[Attitudes of general practitioners and medical practice assistants towards the delegation of medical services: Results of a survey in Berlin, Brandenburg and Thuringia].
The delegation of tasks and responsibilities from general practitioners (GPs) to medical practice assistants (MPAs) can contribute to ensuring primary care in Germany. The aim of the study was to collect and analyze attitudes and procedures of GPs and MPAs regarding the delegation of physician-related tasks and activities. A self-designed, piloted questionnaire was sent to all GPs listed within the regional Associations of Statutory Health Insurance Physicians (KV) in Thuringia, Berlin, and Brandenburg (n=5,516) and their MPAs. Participants were asked to indicate which physician-related activities were already delegated and on which occasions further delegations could be considered. 890 GPs (response rate: 16.1%) and 566 MPAs participated in the written survey. The participants were predominantly female and most of them worked in urban areas. Numerous activities, such as medical history taking, triage, Disease Management Program (DMP) controls, vaccinations and home visits, have already been delegated. The willingness to delegate further tasks (e. g., follow-up prescriptions and referrals, independent takeover of simple consultations, assessing the necessity of physician consultation) was high. The survey showed a high level of willingness of both occupational groups to delegate physician-related activities to MFAs. An expansion seems possible under certain conditions. Many activities have already been delegated to MPAs in primary care practices. Our survey provides suggestions regarding further tasks suitable for delegation, some of which go beyond the delegation agreement valid in Germany.


In vivo wound healing activity of the methanolic extract and its isolated constituent, gulonic acid gamma-lactone, obtained from Grewia tiliaefolia.
Grewia tiliaefolia is a subtropical tree, its stem bark is widely used in traditional Indian medicines to heal chronic wounds, gastric ulcers, burning sensation, itching and other allergic ailments. Bioassay-directed fractionation and chromatography of the methanolic extract of G. tiliaefolia stem bark has resulted in the isolation of gulonic acid gamma-lactone. The methanolic extract and the isolated constituent were studied for their potency on three different cutaneous wound models, VIZ., excision, incision and dead space wounds in Wistar rats. In the excision wound model, healing was assessed by the rate of wound contraction and period of epithelisation. In the incision wound model, the degree of healing was analysed by determining the skin breaking strength. In the dead space wound model, the parameters used to confirm the healing process were weight of granulation tissue, its tensile strength, hydroxyproline content and histological studies. The extract as well as the constituent demonstrated wound healing activity. Topical application of gulonic acid gamma-lactone (0.2% w/w ointment) caused faster epithelialisation with 94.02% wound contraction on day 16 post-wounding, while in control animals the duration of healing was extended up to 22 days with 79.53% wound contraction. The tensile strength of the incision wound was significantly increased (561.12 +/- 5.18 g) compared to the control (327.63 +/- 6.37 g). In the dead space wound model, a significant increase in weight, tensile strength and hydroxyproline content of the granuloma tissue was observed following oral administration of gulonic acid gamma-lactone (60 mg/kg). Histology of the granuloma tissue showed increased collagenation and the absence of monocytes. The wound healing effect was compared with that of the standard skin ointment nitrofurazone. The results of this investigation provide supportive scientific evidence for the medicinal use of G. tiliaefolia for healing of cutaneous wound.


Neuro-endoscopic management of hemorrhagic moyamoya disease in the acute stage: single institute experience.
Background: Management of hemorrhagic moyamoya disease (MMD) is one of the most challenging issues in neurosurgical practice. Recently, surgical revascularization by superficial temporal artery-middle cerebral artery anastomosis was reported to significantly reduce the risk of re-bleeding in hemorrhagic-onset MMD patients in the chronic state, but the optimal treatment strategy in the acute phase of hemorrhagic MMD is undetermined. Thus, we retrospectively analyzed our surgical results for hemorrhagic MMD in the acute stage, focusing on the efficacy of neuro-endoscopic management for hematoma removal. Materials and methods: Among 26 consecutive hemorrhagic MMD patients who were managed at our institution in the acute stage, 8 patients with intracerebral hemorrhage underwent surgical evacuation of the hematoma. All patients were diagnosed with MMD before surgery by magnetic resonance angiography and/or catheter angiography. Results: The initial surgical procedure was neuro-endoscopic hematoma removal in seven patients and microsurgical hematoma removal by craniotomy in one patient. One patient treated by the neuro-endoscopic procedure required subsequent small craniotomy due to difficulty in hemostasis. Satisfactory hematoma evacuation was achieved in all eight patients, as demonstrated by post-operative computed tomography, although one patient who was deeply comatose before surgery died in the early post-operative period. Conclusion: Neuro-endoscopic hematoma removal may be the optimal management method for hemorrhagic MMD in the acute stage in terms of the maximum preservation of pre-existing collateral anastomosis without affecting the potential donor vessels used for future revascularization surgery. Abbreviations: MMD: Moyamoya disease; STA: Superficial temporal artery; MCA: Middle cerebral artery; JAM: Japan Adult Moyamoya; ICH: Intracerebral hemorrhage; IVH: Intraventricular hemorrhage; SAH: Subarachnoid hemorrhage; CT: Computed tomography; TE: Total evacuation; PE: Partial evacuation; SMR: Light mass reduction; MR: Magnetic resonance; mRS: Modified Rankin scale; GCS: Glasgow Coma Scale; ICP: Intracranial pressure.


Classification of residential areas according to physical vulnerability to natural hazards: a case study of Çanakkale, Turkey.
The selection of new settlement areas and the construction of safe buildings, as well as rendering built-up areas safe, are of great importance in mitigating the damage caused by natural disasters. Most cities in Turkey are unprepared for natural hazards. In this paper, Çanakkale, located in a first-degree seismic zone and sprawled around the Sartçay Delta, is examined in terms of its physical vulnerability to natural hazards. Residential areas are analysed using GIS (geographic information system) and remote-sensing technologies in relation to selected indicators. Residential areas of the city are divided into zones according to an evaluation of geological characteristics, the built-up area's features, and urban infrastructure, and four risk zones are determined. The results of the analysis show that the areas of the city suitable for housing are very limited. In addition, the historical centre and the housing areas near Sartçay stream are shown to be most problematic in terms of natural disasters and sustainability.


Challenges and practical approaches with word sense disambiguation of acronyms and abbreviations in the clinical domain.
Although acronyms and abbreviations in clinical text are used widely on a daily basis, relatively little research has focused upon word sense disambiguation (WSD) of acronyms and abbreviations in the healthcare domain. Since clinical notes have distinctive characteristics, it is unclear whether techniques effective for acronym and abbreviation WSD from biomedical literature are sufficient. The authors discuss feature selection for automated techniques and challenges with WSD of acronyms and abbreviations in the clinical domain. There are significant challenges associated with the informal nature of clinical text, such as typographical errors and incomplete sentences; difficulty with insufficient clinical resources, such as clinical sense inventories; and obstacles with privacy and security for conducting research with clinical text. Although we anticipated that using sophisticated techniques, such as biomedical terminologies, semantic types, part-of-speech, and language modeling, would be needed for feature selection with automated machine learning approaches, we found instead that simple techniques, such as bag-of-words, were quite effective in many cases. Factors, such as majority sense prevalence and the degree of separateness between sense meanings, were also important considerations. The first lesson is that a comprehensive understanding of the unique characteristics of clinical text is important for automatic acronym and abbreviation WSD. The second lesson learned is that investigators may find that using simple approaches is an effective starting point for these tasks. Finally, similar to other WSD tasks, an understanding of baseline majority sense rates and separateness between senses is important. Further studies and practical solutions are needed to better address these issues.


Non-steroidal anti-inflammatory drugs decrease the quality of pleurodesis after mechanical pleural abrasion.
Non-steroidal anti-inflammatory drugs (NSAIDs) are often applied for pain management after thoracic surgery. Since these drugs diminish collagen deposition through inhibition of the prostaglandin synthesis, we investigated their effects on adhesion formation after endoscopic mechanical pleural abrasion, which is often applied in the therapy of pneumothorax. Mechanical pleural abrasion was performed unilaterally by the use of video-assisted thoracoscopic surgery technique in an established pig model. Ten animals (41.3+/-3.4 kg) were divided into a treatment group and a control group. In the treatment group, animals received 100 mg diclofenac (2 mg/kg body weight) orally daily for 3 weeks after surgery. At 3 weeks, all animals were sacrificed and efficacy of pleurodesis was macroscopically assessed by three independent reviewers blinded to the treatment of animals using a five-point severity pleurodesis score (from 0, no adhesions to 4, complete symphisis) and obliteration grade rating the distribution of adhesions (from 0, no adhesions to 4, adhesions in the whole chest). Microscopic evaluation was performed by two pathologists blinded to the study groups as well. A four-point score assessed the amount of collagen deposition (from 1, a few collagen fibers to 4, scar). Gross observation showed more dense adhesions in control animals with a median pleurodesis score of 3.67+/-1.0 in comparison to 2+/-2.2 in the treatment group (P = 0.01 *, Mann-Whitney non-parametric test). Distribution of adhesions was comparable in both groups with a median obliteration score of 3.67+/-1.3. Histopathologic examination showed a higher amount of collagen deposition in the control group, suggesting more dense adhesions, whereas in the treatment group there was loose granulation tissue (score of 4.0+/-0.8 vs. 2.3+/-1.0 in the treatment group, P = 0.06). The degree of inflammatory reaction was comparable in the two groups. Our results demonstrate that perioperative use of NSAIDs highly affects the quality of pleural adhesions obtained after mechanical abrasion in this pig model, which further suggests that these drugs should be avoided for pain management when a pleurodesis is performed.


Bacterial Pathogen Channels Medium-Sized Fatty Acids into Malleicyprol Biosynthesis.
Bacterial pathogens of the Burkholderia pseudomallei (BP) group cause life-threatening infections in both humans and animals. Critical for the virulence of these often antibiotic-resistant pathogens is the polyketide hybrid metabolite malleicyprol, which features two chains, a short cyclopropanol-substituted chain and a long hydrophobic alkyl chain. The biosynthetic origin of the latter has remained unknown. Here, we report the discovery of novel overlooked malleicyprol congeners with varied chain lengths and identify medium-sized fatty acids as polyketide synthase (PKS) starter units that constitute the hydrophobic carbon tails. Mutational and biochemical analyses show that a designated coenzyme A-independent fatty acyl-adenylate ligase (FAAL, BurM) is essential for recruiting and activating fatty acids in malleicyprol biosynthesis. In vitro reconstitution of the BurM-catalyzed PKS priming reaction and analysis of ACP-bound building blocks reveal a key role of BurM in the toxin assembly. Insights into the function and role of BurM hold promise for the development of enzyme inhibitors as novel antivirulence therapeutics to combat infections with BP pathogens.


