen uptake (V(.)O(2)) kinetic response to moderate intensity exercise. However, sex differences in the response to maximal exercise are readily apparent even in the prepubertal years. The purpose of this study was therefore to investigate if sex differences exist in the V(.)O(2) kinetic response to heavy-intensity exercise. Forty-eight prepubertal children (25 male, 23 female) completed four transitions from baseline to 40% of the difference between their previously determined T(V-slope) (ventilatory threshold determined by the V-slope method) and peak V(.)O(2) on an electronically braked cycle ergometer. Each subject's breath-by-breath responses were interpolated to 1 s intervals, time aligned and averaged. The data following phase 1 were fit with: (1) a double exponential model and (2) a single exponential model within a fitting window that was previously identified to exclude the slow component. There were no significant differences in the parameters of the primary component between each model. Subsequent analysis was carried out using model 2. The primary time constant (tau(1)) was significantly (P<0.05) faster in boys [17.6 (5.8) s] than girls [21.9 (8.2) s], and the slow component contribution to the total change in amplitude after 9 min was significantly greater in girls [11.8 (5.5)%] than boys [8.9 (3.7)%]. Sex differences in the kinetic response to heavy-intensity exercise were identified and suggest that during the prepubertal years, sex differences exist in the ability to deliver and/or utilise oxygen in children.


Low H-2 polymorphism in some Israeli wild mouse populations.
Two populations of the wild house mouse, Mus domesticus, found living close to each other (one inhabited a chicken coop and the other an open field at the Educational Farm of the Hebrew University of Jerusalem, East Talpiot, Jerusalem) were studied for their H-2 polymorphism. These two populations were selected because they are well characterized in terms of their ecological parameters; they have been under continuous surveillance for several years. Twenty-seven H-2 homozygous lines were produced by mating wild mice from these two populations with laboratory strains. The H-2w homozygotes were then characterized by serological typing with monoclonal and polyclonal antibodies specific for the known allomorphs controlled by the class I H-2K and H-2D loci or the class II H-2A and H-2E loci. They were also used as donors for immunizations and for the selection of antisera defining the H-2 haplotypes carried by these lines. Four new H-2 haplotypes could be identified: H-2w82 (Kw16 Dw82), H-2w83 (Kw83 Dw16), H-2w84 (Kw84 Dw84), and H-2w85 (Kw83 Dw84), the last haplotype being a recombinant derived from H-2w83 and H-2w84. Antisera defining the new haplotypes were then used for a study of the wild populations. This study revealed that the populations contain only the four identified H-2 haplotypes, having three alleles at the H-2K locus (Kw16, Kw83, Kw84) and three alleles at the H-2D locus (Dw16, Dw82, and Dw84). The alleles occur in the populations with a frequency of 0.12-0.54. There were no significant differences in gene frequencies between the two populations, and the allele frequencies remained more or less stable. There was a significant excess of heterozygotes for at least some of the genes, compared with the frequency expected from Hardy-Weinberg equilibrium. The same antisera were also used to type other populations in the vicinity of Jerusalem. In one population, located 30 km west of Jerusalem, the mice failed to react with any of the reagents. In the other two populations, located 15 km west and 40 km northeast of Jerusalem, three of the four H-2 haplotypes found in East Talpiot were present at high frequencies. It appears, therefore, that only three main H-2 haplotypes and two or three minor ones are present in the area around Jerusalem. This study thus provides the first example of a large mainland population in which the H-2 polymorphism is comparable to that of many other non-H-2 loci.


Describing the light intensity dependence of polymer:fullerene solar cells using an adapted Shockley diode model.
Solar cells are generally optimised for operation under AM1.5 100 mW cm(-2) conditions. This is also typically done for polymer solar cells. However, one of the entry markets for this emerging technology is portable electronics. For this market, the spectral shape and intensity of typical illumination conditions deviate considerably from the standard test conditions (AM1.5, 100 mW cm(-2), at 25 °C). The performance of polymer solar cells is strongly dependent on the intensity and spectral shape of the light source. For this reason the cells should be optimised for the specific application. Here a theoretical model is presented that describes the light intensity dependence of P3HT:[C60]PCBM solar cells. It is based on the Shockley diode equation, combined with a metal-insulator-metal model. In this way the observed light intensity dependence of P3HT:[C60]PCBM solar cells can be described using a 1-diode model, allowing fast optimization of polymer solar cells and module design.


