Internal fixation of radiation-induced pathological fractures of the femur has a high rate of failure.
We investigated the clinical outcome of internal fixation for pathological fracture of the femur after primary excision of a soft-tissue sarcoma that had been treated with adjuvant radiotherapy. A review of our database identified 22 radiation-induced fractures of the femur in 22 patients (seven men, 15 women). We noted the mechanism of injury, fracture pattern and any complications after internal fixation, including nonunion, hardware failure, secondary fracture or deep infection. The mean age of the patients at primary excision of the tumour was 58.3 years (39 to 86). The mean time from primary excision to fracture was 73.2 months (2 to 195). The mean follow-up after fracture fixation was 65.9 months (12 to 205). Complications occurred in 19 patients (86%). Nonunion developed in 18 patients (82%), of whom 11 had a radiological nonunion at 12 months, five a nonunion and hardware failure and two an infected nonunion. One patient developed a second radiation-associated fracture of the femur after internal fixation and union of the initial fracture. A total of 13 patients (59%) underwent 24 revision operations. Internal fixation of a pathological fracture of the femur after radiotherapy for a soft-tissue sarcoma has an extremely high rate of complication and requires specialist attention.


Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial.
The effect of extended adjuvant aromatase inhibition in hormone receptor-positive breast cancer after sequential endocrine therapy of tamoxifen followed by an aromatase inhibitor for a 5-year treatment period still needs clarification. To address this issue, we began the DATA study to assess different durations of anastrozole therapy after tamoxifen. DATA was a prospective, randomised, open-label, multicentre, phase 3 study done in 79 hospitals in the Netherlands. We randomly assigned postmenopausal women with hormone receptor-positive early breast cancer with no signs of disease recurrence after 2-3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole treatment (1 mg orally once a day) in a 1:1 ratio. We used TENALEA (Trans European Network for Clinical Trials Services) for the randomisation procedure. Stratification factors were nodal status, hormone receptor status, HER2 status, and tamoxifen treatment duration. The primary study endpoint of this analysis was disease-free survival starting beyond 3 years after randomisation (adapted disease-free survival). Here we report the final analysis from the DATA trial, which is registered with ClinicalTrials.gov, number NCT00301457. Between June 28, 2006, and Aug 10, 2009, we screened 1912 patients of whom 955 were assigned to the 3-year group and 957 to the 6-year anastrozole treatment group. 1860 patients were eligible (931 in the 6-year group and 929 in the 3-year group) and 1660 were disease free 3 years after randomisation. The 5-year adapted disease-free survival was 83·1% (95% CI 80·0-86·3) in the 6-year group and 79·4% (76·1-82·8) in the 3-year group (hazard ratio [HR] 0·79 [95% CI 0·62-1·02]; p=0·066). Patients in the 6-year treatment group had more adverse events than those in the 3-year treatment group, including all-grade arthralgia or myalgia (478 [58%] of 827 in the 6-year treatment group vs 438 [53%] of 833 in the 3-year treatment group) and osteopenia or osteoporosis (173 [21%] vs 137 [16%]). We cannot recommend the use of extended adjuvant aromatase inhibition after 5 years of sequential endocrine therapy in all postmenopausal women with hormone receptor-positive breast cancer. AstraZeneca.


Telephotoscreening to detect retinopathy of prematurity: preliminary study of the optimum time to employ digital fundus camera imaging to detect ROP.
Labor-intensive screening of infants in the neonatal intensive care units is the only way presently to detect retinopathy of prematurity (ROP). Our purpose is to determine if RetCam 120 images (Massie Research Laboratories, Inc, Dublin, Calif), acquired by a neonatal nurse, can be used to screen for ROP by performing 2 screening sessions, at 32 to 34 weeks' (examination 1) and 38 to 40 weeks' (examination 2) postconceptional age. RetCam examinations were performed by a nurse on infants at examination 1 and examination 2 intervals. At the same time, an examination was performed by an experienced ophthalmologist. Masked readers evaluated the digital images for the presence of ROP and, if ROP was present, estimated the risk of that eye progressing to prethreshold or threshold disease. The data were compared to the eye's clinical course. A total of 46 eyes were assessed at examination 1 and 50 eyes at examination 2 from July 1, 1999, to December 15, 1999. For detecting ROP, the sensitivity and specificity were 46% and 100% for examination 1 and 76% and 100% for examination 2. Sensitivity and specificity of predicting prethreshold was 64% and 97%, respectively, for examination 1 and 2. Sensitivity for predicting ROP threshold at examination 1 was 0% (only 1 photo was available for grading of sensitivity) and specificity for predicting ROP threshold at examination 1 was 95%. At examination 2, sensitivity and specificity were 100%. The RetCam examination had insufficient sensitivity to be recommended as a substitute for indirect ophthalmoscopy in screening for ROP. Reasons for low sensitivity are the technical limitation of the camera design itself, which creates difficulty in photographing the peripheral retina in small eyes, and the need for a lid speculum better adapted to the contact camera optical system design. Both of these issues are being addressed as part of an ongoing project to study the feasibility of employing telemetry of digital fundus images from remote, underserved neonatal intensive care units to ophthalmologists capable of diagnosing ROP.


Inhibition of early development stages of rust fungi by the two fungal metabolites cyclopaldic acid and epi-epoformin.
Rusts are a noxious group of plant diseases affecting major economically important crops. Crop protection is largely based on chemical control. There is a renewed interest in the discovery of natural products as alternatives to synthetic fungicides for control. In this study we tested two fungal metabolites, namely cyclopaldic acid and epi-epoformin, for their effectiveness in reducing early stages of development of two major rust fungi from the genera Puccinia and Uromyces, P. triticina and U. pisi. Spore germination and appressorium formation were assessed on pretreated detached leaves under controlled conditions. Cyclopaldic acid and epi-epoformin were also tested in infected plants in order to evaluate the level of control achieved by treatments both before and after inoculation. Cyclopaldic acid and epi-epoformin were strongly effective in inhibiting fungal germination and penetration of both rust species studied. This effect was not dose dependent. These results were further confirmed in planta by spraying the metabolites on plant leaves, which reduced fungal developmental of U. pisi and P. triticina at values comparable with those obtained by application of the fungicide. Our results further demonstrate the potential of fungal metabolites as natural alternatives to synthetic fungicides for the control of crop pathogens of economic importance as rusts. © 2016 Society of Chemical Industry.


Sublethal effect of mercury and lead on monoamine oxidase in different regions of the brain in three freshwater teleosts.
Effect of mercury and lead at 24 and 48 h was investigated on monoamine oxidase (MAO) activity in different regions of the brain (telencephalon, cerebellum, diencephalon and medulla oblongata) in Labeo rohita, Ham., Clarias batrachus, L. and Channa punctatus, Bloch. Highest rise in MAO activity was recorded in telencephalon with mercury followed by lead. Maximum variations in the level of MAO activity in different regions of the brain were recorded at 24 h exposure. The observed alterations were discussed in relation to different parameters.


[Effect of sociodemographic factors, cancer, psychiatric disorder on suicide: gender and age-specific patterns].
We examined the effect of sociodemographic factors, cancer, and psychiatric disorders on suicide by gender and age-specific patterns in South Korea. The study is a case-control study. Claim data was obtained from the national health insurance database and national death registration database. The number of people who committed suicide was 11,523, which was matched with a control group consisting of ten times as many people at 115,230 selected from the national health insurance and medical aids beneficiaries. The medical utilization of the case group was one year before death and that of the control group was from July 1,2003 to June 30, 2004. Four variables-address, economic status, presence of a psychiatric disease, and cancer-were used in multiple logistic regression analyses. Living in cities or in rural areas showed a greater risk for suicide than living in a metropolitan city. Low economic status, the presence of a psychiatric disorder, and cancer were also statistically meaningful risk factors for suicide. The three major psychiatric diseases, schizophrenia, alcohol abuse, and bipolar disorder, were meaningful in all age groups, but the scale of the odds ratio differed by the age group. Only the psychiatric disorder variable was meaningful in the adolescent group, whereas a psychiatric disorder and economic status were meaningful for the young adult group, and all variables were meaningful for the middle-aged group. A psychiatric disorder and cancer were meaningful in the elderly group, economic status was meaningful for male subjects, and address was meaningful for female subjects. Factors such as living in city or rural areas, low economic status, the presence of a psychiatric disorder, and cancer were statistically meaningful risk factors in suicide. These factors also differed by age group. Therefore, policymakers should establish policies for suicide prevention that are relevant for each age group.


Abolished ischemic tricuspid regurgitation by revascularization of left anterior descending artery: The role of collateral circulation.
A 74-year-old man presented with recent inferior wall myocardial infarction. The right ventricle (RV) was strikingly dilated and akinetic along the free wall compatible with right ventricular infarction. Accordingly, severe functional tricuspid regurgitation (TR) was detected. Coronary angiogram revealed total occlusion on the proximal right coronary artery (RCA). There was collateral blood flow from the left anterior descending (LAD) artery to the right ventricular ischemic region. The LAD artery also had a significant stenosis which might limit the required amount of blood supply to collateral blood vessels. Because of the technical difficulty in the intervention of RCA, the patient underwent percutaneous intervention on the LAD artery. After the revascularization of LAD artery, severe TR was abolished accompanied by the right ventricular functional recovery. <Learning objective: Isolated ischemic tricuspid regurgitation was rarely manifested because the right ventricle has a more favorable oxygen supply-demand ratio than the left ventricle and receives extensive collateral flow from the left-to-right collateral system. In our case, the right ventricle was receiving blood flow through collateral circulation from septal branches of the left anterior descending coronary artery due to the total occlusion of proximal right coronary artery. This case displays the remarkable role of collateral circulation in restoring right ventricular function and in treating ischemic tricuspid regurgitation.>.