Family-based suppressive intermittent therapy of hyperendemic trachoma with topical oxytetracycline or oral doxycycline.
A controlled double-blind stratified trial was carried out in a village in Southern Iran to assess the efficacy of family-based intermittent therapy of hyperendemic trachoma with topical oxytetracycline oily suspension twice daily for 7 days each month, or oral doxycycline 5 mg per kilogram of body weight once a month, in comparison with a control group which received vitamin pills once a month. In addition all other members of the selected children's families were also treated with the same regimen of therapy. The treatment was given for a period of 1 year by 3 field technicians, each responsible for one regimen of therapy. Examining the whole conjunctiva 4 months after the start of therapy, we observed no marked difference in the cure rate or the number of patients with moderate to severe trachoma between the groups treated with antibiotics and the control group. When treatment was continued for 12 months, a marked decrease in the prevalence of trachoma and in the grades of intensity of inflammatory responses as well as the positivity rate for Chlamydia trachomatis was observed in the groups treated with the topical oxytetracycline or oral doxycycline compared with the control group. While there was no marked difference between the efficacy of these 2 regimens of mass chemotherapy, the monthly intermittent therapy with a single dose of doxycycline offers the advantage of being more practical and less expensive for mass control of trachoma by requiring approximately one-tenth of the staff, transport, and other facilities required for the intermittent topical therapy with tetracycline eye ointment.


A trait-based approach for predicting species responses to environmental change from sparse data: how well might terrestrial mammals track climate change?
Estimating population spread rates across multiple species is vital for projecting biodiversity responses to climate change. A major challenge is to parameterise spread models for many species. We introduce an approach that addresses this challenge, coupling a trait-based analysis with spatial population modelling to project spread rates for 15 000 virtual mammals with life histories that reflect those seen in the real world. Covariances among life-history traits are estimated from an extensive terrestrial mammal data set using Bayesian inference. We elucidate the relative roles of different life-history traits in driving modelled spread rates, demonstrating that any one alone will be a poor predictor. We also estimate that around 30% of mammal species have potential spread rates slower than the global mean velocity of climate change. This novel trait-space-demographic modelling approach has broad applicability for tackling many key ecological questions for which we have the models but are hindered by data availability.


School-based screening for suicide risk: balancing costs and benefits.
We examined the effects of a scoring algorithm change on the burden and sensitivity of a screen for adolescent suicide risk. The Columbia Suicide Screen was used to screen 641 high school students for high suicide risk (recent ideation or lifetime attempt and depression, or anxiety, or substance use), determined by subsequent blind assessment with the Diagnostic Interview Schedule for Children. We compared the accuracy of different screen algorithms in identifying high-risk cases. A screen algorithm comprising recent ideation or lifetime attempt or depression, anxiety, or substance-use problems set at moderate-severity level classed 35% of students as positive and identified 96% of high-risk students. Increasing the algorithm's threshold reduced the proportion identified to 24% and identified 92% of high-risk cases. Asking only about recent suicidal ideation or lifetime suicide attempt identified 17% of the students and 89% of high-risk cases. The proportion of nonsuicidal diagnosis-bearing students found with the 3 algorithms was 62%, 34%, and 12%, respectively. The Columbia Suicide Screen threshold can be altered to reduce the screen-positive population, saving costs and time while identifying almost all students at high risk for suicide.


Opportunity for inpatient brain injury rehabilitation for persons in a vegetative state: survey of Swedish physicians.
: The aim of this study was to document physicians' opinions on inpatient rehabilitation care for working-age patients in vegetative state after new acquired brain injury, given the absence of an established standard of post-acute care. : A postal survey of 3259 Swedish physicians was conducted. : Survey response rate was 33%. Of survey respondents, 51% reported that they knew the definition of vegetative state. Transfer of vegetative patients from acute care to inpatient rehabilitation was considered always warranted by 54% and never or only sometimes warranted by 31% of survey respondents, whereas 15% did not know or did not answer. Rehabilitation physicians most often considered an inpatient rehabilitation stay of around 3 mos to be appropriate, but there was a lack of consensus. Discharge from acute care direct to social care at least sometimes was reported by 39% of physicians. : Physicians' opinions vary considerably on appropriate post-acute care for patients in vegetative state after acquired brain injury. This may impact on rates of referral and admission to rehabilitation units. Consensus is needed on a minimum period for and extent of rehabilitation interventions. Educational interventions should be targeted broadly to reach the wide range of specialties that may have responsibility for acute care of these patients.


Dietary Supplementation with Sugar Beet Fructooligosaccharides and Garlic Residues Promotes Growth of Beneficial Bacteria and Increases Weight Gain in Neonatal Lambs.
The proper development of the early gastrointestinal tract (GIT) microbiota is critical for newborn ruminants. This microbiota is susceptible to modification by diverse external factors (such as diet) that can lead to long-lasting results when occurring in young ruminants. Dietary supplementation with prebiotics, ingredients nondigestible and nonabsorbable by the host that stimulate the growth of beneficial GIT bacteria, has been applied worldwide as a potential approach in order to improve ruminant health and production yields. However, how prebiotics affect the GIT microbiota during ruminants' early life is still poorly understood. We investigated the effect of milk supplementation with a combination of two well-known prebiotics, fructooligosaccharides (FOS) from sugar beet and garlic residues (all together named as "additive"), exerted on preweaned lamb growth and the composition of their fecal microbiota, by using 16S rRNA gene amplicon high-throughput sequencing. The results showed a significant increase in the mean daily weight gain of lambs fed with the additive. Lamb fecal microbiota was also influenced by the additive intake, as additive-diet lambs showed lower bacterial diversity and were significantly more abundant in Bifidobacterium, Enterococcus, Lactobacillus and Veillonella. These bacteria have been previously reported to confer beneficial properties to the ruminant, including promotion of growth and health status, and our results showed that they were strongly linked to the additive intake and the increased weight gain of lambs. This study points out the combination of FOS from sugar beet and garlic residues as a potential prebiotic to be used in young ruminants' nutrition in order to improve production yields.


Recurrent Gastrointestinal Bleeding in a Middle-Aged Man.
Acquired von Willebrand disease (avWD) arises because of mechanisms that destroy, decrease, absorb, or clear von Willebrand factor (vWF). A 59-year-old man presented with a 3-year history of recurrent gastrointestinal bleeding. Laboratory workup revealed a prolonged platelet function assay-100. The vWF antigen was decreased, and a low vWF immunofunctional activity/antigen ratio, low collagen binding/antigen ratio, and decreased intermediate and high molecular weight multimers were noted. The patient had no high-shear stress conditions, and an antibody-mediated process was suspected. A vWF mixing study showed complete correction of vWF activity, suggesting no direct functional inhibitor. The patient was given a bolus of vWF concentrate with serial measurements of vWF; the vWF half-life was 2.5 hours. The vWF propeptide/antigen ratio was 4:1, supporting a diagnosis of aVWD resulting from increased antibody-mediated vWF clearance. This case study emphasizes the laboratory's role in the diagnosis and treatment of rare, overlooked acquired bleeding disorders.


Exploring the factor structure of the Mood and Anxiety Symptom Questionnaire (MASQ).
L. A. Clark and Watson (1991) proposed a tripartite model of anxiety and depression defined in terms of common symptoms relating to general distress, anxiety-specific symptoms of hyperarousal, and depression-specific symptoms of low positive affect and loss of interest. To aid the measurement of and discrimination between anxiety and depression they developed the Mood and Anxiety Symptom Questionnaire (MASQ). Although potentially useful, the MASQ is still in an early stage of development, and there is an indication that a discrepancy exists between items and scales. Therefore, the aim of this study was to explore the items and factors of the MASQ and determine whether a pattern similar to that suggested by L. A. Clark and Watson would emerge. Factor analysis of the MASQ revealed 3 factors relating to general distress, positive affect, and anxious arousal. Inspection of the individual items indicated that some refinements are required.


Mutations in endothelin 1 cause recessive auriculocondylar syndrome and dominant isolated question-mark ears.
Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch. Mutations in the genes coding for phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 (GNAI3), predicted to function as signal transducers downstream of EDNRA, have recently been reported in ACS. By whole-exome sequencing (WES), we identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents. WES of two cases with vertical transmission of isolated QMEs revealed a stop mutation in EDN1 in one family and a missense substitution of a highly conserved residue in the mature EDN1 peptide in the other. Targeted sequencing of EDN1 in an ACS individual with related parents identified a fourth, homozygous mutation falling close to the site of cleavage by endothelin-converting enzyme. The different modes of inheritance suggest that the degree of residual EDN1 activity differs depending on the mutation. These findings provide further support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway.


Early phosphoproteomic changes in the retina following optic nerve crush.
Retinal ganglion cell (RGC) death causes irreversible blindness in adult mammals. Death of RGC occurs in diseases including glaucoma or injuries to the optic nerve (ON). To investigate mechanisms involved in RGC degeneration, we evaluated the phosphoproteomic changes in the retina induced by ON injury. Intraorbital optic nerve crush (ONC) was performed in adult C57BL/6J mice. Retinas were collected at 0, 6, and 12 h following ONC. Retinal proteins labeled with CyDye-C2 were subject to 2D-PAGE, followed by phosphoprotein staining and in-gel/cross-gel image analysis. Proteins with significant changes in phosphorylation (ratios ≥1.2) in retinas of the injured eyes compared to the control eyes were spot-picked, tryptic digested, and peptide fragments were analyzed by MALDI-TOF (MS) and TOF/TOF (tandem MS/MS). Intraorbital ONC increased phosphorylation of many retinal proteins. Among them, 29 significantly phosphorylated proteins were identified. PANTHER analysis showed that these proteins are associated with a variety of protein classes, cellular components, biological processes and signaling pathways. One of the identified proteins, phosphoprotein enriched in astrocytes 15 (PEA15), was further validated by western blotting and immunofluorescence staining. Functions of PEA15 were determined in cultured astrocytes. PEA15 knockdown reduced astrocyte phagocytic activity but promoted cell migration. Long term PEA15 knockdown also decreased astrocyte ATP level. This study provides new insights into mechanisms of RGC degeneration after ON injury, as well as central nervous system (CNS) neurodegeneration, since the retina is an extension of the CNS. These new insights will lead to novel therapeutic targets for retinal and CNS neurodegeneration.


