Macrophage migration inhibitory factor expression in human renal allograft rejection.
Macrophage migration inhibitory factor (MIF) plays a pivotal role in immune-mediated diseases. Despite the long-standing association of MIF with the delayed-type hypersensitivity response, the potential role of MIF in allograft rejection is unknown. MIF expression was assessed by in situ hybridization and immunohistochemistry staining in 62 biopsies of human renal allograft rejection and in normal human kidney. MIF mRNA and protein is constitutively expressed in normal kidney, being largely restricted to tubular epithelial cells, some glomerular epithelial cells, and vascular smooth muscle cells. In both acute and chronic renal allograft rejection, there was marked up-regulation of MIF mRNA and protein expression by intrinsic kidney cells such as tubular epithelial cells and vascular endothelial and smooth muscle cells. There was also MIF expression by infiltrating macrophages and T cells. Of note, macrophage and T cell infiltrates were largely restricted to areas with marked up-regulation of MIF expression, potentially contributing to the development of severe tubulitis and intimal or transmural arteritis. Quantitative analysis found that increased MIF expression in allograft rejection gave a highly significant correlation with macrophage and T cell accumulation in both the glomerulus and interstitium (P<0.001). In addition, the number of MIF+ tubules and interstitial MIF+ cells correlated significantly with the severity of allograft rejection (P<0.01), and the loss of renal function (P<0.01). In contrast, no up-regulation of renal MIF expression and no leukocyte accumulation was seen in allograft biopsies without evidence of rejection. This is the first study to demonstrate that local MIF expression is up-regulated during allograft rejection. The association between up-regulation of MIF expression, macrophage and T cell infiltration and the severity of renal allograft rejection suggests that MIF may be an important mediator in the process of allograft rejection.


Adrenal renin-angiotensin-aldosterone system in streptozotocin-diabetic rats.
Previous studies have indicated that the local renin-angiotensin system (RAS) plays an important role in the regulation of aldosterone release. We focused this study on examining the dissociating changes in circulating RAS and adrenal RAS, and we produced a low plasma renin status in streptozotocin (STZ)-induced diabetic rats. Four and six weeks after treatment with STZ, the rats showed hyperglycemia, hyporeninemia, decrease in plasma angiotensin II (AII), and a slight, but non-significant increase in plasma aldosterone in the rats. The adrenal renin activity and aldosterone concentration were significantly increased in the group of rats six weeks after induction of diabetes compared to those in control rats. The group of rats four weeks after induction of diabetes showed an increase in adrenal aldosterone concentration and a slight, but non-significant increase in adrenal renin activity. Plasma ACTH, serum sodium, and potassium were unchanged in both treatment groups compared to the control. The present results indicate that hyperactivity or residual activity of adrenal RAS under hyporeninemia is associated with severe diabetes mellitus.


Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis.
Neuroserpin, a recently identified inhibitor of tissue-type plasminogen activator (tPA), is primarily localized to neurons within the central nervous system, where it is thought to regulate tPA activity. In the present study neuroserpin expression and its potential therapeutic benefits were examined in a rat model of stroke. Neuroserpin expression increased in neurons surrounding the ischemic core (ischemic penumbra) within 6 hours of occlusion of the middle cerebral artery and remained elevated during the first week after the ischemic insult. Injection of neuroserpin directly into the brain immediately after infarct reduced stroke volume by 64% at 72 hours compared with control animals. In untreated animals both tPA and urokinase-type plasminogen activator (uPA) activity was significantly increased within the region of infarct by 6 hours after reperfusion. Activity of tPA then decreased to control levels by 72 hours, whereas uPA activity continued to rise and was dramatically increased by 72 hours. Both tPA and uPA activity were significantly reduced in neuroserpin-treated animals. Immunohistochemical staining of basement membrane laminin with a monoclonal antibody directed toward a cryptic epitope suggested that proteolysis of the basement membrane occurred as early as 10 minutes after reperfusion and that intracerebral administration of neuroserpin significantly reduced this proteolysis. Neuroserpin also decreased apoptotic cell counts in the ischemic penumbra by more than 50%. Thus, neuroserpin may be a naturally occurring neuroprotective proteinase inhibitor, whose therapeutic administration decreases stroke volume most likely by inhibiting proteinase activity and subsequent apoptosis associated with focal cerebral ischemia/reperfusion. (Blood. 2000;96:569-576)


A Study on the Effects of Chinese Massage on Physical and Mental Health in Participants Based Smart Healthcare.
The purpose of this study is to understand the influence of the effect of the smart Chinese massage appliance on the participants' sports performance and physical and mental health after intermittent exercises. The study was performed by a mixed-study method. First, the experimental research method was used to design an experimental procedure and specifications such as data collection scope. Next, the quantitative research was carried out, using SPSS 26.0 statistical software to analyze data from the questionnaire. Then, the qualitative research was carried out by interviewing experts and respondents and obtaining their opinions. Finally, all the data were collated and analyzed using the multidimensional review method. Findings. Chinese massage significantly improved the physical fitness, exercise performance, body composition, and physical and mental health status of high-strength cyclic exercise participants. High-strength exercises can improve the physical and mental health of men. Medium-strength exercises could improve current conditions for women. Oxygen intake remained peaked for 8 sessions for men and increased after 30 sessions for women. Both groups required a 1-2-week adaptation period but had different exercise performance periods. After the experiment, head and back pain, as well as stress and negative emotions, was improved. The high intensity of the exercises relieved fear, headache or head stress, overeating, and other problems.


Non-union in an unnoticed neck fracture in resurfacing total hip arthroplasty.
The renewed popularity of resurfacing hip arthroplasty (RHA) in the last five years has generated a remarkable quantity of scientific contributions based on mid- and short-term follow-up. In spite of some large series with extremely low complication rates, more than one paper has reported a consistent early revision rate as a consequence of biological or biomechanical failure. Two major complications are commonly described with resurfacing implants: avascular necrosis and neck fracture. A close relationship between these two events has been suggested, but not firmly demonstrated, while surgical exposure and implant positioning seem to be better understood as potential causes of failure. However, it may happen that neither avascular necrosis nor neck fracture can be clearly recognised in a failed resurfacing implant: it is what we have directly experienced, with a missed fracture at the head-neck junction, evolved in non-union, beneath the dome of the femoral component. The present report, besides a brief clinical history, tries to give a possible interpretation of such an unusual complication.


Photonic crystal fibre enables short-wavelength two-photon laser scanning fluorescence microscopy with fura-2.
We report on a novel and compact reliable laser source capable of short-wavelength two-photon laser scanning fluorescence microscopy based on soliton self-frequency shift effects in photonic crystal fibre. We demonstrate the function of the system by performing two-photon microscopy of smooth muscle cells and cardiac myocytes from the rat pulmonary vein and Chinese hamster ovary cells loaded with the fluorescent calcium indicator fura-2/AM.


Methyl mercury-induced combined inhibition of ATP regeneration and protein synthesis in reticulocyte lysate cell-free translation system.
Methyl mercury inhibits in vitro protein synthesis in the rabbit reticulocyte lysate cell-free translation system and simultaneously leads to reduction of the ATP/ADP index. It has been established that there is a close relationship (r = 0.86) between the rates of ATP resynthesis and protein synthesis in vitro within a wide range of the methyl mercury concentrations tested (0.0001-1.0 mumol/ml). Ammonia, CCl4, cycloheximide and pactamycin inhibit translation in vitro without affecting ATP resynthesis. Methanol does not cause substantial alterations of the parameters of the cell-free translation system. Thus, there are at least two essentially different causes of poison-induced in vitro translation blocking. Suppression of ATP resynthesis (methyl mercury) and direct effect on protein synthesis (cycloheximide, CCl4, etc.)


Diet quality and hearing loss among middle-older aged adults in the USA: findings from National Health and Nutrition Examination Survey.
To examine the associations between overall diet quality and hearing function among middle-older aged adults in the USA. Cross-sectional analysis. Diet quality was examined using the Mediterranean Diet Score (MDS), using data from a single 24 h dietary recall. Hearing function was objectively measured by audiometry assessments and hearing loss, including high- and low-frequency hearing loss, was defined as pure-tone averages at specific ranges of hearing frequencies >25 dB. Weighted logistic regression analyses were performed to examine the associations of MDS (scored 0-9, categorized at the median as ≤3 or >3) with hearing loss and high- and low-frequency hearing loss. National Health and Nutrition Examination Surveys 2000-2006 and 2009-2012. Adults aged ≥50 years (n 1639) with valid dietary and audiometry assessments. After adjusting for potential confounders, a non-significant trend for a protective association of higher MDS was observed for hearing loss (OR = 0·78; 95 % CI 0·49, 1·23). A significant inverse association was observed for high-frequency hearing loss (OR = 0·64; 95 % CI 0·43, 0·95). No association was found for low-frequency hearing loss among women; however, higher MDS was significantly associated with higher odds of low-frequency hearing loss among men (OR = 2·63; 95 % CI 1·39, 4·95). Among middle-older aged adults, adherence to a Mediterranean-style diet was inversely associated with hearing loss, including those at high hearing frequencies, among older adults. However, a detrimental association was observed at low hearing frequencies among men. Future investigations with a longitudinal design are needed to clarify the associations between diet quality and hearing loss.


[Importance of the Therapeutic Products Act for the ENT practitioner].
The Therapeutic Products Act controls therapeutic products and their fields of application, and classifies them legally. The present regulations on therapeutic products are based on a fundamental concept comprising basic demands, harmonized standards, agreement of the product attributes with the basic demands, and assessment of conformity. Therapeutic products (among which in vitro diagnostics are counted) must comply with definite regulations and are separated from medicines by their mode of action. In addition, therapeutic products must be subject to critical testing. The establishment, management, and use of therapeutic products are, with few exceptions, governed by the Regulations for the Use of Therapeutic Products. To avoid possible risks involved in the application of therapeutic products, a well-functioning system of registration is required, controlled by the Regulations on Therapeutic Products Safety.