Molecular imprinting within hydrogels II: progress and analysis of the field.
In the past decade, there has been an exponential increase in the number of papers describing molecular imprinting in hydrogels, a technique which creates memory for template molecules within a flexible macromolecular structure. Macromolecular memory or structural plasticity of polymer chains is a superior description of weakly crosslinked imprinted networks since significant flexibility can occur within the polymer chains. The focus of this article is to review and highlight work in the field describing the imprinting strategy within hydrogels and associated challenges, characterization methods of imprinted gels, current and potential translational applications, and future strategies and directions. This paper also describes ways to improve binding parameter efficacy and presents significant areas of opportunity to further describe, characterize, and understand imprinted gels. An analysis of the literature indicates that imprinting in hydrogels leads to significant improvements in template affinity, capacity, and selectivity over non-templated hydrogels for a number of templates such as ions, small and moderate molecular weight molecules, proteins, viruses, DNA, and cells. However, the influence of imprinting on the transport of template is much more complex, with little attention of most studies to structural analysis or discussion of the gel porosity/tortuosity in the control of template transport. Responsive, intelligent imprinted hydrogels are also highlighted that exhibit reversibly modulated template binding and transport. It is clear that this field has transitioned from infancy and is leading to breakthroughs in a number of areas such as controlled and modulated drug delivery, diagnostic sensors, and separation. For example in drug delivery, imprinting can lead to delayed transport and provides further control of therapeutic transport through the macromolecular structure as well as optimizes the number of therapeutic molecules to polymer chains.


Validity of family history data on primary adult-onset dystonia.
To our knowledge, no study has assessed the validity of family history data provided by probands with adult-onset dystonia. To measure the sensitivity and specificity of interviewing patients with primary adult-onset dystonia as a method for obtaining information on dystonia in first-degree relatives. Seventy probands with primary adult-onset dystonia were asked to identify first-degree relatives who had dystonia. Available relatives were then directly examined by a trained neurologist. The validity of the probands' reports was tested against the neurologists' diagnoses. Among 300 first-degree relatives who were examined, 26 received a diagnosis of dystonia. Only 7 of the 26 were identified by the probands' reports. Among the 274 relatives free of dystonia, the probands reported 5 as having dystonia. The probands' reports therefore yielded a sensitivity of 27.0% and a specificity of 98.2%. Because the family history method yields low sensitivity and incurs a risk of misclassification, it is of limited use in family studies of adult-onset dystonia. The only valid means of ascertaining dystonia among relatives remains neurological examination of at-risk subjects.


Behavioral conditioning and idiopathic environmental intolerance.
Idiopathic environmental intolerance (IEI) is a poorly understood condition that may involve disturbances in immunologic, neurologic, endocrine, behavioral, emotional, and cognitive processes. This chapter reviews theories and evidence that behavioral conditioning processes, including pharmacologic sensitization, conditioned immunomodulation, and conditioned odor and taste aversions, may play a role in the development and maintenance of IEI. It also reviews the psychophysiologic concepts of individual response specificity and situational response stereotypy as potential explanations for the individual differences observed in specific responses to environmental stimuli in patients with IEI. Finally, the treatment implications of a conditioning account of IEI are discussed as part of a more comprehensive treatment approach that incorporates other behavioral and nonbehavioral strategies.


mGluR5/ERK signaling regulated the phosphorylation and function of glycine receptor α1ins subunit in spinal dorsal horn of mice.
Inhibitory glycinergic transmission in adult spinal cord is primarily mediated by glycine receptors (GlyRs) containing the α1 subunit. Here, we found that α1ins, a longer α1 variant with 8 amino acids inserted into the intracellular large loop (IL) between transmembrane (TM)3 and TM4 domains, was expressed in the dorsal horn of the spinal cord, distributed at inhibitory synapses, and engaged in negative control over nociceptive signal transduction. Activation of metabotropic glutamate receptor 5 (mGluR5) specifically suppressed α1ins-mediated glycinergic transmission and evoked pain sensitization. Extracellular signal-regulated kinase (ERK) was critical for mGluR5 to inhibit α1ins. By binding to a D-docking site created by the 8-amino-acid insert within the TM3-TM4 loop of α1ins, the active ERK catalyzed α1ins phosphorylation at Ser380, which favored α1ins ubiquitination at Lys379 and led to α1ins endocytosis. Disruption of ERK interaction with α1ins blocked Ser380 phosphorylation, potentiated glycinergic synaptic currents, and alleviated inflammatory and neuropathic pain. These data thus unraveled a novel, to our knowledge, mechanism for the activity-dependent regulation of glycinergic neurotransmission.


Characterization of porcine growth hormone (pGH) binding to porcine liver microsomes: chronic administration of pGH induces pGH binding.
The effect that GH has on regulating GH binding to its receptors has not been resolved. This report describes the characterization of porcine (p) GH binding to pig liver membranes and clarifies the issue of regulation of GH binding by measuring pGH binding to liver membranes prepared from pigs treated daily for 35 days with different doses of pGH (0, 10, 30, or 70 micrograms/kg BW). Specific binding of [125I]pGH was dependent on time, pH, and membrane protein concentration. At 23 C, pGH binding reached a steady state after 24 h. Maximal pGH binding was observed at pH 7. Binding increased linearly as membrane protein concentration was increased from 150 to 450 micrograms/tube. Specificity studies indicated that the hepatic GH receptor was somatogenic, since porcine PRL poorly inhibited [125I] pGH binding (cross-reactivity, 0.1%). Treatment of microsomes from control pigs with 4 m MgCl2 to remove endogenously bound pGH did not affect pGH binding, whereas binding was significantly increased to microsomes from pGH-treated pigs. Binding of pGH increased in a linear manner with the dose of pGH given for 35 days (r = 0.79), thus establishing the inductive effect of chronic pGH administration on pGH binding in pig liver. GH binding was highly correlated with weight gain in pigs treated with pGH (r = 0.76). In addition, the serum insulin-like growth factor I (IGF-I) concentration was increased linearly (r = 0.87) by pGH. This increase in serum IGF-I was also highly correlated with the increase in pGH binding (r = 0.71). These results suggest that hepatic GH binding plays an important role in regulating pig growth, which may be mediated, in part, by an increase in hepatic IGF-I synthesis and secretion. The present report is also the first to establish that exogenous pGH induces pGH binding to pig hepatic GH receptors and to relate this increase in binding to an enhancement in pig growth.


Mucin ball-producing extrahepatic bile duct carcinoma.
The characteristic features of surgically curable mucin-producing extrahepatic bile duct carcinoma (MPEBC) have not previously been elucidated. Three (6.5%) of 46 patients who underwent surgery in our department for bile duct carcinoma between 1986 and 1997 had MPEBC. Clinicopathological features, diagnostic procedures and operative methods for patients with MPEBC were investigated. Tumors in the bile duct were identified by cholangioscopy combined with cholangiography after removal of mucin balls. Tumors were located close to the hepatic confluence in these patients. Two patients underwent hepatic lobectomy together with caudate lobectomy while the other underwent resection of the hepatic confluence. Absence of residual tumors was confirmed histologically in these patients. All three patients remain alive without evidence of recurrence, 22-54 months after surgery. MPEBC is a curable disease. Accurate localization in the biliary tree is essential and can only be obtained after, i) removal of mucin balls, and ii) extensive diagnostic work-up including cholangiography, cholangioscopy and intraoperative pathological examination.


Complex regional pain syndrome type 1 in a pediatric patient: Case report.
Complex regional pain syndrome type 1 is one of the causes of morbidity of childhood which is also named reflex symphathetic dystrophia. The syndrome is characterized with regional pain and vasomotor, sudomotor and sensory changes in the distal parts of the extremities involved. Complex regional pain syndrome type 1 shows difference in children in terms of clinical picture and imaging methods compared to adults. The most important point is that the prognosis is generally better in children if early diagnosis and treatment is provided. On the other hand, causes including presence of psychological factors or less contribution of imaging methods in children lead to delayed diagnosis or erroneous diagnosis. In this article, a 10 year-old male patient who was diagnosed with complex regional pain syndrome type 1 was described. Thus, we aimed to remind clinicians that this syndrome should also be kept in mind in the differential diagnosis of pain in children.


Fabry-Perot recycling spectrometer.
A new type of Fabry-Perot spectrometer has been developed to achieve multichannel operation with recovery of the light that is lost in conventional systems. The light reflected from the interferometer is recycled in a predetermined way using small right angle prisms. When applied to nanosecond light pulses, the new system allows multichannel recording with a single detector. In this paper the realization of the instrument is presented. It has been tested in a prototype version with five channels. More than ten channels should be attainable. Some characteristic properties of the instrument are discussed.


Continuing medical education: a survey of practitioners' needs and interests.
A number of factors, including legislated recertification or relicensure, have engendered a tremendous increase in the number and type of continuing medical education (CME) programs being offered. There is very sparse documentation of the involvement of the intended recipient or practitioner in the conceptualization, development and conduct of CME programs. In order to more accurately ascertain the factors or circumstances that influence attendance or nonattendance at a CME program, a five-page questionnaire was developed that asked a randomly sampled population of 313 practicing obstetricians ane gynecologists to indicate their preference for CME programs.


Data analysis of high-throughput screening results: application of multidomain clustering to the NCI anti-HIV data set.
The routine use of high-throughput screening (HTS) systems in the drug discovery process has resulted in an increasing need for fast, reliable analysis of massive amounts of data. A new automated multidomain clustering method that thoroughly analyzes screening data sets is used to examine both the active and the inactive compounds in a well-known, publicly available data set based on primary screening. Large and small compound sets that defined both chemical families and potential pharmacophore points were discovered. The detection of structure-activity relationships (SAR), aided by the unique classification method, is described in this article.


Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection.
The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling.


