Chronic granulomatous dermatitis induced by talimogene laherparepvec therapy of melanoma metastases.
Talimogene laherparepvec (TVEC) is the first oncolytic viral immunotherapy approved by the FDA, for advanced melanoma consisting of genetically modified herpes simplex type 1 virus which selectively replicates causing tumor lysis, expressing granulocyte macrophage-colony stimulating factor (GM-CSF) and activating dendritic cells. Intratumoral injection of TVEC produces objective response in 41% of stage IIB-IV M1a melanoma. However, clinical response assessment can be problematic due to immune-related inflammation at established tumor sites. Herein, we report 5 cases of granulomatous dermatitis developing at sites of TVEC injection associated with pathologic complete response in 4 of 5 patients. Over 5 months, TVEC injections were administrated in a median of 20 tumors per patient for 9 median doses prior to biopsy of persistent, indurated nodules. Granulomatous dermatitis with melanophages and melanin pigment incontinence was observed in all samples without evidence of melanoma cells in 4 patients. The fifth patient was rendered melanoma-free by resection of the 1 nodule out of 4 with persistent tumor. Repetitive administration of TVEC or other oncolytic viral immunotherapies mimicking unresolved infection can produce granulomatous inflammation confounding assessment of the degree of tumor response and need for additional TVEC therapy. Tumor biopsies are encouraged after 4 to 6 months of TVEC administration to differentiate melanoma from granulomatous inflammation. Patients with confirmed granulomatous dermatitis replace continued with remained in remission after treatment discontinuation. Inflammatory nodules typically regress spontaneously.


[Primary intradural extramedullary tumors treated at the National Institute of Rehabilitation (Mexico)].
Spine tumors are uncommon injuries affecting a low percentage of the population; however, these tumors can cause significant morbidity and may be related to mortality. They represent 15% of craniospinal tumors. The objective of this study is to determine the frequency of intradural extramedullary spine tumors treated in our Service and to report the definitive histopathological diagnosis. This was a retrospective study in a series of patients treated surgically with a diagnosis of intradural extramedullary tumor in the Spine Service of the National Rehabilitation Institute (Mexico) from 1996 to 2006. The following variables were evaluated: gender, age, tumor localization, symptomatology and type of tumor. Files of 27 patients were reviewed. There were 11 men and 16 women with an average age of 47.33 years. The main symptoms were pain and motor weakness. The most frequent localization was thoracic followed by lumbar. Histopathological diagnosis reported 12 cases of meningioma, 12 cases of schwannoma and 3 cases of neurofibroma. Symptomatology, localization and gender predominance are similar to that reported in the literature. Different from other series, schwannomas and meningiomas were the most frequent tumors in our study. Appropriate diagnosis and opportune treatment consisting of total resection with laminoplasty are crucial in order to avoid permanent neurological consequences.


An efficient forward solver in electrical impedance tomography by spectral element method.
In electrical impedance tomography (EIT), a forward solver capable of predicting the voltages on electrodes for a given conductivity distribution is essential for reconstruction. The EIT forward solver is normally based on the conventional finite element method (FEM). One of the major problems of three-dimensional (3-D) EIT is its high demand in computing power and memory since high precision is required for obtaining a small secondary field which is typical for a small anomaly. This accuracy requirement is also set by the level of noise in the real data; although currently the noise level is still an issue, future EIT systems should significantly reduce the noise level to be capable of detecting very small anomalies. To accurately simulate the forward solution with the FEM, a mesh with large number of nodes and elements is usually needed. To overcome this problem, we proposed the spectral element method (SEM) for EIT forward problem. With the introduction of SEM, a smaller number of nodes and hence less computational time and memory are needed to achieve the same or better accuracy in the forward solution than the FEM. Numerical results demonstrate the efficiency of the SEM in 3-D EIT simulation.


Analysis of ASB10 variants in open angle glaucoma.
Glaucoma is a common cause of visual disability and affects ∼1.6% of individuals over 40 years of age ( 1). Non-synonymous coding sequence variations in the ankyrin repeat and SOCS box containing gene 10 (ASB10) were recently associated with 6.0% of cases of primary open angle glaucoma (POAG) in patients from Oregon and Germany. We tested a cohort of POAG patients (n= 158) and normal control subjects (n= 82), both from Iowa, for ASB10 mutations. Our study had 80% power to detect a 4.9% mutation frequency in POAG patients. A total of 11 non-synonymous coding sequence mutations were detected in the cohort, but no association with POAG was detected when analyzed individually or as a group (P > 0.05). Furthermore, a survey of the National Heart, Lung, and Blood Institute's (NHLBI's) Exome Sequencing Project revealed that non-synonymous ASB10 mutations are present in the general population at a far higher frequency than the prevalence of POAG. These data suggest that non-synonymous mutations in ASB10 do not cause Mendelian forms of POAG.


Lower radiation burden in state of the art fluoroscopic cystography compared to direct isotope cystography in children.
Both, fluoroscopic voiding cystourethrography (fVCUG) and direct isotope cystography (DIC) are diagnostic tools commonly used in pediatric urology. Both methods can detect vesicoureteral reflux (VUR) with a high sensitivity. Whilst the possibility to depict anatomical details and important structures as for instance the urethra in boys or the detailed calyceal anatomy are advantages of fVCUG, a lower radiation burden is thought to be the main advantage of DIC. In the last decade, however, a rapid technical evolution has occurred in fluoroscopy by implementing digital grid-controlled, variable rate, pulsed acquisition technique. As documented in literature this led to a substantial decrease in radiation burden conferred during fVCUGs. To question the common belief that direct isotope cystography confers less radiation burden compared to state of the art fluoroscopic voiding cystography. Radiation burden of direct isotope cystography in 92 children and in additional 7 children after an adaption of protocol was compared to radiation burden of fluoroscopic voiding cystourethrography in 51. The examinations were performed according to institutional protocols. For calculation of mean effective radiation dose [mSv] for either method published physical models correcting for age and sex were used. For DIC the model published by Stabin et al., 1998 was applied, for fVCUG two different physical models were used (Schultz et al., 1999, Lee et al., 2009). The radiation burden conferred by direct isotope cystography was significantly higher as for fluoroscopic voiding cystourethrography. The mean effective radiation dose for direct isotope cystography accounted to 0.23 mSv (± 0.34 m, median 0.085 mSv) compared to 0.015 mSv (± 0.013, median 0.008 mSv, model by Schultz et al.) - 0.024 mSv (± 0.018, median 0.018 mSv, model by Lee et al.) for fluoroscopic voiding cystourethrography. After a protocol adaption to correct for a longer examination time in DIC that was caused by filling until calculated bladder capacity, mean radiation burden accounted to .07 mSv (median 0.07 mSv) and the values were less scattered. As it had to be expected from literature, radiation dose from fVCUG, if modern image acquisition techniques are used, is even less than from DIC. In our protocol, according to nuclear medicine standards, bladders were filled until calculated capacity. This resulted in a longer examination time for the patients with a higher functional capacity, resulting in relatively higher radiation burden. However, also if the protocol is changed or only the patients with relatively fast bladder emptying are considered, radiation burden conferred by DIC is higher (at least × 2.9, comparing the "worst" case for fVCUG with the "best" case for DIC). Absolute radiation burden conferred by either exam is extremely low compared to other medical radiation exposures as well as to environmental radiation. Consequently it is most probably not relevant for the individual childs future risk for cancer or other radiation damage. However, because of repeated investigations with correspondingly higher radiation burden in this patient group the ALARA (as low as reasonably achievable) principle should lead to a optimized use of fVCUG rather than an uncritical use of DIC, given that modern acquisition standards are available and radiation measurement is performed. Also, fVCUG provides more information concerning anatomical details compared to DIC. Contrary to common beliefs, effective radiation dose conferred during fluoroscopic voiding cystourethrography is significantly lower than during direct isotope cystography. The prerequisite for our findings, however, is the use of modern image acquisition tools and an optimized protocol. Both exams confer low radiation doses probably only relevant to children undergoing repeated radiation exposure. Nevertheless, this findings should be considered in indication for either exam in order to reduce the radiation burden to a minimum whilst optimizing the information yield.


The sympathetic nervous system and pain.
The sympathetic nervous system (SNS) and pain interact on many levels of the neuraxis. In healthy subjects, activation of the SNS in the brain usually suppresses pain mainly by descending inhibition of nociceptive transmission in the spinal cord. Furthermore, some experimental data even suggest that the SNS might control peripheral inflammation and nociceptive activation. However, even subtle changes in pathophysiology can dramatically change the effect of SNS on pain, and vice versa. In the periphery, inflammation or nociceptive activation is enhanced, spinal descending inhibition is reversed to spinal facilitation, and finally the awareness of all these changes will induce anxiety, which furthermore amplifies pain perception, affects pain behavior, and depresses mood. Unraveling the detailed molecular mechanisms of how this interaction of SNS and pain is established in health and disease will help us to treat pain more successfully in the future.


[Genetic variability of the bacterium Ralstonia solanacearum (Burkholderiales: Burholderiaceae) in the banana-growing region of Uraba (Colombia)].
The banana moko disease, caused by the bacterium Ralstonia solanacearum, is one of the most important phytopathological problems of the banana agribusiness in tropical countries. In Uraba and Magdalena (Colombia), the main exporting regions of banana in Colombia, this disease causes a destruction estimated in 16.5 ha/year. The bacterium presents an extremely high level of genetic variation that affects control measures. This is the first study of its variation in Colombia and was done with AFLP molecular markers on a population of 100 isolates from banana plants, soils and "weeds". The high level of genetic diversity, with Nei and Shannon indexes of h=0.32 and I=0.48, respectively, and the AMOVA, showed that this population is subestructured (Fst=0.66): the host is the main factor of differentiation. Even so, previous tests show that all varieties have pathogenicity on Musa.


