Treatment with statins and ischemic stroke severity: does the dose matter?
To examine the effects of pretreatment with statins at high doses (40 mg of rosuvastatin or 80 mg of any other statin) and low to moderate doses (<40 mg of rosuvastatin or <80 mg of any other statin) on ischemic stroke (IS) severity in clinical practice. Observational study of IS admissions to our stroke unit over a 3-year period (2008-2010). Mild stroke severity was defined as NIH Stroke Scale score ≤5 on admission. Multivariable regression models and matched propensity score analyses were used to quantify the association of statin pretreatment at high and low to moderate doses with mild stroke severity. Of the 969 IS patients, 23% were taking low to moderate doses and 4.1% were taking high doses of statins prior to the stroke. Statins were associated with lower NIHSS scores on admission (median [interquartile range] 4 [9] for nonstatin patients, 4 [9] for low to moderate doses of statins, and 2 [4] for high doses of statins; p = 0.010). After multivariable adjustment, pretreatment with statins was associated with a higher probability of mild stroke severity in the unmatched analysis (odds ratio [OR] = 1.637, 95% confidence interval [CI] 1.156-2.319 for the low to moderate doses and OR = 3.297, 95% CI 1.480-7.345 for the high doses of statins) as well as in the propensity score matched analysis (OR = 2.023, 95% CI 1.248-3.281 for the low to moderate doses and OR = 3.502, 95% CI 1.477-8.300 for the high doses of statins). Pretreatment with statins is associated with lower stroke severity, at high as well as at low to moderate doses.


Respiratory compromise in children presenting to an urban emergency department of a tertiary hospital in Tanzania: a descriptive cohort study.
Respiratory compromise is the leading cause of cardiac arrest and death among paediatric patients. Emergency medicine is a new field in low-income countries (LICs); the presentation, treatment and outcomes of paediatric patients with respiratory compromise is not well studied. We describe the clinical epidemiology, management and outcomes of paediatric patients with respiratory compromise presenting to the first full-capacity Emergency Department in Tanzania. This was a prospective cohort study of paediatric patients (< 18 years) with respiratory compromise (respiratory distress, respiratory failure or respiratory arrest) presenting to the Emergency Medicine Department of Muhimibili National Hospital (EMD-MNH) in Dar es Salaam, from July-November 2017. A standardized case report form was used to record demographics, presenting clinical characteristics, management and outcomes. Primary outcomes were hospital mortality and secondary outcomes were EMD mortality, 24-h mortality, incidence of cardiac arrest in the EMD, length of stay, ICU admission, and risk factors for mortality. We enrolled 165 children; their median age was 12 months [IQR: 4-36 months], and 90 (54.4%) were male. At presentation 92 (55.8%) children were in respiratory failure. Oxygen therapy was initiated for 143 (86.7%) children, among which 21 (14.7%) were intubated. The most common aetiologies were pneumonia followed by congenital heart disease and sepsis. The majority 147 (89.1%) of children were admitted to the hospital, with 20 (12%) going to ICU. Four (2%) children were discharged from EMD and 14 (8.5%) died in the EMD. In the EMD, 18 children developed cardiac arrest, with two surviving to hospital discharge. Overall 51 (30.9%) children died; 84% of deaths were in children under five years. Risk of mortality was increased in children presenting with decreased consciousness (RR = 2.2 (1.4-3.4)), hypoxia RR = 2.6 (1.6-4.4)) or bradypnoea (RR = 3.9 (2.9-5.0)), and those who received CPR (RR = 3.7 (2.7-5.2)) and intubation (RR = 3.1 (2.1-4.5)). In this EMD of a LICs, respiratory compromise in children carries high mortality, with children of young age being the most vulnerable. Many children arrived in respiratory failure and few children received ICU care. Outcomes can be improved by earlier recognition to prevent cardiac arrest, and more intensive treatment, including ICU and assisted ventilation.


Behavior Change, Egg Consumption, and Child Nutrition: A Cluster Randomized Controlled Trial.
Malnutrition is a significant contributor to child morbidity and mortality globally. Egg consumption has been associated with improved child nutrition yet is rare in rural, resource-poor settings. We test the effects of a culturally tailored behavior change intervention to increase child egg consumption. A 3-arm cluster randomized controlled trial was conducted in rural Burkina Faso with 260 mother-child dyads. Children aged 4 to 17 months from 18 villages were included; those with reported history of malnutrition or egg allergy were excluded. Each child in the full intervention arm received 4 chickens, and mothers received the 10-month behavior change package. Participants in the partial intervention arm received only the behavior change package. In this analysis of 250 children, the full (β = 4.3; P = 6.6 × 10-12) and the partial (β = 1.0; P = .02) interventions significantly increased egg consumption. The full intervention also significantly increased poultry production (β = 11.6; 95% confidence interval 8.3-15; P = 1.1 × 10-5) and women's decision-making about eggs (β = .66; P = .02), and significantly decreased wasting (β = .58; P = .03) and underweight (β = .47; P = .02). The culturally tailored behavior change package significantly increased child egg consumption. When coupled with the gift of chickens, the behavior change intervention yielded a greater increase in egg consumption and significantly reduced wasting and underweight. Behavior change strategies to increase egg consumption should be considered among nutrition and health programs in resource-poor settings where poultry is available.


Left-handed Z-DNA.
Since the Watson-Crick proposal of right-handed B-DNA, numerous studies have been devoted to the conformation of DNA. Both natural DNAs of heterogeneous sequences and synthetic DNAs are capable of adopting more than one conformation. The specific conformation a DNA adopts appears to depend mainly on its base sequence and its environmental conditions. For a given DNA, changes in environmental conditions can induce conformational transitions which occur according to cooperative or non-cooperative processes (for general reviews see Ref. 1a, b). Despite many results, molecular biologists did not put much emphasis on the polymorphism of DNA. The discovery of the intraconversion in helical sense between the right-handed B and left-handed Z conformers of DNA has brought a new interest in the polymorphism of DNA. It is now proposed that this polymorphism has important functions in biological reactions. A recent review, 'The Chemistry and Biology of Left-handed Z-DNA', by Rich et al. has just been published. We here report some of the results published in 1984 on Z-DNA.


The effect of angiotensin 1-7 on tyrosine kinases activity in rat anterior pituitary.
Angiotensin 1-7 (Ang 1-7) is a peptide originated from Ang II. It is known that in vessels Ang 1-7 shows opposite effects to Ang II. Ang 1-7 can modify processes of proliferation. However, Ang 1-7 action in pituitary gland cells was never studied. Moreover, the specific binding sites for Ang 1-7 are still unknown. The aim of this study was to examine the effects of Ang 1-7 on tyrosine kinases (PTKs) activity in the anterior pituitary. The reaction of phosphorylation was carrying out in presence of different concentration of Ang 1-7 and losartan (antagonist of AT1 receptor) and PD123319 (antagonist of AT2). Our results show that Ang 1-7 inhibited activity of PTK to 60% of basic activity. Losartan did not change the Ang 1-7-induced changes in PTKs activity. The presence of PD123319 together with Ang 1-7 caused stronger inhibition PTKs activity than Ang 1-7 alone. These observations suggest that Ang 1-7 binds to the novel, unknown, specific for this peptide receptor.


Lysophosphatidic acid and renal fibrosis.
The development of fibrosis involves a multitude of events and molecules. Until now the majority of these molecules were found to be proteins or peptides. But recent data show significant involvement of the phospholipid lysophosphatidic acid (LPA) in the development of pulmonary, liver and renal fibrosis. The latest data on the role of LPA and the G-protein-coupled LPA1 receptor in the development of renal fibrosis will be discussed. LPA1-receptor activation was found to be associated with increased vascular leakage and increased fibroblast recruitment in pulmonary fibrosis. Furthermore, in renal fibrosis LPA1-receptor activation stimulates macrophage recruitment and connective tissue growth factor expression. The observations make this receptor an interesting alternative and new therapeutic target in fibrotic diseases.


The Key Role of Schools in Youth Suicide Prevention.
The coronavirus disease 2019 (COVID-19) pandemic has presented unprecedented challenges for youth and families dealing with remote school and work, lack of childcare, and social isolation over the course of 2 years. In response, the US Surgeon General recently published an advisory warning of a mental health crisis among youth,1 noting that youth with intellectual and developmental disabilities, racial/ethnic and sexual/gender minority youth, and youth in low-income, rural, and immigrant households were at higher risk of mental health challenges in the pandemic. The advisory arrived on the heels of an emergency declaration about child and adolescent mental health put forth by the American Academy of Pediatrics, American Academy of Child and Adolescent Psychiatry, and Children's Hospital Association in October 2021. Both emphasize that the COVID-19 pandemic exacerbated already growing youth mental health concerns and highlight the key role schools must play in preventing youth suicide. In this commentary, we make the case for why we need schools to be in the business of youth suicide prevention.


Classification of the caspase-hemoglobinase fold: detection of new families and implications for the origin of the eukaryotic separins.
A comprehensive sequence and structural comparative analysis of the caspase-hemoglobinase protein fold resulted in the delineation of the minimal structural core of the protease domain and the identification of numerous, previously undetected members, including a new protease family typified by the HetF protein from the cyanobacterium Nostoc. The first bacterial homologs of legumains and hemoglobinases were also identified. Most proteins containing this fold are known or predicted to be active proteases, but multiple, independent inactivations were noticed in nearly all lineages. Together with the tendency of caspase-related proteases to form intramolecular or intermolecular dimers, this suggests a widespread regulatory role for the inactive forms. A classification of the caspase-hemoglobinase fold was developed to reflect the inferred evolutionary relationships between the constituent protein families. Proteins containing this domain were so far detected almost exclusively in bacteria and eukaryotes. This analysis indicates that caspase-hemoglobinase-fold proteases and their inactivated derivatives are widespread in diverse bacteria, particularly those with a complex development, such as Streptomyces, Anabaena, Mesorhizobium, and Myxococcus. The eukaryotic separin family was shown to be most closely related to the mainly prokaryotic HetF family. The phyletic patterns and evolutionary relationships between these proteins suggest that they probably were acquired by eukaryotes from bacteria during the primary, promitochondrial endosymbiosis. A similar scenario, supported by phylogenetic analysis, seems to apply to metacaspases and paracaspases, with the latter, perhaps, being acquired in an independent horizontal transfer to the eukaryotes. The acquisition of the caspase-hemoglobinase-fold domains by eukaryotes might have been critical in the evolution of important eukaryotic processes, such as mitosis and programmed cell death.