Revealing the sources of arsenic in private well water using Random Forest Classification and Regression.
Exposure to arsenic through private drinking water wells causes serious human health risks throughout the globe. Water testing data indicates there is arsenic contamination in private drinking water wells across New Jersey. To reduce the adverse health risk due to exposure to arsenic in drinking water, it is necessary to identify arsenic sources affecting private wells. Private wells are not regulated by any federal or state agencies through the Safe Drinking Water Act and therefore information is often lacking. To this end, we have developed machine learning algorithms including Random Forest Classification and Regression to decipher the factors contributing to higher arsenic concentration in private drinking water wells in west-central New Jersey. Arsenic concentration in private drinking water wells served as a response variable while explanatory variables were geological bedrock type, soil type, drainage class, land use/cover, and presence of orchards, contaminated sites, and abandoned mines within the 152.4-meter (500 ft) radius of each well. Random Forest Classification and Regression achieved 66 % and 55 % prediction accuracies for arsenic concentration in private drinking water wells, respectively. Overall, both models identify that bedrock, soil, land use/cover, and drainage type (in descending order) are the most important variables contributing to higher arsenic concentration in well water. These models further identify bedrock subgroups at a finer scale including Passaic Formation, Lockatong Formation, Stockton Formation contributing significantly to arsenic concentration in well water. Identification of sources of arsenic contamination in private drinking water wells at such a fine scale facilitates development of more targeted outreach as well as mitigation strategies to improve water quality and safeguard human health.


A potent MAPK13-14 inhibitor prevents airway inflammation and mucus production.
Common respiratory diseases continue to represent a major public health problem, and much of the morbidity and mortality is due to airway inflammation and mucus production. Previous studies indicated a role for mitogen-activated protein kinase 14 (MAPK14) in this type of disease, but clinical trials are unsuccessful to date. Our previous work identified a related but distinct kinase known as MAPK13 that is activated in respiratory airway diseases and is required for mucus production in human cell-culture models. Support for MAPK13 function in these models came from effectiveness of MAPK13 versus MAPK14 gene-knockdown and from first-generation MAPK13-14 inhibitors. However, these first-generation inhibitors were incompletely optimized for blocking activity and were untested in vivo. Here we report the next generation and selection of a potent MAPK13-14 inhibitor (designated NuP-3) that more effectively downregulates type-2 cytokine-stimulated mucus production in air-liquid interface and organoid cultures of human airway epithelial cells. We also show that NuP-3 treatment prevents respiratory airway inflammation and mucus production in new minipig models of airway disease triggered by type-2 cytokine challenge or respiratory viral infection. The results thereby provide the next advance in developing a small-molecule kinase inhibitor to address key features of respiratory disease.NEW & NOTEWORTHY This study describes the discovery of a potent mitogen-activated protein kinase 13-14 (MAPK13-14) inhibitor and its effectiveness in models of respiratory airway disease. The findings thereby provide a scheme for pathogenesis and therapy of lung diseases [e.g., asthma, chronic obstructive pulmonary disease (COPD), Covid-19, postviral, and allergic respiratory disease] and related conditions that implicate MAPK13-14 function. The findings also refine a hypothesis for epithelial and immune cell functions in respiratory disease that features MAPK13 as a possible component of this disease process.


Intracellular Ca(2+) and Ca(2+)/calmodulin-dependent kinase II mediate acute potentiation of neurotransmitter release by neurotrophin-3.
Neurotrophins have been shown to acutely modulate synaptic transmission in a variety of systems, but the underlying signaling mechanisms remain unclear. Here we provide evidence for an unusual mechanism that mediates synaptic potentiation at the neuromuscular junction (NMJ) induced by neurotrophin-3 (NT3), using Xenopus nerve-muscle co-culture. Unlike brain-derived neurotrophic factor (BDNF), which requires Ca(2+) influx for its acute effect, NT3 rapidly enhances spontaneous transmitter release at the developing NMJ even when Ca(2+) influx is completely blocked, suggesting that the NT3 effect is independent of extracellular Ca(2+). Depletion of intracellular Ca(2+) stores, or blockade of inositol 1, 4, 5-trisphosphate (IP3) or ryanodine receptors, prevents the NT3-induced synaptic potentiation. Blockade of IP3 receptors can not prevent BDNF-induced potentiation, suggesting that BDNF and NT3 use different mechanisms to potentiate transmitter release. Inhibition of Ca(2+)/calmodulin-dependent kinase II (CaMKII) completely blocks the acute effect of NT3. Furthermore, the NT3-induced potentiation requires a continuous activation of CaMKII, because application of the CaMKII inhibitor KN62 reverses the previously established NT3 effect. Thus, NT3 potentiates neurotransmitter secretion by stimulating Ca(2+) release from intracellular stores through IP3 and/or ryanodine receptors, leading to an activation of CaMKII.


An Electroreductive Approach to Radical Silylation via the Activation of Strong Si-Cl Bond.
The construction of C(sp3)-Si bonds is important in synthetic, medicinal, and materials chemistry. In this context, reactions mediated by silyl radicals have become increasingly attractive but methods for accessing these intermediates remain limited. We present a new strategy for silyl radical generation via electroreduction of readily available chlorosilanes. At highly biased potentials, electrochemistry grants access to silyl radicals through energetically uphill reductive cleavage of strong Si-Cl bonds. This strategy proved to be general in various alkene silylation reactions including disilylation, hydrosilylation, and allylic silylation under simple and transition-metal-free conditions.


Predation intensity does not cause microevolutionary change in maximum speed or aerobic capacity in trinidadian guppies (Poecilia reticulata Peters).
We measured maximal oxygen consumption (VO(2max)) and burst speed in populations of Trinidadian guppies (Poecilia reticulata) from contrasting high- and low-predation habitats but reared in "common garden" conditions. We tested two hypothesis: first, that predation, which causes rapid life-history evolution in guppies, also impacts locomotor physiology, and second, that trade-offs would occur between burst and aerobic performance. VO(2max) was higher than predicted from allometry, and resting VO(2) was lower than predicted. There were small interdrainage differences in male VO(2max), but predation did not affect VO(2max) in either sex. Maximum burst speed was correlated with size; absolute burst speed was higher in females, but size-adjusted speed was greater in males. For both sexes, burst speed conformed to allometric predictions. There were differences in burst speed between drainages in females, but predation regime did not affect burst speed in either sex. We did not find a significant correlation between burst speed and VO(2max), suggesting no trade-off between these traits. These results indicate that predation-mediated evolution of guppy life history does not produce concomitant evolution in aerobic capacity and maximum burst speed. However, other aspects of swimming performance (response latencies or acceleration) might show adaptive divergence in contrasting predation regimes.


The use of focus groups to develop a culturally relevant quality of life tool for lymphatic filariasis in Bangladesh.
The purpose of this study was to conduct focus groups to operationalise the construct of quality of life (QOL) for people living with lymphatic filariasis (LF) in Bangladesh to develop culturally valid items for a Bangladeshi LF QOL tool. Ten focus groups were conducted with a stratified purposeful sample (n = 60) of LF patients (3 focus groups, n = 17), doctors (1 focus group, n = 5), nurses (1 focus group, n = 6) and other hospital staff (1 focus group, n = 5), community leaders (2 focus groups, n = 14), community volunteer health workers (1 focus group, n = 5) and Bangladeshi LF researchers and planners (1 focus group, n = 8). Focus group methodology was informed by local culture in consultation with cultural mentors and local advisors, often going against standard focus group procedures. Data were collected through note taking, audio taping, transcripts, observational notes and a reflection diary. Open coding of transcript data was completed until data saturation was achieved. Forty-three constructs were identified through the focus groups that had not previously been identified in the literature, including constructs relating to environmental supports and barriers, activities, participation and psychological impacts. There were marked differences between the impacts reported by different groups, highlighting the need for a comprehensive purposive sample. In particular, contributions from participants who would not traditionally be viewed as "experts" were vital. The use of focus groups strongly contributed to the operationalisation of the concept of QOL in Bangladesh for people living with LF. Use of literature review or expert opinion alone would have missed vital constructs.


Posttranscriptional regulation of sodium-iodide symporter mRNA expression in the rat thyroid gland by acute iodide administration.
Iodide is an important regulator of thyroid activity. Its excess elicits the Wolff-Chaikoff effect, characterized by an acute suppression of thyroid hormone synthesis, which has been ascribed to serum TSH reduction or TGF-beta increase and production of iodolipids in the thyroid. These alterations take hours/days to occur, contrasting with the promptness of Wolff-Chaikoff effect. We investigated whether acute iodide administration could trigger events that precede those changes, such as reduction of sodium-iodide symporter (NIS) mRNA abundance and adenylation, and if perchlorate treatment could counteract them. Rats subjected or not to methylmercaptoimidazole treatment (0.03%) received NaI (2,000 microg/0.5 ml saline) or saline intraperitoneally and were killed 30 min up to 24 h later. Another set of animals was treated with iodide and perchlorate, in equimolar doses. NIS mRNA content was evaluated by Northern blotting and real-time PCR, and NIS mRNA poly(A) tail length by rapid amplification of cDNA ends-poly(A) test (RACE-PAT). We observed that NIS mRNA abundance and poly(A) tail length were significantly reduced in all periods of iodide treatment. Perchlorate reversed these effects, indicating that iodide was the agent that triggered the modifications observed. Since the poly(A) tail length of mRNAs is directly associated with their stability and translation efficiency, we can assume that the rapid decay of NIS mRNA abundance observed was due to a reduction of its stability, a condition in which its translation could be impaired. Our data show for the first time that iodide regulates NIS mRNA expression at posttranscriptional level, providing a new mechanism by which iodide exerts its autoregulatory effect on thyroid.


Medium term complications of endoscopic biliary sphincterotomy.
One hundred and fifteen patients were reviewed between 18 months and five years after successful endoscopic biliary sphincterotomy for choledocholithiasis, postcholecystectomy in 93 (81%). Thirteen (14%) postcholecystectomy patients and 11 (50%, p less than 0.001) with intact gall bladders are dead (cause of death was ascertained in each case). Of the others, 43 were interviewed and 48 completed a postal questionnaire. Stone free common ducts had been documented in 69 (76%), presumed in 16 (17%), and not achieved in six (7%, excluded from analysis). None of the responding patients had developed serious new problems. Current symptoms of those with and without gall bladders and those with 'documented' and 'presumed' duct clearance are similar. In no case has an episode of cholangitis since sphincterotomy been confirmed and only one patient has had documented recurrent duct stones. Continued incompetence of the sphincter was shown radiologically by the presence of bile duct gas in 14 (41%) of 32 patients. These results suggest that medium term complications of endoscopic sphincterotomy are unusual.


