Mutually repressive interaction between Brn1/2 and Rorb contributes to the establishment of neocortical layer 2/3 and layer 4.
Although several molecules have been shown to play important roles in subtype specification of neocortical neurons, the entire mechanism involved in the specification, in particular, of upper cortical plate (UCP) neurons still remains unclear. The UCP, which is responsible for intracortical connections in the neocortex, comprises histologically, functionally, and molecularly different layer 2/3 (L2/3) and L4. Here, we report the essential interactions between two types of transcription factors, Rorb (RAR-related orphan receptor beta) and Brn1/2 (Brain-1/Brain-2), for UCP specification. We found that Brn2 expression was detected in all upper layers in the immature UCP, but was subsequently restricted to L2/3, accompanied by up-regulation of Rorb in L4, suggesting demarcation of L2/3 and L4 during cortical maturation. Rorb indeed inhibited Brn2 expression and the expression of other L2/3 characteristics, revealed by ectopic expression and knockdown studies. Moreover, this inhibition occurred through direct binding of Rorb to the Brn2 locus. Conversely, Brn1/2 also inhibited Rorb expression and the expression of several L4 characteristics. Together, these results suggest that a mutually repressive mechanism exists between Brn1/2 and Rorb expression and that the established expression of Brn1/2 and Rorb further specifies those neurons into L2/3 and L4, respectively, during UCP maturation.


Effect of vitamin D3 vs. calcifediol on VDR concentration and fiber size in skeletal muscle.
This study sought to examine the effect of vitamin D3 (VD3) 3200 IU/d, calcifediol (HyD) 20mcg/d, or placebo on intramyonuclear vitamin D receptor (VDR) concentration, muscle fiber cross-sectional area (FCSA), and muscle satellite cell activation. It was conducted on a subset of the VD3 (n = 12), HyD (n = 11), and placebo (n = 13) groups who participated in the 6-month randomized controlled HyD Osteopenia Study in postmenopausal women. Baseline and 6-month vastus lateralis muscle cross sections were probed for VDR, fiber type I and II, and PAX7 (satellite cell marker) using immunofluorescence. Baseline mean ± SD age was 61 ± 4 years and serum 25-hydroxyvitamin D (25OHD) level was 55.1 ± 22.8 nmol/L. Baseline characteristics did not differ significantly by group. Six-month mean ± SD 25OHD levels were 138.7 ± 22.2 nmol/L (VD3), 206.8 ± 68.8 nmol/L (HyD), and 82.7 ± 36.1 nmol/L (placebo), ANOVA P < 0.001. There were no significant group differences in 6-month change in VDR concentration (ANOVA P = 0.227). Mean ± SD percent 6-month changes in type I FCSA were 20.5 ± 32.7% (VD3), - 6.6 ± 20.4% (HyD), and - 0.3 ± 14.0% (placebo, ANOVA P = 0.022). Type II FCSA or PAX7 concentration did not change significantly by group (all P > 0.358). This study demonstrated no significant change in intramyonuclear VDR in response to either form of vitamin D vs. placebo. Type I FCSA significantly increased with VD3, but not with HyD at 6 months. As type I fibers are more fatigue resistant than type II, enlargement in type I suggests potential for improved muscle endurance. Although HyD resulted in the highest 25OHD levels, no skeletal muscle benefits were noted at these high levels. NCT02527668.


The influence of shrinkage-cracking on the drying behaviour of White Portland cement using Single-Point Imaging (SPI).
The removal of water from pores in hardened cement paste smaller than 50 nm results in cracking of the cement matrix due to the tensile stresses induced by drying shrinkage. Cracks in the matrix fundamentally alter the permeability of the material, and therefore directly affect the drying behaviour. Using Single-Point Imaging (SPI), we obtain one-dimensional moisture profiles of hydrated White Portland cement cylinders as a function of drying time. The drying behaviour of White Portland cement, is distinctly different from the drying behaviour of related concrete materials containing aggregates.


A case of hemiparesis associated with cranial nerve lesions due to intravascular lymphomatosis(2003:4b).
Intravascular lymphomatosis is a rare variant of non-Hodgkin's lymphoma with an unusual predilection for the central nervous system. Most cases are not diagnosed until postmortem because of variable clinical presentation and non-specific laboratory findings. We studied a 41-year-old lady who presented with progressive neurological symptoms. MR showed multifocal grey and white matter lesions. Brain biopsy showed an intravascular lymphoma of the B-cell lineage. This report illustrates the ischaemic origin of the radiological lesions, as they are all hyperintense on the diffusion-weighted images. This has, to our knowledge, never been published before. MR did not show any enhancement after intravenous Gadolinium-DTPA (parenchymal or meningeal)which is a very uncommon finding in this entity. Intravascular lymphomatosis should be taken into account in the differential diagnosis of repeated cerebral ischemia of unclear aetiology.


Can the benefits of cannabinoid receptor stimulation on neuroinflammation, neurogenesis and memory during normal aging be useful in AD prevention?
Alzheimer's disease has become a growing socio-economical concern in developing countries where increased life expectancy is leading to large aged populations. While curing Alzheimer's disease or stopping its progression does not appear within reach in a foreseeable future, new therapies capable of delaying the pathogenesis would represent major breakthroughs. The growing number of medical benefits of cannabinoids, such as their ability to regulate age-related processes like neuroinflammation, neurogenesis and memory, raise the question of their potential role as a preventive treatment of AD. To test this hypothesis, epidemiological studies on long term, chronic cannabinoid users could enlighten us on the potential benefits of these compounds in normal and pathological ageing processes. Systematic pharmacological (and thus more mechanistic) investigations using animal models of Alzheimer's disease that have been developed would also allow a thorough investigation of the benefits of cannabinoid pharmacotherapy in the pathogenesis of Alzheimer's disease. The chronic administration of non-selective cannabinoids may delay the onset of cognitive deficits in AD patients; this will dramatically reduce the socio-economic burden of AD and improve the quality of life of the patients and their families.


Sweet's syndrome.
Sweet's syndrome (acute neutrophilic dermatosis) is characterized by fever; polymorphonuclear neutrophilic leukocytosis; elevated ESR; and characteristic, raised, painful red plaques on the face and limbs. Since Sweet first described the syndrome in 1964, more than 150 cases have been reported, but it is assumed that the disorder is far more common than this number would indicate.