Effect of visual experience on face processing: a developmental study of inversion and non-native effects.
In adults, three phenomena are taken to demonstrate an experience effect on face recognition: an inversion effect, a non-native face effect (so-called 'other-race' effect) and their interaction. It is crucial for our understanding of the developmental perception mechanisms of object processing to discover when these effects are present in childhood. Three- to 5-year-old Caucasian children (N = 64) were asked to recognize upright and inverted Caucasian and Asian faces. Recognition was tested with a forced-choice procedure. Overall performance improved with age. However, there was an interaction between the inversion and non-native effects that did not change with age between ages 3 and 5: (a) the inversion effect with native (Caucasian) faces was larger than with non-native (Asian) faces, and (b) upright native faces were recognized better than upright non-native faces. These results show that face orientation and morphology constrain face processing in 3- to 5-year-olds. The first 3 years of life during which the brain and the environment interact are sufficient to build a face-processing system that constrains recognition.


Evolution of propanediol utilization in Escherichia coli: mutant with improved substrate-scavenging power.
Wild-type strains of Escherichia coli are unable to use L-1,2-propanediol as a carbon and energy source. A series of mutants, able to grow on this compound at progressively faster rates, had been isolated by repeated transfers to a medium containing 20 mM L-1,2-propanediol. These strains synthesize at high constitutive levels a propanediolmicotinamide adenine dinucleotide oxidoreductase, an enzyme serving as a lactaldehyde during L-fucose fermentation by wild type cells. In this study, a mutant that can grow rapidly on the novel carbon source was subjected to further selection in a medium containing L-1,2-propanediol never exceeding 0.5 mM to obtain a derivative that has an increased power to extract the substrate from the medium. The emerging mutant exhibited four changes at the enzymatic level: (i) fuculose 1-phosphate aldolase activity is lost; (ii) the constitutive propanediol oxidoreductase activity is increased in its level; (iii) lactaldehyde dehydrogenase becomes constitutive and shows an elevated specific activity in crude extracts; and (iv) at low concentrations of propanediol, the facilitated diffusion across the cell membrane is enhanced. Changes two to four seem to act in concert in the trapping of propanediol by hastening its rate of entry and conversion to an ionized metabolite, lactate.


Pharmacokinetic individualization of high-dose methotrexate chemotherapy for the treatment of localized osteosarcoma.
Individualization of high-dose methotrexate (MTX) dosing is important to achieve therapeutic levels (700-1,000 microM) for osteosarcoma. Therefore we developed a pharmacokinetically (PK) individualized dosage regimen to maintain MTX concentrations of 700 microM (1 h bolus followed by 5 h maintenance infusion) and evaluated its safety and efficacy. Loading and maintenance doses were calculated by the PK parameters based on 2-compartment model analysis. Thirty-two courses of chemotherapy were performed in 9 patients with osteosarcoma. The maximum concentrations during maintenance infusion in 31 courses (97%) were above 700 microM. Only 1 patient developed severe hepatotoxicity as adverse effect. Total body clearance of MTX decreased in 4 patients when weekly MTX chemotherapy was performed for 3 consecutive weeks. Although the clearance was changed, the average MTX concentrations were maintained at about 700 microM by the PK individualization. The 5-year survival rate was 77.8% (7 of 9 patients), and all of them have survived for more than 9 years. This PK individualization is safe and useful for tailoring high-dose MTX therapy to achieve therapeutic levels.


Endovascular therapy for severely calcified plaque at the superficial femoral artery using myocardial biopsy forceps.
Currently, the success rate of EVT for treating CTO of the SFA is high; however, EVT is still found to be insufficient in treating CTOs with severely calcified lesions. Even if the guidewire crosses the lesion, the calcifications may still cause difficulties during stent expansion. A 78-year-old male had been reported to have intermittent claudication with chronic total occlusion (CTO) of the right superficial femoral artery (SFA). Angiography revealed severely calcified plaque (Angiographic calcium score: Group4a [1]) at the ostium of the SFA. Stenting posed a risk of underexpansion, causing the plaque to shift to the deep femoral artery. we decided to remove the calcified plaque using biopsy forceps. After removing the extended calcified plaque, the guidewire could cross easily, and the self-expandable stent was well dilated without causing the plaque to shift to the DFA. Biopsy forceps may be used in some endovascular cases to remove severely calcified lesions. To ensure the safety of the patient, the physician must be adept at performing this technique before attempting it.


Idiopathic convergence paralysis: a rare case.
Convergence paralysis is a rare entity that is usually associated with head trauma or mid-brain pathology. We describe a patient with idiopathic convergence paralysis that resolved without intervention. Idiopathic convergence paralysis is very rare and does not satisfy the criteria for diagnosis as described by Bielschowsky in 1936. Furthermore, this case demonstrates the possibility of spontaneous resolution of convergence paralysis.


Do Outcomes of Arthroscopic Subscapularis Tendon Repairs Depend on Rotator Cuff Fatty Infiltration?
Rotator cuff fatty infiltration has been correlated with poorer radiographic and clinical outcomes in supraspinatus and infraspinatus tendon repairs, but this has not been well-studied in subscapularis tendon repairs. To evaluate the influence of preoperative rotator cuff fatty infiltration on postoperative outcomes for patients undergoing arthroscopic subscapularis tendon repair. Cohort study; Level of evidence, 3. Patients who underwent arthroscopic subscapularis repair between 2010 and 2016 were retrospectively identified, and demographic data and surgical findings were recorded. The extent of fatty infiltration was determined on preoperative magnetic resonance imaging by the Fuchs modification of the Goutallier classification. At the most recent follow-up, patients completed the Patient-Reported Outcomes Measurement Information System for Upper Extremity (PROMIS-UE) computer adaptive test and a postoperative visual analog scale for pain. The distribution of fatty infiltration was compared between patients undergoing subscapularis tendon repair versus subscapularis tendon repair combined with a posterior cuff repair. Outcomes were compared for patients using Goutallier grade 0-1 versus grade ≥2 changes in each rotator cuff muscle. Multivariate linear regression analysis was performed to evaluate the influence of muscle quality, as well as demographic factors, on PROMIS-UE scores. Significance was defined as P < .05. There were 140 shoulders included (mean age, 61.8 years; 42.1% female; mean follow-up, 51.7 months). The prevalence of Goutallier grade 2 changes or higher was significantly greater in patients with multitendon repair relative to isolated subscapularis tendon repair. For the overall group of all patients undergoing subscapularis tendon repair, whether in isolation or as part of a multitendon repair, PROMIS-UE scores were significantly lower for patients with infraspinatus muscle grade 2 or higher Goutallier changes relative to grade 0 or 1. After adjustment for age, body mass index, patient sex, and fatty infiltration in other rotator cuff muscles, poor infraspinatus muscle quality remained the only significant predictor for lower PROMIS-UE scores. Patients undergoing arthroscopic subscapularis tendon repair with poor infraspinatus muscle quality had worse patient-reported outcomes. This was true whether subscapularis tendon repair was isolated or was performed in conjunction with supraspinatus and infraspinatus tendon repairs.


In situ reconstruction with cryopreserved arterial allografts for management of mycotic aneurysms or aortic prosthetic graft infections: a multi-institutional experience.
We designed this study to evaluate a multi-institutional experience regarding the efficacy of cryopreserved aortic allografts in the treatment of infected aortic prosthetic grafts or mycotic aneurysms. We reviewed clinical data of all patients from 4 institutions who underwent in situ aortic reconstruction with cryopreserved allografts for either infected aortic prosthetic graft or mycotic aneurysms from during a 6-year period. Relevant clinical variables and treatment outcomes were analyzed. A total of 42 patients (37 men; overall mean age 63 +/- 13 years, range 41-74 years) were identified during this study period. Treatment indications included 34 primary aortic graft infections (81%), 6 mycotic aneurysms (22%), and 2 aortoenteric erosions (5%). Transabdominal and thoracoabdominal approaches were used in 38 (90%) and 4 patients (10%), respectively. Staphylococcus aureus was the most commonly identified organism (n=27, 64%). Although there was no intraoperative death, the 30-day operative mortality was 17% (n=7). There were 21 (50%) nonfatal complications, including local wound infection (n=8), lower-extremity deep venous thrombosis (n=5), amputation (n=6), and renal failure requiring hemodialysis (n=2). The average length of hospital stay was 16.4 +/- 7 days. During a mean follow-up period of 12.5 months, reoperation for allograft revision was necessary in 1 patient due to graft thrombosis (6%). The overall treatment mortality rate was 21% (n=9). In situ aortic reconstruction with cryopreserved allografts is an acceptable treatment method in patients with infected aortic prosthetic graft or mycotic aneurysms. Our study showed that mid-term graft-related complications such as reinfection or aneurysmal degeneration were uncommon.


Epidemiology of antibiotic and heavy metal resistance in bacteria: resistance patterns in staphylococci isolated from populations not known to be exposed to heavy metals.
Staphylococci were isolated from clinical specimens obtained from patients not known to be exposed to abnormal levels of heavy metals. The antibiotic and heavy metal resistance patterns of these strains were determined by using a disk diffusion test and computer sorting. Though not absolute, an association of resistance to mercury and tetracycline in coagulase-negative strains was found, in contrast to resistance to copper and penicillin in coagulase-producing strains. A high degree of correlation was observed between the resistance to phenyl mercury and inorganic mercury, but no correlation was obtained between resistance to methylmercury and other metals. In general, strains resistant to many agents were usually coagulase negative. A possible mechanism and implications of these associations are considered.


Fine tuning of cytosolic Ca (2+) oscillations.
Ca (2+) oscillations, a widespread mode of cell signaling, were reported in non-excitable cells for the first time more than 25 years ago. Their fundamental mechanism, based on the periodic Ca (2+) exchange between the endoplasmic reticulum and the cytoplasm, has been well characterized. However, how the kinetics of cytosolic Ca (2+) changes are related to the extent of a physiological response remains poorly understood. Here, we review data suggesting that the downstream targets of Ca (2+) are controlled not only by the frequency of Ca (2+) oscillations but also by the detailed characteristics of the oscillations, such as their duration, shape, or baseline level. Involvement of non-endoplasmic reticulum Ca (2+) stores, mainly mitochondria and the extracellular medium, participates in this fine tuning of Ca (2+) oscillations. The main characteristics of the Ca (2+) exchange fluxes with these compartments are also reviewed.