[Renal retransplantation. Study of 91 cases].
Review of 91 retransplantations performed at our hospital between 1975 and 1991. There were 82 second transplants and 9 third transplants. Survival of patients to undergo retransplantations continues to increase. Over the last year, 19.1% of our transplants were the 2nd or 3rd ones for some patients. Analysis of causes for graft loss, which essentially are of immunological and surgical nature.


Self-knowledge in childhood: relations with children's imaginary companions and understanding of mind.
Relations between interior self-knowledge and (a) imaginary companion (IC) status and (b) theory of mind (ToM) abilities were investigated in a sample (N= 80) of 4- to 7-year-olds. Interior self-knowledge was assessed in terms of the extent to which children acknowledged that they (rather than an adult) were the authority on unobservable aspects of themselves (e.g., dreaming, thinking, hunger). Compared with children without an IC, those who possessed a parentally corroborated IC ascribed less interior self-knowledge to an adult, with a trend for them to assign more interior self-knowledge to themselves. Children's interior self-knowledge judgments were not associated with their ToM performance. IC status was also unrelated to ToM performance. We consider how having an IC may provide children with opportunities to distinguish between knowledge that is inaccessible to an external observer and that which an external observer may glean without being told.


[Opinions on Alcohol Consumption During Pregnancy and The Role of The Medical Staff as an Expert in This Regard - A Grounded Theory Analysis of Online Forum Discussions].
Alcohol consumption during pregnancy carries many risks for the unborn child. Despite preventive measures, some pregnant women consume alcohol. The aim of this study is to identify possible reasons for consumption during pregnancy and also to shed light on the attribution of an expert role to medical professionals by those affected. In this study, 9 discussion threads from online forums on the topic of alcohol consumption during pregnancy with a total of 115 discussion participants were analyzed using grounded theory. The discursive validation of the results took place in the research team. It turned out that the individual definition of the mother role has an influence on consumer behavior. Women who are very concerned about the child's well-being occasionally used alcohol in stressful situations or on social occasions, but often reported a guilty conscience after the consumption. Women who gave more weight to their own needs were more likely to consume for pleasure or because they felt they were being patronized by prohibitions. An equitable doctor-patient relationship and detailed, non-directive information were identified as beneficial factors for ascribing the expert role to the gynecologist. On the other hand, a paternalistic attitude and the issuing of bans proved to be a hindrance. All women showed a high need for information about alcohol consumption during pregnancy. The doctor-patient relationship seems to play an important role in conveying information. In addition, it became clear that the desire for support in women striving for abstinence is not being sufficiently fulfilled. Alcohol consumption during pregnancy should be addressed regularly in the care of all pregnant women. In addition to information on consumption risks, information on support offers is relevant.


Divergent metabolic phenotypes in two genetic syndromes of low insulin secretion.
We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS). Adults homozygous for the E180 splice site mutation of GHR [Laron syndrome (LS)], adults with a gain-of-function mutation in CDKN1c [Guevara-Rosenbloom syndrome (GRS)], and controls were evaluated for body composition, leptin, total and high molecular weight (HMW) adiponectin, insulin-like growth factor (IGF) axis molecules, and a 5-hour oral glucose tolerance test (OGTT), with measurements of glucose, insulin, glucagon, ghrelin, pancreatic polypeptide, gastric inhibitory peptide, glucagon-like peptide-1, peptide YY, and islet amyloid polypeptide (IAPP). Both syndromic cohorts displayed DIS during OGTT. LS subjects had higher serum concentrations of total and HMW adiponectin, and lower levels of IGF-I, IGF-II, and IGF-Binding Protein-3 than individuals in other study groups. Furthermore, they displayed normal glycemic responses during OGTT with the lowest IAPP secretion. In contrast, individuals with GRS had higher levels of protein glycation, deficient glucose control during OGTT, and increased secretion of IAPP. A distinct metabolic phenotype depending on GH counter-regulatory status, associates with diabetes development and excess glucose-induced IAPP secretion.


New era of mesenchymal stem cell-based medicine: basis, challenges and prospects.
Stem cells of mesenchymal origin (MSC) arouse special interest due to their regenerative, anti-inflammatory, anti-apoptotic, anti-oxidative stress, antitumor or antimicrobial properties. However, its implementation in the clinic runs into drawbacks of cell therapy (immunological incompatibility, tumor formation, possible transmission of infections, entry into cellular senescence, difficult evaluation of safety, dose and potency; complex storage conditions, high economic cost or impractical clinical use). Considering that the positive effects of MSC are due, to a large extent, to the paracrine effects mediated by the set of substances they secrete (growth factors, cytokines, chemokines or microvesicles), the in vitro obtaining of these biological products makes possible a medicine cell-free regenerative therapy without the drawbacks of cell therapy. However, this new therapeutic innovation implies challenges, such as the recognition of the biological heterogeneity of MSC and the optimization and standardization of their secretome.


Ultrasound and its various modes in use, part II: Real-time scanners.
Real-time scanners process information as they receive it, enabling structures to be viewed as they are scanned. This offers the advantage of faster scanning; however, image quality may not be as good as that of conventional scanners. Real-time scanners are used for a wide range of studies, but have not replaced B-mode and M-mode scanners to the extent envisioned by early developers.


Deregulation of mitochondrial membrane potential by mitochondrial insertion of granzyme B and direct Hax-1 cleavage.
The cytoplasm and the nucleus have been identified as activity sites for granzyme B (GrB) following its delivery from cytotoxic lymphocyte granules into target cells. Here we report on the ability of exogenous GrB to insert into and function within a proteinase K-resistant mitochondrial compartment. We identified Hax-1 (HS-1-associated protein X-1), a mitochondrial protein involved in the maintenance of mitochondrial membrane potential, as a GrB substrate within the mitochondrion. GrB cleaves Hax-1 into two major fragments: an N-terminal fragment that localizes to mitochondria and a C-terminal fragment that localizes to the cytosol after being released from GrB-treated mitochondria. The N-terminal Hax-1 fragment major cellular impact is on the regulation of mitochondrial polarization. Overexpression of wild-type Hax-1 or its uncleavable mutant form protects the mitochondria against GrB or valinomycin-mediated depolarization. The N-terminal Hax-1 fragment functions as a dominant negative form of Hax-1, mediating mitochondrial depolarization in a cyclophilin D-dependent manner. Thus, induced expression of the N-terminal Hax-1 fragment results in mitochondrial depolarization and subsequent lysosomal degradation of such altered mitochondria. This study is the first to demonstrate GrB activity within the mitochondrion and to identify Hax-1 cleavage as a novel mechanism for GrB-mediated mitochondrial depolarization.


Evaluation of binding property of mucilage from Litsea glutinosa wall.
Litsea glitinosa is an evergreen tree of medium size which grows to a height of about 20 to 30 feet. It belongs to family Lauraceae. In India it is found mainly in North Eastern region. The leaves and the mucilage from the bark of plant is utilized in the gum for poultices. Mucilage of Litsea glutinosa was isolated from powdered bark by continuous hot extraction technique using water and precipitation by absolute alcohol (38% w/w yield). The mucilage was evaluated for binding properties in tablets and granules, using paracetamol as a model drug. The granules were prepared using 4 different concentrations of mucilage (4%, 6%, 8%, and 10%) and evaluated for percentage of fines, average particle size, total porosity, compressibility index, and flow properties. The prepared tablets were evaluated for content uniformity, hardness, friability, disintegration time, and in vitro dissolution profiles. The results obtained with the lower concentrations of mucilage, that is, less than 6% were not so encouraging. The tablets prepared by using 10% mucilage of L. glutinosa as binder exhibited more hardness as compared with the starch. It may be concluded that the concentration ranging from 6% to 8% of L. glutinosa mucilage may be considered as better option as a binding agent for the preparation of tablets as compared to the starch (10%).


Phenotypic effect of mutations in evolving populations of RNA molecules.
The secondary structure of folded RNA sequences is a good model to map phenotype onto genotype, as represented by the RNA sequence. Computational studies of the evolution of ensembles of RNA molecules towards target secondary structures yield valuable clues to the mechanisms behind adaptation of complex populations. The relationship between the space of sequences and structures, the organization of RNA ensembles at mutation-selection equilibrium, the time of adaptation as a function of the population parameters, the presence of collective effects in quasispecies, or the optimal mutation rates to promote adaptation all are issues that can be explored within this framework. We investigate the effect of microscopic mutations on the phenotype of RNA molecules during their in silico evolution and adaptation. We calculate the distribution of the effects of mutations on fitness, the relative fractions of beneficial and deleterious mutations and the corresponding selection coefficients for populations evolving under different mutation rates. Three different situations are explored: the mutation-selection equilibrium (optimized population) in three different fitness landscapes, the dynamics during adaptation towards a goal structure (adapting population), and the behavior under periodic population bottlenecks (perturbed population). The ratio between the number of beneficial and deleterious mutations experienced by a population of RNA sequences increases with the value of the mutation rate mu at which evolution proceeds. In contrast, the selective value of mutations remains almost constant, independent of mu, indicating that adaptation occurs through an increase in the amount of beneficial mutations, with little variations in the average effect they have on fitness. Statistical analyses of the distribution of fitness effects reveal that small effects, either beneficial or deleterious, are well described by a Pareto distribution. These results are robust under changes in the fitness landscape, remarkably when, in addition to selecting a target secondary structure, specific subsequences or low-energy folds are required. A population perturbed by bottlenecks behaves similarly to an adapting population, struggling to return to the optimized state. Whether it can survive in the long run or whether it goes extinct depends critically on the length of the time interval between bottlenecks.