Beta-arrestin-biased ligands at seven-transmembrane receptors.
Seven-transmembrane receptors (7TMRs), the most common molecular targets of modern drug therapy, are critically regulated by beta-arrestins, which both inhibit classic G-protein signaling and initiate distinct beta-arrestin signaling. The interplay of G-protein and beta-arrestin signals largely determines the cellular consequences of 7TMR-targeted drugs. Until recently, a drug's efficacy for beta-arrestin recruitment was believed to be proportional to its efficacy for G-protein activities. This paradigm restricts 7TMR drug effects to a linear spectrum of responses, ranging from inhibition of all responses to stimulation of all responses. However, it is now clear that 'biased ligands' can selectively activate G-protein or beta-arrestin functions and thus elicit novel biological effects from even well-studied 7TMRs. Here, we discuss the current state of beta-arrestin-biased ligand research and the prospects for beta-arrestin bias as a therapeutic target. Consideration of ligand bias might have profound influences on the way scientists approach 7TMR-targeted drug discovery.


Detectability of simulated interstitial pneumonia on chest radiographs: comparison between irradiation side sampling indirect flat-panel detector and computed radiography.
To compare the detectability of simulated interstitial pneumonia on chest radiographs between an irradiation side sampling indirect flat-panel detector (ISS-FPD) and computed radiography (CR). Simulated interstitial pneumonia findings (ground-glass opacity, reticular opacity and honeycomb lung) were superimposed on an anthropomorphic chest phantom. Chest radiographs were acquired under three exposure levels (4.0, 3.2 and 2.0 mAs) with an ISS-FPD and with CR. 5 thoracic radiologists evaluated 72 images for the presence or absence of a lesion over each of 6 areas. A total of 1296 observations were analysed in a receiver-operating characteristic analysis. A jackknife method was used for the statistical analysis. The areas under the curves (AUCs) for the detection of simulated honeycomb lung obtained with the ISS-FPD were significantly larger than those obtained with CR at all exposure conditions. For the detection of simulated ground-glass opacity and reticular opacity, there were no significant differences between the two systems. In addition, the AUCs for the detectability of simulated honeycomb lung obtained with the ISS-FPD at all exposure levels were significantly larger than those obtained with CR at 4 mAs. The ISS-FPD was superior to CR for the detection of simulated honeycomb lung. Provided that the chosen model is representative of interstitial pneumonia, the use of an ISS-FPD might reduce a patient's exposure dose during the detection of interstitial pneumonia. The ISS-FPD has shown its advantage compared with CR in the detection of honeycombing, one sign of interstitial pneumonia.


[A micronucleus analysis of the peripheral blood lymphocytes of the professional contingent and of the self-settlers in the exclusion zone of the Chernobyl Atomic Electric Power Station].
The chromosomal damage (micronuclei) of the peripheral blood lymphocytes of the group of professionals who had participated in the liquidation of the Chernobyl NPP accident and have continued their work at the "Shelter" and of the group of self-settlers who living for about ten year in the Chernobyl NPP alienation zone were studied. Residents of Kyïv were the group for comparison. It was found that in professionals the number of micronuclei was higher due to the presence of cells with several micronuclei while in the self-settlers it was due to the increase in the number of cells with one micronucleus. Also was determined the correlation between the frequency of micronuclei in the lymphocytes of the self-settlers on the one hand and the level of radionuclides contamination of territory and dose loading on the other.


Prostatic acid phosphatase is not a prostate specific target.
Prostatic acid phosphatase (PAP) is currently evaluated as a target for vaccine immunotherapy of prostate cancer. This is based on the previous knowledge about secretory PAP and its high prostatic expression. We describe a novel PAP spliced variant mRNA encoding a type I transmembrane (TM) protein with the extracellular NH(2)-terminal phosphatase activity and the COOH-terminal lysosomal targeting signal (YxxPhi). TM-PAP is widely expressed in nonprostatic tissues like brain, kidney, liver, lung, muscle, placenta, salivary gland, spleen, thyroid, and thymus. TM-PAP is also expressed in fibroblast, Schwann, and LNCaP cells, but not in PC-3 cells. In well-differentiated human prostate cancer tissue specimens, the expression of secretory PAP, but not TM-PAP, is significantly decreased. TM-PAP is localized in the plasma membrane-endosomal-lysosomal pathway and is colocalized with the lipid raft marker flotillin-1. No cytosolic PAP is detected. We conclude that the wide expression of TM-PAP in, for instance, neuronal and muscle tissues must be taken into account in the design of PAP-based immunotherapy approaches.