In vivo irreversible electroporation kidney ablation: experimentally correlated numerical models.
Irreversible electroporation (IRE) ablation uses brief electric pulses to kill a volume of tissue without damaging the structures contraindicated for surgical resection or thermal ablation, including blood vessels and ureters. IRE offers a targeted nephron-sparing approach for treating kidney tumors, but the relevant organ-specific electrical properties and cellular susceptibility to IRE electric pulses remain to be characterized. Here, a pulse protocol of 100 electric pulses, each 100 μs long, is delivered at 1 pulse/s to canine kidneys at three different voltage-to-distance ratios while measuring intrapulse current, completed 6 h before humane euthanasia. Numerical models were correlated with lesions and electrical measurements to determine electrical conductivity behavior and lethal electric field threshold. Three methods for modeling tissue response to the pulses were investigated (static, linear dynamic, and asymmetrical sigmoid dynamic), where the asymmetrical sigmoid dynamic conductivity function most accurately and precisely matched lesion dimensions, with a lethal electric field threshold of 575 ± 67 V/cm for the protocols used. The linear dynamic model also attains accurate predictions with a simpler function. These findings can aid renal IRE treatment planning under varying electrode geometries and pulse strengths. Histology showed a wholly necrotic core lesion at the highest electric fields, surrounded by a transitional perimeter of differential tissue viability dependent on renal structure.


Characterization of a genomic clone for rat seminal vesicle secretory protein IV.
The entire coding region for rat seminal vesicle secretory protein IV was obtained on a 3.5 kb Eco RI fragment isolated from a genomic library in lambda Charon 4A. The coding sequence for SVS IV message is interrupted twice by introns. The first lies just downstream from the juncture of the 21 amino acid secretory signal peptide with the start of the mature protein, and the second lies in the 3'-nontranslated region. The major transcriptional start site was mapped by primer extention and is 22 nucleotides upstream from the translational initiation codon. S1 protection experiments indicated additional minor transcriptional starts about 27 and 50 nucleotides further upstream from the major cap site. The entire transcriptional unit comprises about 1740 nucleotides. The SVS IV gene does not belong to an obvious gene family, and it is conserved in mice and guinea pigs.


Regulation of macrophage motility by the water channel aquaporin-1: crucial role of M0/M2 phenotype switch.
The water channel aquaporin-1 (AQP1) promotes migration of many cell types. Although AQP1 is expressed in macrophages, its potential role in macrophage motility, particularly in relation with phenotype polarization, remains unknown. We here addressed these issues in peritoneal macrophages isolated from AQP1-deficient mice, either undifferentiated (M0) or stimulated with LPS to orientate towards pro-inflammatory phenotype (classical macrophage activation; M1). In non-stimulated macrophages, ablation of AQP1 (like inhibition by HgCl2) increased by 2-3 fold spontaneous migration in a Src/PI3K/Rac-dependent manner. This correlated with cell elongation and formation of lamellipodia/ruffles, resulting in membrane lipid and F4/80 recruitment to the leading edge. This indicated that AQP1 normally suppresses migration of resting macrophages, as opposed to other cell types. Resting Aqp1-/- macrophages exhibited CD206 redistribution into ruffles and increased arginase activity like IL4/IL13 (alternative macrophage activation; M2), indicating a M0-M2 shift. In contrast, upon M1 orientation by LPS in vitro or peritoneal inflammation in vivo, migration of Aqp1-/- macrophages was reduced. Taken together, these data indicate that AQP1 oppositely regulates macrophage migration, depending on stimulation or not by LPS, and that macrophage phenotypic and migratory changes may be regulated independently of external cues.


Discussion of the health benefits of breastfeeding within small groups.
Breastfeeding is as a key target in Sefton as rates fall well below the national average. This paper reports on an evaluation that set out to examine the usefulness of an interactive group session designed to explore the health benefits of breastfeeding. The session used a tool called the Breastfeeding Treasure Box, developed in the US but not previously evaluated. It consists of a box containing 14 items, each chosen to indicate a benefit of breastfeeding, together with a lesson plan. The evaluation was conducted in parentcraft sessions. Five staff with experience of delivering the session completed qualitative questionnaires and 48 clients completed questionnaires about their experiences. Overall, the tool was found to stimulate learning and change thinking about breastfeeding. Staff thought the tool could be used in a range of different situations and, although there was mixed opinion on who should deliver it, knowledge, experience and enthusiasm were seen as essential. Clients said the session was fun, they would recommend it to others and they learned health benefits. There is potential for further development of the tool to reflect the specific health benefits identified by the Baby Friendly Initiative, though messages about breastfeeding benefits would still need reinforcement at all opportunities using other resources.


Vaginal Hysterectomy Suturing Skills Training Model and Curriculum.
Declining vaginal hysterectomy numbers in obstetrics and gynecology training programs highlights the need for innovative methods to teach vaginal surgical skills. We describe our experience with a vaginal hysterectomy skills simulation curriculum. A low-fidelity bench model was constructed to simulate four vaginal hysterectomy suturing tasks. A polyvinyl chloride downspout adapter and low-cost materials simulate the Heaney pedicle stitch, simple pedicle stitch, double ligature, and continuous running stitch. Faculty expert vaginal surgeons established proficiency levels for each task. Resident (N=30) pass rates for tasks 1, 2, and 3 were 1 of 30 (3.3%), 7 of 30 (23.3%), and 4 of 30 (13.3%), respectively, for the left side, and 3 of 30 (10%), 9 of 30 (30%), and 10 of 30 (33.3%), respectively, for the right side. For task 4, the pass rate was 14 of 30 (46.7%). The majority of residents felt that the model simulates the technical skills required for vaginal hysterectomy and agreed that vaginal skills laboratory training would improve their ability to perform procedures in the operating room. Ninety-two percent of residents felt that a vaginal surgery skills curriculum would be a useful addition to their simulation education. A proficiency-based vaginal hysterectomy skills simulation curriculum using a low-fidelity model may be an important training and evaluation tool for vaginal surgical skills training.


Regulation of IL-5 receptor on eosinophil progenitors in allergic inflammation: role of retinoic acid.
We and others have shown that IL-5 plays a central role in eosinophil and basophil differentiation, exerting its effects through the IL-5 receptor (IL-5R). Little is currently known concerning regulation of IL-5Ralpha gene transcription in the context of commitment of hemopoietic progenitor cells to the eosinophil and basophil lineages; recent studies have indicated that IL-5 itself can regulate IL-5Ralpha expression on mature eosinophils. We now provide evidence to indicate that IL-5 can upregulate IL-5Ralpha on bone marrow CD34+ progenitors in vitro, as we have demonstrated in vivo in atopic asthmatics. Given that all-trans retinoic acid (ATRA) is known to modulate some granulopoiesis, causing neutrophilic differentiation, we examined the effects of ATRA on eosinophil/basophil differentiation and IL-5Ralpha expression. In cultures of normal human bone marrow, ATRA selectively suppressed eosinophil/basophil differentiation. Similarly, ATRA inhibited eosinophil/basophil differentiation of cord blood CD34+ cells, while neutrophil differentiation proceeded without impediment. Most importantly, these effects of ATRA on CD34+ cells were associated with selective, dose-dependent inhibition of membrane-bound IL-5Ralpha, upregulation of soluble IL-5Ralpha transcription, but no change in GM-CSF receptor expression. These findings indicate that retinoids can differentially regulate membrane and soluble isoforms of IL-5Ralpha, and that these effects have functional consequences in vitro on eosinophil and basophil differentiation. ATRA may be of therapeutic benefit in allergic inflammatory disorders in which eosinophil differentiation and membrane-bound IL-5R are upregulated.


Interleukin-8 induces the endothelial cell migration through the Rac 1/RhoA-p38MAPK pathway.
Endothelial cell migration is essential for tumor angiogenesis, and interleukin-8 (IL-8) has been shown to play an important role in tumor growth, angiogenesis, and metastasis. The objective of this study was to investigate the molecular mechanism of IL-8 induced endothelial cell migration in vitro. Fluorescence microscope was used to study the distribution of cytoskeleton. The expression of Rac1 and RhoA protein was detected by western blotting. After endothelial cells were transfected by lipofectamine 2000 reagent, the Transwell chamber motility assay was applied to observe the migration of endothelial cells induced by IL-8. The active p38MAPK (mitogen-activated protein kinase) was evaluated by the p38MAPK activation assay. We demonstrated that IL-8 activated cell migration can be impaired by p38MAPK inhibitor, suggesting the participation of p38MAPK in the cell migration. Our results indicated that p38MAPK signaling is required for membrane ruffles, lamellipodia extensions, and actin stress fibers formation induced by IL-8. Furthermore, p38MAPK inhibitor led to increased Rac1 and RhoA expression in IL-8 treated EA.hy926 cells. In addition, IL-8 induced p38MAPK activation was suppressed by dominant-negative mutant for Rac1 and RhoA. Our study demonstrates that IL-8-Rac1/RhoA-p38MAPK signaling pathway plays a vital role in the IL-8-induced endothelial cell migration, and it provides new insight into the molecular mechanisms by which IL-8 contributes to tumor angiogenesis and metastasis.


Applying Restorative Environments in the Home Office While Sheltering-in-Place.
The objective of this review was to spotlight specific methods for people working from home to apply restorative environment research to improve productivity and mental health during shelter-in-place. The COVID-19 pandemic has led to sheltering-in-place and telework. While necessary, these strategies may lead to negative consequences such as social isolation and worse performance. However, nature environments have been shown to have a variety of positive effects in several different settings, including improved attention, positive affect, and increased job satisfaction, and these may be translated to the home workspace setting. This provides a narrative review of the environmental psychology literature, describing articles involving nature in a task performance or stress context and how it has been applied. It then moves on to discuss how these findings could possibly be applied in the context of workers during the COVID-19 pandemic. Although beneficial results are mixed, the review found a variety of relatively simple and cost-effective methods that could assist workers during the COVID-19 pandemic, including taking a break in nature and implementing nature in the workspace. The application of restorative environment research could be an efficient way of mitigating the negative psychological effects due to at-home sheltering and telework in order to combat COVID-19.