Cost comparison of arthroscopic rotator cuff repair with arthroscopic vs. open biceps tenodesis.
To use a nationwide database to determine differences in cost between patients who underwent arthroscopic rotator cuff tear with open vs. arthroscopic biceps tenodesis (BT). The 2014 State Ambulatory Surgical and Services Databases from 6 US states was utilized. All cases with CPT codes 29827 (arthroscopic rotator cuff repair [RCR]) and either 23430 (tenodesis of long tendon of biceps) or 29828 (arthroscopic BT) were selected. Cases that included both 23430 and 29828 were excluded, as were those missing demographic data. Generalized linear models were used to model costs based on the surgical and patient variables that were significant in the initial bivariate analysis (P < .05). A total of 3635 RCR and BT cases were identified. There were 2847 (78.3%) with arthroscopic BT and 788 (21.7%) with open BT. Patients undergoing arthroscopic BT were 3.1 years older than patients undergoing open BT (P < .001). For arthroscopic BT, 39.2% of the cases were women compared with 22.6% of the open cases (P < .001). For operative variables, arthroscopic BT required 9 fewer minutes in the OR than open cases (P = .002). Concomitant distal clavicle resection was performed in 35.5% of arthroscopic BT cases compared with 29.8% of open cases (P = .004). While controlling for other significant factors, open BT was associated with $5542 lower costs than arthroscopic BT in the setting of RCR (P < .001). In either case, concomitant subacromial decompression added $10,669 (P < .001), and distal clavicle resection added $3210 (P < .001). High-volume surgical facilities were associated with $4107 lower costs (P < .001). In a large series of patients undergoing arthroscopic RCR with open vs. arthroscopic BT, open BT was associated with $5542 lower costs than arthroscopic. Given that both techniques have been shown to be similarly effective in long-term follow-up, surgeons should be aware of opportunities for cost saving, particularly with the advent of bundled surgical reimbursements.


A double-blind, cross-over trial of O-(beta-hydroxyethyl)-rutosides (benzo-pyrones) in the treatment of lymphoedema of the arms and legs.
A randomised, double-blind, cross-over trial was performed on 26 patients with postmastectomy lymphoedema of the arm, and 14 with lymphoedema of the leg. For 6 months, patients took 0-(beta-hydroxyethyl)-rutosides (oxerutin; "Paroven", "Venoruton", Zyma) in doses of 3 g/day, or the placebos; then they took the reverse. Measurements (volume, circumferences, tonometry and skin temperature) were made monthly. The active drug reduced the volumes of the limbs (p less than 0.05 to 0.01) and their circumferences (p less than 0.05 to 0.001). It increased the softness of the limbs, as shown by the increases in the tonometry values (p less than 0.01 to 0.001). There was a lowering of the elevated skin temperatures (p less than 0.05 to 0.001). Patients reported increased comfort and freedom of movement, a lessening of their bursting pains, heaviness and tension (p less than 0.05 to 0.01), and an increased mobility of their limbs (p less than 0.0001). Most patients (70%) preferred the active drug (p less than 0.0001). An increase in general well-being was reported by 97% of patients when taking the active drug compared with 4% for placebo (p less than 0.0001).


Comparative study of the function of the Abiomed polyurethane heart valve for use in left ventricular assist devices.
Hydrodynamic testing of the Abiomed polyurethane trileaflet valve has been carried out to establish performance data of valve function. A Medtronic Hall tilting disk, a Carbomedics bileaflet, a Hancock II bioprosthesis and an Abiomed polyurethane trileaflet valve, all size 27 mm, underwent both pulsatile and steady-flow hydrodynamic testing. Results of the variation of pressure difference with RMS pulsatile flow and steady flow, and effective orifice area, showed that the Abiomed valve had significantly poorer opening characteristics than the tissue valve and the two mechanical valves. The Abiomed valve's performance was seen to be related to its construction and manufacture. This study highlights some of the problems associated with the design and development of synthetic trileaflet heart valve prostheses.


Circ_0109046 promotes the malignancy of endometrial carcinoma cells through the microRNA-105/SOX9/Wnt/β-catenin axis.
Emerging evidence suggests the important involvements of circular RNAs (circRNAs) in cancer progression. This study focuses on the function of Circ_0109046 on the malignancy of endometrial carcinoma (EC) cells and the molecules involved. First, high expression of Circ_0109046 was found in EC tissues compared to the adjacent tissues, and it predicted unfavorable prognosis in patients. Similarly, high expression of Circ_0109046 was confirmed in EC cells relative to that in normal endometrial epithelial cells. Silencing of Circ_0109046 in AN3-CA cells inhibited proliferation and aggressiveness but increased apoptosis of cells. Circ_0109046 was mainly sub-localized in cytoplasm, and it mediated SOX9 expression through sponging microRNA (miR)-105. The proliferation and aggressiveness of EC cells suppressed by Circ_0109046 downregulation was recovered upon SOX9 overexpression. SOX9 activated the Wnt/β-catenin pathway. Furthermore, downregulation of Circ_0109046 reduced the growth of xenograft tumors in nude mice. This study evidenced that Circ_0109046 upregulates SOX9 expression through sponging miR105, leading to activation of Wnt/β-catenin signaling and the malignant growth of EC. This study may offer novel understanding in EC treatment.


The role of serotonin in impulsive aggression, suicide, and homicide in adolescents and adults: a literature review.
This is a literature review discussing previous studies on the associations between impulsive aggression and the serotonergic system in adults, adolescents, and children. The review demonstrates that there is a clear association between low cerebrospinal fluid serotonin and impulsive aggression. However, studies on neurotransmitter receptor profiles, functional imaging, genetics, and epigenetics reviewed in this article suggest a more complicated picture that includes consideration of gene vs. environment in the evaluation of risk. Serotonin supplementation studies suggest that selective serotonin reuptake inhibitors may reduce impulsive aggression in some adults but are less effective in adults with pathological aggression and also in children and adolescents. Child and adolescent studies are less conclusive, in part due to the heterogeneous physiologic and psychosocial changes occurring over the course of development. The author thus concludes that psychiatrists can reduce risk in these special patient populations by creating safer environments in the form of changes in policy and increased support services.


RecQL4-Aurora B kinase axis is essential for cellular proliferation, cell cycle progression, and mitotic integrity.
Human RecQL4 helicase plays critical roles in the maintenance of genomic stability. Mutations in RecQL4 helicase results in three clinically related autosomal recessive disorders: Rothmund-Thomson syndrome (RTS), RAPADILINO, and Baller-Gerold syndrome. In addition to several premature aging features, RTS patients are characterized by aneuploidy involving either loss or gain of a single chromosome. Chromosome mosaicism and isochromosomes involving chromosomes 2, 7, and 8 have been reported in RecQL4-deficient RTS patients, but the precise role of RecQL4 in chromosome segregation/stability remains to be elucidated. Here, we demonstrate that RecQL4 physically and functionally interacts with Aurora B kinase (AURKB) and stabilizes its expression by inhibiting its ubiquitination process. Our study indicates that the N-terminus of RecQL4 interacts with the catalytic domain of AURKB. Strikingly, RecQL4 suppression reduces the expression of AURKB leading to mitotic irregularities and apoptotic cell death. RecQL4 suppression increases the proportion of cells at the G2/M phase followed by an extensive cell death, presumably owing to the accumulation of mitotic irregularities. Both these defects (accumulation of cells at G2/M phase and an improper mitotic exit to sub-G1) are complemented by the ectopic expression of AURKB. Finally, evidence is provided for the requirement of both human telomerase reverse transcriptase and RecQL4 for stable immortalization and longevity of RTS fibroblasts. Collectively, our study suggests that the RecQL4-AURKB axis is essential for cellular proliferation, cell cycle progression, and mitotic stability in human cells.


Severe liver injury with traumatic cardiac arrest successfully treated by damage control surgery and transcatheter arterial embolization in the hybrid operating room: a case report.
The damage control approach is known to reduce the mortality rate in severely injured patients and has now become a common practice. Transcatheter arterial embolization (TAE) has been shown to be useful with combining with damage control laparotomy in identifying and controlling active arterial hemorrhage. Hybrid operating room (OR) allows both damaged control surgery and TAE in the same location in minimal time. We report a case of a patient with three cardiac arrests who was saved by early intervention using damage control surgery (DCS) with interventional radiology (IVR) in the hybrid OR. A 46-year-old woman was injured in a collision with a tree while snowboarding. She was eventually transported to hybrid operating room in our hospital with the diagnosis of significant liver laceration and hemorrhagic shock. Damage control surgery was performed with perihepatic packing (PHP) and TAE was conducted to stop active bleeding from right hepatic artery. She experienced 3 times of cardiopulmonary arrest, which was successfully resuscitated on each occasion. Although she had total of 3 times of laparotomy but tolerated well. She was discharged on day 82 of hospitalization and showed no neurological sequelae. Saving the life of a patient with severe trauma requires a multidisciplinary approach with cooperation and early information sharing among trauma team members. Sharing treatment strategy with the trauma team and early intervention using DCS with IVR in the hybrid operating room could save the patient's life.


Revertants of a Chinese hamster ovary cell mutant resistant to suppression by an analogue of cholesterol: isolation and partial biochemical characterization.
A highly efficient selection procedure was developed for isolating revertants of Chinese hamster ovary (CHO) cell mutants resistant to suppression by 25-hydroxy-cholesterol. The procedure is based on the fact that the specific polyene antibiotic amphotericin B caused a lethal porous complex formation with membrane cholesterol only in cholesterol-rich cells. The wild-type cells and the revertant cells switched to grow from fetal calf serum medium to delipidated fetal calf serum medium for approximately 1 day became deficient in cellular cholesterol content. These cells, unlike the cholesterol-rich mutant cells, became much less sensitive to amphotericin B cytotoxicity. The spontaneous reversion frequency of a previously reported 25-hydroxycholesterol-resistant cell clone, 25-RA [Chang, T.-Y., & Limanek, J.S. (1980) J. Biol. Chem. 255, 7787-7795], was found to be approximately 3 X 10(-6), a frequency comparable to other single gene mutations of CHO cells. Biochemical analyses of three of these revertants showed that all defects manifested in 25-RA cells reverted back in parallel, a result suggesting that these observed defects in 25-RA cells are due to a single mutation event, thus supporting the hypothesis (Chang & Limanek, 1980) that a common controlling factor may be involved in mediating the suppressive action(s) of the cholesterol analogue on various cholesterogenic enzyme activities. The function of this common controlling factor is rendered abnormal in 25-RA cells by mutation.