An internet-based epidemiological investigation of the outbreak of H7N9 Avian influenza A in China since early 2013.
In early 2013, a new type of avian influenza, H7N9, emerged in China. It quickly became an issue of great public concern and a widely discussed topic on the Internet. A considerable volume of relevant information was made publicly available on the Internet through various sources. This study aimed to describe the outbreak of H7N9 in China based on data openly available on the Internet and to validate our investigation by comparing our findings with a well-conducted conventional field epidemiologic study. We searched publicly accessible Internet data on the H7N9 outbreak primarily from government and major mass media websites in China up to February 10, 2014. Two researchers independently extracted, compared, and confirmed the information of each confirmed H7N9 case using a self-designed data extraction form. We summarized the epidemiological and clinical characteristics of confirmed H7N9 cases and compared them with those from the field study. According to our data updated until February 10, 2014, 334 confirmed H7N9 cases were identified. The median age was 58 years and 67.0% (219/327) were males. Cases were reported in 15 regions in China. Five family clusters were found. Of the 16.8% (56/334) of the cases with relevant data, 69.6% (39/56) reported a history of exposure to animals. Of the 1751 persons with a close contact with a confirmed case, 0.6% (11/1751) of them developed respiratory symptoms during the 7-day surveillance period. In the 97.9% (327/334) of the cases with relevant data, 21.7% (71/327) died, 20.8% (68/327) were discharged from a hospital, and 57.5% (188/327) were of uncertain status. We compared our findings before February 10, 2014 and those before December 1, 2013 with those from the conventional field study, which had the latter cutoff date of ours in data collection. Our study showed most epidemiological and clinical characteristics were similar to those in the field study, except for case fatality (71/327, 21.7% for our data before February 10; 45/138, 32.6% for our data before December 1; 47/139, 33.8% for the field study), time from illness onset to first medical care (4 days, 3 days, and 1 day), and time from illness onset to death (16.5 days, 17 days, and 21 days). Findings from our Internet-based investigation were similar to those from the conventional field study in most epidemiological and clinical aspects of the outbreak. Importantly, publicly available Internet data are open to any interested researchers and can thus greatly facilitate the investigation and control of such outbreaks. With improved efforts for Internet data provision, Internet-based investigation has a great potential to become a quick, economical, novel approach to investigating sudden issues of great public concern that involve a relatively small number of cases like this H7N9 outbreak.


Outcomes in pediatrics patients diagnosed with bone marrow failure disorders treated in a tertiary care center.
Bone marrow failure (BMF) syndromes are rare disorders with an annual incidence of 2-4 cases per million. Treatment options include immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). To analyze the outcomes of pediatric patients diagnosed with BMF treated in a tertiary care center. Retrospective study of pediatric patients diagnosed with BMF who consulted at Fundación Valle de Lili, Cali. Descriptive statistical analysis was performed according to Acquired BMF (ABMF) and Inherited BMF (IBMF). The outcomes include treatment, complications, overall survival (OS) in transplant patients, calculated using the Kaplan Meier method. We included 24 patients with BMF, average age 6.5 ± 4 years, and 50% were women. 58% presented IBMF, 9 with Fanconi anemia (FA), 2 dyskeratosis congenita, 2 congenital amegakaryocytic thrombocytopenia, and 1 presented Diamond-Blackfan anemia. 12 patients treated with HSCT had a 5-year OS of 83%. ABMF represented 42%. 6 patients received IST-HSCT, 3 received IST, and 1 received HSCT. The OS of the IST-HSCT group was 86%. Six patients died, four of them related to infection. In this series, there was a higher number of cases with IBMF. The OS of patients treated with HSCT is similar to that reported in recent studies. The most frequent cause of death was of infectious origin which has also been previously reported. The treatment esta blished in the patients showed favorable results in a Latin American tertiary care center.