[The present and future of controlled transport of the drug into the organism].
The problems of the systems of controlled (and thus also targeted) transport of the drug into the organism is one of the burning questions of contemporary biogalenics. Various more or less successful solutions were elaborated and applied, beginning with the retardette via the so-called intelligent hydrogels to various automatically controlled implants. Modem microfluidic intelligent biomicrosystems, composed of mutually interconnected microtanks, microjets, micropumps, or microcylinders, are very promising. A natural component of the complex biomicrosystem is a sensory subsystem for the collection of information from the bio-environment and a processor for the control of the process of drug supply to the organism. The present technologies of such Bio-Micro-Electro-Mechanical Systems (BioMEMSs) make it possible to revolutionize drug transport not only by facilitating precise dosing and long-term control of the immediate amount of the supplied drug on the basis of the current condition of the patient, but also to target the drug to the site of its pharmacological effect. Though at present there are still many unsolved problems, transition from laboratory conditions to clinical practice has started, and it is only a matter of five to ten years that intelligent BioMEMSs will gradually become a routinely used dosage microform. The paper briefly surveys the present state and the next development of intelligent systems of drug supply into the body of the patient, termed Intelligent Drug Delivery Systems, Intelligent DDSs, or briefly IDDSs.


Transfer of upper pectoralis major flap for functional reconstruction of deltoid muscle.
Since January 1984, functional reconstruction of the deltoid muscle using transfer of the upper part of the pectoralis major muscle has been performed in 7 patients with deltoid dysfunction. 5-20 months follow-up (average 11) revealed marked improvement in 6 patients. During the operation, the superior and inferior parts of the pectoralis major muscle were bluntly dissected and sectioned. The upper part of this muscle was turned over and transferred to the site normally occupied by the deltoid muscle. The transposed muscle contributed to both abduction and flexion of the shoulder. The efficacy of abduction was reinforced by the increased arm of action.


A functionally essential domain of RFX5 mediates activation of major histocompatibility complex class II promoters by promoting cooperative binding between RFX and NF-Y.
Major histocompatibility complex class II (MHC-II) molecules occupy a pivotal position in the adaptive immune system, and correct regulation of their expression is therefore of critical importance for the control of the immune response. Several regulatory factors essential for the transcription of MHC-II genes have been identified by elucidation of the molecular defects responsible for MHC-II deficiency, a hereditary immunodeficiency disease characterized by regulatory defects abrogating MHC-II expression. Three of these factors, RFX5, RFXAP, and RFXANK, combine to form the RFX complex, a regulatory protein that binds to the X box DNA sequence present in all MHC-II promoters. In this study we have undertaken a dissection of the structure and function of RFX5, the largest subunit of the RFX complex. The results define two distinct domains serving two different essential functions. A highly conserved N-terminal region of RFX5 is required for its association with RFXANK and RFXAP, for assembly of the RFX complex in vivo and in vitro, and for binding of this complex to its X box target site in the MHC-II promoter. This N-terminal region is, however, not sufficient for activation of MHC-II expression. This requires an additional domain within the C-terminal region of RFX5. This C-terminal domain mediates cooperative binding between the RFX complex and NF-Y, a transcription factor binding to the Y box sequence of MHC-II promoters. This provides direct evidence that RFX5-mediated cooperative binding between RFX and NF-Y plays an essential role in the transcriptional activation of MHC-II genes.


The accuracy of medical history information in referral letters.
Accurate medical history information is essential for good patient care and should be notified in the letter of referral. The aim of this study was to investigate the subjective opinion that the medical information in a large number of referrals is either inaccurate or non-existent. Medical histories from 54 patients with positive medical history findings upon taking the medical history at the initial consultation appointment were compared to the medical information supplied in the referral letter. Overall, medical information was only 58.8% complete with dental referrals being 55.2% complete and medical referrals 62.4%. The majority of referral letters (70.4%) missed at least one relevant finding and only 29.6% of referrals were 100% complete. The results of this study suggest that the standard of referral letters needs to be improved as the received referrals were generally incomplete and contained inaccurate information. This highlights the need for each and every practitioner to take their own detailed medical history and not rely on the information supplied in the referral.


An increase in mean platelet volume during admission can predict the prognoses of patients with pneumonia in the intensive care unit: A retrospective study.
Platelets play an important role in hemostasis, inflammation, and immunity. Mean platelet volume (MPV), considered a marker of platelet function and activation, is associated with increased morbidity and mortality in sepsis, coronary artery disease, and chronic inflammatory disease. However, the clinical characteristics and prognostic significance of MPV changes for patients with pneumonia in the intensive care unit (ICU) have not been investigated. This retrospective study was conducted using data from an operational database of patients admitted to a medical ICU between October 2010 and October 2017. Of 235 adult patients with pneumonia admitted to the ICU, clinical characteristics and in-hospital mortality values were compared according to MPV, ΔMPVday1-2, ΔMPVday1-3, ΔMPVday1-4, and ΔMPVday1-Discharge between those who survived and those who did not. The MPV increased during the first four days for both non-survivors and survivors (P < 0.001). However, repeated measures analysis of variance revealed a significantly higher MPV rate over the first four days in non-survivors than in survivors. Additionally, the ΔMPVday1-2, ΔMPVday1-3, ΔMPVday1-4, and ΔMPVday1-Discharge values were significantly greater in non-survivors than in survivors. For in-hospital mortality, the optimal ΔMPV values were >0.9 fL, P = 0.020; >0.9 fL, P < 0.001; >0.8 fL, P < 0.001; and >1.3 fL, P < 0.001 on day 2, day 3, day 4, and at discharge, respectively. In conclusion, our findings demonstrate that ΔMPV during ICU admission may be used as a prognostic marker of mortality in ICU patients with pneumonia. Repeated MPV measurements throughout hospitalization may improve risk stratification for these patients, which could aid in improving patient outcomes.


Impact of fast-track regulatory designations on strategic commercialization decisions for autologous cell therapies.
Background: Regulatory authorities around the world have introduced incentives to improve the speed-to-market of innovative therapies. Aim & methods: To better understand the capacity and portfolio planning decisions of autologous cell therapies and particularly the impact of fast-tracking designations, this paper describes a mixed-integer linear programming approach for the optimization of capacity investment and portfolio selection decisions to maximize the net present value of a candidate portfolio of therapies under different regulatory programs. Results: The illustrative example shows that fast-track designations allow a 25% earlier breakeven, 42-86% higher net present value over a 20-year horizon with earlier upfront capital and reduce the portfolio's sensitivity to uncertainties. Conclusion: Fast-track designations are effective in providing commercialization incentives, but high capital risks given the compressed timeline should be better considered.


Epidemiology of Influenza Viruses and Viruses Causing Influenza-Like Illness in Children Under 14 Years Old in the 2018-2019 Epidemic Season in Poland.
BACKGROUND This study aimed to investigate the epidemiology of influenza viruses and viruses that caused influenza-like disease in children under 14 years of age in the 2018-2019 epidemic season in Poland, and to identify the public health lessons that can be learned. MATERIAL AND METHODS Nose and throat swabs were used to obtain samples. The samples were analyzed in the National Influenza Center, Department of Influenza Research at the National Institute of Public Health-National Institute of Hygiene as well as in 16 Voivodship Sanitary Epidemiological Stations across the country. Methods of RNA isolation depended on the laboratory where the isolation was performed. In all laboratories, quantitative polymerase chain reactions were used to determine the influenza virus type as well as the subtype. RESULTS The study group was confirmed to be infected with influenza A and B, with influenza A/H1N1/pdm09 as the dominant subtype. Among the age group of children up to 14 years of age, cases of infection with viruses that cause influenza-like disease were also reported. It was noticeable that the largest number of confirmed cases of infection was recorded in the group of the youngest children (0-4 years). In addition, several different variants of co-infection were registered. CONCLUSIONS This population study showed that in the 2018-2019 epidemic season in Poland children aged under 14 years were at risk of influenza virus infection and its complications. The presented data support increasing the percentage of children being vaccinated in Poland.


Xylan catabolism is improved by blending bioprospecting and metabolic pathway engineering in Saccharomyces cerevisiae.
Complete utilization of all available carbon sources in lignocellulosic biomass still remains a challenge in engineering Saccharomyces cerevisiae. Even with efficient heterologous xylose catabolic pathways, S. cerevisiae is unable to utilize xylose in lignocellulosic biomass unless xylan is depolymerized to xylose. Here we demonstrate that a blended bioprospecting approach along with pathway engineering and evolutionary engineering can be used to improve xylan catabolism in S. cerevisiae. Specifically, we perform whole genome sequencing-based bioprospecting of a strain with remarkable pentose catabolic potential that we isolated and named Ustilago bevomyces. The heterologous expression of xylan catabolic genes enabled S. cerevisiae to grow on xylan as a single carbon source in minimal medium. A combination of bioprospecting and metabolic pathway evolution demonstrated that the xylan catabolic pathway could be further improved. Ultimately, engineering efforts were able to achieve xylan conversion into ethanol of up to 0.22 g/L on minimal medium compositions with xylan. This pathway provides a novel starting point for improving lignocellulosic conversion by yeast.


Histone methylation has dynamics distinct from those of histone acetylation in cell cycle reentry from quiescence.
Cell growth is attuned to nutrient availability to sustain homeostatic biosynthetic processes. In unfavorable environments, cells enter a nonproliferative state termed quiescence but rapidly return to the cell cycle once conditions support energetic needs. Changing cellular metabolite pools are proposed to directly alter the epigenome via histone acetylation. Here we studied the relationship between histone modification dynamics and the dramatic transcriptional changes that occur during nutrient-induced cell cycle reentry from quiescence in the yeast Saccharomyces cerevisiae. SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry showed that histone methylation-in contrast to histone acetylation-is surprisingly static during quiescence exit. Chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) revealed genome-wide shifts in histone acetylation at growth and stress genes as cells exit quiescence and transcription dramatically changes. Strikingly, however, the patterns of histone methylation remain intact. We conclude that the functions of histone methylation and acetylation are remarkably distinct during quiescence exit: acetylation rapidly responds to metabolic state, while methylation is independent. Thus, the initial burst of growth gene reactivation emerging from quiescence involves dramatic increases of histone acetylation but not of histone methylation.


