The MAR databases: development and implementation of databases specific for marine metagenomics.
We introduce the marine databases; MarRef, MarDB and MarCat (https://mmp.sfb.uit.no/databases/), which are publicly available resources that promote marine research and innovation. These data resources, which have been implemented in the Marine Metagenomics Portal (MMP) (https://mmp.sfb.uit.no/), are collections of richly annotated and manually curated contextual (metadata) and sequence databases representing three tiers of accuracy. While MarRef is a database for completely sequenced marine prokaryotic genomes, which represent a marine prokaryote reference genome database, MarDB includes all incomplete sequenced prokaryotic genomes regardless level of completeness. The last database, MarCat, represents a gene (protein) catalog of uncultivable (and cultivable) marine genes and proteins derived from marine metagenomics samples. The first versions of MarRef and MarDB contain 612 and 3726 records, respectively. Each record is built up of 106 metadata fields including attributes for sampling, sequencing, assembly and annotation in addition to the organism and taxonomic information. Currently, MarCat contains 1227 records with 55 metadata fields. Ontologies and controlled vocabularies are used in the contextual databases to enhance consistency. The user-friendly web interface lets the visitors browse, filter and search in the contextual databases and perform BLAST searches against the corresponding sequence databases. All contextual and sequence databases are freely accessible and downloadable from https://s1.sfb.uit.no/public/mar/.


Tissue-engineered vascular grafts demonstrate evidence of growth and development when implanted in a juvenile animal model.
The development of a living, autologous vascular graft with the ability to grow holds great promise for advancing the field of pediatric cardiothoracic surgery. To evaluate the growth potential of a tissue-engineered vascular graft (TEVG) in a juvenile animal model. Polyglycolic acid nonwoven mesh tubes (3-cm length, 1.3-cm id; Concordia Fibers) coated with a 10% copolymer solution of 50:50 L-lactide and epsilon-caprolactone were statically seeded with 1 x 10 cells/cm autologous bone marrow derived mononuclear cells. Eight TEVGs (7 seeded, 1 unseeded control) were implanted as inferior vena cava (IVC) interposition grafts in juvenile lambs. Subjects underwent bimonthly magnetic resonance angiography (Siemens 1.5 T) with vascular image analysis (www.BioimageSuite.org). One of 7-seeded grafts was explanted after 1 month and all others were explanted 6 months after implantation. Neotissue was characterized using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis. All grafts explanted at 6 months were patent and increased in volume as measured by difference in pixel summation in magnetic resonance angiography at 1 month and 6 months. The volume of seeded TEVGs at explant averaged 126.9% +/- 9.9% of their volume at 1 month. Magnetic resonance imaging demonstrated no evidence of aneurysmal dilation. TEVG resembled the native IVC histologically and had comparable collagen (157.9 +/- 26.4 microg/mg), elastin (186.9 +/- 16.7 microg/mg), and glycosaminoglycan (9.7 +/- 0.8 microg/mg) contents. Immunohistochemical staining and Western blot analysis showed that Ephrin-B4, a determinant of normal venous development, was acquired in the seeded grafts 6 months after implantation. TEVGs demonstrate evidence of growth and venous development when implanted in the IVC of a juvenile lamb model.


A consumer perspective of diagnosis and treatment of chronic major depression.
The National Depressive and Manic-Depressive Association (National DMDA) is a nonprofit, mission-driven, consumer advocacy organization that was founded to educate patients, their families, and the public about the nature and management of depressive and manic depressive illness. Although treatments for mood disorders have been available for decades, individuals with chronic major depression are often misdiagnosed or inappropriately treated. Serious gaps in the translation of research findings into clinical management exist and are attributable to patient, provider, and health care system factors. This article discusses the barriers to diagnosis and the ways to improve recognition and treatment of chronic major depression from the consumer perspective.


"Hard to reach, but not out of reach": Barriers and facilitators to recruiting Black African and Black Caribbean men with prostate cancer and their partners into qualitative research.
Access and recruitment barriers may have contributed to the underrepresentation of Black African/Caribbean men and their partners in current psychosocial research related to prostate cancer survivors. Whilst some studies have explored recruitment barriers and facilitators from participants' perspectives, little is known from researchers' point of view. This paper aimed to address this gap in the literature. Recruitment strategies included the following: cancer support groups, researchers' networks, media advertisement, religious organisations, National Health Service hospitals and snowball sampling. Thirty-six eligible participants (men = 25, partners = 11) were recruited into the study. Recruitment barriers comprised of gate-keeping and advertisement issues and the stigma associated with prostate cancer disclosure. Facilitators which aided recruitment included collaborating with National Health Service hospitals, snowball sampling, flexible data collection, building rapport with participants to gain their trust and researcher's attributes. Findings highlight that "hard to reach" Black African/Caribbean populations may be more accessible if researchers adopt flexible but strategic and culturally sensitive recruitment approaches. Such approaches should consider perceptions of stigma associated with prostate cancer within these communities and the influence gatekeepers can have in controlling access to potential participants. Increased engagement with healthcare professionals and gatekeepers could facilitate better access to Black African/Caribbean populations so that their voices can be heard and their specific needs addressed within the healthcare agenda.


[Myocardial contraction in ischemic heart disease].
The indices of contractility of the left ventricular myocardium were studied by means of ventriculography and catheterization in 84 patients with ischemic heart disease according to the extent of damage to the coronary arteries and the course of the disease. Changes in the coronary arteries were encountered twice as frequently among patients with postinfarction cardiosclerosis as among patients with angina pectoris and no history of infarction. The main cause of disorders of myocardial contractility in patients with ischemic heart disease is post-infarction cardiosclerosis (56% of cases). Signs of impaired functional capacity of the left ventricle appeared in segmental asynergy involving 20 to 25% of its circumference. Changes in the indices of contractility were revealed in 13% of patients with angina pectoris.


Root exudation of carbon and nitrogen compounds varies over the day-night cycle in pea: The role of diurnal changes in internal pools.
Rhizodeposition is the export of organic compounds from plant roots to the soil. Carbon allocation towards rhizodeposition has to be balanced with allocation for other physiological functions, which depend on both newly assimilated and stored nonstructural carbohydrate (NSC). To test whether the exudation of primary metabolites scales with plant NSC status, we studied diurnal dynamics of NSC and amino acid (AA) pools and fluxes within the plant and the rhizosphere. These diurnal dynamics were measured in the field and under hydroponic-controlled conditions. Further, C-limiting treatments offered further insight into the regulation of rhizodeposition. The exudation of primary metabolites fluctuated diurnally. The diurnal dynamics of soluble sugars (SS) and AA concentrations in tissues coincided with exudate pool fluctuations in the rhizosphere. SS and AA pools in the rhizosphere increased with NSC and AA pools in the roots. C starvation treatments offset the balance of exudates: AA exudate content in the rhizosphere significantly decreased while SS exudate content remained stable. Our results suggest that rhizodeposition is to some extent controlled by plant C:N status. We propose that SS exudation is less controlled than AA exudation because N assimilation depends on controlled C supply while SS exudation relies to a greater extent on passive diffusion mechanisms.


Modulation of the epidermal growth factor receptor by platelet-derived growth factor and choleragen: effects on mitogenesis.
The addition of fresh medium supplemented with partially purified platelet-derived growth factor (PDGF) to quiescent density-arrested cultures of BALB/c-3T3 cells decreases the subsequent binding of radiolabeled epidermal growth factor (EGF). The decrease in EGF binding can be observed 1 hr after the addition of PDGF. This effect is maximal in 2-3 hr, and binding remains diminished for at least 6 hr. These effects can be accounted for by a decrease in the number of EGF receptors with no change in receptor affinity. The action of PDGF is concentration dependent, but even at very high concentrations of PDGF the reduction in EGF binding is never more than 50%. Similar decreases in EGF binding are produced by other treatments that render BALB/c-3T3 cells competent, such as the addition of fibroblast growth factor or medium previously exposed to the macrophage-like cell line P388D(1). Cholera toxin (choleragen), which alone had no effect on EGF binding, dramatically potentiated the ability of PDGF to down regulate EGF receptors. Two to three hours after the addition of PDGF and choleragen, EGF binding was reduced by 80-90% compared with control values. The ability of PDGF and choleragen together to decrease EGF binding was substantially inhibited by cycloheximide. Autoradiography of [(3)H]thymidine-labeled cells shows that choleragen potentiates the action of PDGF; lower concentrations of PDGF are required to make cells competent after choleragen treatment. Furthermore, cells treated with PDGF and choleragen no longer require EGF for traverse of G(1) phase and initiation of DNA synthesis in defined medium. The reduction in receptor number produced by choleragen and PDGF, which may be due to internalization of the EGF receptor, may mimic the action of EGF and thereby remove the EGF requirement for DNA synthesis.


Behavior therapy and sex therapy.
Behavior therapy is characterized by the way in which clinical data are collected, analyzed, and used in the treatment program-specifically, the application of the methods of experimental and social psychology. A case history of the behavioral treatment of a sexual problem is presented to illustrate this process. Many people have assumed that the "new sex therapy" is behavior therapy because of its focus on the here and now and similarities in particular treatment maneuvers. However, the author notes that sex therapy is behavior therapy only to the extent that it deals comprehensively with environmental, interpersonal, and organismic factors that operate to maintain the sexual problem.


Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes.
The hypoxia-inducible factor 1 transcriptional activator complex (HIF-1) is involved in the activation of the erythropoietin and several other hypoxia-responsive genes. The HIF-1 complex is composed of two protein subunits: HIF-1beta/ARNT (aryl hydrocarbon receptor nuclear translocator), which is constitutively expressed, and HIF-1alpha, which is not present in normal cells but induced under hypoxic conditions. The HIF-1alpha subunit is continuously synthesized and degraded under normoxic conditions, while it accumulates rapidly following exposure to low oxygen tensions. The involvement of the ubiquitin-proteasome system in the proteolytic destruction of HIF-1 in normoxia was studied by the use of specific inhibitors of the proteasome system. Lactacystin and MG-132 were found to protect the degradation of the HIF-1 complex in cells transferred from hypoxia to normoxia. The same inhibitors were able to induce HIF-1 complex formation when added to normoxic cells. Final confirmation of the involvement of the ubiquitin-proteasome system in the regulated degradation of HIF-1alpha was obtained by the use of ts20TGR cells, which contain a temperature-sensitive mutant of E1, the ubiquitin-activating enzyme. Exposure of ts20 cells, under normoxic conditions, to the non-permissive temperature induced a rapid and progressive accumulation of HIF-1. The effect of proteasome inhibitors on the normoxic induction of HIF-1 binding activity was mimicked by the thiol reducing agent N-(2-mercaptopropionyl)-glycine and by the oxygen radical scavenger 2-acetamidoacrylic acid. Furthermore, N-(2-mercaptopropionyl)-glycine induced gene expression as measured by the stimulation of a HIF-1-luciferase expression vector and by the induction of erythropoietin mRNA in normoxic Hep 3B cells. These last findings strongly suggest that the hypoxia induced changes in HIF-1alpha stability and subsequent gene activation are mediated by redox-induced changes.


Valproate-associated reversible encephalopathy in a 3-year-old girl with Pallister-Killian syndrome.
Valproic acid (VPA) is considered to be a drug of first choice for the therapy of generalized and focal epilepsies, including special epileptic syndromes. The drug is usually well tolerated, rare serious complications may occur in some patients, including hemorrhagic pancreatitis, coagulapathies, bone marrow suppression, VPA-induced hepatotoxicity and encephalopathy. We report a case of VPA-associated encephalopathy without hyperammonemia in a 3-year-old girl with Pallister-Killian-Syndrom, combined with a mild hepatopathy and thrombopathy. After withdrawal of VPA, the clinical symptoms and the electroencephalography-alterations vanished rapidly.


US assessment of the fetal head and neck: a state-of-the-art pictorial review.
When attention is paid to the details of normal and abnormal fetal head and neck anatomy, abnormalities that normally would be missed at prenatal ultrasonography can routinely be diagnosed. Five basic views are used to assess the fetal head and neck: a transverse view of the head in the plane of the cavum septum pellucidum and cerebellum, a sagittal and a coronal view of the face to visualize the nose and lips, a sagittal view of the cervical spine, and a transverse view of the orbits to measure the biorbital and interorbital distances. Thickened nuchal fold, a common sign of Down syndrome, can be assessed with transverse images of the head. Transverse views are also useful to demonstrate cystic hygroma, occipital meningocele, and encephalocele, all of which can be associated with other severe anomalies. Micrognathia, cleft lip and palate, and macroglossia, which are best depicted with sagittal and coronal views of the face, are also associated with other fetal abnormalities. Visualization of these entities should prompt further search and amniocentesis. Lymphangioma of the tongue appears similar to macroglossia but is an isolated anomaly. Transverse views through the orbits are helpful for demonstrating orbital teratoma, orbital encephalocele, and hypo- and hypertelorism (the latter two being associated with other abnormalities). Sagittal views of the neck can demonstrate cystic hygroma, teratoma, and an enlarged thyroid.


A paradoxical cerebral hemodynamic effect of hydralazine.
Hydralazine is shown to have a very complex cerebral hemodynamic effect. It raises the intracranial pressure which, together with its effect upon systemic blood pressure, reduces the cerebral perfusion pressure. In spite of this and a concomitantly induced hyperventilation by hydralazine, CBF increases with some delay. The conclusion is that hydralazine is a cerebral vasodilator acting immediately upon cerebral capacitance vessels but later upon the resistance vessels as well.


Combined resection and recession of a single rectus muscle for the treatment of incomitant strabismus.
The treatment of incomitant strabismus is challenging. Traditional approaches include the use of asymmetric bilateral surgery and the fadenoperation (posterior fixation suture). We report our experience with a different approach: combined resection and recession of a single rectus muscle. The charts of 12 patients who underwent resection of a single rectus muscle with an equal or greater amount of recession of the same muscle were identified. In 5 patients, the procedure was performed using the adjustable suture technique, and the adjustment was performed later the same day (Group 1). In the remaining 7 patients, permanent sutures were placed at the time of surgery (Group 2). The procedure was performed for horizontal and vertical gaze incomitance, dissociated horizontal deviation, and distance-near disparity. Four of the 5 patients in Group 1 showed stable, long-term correction of their incomitance, both in primary gaze and in gaze in the direction of the muscle operated on. The results for patients in Group 2 showed stable, long-term correction of incomitance in 3 patients; however, these patients also had slight overcorrections in the direction of gaze opposite to the muscle operated on. An additional patient in Group 2 had a shift of her distance-near disparity, shifting from relatively exotropic to relatively esotropic disparity postoperatively. All patients in Group 2 showed at least some decrease in the amount of measured incomitance. We did not encounter complications such as muscle slippage or loss, scleral perforation, or late overcorrection in the field of gaze of the operated muscle. The technique of combined resection and recession of a single rectus muscle shows promise in the treatment of incomitant strabismus. It offers the advantages of posterior fixation combined with the greater technical ease of a standard hangback recession. The muscle may also be placed on an adjustable suture, allowing for postoperative adjustment in selected patients.


The resolution of agonist alpha 2-adrenergic receptor complexes from unoccupied receptors or antagonist-alpha 2 receptor complexes using DEAE chromatography.
Alpha 2-adrenergic receptors linked to inhibition of adenylate cyclase activity in human platelet membranes can be isolated using DEAE chromatography following solubilization into digitonin-containing buffers. This procedure permits resolution of agonist-occupied receptors from antagonist-occupied receptors. Antagonist-occupied receptors co-elute with unoccupied receptors. Adenylate cyclase activity elutes independently of all alpha 2-receptor activities. A greater resolution of agonist-receptor complexes from antagonist-receptor complexes is obtained using DEAE chromatography than reported earlier using approaches that rely entirely on agonist-stabilized increases in apparent receptor size. Consequently, DEAE chromatography may be of considerable value in isolating these agonist-receptor complexes to permit identification of the membrane component(s) which are more stably associated with the receptor subsequent to agonist occupancy and thus might be involved in receptor-cyclase coupling.


The devil in the tiers.
Prescription drug spending in the USA has soared, fueled by rising drug prices. A critical mechanism for restraining drug prices is the formulary tiering system. Although tiering should reflect the cost of a drug-and reward patients who choose less-expensive drugs-something is seriously amiss. Using Medicare claims data from roughly one million patients between 2010 and 2017, this article finds troubling amounts of distorted tiering and wasted cost. Increasingly, generics are shifted to more expensive-and therefore less accessible-tiers. The percentage of generics on the least-expensive tier drops from 73% to 28%; the percentage of drugs on inappropriate tiers rises from 47% to 74%. Considering only costs paid by patients and the federal Low-Income Subsidy Program, tier misplacement cumulatively costs society $13.25 billion over the time period. An unruly problem demands a disruptive solution. This article advances the counterintuitive regulatory reform that tiering should be based on a drug's list price. Yes, list price-that roundly dismissed figure-should become the touchstone. This would deter incentive-distorting rebate schemes while recognizing that many people already pay list price. It is a remarkably streamlined approach for cutting through a wide swath of perverse incentives and manipulations.


In situ estimation of sediment sound speed and critical angle
Understanding the basic physics of sound penetration into ocean sediments is essential for the design of sonar systems that can detect, localize, classify, and identify buried objects. In this regard the sound speed of the sediment is a crucial parameter as the ratio of sound speed at the water-sediment interface determines the critical angle. Sediment sound speed is typically measured from core samples using high frequency (100's of kHz) pulsed travel time measurements. Earlier experimental work on subcritical penetration into sandy sediments has suggested that the effective sound speed in the 2-20 kHz range is significantly lower than the core measurement results. Simulations using Biot theory for propagation in porous media confirmed that sandy sediments may be highly dispersive in the range 1-100 kHz for the type of sand in which the experiments were performed. Here it is shown that a direct and robust estimate of the critical angle, and therefore the sediment sound speed, at the lower frequencies can be achieved by analyzing the grazing angle dependence of the phase delays observed on a buried array. A parametric source with secondary frequencies in the 2-16 kHz range was directed toward a sandy bottom similar to the one investigated in the earlier study. An array of 14 hydrophones was used to measure penetrated field. The critical angle was estimated by analyzing the variations of signal arrival times versus frequency, burial depth, and grazing angle. Matching the results with classical transmission theory yielded a sound speed estimate in the sand of 1626 m/s in the frequency range 2-5 kHz, again significantly lower the 1720 m/s estimated from the cores at 200 kHz. However, as described here, this dispersion is consistent with the predictions of the Biot theory for this type of sand.


Multidimensional evaluation of changes in limb function following botulinum toxin injection in persons with stroke.
There are limited evidence of instrumented measures of gait and balance to determine the functional effects of botulinum toxin injections (BoNT-A) in spasticity after stroke. To evaluate the functional changes in gait and balance following upper limb and lower limb BoNT-A in persons with stroke. A pre-post prospective study of 35 stroke patients with upper and/or lower limb spasticity after focal treatment with BoNT-A. Assessments were at baseline (T0), 6-weeks (T1) and 12-weeks (T2), using validated subjective and objective physical activity measures. After BoNT-A injections, significant improvements in most measures of impairments, activity and participation domains were found at T1 (p < 0.05, effect sizes (r) = 0.5-0.9). There was a significant increase in low intensity physical activity (at T1) and sedentary time reductions at both follow-up periods. Instrumented gait/balance measures showed a significant increase in cadence and turn velocity, but no changes in sway measures were found using posturography. Improvements in most outcome measures were maintained at 12-weeks. BONT-A improved scores in most clinical measures but only in some of the objective gait/balance and physical activity measures. Further robust studies should utilize a larger sample size to better determine the benefits of BoNT-A for stroke-related spasticity.