Spatial association between primary Middle East respiratory syndrome coronavirus infection and exposure to dromedary camels in Saudi Arabia.
Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging zoonotic disease. Exposure to dromedary camels (Camelus dromedaries) has been consistently considered the main source of primary human infection. Although Saudi Arabia reports the highest rate of human MERS-CoV infection and has one of the largest populations of dromedary camels worldwide, their spatial association has not yet been investigated. Thus, this study aimed to examine the correlation between the spatial distribution of primary MERS-CoV cases with or without a history of camel exposure reported between 2012 and 2019 and dromedary camels at the provincial level in Saudi Arabia. In most provinces, a high proportion of older men develop infections after exposure to camels. Primary human infections during spring and winter were highest in provinces characterized by seasonal breeding and calving, increased camel mobilization and camel-human interactions. A strong and significant association was found between the total number of dromedary camels and the numbers of primary camel-exposed and non-exposed MERS-CoV cases. Furthermore, spatial correlations between MERS-CoV cases and camel sex, age and dairy status were significant. Via a cluster analysis, we identified Riyadh, Makkah and Eastern provinces as having the most primary MERS-CoV cases and the highest number of camels. Transmission of MERS-CoV from camels to humans occurs in most primary cases, but there is still a high proportion of primary infections with an ambiguous link to camels. The results from this study include significant correlations between primary MERS-CoV cases and camel populations in all provinces, regardless of camel exposure history. This supports the hypothesis of the role of an asymptomatic human carrier or, less likely, an unknown animal host that has direct contact with both infected camels and humans. In this study, we performed a preliminary risk assessment of prioritization measures to control the transmission of infection from camels to humans.


The significance of calcified fibrocartilage on the cortical endplate of the translational sheep spine model.
To gain an understanding of the vertebral cortical endplate and factors that may affect the ability to achieve skeletal attachment to intervertebral implants and fusion, this study aimed to characterize the hypermineralized tissue on the cortical endplate of the vertebral body on a commonly used animal model. Skeletally mature sheep were injected with tetracycline prior to euthanasia and the C2-C3, T5-T6, and L2-L3 spinal motion segments were excised and prepared. Vertebral tissues were imaged using backscatter electron (BSE) imaging, histology, and tetracycline labeling was used to assess bone remodeling within different tissue layers. It was determined that the hypermineralized tissue layer was calcified fibrocartilage (CFC). No tetracycline labels were identified in the CFC layer, in contrast to single and double labels that were present in the underlying bone, indicating the CFC present on the cortical endplate was not being actively remodeled. The average thickness of the CFC layer was 146.3 ± 70.53 µm in the cervical region, 98.2 ± 40.29 µm in the thoracic region, and 150.89 ± 69.25 µm in the lumbar region. This difference in thickness may be attributed to the regional biomechanical properties of the spine. Results from this investigation indicate the presence of a nonremodeling tissue on the cortical endplate of the vertebral body in sheep spines, which attaches the intervertebral disc to the vertebrae. This tissue, if not removed, would likely prevent successful bony attachment to an intervertebral device in spinal fusion studies and total disc replacement surgeries.


Exploring the impact of out-of-pocket costs on the quality of life of Canadian cancer patients.
To explore cancer patients' perspective about the impact of financial burden on quality of life. A qualitative descriptive approach was utilized. In-depth interview transcripts from 14 survivors were subjected to a thematic analysis. All participants experienced reduced income and increased out-of-pocket costs following their diagnosis. None worked during their treatment interval. They described profound impacts on the social, psychological, and spiritual domains of quality of life from the financial challenges. Many were worried about having sufficient funds to support themselves in the long term and felt this added to the burden they were carrying. Most found the financial challenges surprising and unexpected. Additionally, the impact was also experienced by their family members. Healthcare providers ought to be aware of the potential impact financial challenges can have and the distress they bring about. A discussion about financial concerns needs to occur at the beginning of the cancer journey, with appropriate resources made available, and monitored regularly.


Insights into current bio-processes and future perspectives of carbon-neutral treatment of industrial organic wastewater: A critical review.
With the rise of the concept of carbon neutrality, the current wastewater treatment process of industrial organic wastewater is moving towards the goal of energy conservation and carbon emission reduction. The advantages of anaerobic digestion (AD) processes in industrial organic wastewater treatment for bio-energy recovery, which is in line with the concept of carbon neutrality. This study summarized the significance and advantages of the state-of-the-art AD processes were reviewed in detail. The application of expanded granular sludge bed (EGSB) reactors and anaerobic membrane bioreactor (AnMBR) were particularly introduced for the effective treatment of industrial organic wastewater treatment due to its remarkable prospect of engineering application for the high-strength wastewater. This study also looks forward to the optimization of the AD processes through the enhancement strategies of micro-aeration pretreatment, acidic-alkaline pretreatment, co-digestion, and biochar addition to improve the stability of the AD system and energy recovery from of industrial organic wastewater. The integration of anaerobic ammonia oxidation (Anammox) with the AD processes for the post-treatment of nitrogenous pollutants for the industrial organic wastewater is also introduced as a feasible carbon-neutral process. The combination of AnMBR and Anammox is highly recommended as a promising carbon-neutral process for the removal of both organic and inorganic pollutants from the industrial organic wastewater for future perspective. It is also suggested that the AD processes combined with biological hydrogen production, microalgae culture, bioelectrochemical technology and other bio-processes are suitable for the low-carbon treatment of industrial organic wastewater with the concept of carbon neutrality in future.