Two fast methods for high-quality line visibility.
Lines drawn over or in place of shaded 3D models can often provide greater comprehensibility and stylistic freedom than shading alone. A substantial challenge for making stylized line drawings from 3D models is the visibility computation. Current algorithms for computing line visibility in models of moderate complexity are either too slow for interactive rendering, or too brittle for coherent animation. We introduce two methods that exploit graphics hardware to provide fast and robust line visibility. First, we present a simple shader that performs a visibility test for high-quality, simple lines drawn with the conventional implementation. Next, we offer a full optimized pipeline that supports line visibility and a broad range of stylization options.


Vasopeptidase Inhibition Corrects the Structure and Function of the Small Arteries in Experimental Renal Insufficiency.
We studied whether vasopeptidase inhibition corrects the structure and function of the small arteries in experimental chronic renal insufficiency (CRI). After 5/6 nephrectomy (NX) surgery was performed on rats, there was a 14-week follow-up, allowing CRI to become established. Omapatrilat (40 mg/kg/day in chow) was then given for 8 weeks, and the small mesenteric arterial rings were investigated in vitro using wire and pressure myographs. Plasma and ventricular B-type natriuretic peptide (BNP) concentrations were increased 2- to 2.7-fold, while systolic blood pressure (BP) increased by 32 mm Hg after NX. Omapatrilat treatment normalized the BNP and reduced the BP by 45 mm Hg in the NX rats. Endothelium-dependent vasorelaxation was impaired but the response to acetylcholine was normalized after omapatrilat treatment. Vasorelaxations induced by nitroprusside, isoprenaline and levcromakalim were enhanced after omapatrilat, and the responses were even more pronounced than in untreated sham-operated rats. Arterial wall thickness and wall-to-lumen ratio were increased after NX, whereas omapatrilat normalized these structural features and improved the strain-stress relationship in the small arteries; this suggests improved arterial elastic properties. Omapatrilat treatment reduced BP, normalized volume overload, improved vasorelaxation and corrected the dimensions and passive elastic properties of the small arteries in the NX rats. Therefore, we consider vasopeptidase inhibition to be an effective treatment for CRI-induced changes in the small arteries.


[An improved back-projection algorithm of dynamic electrical impedance tomography].
In this paper, an improved back-projection algorithm of dynamic electrical impedance tomography (EIT) was described. The improved back-projection algorithm modified the computing method of back-projection matrix B. Dynamic reconstruction image was obtained by the improved algorithm, and it was compared to the image obtained by the traditional method of equi-potential back-projection. The results showed that the improved algorithm of equi-potential back-projection could locate the object's position in the field with higher precision, and its speed was very fast. It also could improve the resolution of the reconstructed image in some extent.


Feedback signals in myelodysplastic syndromes: increased self-renewal of the malignant clone suppresses normal hematopoiesis.
Myelodysplastic syndromes (MDS) are triggered by an aberrant hematopoietic stem cell (HSC). It is, however, unclear how this clone interferes with physiologic blood formation. In this study, we followed the hypothesis that the MDS clone impinges on feedback signals for self-renewal and differentiation and thereby suppresses normal hematopoiesis. Based on the theory that the MDS clone affects feedback signals for self-renewal and differentiation and hence suppresses normal hematopoiesis, we have developed a mathematical model to simulate different modifications in MDS-initiating cells and systemic feedback signals during disease development. These simulations revealed that the disease initiating cells must have higher self-renewal rates than normal HSCs to outcompete normal hematopoiesis. We assumed that self-renewal is the default pathway of stem and progenitor cells which is down-regulated by an increasing number of primitive cells in the bone marrow niche--including the premature MDS cells. Furthermore, the proliferative signal is up-regulated by cytopenia. Overall, our model is compatible with clinically observed MDS development, even though a single mutation scenario is unlikely for real disease progression which is usually associated with complex clonal hierarchy. For experimental validation of systemic feedback signals, we analyzed the impact of MDS patient derived serum on hematopoietic progenitor cells in vitro: in fact, MDS serum slightly increased proliferation, whereas maintenance of primitive phenotype was reduced. However, MDS serum did not significantly affect colony forming unit (CFU) frequencies indicating that regulation of self-renewal may involve local signals from the niche. Taken together, we suggest that initial mutations in MDS particularly favor aberrant high self-renewal rates. Accumulation of primitive MDS cells in the bone marrow then interferes with feedback signals for normal hematopoiesis--which then results in cytopenia.


Antibiotics for exacerbations of asthma.
Asthma is a chronic respiratory condition that affects over 300 million adults and children worldwide. It is characterised by wheeze, cough, chest tightness, and shortness of breath. Symptoms typically are intermittent and may worsen over a short time, leading to an exacerbation. Asthma exacerbations can be serious, leading to hospitalisation or even death in rare cases. Exacerbations may be treated by increasing an individual's usual medication and providing additional medication, such as oral steroids. Although antibiotics are sometimes included in the treatment regimen, bacterial infections are thought to be responsible for only a minority of exacerbations, and current guidance states that antibiotics should be reserved for cases in which clear signs, symptoms, or laboratory test results are suggestive of bacterial infection. To determine the efficacy and safety of antibiotics in the treatment of asthma exacerbations. We searched the Cochrane Airways Trials Register, which contains records compiled from multiple electronic and handsearched resources. We also searched trial registries and reference lists of primary studies. We conducted the most recent search in October 2017. We included studies comparing antibiotic therapy for asthma exacerbations in adults or children versus placebo or usual care not involving an antibiotic. We allowed studies including any type of antibiotic, any dose, and any duration, providing the aim was to treat the exacerbation. We included parallel studies of any duration conducted in any setting and planned to include cluster trials. We excluded cross-over trials. We included studies reported as full-text articles, those published as abstracts only, and unpublished data. At least two review authors screened the search results for eligible studies. We extracted outcome data, assessed risk of bias in duplicate, and resolved discrepancies by involving another review author. We analysed dichotomous data as odds ratios (ORs) or risk differences (RDs), and continuous data as mean differences (MDs), all with a fixed-effect model. We described skewed data narratively. We graded the results and presented evidence in 'Summary of findings' tables for each comparison. Primary outcomes were intensive care unit/high dependence unit (ICU/HDU) admission, duration of symptoms/exacerbations, and all adverse events. Seconday outcomes were mortality, length of hospital admission, relapse after index presentation, and peak expiratory flow rate (PEFR). Six studies met our inclusion criteria and included a total of 681 adults and children with exacerbations of asthma. Mean age in the three studies in adults ranged from 36.2 to 41.2 years. The three studies in children applied varied inclusion criteria, ranging from one to 18 years of age. Five studies explicitly excluded participants with obvious signs and symptoms of bacterial infection (i.e. those clearly meeting current guidance to receive antibiotics). Four studies investigated macrolide antibiotics, and two studies investigated penicillin (amoxicillin and ampicillin) antibiotics; both studies using penicillin were conducted over 35 years ago. Five studies compared antibiotics versus placebo, and one was open-label. Study follow-up ranged from one to twelve weeks. Trials were of varied methodological quality, and we were able to perform only limited meta-analysis.None of the included trials reported ICU/HDU admission, although one participant in the placebo group of a study including children with status asthmaticus experienced a respiratory arrest and was ventilated. Four studies reported asthma symptoms, but we were able to combine results for only two macrolide studies of 416 participants; the MD in diary card symptom score was -0.34 (95% confidence interval (CI) -0.60 to -0.08), with lower scores (on a 7 point scale) denoting improved symptoms. Two macrolide studies reported symptom-free days. One study of 255 adults authors reported the percentage of symptom-free days at 10 days as 16% in the antibiotic group and 8% in the placebo group. In a further study of 40 children study authors reported significantly more symptom-free days at all time points in the antibiotic group compared with the usual care group. The same study reported the duration in days of the index asthma exacerbation, again favouring the antibiotic group. One study of a penicillin including 69 participants reported asthma symptoms at hospital discharge; the between-group difference for both studies was reported as non-significant.We combined data for serious adverse events from three studies involving 502 participants, but events were rare; the three trials reported only 10 events: five in the antibiotic group and five in the placebo group. We combined data for all adverse events (AEs) from three studies, but the effect estimate is imprecise (OR 0.99, 95% CI 0.69 to 1.43). No deaths were reported in any of the included studies.Two studies investigating penicillins reported admission duration; neither study reported a between-group difference. In one study (263 participants) of macrolides, two participants in each arm were reported as experiencing a relapse, defined as a further exacerbation, by the six-week time points. We combined PEFR endpoint results at 10 days for two macrolide studies; the result favoured antibiotics over placebo (MD 23.42 L/min, 95% CI 5.23 to 41.60). One study in children reported the maximum peak flow recorded during the follow-up period, favouring the clarithromycin group, but the confidence interval includes no difference (MD 38.80, 95% CI -11.19 to 88.79).Grading of outcomes ranged from moderate to very low quality, with quality of outcomes downgraded for suspicion of publication bias, indirectness, imprecision, and poor methodological quality of studies. We found limited evidence that antibiotics given at the time of an asthma exacerbation may improve symptoms and PEFR at follow-up compared with standard care or placebo. However, findings were inconsistent across the six heterogeneous studies included, two of the studies were conducted over 30 years ago and most of the participants included in this review were recruited from emergency departments, limiting the applicability of findings to this population. Therefore we have limited confidence in the results. We found insufficient evidence about several patient-important outcomes (e.g. hospital admission) to form conclusions. We were unable to rule out a difference between groups in terms of all adverse events, but serious adverse events were rare.