Improved Cathepsin Probes for Sensitive Molecular Imaging.
Cysteine cathepsin proteases are found under normal conditions in the lysosomal compartments of cells, where they play pivotal roles in a variety of cellular processes such as protein and lipid metabolism, autophagy, antigen presentation, and cell growth and proliferation. As a consequence, aberrant localization and activity contribute to several pathologic conditions such as a variety of malignancies, cardiovascular diseases, osteoporosis, and other diseases. Hence, there is a resurgence of interest to expand the toolkit to monitor intracellular cathepsin activity and better ascertain their functions under these circumstances. Previous fluorescent activity-based probes (ABPs) that target cathepsins B, L, and S enabled detection of their activity in intact cells as well as non-invasive detection in animal disease models. However, their binding potency is suboptimal compared to the cathepsin inhibitor on which they were based, as the P1 positive charge was capped by a reporter tag. Here, we show the development of an improved cathepsin ABP that has a P1 positive charge by linking the tag on an additional amino acid at the end of the probe. While enhancing potency towards recombinant cathepsins, the new probe had reduced cell permeability due to additional peptide bonds. At a second phase, the probe was trimmed; the fluorophore was linked to an extended carbobenzoxy moiety, leading to enhanced cell permeability and superb detection of cathepsin activity in intact cells. In conclusion, this work introduces a prototype design for the next generation of highly sensitive ABPs that have excellent detection of cellular cathepsin activity.


Why have Non-communicable Diseases been Left Behind?
Non-communicable diseases are no longer largely limited to high-income countries and the elderly. The burden of non-communicable diseases is rising across all country income categories, in part because these diseases have been relatively overlooked on the global health agenda. Historically, communicable diseases have been prioritized in many countries as they were perceived to constitute the greatest disease burden, especially among vulnerable and poor populations, and strategies for prevention and treatment, which had been successful in high-income settings, were considered feasible and often affordable in low-income settings. This prioritization has reduced the communicable diseases burden globally but has left non-communicable diseases largely neglected. A new approach is urgently needed to tackle non-communicable diseases. Based on an analysis of potential features which may have underlain the different approaches to non-communicable diseases and communicable diseases until now, including acuity of disease, potential for control or cure, cost, infectiousness, blaming of individuals and logistical barriers, little ethical or rational justification can be found to support continued neglect of non-communicable diseases. Justice demands access to quality and affordable care for all. An equitable approach to non-communicable diseases is therefore strongly mandated on medical, ethical, economic, and public health grounds. Funding must not however be diverted away from communicable diseases, which continue to require attention-but concomitantly, funding for non-communicable diseases must be increased. International and multi-sectoral action is required to accelerate progress towards true universal health coverage and towards achievement of all of the sustainable development goals, such that prevention and access to care for non-communicable disease can become a global reality.


Penumbral thoughts: Contents of consciousness upon waking.
Thoughts shape our experience, choice, and behaviour throughout the day. Yet the content of 'penumbral thoughts'-first thoughts upon waking-has received very little research attention. Across seven independent samples (total N = 829), we used recall and reflection methods, solicited the same day, to understand what individuals think as they regain consciousness. These penumbral thoughts show remarkable thematic consistency: individuals were most likely to reflect on their somatic or psychological state, focus on temporal orientation, and prioritise waking actions. Survey results demonstrate that temporal and spatial orientation are dominated by the current time and the day ahead, rather than the past or other future timescales. Our results provide some insight into the order of priority in consciousness. We conclude that establishing one's temporal position is important to the daily process of 'rebooting' conscious awareness.


Race and medication adherence and glycemic control: findings from an operational health information exchange.
The Central Indiana Beacon Community leads efforts for improving adherence to oral hypoglycemic agents (OHA) to achieve improvements in glycemic control for patients with type 2 diabetes. In this study, we explored how OHA adherence affected hemoglobin A1C (HbA1c) level in different racial groups. OHA adherence was measured by 6-month proportion of days covered (PDC). Of 3,976 eligible subjects, 12,874 pairs of 6-month PDC and HbA1c levels were formed between 2002 and 2008. The average HbA1c levels were 7.4% for African-Americans and 6.5% for Whites. The average 6-month PDCs were 40% for African-Americans and 50% for Whites. In mixed effect generalized linear regression analyses, OHA adherence was inversely correlated with HbA1c level for both African-Americans (-0.80, p<0.0001) and Whites (-0.53, p<0.0001). The coefficient was -0.26 (p<0.0001) for the interaction of 6-month PDC and African-Americans. Significant risk factors for OHA non-adherence were race, young age, non-commercial insurance, newly-treated status, and polypharmacy.


A panel study in congestive heart failure to estimate the short-term effects from personal factors and environmental conditions on oxygen saturation and pulse rate.
Recent studies suggest that persons with congestive heart failure (CHF) may be at higher risk for short-term effects of air pollution. This daily diary panel study in Montreal, Quebec, was carried out to determine whether oxygen saturation and pulse rate were associated with selected personal factors, weather conditions and air pollution. Thirty-one subjects with CHF participated in this study in 2002 and 2003. Over a 2-month period, the investigators measured their oxygen saturation, pulse rate, weight and temperature each morning and recorded these and other data in a daily diary. Air pollution and weather conditions were obtained from fixed-site monitoring stations. The study made use of mixed regression models, adjusting for within-subject serial correlation and temporal trends, to determine the association between oxygen saturation and pulse rate and personal and environmental variables. Depending on the model, we accounted for the effects of a variety of personal variables (eg, body temperature, salt consumption) as well as nitrogen dioxide (NO2), ozone, maximum temperature and change in barometric pressure at 8:00 from the previous day. In multivariable analyses, the study found that oxygen saturation was reduced when subjects reported that they were ill, consumed salt, or drank liquids on the previous day and had higher body temperatures on the concurrent day (only the latter was statistically significant). Relative humidity and decreased atmospheric pressure from the previous day were associated with oxygen saturation. In univariate analyses, there was negative associations with concentrations of fine particulates, ozone, and sulphur dioxide (SO2), but only SO2 was significant after adjustment for the effects of weather. For pulse rate, no associations were found for the personal variables and in univariate analyses the study found positive associations with NO(2), fine particulates (aerodynamic diameter of 2.5 microm or under, PM(2.5)), SO2, and maximum temperature, although only the latter two were significant after adjustment for environmental effects. The findings from the present investigation suggest that personal and environmental conditions affect intermediate physiological parameters that may affect the health of CHF patients.


Cardiac hypertrophy induced by active Raf depends on Yorkie-mediated transcription.
Organ hypertrophy can result from enlargement of individual cells or from cell proliferation or both. Activating mutations in the serine-threonine kinase Raf cause cardiac hypertrophy and contribute to Noonan syndrome in humans. Cardiac-specific expression of activated Raf also causes hypertrophy in Drosophila melanogaster. We found that Yorkie (Yki), a transcriptional coactivator in the Hippo pathway that regulates organ size, is required for Raf-induced cardiac hypertrophy in flies. Although aberrant activation of Yki orthologs stimulates cardiac hyperplasia in mice, cardiac-specific expression of an activated mutant form of Yki in fruit flies caused cardiac hypertrophy without hyperplasia. Knockdown of Yki caused cardiac dilation without loss of cardiomyocytes and prevented Raf-induced cardiac hypertrophy. In flies, Yki-induced cardiac hypertrophy required the TEA domain-containing transcription factor Scalloped, and, in mammalian cells, expression of mouse Raf(L613V), an activated form of Raf with a Noonan syndrome mutation, increased Yki-induced Scalloped activity. Furthermore, overexpression of Tgi (a Tondu domain-containing Scalloped-binding corepressor) in the fly heart abrogated Yki- or Raf-induced cardiac hypertrophy. Thus, crosstalk between Raf and Yki occurs in the heart and can influence Raf-mediated cardiac hypertrophy.


Clinical profile of dengue haemorrhagic fever from Jan 2009 to Dec 2009 in and around Aurangabad.
In present study 890 serum samples suspected of dengue fever on clinical grounds were received in department of Microbiology. Out of these 249 cases showed thrombocytopenia (platelet count < 1 lakh/cumm) and were subjected to rapid dengue serological test as well as IgM capture ELISA. 11(4%) cases were diagnosed as primary dengue infection (only IgM positive) by rapid dengue IgG/IgM bispot immunocomb test. There were 123(49%) cases with only IgG positive suggesting secondary/past dengue infection. Both IgM and IgG were seen in 24(10%) cases. Number of cases negative for both IgM and IgG were 91(37%). IgM positive cases were confirmed by IgM capture ELISA. Classical dengue fever (DF) was noted in 168 (67%) patients and dengue hemorrhagic fever (DHF) in 81(33%) cases. Common clinical presentations of DHF were fever 78 (96%), body-ache 74 (91%), arthralgia 74 (91%), retro-orbital pain 65 (80%), abdominal pain 07 (09%). Bleeding manifestation were in the form of petechiae, melena, epistaxis, hematuria, hemoptysis, hematemesis, bleeding gums and conjunctival hemorrhages. Out of 81 DHS patients 13 (16%) patients had platelet count between 50,000 and 1 lakh. 68 (84%) patients had platelet count below 50,000. Majority of these patients 47 (58%) had platelet below 20000 and were IgG positive. Thrombocytopenia correlated well with bleeding manifestations in our patients. In an epidemic setting if the patients present with fever, vomiting, musculoskeletal pain and bleeding along with low platelet count a strong possibility of DHF/DSS should be kept.


Study of orthoexciton-to-paraexciton conversion in Cu(2)O by excitonic Lyman spectroscopy.
Using time-resolved 1s-2p excitonic Lyman spectroscopy, we study the orthoexciton-to-paraexciton transfer, following the creation of a high density population of ultracold 1s orthoexcitons by resonant two-photon excitation with femtosecond pulses. An observed fast exciton-density dependent conversion rate is attributed to spin exchange between pairs of orthoexcitons. Implication of these results on the feasibility of Bose-Einstein condensation of paraexcitons in Cu(2)O is discussed.