Cardiac function is preserved following 4 weeks of voluntary wheel running in a rodent model of chronic kidney disease.
The purpose of this investigation was to determine the effect of 4 wk of voluntary wheel running on cardiac performance in the 5/6 ablation-infarction (AI) rat model of chronic kidney disease (CKD). We hypothesized that voluntary wheel running would be effective in preserving cardiac function in AI. Male Sprague-Dawley rats were divided into three study groups: 1) sham, sedentary nondiseased control; 2) AI-SED, sedentary AI; and 3) AI-WR, wheel-running AI. Animals were maintained over a total period of 8 wk following AI and sham surgery. The 8-wk period included 4 wk of disease development followed by a 4-wk voluntary wheel-running intervention/sedentary control period. Cardiac performance was assessed using an isolated working heart preparation. Left ventricular (LV) tissue was used for biochemical tissue analysis. In addition, soleus muscle citrate synthase activity was measured. AI-WR rats performed a low volume of exercise, running an average of 13 ± 2 km, which resulted in citrate synthase activity not different from that in sham animals. Isolated AI-SED hearts demonstrated impaired cardiac performance at baseline and in response to preload/afterload manipulations. Conversely, cardiac function was preserved in AI-WR vs. sham hearts. LV nitrite + nitrate and expression of LV nitric oxide (NO) synthase isoforms 2 and 3 in AI-WR were not different from those of sham rats. In addition, LV H2O2 in AI-WR was similar to that of sham and associated with increased expression of LV superoxide-dismutase-2 and glutathione peroxidase-1/2. The findings of the current study suggest that a low-volume exercise intervention is sufficient to maintain cardiac performance in rats with CKD, potentially through a mechanism related to improved redox homeostasis and increased NO.


Effect of clustering on ellipsometric spectra of randomly distributed gold nanoparticles on a substrate.
We present a theoretical model for describing light scattering from randomly distributed Au nanoparticles on a substrate, including the clustering effect. By using the finite-element Green's function method and spherical harmonic basis functions, we are able to calculate the polarization-dependent reflectivity spectra of the system (modeled by randomly distributed nanoparticles coupled with clusters) efficiently and accurately. The calculated ellipsometric spectra of the system with clusters can adequately describe the experimental data for the whole frequency range. We find that the clustering effect leads to some prominent features in the low frequency range of the ellipsometric spectra, which are attributed to plasmonic resonances associated with the coupling of Au nanoparticles and clusters.


The diagnostic approach to monogenic very early onset inflammatory bowel disease.
Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.


Epidemiology of acute kidney injury in Canadian critical care units: a prospective cohort study.
We undertook this study to characterize the epidemiology of acute kidney injury (AKI) in Canadian critical care units. We aimed to identify predictors of mortality for patients diagnosed with AKI. We conducted a prospective cohort study of consecutive patients admitted to critical care units at five Canadian hospitals over a 30-day period. Each patient was followed until hospital discharge or for a maximum of 30 days. The serum creatinine criteria for the Acute Kidney Injury Network (AKIN-SCr) system were used to identify, classify, and characterize patients who developed AKI. We used multivariable logistic regression to predict 30-day mortality among patients with AKI. We identified 603 patients, 161 (26.7%) of whom developed AKI. Compared to patients without AKI, those with AKI were more likely to die (29.2% vs 8.6%, P < 0.001). The risk of death increased with increasing AKIN-SCr stage (P < 0.001). In all, 19 patients (11.8% of those with AKI) commenced dialysis a median of one day (interquartile range, one to two days) after AKI diagnosis. At AKI diagnosis, the blood urea nitrogen (BUN) level (adjusted odds ratio [OR] 1.68, 95% confidence interval [CI] 1.01 to 2.79/10 mmol·L(-1)) and serum bicarbonate (adjusted OR 0.88, 95% CI 0.81 to 0.95/1 mmol·L(-1)) were associated with 30-day mortality and predicted death with an area under the receiver-operating characteristic curve of 0.79 (95% CI 0.71 to 0.86). Acute kidney injury is a common complication of critical illness in Canada. The development of even the mildest stage of AKI is associated with a substantially higher risk of death. At AKI diagnosis, routine clinical data may be helpful for predicting adverse outcomes.