Calmodulin controls organization of the actin cytoskeleton via regulation of phosphatidylinositol (4,5)-bisphosphate synthesis in Saccharomyces cerevisiae.
Phosphoinositides regulate a wide range of cellular processes, including proliferation, survival, cytoskeleton remodelling and membrane trafficking, yet the mechanisms controlling the kinases, phosphatases and lipases that modulate phosphoinositide levels are poorly understood. In the present study, we describe a mechanism controlling MSS4, the sole phosphatidylinositol (4)-phosphate 5-kinase in Saccharomyces cerevisiae. Mutations in MSS4 and CMD1, encoding the small Ca(2+)-binding protein calmodulin, confer similar phenotypes, including loss of viability and defects in endocytosis and in organization of the actin cytoskeleton. Overexpression of MSS4 suppresses the growth and actin defects of cmd1-226, a temperature-sensitive calmodulin mutant which is defective in the organization of the actin cytoskeleton. Finally, the cmd1-226 mutant exhibits reduced levels of phosphatidylinositol (4,5)-bisphosphate. These findings suggest that calmodulin positively controls MSS4 activity and thereby the actin cytoskeleton.


Characterization of serologic and cell-mediated reactivity of a 38-kDa antigen isolated from Mycobacterium tuberculosis.
An antigen of Mycobacterium tuberculosis with an m.w. of 38,000 has been isolated by affinity chromatography using a monoclonal antibody. This antibody bound only to an antigen found in M. tuberculosis and Mycobacterium bovis BCG. The specificity of the antigen was tested in a vertical study by immunodetection on western blots reacted with hyperimmune sera against M. tuberculosis, M. bovis, and 10 other Mycobacterium species. The antigen was detected only by antisera to M. tuberculosis and M. bovis. Specificity in cell-mediated immunity was tested by skin tests in guinea pigs sensitized with M. tuberculosis, Mycobacterium intracellulare, and Mycobacterium kansasii and by lymphocyte proliferation tests. The 38-kDa antigen induced positive skin test reactions regardless of the Mycobacterium species used to sensitize the animal. The ability of the 38-kDa antigen to sensitize for cell-mediated immunity was tested by injecting mice with the 38-kDa antigen and challenging their lymphocytes in vitro with various mycobacterial antigens. Lymphocyte proliferation was observed in the presence of 38-kDa antigen, M. tuberculosis sonicate antigen, and tuberculin purified protein derivative and to M. kansasii and M. intracellulare. The 38-kDa antigen may contain a specific epitope detected by serology, but also contains epitopes that are cross-reactive for cellular immunity.


Chickens prefer beautiful humans.
We trained chickens to react to an average human female face but not to an average male face (or vice versa). In a subsequent test, the animals showed preferences for faces consistent with human sexual preferences (obtained from university students). This suggests that human preferences arise from general properties of nervous systems, rather than from face-specific adaptations. We discuss this result in the light of current debate on the meaning of sexual signals and suggest further tests of existing hypotheses about the origin of sexual preferences.


Worsening of imiquimod-induced psoriasiform inflammation in mice by environmental pollutant, di-(2-ethylhexyl) phthalate through dysregulation in IL-17A and Nrf2/iNOS signaling in peripheral myeloid and CD4 + T cells.
Psoriasis is a devastating autoimmune illness resulting from excessive keratinocyte growth and leukocyte infiltration into the dermis/epidermis. In the pathogenesis of psoriasis, different immune cells such as myeloid cells and CD4 + T cells play a key role. Th17/Th1 immune responses and oxidant-antioxidant responses are critical in regulation of psoriatic inflammation. Di-2-ethylhexyl phthalate (DEHP) is one of the well-known plasticizers and has widespread use worldwide. DEHP exposure through ingestion may produce harmful effects on the skin through systemic inflammation and oxidative stress, which may modify psoriatic inflammation. However, the effect of oral DEHP exposure on inflammatory cytokines and Nrf2/iNOS signaling in myeloid cells and CD4 + T cells in the context of psoriatic inflammation has not been investigated earlier. Therefore, this study explored the effect of DEHP on systemic inflammation in myeloid cells (IL-6, IL-17A, IL-23), Th17 (p-STAT3, IL-17A, IL-23R, TNF-α), Th1 (IFN-γ), Treg (Foxp3, IL-10), and Nrf2/iNOS signaling in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our study showed increased Th17 signaling in imiquimod model which was further aggravated by DEHP exposure. Further, Nrf2 and iNOS signaling were also elevated in IMQ model where DEHP exposure further increased iNOS expression but did not modify the Nrf2 expression. Most importantly, IL-17A levels were also elevated in myeloid cells along with IL-6 which were further elevated by DEHP exposure. Overall, this study shows that IL-17A signaling is upregulated, whereas there is deficiency of Nrf2/HO-1 signaling by DEHP exposure in mice with psoriasiform inflammation. These observations suggest that DEHP aggravates IL-17A-mediated signaling both in CD4 + T cells as well as myeloid cells which is linked to exacerbation of IMQ-induced psoriatic inflammation in mice. Strategies that counteract the effect of DEHP exposure in the context of psoriatic inflammation through downregulation of IL-17A may be fruitful.


Lymphatic vessel assembly is impaired in Aspp1-deficient mouse embryos.
We previously identified apoptosis stimulating protein of p53 (Aspp1) as an endothelial-specific gene functioning in mouse embryogenesis. To investigate the in vivo role of Aspp1, we generated Aspp1 knockout mice by targeted disruption. Aspp1(-/-) embryos showed subcutaneous edema and disorganized lymphatic vasculature. Morphological changes in lymphatic endothelial cells and isolated lymphatic islands were detected in Aspp1(-/-) embryos. Lymphangiography by injecting dye subcutaneously into the embryonic forelimb showed defective lymphatic drainage function and obstruction in collecting lymphatic vessels of Aspp1(-/-) embryos. Interestingly, Aspp1(-/-) adult mice resolved these lymphatic functional defects seen during embryogenesis, but lymphangiography in Aspp1(-/-) adult mice revealed abnormal patterns in collecting lymphatic vessels. Since Aspp proteins reportedly enhance apoptotic activity of p53, we asked whether p53 deficiency also affected lymphatic vessel development. Analysis of p53 knockout or Aspp1; p53 double knockout mice showed that p53 loss did not affect lymphatic vessels. These results indicate that Aspp1 plays a crucial role in the initial assembly and function of lymphatic vessels during mouse development in a p53-independent manner. Here we report novel lymphatic vascular phenotypes in Aspp1(-/-) mice; subcutaneous edema detected only during embryogenesis, delayed lymphatic vessel formation, and mispatterned collecting lymphatic vessels.


Pantothenate kinase-associated neurodegeneration: MR imaging, proton MR spectroscopy, and diffusion MR imaging findings.
We herein report the case of a 15-year-old male patient with pantothenate kinase-associated neurodegeneration. The classic "eye-of-the-tiger" appearance was initially present on the globus pallidi on T2-weighted MR images and had disappeared by the time of the 10-month follow-up examination. Fluid-attenuated inversion recovery images revealed marked hypointensity in the globus pallidi and dentate nuclei and high signal intensity changes in the deep cerebral white matter. Proton MR spectroscopy revealed markedly decreased N-acetylaspartate in the globus pallidi, associated with decreased N-acetylaspartate and increased myoinositol in the deep cerebral white matter. Diffusion MR images (b=1000 s/mm(2)) were negative (normal appearing) for deep cerebral white matter lesions, whereas apparent diffusion coefficient values were slightly increased (1.08-1.12 x 10(-3) mm(2)/s), compared with the apparent diffusion coefficient values from the normal white matter regions. Apparent diffusion coefficient values in the globus pallidi were lower than those in the unaffected thalamus.


Distinct brain dynamics and networks for processing short and long auditory time intervals.
Psychophysical studies suggest that time intervals above and below 1.2 s are processed differently in the human brain. However, the neural underpinnings of this dissociation remain unclear. Here, we investigate whether distinct or common brain networks and dynamics support the passive perception of short (below 1.2 s) and long (above 1.2 s) empty time intervals. Twenty participants underwent an EEG recording during an auditory oddball paradigm with .8- and 1.6-s standard time intervals and deviant intervals either shorter (early) or longer (delayed) than the standard interval. We computed the auditory ERPs for each condition at the sensor and source levels. We then performed whole brain cluster-based permutation statistics for the CNV, N1 and P2, components, testing deviants against standards. A CNV was found only for above 1.2 s intervals (delayed deviants), with generators in temporo-parietal, SMA, and motor regions. Deviance detection of above 1.2 s intervals occurred during the N1 period over fronto-central sensors for delayed deviants only, with generators in parietal and motor regions. Deviance detection of below 1.2 s intervals occurred during the P2 period over fronto-central sensors for delayed deviants only, with generators in primary auditory cortex, SMA, IFG, cingulate and parietal cortex. We then identified deviance related changes in directed connectivity using bivariate Granger causality to highlight the networks dynamics associated with interval processing above and below 1.2. These results suggest that distinct brain dynamics and networks support the perception of time intervals above and below 1.2 s.


Chemical hazard for dental hygienists: a systematic review.
Dental hygienists (DHs) are professionals responsible for oral health. They deal with professional oral hygiene, counselling, and screening patients for oral health, as well as preventing and treating oral diseases. However, DH responsibilities and duties may vary worldwide, characterising changeable occupational exposure scenarios and making it difficult to achieve a suitable evaluation of workplace risks, particularly regarding chemical exposure. Therefore, the aim of the present work was to provide a comprehensive overview on the current knowledge on DH chemical risks. According to the PRISMA guidelines, a systematic review of PubMed, Scopus, and Isi Web of Knowledge databases was performed to retrieve all articles assessing DH occupational chemical exposures. Fragmented data are currently available on DH chemical risk, due to the limited number of studies on the topic and few DHs enrolled, as well as their frequent assimilation to other oral healthcare professionals. The majority of the retrieved investigations focused on possible hypersensitivity reactions caused by natural rubber latex exposure, but not on potential risks derived from other currently employed substances or innovative wide-spreading compounds. Future research should be focused on assessing DH chemical risks according to a more comprehensive and toxicologically standardised approach to achieve an appropriate awareness among the DH workforce concerning the possibility for hazardous exposure and adverse health effects. Overall, this may lead to the adoption/implementation of adequate preventive measures to protect the health and safety of these oral healthcare professionals.