CCR4-expressing T cell tumors can be specifically controlled via delivery of toxins to chemokine receptors.
Expression of chemokine receptors by tumors, specifically CCR4 on cutaneous T cell lymphomas, is often associated with a poor disease outcome. To test the hypothesis that chemokine receptor-expressing tumors can be successfully controlled by delivering toxins through their chemokine receptors, we have generated fusion proteins designated chemotoxins: chemokines fused with toxic moieties that are nontoxic unless delivered into the cell cytosol. We demonstrate that chemokines fused with human RNase eosinophil-derived neurotoxin or with a truncated fragment of Pseudomonas exotoxin 38 are able to specifically kill tumors in vitro upon internalization through their respective chemokine receptors. Moreover, treatment with the thymus and activation-regulated chemokine (CCL17)-expressing chemotoxin efficiently eradicated CCR4-expressing cutaneous T cell lymphoma/leukemia established in NOD-SCID mice. Taken together, this work represents a novel concept that may allow control of growth and dissemination of tumors that use chemokine receptors to metastasize and circumvent immunosurveillance.


Childhood physical abnormalities following paternal exposure to sulfur mustard gas in Iran: a case-control study.
Mustard gas, a known chemical weapon, was used during the Iran-Iraq war of 1980-1988. We aimed to determine if exposure to mustard gas among men was significantly associated with abnormalities and disorders among progenies. Using a case-control design, we identified all progenies of Sardasht men (exposed group, n = 498), who were born at least nine months after the exposure, compared to age-matched controls in Rabat, a nearby city (non-exposed group, n = 689). We conducted a thorough medical history, physical examination, and appropriate paraclinical studies to detect any physical abnormality and/or disorder. Given the presence of correlated data, we applied Generalized Estimating Equation (GEE) multivariable models to determine associations. The overall frequency of detected physical abnormalities and disorders was significantly higher in the exposed group (19% vs. 11%, Odds Ratio [OR] 1.93, 95% Confidence Interval [CI], 1.37-2.72, P = 0.0002). This was consistent across sexes. Congenital anomalies (OR 3.54, 95% CI, 1.58-7.93, P = 0.002) and asthma (OR, 3.12, 95% CI, 1.43-6.80, P = 0.004) were most commonly associated with exposure. No single abnormality was associated with paternal exposure to mustard gas. Our study demonstrates a generational effect of exposure to mustard gas. The lasting effects of mustard gas exposure in parents effects fertility and may impact child health and development in the long-term.


A multi-layered computational model of coupled elastin degradation, vasoactive dysfunction, and collagenous stiffening in aortic aging.
Arterial responses to diverse pathologies and insults likely occur via similar mechanisms. For example, many studies suggest that the natural process of aging and isolated systolic hypertension share many characteristics in arteries, including loss of functional elastin, decreased smooth muscle tone, and altered rates of deposition, and/or crosslinking of fibrillar collagen. Our aim is to show computationally how these coupled effects can impact evolving aortic geometry and mechanical behavior. Employing a thick-walled, multi-layered constrained mixture model, we suggest that a coupled loss of elastin and vasoactive function are fundamental mechanisms by which aortic aging occurs. Moreover, it is suggested that collagenous stiffening, although itself generally an undesirable process, can play a key role in attenuating excessive dilatation, perhaps including the enlargement of abdominal aortic aneurysms.


Tailoring H2O2 generation kinetics with magnesium alloys for efficient disinfection on titanium surface.
A new antibacterial strategy for Ti has been developed without the use of any external antibacterial agents and surface treatments. By combining Mg alloys with Ti, H2O2, which is an oxidizing agent that kills bacteria, was spontaneously generated near the surface of Ti. Importantly, the H2O2 formation kinetics can be precisely controlled by tailoring the degradation rates of Mg alloys connected to Ti. Through microstructural and electrochemical modification of Mg with alloying elements (Ca, Zn), the degradation rates of Mg alloys were controlled, and the H2O2 release kinetics was accelerated when the degradation rate of Mg alloys increased. With the introduction of an in vivo assessment platform comprised of Escherichia coli (E. coli) and transgenic zebrafish embryos, we are able to design optimized antibacterial systems (Ti-Mg and Ti-Mg-3wt% Zn) that can selectively eradicate E. coli while not harming the survival rate, development, and biological functions of zebrafish embryos. We envision that our antibacterial strategy based on utilization of sacrificial Mg alloys could broaden the current palette of antibacterial platforms for metals.


Identification of time-varying stiffness, damping, and equilibrium position in human forearm movements.
Knowledge of how stiffness, damping, and the equilibrium position of specific limbs change during voluntary motion is important for understanding basic strategies of neuromotor control. Presented here is an algorithm for identifying time-dependent changes in joint stiffness, damping, and equilibrium position of the human forearm. The procedure requires data from only a single trial. The method relies neither on an analysis of the resonant frequency of the arm nor on the presence of an external bias force. Its validity was tested with a simulated forward model of the human forearm. Using the parameter estimations as forward model input, the angular kinematics (model output) were reconstructed and compared to the empirically measured data. Identification of mechanical impedance is based on a least-squares solution of the model equation. As a regularization technique and to improve the temporal resolution of the identification process, a moving temporal window with a variable width was imposed. The method's performance was tested by (a) identifying a priori known hypothetical time-series of stiffness, damping, and equilibrium position, and (b) determining impedance parameters from recorded single-joint forearm movements during a hold and a goal-directed movement task. The method reliably reconstructed the original angular kinematics of the artificial and human data with an average positional error of less than 0.05 rad for movement amplitudes of up to 0.9 rad, and did not yield hypermetric trajectories like previous procedures not accounting for damping.


What do we know about Lorentz invariance?
The realization that Planck-scale physics can be tested with existing technology through the search for spacetime-symmetry violation brought about the development of a comprehensive framework, known as the gravitational standard-model extension (SME), for studying deviations from exact Lorentz and CPT symmetry in nature. The development of this framework and its motivation led to an explosion of new tests of Lorentz symmetry over the past decade and to considerable theoretical interest in the subject. This work reviews the key concepts associated with Lorentz and CPT symmetry, the structure of the SME framework, and some recent experimental and theoretical results.


Molecular cytogenetic characterization of breakpoints in 19 patients with hematologic malignancies and 12p unbalanced translocations.
Structural rearrangements of the short arm of chromosome 12 are frequent cytogenetic findings in various hematologic malignancies. The ETV6 gene is the most common target for rearrangements in 12p13. Fluorescence in situ hybridization (FISH) investigations have shown that translocations of 12p other than t(12;21) are frequently accompanied by small interstitial deletions that include ETV6. Unbalanced translocations involving ETV6 have rarely been described, and breakpoints outside ETV6 appear to be strongly associated with complex karyotypes. We studied bone marrow samples from 19 patients known to have 12p unbalanced translocations and complex karyotypes, using FISH and spectral karyotyping. FISH analysis confirmed the hemizygous deletion of the ETV6 and CDKN1B genes in 74% of cases. We found four cases with interstitial deletions. In these four cases and in two others (6/19, 31.5%), the fusion with the partner chromosome was in the subtelomeric region of 12p13.3, confirming that there is a recurrent breakpoint in this region.


Serotypes of Pasteurella haemolytica in sheep in the midwestern United States.
Nasal secretions were collected from healthy lambs from flocks in Iowa and the surrounding states for 2 consecutive years. The 1st year, 322 lambs from 61 flocks yielded 202 Pasteurella haemolytica isolates, representing 9 established serotypes and 30 untypeable isolates. The 2nd year, 249 lambs from 49 flocks yielded 73 isolates, representing 9 established serotypes and 7 untypeable isolates. More isolates belonged to serotype 2 than to any other serotype. Serotypes 3, 4, and 10 (members of biotype T), were not isolated. Serotype 12 was also isolated and identified.


Cricopharyngeal myotomy.
Cricopharyngeal myotomy has been used in the treatment of pharyngoesophageal diverticulum and various neurogenic, myogenic and myoneurogenic disorders. An appreciable number of patients with pseudobulbar palsy due to cerebrovascular accidents and patients with idiopathic hypertrophy of the cricopharyngeal muscle will greatly benefit from this procedure. This paper describes the indications for, and results of, 20 consecutive cricopharyngeal myotomies carried out with or without diverticulectomy. All 20 patients experienced cervical esophageal dysphagia and 55% had substantial weight loss. The most valuable investigation is roentgenography of the pharynx and esophagus, which will confirm megapharynx, hypopharyngeal stasis, weak or absent pharyngeal contractions and regurgitation. Hypertrophic cricopharyngeal muscle was demonstrated in 9 of the 20 patients. The diagnostic value of endoscopy and esophageal manometry is limited. The results were considered excellent in all patients with pharyngoesophageal diverticulum and idiopathic hypertrophy of the cricopharyngeal muscle. Marked symptomatic and objective improvement was achieved in patients with cerebrovascular accidents, vagal injuries and amyotrophic lateral sclerosis. However, the result was poor in patients with myoneurogenic disorders.


Neutralizing host responses in hepatitis C virus infection target viral entry at postbinding steps and membrane fusion.
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis worldwide. Viral attachment and entry, representing the first steps of virus-host cell interactions, are major targets of adaptive host cell defenses. The mechanisms of antibody-mediated neutralization by host neutralizing responses in HCV infection are only poorly understood. Retroviral HCV pseudotypes (HCVpp) and recombinant cell culture-derived HCV (HCVcc) have been successfully used to study viral entry and antibody-mediated neutralization. In this study, we used these model systems to investigate the mechanism of antibody-mediated neutralization by monoclonal antienvelope antibodies and polyclonal anti-HCV immunoglobulins purified from HCV-infected patients. Using a panel of monoclonal antienvelope antibodies, we identified an epitope within the E1 glycoprotein targeted by human neutralizing antibodies during postbinding events. Interestingly, we observed that host neutralizing responses in the majority of HCV-infected individuals include antibodies targeting HCV entry after binding of the virus to the target cell membrane. Using a kinetic assay based on HCVpp and HCVcc entry, we demonstrate that purified antiviral immunoglobulins derived from individual HCV-infected patients appear to inhibit HCV infection at an entry step closely linked to CD81 and scavenger receptor BI (SR-BI). Our results indicate that host neutralizing responses in HCV-infected patients target viral entry after HCV binding most likely related to HCV-CD81, and HCV-SR-BI interactions, as well as membrane fusion. These findings have implications not only for the understanding of the pathogenesis of HCV infection but also for the design of novel immunotherapeutic and preventive strategies.


