Carnosine Stimulates Macrophage-Mediated Clearance of Senescent Skin Cells Through Activation of the AKT2 Signaling Pathway by CD36 and RAGE.
Background: Macrophages can selectively recognize and eliminate senescent cells, but this function is impaired with age, resulting in excessive accumulation of senescent cells in the skin, which ultimately causes skin aging. Therefore, enhancing the immune surveillance ability of macrophages to clear senescent keratinocytes and fibroblasts from aging skin may be an effective skin rejuvenation strategy. Methods: In this study, a macrophage and senescent skin cell co-culture model was established whereby THP-1-derived macrophages and tert-butyl hydroxide-induced senescent skin cells (HaCaT and HFF-1) were grown in the same culture. Senescent skin cells were detected by the SPiDER-βgal assay, and the expression of secretory phenotype factors related to senescence was assayed by qPCR. The effect of carnosine on the number of SA-β-gal positive skin cells in the macrophage-senescent skin cell co-culture was evaluated and compared with that in the senescent skin cell monoculture. Results: Carnosine promoted macrophage-mediated elimination of senescent skin cells in the co-culture. Through the AKT2 signaling pathway, carnosine upregulated the expression of CD36 and receptors for advanced glycation end products and elevated the phagocytic capacity of the macrophages, thereby promoting the ability of the macrophages to eliminate the senescent skin cells. Conclusions: Carnosine could boost the immune surveillance ability of macrophages to clear senescent keratinocytes and fibroblasts in the macrophage-senescent skin cell co-culture by activating the AKT2 signaling pathway, suggesting the possibility of using carnosine as an agent to reverse skin aging.


Biogenesis of Tim23 and Tim17, integral components of the TIM machinery for matrix-targeted preproteins.
We analysed the import pathway of Tim23 and of Tim17, components of the mitochondrial import machinery for matrix-targeted preproteins. Tim23 contains two independent import signals. One is located within the first 62 amino acid residues of the hydrophilic domain that, in the assembled protein, is exposed to the intermembrane space. This signal mediates translocation of Tim23 across the outer membrane independently of the membrane potential, DeltaPsi. A second import signal is located in the C-terminal membrane-integrated portion of Tim23. It mediates translocation across the outer membrane and insertion into the inner membrane in a strictly DeltaPsi-dependent fashion. Structurally, Tim17 is related to Tim23 but lacks a hydrophilic domain. It contains an import signal in the C-terminal half and its import requires DeltaPsi. The DeltaPsi-dependent import signals of Tim23 and Tim17 are located at corresponding sites in these two homologous proteins. They exhibit features reminiscent of the positively charged N-terminal presequences of matrix-targeted precursors. Import of Tim23 and its insertion into the inner membrane requires Tim22 but not functional Tim23. Thus, biogenesis of the Tim23.17 complex depends on the Tim22 complex, which is the translocase identified as mediating the import of carrier proteins.


Structure, flexibility, and repair of two different orientations of the same alkyl interstrand DNA cross-link.
Interstrand DNA cross-links are the principal cytotoxic lesions produced by chemotherapeutic bifunctional alkylating agents. Using an N(4)C-ethyl-N(4)C interstrand DNA cross-link to mimic this class of clinically important cancer chemotherapeutic agents, we have characterized the repair, structure, and flexibility of DNA that contains this cross-link in two different orientations. Plasmid DNAs in which the cytosines of single CpG or GpC steps are covalently linked were efficiently processed by repair proficient and homologous recombination deficient strains of Escherichia coli. Repair in a nucleotide excision repair (NER) deficient strain was less efficient overall and displayed a 4-fold difference between the two cross-link orientations. Both the structure and flexibility of DNA containing these cross-links were examined using a combination of (1)H NMR, restrained molecular dynamics simulations, and atomic force microscopy (AFM). The NMR structure of a decamer containing a CpG interstrand cross-link shows the cross-link easily accommodated within the duplex with no disruption of hydrogen bonding and only minor perturbations of helical parameters. In contrast, disruptions caused by the GpC cross-link produced considerable conformational flexibility that precluded structure determination by NMR. AFM imaging of cross-link-containing plasmid DNA showed that the increased flexibility observed in the GpC cross-link persists when it is embedded into much larger DNA fragments. These differences may account for the different repair efficiencies seen in NER deficient cells.


High-sensitivity cardiac troponin T, left ventricular function, and outcome in non-ST elevation acute coronary syndrome.
Cardiac troponin (cTn) levels reflect infarct size and depressed left ventricular ejection fraction (LVEF) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS). However, there is very limited information on whether cTn measured with a high-sensitivity (hs) assay would provide incremental prognostic information to the LVEF in NSTE-ACS patients. This was a registry-based study (SWEDEHEART registry) investigating 20,652 NSTE-ACS patients with available information on hs-cTnT (highest level recorded during the hospitalization) and the LVEF estimated using echocardiography. All patients had been followed for 1 year. Hs-cTnT levels independently predicted major cardiovascular events (MACE) in cohorts with normal, slightly depressed, moderately depressed, and severely depressed LVEF. The adjusted hazard ratios in these cohorts were 1.18 (95% CI 1.13-1.23), 1.12 (95% CI 1.06-1.18), 1.12 (95% CI 1.06-1.19), and 1.21 (95% CI 1.13-1.30), respectively. Hs-cTnT levels were particularly predictive for cardiovascular mortality and readmission for heart failure. Excluding patients with previous cardiac disease did not affect the overall interrelations of hs-cTnT and LVEF with MACE. Hs-cTnT levels provide incremental prognostic value independent of the LVEF in patients with NSTE-ACS. Hs-cTnT is particularly predictive for MACE in patients with severely depressed LVEF but also in those with a normal LVEF. Accordingly, a normal LVEF should not be used as an argument not to target patients to thorough workup.


The role of prevention in promoting continuity of health care in prisoner reentry initiatives.
Most incarcerated individuals will return to the community, and their successful reentry requires consideration of their health and how their health will affect their families and communities. We propose the use of a prevention science framework that integrates universal, selective, and indicated strategies to facilitate the successful reentry of men released from prison. Understanding how health risks and disparities affect the transition from prison to the community will enhance reentry intervention efforts. To explore the application of the prevention rubric, we evaluated a community-based prisoner reentry initiative. The findings challenge all involved in reentry initiatives to reconceptualize prisoner reentry from a program model to a prevention model that considers multilevel risks to and facilitators of successful reentry.


"Maxim"izing time.
"You have to live on this 24 hours of daily time. Out of it you have to spin wealth, pleasure, money, content, respect, and the evolution of your immortal soul. Its right use, its most effective use, is a matter of the highest urgency...all depends on that."--Arnold Bennett The items presented here are not meant to contain all the answers to your time management challenges. However, these thoughts should spark your thinking process. Take these ideas, turn them over in your mind, play with them, develop your own thoughts on the subject, and force yourself to become more effective, more efficient, and more systematic. Acquiring this discipline now will ensure the most efficient path to your life's dreams.


Utility of Repeat Head Computed Tomography in Detecting Delayed Intracranial Hemorrhage in Falls on Direct Oral Anticoagulants.
Ground level falls in the elderly often lead to complications due to use of anticoagulants (ACs). Intracranial hemorrhage (ICH), immediate or delayed, is a feared consequence of such falls. The rate of delayed ICH (dICH) in patients taking anticoagulants or antiplatelet (AP) agents ranges from .6% to 6%. Patients on warfarin have a persistent rate of dICH, leading to implementation of routine repeat head CTs at our institution. This policy was extended to direct oral anticoagulants (DOACs). This study aims to determine institutional incidence of DOAC-associated dICH. With IRB waiver approval, we conducted a retrospective review of trauma evaluations for falls on DOACs from 2016 to 2018. We reviewed records for neurologic status, DOAC use, and results of initial and delayed head CTs. Exclusion criteria included initial GCS ≤14, new neurologic deficits, traumatic findings on initial CT, concurrent use of additional AC/AP, or absence of repeat head CT. Among 632 patients evaluated for falls on AC/AP therapy, 159 (25%) of patients were included in the review. The age range was 19-98 years old, with 99 females and 60 males. Half of the patients were on apixaban, with the rest on dabigatran or rivaroxaban. Ten patients presented with GCS of 14. No delayed hemorrhages were detected in this population. The necessity of a repeat head CT in patients taking DOACs is debated in the literature. Our analysis failed to demonstrate any delayed hemorrhage in neurologically intact patients after head strike on DOAC, suggesting no indication for follow-up imaging in this group.


Why involve families in acute mental healthcare? A collaborative conceptual review.
Family involvement is strongly recommended in clinical guidelines but suffers from poor implementation. To explore this topic at a conceptual level, a multidisciplinary review team including academics, clinicians and individuals with lived experience undertook a review to explore the theoretical background of family involvement models in acute mental health treatment and how this relates to their delivery. A conceptual review was undertaken, including a systematic search and narrative synthesis. Included family models were mapped onto the most commonly referenced underlying theories: the diathesis-stress model, systems theories and postmodern theories of mental health. Common components of the models were summarised and compared. Lastly, a thematic analysis was undertaken to explore the role of patients and families in the delivery of the approaches. General adult acute mental health treatment. Six distinct family involvement models were identified: Calgary Family Assessment and Intervention Models, ERIC (Equipe Rapide d'Intervention de Crise), Family Psychoeducation Models, Family Systems Approach, Open Dialogue and the Somerset Model. Findings indicated that despite wide variation in the theoretical models underlying family involvement models, there were many commonalities in their components, such as a focus on communication, language use and joint decision-making. Thematic analysis of the role of patients and families identified several issues for implementation. This included potential harms that could emerge during delivery of the models, such as imposing linear 'patient-carer' relationships and the risk of perceived coercion. We conclude that future staff training may benefit from discussing the chosen family involvement model within the context of other theories of mental health. This may help to clarify the underlying purpose of family involvement and address the diverse needs and world views of patients, families and professionals in acute settings.