Genetic analysis of atypical progesterone profiles in Holstein-Friesian cows from experimental research herds.
The objective of this study was to quantify the genetic variation in normal and atypical progesterone profiles and investigate if this information could be useful in an improved genetic evaluation for fertility for dairy cows. The phenotypes derived from normal profiles included cycle length traits, including commencement of luteal activity (C-LA), interluteal interval, luteal phase length. and interovulatory interval. In total, 44,977 progesterone test-day records were available from 1,612 lactations on 1,122 primiparous and multiparous Holstein-Friesian cows from Ireland, the Netherlands, Sweden, and the United Kingdom. The atypical progesterone profiles studied were delayed cyclicity, prolonged luteal phase, and cessation of cyclicity. Variance components for the atypical progesterone profiles were estimated using a sire linear mixed model, whereas an animal linear mixed model was used to estimate variance components for the cycle length traits. Heritability was moderate for delayed cyclicity (0.24 ± 0.05) and C-LA (0.18 ± 0.04) but low for prolonged luteal phase (0.02 ± 0.04), luteal phase length (0.08 ± 0.05), interluteal interval (0.08 ± 0.14), and interovulatory interval (0.03 ± 0.04). No genetic variation was detected for cessation of cyclicity. Commencement of luteal activity, luteal phase length, and interovulatory interval were moderately to strongly genetically correlated with days from calving to first service (0.35 ± 0.12, 0.25 ± 0.14, and 0.76 ± 0.24, respectively). Delayed cyclicity and C-LA are traits that can be important in both genetic evaluations and management of fertility to detect (earlier) cows at risk of compromised fertility. Delayed cyclicity and C-LA were both strongly genetically correlated with milk yield in early lactation (0.57 ± 0.14 and 0.45 ± 0.09, respectively), which may imply deterioration in these traits with selection for greater milk yield without cognizance of other traits.


Isoflurane postconditioning with cardiac support promotes recovery from early brain injury in mice after severe subarachnoid hemorrhage.
Neurocardiac dysfunction is a life-threatening systemic consequence of subarachnoid hemorrhage (SAH) that contributes to triggering delayed cerebral ischemia (DCI). This study aimed to determine the impact of dobutamine cardiac support during isoflurane postconditioning on post-SAH DCI. Male C57BL/6 mice were subjected to SAH, SAH plus isoflurane postconditioning, or SAH plus isoflurane postconditioning with dobutamine. Severity of SAH was graded from 1 to 4 (mild, 1-2; severe, 3-4) based on T2*-weighted magnetic resonance imaging (MRI). Cardiac output (CO) measured by transthoracic pulsed wave Doppler-echocardiography was titrated at a supra-normal level with intravenous dobutamine infusion. Neurological function was examined daily by neurological score and Rotarod tests. DCI was analyzed 3days later by determining new infarction on diffusion-weighted MRI. In a separate experiment, mice were pretreated with hypoxia-inducible factor (HIF) inhibitor 2-methoxyestradiol (2ME2). Clinically relevant CO depression was notable in severe SAH grade mice, in which dobutamine CO management combined with isoflurane postconditioning showed earlier and improved functional recovery than postconditioning with single isoflurane inhalation. Incidence of infarction and volumes on day 3 reduced significantly in this subgroup. All of the effects during preconditioning were attenuated by 2ME2 pretreatment. Isoflurane postconditioning under dobutamine cardiac support improves recovery from SAH-induced early brain injury, leading to reduced DCI resultant from severe experimental SAH. These results indicate the importance of neuro-cardiac protection, in which HIF may be acting as a critical mediator, as a promising therapeutic approach to SAH.


A fully immersive set-up for remote interaction and neurorehabilitation based on virtual body ownership.
Although telerehabilitation systems represent one of the most technologically appealing clinical solutions for the immediate future, they still present limitations that prevent their standardization. Here we propose an integrated approach that includes three key and novel factors: (a) fully immersive virtual environments, including virtual body representation and ownership; (b) multimodal interaction with remote people and virtual objects including haptic interaction; and (c) a physical representation of the patient at the hospital through embodiment agents (e.g., as a physical robot). The importance of secure and rapid communication between the nodes is also stressed and an example implemented solution is described. Finally, we discuss the proposed approach with reference to the existing literature and systems.


The effect of ultrasound or phonophoresis as an adjuvant treatment for non-specific neck pain: systematic review of randomised controlled trials.
To determine the effectiveness of ultrasound/phonophoresis as an adjuvant to exercise or manual therapy for the improvement of patient-centred outcomes in adults with non-specific neck pain (NSNP). Seven electronic databases were systematically searched up to September 2020. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to judge the Quality of Evidence (QoE). Six studies involving 249 participants were included. The QoE was very low GRADE. Phonophoresis with capsaicin plus exercise improved pain at immediate post-treatment (MD: -3.30 [-4.05, -2.55]) but not with diclofenac sodium plus exercise as compared to exercise. Continuous ultrasound (CUS) plus exercise improved pain and pressure pain threshold (PPT) at immediate post-treatment (pain: MD: -3.42 [-4.08, -2.7]); (PPT: MD: 0.91 [0.68, 1.14]) and at intermediate-term as compared to exercise. CUS or high power pain threshold (HPPT) ultrasound plus manual therapy and exercise showed no benefit for pain reduction (MD: -0.75 [-2.08, 0.58]) did not improve function/disability (MD: -1.05 [-4.27, 2.17]) at immediate or short-term as compared to manual therapy and exercise. Due to high risk of bias, inconsistency, and indirectness the QoE is very low in support of benefit of ultrasound/phonophoresis as an adjuvant treatment for NSNP.Implication for rehabilitationDue to high risk of bias, inconsistency, and indirectness the quality of evidence (QoE) is very low in support of benefit of adding ultrasound or phonophoresis to exercise or manual therapy for pain reduction or improvement in function/disability for those with sub-acute and chronic myofascial associated neck pain. However, our confidence in the findings is very low and conclusions are likely to change as more evidences emerges.Clinicians using ultrasound therapy as an adjuvant intervention for management of chronic myofascial associated neck pain should carefully consider the available evidence on ultrasound, including the benefits and costs involved.


Partial splenectomy before a hematopoietic stem cell transplantation in children.
Hematopoietic stem cell (HSC) engraftment is delayed in children with hypersplenism, and splenectomy may improve HSC engraftment. However, the use of total splenectomy in children is limited because of concerns for postsplenectomy sepsis. In this study, the authors sought to assess the role of partial splenectomy for children with hypersplenism undergoing HSC transplantation. Five children with a variety of conditions and associated hypersplenism underwent partial splenectomy before an HSC transplantation at the authors' institution between 2000 and 2003. Primary outcome measures were rates of neutrophil and platelet engraftment. Secondary outcome measures included perioperative complications, splenic regrowth, graft-versus-host disease, and infection rate. All outcomes were compared with recipients of an HSC transplant from both age-matched nonsplenectomized children (n = 497) and hypersplenic children who underwent total splenectomy (n = 10). Outcomes were compared using Wilcoxon's rank sum test. The rate of both neutrophil and platelet engraftment was faster in children who underwent either partial or total splenectomy as compared with nonsplenectomized children (mean rates of neutrophil engraftment were 26, 19, and 19 days for the nonsplenectomy, total splenectomy, and partial splenectomy groups, respectively; mean rates of platelet engraftment were 97, 37, and 45 days for the nonsplenectomy, total splenectomy, and partial splenectomy groups, respectively). Graft-versus-host disease rates were similar between the 3 groups. The mean percentage of splenic regrowth after partial splenectomy was 39%. There were no perioperative complications. Partial splenectomy may be safely performed before HSC transplantation and, similar to total splenectomy, may improve the rate of HSC engraftment. Although this series has a limited number of patients, the use of partial splenectomy appears to be safe and may allow for splenic salvage to minimize the risk of postsplenectomy sepsis.


Combination disease-modifying treatment in spinal muscular atrophy: A proposed classification.
We sought to devise a rational, systematic approach for defining/grouping survival motor neuron-targeted disease-modifying treatment (DMT) scenarios. The proposed classification is primarily based on a two-part differentiation: initial DMT, and persistence/discontinuation of subsequent DMT(s). Treatment categories were identified: monotherapy add-on, transient add-on, combination with onasemnogene abeparvovec, bridging to onasemnogene abeparvovec, and switching to onasemnogene abeparvovec. We validated this approach by applying the classification to the 443 patients currently in the RESTORE registry and explored the demographics of these different groups of patients. This work forms the basis to explore the safety and efficacy profile of the different combinations of DMT in SMA.


Stable isolated metal atoms as active sites for photocatalytic hydrogen evolution.
The process of using solar energy to split water to produce hydrogen assisted by an inorganic semiconductor is crucial for solving our energy crisis and environmental problems in the future. However, most semiconductor photocatalysts would not exhibit excellent photocatalytic activity without loading suitable co-catalysts. Generally, the noble metals have been widely applied as co-catalysts, but always agglomerate during the loading process or photocatalytic reaction. Therefore, the utilization efficiency of the noble co-catalysts is still very low on a per metal atom basis if no obvious size effect exists, because heterogeneous catalytic reactions occur on the surface active atoms. Here, for the first time, we have synthesized isolated metal atoms (Pt, Pd, Rh, or Ru) stably by anchoring on TiO2 , a model photocatalystic system, by a facile one-step method. The isolated metal atom based photocatalysts show excellent stability for H2 evolution and can lead to a 6-13-fold increase in photocatalytic activity over the metal clusters loaded on TiO2 by the traditional method. Furthermore, the configurations of isolated atoms as well as the originality of their unusual stability were analyzed by a collaborative work from both experiments and theoretical calculations.