HER-2/neu-specific monoclonal antibodies collaborate with HER-2/neu-targeted granulocyte macrophage colony-stimulating factor secreting whole cell vaccination to augment CD8+ T cell effector function and tumor-free survival in Her-2/neu-transgenic mice.
HER-2/neu is overexpressed in several cancers including 30% of breast carcinomas, and correlates with a poor outcome. HER-2/neu-transgenic (neu-N) mice that overexpress the non-transforming rat neu develop spontaneous mammary carcinomas and demonstrate immunotolerance to the neu protein similar to that observed in patients with neu-expressing cancers. In neu-N mice, neu-targeted vaccination induces weak T cell and negligible Ab responses sufficient to delay but not eradicate transplanted neu-expressing tumor. Here we demonstrate that passive infusion of neu-specific mAbs in sequence with whole cell vaccination significantly improves tumor-free survival over either modality alone. Importantly, treatment of neu-N mice with vaccine in combination with two distinct neu-specific Abs is particularly efficacious, preventing tumor in 70% and eradicating established tumor in 30% of neu-N mice. In vivo lymphocyte subpopulation depletion experiments demonstrate that the efficacy of Ab, alone or combined with vaccine, is dependent on both CD4(+) and CD8(+) T cells. Furthermore, the in vivo antitumor effects of vaccine and Ab are associated with a significant increase in the number and function of neu-specific CD8(+) T cells. Collectively, these observations suggest that similarly increased efficacy could be obtained by combining neu-targeted vaccination and neu-specific Abs such as trastuzumab (Herceptin) in patients with neu-expressing cancers.


KRAS Exon 2 Mutations as Prognostic Indicators in Advanced Colorectal Cancer in Clinical Practice: A Mono-Institutional Study.
Kirsten-Ras (KRAS) mutations are widely accepted negative predictive factors for anti-EGFR therapies in metastatic colorectal cancer (mCRC), while their prognostic significance is still under discussion. This mono-institutional retrospective study aims to investigate the real-life impact of exon 2 codon 12 and 13 mutations in mCRC. All mCRC patients treated at our institution between 2008 and 2014 carrying KRAS exon 2 mutations were included. The primary endpoint was to determine any significant difference in overall survival (OS) between codon 12 and 13 mutations. Secondary endpoints included progression-free survival (PFS), OS in both populations according to antiangiogenic treatment, and OS in liver-limited disease (LLD). Of 620 mCRC patients, 218 carried KRAS exon 2 mutations (35.1%): 162 (26.1%) at codon 12 and 56 (9.0 %) at codon 13. Median OS results were similar: 32.0 months (codon 12) and 31.0 months (codon 13). PFS was also comparable, reaching 10.8 months in both populations. The addition of bevacizumab to chemotherapy conferred a trend toward survival advantage in codon 12 but not codon 13 mutation (p = 0.058). A high proportion of LLD patients underwent hepatic surgery with radical purpose (62.3%): in these patients, median OS has not yet been reached, while OS in non-LLD patients was 30.2 months. No difference in OS between KRAS codon 12/13 mutated disease was found. This analysis showed a very prolonged OS for KRAS-mutated patients, even when LLD patients were excluded; OS of our real-life series favorably compares with OS of all-RAS wild-type patients in recent randomized studies.


Tiam1 mediates Rac1 activation and contraction-induced glucose uptake in skeletal muscle cells.
Contraction-stimulated glucose uptake in skeletal muscle requires Rac1, but the molecular mechanism of its activation is not fully understood. Treadmill running was applied to induce C57BL/6 mouse hind limb skeletal muscle contraction in vivo and electrical pulse stimulation contracted C2C12 myotube cultures in vitro. The protein levels or activities of AMPK or the Rac1-specific GEF, Tiam1, were manipulated by activators, inhibitors, siRNA-mediated knockdown, and adenovirus-mediated expression. Activated Rac1 was detected by a pull-down assay and immunoblotting. Glucose uptake was measured using the 2-NBD-glucose fluorescent analog. Electrical pulse stimulated contraction or treadmill exercise upregulated the expression of Tiam1 in skeletal muscle in an AMPK-dependent manner. Axin1 siRNA-mediated knockdown diminished AMPK activation and upregulation of Tiam1 protein expression by contraction. Tiam1 siRNA-mediated knockdown diminished contraction-induced Rac1 activation, GLUT4 translocation, and glucose uptake. Contraction increased Tiam1 gene expression and serine phosphorylation of Tiam1 protein via AMPK. These findings suggest Tiam1 is part of an AMPK-Tiam1-Rac1 signaling pathway that mediates contraction-stimulated glucose uptake in skeletal muscle cells and tissue.


Rapid changes in arousal states of healthy volunteers during robot-assisted gait training: a quantitative time-series electroencephalography study.
Robot-assisted gait training (RAGT) is expected to be an effective rehabilitative intervention for patients with gait disturbances. However, the monotonous gait pattern provided by robotic guidance tends to induce sleepiness, and the resultant decreased arousal during RAGT may negatively affect gait training progress. This study assessed electroencephalography (EEG)-based, objective sleepiness during RAGT and examined whether verbal or nonverbal warning sounds are effective stimuli for counteracting such sleepiness. Twelve healthy men walked on a treadmill for 6 min, while being guided by a Gait-Assistance Robot, under 3 experimental conditions: with sine-wave sound stimulation (SS), verbal sound stimulation (VS), and no sound stimulation (NS). The volunteers were provided with warning sound stimulation at 4 min (ST1), 4 min 20 s (ST2), 4 min 40 s (ST3), and 5 min (ST4) after the start of RAGT. EEGs were recorded at the central (Cz) and occipital (O1 and O2) regions (International 10-20 system) before and during RAGT, and 4-s segments of EEG data were extracted from the filtered data during the 8 experimental periods: middle of the eyes-closed condition; middle of the eyes-open condition; beginning of RAGT; immediately before ST1; immediately after ST1, ST2, ST3, and ST4. According to the method used in the Karolinska drowsiness test, the power densities of the theta, alpha 1, and alpha 2 bands were calculated as indices of objective sleepiness. Comparisons of the findings between baseline and before ST showed that the power densities of the alpha 1 and 2 bands tended to increase, whereas the theta power density increased significantly (P < .05). During NS, the power densities remained at a constant high level until after ST4. During SS and VS, the power densities were attenuated immediately to the same degree and maintained at a constant low level until after ST4. This study is the first to demonstrate that EEG-measured arousal levels decrease within a short time during RAGT, but are restored and maintained by intermittent warning sound stimulation.