General solution to the multiple-metallic-grooves scattering problem: the fast-polarization case.
The boundary value techniques in vector-field diffraction theories are generalized to describe electromagnetic scattering of plane waves by a finite number of parallel, rectangular grooves corrugated on a metallic (infinitely conducting) ground plane. Each of the grooves has its own feature size and location for representing a general grating structure in multilevel binary optics. The multiple-scattering matrix is derived for determining the scattering coefficients that lead to a fast convergence in the Bessel-function series representation of the scattered-field angular spectrum. The solution remains stable from the long-wavelength (the Rayleigh limit) to the short-wavelength region (the geometrical optics limit). It is found that any N-groove scattered field can be treated as the sum of N single-groove radiation fields and the cross-groove coupling fields. A coupling index is introduced to measure the coupling effect. Numerical examples of two, six, and twelve grooves are examined in differentspectral regions. Plots of the coupling index are generated to show the feasibility of using pattern superposition for an approximate solution.


Comparison of Ipragliflozin and Pioglitazone Effects on Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Randomized, 24-Week, Open-Label, Active-Controlled Trial.
To compare the efficacy of ipragliflozin versus pioglitazone in patients with type 2 diabetes complicated by nonalcoholic fatty liver disease (NAFLD). In this open-label, randomized, active-controlled trial, we randomly assigned 66 patients with type 2 diabetes and NAFLD to receive ipragliflozin 50 mg (n = 32) or pioglitazone 15-30 mg (n = 34) orally once daily. The primary outcome was a change from baseline in the liver-to-spleen attenuation ratio (L/S ratio) on computed tomography at week 24. At week 24, the mean ± SD L/S ratio had increased by 0.22 (from 0.80 ± 0.24 to 1.00 ± 0.18) in the ipragliflozin group and 0.21 (from 0.78 ± 0.26 to 0.98 ± 0.16) in the pioglitazone group (P = 0.90). Serum aspartate and alanine aminotransferase levels, HbA1c, and fasting plasma glucose were similarly reduced in the two treatment groups. Nevertheless, body weight and visceral fat area showed significant reductions only in the ipragliflozin group compared with the pioglitazone group (P < 0.0001 and P = 0.0013, respectively). There were no serious adverse events in either group. Compared with pioglitazone, ipragliflozin exerts equally beneficial effects on NAFLD and glycemic control during the treatment of patients with type 2 diabetes complicated by NAFLD. Furthermore, ipragliflozin significantly reduced body weight and abdominal fat area.


Subfunctionalization of phytochrome B1/B2 leads to differential auxin and photosynthetic responses.
Gene duplication and polyploidization are genetic mechanisms that instantly add genetic material to an organism's genome. Subsequent modification of the duplicated material leads to the evolution of neofunctionalization (new genetic functions), subfunctionalization (differential retention of genetic functions), redundancy, or a decay of duplicated genes to pseudogenes. Phytochromes are light receptors that play a large role in plant development. They are encoded by a small gene family that in tomato is comprised of five members: PHYA, PHYB1, PHYB2, PHYE, and PHYF. The most recent gene duplication within this family was in the ancestral PHYB gene. Using transcriptome profiling, co-expression network analysis, and physiological and molecular experimentation, we show that tomato SlPHYB1 and SlPHYB2 exhibit both common and non-redundant functions. Specifically, PHYB1 appears to be the major integrator of light and auxin responses, such as gravitropism and phototropism, while PHYB1 and PHYB2 regulate aspects of photosynthesis antagonistically to each other, suggesting that the genes have subfunctionalized since their duplication.


Hepatotoxicity induced by herbal and dietary supplements.
Herbals and dietary supplements (HDS) can cause hepatotoxicity. Regulation of HDS varies across the globe. In the United States, it is defined by a law that is now two decades old. More recent regulatory approaches in Europe still do not require testing for premarket safety. The true incidence of hepatotoxicity from HDS is unknown. The presentation is most often with a hepatocellular enzyme pattern, and the outcomes can be severe, leading to transplantation in some circumstances. The diagnosis of hepatotoxicity due to HDS is made in the same way as for drugs. However, patients often must be coaxed into revealing a history of use. No causality assessment approach is perfectly suited for hepatotoxicity from HDS, but the Roussel Uclaf Causality Assessment Method is most used. Future endeavors must focus on defining epidemiology, establishing an accepted nomenclature, and identifying culprit ingredients, predisposing host factors, and useful biomarkers for injury.


Treatment of acute variceal bleeding.
The management of variceal bleeding remains a clinical challenge with a high mortality. Standardisation in supportive and new therapeutic treatments seems to have improved survival within the last 25 years. Although overall survival has improved in recent years, mortality is still closely related to failure to control initial bleeding or early re-bleeding occurring in up to 30-40% of patients. Initial procedures are to secure and protect the airway, and administer volume replacement to stabilize the patient. Treatment with vasoactive drugs should be started as soon as possible, since a reduction in portal pressure is associated with a better control of bleeding and may facilitate later endoscopic procedures. Vasopressin and its analogues Terlipressin and somatostatin and analogues are the two types of medicine, which has been evaluated. In meta-analysis, only Terlipressin have demonstrated effects on control of bleeding and on mortality. Somatostatin and its analogues improve control of bleeding, but show in meta-analysis no effects on mortality. Approximately 20% of patients with variceal bleeding will suffer from an infection, when they are hospitalized. Invasive procedures will further increase the risk of bacterial infections. Meta-analysis of clinical trials comparing antibiotics with placebo demonstrates that antibiotic prophylaxis improves survival with 9% (p<0.004). Quinolones or intravenous cephalosporins should be preferred. Early endoscopy should be performed in patients with major bleeding. Endoscopic therapy increases control of bleeding and decreases the risks of rebleeding and mortality. Ligation is probably more effective than sclerotherapy with fewer complications and should therefore be preferred, if possible. In case of gastric variceal bleeding, tissue adhesives should be used. Improvements in resuscitation and prevention of complications have together with introduction of vasoactive drugs and refinement of endoscopic therapy majorily changed the prognosis of the patient presenting with variceal bleeding.


NIH conference. Immunomodulators in clinical medicine.
A major difficulty limiting the use of immunomodulators in clinical medicine has been the complexity of the immunoregulatory network in which modulation of one component usually perturbs the entire system, thus diminishing the specificity of the approach. Lymphokine-activated killer cells infused with interleukin-2 have proved effective in inducing remissions in several advanced cancers, particularly metastatic renal cell carcinomas. The interferons have shown direct antiproliferative effects as well as specific effects on immune function. Alpha-interferon has shown impressive antitumor effects in hairy cell leukemia and significant antiviral effects in papillomavirus infection of the genital tract. Interleukin-2 has multifaceted effects on various limbs of the inflammatory and immune responses and may be the critical common denominator in the adjuvant effects of several other compounds. Monoclonal antibodies have assumed an increasing role in diagnostic and therapeutic approaches to neoplastic and immune-mediated diseases. Finally, several immunomodulators are currently being tested in the treatment of the immune defect of the acquired immunodeficiency syndrome.


Delayed diagnosis of infants with abnormal neonatal screens.
To identify infants who were diagnosed clinically with a condition that previously had been detected by a state neonatal screening program, but who had failed to receive medical attention in a timely fashion. A descriptive case series of infants over a 2-year period from 1989 to 1991. An academically affiliated tertiary care pediatric hospital, a major referral center for children with abnormal results on state neonatal screening tests. All patients who (1) had a diagnosis suspected clinically, (2) had confirmation of disease, and (3) were subsequently found to have had abnormal screening results. Age at clinical diagnosis, morbidity due to delay in diagnosis, and postnatal medical follow-up. Ten children were identified, three with 21-hydroxylase deficiency and seven with a hemoglobinopathy. In each case, the screening program had clear documentation that the office of the physician of record had received prompt telephone communication of the abnormal result. The mean age at clinical diagnosis was 32 days for the children with 21-hydroxylase deficiency and 215 days for those with sickle cell anemia, substantially longer than is mandated by proper neonatal screening practice. Potentially life-threatening complications of the underlying disease were present in six children. A significant number of neonates who have metabolic disorders appropriately identified by a neonatal screening test may fail to receive timely treatment. Consideration should be given to implementing a system of directly contacting the parents of all presumptive positive cases by the state screening program.


Current Concepts and Controversies in the Management of REM Sleep Behavior Disorder.
Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream enactment and the loss of muscle atonia during REM sleep, known as REM sleep without atonia (RSWA). RBD can result in significant injuries, prompting patients to seek medical attention. However, in others, it may present only as non-violent behaviors noted as an incidental finding during polysomnography (PSG). RBD typically occurs in the context of synuclein-based neurodegenerative disorders but can also be seen accompanying brain lesions and be exacerbated by medications, particularly antidepressants. There is also an increasing appreciation regarding isolated or idiopathic RBD (iRBD). Symptomatic treatment of RBD is a priority to prevent injurious complications, with usual choices being melatonin or clonazepam. The discovery that iRBD represents a prodromal stage of incurable synucleinopathies has galvanized the research community into delineating the pathophysiology of RBD and defining biomarkers of neurodegeneration that will facilitate future disease-modifying trials in iRBD. Despite many advances, there has been no progress in available symptomatic or neuroprotective therapies for RBD, with recent negative trials highlighting several challenges that need to be addressed to prepare for definitive therapeutic trials for patients with this disorder. These challenges relate to i) the diagnostic and screening strategies applied to RBD, ii) the limited evidence base for symptomatic therapies, (iii) the existence of possible subtypes of RBD, (iv) the relevance of triggering medications, (v) the absence of objective markers of severity, (vi) the optimal design of disease-modifying trials, and vii) the implications around disclosing the risk of future neurodegeneration in otherwise healthy individuals. Here, we review the current concepts in the therapeutics of RBD as it relates to the above challenges and identify pertinent research questions to be addressed by future work.