NFATc3 contributes to intermittent hypoxia-induced arterial remodeling in mice.
Sleep apnea (SA) is defined as intermittent respiratory arrest during sleep and affects up to 20% of the adult population. SA is also associated with an increased incidence of hypertension and peripheral vascular disease. Exposing rodents to intermittent hypoxia during sleep mimics the cyclical hypoxia/normoxia of SA. We have previously shown that in mice and rats intermittent hypoxia induces ET-1 upregulation and systemic hypertension. Furthermore, intermittent hypoxia (IH) in mice increases nuclear factor of activated T cells isoform 3 (NFATc3) transcriptional activity in aorta and mesenteric arteries, whereas the calcineurin/NFAT inhibitor cyclosporin A prevents IH-induced hypertension. More importantly, NFATc3 knockout (KO) mice do not develop IH-induced hypertension. The goals of this study were to determine the role of NFATc3 in IH-induced arterial remodeling and whether IH-induced NFATc3 activation is mediated by ET-1. Oral administration of both a dual (bosentan) and a selective endothelin receptor type A antagonist (PD155080) during 2 days of IH exposure attenuated NFAT activation in aorta and mesenteric arteries. Rho kinase inhibition with fasudil also prevented IH-induced NFAT activation. Mesenteric artery cross-sectional wall thickness was increased by IH in wild-type (WT) and vehicle-treated mice but not in bosentan-treated and NFATc3 KO mice. The arterial remodeling in mesenteric arteries after IH was characterized by increased expression of the hypertrophic NFATc3 target smooth muscle-alpha-actin in WT but not in KO mice. These results indicate that ET-1 is an upstream activator of NFATc3 during intermittent hypoxia, contributing to the resultant hypertension and increased wall thickness.


Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.
The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage.


Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors.
Cystathionine β-synthase (CBS) is a key enzyme in the production of the signaling molecule hydrogen sulfide, deregulation of which is known to contribute to a range of serious pathological states. Involvement of hydrogen sulfide in pathways of paramount importance for cellular homeostasis renders CBS a promising drug target. An in-house focused library of heteroaromatic compounds was screened for CBS modulators by the methylene blue assay and a pyrazolopyridine derivative with a promising CBS inhibitory potential was discovered. The compound activity was readily comparable to the most potent CBS inhibitor currently known, aminoacetic acid, while a promising specificity over the related cystathionine γ-lyase was identified. To rule out any possibility that the inhibitor may bind the enzyme regulatory domain due to its high structural similarity with cofactor s-adenosylmethionine, differential scanning fluorimetry was employed. A sub-scaffold search guided follow-up screening of related compounds, providing preliminary structure-activity relationships with respect to requisites for efficient CBS inhibition by this group of heterocycles. Subsequently, a hypothesis regarding the exact binding mode of the inhibitor was devised on the basis of the available structure-activity relationships (SAR) and a deep neural networks analysis and further supported by induced-fit docking calculations.


[Molecular mechanisms of Ebola virus reproduction].
The review presents recent data on the molecular mechanisms of the stages of an Ebola virus replication cycle, on the interaction of viral and cellular components at each stage, as well as on the mechanisms responsible for he realization of viral genetic information in the infected cell.


Iron overload in myelodysplastic syndromes: diagnosis and management.
Myelodysplastic syndrome (MDS) is composed of a diverse spectrum of hematopoietic stem cell malignancies characterized by ineffective blood cell production. Many MDS patients are dependent on red blood cell (RBC) transfusions for symptomatic management of refractory anemia. Iron overload ensues when the iron acquired from transfused RBCs exceeds body storage capacity, thereby raising the risk for end organ damage. This is of greatest concern in patients with lower-risk MDS whose expected survival is measured in years. Transfusion dependence is associated with shorter survival and an increased risk for progression to acute myeloid leukemia (AML) in transfusion-dependent patients. Application of recent advances in the treatment of MDS can reduce or eliminate the need for transfusions, thus minimizing the risk of iron overload. Case control studies, prospective surveys, and phase II studies indicate that iron chelation therapy reduces iron load as measured by changes in serum ferritin and may prolong overall survival. Iron chelation strategies include oral agents such as deferasirox (Exjade, Novartis Pharmaceuticals Corp, East Hanover, NJ), deferiprone (Ferriprox, Apotex Europe BV, Leiden, the Netherlands) and, for those patients who are intolerant of or for whom oral therapy is ineffective, parenteral administration of deferoxamine (Desferal, Novartis). This review presents the data related to iron overload in MDS, including its prevalence, diagnosis, clinical impact, and management.


Laparoscopic Adrenalectomy Is Beneficial for the Health-Related Quality of Life of Older Patients with Primary Aldosteronism.
Laparoscopic adrenalectomy (LADX) improves hypertension in patients with primary aldosteronism (PA). However, the antihypertensive impact of LADX appears restricted in older patients with PA. In this study, we evaluated the impact of LADX in older patients focusing on the health-related quality of life (HRQoL). A total of 156 patients with PA who underwent LADX in a single institution were enrolled in this prospective cohort study. The patients were divided into 2 groups, with a boundary of 60 years. The HRQoL was evaluated using the Medical Outcomes Study's 36-Item Short-Form Health Survey version 2 (SF-36v2) questionnaire before and after LADX. Demographics, clinical features, antihypertensive drugs before and after surgery, and perioperative evaluation were recorded. We compared all scale scores and summed scores between groups. Multivariate regression models were used to determine the associations between various covariables and the HRQoL. In the older PA patients, most subscales of HRQoL at baseline were lower than the national standard values. The antihypertensive drug-free rate by LADX was only 21% in older patients, compared to 58% in younger patients. However, a significant improvement in mental HRQoL was observed after LADX (p = 0.002). The much preoperative antihypertensive drugs, lower preoperative potassium level, and smaller degree of comorbidities were predictors of improved mental HRQoL by LADX on multivariate analyses. The older PA patients showed lower mental HRQOL than the national standard populations. Although antihypertensive effects were limited for these patients, LADX was beneficial as PA treatment via improvement of mental HRQoL.


The implant-supported overdenture as an alternative to the complete mandibular denture.
Approximately one-third of Americans older than 65 years of age are fully edentulous, requiring replacement of missing teeth. While the conventional denture may meet the needs of many patients, others require more retention, stability, function and esthetics, especially in the mandible. The implant-supported prosthesis is an alternative to the conventional removable denture. This article describes the strengths of the implant-supported mandibular overdenture. The authors also outline the risks of this approach. They performed a review of recent literature to summarize the reported success rate of implants used to support a mandibular overdenture. The literature review indicates that implants placed in the anterior mandible (anterior to the foramen) have a success rate better than 95 percent. Patients have reported a high degree of satisfaction with the implant-supported overdenture. The literature indicates that implant-supported overdentures in the mandible provide predictable results with improved stability, retention, function and patient satisfaction compared with conventional dentures. Implants placed in the anterior mandible have a success rate equal to or greater than 95 percent. When planning treatment for patients with edentulous mandibles, clinicians should consider the implant-supported prosthesis.


Factors influencing participation in worksite wellness programs among minority and underserved populations.
In the United States, employers and employees are increasingly paying a larger portion of the nation's healthcare bill. Preventive measures are being employed by businesses in an effort to contain the escalating costs of employee healthcare. The work site is an ideal setting for health promotion because 130 million Americans are employed and spend one third of their time at work. However, unhealthy workers tend to be the least likely to participate in health promotion activities. Worksite Wellness Programs must be designed to engage segments of the work force with the greatest health needs. Culturally sensitive and appropriate programs must be developed to engage economically challenged minority and other underserved populations.


Molecular cloning and expression of the early auxin-responsive Aux/IAA gene family in Nicotiana tabacum.
Early auxin-regulated tobacco cDNAs, belonging to the Aux/IAA gene family have been isolated by screening of a cDNA library prepared from auxin-treated suspension-grown etiolated seedlings of Nicotiana tabacum. The probes used were either RT-PCR fragments or an insert resulting from mRNA differential display selection. All of them possessed the structural features which characterize the Aux/IAA gene products. The auxin response of three distinct Nt-iaa subclasses has been characterized in terms of kinetics, dose-response and specificity as several plant hormones and chemicals have been tested for their ability to alter Nt-iaa mRNA accumulation. Differences of auxin responses have been observed between the Nt-iaa analysed, revealing significant differences of regulation. The effect of the protein synthesis inhibitor cycloheximide suggested that Nt-iaa2.3, Nt-iaa4.3 and strictly related genes can be classified as primary auxin-responsive genes and Nt-iaa28 as a late one. The steady-state mRNA level of these Nt-iaa has also been determined in organs of tobacco plants.


The use of highly crosslinked polyethylene in total knee arthroplasty.
Advances in polyethylene (PE) in total hip arthroplasty have led to interest and increased use of highly crosslinked PE (HXLPE) in total knee arthroplasty (TKA). Biomechanical data suggest improved wear characteristics for HXLPE inserts over conventional PE in TKA. Short-term results from registry data and few clinical trials are promising. Our aim is to present a review of the history of HXLPEs, the use of HXLPE inserts in TKA, concerns regarding potential mechanical complications, and a thorough review of the available biomechanical and clinical data. Cite this article: Bone Joint J 2017;99-B:996-1002.


Liquefaction necrosis of mitral annular calcification (LNMAC): review of pathology, prevalence, imaging and management: proposed diagnostic imaging criteria with detailed multi-modality and MRI image characterization.
Liquefactive necrosis within a large spheroid zone of mitral annular calcification (LNMAC) is an atypical but increasingly recognized variant of mitral annular calcification (MAC). Proposed MRI, echo, and CT imaging criteria for diagnosis of this unusual disease entity are discussed along with a review of the prognosis, histopathology, and management implications. A comprehensive ECHO, CT, and MRI imaging approach to diagnostic differentiation from other cardiac masses, allowing characterization of the differing components of this unusual lesion is emphasized. Differentiation from surrounding myocardium, and demonstration of peripheral ring type hyperenhancement, or hyperintense signal in the wall of this lesion, seen with specific inversion recovery MRI sequences is presented as a major diagnostic criterion. The relationship of these MRI image findings to underlying pathology is also discussed. An illustrative case vignette is provided for clinical reference.