Angiotensin II Type 1 Receptor Antibody-mediated Rejection Following Orthotopic Heart Transplant: A Single-center Experience.
Antibody-mediated rejection (AMR) following orthotopic heart transplant (OHT) causes significant morbidity and mortality. There are limited data on antibodies to the angiotensin II type 1 receptor antibody (AT1R-Ab) causing rejection following OHT. This is a retrospective, single-center study that presents our 2-y experience with a series of 11 patients with evidence of nonspecific graft dysfunction and pathologic levels of AT1R-Ab. The clinical outcomes and treatments were compared to a group of 10 patients, also with evidence of nonspecific graft dysfunction, but who had nonsignificant AT1R-Ab titers. The mean age of the AT1R-Ab cohort was 52% and 73% were bridged to transplant with an left ventricular assist device. The average left ventricular ejection fraction at presentation was 45%, and most were not on an angiotensin receptor blocker (ARB). Endomyocardial biopsies in those with elevated AT1R-Ab levels frequently showed reactive endothelium/endocardium without C4d or intravascular CD68 staining. Ten patients (91%) were started on an ARB. Other therapies included plasmapheresis and IVIg (64%), with 4 patients also receiving rituximab. Most patients had symptom improvement, but minimal change in graft function at an average 6 mo of follow-up. The role of AT1R-Ab-mediated rejection in OHT recipients remains poorly understood. More than half of patients at our center who presented with graft dysfunction in the absence of acute cellular rejection or AMR were found to have elevated AT1R-Ab titers. Empiric AMR treatment in conjunction with ARB therapy may improve patient outcomes. Future studies are needed to better define the optimal treatment modalities for ATR1-Ab-mediated AMR.


Smoking cessation programmes for women living in disadvantaged communities, "We Can Quit 2": A systematic review protocol.
Tobacco use is the leading cause of preventable death in Ireland with almost 6,000 smokers dying each year from smoking-related diseases. Amongst younger Irish women, smoking rates are considerably higher in those from socially disadvantaged areas compared to women from affluent areas. Women from poorer areas also experience higher rates of lung cancer. To our knowledge, there are no peer reviewed published systematic reviews on the effectiveness of interventions tailored to reduce smoking rates in women from disadvantaged areas. This systematic review protocol will aim to examine the effectiveness of such interventions and to describe trial processes such as recruitment, follow-up and dropout prevention strategies, as well as barriers and enablers of successful implementation. A systematic review will be conducted of peer-reviewed randomised controlled trials and associated process evaluations of smoking cessation interventions designed for women living in socially disadvantaged areas. If the search returns, less than five studies are review criteria will expand to include quasi-experimental studies. A number of databases of scholarly literature will be searched from inception using a detailed search strategy. Two independent reviewers will screen titles, abstracts and full-text articles to identify relevant studies using a pre-defined checklist based on PICOS. In the case of disagreement, a third reviewer will be consulted. The quality of included studies will be assessed using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) criteria. Quantitative data will be extracted and, if comparable, will be assessed using meta-analysis. A narrative meta-synthesis of qualitative data will be conducted. This review aims to synthesise information from relevant studies on smoking cessation interventions tailored for women from socially disadvantaged areas. The evidence obtained from studies and presented in this review will help guide future research in this area. Registration: This review will be registered with International Prospective Register of Systematic Reviews (PROSPERO).


Tests for the measurement of factor VII-activating protease (FSAP) activity and antigen levels in citrated plasma, their correlation to PCR testing, and utility for the detection of the Marburg I-polymorphism of FSAP.
The single nucleotide Marburg I (MRI) polymorphism of the factor VII-activating protease (FSAP) gene, the prourokinase-activating activity of FSAP, and antigen levels of FSAP in plasma have been associated with incidence and progression of carotid stenosis and venous thromboembolism. However, more information on the extent of these associations, potential further ones, and respective clinical utilities remain to be determined. At present, testing is performed mainly by PCR assays based on probes or SYBR Green I. Some studies include testing for antigen levels of total FSAP and its ability to activate prourokinase. To test large cohorts, it is beneficial to rely on assays that are cost-effective, reliable, easy to use, rapid to perform, and that may eventually be automated. In addition, it appears advantageous to use functional tests or tests that determine antigen levels as they may relate more closely to the phenotype than the genotype does. Tests for the measurements of antigen levels of FSAP and its prourokinase-activating activity were improved and performance characteristics assessed. To determine the FSAP genotypes, an amplification created restriction site (ACRS) PCR test was developed. Key performance characteristics of the FSAP activity and antigen tests were as follows: measuring range: 350-1400 mPEU/mL and 1.8-120 ng/mL, total coefficients of variation (CV): 5%-20% and 5%-14%, within-run CV: 4%-11% and 2.3%-12%, and run-to-run CV: 2%-17% and 4.3%-8.3%, respectively. The ratio of the activity and antigen level of FSAP correctly identified the FSAP genotypes of 126 samples tested. The ACRS PCR test is useful for laboratories that do not have the equipment to perform probe or SYBR Green I based real-time PCR. Furthermore, the tests developed for the determination of FSAP activity and antigen levels are convenient for determining clinical correlations, even for large population studies. The ratio of activity and antigen level of FSAP appears to be a promising and efficient alternative to molecular diagnostic techniques to detect the MRI polymorphism of FSAP.


The expanding role of mass spectrometry in the field of vaccine development.
Biological mass spectrometry has evolved as a core analytical technology in the last decade mainly because of its unparalleled ability to perform qualitative as well as quantitative profiling of enormously complex biological samples with high mass accuracy, sensitivity, selectivity and specificity. Mass spectrometry-based techniques are also routinely used to assess glycosylation and other post-translational modifications, disulfide bond linkage, and scrambling as well as for the detection of host cell protein contaminants in the field of biopharmaceuticals. The role of mass spectrometry in vaccine development has been very limited but is now expanding as the landscape of global vaccine development is shifting towards the development of recombinant vaccines. In this review, the role of mass spectrometry in vaccine development is presented, some of the ongoing efforts to develop vaccines for diseases with global unmet medical need are discussed and the regulatory challenges of implementing mass spectrometry techniques in a quality control laboratory setting are highlighted.


Decoding cognitive concepts from neuroimaging data using multivariate pattern analysis.
Multivariate pattern analysis (MVPA) methods are now widely used in life-science research. They have great potential but their complexity also bears unexpected pitfalls. In this paper, we explore the possibilities that arise from the high sensitivity of MVPA for stimulus-related differences, which may confound estimations of class differences during decoding of cognitive concepts. We propose a method that takes advantage of concept-unrelated grouping factors, uses blocked permutation tests, and gradually manipulates the proportion of concept-related information in data while the stimulus-related, concept-irrelevant factors are held constant. This results in a concept-response curve, which shows the relative contribution of these two components, i.e. how much of the decoding performance is specific to higher-order category processing and to lower order stimulus processing. It also allows separating stimulus-related from concept-related neuronal processing, which cannot be achieved experimentally. We applied our method to three different EEG data sets with different levels of stimulus-related confound to decode concepts of digits vs. letters, faces vs. houses, and animals vs. fruits based on event-related potentials at the single trial level. We show that exemplar-specific differences between stimuli can drive classification accuracy to above chance levels even in the absence of conceptual information. By looking into time-resolved windows of brain activity, concept-response curves can help characterize the time-course of lower-level and higher-level neural information processing and detect the corresponding temporal and spatial signatures of the corresponding cognitive processes. In particular, our results show that perceptual information is decoded earlier in time than conceptual information specific to processing digits and letters. In addition, compared to the stimulus-level predictive sites, concept-related topographies are spread more widely and, at later time points, reach the frontal cortex. Thus, our proposed method yields insights into cognitive processing as well as corresponding brain responses.


[Doppler-echocardiographic assessment of the degree of pulmonary hypertension and right-ventricular pressure in patients with ventricular septal defects].
The study was performed in 53 children aged 3 months to 4 years who had ventricular septal defect. Systolic pressure in the right ventricle, pulmonary artery and the severity of pulmonary hypertension were determined by two way: 1) from arteriovenous shunt via ventricular septal defect before its surgical closure; 2) from systolic regurgitation via the tricuspid valve after its seal. Right ventricular diastolic pressure was measured by Doppler echocardiography using diastolic blood flow through the tricuspid valve. Before ventricular septal defect closure, the correlation ratio of Doppler echocardiographic to cardiac catheterization values was 0.76 and that of Doppler echocardiographic to intrasurgical manometry was 0.79. In the postoperative period, a catheter was left in the right ventricle in 14 children and its pressure was simultaneously measured by the blind method. The correlation was 0.97 for right ventricular systolic pressure and 0.89 for diastolic one.


Natural cycles for in-vitro fertilization: cost-effectiveness analysis and factors influencing outcome.
Improvements in oocyte culture technique, sperm preparation, oocyte retrieval method and ovarian stimulation regimens have produced higher pregnancy rates with in-vitro fertilization (IVF) treatment. However, because ovarian stimulation is expensive and not without risk, there is increasing interest in the option of using natural cycles for IVF. This study was performed to document the experience and outcome in 240 natural cycles. Cancellation occurred in 28 cycles (12%), and LH surge was observed in 56 (23%), leaving 156 (65%) cycles which progressed to oocyte retrieval. No oocytes were retrieved in 26 cycles. Among the successful oocyte retrievals, the majority yielded one oocyte. There was no evidence of fertilization in 26 cases, and triploid fertilization was observed in 12 cases. Embryos suitable for transfer were available in 92 cycles in which 11 (12%) clinical pregnancies were confirmed. Despite the high failure rate at each step in the process, natural cycles are more cost-effective than stimulated cycles which incur an incremental cost per live birth of $48,000. Natural cycles offer a low-cost alternative that may be more accessible to patients.