Intestinal physiology and pathology in gene-targeted mouse models of cystic fibrosis.
Cystic fibrosis (CF) is a fatal genetic disorder that affects approximately 1 in 2,500 live Caucasian births. The disease can be described as a generalized exocrine disease affecting a variety of epithelial tissues, with early manifestation as meconium ileus in a significant number of neonates. Cloning of the gene causing CF was accomplished in 1989, and the protein product, cystic fibrosis transmembrane conductance regulator (CFTR), has been conclusively shown to be an adenosine 3',5'-cyclic monophosphate (cAMP)-regulated Cl- channel. Subsequently, several mouse models of CF were generated by gene-targeting approaches in an attempt to further understand this disease. The initial excitement generated by the emergence of these mouse models was somewhat tempered by the finding that none of the models developed airway disease, which is currently responsible for most of the morbidity and mortality in the human CF population. However, the various CF mouse models, of which there are now 10, are remarkably similar to their human counterparts with respect to intestinal pathophysiology. Most importantly, the intestinal tract of the CF mouse models demonstrates the absence of cAMP-mediated Cl- transport, which is a hallmark of CF disease. Furthermore, the murine CF intestinal tract also shows an inability to secrete HCO3-, defective cAMP regulation of electroneutral NaCl absorption, and elevated electrogenic Na+ transport in the distal colon, as well as other ion transport perturbations. Besides the fundamental mechanisms of ion transport studied in the murine CF intestinal tract, these models have also been important in understanding other tissues with regard to CF. Mice heterozygous for the CFTR knockout gene have a reduced ability to secret Cl- and fluid and therefore provide further support for the CF "heterozygote advantage" hypothesis. Some CF mouse models maintain a limited ability to secrete Cl-, which may be due to accessory genes that are hypothesized to ameliorate disease severity in the intestines of these mice. This review describes the CF models generated and compares the murine defects in ion transport with observed abnormalities in the human CF intestine.


Diagnosing Middle Ear Dysfunction in 10- to 16-Month-Old Infants Using Wideband Absorbance: An Ordinal Prediction Model.
Purpose The aim of this study was to develop an ordinal prediction model for diagnosing middle ear dysfunction in 10- to 16-month-old infants using wideband absorbance. Method Wideband absorbance, tympanometry, and distortion product otoacoustic emissions were measured in 358 ears of 186 infants aged 10-16 months (M age = 12 months). An ordinal reference standard (normal, mild, and severe middle ear dysfunction) was created from the tympanometry and distortion product otoacoustic emission results. Absorbance from 1000 to 5657 Hz was used to model the probability of middle ear dysfunction with ordinal logistic regression. Model performance was evaluated using measures of discrimination (c-index) and calibration (calibration curves). Performance measures were adjusted for overfitting (bias) using bootstrap resampling. Probabilistic and simplified methods for interpreting the model are presented. The probabilistic method displays the probability of ≥ mild and ≥ severe middle ear dysfunction, and the simplified method presents the condition with the highest probability as the most likely diagnosis (normal, mild, or severe middle ear dysfunction). Results The c-index of the fitted model was 0.919 (0.914 after correction for bias), and calibration was satisfactory for both the mild and severe middle ear conditions. The model performed well for the probabilistic method of interpretation, and the simplified (most likely diagnosis) method was accurate for normal and severe cases but diagnosed some cases with mild middle ear dysfunction as normal. Conclusions The model may be clinically useful, and either the probabilistic or simplified paradigm of interpretation could be applied, depending on the context. In situations where the main goal is to identify severe middle ear dysfunction and ease of interpretation is highly valued, the simplified interpretation may be preferable (e.g., in a screening clinic that may not be concerned about missing some mild cases). In a diagnostic clinical environment, however, it may be beneficial to use the probabilistic method of interpretation.


Hip hemiarthroplasty for fractured neck of femur; a freedom of information study to assess national variation in implant selection and procurement.
During 2016, according to the National Hip Fracture Database (NHFD), over 65,000 patients suffered a hip fracture of which approximately half underwent hemiarthroplasty. Clear guidelines exist on the usage of proven cemented implants. The Getting It Right First Time (GIRFT) Report highlighted the financial implications of 'unwarranted variation' and stressed the importance of rationalising and standardising service provision, in particular implant usage. The primary aims of this study were to investigate the variation in hip hemiarthroplasty implant usage and associated costs. We hypothesised there to be large variation in implants used and procurement costs. Freedom of Information Requests (FOI) were sent to all 177 hospitals listed in the 2017 NHFD Report as treating hip fracture patients. All hospitals were asked for their most commonly used hemiarthroplasty implant and the cost of this, per patient. One hundred sixty six (94%) responses were received. Eighty four (51%) provided implant name and cost, 78 (47%) provided implant name but refused costs and 4 (3%) refused to provide any details. Nineteen different prostheses were used nationally with 20 hospitals using a non-ODEP (Orthopaedic Data Evaluation Panel) 10A implant. Average total cost was £725.00 (range £71-£1378). Significant cost variation was demonstrated for the same implants; one implant was £978.19 at it's most costly and £285.59 at it's cheapest. The aims of this study have been met. We have demonstrated huge variation in the implants used for hip hemiarthroplasty and their costs. Notwithstanding the nuances of departmental procurement processes, the financial implications for this variation are significant. This article demonstrates a requirement for rationalisation of implant usage and procurement in order to potentially improve patient outcomes and provide opportunities for significant cost saving in an already overstretched health service.


Self-report and linguistic indicators of emotional expression in narratives as predictors of adjustment to cancer.
Emotional expression and cognitive efforts to adapt to cancer have been linked to better psychological adjustment. However, little is known about the relationship between linguistic indicators of emotional and cognitive coping efforts and corresponding self-report measures of related constructs. In this study, we sought to evaluate the interrelationships between self-reports of emotional suppression and linguistic indicators of emotional and cognitive coping efforts in those living with cancer. Seventy-one individuals attending a community cancer support group completed measures of emotional suppression and mood disturbance and provided a written narrative describing their cancer experience. Self-reports of emotional suppression were associated with more rather than less distress. Although linguistic indicators of both emotional expression and cognitive processing were generally uncorrelated with self-report measures of emotional suppression and mood disturbance, a significant interaction was observed between emotional suppression and use of cognitive words on mood disturbance. Among those using higher levels of emotional suppression, increasing use of cognitive words was associated with greater levels of mood disturbance. These findings have implications for a) the therapeutic use of emotion in psychosocial interventions and b) the use of computer-assisted technologies to conduct content analysis.


Life cycles shape parasite evolution: comparative population genetics of salmon trematodes.
Little is known about what controls effective sizes and migration rates among parasite populations. Such data are important given the medical, veterinary, and economic (e.g., fisheries) impacts of many parasites. The autogenic-allogenic hypothesis, which describes ecological patterns of parasite distribution, provided the foundation on which we studied the effects of life cycles on the distribution of genetic variation within and among parasite populations. The hypothesis states that parasites cycling only in freshwater hosts (autogenic life cycle) will be more limited in their dispersal ability among aquatic habitats than parasites cycling through freshwater and terrestrial hosts (allogenic life cycle). By extending this hypothesis to the level of intraspecific genetic variation, we examined the effects of host dispersal on parasite gene flow. Our a priori prediction was that for a given geographic range, autogenic parasites would have lower gene flow among subpopulations. We compared intraspecific mitochondrial DNA variation for three described species of trematodes that infect salmonid fishes. As predicted, autogenic species had much more highly structured populations and much lower gene flow among subpopulations than an allogenic species sampled from the same locations. In addition, a cryptic species was identified for one of the autogenic trematodes. These results show how variation in life cycles can shape parasite evolution by predisposing them to vastly different genetic structures. Thus, we propose that knowledge of parasite life cycles will help predict important evolutionary processes such as speciation, coevolution, and the spread of drug resistance.


Genetic incompatibilities in killifish and the role of environment.
Measuring reproductive isolation across multiple generations and environments is a key endeavor in speciation research because it indicates which isolating barriers currently prevent introgression and the extent to which they are intrinsic versus environmentally dependent. Here, I present data from several crosses (parental crosses, F1s, F2s, back-crosses) between two species of killifish (Lucania goodei and L. parva) that have diverged along a salinity gradient (L. goodei--freshwater, L. parva--euryhaline). Offspring were raised under high and low salinity to test for (1) extrinsic isolation, (2) intrinsic isolation manifested through genetic incompatibilities, and (3) environmentally dependent genetic incompatibilities. I found evidence for both intrinsic and extrinsic isolation, but no evidence for environmentally dependent genetic incompatibilities. The presence of extrinsic and intrinsic isolation varied among fitness measures, and all forms of reproductive isolation were asymmetric. Early egg survival was independent of salinity, but demonstrated pronounced intrinsic isolation. Both extrinsic and intrinsic isolation existed for egg hatching and survival of fry to the eating stage. Unfortunately, the order in which extrinsic and intrinsic isolation arose is unresolved. Understanding the extent to which adaptation to salinity creates multiple forms of reproductive isolation is critical for understanding diversification in many fish taxa.


Independent regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and chylomicron remnant receptor activities in rat liver.
Treatment of rats with pharmacological doses of oestrogen resulted in a 3-fold decrease in the activity of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and a 4-fold increase in saturable binding of 125I-labelled chylomicron remnants to liver membranes in vitro. Intragastric administration of mevalonolactone to rats did not affect the capacity of the liver membranes to bind to labelled chylomicron remnants even though there was a substantial decrease in the activity of HMG-CoA reductase. Similar results were obtained after cholesterol feeding. Simultaneous treatment of rats with cholestyramine and compactin increased hepatic HMG-CoA reductase activity 6-fold. However, liver membranes derived from these animals showed no change in their capacity to bind to labelled chylomicron remnants in vitro. Administration of mevalonolactone to the cholestyramine/compactin-treated animals also failed to produce a change in remnant-binding capacity. Although administration of mevalonolactone alone produced a significant 3-fold decrease in the activity of hepatic HMG-CoA reductase it was unable to suppress significantly the increase in enzyme activity caused by treatment with cholestyramine and compactin.