The NAB-Brk signal bifurcates at JNK to independently induce apoptosis and compensatory proliferation.
Apoptosis operates to eliminate damaged or potentially dangerous cells. This loss is often compensated by extra proliferation of neighboring cells. Studies in Drosophila imaginal discs suggest that the signal for the additional growth emanates from the dying cells. In particular, it was suggested that the initiator caspase Dronc mediates compensatory proliferation (CP) through Dp53 in wing discs. However, the exact mechanism that governs this CP remained poorly understood. We have previously shown that elimination of misspecified cells due to reduced Dpp signaling is achieved by the interaction of the co-repressor NAB with the transcriptional repressor Brk, which in turn induces Jun N-terminal kinase-dependent apoptosis. Here, we performed a systematic in vivo loss- and gain-of-function analysis to study NAB-induced death and CP. Our findings indicate that the NAB primary signal activates JNK, which in turn transmits two independent signals. One triggers apoptosis through the pro-apoptotic proteins Reaper and Hid, which in turn promote activation of caspases by the apoptosome components Ark and Dronc. The other signal induces CP in a manner that is independent of the death signal, Dronc, or Dp53. Once induced, the apoptotic pathway further activates a CP response. Our data suggest that JNK is the candidate factor that differentiates between apoptosis that involves CP and apoptosis that does not.


[Primary isolated amyloidosis--a rare corneal degeneration].
Report on a 47-year-old woman patient in whom an eccentric tumorlike corneal change was found in the left eye. Only after penetrating keratoplasty was the exact diagnosis--a primary isolated corneal amyloidosis--established, by light microscopic examination. The graft remained clear. Familial and systemic amyloidosis were ruled out by further examinations. The prognosis is favorable.


Autonomous decision-making: a data mining approach.
The researchers and practitioners of today create models, algorithms, functions, and other constructs defined in abstract spaces. The research of the future will likely be data driven. Symbolic and numeric data that are becoming available in large volumes will define the need for new data analysis techniques and tools. Data mining is an emerging area of computational intelligence that offers new theories, techniques, and tools for analysis of large data sets. In this paper, a novel approach for autonomous decision-making is developed based on the rough set theory of data mining. The approach has been tested on a medical data set for patients with lung abnormalities referred to as solitary pulmonary nodules (SPNs). The two independent algorithms developed in this paper either generate an accurate diagnosis or make no decision. The methodolgy discussed in the paper depart from the developments in data mining as well as current medical literature, thus creating a variable approach for autonomous decision-making.


Permanent rescue of a non-Mendelian mutation of Paramecium by microinjection of specific DNA sequences.
The mutant Paramecium tetraurelia cell line d48 is unable to express the serotype A protein on its surface. Although the A gene is intact in the micronuclei of d48, the A gene copies in the macronucleus contain a large deletion eliminating virtually the entire coding sequence. Previous studies showed that microinjection of a plasmid containing the entire A gene into the macronucleus of d48 permanently restored A expression after autogamy. Together with other data, this result suggests that in wild type cells the A gene in the old macronucleus ensures the presence of a cytoplasmic factor that prevents A gene deletions at autogamy. In d48, where there are few, if any copies of the intact A gene in the old macronucleus, deletions occur during macronuclear formation. To elucidate the specific molecular mechanisms involved in this unusual phenomenon, we attempted to define the region(s) of the A gene necessary for rescuing d48. We show that microinjection of a 4.5-kb internal A gene fragment is sufficient for proper processing at autogamy and leads to permanent rescue of d48; i.e., the rescued strain is indistinguishable from wild type. Thus, rescue of d48 does not require upstream transcriptional control sequences, intact A mRNA or A serotype protein. We also show that various fragments of the A gene have the ability to rescue d48 to different extents, some being more efficient than others. We find no evidence to suggest that the A gene gives rise to a small stable RNA that might act as or encode a cytoplasmic factor. Molecular mechanisms that may be involved in the rescue of d48 are discussed.


Variable linear polarization from an X-ray undulator.
A new X-ray undulator has been designed and constructed which produces linearly polarized X-rays in which the plane of polarization can be oriented to a user selectable angle, from horizontal to vertical. Based on the Apple-II elliptically polarizing undulator (EPU), the undulator rotates the angle of the linear polarization by a simple longitudinal motion of the undulator magnets. Combined with the circular and elliptical polarization capabilities of the EPU operating in the standard mode, this new undulator produces soft X-ray radiation with versatile polarization control. This paper describes the magnetic structure of the device and presents an analysis of the magnetic field with varying undulator parameters. The variable linear polarization capability is then exhibited by measuring the X-ray absorption spectrum of an oriented polytetrafluoroethylene thin film. This experiment, which measures the linear dichroism of the sample at two peaks near the C 1s absorption edge, demonstrates the continuous polarization rotation capabilities of the undulator.


Helicobacter pylori: Genomic Insight into the Host-Pathogen Interaction.
The advent of genomic analyses has revolutionized the study of human health. Infectious disease research in particular has experienced an explosion of bacterial genomic, transcriptomic, and proteomic data complementing the phenotypic methods employed in traditional bacteriology. Together, these techniques have revealed novel virulence determinants in numerous pathogens and have provided information for potential chemotherapeutics. The bacterial pathogen, Helicobacter pylori, has been recognized as a class 1 carcinogen and contributes to chronic inflammation within the gastric niche. Genomic analyses have uncovered remarkable coevolution between the human host and H. pylori. Perturbation of this coevolution results in dysregulation of the host-pathogen interaction, leading to oncogenic effects. This review discusses the relationship of H. pylori with the human host and environment and the contribution of each of these factors to disease progression, with an emphasis on features that have been illuminated by genomic tools.


Prevalence of cutaneous adverse effects of hairdressing: a systematic review.
To identify studies of the prevalence of cutaneous complications of hairdressing in (1) hairdressers and the general population and (2) those more common in people of African ancestry. Three versions of MEDLINE were searched from January 1966 through December 2004 and with a repeated search in August 2005 using 2 groups of search terms: group 1, terms used for hair care and specific study designs: survey, cross-sectional study, and cohort study; group 2, the terms African hair, Afro-Caribbean hair, African American hair, central centrifugal cicatricial alopecia, acne keloidalis nuchae, traction alopecia, and synonyms for each. All identified cross-sectional and cohort studies of cutaneous adverse effects were included and their quality assessed using criteria developed by Radulescu et al. Four studies used either questionnaires or patch testing to estimate the prevalence of cutaneous adverse effects of hair chemicals in the general population and found a prevalence of contact dermatitis, secondary to use of hair dye, of 5.3% and of allergy to paraphenylenediamine of 0.1% to 2.3%. Working as a hairdresser is associated with a prevalence of contact dermatitis ranging from 16.4% in larger cohort studies that included a clinical examination to 80% in the smaller, questionnaire-based studies. Three studies of people of African ancestry found a prevalence of acne keloidalis nuchae ranging from 1.3% to 13.7% and of traction alopecia of 1%. None of these were in the general population. Working as a hairdresser is associated with an increased risk of contact allergy and/or hand dermatitis. Studies of skin disorders of individuals of African ancestry are needed to quantify the health burden and clarify causal variables of these disorders. It is not clear how much the unique shape of the African hair follicle contributes to the development of these conditions.


Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles.
The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10(-15)) and rs3817963 (p = 5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.


[Ultroser-G and 5-azacytidine prolong the development of parthenogenetic mouse embryos].
We studied the effects of Ultroser-G, a substitute of embryonal serum, and 5-azacytidine, a DNA-demethylating compound, on development of diploid parthenogenetic embryos of the mouse inbred strain CBA and hybrids (CBA x C57BL/6)F1. Addition of Ultroser-G to the nutrient medium for in vitro cultivation of the embryos to a final concentration of 0.5% leads after their transplantation into the uterus of pseudopregnant females to development of parthenogenetic postimplantation embryos to a stage of 30-33 somites with the buds of fore- and hindlimbs. Additional introduction of 5-azacytidine at 0.24 mg/kg to the females on day 8 of gestation prolonged development of some parthenogenetic embryos treated with Ultroser-G during the preimplantation period to the stage of 45 somites. The control embryos developed to the stage of 25 somites. The mechanism of genomic imprinting and influence of the embryonal serum components and demethylating compounds on viability of the parthenogenetic embryos are discussed.


A Prospective Screening of HLA-B*57.01 Allelic Variant for Preventing the Hypersensivity Reaction to Abacavir: Experience from the Laboratory of Molecular Biology of the Infectious Diseases Division at the University Hospital of Salerno.
Abacavir is a nucleoside reverse transcriptase inhibitor largely used as part of the antiretroviral therapy in Human Immunodeficiency Virus (HIV)-infected patients. Some individuals (2-9%) who start an abacavir treatment show an immunologic reaction indicated as hypersensitivity reaction syndrome (HSR) that is often responsible for therapy discontinuation and could represent a life-threatening event. Some studies demonstrated a correlation between this adverse reaction and the class I of the major histocompatibility complex (MHC) allele, HLA-B*57.01, in several populations, including Caucasians. Nowadays, International HIV treatment guidelines recommend the HLA-B*57.01 genotyping before abacavir administration to reduce the incidence of HSR. Both male and female HIV-infected patients were enrolled at the Infectious Diseases Division at the University Hospital of Salerno, and admitted to a prospective HLAB*57.01 screening. Genetic analysis was carried out through two sequential Real-Time PCR reactions in which Sybr-Green was used. Out of 248 patients, 215 were Italians from Southern Italy and 33 were coming from several non-EU members countries. All were genotyped: 6 Italians (2.8%) and 1 of the non-EU group (3%) were identified as HLAB*57.01 carriers. In this paper we present our experience in the field of abacavir pharmacogenetic and confirm the importance of Real Time PCR as a valid and cost-effective HLA-B*57.01 typing methodology.


Mechanisms of Collagen Crosslinking in Diabetes and Keratoconus.
Collagen crosslinking provides the mechanical strength required for physiological maintenance of the extracellular matrix in most tissues in the human body, including the cornea. Aging and diabetes mellitus (DM) are processes that are both associated with increased collagen crosslinking that leads to increased corneal rigidity. By contrast, keratoconus (KC) is a corneal thinning disease associated with decreased mechanical stiffness leading to ectasia of the central cornea. Studies have suggested that crosslinking mediated by reactive advanced glycation end products during DM may protect the cornea from KC development. Parallel to this hypothesis, riboflavin-mediated photoreactive corneal crosslinking has been proposed as a therapeutic option to halt the progression of corneal thinning by inducing intra- and intermolecular crosslink formation within the collagen fibrils of the stroma, leading to stabilization of the disease. Here, we review the pathobiology of DM and KC in the context of corneal structure, the epidemiology behind the inverse correlation of DM and KC development, and the chemical mechanisms of lysyl oxidase-mediated crosslinking, advanced glycation end product-mediated crosslinking, and photoreactive riboflavin-mediated corneal crosslinking. The goal of this review is to define the biological and chemical pathways important in physiological and pathological processes related to collagen crosslinking in DM and KC.


