Interventions for reducing red blood cell transfusion in adults undergoing hip fracture surgery: an overview of systematic reviews.
Following hip fracture, people sustain an acute blood loss caused by the injury and subsequent surgery. Because the majority of hip fractures occur in older adults, blood loss may be compounded by pre-existing anaemia. Allogenic blood transfusions (ABT) may be given before, during, and after surgery to correct chronic anaemia or acute blood loss. However, there is uncertainty about the benefit-risk ratio for ABT. This is a potentially scarce resource, with availability of blood products sometimes uncertain. Other strategies from Patient Blood Management may prevent or minimise blood loss and avoid administration of ABT. To summarise the evidence from Cochrane Reviews and other systematic reviews of randomised or quasi-randomised trials evaluating the effects of pharmacological and non-pharmacological interventions, administered perioperatively, on reducing blood loss, anaemia, and the need for ABT in adults undergoing hip fracture surgery. In January 2022, we searched the Cochrane Library, MEDLINE, Embase, and five other databases for systematic reviews of randomised controlled trials (RCTs) of interventions given to prevent or minimise blood loss, treat the effects of anaemia, and reduce the need for ABT, in adults undergoing hip fracture surgery. We searched for pharmacological interventions (fibrinogen, factor VIIa and factor XIII, desmopressin, antifibrinolytics, fibrin and non-fibrin sealants and glue, agents to reverse the effects of anticoagulants, erythropoiesis agents, iron, vitamin B12, and folate replacement therapy) and non-pharmacological interventions (surgical approaches to reduce or manage blood loss, intraoperative cell salvage and autologous blood transfusion, temperature management, and oxygen therapy). We used Cochrane methodology, and assessed the methodological quality of included reviews using AMSTAR 2. We assessed the degree of overlap of RCTs between reviews. Because overlap was very high, we used a hierarchical approach to select reviews from which to report data; we compared the findings of selected reviews with findings from the other reviews. Outcomes were: number of people requiring ABT, volume of transfused blood (measured as units of packed red blood cells (PRC)), postoperative delirium, adverse events, activities of daily living (ADL), health-related quality of life (HRQoL), and mortality. We found 26 systematic reviews including 36 RCTs (3923 participants), which only evaluated tranexamic acid and iron. We found no reviews of other pharmacological interventions or any non-pharmacological interventions. Tranexamic acid (17 reviews, 29 eligible RCTs) We selected reviews with the most recent search date, and which included data for the most outcomes. The methodological quality of these reviews was low. However, the findings were largely consistent across reviews. One review included 24 RCTs, with participants who had internal fixation or arthroplasty for different types of hip fracture. Tranexamic acid was given intravenously or topically during the perioperative period. In this review, based on a control group risk of 451 people per 1000, 194 fewer people per 1000 probably require ABT after receiving tranexamic acid (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.46 to 0.68; 21 studies, 2148 participants; moderate-certainty evidence). We downgraded the certainty for possible publication bias. Review authors found that there was probably little or no difference in the risks of adverse events, reported as deep vein thrombosis (RR 1.16, 95% CI 0.74 to 1.81; 22 studies), pulmonary embolism (RR 1.01, 95% CI 0.36 to 2.86; 9 studies), myocardial infarction (RR 1.00, 95% CI 0.23 to 4.33; 8 studies), cerebrovascular accident (RR 1.45, 95% CI 0.56 to 3.70; 8 studies), or death (RR 1.01, 95% CI 0.70 to 1.46; 10 studies). We judged evidence from these outcomes to be moderate certainty, downgraded for imprecision. Another review, with a similarly broad inclusion criteria, included 10 studies, and found that tranexamic acid probably reduces the volume of transfused PRC (0.53 fewer units, 95% CI 0.27 to 0.80; 7 studies, 813 participants; moderate-certainty evidence). We downgraded the certainty because of unexplained high levels of statistical heterogeneity. No reviews reported outcomes of postoperative delirium, ADL, or HRQoL. Iron (9 reviews, 7 eligible RCTs) Whilst all reviews included studies in hip fracture populations, most also included other surgical populations. The most current, direct evidence was reported in two RCTs, with 403 participants with hip fracture; iron was given intravenously, starting preoperatively. This review did not include evidence for iron with erythropoietin. The methodological quality of this review was low. In this review, there was low-certainty evidence from two studies (403 participants) that there may be little or no difference according to whether intravenous iron was given in: the number of people who required ABT (RR 0.90, 95% CI 0.73 to 1.11), the volume of transfused blood (MD -0.07 units of PRC, 95% CI -0.31 to 0.17), infection (RR 0.99, 95% CI 0.55 to 1.80), or mortality within 30 days (RR 1.06, 95% CI 0.53 to 2.13). There may be little or no difference in delirium (25 events in the iron group compared to 26 events in control group; 1 study, 303 participants; low-certainty evidence). We are very unsure whether there was any difference in HRQoL, since it was reported without an effect estimate. The findings were largely consistent across reviews. We downgraded the evidence for imprecision, because studies included few participants, and the wide CIs indicated possible benefit and harm. No reviews reported outcomes of cognitive dysfunction, ADL, or HRQoL. Tranexamic acid probably reduces the need for ABT in adults undergoing hip fracture surgery, and there is probably little or no difference in adverse events. For iron, there may be little or no difference in overall clinical effects, but this finding is limited by evidence from only a few small studies. Reviews of these treatments did not adequately include patient-reported outcome measures (PROMS), and evidence for their effectiveness remains incomplete. We were unable to effectively explore the impact of timing and route of administration between reviews. A lack of systematic reviews for other types of pharmacological or any non-pharmacological interventions to reduce the need for ABT indicates a need for further evidence syntheses to explore this. Methodologically sound evidence syntheses should include PROMS within four months of surgery.


Cerebrovascular injuries found in acute type B aortic dissections are associated with blood pressure derangements and poor outcome.
Cerebrovascular injury (CVI) is a recognized but underappreciated complication of acute type B aortic dissection (ATBAD). This study was performed to determine risk factors for CVI associated with ATBAD and, in particular, the possible contributory role of aggressive anti-impulse therapy. A retrospective review of all patients presenting to a tertiary medical center with an ATBAD between January 2003 and October 2012 was conducted. All CVIs were adjudicated by a vascular neurologist and assigned a probable cause. The initial intensity of anti-impulse therapy was defined as the difference in mean arterial pressure (ΔMAP) from presentation to subsequent admission to the intensive care unit. A total of 112 patients were identified. The average age was 61 years; 64% were male, and 59% were African American. Twenty patients required operative intervention (14 thoracic endovascular aortic repairs and 6 open). CVI occurred in 13 patients (11.6%): 9 were hypoperfusion related (6 diffuse hypoxic brain injuries and 3 watershed infarcts), 2 were procedure related (both thoracic endovascular aortic repairs), 1 was an intracranial hemorrhage on presentation, and 1 was a probable embolic stroke on presentation. CVI patients had demographics and comorbidities comparable to those of the non-CVI patients. CVI was associated with operative intervention (54% vs 13%; P = .002). Thirty-day mortality was significantly higher in CVI patients (54% vs 6%; P < .001). Patients who suffered a hypoperfusion brain injury had a higher MAP on presentation to the emergency department (142 mm Hg vs 120 mm Hg; P = .034) and a significantly greater reduction in MAP (ΔMAP 49 mm Hg vs 15 mm Hg; P < .001) by the time they reached the intensive care unit compared with the non-CVI patients. In our series, CVI in ATBAD is more frequent than previously reported and is associated with increased mortality. The most common causes are related to cerebral hypoperfusion. Higher MAP on presentation and greater decline in MAP are associated risk factors for hypoperfusion-related CVI. A less aggressive approach to lowering MAP in ATBAD warrants further study in an attempt to reduce CVI in ATBAD.


The Radical SAM Superfamily.
The radical S-adenosylmethionine (SAM) superfamily currently comprises more than 2800 proteins with the amino acid sequence motif CxxxCxxC unaccompanied by a fourth conserved cysteine. The charcteristic three-cysteine motif nucleates a [4Fe-4S] cluster, which binds SAM as a ligand to the unique Fe not ligated to a cysteine residue. The members participate in more than 40 distinct biochemical transformations, and most members have not been biochemically characterized. A handful of the members of this superfamily have been purified and at least partially characterized. Significant mechanistic and structural information is available for lysine 2,3-aminomutase, pyruvate formate-lyase, coproporphyrinogen III oxidase, and MoaA required for molybdopterin biosynthesis. Biochemical information is available for spore photoproduct lyase, anaerobic ribonucleotide reductase activation subunit, lipoyl synthase, and MiaB involved in methylthiolation of isopentenyladenine-37 in tRNA. The radical SAM enzymes biochemically characterized to date have in common the cleavage of the [4Fe-4S](1 +) -SAM complex to [4Fe-4S](2 +)-Met and the 5' -deoxyadenosyl radical, which abstracts a hydrogen atom from the substrate to initiate a radical mechanism.


Misconceptions in electronic energy transfer: bridging the gap between chemistry and physics.
Many treatments of energy transfer (ET) phenomena in current literature employ incorrect arguments and formulae and are not quantitative enough. This is unfortunate because we witness important breakthroughs from ET experiments in nanoscience. This review aims to clarify basic principles by focusing upon Förster-Dexter electric dipole-electric dipole (ED-ED) ET. The roles of ET in upconversion, downconversion and the antenna effect are described and the clichés and simple formulae to be avoided in ET studies are highlighted with alternative treatments provided.


Decitabine.
Besides 5-azacytidine (azacitidine, Vidaza®), 5-aza-2'-deoxycytidine (decitabine, Dacogen®) is the most widely used inhibitor of DNA methylation, which triggers demethylation leading to consecutive reactivation of epigenetically silenced tumor suppressor genes in vitro and in vivo. Although antileukemic activity of decitabine is known for almost 40 years, its therapeutic potential in hematologic malignancies has only recently led to its approval in higher-risk MDS patients and as first-line treatment in AML patients>65 years who are not candidates for intensive chemotherapy. Several clinical trials showed promising activity of low-dose decitabine also in CML and hemoglobinopathies, whereas its efficacy in solid tumors is very limited. Clinical responses appear to be exerted both by epigenetic alterations and by induction of cell-cycle arrest and/or apoptosis. Recent and ongoing clinical trials investigate new dosing schedules, routes of administration, and combination of decitabine with other agents, including histone deacetylase inhibitors.