Novel nanoparticles of cerium-doped zeolitic imidazolate frameworks with dual benefits of antibacterial and anti-inflammatory functions against periodontitis.
Periodontitis is a common bacteria-borne inflammatory disease that can damage the supporting structures of teeth, eventually leading to tooth loss and systemic inflammations. The present study developed novel nanoparticles (ZIF-8:Ce) by doping cerium (Ce) into zeolitic imidazolate framework-8 (ZIF-8) to simultaneously obtain antibacterial and anti-inflammatory capabilities. The objectives of this study were to: (1) develop novel ZIF-8 nanoparticles doped with different Ce/(Ce + Zn) molar ratios of 1%, 5% and 10% to combat periodontitis; (2) investigate the inhibition efficacy of different nanoparticles against biofilms of periodontal pathogens; and (3) evaluate the effects of different ZIF-8:Ce on inflammatory secretion and macrophage polarization in vitro. The results showed that Ce doping at a ratio from 1% to 10% did not compromise the regular and uniform structure of ZIF-8. ZIF-8:Ce possessed a sustained Zn2+ and Ce3+/Ce4+ release and favorable superoxide dismutase/catalase activities without cytotoxicity at a concentration below 30 μg mL-1. ZIF-8 exhibited an excellent anti-biofilm function against periodontal pathogens. Although 10% Ce doping into ZIF-8 slightly reduced the antibacterial effects, the CFU reduction still remained at approximately 2 orders of magnitude. More importantly, ZIF-8:Ce exhibited increasing anti-inflammatory effects with increasing amounts of Ce doping. In addition, ZIF-8:Ce10% exerted much better anti-inflammatory effects by inhibiting pro-inflammatory factor expression via restraining the NF-kB/p65 subunit translocation (p < 0.05). Meanwhile, ZIF-8:Ce10% elevated the polarization of the M2 phenotype of macrophages and promoted anti-inflammatory cytokine secretion. Therefore, the novel ZIF-8:Ce nanoparticles provided a unique insight into the development of effective anti-inflammatory and antibacterial platforms for treating periodontitis.


The pattern of corneal graft rejection.
A series of 160 consecutive penetrating keratoplasties was analysed for patterns of graft rejection. All surgery was performed between January 1981 and December 1987. The incidence of homograft rejection was 34% (54 grafts). The site of the initial rejection episode was analysed. It was found that when grafts with either preexisting vascularisation or loose sutures were removed from our analysis, the site of initial graft rejection was from the superior limbus in one case and from the inferior limbus in 17 cases. In eight others, there was diffuse corneal oedema at initial appearance. We feel that the increased incidence of graft rejection occurring inferiorly is significant and probably relates to the presence of some factor(s) present in the tears. By bathing the inferior corneal surface and, more importantly, the inferior graft-host interface, the risk of rejection occurring at this site is increased.


A 5`-tRNA Derived Fragment NamedtiRNA-Val-CAC-001 Works as a Suppressor in Gastric Cancer.
Gastric cancer (GC) is a common type of gastrointestinal tumor in the world. Transfer RNA (tRNA) derived fragments (tsRNAs) implicate various cancers, but their roles in GC remain unclear. Our study aimed to investigate the potential biological functions and molecular mechanisms of tsRNAs in GC. Differentially expressed tsRNAs were identified using high-throughput sequencing. The expression levels of tsRNAs were validated in 62 paired GC tissues and adjacent normal tissues using RT-qPCR. In vitro functional assays were used to evaluate the influences of tsRNAs on GC cells. The potential mechanisms underlying tsRNAs were explored using bioinformatics analysis,RT-qPCR, RNA immunoprecipitation assays and Western blot. We found that tiRNA-Val-CAC-001 was downregulated in GC tissues and cells, and demonstrated that tiRNA-Val-CAC-001 was a tsRNA sheared from mature tRNA-Val and mainly localized in the cytoplasm. tiRNA-Val-CAC-001 overexpression inhibited metastasis and proliferation but promoted apoptosis of GC cells; nevertheless, tiRNA-Val-CAC-001 knockdown increased metastasis and proliferation and reduced apoptosis (P<0.05). GO and KEGG analyses indicated tiRNA-Val-CAC-001 may exert its effects via Wnt/β-catenin signaling pathway by targeting LRP6. Following experiments showed that tiRNA-Val-CAC-001 could downregulated the protein levels of LRP6 and β-catenin, but up-regulated p-β-catenin, which confirmed the findings in bioinformatics analysis. In conclusion, tiRNA-Val-CAC-001 works as a cancer suppressor in GC by targeting LRP6 via Wnt/β-catenin signaling pathway. tiRNA-Val-CAC-001 may serve as a therapy target and a biomarker of GC in the future. tiRNA-Val-CAC-001 is downregulated in gastric cancer tissues and cell lines, tiRNA-Val-CAC-001 has potential to become a novel diagnostic biomarker in gastric cancer, and tiRNA-Val-CAC-001 regulates gastric cancer cells by targeting LRP6.


Intestinal gas distribution determines abdominal symptoms.
Patients with functional gut disorders manifest poor tolerance to intestinal gas loads but the mechanism of this dysfunction is unknown. Our aims were firstly, to explore the relative importance of the amount of intestinal gas versus its distribution on symptom production, and secondly, to correlate gut motility and perception of gas loads. Fourteen healthy subjects with no gastrointestinal symptoms. In each subject a gas mixture was infused (12 ml/min) either into the jejunum or rectum for one hour during blocked rectal gas outflow, and subsequently gas clearance was measured over one hour of free rectal evacuation. We measured abdominal perception, distension, and gut tone by duodenal and rectal barostats. Similar magnitude of gas retention (720 ml) produced significantly more abdominal symptoms with jejunal compared with rectal infusion (perception score 4.4 (0.4) v 1.5 (0.5), respectively; p<0.01) whereas abdominal distension was similar (15 (2) mm and 14 (1) mm girth increment, respectively). Jejunal gas loads were associated with proximal contraction (by 57 (5)%) and colonic loads with distal relaxation (by 99 (20)%). The volume of gas within the gut determines abdominal distension whereas symptom perception depends on intraluminal gas distribution and possibly also on the gut motor response to gas loads.


Ultra-long Magnetic Nanochains for Highly Efficient Arsenic Removal from Water.
The contamination of drinking water with naturally occurring arsenic is a global health threat. Filters that are packed with adsorbent media with a high affinity for arsenic have been used to de-contaminate water - generally iron or aluminium oxides are favored materials. Recently, nanoparticles have been introduced as adsorbent media due to their superior efficiency compared to their bulk counter-parts. An efficient nanoadsorbent should ideally possess high surface area, be easy to synthesize, and most importantly offer a high arsenic removal capacity. Achieving all the key features in a single step synthesis is an engineering challenge. We have successfully engineered such a material in the form of nanochains synthesized via a one step flame synthesis. The ultra-long γ-Fe2O3 nanochains possess high surface area (151.12 m2 g-1), large saturation magnetization (77.1 emu g-1) that aids in their gas phase self-assembly into long chains in an external magnetic field, along with an extraordinary arsenic removal capacity (162 mg.g-1). A filter made with this material exhibited a relatively low-pressure drop and very little break-through of the iron oxide across the filter.


Multidisciplinary team and team oncology medicine research and development in China.
In the context of transition from "Biomedical Model" to "Biology-Psychology-Society Medical Model", the treatment model of malignant tumors has changed from single-subject treatment to multidisciplinary collaboration treatment led by a Multidisciplinary Team (MDT). On this basis, the concept of "Team Oncology Medicine" strengthens the focus of malignant tumor treatment. This is not only improving cure rate and extending life span, but also paying close attention to patients' actual demands to improve their quality of life. There are many good studies and practices of Multidisciplinary Team and Team Oncology Medicine in the world. China is currently in the exploratory phase of the malignant tumor Multidisciplinary Team treatment model. Many hospitals have investigated and practiced a Multidisciplinary Team treatment model. China is faced with many problems to scientifically construct a malignant tumor treatment model which conforms to national conditions. These conditions include a medical model, a medical care insurance system, public hospitals reform, hospital management approaches, personnel framework, concern with patients' psychosis and psychology, and whether to tell patients their actual condition and how they should express their will, and so on.


Restoration of elbow extension via functional electrical stimulation in individuals with tetraplegia.
Functional electrical stimulation of the triceps is a method of restoring elbow extension to individuals with paralyzed triceps. Eleven arms of individuals with cervical-level spinal cord injuries (SCIs) received a triceps electrode as an addition to a hand-grasp neuroprosthesis. Stimulation was controlled either as part of a preprogrammed pattern or via a switch or an accelerometer that was connected to the neuroprosthesis external controller. The outcome measures were (1) elbow extension moments at different elbow positions, (2) performance in controllable workspace experiments, and (3) comparison to an alternative method of providing elbow extension in these individuals--a posterior deltoid (PD) to triceps tendon transfer. Stimulated elbow extension moments in 11 arms ranged from 0.8 to 13.3 N.m. The stimulated elbow extension moments varied with elbow angle in a manner consistent with the length-tension properties of the triceps. Triceps stimulation provided a significantly stronger elbow extension moment than the PD to triceps tendon transfer. The elbow extension moment generated by the tendon transfer and triceps electrode being activated together was always greater than either method used separately. Stimulation of the long head of the triceps should be avoided in persons with weak shoulder abduction, since the long head adducts the shoulder and limits shoulder function in these cases. Statistically, elbow extension neuroprostheses significantly increased the ability to successfully reach and move an object and significantly decreased the time required to acquire an object while reaching.


Technical advance: potato virus X amplicon-mediated silencing of nuclear genes.
Transgenic expression of a replicating potato virus X (PVX) construct (termed an 'amplicon') reproducibly and consistently activates post-transcriptional gene silencing (PTGS) in every plant. The amplicon-mediated PTGS mechanism can target transiently expressed RNAs that share homology with the amplicon transgene. We show that amplicons can also be used to silence stably integrated transgenes and endogenous genes. Plants expressing both a transgene and an amplicon targeting part of the transgene show low accumulation of the transgene RNA. Similarly, plants expressing an amplicon targeting an endogenous gene show low accumulation of the endogenous RNA and display a mutant phenotype matching a previously characterised mutation. These data demonstrate that PVX amplicons present a novel approach for the consistent activation of PTGS that can be used to specifically target and suppress gene expression in plants.