Evaluation of a bone groove geometry for fixation of a cochlear implant electrode.
Electrode migration is a rare, but relevant complication in cochlear implant (CI) surgery. An effective countermeasure is to create a bone groove in the facial recess to secure the electrode lead. We use this method routinely since 2013, but still experienced sporadic electrode migration events most likely due to an improper surgical execution. The aim of this study was to determine the optimum groove geometry. Grooves of defined geometry were created in specimens of fresh porcine femur compacta by use of a CNC milling machine. Electrode dummies were fixed in the groove and then exposed to tensile stress. Force measurements were carried out to examine the effect of groove diameter and opening width on the holding force. The mechanical impact on the electrode cable during insertion into the groove was recorded and the electrode lead was examined under microscopic magnification to assess potential structural damage. Optimum groove geometry (diameter 1.10 mm, opening width 0.90 mm) ensured an average holding force of 830 mN which is equivalent to the established fixation by use of a titanium clip. None of the microscopic inspections revealed any morphological deterioration of the electrode lead. The fixation of a CI electrode in a bone groove in the facial recess appears to be effective and safe. Furthermore, this method does not require additional costs or foreign material. The optimum geometry defined in this study helped us to refine our surgical standard produce and to generate more consistent results.


Thermoluminescence property of LiMgF3 erbium activated phosphor.
The perovskite-like LiMgF(3):ErF(3) pellets were obtained from the melt formed by LiF and MgF(2) mixed salts in the stoichiometric ratio. The perovskite material was doped with 1, 2 and 4 mol% of ErF(3) impurity. The pellets samples were (60)Co gamma irradiated and their thermoluminescence (TL) properties were analyzed, i.e., dose-response, fading at RT and under UV irradiation, TL signal reproducibility, and kinetic parameters. The intensity of the TL response against irradiation dose was increased remarkably by the high concentration of impurity, and a linear dose-response was observed in the range of 1-10 Gy. The fading observed at RT was about 10-30% after 24h from irradiation. All samples were exposed from 1 to 200 Gy gamma dose range. The TL glow peaks were found around 367-376, 438-447, 509-521, and 594-611 K, when the doped samples were 1, 2 and 4 mol% of the erbium impurity concentration. The thermoluminescence kinetics parameters of the glow curves have been analyzed using the Computerized Glow Curve Deconvolution (CGCD) method.


Development and validation of the excess mortality ratio-based Emergency Severity Index.
The purpose of this study is to develop and validate the excess mortality ratio-based Emergency Severity Index (EMR-ESI) that feasibly and objectively assesses the severity of emergency department (ED) patients based on their chief complaints. We used data from the National Emergency Department Information System of Korea from January 2006 to December 2009. We obtained information on mortality and the corresponding chief complaints exhibited by patients presenting to all EDs. The EMR-ESI was computed from the ratio of sex-age standardized hospital mortality for each chief complaint and the sex-age standardized mortality of the entire population of Korea. We tested the discriminatory power of the EMR-ESI on the prediction of hospital outcomes using the area under the receiver operating characteristic curve (AUC) from a multivariate logistic regression model. This model was adjusted for clinical parameters, and the goodness of fit was estimated using the Hosmer-Lemeshow logistic model. Included in the study were 4 713 462 patients who presented 7557 chief complaint codes from 2006 to 2008. The EMR-ESI had a range of 0 to 6389.45 (mean ± SD, 1.11 ± 4.67; median, 0.70). The adjusted odds ratio of the EMR-ESI (unit, 1.0) for hospital mortality was 1.11 (95% confidence interval, 1.11-1.12). The AUCs for predicting hospital mortality, ED mortality, admission mortality, and admission were 0.95, 0.98, 0.90, and 0.74, respectively. There were 3 422 865 patients from 2009 who were included for external validation, and the AUCs for predicting mortality in the hospital, the ED, the inpatient ward, and for predicting admission were 0.95, 0.99, 0.90, and 0.75, respectively. The EMR-ESI was notably useful in predicting hospital mortality and the admission of emergency patients.


Chemical reactions in liquid-phase microextraction.
In recent years, liquid-phase microextraction (LPME), a microscale implementation of liquid-liquid extraction, has become a very popular sample pretreatment technique because it combines extraction and enrichment, and is inexpensive, easy to operate and nearly solvent-free. Especially so in hollow fiber-protected LPME, sample cleanup is also effected. Essentially, owing to its high sample-to-extracting solvent volume ratio, LPME can achieve high analyte enrichment. Since its advent, the technique has been widely used, and applied to environmental, pharmaceutical, biological and forensic analyses. This review focuses on developments relating to chemical reactions associated with LPME applications, in contrast to conventional, straightforward extractions in which analytes remain as they are during the extraction process. Chemical reactions brought about during LPME serve to promote the extractability of the analytes (thus expanding the scope of applicability of the technique), facilitate their (analyte) compatibility with the analytical system and/or improve detection sensitivity. The reactions that are usually enabled during LPME include ion-pair extraction (carrier-mediated membrane transport), complexation, chemical (pre-extraction, in situ, and post-extraction) derivatization, phase-transfer catalysis and other "special affinity" reactions. Strategies on chemical reactions in LPME are overviewed in this report.


Second-trimester sonography and trisomy 18: the significance of isolated choroid plexus cysts after an examination that includes the fetal hands.
To estimate the risk of trisomy 18 with the finding of isolated choroid plexus cysts after a standard sonographic examination that is extended to include the fetal hands. Aretrospective chart review was performed on all fetuses with choroid plexus cysts on second-trimester sonographic examinations. When choroid plexus cysts were identified, our standard protocol for fetal evaluation was expanded to include the hands. If no other findings were noted on completion of this examination, the choroid plexus cysts were classified as "isolated." These results were correlated with the presence or absence of trisomy 18 to determine the impact of this approach for the detection of fetuses with this aneuploidy. From March 1990 to the end of 2001, 49,435 fetuses that were subsequently delivered at our hospital were scanned between 16 and 25 menstrual weeks. At least 1 choroid plexus cyst was detected in 1209 fetuses (2.3%), of which 1060 were isolated. No fetuses with isolated choroid plexus cysts had trisomy 18. However, 3 fetuses with trisomy 18 had choroid plexus cysts and abnormal hands as their only abnormal findings. Fetuses with an apparently isolated finding of choroid plexus cysts can be further evaluated by extending the standard examination to include the hands. If no other findings are identified, the risk of trisomy 18 appears to be low.


Risk of osteoarthritis secondary to partial or total arthrodesis of the subtalar and midtarsal joints after a minimum follow-up of 10 years.
The goal of this retrospective, multicentre study was to evaluate the long-term outcomes in patients who have undergone partial or total arthrodesis of the subtalar and midtarsal joints. Secondary osteoarthritis of the adjacent joints can negatively affect the outcomes more than 10 years after these fusion procedures. The outcomes of 72 fusions (total: 22; partial: 50) performed between 1981 and 2002 were evaluated using the Maryland Foot Score (MFS), self-evaluation questionnaire and three weight-bearing X-ray views (Meary's with cerclage wire around heel, lateral and dorsoplantar). The average follow-up was 15 ± 5 years (range 10-31). There were two deep infections that resolved after lavage and antibiotics therapy. There were 21 early complications (10 complex regional pain syndrome, 7 delayed wound healing, 2 superficial infections, 2 venous thrombosis) that all resolved. There were five cases of non-union (6.9%) that healed after being re-operated. After five years, secondary osteoarthritis led to the fusion being extended to the tibotalar joint (1 case) and midtarsal joint (1 case). At the last follow-up, the average MFS was 71.5 (range 25-100). Patient deemed the result as either excellent (10%), very good (9%), good (55%), poor (19%) or bad (7%). Pain at the last follow-up was present in 84% of cases. The rear-foot was normally aligned in 45% of cases, varus aligned in 22% and valgus aligned in 33%. The MFS was significantly better in patients with normal alignment. Patients with neurological foot disorders had significantly more preoperative (80% cavovarus) and postoperative foot deformity (P<0.05). At the last follow-up, the rate of secondary osteoarthritis in the surrounding joints was elevated: 73% tibiotalar, 58.3% subtalar, 65.8% talonavicular, 53.5% calaneocuboid. The presence of osteoarthritis was not correlated with pain or lower MFS. However there was significantly more pain at last follow-up than at 12 months postoperative and two fusions were required in patients with secondary osteoarthritis. Although partial or total arthrodesis of the subtalar and midtarsal joints is a reliable procedure, it induces secondary osteoarthritis. Even though it seems to be well tolerated more than 10 years after the initial procedure, this possibility must be discussed with young, active patients. IV, retrospective study.


Structural brain differences in essential tremor and Parkinson's disease deep brain stimulation patients.
Essential tremor (ET) and Parkinson's disease (PD) are the most common tremor disorders and are common indications for deep brain stimulation (DBS). In some patients, PD and ET symptoms overlap and diagnosis can be challenging based on clinical criteria alone. The objective of this study was to identify structural brain differences between PD and ET DBS patients to help differentiate these disorders and improve our understanding of the different brain regions involved in these pathologic processes. We included ET and PD patients scheduled to undergo DBS surgery in this observational study. Patients underwent 3T brain MRI while under general anesthesia as part of their procedure. Cortical thicknesses and subcortical volumes were quantified from T1-weighted images using automated multi-atlas segmentation. We used logistic regression analysis to identify brain regions associated with diagnosis of ET or PD. 149 ET and 265 PD patients were included. Smaller volumes in the pallidum and thalamus and reduced thickness in the anterior orbital gyrus, lateral orbital gyrus, and medial precentral gyrus were associated with greater odds of ET diagnosis. Conversely, reduced volumes in the caudate, amygdala, putamen, and basal forebrain, and reduced thickness in the orbital part of the inferior frontal gyrus, supramarginal gyrus, and posterior cingulate were associated with greater odds of PD diagnosis. These findings identify structural brain differences between PD and ET patients. These results expand our understanding of the different brain regions involved in these disorders and suggest that structural MRI may help to differentiate patients with these two disorders.


Prokaryotic transcription regulators: more than just the helix-turn-helix motif.
Over the past two years, the structures of many prokaryotic transcriptional regulators have been solved, and several of them have revealed the structural mechanism of gene regulation. The crystal structure of BmrR-TPP-DNA reveals a novel mechanism of transcription activation, whereby the drug-bound protein activates the bmr promoter by local DNA unwinding and base pair disruption. Myristoyl-CoA induces FadR by a three-helix pushing mechanism, whereas TetR employs a helical pendulum motion to regulate expression. The structures of AbrB, and DNA complexes of Rob and MuR unveil a novel DNA-binding motif, 'the looped-hinge helix', and new uses of the helix-turn-helix and winged helix motifs in DNA binding.