Relationships between major epitopes of the IA-2 autoantigen in Type 1 diabetes: Implications for determinant spreading.
Diversification of autoimmunity to islet autoantigens is critical for progression to Type 1 diabetes. B-cells participate in diversification by modifying antigen processing, thereby influencing which peptides are presented to T-cells. In Type 1 diabetes, JM antibodies are associated with T-cell responses to PTP domain peptides. We investigated whether this is the consequence of close structural alignment of JM and PTP domain determinants on IA-2. Fab fragments of IA-2 antibodies with epitopes mapped to the JM domain blocked IA-2 binding of antibodies that recognise epitopes in the IA-2 PTP domain. Peptides from both the JM and PTP domains were protected from degradation during proteolysis of JM antibody:IA-2 complexes and included those representing major T-cell determinants in Type 1 diabetes. The results demonstrate close structural relationships between JM and PTP domain epitopes on IA-2. Stabilisation of PTP domain peptides during proteolysis in JM-specific B-cells may explain determinant spreading in IA-2 autoimmunity.


Selective bronchial blocking in children.
The use of the Fogarty arterial embolectomy catheter as an endobronchial blocker in infants and children has previously been reported. The further development of this technique is outlined and its use in two patients is described.


Normal coronary arteriogram. An avoidable test?
Between 10 and 20% of coronary arteriograms in patients with chest pain show normal vessels, often in association with a history of "atypical" angina. Conventional non-invasive tests are inaccurate in this group of patients compared with those with classical angina. This study prospectively evaluates combined 12 lead exercise electrocardiography and thallium-201 scintigraphy as a screening test in patients with atypical angina in order to determine whether normal arteriograms are avoidable in this important subgroup of patients presenting with chest pain. Sixty seven consecutive patients with atypical angina underwent both maximal exercise testing and thallium scintigraphy before coronary arteriography. Chest pain during exercise was a poor predictor of coronary disease in this group. Eleven (16%) had abnormal arteriography, with the sensitivity of exercise and thallium tests being 45% and 73%, respectively. When both tests were applied the predictive accuracy for normal coronary arteries was 96% (54/56) and that for the presence of coronary disease was 82% (9/11). If coronary arteriography was withheld in patients in whom both the exercise test and thallium scintigraphy were negative, the number of normal coronary arteriograms could be reduced with only a very small risk of failing to detect individuals with coronary disease.


Non-Binary and Binary Gender Identity in Australian Trans and Gender Diverse Individuals.
Many trans and gender diverse (TGD) people have gender identities that are not exclusively male or female but instead fall in-between or outside of the gender binary (non-binary). It remains unclear if and how those with non-binary gender identity differ from TGD individuals with binary identities. We aimed to understand the sociodemographic and mental health characteristics of people with non-binary identities compared with binary TGD identities. We performed a retrospective audit of new consultations for gender dysphoria between 2011 and 2016 in three clinical settings in Melbourne, Australia; (1) Equinox Clinic, an adult primary care clinic, (2) an adult endocrine specialist clinic, and (3) the Royal Children's Hospital, a child and adolescent specialist referral clinic. Age (grouped by decade), gender identity, sociodemographic, and mental health conditions were recorded. Of 895 TGD individuals, 128 (14.3%) had a non-binary gender. Proportions differed by clinical setting; 30.4% of people attending the adult primary care clinic, 7.4% attending the adult endocrine specialist clinic, and 8.0% attending the pediatric clinic identified as non-binary. A total of 29% of people in the 21-30-year-old age-group had a non-binary gender identity, higher than all other age-groups. Compared to TGD people with a binary gender identity, non-binary people had lower rates of gender-affirming interventions, and a higher prevalence of depression, anxiety, and illicit drug use. Tailoring clinical services to be inclusive of non-binary people and strategies to support mental health are required. Further research to better understand health needs and guide evidence-based gender-affirming interventions for non-binary people are needed.


Polymorphonuclear leukocyte apoptosis is inhibited by platelet-released mediators, role of TGFbeta-1.
Platelets regulate several polymorphonuclear leukocyte (PMN) functions. We have found that thrombin-stimulated platelets potently inhibited PMN apoptosis. Cell-free supernatant from increasing concentrations of stimulated platelets inhibited PMN apoptosis in a dose-dependent manner, with an effect similar to that of corresponding concentrations of platelets. At the plateau, platelet supernatant inhibited PMN apoptosis by 54.6 +/- 6.8%, the anti-apoptotic activity being higher than that of GM-CSF and comparable to that of LPS. Neither IL-1ra nor a combination of anti-IL1alpha + betamAb affected the activity of platelet supernatant. In contrast a mAb recognizing the active form of TGF-beta1 significantly decreased this activity. Moreover, exogenous TGF-beta1 inhibited PMN apoptosis in a dose-dependent manner. The active form of this cytokine was indeed present in the supernatant of stimulated platelets at a concentration able to elicit an anti-apoptotic effect. The p38 MAPK inhibitor SB203580 prevented the anti-apoptotic effect of TGF-beta1 in a dose-dependent manner. Interestingly, it also prevented the anti-apoptotic effect of IL-1alpha, but not that of GM-CSF, LPS and dexamethasone. In conclusion, we report for the first time that PMN apoptosis is potently inhibited by platelet-released mediators, that TGF-beta1 mediates an important part of this effect, and that p38 MAPK is involved in the TGF-beta1 signaling leading to its anti-apoptotic effect. These results provide novel evidence to support the central role of platelets in inflammation.


Mullerian adenosarcoma (heterologous) of the cervix with sarcomatous overgrowth: a case report with review of literature.
Mullerian adenosarcoma is a rare biphasic malignant neoplasm of the cervix characterized by an admixture of benign epithelial elements and a malignant sarcomatous stromal component, which may be either homologous or heterologous. An aggressive variant of adenosarcoma, mullerian adenosarcoma with sarcomatous overgrowth (MASO) is extremely rare, with only two such cases being reported in the English literature to date. In this report we present a case of MASO of uterine cervix with heterologous elements in a 15-year-old unmarried girl presenting with foul smelling menstrual bleeding and passage of fleshy masses. Because MASO with heterologous elements seems to appear at the earliest stages of reproductive lifespan in women, and have an uncertain malignant potential, gynecologists and pathologists should be aware and think about the possibility of this tumor.


[The phospholipid composition of the liver in root voles living under different radioecological conditions].
The effect of the increased natural radiation background (within some areas in Komi Republic) and man-caused radioactive contamination in the Chernobyl NPP accident zone on the composition of liver phospholipids in Microtus oeconomus inhabiting these areas was studied. The significant changes in the liver lipid composition in rodents inhabiting both the Chernobyl accident zone and the areas with the increased natural radiation background were found. The maximal changes in the liver phospholipid composition were revealed during the first year after the accident. The reverse dependence between the phosphatidyl choline/phosphatidyl ethanolamine ratio and the ratio between the sum of more readily oxidizable phospholipids and the sum of more poorly oxidizable ones was found. However, the slope of corresponding curves significantly depends on the radioactive state in the area of the population inhabitance. The conclusion about high sensitivity of the lipid composition of hepatocytes in Microtus oeconomus both to the impact of the man-caused radioactive contamination and the increased level of the natural radioactivity was drawn.


ER translocation intermediates are adjacent to a nonglycosylated 34-kD integral membrane protein.
We have used the homobifunctional cross-linking reagent disuccinimidyl suberate (DSS) to identify proteins that are adjacent to nascent polypeptides undergoing translocations across mammalian rough ER. Translocation intermediates were assembled by supplementing cell free translations of truncated mRNAs with the signal recognition particle (SRP) and microsomal membrane vesicles. Two prominent cross-linked products of 45 and 64 kD were detected. The 64-kD product was obtained when the cell free translation contained SRP, while formation of the 45-kD product required both SRP and translocation competent microsomal membrane vesicles. In agreement with previous investigators, we suggest that the 64-kD product arises by cross-linking of the nascent polypeptide to the 54-kD subunit of SRP. The 45-kD product resists alkaline extraction from the membrane, so we conclude that the 11-kD nascent polypeptide has been crosslinked to an integral membrane protein of approximately 34 kD (imp34). The cross-linked product does not bind to ConA Sepharose, nor is it sensitive to endoglycosidase H digestion; hence imp34 is not identical to the alpha or beta subunits of the signal sequence receptor (SSR). We propose that imp34 functions in concert with SSR to form a translocation site through which nascent polypeptides pass in traversing the membrane bilayer of the rough endoplasmic reticulum.


Evaluation of quality of life in patients surgically treated for potentially malignant oral lesions.
The oral potentially malignant disorders (OPMDs) can impair the quality of life (QOL) of an individual. The evaluation of various aspects of life getting affected will help the health service providers to better comprehend the problems faced by the patients. This study aimed to evaluate the postoperative QOL of surgically treated patients for OPMDs. It was a cross-sectional study done on 45 follow-up patients, aged 24-80 years, who were surgically treated for OPMDs. A performa with questions regarding sociodemographics, personal, and abusive habits and a questionnaire on QOL was used. Oral examination was done to analyze the oral mucosa for recurrence. Data were analyzed using frequency analysis and unpaired student's t-test to compare the mean scores. Several patients reported to have experienced a lot of pain (15, 33%), burning sensation on having spicy food (36, 80%), great difficulty in opening mouth (15, 33%), alteration in taste sensation (36, 80%), limiting of eating desired food (24, 53%), and dryness of mouth (7, 16%). Many patients felt very frustrated, depressed (9, 20%), and reported their condition to have affected their satisfaction with life (19, 42%). However, neither did social relationship with family and friends got affected by this nor did it add discomfort to them at parties, social functions, or get together. Their main concern was the likelihood of their oral condition progressing into cancer. There was a statistically significant difference in the QOL scores for habit of areca nut chewing (P = 0.05), erythroplakia lesions (P = 0.05), and recurrence of lesion (P = 0.02). OPMDs affected the physical, functional, and psychological well-being of study patients, caused discomfort, and affected their daily activities. However, the social well-being of patients was unaltered and a large number of patients were reportedly satisfied with their treatments. The timely diagnosis and management can improve the quality of life and prevent its progression to malignancy.