Effects of hepatitis B virus infection on human sperm chromosomes.
To evaluate the level of sperm chromosome aberrations in male patients with hepatitis B, and to directly detect whether there are HBV DNA integrations in sperm chromosomes of hepatitis B patients. Sperm chromosomes of 14 tested subjects (5 healthy controls, 9 patients with HBV infection, including 1 with acute hepatitis B, 2 with chronic active hepatitis B, 4 with chronic persistent hepatitis B, 2 chronic HBsAg carriers with no clinical symptoms) were prepared using interspecific in vitro fertilization between zona-free golden hamster ova and human spermatozoa, and the frequencies of aberration spermatozoa were compared between subjects of HBV infection and controls. Fluorescence in situ hybridization (FISH) to sperm chromosome spreads was carried out with biotin-labeled full length HBV DNA probe to detect the specific HBV DNA sequences in the sperm chromosomes. The total frequency of sperm chromosome aberrations in HBV infection group (14.8 %, 33/223) was significantly higher than that in the control group (4.3 %, 5/116). Moreover, the sperm chromosomes in HBV infection patients commonly presented stickiness, clumping, failure to staining, etc, which would affect the analysis of sperm chromosomes. Specific fluorescent signal spots for HBV DNA were seen in sperm chromosomes of one patient with chronic persistent hepatitis. In 9 (9/42) sperm chromosome complements containing fluorescent signal spots, one presented 5 obvious FISH spots, others presented 2 to 4 signals. There was significant difference of fluorescence intensity among the signal spots. The distribution of signal sites among chromosomes was random. HBV infection can bring about mutagenic effects on sperm chromosomes. Integrations of viral DNA into sperm chromosomes which are multisites and nonspecific, can further increase the instability of sperm chromosomes. This study suggested that HBV infection can create extensively hereditary effects by alteration genetic constituent and/or induction chromosome aberrations, as well as the possibility of vertical transmission of HBV via the germ line to the next generation.


Direct Binding of the Flexible C-Terminal Segment of Periaxin to β4 Integrin Suggests a Molecular Basis for CMT4F.
The process of myelination in the nervous system requires a coordinated formation of both transient and stable supramolecular complexes. Myelin-specific proteins play key roles in these assemblies, which may link membranes to each other or connect the myelinating cell cytoskeleton to the extracellular matrix. The myelin protein periaxin is known to play an important role in linking the Schwann cell cytoskeleton to the basal lamina through membrane receptors, such as the dystroglycan complex. Mutations that truncate periaxin from the C terminus cause demyelinating peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease type 4F, indicating a function for the periaxin C-terminal region in myelination. We identified the cytoplasmic domain of β4 integrin as a specific high-affinity binding partner for periaxin. The C-terminal region of periaxin remains unfolded and flexible when bound to the third fibronectin type III domain of β4 integrin. Our data suggest that periaxin is able to link the Schwann cell cytoplasm to the basal lamina through a two-pronged interaction via different membrane protein complexes, which bind close to the N and C terminus of this elongated, flexible molecule.


Inhibition of avian myeloblastosis virus reverse transcriptase by aurochloric acid.
We investigated the inhibitory effects of aurochloric acid (AuCl4H) on reverse transcriptase (RT) derived from avian myeloblastosis virus and DNA polymerase alpha (pol. alpha) purified from HeLa S3 cells. The activities of RT, pol. alpha and E. coli DNA polymerase I (pol. I) with dTTP as the substrate were inhibited 50% at AuCl4H concentrations of 18 microM, 43 microM and 230 microM, respectively. AuCl4H inhibited RT activity competitively with respect to the substrate, dTTP, and uncompetitively with the template/primer, (rA)n(dT)12-18. In assays with dGTP as the substrate, 50% inhibitions of RT, pol. alpha and pol. I activities were observed at AuCl4H concentrations of 100 microM, 450 microM and 580 microM, respectively. AuCl4H inhibited RT activity uncompetitively with respect to the substrate, dGTP, and noncompetitively with the template/primer, (rC)n(dG)12-18. AuCl4H at concentrations causing more than 50% inhibition of RT activity had little inhibitory effect on the colony-forming ability of HeLa cells or their syntheses of DNA, RNA and protein.


Power laws in covariability of anxiety and depression among newly diagnosed patients with major depressive episode, panic disorder and controls.
Although symptoms of anxiety and depression correlate, they may covary in irregular and unpredictable ways. This non-linear covariation may be important to psychiatric diagnosis, treatment and relapse. This non-linear anxiety-depression interaction suggests that power laws may be observed. Power laws are statistical distributions found when systems vary in complex ways at the interface between chaotic dynamics and periodic dynamics, such that data points vary randomly but are still partially correlated with each other. Such non-linear dynamics and relationships should result in characteristic patterns of interaction among patients, stressors and treatment. This is important because non-linear dynamics could affect our understanding of mental disorders, the need for varied treatment approaches and patterns of early response to treatment. To determine whether the relationships between anxiety and depression levels, changes and rates of change follow power law distributions among patients with newly diagnosed major depressive episode (MDE), panic disorder (PD) and neither disorder (controls). Time series of hourly mood variation. Setting Acute and continuity primary care clinics. Five adult patients presenting each with MDE, PD and controls based on DSM-IV criteria. Four patients in each group completed 30 days of assessments. MAIN AND SECONDARY OUTCOME MEASURES: Hourly self-assessments (while awake) of levels of anxiety and depression using visual analogue scales for a 30-day period. Covariation in level of symptoms, in the change of symptoms and in the rate of change were assessed. Anxiety-depression matrices were prepared for pooled subjects. Power laws were sought using log-log plots of frequency versus order of that frequency. Although visual inspection of plots for symptoms levels, change and rates of change all suggest power laws, statistical assessments provide stronger support for power laws in symptom change than for either symptom levels or rates of change. Adjusted R(2) terms are larger for MDE and PD subjects compared with controls while the inverse slope is about 2.5 for controls and 1.7-1.9 for those with MDE or PD. This study found that power laws may be present in both the symptom change data for all three diagnostic groups. Evidence for power laws in symptom levels and rates of change was less compelling. The inverse slopes suggest that the anxiety-depression relationships among subjects with PD and major depression are similar but differ from those among controls. First, power laws suggest a scale-free relationship; the differences seen in transition from symptom level to change level may reflect that complex events at the level of mood assessment affect change in mood. Second, this covariation may be due to external factors acting on the patient or multiple internal interrelated factors. Third, different factors and populations can yield different slopes. Future research is needed to confirm these preliminary findings and to understand the origin of these dynamics.


Tobacco advertising restrictions, price, income and tobacco consumption in OECD countries, 1960-1986.
Factors affecting tobacco consumption per adult in 22 countries of the OECD between 1960 and 1986, were studied using pooled cross-section time-series analysis. The resulting log-linear model was estimated using Generalized Least Squares. The severity of tobacco advertising restrictions in each country and year was scored from published legislation and information from health agencies. Tobacco advertising restrictions have since 1973 increasingly been associated with lower tobacco consumption. Lower consumption levels were also associated with higher real tobacco prices, and with increased female labour force participation. Higher levels of consumption were associated with higher per capita real income and with a larger fraction of tobacco consumed as manufactured cigarettes. The model explains 99.5% of the variance in the average annual level of tobacco consumption across these countries. Ten-fold differences in purchasing power for tobacco products were found across the countries and years studied. In all countries tobacco products became more affordable between 1960 and 1986. In 1986 either a 36% inflation-indexed increase in real tobacco prices, or legislation to end tobacco promotion in those countries without a total ban, would have lowered average consumption by 6.8% and both together, by 13.5%. Across the OECD, if in 1986 all governments had raised tobacco product prices relative to income to Irish levels, and had banned all tobacco promotion, tobacco products consumption per adult would have fallen by 40% in that year.


Glutamate transport and cellular glutamine metabolism: regulation in LLC-PK1 vs. LLC-PK1-F+ cell lines.
The glutamate (Glu) transporter may modulate cellular glutamine (Gln) metabolism by regulating both the rates of hydrolysis and subsequent conversion of Glu to alpha-ketoglutarate and NH+4. By delivering Glu, a competitive inhibitor of Gln for the phosphate-dependent glutaminase (PDG) as well as an acid-load activator of glutamate dehydrogenase (GDH) flux, the transporter may effectively substitute extracellularly generated Glu from the gamma-glutamyltransferase for that derived intracellularly from Gln. We tested this hypothesis in two closely related porcine kidney cell lines, LLC-PK1 and LLC-PK1-F+, the latter selected to grow in the absence of glucose, relying on Gln as their sole energy source. Both cell lines exhibited PDG suppression as the result of Glu uptake while disrupting the extracellular L-Glu uptake, with D-aspartate-accelerated intracellular Glu formation coupled primarily to the ammoniagenic pathway (GDH). Conversely, enhancing the extracellular Glu formation with p-aminohippurate and Glu uptake suppressed intracellular Gln hydrolysis while NH+4 formation from Glu increased. Thus these results are consistent with the transporter's dual role in modulating both PDG and GDH flux. Interestingly, PDG flux was actually higher in the Gln-adapted LLC-PK1-F+ cell line because of a two- to threefold enhancement in Gln uptake despite greater Glu uptake than in the parental LLC-PK1 cells, revealing the importance of both Glu and Gln transport in the modulation of PDG flux. Nevertheless, when studied at physiological Gln concentration, PDG flux falls under tight Glu transporter control as Gln uptake decreases, suggesting that cellular Gln metabolism may indeed be under Glu transporter control in vivo.