Orbital floor reconstruction.
This is a retrospective study with the aim to evaluate orbital floor reconstruction with autogenous bone and alloplastic materials consisting of Medpor, Medpor Titan, Titanium, and resorbable plates. We evaluated 101 patients with pure blow-out fracture or concomitant with zygomatic maxillary fracture. We reviewed patients' documentation before and after surgery and 12 months after reconstruction. Thirteen patients with Medpor, 42 patients with Medpor Titan, 30 patients with Titanium, 5 patients with calvarial bone graft, 8 patients with iliac bone graft, and 3 patients with bioresorbable plates were treated. Medpore and Medpor-Titan-Medpor 1.5 to 2 mm in thickness were used. Autogenous bone graft 3 to 5 mm in thickness was used. Results showed that autogenous and alloplastic materials could be used in orbital floor reconstruction; autogenous bone graft had minimal postoperative infection, and it is a good choice in major orbital defects. Titanium mesh and MTM with excellent structural support are used in large orbital floor defects. Resorbable plates are good alternative materials in pediatric patients.


Daily Cholecalciferol Supplementation during Pregnancy Alters Markers of Regulatory Immunity, Inflammation, and Clinical Outcomes in a Randomized Controlled Trial.
Vitamin D deficiency is widespread in pregnancy and has been associated with adverse health conditions in mothers and infants. Vitamin D supplementation in pregnancy may support the maintenance of pregnancy by its effects on innate and adaptive immunity. We assessed the effects of vitamin D supplementation during pregnancy on vitamin D status and markers of immune function associated with adverse pregnancy outcomes. We conducted a randomized, controlled, double-blind intervention of 2 doses of cholecalciferol (400 and 2000 IU/d) from <20 wk to delivery in 57 pregnant women. Vitamin D status, regulatory and inflammatory T cells, markers of innate immunity and systemic inflammation, and clinical outcomes including maternal blood pressure and birth weight were assessed at 26 and 36 wk of pregnancy. Supplementation with 2000 IU/d vitamin D had a greater effect on the change in vitamin D status over pregnancy (P < 0.0001) and the final value at 36 wk (P < 0.0001) than 400 IU/d, increasing serum 25-hydroxyvitamin D from 81.1 nmol/L at baseline to 116 nmol/L at 36 wk and from 69.6 nmol/L at baseline to 85.6 nmol/L at 36 wk, respectively. The 2000-IU/d group had 36% more interleukin-10+ regulatory CD4+ T cells at 36 wk than did the 400-IU/d group (P < 0.007). The daily intake of 2000 compared with 400 IU/d tended to dampen the pregnancy-related increase in diastolic blood pressure by 1.3-fold (P = 0.06) and increase birth weight by 8.6% (P = 0.06), but these differences were not statistically significant. Supplementation with 2000 IU/d is more effective at increasing vitamin D status in pregnant women than 400 IU/d and is associated with increased regulatory T cell immunity that may prevent adverse outcomes caused by excess inflammation. This trial was registered at clinicaltrials.gov as NCT01417351.


Preconceptual caffeine exposure increases glucose utilization and accelerates development in the preimplantation rat embryo.
The present study was designed to investigate whether caffeine administered daily throughout the estrous cycle prior to fertilization affected the development of the subsequent preimplantation day 5 rat embryo. The viability parameters chosen for assessment were glucose utilization, cell number, and stage of embryonic development (morula to hatched blastocyst). Two independently replicated experiments were conducted. Together these experiments demonstrated that after fertilization, a proportion of affected oocytes maturing in a caffeine-perfused ovarian environment used and oxidised glucose at a significantly higher rate and were significantly more advanced developmentally compared with their litter mates or with the control counterparts. Cell number per embryo and the number of embryos recovered (litter size) remained constant, suggesting that caffeine, at the doses used, is unlikely to affect the ovulation rate or prevent fertilization. This study is significant because it demonstrates for the first time that a drug such as caffeine, when administered prior to ovulation and genomic activation, causes a quantitative difference in growth promoting energy utilization in a proportion of susceptible embryos after genome activation. A link between genomic imprinting and changed developmental program in the preimplantation embryos was suggested.


[Spinal stabilizations in our department (1989-2002)].
With the aim to compare results to those found in the literature, authors present a retrospective overview of the spinal stabilizations carried out in the Neurosurgical Department at the St. John's Hospital, Budapest, Hungary between 1989 and 2002. This 37 bed department provides neurosurgical services to the Buda region with its one million inhabitants. Out of 156,000 injuries in total in the past 13 years, the department has dealt with 9360 neurotraumatologic cases, 560 of them suffering from spinal injuries. In parallel, non-traumatic cases were also treated for tumour, infections, degenerative diseases and for the instability of the spine. The 224 stabilised cases were classified into three groups: cervical, thoracic, lumbar. The authors enumerate the type of operation in each level and they present the number of cases belonging to each type. Septic complications occurred in 2.5% of cases. Screw breaking or slackening of the implanted devices was observed in 2% of the cases. The types of spinal operations applied provide satisfactory method for controlling the problems caused by the instability the spinal trauma, degenerative and tumourous cases. These results do not diverge from those found in the literature.


[Correlation between the organoleptic evaluation and the laboratory analysis of white brined cheese].
Satisfactory correlation was found to exist between the organoleptic evaluation and the chemical analysis of ewe's and cow's white brine cheese on the basis of the taste assessment for "normal acidity", while with the remaining degrees of acidity--"slightly acid", and "strongly acid"--no such correlation was established. The organoleptic and chemical analysis on the basis of "saltiness" degrees of the white brine types of cheese proved to correlate comparatively well. It is up to the expert to decide whether the organoleptic evaluation will be sufficient in a given case.


A comparative study on the application of hierarchical-agglomerative clustering approaches to organize outputs of reiterated docking runs.
Reiterated runs of standard docking protocols usually provide a collection of possible binding modes rather than pinpoint a single solution. Usually, this ensemble is then ranked by means of an energy-based scoring function. However, since many degrees of approximation have to be introduced in the computation of the binding free energy, scoring functions cannot always rank the experimental pose among the top scorers. Cluster analysis might help to overcome this limit, provided that data clusterability has been earlier assessed. In this paper, first, we present a modified version of a test earlier developed by Hopkins to assess whether or not docking outputs show the natural tendency to be grouped in clusters. Then, we report the results of a comparative study on the application of different hierarchical-agglomerative cluster rules to partition docking outputs. The rule that was able to best manage the observed data was finally applied to the whole ensemble of poses collected from several docking tools. The combination of the average linkage rule with the cutting function developed by Sutcliffe and co-workers turned out to be an approach that meets all of the criteria required for a robust clustering protocol. Furthermore, a consensus clustering allowed us to identify the pose closest to the experimental one within a statistically significant cluster, whose number was always of few units.


[Gamma-irradiation induces in HeLa cells radioresistant DNA synthesis].
Cells of a suspension HeLa culture at the logarithmic phase of growth were exposed to 60Co-gamma-rays (5 Gy), incubated in the nutritious medium, and in 4 h subjected to repeated irradiation: the dose-response function and the dynamics of DNA synthesis inhibition were determined. It was shown that DNA synthesis was inhibited to a lesser extent after preirradiation, in other words, DNA synthesis was radioresistant. A correlation between this synthesis and reproductive cell death is discussed.


The comparison of the immediate effects of application of the suboccipital muscle inhibition and self-myofascial release techniques in the suboccipital region on short hamstring.
[Purpose] The purpose of this study was to research the effect of performing the suboccipital muscle inhibition (SMI) and self-myofascial release (SMFR) techniques in the suboccipital area on the flexibility of the hamstring. [Subjects] Fifty persons with short hamstrings participated in this research. According to the results of the finger-floor distance (FFD) test, the subjects were allocated to SMI and SMFR groups of 25 subjects each. [Methods] The SMI and SMFR techniques were applied to the groups. For the analysis, we used the FFD test and the straight leg raise (SLR) test for the flexibility of hamstring. The evaluator was blindfolded. [Results] In the SMI group, FFD, SLR, and PA were significantly changed after the intervention, and in the SMFR group, there was a significant change in SLR after the intervention. In a comparison between the groups, FED was found to be significantly increased in the SMI group. [Conclusion] Application of the SMI and SMFR to persons with short hamstrings resulted in immediate increases in flexibility of the hamstring. However, we could see that the SMI technique was more effective.


Leber's Hereditary Optic Neuropathy: Novel Views and Persisting Challenges.
Leber's hereditary optic neuropathy is an inherited form of optic neuropathy, genetically and pathophysiologically based on mitochondrial insufficiency causing bilateral loss of central vision mostly amongst young adults. Despite being one of the most common mitochondrial diseases, the explanation for its pathophysiological background and effective clinical solutions remain elusive. Widening the scope in the search for pathological findings beyond the optic system has yielded several non-ophthalmologic findings, which might imply that Leber's hereditary optic neuropathy is in fact a multi-systemic disease. The aim of this review is to provide an overview of literature regarding the epidemiology, etiology, pathogenesis, clinical features, diagnostics and possible treatment options and drug targets, as well as presenting challenges related to the disease and proposing a diagnostic algorithm based on current clinical experience.


Socioeconomic position and stage at diagnosis of head and neck cancer - a nationwide study from DAHANCA.
Socioeconomic differences in survival after head and neck squamous cell carcinoma (HNSCC) are among the greatest for any malignancy. To improve our understanding of the mechanisms by which socioeconomic position influences HNSCC survival, we investigated the association between socioeconomic position and advanced stage HNSCC at diagnosis. Men and women with HNSCC diagnosed between 1992 and 2008 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database, which contains detailed information on all cases of HNSCC treated in Denmark. Individual information on the following four socioeconomic indicators: highest attained educational level, cohabitation status, disposable income and degree of urbanisation were obtained from Statistics Denmark. For the 9683 cases on which there was full information, we estimated odds ratios (ORs) for a diagnosis of advanced stage (TNM III-IV) HNSCC in multivariate logistic regression models by site (glottic, non-glottic larynx, oropharynx, hypopharynx and oral cancer), with adjustment for age, gender, period of diagnosis, education, income, cohabitation status, degree of urbanisation and comorbidity in accordance with a causal diagram. For all HNSCC sites, the ORs for advanced stage at diagnosis were increased for patients with low income and for men living alone. For glottic and oral cancers, the ORs for advanced stage HNSCC increased systematically by decreasing length of education. Increased ORs were found for hypopharynx cancer patients living in rural areas or provincial cities. Having one or more comorbid conditions was associated with an increased OR for advanced stage oral cancer but with a decreased OR for oropharynx cancer. In this nationwide population-based study, socioeconomic differences in stage at diagnosis were found for all HNSCC subsites. Focus on the high risk for advanced stage HNSCC among vulnerable patients may be beneficial during referral and diagnosis in order to improve HNSCC outcomes.