Visual aids and structured criteria for improving visual inspection and interpretation of single-case designs.
Because behavior analysis is a data-driven process, a critical skill for behavior analysts is accurate visual inspection and interpretation of single-case data. Study 1 was a basic study in which we increased the accuracy of visual inspection methods for A-B designs through two refinements of the split-middle (SM) method called the dual-criteria (DC) and conservative dual-criteria (CDC) methods. The accuracy of these visual inspection methods was compared with one another and with two statistical methods (Allison & Gorman, 1993; Gottman, 1981) using a computer-simulated Monte Carlo study. Results indicated that the DC and CDC methods controlled Type I error rates much better than the SM method and had considerably higher power (to detect real treatment effects) than the two statistical methods. In Study 2, brief verbal and written instructions with modeling were used to train 5 staff members to use the DC method, and in Study 3, these training methods were incorporated into a slide presentation and were used to rapidly (i.e., 15 min) train a large group of individuals (N = 87). Interpretation accuracy increased from a baseline mean of 55% to a treatment mean of 94% in Study 2 and from a baseline mean of 71% to a treatment mean of 95% in Study 3. Thus, Study 1 answered basic questions about the accuracy of several methods of interpreting A-B designs; Study 2 showed how that information could be used to increase the accuracy of human visual inspectors; and Study 3 showed how the training procedures from Study 2 could be modified into a format that would facilitate rapid training of large groups of individuals to interpret single-case designs.


Chlorin, Phthalocyanine, and Porphyrin Types Derivatives in Phototreatment of Cutaneous Manifestations: A Review.
Recent scientific research has shown the use of chlorin, phthalocyanines, and porphyrins derivatives as photosensitizers in photodynamic therapy in the treatment of various pathologies, including some of the major skin diseases. Thus, the main goal of this critical review is to catalog the papers that used these photosensitizers in the treatment of acne vulgaris, psoriasis, papillomavirus infections, cutaneous leishmaniasis, and skin rejuvenation, and to explore the photodynamic therapy mechanisms against these conditions alongside their clinical benefits.


Association between serum cotinine level and prevalence of non-alcoholic fatty liver disease: a cross-sectional study from the Third National Health and Nutrition Examination Survey.
The data on the effect of smoking on non-alcoholic fatty liver disease (NAFLD) has been controversial. The aim of this study was to investigate if an association exists between serum cotinine level (a tobacco biomarker) and NAFLD prevalence in the general US population. We conducted a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III). We included 11,003 adults aged 20-74 years who underwent ultrasonography. Of those, 4036 were identified as having NAFLD and 6967 were recognized as controls. The percentage of current smokers was significantly lower in subjects with NAFLD compared with those in controls (21.5% vs 26.0%, p<0.01). After adjustment for potential confounders, there was no association between current or former smokers with NAFLD. Additionally, no associations were observed between the levels of serum cotinine and NAFLD. No association between serum cotinine levels at each quartile level and NAFLD was observed regardless of smoking status. In this large US population-based study, we did not find an association between NAFLD and self-reported smoking status or measured serum cotinine level.


Adolescents' and Young Adults' Perceptions of Electronic Cigarettes for Smoking Cessation: A Focus Group Study.
Research has shown that adults perceive that electronic cigarettes (e-cigarettes) are effective for smoking cessation, yet little is known about adolescents and young adults' perceptions of e-cigarettes for quitting cigarette smoking. This study describes middle, high school, and college students' beliefs about, and experiences with, e-cigarettes for cigarette smoking cessation. We conducted 18 focus groups (n = 127) with male and female cigarette smokers and nonsmokers in 2 public colleges, 2 high schools, and 1 middle school in Connecticut between November 2012 and April 2013. Participants discussed cigarette smoking cessation in relation to e-cigarettes. Verbatim transcripts were analyzed using thematic analysis. All participants, regardless of age and smoking status, were aware that e-cigarettes could be used for smoking cessation. College and high school participants described different methods of how e-cigarettes could be used for smoking cessation: (a) nicotine reduction followed by cessation; (b) cigarette reduction/dual use; and (c) long-term exclusive e-cigarette use. However, overall, participants did not perceive that e-cigarette use led to successful quitting experiences. Participants described positive attributes (maintenance of smoking actions, "healthier" alternative to cigarettes, and parental approval) and negative attributes (persistence of craving, maintenance of addiction) of e-cigarettes for cessation. Some college students expressed distrust of marketing of e-cigarettes for smoking cessation. Adolescent and young adult smokers and nonsmokers perceive that there are several methods of using e-cigarettes for quitting and are aware of both positive and negative aspects of the product. Future research is needed to determine the role of e-cigarettes for smoking cessation in this population.


Improvement of neuropsychological function in cognitively impaired multiple sclerosis patients treated with natalizumab: a preliminary study.
Treatment with natalizumab has been shown to reduce physical disability in people with multiple sclerosis (MS). However, its effect on neuropsychological dysfunction is not well understood. A single-center, open-label, retrospective study was conducted to evaluate the effect of natalizumab treatment on neuropsychological function in individuals with relapsing-remitting multiple sclerosis (RRMS) who had a measurable neuropsychological deficit prior to natalizumab treatment. A total of 40 MS patients (mean age, 48.5 years; 77.5% female) were evaluated on a neuropsychological battery of nine tests designed for MS patients before and after 6 or more months of treatment with natalizumab. Posttreatment neuropsychological testing results were compared to baseline results. The mean baseline Neuropsychological Impairment Index was 0.49, which improved to 0.41 after treatment (P = .0002) as analyzed using the Wilcoxon signed rank test. The mean Beck Depression Inventory-II (BDI-II) score improved by 2.45 points (P = .001). The mean Expanded Disability Status Scale (EDSS) score improved by 0.30 (P = .02). A total of 52.5% of patients showed neuropsychological improvement, while 30.0% showed no change and 17.5% had worsening. Magnetic resonance imaging showed no changes. The specific prior disease-modifying therapy had no influence on the results for natalizumab effect. The results of this study show that natalizumab can stabilize or improve neuropsychological function in RRMS patients. The improvement was consistent with, but apparently independent of, improvement in depression and physical disability.


Comparison of three injectable anaesthetic techniques in pigs.
Forty-six near-adult pigs (mean age 10 months, mean weight 156 kg) were anaesthetised for laparoscopy. After intramuscular azaperone (1.0 mg/kg) and ketamine (2.5 mg/kg), 14 of the pigs received intravenous etomidate (200 micrograms/kg) and midazolam (100 micrograms/kg) and 17 were given ketamine (2 mg/kg) and midazolam (100 micrograms/kg). The other 15 pigs were anaesthetised with pentobarbitone (15 to 20 mg/kg) without pre-anaesthetic medication. The duration and adequacy of anaesthesia, recovery rate, and seven physiological variables (ECG, heart rate, indirect arterial blood pressure, respiratory rate, minute volume, mean end-tidal carbon dioxide concentration and percentage oxygen saturation of haemoglobin) were compared. Repeated injections were needed in 29 of the 46 cases. Pentobarbitone was the least satisfactory drug because although the haemodynamic variables were greater, it caused more respiratory depression and a higher overall complication rate than the other methods. Apnoea occurred in two pigs, and was fatal in one, and positive pressure ventilation with oxygen was needed in three others. Intubation conditions were poorer and the times to standing, walking and rooting were longer in the pigs anaesthetised with pentobarbitone.


Glycan Binding Profiling of Jacalin-Related Lectins from the Pteria Penguin Pearl Shell.
We determined the primary structures of jacalin-related lectins termed PPL3s (PPL3A, 3B, and 3C, which are dimers consisting of sequence variants α + α, α + β, β + β, respectively) and PPL4, which is heterodimer consisting of α + β subunits, isolated from mantle secretory fluid of Pteria penguin (Mabe) pearl shell. Their carbohydrate-binding properties were analyzed, in addition to that of PPL2A, which was previously reported as a matrix protein. PPL3s and PPL4 shared only 35-50% homology to PPL2A, respectively; they exhibited significantly different carbohydrate-binding specificities based on the multiple glycan binding profiling data sets from frontal affinity chromatography analysis. The carbohydrate-binding specificity of PPL3s was similar to that of PPL2A, except only for Man3Fuc1Xyl1GlcNAc2 oligosaccharide, while PPL4 showed different carbohydrate-binding specificity compared with PPL2A and PPL3s. PPL2A and PPL3s mainly recognize agalactosylated- and galactosylated-type glycans. On the other hand, PPL4 binds to high-mannose-and hybrid-type N-linked glycans but not agalactosylated- and galactosylated-type glycans.


Standardizing measurement of chronic obstructive pulmonary disease exacerbations. Reliability and validity of a patient-reported diary.
Although exacerbations are an important problem in chronic obstructive pulmonary disease (COPD) and a target of intervention, there is no valid, standardized tool for assessing their frequency, severity, and duration. This study tested the properties of the Exacerbations of Chronic Pulmonary Disease Tool (EXACT), a new patient-reported outcome diary. A prospective, two-group, observational study was conducted in patients with COPD. The acute group (n = 222) was enrolled during a clinic visit for exacerbation with follow-up visits on Days 10, 29, and 60. The stable group (n = 188), recruited by telephone or during routine visits, was exacerbation free for at least 60 days. Acute patients completed the diary on Days 1-29 and 60-67; stable patients for 7 days. All patients provided stable-state spirometry and completed the St. George Respiratory Questionnaire-COPD (SGRQ-C). Acute patient assessments included clinician and patient global ratings of exacerbation severity and recovery. Mean age of the sample (n = 410) was 65 (± 10) years; 48% were male; stable FEV₁ was 51% predicted (± 20). Internal consistency (Pearson separation index) for the EXACT was 0.92, 1-week reproducibility (stable patients; intraclass correlation) was 0.77. EXACT scores correlated with SGRQ-C (r = 0.64; P < 0.0001) and differentiated acute and stable patients (P < 0.0001). In acute patients, scores improved over time (P < 0.0001) and differentiated between degrees of clinician-rated exacerbation severity (P < 0.05). EXACT change scores differentiated responders and nonresponders on Day 10, as judged by clinicians or patients (P < 0.0001). Results suggest the EXACT is reliable, valid, and sensitive to change with exacerbation recovery.