Studies of blood pressures in children, ages 5-14 years, in a total biracial community: the Bogalusa Heart Study.
Blood pressure, height, weight, maturation, triceps skinfold thickness, serum lipids, and hemoglobin were measured as risk factors for coronary artery disease in 3,524 children (93% of the eligible population) in Bogalusa, Louisiana. Nine blood pressures were taken on each child by trained observers with mercury sphygmomanometers (Baumanometer) and Physiometrics automatic recorders in a rigid randomized design in a relaxed atmosphere with other children present. The pressures observed were low compared to reported data. Black children had significantly higher blood pressures than white children. This difference, starting before age 10, was largest in the children in the upper five percent of the pressure ranks. Stepwise multiple regression analysis revealed that this racial differnce was significant when measured by an automatic recorder. Body size, expressed by height and by weight/height3 index, was a strong determinant of blood pressure level. Other positive determinants were blood hemoglobin and external maturation.


Unicoronal Craniosynostosis and Plagiocephaly Correction with Fronto-orbital Bone Remodeling and Advancement.
The standard surgical treatment for unilateral coronal synostosis is fronoto-orbital advancement. The technique is known for its high recurrence rate and established plagiocephaly remains a challenge. In this case report, the management of a 5-year-old with unicoronal plagiocephaly correction with fronto-orbital bone remodeling and advancement is presented. The previous surgery done at 6 months of age resulted in failure with establishment of hypertelorism and sudden progressive diminishing vision. Furthermore, temporal hallowing was evident in the imaging technique. As the child is in the active growing phase, only one end of the bandeau was secured with plates and screws while the other end was welded with ultrasonic waves. This ensured that the plate was held in position while bone remodeling will ensure normal healing and establish regular sutural growth. The child recovered well with regaining of vision. The report also discusses the possible reason for failures and the effectiveness of modification of the standard technique for growing child.


Assessing the management of healthcare waste in Hawassa city, Ethiopia.
Inadequate management of healthcare waste is a serious concern in many developing countries due to the risks posed to human health and the environment. This study aimed to evaluate healthcare waste management in Hawassa city, Ethiopia. The study was conducted in nine healthcare facilities (HCFs) including hospitals (four), health centres (two) and higher clinics (three) in two phases, first to assess the waste management aspect and second to determine daily waste generation rate. The result showed that the median quantity of waste generated at the facilities was 3.46 kg bed(-1) day(-1) (range: 1.48-8.19 kg bed(-1) day(-1)). The quantity of waste per day generated at a HCF increased as occupancy increased (p < 0.001). The percentage hazardous waste generated at government HCFs was more than at private HCFs (p < 0.05). The proportion of hazardous waste (20-63.1%) generated at the different HCFs was much higher than the WHO recommendation (10-25%). There was no waste segregation in most HCFs and only one used a complete color coding system. Solid waste and wastewater were stored, transported, treated and disposed inappropriately at all HCFs. Needle-stick injuries were prevalent in 25-100% of waste handlers employed at these HCFs. Additionally, low levels of training and awareness of waste legislation was prevalent amongst staff. The study showed that management of healthcare waste at HCFs to be poor. Waste management practices need to be improved through improved legislation and enforcement, and training of staff in the healthcare facilities in Hawassa.


To what extent are microplastics from the open ocean weathered?
It is necessary to better characterize plastic marine debris in order to understand its fate in the environment and interaction with organisms, the most common type of debris being made of polyethylene (PE) and polypropylene (PP). In this work, plastic debris was collected in the North Atlantic sub-tropical gyre during the Expedition 7th Continent sea campaign and consisted mainly in PE. While the mechanisms of PE photodegradation and biodegradation in controlled laboratory conditions are well known, plastic weathering in the environment is not well understood. This is a difficult task to examine because debris comes from a variety of manufactured objects, the original compositions and properties of which vary considerably. A statistical approach was therefore used to compare four sample sets: reference PE, manufactured objects, mesoplastics (5-20 mm) and microplastics (0.3-5 mm). Infrared spectroscopy showed that the surface of all debris presented a higher oxidation state than the reference samples. Differential scanning calorimetry analysis revealed that the microplastics were more crystalline contrarily to the mesoplastics which were similar to references samples. Size exclusion chromatography showed that the molar mass decreased from the references to meso- and microplastics, revealing a clear degradation of the polymer chains. It was thus concluded that the morphology of marine microplastic was much altered and that an unambiguous shortening of the polymer chains took place even for this supposedly robust and inert polymer.


The fetal occiput posterior position: state of the science and a new perspective.
The fetal occiput posterior position poses challenges in every aspect of intrapartum care-prevention, diagnosis, correction, supportive care, labor management, and delivery. Maternal and newborn outcomes are often worse and both physical and psychological traumas are more common than with fetal occiput anterior positions. The purpose of this paper is to describe nine prevailing concepts that guide labor and birth management with an occiput posterior fetus, and summarize evidence to clarify the state of the science. A search was conducted of the databases of PubMed and the Cochrane Library. Additional valuable information was obtained from obstetric and midwifery textbooks, books and websites for the public, conversations with maternity care professionals, and years of experience as a doula. Nine prevailing concepts are as follows: (1) prenatal maneuvers rotate the occiput posterior fetus to occiput anterior; (2) it is possible to detect the occiput posterior fetus prenatally; (3) a fetus who is occiput anterior at the onset of labor will remain in that position throughout labor; (4) back pain in labor is a reliable sign of an occiput posterior fetus; (5) the occiput posterior fetus can be identified during labor by digital vaginal examination; (6) an ultrasound scan is a reliable way to detect fetal position; (7) maternal positions facilitate rotation of the occiput posterior fetus; (8) epidural analgesia facilitates rotation; (9) manual rotation of the fetal head to occiput anterior improves the rate of occiput anterior deliveries. Concepts 1, 2, 3, 4, 5, and 8 have little scientific support whereas concepts 6, 7, and 9 are supported by promising evidence. Many current obstetric practices with respect to the occiput posterior position are unsatisfactory, resulting in failure to identify and correct the problem and thus contributing to high surgical delivery rates and traumatic births. The use of ultrasound examination to identify fetal position is a method that is far superior to other methods, and has the potential to improve outcomes. Research studies are needed to examine the efficacy of midwifery methods of identification, and the effect of promising methods to rotate the fetus (simple positional methods and digital or manual rotation). Based on the findings of this review, a practical approach to care is suggested.


Consolidation therapy revisited: intravenous chemotherapy.
The administration of 'consolidation' therapy is designed to maximize the benefits achieved from primary chemotherapy, to both improve progression-free and overall survival. Paclitaxel is an excellent agent to consider for a consolidation strategy in ovarian cancer, based on its activity in the disease, its cycle-specificity, and the lack of serious cumulative toxicity (except for neuropathy). A recently reported randomized trial conducted by the South-west Oncology Group and the Gynecologic Oncology Group revealed that 12-monthly cycles of single-agent paclitaxel (175 mg/m2 over 3 h) improves progression-free survival (PFS), compared to 3-monthly cycles of the agent (median PFS: 28 months versus 21 months, P = 0.0023, and hazard ratio 2.31). Further exploration of consolidation/maintenance therapy in the management of ovarian cancer is indicated, focusing on agents that are easy to administer (eg, oral) and that result in limited cumulative toxicity.


Epigenetic control of neural precursor cell fate during development.
The temporally and spatially restricted nature of the differentiation capacity of cells in the neural lineage has been studied extensively in recent years. Epigenetic control of developmental genes, which is heritable through cell divisions, has emerged as a key mechanism defining the differentiation potential of cells. Short-term or reversible repression of developmental genes puts them in a 'poised state', ready to be activated in response to differentiation-inducing cues, whereas long-term or permanent repression of developmental genes restricts the cell fates they regulate. Here, we review the molecular mechanisms that underlie the establishment and regulation of differentiation potential along the neural lineage during development.


WILLIAM MCDOUGALL, AMERICAN PSYCHOLOGIST: A RECONSIDERATION OF NATURE-NURTURE DEBATES IN THE INTERWAR UNITED STATES.
The British-born psychologist William McDougall (1871-1938) spent more than half of his academic career in the United States, holding successive positions after 1920 at Harvard and Duke universities. Scholarly studies uniformly characterize McDougall's relationship with his New World colleagues as contentious: in the standard view, McDougall's theory of innate drives clashed with the Americans' experimentation into learned habits. This essay argues instead that rising American curiosity about inborn appetites-an interest rooted in earlier pragmatic philosophy and empirically investigated by interwar scientists-explains McDougall's migration to the United States and his growing success there. A review of McDougall's intellectual and professional ties, evolving outside public controversy, highlights persistent American attention to natural agency and complicates arguments voiced by contemporaries in favor of nurture.


The product of a developmental gene, crgA, that coordinates reproductive growth in Streptomyces belongs to a novel family of small actinomycete-specific proteins.
On solid media, the reproductive growth of Streptomyces involves antibiotic biosynthesis coincident with the erection of filamentous aerial hyphae. Following cessation of growth of an aerial hypha, multiple septation occurs at the tip to form a chain of unigenomic spores. A gene, crgA, that coordinates several aspects of this reproductive growth is described. The gene product is representative of a well-conserved family of small actinomycete proteins with two C-terminal hydrophobic-potential membrane-spanning segments. In Streptomyces avermitilis, crgA is required for sporulation, and inactivation of the gene abolished most sporulation septation in aerial hyphae. Disruption of the orthologous gene in Streptomyces coelicolor indicates that whereas CrgA is not essential for sporulation in this species, during growth on glucose-containing media, it influences the timing of the onset of reproductive growth, with precocious erection of aerial hyphae and antibiotic production by the mutant. Moreover, CrgA subsequently acts to inhibit sporulation septation prior to growth arrest of aerial hyphae. Overexpression of CrgA in S. coelicolor, uncoupling any nutritional and growth phase-dependent regulation, results in growth of nonseptated aerial hyphae on all media tested, consistent with a role for the protein in inhibiting sporulation septation.


Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction.
The role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor alpha (ESR1) gene may influence IHD risk, but the role of common sequence variations in the ESR1 gene is unclear. To determine whether the ESR1 haplotype created by the c.454-397T>C (PvuII) and c.454-351A>G (XbaI) polymorphisms is associated with myocardial infarction (MI) and IHD risk. In 2617 men and 3791 postmenopausal women from The Rotterdam Study (enrollment between 1989-1993 and follow-up to January 2000), a population-based, prospective cohort study of participants aged 55 years and older, ESR1 c.454-397T>C and c.454-351A>G haplotypes were determined. Detailed interviews and physical examinations were performed, blood samples were obtained, and cardiovascular risk factors were assessed. The primary outcome was MI and IHD defined as MIs, revascularization procedures, and IHD mortality. Approximately 29% of women and 28.2% of men were homozygous carriers of the ESR1 haplotype 1 (-397 T and -351 A) allele, 49% of women and 50% of men were heterozygous carriers, and 22% of women and 21.4% of men were noncarriers. During a mean follow-up of 7.0 years, 285 participants (115 women; 170 men) had MI, and 440 (168 women; 272 men) had an IHD event, of which 97 were fatal. After adjustment for known cardiovascular risk factors, female heterozygous carriers of haplotype 1 had an increased risk of MI (event rate, 2.8%; relative risk [RR], 2.23; 95% confidence interval [CI], 1.13-4.43) compared with noncarriers (event rate, 1.3%), whereas homozygous carriers had an increased risk (event rate, 3.2%; RR, 2.48; 95% CI, 1.22-5.03). For IHD events, we observed a similar association. In women, the effect of haplotype 1 on fatal IHD was larger than on nonfatal IHD. In men, the ESR1 haplotypes were not associated with an increased risk of MI (event rate, 5.7%; RR, 0.93; 95% CI, 0.59-1.46 for heterozygous carriers; and event rate, 5.1%; RR, 0.82; 95% CI, 0.49-1.38 for homozygous carriers) compared with noncarriers (event rate, 5.8%) and were not associated with an increased risk of IHD. In this population-based, prospective cohort study, postmenopausal women who carry ESR1 haplotype 1 (c.454-397 T allele and c.454-351 A allele) have an increased risk of MI and IHD, independent of known cardiovascular risk factors. In men, no association was observed.


Blind, one-eyed, or eagle-eyed? pKa calculations during blind predictions with staphylococcal nuclease.
In the current contribution, the performance of Poisson-Boltzmann-based pK(a) calculations of SNase mutants as part of a blind prediction exercise facilitated by the pK(a) cooperative ("pK(a) _coop") is described. A one parameter setting ("quick&dirty" approach) is used to provide an industry perspective where strong time constraints are frequently encountered. On the one hand, results are analyzed in terms of root mean square deviation performance. Furthermore, the pK(a) calculations are assessed for their ability to properly assign protonation state. For this purpose, a new measure called BIPS (binary protonation state at physiological pH) is introduced. Significant differences were found with both comparison measures based on the class of residues examined. In addition, the performance of PROPKA3 as well as the NULL model is examined on the same data set. Finally, pK(a) calculations on SNase mutants with available structural information have been performed and provide support for our calculation methods. The performance on this subset is better than on the pK(a) cooperative mutation data. In the pK(a) _coop data, no structural information on the generated mutants is available. This suggests the occurrence of a substantial structural rearrangement on the insertion of additional charged groups into SNase, which leads to improved prediction quality.


Overexpression of NLRP3, NLRC4 and AIM2 inflammasomes and their priming-associated molecules (TLR2, TLR4, Dectin-1, Dectin-2 and NFκB) in Malassezia folliculitis.
The activation of NLRP3, NLRC4 and AIM2 inflammasomes is pivotal for innate immunity against some pathogenic fungi, but their role in the pathogenesis of Malassezia folliculitis (MF) remains unclear. The objective of the study was to determine the expression of 4 canonical inflammasomes (NLRP1, NLRP3, NLRC4 and AIM2) and their priming-associated molecules (TLR2, TLR4, Dectin-1, Dectin-2 and NFκB) in MF lesion. Expression of NLRP1, NLRP3, NLRC4, AIM2, caspase-1, IL-1β, TLR2, TLR4, Dectin-1, Dectin-2 and NFκB was detected by immunohistochemistry in skin lesion of 23 MF patients and normal skin of 12 healthy subjects. Furthermore, NLRP1, NLRP3, NLRC4, AIM2, caspase-1 and IL-1β mRNA was measured by quantitative real-time PCR (qRT-PCR) in 12 MF cases and 10 controls. Immunohistochemical analysis revealed that NLRP3, NLRC4, AIM2, Casp-1, IL-1β, TLR2, TLR4, Dectin-1, Dectin-2 and NFκB expression was up-regulated in the epidermis and dermal inflammatory cells of MF lesion compared with control skin (P < .01-.05), but NLRP1 expression was not different between both groups (P > .05). qRT-PCR showed that levels of NLRP3, Casp-1 and IL-1β mRNA were significantly increased (P < .01-.05), whereas those of NLRP1, NLRC4 and AIM2 mRNA were slightly augmented compared to control skin (P > .05). Our observation suggests that simultaneous activation of NLRP3, NLRC4 and AIM2 inflammasomes may play an important role in the pathogenesis of MF.


Structure and Function of Filamin C in the Muscle Z-Disc.
Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.


Anterior Tarsal Tunnel Syndrome: Entrapment of the Articular Branch of Deep Peroneal Nerve: A Case Report.
A 28-year-old male patient who injured his ankle 2 years ago presented with unilateral ankle pain, tingling, and numbness for 1 year. Clinically, tenderness and positive Tinel sign were localized on anterior aspect of ankle. On exploration, deep peroneal nerve and mainly its articular branch were encased in fibrotic tissue. Decompression of both nerves resulted in symptomatic relief after surgery. High index of suspicion, a thorough medical history, meticulous clinical examination, complete knowledge of nerve anatomy, proper radiological studies, and careful surgical decompression are all necessary for the diagnosis and management of such atypical cases.


Sirt1 Regulates Microtubule Dynamics Through Negative Regulation of Plk1 in Mitosis.
Although loss of Sirt1 leads to chromosome aneuploidy, which accounts for higher tumor susceptibility, the molecular mechanisms remain unclear. Herein, we demonstrate that Sirt1 directly regulates Plk1, of which activity is critical for mitotic progression and spindle dynamics. Depletion or inhibition of Sirt1 significantly perturbs the formation of the mitotic spindle, leading to defective chromosome segregation. Elevated depolymerization of the mitotic spindle following loss of Sirt1 was associated with the deregulation of Plk1 activity. Thus, we conclude that Sirt1 may contribute to a mitotic regulator that controls spindle dynamics through Plk1 activity, resulting in fine-tuning of Plk1 dependent microtubule dynamics.


Epigenetic mechanisms of tumorigenicity manifesting in stem cells.
One of the biggest roadblocks to using stem cells as the basis for regenerative medicine therapies is the tumorigenicity of stem cells. Unfortunately, the unique abilities of stem cells to self-renew and differentiate into a variety of cell types are also mechanistically linked to their tumorigenic behaviors. Understanding the mechanisms underlying the close relationship between stem cells and cancer cells has therefore become a primary goal in the field. In addition, knowledge gained from investigating the striking parallels between mechanisms orchestrating normal embryogenesis and those that invoke tumorigenesis may well serve as the foundation for developing novel cancer treatments. Emerging discoveries have demonstrated that epigenetic regulatory machinery has important roles in normal stem cell functions, cancer development and cancer stem cell (CSC) identity. These studies provide valuable insights into both the shared and distinct mechanisms by which pluripotency and oncogenicity are established and regulated. In this review, the cancer-related epigenetic mechanisms found in pluripotent stem cells and cancer cells will be discussed, focusing on both the similarities and the differences.


[Awareness on nutritional problems at hospitals: which solutions?].
Malnutrition is very frequent in hospitalized patients, particularly if they are elderly and suffer of chronic diseases. Many studies show the correlation between the degree of malnutrition and the frequency of complications, the length of hospital stay and the rate of mortality. However, despite the rising interest of scientists for the role of nutrition in the pathogenesis of the diseases, little attention is devoted to the nutritional status of patients. This article reviews the recent literature regarding hospital malnutrition. At hospital admission, 30 to 40% of patients presents a certain degree of malnutrition. However, only a small percentage is recognized to be malnourished and receive an adequate treatment. The reason for this attitude of medical and paramedical teams seems to be a low priority assigned to nutrition. In addition, they seem to lack the most basic knowledge regarding the metabolic needs of their patients. Another finding, reported by several surveys, is that a large portion of hospital food is not consumed by the patients but is wasted. In fact, meals are not sufficiently-adapted to the taste and the appetite of those for whom they are prepared. This article summarizes the recommendation of the Europe Council regarding the nutritional evaluation and treatment of patients.


Developing an App for Cardiovascular Prevention and Scientific Data Collection.
Mobile apps may encourage a lifestyle that avoids unhealthy behaviors, such as smoking or poor nutrition, which promotes cardiovascular diseases (CVD). Yet, little data is available on the utilization, perception, and long-term effects of such apps to prevent CVD. To develop a mobile app concept to reduce the individual CVD risk and collect information addressing research questions on CVD prevention while preserving data privacy and security. To validate the concept, a prototype will be built, and usability studies will be performed. We expect to determine whether it is possible to reach a broad user base and to collect scientific information while protecting user data sufficiently. To address CVD prevention, we propose a mobile coaching app. We expect high acceptance rates in validation studies.