Avian nephroblastoma virus MAV-2(N) and avian osteopetrosis virus MAV-2(O) are genetically distinct.
Avian myeloblastosis virus consists of a mixture of a defective leukaemia virus and several non-defective associated avian leukosis viruses. The genomes of two of the associated avian leukosis viruses were examined in this study and were chosen because one of them, MAV-2(N), induces predominantly nephroblastoma, while the other, MAV-2(O), induces predominantly osteopetrosis. Competitive hybridization studies employing labelled virion RNA and DNA from normal and malignant tissue failed to demonstrate a difference the genomes. However, examination of ribonuclease T1-resistant oligonucleotide maps revealed that MAV-2(N) RNA had five oligonucleotide fragments which were not present in the MAV-2(O) genome. Poly(A) selection of the oligonucleotides at the 3' end of the genome showed that the fragments unique to MAV-2(N) were not present at this end of the genome. These results suggest that two viruses differing in oncogenic manifestation also differ in genome composition.


Comparison of the Hydraulic Fracturing Water Cycle in China and North America: A Critical Review.
There is considerable debate about the sustainability of the hydraulic fracturing (HF) water cycle in North America. Recently, this debate has expanded to China, where HF activities continue to grow. Here, we provide a critical review of the HF water cycle in China, including water withdrawal practices and flowback and produced water (FPW) management and their environmental impacts, with a comprehensive comparison to the U.S. and Canada (North America). Water stress in arid regions, as well as water management challenges, FPW contamination of aquatic and soil systems, and induced seismicity are all impacts of the HF water cycle in China, the U.S., and Canada. In light of experience gained in North America, standardized practices for analyzing and reporting FPW chemistry and microbiology in China are needed to inform its efficient and safe treatment, discharge and reuse, and identification of potential contaminants. Additionally, conducting ecotoxicological studies is an essential next step to fully reveal the impacts of accidental FPW releases into aquatic and soil ecosystems in China. From a policy perspective, the development of China's unconventional resources lags behind North America's in terms of overall regulation, especially with regard to water withdrawal, FPW management, and routine monitoring. Our study suggests that common environmental risks exist within the world's two largest HF regions, and practices used in North America may help prevent or mitigate adverse effects in China.


Socioeconomic Status and Glycemic Control in Type 2 Diabetes; Race by Gender Differences.
Background: This study aimed to investigate differences in the association between socioeconomic status (SES) and glycemic control in type 2 diabetes mellitus (DM) across race by gender groups. Methods: Using a convenient sampling strategy, participants were 112 patients with type 2 DM who were prescribed insulin (ns = 38 Black women, 34 Black men, 14 White women, and 26 White men, respectively). Linear regression was used to test the associations between sociodemographic variables (race, gender, SES, governmental insurance) and Hemoglobin A1c (HbA1c) in the pooled sample and within subgroups defined by race and gender. Results: In the pooled sample, neither SES nor governmental insurance were associated with HbA1c. However, the race by gender interaction approached statistical significance (B = 0.34, 95% CI = -0.24-3.00, p =0.094), suggesting higher HbA1c in Black women, compared to other race by gender groups. In stratified models, SES (B = -0.33, 95% CI = -0.10-0.00, p = 0.050), and governmental insurance (B = 0.35, 95% CI = 0.05-2.42, p = 0.042) were associated with HbA1c for Black men, but not for any of the other race by gender subgroups. Conclusion: Socioeconomic factors may relate to health outcomes differently across race by gender subgroups. In particular, SES may be uniquely important for glycemic control of Black men. Due to lack of generalizability of the findings, additional research is needed.


[Synthesis and identification of bromoacetylalprenololmenthane (BAlpM)].
A highly potent beta-adrenergic irreversible antagonist--Bromoacetylalprenololmenthane (BAlpM) was synthesized by a six step method with phenol and allychloride as the starting materials. Some improvement on purification of the product was described. The final product is identified by melting point, elemental analysis, UV and IR spectral analysis and mass spectrometry as well as beta-adrenergic receptor binding assays. [125I] +/- IODOPINDOLOL binding assay of mouse lung cell membrane preparations treated with BAlpM in vitro or in vivo showed that there was a dose-dependent decrease in the density of specific binding sites with no change in the Kd values. This result confirms that BAlpM is a beta-adrenergic irreversible antagonist.


Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors.
The aryl hydrocarbon receptor (AHR) pathway plays a critical role in the biology of Growth Hormone (GH)-secreting pituitary tumor (somatotropinoma). Germline rs2066853 AHR variant was found to be more frequent among acromegaly patients and associated with a more severe disease with larger invasive somatropinoma, and with resistance to somatostatin analogs treatment in patients living in polluted areas. However, no somatic changes in AHR gene have been reported so far in acromegaly patients. On that basis, the aim of the study was to assess at the somatic level the AHR gene status encompassing exon 10 region, also because of the high rate of variants found in this genomic region. A cohort of 13 patients aged 20-76 years with biochemical, clinical and histological diagnosis of somatotropinoma was studied. DNA and RNA from pituitary tumor histological samples have been extracted and analyzed by PCR and direct sequencing for AHR gene variants, and compared with corresponding patients' germline DNA as well as normal pituitary tissue as reference control. A degenerated letter codes in the region corresponding to AHR exon 10 (c.1239-c.2056) was detected in somatotropinomas-derived DNA but not in that of matched germline and pituitary normal tissue. By multiple PCR and sequencing analysis, we observed amplification only before codon 1246 and after codon 1254, confirming the presence of a tumor-restricted somatic deletion in the 5' upstream region of AHR exon 10. Analysis of PCR-amplified cDNA revealed a wildtype sequence of exon 9 and 10 in normal pituitary tissue, and a wildtype sequence of exon 9 and 10 up to codon 1246 and no sequence after the deletion region (c.1246-c.1254) in 6 out of 9 tumor samples. Patients carrying the germline rs2066853 AHR variant showed no somatic LOH at the corresponding genetic locus. This is the first demonstration of a recurrent somatic deletion in the exon 10 of the AHR gene in somatotropinomas. The functional impact of this genetic finding needs to be clarified.


Epidermal hyperplasia and appendage abnormalities in mice lacking CD109.
CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is highly expressed in several types of human cancer tissues, in particular, squamous cell carcinomas. In normal human tissues, human CD109 expression is limited to certain cell types including myoepithelial cells of the mammary, lacrimal, salivary, and bronchial glands and basal cells of the prostate and bronchial epithelium. Although CD109 has been reported to negatively regulate transforming growth factor-β signaling in keratinocytes in vitro, its physiologic role in vivo remains largely unknown. To investigate the function of CD109 in vivo, we generated CD109-deficient (CD109(-/-)) mice. Although CD109(-/-) mice were born normally, transient impairment of hair growth was observed. At histologic analysis, kinked hair shafts, ectatic hair follicles with an accumulation of sebum, and persistent hyperplasia of the epidermis and sebaceous glands were observed in CD109(-/-) mice. Immunohistochemical analysis revealed thickening of the basal and suprabasal layers in the epidermis of CD109(-/-) mice, which is where endogenous CD109 is expressed in wild-type mice. Although CD109 was reported to negatively regulate transforming growth factor-β signaling, no significant difference in levels of Smad2 phosphorylation was observed in the epidermis between wild-type and CD109(-/-) mice. Instead, Stat3 phosphorylation levels were significantly elevated in the epidermis of CD109(-/-) mice compared with wild-type mice. These results suggest that CD109 regulates differentiation of keratinocytes via a signaling pathway involving Stat3.


Neutrophil kinetics of recombinant human granulocyte colony-stimulating factor-induced neutropenia in rats.
Single injection of recombinant human granulocyte colony-stimulating factor (rhG-CSF) immediately induced a decrease in the number of circulating neutrophils in rats. This neutropenia occurred 10 minutes after the injection but disappeared 40 minutes after injection. This transient neutropenia was dose-dependently induced by rhG-CSF and also induced by repeated injections. We studied the kinetics of circulating neutrophils in transient neutropenia. rhG-CSF markedly decreased the number of 3H-diisopropylfluorophosphate (3H-DFP) labeled neutrophils in the circulation 10 minutes after injection but the labeled neutrophils recovered to near the control level 40 minutes after the injection. These results indicate that the neutrophil margination accounts for the neutropenia and the marginated neutrophils return to the circulation.


Bilateral carotid paraganglioma: surgery and radiotherapy.
Paragangliomas are relatively rare vascular tumors that develop from the neural crest cells of carotid bifurcation. They usually present as slow-growing, painless unilateral neck masses; bilateral presentation is rare and is mostly associated with familial forms. Bilateral total resection is not always possible for high-grade bilateral tumors, and radiotherapy is a good alternative, with cure rates similar to surgery. A 35-year-old female patient was admitted with a chief complaint of a bilateral, painless mass located on her neck. Subsequent magnetic resonance imaging (MRI) and angiographic imaging revealed bilateral hypervascular masses surrounding her carotid at 360°, and they were interpreted as stage 3 carotid paragangliomas according to the Shamblin classification protocol. Surgery was carried out on the left carotid paraganglioma and the mass was totally resected. It was thought that the patient could not tolerate bilateral surgery. Primary radiotherapy was planned on the right carotid paraganglioma: 59.8 gray (Gy) conformal, Linac-based multileaf collimator radiotherapy with a 180 cGy daily dosage, and five fractions per week were planned. Follow-up at 3 months following the conclusion of radiotherapy revealed no significant regression. A follow-up MRI 6 months and 24 months later revealed 59% regression. Grade 2 esophagitis and minimal neck edema were the only complications noted during the course of radiotherapy and during the 24-month follow-up period. No complications or relapse were observed except for edema following neck surgery.