A clinicopathological study of C1q nephropathy at King Abdulaziz University.
C1q nephropathy is a relatively rare idiopathic glomerulopathy characterized by mesangial immunoglobulin and complement deposits with dominance or co-dominance of C1q, with no evidence of systemic lupus erythematosus. We describe the incidence, clinical manifestation, histopathological features, and follow-up of patients with C1q nephropathy at our institute. Of 750 kidney biopsy specimens obtained in the period of January 2000 to December 2011, all the cases that meet the criteria for the diagnosis of C1q nephropathy were retrieved. The histological slides were examined and the clinical charts were reviewed by 2renal pathologists. We had 11 patients, all children, that met the criteria for the diagnosis of C1q nephropathy accounting for an incidence of 1.5%. The mean age at the time of presentation was 3.7 years and all the patients were presented with nephrotic syndrome. Two patients had microhematuria and 2 had hypertension. Histological examination of these cases showed variable degrees of mesangial cells hypercellularity and matrix expansion with focal segmental glomerulosclerosis observed in 2 cases. Nine patients were steroid resistant (82%) and 2 were steroid dependent. Six patients required immunosuppressive therapy and 1 patient developed end-stage renal disease. In our series, C1q nephropathy affected predominantly young children. Mesangioproliferative pattern was the most frequent histopathological finding in these patients. Clinically, despite steroid resistance, the patients had a relatively good outcome; the worst prognostic outcome was associated with collapsing glomerulopathy.


Interindividual Variability of Lower-Limb Motor Cortical Plasticity Induced by Theta Burst Stimulation.
Theta burst stimulation (TBS) has been used as a tool to induce synaptic plasticity and improve neurological disorders. However, there is high interindividual variability in the magnitude of the plastic changes observed after TBS, which hinders its clinical applications. The electric field induced by transcranial magnetic stimulation (TMS) is strongly affected by the depth of the stimulated brain region. Therefore, it is possible that the variability in the response to TBS over the lower-limb motor cortex is different for the hand area. This study investigated the variability of TBS-induced synaptic plasticity in the lower-limb motor cortex, for intermittent TBS (iTBS), continuous TBS (cTBS), and sham iTBS, in 48 healthy young participants. The motor cortical and intracortical excitability of the tibialis anterior was tested before and after TBS using TMS. The results showed that iTBS had facilitatory effects on motor cortex excitability and intracortical inhibition, whereas cTBS exerted opposite effects. Twenty-seven percent of individuals exhibited enhanced motor cortical plasticity after iTBS, whereas 63% of participants showed enhanced plasticity after cTBS. In addition, the amount of TBS-induced plasticity was correlated with the intracortical excitability and the variability of the motor evoked potential prior to TBS. Our study demonstrated the high variability of the iTBS-induced lower-limb motor cortical plasticity, which was affected by the sensitivity of intracortical interneuronal circuits. These findings provide further insights into the variation of the response to TBS according to the anatomy of the stimulated brain region and the excitability of the intracortical circuit.


GCNA-cluster: A Gene Co-expression Network Alignment to Cluster Cancer Patients Algorithm for Identifying Subtypes of Pancreatic Ductal Adenocarcinoma.
Cancer heterogeneity makes it necessary to use different treatment strategies for patients with the same pathological features. Accurate identification of cancer subtypes is a crucial step in this approach. The current studies of pancreatic ductal adenocarcinoma (PDAC) subtypes mainly focus on single genes and ignore the synergistic effects of genes. Here we proposed a network alignment algorithm GCNA-cluster to cluster patients based on gene co-expression networks. We constructed weighted gene co-expression networks for patients and aligned the networks of two patients to estimate the similarity of patients and their cancer subtypes. A scoring function is defined to measure the network alignment result and the score can indicate the similarity between patients. Then, the patients are clustered based on their similarities. We validated the accuracy of the algorithm on the GEO-PDAC dataset with real labels, and the experimental results show that the GCNA-cluster algorithm has better results than classical cancer subtyping algorithms. In addition, the GCNA-cluster algorithm applied to the TCGA-PDAC dataset identified two subtypes based on the Silhouette Coefficient. Biomarkers identified for the PDAC subtypes hint to cell growth, cell cycle or apoptosis as targets for new therapeutic strategies.


The modified biochar from wheat straw by the combined composites of MnFe2O4 nanoparticles and chitosan Schiff base for enhanced removal of U(VI) ions from aqueous solutions.
In the last few decades, U(VI) is a significant environmental threat. The innovative and environmentally friendly adsorbent materials for U(VI) removal were urgent. Preparation of the modified biochar from wheat straw by combined composites of MnFe2O4 nanoparticles and chitosan Schiff base (MnFe2O4@CsSB/BC) was characterized, and adsorption experiments were carried out to investigate the performance and interfacial mechanism of U(VI) removal. The results showed that MnFe2O4@CsSB/BC exhibited high adsorption capacity of U(VI) compared with BC. The adsorption process of U(VI) removal by MnFe2O4@CsSB/BC could be ascribed as pseudo-second-order model and Langmuir model. The maximum adsorption capacity of U(VI) removal by MnFe2O4@CsSB/BC reached 19.57 mg/g at pH4.0, 30 mg/L of U(VI), and 25 °C. The possible mechanism was a chemical adsorption process, and it mainly contained electrostatic attraction and surface complexation. Additionally, it also was an economic and environmental friendly adsorbent.


Microstructural matrix-crystal interactions in calcium oxalate monohydrate kidney stones.
The role of the proteinaceous matrix in the formation of calcium oxalate kidney stones is still not well understood. Simple scanning electron microscopy (SEM) has been of somewhat limited value in visualizing the organic and inorganic microstructure due to difficulties in obtaining detailed structural information for cut or fractured surfaces. To help clarify matrix-crystal microstructure, serial sections from 10-20 mm calcium oxalate calculi were partially demineralized with ethylenediamine tetraacetic acid (EDTA) and examined by SEM. Sections etched by EDTA showed a radial crystal structure composed of "microcrystal" subunits. Sections simultaneously EDTA etched and fixed with glutaraldehyde to insolubilize all matrix mucoprotein showed interesting forms of matrix structure: an amorphous sometimes membrane-like material, and a fibrous material that exhibited an apparent affinity for the inorganic crystalline phase. These observations give evidence for a more important etiological and structural role for the matrix than may be suggested by the relatively low matrix concentration in stones (2-6 wt. %).


Obstructive Jaundice with skin involvement - An unusual presentation of Myeloid Sarcoma.
Biliary obstruction secondary to malignancy is a common clinical problem. Rarely, biliary obstruction is due to leukemia, and obstructive jaundice in these patients usually presents late in the course of the disease. We present a rare case of a patient who presented with fever, jaundice, and pruritus with multiple nodular swellings in the left shoulder, left thigh, and lower back. Magnetic resonance cholangiopancreatography (MRCP) revealed periampullary mass lesion causing dilated common bile duct (CBD) and intrahepatic bile ducts; hence, endoscopic retrograde cholangiography with plastic stenting was done. Biopsy from the shoulder lesion revealed a mesenchymal tumor, and immunohistochemistry (IHC) confirmed the lesion as myeloid sarcoma. Myeloid sarcoma is an extramedullary tumor, a subtype of acute myeloid leukemia, and presentation as biliary lesions with multiple anatomical sites is very rare. The patient was started on chemotherapy after the normalization of bilirubin. The patient showed improvement of skin lesions and normalization of liver function test (LFT) after 3 weeks of chemotherapy.


FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity.
Bile acids are ligands for the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. We have shown that FXR and TGR5 have renoprotective roles in diabetes- and obesity-related kidney disease. Here, we determined whether these effects are mediated through differential or synergistic signaling pathways. We administered the FXR/TGR5 dual agonist INT-767 to DBA/2J mice with streptozotocin-induced diabetes, db/db mice with type 2 diabetes, and C57BL/6J mice with high-fat diet-induced obesity. We also examined the individual effects of the selective FXR agonist obeticholic acid (OCA) and the TGR5 agonist INT-777 in diabetic mice. The FXR agonist OCA and the TGR5 agonist INT-777 modulated distinct renal signaling pathways involved in the pathogenesis and treatment of diabetic nephropathy. Treatment of diabetic DBA/2J and db/db mice with the dual FXR/TGR5 agonist INT-767 improved proteinuria and prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis. INT-767 exerted coordinated effects on multiple pathways, including stimulation of a signaling cascade involving AMP-activated protein kinase, sirtuin 1, PGC-1α, sirtuin 3, estrogen-related receptor-α, and Nrf-1; inhibition of endoplasmic reticulum stress; and inhibition of enhanced renal fatty acid and cholesterol metabolism. Additionally, in mice with diet-induced obesity, INT-767 prevented mitochondrial dysfunction and oxidative stress determined by fluorescence lifetime imaging of NADH and kidney fibrosis determined by second harmonic imaging microscopy. These results identify the renal signaling pathways regulated by FXR and TGR5, which may be promising targets for the treatment of nephropathy in diabetes and obesity.