Descending pathways to the spinal cord, IV: Some factors related to the amount of cortex devoted to the corticospinal tract.
In the companion paper to this one (Nudo and Masterton: J. Comp. Neurol. 296:559-583, '90), we have presented data indicating that in each of 22 mammals, there are either 2 or 3 separate regions of neocortex contributing corticospinal fibers. In this paper, we describe the variation in the absolute size of these cortical regions, the total amount of neocortex contributing corticospinal fibers (CST cortex), and the total amount of neocortex (total cortex) in each of the animals. We then use strict statistical tests to examine the relationships between these measures and several other quantitative measures or descriptions of the animals' size, ancestral heritage, motor prowess, and ecological adaptation. The results show that the absolute amount of CST cortex is more closely related to the total amount of neocortex than to any other quantitative measure available. The further variation--that is, the variation in the amount of CST cortex relative to total neocortex--appears to have been random over the inferred ancestral lineages of most animals in the sample, but seems to have been almost absent along the anthropoid lineage. Because this constancy in the relative amount of CST cortex over a very long period of anthropoid ancestry is apparently unusual if not unique among mammals, it may contain a clue to the special role of the corticospinal tract among primates. Finally, the distribution of the CST among the 3 cortical regions in primates was found to be more closely related to their particular mode of ecological adaptation than to their particular combination of digital dexterity and hand-eye coordination.


A history of the treatment of craniopharyngiomas.
Nearly 100 years have passed since the first surgical attempt to remove a craniopharyngioma was undertaken, and the management of patients with these tumors continues to both challenge and frustrate those involved with their treatment. By constructing a historical framework from past literature on the treatment of craniopharyngioma, the authors have attempted to document the early and important events in the treatment of these tumors in order to add a historical dimension to their current treatment and to engender a more comprehensive understanding of the modern treatment of craniopharyngioma. The application of radiotherapeutic techniques to the management of craniopharyngioma would begin to complement the role of surgery, but debate would soon emerge as to what constituted the most appropriate management for craniopharyngioma in children.


Inter-observer variability of two grading systems for equine glandular gastric disease.
Equine glandular gastric disease (EGGD) is recognised as a separate entity to equine squamous gastric disease (ESGD) and it is recommended that lesions are graded differently. Currently, no validated scoring system exists for EGGD. To determine inter-observer reliability of two previously described grading systems for EGGD and to assess if agreement improved with gastroscopy experience, specialist training or familiarity with the descriptive system. Cross-sectional survey. A link to an electronic questionnaire containing 20 images of glandular lesions was circulated. Respondents were asked to score lesions using descriptive terminology and a 0-2 verbal rating scale (VRS). Krippendorff's alpha reliability estimate was used to assess inter-rater agreement. A mixed effects model was used to determine which descriptive categories were associated with lesions being described as severe and decision to treat. Eighty-two veterinarians responded, 49 diplomates and 33 non-diplomates. There was no agreement when all four descriptive variables were combined (α = 0.19). Agreement was fair to moderate for severity (α = 0.52), distribution (α = 0.44), appearance (α = 0.38) and shape (α = 0.32). Agreement for the VRS was similar to that for severity (α = 0.53). Agreement was better among diplomates across all categories. Lesion appearance and shape, but not distribution, were associated with both a decision to treat; and lesions being described as severe (P =< .05). A VRS score 2/2 was associated with a lesion being described as severe (OR 75.2, 95% CI 51.12-110.48, P =< .001). Intra-observer variability was not assessed. The number of images is relatively small, and the decision to treat is based on several factors in practice. Overall, agreement for the descriptive system was poor. Better delineation of descriptive category boundaries and characteristics should be determined. Agreement was similar when comparing the severity category and the VRS. Extrapolation to a VRS based on lesion severity may therefore be possible.


[Is it necessary for obstetricians to have their own opinion concerning cesarean delivery in patients with non-obstetric diseases].
The Bulgarian obstetricians always consider the recommendations of their non-obstetrician colleagues when a pregnant woman has a non-obstetrician disease. However the practice in the foreign countries is not the same. The modern obstetrician literature and our own experience tell us that the obstetrician must have his own opinion which might be different from the opinion of the "other" specialists.


Pancreatic intraductal tubulopapillary neoplasm progression requiring completion pancreatectomy: A case report and literature review.
Intraductal tubulopapillary neoplasm (ITPN) is a recently described rare tumor of the pancreas. Diagnostic approach and treatment are based on relatively few cases. Here we report a case of a 68-year-old male presenting with an ampullary adenoma with high grade dysplasia who underwent pancreaticoduodenectomy and was incidentally found to have an ITPN at the pancreatic resection margin with areas of microinvasion throughout the resected specimen. He went on to rapidly develop an invasive adenocarcinoma arising in association with recurrent ITPN in the remnant pancreas requiring a completion total pancreatectomy. Patients with ITPN present with non-specific symptoms and diagnosis can be challenging. Radiographic evaluation will reveal tumor ingrowth into the main pancreatic duct and distal duct dilatation without upstream dilation or mucinous engorgement. ITPNs are treated with formal resection given that determination of an invasive component can be difficult and the risk of malignant transformation. Following resection, recurrences are infrequent and 5-year survival is over 70 % even with microinvasion. ITPNs can follow a variable clinical course but hold the potential for malignant transformation. When ITPN is incidentally found at a pancreatic resection margin, we recommend completion resection due to the risk of local recurrence.


Rhabdomyosarcoma in middle-aged and elderly individuals.
In a review of a national series of malignant tumors in middle-aged and elderly individuals (over 40 years of age), in all 107 cases primarily diagnosed and reported to the Swedish Cancer Registry as rhabdomyosarcomas during the period 1972-1981, 4 cases were accepted as botryoid, embryonal or alveolar rhabdomyosarcoma, using light-microscopic criteria for the diagnosis. An electron-microscopic and immunohistochemical analysis was performed on the 4 cases along with 7 cases of botryoid, embryonal and alveolar rhabdomyosarcoma in patients of over 40 years of age obtained from our own files. Rhabdomyoblastic differentiation was established ultrastructurally by the presence of myofilaments and Z-like densities in 10 of these 11 cases. There were tumor cells in the formaldehyde-fixed, paraffin-embedded material which were positively stained for desmin in all cases, for myoglobin in 7/11 cases, for vimentin in 5/11 cases and for actin in all cases, using monoclonal antibodies. The demonstration of desmin by the monoclonal antibody which was used on the formaldehyde-fixed, paraffin-embedded material is of particular value in the diagnosis of rhabdomyosarcoma. Another tumor, located in the minor pelvis, lacked the light-microscopic features of botryoid, embryonal or alveolar rhabdomyosarcoma, but presented ultrastructural and immunohistochemical evidence of a rhabdomyoblastic differentiation. This tumor was epithelioid in appearance and shared features with alveolar soft part sarcoma. The label epithelioid rhabdomyosarcoma is proposed for this tumor. Nine pleomorphic sarcomas were selected from the national series as possible pleomorphic rhabdomyosarcomas because of the presence of ribbon-shaped tumor cells with an eosiniphilic cytoplasm. There was no electron-microscopic or immunohistochemical evidence of a myogenic differentiation in any of these 9 tumors. The present investigation indicates that a pleomorphic type of rhabdomyosarcoma, indistinguishable from embryonal, botryoid and alveolar rhabdomyosarcoma, is extremely rare or non-existent.


[Telangiectatic osteosarcoma: report of 10 cases].
To raise the level of early diagnosis of telangiectatic osteosarcoma (TOS). Ten patients with TOS were treated from July 1991 to December 1998. The patients included men 6 and 4 women, aged from 4 to 44 years (average 23.7 years). The lesions were located at the proximal femur (1 patient), distal femur metaphysis (2), femur shaft (1), proximal tibia metaphysis (2), distal tibia (1) and humerus shaft (3). Preoperative pathologic examination showed two cases of TOS by open biopsy(negative by needle biopsy); the rest were found negative (2 patients), metastasis (1), and sarcoma (5) by needle biopsy. Eight patients received preoperative chemotherapy. Operations including limb-salvage (3) and amputation (7) were performed in all patients. All patients accepted postoperative chemotherapy. 10 Follow-up for a mean of 28 months (range 6 - 72 months) showed no local recurrences: disease-free in 4 patients and pulmonary metastasis in, 6, of whom 5 died and 1 is still alive with lung metastasis. TOS is often misdiagnosed and needs early diagnosis and correct treatment under the cooperation of clinicians, radiologists and pathologists.


[Dermatofibrosarcoma protuberans].
Dermatofibrosarcoma protuberans (DFSP) is a rare tumor but still the most common cutaneous sarcoma. DFSP is a tumor of fibroblastic origin, characterized by a slow, undermining and locally destructive growth pattern, which only rarely metastasizes. The clinical appearance, especially of smaller lesions, is often not characteristic, so that diagnosis is often made late and only on biopsy findings. The standard treatment of DFSP is excision with safety margins of 2 to 3 cm. If smaller margins are employed, the risk of local relapse is high. Surgically incurable or metastatic DFSP can be irradiated; the cells are generally radiation-sensitive. 90% of DFSP carry a chromosome translocation of 17 and 22, harboring a gene fusion, which results in a continuous activation of the PDGFbeta signal transduction pathway. This finding led the way to a new molecular targeted therapy of DFSP using inhibitors of the PDGFbeta pathway. The first drug to be registered for targeted treatment of locally advanced or metastasized DFSP is the multikinase inhibitor imatinib, showing a response of about 70% in clinical trials.


The sequence analysis of Epstein-Barr virus EBNA1 gene: could viral screening markers for nasopharyngeal carcinoma be identified?
Epstein-Barr virus (EBV) has been identified as a group 1 carcinogenic agent, particularly for nasopharyngeal carcinoma (NPC). The sequence diversity of EBV nuclear antigen 1 (EBNA1) reflects region-restricted polymorphisms, which may be associated with the development of certain malignancies. The aims of the present study were to evaluate EBV EBNA1 gene polymorphisms circulating in NPC, infectious mononucleosis, and isolates from patients with transplanted organs to determine if EBNA1 sequence specificities are useful as viral biomarkers for NPC. Forty biopsies of undifferentiated carcinoma of nasopharyngeal type (UCNT), 31 plasma samples from patients with mononucleosis syndrome, and 16 plasma samples from patients after renal transplantation were tested in this study. The EBNA1 gene was amplified by nested PCR. Further investigation included sequencing, phylogenetic, and statistical evaluations. Eighty-seven sequences were identified as one of the four EBNA1 subtypes, P-Ala, P-Thr, V-Val, and V-Ala, with further classification into ten subvariants. Of these, P-Thr-sv-1 and P-Thr-sv-3 have never been identified in Europe, while V-Val-sv-1 was newly discovered. Statistical analysis revealed significant differences in the distribution of EBNA1 P-Thr subvariants between the three groups of patients, with noticeable clustering of P-Thr-sv-5 in NPC isolates (p < 0.001). EBV EBNA1 showed no sequence specificity in primary infection. This research revealed a newly discovered EBNA1 subvariant. Importantly, EBNA1 P-Thr-sv-5 showed carcinoma-specific EBNA1 variability. Thus, identification of this subvariant should be considered as a viral screening marker for NPC or UCNT.