Cyclothiazide treatment unmasks AMPA excitotoxicity in rat primary hippocampal cultures.
Mechanisms of non-NMDA receptor-mediated excitotoxicity were studied in embryonic rat hippocampal cultures using kainic acid (KA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) as agonists. Under basal culture conditions, overnight treatment with AMPA resulted in negligible excitotoxicity as assessed by phase-contrast microscopy and measurement of lactate dehydrogenase (LDH) release. In contrast, similar treatment with KA resulted in marked excitotoxic morphologic changes and release of LDH. Cotreatment of cultures with AMPA but not NMDA effectively blocked KA toxicity, suggesting that AMPA-induced rapid desensitization of the AMPA/KA receptor could account for the lack of prominent direct toxicity as well as AMPA's ability to block KA toxicity. To test this hypothesis, cultures were briefly pretreated with 10 microM cyclothiazide, a drug reported to block desensitization of the AMPA/KA receptor, and then exposed overnight to cyclothiazide plus AMPA and/or KA. Cyclothiazide-treated cultures were now vulnerable to AMPA as well as KA; moreover, AMPA was unable to block KA toxicity completely, suggesting that cyclothiazide impaired AMPA/KA receptor desensitization. These and related studies suggest that a regulatory site may exist on the AMPA/KA receptor that modulates non-NMDA receptor-mediated excitotoxicity.


Nasopharyngeal cyst (report of eight cases).
Eight cases of nasopharyngeal cyst are reviewed. Five were asymptomatic. Marsupialization of the cyst provided adequate treatment in the three symptomatic cases.


Repair of partial anomalous pulmonary venous connection with a minimal atriotomy.
We present an alternative surgical technique for the repair of a partial anomalous pulmonary venous connection to the higher segment of the superior vena cava. Although the atriotomy is limited in this technique, a sufficiently large systemic venous chamber overlapping to the outside of the superior vena cava can be created.


Rapid customised operon assembly by yeast recombinational cloning.
We have developed a system called the Operon Assembly Protocol (OAP), which takes advantage of the homologous recombination DNA repair pathway in Saccharomyces cerevisiae to assemble full-length operons from a series of overlapping PCR products into a specially engineered yeast-Escherichia coli shuttle vector. This flexible, streamlined system can be used to assemble several operon clones simultaneously, and each clone can be expressed in the same E. coli tester strain to facilitate direct functional comparisons. We demonstrated the utility of the OAP by assembling and expressing a series of E. coli O1A O-antigen gene cluster clones containing various gene deletions or replacements. We then used these constructs to assess the substrate preferences of several Wzx flippases, which are responsible for translocation of oligosaccharide repeat units (O units) across the inner membrane during O-antigen biosynthesis. We were able to identify several O unit structural features that appear to be important determinants of Wzx substrate preference. The OAP system should be broadly applicable for the genetic manipulation of any bacterial operon and can be modified for use in other host species. It could also have potential uses in fields such as glycoengineering.


Treatment of patients with high-grade non-Hodgkin's lymphoma aged over 70 years with an all-oral regimen combining idarubicin, etoposide and alkylators.
In elderly patients age-specific comorbidity often reduces the possibility of administering intensive chemotherapy and of obtaining response to treatment. Therefore, chemotherapy must differ from that for non-elderly patients, while maintaining the primary goal of a complete clinical response. We treated 19 patients over the age of 70 years (median age 75 years, range 70-86) with stage II-IV high-grade non-Hodgkin's lymphoma (NHL) with a combination regimen including idarubicin plus etoposide and prednimustine (or chlorambucil+prednisone), all administered orally on an outpatient basis. The therapeutic schedule included six 5-day courses of idarubicin 20 mg/sqm on day 1 (or 10 mg/sqm on days 1 and 3 in the nine patients last treated), etoposide 60 mg/sqm/12 h days 2-5, prednimustine 60 mg/sqm days 2-5, G-CSF 300 microg/day from day+7 until PMN>1000/microl. In ten patients prednimustine was replaced by chlorambucil 10 mg/sqm, days 2-5, and prednisone 50 mg days 2-5, because of non-availability of the drug. Of the 19 patients submitted to this regimen 15 (79%) obtained a clinical response: eight reached a complete response (CR), and seven a partial response (PR). Hematologic toxicity was generally mild. Only three patients had to be hospitalised for infection. Except alopecia, non-hematologic toxicities were negligible. At a median follow-up of 16 months, five of eight patients who obtained CR relapsed (median CR duration 7 months). The actuarial median survival is 34 months (range 6-46). This study demonstrates the feasibility and efficacy of an all-oral regimen including idarubicin, plus etoposide and prednimustine (or chlorambucil+prednisone) in NHL patients aged over 70 years.


Novel environmentally friendly fuel: The effect of adding graphene quantum dot (GQD) nanoparticles with ethanol-biodiesel blends on the performance and emission characteristics of a diesel engine.
Biodiesel fuel has some disadvantages including increase in NOx, poor atomization and incomplete combustion. Additives and catalysts can be used to reduce the negative effects of biodiesel fuel. In addition, the use of metal oxide and metal nanoparticles causes environmental hazards. However, using biodegradable nanoparticles can significantly reduce such concerns. The present study investigated the effect of adding GQD + E to B10 fuel on the emission and performance characteristics of a diesel engine. B10 was blended with GQD (90 ppm) and bioethanol (E2, E4, E6 and E8% vol). Performance and emission characteristics, including power, torque, SFC, CO, CO2, UHC and NOx emissions were measured at the speeds of 1800, 2100 and 2400 rpm and full load mode. According to the results, the addition of GQD + E to B10 improved torque and power and decreased SFC, CO, UHC and NOx. Finally, the B10 + E6 + GQD90 fuel was the best fuel regarding improved engine performance and reduced exhaust emission. The average of changes in power and torque, SFC, CO, UHC and NOx compared to D100 for B10 + E6 + GQD90 were + 15.69%, +15.39%, -17.58%, -30.30%, -38.91% and -1.54%, respectively.