[Correlation between chest CT features and clinical characteristics of patients with bronchiectasis].
Objective: To analyze the features of chest CT imaging in adult patients with bronchiectasis and explore its correlation with clinical characteristics. Methods: From January 2010 to December 2017, patients with bronchiectasis diagnosed by chest high-resolution CT (HRCT) and aged at or above 18 years old in 5 general hospitals of Shandong province were included in the study. The correlations between the HRCT imaging features and etiology, clinical manifestations, lung function, sputum culture, prognosis and other characteristics were analyzed. Results: There were 410 bronchiectasis patients included in the study. The chest HRCT imaging of bronchiectasis were divided into three types, including columnar 46.8%, cystic 45.9% and varicose 7.3%, respectively. The HRCT imaging score was [6.0 (4.0, 7.0)]. In addition, the most common etiology of bronchiectasis was idiopathic (262, 69.3%). The proportion of idiopathic bronchiectasis in cystic bronchiectasis patients was significantly higher than that in columnar and varicose bronchiectasis (71.8% vs 58.3%, 50.0%; both P<0.017). Compared with columnar bronchiectasis, patients with cystic bronchiectasis were more likely to suffer from clinical manifestations such as cough, dyspnea, fever and wet rales (P<0.017). Compared with patients with HRCT scores of 1 to 4, patients with scores ≥8 were more likely to suffer from cough, dyspnea, fever, wet rales and clubbing (P<0.017). The proportions of pulmonary ventilatory dysfunction were significantly greater in patients with cystic bronchiectasis and varicose bronchiectasis than columnar bronchiectasis (86.7%, 86.7% vs 51.0%; both P<0.017). The HRCT scores were significantly negatively correlated with pulmonary function (P<0.001). The number of acute exacerbations, hospitalizations, and bronchiectasis severe index scores in patients with cystic bronchiectasis were significantly higher than those with columnar bronchiectasis (P<0.017). There was a significantly positive correlation between HRCT scores and the number of acute exacerbations, hospitalizations and the bronchiectasis severity index scores (P<0.001). The mortality of patients with cystic and varicose bronchiectasis was significantly higher than that of patients with columnar bronchiectasis (9.0%, 10.0% vs 2.1%; both P<0.017). Compared with patients with HRCT scores of 1 to 4, patients with scores ≥8 had a higher mortality rate (15.9% vs 0.9%; P<0.017). Conclusions: There is a correlation between HRCT findings and clinical manifestations in patients with bronchiectasis. The clinical manifestations, lung function and prognosis of patients with cystic bronchiectasis are worse than those of the columnar bronchiectasis; the higher the HRCT scores are, the worse the clinical manifestations, lung function and prognosis of the patients are.


Consequences of violence across the lifespan: Mental health and sleep quality in pregnant women.
Research has demonstrated that exposure to violence and adversity has negative effects on both mental health and biobehavioral outcomes, such as sleep health. Research examining the relationship between past and recent violence exposure and mental health suggests that the effects of childhood adversity are especially pernicious, but to date, no studies have attempted to disentangle the direct, indirect and relative effects of past year versus childhood exposure to violence and adversity on sleep. The objective of the current study was to examine the direct effects of adverse childhood experiences (ACEs) and past year intimate partner violence (IPV) on different aspects of sleep health in pregnant women. A sample of high-risk pregnant women (n = 101) were interviewed. Mediation analysis with bias-corrected, bootstrapped confidence intervals was used to evaluate direct and indirect effects. Findings indicated that while ACEs had significant direct effects on mental health, past year IPV had stronger effects on sleep quality, latency, and efficiency. ACEs did, however, indirectly affect subjective sleep quality via past year psychological IPV. These findings suggest that sleep disturbance may be a regulatory stress response that is most clearly linked to past year violence and trauma. That is, though long-term sleep disturbance may be evident following childhood adversity, it is likely that this relationship is better explained by the role of childhood adversity in predicting adulthood revictimization or due to long-term mental health difficulties associated with early trauma. (PsycINFO Database Record


Genetic and Epigenetic Factors in Gestational Diabetes Mellitus Pathology.
Gestational diabetes (GDM) is the carbohydrate intolerance occurring during pregnancy. The risk factors of GDM include obesity, advanced maternal age, polycystic ovary syndrome, multigravidity, a sedentary lifestyle, and pre-existing hypertension. Additionally, complex genetic and epigenetic processes are also believed to play a crucial role in the development of GDM. In this narrative review, we discuss the role of genetic and epigenetic factors in gestational diabetes mellitus pathogenesis.


Immunoregulation in cutaneous allergy: prevention and control.
The cutaneous surface is exposed to a myriad of encounters with chemicals, allergens and microbes. Nevertheless, it withstands these environmental assaults without overt inflammation. We will discuss the role of T regulatory cells in a situation where this tissue homeostasis fails - cutaneous allergy, in particular contact hypersensitivity. Immune regulation is a complex process that is mediated by many cellular players. T regulatory cells have risen to particular prominence as potent immunosuppressors because their absence results in inflammation including skin allergy. Recent findings revealed that T regulatory cells comprise a heterogeneous group of subpopulations with specialized homing capabilities and suppressor functions. The stability of the T regulatory cell subset in proinflammatory microenvironments is controversially discussed. In addition, it has recently been shown that mechanisms by which T regulatory cells exert their immunosuppressive functions can be adopted by pathogenic effector T cells in certain situations. In cutaneous allergy, immunoregulatory mechanisms are dysfunctional. The cellular players comprise classical T regulatory cells as well as effector T cells with regulatory activities. Understanding their role in skin homeostasis and the mechanisms by which their regulatory functions are abrogated will yield novel therapeutic targets for the treatment of cutaneous allergies.


A compromise phase position for permanent night shift workers: circadian phase after two night shifts with scheduled sleep and light/dark exposure.
Night shift work is associated with a myriad of health and safety risks. Phase-shifting the circadian clock such that it is more aligned with night work and day sleep is one way to attenuate these risks. However, workers will not be satisfied with complete adaptation to night work if it leaves them misaligned during days off. Therefore, the goal of this set of studies is to produce a compromise phase position in which individuals working night shifts delay their circadian clocks to a position that is more compatible with nighttime work and daytime sleep yet is not incompatible with late nighttime sleep on days off. This is the first in the set of studies describing the magnitude of circadian phase delays that occurs on progressively later days within a series of night shifts interspersed with days off. The series will be ended on various days in order to take a "snapshot" of circadian phase. In this set of studies, subjects sleep from 23:00 to 7:00 h for three weeks. Following this baseline period, there is a series of night shifts (23:00 to 07:00 h) and days off. Experimental subjects receive five 15 min intermittent bright light pulses (approximately 3500 lux; approximately 1100 microW/cm2) once per hour during the night shifts, wear sunglasses that attenuate all visible wavelengths--especially short wavelengths ("blue-blockers")--while traveling home after the shifts, and sleep in the dark (08:30-15:30 h) after each night shift. Control subjects remain in typical dim room light (<50 lux) throughout the night shift, wear sunglasses that do not attenuate as much light, and sleep whenever they want after the night shifts. Circadian phase is determined from the circadian rhythm of melatonin collected during a dim light phase assessment at the beginning and end of each study. The sleepiest time of day, approximated by the body temperature minimum (Tmin), is estimated by adding 7 h to the dim light melatonin onset. In this first study, circadian phase was measured after two night shifts and day sleep periods. The Tmin of the experimental subjects (n=11) was 04:24+/-0.8 h (mean+/-SD) at baseline and 7:36+/-1.4 h after the night shifts. Thus, after two night shifts, the Tmin had not yet delayed into the daytime sleep period, which began at 08:30 h. The Tmin of the control subjects (n=12) was 04:00+/-1.2 h at baseline and drifted to 4:36+/-1.4 h after the night shifts. Thus, two night shifts with a practical pattern of intermittent bright light, the wearing of sunglasses on the way home from night shifts, and a regular sleep period early in the daytime, phase delayed the circadian clock toward the desired compromise phase position for permanent night shift workers. Additional night shifts with bright light pulses and daytime sleep in the dark are expected to displace the sleepiest time of day into the daytime sleep period, improving both nighttime alertness and daytime sleep but not precluding adequate sleep on days off.


The effect of body positioning upon maximal oxygenation of patients with unilateral lung pathology.
A quasi-experimental, repeated-measures cross-over design study on the effect of body position on oxygenation (SaO2) blood pressure, respiration and pulse in patients with unilateral lung pathology was conducted. Previous research strongly suggests that positioning with the healthy (unaffected) lung in the dependent lateral (down) position is related to improved oxygenation, but knowledge about whether this effect is maintained over time is lacking. The purpose of this investigation was to determine: (1) Is positioning with the unaffected lung in the dependent lateral position related to increased arterial blood saturation levels and decreased blood pressure, pulse and respiration? (2) What is the relationship between the dependent variables--oxygenation saturation levels, blood pressure, pulse and respiration--and the independent variables--body position and time in the position? Thirty-nine patients with unilateral lung pathology were positioned on their sides with the unaffected lung down, on their sides with the affected lung down, and also in semi-Fowler's position. Arterial (SaO2) blood saturation and vital signs were measured at baseline 0, 15 and 30 minutes. There was no statistically significant relationship between oxygenation level or systolic blood pressure. Diastolic blood pressure, respiration and pulse did vary significantly with position.


Lessons Learned from the Development and Implementation of Two Internet-enhanced Culturally Relevant Physical Activity Interventions for Young Overweight African-American Women.
This research team has designed and implemented 2 culturally relevant, Internet-enhanced physical activity (PA) interventions for overweight/obese African-American female college students. Presumably, these are the only prospectively designed, culturally relevant interventions using the Internet to promote PA among African-American women. Due to the limited research on this topic, the experiences associated the design and implementation of these studies were syntesized and 5 key lessons learned from this research were formulated. Findings provide insight for researchers to consider when developing Internet-based PA promotion interventions for African-American women. Lessons learned included: 1) Elicit and incorporate feedback from the target population throughout development of an Internet-based PA promotion tool; 2) Incorporate new and emerging technologies into Internet-enhanced PA programs; 3) Maintain frequent participant contact and provide frequent incentives to promote participant engagement; 4) Supplement Internet-based efforts with face-to-face interactions; 5) Include diverse images of African-American women and culturally relevant PA-related information in Internet-based PA promotion materials.