Production of ethylene glycol or glycolic acid from D-xylose in Saccharomyces cerevisiae.
The important platform chemicals ethylene glycol and glycolic acid were produced via the oxidative D-xylose pathway in the yeast Saccharomyces cerevisiae. The expression of genes encoding D-xylose dehydrogenase (XylB) and D-xylonate dehydratase (XylD) from Caulobacter crescentus and YagE or YjhH aldolase and aldehyde dehydrogenase AldA from Escherichia coli enabled glycolic acid production from D-xylose up to 150 mg/L. In strains expressing only xylB and xylD, 29 mg/L 2-keto-3-deoxyxylonic acid [(S)-4,5-dihydroxy-2-oxopentanoic acid] (2K3DXA) was produced and D-xylonic acid accumulated to ca. 9 g/L. A significant amount of D-xylonic acid (ca. 14%) was converted to 3-deoxypentonic acid (3DPA), and also, 3,4-dihydroxybutyric acid was formed. 2K3DXA was further converted to glycolaldehyde when genes encoding by either YagE or YjhH aldolase from E. coli were expressed. Reduction of glycolaldehyde to ethylene glycol by an endogenous aldo-keto reductase activity resulted further in accumulation of ethylene glycol of 14 mg/L. The possibility of simultaneous production of lactic and glycolic acids was evaluated by expression of gene encoding lactate dehydrogenase ldhL from Lactobacillus helveticus together with aldA. Interestingly, this increased the accumulation of glycolic acid to 1 g/L. The D-xylonate dehydratase activity in yeast was notably low, possibly due to inefficient Fe-S cluster synthesis in the yeast cytosol, and leading to D-xylonic acid accumulation. The dehydratase activity was significantly improved by targeting its expression to mitochondria or by altering the Fe-S cluster metabolism of the cells with FRA2 deletion.


Effects of fetal tobacco exposure on focused attention in infancy.
This study examined the association between fetal tobacco exposure (FTE) and focused attention at 9 months of child age, and the role of child sex and infant behavioral reactivity as potential moderators of this association. Data were obtained from 203 mothers and their infants (105 fetally exposed and 98 non-exposed) on infant focused attention and behavioral reactivity to a frustration task. FTE was ascertained via nicotine metabolites in infant meconium, reflecting primarily third trimester fetal exposure. Results demonstrated a main effect of FTE on focused attention, such that exposed infants exhibited lower levels of focused attention than non-exposed infants. Behavioral reactivity, but not infant sex, moderated the relationship between FTE and focused attention, such that exposed infants who were highly reactive to frustration had the lowest levels of focused attention. Results suggest that smoking interventions, even in the third trimester, may have a positive impact on attentional outcomes for infants.


Radiation Exposure During Uterine Fibroid Embolization (UFE): A Confounder-Controlled Comparison Between a State-of-the-Art Angiography Unit and a Conventional Angiography unit.
To compare radiation exposure of a state-of-the-art and a conventional angiography unit in patients undergoing uterine fibroid embolization (UFE). Between January 2009 and December 2016, 286 patients underwent UFE in our Interdisciplinary Fibroid Center. The inclusion criteria for this retrospective analysis were first-time transarterial embolization for symptomatic fibroids, bilateral embolization, procedures applying a state-of-the-art (Group 1) or a conventional angiography unit (Group 2), and bilateral technical success with an adequate embolization endpoint after the injection of microspheres. Study endpoints included radiation exposure, major complications, morphological success (MRI), and clinical success (questionnaire on quality-of-life). Propensity score matching controlled for confounders. The inclusion criteria were met by 58 (Group 1) and 177 (Group 2) patients. After propensity score matching, there was no significant difference between Group 1 (n = 46) and Group 2 (n = 92) regarding age, body-mass index, volume of the dominant fibroid and the uterus, fluoroscopy time, and amount of embolic agent (p ≥ 0.10 each). The dose-area product was significantly lower in Group 1 than in Group 2 (1159.0 cGycm2 vs. 3123.5 cGycm2; p < 0.001), while major complication rates (both groups 0 %) and dominant fibroid devascularization (both groups 100 %) were equal (p > 0.99). There were no significant differences between both groups regarding shrinkage of the dominant fibroid and the uterus and no relevant differences regarding patient-reported quality-of-life. A state-of-the-art angiography unit has the potential to reduce radiation exposure in patients undergoing UFE without increasing the risk of major complications and with comparably high morphological and clinical success. · A state-of-the-art angiography unit potentially reduces radiation exposure in patients undergoing UFE.. · Reduced radiation exposure does not seem to negatively influence the rate of major complications.. · Reduced exposure does not seem to negatively affect morphological and clinical success.. · Sommer C, Voigt W, Oliger MK et al. Radiation Exposure During Uterine Fibroid Embolization (UFE): A Confounder-Controlled Comparison Between a State-of-the-Art Angiography Unit and a Conventional Angiography unit. Fortschr Röntgenstr 2018; 190: 250 - 258.


Alfalfa response to heat stress is modulated by microRNA156.
Heat stress and extreme temperatures negatively affect plant development by disrupting regular cellular and biochemical functions, ultimately leading to reduced crop production. Alfalfa (Medicago sativa) is an important forage crop grown worldwide as forage for livestock feed. Limiting the effects of abiotic stress by developing alfalfa cultivars that are stress tolerant would help mitigate losses to crop production. Members of the microRNA156 (miR156) family regulate the Squamosa Promoter-Binding Protein-Like (SPL) genes that in turn impact plant growth and development by regulating downstream genes in response to various abiotic stresses. In this study, alfalfa with miR156 overexpression and SPL13 RNAi knockdown show increased tolerance to heat stress (40°C). Transgenic plants show high water potential and increased non-enzymatic antioxidant content under heat stress. Moreover, anthocyanin content and chlorophyll abundance were increased under stress. Expression of some important transcription factors and downstream genes involved in abiotic stress response were altered in miR156-overexpressing genotypes under heat. Taken together, our results demonstrate that the miR156/SPL13 network contributes to improving heat stress tolerance in alfalfa.


Assessing the impact of physical activity on bone density, cardiopulmonary function, and metabolic health in stroke survivors.
Stroke survivors often face motor impairments leading to decreased physical activity, which can, in turn, result in secondary health-related issues like cardiovascular and pulmonary impairment and osteoporosis. This research finds out the impact of physical activity on bone mineral density, cardiopulmonary health, and metabolic status in stroke survivors. The goal is to generate knowledge to inform rehabilitation strategies, emphasizing the significant role of regular exercise in enhancing the health of individuals recovering from stroke. This study was conducted using a cross-sectional study design, and involved 100 stroke survivors selected through stratified random sampling. Physical activity was measured using the validated Stroke-Specific Physical Activity Questionnaire. Health outcomes were assessed through various means: bone mineral density via the OSTEOKJ3000 ultrasonic bone densitometer; resting heart rate and blood pressure via an automated monitor; lipid profiles through the CardioChek PA analyzer; Hb1Ac levels via the A1CNow + System; and respiratory parameters through a spirometer. Statistical analysis revealed bone mineral density is positively correlated with physical activity (R = 0.53, P < .001). Additionally, an association was found between physical activity and improved cardiopulmonary function (resting heart rate r = -0.45, P < .001; forced expiratory volume in one second R = 0.30, P = .0023; forced vital capacity R = 0.28, P = .0041). Moreover, higher physical activity levels correlated with lower low-density lipoprotein cholesterol levels (r = -0.35, P = .0007), higher high-density lipoprotein cholesterol levels (R = 0.33, P = .0012), and better glycaemic control (HbA1c r = -0.40, P = .0002). This study highlights the significant benefits of physical activity for stroke survivors, showing positive impacts on bone density, cardiopulmonary function, and metabolic health. It underscores the need to include regular exercise in rehabilitation strategies to mitigate secondary health complications and enhance the overall health of stroke survivors. Future research should continue investigating the potential benefits of physical activity in this population.


The role of osteocytes in bone regulation: mineral homeostasis versus mechanoreception.
Early work on the role of osteocytes in bone regulation suggested that the primary function of these cells was osteolysis. This lytic function was not precisely defined but included mineral homeostasis and at least the initiation of matrix remodeling, if not a primary role in remodeling. This paper is an attempt to promote the concept of osteocytic osteolysis as a method of systemic mineral homeostasis and to separate it from bone remodeling. Although recent investigations have pointed to mechanotransduction as a primary function of osteocytes, resulting in a general abandonment of the osteocytic osteolysis concept, the corpus of evidence suggests that osteocytes likely have a multipurpose role in the biology of bone. The osteocyte network represents an enormous surface area over which the cells interface with the surrounding matrix, useful for both strain detection and matrix mineral access. Osteocytes have been found to possess receptors for PTH, a known regulator of mineral ion homeostasis. Cultured osteocytes placed on dentin slices demonstrated no capacity to pit the dentin, but they were not treated with a regulating factor such as PTH, nor does mineral homeostasis require substantial bone volume removal. Scaling relationships suggest that osteocyte density is inversely proportional to body mass, R(2) = 0.86, and thus directly proportional to metabolic rate. Thus, species with higher metabolic rates (and therefore a greater demand for immediate access to minerals) have more osteocytes per bone volume. Finally, osteocytes express molecules typically associated with nerve cells and which are involved with glutamate neurotransmission. By this system, almost instantaneous messages may be transmitted throughout the network, an important feature in cells whose homeostatic function would be utilized on a scale of seconds, rather than hours or days. Experimental procedures for determining the role of the osteocyte in mineral homeostasis would require calcium mobilization from the bone matrix on a relatively immediate time scale. The experimental procedure would then be coupled with a high resolution histomorphometric analysis of lacunar radiographic area and mineral density. Added to this would be an in vitro study of mineral activation capacity via cultured osteocytes treated with PTH. Osteocytic osteolysis would be confirmed by an increase in the demineralized volume of osteocytic lacunae and the identification of a chemical mechanism by which osteocytes can readily access the mineral portion of their immediate bone matrix. It should also be true that a reverse capacity exists by which osteocytes can remineralize their immediate matrix utilizing alkaline phosphatase for example, a chemical which they, like osteoblasts, are known to generate. It is thus proposed that osteocytes are both mechanoreceptors and systemic mineral homeostasis regulators.