Involvement of Chk1 kinase in prophase I arrest of Xenopus oocytes.
Chk1 kinase, a DNA damage/replication G2 checkpoint kinase, has recently been shown to phosphorylate and inhibit Cdc25C, a Cdc2 Tyr-15 phosphatase, thereby directly linking the G2 checkpoint to negative regulation of Cdc2. Immature Xenopus oocytes are arrested naturally at the first meiotic prophase (prophase I) or the late G2 phase, with sustained Cdc2 Tyr-15 phosphorylation. Here we have cloned a Xenopus homolog of Chk1, determined its developmental expression, and examined its possible role in prophase I arrest of oocytes. Xenopus Chk1 protein is expressed at approximately constant levels throughout oocyte maturation and early embryogenesis. Overexpression of wild-type Chk1 in oocytes prevents the release from prophase I arrest by progesterone. Conversely, specific inhibition of endogenous Chk1 either by overexpression of a dominant-negative Chk1 mutant or by injection of a neutralizing anti-Chk1 antibody facilitates prophase I release by progesterone. Moreover, when ectopically expressed in oocytes, a Chk1-nonphosphorylatable Cdc25C mutant alone can induce prophase I release much more efficiently than wild-type Cdc25C; if endogenous Chk1 function is inhibited, however, even wild-type Cdc25C can induce the release very efficiently. These results suggest strongly that Chk1 is involved in physiological prophase I arrest of Xenopus oocytes via the direct phosphorylation and inhibition of Cdc25C. We discuss the possibility that Chk1 might function either as a G2 checkpoint kinase or as an ordinary cell cycle regulator in prophase-I-arrested oocytes.


Effects of rosmarinic acid on liver and kidney antioxidant enzymes, lipid peroxidation and tissue ultrastructure in aging mice.
Rosmarinic acid (RA), which is a natural polyphenol, was isolated from Rosmarinus. officinalis L. The aim of this study is to evaluate the effects of rosmarinic acid on liver and kidney antioxidant enzymes and the tissue ultrastructure in aging mice. RA was administrated at a dosage of 50, 100 or 200 mg kg(-1) once a day with a normal control group and an aging control group for 30 days. The livers and kidneys of the mice were harvested for antioxidant enzyme activities and histological assessments. RA produced significant (p < 0.05 or p < 0.01) increases in the activity of superoxide dismutase (SOD) catalase (CAT) and glutathione peroxidase (GSH-Px) with a decrease in malondialdehyde (MDA) at 200 mg kg(-1) compared to the aging control. The histopathological study showed RA may induce significant structural changes in liver and kidney tissues at 200 mg kg(-1). The results in this study demonstrate that RA has the potential for promoting in vivo antioxidant enzyme activity.


[Therapeutic effectiveness of clindamycin phosphate (1% solution) compared with tetracycline (solution) administered topically in the treatment of acne vulgaris].
This study consists on an eight week completely randomized investigator blind trial designed to compare the relative efficacy and tolerance of clindamycin phosphate topical solution and tetracycline in the treatment of patients with mild to moderate acne vulgaris. Patients were seen at baseline, weeks 2, 4, 6 and 8. Of the forty-five case report forms received in house, thirty-four are considered to be evaluable. Seven patients failed the entry criteria, two patients were lost to follow-up and two patients left due to lack of tolerance to the medication. All patients receiving medication were examined for both local and global tolerance indices. Within group analyses show significant improvement for both medication groups with respect to the continuous efficacy parameters: inflammatory lesions, pustules, papules and comedo counts. After adjusting for initial baseline differences, no differences between the two groups arose for these variables. The investigating physician on the average judged clindamycin phosphate to be significantly more efficacious than tetracycline trends for the patients evaluation supported these results. Throughout the study, the incidence of peeling, erythema and itching was low and similar for both groups. Two tetracycline patients did however terminate participation in the study due to itching. Significantly more patients receiving tetracycline complained of a burning sensation. No diarrhea or other side effects were recorded.


Mathematical Modeling and Validation of Retransmission-Based Mutant MQTT for Improving Quality of Service in Developing Smart Cities.
Unreliable networks often use excess bandwidth for data integration in smart cities. For this purpose, Messaging Queuing Telemetry Transport (MQTT) with a certain quality of service (QoS) is employed. Data integrity and data security are frequently compromised for reducing bandwidth usage while designing integrated applications. Thus, for a reliable and secure integrated Internet of Everything (IoE) service, a range of network parameters are conditioned to achieve the required quality of a deliverable service. In this work, a QoS-0-based MQTT is developed in such a manner that the transparent MQTT protocol uses Transmission Control Protocol (TCP)-based connectivity with various rules for the retransmission of contents if the requests are not entertained for a fixed duration. The work explores the ways to improve the overall content delivery probability. The parameters are examined over a transparent gateway-based TCP network after developing a mathematical model for the proposed retransmission-based mutant QoS-0. The probability model is then verified by an actual physical network where the repeated content delivery is explored at VM-based MQTT, local network-based broker and a remote server. The results show that the repeated transmission of contents from the sender improves the content delivery probability over the unreliable MQTT-based Internet of Things (IoT) for developing smart cities' applications.


Functional role of dendritic spines.
A number of speculations have been made on the functional role of dendritic spines. Some emphasize that a spine modulates the effect of a chemical synapse on the spine head. Others propose that spines isolate neighboring synapses from each others' effects. Still others suggest that spines play a role in short- or long-term plasticity, while others deny any functional role for spines at all. This paper brings some quantitative calculations to bear on these questions. In contrast to previous studies of the steady-state voltage attenuation in dendrites having spines, our calculations predict the voltage transient throughout a dendrite due to activation of a chemical synapse on a spine-head, causing a time-dependent postsynaptic conductance change associated with a depolarizing reversal potential. We assume passive membrane in the spine and the dendrite. Computations were performed using a compartmental model of a long dendrite and a single spine, having parameters described by Jack et al. (1975). Voltage-divider approximations to the spine-neck were compared with direct compartmental models and with eigenfunction expansions to check the validity of the numerical integrations. In the spine-head, a pronounced transient depolarization is produced, more than twice that predicted by Jack et al. (1975) for steady-state current injection. The EPSP amplitude at the base of the spine was much smaller, and was slightly reduced by placing the synapse on the head of the spine rather than on the dendritic shaft.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparative Efficacy of Chinese Herbal Injections for the Treatment of Herpangina: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.
Considering the limitations of broad-spectrum antiviral drugs for the treatment of herpangina and the extensive exploration of Chinese herbal injections (CHIs), systematic evaluation of the efficacy of different CHIs in the treatment of herpangina is a key imperative. In this study, we performed a network meta-analysis to investigate the efficacy of CHIs, including Reduning injection (RDN), Shuanghuanglian injection (SHL), Tanreqing injection (TRQ), Xiyanping injection (XYP), and Yanhuning injection (YHN), in the treatment of herpangina. A systematic literature review including studies published before December 17, 2018, was conducted in several databases. The quality of the included studies was assessed using the Cochrane risk of bias tool. Data were analyzed using STATA 13.0 and WinBUGS 1.4.3 software. Surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the examined treatments. Clustering analysis was performed to compare the effects of CHIs between two different outcomes. A total of 72 eligible randomized controlled trials involving 8,592 patients and five CHIs were included. All patients were under the age of 15 years, and most were under 7 years. The results of the network meta-analysis showed that RDN, XYP, and YHN had significantly better treatment performance than ribavirin. SHL (OR: 0.18; 95% CI: 0.09-0.34) and TRQ (OR: 0.18; 95% CI: 0.10-0.31) were obviously superior to ribavirin with respect to total clinical effectiveness. The results of SUCRA and cluster analysis indicated that RDN is the best intervention with respect to total clinical effectiveness, antipyretic time, and blebs disappearing time. Fifty-four studies described adverse drug reactions/adverse drug events (ADRs/ADEs), and 32 studies reported ADRs/ADEs in detail. CHIs were found to be superior to ribavirin in terms of treatment performance and may be beneficial for patients with herpangina. RDN had the potential to be the best CHI with respect to all outcome measures. More evidence is needed to assess the safety aspects of CHIs.


Determination of DNA damage and telomerase activity in stanozolol-treated rats.
Anabolic androgenic steroids (AAS) are performance-enhancing drugs commonly abused by atheletes. Stanozolol is a synthetic testosterone-derived anabolic steroid. Although it is well known that AAS have several side-effects, there are only few toxicological studies available on the toxic effects and mechanisms of action of stanozolol. The aim of this study was to investigate the genotoxic effects of stanozolol and to determine its effects on telomerase activity in Sprague-Dawley male rats. For this purpose, 34 male rats were divided into 5 groups as follows: i) the control group (n=5); ii) the propylene glycol (PG)-treated group (n=5); iii) the stanozolol-treated group (n=8); iv) the PG-treated group subjected to exercise (n=8); and v) the stanozolol-treated group subjected to exercise (n=8). PG is used as a solvent control in our study. Stanozolol (5 mg/kg) and PG (1 ml/kg) were injected subcutaneously 5 days/week for 28 days. After 28 days, the animals were sacrificed, and DNA damage evaluation (comet assay) and telomerase activity assays were then performed using peripheral blood mononuclear cells (PBMCs). Telomerase activity was measured by using the TeloTAGGG Telomerase PCR ELISA PLUS kit. The results of this study revealed that stanozolol treatment induced DNA damage, while exercise exerted a protective effect. Stanozolol treatment without exercise stimulation was associated with a significant increase in telomerase activity in the PBMCs.


Role of Regulatory T cells in Atorvastatin Induced Absorption of Chronic Subdural Hematoma in Rats.
Chronic subdural hematoma (CSDH) is a neurological disorder with a substantial recurrence rate. Atorvastatin is an effective drug for treating hyperlipidemia and known to improve neurological outcome after intracerebral hemorrhage. Previous studies have reported that atorvastatin treatment promotes hematoma absorption in CSDH, while the underlying mechanisms remain unclear. In this study, we investigated whether the anti-inflammatory effects of atorvastatin mediate absorption of CSDH. 144 male, Wistar rats (6 months old) were randomly divided into the following groups: 1) sham surgery control, 2) treatment: CSDH + atorvastatin, and 3) vehicle control: CSDH + saline. Atorvastatin or saline was orally administered daily for 19 days after CSDH procedure. A T2WI MRI was used to evaluate CSDH volume changes during the time course of the study. Flow cytometry and immunohistochemical staining were used to measure the number of regulatory T cells (Treg). ELISA was used to measure cytokine level in the hematoma border. Neurological function and cognitive outcome were evaluated using Foot-Fault test and Morris Water Maze test, respectively. When compared to saline treatment, atorvastatin treatment accelerated the absorption of CSDH as indicated by decreased hematoma volume in T2WI MRI data on 14th and 21st day after CSDH (P<0.05). Atorvastatin treatment significantly increased the number of Treg in circulation and hematoma border from 3rd to 21st day after CSDH. Atorvastatin treatment significantly decreased the levels of interleukins (IL-6 and IL-8) and tumor necrosis factor-α (TNF-α), but increased IL-10 level in the hematoma border. Atorvastatin treatment also improved neurological function and cognitive outcome compared to vehicle treated group. Atorvastatin induced anti-inflammatory responses and increased Treg in circulation and brain which may contribute to the accelerated CSDH absorption in rats.