Functional connexin35 increased in the myopic chicken retina.
Our previous research showed that increased phosphorylation of connexin (Cx)36 indicated extended coupling of AII amacrine cells (ACs) in the rod-dominant mouse myopic retina. This research will determine whether phosphorylation at serine 276 of Cx35-containing gap junctions increased in the myopic chicken, whose retina is cone-dominant. Refractive errors and ocular biometric dimensions of 7-days-old chickens were determined following 12 h and 7 days induction of myopia by a -10D lens. The expression pattern and size of Cx35-positive plaques were examined in the early (12 h) and compensated stages (7 days) of lens-induced myopia (LIM). At the same time, phosphorylation at serine 276 (functional assay) of Cx35 in strata 5 (S5) of the inner plexiform layer was investigated. The axial length of the 7 days LIM eyes was significantly longer than that of non-LIM controls (P < 0.05). Anti-phospho-Ser276 (Ser276-P)-labeled plaques were significantly increased in LIM retinas at both 12 h and 7 days. The density of Ser276-P of Cx35 was observed to increase after 12 h LIM. In the meanwhile, the areas of existing Cx35 plaques did not change. As there was more phosphorylation of connexin35 at Ser276 at both the early and late stages (12 h) and 7 days of LIM chicken retinal activity, the coupling with ACs could be increased in myopia development of the cone-dominated chicken retina.


Early results after percutaneous transluminal coronary angioplasty in 400 patients.
In a consecutive series of 400 patients treated by percutaneous transluminal coronary angioplasty 212 had single vessel disease, 142 had multivessel disease with only one vessel dilated, and 46 had multivessel dilatation. In addition sequential stenoses were dilated in the same vessel in all groups. There was no mortality among patients with single vessel disease. Success rates varied from 83% to 90% according to the artery in which angioplasty was attempted. Urgent surgery was required by 3.8%. Primary success was lower (74%) in the presence of multivessel disease and complications were more frequent, with four deaths (2.8%). In 46 patients with multivessel disease in whom all important lesions were dilated during the same procedure the overall primary success rate was 76% and within the last year of the study it was 91%. One (2%) patient died and three (7%) required urgent surgery. Twelve (86%) out of 14 stenosed vein grafts were successfully dilated and eight (53%) chronically occluded vessels were re-opened; in both groups there were no deaths, no infarctions, and no need for urgent surgery. In all groups symptoms improved greatly and predischarge exercise tests showed that there was no reversible ischaemia in 94% of patients with single vessel disease or in 65% of patients with incomplete revascularisation. Six months after the procedure 95% of the patients had improved symptomatically and 80% had normal exercise tests after one year. Percutaneous transluminal coronary angioplasty is the method of choice in single vessel disease and its use also results in a high proportion of other patients becoming symptom free. Complication rates are low and for selected patients results that are equivalent to those of cardiac surgery are obtained.


A case of drug-induced hypersensitivity syndrome-like symptoms following HHV-6 encephalopathy.
Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe disorder due to a systemic hypersensitivity reaction. We report on a case with DIHS-like symptoms following human herpes virus 6 (HHV-6) infection complicated with encephalopathy. An 11-month-old girl suffered from a human herpes virus 6 (HHV-6) infection (exanthema subitum) complicated with encephalopathy. We treated the patient with continuous infusion of thiopental, assisted mechanical ventilation, methylprednisolone pulse therapy, and gamma-globulin infusion therapy starting on the fifth day of the illness and started phenobarbital administration on the eleventh day. The patient developed a fever, systemic erythematous exanthema, lymphadenopathy, and eosinophilia two weeks after the start of phenobarbital administration. Steroid therapy, methylprednisolone (4 mg/kg/day) followed by oral prednisolone (1 mg/kg/day), was started on the 28th day and was tapered off on the 72nd day after admission. Serum anti-HHV-6 IgG antibody elevation and the presence of HHV-6 DNA in the peripheral blood detected by polymerase chain reaction (PCR) analysis suggested reactivation of HHV-6 after the primary infection of HHV-6. Lymphocyte transformation test for phenobarbital was positive three weeks after the DIHS crisis. HHV-6 reactivation is a unique feature in DIHS. In general one develops DIHS accompanied by reactivation of HHV-6 which has been residing in the body since the initial infection (exanthema subitum) in early childhood. This is the first report of a patient with DIHS-like symptoms which developed immediately following the primary infection of HHV-6.


Depression in veterans of the first Gulf War and comparable military controls.
Depression is a common mental disorder associated with poor health outcomes. The purpose of this study is to examine the prevalence of depression, mental health comorbidity, illness variables, and quality of life in a sample of military veterans serving during the first Gulf War. The Iowa Gulf War Case Validation Study involved face-to-face evaluations in 1999--2002 of 602 military personnel--either deployed ("deployed veterans") or eligible but not deployed ("non-deployed veterans") to the Gulf. Subjects were sampled by conducting a series of case-control studies nested within a population-based survey of 4,886 military personnel. All subjects were interviewed using the Structured Clinical Interview for DSM-IV (SCID-IV), and a series of semi-structured interviews and validated questionnaires. Best estimate psychiatric diagnoses were assigned based on all available data. One-hundred-ninety-two (32%) of the 602 surveyed veterans met criteria for a current or lifetime depressive disorder (major depression, dysthymia, depressive disorder--not otherwise specified). Depressed non-deployed veterans were more likely to be female and to have served in the Air Force than depressed deployed veterans. There were few significant differences between the depressed deployed veterans and the depressed non-deployed veterans. Depressed deployed veterans had significantly higher lifetime rates of comorbid cognitive dysfunction (55% vs. 35%), and anxiety disorders (59% vs. 33%)--mainly accounted for by specific phobias (12% vs. 2%) and posttraumatic stress disorder (33% vs. 10%)--than did depressed non-deployed veterans. Lifetime substance use disorders were significantly more frequent in deployed veterans than non-deployed veterans (70% vs. 52%), particularly alcohol disorders (68% vs. 52%). There were no differences in rates of personality characteristics, family psychiatric history, stressors, hypochondriasis, and level of functioning between the two study groups showed no significant differences. Depressive illness is frequent in military samples, as it is in the general population. The prevalence, pattern of comorbidity, and illness features were similar in deployed veterans and non-deployed veterans, suggesting that the depression suffered by both groups of veterans is qualitatively comparable. The main difference between study, groups was that depressed deployed veterans had higher rates than depressed non-deployed veterans of comorbid anxiety disorders, hypothesized to be part of the stress-related syndromes seen in those who experience combat.


The potential effects of anabolic-androgenic steroids and growth hormone as commonly used sport supplements on the kidney: a systematic review.
Anabolic-androgenic steroids and growth hormone are among the most commonly used supplements by sportsmen and sportswomen. The aim of this systematic review is to collect and report available data about renal safety of anabolic-androgenic steroids and growth hormone (GH). The search strategy was in accordance with the PRISMA guideline. Seven databases such as Scopus, Medline, Embase, and ISI Web of Knowledge were searched using keywords, such as "growth hormone", "anabolic-androgenic steroids", and "kidney injury". Articles published from 1950 to December 2017 were considered. Randomized clinical trials, prospective or retrospective human studies, case series as well as case reports, and experimental (in vivo) studies were included. Twenty one clinical and experimental articles were selected (12 for anabolic-androgenic steroids and 9 for GH). Anabolic-androgenic steroids can affect the kidney in different aspects. They can induce or aggravate acute kidney injury, chronic kidney disease, and glomerular toxicity. These adverse effects are mediated through pathways such as stimulating renin-angiotensin-aldosterone system, enhancing the production of endothelin, producing reactive oxygen species, over-expression of pro-fibrotic and pro-apoptotic mediators (e.g., TGF-β1), as well as inflammatory cytokines (e.g., TNF-α, IL-1b, and IL-6). Although GH may affect the kidney in different aspects, such as size, glomerular filtration rate, and tubule functions, either directly or indirectly, there is no conclusive clinical evidence about its detrimental effects on the kidney in athletes and body builders. Evidence regarding effects of anabolic-androgenic steroids exists; However, GH's exact effect on the kidney at doses used by athletes and body builders has not yet been clarified. Cohort clinical studies with long-term follow-up are warranted in this regard.


Proteomics in rheumatology: The beginning of a fairy tale?
One of the major challenges in proteome research is to translate its applications to the setting of human diseases. Proteomics in rheumatology is an area with marked potential including applications ranging from diagnostics, over therapeutic monitoring to discovery of new potential therapeutic targets. Biomarkers will be essential to discriminate between clinical similar rheumatic diseases, to monitor disease-states or to install the best appropriate therapy. Especially in the field of rheumatology, analysis of specific genes and/or their expression products by pharmacogenetics/-genomics or pharmacoproteomics could be necessary to enable an effective, patient-tailored therapy. In rheumatology, direct examination of proteins may be of utmost importance, as it is already known that PTMs, such as citrullination of proteins or peptides, may be involved in certain rheumatic diseases. The discovery and validation of antibodies directed against citrullinated proteins/peptides in rheumatic diseases using proteome analysis approaches has been described. Gel-free methods, SELDI-approaches and classic 2-DE approaches have been deployed on body fluids as well as on target tissues in different rheumatic diseases. Proteomics in rheumatology is on the rise and pilot studies have indicated that the application of proteomics-based technologies in rheumatic diseases appears to be an exciting example of translational research.


Siblings of individuals with autism spectrum disorders across the life course.
In this article, we review the literature on siblings of individuals with autism spectrum disorders (ASD) from a lifespan developmental perspective, from infancy through adulthood, focusing on the sibling relationship and sibling well-being. We situate this review within the larger body of research on siblings of individuals with developmental disabilities (DD) across the lifespan. We then consider the genetic aspects of ASDs and their implications for siblings. We conclude that there is an evidence of atypical social and communication development in some siblings of children with an ASD during infancy. During childhood and adolescence, siblings describe both positive and negative aspects of their sibling relationship and there is some evidence that siblings of children with an ASD may be at heightened risk for social and behavioral adjustment problems. The limited research on adulthood suggests that lack of closeness in the sibling relationship and social and emotional difficulties may continue. We encourage more attention focused on developmental issues, specifically with respect to samples in narrower age groups and in longitudinal research. Finally, we note the variability in sibling outcomes, and suggest further examination of potential moderating and mediating factors, including genetic predispositions.


Preparation and Characterization of Chitosan-Alginate Microspheres Loaded with Quercetin.
The aim of this paper was to formulate microspheres based on biodegradable polymers (chitosan and sodium alginate), using the complex coacervation technique. Subsequently, the prepared microspheres were loaded with quercetin (QUE), a pharmacological active ingredient insoluble in water and unstable to light, temperature and air. After preparation, the loaded microspheres underwent several studies for physical chemical characterization (performed by scanning electron microscopy-SEM, laser 3D scanning, and thermal analysis-TA). Furthermore, they were analyzed in order to obtain information regarding swelling index, drug entrapment, and in vitro release capacity. The obtained experimental data demonstrated 86.07% entrapment of QUE into the microspheres, in the case of the one with the highest Ch concentration. Additionally, it was proved that such systems allow the controlled release of the active drug over 24 h at the intestinal level. SEM micrographs proved that the prepared microspheres have a wrinkled surface, with compact structures and a large number of folds. On the basis of the TA analysis, it was concluded that the obtained microspheres were thermally stable, facilitating their usage at normal physiological temperatures as drug delivery systems.