The impact of cervical cancer on quality of life--the components and means for management.
To review how cervical cancer patients are affected on a psychological, psychosocial, and sexual level, resulting in an overall decrease in quality of life (QoL). This article reviews influential studies on QoL in women with cervical cancer, as well as the effects on patients' partners. Based on the decreased QoL, we present three suggestions on how clinicians can better patients' QoL after an abnormal Papanicolaou (Pap) test or diagnosis and treatment of cervical cancer. Fear, self-blame, distress, and anxiety about cervical cancer are common in women who receive abnormal Pap test results or positive human papillomavirus DNA tests. Such results impact body image, self-esteem, relationships with partners, and sexual and reproductive issues, while adding to an overall decrease of QoL in women with cervical cancer. In order to minimize the deleterious effects, the impact of cervical cancer and precancerous lesions on QoL should be managed as part of a complete healthcare plan. To improve QoL, cervical cancer patients should seek supportive counseling and education about self-care and adherence to treatment and follow-up plans, continue cervical cancer screening, and receive vaccination against prevalent oncogenic virus types.


Chronic kidney disease and the risk of end-stage renal disease versus death.
Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown. To compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants. The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older. 1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2) were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003. The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol. During 9.7 years of follow-up, 5% of the cohort progressed to ESRD, and 61% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD. Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD.


Mechanisms of ventricular tachycardia termination and acceleration during transvenous cardioversion as determined by cardiac mapping in man.
We examined the EP mechanisms underlying efficacy and inefficacy of transvenous cardioversion shocks in 13 patients with coronary artery disease and sustained VT during preoperative and intraoperative cardiac mapping procedures. Shocks were delivered at the right ventricular apex with a Medtronic 6880 catheter and a Model 5350 external cardioverter/defibrillator with two or three electrode configurations, resulting in unidirectional or bidirectional shocks, respectively. Single transvenous shocks with incremental energies ranging from 0.03 to 25 J were delivered in sinus rhythm and VT, and simultaneous right and left ventricular electrograms were obtained. Transvenous cardioversion shocks of 0.03 J in sinus rhythm and VT produced immediate local right ventricular depolarization and subsequently conducted to distant right ventricular and left ventricular sites after 30 to 100 msec. Shocks of 0.05 to 0.5 J produced immediate depolarization of progressively larger right ventricular and left ventricular regions, with shocks greater than or equal to 0.5 J producing immediate depolarization of distant left ventricular sites in sinus rhythm. High energy (greater than 5 J) shocks produced instantaneous depolarization of multiple right ventricular and left ventricular sites in VT. VT termination occurred due to either delay or interruption of conduction in the tachycardia circuit, despite prior depolarization of the early sites of ventricular activation during the QRS complex. This could be due to instantaneous or paced depolarization of critical "excitable" components of the VT circuit, resulting either in immediate conduction block or in instability followed by termination. VT acceleration with transvenous cardioversion was due to modification of the "excitable," slowly conducting components of the VT circuit with the development of new areas of conduction block, along with altered intraventricular conduction. Similar EP mechanisms were observed with unidirectional and bidirectional transvenous shock patterns. We conclude that transvenous shocks alter conduction in human ventricle, and clinical effects of QRS synchronized shocks are related to conduction changes induced in the excitable components of the VT circuit.


Comparison of Tumor Control After Stereotactic Radiosurgery or Pencil Beam Proton Therapy for Newly Diagnosed Clival Chordomas: A Single-Center Retrospective Study.
To compare outcomes of proton radiation therapy (PRT), stereotactic radiosurgery (SRS), and x-ray-based radiation with an SRS boost (XRT + SRS) for newly diagnosed clival chordoma. Consecutive patients who underwent PRT or SRS in our facility were retrospectively reviewed. A total of 59 patients were identified (PRT, 36; SRS, 11; XRT + SRS, 12). The mean age (± standard deviation) was 46 ± 20 years, with 54% being male. The mean tumor diameter (± standard deviation) was 3.7 ± 1.5 cm, and 21 (36%) involved the lower clivus. Gross total or near-total resection was attained in 27 patients (46%), all of whom received PRT. PRT was administered with a median prescribed dose of 70.8 Gy (range, 66.0-76.0). SRS involved a median marginal dose of 16 Gy (range, 14-20) and a median maximal dose of 36 Gy (range, 30-45). The XRT + SRS group was treated with an SRS marginal dose of 12.5 Gy (range, 10-20), a maximal dose of 27 Gy (range, 20-40), and an XRT prescription dose of 50.4 Gy (range, 45.0-59.4). Fifteen recurrences were observed (PRT, 6; SRS, 5; XRT + SRS, 4). For the entire cohort (n = 59), recurrence was associated with the degree of resection (P = 0.042), but not with radiation groups (P = 0.98). For patients after subtotal resection or biopsy (n = 32), the SRS ± XRT group was associated with few recurrences (hazard ratio, 0.260; 95% confidence interval, 0.069-0.98; P = 0.046). Patients after subtotal resection or biopsy may benefit from the incorporation of SRS.


Toward the Total Synthesis of Scleritodermin A: Preparation of the C(1)-N(15) Fragment.
The synthesis of the C(1)-N(15) fragment of the marine natural product Scleritodermin A has been accomplished through a short and stereocontrolled sequence. Highlights of this route include the synthesis of the novel ACT fragment and the formation of the alpha-keto amide linkage by the use of a highly activated alpha, beta-ketonitrile.


Use of the mandibular ramus as a donor site for onlay bone grafting.
Cortical bone grafts harvested from the posterior mandible offer several advantages for bone augmentation prior to implant placement. These grafts maintain their dense quality and exhibit minimal resorption upon incorporation. Considerable amounts of bone can be harvested from this area for use as an onlay graft. In addition, the ramus area has some inherent advantages over other donor sites. This article describes the indications and surgical technique for harvesting bone from the ramus region.