Indirect pulp therapy and stepwise excavation.
Various treatment concepts have been suggested to solve the deep carious lesion dilemma. Recent systematic reviews are presented. Their conclusions are based on very few studies, and the main message is that optimal randomized clinical studies are lacking. Observational studies on indirect pulp treatment and stepwise excavation demonstrate that these treatments avoid pulp exposures, but it cannot be said which approach is best. A less invasive modified stepwise excavation approach is described, focusing on changing an active lesion into an arrested lesion even without performing an excavation close to the pulp. In Denmark and Sweden a randomized clinical multi-center trial is currently taking place, the Caries and Pulp (CAP) trial. This trial is investigating the effects of stepwise excavation over 2 visits versus 1 complete excavation of deep caries in permanent teeth. Guidelines for treatment are presented.


High grade urothelial carcinoma in kidney transplant patients with a history of BK viremia - Just a coincidence?
Kidney transplant recipients (KTR) have a three-to-four-fold increased risk of developing urothelial carcinoma (UC) compared to the general population. BK polyoma virus (BKV) infection is known to affect approximately 15% of KTR. In vitro models support a potential pathogenic role for BKV in the development of UC. We describe a series of UC in kidney transplant recipients. Electronic patient records were searched to identify KTR with UC who had undergone kidney only or simultaneous kidney and pancreas transplantation in a single UK center between 2009 and 2015. Where available, stored pathological samples were retrieved, re-examined and stained for SV40 as a marker of BKV using standard staining protocols for kidney biopsy samples. Fourteen KTR had developed UC post-transplant. Of these, 10 KTR had a history of BKV infection post-transplant. Six of these 10 KTR developed a rare micropapillary tumor subtype of UC which is typically only found in <1% of UC cases. All six micropapillary tumor samples stained positive for SV40, including samples from metastases. Three tumor samples were available from the four KTR with no history of BKV infection and were not micropapillary subtype and were negative for SV40. Three micropapillary tumors from immunocompetent patients were examined as controls and were negative for SV40. These findings would support a pathogenic role for BK virus in the development of rare micropapillary subtype urothelial tumors in the kidney transplant population.


Vision-Guided Attention-Enhanced Network for Predicting Microvascular Invasion in Hepatocellular Carcinoma.
As the most common malignant tumor worldwide, hepatocellular carcinoma (HCC) has a high rate of death and recurrence, and microvascular invasion (MVI) is considered to be an independent risk factor affecting its early recurrence and poor survival rate. Accurate preoperative prediction of MVI is of great significance for the formulation of individualized treatment plans and long-term prognosis assessment for HCC patients. However, as the mechanism of MVI is still unclear, existing studies use deep learning methods to directly train CT or MR images, with limited predictive performance and lack of explanation. We map the pathological "7-point" baseline sampling method used to confirm the diagnosis of MVI onto MR images, propose a vision-guided attention-enhanced network to improve the prediction performance of MVI, and validate the prediction on the corresponding pathological images reliability of the results. Specifically, we design a learnable online class activation map (CAM) to guide the network to focus on high-incidence regions of MVI guided by an extended tumor mask. Further, an attention-enhanced module is proposed to force the network to learn image regions that can explain the MVI results. The generated attention maps capture long-distance dependencies and can be used as spatial priors for MVI to promote the learning of vision-guided module. The experimental results on the constructed multi-center dataset show that the proposed algorithm achieves the state-of-the-art compared to other models.


Electric Nutrition: The Surprising Health and Healing Benefits of Biological Grounding (Earthing).
Context • Modern biomedicine has discovered that many of the most debilitating diseases, as well as the aging process itself, are caused by or associated with chronic inflammation and oxidative stress. Emerging research has revealed that direct physical contact with the surface of the planet generates a kind of electric nutrition, with surprisingly potent and rapid anti-inflammatory and antioxidant effects. Objectives • The objective of this study was to explain the potential of grounding to clinicians as a simple strategy for prevention, therapy, and improving patient outcomes. The research summarized here has pursued the goal of determining the physiological and clinical significance of biological grounding. Design • The research team has summarized more than 12 peer-reviewed reports. Where appropriate, blinded studies examined in this paper were conducted using a variety of statistical procedures. Interventions • In all cases, the intervention examined conductive contact between the surface of Earth and the study's participants, using conductive bed sheets, floor or desk pads, and electrode patches, such as those used in electrocardiography. Results • All studies discussed revealed significant physiological or clinical outcomes as a result of grounding. Conclusion • This body of research has demonstrated the potential of grounding to be a simple, natural, and accessible clinical strategy against the global epidemic of noncommunicable, degenerative, inflammatory-related diseases.


cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity.
cDNA microarray analysis of the regions of pathologically proven different activity of multiple sclerosis lesions was performed. Major differences in gene expression (DGE) occurred between the lesion margin and lesion centre in active lesions studied (57 and 69 genes differentially expressed, respectively), whereas the margins and centres of silent lesions showed markedly reduced heterogeneity (only 11 and two genes differentially expressed, respectively). To compare differences between chronic active and silent lesions, we performed DGE comparison of the pooled data from both types of lesions. The major DGE occurred at the lesion margin, 156 (26; 5%), the greater number representing upregulated genes at the margin of active lesions (15%). Fourteen genes were found to be significantly upregulated in marginal versus central zones in active lesions examined. These genes comprised predominantly inflammation/immune-related factors. We also performed DGE analysis of pooled genes upregulated at the margin of active lesions and found that among the 50 genes showing differences, nine out of 14 were identified in the previous analysis of overlapping differentially expressed genes. Thus this microarray analysis has identified a novel set of genes associated with lesion activity in multiple sclerosis, many of them not previously linked with the disease.


The purity of allergenic extracts.
The purity of allergenic extracts is usually taken for granted but we know that trace amounts of impurities may be the most important determinant causing clinical symptoms. We know that many commercial extracts are grossly contaminated with other allergens and this is easy to demonstrate by skin tests. Horse or dog scurf collected in the summer months will be contaminated by pollens. Patients can be shown to have organ specific inhalant allergic complaints due to one animal. Sometimes the allergenicity is at first only towards an antigen in the saliva, then skin antigen(s) and finally all organs of the body may cause allergic symptoms, so that urinary protein as well as serum albumin cause reactions to the patients. When collecting individual pollens, it is very difficult not to get these contaminated by other pollens. Named grass pollens will be contaminated by other grass pollens and fungal spores which are airborne at the same time. An extract which has been labelled plantain pollen will often be contaminated by 1% or more of grass pollen. A tree pollen such as Tilia is always grossly contaminated with other pollens. A mite extract has in it fish, human serum albumin from skin scales or horse, depending on the culture media used for feeding the mites. Animal scurf extracts are nearly always contaminated with mites. We can conclude that allergenic extracts are difficult to produce immunologically pure and they are often grossly contaminated.


Podiatric manifestations in patients with acute and chronic neurologic disorders.
It is impossible to delineate, in the short space provided, the entire spectra of possible and potential podiatric manifestations of acute and chronic neurologic disease. An attempt has been made to delineate the neuroanatomic, neurophysiologic, etiologic, and diagnostic procedural knowledge required to fully comprehend, evaluate, and manage neurologic complaints in presenting patients. By following a specific outline for evaluation, a functional and meaningful differential diagnosis can be formulated. By properly employing the ancillary procedures discussed, a correct diagnosis will be attained. Concurrently, at this point in evaluation, a grasp of the location and gravity of the discovered lesion will allow us to intelligently treat or refer the patient for proper management. Since the vast majority of neurologic manifestations involve and cross-effect several bodily systems, not all neurologic diagnoses are or will be easy. Only through a constant awareness of the mechanisms, symptomatology, clinical findings, and a careful, precise, and thorough neurologic evaluation and test selection will these patients be helped.


Gingival transcriptomics of follicular T cell footprints in progressing periodontitis.
Follicular helper T cells (Tfh) cells have been identified in the circulation and in tertiary lymphoid structures in chronic inflammation. Gingival tissues with periodontitis reflect chronic inflammation, so genomic footprints of Tfh cells should occur in these tissues and may differ related to aging effects. Macaca mulatta were used in a ligature-induced periodontitis model [adult group (aged 12-23 years); young group (aged 3-7 years)]. Gingival tissue and subgingival microbiome samples were obtained at matched healthy ligature-induced disease and clinical resolution sites. Microarray analysis examined Tfh genes (n = 54) related to microbiome characteristics documented using 16S MiSeq. An increase in the major transcription factor of Tfh cells, BCL6, was found with disease in both adult and young animals, while master transcription markers of other T cell subsets were either decreased or showed minimal change. Multiple Tfh-related genes, including surface receptors and transcription factors, were also significantly increased during disease. Specific microbiome patterns were significantly associated with profiles indicative of an increased presence/function of Tfh cells. Importantly, unique microbial complexes showed distinctive patterns of interaction with Tfh genes differing in health and disease and with the age of the animals. An increase in Tfh cell responsiveness occurred in the progression of periodontitis, affected by age and related to specific microbial complexes in the oral microbiome. The capacity of gingival Tfh cells to contribute to localized B cell activation and active antibody responses, including affinity maturation, may be critical for controlling periodontal lesions and contributing to limiting and/or resolving the lesions.