Mild hyperthermia enhances human monocyte-derived dendritic cell functions and offers potential for applications in vaccination strategies.
Dendritic cell (DC)-based immunotherapy has been shown to be a promising strategy for anti-cancer therapy. Nevertheless, only a low overall clinical response rate has been observed in vaccinated patients with advanced cancer and therefore methods to improve DC immuno-stimulatory functions are currently under intense investigation. In this respect, we exposed human monocyte-derived DCs to a physiological temperature stress of 40°C for up to 24 h followed by analysis for (i) expression of different heat shock proteins, (ii) survival, (iii) cell surface maturation markers, (iv) cytokine secretion, and (v) migratory capacity. Furthermore, we examined the ability of heat-shocked DCs to prime naïve CD8(+) T cells after loading with MelanA peptide, by transfection with MelanA RNA, or by transduction with MelanA by an adenovirus vector. The results clearly indicate that in comparison to control DCs, which remained at 37°C, heat-treated cells revealed no differences concerning the survival rate or their migratory capacity. However, DCs exposed to thermal stress showed a time-dependent enhanced expression of the immune-chaperone heat shock protein 70A and both an up-regulation of co-stimulatory molecules such as CD80, CD83, and CD86 and of the inflammatory cytokine TNF-α. Moreover, these cells had a markedly improved capacity to prime autologous naïve CD8(+) T cells in vitro in an antigen-specific manner, independent of the method of antigen-loading. Thus, our strategy of heat treatment of DCs offers a promising means to improve DC functions during immune activation which, as a physical method, facilitates straight-forward applications in clinical DC vaccination protocols.


Osteogenic and angiogenic activities of silicon-incorporated TiO2 nanotube arrays.
Osteogenesis and angiogenesis that have interaction in vivo are two pivotal processes for implant osseointegration, so implant surfaces with both enhanced osteogenic and angiogenic activities are in need. Developing silicon (Si) doped TiO2 nanotube array (TNA-Si) coatings shall be a promising strategy to yield favorable implant osseointegration with the combined effects of TiO2 nanotube arrays (TNAs) and Si in the enhancement of both osteogenic and angiogenic activities. To achieve this purpose, TNA-Sis are fabricated through the unique strategy of anodization of magnetron-sputtered TiSi coatings. Under optimized conditions, a highly ordered nanotubular structure with even dispersion of Si throughout the nanotubes in the form of SiO2 can be obtained. Si incorporation has little influence on the nanotube length, but slightly decreases the diameter, thickens the nanotube wall, and increases the hydrophilicity. TNA-Sis show good cytocompatibility to both osteoblasts and endothelial cells (ECs). TNA-Sis show enhanced proliferation, spreading, alkaline phosphatase activity, collagen secretion, and matrix mineralization of osteoblasts. Meanwhile, TNA-Sis induce better EC proliferation, and the conditioned culture media from TNA-Sis generate better angiogenic ability, nitric oxide production, and vascular endothelial growth factor secretion from ECs. In particular, TNA-Si4.6 with the strongest osteogenic and angiogenic activities in the context of the present study is highly promising as the next-generation hard tissue implant coating.


Glaucoma drops control intraocular pressure and protect optic nerves in a rat model of glaucoma.
To determine whether chronic topical glaucoma therapy can control intraocular pressure (IOP) and protect nerve fibers in a rat model of pressure-induced optic nerve damage. Sixteen adult Brown Norway rats were-administered unilateral episcleral vein injections of hypertonic saline to produce scarring of the aqueous humor outflow pathways. Twice daily applications of either artificial tears (n = 6), 0.5% betaxolol (n = 5), or 0.5% apraclonidine (n = 5) were delivered to both eyes, and awake pressures were monitored with a TonoPen XL tonometer for 17 days before the rats were killed. For animals administered artificial tears, the mean IOP of the experimental eyes was 39 +/- 2 mm Hg compared with 29 +/- 1 mm Hg for the control eyes. This difference was statistically significant (P < 0.001). Mean IOPs in the experimental eyes of animals administered betaxolol and apraclonidine were 29 +/- 7 and 29 +/- 4 mm Hg, respectively, whereas the mean IOP in the control eyes was 28 +/- 1 mm Hg for both groups. There was no statistically significant difference among these values. The mean IOP for the experimental eyes in the betaxolol and apraclonidine groups was lower than that in animals administered artificial tears (P = 0.003). Quantitative histologic analysis of optic nerve damage in experimental eyes showed that four of the six animals administered artificial tears had damage involving 100% of the neural area. This degree of damage appeared in only 3 of 10 animals administered glaucoma therapy. Optic nerve protection was closely correlated with IOP history because damage was limited to less than 10% of the cross-sectional area in all animals in which the maximal IOP was less than or equal to 39 mm Hg, more than 2 SD below the mean value for eyes administered artificial tears. Topical glaucoma therapy in this model can prevent IOP elevation and protect optic nerve fibers.


Listed for sale: Analyzing data on fentanyl, fentanyl analogs and other novel synthetic opioids on one cryptomarket.
The United States is facing a "triple wave" epidemic fueled by novel synthetic opioids. Cryptomarkets, anonymous marketplaces located on the deep web, play an increasingly important role in the distribution of illicit substances. This article presents the data collected and processed by the eDarkTrends platform concerning the availability trends of novel synthetic opioids listed on one cryptomarket. Listings from the DreamMarket cryptomarket "Opioids" and "Research Chemicals" sections were collected between March 2018 and January 2019. Collected data were processed using eDarkTrends Named Entity Recognition algorithm to identify opioid drugs, and to analyze their availability trends in terms of frequency of listings, available average weights, average prices, and geographic indicators of shipment origin and destination information. 95,011 opioid-related listings were collected through 26 crawling sessions. 33 novel synthetic opioids were identified in 3.3 % of the collected listings. 44.7 % of these listings advertised fentanyl (pharmaceutical and non-pharmaceutical) or fentanyl analogs for an average of 2.8 kgs per crawl. "Synthetic heroin" accounted for 33.2 % of novel synthetic opioid listings for an average 1.1 kgs per crawl with 97.7 % of listings advertised as shipped from Canada. Other novel synthetic opioids (e.g., U-47,700, AP-237) represented 22 % of these listings for an average of 6.1 kgs per crawl with 97.2 % of listings advertised as shipped from China. Our data indicate consistent availability of a wide variety of novel synthetic opioids both in retail and wholesale-level amounts. Identification of new substances highlights the value of cryptomarket data for early warning systems of emerging substance use trends.


Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood.
Dyskeratosis congenita (DC) is a telomere biology disorder characterized by a mucocutaneous triad, aplastic anemia, and predisposition to cancer. Mutations in a narrow segment of TINF2 exon 6 have been recognized to cause often-severe DC that is either sporadic or autosomal dominant. We describe three children with very early presentations of DC, including one with the severe variant known as Revesz syndrome. Although most TINF2 mutations reported to date are missense changes, each of our patients carried a novel heterozygous nonsense or frameshift mutation, revealing a new 5' boundary to the affected gene segment in patients with DC. Examination of patient-derived lymphoblastoid cell lines revealed stable expression of the predicted truncated TIN2 proteins. In co-immunoprecipitation assays, the ability of a truncation mutant to interact with TRF1 was severely impaired, whereas the ability of the most common DC-associated mutant was much less affected. This suggests that the disruption of TIN2-TRF1 interaction may contribute to the severe clinical phenotype observed in the context of the TIN2 truncation mutation, but is unlikely to be the primary cause of telomere shortening associated with the more prevalent TIN2 missense mutations. Telomere flow-fluorescent in situ hybridization (FISH) analysis of one pedigree showed the dramatic effect a de novo nonsense TINF2 mutation had on telomere length in early development. These cases underscore the severe manifestations of truncating TINF2 mutations.


[Ca(2+)](i) oscillation frequency regulates agonist-stimulated NF-kappaB transcriptional activity.
In nonexcitable cells, stimulation by high agonist concentrations typically produces a biphasic increase in cytosolic Ca(2+) ([Ca(2+)](i)). This response is characterized by a transient initial increase because of intracellular Ca(2+) release followed by a sustained elevation which varies in amplitude depending on the nature of the stimulus. In contrast, low-level stimulation often evokes oscillatory changes in [Ca(2+)](i). The specific information provided by repetitive [Ca(2+)](i) spikes appears to be encoded in the frequency rather than in the amplitude of [Ca(2+)](i) oscillations. The specific, membrane-permeable inositol 1,4, 5-trisphosphate (Ins-1,4,5-P(3)) receptor blocker Xestospongin C (XeC, 2-20 microM) was used to affect [Ca(2+)](i) signaling in human aortic endothelial cells (HAEC) during an established response to low-level (1 microM) histamine stimulation. XeC produced a dose-dependent decrease in the frequency of [Ca(2+)](i) oscillations during histamine stimulation without affecting oscillation amplitude. Histamine stimulated a 14-fold increase in NF-kappaB-chloramphenicol acetyltransferase reporter gene activity that was dose-dependently decreased by XeC. Thus, during low-level agonist stimulation, [Ca(2+)](i) oscillation frequency regulates nuclear transcription in HAEC.


[Current point of view on medical treatment of unstable angina].
The combined death/infarct rate in the weeks following unstable angina ranges from 10 to 40%. Aspirin and GP IIb/IIIa antagonists reduce the mortality and morbidity, which has not been demonstrated with heparin. The short term clinical results of treatment with hirudin are better than those with heparin. A rebound biological effect after heparin or hirudin therapy may have adverse clinical consequences. Nitrate derivatives have a role to play and adjuvant therapy includes the betablockers and some calcium antagonists in special indications.