Asymmetric imine-ene reactions: diastereofacial selective reactions with chiral glyoxylate-derived alpha-imino esters and asymmetric catalysis of enantiofacial selective reactions with prochiral alpha-imino esters.
The diastereofacial selective "imine-ene" reactions with alpha-imino esters, prepared from (-)-8-phenylmenthyl glyoxylate, are shown to provide an efficient entry to the asymmetric synthesis of alpha-amino acids. The feasibility study of the asymmetric catalysis is also reported on the enantiofacial selective ene reactions with prochiral alpha-imino esters.


Cachexia Is Associated With Adverse Outcomes in Patients Admitted With Heart Failure.
Cachexia is often seen in patients with heart failure (HF). This study aimed to examine the association between cachexia and clinical outcomes in patients hospitalized for HF. We extracted all adult cases with a primary diagnosis of HF that were discharged between January and November, identified in the Nationwide Readmissions Database for 2016 through 2019. Exclusion criteria included cases with missing data or a diagnosis of acquired immunodeficiency syndrome, advanced liver disease, end-stage renal disease, chronic lung disease, or malignancy. Appropriate weighting was used to obtain national estimates. Primary outcomes were inpatient mortality, length of stay, and 30-day readmission in patients with HF with cachexia compared with patients with no cachexia. Multivariable logistic regression was used to estimate the association between cachexia and clinical outcomes. Survey procedures were applied using Statistical Analysis Software 9.4. The final analysis included 2,360,307 HF-related hospitalizations. Cachexia was present in about 7% of the study population. A greater percentage of patients with cachexia were female and older than patients without cachexia (52% vs 47% female, the mean age of 77 vs 72 years, respectively). However, after adjusting for demographics and co-morbidities, including coronary artery disease and atrial fibrillation, patients with cardiac cachexia had higher inpatient mortality (odds ratio 3.01, 95% confidence interval 2.88 to 3.15, p <0.001), prolonged hospital stays (9 vs 5 days, p <0.0001), and greater all-cause 30-day readmissions (23% vs 21%, p <0.0001). HF-related cachexia is associated with increased inpatient mortality, greater resource use, and additional healthcare costs.


Streamlined microfluidic analysis of phosphopeptides using stable isotope-labeled synthetic peptides and MRM-MS detection.
Modern high-throughput and high-content biological research is performed with advanced instrumentation and complex and time-consuming protocols, which, as a whole, pose a challenge for routine implementation in a research laboratory. In support of a "bioanalytical toolbox" with potential utility for exploring cellular functions mediated via protein phosphorylation-a post-translational modification (PTM) with essential regulatory roles in a variety of cellular processes-in this work, we describe the development of a simple, integrated microfluidic chip that can perform targeted, quantitative analysis of phosphopeptides involved in cancer-relevant signaling pathways. The microfluidic device comprises microreactors packed with C18 and TiO2 particles for on-chip solid phase extraction (SPE) and phosphopeptide enrichment, and an ESI interface for facilitating multiple reaction monitoring (MRM)-mass spectrometry (MS) detection. The chips are demonstrated for the detection of three phosphopeptides involved in ERBB2/MAPK signaling pathways, selected from the outcome of a proteomic study involving EGF stimulation of SKBR3/HER2+ breast cancer cells. The data demonstrate that the proposed microfluidic strategy can be used for the MS quantification of phosphopeptides in the low nM range from cell lysates without any prior sample pretreatment, fractionation or bioaffinity enrichment, and is generally applicable to the analysis of any phosphopeptide targets.


Decreased adrenergic tone in acromegaly: evidence from direct recording of muscle sympathetic nerve activity.
Sympathovagal imbalance has been shown in acromegaly by indirect measurements of adrenergic tone. Data regarding direct measurement of sympathetic activity are lacking as yet. Aim of this study was to assess the adrenergic tone through direct recording of muscle sympathetic nerve activity (MSNA) in acromegalic patients. Fifteen patients (age 26-66 years, eight women) with newly diagnosed active acromegaly without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy, and 15 healthy subjects matched for age, sex and body mass index were recruited. After evaluating anthropometric and echocardiographic parameters, anterior pituitary function, glucose and lipid metabolism, and measuring plasma leptin, direct recording of sympathetic outflow via the microneurographic technique was performed. For similar anthropometric and metabolic parameters in patients and controls, HOMA index was significantly increased in the former (4·2 ± 2·39 vs 1·6 ± 0·19, P < 0·001). Surprisingly, this finding of insulin resistance was accompanied by a marked sympathetic inhibition (MSNA 18·3 ± 8·10 vs 37·3 ± 6·48 bursts/min, P < 0·0001, respectively in patients and controls). A reduction in plasma leptin (1·6 ± 1·04 vs 6·5 ± 2·01 μg/l, P < 0·0001) was also recorded in the patients. MSNA was positively correlated with leptin (P < 0·0001). Newly diagnosed acromegalic patients without cardiac hypertrophy display a decreased sympathetic outflow in spite of insulin resistance. This finding might be related to hypoleptinaemia.


Trastuzumab labeled to high specific activity with ¹¹¹In by conjugation to G4 PAMAM dendrimers derivatized with multiple DTPA chelators exhibits increased cytotoxic potency on HER2-positive breast cancer cells.
To conjugate trastuzumab with/without NLS peptides to G4 PAMAM dendrimers derivatized with DTPA and determine the specific radioactivity (SA) for (111)In labeling, HER2 immunoreactivity and cytotoxicity on breast cancer (BC) cells. G4 dendrimers were reacted with DTPA then conjugated through a thiol to maleimide-derivatized trastuzumab. The SA achievable was determined by incubating 2 to 20 μg with 60 MBq of (111)In. HER2 immunoreactivity, internalization and nuclear importation were measured. The effect of (111)In-DTPA-G4-trastuzumab (5.9 MBq/μg) on the clonogenic survival (CS) of SK-Br-3 or MDA-MB-231 cells with high or low HER2 density, respectively was compared to (111)In-DTPA-NLS-trastuzumab (0.5 MBq/μg). DNA double-strand breaks (DSBs) were measured. DTPA-G4-trastuzumab was labeled with (111)In to a SA (23.6 MBq/μg) which was 100-fold higher than (111)In-DTPA-NLS-trastuzumab. (111)In-DTPA-G4-trastuzumab and (111)In-DTPA-G4-NLS-trastuzumab retained HER2 immunoreactivity and were internalized and imported into the nucleus of BC cells. G4-radioimmunoconjugates were 2-4 fold and 9-fold more cytotoxic to SK-Br-3 and MDA-MB-231 cells, respectively than (111)In-DTPA-NLS-trastuzumab which was associated with an increase in DNA DSBs. Conjugation of trastuzumab to G4 PAMAM dendrimers modified with 30 DTPA permitted high SA (111)In labeling which increased their cytotoxic potency for BC cells with high or low HER2 density.