Seroprevalence of Adeno-Associated Virus Neutralizing Antibodies in Males with Duchenne Muscular Dystrophy.
Adeno-associated virus (AAV)-based gene therapies are emerging strategies in Duchenne muscular dystrophy (DMD) treatment. Exposure to wild-type AAV can lead to development of neutralizing antibodies (NAbs) and blocking of AAV transduction, thereby limiting the delivery of AAV vector-based gene therapy. Therefore, it is imperative to check for the presence of AAV NAbs in a patient who is a candidate for gene therapy. We prospectively enrolled 101 genetically confirmed males with DMD (median age 11 years, 48% ambulatory and 59% on steroids) and performed AAV neutralization assays against AAV2, AAV8, AAV9, and AAVrh74 serotypes. The serotype analysis showed that AAV9 (36%) and AAVrh74 (32%) seroprevalence was lower compared with AAV2 (56%) and AAV8 (47%). Interestingly, age was not correlated with NAb titer for any of the capsids. NAb responses were observed at a higher frequency in African American participants and at a lower frequency in Caucasian participants for all four serotypes. Further analysis showed no significant differences in NAb titers regardless of serotype and whether participants were taking steroids or not. Finally, we observed higher AAV8, AAV9, and AAVrh74 seroprevalence and significantly higher AAV2 and AAV8 NAb titers in participants who were ambulatory compared with nonambulatory participants. Overall, these data identify AAV9 and AAVrh74 as the two serotypes with lower pre-existing NAb titers in this study's cohort of 101 males with DMD, possibly showing their utility in future gene therapy applications in treatment of this cohort of patients with DMD.


C2C12 cell model: its role in understanding of insulin resistance at the molecular level and pharmaceutical development at the preclinical stage.
The myoblast cell line, C2C12, has been utilised extensively in vitro as an examination model in understanding metabolic disease progression. Although it is indispensable in both preclinical and pharmaceutical research, a comprehensive review of its use in the investigation of insulin resistance progression and pharmaceutical development is not available. C2C12 is a well-documented model, which can facilitate our understanding in glucose metabolism, insulin signalling mechanism, insulin resistance, oxidative stress, reactive oxygen species and glucose transporters at cellular and molecular levels. With the aid of the C2C12 model, recent studies revealed that insulin resistance has close relationship with various metabolic diseases in terms of disease progression, pathogenesis and therapeutic management. A holistic, safe and effective disease management is highly of interest. Therefore, significant efforts have been paid to explore novel drug compounds and natural herbs that can elicit therapeutic effects in the targeted sites at both cellular (e.g. mitochondria, glucose transporter) and molecular level (e.g. genes, signalling pathway). The use of C2C12 myoblast cell line is meaningful in pharmaceutical and biomedical research due to their expression of GLUT-4 and other features that are representative to human skeletal muscle cells. With the use of the C2C12 cell model, the impact of drug delivery systems (nanoparticles and quantum dots) on skeletal muscle, as well as the relationship between exercise, pancreatic β-cells and endothelial cells, was discovered.


Bioaugmentation of soil contaminated with high-level crude oil through inoculation with mixed cultures including Acremonium sp.
Heavy contamination of soil with crude oil has caused significant negative environmental impacts and presents substantial hazards to human health. To explore a highly efficient bioaugmentation strategy for these contaminations, experiments were conducted over 180 days in soil heavily contaminated with crude oil (50,000 mg kg(-1)), with four treatments comprised of Bacillus subtilis inoculation with no further inoculation (I), or reinoculation after 100 days with either B. subtilis (II), Acremonium sp.(III), or a mixture of both organisms (IV). The removal values of total petroleum hydrocarbons were 60.1 ± 2.0, 60.05 ± 3.0, 71.3 ± 5.2 and 74.2 ± 2.7 % for treatment (I-IV), respectively. Treatments (III-IV) significantly enhanced the soil bioremediation compared with treatments (I-II) (p < 0.05). Furthermore, significantly (p < 0.05) greater rates of degradation for petroleum hydrocarbon fractions were observed in treatments (III-IV) compared to treatments (I-II), and this was especially the case with the degradative rates for polycyclic aromatic hydrocarbons and crude oil heavy fractions. Dehydrogenase activity in treatment (III-IV) containing Acremonium sp. showed a constant increase until the end of experiments. Therefore reinoculation with pure fungus or fungal-bacterial consortium should be considered as an effective strategy in bioaugmentation for soil heavily contaminated with crude oil.


Correction: A Prospective Cohort Study of Antipsychotic Medications in Pregnancy: The First 147 Pregnancies and 100 One Year Old Babies.
[This corrects the article DOI: 10.1371/journal.pone.0094788.].


Titanium implant materials with improved biocompatibility through coating with phosphonate-anchored cyclic RGD peptides.
One key point for improving osseous integration of implants is to render them osteopromotive by specifically favoring the adhesion of osteoblasts. Mimicking the physiological adhesion process of osteoblasts to the extracellular matrix improves cell adhesion in vitro and results in improved and earlier osseous integration of implants in vivo. Our approach involves coating titanium implants with a tailor-made cyclic-RGD peptide, thus allowing them to bind to specific integrin receptors on the cell surface through multimeric phosphonates. The advantages of this very stable, new type of anchoring for practical application are presented.


Human-associated bacteria adopt an unusual route for synthesizing 3-acetylated tetramates for environmental adaptation.
Tetramates or tetramic acid-containing compounds (TACs) are a group of bioactive natural products featuring a pyrrolidine-2,4-dione ring acknowledged being closed via Dieckmann cyclization. The cariogenic Streptococcus mutans strains bearing a muc biosynthetic gene cluster (BGC) can synthesize mutanocyclin (MUC), a 3-acetylated TAC that can inhibit both leukocyte chemotaxis and filamentous development in Candida albicans. Some strains can also accumulate reutericyclins (RTCs), the intermediates of MUC biosynthesis with antibacterial activities. However, the formation mechanism of the pyrrolidine-2,4-dione ring of MUC and the distribution of muc-like BGCs along with their ecological functions has not been explored extensively. We demonstrated that a key intermediate of MUC biosynthesis, M-307, is installed by a hybrid nonribosomal peptide synthetase-polyketide synthase assembly line and its pyrrolidine-2,4-dione ring is closed via an unprecedented lactam bond formation style. Subsequent C-3 acetylation will convert M-307 to RTCs, which is then hydrolyzed by a deacylase, MucF, to remove the N-1 fatty acyl appendage to generate MUC. Distribution analysis showed that the muc-like BGCs distribute predominantly in human-associated bacteria. Interestingly, most of the muc-like BGCs possessing a mucF gene were isolated from human or livestock directly, indicating their involvement in alleviating the host's immune attacks by synthesizing MUC; while those BGCs lacking mucF gene distribute mainly in bacteria from fermented products, suggesting that they tend to synthesize RTCs to compete with neighboring bacteria. It is noteworthy that many bacteria in the same habitats (e.g., the oral cavity) lack the muc-like BGC, but possess functional MucF homologues to "detoxify" RTCs to MUC, including several competitive bacteria of S. mutans. We also comparably studied the distribution of TAS1, a fungal enzyme responsible for the production of phytotoxic tenuazonic acids (TeAs), a class of 3-acetylated TACs with similar structure but distinct biosynthetic mechanism to MUC, and found that it mainly exists in plants or crops. The in vivo and in vitro experiments revealed that the pyrrolidine-2,4-dione ring of MUC is closed via lactam bond formation, which may be adopted by many TACs without 3-acyl decorations. Besides, we found that muc-like BGCs are widespread in human-associated bacteria and their shapes and main products can be influenced by the habitat environment and vice versa. By comparing with TeAs, we provided thought-provoking insights into how ecological and evolutionary forces drive bacteria and fungi to construct a common 3-acetylated pyrrolidine-2,4-dione core through different routes, and how the biosynthetic processes are delicately controlled to generate diverse 3-acetylated TACs for environmental adaptation. Video Abstract.


The activity and sedimentation properties of the aminoacyl-tRNA synthetases of rat skeletal muscle.
The aminoacyl-tRNA synthetases of the postribosomal supernatant fraction of rat skeletal muscle were characterized by their activity and sedimentation properties. The synthetases of muscle were compared with those of liver in terms of these parameters. Extraction of the synthetases of muscle with a buffer containing 4 mM adenosine triphosphate (ATP) resulted in a 50--100% increase in the activities of glutaminyl-, glutamyl-, isoleucyl-, leucyl-, lysyl-, methionyl-, and prolyl-tRNA synthetases in the postribosomal fraction, over those activities extracted in the absence of ATP. This effect of ATP was specific for those synthetases which sedimented as particulate elements in sucrose gradients, and appeared to be unique to muscle. The individual synthetase activities of muscle, except alanyl-, leucyl-, and valyl-tRNA synthetases, were aprrox. 25% of the corresponding synthetase activities of liver. Sucrose density gradient analysis of the postribosomal fraction of muscle and liver revealed that the sedimentation profiles of the synthetases of the two tissues were similar, with nine synthetase activities sedimenting as large particulate entities at 18 S. The findings suggest that the particulate forms of the synthetases reflect true association of the enzymes with a high molecular weight cellular component common to both tissues.


Location of stents in the left anterior descending coronary artery using three dimensionally acquired, two dimensionally displayed transthoracic echocardiography.
The location of left anterior descending arterial stents was documented in 10 of 13 patients using 3-dimensionally acquired, 2-dimensionally displayed transthoracic echocardiography. The echocardiographic appearance of stents was characterized, and the location of the proximal and mid-left anterior descending artery was objectively documented.


Low doses of apomorphine transiently reduce locomotor activity in MPTP-treated mice.
Parkinson's disease patients sometimes experience deterioration of motor function to below their baseline "off" state, termed the "super-off" state. We used low subthreshold (0.05 mg/kg) to threshold (0.10 and 0.20 mg/kg) doses of apomorphine to demonstrate the "super-off" state in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned mice. Twenty-four mice were randomized to receive apomorphine or vehicle. Within 20 min of administration, 0.10 and 0.20 mg/kg apomorphine-treated mice had less locomotion than controls. At the 100 min time point, 0.10 mg/kg apomorphine-treated mice had greater locomotion than controls. One week of suprathreshold levodopa pretreatment did not alter the response to these low apomorphine doses. Our results suggest that low doses of apomorphine can initially depress locomotion and subsequently stimulate locomotion, in a manner similar to what is seen in Parkinson's disease patients.