Proliferation and survival signaling from both Jak2-V617F and Lyn involving GSK3 and mTOR/p70S6K/4EBP1 in PVTL-1 cell line newly established from acute myeloid leukemia transformed from polycythemia vera.
The gain of function mutation JAK2-V617F is very frequently found in myeloproliferative neoplasms (MPNs) and is strongly implicated in pathogenesis of these and other hematological malignancies. Here we report establishment of a new leukemia cell line, PVTL-1, homozygous for JAK2-V617F from a 73-year-old female patient with acute myeloid leukemia (AML) transformed from MPN. PVTL-1 is positive for CD7, CD13, CD33, CD34, CD117, HLA-DR, and MPO, and has complex karyotypic abnormalities, 44,XX,-5q,-7,-8,add(11)(p11.2),add(11)(q23),-16,+21,-22,+mar1. Sequence analysis of JAK2 revealed only the mutated allele coding for Jak2-V617F. Proliferation of PVTL-1 was inhibited and apoptosis was induced by the pan-Jak inhibitor Jak inhibitor-1 (JakI-1) or dasatinib, which inhibits the Src family kinases as well as BCR/ABL. Consistently, the Src family kinase Lyn was constitutively activated with phosphorylation of Y396 in the activation loop, which was inhibited by dasatinib but not by JakI-1. Further analyses with JakI-1 and dasatinib indicated that Jak2-V617F phosphorylated STAT5 and SHP2 while Lyn phosphorylated SHP1, SHP2, Gab-2, c-Cbl, and CrkL to induce the SHP2/Gab2 and c-Cbl/CrkL complex formation. In addition, JakI-1 and dasatinib inactivated the mTOR/p70S6K/4EBP1 pathway and reduced the inhibitory phosphorylation of GSK3 in PVTL-1 cells, which correlated with their effects on proliferation and survival of these cells. Furthermore, inhibition of GSK3 by its inhibitor SB216763 mitigated apoptosis induced by dasatinib but not by JakI-1. Together, these data suggest that apoptosis may be suppressed in PVTL-1 cells through inactivation of GSK3 by Lyn as well as Jak2-V617F and additionally through activation of STAT5 by Jak2-V617F. It is also speculated that activation of the mTOR/p70S6K/4EBP1 pathway may mediate proliferation signaling from Jak2-V617F and Lyn. PVTL-1 cells may provide a valuable model system to elucidate the molecular mechanisms involved in evolution of Jak2-V617F-expressing MPN to AML and to develop novel therapies against this intractable condition.


[Immunomodulator sensitivity in patients with peritonitis].
The indexes of the loading rosetteforming tests were studied up in vitro in 10 healthy persons and in 12 patients with peritonitis. In the patients the hyporeactive type of reactivity and multidirectional reaction on immunomodulators was revealed more frequently by comparison with such in a healthy persons. The individual option of the immunocorrecting agents is mandatory in patients with an acute peritonitis.


Access to the CNS: Biomarker Strategies for Dopaminergic Treatments.
Despite substantial research carried out over the last decades, it remains difficult to understand the wide range of pharmacological effects of dopaminergic agents. The dopaminergic system is involved in several neurological disorders, such as Parkinson's disease and schizophrenia. This complex system features multiple pathways implicated in emotion and cognition, psychomotor functions and endocrine control through activation of G protein-coupled dopamine receptors. This review focuses on the system-wide effects of dopaminergic agents on the multiple biochemical and endocrine pathways, in particular the biomarkers (i.e., indicators of a pharmacological process) that reflect these effects. Dopaminergic treatments developed over the last decades were found to be associated with numerous biochemical pathways in the brain, including the norepinephrine and the kynurenine pathway. Additionally, they have shown to affect peripheral systems, for example the hypothalamus-pituitary-adrenal (HPA) axis. Dopaminergic agents thus have a complex and broad pharmacological profile, rendering drug development challenging. Considering the complex system-wide pharmacological profile of dopaminergic agents, this review underlines the needs for systems pharmacology studies that include: i) proteomics and metabolomics analysis; ii) longitudinal data evaluation and mathematical modeling; iii) pharmacokinetics-based interpretation of drug effects; iv) simultaneous biomarker evaluation in the brain, the cerebrospinal fluid (CSF) and plasma; and v) specific attention to condition-dependent (e.g., disease) pharmacology. Such approach is considered essential to increase our understanding of central nervous system (CNS) drug effects and substantially improve CNS drug development.


Calcium-induced compaction and its inhibition in embryonal carcinoma cell aggregates.
H6 embryonal carcinoma cells form aggregates of cells in culture medium which contains 2 mM calcium. These aggregates are described as uncompacted, indicating that the individual cells of the aggregate are spherical and are in limited contact with each other. In contrast, compaction of the aggregate, induced by increasing the calcium concentration, results in a tight mass of cells flattened against one another and connected by intercellular junctions. At least 85-97% of the aggregates undergo compaction in 7 mM calcium and are subsequently decompacted if removed to 2 mM calcium. Since calcium ionophore A23187 does not induce compaction, extracellular rather than intracellular calcium seems to be the limiting factor. We have demonstrated that this calcium-induced morphogenetic change is sensitive to inhibition by agents which also prevent the calcium-dependent compaction of the 8-cell mouse embryo. The cytoskeletal-binding drugs tetracaine HCl, colcemid, vinblastine, colchicine, and cytochalasin B each inhibit compaction of H6 aggregates. Interference at surface molecule sites by exposure to the lectins wheat germ agglutinin or concanavalin A or by interruption of glycosylation with exposure to tunicamycin, or by reaction with anti-H6 Fab or anti-F9, also prevent compaction. Since the mouse embryo and embryonal carcinoma cells share certain processes which are involved in initiating and maintaining compaction, these processes and their subsequent roles in differentiation may be examined using embryonal carcinoma cell aggregates.


Measurement and Calibration of Plant-Height from Fixed-Wing UAV Images.
Continuing population growth will result in increasing global demand for food and fiber for the foreseeable future. During the growing season, variability in the height of crops provides important information on plant health, growth, and response to environmental effects. This paper indicates the feasibility of using structure from motion (SfM) on images collected from 120 m above ground level (AGL) with a fixed-wing unmanned aerial vehicle (UAV) to estimate sorghum plant height with reasonable accuracy on a relatively large farm field. Correlations between UAV-based estimates and ground truth were strong on all dates (R² > 0.80) but are clearly better on some dates than others. Furthermore, a new method for improving UAV-based plant height estimates with multi-level ground control points (GCPs) was found to lower the root mean square error (RMSE) by about 20%. These results indicate that GCP-based height calibration has a potential for future application where accuracy is particularly important. Lastly, the image blur appeared to have a significant impact on the accuracy of plant height estimation. A strong correlation (R² = 0.85) was observed between image quality and plant height RMSE and the influence of wind was a challenge in obtaining high-quality plant height data. A strong relationship (R² = 0.99) existed between wind speed and image blurriness.


The Versatility of Opportunistic Infections Caused by Gemella Isolates Is Supported by the Carriage of Virulence Factors From Multiple Origins.
The molecular basis of the pathogenesis of the opportunistic invasive infections caused by isolates of the Gemella genus remains largely unknown. Moreover, inconsistencies in the current species assignation were detected after genome-level comparison of 16 public Gemella isolates. A literature search detected that, between the two most pathogenic species, Gemella morbillorum causes about twice the number of cases compared to Gemella haemolysans. These two species shared their mean diseases - sepsis and endocarditis - but differed in causing other syndromes. A number of well-known virulence factors were harbored by all species, such as a manganese transport/adhesin sharing 83% identity from oral endocarditis-causing streptococci. Likewise, all Gemellae carried the genes required for incorporating phosphorylcholine into their cell walls and encoded some choline-binding proteins. In contrast, other proteins were species-specific, which may justify the known epidemiological differences. G. haemolysans, but not G. morbillorum, harbor a gene cluster potentially encoding a polysaccharidic capsule. Species-specific surface determinants also included Rib and MucBP repeats, hemoglobin-binding NEAT domains, peptidases of C5a complement factor and domains that recognize extracellular matrix molecules exposed in damaged heart valves, such as collagen and fibronectin. Surface virulence determinants were associated with several taxonomically dispersed opportunistic genera of the oral microbiota, such as Granulicatella, Parvimonas, and Streptococcus, suggesting the existence of a horizontally transferrable gene reservoir in the oral environment, likely facilitated by close proximity in biofilms and ultimately linked to endocarditis. The identification of the Gemella virulence pool should be implemented in whole genome-based protocols to rationally predict the pathogenic potential in ongoing clinical infections caused by these poorly known bacterial pathogens.


A winning smile? Smile intensity, physical dominance, and fighter performance.
The smile is perhaps the most widely studied facial expression of emotion, and in this article we examine its status as a sign of physical dominance. We reason, on the basis of prior research, that prior to a physical confrontation, smiles are a nonverbal sign of reduced hostility and aggression, and thereby unintentionally communicate reduced physical dominance. Two studies provide evidence in support of this prediction: Study 1 found that professional fighters who smiled more in a prefight photograph taken facing their opponent performed more poorly during the fight in relation to their less intensely smiling counterparts. In Study 2, untrained observers judged a fighter as less hostile and aggressive, and thereby less physically dominant when the fighters' facial expression was manipulated to show a smiling expression in relation to the same fighter displaying a neutral expression. Discussion focused on the reasons why smiles are associated with decreased physical dominance.


Measurement of cytoplasmic free Ca2+ concentration in rabbit aorta using the photoprotein, aequorin. Effect of atrial natriuretic peptide on agonist-induced Ca2+ signal generation.
Addition of norepinephrine, angiotensin II, or histamine leads to a transient rise in the cytoplasmic Ca2+ concentration ([Ca2+]i), as measured with aequorin, in rabbit aortic strips. Each induces a [Ca2+]i transient which peaks in 2 min and then falls either back to baseline (angiotensin II) or to a plateau (norepinephrine and histamine). The [Ca2+]i transient is due to the mobilization of Ca2+ from a caffeine-sensitive, intracellular pool. An elevation of [K+] to 35 mM leads to a monotonic sustained rise in [Ca2+]i which depends entirely on extracellular Ca2+, but an increase to 100 mM leads to a [Ca2+]i transient from the mobilization of intracellular Ca2+. Atrial natriuretic peptide does not alter basal [Ca2+]i nor inhibit the [Ca2+]i transient induced by either histamine or angiotensin II, but blocks that induced by norepinephrine, and blocks the plateau phase induced by either histamine or norepinephrine. The peptide inhibits the contractile response to all three agonists and to K+.