A simpler and more cost-effective peptide biosynthetic method using the truncated GST as carrier for epitope mapping.
There is a need to develop better methods for epitope mapping and/or identification of antibody-recognizing motifs. Here, we describe improved biosynthetic peptide (BSP) method using a newly developed plasmid pXXGST-3 as vector, which has a viral E7 gene in the cloning sites of pXXGST-1. It is crucial to employ pXXGST-3 instead of pXXGST-1, since it makes use of the BSP method simpler and easier to perform, and more cost-effective for epitope mapping. These merits are embodied in two aspects: i) convenient recovery of double enzyme-digested product due to the existence of 315 bp inserted between BamH I and Sal I sites, and thus greatly reducing the production of self-ligation clones, and ii) no longer requiring control protein when screening recombinant (r-) clones expressing 8/18mer peptides by running polyacrylamide gel electrophoresis. The protocol involves the following core steps: (i) design of plus and minus strands of DNA fragments encoding overlapping 8/18mer peptides; (ii) chemical synthesis of the designed DNA fragments; (iii) development of r-clones using pXXGST-3 vector expressing each 8/18mer peptide fused with truncated GST188 protein; (iv) screening r-clones by running the cell pellets from each induced clone on SDS-PAGE gel followed by sequencing of inserted DNA fragments for each verified r-clone; and (v) Western blotting with either monoclonal antibodies or polyclonal antibodies. This improved GST188-BSP method provides a powerful alternative tool for epitope mapping.


Should management of pneumonia be an indicator of quality of care?
Many regulatory bodies and payers measure the quality of care provided to patients admitted to the hospital with pneumonia. Some pneumonia quality measures were not based on high-level evidence, and there is also concern that public reporting of performance could drive excessive use of diagnostic testing and antibiotic treatment. There have been significant increases in the performance rate of several process of care recommended for patients hospitalized with pneumonia, accompanied by a decrease in 30-day mortality. To maximize the potential for improved patient outcomes, physicians and regulators must remain vigilant to detect unintended negative consequences related to performance measurement.


Epidemiology and management of candidaemia--a retrospective, multicentre study in five hospitals in the UK.
Candidaemia is associated with high mortality. Despite the fact that Candida species account for close to 10% of all nosocomial bloodstream infections, relatively few studies have investigated the management of candidaemia in hospitals. Our objective was to find out how candidaemia is managed in hospitals. Data relating to all episodes of candidaemia for the year 2008 were retrospectively collected in five centres in Scotland and Wales. A total of 96 candidaemic episodes were recorded in the year 2008, yielding 103 isolates of Candida. Fifty candidaemic episodes were caused by Candida albicans. Fluconazole was the most common agent prescribed for the treatment of candidaemia. There was great variation in the prescribed dose of fluconazole. Forty per cent of patients who survived received <2 weeks of systemic antifungal therapy. Central venous catheters (CVC) were removed in 57% of patients. CVC removal was not associated with better survival. The overall mortality was 40.4%. Management of candidaemia varies between the UK centres and is often inadequate. There is need to have consensus on the dosages of antifungal agents and the duration of therapy. The current guidance on removal of CVC in all cases of candidaemia should be reviewed.


Antithrombotics and anticoagulants in coronary syndromes and stroke.
The low-molecular-weight heparins (LMWHs) have been proven superior to placebo in reducing the incidence of acute coronary ischemic syndromes. Comparative studies vs. unfractionated heparin have not demonstrated superiority in favor of the LMWH dalteparin. In the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) trial, enoxaparin was demonstrated to have a benefit over heparin. The results have contributed to a better understanding of the relative efficacy of LMWHs in acute coronary syndromes. A second trial with enoxaparin supported the conclusions of the ESSENCE trial. The antithrombotic effects of LMWHs have also been evaluated for the management of ischemic stroke with varied results. A trial assessing tinzaparin in acute ischemic stroke has completed enrollment, and its results may shed new light on the use of an LMWH for the management of stroke.


CD-BFT: Canonical Decomposition-Based Belief Functions Transformation in Possibility Theory.
Based on subjective possibilistic semantics, an agent's subjective probability mass function is dominated by a qualitative Possibility Mass Function (PossMF), which can also be transformed into a unique consonant mass function. However, the existing transformation method cannot maintain the consistency of combination rules, i.e., fusing PossMFs and consonant mass functions with same information content, respectively, the results no longer maintain the reversible transformation. To address the above issue, a novel belief functions transformation is proposed, which can be interpreted based on both Smets' canonical decomposition and Pichon's canonical decomposition. The proposed method is validated based on consistency of combination rules, the least commitment principle, and its application in the fusion of information. In addition, based on the two canonical decompositions, we extend the transformation to possibilistic belief structure, and offer a new perspective of relationship between possibilistic information and evidential information.


Health Behavior Education, e-research and a (H1N1) Influenza (Swine Flu): Bridging the Gap between Intentions and Health Behavior Change.
This study examined relations between risk perception/self-efficacy and handwashing intentions/behaviors during the A (H1N1) pandemic influenza. Data were collected from a longitudinal sample of Costa Ricans (NT1/T2 = 449/97). Results revealed that males and females presented a different social cognitive pattern in reaction to A (H1N1) pandemic. In females, the effects of risk perception/self-efficacy on handwashing behaviors were fully mediated by handwashing intentions. In males, self-efficacy influenced both directly and indirectly on handwashing behaviors, and risk perceptions showed no significant effect on handwashing behaviors. These results suggest that gender oriented protocols should be adopted by public health authorities in order to educate males and females in preventing both A (H1N1) and seasonal influenza.


GABA systems, benzodiazepines, and substance dependence.
Alterations in the gamma-aminobutyric acid (GABA) receptor complex and GABA neurotransmission influence the reinforcing and intoxicating effects of alcohol and benzodiazepines. Chronic modulation of the GABA(A)-benzodiazepine receptor complex plays a major role in central nervous system dysregulation during alcohol abstinence. Withdrawal symptoms stem in part from a decreased GABAergic inhibitory function and an increase in glutamatergic excitatory function. GABA(A) receptors play a role in both reward and withdrawal phenomena from alcohol and sedative-hypnotics. Although less well understood, GABA(B) receptor complexes appear to play a role in inhibition of motivation and diminish relapse potential to reinforcing drugs. Evidence suggests that long-term alcohol use and concomitant serial withdrawals permanently alter GABAergic function, down-regulate benzodiazepine binding sites, and in preclinical models lead to cell death. Benzodiazepines have substantial drawbacks in the treatment of substance use-related disorders that include interactions with alcohol, rebound effects, alcohol priming, and the risk of supplanting alcohol dependency with addiction to both alcohol and benzodiazepines. Polysubstance-dependent individuals frequently self-medicate with benzodiazepines. Selective GABA agents with novel mechanisms of action have anxiolytic, anticonvulsant, and reward inhibition profiles that have potential in treating substance use and withdrawal and enhancing relapse prevention with less liability than benzodiazepines. The GABA(B) receptor agonist baclofen has promise in relapse prevention in a number of substance dependence disorders. The GABA(A) and GABA(B) pump reuptake inhibitor tiagabine has potential for managing alcohol and sedative-hypnotic withdrawal and also possibly a role in relapse prevention.


Expression of xanthophyll biosynthetic genes during light-dependent chloroplast differentiation.
In higher plants, etioplast to chloroplast differentiation is characterized by dramatic ultrastructural changes of the plastid and a concomitant increase in chlorophylls and carotenoids. Whereas the formation and function of carotenes and their oxygenated derivatives, the xanthophylls, have been well studied, little is known about the regulation of the genes involved in xanthophyll biosynthesis. Here, we analyze the expression of three xanthophyll biosynthetic genes (i.e. beta-carotene hydroxylase [bhy], zeaxanthin epoxidase [zep], and violaxanthin de-epoxidase [vde]) during de-etiolation of seedlings of tobacco (Nicotiana tabacum L. cv Samsun) under different light conditions. White-light illumination caused an increase in the amount of all corresponding mRNAs. The expression profiles of bhy and zep not only resembled each other but were also similar to the pattern of a gene encoding a major light-harvesting protein of photosystem II. This finding indicates a coordinated synthesis during formation of the antenna complex. In contrast, the expression pattern of vde was clearly different. Furthermore, the gene expression of bhy was shown to be modulated after illumination with different white-light intensities. The expression of all xanthophyll biosynthetic genes under examination was up-regulated upon exposure to red, blue, and white light. Gene expression of bhy and vde but not of zep was more pronounced under red-light illumination, pointing at an involvement of the phytochrome system. Expression analysis in the presence of the photosynthetic electron transport inhibitors 3-(3,4-dichlorophenyl)-1,1-dimethyl-urea and 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone indicated a redox control of transcription of two of the xanthophyll biosynthetic genes (bhy and zep).


Benign gallbladder diseases: Imaging techniques and tips for differentiating with malignant gallbladder diseases.
Benign gallbladder diseases usually present with intraluminal lesions and localized or diffuse wall thickening. Intraluminal lesions of the gallbladder include gallstones, cholesterol polyps, adenomas, or sludge and polypoid type of gallbladder cancer must subsequently be excluded. Polyp size, stalk width, and enhancement intensity on contrast-enhanced ultrasound and degree of diffusion restriction may help differentiate cholesterol polyps and adenomas from gallbladder cancer. Localized gallbladder wall thickening is largely due to segmental or focal gallbladder adenomyomatosis, although infiltrative cancer may present similarly. Identification of Rokitansky-Aschoff sinuses is pivotal in diagnosing adenomyomatosis. The layered pattern, degree of enhancement, and integrity of the wall are imaging clues that help discriminate innocuous thickening from gallbladder cancer. High-resolution ultrasound is especially useful for analyzing the layering of gallbladder wall. A diffusely thickened wall is frequently seen in inflammatory processes of the gallbladder. Nevertheless, it is important to check for coexistent cancer in instances of acute cholecystitis. Ultrasound used alone is limited in evaluating complicated cholecystitis and often requires complementary computed tomography. In chronic cholecystitis, preservation of a two-layered wall and weak wall enhancement are diagnostic clues for excluding malignancy. Magnetic resonance imaging in conjunction with diffusion-weighted imaging helps to differentiate xathogranulomatous cholecystitis from gallbladder cancer by identifying the presence of fat and degree of diffusion restriction. Such distinctions require a familiarity with typical imaging features of various gallbladder diseases and an understanding of the roles that assorted imaging modalities play in gallbladder evaluations.