Tocilizumab in patients with severe COVID-19: a retrospective cohort study.
No therapy is approved for COVID-19 pneumonia. The aim of this study was to assess the role of tocilizumab in reducing the risk of invasive mechanical ventilation and death in patients with severe COVID-19 pneumonia who received standard of care treatment. This retrospective, observational cohort study included adults (≥18 years) with severe COVID-19 pneumonia who were admitted to tertiary care centres in Bologna and Reggio Emilia, Italy, between Feb 21 and March 24, 2020, and a tertiary care centre in Modena, Italy, between Feb 21 and April 30, 2020. All patients were treated with the standard of care (ie, supplemental oxygen, hydroxychloroquine, azithromycin, antiretrovirals, and low molecular weight heparin), and a non-randomly selected subset of patients also received tocilizumab. Tocilizumab was given either intravenously at 8 mg/kg bodyweight (up to a maximum of 800 mg) in two infusions, 12 h apart, or subcutaneously at 162 mg administered in two simultaneous doses, one in each thigh (ie, 324 mg in total), when the intravenous formulation was unavailable. The primary endpoint was a composite of invasive mechanical ventilation or death. Treatment groups were compared using Kaplan-Meier curves and Cox regression analysis after adjusting for sex, age, recruiting centre, duration of symptoms, and baseline Sequential Organ Failure Assessment (SOFA) score. Of 1351 patients admitted, 544 (40%) had severe COVID-19 pneumonia and were included in the study. 57 (16%) of 365 patients in the standard care group needed mechanical ventilation, compared with 33 (18%) of 179 patients treated with tocilizumab (p=0·41; 16 [18%] of 88 patients treated intravenously and 17 [19%] of 91 patients treated subcutaneously). 73 (20%) patients in the standard care group died, compared with 13 (7%; p<0·0001) patients treated with tocilizumab (six [7%] treated intravenously and seven [8%] treated subcutaneously). After adjustment for sex, age, recruiting centre, duration of symptoms, and SOFA score, tocilizumab treatment was associated with a reduced risk of invasive mechanical ventilation or death (adjusted hazard ratio 0·61, 95% CI 0·40-0·92; p=0·020). 24 (13%) of 179 patients treated with tocilizumab were diagnosed with new infections, versus 14 (4%) of 365 patients treated with standard of care alone (p<0·0001). Treatment with tocilizumab, whether administered intravenously or subcutaneously, might reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia. None.


Anesthetic Care of a Child With Acute Flaccid Myelitis.
Acute flaccid myelitis (AFM) is a neurological disorder that affects the anterior horn of the spinal cord, resulting in progressive weakness, loss of motor function, hypotonia and hyporeflexia. Given the progressive and frequently long-term neurological involvement of AFM, patients may require anesthetic care during radiological imaging or other surgical procedures, such as a tracheostomy or the placement of a gastrostomy tube. We present a 4-year-old girl with AFM who required anesthetic care during a tracheostomy. The end-organ involvement of the disease is discussed, pathogenesis and treatment options are reviewed and anesthetic implications are presented.


Absence of anxiolytic response to chlordiazepoxide in two common background strains exposed to the elevated plus-maze: importance and implications of behavioural baseline.
Although genetic background is acknowledged as a potentially important determinant of mutant phenotypes, publications on genetically modified mice far outnumber those on progenitor strains. We have recently reported major differences in basal anxiety levels (elevated plus-maze & light/dark exploration) among three strains (C57BL/6JOlaHsd, 129/SvEv and 129S2/SvHsd) employed as progenitor stock in European laboratories (Rodgers et al. in press). Furthermore, the phenotypes of these inbred strains differed significantly from that of an outbred strain (Swiss-Webster) commonly used in behavioural pharmacology. In view of these findings, the present study assessed possible differences in the anxiolytic efficacy of chlordiazepoxide (0, 7.5 & 15.0 mg/kg, IP) in three of these strains (Swiss-Webster (SW), C57BL/6JOIaHsd (C57) & 129S2/SvHsd (129)). Experimentally naive mice were exposed to the elevated plus-maze, sessions were videotaped and behaviour analysed using ethological software. The performance of control subjects confirmed significant strain differences in basal levels of activity (SW > C57 > 129) and anxiety-related behaviours (129 = SW > C57), with hypolocomotion dominating the 129 profile. SW mice displayed an anxioselective response to both doses of chlordiazepoxide (CDP), with significant reductions in open arm avoidance and risk assessment observed in the absence of any change in general activity. In direct contrast, the lower dose of CDP (7.5 mg/kg) was without effect in either inbred strain, whereas treatment with 15.0 mg/kg induced a profile indicative of muscle relaxation/mild sedation in C57 mice and virtually abolished all behavioural activity in 129 mice. Although the absence of an anxiolytic response to CDP in C57 mice may be attributed to their low basal anxiety levels, the profile of 129 mice strongly suggests an abnormality in benzodiazepine/GABAA receptor function. The implications of these findings for research on mutant mice are discussed.


The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation.
Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype. We found that Per2(Brdm1) mutant mice as well as mice lacking Cry2(-/-) displayed significantly increased bone volume at 12 weeks of age, when bone turnover is high. Per2(Brdm1) mutant mice showed alterations in parameters specific for osteoblasts whereas mice lacking Cry2(-/-) displayed changes in osteoclast specific parameters. Interestingly, inactivation of both Per2 and Cry2 genes leads to normal bone volume as observed in wild type animals. Importantly, osteoclast parameters affected due to the lack of Cry2, remained at the level seen in the Cry2(-/-) mutants despite the simultaneous inactivation of Per2. This indicates that Cry2 and Per2 affect distinct pathways in the regulation of bone volume with Cry2 influencing mostly the osteoclastic cellular component of bone and Per2 acting on osteoblast parameters.


Adherence to pharmacological thromboprophylaxis orders in hospitalized patients.
We compared adherence to unfractionated heparin (UFH) 2 or 3 times daily prophylaxis orders versus low-molecular-weight heparin (LMWH) once daily orders. Our goals were to determine which strategy demonstrated the best adherence in terms of timing and frequency of dose administration, and to determine reasons for ordered heparin not being administered. We queried our electronic medication administration record where nurses document reasons for delayed administration or omitted doses. We identified 250 consecutive patients who were prescribed prophylaxis with UFH 2 or 3 times daily or LMWH once daily. We followed patients for their hospitalization to determine adherence to physicians' prophylaxis orders. Adherence, defined as the ratio of prophylaxis doses given to doses ordered, was greater with LMWH (94.9%) than UFH 3 times daily (87.8%) or UFH twice daily (86.8%) regimens (P <.001). Patients receiving LMWH more often received all of their scheduled prophylaxis doses (77%) versus UFH 3 times daily (54%) or UFH twice daily (45%) (P <.001). There were no differences between regimens regarding reasons for omitted doses. The most common reason for late or omitted doses was patient refusal, which explained 44% of the UFH and 39% of the LMWH orders that were not administered. LMWH once a day had better adherence than UFH 2 or 3 times daily. For both LMWH and UFH, patient refusal was the most common reason for not administering prophylaxis as prescribed. These findings require consideration when evaluating pharmacological prophylaxis strategies. Educational programs, explaining the rationale, may motivate patients to improve adherence during hospitalization.


Low-threshold nanolasers based on miniaturized bound states in the continuum.
The pursuit of compact lasers with low thresholds has imposed strict requirements on tight light confinements with minimized radiation losses. Bound states in the continuum (BICs) have been recently demonstrated as an effective mechanism to trap light. However, most reported BIC lasers are still bulky due to the absence of in-plane light confinement. Here, we combine BICs and photonic bandgaps to realize three-dimensional light confinements, as referred to miniaturized BICs (mini-BICs). We demonstrate highly compact active mini-BIC resonators with a record high-quality (Q) factor of up to 32,500, which enables single-mode lasing with the lowest threshold of 80 W/cm2 among the reported BIC lasers. In addition, photon statistics measurements further confirm the occurrence of the stimulated emission in our devices. Our work reveals a path toward compact BIC lasers with ultralow power consumption and potentially boosts the applications in cavity quantum electrodynamics, nonlinear optics, and integrated photonics.


SS-HCNN: Semi-Supervised Hierarchical Convolutional Neural Network for Image Classification.
The availability of large-scale annotated data and uneven separability of different data categories become two major impediments of deep learning for image classification. In this paper, we present a Semi-Supervised Hierarchical Convolutional Neural Network (SS-HCNN) to address these two challenges. A large-scale unsupervised maximum margin clustering technique is designed, which splits images into a number of hierarchical clusters iteratively to learn cluster-level CNNs at parent nodes and category-level CNNs at leaf nodes. The splitting uses the similarity of CNN features to group visually similar images into the same cluster, which relieves the uneven data separability constraint. With the hierarchical cluster-level CNNs capturing certain high-level image category information, the category-level CNNs can be trained with a small amount of labelled images, and this relieves the data annotation constraint. A novel cluster splitting criterion is also designed which automatically terminates the image clustering in the tree hierarchy. The proposed SS-HCNN has been evaluated on the CIFAR-100 and ImageNet classification datasets. Experiments show that the SS-HCNN trained using a portion of labelled training images can achieve comparable performance with other fully trained CNNs using all labelled images. Additionally, the SS-HCNN trained using all labelled images clearly outperforms other fully trained CNNs.


A survey of Fusobacterium nucleatum genes modulated by host cell infection.
Here, we report comprehensive transcriptomic profiles from Fusobacterium nucleatum under conditions that mimic the first stages of bacterial infection in a highly differentiated adenocarcinoma epithelial cell line. Our transcriptomic in vitro adenocarcinoma approach allows us to measure the expression dynamics and regulation of bacterial virulence and response factors in real time, and is a novel strategy for clarifying the role of F. nucleatum infection in colorectal cancer (CRC) progression. Our data show that: (i) infection alters metabolic and functional pathways in F. nucleatum, allowing the bacterium to adapt to the host-imposed milieu; (ii) infection also stimulates the expression of genes required to help induce and promote a hypoxic and inflammatory microenvironment in the host; and (iii) F. nucleatum invasion occurs by a haematogenous route of infection. Our study identifies novel gene targets from F. nucleatum that are activated during invasion and which may aid in determining how this species invades and promotes disease within the human gastrointestinal tract. These invasion-specific genes may be useful as biomarkers for CRC progression in a host and could also assist in the development of new diagnostic tools and treatments (such as vaccines or small molecule drug targets), which will be able to combat infection and inflammation in the host while circumventing the potential problem of F. nucleatum tolerization.