Review of supplemental views and stress radiography in musculoskeletal trauma: upper extremity.
The standard radiographic series is not always sufficient to diagnose and characterize subtle musculoskeletal injuries. Missed or delayed diagnoses can negatively affect patient acute morbidity and long-term outcomes. Similarly, management based on erroneous diagnoses may lead to unnecessary treatment and restrictions. Body part or joint specific supplemental radiographic views and stress radiography offer an alternative for further evaluation of subtle injuries in specific clinical situations and may obviate the need for the added cost and potential ionizing radiation exposure of further cross-sectional imaging. Familiarity with these complementary exams allows radiologists to play an important role in patient care, as their utilization can improve diagnostic accuracy, clarify subtle or uncertain findings, and direct timely patient management. This review highlights important supplemental views and stress radiographic examinations useful in the evaluation of emergent upper extremity musculoskeletal trauma.


Risk factors for leptospirosis infection in humans and implications for public health intervention in Indonesia and the Asia-Pacific region.
Prevention and control of leptospirosis require an understanding of risk factors. This review identifies risk factors associated with leptospirosis infection from countries in the Asia-Pacific region, and compares and contrasts these data with those available from Indonesia. MEDLINE, PubMed, and Scopus databases were used to search for relevant articles. Indonesian gray literature was searched for leptospirosis risk factor studies in Indonesia. A total of 34 articles were included in this review. The contrast between peer-reviewed publications and Indonesian gray literature revealed that the variety of risk factors associated with leptospirosis infection is region or area specific. The presence of skin wounds, the existence of rodents, especially rats, and activities related to contact with contaminated surface water are factors frequently reported to have significant association with leptospirosis infection in human in Indonesia and in other Asia-Pacific countries.


LC-Orbitrap-HRMS Determination of Two Novel Plastochromanol Homologues.
The antioxidant plastochromanol-8 (PC-8) is a tocochromanol which differs from γ-tocotrienol in having an unsaturated side chain of eight instead of three isoprene units. The recent isolation of PC-8 from flaxseed oil indicates the additional presence of lower shares of two previously unknown homologues, plastochromanol-7 (PC-7) and plastochromanol-9 (PC-9), which feature seven and nine isoprenoid units respectively on the γ-chromanol backbone. Here, a fast LC-Orbitrap-HRMS method is applied for the determination of PC-7 and PC-9 in seven plant oils and a plant extract. The presence of PC-7, PC-8, and PC-9 is confirmed in all eight investigated samples by LC-Orbitrap-HRMS analysis after saponification. PC-8 amounts of ≈315-350 mg kg-1 in two flaxseed oils, ≈75 mg kg-1 in rapeseed oil, ≈38 mg kg-1 in camelina oil, ≈80-120 mg kg-1 in two mustard oils, ≈90 mg kg-1 in candle nut oil, and ≈900 mg kg-1 dry weight in Cecropia leaves are determined by quantification. Semi-quantification of PC-7 and PC-9 indicated the presence of ≈0.1-1% of PC-7 and PC-9 in varied relative ratios. The novel plastochromanol homologues are of particular interest to researchers with focus on vitamin E and other tocochromanols because of their unexplored bioactivity.


Medicare program; coverage of epoetin (EPO) used by competent home dialysis patients--HCFA. Final rule.
This final rule adopts as final the interim final rule that provided for Medicare coverage of EPO used by ESRD beneficiaries who dialyze at home and are competent to use the drug without medical or other supervision and established criteria for selection of patients that can be considered "competent" and for monitoring of the patients who are selected. It also makes minor changes in response to public comments on the interim rule. The interim rule was necessary to implement section 4201(d)(1) of the Omnibus Budget Reconciliation Act of 1990 (OBRA '90). The purpose of the amendments is to facilitate use of EPO at home, while ensuring that such use of the drug is safe.


Skeletal unloading inhibits the in vitro proliferation and differentiation of rat osteoprogenitor cells.
Loss of weight bearing in the growing rat decreases bone formation, osteoblast numbers, and bone maturation in unloaded bones. These responses suggest an impairment of osteoblast proliferation and differentiation. To test this assumption, we assessed the effects of skeletal unloading using an in vitro model of osteoprogenitor cell differentiation. Rats were hindlimb elevated for 0 (control), 2, or 5 days, after which their tibial bone marrow stromal cells (BMSCs) were harvested and cultured. Five days of hindlimb elevation led to significant decreases in proliferation, alkaline phosphatase (AP) enzyme activity, and mineralization of BMSC cultures. Differentiation of BMSCs was analyzed by quantitative competitive polymerase chain reaction of cDNA after 10, 15, 20, and 28 days of culture. cDNA pools were analyzed for the expression of c-fos (an index of proliferation), AP (an index of early osteoblast differentiation), and osteocalcin (a marker of late differentiation). BMSCs from 5-day unloaded rats expressed 50% less c-fos, 61% more AP, and 35% less osteocalcin mRNA compared with controls. These data demonstrate that cultured osteoprogenitor cells retain a memory of their in vivo loading history and indicate that skeletal unloading inhibits proliferation and differentiation of osteoprogenitor cells in vitro.


[Hermetic sealing of the cataract incision with intracorneal mattress sutures].
Main factors of hermetic closure of an operative wound in cataract extraction with intracapsular implantation of intraocular lens are discussed. A new method for closure of operation wound in this operation is proposed. Opposition intracorneal mattress sutures are made over the incision plane. Their principal feature is that the thread is not thrown over the external edge of corneal incision, as in traditional non-opposition sutures, and during pulling and suture the thread does not deform the external surface of the cornea in the central zone and hence, causes no postoperative corneal astigmatism. A method combining opposition and interrupted non-opposition sutures is proposed, and various combinations of these sutures are compared. Forty-five patients (45 eyes) were operated on using the proposed technique. Opposition sutures made in accordance with the methods proposed by the authors do not cause high postoperative corneal astigmatism, or it approximates the normal values of corneal astigmatism. A special marker is proposed for preliminary marking of sites for nonperforating incisions on the cornea and the site of cataract incision.


Prevention and treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative diseases in immune deficient patients.
Prevention of EBV-associated lymphoproliferative diseases in immune deficient individuals is preferred; however, standard therapy for the B cell lymphomas has been successful. Chemotherapy must be given cautiously lest further immune compromise result in opportunistic infections. Recently, Acyclovir has decreased morbidity of patients with acute infectious mononucleosis in immune competent persons. In contrast, immunodeficient patients with X-linked lymphoproliferative (XLP) syndrome do not seem to respond favorably. Hence, a prospective study is underway using prophylactic immunoglobulin containing (EBV)-specific antibodies. The mortality rate is 85% following EBV infection in XLP due to fatal infectious mononucleosis associated with fulminant hepatitis and virus-associated hemophagocytic syndrome, acquired hypogammaglobulinemia or malignant B cell lymphoma. We can detect XLP by noting failure of switching from IgM to IgG antibody production on secondary challenge with bacteriophage phi X174. Also, linkage studies with the XLP locus using restriction fragment length polymorphisms are being done to detect affected males pre-EBV infection. Our rationale for prevention of phenotypes of XLP is based on observations that infants in tropical Africa and males with XLP do not develop EBV-induced diseases while neutralizing maternal antibodies are present. An EBV vaccine will be used, when available, in seronegative males with XLP. Prevention of acquired immune deficiency by screening blood for human immune deficiency virus, encouraging prudent life styles, development of specific immunosuppressive agents, development of new antiviral agents (i.e., DHPG), and identification of high risk seronegative patients offer possibilities for preventing life-threatening EBV-induced diseases.


Biological evaluation of intervertebral disc cells in different formulations of gellan gum-based hydrogels.
Gellan gum (GG)-based hydrogels are advantageous in tissue engineering not only due to their ability to retain large quantities of water and provide a similar environment to that of natural extracellular matrix (ECM), but also because they can gelify in situ in seconds. Their mechanical properties can be fine-tuned to mimic natural tissues such as the nucleus pulposus (NP). This study produced different formulations of GG hydrogels by mixing varying amounts of methacrylated (GG-MA) and high-acyl gellan gums (HA-GG) for applications as acellular and cellular NP substitutes. The hydrogels were physicochemically characterized by dynamic mechanical analysis. Degradation and swelling abilities were assessed by soaking in a phosphate buffered saline solution for up to 170 h. Results showed that as HA-GG content increased, the modulus of the hydrogels decreased. Moreover, increases in HA-GG content induced greater weight loss in the GG-MA/HA-GG formulation compared to GG-MA hydrogel. Potential cytotoxicity of the hydrogel was assessed by culturing rabbit NP cells up to 7 days. An MTS assay was performed by seeding rabbit NP cells onto the surface of 3D hydrogel disc formulations. Viability of rabbit NP cells encapsulated within the different hydrogel formulations was also evaluated by Calcein-AM and ATP assays. Results showed that tunable GG-MA/HA-GG hydrogels were non-cytotoxic and supported viability of rabbit NP cells.


Nursing curricula relating to care for disabled children: literature review.
To provide a literature review of nursing curricula relating to care for children with disabilities. Children with disabilities do not receive adequate attention in nursing curricula for children. The best approach to promoting the standard of care delivery to children with disabilities is to improve the quantity and quality of training among health professionals. We conducted the review using three databases, CINAHL, MEDLINE and ProQuest, between the years 1990 and 2015. The review commenced in 2012 and was updated in 2015. Seventy-eight studies were initially identified. Out of 78 retrieved articles, only six research articles contained all the keywords 'education', 'disability' and 'curriculum'; no articles contained all the keywords 'nursing education, 'children with disabilities' and 'curriculum'. Five themes have been generated from the literature review relating to disability content within nursing curricula, namely: overloaded curriculum, gaps in the contemporary curricula, lack of faculty expertise, problems with teaching methods and focus on the medical model. There was a paucity of evidence for the way that disability was presented in the nursing curricula for children. Improving the provision of care delivery to children with disabilities should be paid adequate attention in nursing curricula for children. Additionally, there is a need for policy-makers to identify the best coverage of nursing curricula, as well as the most effective nurse training methods that enhance knowledge and clinical skills relating to the care of children with disabilities.


[Treatment of membranous glomerulonephritis].
Forty-two patients with membranous glomerulonephritis were treated. Complete regression of the disease and nephrotic syndrome was attained in 46.3%, partial in 27.3% of all the cases of disease exacerbations. The importance of the individualized choice of the most efficacious drug therapy and promising results of the many-month treatment to raise the time of an ensuing remission are shown.