Encapsulation of sodium nimesulide and precursors in beta-cyclodextrin.
Crystalline 1:1 inclusion complexes with beta-cyclodextrin (beta-CD) and the sodium salt of nimesulide (4-nitro-2-phenoxymethanesulfonanilide), and the sodium salt of the derivative 2-phenoxymethanesulfonanilide, have been prepared by co-precipitation from aqueous solution. The presence of true inclusion complexes was supported by elemental analysis, thermogravimetry and powder X-ray diffraction. FTIR and 13C CP MAS NMR spectroscopy confirmed that no chemical modification of the guests occurred upon formation of inclusion complexes. The reaction of the precursors 2-phenoxynitrobenzene and 2-phenoxyaniline with beta-CD was also studied and crystalline inclusion complexes with a 2:1 (host-to-guest) stoichiometry were isolated. The interaction of the different guest species with beta-CD host molecules was studied theoretically by carrying out ab initio calculations. Favourable inclusion geometries were obtained for the four guests mentioned above. On the other hand, it was found that the inclusion of the neutral guests nimesulide and 2-phenoxymethanesulfonanilide was considerably less favourable. This is in agreement with the experimentally observed difficulty in isolating true inclusion complexes containing these guests and beta-CD. The calculated lower stability is attributed to the different steric hindrance arising from the different conformational preferences of neutral and anionic forms.


Occurrence of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) across the Gulf Corporation Council countries: Four years update.
The emergence of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infections has become a global issue of dire concerns. MERS-CoV infections have been identified in many countries all over the world whereas high level occurrences have been documented in the Middle East and Korea. MERS-CoV is mainly spreading across the geographical region of the Middle East, especially in the Arabian Peninsula, while some imported sporadic cases were reported from the Europe, North America, Africa, and lately Asia. The prevalence of MERS-CoV infections across the Gulf Corporation Council (GCC) countries still remains unclear. Therefore, the objective of the current study was to report the prevalence of MERS-CoV in the GCC countries and to also elucidate on its demographics in the Arabian Peninsula. To date, the World Health Organization (WHO) has reported 1,797 laboratory-confirmed cases of MERS-CoV infection since June 2012, involving 687 deaths in 27 different countries worldwide. Within a time span of 4 years from June 2012 to July 2016, we collect samples form MERS-CoV infected individuals from National Guard Hospital, Riyadh, and Ministry of health Saudi Arabia and other GCC countries. Our data comprise a total of 1550 cases (67.1% male and 32.9% female). The age-specific prevalence and distribution of MERS-CoV was as follow: <20 yrs (36 cases: 3.28%), 20-39 yrs (331 cases: 30.15%), 40-59 yrs (314 cases: 28.60%), and the highest-risk elderly group aged ≥60 yrs (417 cases: 37.98%). The case distribution among GCC countries was as follows: Saudi Arabia (1441 cases: 93%), Kuwait (4 cases: 0.3%), Bahrain (1 case: 0.1%), Oman (8 cases: 0.5%), Qatar (16 cases: 1.0%), and United Arab Emirates (80 cases: 5.2%). Thus, MERS-CoV was found to be more prevalent in Saudi Arabia especially in Riyadh, where 756 cases (52.4%) were the worst hit area of the country identified, followed by the western region Makkah where 298 cases (20.6%) were recorded. This prevalence update indicates that the Arabian Peninsula, particularly Saudi Arabia, is the hardest hit region regarding the emerging MERS-CoV infections worldwide. GCC countries including Saudi Arabia now have the infrastructure in place that allows physicians and scientific community to identify and immediately respond to the potential risks posed by new outbreaks of MERS-CoV infections in the region. Given the continuum of emergence and the large magnitude of the disease in our region, more studies will be required to bolster capabilities for timely detection and effective control and prevention of MERS-CoV in our region.


[Correction of immunologic deficiency in experimental tuberculosis and chronic effect of pesticides].
The paper deals with the findings of comparative morphologic and immunologic studies of immunomodulatory therapy for experimental tuberculosis on chronic exposure to pesticides (alpha-3) of 117 guinea pigs receiving decaris (levamisole), as an immunostimulator, and "mumiyo-acil", as a biostimulator. The specific features of every pathogenetic drug's effect on the tuberculous inflammation morphology, cellular-tissue reactions, cellular immune response and repair processes were defined. An optimum effect in the treatment of the pesticide-induced experimental tuberculosis can be achieved by the use of anti-bacterial drugs and "mumiyo-acil".


Offsets in tide-gauge reference levels detected by satellite altimetry: ten case studies.
Comparing measurements of absolute sea level by satellite altimetry and relative sea level by a tide gauge can reveal errors in either measurement system. Combining the measurements can determine vertical land motion (VLM) at the tide gauge. We here discuss ten case studies in which a tide gauge has likely experienced a small (≤10 cm), discontinuous offset in the vertical, suggesting inadvertent loss of reference-level stability. Proper interpretation of offsets is helped if independent VLM measurements from nearby geodetic stations are available. In two cases, earthquake-induced VLM cannot be ruled out, although it appears unlikely. Offsets as small as 1-2 cm can be detected when both altimeter and tide gauge successfully observe the same ocean signal. This is most likely to occur for tide gauges located on small, open-ocean islands. Tide gauges near large land masses are typically more challenging owing to inadequacies of satellite altimetry near land and to differences between coastal and open-ocean sea levels. The case studies highlight the utility of satellite altimetry for tide-gauge quality control. The online version contains supplementary material available at 10.1007/s00190-023-01800-7.


Synergistic impacts of malathion and predatory stress on six species of North American tadpoles.
The decline of many amphibian populations is associated with pesticides, but for most pesticides we know little about their toxicity to amphibians. Malathion is a classic example; it is sprayed over aquatic habitats to control mosquitoes that carry malaria and the West Nile virus, yet we know little about its effect on amphibians. I examined the survival of six species of tadpoles (wood frogs, Rana sylvatica; leopard frogs, R. pipiens; green frogs, R. clamitans; bullfrogs, R. catesbeiana; American toads, Bufo americanus; and gray tree frogs, Hyla versicolor) for 16 d in the presence or absence of predatory stress and six concentrations of malathion. Malathion was moderately toxic to all species of tadpoles (median lethal concentration [LC50] values, the concentration estimated to kill 50% of a test population, ranged from 1.25-5.9 mg/L). These values are within the range of values reported for the few amphibians that have been tested (0.2-42 mg/L). In one of the six species, malathion became twice as lethal when combined with predatory stress. Similar synergistic interactions have been found with the insecticide carbaryl, suggesting that the synergy may occur in many carbamate and organophosphate insecticides. While malathion has the potential to kill amphibians and its presence is correlated with habitats containing declining populations, its actual role in amphibian declines is uncertain given the relatively low concentration in aquatic habitats.


Conservation and progressive methylation of Epstein-Barr viral DNA sequences in transformed cells.
The structure of intracellular viral DNA from a number of cell lines arising by clonal transformation of human lymphocytes in vitro with Epstein-Barr virus was analyzed. Intracellular viral DNAs were partially purified and digested with several restriction endonucleases, and the products of digestion were separated by electrophoresis in agarose gels. The viral fragments were detected by transferring the DNA from the gel to nitrocellulose sheets, hybridizing radiolabeled recombinant vectors carrying fragments of viral DNA to those transfers, and visualizing the hybrids by autoradiography. These analyses indicated that: (i) regions of repetitious viral DNA do undergo expansion and contraction although one size predominates; (ii) novel sequence arrangements appear in the intracellular viral DNA of different clones but are not found in clones analyzed serially and propagated extensively; (iii) the viral DNA is increasingly methylated upon cell propagation. We have not identified a transformed cell phenotype or a viral phenotype that segregates with the observed progressive methylation. We have not detected in Epstein-Barr viral plasmids analogs of the gross rearrangements of viral DNAs observed after lytic infections with high multiplicities of papova-, adeno-, or herpes simplex viruses.


Autophagy and Senescence: The Molecular Mechanisms and Implications in Liver Diseases.
The liver is the primary organ accountable for complex physiological functions, including lipid metabolism, toxic chemical degradation, bile acid synthesis, and glucose metabolism. Liver function homeostasis is essential for the stability of bodily functions and is involved in the complex regulation of the balance between cell proliferation and cell death. Cell proliferation-halting mechanisms, including autophagy and senescence, are implicated in the development of several liver diseases, such as cholestasis, viral hepatitis, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Among various cell death mechanisms, autophagy is a highly conserved and self-degradative cellular process that recycles damaged organelles, cellular debris, and proteins. This process also provides the substrate for further metabolism. A defect in the autophagy machinery can lead to premature diseases, accelerated aging, inflammatory state, tumorigenesis, and cellular senescence. Senescence, another cell death type, is an active player in eliminating premalignant cells. At the same time, senescent cells can affect the function of neighboring cells by secreting the senescence-associated secretory phenotype and induce paracrine senescence. Autophagy can promote and delay cellular senescence under different contexts. This review decodes the roles of autophagy and senescence in multiple liver diseases to achieve a better understanding of the regulatory mechanisms and implications of autophagy and senescence in various liver diseases.


Expert communities and interest-formation in the Brazilian AIDS program.
This paper examines the role of the Technical Advisory Committee for antiretroviral therapy of the Brazilian AIDS program in mediating the decision-making process of including new antiretroviral (ARV) drugs in the Unified Health System services by the end of the 2000s. We conducted documental analysis and interviews with key informants from the governmental sphere and professionals. The work features the Technical Advisory Committee as an "expert community", defined as a network of individuals with expertise and competence in a particular sphere and whose knowledge is relevant in critical public policy decision areas. It also indicates that the decision-making process for inclusion of antiretroviral drugs in the Brazilian program was incremental, considering the expectations of the innovative leader companies of pharmaceutical market. The work describes thus the results of the interaction of government interests, pharmaceutical industry and experts in the implementation of a relevant international policy. It provides arguments and evidence for understanding the role of expert communities on a sectorial public policy so far analyzed predominantly from the perspective of social movements.