Toward Multiscale Modeling of Proteins and Bioagglomerates: An Orientation-Sensitive Diffusion Model for the Integration of Molecular Dynamics and the Discrete Element Method.
Most processes involved in biological and biotechnological systems spread over many scales in space and time. For example, the interaction of multiple enzymes in heterogeneous enzymatic agglomerates or clusters, necessary for efficient enzymatic conversion, is of high interest for research and enzyme engineering. In order to understand and predict their overall behavior and performance, it is important to describe these scales as completely as possible, known as multiscale modeling. While many different approaches have been presented in recent years, knowledge about protein formation and bioagglomeration at the micro scale is still very limited. In an attempt to address such systems, we propose a bottom- up multiscale modeling methodology, bridging the gaps between molecular dynamics (MD) with an explicit solvent and the larger scale discrete element method (DEM) using an implicit solvent and abstracting macromolecules (e.g., proteins) as objects with anisotropic properties. We term this approach the molecular discrete element method (MDEM). For this, we present an orientation-sensitive diffusion model for DEM, which describes the dynamics of anisotropic translational and rotational diffusion, while implicitly considering solvent molecules and enforcing a canonical ensemble. A general-purpose model and parametrization approach is presented, which can be used to simulate any process involving diffusion of discrete particles. Effects of temperature and viscosity changes can be considered, and guidance is provided concerning time step selection. This model is generally applicable and serves as a precondition to enforce the proper dynamics (i.e., diffusion characteristics and canonical ensemble, similar to a thermostat in MD) for the proposed multiscale modeling methodology with anisotropic properties. Thereby, it presents a first step toward modeling at the micro scale and is integral to enforcing dynamics of such systems and therefore extensively validated. As a next step, interaction models are to be defined and added to the presented model. In comparison to atomistic and coarse-grained (CG) MD, a speedup of 5-7 orders of magnitude can be achieved. The approach is demonstrated on multiple components of the pyruvate dehydrogenase enzyme complex, a multienzymatic machinery that involves very different types of enzymes and is of high value to further elucidate the mechanisms of bioagglomeration and metabolic channeling.


Building a Sustainable Primary Care Workforce: Where Do We Go from Here?
The article by Puffer et al in this month's JABFM confirms a high burnout rate (25%) among family physicians renewing their credentials, with a higher rate among young and female doctors. Recent reports confirm high burnout rates among general internists. Thus, mechanisms to monitor and improve worklife in primary care are urgently needed. We describe the Mini Z (for "zero burnout program") measure, designed for these purposes, and suggest interventions that might improve satisfaction and sustainability in primary care, including longer visits, clinician control of work schedules, scribe support for electronic medical record work, team-based care, and an explicit emphasis on work-home balance.


Aortic medial elastic fiber loss in acute ascending aortic dissection.
The cause of acute aortic dissection continues to be debated. One school of thought suggests that underlying aortic medial cystic necrosis is the common denominator. The purpose of the present study was to determine if there was loss and, if so, how much loss of medial elastic fibers in the ascending aorta in patients with acute aortic dissection with the entrance tear in the ascending aorta. We examined operatively excised ascending aortas in 69 patients having acute dissection with tears in the ascending aorta. Patients with previous aortotomy, healed dissection, and connective tissue disorders were excluded. The 69 patients' ages ranged from 31 to 88 years (mean 56); 49 were men and 20 were women. Loss of aortic medial elastic fibers was graded as 0 (no loss), 1+ (trace), 2+ (mild), 3+ (moderate), and 4+ (full thickness loss). Of these 69 patients, 56 (82%) had 0 or 1+ elastic fiber loss; 13 patients (18%), 2+ to 4+ loss including 4 with 2+, 6 with 3+, and 2 with 4+. Nearly all patients (97%) had a history of systemic hypertension and/or had received antihypertensive drug therapy. In conclusion, most patients (82% in this study) having acute aortic dissection with entrance tears in the ascending aorta have normal numbers or only trace loss of aortic medial elastic fibers. Thus, underlying abnormal ascending aortic structure uncommonly precedes acute dissection.


[Whole-body MRA on a rolling table platform (AngioSURF)].
Development of a technique for whole-body MR angiography based on a rolling table platform and integration of a surface coil. The developed rolling table platform AngioSURF (System for Unlimited Rolling Field-of-view) with integrated surface coil can be mounted on top of the original patient table of a Siemens Symphony System. Data acquisition was performed with a standard body array surface coil. The system was tested on three volunteers and one patient with angiographically documented vascular pathology. Data acquisition was performed with a 3D-FLASH-sequence (TR/TE 2.1/0.7 ms, flip angle: 20 degrees, FOV 40 x 40 cm, 80 partitions, matrix 512 x 420 with zero interpolation). Five data sets were collected in immediate succession during continuous injection of a paramagnetic contrast agent. Time of acquisition per data set was 10 seconds. Table repositioning was performed manually within 3 seconds. Thus the total acquisition time amounted to 72 seconds. No problems with handling occurred in any of the four cases. The excellent image quality enables detailed assessment of the displayed vascular territories. The rolling table platform with integrated surface coil (AngioSURF) allows diagnostic display of the arterial vascular system from supraaortic vessels to the distal trifurcation arteries in only 72 seconds.


Searching for Novel Biomarkers in Thymic Epithelial Tumors: Immunohistochemical Evaluation of Hippo Pathway Components in a Cohort of Thymic Epithelial Tumors.
Given the pivotal role of the Hippo pathway in different facets of tumorigenesis, which has been vigorously established in multiple heterogenous malignancies, we attempted to evaluate its potential utility as a prognostic-predictive biomarker in thymic epithelial tumors (TETs). For this purpose, we performed a comprehensive immunohistochemical analysis of four Hippo cascade components (YAP, TAZ, TEAD4 and LATS1) in a sizeable cohort of TETs and attempted to identify possible correlations of their H-score with various clinicopathological parameters. TAZ and TEAD4 displayed both cytoplasmic and nuclear immunoreactivity in almost equal frequency, with their cytoplasmic H-score being strongly associated with more aggressive high-grade tumors (type B3, thymic carcinoma) and more advanced pathological stages. On the other hand, a primarily nuclear staining pattern was encountered in both YAP and LATS1, with the YAP nuclear H-score being higher in more indolent (type A) and earlier stage tumors. Interestingly, none of the four examined factors displayed any statistically significant correlation with patient overall (OS) or disease-free survival (DFS). In summary, our results provide some initial insight into the expression profile of these core Hippo pathway components in thymic neoplasms and point towards some clear associations with tumor characteristics, which are of paramount translational-clinical research with profound implications in therapeutic targeting of this pathway in the context of precision medicine.


Laparoscopic Splenectomy of a Wandering Pelvic Splenomegaly in a Young Woman Treated in Childhood with Surgery for Diaphragmatic Hernia and Adhesiolysis for Intestinal Obstruction.
BACKGROUND Wandering spleen (WS) is a rare medical condition in which the spleen migrates from its usual position commonly to the pelvis or lower abdomen assuming an ever-wandering state. The incidence of ectopic spleen is 0.2%, with variable clinical manifestations from asymptomatic to abdominal emergency. Symptoms are most attributed to complications related to torsion, so that a nonoperative management of a WS is not advised. According to the literature, 69.5% of patients with WS need splenectomy and 78.6% need laparotomy. CASE REPORT The patient exhibited vague intermittent lower abdominal pain for 6 months due to progressive torsion of the spleen, which resulted in venous congestion. Abdominal investigation revealed a mobile intra-abdominal mass and parenchymatous consistency in the pelvis. Diagnosis by computed tomography outlined abdominal splenomegaly with abnormal position both of pancreas and stomach. Laparoscopy established a giant spleen, with a lengthened pelvic and twisty vascular pedicle. In its ectopic location, the spleen had dragged the pancreas with it, which had taken a vertical position. The classic splenic ligaments were not recognizable. Spleen was removed with median laparotomic incision. Splenectomy was performed to prevent any traumatic fractures of the spleen, a complete twist of the splenic hilum, and the onset of recurrent acute pancreatitis. CONCLUSIONS Wandering spleen is rare in patients presenting with acute abdominal pain. An approach supported by clinical findings and investigation, even considering splenectomy over splenopexy, and laparoscopy over open surgery, may solve and prevent complications and health risks.


Bifidobacterium dentium-derived y-glutamylcysteine suppresses ER-mediated goblet cell stress and reduces TNBS-driven colonic inflammation.
Endoplasmic reticulum (ER) stress compromises the secretion of MUC2 from goblet cells and has been linked with inflammatory bowel disease (IBD). Although Bifidobacterium can beneficially modulate mucin production, little work has been done investigating the effects of Bifidobacterium on goblet cell ER stress. We hypothesized that secreted factors from Bifidobacterium dentium downregulate ER stress genes and modulates the unfolded protein response (UPR) to promote MUC2 secretion. We identified by mass spectrometry that B. dentium secretes the antioxidant γ-glutamylcysteine, which we speculate dampens ER stress-mediated ROS and minimizes ER stress phenotypes. B. dentium cell-free supernatant and γ-glutamylcysteine were taken up by human colonic T84 cells, increased glutathione levels, and reduced ROS generated by the ER-stressors thapsigargin and tunicamycin. Moreover, B. dentium supernatant and γ-glutamylcysteine were able to suppress NF-kB activation and IL-8 secretion. We found that B. dentium supernatant, γ-glutamylcysteine, and the positive control IL-10 attenuated the induction of UPR genes GRP78, CHOP, and sXBP1. To examine ER stress in vivo, we first examined mono-association of B. dentium in germ-free mice which increased MUC2 and IL-10 levels compared to germ-free controls. However, no changes were observed in ER stress-related genes, indicating that B. dentium can promote mucus secretion without inducing ER stress. In a TNBS-mediated ER stress model, we observed increased levels of UPR genes and pro-inflammatory cytokines in TNBS treated mice, which were reduced with addition of live B. dentium or γ-glutamylcysteine. We also observed increased colonic and serum levels of IL-10 in B. dentium- and γ-glutamylcysteine-treated mice compared to vehicle control. Immunostaining revealed retention of goblet cells and mucus secretion in both B. dentium- and γ-glutamylcysteine-treated animals. Collectively, these data demonstrate positive modulation of the UPR and MUC2 production by B. dentium-secreted compounds.