Marrow transplantation for non-Hodgkin's lymphoma: a multi-centre study from the European Co-operative Bone Marrow Transplant Group.
Twenty-five patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) were treated by allogeneic bone marrow transplantation. For the nine patients transplanted in first complete remission the disease-free survival was 100%; of the nine patients transplanted in subsequent remissions four (44%) achieved long-term disease-free survival but two died of relapsed lymphoma. For the seven patients transplanted at a time when they had active disease, the initial complete remission rate was high but four died of progressive lymphoma and no patient achieved long-term disease-free survival. The incidence of complications associated with allogeneic bone marrow transplantation was similar to that observed in other series of patients transplanted for haematological malignancy and was related to the status of the disease at the time of transplant. Thus allogeneic bone marrow transplantation is a radical but effective treatment for patients with NHL who have 'minimal residual disease'. Efforts to define further the subset of patients who can most successfully be treated by transplantation may improve the overall results.


Incorporation of Collagen from Marine Sponges (Spongin) into Hydroxyapatite Samples: Characterization and In Vitro Biological Evaluation.
Biomaterial-based bone grafts have an important role in the field of bone tissue engineering. One of the most promising classes of biomaterials is collagen, including the ones from marine biodiversity (in general, called spongin (SPG)). Also, hydroxyapatite (HA) has an important role in stimulating bone metabolism. Therefore, this work investigated the association of HA and SPG composites in order to evaluate their physico-chemical and morphological characteristics and their in vitro biological performance. For this, pre-set composite disks were evaluated by means of mass loss after incubation, pH, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and "in vitro" cell viability. pH measurements showed no statistical difference between groups. Moreover, a higher mass loss was observed for HA/SPG70/30 compared to the other groups for all experimental periods. Moreover, SEM representative micrographs showed the degradation of the samples with and without immersion. FTIR analysis demonstrated the absorption peaks for poly(methyl methacrylate) (PMMA), HA, and SPG. A higher L292 cell viability for control and PMMA was observed compared to HA and HA/SPG 90/10. Also, HA/SPG 70/30 showed higher cell viability compared to HA and HA/SPG 90/10 on days 3 and 7 days of culture. Furthermore, HA showed a significant lower MC3T3 cell viability compared to control and HA/SPG 70/30 on day 3 and no significant difference was observed between the composites in the last experimental period. Based on our investigations, it can be concluded that the mentioned composites were successfully obtained, presenting improved biological properties, especially the one mimicking the composition of bone (with 70% of HA and 30% of SPG). Consequently, these data highlight the potential of the introduction of SPG into HA to improve the performance of the graft for bone regeneration applications. Further long-term studies should be carried out to provide additional information concerning the late stages of material degradation and bone healing in the presence of HA/SPG.


Photocatalysis-Assisted Co3O4/g-C3N4 p-n Junction All-Solid-State Supercapacitors: A Bridge between Energy Storage and Photocatalysis.
Supercapacitors with the advantages of high power density and fast discharging rate have full applications in energy storage. However, the low energy density restricts their development. Conventional methods for improving energy density are mainly confined to doping atoms and hybridizing with other active materials. Herein, a Co3O4/g-C3N4 p-n junction with excellent capacity is developed and its application in an all-solid-state flexible device is demonstrated, whose capacity and energy density are considerably enhanced by simulated solar light irradiation. Under photoirradiation, the capacity is increased by 70.6% at the maximum current density of 26.6 mA cm-2 and a power density of 16.0 kW kg-1. The energy density is enhanced from 7.5 to 12.9 Wh kg-1 with photoirradiation. The maximum energy density reaches 16.4 Wh kg-1 at a power density of 6.4 kW kg-1. It is uncovered that the lattice distortion of Co3O4, reduces defects of g-C3N4, and the facilitated photo-generated charge separation by the Co3O4/g-C3N4 p-n junction all make contributions to the promoted electrochemical storage performance. This work may provide a new strategy to enhance the energy density of supercapacitors and expand the application range of photocatalytic materials.


Comparison of survival and renal function between partial and radical laparoscopic nephrectomy for T1b renal cell carcinoma.
Partial nephrectomy has been persuaded as a widely accepted surgical procedure for T1a (≤ 4 cm) renal tumors. However, when treating T1b (4-7 cm) renal cell carcinoma (RCC), the "optimal" method of surgery is still debatable. The aim of the research is to evaluate the long-term oncological and renal functional outcomes of laparoscopic radical nephrectomy (LRN) versus laparoscopic partial nephrectomy (LPN) for patients with T1b RCC. From March 1, 2003 to July 1, 2016, 331 patients were included in the current study. Patients presented with unilateral T1b RCC and underwent either LPN (n = 177) or LRN (n = 154). Relevant clinical data including follow-ups were acquired from patients. The operation time of the LPN group patients was longer than that of LRN group (94.3 min vs 88.3 min, p = 0.021) and LPN group patients required shorter stays in hospital (11.5 days vs. 13.4 days, p = 0.009). Contrast to LRN, level of eGFR was superior in LPN at the postoperative time of 1 day, 3 months, 6 months, 12 months and 24 months (all p < 0.001). Kaplan-Meier plots and log-rank tests showed that patients undergoing LPN had a much higher overall survival (OS) (p = 0.007), cancer-specific survival (CSS) (p = 0.006) and metastasis-free survival (MFS) (p = 0.008) than those receiving LRN. In comparison with the LRN group, multivariable Cox analysis indicated that patients of the LPN group had a 1.9-fold OS, 2.9-fold CSS and 2.3-fold MFS. For patients with T1b RCC, our findings revealed that OS, CSS and MFS are superior in patients receiving LPN than those treated with LRN. With the benefit of preserving renal function of LPN, which leads a less incidence risk of other systematic diseases, LPN may be the preferred option when condition permits for cases involving T1b RCC.