Fetal nucleated red blood cell analysis for non-invasive prenatal diagnostics using a nanostructure microchip.
Cell-free DNA has been widely used in non-invasive prenatal diagnostics (NIPD) nowadays. Compared to these incomplete and multi-source DNA fragments, fetal nucleated red blood cells (fNRBCs), once as an aided biomarker to monitor potential fetal pathological conditions, have re-attracted research interest in NIPD because of their definite fetal source and the total genetic information contained in the nuclei. Isolating these fetal cells from maternal peripheral blood and subsequent cell-based bio-analysis make maximal genetic diagnosis possible, while causing minimal harm to the fetus or its mother. In this paper, an affinity microchip is reported which uses hydroxyapatite/chitosan nanoparticles as well as immuno-agent anti-CD147 to effectively isolate fNRBCs from maternal peripheral blood, and on-chip biomedical analysis was demonstrated as a proof of concept for NIPD based on fNRBCs. Tens of fNRBCs can be isolated from 1 mL of peripheral blood (almost 25 mL-1 in average) from normal pregnant women (from the 10th to 30th gestational week). The diagnostic application of fNRBCs for fetal chromosome disorders (Trisomy 13 and 21) was also demonstrated. Our method offers effective isolation and accurate analysis of fNRBCs to implement comprehensive NIPD and to enhance insights into fetal cell development.


Clinical and morpho-molecular classifiers for prediction of hepatocellular carcinoma prognosis and recurrence after surgical resection.
Approximately 50% hepatocellular carcinoma (HCC) patients die within 5 year after surgical resection. The present staging systems do not fully allow to accurately predict the HCC prognosis and recurrence. This study aimed to identify clinicopathological characteristics and molecular markers to establish classifiers to predict the 5-year overall survival (OS) and the 3-year recurrence in HCC patients post-operatively. We enrolled 647 HCC patients from two institutions, underwent surgical resection and divided the patients into one training and two validation cohorts. Clinicopathologic characteristics and tumor protein expression of 29 biomarkers by immunohistochemical (IHC) analysis were used to develop and validate a prognostic and a recurrent classifier, using the maximum relevance minimum redundancy algorithm jointly with the multivariable regression method. The prognostic classifier distinguished HCC patients into high- and low-probability survival groups with significant differences in 5-year OS rate in all three cohorts (training cohort: 57.36% vs. 22.97%; p < 0.0001; internal validation cohort: 61.90% vs. 28.85%; p < 0.0001; independent validation cohort: 64.28% vs. 22.45%; p < 0.0001). The recurrent classifier also demonstrated good discrimination in all three cohorts. This study presented a prognostic classifier and a recurrent classifier using clinicopathologic and IHC characteristics. The developed classifiers stratified HCC patients into high- and low-probability survival or recurrent groups, which can help clinicians judge whether adjuvant therapy is beneficial post-operatively.


[Effect of cocultivating fungal species on the degradation of lignocellulose residues].
The degradation potential of Phanerochaete sordida, Trametes trogii, Coprinus truncorum and Paecilomyces sp. upon yard wastes was evaluated. The species had been inoculated individually or in pairs formed by P. sordida and Paecilomyces sp., T. trogii and Paecilomyces sp., and C. truncorum and Paecilomyces sp. The highest level of endoxilanase activity was produced by P. sordida growing alone, during day 21 (1.09 U/g of dry material), but in P. sordida and Paecilomyces sp. cultures, the detected activity did not overcome 0.27 U/g of dry material during the whole experiment. T. trogii showed maximum activity on day 14 (0.78 U/g of dry material), but in T. trogii and Paecilomyces sp. cultures, the values increased until day 21 (1.07 U/g of dry material). P. sordida endocellulase activity reached its maximum on day 28 (0.08 U/g of dry material), but in P. sordida and Paecilomyces sp. cultures, this activity increased during the whole experiment (0.04 U/g of dry material). The major weight loss was found in P. sordida (27.6%). The possible beneficial effect of co-culture in yard wastes biodegradation is discussed.


Why does outer joint motion predominate in bipolar hip prosthesis? Experimental and clinical studies.
Theoretically, the motion of a bipolar hip prosthesis is most likely to occur at the inner joint if the frictional coefficients are equal at both surfaces. However, many studies have suggested that most motion occurs at the outer joint. We performed an analysis of motion in a cadaveric bone model and in 50 patients during fluoroscopic examination, to determine how the motion is distributed between the two joints and what factors contribute to this distribution. The motion distributions varied widely between the patients. However, there was a relative pre-ponderance (63-90%) of outer motion in all directions of leg movement in addition to a persistent coexistence of motion at both joints in 44 of 50 patients. This preponderance of outer motion was the result of an early impingement of the acetabular cup and structural differences between the two joints. An adjustment of the positive eccentricity and a decrease in the frictional torque of the inner joint as a result of better lubrication and smoothness can be expected to improve the motion distribution, thus reducing the amount of acetabular erosion.


[Wilson-Mikity syndrome as a cause of respiratory insufficiency of prematurity].
The Wilson-Mikity syndrome is a differential diagnosis of chronic lung disease in the neonate and primarily related to immaturity. It is characterized by the absence of typical clinical and radiological findings of the respiratory distress syndrome (RDS). Infectious causes are being discussed.


Cultural pressure and biased responding in free will attitudes.
Whether you believe free will exists has profound effects on your behaviour, across different levels of processing, from simple motor action to social cognition. It is therefore important to understand which specific lay theories are held in the general public and why. Past research largely focused on investigating free will beliefs (FWB, 'Do you think free will exists?'), but largely ignored a second key aspect: free will attitudes (FWA, 'Do you like/value will?'). Attitudes are often independently predictive of behaviour, relative to beliefs, yet we currently know very little about FWAs in the general public. One key issue is whether such attitudes are subject to biased, socially desirable responding. The vast majority of the general public strongly believes in the existence of free will, which might create cultural pressure to value free will positively as well. In this registered report, we used a very large (N = 1100), open available dataset measuring implicit and explicit attitudes towards free will and determinism to address this issue. Our results indicate that both explicit and implicit attitudes towards free will are more positive than attitudes towards determinism. We also show that people experience cultural pressure to value free will, and to devalue determinism. Yet, we found no strong evidence that this cultural pressure affected either implicit or explicit attitudes in this dataset.


Caring Burden and Quality of Life of Family Caregivers in Patients Undergoing Hemodialysis: A Descriptive-Analytic Study.
Caring role, especially in chronic diseases, has a negative impact on the health of family caregivers and can affect their quality of life. Therefore, this study aimed to investigate the care burden and quality of life in family caregivers of hemodialysis patients and their relationship with some characteristics of caregivers and patients. This study was conducted as a descriptive-analytic study in Isfahan from January to February 2017. Sampling was done using census. The number of participants was 254. The data gathering tools consisted of a three-part questionnaire including demographic characteristics, the Zarit questionnaire for caring burden, and SF-36 quality of life questionnaire. Data were analyzed using descriptive statistics, Pearson correlation coefficient test, Spearman's coefficient, ANOVA, and univariate general linear regression. A significant level of 5% was considered. The mean scores of the quality of life and caring burden were 30.54±9.89 and 44.98±6.82, respectively in caregivers. The age of the patient under care (P<0.001), cost of medications (P=0.008), and hours of care in 24 hours (P<0.001) had a significant relationship with care givers' quality of life. Also, univariate general linear regression revealed that care burden had a significant relationship with the quality of life (P=0.003). Family caregivers who experienced more caring burden had a low quality of life. The researchers suggest that supportive and educational programs should be designed and implemented for this group of patients and their caregivers.


Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes.
Bitter orange (Citrus aurantium) extract is widely used in dietary supplements for weight management and sports performance. Its primary protoalkaloid is p-synephrine. Most studies involving bitter orange extract and p-synephrine have used products with multiple ingredients. The current study assessed the thermogenic effects of p-synephrine alone and in conjunction with the flavonoids naringin and hesperidin in a double-blinded, randomized, placebo-controlled protocol with 10 subjects per treatment group. Resting metabolic rates (RMR), blood pressure, heart rates and a self-reported rating scale were determined at baseline and 75 min after oral ingestion of the test products in V-8 juice. A decrease of 30 kcal occurred in the placebo control relative to baseline. The group receiving p-synephrine (50 mg) alone exhibited a 65 kcal increase in RMR as compared to the placebo group. The consumption of 600 mg naringin with 50 mg p-synephrine resulted in a 129 kcal increase in RMR relative to the placebo group. In the group receiving 100 mg hesperidin in addition to the 50 mg p-synephrine plus 600 mg naringin, the RMR increased by 183 kcal, an increase that was statistically significant with respect to the placebo control (p<0.02). However, consuming 1000 mg hesperidin with 50 mg p-synephrine plus 600 mg naringin resulted in a RMR that was only 79 kcal greater than the placebo group. None of the treatment groups exhibited changes in heart rate or blood pressure relative to the control group, nor there were no differences in self-reported ratings of 10 symptoms between the treatment groups and the control group. This unusual finding of a thermogenic combination of ingredients that elevated metabolic rates without corresponding elevations in blood pressure and heart-rates warrants longer term studies to assess its value as a weight control agent.


Influenza surveillance in England and Wales: October 1996 to June 1997.
This report summarises information collected for the surveillance of influenza in England and Wales during the winter of 1996/97. Consultations for 'influenza and influenza-like illness' with sentinel general practitioners in England and Wales began to increase towards the end of November and peaked at the start of January. In England, consultations for 'aggregated respiratory disease' (ARD) began to increase a little earlier, perhaps as a result of increased respiratory syncytial virus activity, but also peaked in early January. Influenza A (H3N2) viruses were first detected in early October, but rarely until November, and activity peaked in early January, coinciding with the peak in consultations for flu-like illness. A few influenza B viruses were detected in late November and early December, and substantial activity was recorded in mid-January. Approximately equal numbers of influenza A(H3N2) and B viruses were identified over the winter as a whole, and circulating strains were antigenically similar to those included in the vaccine for 1996/97. Although influenza activity was 'moderate' in terms of consultations and laboratory confirmed infections, a large peak in death registrations occurred at the same time as influenza A(H3N2) virus activity peaked. The number of deaths during the winter was similar to that seen in 1989/90, when the last severe influenza epidemic occurred in England and Wales.