Complement evasion factor (CEF), a novel immune evasion factor of Streptococcus pyogenes.
Streptococcus pyogenes, a leading human pathogen, is responsible for a wide range of diseases, including skin and soft tissue infections and severe invasive diseases. S. pyogenes produces a large arsenal of virulence factors, including several immune evasion factors. We have identified an open reading frame (spy0136) in the S. pyogenes SF370 genome encoding a protein of unknown function. Using recombinant Spy0136 in a pull-down assay with human plasma and ELISA, we have identified four complement proteins (C1r, C1s, C3, and C5) as binding partners. Treatment of the complement proteins with PNGase F abrogated binding to C1s, C3, and C5, indicating glycan-dependent interactions. rSpy0136 inhibited complement-mediated hemolysis and interfered with all three complement pathways in a Wieslab complement assay. Furthermore, rSpy0136 inhibited deposition of the C3b opsonin and the membrane attack complex (MAC) on the surface of S. pyogenes. We therefore named the previously unknown protein 'complement evasion factor' (CEF).An S. pyogenes Δspy0136/cef deletion mutant showed decreased virulence in an in-vitro whole blood killing assay and a Galleria mellonella (wax moth) infection model. Furthermore, an L. lactis spy0136/cef gain-of-function mutant showed increased survival during growth in whole human blood. Analysis of serum samples from patients with invasive S. pyogenes revealed Spy0136/CEF sero-conversion indicating expression during disease. In summary, we have identified a novel S. pyogenes immune evasion factor that binds to several complement proteins to interfere with complement function. This is the first example of a S. pyogenes virulence factor binding to several different target proteins via glycan-dependent interactions.


Agonist-promoted coupling of the beta-adrenergic receptor with the guanine nucleotide regulatory protein of the adenylate cyclase system.
Binding of the beta-adrenergic agonist [3H]hydroxybenzylisoproterenol to the beta-adrenergic receptor of rat reticulocyte membranes results in the coupling of the receptor to the guanine nucleotide regulatory protein associated with the adenylate cyclase system. This regulatory component, referred to as the G-protein, was identified by its specific [32P]-ADP-ribosylation catalyzed by cholera toxin. Incubation of [32P]ADP-ribosylated rat reticulocyte membranes with the [3H]hydroxybenzylisoproterenol agonist prior to membrane solubilization and gel exclusion chromatography resulted in the coelution of the 42,000 Mr [32P]ADP-ribosylated G-proteins with the agonist-occupied beta-adrenergic receptors. The receptor-G-protein complex was not formed when receptors were unoccupied or occupied with antagonists at the time of solubilization. Incubation of rat reticulocyte membranes with [3H]hydroxybenzylisoproterenol in the presence of guanine nucleotides reversed or prevented the formation of this receptor-G-protein complex. These data provide direct evidence for the molecular interactions promoted by agonist occupancy of beta-adrenergic receptors. It is probable that the formation of a receptor-G-protein complex is crucial for catecholamine stimulation of the adenylate cyclase enzyme and, hence, transmembrane information transfer.


Randomized clinical trial of four adhesion strategies in cervical lesions: 12-month results.
The aim of this study was to evaluate the 6- and 12-month clinical performance of four adhesion strategies from the same manufacturer (Kerr) in non-carious cervical lesions (NCCLs) using two evaluation criteria. Thirty-five patients, with at least four NCCLs each, participated in this study. After samplesize calculation, 180 restorations were assigned to one of the following groups: OFL (Optibond FL), OSP (Optibond Solo Plus), XTR (Optibond XTR), and AIO (Optibond All-In-One). The composite resin Filtek Supreme Ultra (3M ESPE) was placed incrementally. The restorations were evaluated at baseline, after 6 months, and after 12 months, using both the FDI and the USPHS-modified criteria. Statistical analyses were performed with Friedman repeated measures, ANOVA by rank, and the McNemar test for significance in each pair (α=0.05). Six restorations (2 for OFL, 1 for OSP, 2 for XTR, and 1 for AIO) were lost at 12 months (P>0.05 for both evaluation criteria). Marginal staining was observed in seven restorations using the FDI criteria (P>0.05) and three restorations using the USPHSmodified criteria (P>0.05). Eight restorations (2 for OSP, 3 for XTR, and 3 for AIO) were classified as Bravo for marginal adaptation using the USPHSmodified criteria (P>0.05). However, 62 restorations (14 for OFL, 12 for OSP, 15 for XTR, and 21 for AIO) were classified as Bravo using the FDI criteria (P>0.05). The four adhesion strategies showed similar clinical retention at 6 and 12 months. The FDI evaluation criteria tend to be more sensitive than the USPHS-modified criteria.


Prognostic significance of c-KIT in vulvar cancer: bringing this molecular marker from bench to bedside.
Vulvar carcinomas are rare tumors, and there is limited data regarding molecular alterations. To our knowledge there are no published studies on c-KIT and squamous cell carcinomas of the vulva (VSCC). Although there are a significant number of other tumor types which express c-KIT, there remains controversy as to its relationship to patient outcome. Thus, we wished to investigate such controversial findings to determine the prognostic importance of c-KIT by evaluating its protein and mRNA expression in VSCCs, correlating these findings with clinicopathological features and Human Papillomavirus (HPV) infection. c-KIT expression was scored by immunohistochemistry (IHC) as positive or negative in 139 formalin-fixed paraffin-embedded (FFPE) cases of vulvar carcinomas arrayed in a tissue microarray (TMA) using the DAKO A4502 rabbit polyclonal c-KIT antibody (diluted 1:100). c-KIT mRNA was evaluated by qRT-PCR in 34 frozen samples from AC Camargo Hospital Biobank (17 tumoral and 17 non-tumoral samples) using TaqMan probes-Applied Biosystems [Hs00174029_m1]. HPV genotyping was assessed in 103 samples using Linear Array® HPV Genotyping Test kit (Roche Molecular Diagnostics, Basel, Switzerland). All results obtained were correlated with clinical and pathological data of the patients. c-KIT protein was positive by immunohistochemistry in 70.5% of the cases and this was associated with a higher global survival (p = 0.007), a higher recurrence-free survival (p < 0.0001), an absence of associated lesions (p = 0.001), lymph node metastasis (p = 0.0053), and HPV infection (p = 0.034). Furthermore, c-KIT mRNA quantitation revealed higher levels of transcripts in normal samples compared to tumor samples (p = 0,0009). Our findings indicate that those vulvar tumors staining positively for c-KIT present better prognosis. Thus, positivity of c-KIT as evaluated by IHC may be a good predictor for use of more conservative surgery techniques and lymph node dissection in vulvar cancer. So part of the essence of our study is to see the possibility of translating our current results from the bench to the bedside. This will help provide patients a more appropriate, less mutilating treatment, in order to keep the maximum physical and psychic quality as possible to these women.


Determinants of condom use in female sex workers in Surabaya, Indonesia.
In the developing world condom use among sex workers and their clients plays a dominant role in the transmission of HIV/STD. In Surabaya, Indonesia, data from the 1993 STD prevalence survey in female sex workers (brothels, street, massage parlours, barber shops, call-girl houses, and nightclubs) reveal that only 5% (33/692) of the brothel workers and 14% (25/177) of the street walkers had condoms in their possession at the time of the interview. During the last paid sexual intercourse, sex workers from the brothels, streets, and nightclubs used condoms infrequently (14%, 20%, and 25%, respectively). Sex workers from massage parlours, barber shops, and call girls were about 5 to 3 times more likely to use condoms than sex workers from nightclubs (adjusted odds ratio of 3.5, 4.9, and 4.2, respectively); thus condom promotion programmes should be targeted at sex workers at brothels, streets, and nightclubs. Programmes should include: (1) free distribution of condoms to sex establishments at the initial stage, and condom social marketing at later stages; (2) penalties, including legal sanctions, against any sex establishments that do not consistently use condoms; (3) participation of brothel owners and madams in encouraging sex workers to consistently have clients use condoms during sexual intercourse; and (4) establishment of sentinel surveillance to monitor STD/HIV and condom-use compliance.


Physicochemical stimuli as tuning parameters to modulate the structure and stability of nanostructured lipid carriers and release kinetics of encapsulated antileprosy drugs.
To unveil the effect of electrolyte concentration, pH and polymer addition on Tween 80 stabilized nanostructured lipid carriers (NLCs, based on dialkyldimethylammonium bromides DxDAB and Na oleate), an in-depth scattering analysis was performed. Dynamic and static light scattering (DLS/SLS) and small-angle neutron scattering (SANS) techniques along with zeta potential studies were exploited to understand the structural evolution and physical stability of NLCs. In these experiments, we varied the salt concentration, pH, and the admixture of Pluronic F127 in order to elucidate their effect on NLC morphologies. In most cases, two populations of different sizes are present which differ by one order of magnitude. The antileprosy drugs (ALD) Rifampicin and Dapsone were encapsulated in NLCs and the vector properties were assessed for a series of DxDAB (where x = 12, 14, 16 and 18) NLCs. The influence of composition on the entrapment and release behavior of NLCs was investigated: The size of NLCs correlates with the release rate of the incorporated drug. The interaction of drug-loaded NLCs with bovine serum albumin was studied to understand the release of ALD in the plasma.


[Contribution to investigation of leprosy ocular disease in madagascar (author's transl)].
250 leprous from National Leprosery of Manankavaly (distant of 30 km from Tananarive) were examined. Among them, 31 patients present ocular disease which occur with that of leper isn't accurately known. Conjuntival reactions as prickling, watering of the eyes with inability to assimilate wind light constitute initial symptoms. Cataract is exceptional (only one case); but we point out; first the superiority of "uveal tractus" disease with 32% of rate; then, the frequency of deep of interstitial keratitis (35%). These lesions are and seem to evolute freely in spite of Iper therapeutic and its stabilisation. So cured of leprosy patients two sided may come back because of the increasing of their ocular sickness. Due to lesion of anterior segment, eye fundus is difficult to analyse, but nervous disease may exist on optical papilla, considering the disproportion between the degrees of uveitis and sight alteration. Researching hansen Bacillus and other germs responsible of eye lesions, we sampled secretions of conjonctiva. We haven't anatome-pathological results because of failure of enucleated eye-ball. Leprosy ocular disease invariably end in blindness by eye-ball atrophy.