Hydrothermal processes and simultaneous enzymatic hydrolysis in the production of modified cassava starches with porous-surfaces.
The amylolytic action of α-amylase and amyloglucosidase has been directly implemented in native cassava starches for the formation of cassava microporous granules with unsatisfactory results, however, its incidence in hydrothermally treated granules has never been evaluated. The effect of hydrothermal processes and simultaneous enzymatic hydrolysis on the physicochemical, morphological and structural properties of native cassava starch was evaluated. Native cassava starch presented a rigid, smooth surface, and was exempt from porosities, whereas hydrothermal processes altered the semicrystalline order and increasing the size and number of pores and increasing the size (4.11 ± 0.09 nm) and volume of pores (0.82 ± 0.00 cm3/g × 10-3). The hydrothermal action followed by enzymatic processes with α-amylase and amyloglucosidase, augmented the processes of internal degradation (endo-erosion) and pore widening (exo-erosion), improving the hydrophilic properties compared to the hydrothermal treatment. Likewise, the hydrothermally process followed by enzymatic hydrolysis for 24 h (HPS + EMS-24) increased the degradation of the amorphous lamellae, consistent with a significant decrease in amylose content. This same dual treatment increased the pore size at 17.68 ± 0.13 nm relative to the native counterpart; therefore, they are considered an effective method in the development of modified cassava starches with porous surfaces.


Promoter polymorphism of the CD14 endotoxin receptor gene is associated with biliary atresia and idiopathic neonatal cholestasis.
To investigate whether single-nucleotide polymorphisms in the promoter regions of endotoxin-responsive genes CD14 and tumor necrosis factor-alpha (TNF-alpha) are associated with biliary atresia (BA) and idiopathic neonatal cholestasis (INC). We obtained genomic DNA from 90 patients with established diagnosis of BA and 28 patients with INC. Forty-two adult patients with hepatitis B-related cirrhosis and 143 healthy children served as control populations. The genotypes of CD14/C(-159)T and TNF-alpha/G(-308)A (G allele, TNF*1; A allele, TNF*2) were determined by using a restriction enzyme-based assay. Plasma soluble CD14 levels were determined in different disease stages and genotypes of BA. The frequencies of T allele and T/T homozygosity of the CD14/-159 promoter polymorphism were significantly higher in patients with BA (T allele: 61.7%; T/T genotype: 42.2%) and in patients with INC (T allele: 67.9%; T/T genotype: 53.6%) but not in control populations. Decrease of plasma soluble CD14 from the early stage of BA when the patients received a Kasai operation to the late stage of liver cirrhosis was observed in carriers of the T/T and T/C genotypes but not in carriers of the C/C genotype. The TNF-alpha/-308 promoter polymorphisms (TNF*1 and TNF*2) were not associated with BA. These findings show that the single-nucleotide polymorphism at CD14/-159 is associated with the development of BA and INC. Endotoxin susceptibility may play a role in the pathogenesis of infantile cholestasis.


Indocyanine green angiography-guided focal navigated laser photocoagulation for diabetic macular edema.
To evaluate the efficacy of indocyanine-green angiography (ICGA)-guided navigated focal laser photocoagulation for diabetic macular edema (DME). Prospective, interventional case series. Six patients (8 eyes) were enrolled in this study. Fluorescein angiography (FA) and ICGA were performed using the Heidelberg Retina Angiogram 2 (Heidelberg Engineering). Navigated focal laser photocoagulation was delivered to the microaneurysms on ICGA using Navilas® (OD-OS GmbH, Germany). Central retinal thickness (CRT) and macular volume (MV) were measured by Cirrus HD-OCT (Carl Zeiss Meditec). At 6 months, the best-corrected visual acuity (BCVA), CRT and MV were compared to the values measured on day 0. The distances from the center of fovea to the closest microaneurysms (MAs) were measured on the pre-planned Navilas® image. All eyes had previous treatment history. At 6 months, ICGA-guided navigated focal laser photocoagulation significantly reduced the CRT and the MV (p<0.05), and there was improvement in the BCVA (p<0.05). At 3 months, 5 out of the 8 eyes (63%) underwent additional ICGA-guided navigated focal laser photocoagulation due to remnants of MAs that had been confirmed by ICGA. There was no observed recurrence of edema after the ICGA-guided navigated focal laser photocoagulation during the 6-month follow-up. The mean distance from the center of fovea to the closest MAs was 624.8 ± 377.7 μm (range 336.0-1438.9 μm). Our data suggest ICGA-guided navigated focal laser photocoagulation may be effective for the treatment of DME.


Molecular dynamics investigations of the polysaccharide scleroglucan: first study on the triple helix structure.
Explicit solvent molecular dynamics (MD) simulations on the triple helix of the polysaccharide Scleroglucan (Sclg) at two temperatures (273 and 300 K) were carried out. Owing to the complexity of the system, a united-atom force field, based on the properly modified GROMACS parameters, was adopted. To test these parameters for our system, MD simulations of the two disaccharidic units, representing the main chain and the side-chain linkages of the Sclg repeating unit, were performed and the results were compared with the literature data. The simulated triple helix of Sclg retained the main experimentally determined features of the polymer. The residence times of the solvent molecules at 273 and 300 K were analyzed. The results show that the more internal water molecules, interacting with the core of the Sclg triplex are not influenced substantially by changing the temperature, on the contrary the water molecules, interacting with the side-chain glucose residues show more significant differences. These data suggest that the more external water molecules, interacting with the side chain, play a major role in the conformational transition experimentally observed at low temperature.


The use of pulse methylprednisolone and chlorambucil in the treatment of Sweet's syndrome.
A patient with an unusual variant of Sweet's syndrome, in which the course of the disease was chronic and relapsing, was treated successfully with intravenous methylprednisolone (pulse therapy). Remission was then maintained with oral chlorambucil.