Defense responses of lentil (Lens culinaris) genotypes carrying non-allelic ascochyta blight resistance genes to Ascochyta lentis infection.
Ascochyta blight of lentil is an important fungal disease in many lentil-producing regions of the world causing major yield and grain quality losses. Quick shifts in aggressiveness of the population of the causal agent Ascochyta lentis mandates developing germplasm with novel and durable resistance. In the absence of complete resistance, lentil genotypes CDC Robin and 964a-46 have frequently been used as sources of partial resistance to ascochyta blight and carry non-allelic ascochyta blight resistance genes. RNA-seq analysis was conducted to identify differences in the transcriptome of CDC Robin, 964a-46 and the susceptible check Eston after inoculation with A. lentis. Candidate defense genes differentially expressed among the genotypes had hypothetical functions in various layers of plant defense, including pathogen recognition, phytohormone signaling pathways and downstream defense responses. CDC Robin and 964a-46 activated cell surface receptors (e.g. receptor like kinases) tentatively associated with pathogen-associated molecular patterns (PAMP) recognition and nucleotide-binding site leucine-rich repeat (NBS-LRR) receptors associated with intracellular effector recognition upon A. lentis infection, and differed in their activation of salicylic acid, abscisic acid and jasmonic acid / ethylene signal transduction pathways. These differences were reflected in the differential expression of downstream defense responses such as pathogenesis-related proteins, and genes associated with the induction of cell death and cell-wall reinforcement. A significant correlation between expression levels of a selection of genes based on quantitative real-time PCR and their expression levels estimated through RNA-seq demonstrated the technical and analytical accuracy of RNA-seq for identification of genes differentially expressed among genotypes. The presence of different resistance mechanisms in 964a-46 and CDC Robin indicates their value for pyramiding gene leading to more durable resistance to ascochyta blight.


Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies.
Proximal renal tubular acidosis (RTA) (Type II RTA) is characterized by a defect in the ability to reabsorb HCO(3) in the proximal tubule. This is usually manifested as bicarbonate wastage in the urine reflecting that the defect in proximal tubular transport is severe enough that the capacity for bicarbonate reabsorption in the thick ascending limb of Henle's loop and more distal nephron segments is overwhelmed. More subtle defects in proximal bicarbonate transport likely go clinically unrecognized owing to compensatory reabsorption of bicarbonate distally. Inherited proximal RTA is more commonly autosomal recessive and has been associated with mutations in the basolateral sodium-bicarbonate cotransporter (NBCe1). Mutations in this transporter lead to reduced activity and/or trafficking, thus disrupting the normal bicarbonate reabsorption process of the proximal tubules. As an isolated defect for bicarbonate transport, proximal RTA is rare and is more often associated with the Fanconi syndrome characterized by urinary wastage of solutes like phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins as well as bicarbonate. A vast array of rare tubular disorders may cause proximal RTA but most commonly it is induced by drugs. With the exception of carbonic anhydrase inhibitors which cause isolated proximal RTA, drug-induced proximal RTA is associated with Fanconi syndrome. Drugs that have been recently recognized to cause severe proximal RTA with Fanconi syndrome include ifosfamide, valproic acid and various antiretrovirals such as Tenofovir particularly when given to human immunodeficiency virus patients receiving concomitantly protease inhibitors such as ritonavir or reverse transcriptase inhibitors such as didanosine.


Vascular Endothelial Growth Factor as an Angiogenic Marker in Malignant Astrocytoma and Oligodendroglioma: An Indian Scenario.
The role of Vascular Endothelial Growth Factor (VEGF) in angiogenesis has been extensively studied in gliomas, such as astrocytoma and oligodendrogliomas, worldwide. However, there is limited information available with regard to the Indian population. To study, whether VEGF is expressed in the Indian population in a pattern similar to that in other population. In this prospective study approved by the Institute Ethics Committee for Human Studies at Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER) the patients operated for glioma in 2014 and 2015 (n = 60) were included. Tumours were graded as per the World Health Organization (WHO) grading system. VEGF expression in various grades was analysed using immunohistochemistry. Of the 60 patients included in this study, 15 were Grade II- (diffuse astrocytomas - 12; oligodendrogliomas- 3), 15 were Grade III-(anaplastic astrocytomas- 2; anaplastic oligodendrogliomas - 13) and 30 were Grade IV-glioblastomas. For VEGF antibody staining, two patients (3.33%) showed negative results and 58 patients (96%) showed positive results. VEGF positivity was 100% in Grade II and III, while it was 93.3% (28/30) in Grade IV tumours (p=0.012). The expression of VEGF was associated with the grade of tumour, which gradually increased from Grade II to Grade IV. We conclude that VEGF-regulated angiogenesis plays an important role in tumour progression of astrocytomas and oligodendrogliomas in the Indian population as observed worldwide.


A 0D-3D multi-scale model of the portal venous system coupled with the entire cardiovascular system applied to predict postsplenectomy hemodynamic metrics.
Splenectomy is a common surgery for portal hypertensive patients with splenomegaly. Although splenectomy is able to effectively relieve the complications of portal hypertension, it also increases the risk of portal venous system thrombosis remarkably. Previous studies demonstrated that the hemodynamic metrics of the portal venous system could be employed in predicting the risk of postsplenectomy thrombosis, and 3D models were utilized to simulate the blood flow in the portal venous system. Aiming to reflect the global effect of splenectomy and better simulate the hemodynamic metrics, in this study, a 0D-3D multi-scale model of the portal venous system coupled with the entire cardiovascular system was constructed based on population-averaged data in combination with patient-specific preoperative clinical measurements. The pre- and postoperative global blood flows as well as the variations were calculated successfully, and the flow field and time-averaged wall shear stress of the portal venous system were simulated. The model-simulated spatial distributions of the hemodynamic metrics in the portal venous system were comparable with the regions suffering from thrombosis after splenectomy. These results imply that the present model could reflect the reallocation of the blood flow in the splanchnic circulation after splenectomy and simulate the hemodynamic metrics of the portal venous system, which would promote the more accurate risk stratification of postsplenectomy thrombosis and improve the patient-specific postoperative management.Clinical Relevance- The computational model developed by the present study provides a feasible scheme for simulating postsplenectomy hemodynamic metrics of the portal venous system more accurately, which would benefit the risk prediction and prophylaxis of portal venous system thrombosis for portal hypertensive patients receiving splenectomy.


Quality comparability assessment of a SARS-CoV-2-neutralizing antibody across transient, mini-pool-derived and single-clone CHO cells.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a serious public health crisis worldwide, and considering the novelty of the disease, preventative and therapeutic measures alike are urgently needed. To accelerate such efforts, the development of JS016, a neutralizing monoclonal antibody directed against the SARS-CoV-2 spike protein, was expedited from a typical 12- to 18-month period to a 4-month period. During this process, transient Chinese hamster ovary cell lines are used to support preclinical, investigational new drug-enabling toxicology research, and early Chemistry, Manufacturing and Controls development; mini-pool materials to supply Phase 1 clinical trials; and a single-clone working cell bank for late-stage and pivotal clinical trials were successively adopted. Moreover, key process performance and product quality investigations using a series of orthogonal and state-of-the-art techniques were conducted to demonstrate the comparability of products manufactured using these three processes, and the results indicated that, despite observed variations in process performance, the primary and high-order structures, purity and impurity profiles, biological and immunological functions, and degradation behaviors under stress conditions were largely comparable. The study suggests that, in particular situations, this strategy can be adopted to accelerate the development of therapeutic biopharmaceuticals and their access to patients.


Efficacy outcome selection in the therapeutic hypothermia after pediatric cardiac arrest trials.
The Therapeutic Hypothermia After Pediatric Cardiac Arrest trials will determine whether therapeutic hypothermia improves survival with good neurobehavioral outcome, as assessed by the Vineland Adaptive Behavior Scales Second Edition, in children resuscitated after cardiac arrest in the in-hospital and out-of-hospital settings. We describe the innovative efficacy outcome selection process during Therapeutic Hypothermia After Pediatric Cardiac Arrest protocol development. Consensus assessment of potential outcomes and evaluation timepoints. None. We evaluated practical and technical advantages of several follow-up timepoints and continuous/categorical outcome variants. Simulations estimated power assuming varying hypothermia benefit on mortality and on neurobehavioral function among survivors. Twelve months after arrest was selected as the optimal assessment timepoint for pragmatic and clinical reasons. Change in Vineland Adaptive Behavior Scales Second Edition from prearrest level, measured as quasicontinuous with death and vegetative status being worst-possible levels, yielded optimal statistical power. However, clinicians preferred simpler multicategorical or binary outcomes because of easier interpretability and favored outcomes based solely on postarrest status because of concerns about accurate parental assessment of prearrest status and differing clinical impact of a given Vineland Adaptive Behavior Scales Second Edition change depending on prearrest status. Simulations found only modest power loss from categorizing or dichotomizing quasicontinuous outcomes because of high expected mortality. The primary outcome selected was survival with 12-month Vineland Adaptive Behavior Scales Second Edition no less than two SD below a reference population mean (70 points), necessarily evaluated only among children with prearrest Vineland Adaptive Behavior Scales Second Edition greater than or equal to 70. Two secondary efficacy outcomes, 12-month survival and quasicontinuous Vineland Adaptive Behavior Scales Second Edition change from prearrest level, will be evaluated among all randomized children, including those with compromised function prearrest. Extensive discussion of optimal efficacy assessment timing, and of the advantages versus drawbacks of incorporating prearrest status and using quasicontinuous versus simpler outcomes, was highly beneficial to the final Therapeutic Hypothermia After Pediatric Cardiac Arrest design. A relatively simple, binary primary outcome evaluated at 12 months was selected, with two secondary outcomes that address the potential disadvantages of primary outcome.