Taking dietary habits into account: A computational method for modeling food choices that goes beyond price.
Computational models have gained popularity as a predictive tool for assessing proposed policy changes affecting dietary choice. Specifically, they have been used for modeling dietary changes in response to economic interventions, such as price and income changes. Herein, we present a novel addition to this type of model by incorporating habitual behaviors that drive individuals to maintain or conform to prior eating patterns. We examine our method in a simulated case study of food choice behaviors of low-income adults in the US. We use data from several national datasets, including the National Health and Nutrition Examination Survey (NHANES), the US Bureau of Labor Statistics and the USDA, to parameterize our model and develop predictive capabilities in 1) quantifying the influence of prior diet preferences when food budgets are increased and 2) simulating the income elasticities of demand for four food categories. Food budgets can increase because of greater affordability (due to food aid and other nutritional assistance programs), or because of higher income. Our model predictions indicate that low-income adults consume unhealthy diets when they have highly constrained budgets, but that even after budget constraints are relaxed, these unhealthy eating behaviors are maintained. Specifically, diets in this population, before and after changes in food budgets, are characterized by relatively low consumption of fruits and vegetables and high consumption of fat. The model results for income elasticities also show almost no change in consumption of fruit and fat in response to changes in income, which is in agreement with data from the World Bank's International Comparison Program (ICP). Hence, the proposed method can be used in assessing the influences of habitual dietary patterns on the effectiveness of food policies.


Persistent chromosome aberrations in the somatic cells of A-bomb survivors, Hiroshima and Nagasaki.
Current status of knowledge on the radiation-induced chromosome aberrations persisting since their induction in 1945 to date in the somatic cells of A-bomb survivors in Hiroshima and Nagasaki is reviewed. Dose-response relationship for chromosome aberration frequencies observed with the use of the old A-bomb dosimetry system (T65D) is also demonstrable based on the new dosimetry system (DS86). Despite the fact that the remarkable decrease in the amount of neutron component relative to the total dose in Hiroshima, there still exist inter-city differences in aberration frequency per unit dose both for kerma and bone marrow dose; the dose-square term is smaller in Hiroshima than in Nagasaki. The differential contribution of neutron radiation may be responsible in some part for the observed difference between Hiroshima and Nagasaki, although proof still remains to be obtained. There is a wide variability of the frequency of cells with chromosome aberrations between survivors within a given dose range. Random errors in the dose estimates assigned to individual survivors seem responsible, to a large extent, for the observed overdispersions in aberration frequencies in both cities. New molecular biology-oriented techniques to differentially stain specific chromosomes using fluorescence in situ hybridization with chromosome-specific composite DNA probes seem extremely promising for future rapid, accurate and extensive screening of reciprocal translocations observed predominantly in A-bomb survivors. Such data may be utilized to establish a better biological dosimetry system, especially for those persons who are irradiated in vivo many years before cytogenetic examinations.


Review: Synergy between mechanistic modelling and data-driven models for modern animal production systems in the era of big data.
Mechanistic models (MMs) have served as causal pathway analysis and 'decision-support' tools within animal production systems for decades. Such models quantitatively define how a biological system works based on causal relationships and use that cumulative biological knowledge to generate predictions and recommendations (in practice) and generate/evaluate hypotheses (in research). Their limitations revolve around obtaining sufficiently accurate inputs, user training and accuracy/precision of predictions on-farm. The new wave in digitalization technologies may negate some of these challenges. New data-driven (DD) modelling methods such as machine learning (ML) and deep learning (DL) examine patterns in data to produce accurate predictions (forecasting, classification of animals, etc.). The deluge of sensor data and new self-learning modelling techniques may address some of the limitations of traditional MM approaches - access to input data (e.g. sensors) and on-farm calibration. However, most of these new methods lack transparency in the reasoning behind predictions, in contrast to MM that have historically been used to translate knowledge into wisdom. The objective of this paper is to propose means to hybridize these two seemingly divergent methodologies to advance the models we use in animal production systems and support movement towards truly knowledge-based precision agriculture. In order to identify potential niches for models in animal production of the future, a cross-species (dairy, swine and poultry) examination of the current state of the art in MM and new DD methodologies (ML, DL analytics) is undertaken. We hypothesize that there are several ways via which synergy may be achieved to advance both our predictive capabilities and system understanding, being: (1) building and utilizing data streams (e.g. intake, rumination behaviour, rumen sensors, activity sensors, environmental sensors, cameras and near IR) to apply MM in real-time and/or with new resolution and capabilities; (2) hybridization of MM and DD approaches where, for example, a ML framework is augmented by MM-generated parameters or predicted outcomes and (3) hybridization of the MM and DD approaches, where biological bounds are placed on parameters within a MM framework, and the DD system parameterizes the MM for individual animals, farms or other such clusters of data. As animal systems modellers, we should expand our toolbox to explore new DD approaches and big data to find opportunities to increase understanding of biological systems, find new patterns in data and move the field towards intelligent, knowledge-based precision agriculture systems.


Assessment of risks related to medicine dispensing by nonprofessionals in Colombia: clinical case simulations.
Appropriate dispensing is one of the steps for rational drug use, so it is generally advised that the dispenser should have relevant and updated knowledge, skills, and attitudes. To assess pharmacies and nonprofessional employees' (NEs) skills and knowledge, as well as their response to several specific case simulations in Bogota, Colombia. A descriptive cross-sectional study was performed on a random sample of 371 pharmacies in Bogota. Information from each pharmacy was obtained using 2 approaches: (1) direct interview to collect data on organizational aspects of the store and characteristics of NEs, and (2) simulation (both by direct interview and by telephone) to assess dispensing responses in 6 simulated clinical cases. More than half of the simulated clinical situations resulted in inappropriate dispensing (direct simulations 57%; telephone simulations 55%). The proportion of correct answers to theoretical questions regarding a specific therapeutic problem during interviews was higher than the response when a simulation presented that same case and a dispensing act was expected. The educational background of the NEs included in the study points to a specific problem: two-thirds of the individuals selling medicines had completed only secondary-level education and only 2% of the sample had a pharmacist as technical director. Continuing education courses were either directly organized by drug manufacturers (one-third of the courses attended by pharmacists) or sponsored by them (more than an additional one-third). NEs should be considered part of the therapeutic chain and, if appropriately updated or instructed, could play a very important role in the always difficult promotion of rational drug use. Public health institutions and universities should be more actively involved in the provision of independent, unbiased, and essential information on common therapeutic problems, safety concerns, and new drug prescription restrictions.


Stabilizing g-States in Centrosymmetric Tetrapyrroles: Two-Photon-Absorbing Porphyrins with Bright Phosphorescence.
Using time-dependent density functional theory (TDDFT) and sum-overstates (SOS) formalism, we predicted significant stabilization of 2P-active g-states in a compact fully symmetric porphyrin, in which all four pyrrolic fragments are fused with phathalimide residues via the β-carbon positions. The synthesis of a soluble, nonaggregating meso-unsubstituted tetraarylphthalimidoporphyrin (TAPIP) was then developed, and the spectroscopic measurements confirmed that a strongly 2P-active state in this porphyrin is stabilized below the B (Soret) state level. Single-crystal X-ray analysis revealed near-ideally planar geometry of the TAPIP macrocycle, while its tetra-meso-arylated analogue (meso-Ar4TAPIP) was found to be highly saddled. Consistent with these structural features, Pt meso-Ar4TAPIP phosphoresces rather weakly (ϕphos = 0.05 in DMF at 22 °C), while both Pt and Pd complexes of TAPIP are highly phosphorescent (ϕphos = 0.45 and 0.23, respectively). In addition PdTAPIP exhibits non-negligible thermally activated (E-type) delayed fluorescence (ϕfl(d) ∼ 0.012). Taken together, these photophysical properties make metal complexes of meso-unsubstituted tetaarylphthalimidoporphyrins the brightest 2P-absorbing phosphorescent chromophores known to date.


Lessons Learned in Protection of the Public for the Accident at the Fukushima Daiichi Nuclear Power Plant.
What insights can the accident at the Fukushima Daiichi nuclear power plant provide in the reality of decision making on actions to protect the public during a severe reactor and spent fuel pool emergency? In order to answer this question, and with the goal of limiting the consequences of any future emergencies at a nuclear power plant due to severe conditions, this paper presents the main actions taken in response to the emergency in the form of a timeline. The focus of this paper is those insights concerning the progression of an accident due to severe conditions at a light water reactor nuclear power plant that must be understood in order to protect the public.


High-dose naloxone infusions in normals. Dose-dependent behavioral, hormonal, and physiological responses.
Hypotheses of involvement of the endogenous opioid system (EOS) in the regulation of human behavior suggest that functional blockade of the EOS should have behavioral consequences. Clinical administration of the opiate receptor antagonist naloxone hydrochloride, however, has had little or inconsistent behavioral effects in normals. This may be attributable to the use of doses insufficient to yield a complete EOS blockade. To assess this explanation, normals were administered increasing doses of naloxone hydrochloride (0.3 to 4 mg/kg) in a single-blind design. Significant dose-dependent behavioral, hormonal, and physiological effects were found. With increasing doses of naloxone, volunteers demonstrated increasingly dysphoric affects, a deterioration of performance on memory testing, increasing systolic BP and respiratory rate, and increasing plasma cortisol and growth hormone levels. These results are consistent with the expected effects of increasing EOS blockade, and thus suggest that lower doses of naloxone used in previous clinical studies may not have been sufficient to produce a complete EOS blockade. Specifically, they suggest involvement of the EOS in the tonic regulation of normal human mood, memory, BP, respirations, and plasma growth hormone and cortisol levels.


[1995 Berlin social structure atlas--a planning instrument for health and social planning within the scope of administrative reform in Berlin].
Social unequality and social differences of a population can be defined as social structure. The objective of this study is the construction of indices with which an analysis of space-related social disparities from their spacious dimensions can be made. Each dimension has to be described with a multitude of space-related social indicators first, and then identified and calculated with a multivariate statistic procedure (Factor Analysis). With the existing analysis basic dates are provided. This information about the social situation of Berlin districts as well as the resulting political plannings shall contribute to the reduction of existing differences, in particular to the reduction of social disadvantages. In general, decisions regarding allocation on the private as well as on the public sector should be supported by the social structure analysis.