Hypercoagulability and ischaemic heart disease.
Thrombogenesis is increasingly recognised as an immediate cause of most major clinical episodes of ischaemic heart disease (IHD) and the haemostatic system makes a significant contribution to the development of atheroma. It is therefore important to consider how far concepts of increased thrombotic tendency and hypercoagulability can be demonstrated in reality. A number of general observations do suggest that characteristics of the circulating blood influence the course of events in IHD--for example, the occurrence of IHD or stroke in young women using oral contraceptives in whom advanced arterial wall changes are not a feature. Epidemiologically, the coagulation system has been more rewarding than the study of platelets. The Northwick Park Heart Study (NPHS) has demonstrated a strong relationship between the level of factor VII activity and the later incidence of IHD. Several biochemical characteristics of factor VII suggest that this relationship may well be one of cause and effect. There is growing evidence that high levels of factor VII activity lead to high levels of thrombin production. In addition to NPHS, three other prospective studies have shown an association between high levels of plasma fibrinogen and IHD incidence. Again, there are several reasons for believing that this association, too, is of pathogenetic significance. Dietary fat intake is a major determinant of the factor VII activity level, and smoking of the fibrinogen level. Hypercoagulability determining IHD is best defined, on present evidence, as over-activity of procoagulatory influences (whereas hypercoagulability leading to venous thrombosis is predominantly manifested as underactivity of natural defence mechanisms).(ABSTRACT TRUNCATED AT 250 WORDS)


CT findings of 144 in-hospital patients with influenza pneumonia: A retrospective analysis.
Patients with influenza infection during their period of admission may have worse computed tomography (CT) manifestation according to the clinical status. This study aimed to evaluate the CT findings of in-hospital patients due to clinically significant influenza pneumonia with correlation of clinical presentations. In this retrospective, single center case series, 144 patients were included. All in-hospital patients were confirmed influenza infection and underwent CT scan. These patients were divided into three groups according to the clinical status of the most significant management: (1) without endotracheal tube and mechanical ventilator (ETTMV) or extracorporeal membrane oxygenation (ECMO); (2) with ETTMV; (3) with ETTMV and ECMO. Pulmonary opacities were scored according to extent. Spearman rank correlation analysis was used to evaluate the correlation between clinical parameters and CT scores. The predominant CT manifestation of influenza infection was mixed ground-glass opacity (GGO) and consolidation with both lung involvement. The CT scores were all reach significant difference among all three groups (8.73 ± 6.29 vs 12.49 ± 6.69 vs 18.94 ± 4.57, p < 0.05). The chest CT score was correlated with age, mortality, and intensive care unit (ICU) days (all p values were less than 0.05). In addition, the CT score was correlated with peak lactate dehydrogenase (LDH) level and peak C-reactive protein (CRP) level (all p values were less than 0.05). Concomitant bacterial infection had higher CT score than primary influenza pneumonia (13.02 ± 7.27 vs 8.95 ± 5.99, p < 0.05). Thin-section chest CT scores correlated with clinical and laboratory parameters in in-hospital patients with influenza pneumonia.


Kidney Clinicians' Perceptions of Challenges and Aspirations to Improve End-Of-Life Care Provision.
End-of-life care is an essential part of integrated kidney care. However, renal clinicians' experiences of care provision and perceptions of end-of-life care needs are limited. This study explored renal clinicians' experiences of providing end-of-life care and developed recommendations to improve experiences. An exploratory qualitative study using semistructured focus groups and 1 interview was undertaken at 5 kidney services in Victoria, Australia. The transcripts were analyzed thematically. Between February and December 2017, 54 renal clinicians (21 doctors and 33 nurses) participated in the study. Clinicians reported multiple challenges of end-of-life care experiences resulting in compromised treatment planning and decision making and highlighted priorities to guide better care experiences. Challenges of providing end-of-life care were underpinned by mismatches in illness and treatment expectations, limited engagement in advance care planning, medical complexity, and differences between clinicians and patients in what constituted quality of life. These challenges were associated with compromised end-of-life care planning, which resulted in care experiences that were rushed with a prolonged treatment focus, risking limited preparation for death and moral distress. Clinicians aspired for positive end-of-life care experiences, including patient control and consensus in decision making, and a coordinated and collaborative approach across healthcare providers. Renal clinicians highlighted multiple factors and circumstances which resulted in experiences of compromised end-of-life care for patients with kidney disease. To improve care experiences, clinician-directed priorities included more training and support to facilitate systematic and earlier discussions about illness expectations and end-of-life care planning and greater communication and collaboration across healthcare providers is required.


Comparison of oral microbiome profiles in stimulated and unstimulated saliva, tongue, and mouth-rinsed water.
Epidemiological studies using saliva have revealed relationships between the oral microbiome and many oral and systemic diseases. However, when collecting from a large number of participants such as a large-scale cohort study, the time it takes to collect saliva can be a problem. Mouth-rinsed water, which is water that has been used to rinse the oral cavity, can be used as an alternative method for collecting saliva for oral microbiome analysis because it can be collected in a shorter time than saliva. The purpose of this study was to verify whether mouth-rinsed water is a suitable saliva substitute for analyzing the oral microbiome. We collected samples of mouth-rinsed water, stimulated saliva, unstimulated saliva, and tongue coating from 10 systemic healthy participants, and compared the microbial diversity and composition of the samples using next-generation sequencing of 16S rRNA-encoding genes. The results showed that the microbial diversity of mouth-rinsed water was similar to that of unstimulated and stimulated saliva, and significantly higher than that of tongue-coating samples. The microbial composition at the species level of mouth-rinsed water also showed a very high correlation with the composition of unstimulated and stimulated saliva. These results suggest that the mouth-rinsed water is a suitable collection method instead of saliva for oral microbiome analysis.


Acquisition and retention of military surgical competencies: a survey of surgeons' experiences in the UK Defence Medical Services.
The acquisition and retention of militarily relevant surgical knowledge and skills are vital to enable expert management of combat casualties on operations. Opportunities for skill sustainment have reduced due to the cessation of combat operations in Iraq and Afghanistan and lack of military-relevant trauma in UK civilian practice. A voluntary, anonymous online survey study was sent to all UK Defence Medical Services (DMS) surgical consultants and higher surgical trainees in Trauma and Orthopaedics, Plastic and Reconstructive, and General and Vascular surgical specialties (three largest surgical specialties in the DMS in terms of numbers). The online questionnaire tool included 20 questions using multiple choice and free text to assess respondents' subjective feelings of preparedness for deployment as surgeons for trauma patients. There were 71 of 108 (66%) responses. Sixty-four (90%) respondents were regular armed forces, and 46 (65%) worked in a Major Trauma Centre (MTC). Thirty-three (47%) had never deployed on operations in a surgical role. Nineteen (27%) felt they had sufficient exposure to penetrating trauma. When asked 'How well do you feel your training and clinical practice prepares you for a surgical deployment?' on a scale of 1-10, trainees scored significantly lower than consultants (6 (IQR 4-7) vs 8 (IQR 7-9), respectively; p<0.001). There was no significant difference in scores between regular and reservists, or between those working at an MTC versus non-MTC. Respondents suggested high-volume trauma training and overseas trauma centre fellowships, simulation, cadaveric and live-tissue training would help their preparedness. There was a feeling among a sample of UK DMS consultants and trainees that better preparedness is required for them to deploy confidently as a surgeon for combat casualties. The responses suggest that UK DMS surgical training requires urgent attention if current surgeons are to be ready for their role on deployed operations.


Do cancer patients use the term resilience? A systematic review of qualitative studies.
Resilience is a dynamic process of positive adaptation to adversity, including cancer. While the term is used frequently by researchers, controversy exists over its conceptualisation and little is known if and how cancer patients use the term resilience. We examined qualitative studies exploring cancer patient experiences/perceptions of resilience to understand: (a) definitions of resilience as identified by patients and researchers and (b) the themes relating to attributes of resilience as identified by patients. Four electronic databases (MEDLINE, PsycINFO, SCOPUS, and CINAHL) were searched from database inception to November 2017, identifying qualitative studies of adult cancer patients/survivors which included resilience and cancer in the title, abstract, or medical subject headings. Articles were excluded if resilience was not a theme or outcome or was discussed primarily in the context of non-individuals. Thematic analysis was used to code studies and generate analytical themes, and a single author identified definitions of resilience within the studies. Five hundred and seventy-three non-duplicate citations were screened, resulting in 65 citations screened for full-text review. Of these, 33 were excluded, leaving 32 studies. Four thematic categories emerged; coping strategies, social support, spirituality, and growth, within which 79 individual themes were identified. Eight researcher definitions and no patient definitions of resilience were identified. This review found no cancer patient definitions of resilience and that cancer patients are seldom quoted using the term resilience directly, instead identifying coping strategies, social support, growth, and spirituality as attributes associated with resilience.


Nutrient dynamics and retention in a vegetated drainage ditch receiving nutrient-rich sewage at low temperatures.
Vegetated agricultural drainage ditches (VDs) are a relatively new best management practice for pesticide and nutrient mitigation that is receiving increasing global interest. However, VDs are seldom used during winter due to considerable deterioration of pollutants reduction efficiencies driven by low-temperature effects. Limited knowledge on the internal loading of nutrient in VDs due to vegetation decomposition calls for further evaluation. Here, we assessed plants growth characteristics and nutrient dynamics in a field-scale VD receiving nutrient-rich sewage and planted with the overwintering plants: Acorus gramineus, Myriophyllum aquaticum and Iris sibirica. Water purification performance showed average TN, NH4-N, NO3-N, TP and PO4-P reduction efficiencies of 44, 46, 43, 52 and 46%, respectively, over the winter period. Maximum reduction rates of TN and TP were 5.31 and 0.34 g-2 d-1, respectively. Of the total nutrient removal by plants of 5.37 × 103 kg N y-1 and 0.65 × 103 kg P y-1 from the VD system, A. gramineus contributed 65.7% and 72.1%, respectively. Nonetheless, substantial amounts of N and P retained within the aboveground biomass were released into the water column as ditch plant shoots decayed to deteriorate the water quality. All three species, A. gramineus, M. aquaticum and I. sibirica demonstrated considerable nutrient accumulation during winter and facilitated nutrient retention in the VD system. Consequently, they can be considered effective overwintering species of choice in VDs for purifying nutrient-rich water and potentially appropriate for vulgarizing elsewhere, particularly throughout the winter season.