Variability observed in mechano-regulated in vivo tissue differentiation can be explained by variation in cell mechano-sensitivity.
Computational simulations of tissue differentiation have been able to capture the main aspects of tissue formation/regeneration observed in animal experiments-except for the considerable degree of variability reported. Understanding and modelling the source of this variability is crucial if computational tools are to be developed for clinical applications. The objective of this study was to test the hypothesis that differences in cell mechano-sensitivity between individuals can explain the variability of tissue differentiation patterns observed experimentally. Simulations of an experiment of tissue differentiation in a mechanically loaded bone chamber were performed. Finite element analysis was used to determine the biophysical environment, and a lattice-modelling approach was used to simulate cell activity. Differences in cell mechano-sensitivity among individuals were modelled as differences in cell activity rates, with the activation of cell activities regulated by the mechanical environment. Predictions of the tissue distribution in the chambers produced the two different classes of results found experimentally: (i) chambers with a layer of bone across the chamber covered by a layer of cartilage on top and (ii) chambers with almost no bone, mainly fibrous tissue and small islands of cartilage. This indicates that the differing cellular response to the mechanical environment (i.e., subject-specific mechano-sensitivity) could be a reason for the different outcomes found when implants (or tissue engineered constructs) are used in a population.


Genetic analysis of the nuo locus, which encodes the proton-translocating NADH dehydrogenase in Escherichia coli.
Complex I (EC 220.127.116.11) of the bacterium Escherichia coli is considered to be the minimal form of the type I NADH dehydrogenase, the first enzyme complex in the respiratory chain. Because of its small size and relative simplicity, the E. coli enzyme has become a model used to identify and characterize the mechanism(s) by which cells regulate the synthesis and assembly of this large respiratory complex. To begin dissecting the processes by which E. coli cells regulate the expression of nuo and the assembly of complex I, we undertook a genetic analysis of the nuo locus, which encodes the 14 Nuo subunits comprising E. coli complex I. Here we present the results of studies, performed on an isogenic collection of nuo mutants, that focus on the physiological, biochemical, and molecular consequences caused by the lack of or defects in several Nuo subunits. In particular, we present evidence that NuoG, a peripheral subunit, is essential for complex I function and that it plays a role in the regulation of nuo expression and/or the assembly of complex I.


Cationic tantalum oxide nanoparticle contrast agent for micro computed tomography reveals articular cartilage proteoglycan distribution and collagen architecture alterations.
Cationic tantalum oxide nanoparticles (Ta2O5-cNPs), as a newly introduced contrast agent for computed tomography (CT) of cartilage, offer quantitative evaluation of proteoglycan content and biomechanical properties. However, knowledge on the depth-wise impact of cartilage constituents on NP diffusion, particularly the influence of the collagen network, is lacking. In this study, we aim to establish the depth-dependent relationship between Ta2O5-cNP diffusion and cartilage constituents (proteoglycan content, collagen content and network architecture). Osteochondral samples (n = 30) were harvested from healthy equine stifle joints (N = 15) and the diffusion of 2.55 nm diameter cationic Ta2O5-cNPs into the cartilage was followed with µCT imaging for up to 96 hours. The diffusion-related parameters, Ta2O5-cNP maximum partition (Pmax) and diffusion time constant, were compared against biomechanical and depth-wise structural properties. Biomechanics were assessed using a stress-relaxation and sinusoidal loading protocols, whereas proteoglycan content, collagen content and collagen network architecture were determined using digital densitometry, Fourier-transform infrared spectroscopy and polarized light microscopy, respectively. The Pmax correlates with the depth-wise distribution of proteoglycans (bulk Spearman's ρ = 0.87, p < 0.001). More open collagen network architecture at the superficial zone enhances intake of Ta2O5-cNPs, but collagen content overall decreases the intake. The Pmax values correlate with the equilibrium modulus (ρ = 0.80, p < 0.001) of articular cartilage. This study establishes the feasibility of Ta2O5-cNPs for the precise and comprehensive identification of biomechanical and structural changes in articular cartilage via contrast-enhanced µCT.


Cell cycle-independent regulation of p21Waf1/Cip1 and retinoblastoma protein during okadaic acid-induced apoptosis is coupled with induction of Bax protein in human breast carcinoma cells.
Okadaic acid (OA) is a serine/threonine protein phosphatase inhibitor and has been shown to induce apoptosis in a number of different tumor cell lines, including human breast carcinoma (HBC) cells. The molecular basis of OA-induced apoptosis remains to be investigated. Here, we demonstrate that the OA concentration that inhibits only protein phosphatase 1 and 2A was sufficient to induce apoptosis in HBC cells. In MCF-7 cells, the OA-induced apoptosis was coupled with the overexpression of endogenous p53, p21Waf1/Cip1, and Bax proteins, whereas the Rb protein levels were decreased. OA also induced apoptosis and concomitantly enhanced the p21Waf1/Cip1 and Bex levels in human papilloma virus protein E6-transfected variants of MCF-7 cells, in which p53 function had been disrupted. OA, by contrast, had no effect on the levels or the subcellular localization of Gadd45 and Bcl2 proteins in either wild-type of E6-transfected MCF-7 cells. Bcl-xL, Bcl-xS, and Bak levels were also unchanged after OA treatment in both cell types. OA-induced apoptosis and its effect on the expression of the above molecular markers occurred in the absence of any detectable changes in the cell cycle phase distribution. On the basis of our findings, we conclude the following: (a) OA-induced apoptosis in HBC cells occurs independently of cell cycle arrest; (b) the wild-type p53 function is not an absolute prerequisite for OA-induced cell death; and (c) OA-induced apoptosis is associated with up-regulation of endogenous p21Waf1/Cip1 and Bax protein levels.


Skin allograft and vascularized composite allograft: potential for long-term efficacy in the context of lymphatic modulation.
Tissue transplantation restores form and function in burn patients. The treatment of burn injuries is influenced by severity, location, and the percentage of total body surface area. There have been a number of different techniques developed to temporize and repair the destroyed tissue. However, in patients with large wound burden, sufficient donor site tissue may not be available for autograft harvesting. Such extensive burns necessitate other temporary and permanent options for wound coverage such as skin or vascularized composite allografts (VCA). Rejection of these tissues presents an ongoing problem which is currently managed using a host of systemic immunosuppressive medications. This article discusses the mechanism behind the innate and adaptive immune systems rejection of the allografts. By understanding these pathways, various techniques using immunomodulatory protocols have led to increased allograft survival. However, our primary interest lies in the initial recognition of the graft. We tailor this article to have a specific emphasis on lymphatic modulation as a potential adjunctive therapy. Reviews of the studies evaluating the effect of lymph node modulation on graft survival are described with future implications to allograft transplant research.


Bringing Together Research and Quality Improvement: The Saskatchewan Approach.
Improving health and health services requires both better knowledge (a key function of research) and better action to adapt and use what is already known (quality improvement). However, organizational and cultural divides between academic research institutions and health system organizations too often result in missed opportunities to integrate research and improvement. The Saskatchewan Health Quality Council's experience and relationships, from linking research, quality improvement and patient engagement in its leadership of the province's healthcare quality improvement journey, provided core support and leadership in the development of Saskatchewan's Strategy for Patient-Oriented Research SUPPORT Unit. The vision is for the SUPPORT Unit to integrate research and quality improvement into a continuous learning health system.


Behavior of Blood Pressure Variables in Children and Adolescents with Duchenne Muscular Dystrophy.
Duchenne muscular dystrophy is an X-chromosome-linked genetic disorder (locus Xp21). Involvement of the cardiovascular system is characterized by fibrous degeneration/replacement of myocytes with consequent ventricular hypertrophy and arterial hypertension. To assess, by using 24-hour ambulatory blood pressure monitoring, the behavior of blood pressure variables in children and adolescents with a confirmed diagnosis of Duchenne muscular dystrophy. Prospective observational cohort study, which selected 46 patients followed up on an outpatient basis, divided according to age groups. Blood pressure was classified according to the age percentile. The monitoring interpretation includes systolic and diastolic blood pressure means, systolic and diastolic blood pressure loads, and nocturnal dipping. The blood pressure means were calculated for the 24-hour, wakefulness and sleep periods. Nocturnal dipping was defined as a drop in blood pressure means during sleep greater than 10%. The significance level adopted was p < 0.05. Nocturnal dipping for systolic blood pressure was present in 29.9% of the participants. Approximately 53% of them had attenuated nocturnal dipping, and 15%, reverse nocturnal dipping. The age groups of 9-11 years and 6-8 years had the greatest percentage of attenuation, 19.1% and 14.9%, respectively. Regarding diastolic blood pressure, nocturnal dipping was identified in 53.2% of the children, being extreme in 27.7% of those in the age group of 6-11 years. The early diagnosis of blood pressure changes can allow the appropriate and specific therapy, aimed at increasing the life expectancy of patients with Duchenne muscular dystrophy.


Promoter sequences of eukaryotic protein-coding genes.
In vitro genetic techniques were used to study the sequence requirements for the initiation of specific transcription. Deletion mutants were constructed around the putative promoter of the adenovirus-2 major late and chicken conalbumin genes. Specific transcription in vitro by RNA polymerase B together with a HeLa cell cytoplasmic extract was used as the test for promoter function. With this approach sequences which are essential for the initiation of specific transcription in vitro, were shown to be located between 12 and 32 base pairs upstream from the 5' end of these genes.


Regulation of intestinal permeability: The role of proteases.
The gastrointestinal barrier is - with approximately 400 m2 - the human body's largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins via activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.