The effect of different brightness conditions on visually and memory guided saccades.
It is commonly assumed that saccades in the dark are slower than saccades in a lit room. Early studies that investigated this issue using electrooculography (EOG) often compared memory guided saccades in darkness to visually guided saccades in an illuminated room. However, later studies showed that memory guided saccades are generally slower than visually guided saccades. Research on this topic is further complicated by the fact that the different existing eyetracking methods do not necessarily lead to consistent measurements. In the present study, we independently manipulated task (memory guided/visually guided) and screen brightness (dark, medium and light) in an otherwise completely dark room, and measured the peak velocity and the duration of the participant's saccades using a popular pupil-cornea reflection (p-cr) eyetracker (Eyelink 1000). Based on a critical reading of the literature, including a recent study using cornea-reflection (cr) eye tracking, we did not expect any velocity or duration differences between the three brightness conditions. We found that memory guided saccades were generally slower than visually guided saccades. In both tasks, eye movements on a medium and light background were equally fast and had similar durations. However, saccades on the dark background were slower and had shorter durations, even after we corrected for the effect of pupil size changes. This means that this is most likely an artifact of current pupil-based eye tracking. We conclude that the common assumption that saccades in the dark are slower than in the light is probably not true, however pupil-based eyetrackers tend to underestimate the peak velocity of saccades on very dark backgrounds, creating the impression that this might be the case.


Criteria for selection of appropriate benzodiazepine hypnotic therapy.
The several benzodiazepine hypnotics currently marketed differ in onset and duration of action and in side effect profile. These differences are largely based on the varying pharmacodynamic properties of these agents. The selection of a drug for treating an individual patient should be based on consideration of these pharmacologic differences, as well as assessment of the sleep-wake disorder. The initial objective for the clinician who intends to manage a patient with insomnia is to determine which factors are contributing to the sleep disturbance and to decide on a treatment strategy. If medication is to be used, then the physician should select the most effective and safest hypnotic, prescribe it at the lowest effective dose and for the fewest number of nights. Individual patient response to the chosen medication should be monitored.


Non-canonical WOX11-mediated root branching contributes to plasticity in Arabidopsis root system architecture.
Lateral roots (LRs), which originate from the growing root, and adventitious roots (ARs), which are formed from non-root organs, are the main contributors to the post-embryonic root system in Arabidopsis However, our knowledge of how formation of the root system is altered in response to diverse inductive cues is limited. Here, we show that WOX11 contributes to root system plasticity. When seedlings are grown vertically on medium, WOX11 is not expressed in LR founder cells. During AR initiation, WOX11 is expressed in AR founder cells and activates LBD16LBD16 also functions in LR formation and is activated in that context by ARF7/19 and not by WOX11 This indicates that divergent initial processes that lead to ARs and LRs may converge on a similar mechanism for primordium development. Furthermore, we demonstrated that when plants are grown in soil or upon wounding on medium, the primary root is able to produce both WOX11-mediated and non-WOX11-mediated roots. The discovery of WOX11-mediated root-derived roots reveals a previously uncharacterized pathway that confers plasticity during the generation of root system architecture in response to different inductive cues.


Vascular and neural pathology of lumbosacral spinal stenosis.
During a study of the intrinsic vasculature of the lumbosacral spinal nerve roots in cadavers, a typical case of spinal stenosis was encountered. A review of the antemortem anamnesis revealed that this patient had had an intermittent claudication of the cauda equina. Investigation of the concomitant vascular and histopathological alterations of the affected nerve roots suggested that the claudication may have resulted from ectopic nerve impulse discharges elicited by rapid changes in the blood supply following exertion. The unexpectedly slight apparent neural deficit relative to observed root damage may be attributed to a neuronal plasticity within the spinal cord that permitted functional compensations to develop during the slow acquisition of the chronic nerve root pathology.


Inflammatory dietary pattern and risk of depression among women.
Inflammation is considered as a mechanism leading to depression, but the association between inflammatory dietary pattern and depression risk is unknown. Using reduced-rank regression, we identified a dietary pattern that was related to plasma levels of inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor α receptor 2), and we conducted a prospective analysis of the relationship of this pattern and depression risk among participants in the Nurses' Health Study. A total of 43,685 women (aged 50-77) without depression at baseline (1996) were included and followed up until 2008. Diet information was obtained from food frequency questionnaires completed between 1984 through 2002 and computed as cumulative average of dietary intakes with a 2-year latency applied. We used a strict definition of depression that required both self-reported physician-diagnosed depression and use of antidepressants, and a broader definition that included women who reported either clinical diagnosis or antidepressant use. During the 12-year follow-up, we documented 2594 incident cases of depression using the stricter definition and 6446 using the broader definition. After adjustment for body mass index and other potential confounders, relative risks comparing extreme quintiles of the inflammatory dietary pattern were 1.41 (95% confidence interval [CI], 1.22, 1.63; P-trend<.001) for the strict definition and 1.29 (95% CI, 1.18, 1.41; P-trend<.001) for the broader definition of depression. The inflammatory dietary pattern is associated with a higher depression risk. This finding suggests that chronic inflammation may underlie the association between diet and depression.


Effects of preventive antibiotics on neutrophil phagocytosis as measured by the nitroblue tetrazolium dye test.
White blood cell counts and nitroblue tetrazolium dye tests were performed in three groups of dogs before and after the injection of Escherichia coli using colistimethate sodium and cephalothin sodium in the second and third groups, respectively, prior to the induction of sepsis. The response was a diminished white blood count and increased nitroblue tetrazolium dye test percentage in all groups. When antibiotic administration was performed prior to the induction of sepsis, the increase in the nitroblue tetrazolium reduction dye test was much more evident despite the overwhelming dose of bacteria given, suggesting that antibiotics given preoperatively will prevent the toxic effects of bacteria on the neutrophil and will enhance the phagocytic activity of the neutrophil.


How are patients with atrial fibrillation approached and informed about their risk profile and available therapies in Europe? Results of the European Heart Rhythm Association Survey.
This European Heart Rhythm (EHRA) Scientific Initiatives Committee EP Wire Survey aimed at exploring the common practices in approaching patients with atrial fibrillation (AF) and informing them about their risk profiles and available therapies in Europe. In the majority of 53 responding centres, patients were seen by cardiologists (86.8%) or arrhythmologists (64.2%). First- and follow-up visits most commonly lasted 21-30 and 11-20 min (41.5 and 69.8% of centres, respectively). In most centres (80.2%) stroke and bleeding risk had the highest priority for discussion with AF patients; 50.9% of centres had a structured patient education programme for stroke prevention. Individual patient stroke risk was assessed at every visit in 69.2% of the centres; 46.1% of centres had a hospital-based anticoagulation clinic. Information about non-vitamin K oral anticoagulants (NOACs) was communicated to all AF patients eligible for oral anticoagulation (38.5% of centres) or to warfarin-naive/unstable patients (42.3%). Only two centres (3.8%) had a structured NOAC adherence follow-up programme; in eight centres (15.4%) patients were requested to sign the statement they have been informed about the risks of non-adherence to NOAC therapy, and three centres (5.8%) had a patient education programme. Patient preferences were of the highest relevance regarding oral anticoagulation and AF ablation (64.7 and 49.0% of centres, respectively). This EP Wire Survey shows that in Europe considerable amount of time and resources are used in daily clinical practice to inform AF patients about their risk profile and available therapies. However, a diversity of strategies used across the European hospitals was noted, and further research is needed to better define optimal strategies for informing AF patients about their risk profile and treatment options.


Apolipoprotein E (ApoE) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy?
The alleles that are detrimental to health, especially in older age, are thought to persist in populations because they also confer some benefits for individuals (through antagonistic pleiotropy). The ApoE4 allele at the ApoE locus, encoding apolipoprotein E (ApoE), significantly increases risk of poor health, and yet it is present in many populations at relatively high frequencies. Why has it not been replaced by natural selection with the health-beneficial ApoE3 allele? ApoE is a major supplier of cholesterol precursor for the production of ovarian oestrogen and progesterone, thus ApoE has been suggested as the potential candidate gene that may cause variation in reproductive performance. Our results support this hypothesis showing that in 117 regularly menstruating women those with genotypes with at least one ApoE4 allele had significantly higher levels of mean luteal progesterone (144.21 pmol l(-1)) than women with genotypes without ApoE4 (120.49 pmol l(-1)), which indicates higher potential fertility. The hormonal profiles were based on daily data for entire menstrual cycles. We suggest that the finding of higher progesterone in women with ApoE4 allele could provide first strong evidence for an evolutionary mechanism of maintaining the ancestral and health-worsening ApoE4 allele in human populations.


Active suppression of immunoglobulin allotype synthesis. I. Chronic suppression after perinatal exposure to maternal antibody to paternal allotype in (SJL x BALB-c)F 1 mice.
Long-term (chronic) allotype suppression, previously reported only in rabbits, is shown here to occur in at least one strain combination of mice as well. Close to 50% of the offspring of SJL (Ig(b)) males mated to BALB/c (Ig(a)) females immunized against the paternal allotype were found to be suppressed for Ig-1b (gammaG(2a)) at 6 months of age. These mice are called "chronically" suppressed. The percentage of offspring in this strain combination suppressed for the paternal allotype at 8 wk of age is the same as that seen in an earlier strain combination tested, [(C57 x BALB/c)F(1)], in which all mice recover from suppression by 10-12 wk. After 8 wk, two distinct patterns of long-term (chronic) suppression emerge in (SJL x BALB/c)F(1) mice: a small number of these mice never produce detectable amounts of Ig-1b throughout their lives, while the majority produce detectable Ig-1b sporadically, sometimes over a period of several weeks, the level of which eventually falls below detectability. Attempts to "cure" suppression by destroying the existent lymphoid population and forcing endogenous repopulation in chronically suppressed animals were unsuccessful. Furthermore, attempts to restore Ig-1b production by injection of cells from syngeneic Ig(a)/Ig(b) donors into irradiated, chronically suppressed recipients were also unsuccessful, although the same cell inocula, when injected into irradiated BALB/c (Ig(a)/Ig(a)) mice produced high levels of gamma globulin carrying the allotype. These results suggest that long-term allotype suppression resulting from perinatal exposure of offspring to specific anti-allotype antibody (anti-Ig-1b), is not due merely to an absence of Ig-1b-producing cells or their progenitors, but appears to be an active process, which dominates physiologically over normal production.