A 3D printed microfluidic device for scalable multiplexed CRISPR-cas12a biosensing.
Accurate, rapid, and multiplexed nucleic acid detection is critical for environmental and biomedical monitoring. In recent years, CRISPR-Cas12a has shown great potential in improving the performance of DNA biosensing. However, the nonspecific trans-cleavage activity of Cas12a complicates the multiplexing capability of Cas12a biosensing. We report a 3D-printed composable microfluidic plate (cPlate) device that utilizes miniaturized wells and microfluidic loading for a multiplexed CRISPR-Cas12a assay. The device easily combines loop-mediated isothermal amplification (LAMP) and CRISPR-Cas12a readout in a simple and high-throughput workflow with low reagent consumption. To ensure the maximum performance of the device, the concentration of Cas12a and detection probe was optimized, which yielded a four-fold sensitivity improvement. Our device demonstrates sensitive detection to the fg mL- 1 level for four waterborne pathogens including shigella, campylobacter, cholera, and legionella within 1 h, making it suitable for low-resource settings.


Highly-efficient, Rapid and continuous separation of surfactant-stabilized Oil/Water emulsions by selective under-liquid adhering emulsified droplets.
Anti-adhesion is considered to be the basis for oil/water separation. However, this principle may not the superior choice for surfactant-stabilized oil/water emulsions owing to the inevitable adhesion of surfactant on the membrane, resulting in further adhesion of emulsified droplets and therefore attenuation in separation performance. Herein, we demonstrated a novel separation strategy for surfactant-stabilized oil/water emulsions by exploiting rather than preventing adhesion. A modified filter paper (mFP) with strong under-liquid adhesion to emulsified droplets was prepared, endowing it excellent separation performance for both surfactant-stabilized and surfactant free emulsions with very high separation efficiency (up to 99.9 %). Furthermore, the Random layer stacked scraps of mFP (RLS-mFP) were used to construct the separation device, which provided a labyrinthine but unobstructed flow path for emulsion because of the randomly stacked form and relatively large interspace among mFP scraps. The RLS-mFP has excellent separation performance with the separation flux for surfactant-stabilized oil-in-water and water-in-oil emulsions achieving 1035 and 3570 L m-2 h-1 respectively only under gravity. After 1-hour continuous separation, both flux and separation efficiency of RLS-mFP showed almost no decline comparing to initial flux for surfactant-stabilized emulsions. Meanwhile, the mFP could be easily recycled by rinsing and reused at least 50 times without sacrificing separation performance.


Dominant cataract and recessive specific-locus mutations detected in offspring of procarbazine-treated male mice.
The induction of dominant cataract mutations by procarbazine was studied concomitantly with the induction of specific-locus mutations in treated male mice. The most effective dose in the specific-locus test, 600 mg/kg of procarbazine, and a fractionated dose of 5 X 200 mg/kg were used. The frequencies of dominant cataract mutations were higher, but not significantly different from the historical control. The ratio between the number of recovered specific-locus and dominant cataract mutations was in accordance with that found in our experiments with gamma-rays (Ehling et al., 1982; Kratochvilova, 1981) or in experiments with ethylnitrosourea (Favor, 1986). A total of 3 dominant cataract mutations were recovered in the offspring of procarbazine-treated spermatogonial stem cells. Two mutations had complete penetrance while the third exhibited a reduced penetrance of approximately 70%. The viability and fertility of the heterozygotes of all 3 mutations were not affected. Only 1 mutation was shown to be viable as a homozygote.


Crystallization of a Keplerate-type polyoxometalate into a superposed kagome-lattice with huge channels.
Crystal structures of two Sr(2+) salts of the Keplerate-type polyoxometalate, [Mo(VI)(72)Mo(V)(60)O(372)(CH(3)COO)(30)(H(2)O)(72)](42-), have been determined by single crystal X-ray diffraction. One compound exhibits a superposed kagome-lattice with huge channels whose diameters measure approximately 3.0 nm, while the arrangement of the Keplerate anions in the other compound approximates to a distorted cubic close packing.


Correct identification and explanation of age-related changes are always possible.
In this commentary, it is argued that the definition of the time or the age variable in the models presented by Hofer and Sliwinski is ambiguous, and a standard interpretation of this time of age variable is proposed instead. Some simulation studies are presented, the results of which indicate that, even with age-heterogeneous cross-sectional data, correct identification of the true sources of age-dependent variation is possible. An important qualification, based on new methodological work in progress, is given of the scope of longitudinal designs. It is concluded that all kinds of age-related changes are potentially interesting and can be correctly identified and explained.


Radiomics models based on multi-sequence MRI for preoperative evaluation of MUC4 status in pancreatic ductal adenocarcinoma: a preliminary study.
Mucin 4 (MUC4) overexpression promotes tumorigenesis and increases the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). To date, no study has reported the association between radiomics and MUC4 expression in PDAC. Thus, we aimed to explore the utility of radiomics based on multi-sequence magnetic resonance imaging (MRI) to predict the status of MUC4 expression in PDAC preoperatively. This retrospective study included 52 patients with PDAC who underwent MRI. The patients were divided into two groups based on MUC4 expression status. Two feature sets were extracted from the arterial and portal phases (PPs) of dynamic contrast-enhanced MRI (DCE-MRI). Univariate analysis, minimum redundancy maximum relevance (MRMR), and principal component analysis (PCA) were performed for the feature selection of each dataset, and features with a cumulative variance of 90% were selected to develop radiomics models. Clinical characteristics were gathered to develop a clinical model. The selected radiomics features and clinical characteristics were modeled by multivariable logistic regression. The combined model integrated radiomics features from different selected data sets and clinical characteristics. The classification metrics were applied to assess the discriminatory power of the models. There were 22 PDACs with a high expression of MUC4 and 30 PDACs with a low expression of MUC4. The area under the receiver operating characteristic (ROC) curve (AUC) values of the arterial phase (AP) model, the PP model, and the combined model were 0.732 (0.591-0.872), 0.709 (0.569-0.849), and 0.861 (0.760-0.961), respectively. The AUC of the clinical model was 0.666 (0.600-0.682). The combined model that was constructed outperformed the AP, the PP, and the clinical models (P<0.05, although no statistical significance was observed in the combined model vs. AP model). Radiomics models based on multi-sequence MRI have the potential to predict MUC4 expression levels in PDAC.


Signature MicroRNA expression profile is associated with lipid metabolism in African green monkey.
Non-human primates (NHPs) are important models of medical research on obesity and cardiovascular diseases. As two of the most commonly used NHPs, cynomolgus macaque (CM) and African green monkey (AGM) own different capacities in lipid metabolism of which the mechanism is unknown. This study investigated the expression profiles of lipid metabolism-related microRNAs (miRNAs) in CM and AGM and their possible roles in controlling lipid metabolism-related gene expression. By small RNA deep sequencing, the plasma miRNA expression patterns of CM and AGM were compared. The lipid metabolism-related miRNAs were validated through quantitative reverse-transcription (RT) polymerase chain reaction (PCR). Related-target genes were predicted by TargetScan and validated in Vero cells. Compared to CM, 85 miRNAs were upregulated with over 1.5-fold change in AGM of which 12 miRNAs were related to lipid metabolism. miR-122, miR-9, miR-185, miR-182 exhibited the greatest fold changes(fold changes are 51.2, 3.8, 3.7, 3.3 respectively; all P < 0.01). And 77 miRNAs were downregulated with over 1.5-fold change in AGM of which 3, miR-370, miR-26, miR-128 (fold changes are 9.3, 1.8, 1.7 respectively; all P < 0.05) were related to lipid metabolism. The lipid metabolism-related gene targets were predicted by TargetScan and confirmed in the Vero cells. We report for the first time a circulating lipid metabolism-related miRNA profile for CM and AGM, which may add to knowledge of differences between these two non-human primate species and miRNAs' roles in lipid metabolism.


Glycerol acts as alternative electron sink during syngas fermentation by thermophilic anaerobe Moorella thermoacetica.
Moorella thermoacetica is an anaerobic thermophilic acetogen that is capable of fermenting sugars, H(2)/CO(2) and syngas (H(2)/CO). For this reason, this bacterium is potentially useful for biotechnology applications, particularly the production of biofuel from CO(2). A soil isolate of M. thermoacetica, strain Y72, produces both ethanol and acetate from H(2)/CO(2); however, the maximum concentrations of these two products are too low to enable commercialization of the syngas fermentation process. In the present study, glycerol was identified as a novel electron sink among the fermentation products of strain Y72. Notably, a 1.5-fold increase in the production of ethanol (1.4 mM) was observed in cultures supplemented with glycerol during syngas fermentation. This discovery is expected to aid in the development of novel methods that allow for the regulation of metabolic pathways to direct and increase the production of desirable fermentative compounds.


Effect of testosterone therapy on bone formation in an osteoporotic hypogonadal male.
Osteoporosis has been reported to complicate androgen deficiency in males. Accordingly, we have evaluated an osteoporotic hypogonadal male with bone histomorphometry before and after 6 months of testosterone replacement. Androgen therapy resulted in increases in relative osteoid volum, total osteoid surface, linear extent of bone formation, and bone mineralization. The dramatic histological response to hormonal replacement confirms the importance of androgens in bone modeling and remodeling.


Dual mode of binding of anti cancer drug epirubicin to G-quadruplex [d-(TTAGGGT)]4 containing human telomeric DNA sequence induces thermal stabilization.
Epirubicin exerts its anti cancer action by blocking DNA/RNA synthesis and inhibition of topoisomerase-II enzyme. Recent reports on its influence on telomere maintenance, suggest interaction with G-quadruplex DNA leading to multiple strategies of action. The binding of epirubicin with parallel stranded inter molecular G-quadruplex DNA [d-(TTAGGGT)]4 comprising human telomeric DNA sequence TTAGGG was investigated by absorption, fluorescence, circular dichroism and nuclear magnetic resonance spectroscopy. The epirubicin binds as monomer to G-quadruplex DNA with affinity, Kb1 = 3.8 × 106 M-1 and Kb2 = 2.7 × 106 M-1, at two independent sites externally. The specific interactions induce thermal stabilization of DNA by 13.2-26.3 °C, which is likely to come in the way of telomere association with telomerase enzyme and contribute to epirubicin-induced apoptosis in cancer cell lines. The findings pave the way for drug designing in view of the possibility of altering substituent groups on anthracyclines to enhance efficacy using alternate mechanism of its interaction with G4 DNA, causing interference in telomere maintenance pathway by inducing telomere dysfunction.


Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors.
Hemophilic patients with factor VIII (FVIII) and FIX inhibitors suffer from frequent bleeding episodes and reduced quality of life. To evaluate whether secondary prophylaxis with activated recombinant factor VII (rFVIIa) can safely and effectively reduce bleeding frequency as compared to conventional on-demand therapy. Thirty-eight male patients entered a 3-month preprophylaxis period to confirm high baseline bleeding frequency (mean > or = 4 bleeds per month). Twenty-two patients were randomized 1:1 to receive daily rFVIIa prophylaxis with either 90 or 270 microg kg(-1) for 3 months, followed by a 3-month postprophylaxis period. Bleeding frequency was reduced by 45% and 59% during prophylaxis with 90 and 270 microg kg(-1), respectively (P < 0.0001); however, there was no significant difference detected between doses. The majority of this reduction was maintained during the postprophylaxis period. Although all types of bleed were similarly reduced, the effect was most pronounced for spontaneous joint bleeds. Patients reported significantly fewer hospital admissions and days absent from work/school during prophylaxis as compared to the preprophylaxis period. No thromboembolic events were reported during prophylaxis. Clinically relevant reductions in bleeding frequency during prophylaxis as compared to conventional on-demand therapy were achieved without raising safety concerns. These results provide evidence for the concept of secondary rFVIIa prophylaxis in inhibitor patients with frequent bleeds.


Immunological tolerance loss vs. erythrocyte self antigens and cytokine network disregulation in autoimmune hemolytic anaemia.
Recent studies on animal and human autoimmune hemolytic anaemia (AIHA) suggest that the loss of immunological tolerance vs. erythrocyte (Er) self antigens (Ag) may be primed by different mechanisms: ignorance of Er self Ag, molecular mimicry between self and non-self Ag, polyclonal T and/or B cells activation, errors in central or peripheral tolerance, immunoregulatory disturbances including the alteration of cytokines network. In vitro stimulation by synthetic Rh peptides indicates that ignorant T and/or B cells from patients with AIHA may recognize criptic Er self Ag. The AIHA associated with bacterial or viral infections seems to be produced by polyclonal T and/or B cell activation against foreign Ag that mimics protein or carbohydrate epitopes on Er. Polyclonal activation of host B cell clones by donor T cells causes the AIHA in chronic graft-versus-host disease. Mouse lines expressing a transgene with autoantibody (autoAb) activity against murine Er have shown that non-deleted peripheral B cell clones may produce Er autoAb. In human a genetic defect of Fas/FasL autoreactive lymphocyte apoptosis may be associated with AIHA. Th1/Th2 cytokines or IL10/IL12 imbalance may induce AIHA: in NZB mice and in human AIHA there is an increased production of Th2 cytokines such as IL4 and IL10 but INF-gamma and IL12 reduced production. Particularly, IL10 seems to act as critical mediator for the Er autoAb production.


Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience.
Intensity-modulated radiation therapy (IMRT) is an advanced treatment delivery technique that can improve the therapeutic dose ratio. Its use in the treatment of inoperable non-small cell lung cancer (NSCLC) has not been well studied. This report reviews our experience with IMRT for patients with inoperable NSCLC. We performed a retrospective review of 55 patients with stage I-IIIB inoperable NSCLC treated with IMRT at our institution between 2001 and 2005. The study endpoints were toxicity, local control, and overall survival. With a median follow-up of 26 months, the 2-year local control and overall survival rates for stage I/II patients were 50% and 55%, respectively. For the stage III patients, 2-year local control and overall survival rates were 58% and 58%, respectively, with a median survival time of 25 months. Six patients (11%) experienced grade 3 acute pulmonary toxicity. There were no acute treatment-related deaths. Two patients (4%) had grade 3 or worse late treatment-related pulmonary toxicity. IMRT treatment resulted in promising outcomes for inoperable NSCLC patients.


The Impact of Surgical Staging on the Prognosis of Mucinous Borderline Tumors of the Ovaries: A Multicenter Study.
The purpose of this study was to prove the effect of complete surgical staging of patients with mucinous borderline ovarian tumors (mBOTs) especially appendectomy on progression-free survival (PFS) and overall survival (OS). The database of 14 gynecological oncology departments from Turkey and Germany were comprehensively searched for women who underwent primary surgery for an ovarian tumor between January 1, 1998, and December 31, 2015, and whose final diagnosis was mBOT. A total of 364 patients with mBOT with a median age of 43.1 years were included in this analysis. The median OS of all patients was 53.1 months. The majority of cases had Stage IA (78.6%). In univariate and multivariate analyses, radical surgery, omentectomy, appendectomy, lymphadenectomy, and adding adjuvant chemotherapy were not independent prognostic factors for PFS and OS. Furthermore, FIGO stage (≥IC vs. <IC), radical surgery, and staging surgery were not independent risk factors for recurrence of mBOTs. Finally, abnormal macroscopic appendix and FIGO stage (≥IC vs. <IC) were independent risk factors for appendiceal involvement (p=0.032). Patients with conservative surgery do not have higher recurrence rates. Fertility-sparing surgery should be considered in the reproductive age group. Detailed surgical staging including lymphadenectomy, appendectomy, and omentectomy does not have an impact on survival rates.


Digital PCR for discriminating mosaic deletions and for determining proportion of tumor cells in specimen.
Mosaicism, presence of a genetic feature in only a subpopulation of cells, is frequent in de novo genetic diseases. Among large deletions covering the NF1 tumor suppressor gene, the frequency of mosaicism can be as high as 40% in de novo patients. In this study, we demonstrate the high potential of digital PCR in detecting large NF1 deletions and in discriminating mosaic cases. By simultaneously assessing the NF1 gene and a reference gene RPP30, deletions could be unambiguously distinguished from non-deletion samples. Performing the same assay for mixed samples from a DNA with a deletion and a non-deletion DNA, a highly significant linear relation was obtained between the set-up ratio of the two samples and the measured ratio of NF1/RPP30 (P<0.0001), suggesting the high potential of digital PCR in discriminating mosaic deletions. Furthermore, digital PCR detects NF1 allele loss in a tumor specimen that was not detected by loss of heterozygosity analysis using polymorphic markers due to high content of non-tumor cells. Based on the measured ratio of NF1/RPP30, the proportion of the tumor cells in this specimen could be calculated as 25%. Our results demonstrate that dual-probe digital PCR is a simple and effective method for detecting deletions and for discriminating mosaic deletions. Furthermore, this method is sensitive for assigning somatic allele loss in tumor specimen and enables determining proportion of tumor cells.


Probiotics can treat hepatic encephalopathy.
Hepatic encephalopathy (HE) is a common and dreaded complication of liver disease. The effects of HE can range from minimal to life threatening. Even 'minimal HE' causes major dysfunction in many aspects of daily living. The exact pathogenesis of HE remains unknown. However, the products of gut flora metabolism are universally recognized as critical. Present treatments for HE include the cathartic agent lactulose and poorly absorbable antibiotics. While effective, these treatments incur numerous side-effects and cost. Probiotics are viable bacteria given orally to improve health. Probiotics have multiple mechanisms of action that could disrupt the pathogenesis of HE and may make them superior to conventional treatment.


From Fad to Fact: Evaluating the Impact of Emerging Diets on the Prevention of Cardiovascular Disease.
Cardiovascular disease remains one of the most prevalent and preventable chronic conditions worldwide. Diet modification is the foundation of cardiovascular disease prevention. Several dietary approaches have emerged to promote better cardiovascular health. The rapid dissemination of anecdotal and observational data through the internet and social media has caused confusion amongst providers and patients. The aim of this comprehensive review is to present objective insights into 2 of today's most popular fad diets: ketogenic diet and intermittent fasting. We will evaluate the performance of these diets based on their impact on cardiovascular risk factors.


Incomplete effector/memory differentiation of antigen-primed CD8+ T cells in gene gun DNA-vaccinated mice.
DNA vaccination is an efficient way to induce CD8+ T cell memory, but it is still unclear to what extent such memory responses afford protection in vivo. To study this, we induced CD8+ memory responses directed towards defined viral epitopes, using DNA vaccines encoding immunodominant MHC class I-restricted epitopes of lymphocytic choriomeningitis virus covalently linked to beta2-microglobulin. This vaccine construct primed for a stronger recall response than did a more conventional minigene construct. Despite this, vaccinated mice were only protected against systemic infection whereas protection against the consequences of peripheral challenge was limited. Phenotypic analysis revealed that DNA vaccine-primed CD8+ T cells in uninfected mice differed from virus-primed CD8+ T cells particularly regarding expression of very-late antigen (VLA)-4, an adhesion molecule important for targeting T cells to inflammatory sites. Thus, our DNA vaccine induces a long-lived memory CD8+ T cell population that provides efficient protection against high-dose systemic infection. However, viral replication in solid non-lymphoid organs is not curtailed sufficiently fast to prevent significant virus-induced inflammation. Our results suggest that this is due to qualitative limitations of the primed CD8+ T cells.


Parotid gland tumors: comparison of conventional and diffusion-weighted MRI findings with histopathological results.
The aim of this study was to investigate the relationship between pathological classification of parotid gland tumors and conventional MRI - diffusion-weighted imaging findings and also contribute the possible effect of apparent diffusion coefficient (ADC) to diagnosis. 60 patients with parotid masses diagnosed using histopathology and/or cytology were enrolled in this retrospective study. All patients were evaluated using a 1.5 T MRI. Demographic features, conventional MRI findings, and ADC values (mean, minimum, maximum, and relative) were recorded. MRI findings and ADC values were compared between benign-malignant groups and pleomorphic adenoma vs Warthin's tumor groups. 60 tumors (48 benign, 12 malignant) were evaluated in a total of 60 patients (39 males, 21 females). The mean age was 59 (±14, 18-86) years old; the mean lesion size was 26 (±10, 11-61) mm. On the texture of conventional MRI, T2 dominantly hyperintense/with hypointensity signal was seen in 87% of pleomorphic adenomas and T2 dominantly hypointense/with hyperintesity signal was encountered in 64% of all Warthin's tumors. Seven (28%) Warthin's tumors were misdiagnosed as pleomorphic adenomas and two others (8%) as malignant tumors. The commonly used mean ADC value was 1.6 ± 0.6 × 10-3 mm2 s-1 for benign tumors, 0.8 ± 0.3 × 10-3 mm2 s-1 for malign tumors, 1 (0.9-1.8) × 10-3 mm2 s-1 for Warthin's tumors, and 1.9 ± 0.3 × 10-3 mm2 s-1 for pleomorphic adenomas. There was a statistically significant difference in ADC values between benign-malignant tumors and pleomorphic adenomas-Warthin's tumors. Warthin's tumor may occasionally be misdiagnosed as pleomorphic adenoma and malignant tumor because of variable morphologic features. In addition to benign-malignant differentiation, the added ADC measurement may also be useful for differentiating Warthin's tumors from pleomorphic adenomas.