Are the Sanders-Frykberg and Brodsky-Trepman Classifications Reliable in Diabetic Charcot Neuroarthropathy?
The purpose of this study was to assess the intra- and inter-reader reliability of the 2 Charcot neuroarthropathy classifications (Sanders-Frykberg and Brodsky-Trepman), as well as Eichenholtz staging. We hypothesized that the inter-reader reliability, with respect to these 3 classification systems, would be moderate at best. Digital radiographic images were organized in a digital slide presentation without clinical information. All 5 reviewers underwent a standard training session administered by the principal investigator, reviewing 5 cases of Charcot neuroarthropathy. Images of 55 cases of Charcot neuroarthropathy and 5 normal cases were distributed to each of the 5 physicians electronically, who independently rated all 60 cases according to the 3 classification systems. The 95% confidence interval of the intraclass correlation coefficient estimate for Sanders-Frykberg was 0.9601 to 0.9833 at week 0 and 0.9579 to 0.9814 at week 8, which can be regarded as "excellent" reliability. For Trepman-Brodsky, the 95% confidence interval of the intraclass correlation coefficient estimate was 0.8463 to 0.9327 at week 0 and 0.8129 to 0.9226 at week 8, which can be regarded as "good" to "excellent" reliability. For Eichenholtz, the 95% confidence interval of the intraclass correlation coefficient estimate was 0.6841 to 0.8640 and 0.6931 to 0.8730 at weeks 0 and 8, respectively, which can be regarded as "moderate" to "good" reliability. The classification systems of Charcot neuroarthropathy are an important tool for communication among physicians. Based on the results at our institution, the Sanders-Frykberg classification exhibited the best inter-reader performance. The Trepman-Brodsky classification exhibited good to excellent reliability as well. The intraclass correlation coefficient of the Eichenholtz classification was moderate to good.


Susceptibility of Chlamydia pneumoniae to azithromycin and doxycycline: methodological aspects on the determination of minimal inhibitory and minimal bactericidal concentrations.
An in vitro assay for measuring and comparing the efficacy of different antimicrobial agents against Chlamydia pneumoniae was developed. Azithromycin, a representative of the new azalide group of antibiotics, and doxycycline were evaluated with respect to their antibacterial effect and capacity for intracellular killing under different experimental conditions. For both study drugs, the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values increased significantly with longer bacterial preincubation time. The effect of different exposure times of antibiotics on the bacteria was also studied.


Human Respiratory Syncytial Virus Subgroup A and B Infections in Nasal, Bronchial, Small-Airway, and Organoid-Derived Respiratory Cultures.
Human respiratory syncytial virus (HRSV) is the leading cause of bronchiolitis in infants. Two subgroups of HRSV (A and B) routinely cocirculate. Most research has been performed with HRSV-A strains because these are easier to culture than HRSV-B strains. In this study, we aimed to compare the replicative fitness and HRSV-induced innate cytokine responses of HRSV-A and HRSV-B strains in disease-relevant cell culture models. We used two recombinant (r) clinical isolate-based HRSV strains (A11 and B05) and one recombinant laboratory-adapted HRSV strain (A2) to infect commercially available nasal, bronchial, and small-airway cultures. Epithelial cells from all anatomical locations were susceptible to HRSV infection despite the induction of a dominant type III interferon response. Subgroup A viruses disseminated and replicated faster than the subgroup B virus. Additionally, we studied HRSV infection and innate responses in airway organoids (AOs) cultured at air-liquid interface (ALI). Results were similar to the commercially obtained bronchial cells. In summary, we show that HRSV replicates well in cells from both the upper and the lower airways, with a slight replicative advantage for subgroup A viruses. Lastly, we showed that AOs cultured at ALI are a valuable model for studying HRSV ex vivo and that they can be used in the future to study factors that influence HRSV disease severity.IMPORTANCE Human respiratory syncytial virus (HRSV) is the major cause of bronchiolitis and pneumonia in young infants and causes almost 200,000 deaths per year. Currently, there is no vaccine or treatment available, only a prophylactic monoclonal antibody (palivizumab). An important question in HRSV pathogenesis research is why only a fraction (1 to 3%) of infants develop severe disease. Model systems comprising disease-relevant HRSV isolates and accurate and reproducible cell culture models are indispensable to study infection, replication, and innate immune responses. Here, we used differentiated AOs cultured at ALI to model the human airways. Subgroup A viruses replicated better than subgroup B viruses, which we speculate fits with epidemiological findings that subgroup A viruses cause more severe disease in infants. By using AOs cultured at ALI, we present a highly relevant, robust, and reproducible model that allows for future studies into what drives severe HRSV disease.


Recurrent ectopic pregnancy in a cesarean scar.
Ectopic pregnancy in a cesarean scar is a rare but well-recognized potential complication of cesarean delivery. Multiple risk factors exist, including prior uterine surgery, a history of uterine infections such as endomyometritis, and a brief interval between uterine surgery and subsequent conception. It is important to recognize such cases early, due to the risk for uterine rupture and catastrophic hemorrhage at early gestational ages. This patient presented for a dating ultrasound examination at 4 6/7 weeks of gestation. Her history was significant for an ectopic pregnancy in her cesarean scar 3 years prior that was managed by surgical resection. The initial ultrasound examination was suspicious for a recurrent ectopic pregnancy in her cesarean scar. The diagnosis was confirmed on repeat ultrasonography at 6 weeks of gestation. She was treated with methotrexate, and the pregnancy resolved without complication. Ectopic pregnancy in a cesarean scar is an important diagnosis to consider in a woman who has had a history of cesarean delivery and whose early ultrasonography shows a thin, lower uterine segment or a low implantation site. If the diagnosis is not clear on initial ultrasound examination, the patient should be followed up with serial ultrasound examinations. Once recognized, patients with this complication may be treated either surgically or medically as indicated by the clinical situation.


GABA and epilepsy: their complex relationship and the evolution of our understanding.
Because of its abundance in the brain, its ability to produce hyperpolarizing inhibition of almost all neurons, its association with benzodiazepines, and the discovery that many convulsants inhibited its synthesis, gamma-aminobutyric acid (GABA) has often appeared to be the key to epilepsy. Many assumed that "primary" or "genetic" epilepsy must be a disorder of GABA synapses and that GABA agonists would be universal anticonvulsants if permeability and drug metabolism were controlled. The GABA synthetic gene was a logical "candidate gene" for epilepsy. However, the GABA-deficiency theory of epilepsy is less convincing today. GABA agonists were found to intensify seizures in some rodent and human cases. Absence and other generalized seizures in humans often worsened when treated with GABA transaminase inhibitors such as gamma-vinyl-GABA. Surprisingly, the GABA transaminase inhibitors appear to be more useful in partial than in generalized epilepsies. Neuronal GABA uptake blockers are proconvulsant. GABA agonists aggravate seizures in several mutants, ranging from the photosensitive baboon to the genetically epilepsy-prone rat. How can this be understood? Muscimol injections into the pedunculopontine nucleus increase seizures due to systematically administered convulsants, while the receptor blocker bicuculline suppresses seizures after injection into several brain regions, including the striatum. The result of inhibiting inhibitory circuits is excitation. Studies with GABA uptake blockers and the GABAB agonist baclofen are presented in which their combined administration provoked seizures in rats. Baclofen was shown also to increase the incidence of seizures evoked by pentylenetetrazole without increasing seizures due to local injections of excitatory amino acids. Baclofen antagonized the myoclonic effect of 5-hydroxytryptophan in rats with serotonin lesions. Baclofen augments some seizures and inhibits others. Selective inhibition of a particular tract, whether GABAergic or not, may have convulsant or anticonvulsant effects, depending on its connections and the state of the organism. GABAA receptor stimulation is usually but not always anticonvulsant. GABAB receptor stimulation may facilitate absence seizures and related primary generalized seizures. GABAB receptors may be abnormal in some forms of nonfocal epilepsy seen in childhood. It is likely that mutations of GABA transporter and GABAA receptor genes will be found in humans but they will probably not be patients with "pure epilepsy."


Palaeo leaf economics reveal a shift in ecosystem function associated with the end-Triassic mass extinction event.
Climate change is likely to have altered the ecological functioning of past ecosystems, and is likely to alter functioning in the future; however, the magnitude and direction of such changes are difficult to predict. Here we use a deep-time case study to evaluate the impact of a well-constrained CO2-induced global warming event on the ecological functioning of dominant plant communities. We use leaf mass per area (LMA), a widely used trait in modern plant ecology, to infer the palaeoecological strategy of fossil plant taxa. We show that palaeo-LMA can be inferred from fossil leaf cuticles based on a tight relationship between LMA and cuticle thickness observed among extant gymnosperms. Application of this new palaeo-LMA proxy to fossil gymnosperms from East Greenland reveals significant shifts in the dominant ecological strategies of vegetation found across the Triassic-Jurassic transition. Late Triassic forests, dominated by low-LMA taxa with inferred high transpiration rates and short leaf lifespans, were replaced in the Early Jurassic by forests dominated by high-LMA taxa that were likely to have slower metabolic rates. We suggest that extreme CO2-induced global warming selected for taxa with high LMA associated with a stress-tolerant strategy and that adaptive plasticity in leaf functional traits such as LMA contributed to post-warming ecological success.


[Choledocholithiasis: etiology, pathogenesis, diagnosis].
Cholelithiasis is one of the basic pathologies of the digestive apparatus. A certain progress in the study of biliary production and excretion processes has been achieved for the past two decades. This contributed to a deeper understanding of causes and factors promoting the formation of the lithogenic bile. Possibilities for cholelithiasis diagnostics (including precholelithiatic stages) have greatly expanded. The ultrasound method, which is quite efficient for diagnostics of cholecystolithiasis, has become a basic method of cholelithiasis diagnostics. Nevertheless, the course of cholelithiasis is not restricted to the formation of gallstones only. In 5-20% of cases cholecystolithiasis is combined with choledocholithiasis. The latest literature data related to problems of choledocholithiasis etiology, pathogenesis and diagnostics are given in this review of literature.