Comprehensive one-step molecular analyses of mitochondrial genome by massively parallel sequencing.
Mitochondrial diseases are clinically and genetically heterogeneous, with variable penetrance, expressivity, and differing age of onset. Disease-causing point mutations and large deletions in the mitochondrial genome often exist in a heteroplasmic state. Current molecular analyses require multiple different and complementary methods for the detection and quantification of mitochondrial DNA (mtDNA) mutations. We developed a novel approach to analyze the mtDNA in 1 step. The entire human mitochondrial genome was enriched by a single amplicon long-range PCR followed by massively parallel sequencing to simultaneously detect mtDNA point mutations and large deletions with heteroplasmic levels of the mutations and variants quantified. QC samples were designed and analyzed along with each sample. A total of 45 samples were analyzed for the evaluation of analytic sensitivity and specificity. Our analysis demonstrated 100% diagnostic sensitivity and specificity of base calls compared to the results from Sanger sequencing. The deep coverage allowed the detection and quantification of heteroplasmy at every single nucleotide position of the 16 569-bp mitochondrial genome. Moreover, the method also detected large deletions with the breakpoints mapped. This "deep" sequencing approach provides a 1-step comprehensive molecular analysis of the whole mitochondrial genome for patients in whom a mitochondrial disease is suspected.


Migration of styrene oligomers from food contact materials: in silico prediction of possible genotoxicity.
Styrene oligomers (SO) are well-known side products formed during styrene polymerization. They consist mainly of dimers (SD) and trimers (ST) that have been shown to be still residual in polystyrene (PS) materials. In this study migration of SO from PS into sunflower oil at temperatures between 5 and 70 °C and contact times between 0.5 h and 10 days was investigated. In addition, the contents of SD and ST in the fatty foodstuffs créme fraiche and coffee cream, which are typically enwrapped in PS, were measured and the amounts detected (of up to 0.123 mg/kg food) were compared to literature data. From this comparison, it became evident, that the levels of SO migrating from PS packaging into real food call for a comprehensive risk assessment. As a first step towards this direction, possible genotoxicity has to be addressed. Due to technical and experimental limitations, however, the few existing in vitro tests available are unsuited to provide a clear picture. In order to reduce uncertainty of these in vitro tests, four different knowledge and statistics-based in silico tools were applied to such SO that are known to migrate into food. Except for SD4 all evaluated SD and ST showed no alert for genotoxicity. For SD4, either the predictions were inconclusive or the substance was assigned as being out of the chemical space (out of domain) of the respective in silico tool. Therefore, the absence of genotoxicity of SD4 requires additional experimental proof. Apart from SD4, in silico studies supported the limited in vitro data that indicated the absence of genotoxicity of SO. In conclusion, the overall migration of all SO together into food of up to 50 µg/kg does not raise any health concerns, given the currently available in silico and in vitro data.


The medical student summer research program in family medicine.
A variety of clinical research training programs exist throughout the United States, although little is known about their methods, content, and outcomes. This report describes a model of clinical research training designed to teach medical students research processes in family medicine, while yielding data for research studies. Authors present a description and evaluation of the program, focusing on students' research productivity. Forty medical students participated in a 6-week clinical research training program from 2006--2012. This program was led by an experienced investigator and 10 family medicine faculty mentors. Classroom instruction provided an introduction to research design in Week 1 and research writing and dissemination in Week 6. In between, medical students implemented studies in multiple outpatient clinical settings in the Residency Research Network of Texas (RRNET). The Medical Student Summer Research Program in Family Medicine was well received by medical students who demonstrated consistent productivity year after year. All students displayed findings during Medical Student Research Day, and one third continued their work beyond that event, producing 22 presentations, two manuscripts, seven published abstracts, and seven research honors. Opportunities for medical students to develop research skills should be central to medical school education. Familiarity with the research process improves medical students' ability to understand, critique, and use evidence-based medicine in practice, to explain the latest findings to their patients, and to consider careers as clinician-scientists.


Noninvasive Neuromodulation in Migraine.
The past two decades has seen an influx of noninvasive neuromodulation devices aimed at treatment of various primary headache disorders, including cluster headache and migraine. This narrative review is to summarize the current options in noninvasive neuromodulation in migraine. A variety of noninvasive neuromodulation devices have been FDA cleared and marketed for use in migraine, including single-pulse transcranial magnetic stimulation (sTMS), noninvasive vagal nerve stimulators (nVNS), and external trigeminal nerve stimulators (eTNS). Newer devices include peripheral electrical stimulation devices (PES), caloric stimulation, and others. Each has varying levels of evidence supporting its use in migraine, tolerability profiles, and access issues. Noninvasive neuromodulation devices can be beneficial when used in patients with migraine, with minimal side effects. As more devices are developed, approved, and marketed in the future, rigorous research on efficacy and safety remain a top priority.


Domestic violence in Iranian infertile women.
Millions of men and women suffer from infertility worldwide. In many cultures, infertile women are at risk of social and emotional problems. Infertility may affect the public health in many countries. Domestic violence is the intentional use of physical force, power or threat against oneself, another person or another group or community which leads to injury, death, mental harm, lack of development or deprivation. This study aimed to assess the prevalence of domestic violence against infertile women who referred to the infertility centres of Tehran, Iran in 2011. This was cross- sectional descriptive study conducted on 400 infertile women who were selected through convenient sampling method. The questionnaire used in this study included two sections: a demographic section with questions about demographic characteristics of the infertile women and their husbands; and the domestic violence questionnaire with questions about physical, emotional and sexual violence. Data were analysed by SPSS16; descriptive statistics, Spearman's test, t- test, one-way analysis of variance (ANOVA) and logistic regression were used for data analysis. Four hundred women with the average age of 30.50 ± 6.16 years participated in the study; of whom, 34.7% experienced domestic violence physical violence (5.3%), emotional violence (74.3%) and sexual violence (47.3%). Domestic violence was significantly associated with unwanted marriage, number of IVFs, drug abuse, emotional status of the women, smoking and addiction or drug abuse of the spouse, mental and physical diseases of the husband (p< 0.05). Many of the current problems in this society, particularly in families are due to the transition of the society from a traditional model to a modern one. The majority of the infertile women experience violence in Iran. Domestic violence against infertile women is a problem that should not be ignored. Clinicians should identify abused women. Providing counseling services to women in infertility treatment centers is suggested to prevent domestic violence against infertile women.


Antibodies against vaccinia virus do not neutralize extracellular enveloped virus but prevent virus release from infected cells and comet formation.
Vaccinia virus (VV) produces two antigenically and structurally distinct infectious virions, intracellular mature virus (IMV) and extracellular enveloped virus (EEV). EEV is important for the efficient dissemination of virus both in vivo and in vitro where it causes formation of comet-shaped virus plaques. Here, we show that EEV, in contrast to IMV, is resistant to neutralization by antibodies bound to its surface. However, antibodies against EEV can prevent comet formation in cell culture. To explain this apparent paradox, we investigated the mechanism by which antibodies inhibit comet formation and demonstrated that antibodies prevent EEV release from infected cells, and consequently comet formation, by agglutination of the virus on the cell surface. Two complementary observations allow this conclusion: first, electron microscopy showed that infected cells incubated with medium containing anti-vaccinia virus antibodies have virus aggregates on their surface; second, culture medium from these cells contained a 4 log10 fold reduction in the physical particle/ml titre in comparison with control culture. A mechanism by which antibodies to EEV proteins provide immunological protection is thus restriction of EEV release rather than neutralization of free EEV particles.


Stem Cell Differentiation Stage Factors and their Role in Triggering Symmetry Breaking Processes during Cancer Development: A Quantum Field Theory Model for Reprogramming Cancer Cells to Healthy Phenotypes.
A long history of research has pursued the use of embryonic factors isolated during cell differentiation processes for the express purpose of transforming cancer cells back to healthy phenotypes. Recent results have clarified that the substances present at different stages of cell differentiation-which we call stem cell differentiation stage factors (SCDSFs)-are proteins with low molecular weight and nucleic acids that regulate genomic expression. The present review summarizes how these substances, taken at different stages of cellular maturation, are able to retard proliferation of many human tumor cell lines and thereby reprogram cancer cells to healthy phenotypes. The model presented here is a quantum field theory (QFT) model in which SCDSFs are able to trigger symmetry breaking processes during cancer development. These symmetry breaking processes, which lie at the root of many phenomena in elementary particle physics and condensed matter physics, govern the phase transitions of totipotent cells to higher degrees of diversity and order, resulting in cell differentiation. In cancers, which share many genomic and metabolic similarities with embryonic stem cells, stimulated redifferentiation often signifies the phenotypic reversion back to health and nonproliferation. In addition to acting on key components of the cellular cycle, SCDSFs are able to reprogram cancer cells by delicately influencing the cancer microenvironment, modulating the electrochemistry and thus the collective electrodynamic behaviors between dipole networks in biomacromolecules and the interstitial water field. Coherent effects in biological water, which are derived from a dissipative QFT framework, may offer new diagnostic and therapeutic targets at a systemic level, before tumor instantiation occurs in specific tissues or organs. Thus, by including the environment as an essential component of our model, we may push the prevailing paradigm of mutation-driven oncogenesis toward a closer description of reality.


A new device to expose cells to changing dose rates of ionising radiation.
In many exposure scenarios to ionising radiation, the dose rate is not constant. Despite this, most in vitro studies aimed at investigating the effects of ionising radiation are carried out exposing samples at constant dose rates. Consequently, very little data exist on the biological effects of exposures to changing dose rates. This may be due to technical limitations of standard irradiation facilities, but also to the fact that the importance of research in this area has not been appreciated. We have recently shown that cells exposed to a decreasing dose rate suffer higher levels of cytogenetic damage than do cells exposed to an increasing or a constant dose rate. To further study the effects of changing dose rates, a new device was constructed that permits the exposure of cell samples in tubes, flasks or Petri dishes to changing dose rates of X-rays. This report presents the technical data, performance and dosimetry of this novel device.