Evaluation of patients with chronic thromboembolic pulmonary hypertension for pulmonary endarterectomy.
Pulmonary hypertension as a result of chronic thromboembolic disease (CTEPH) is potentially curable with pulmonary endarterectomy surgery. Consequently, correctly diagnosing patients with this type of pulmonary hypertension and evaluating these patients with the goal of establishing their candidacy for surgical intervention is of utmost importance. And as advancements in surgical techniques have allowed successful resection of segmental-level chronic thromboembolic disease, the number of CTEPH patients that are deemed suitable surgical candidates has expanded, making it even more important that the evaluation be conducted with greater precision. This article will review a diagnostic approach to patients with suspected chronic thromboembolic disease with an emphasis on the criteria considered in selecting patients for pulmonary endarterectomy surgery.


Immunomodulation by Bordetella pertussis: antiviral effects.
Treatment of mice by intraperitoneal inoculation of pertussis vaccine or lipopolysaccharide extracted from B. pertussis will effect resistance to rabies virus, encephalomyocarditis virus, Semliki Forest virus, and Herpes simplex virus. Our previous observations indicated that treatment of C3H/HeN (+/nu) and BDF1 mice with pertussis vaccine injected i.p. five days prior to a mouse adenovirus lethal dose i.p. challenge elicited resistance to clinical disease and death. Susceptibility returned to a portion of the test population 35 days after pertussis vaccine treatment. The pertussis vaccine induced resistance developed in athymic (nude) mice also; however, the population succumbed to infection 35 days later. Titration of pertussis vaccine with respect to induction of resistance indicated the median effective dose (ED50) was approximately 25 micrograms dry weight. This report describes the antiviral activity of acellular components extracted from pertussis vaccine. Extraction of B. pertussis cells with 1.0M NaCl and ammonium sulfate fractionation (20-40% saturation) of the extract resulted in an acellular preparation that induced resistance to lethal dose mouse adenovirus infection. The resistance inducing activity was retained after treatment of the extract with detergent (GAF Emulphogene BC 720) to remove lipopolysaccharide and adsorption to alum gel. Comparison of endotoxin content of pertussis vaccine acellular fractions, polysaccharide fraction and purified lipopolysaccharide suggested that endotoxin probably plays a role in the induction of resistance. The endotoxin content of a Emulphogene-treated preparation that protected 80% of a test population was 39 ng. The lipopolysaccharide extracted from Escherichia coli, Vibrio cholerae, Salmonella typhimurium, and Salmonella minnesota did not induce a resistant state seven days after administration; however, lipopolysaccharide extracted from B. pertussis induced a resistant state.(ABSTRACT TRUNCATED AT 250 WORDS)


Anti-TNF-alpha (infliximab) used as induction treatment in case of active proctitis in a multistep strategy followed by definitive surgery of complex anal fistulas in Crohn's disease: a preliminary report.
This study was designed to assess the healing rate of complex perianal fistulas in Crohn's disease after a multistep strategy, including induction treatment with Infliximab in case of active proctitis, followed by definitive surgery. From 2000 to 2003, all consecutive patients with complex fistulas and Crohn's disease underwent pretreatment with noncutting setons and, in case of severe recurrent fistulas or abscesses, a diverting stoma. Infliximab was added in cases of active proctitis. After definitive surgical treatment, patients were examined. Seventeen patients were included (median age, 34 (range, 22-58) years). Seven patients were treated by surgery only, and in ten patients Infliximab was added. After a median follow-up of 19 (range, 8-40) months, fistula healing was observed in 17 patients (100 percent). One patient of the Infliximab group developed a recurrent fistula (10 percent) after 24 months, and in one patient (10 percent) soiling occurred. Two patients of the surgical group developed a recurrent fistula (29 percent) and soiling occurred in two patients (29 percent). A multistep strategy followed by definitive surgery for the treatment of complex perianal fistulas in patients with Crohn's disease is a promising treatment modality. The preliminary results of this study suggest that Infliximab treatment has a beneficial additive effect in the multistep treatment followed by definitive surgery of complex anal fistulas and active proctitis in Crohn's disease.


Complete Genome Sequence of a Gram-Positive Bacterium, Leifsonia sp. Strain PS1209, a Potato Endophyte.
We report the complete and annotated genome sequence of a Gram-positive bacterium, Leifsonia sp. strain PS1209, a potato endophyte that was isolated from apparently healthy tubers of potato cultivar NY166. The circular genome is 4,091,164 bp long, with a GC content of 69.08%, containing 3,926 genes.


Simulation in ENT medical education.
Computer-based medical simulation has recently been adopted as a new method of medical education. This paper reviews the uses of medical simulation within the ENT specialty, and reports how such simulation is used in Al-Ahsa College of Medicine, Saudi Arabia. We review our use of a simulation laboratory in ENT training. Students are taught ENT anatomy using physical models, ear diseases using physical models, and ENT examination by watching video recordings, and are taught the principles of common ENT surgery using a computerised mannequin (for laryngoscopy and bronchoscopy). A haptic temporal bone surgery simulator is used for mastoidectomy and functional endoscopic sinus surgery training, and a mannequin for cricothyrotomy and tracheotomy training. The use of such simulation methods has greatly improved our students' perception and comprehension.


Variable Impedance Control of Powered Knee Prostheses Using Human-Inspired Algebraic Curves.
Achieving coordinated motion between transfemoral amputee patients and powered prosthetic joints is of paramount importance for powered prostheses control. In this article, we propose employing an algebraic curve representation of nominal human walking data for a powered knee prosthesis controller design. The proposed algebraic curve representation encodes the desired holonomic relationship between the human and the powered prosthetic joints with no dependence on joint velocities. For an impedance model of the knee joint motion driven by the hip angle signal, we create a continuum of equilibria along the gait cycle using a variable impedance scheme. Our variable impedance-based control law, which is designed using the parameter-dependent Lyapunov function framework, realizes the coordinated hip-knee motion with a family of spring and damper behaviors that continuously change along the human-inspired algebraic curve. In order to accommodate variability in the user's hip motion, we propose a computationally efficient radial projection-based algorithm onto the human-inspired algebraic curve in the hip-knee plane.


Molecular Design, Synthetic Strategies, and Applications of Cationic Polythiophenes.
This review delves into the synthesis of cationic-functionalized oligothiophenes and polythiophenes, their properties, and their diverse applications from the year 2002 to 2019. Pristine polythiophene chains are hydrophobic and are not easily converted into a form that is useful for broad applications or for device fabrications. Functional modification of the polymer side chain especially with cationic pendant groups imparts favorable properties to the system, such as solubility in aqueous medium and affinity with anions and negatively charged species, alongside the extensive π conjugation that provides unique optoelectronic characteristics. This review provides a detailed account of the design and the different synthetic strategies to access cationic polythiophenes (CPTs) via chemical oxidation using iron(III) chloride (FeCl3), via metal catalyzed and initiated polymerization, and via postpolymerization functionalization approaches. CPTs have been traditionally used in sensing and as a component in optoelectronic devices; the utility of these systems has been extended to biomedical applications, such as nonviral gene delivery, cell targeting and imaging, anticancer, antifungal, and bactericidal actions, and biofilm formation, and to use as a molecular probe. A summary and outlook are also presented, discussing the remaining challenges and the future direction for this field.


Complex coacervates as extraction media.
Various solvents such as ionic liquids, deep eutectic solvents, and aqueous two phase systems have been suggested as greener alternatives to existing extraction processes. We propose to add macroscopic complex coacervates to this list. Complex coacervates are liquid-like forms of polyion condensates and consist of a complex of oppositely charged polyions and water. Previous research focussing on the biological significance of these polyion-rich phases has shown that polyion condensates have the ability to extract certain solutes from water and back-extract them by changing parameters such as ionic strength and pH. In this study, we present the distribution coefficients of five commonly used industrial chemicals, namely lactic acid, butanol, and three types of lipase enzymes in poly(ethylenimine)/poly(acrylic acid) complex coacervates. It was found that the distribution coefficients can vary strongly upon variation of tunable parameters such as polyion ratio, ionic strength, polyion and compound concentrations, and temperature. Distribution coefficients ranged from approximately 2 to 50 depending on the tuning of the system parameters. It was also demonstrated that a temperature-swing extraction is possible, with back-extraction of butanol from complex coacervates with a recovery of 21.1%, demonstrating their potential as extraction media.


[Dinityrosyl Iron Complexes with Thiol-Containing Ligands as a Functionally Active "Working Form" of Nitric Oxide System in Living Organisms: A Review].
Experimental data were summarized to assume that dinitrosyl iron complexes (DNICs) with thiol-containing ligands are an endogenous "working form" of the nitric oxide (NO) system in living organisms. DNICs can function as donors of both neutral NO molecules, which are responsible for positive regulatory effects of the NO system on various physiological and biochemical processes in humans and animals, and nitrosonium cations (NO^(+)), which are responsible mostly for negative cytotoxic activity of the system. Special attention is paid to the finding that DNICs, especially in combination with dithiocarbamate derivatives, suppress SARS-CoV-2 infection in Syrian hamsters.


Small area estimation of child undernutrition in Ethiopian woredas.
Reducing child undernutrition is a key social policy objective of the Ethiopian government. Despite substantial reduction over the last decade and a half, child undernutrition is still high; with 48 percent of children either stunted, underweight or wasted, undernutrition remains an important child health challenge. The existing literature highlights that targeting of efforts to reduce undernutrition in Ethiopia is inefficient, in part due to lack of data and updated information. This paper remedies some of this shortfall by estimating levels of stunting and underweight in each woreda for 2014. The estimates are small area estimations based on the 2014 Demographic and Health Survey and the latest population census. It is shown that small area estimations are powerful predictors of undernutrition, even compared to household characteristics, such as wealth and education, and hence a valuable targeting metric. The results show large variations in share of children undernourished within each region, more than between regions. The results also show that the locations with larger challenges depend on the chosen undernutrition statistic, as the share, number and concentration of undernourished children point to vastly different locations. There is also limited correlation between share of children underweight and stunted across woredas, indicating that different locations face different challenges.