Cyclical vomiting syndrome: Recognition, assessment and management.
Cyclical vomiting syndrome (CVS) is a functional, debilitating disorder of childhood frequently leading to hospitalization. Affected children usually experience a stereotypical pattern of vomiting though it may vary between different individuals. The vomiting is intense often bilious, and accompanied by disabling nausea. Identifiable precipitating factors for CVS include psychosocial stressors, infections, lack of sleep and occasionally even food triggers. Often, it may be difficult to distinguish episodes of CVS from other causes of acute abdomen and altered consciousness. Thus, the diagnosis of CVS remains largely one of exclusion. Investigations routinely done during the work-up of a child with suspected CVS include both blood and imaging modalities. Plasma lactate, ammonia, amino acid and acylcarnitine profiles as well as urine organic acid profile are indicated to exclude inborn errors of metabolism. The treatment remains challenging and targeted at prevention or shortening of the attacks and can be considered as abortive, supportive and prophylactic. Use of non-pharmacological therapy is also part of the management of CVS. The prognosis of CVS is variable. More insight into the pathogenesis of this disorder as well as role of non-pharmacological therapy is needed.


Phytic acid effect on periodontal ligament fibroblast: An in-vitro study.
This study evaluated phytic acid (IP6) effect on the viability, alkaline phosphatase (ALP) activity and calcium release of human periodontal ligament (HPDL) cells in optimal (OGL) and elevated glucose level (EGL) in cell culture media. Cells were seeded in OGL (1000mg/L) or EGL (4500 mg/L) media. IP6 was added at 0.005%, 0.01% or 0.02% concentrations for 24 or 48h, and XTT assay was performed. Cell differentiation and calcium release in presence of 0.02% IP6 in OGL or EGL in non-osteogenic or osteogenic media were analyzed using ALP assay and alizarin red staining, respectively. In OGL, IP6 enhanced the viability of the cells at both exposure times (P<0.05). However, IP6 lowered the viability of the cells with the presence of EGL compared to the control at both exposure times, except for 0.02% IP6 which showed comparable viability to the control at 48 h. In OGL and EGL, ALP activity of the cells was not affected by the presence of IP6 in non-osteogenic media; however, in osteogenic media IP6 lowered the ALP activity. Meanwhile, calcium release was the highest with IP6 within osteogenic media of EGL. IP6 effects on the HPDL cells were dependent on IP6 concentration, time of exposure, glucose levels and the osteogenic condition of the media. This study gives insights on the potential therapeutic effect of IP6 as adjunctive periodontal therapy in patients with diabetes.


Characterization of inhibition of the spinal nociceptive tail-flick reflex in the rat from the medullary lateral reticular nucleus.
Inhibition of the spinal nociceptive tail-flick (TF) reflex by focal electrical stimulation in the caudal medulla was examined and characterized in lightly pentobarbital-anesthetized rats. Systematic mapping studies revealed that inhibition of the TF reflex was produced at low intensities of stimulation (12.5-25 microA) only from the lateral reticular nucleus (LRN). Areas dorsal and medial to the LRN required higher intensities of stimulation to produce descending inhibition of the TF reflex, likely reflecting spread of current to the LRN at these higher intensities of stimulation (50-100 microA). At threshold inhibitory intensities of stimulation in the LRN, changes in blood pressure were not produced. Strength-duration characterization of stimulation and the microinjection of glutamate into the LRN at the same site where focal electrical stimulation was effective suggest that the descending inhibition produced arises from activation of cell bodies in the LRN. The intrathecal administration of a variety of pharmacological antagonists revealed the descending inhibition produced by stimulation in the LRN to be mediated at least in part by spinal alpha 2-adrenoceptors. These findings, together with previous observations, suggest a role for the LRN in the centrifugal modulation of spinal nociceptive transmission.