Genetic Potential of the Biocontrol Agent Pseudomonas brassicacearum (Formerly P. trivialis) 3Re2-7 Unraveled by Genome Sequencing and Mining, Comparative Genomics and Transcriptomics.
The genus Pseudomonas comprises many known plant-associated microbes with plant growth promotion and disease suppression properties. Genome-based studies allow the prediction of the underlying mechanisms using genome mining tools and the analysis of the genes unique for a strain by implementing comparative genomics. Here, we provide the genome sequence of the strain Pseudomonas brassicacearum 3Re2-7, formerly known as P. trivialis and P. reactans, elucidate its revised taxonomic classification, experimentally verify the gene predictions by transcriptome sequencing, describe its genetic biocontrol potential and contextualize it to other known Pseudomonas biocontrol agents. The P. brassicacearum 3Re2-7 genome comprises a circular chromosome with a size of 6,738,544 bp and a GC-content of 60.83%. 6267 genes were annotated, of which 6113 were shown to be transcribed in rich medium and/or in the presence of Rhizoctonia solani. Genome mining identified genes related to biocontrol traits such as secondary metabolite and siderophore biosynthesis, plant growth promotion, inorganic phosphate solubilization, biosynthesis of lipo- and exopolysaccharides, exoproteases, volatiles and detoxification. Core genome analysis revealed, that the 3Re2-7 genome exhibits a high collinearity with the representative genome for the species, P. brassicacearum subsp. brassicacearum NFM421. Comparative genomics allowed the identification of 105 specific genes and revealed gene clusters that might encode specialized biocontrol mechanisms of strain 3Re2-7. Moreover, we captured the transcriptome of P. brassicacearum 3Re2-7, confirming the transcription of the predicted biocontrol-related genes. The gene clusters coding for 2,4-diacetylphloroglucinol (phlABCDEFGH) and hydrogen cyanide (hcnABC) were shown to be highly transcribed. Further genes predicted to encode putative alginate production enzymes, a pyrroloquinoline quinone precursor peptide PqqA and a matrixin family metalloprotease were also found to be highly transcribed. With this study, we provide a basis to further characterize the mechanisms for biocontrol in Pseudomonas species, towards a sustainable and safe application of P. brassicacearum biocontrol agents.


Seismology and geodesy of the sun: Low-frequency oscillations.
The hourly averages of the solar ellipticity measured from June 13 to Sept. 17, 1966, are analyzed for indications of solar oscillations with periods in excess of 2 hr nu < 0.5 hr(-1). Nothing significant is found for frequencies nu > 0.1 hr(-1) but for lower frequencies the power spectrum shows a very complex structure containing about 20 strong narrow peaks. The complexity is illusionary. The signal apparently consists of only two frequencies. The complexity is due to aliasing by the window function with its basic 24-hr period, with many observational days missing, and with different numbers of hourly averages for the various observational days. Both signal frequencies are apparently due to odd-degree spherical harmonic oscillations of the sun.


Warning signals for eruptive events in spreading fires.
Spreading fires are noisy (and potentially chaotic) systems in which transitions in dynamics are notoriously difficult to predict. As flames move through spatially heterogeneous environments, sudden shifts in temperature, wind, or topography can generate combustion instabilities, or trigger self-stabilizing feedback loops, that dramatically amplify the intensities and rates with which fires propagate. Such transitions are rarely captured by predictive models of fire behavior and, thus, complicate efforts in fire suppression. This paper describes a simple, remarkably instructive physical model for examining the eruption of small flames into intense, rapidly moving flames stabilized by feedback between wind and fire (i.e., "wind-fire coupling"-a mechanism of feedback particularly relevant to forest fires), and it presents evidence that characteristic patterns in the dynamics of spreading flames indicate when such transitions are likely to occur. In this model system, flames propagate along strips of nitrocellulose with one of two possible modes of propagation: a slow, structured mode, and a fast, unstructured mode sustained by wind-fire coupling. Experimental examination of patterns in dynamics that emerge near bifurcation points suggests that symptoms of critical slowing down (i.e., the slowed recovery of the system from perturbations as it approaches tipping points) warn of impending transitions to the unstructured mode. Findings suggest that slowing responses of spreading flames to sudden changes in environment (e.g., wind, terrain, temperature) may anticipate the onset of intense, feedback-stabilized modes of propagation (e.g., "blowup fires" in forests).


A new concept in the control of acute gingival hemorrhage.
The topical application of epsilon-aminocaproic acid may be life-saving therapy for control of acute gingival hemorrhage in patients who are debilitated because of systemic diseases. When low doses were used, there have been no reports of adverse reactions.


Systemic inflammation adversely affects response to anamorelin in patients with pancreatic cancer.
Anamorelin, a selective ghrelin receptor agonist, has been approved for pancreatic cancer treatment in Japan. We aimed to investigate whether systemic inflammation, represented by the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein (CRP)-albumin ratio (CAR), could predict the effect of anamorelin in patients with advanced pancreatic cancer. This study included 31 patients who had received anamorelin for advanced pancreatic cancer between 2021 and 2023. Patients' NLR, PLR, LMR, and CAR were evaluated before anamorelin administration. The patients were classified as responders and non-responders based on whether they gained body weight after 3 months of anamorelin administration. We investigated the association between systemic inflammation and anamorelin efficacy using a univariate analysis. Twelve (39%) patients were non-responders. A high serum CRP level (p = 0.007) and high CAR (p = 0.013) was associated with non-response to anamorelin. According to the receiver operating characteristics analysis, the CAR cutoff value was 0.06, and CAR ≥ 0.06 was a risk factor (odds ratio, 5.6 [95% confidence interval 1.2-27.1], p = 0.032) for non-response to anamorelin. CAR can be a predictor of non-response to anamorelin in patients with advanced pancreatic cancer, suggesting the importance of a comprehensive assessment of the inflammatory status.


The challenge of localizing vehicle backup alarms: effects of passive and electronic hearing protectors, ambient noise level, and backup alarm spectral content.
A human factors experiment employed a hemi-anechoic sound field in which listeners were required to localize a vehicular backup alarm warning signal (both a standard and a frequency-augmented alarm) in 360-degrees azimuth in pink noise of 60 dBA and 90 dBA. Measures of localization performance included: (1) percentage correct localization, (2) percentage of right--left localization errors, (3) percentage of front-rear localization errors, and (4) localization absolute deviation in degrees from the alarm's actual location. In summary, the data demonstrated that, with some exceptions, normal hearing listeners' ability to localize the backup alarm in 360-degrees azimuth did not improve when wearing augmented hearing protectors (including dichotic sound transmission earmuffs, flat attenuation earplugs, and level-dependent earplugs) as compared to when wearing conventional passive earmuffs or earplugs of the foam or flanged types. Exceptions were that in the 90 dBA pink noise, the flat attenuation earplug yielded significantly better accuracy than the polyurethane foam earplug and both the dichotic and the custom-made diotic electronic sound transmission earmuffs. However, the flat attenuation earplug showed no benefit over the standard pre-molded earplug, the arc earplug, and the passive earmuff. Confusions of front-rear alarm directions were most significant in the 90 dBA noise condition, wherein two types of triple-flanged earplugs exhibited significantly fewer front-rear confusions than either of the electronic muffs. On all measures, the diotic sound transmission earmuff resulted in the poorest localization of any of the protectors due to the fact that its single-microphone design did not enable interaural cues to be heard. Localization was consistently more degraded in the 90 dBA pink noise as compared with the relatively quiet condition of the 60 dBA pink noise. A frequency-augmented backup alarm, which incorporated 400 Hz and 4000 Hz components to exploit the benefits of interaural phase and intensity cues respectively, slightly but significantly improved localization compared with the standard, more narrow-bandwidth backup alarm, and these results have implications for the updating of backup alarm standards.


Coordinated primary and specialty care for type 2 diabetes mellitus, guidelines, and systems: an educational needs assessment.
To determine knowledge, competence, and attitudinal issues among primary care providers (PCPs) and diabetes specialists regarding the use and application of evidence-based clinical guidelines and the coordination of care between PCPs and diabetes specialists specifically related to referral practices for patients with diabetes. A survey tool was completed by 491 PCPs and 249 diabetes specialists. Data were collected from specialists online and from PCP attendees at live symposia across the United States. Results were analyzed for frequency of response and evaluation of significant relationships among the variables. Suboptimal practice patterns and interprofessional communication as well as gaps in diabetes-related knowledge and processes were identified. PCPs reported a lack of clarity about who, PCP or specialist, should assume clinical responsibility for the management of diabetes after a specialty referral. PCPs were most likely to refer patients to diabetes specialists for management issues relating to insulin therapy and use of advanced treatment strategies, such as insulin pens and continuous glucose monitoring. A minority of PCPs and even fewer specialists reported the routine use of clinical guidelines in practice. This research-based assessment identified critical educational needs and gaps related to coordinated care for patients with diabetes as well as the need for quality- and performance-based educational interventions.


Activating KRAS mutations in arteriovenous malformations of the brain: frequency and clinicopathologic correlation.
Arteriovenous malformations (AVM) of the brain are considered congenital. Most AVMs are presumably sporadic; however, rare familial cases occur and they may be observed in certain genetic disorders. We sought to determine the frequency of KRAS mutations and their association with clinicopathologic characteristics. We searched our neuropathology database from 2014-2017 for resected AVMs of the brain or dura mater. Twenty-one AVMs were tested (12 females, 9 males; average age: 32 years). KRAS mutations were found in 6/21 cases (28.5%). Five mutations were p.G12 V, and one p.G12C. The KRAS-mutant group contained 4 females and 2 males, with an average age of 28 years, compared to 34 years in the non-mutant group (P = .54). The average AVM size in the KRAS-mutant group was 3.9 cm, compared to 3.1 cm in the non-mutant group (P = .52). There were no histologic differences between KRAS-mutant and non-mutant cases. In summary, KRAS mutations occur in almost one-third of brain AVMs. KRAS p.G12 V was the most common mutation identified. We also demonstrate the first reported instance of a KRAS p.G12C mutation in a brain AVM. The mean age of patients with KRAS-mutant AVMs was lower than the non-mutant group, and the mean size larger. Histologic characteristics were equally distributed between KRAS-mutant and non-mutant groups.


Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib.
Our objective was to explore the relationships between imatinib pharmacokinetics and 9 allelic variants in 7 genes coding for adenosine triphosphate-binding cassette transporters (ABCB1 and ABCG2) and enzymes (cytochrome P450 [CYP] 2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) of putative relevance for imatinib. Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild-type ABCG2 and an ABCG2 Q141K clone. Steady-state pharmacokinetics of imatinib was obtained in 82 patients with gastrointestinal stromal tumors treated with oral imatinib at doses ranging from 100 to 1000 mg/d. Genotyping was carried out via direct sequencing or restriction fragment length polymorphism-based techniques. Human embryonic kidney 293 cells transfected with ABCG2 Q141K exhibited greater drug accumulation in vitro in comparison with cells expressing wild-type ABCG2 (P = .028). However, pharmacokinetic parameters of imatinib in vivo were not statistically significantly different in 16 patients who were heterozygous for ABCG2 421C>A compared with 66 patients carrying the wild-type sequence (P = .479). The apparent oral clearance of imatinib was potentially reduced in individuals with at least 1 CYP2D6*4 allele (median, 7.78 versus 10.6 L/h; P = .0695). Pharmacokinetic parameters were not related to any of the other multiple-variant genotypes (P >or= .230), possibly because of the low allele frequencies. This study indicates that common genetic variants in the evaluated genes have only a limited impact on the pharmacokinetics of imatinib. Further investigation is required to quantitatively assess the clinical significance of homozygous variant ABCG2 and CYP2D6 genotypes in patients treated with imatinib.


[Risk of hepatitis B infection in Peruvian medical students following occupational exposure to blood and body fluids].
An anonymous, self-administered and voluntary survey was performed on medical students participating in the 17th International Scientific Meeting of the Latin American Federation of Scientific Societies of Medical Students, which took place in Lima, on October 2002. A total of 198 students responded, 150 of them were Peruvian. The results showed that 46.7% of these students have been exposed, at least once during the first nine months of 2002, to blood or body fluids; 29.4% of these cases were high risk expositions and none of these accidents were properly examined. Only 35.4% of the students surveyed reported having complete Hepatitis B vaccination. The high incidence of biological accidents among Peruvian students, added to the low degree of Hepatitis B vaccination and to the lack of adequate post-exposure care, places Peruvian medical students in high risk for acquiring Hepatitis B.


Pneumococcal cell wall activates NF-kappa B in human monocytes: aspects distinct from endotoxin.
The transcription factor NF-kappa B plays a central role in inflammation by controlling the transcription of multiple genes which participate in the acute phase response. Mice with a targeted disruption of the p50 subunit of NF-kappa B are hyper-susceptible to challenge with pneumococci but not endotoxin. We sought to clarify the role of NF-kappa B in the host response to the critical inflammatory component of pneumococci, the cell wall. Activation of NF-kappa B was monitored by expression of luciferase from cells transfected with an NF-kappa B dependent luciferase reporter construct. 70Z/3 murine pre-B cells and U937 human monocytes failed to produce luciferase in response to 10(7) pneumococci or 10 mu g cell wall; strong responses were obtained with lO mu g of LPS. In contrast, THP-1 human monocytes showed strong luciferase production with all three stimuli: LPS, intact pneumococci and cell wall. The response was time and dose dependent. Cell wall activity was retained despite alteration of the choline of the teichoic acid or protease treatment suggesting the glycopeptide backbone to be a critical determinant of bioactivity. We conclude that activation of NF-kappa B by pneumococci is restricted to certain cells and that this proinflammatory activity may be a specific feature of the pneumococcal cell wall glycopeptide backbone.


Combined Intracapsular And Extracapsular Neck Of Femur Fractures Case Series, Literature Review And Management Recommendations.
Concomitant ipsilateral intracapsular and extracapsular fractures of the femoral neck are rare injuries with only 14 cases described in the literature as single case reports. We present three cases that were successfully and uniquely treated by uncemented hip arthroplasties. Two patients underwent complex primary uncemented total hip replacements, and one patient underwent an uncemented bipolar fluted stem hemiarthroplasty. The level of bearing constraint varied between implants. After describing our cases we review the literature and make recommendations on the management of these injuries. We believe that these are significant injuries and best functional results can be achieved with an early diagnosis and patient-specific approach that can include a total hip replacement in appropriate cases.


Repurposing of Nitroxoline as an Alternative Primary Amoebic Meningoencephalitis Treatment.
Among the pathogenic free-living amoebae (FLA), Naegleria fowleri is the etiological agent of a fatal disease known as primary amoebic meningoencephalitis (PAM). Once infection begins, the lesions generated in the central nervous system (CNS) result in the onset of symptoms leading to death in a short period of time. Currently, there is no standardized treatment against the infection, which, due to the high virulence of the parasite, results in a high case fatality rate (>97%). Therefore, it is essential to search for new therapeutic sources that can generate a rapid elimination of the parasite. In recent years, there have already been several successful examples of drug repurposing, such as Nitroxoline, for which, in addition to its known bioactive properties, anti-Balamuthia activity has recently been described. Following this approach, the anti-Naegleria activity of Nitroxoline was tested. Nitroxoline displayed low micromolar activity against two different strains of N. fowleri trophozoites (IC50 values of 1.63 ± 0.37 µM and 1.17 ± 0.21 µM) and against cyst stages (IC50 of 1.26 ± 0.42 μM). The potent anti-parasitic activity compared to the toxicity produced (selectivity index of 3.78 and 5.25, respectively) in murine macrophages and human cell lines (reported in previous studies), together with the induction of programmed cell death (PCD)-related events in N. fowleri make Nitroxoline a great candidate for an alternative PAM treatment.


Phyllite/bentonite mixture-an alternative effective buffer material for a geological disposal of radioactive waste.
The use of phyllite (Phy) instead of quartz in mixtures with bentonite (B) is recommended as a buffer material for engineering barriers in a geological repository of nuclear waste. The recommendation is based on experimentally determined sorption properties of various Phy/B mixtures. The adsorption capacity of Phy/B mixtures (Phy/B: 75/25, 50/50, and 25/75), the removal efficacy of Eu(III) ions (an analog for fissiongenic lanthanides and actinides), and the rate of their binding reaction were studied using the batch adsorption equilibrium and kinetic experiments at different Eu(III) initial concentrations, solution pH, and solution to adsorbent (L/S) ratio. The adsorption capacity of the Phy/B mixtures increased with the increased bentonite content in the mixture depending on the L/S ratio and solution pH. The highest increase in the adsorption capacity of the Phy/B mixtures compared to phyllite was observed for the Phy/B proportions of 25/75 and 50/50. The rate of the Eu(III) adsorption was the best fitted by the pseudo-second-order kinetic model indicating that the adsorption rate was controlled by chemisorption. The Sips model provided the best correlation of the adsorption experimental data, indicative of more than one adsorption site. The results of this study show the advantage of the Phy/B mixtures in immobilizing Eu and certain fission products by combining adsorption properties of the materials.


Analysis of mRNA vaccination-elicited RBD-specific memory B cells reveals strong but incomplete immune escape of the SARS-CoV-2 Omicron variant.
The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals.


DNA barcoding and scanning electron microscopy reveals Erysiphe ahmadii sp. nov. and a new record Erysiphe populicola (Erysiphaceae, Helotiales) on salicaceous hosts from Pakistan.
A new species of powdery mildew fungus Erysiphe ahmadii and a new record, Erysiphe populicola, on Salicaceae are described from Pakistan. In addition to light microscopy, scanning electron microscopy is also done to clearly demonstrate the surface characters of chasmothecia. E. ahmadii sp. nov. is characterized by large conidia ((-26)29-35(-37) × (-16)17-21(-23) μm), long chasmothecial appendages (198-286 μm) and small conidiophores. The novelty is confirmed by analyzing the genetic variation of internal transcribed spacer region (ITS1-5.8S-ITS2) of the ribosomal DNA gene, a universal fungal marker. E. populicola is characterized for the first time using molecular phylogenetic markers. Detailed descriptions along with scanning electron microscopy (SEM) photographs are provided in this paper. RESEARCH HIGHLIGHTS: Powdery mildews are obligate biotrophic pathogens of plants. Erysiphe ahmadii, a new powdery mildew fungus on willow trees, is described. First reference sequence of Erysiphe populicola is also generated. Both taxa are discussed in detail using macro- and micro-morphological and DNA barcoding techniques.


Evidence of water molecules--a statistical evaluation of water molecules based on electron density.
Water molecules play important roles in many biological processes, especially when mediating protein-ligand interactions. Dehydration and the hydrophobic effect are of central importance for estimating binding affinities. Due to the specific geometric characteristics of hydrogen bond functions of water molecules, meaning two acceptor and two donor functions in a tetrahedral arrangement, they have to be modeled accurately. Despite many attempts in the past years, accurate prediction of water molecules-structurally as well as energetically-remains a grand challenge. One reason is certainly the lack of experimental data, since energetic contributions of water molecules can only be measured indirectly. However, on the structural side, the electron density clearly shows the positions of stable water molecules. This information has the potential to improve models on water structure and energy in proteins and protein interfaces. On the basis of a high-resolution subset of the Protein Data Bank, we have conducted an extensive statistical analysis of 2.3 million water molecules, discriminating those water molecules that are well resolved and those without much evidence of electron density. In order to perform this classification, we introduce a new measurement of electron density around an individual atom enabling the automatic quantification of experimental support. On the basis of this measurement, we present an analysis of water molecules with a detailed profile of geometric and structural features. This data, which is freely available, can be applied to not only modeling and validation of new water models in structural biology but also in molecular design.