The role of pyrosequencing in head and neck cancer epigenetics: correlation of quantitative methylation data with gene expression.
To evaluate promoter methylation quantitation using recently described pyrosequencing techniques by correlation with messenger RNA (mRNA) expression. DNA was extracted from tissue samples and was subjected to bisulphite conversion. Quantitative methylation data for multiple CpG sites in each of 9 gene promoters were obtained for tumors using pyrosequencing. RNA was extracted and converted to complementary DNA, and this formed the template for relative quantitation assays of the expression of each gene by real-time reverse transcription-polymerase chain reaction. Academic research. Thirty-seven patients with head and neck squamous cell carcinoma. The genes studied were P16 (OMIM 600160), cyclin A1 (OMIM 604036), RARB (OMIM 180220), E-cadherin (OMIM 192090), MGMT (OMIM 156569), STAT1 (OMIM 600555), ATM (OMIM 607585), hMLH1 (OMIM 120436), and TIMP3 (OMIM 188826). Immunohistochemistry was also performed for p16. STAT1, TIMP3, ATM, and hMLH1 promoters were essentially unmethylated in all cases. The data for cyclin A1 (Spearman rank correlation, rho = -0.53; P < .001), MGMT (rho = -0.53, P < .001), and RARB (rho = -0.34, P =.02) showed the expected negative correlation between levels of methylation and mRNA expression. The data relating to E-cadherin were inconclusive. Surprisingly, P16 expression was statistically significantly greater in those cases with higher levels of methylation (rho = 0.57, P < .001), a finding at odds with assumptions usually made in the literature relating gene promoter methylation to reduced gene expression. The results from p16 immunohistochemistry were in keeping with the mRNA data, but the number of positive staining samples proved too few for statistical analysis. These data present a novel perspective on head and neck cancer epigenetics and reveal new and some unexpected associations and findings. The advantages of pyrosequencing over nonquantitative techniques are discussed in analyses of this nature.


A novel strain of Brevibacillus laterosporus produces chitinases that contribute to its biocontrol potential.
A novel strain exhibiting entomopathogenic and chitinolytic activity was isolated from mangrove marsh soil in India. The isolate was identified as Brevibacillus laterosporus by phenotypic characterization and 16S rRNA sequencing and designated Lak1210. When grown in the presence of colloidal chitin as the sole carbon source, the isolate produced extracellular chitinases. Chitinase activity was inhibited by allosamidin indicating that the enzymes belong to the family 18 chitinases. The chitinases were purified by ammonium sulfate precipitation followed by chitin affinity chromatography yielding chitinases and chitinase fragments with 90, 75, 70, 55, 45, and 25 kDa masses. Mass spectrometric analyses of tryptic fragments showed that these fragments belong to two distinct chitinases that are almost identical to two putative chitinases, a 89.6-kDa four-domain chitodextrinase and a 69.4-kDa two-domain enzyme called ChiA1, that are encoded on the recently sequenced genome of B. laterosporus LMG15441. The chitinase mixture showed two pH optima, at 6.0 and 8.0, and an optimum temperature of 70 °C. The enzymes exhibited antifungal activity against the phytopathogenic fungus Fusarium equiseti. Insect toxicity bioassays with larvae of diamondback moths (Plutella xylostella), showed that addition of chitinases reduced the time to reach 50 % mortality upon infection with non-induced B. laterosporus from 3.3 to 2.1 days. This study provides evidence for the presence of inducible, extracellular chitinolytic enzymes in B. laterosporus that contribute to the strain's antifungal activity and insecticidal activity.


Adverse Effects of Higher Preoperative Pain at Rest, a Central Sensitization-Related Symptom, on Outcomes After Total Hip Arthroplasty in Patients with Osteoarthritis.
In patients with hip osteoarthritis (OA), pain at rest, unlike pain on activity, is due to pain mechanisms that cannot be explained by nociceptive pain. However, it remains unclear whether central sensitization (CS) is one of the causes of exacerbated pain at rest in patients with hip OA. Therefore, we investigated the differences in causative factors and postoperative course of total hip arthroplasty (THA) between preoperative pain at rest and on activity in patients with hip OA. In total, 120 patients (125 hips, 22 men and 98 women, aged 64.5±1.0 years) with hip OA were included. Preoperative pain at rest and on activity and CS were assessed using the visual analog scale (VAS) and CS Inventory (CSI), respectively. Postoperative assessments were evaluated using the Japanese Orthopedic Association Hip Disease Evaluation Questionnaire (JHEQ); pain, satisfaction, function, and mental scores were evaluated 6 and 12 months after THA. Multivariate regression analysis indicated the CSI score as affecting VAS for pain at rest (β=0.067, P=0.002) but not VAS for pain on activity (β=0.036, P=0.073). VAS for pain at rest had a weak negative correlation with satisfaction and pain scores at both 6 and 12 months after THA (satisfaction, r=-0.309, -0.278; pain, r=-0.202, -0.22). VAS for pain on activity was not correlated with JHEQ. The CSI score had a weak or moderate negative correlation with three scores other than the function score at both 6 and 12 months after THA (satisfaction, r=-0.266, -0.213; pain, r=-0.332, -0.203, mental, r=-0.427, -0.370). The function score was weakly correlated with the CSI score only 6 months after THA (function, r=-0.231, -0.190). A higher level of preoperative pain at rest, a CS-related symptom, may affect postoperative pain persistence and dissatisfaction in patients with hip OA.


Systematic imaging in medicine: a comprehensive review.
Systematic imaging can be broadly defined as the systematic identification and characterization of biological processes at multiple scales and levels. In contrast to "classical" diagnostic imaging, systematic imaging emphasizes on detecting the overall abnormalities including molecular, functional, and structural alterations occurring during disease course in a systematic manner, rather than just one aspect in a partial manner. Concomitant efforts including improvement of imaging instruments, development of novel imaging agents, and advancement of artificial intelligence are warranted for achievement of systematic imaging. It is undeniable that scientists and radiologists will play a predominant role in directing this burgeoning field. This article introduces several recent developments in imaging modalities and nanoparticles-based imaging agents, and discusses how systematic imaging can be achieved. In the near future, systematic imaging which combines multiple imaging modalities with multimodal imaging agents will pave a new avenue for comprehensive characterization of diseases, successful achievement of image-guided therapy, precise evaluation of therapeutic effects, and rapid development of novel pharmaceuticals, with the final goal of improving human health-related outcomes.


Development of reverse transcription loop-mediated isothermal amplification assays to detect Hantaan virus and Seoul virus.
We developed two assays based on one-step reverse transcription loop-mediated isothermal amplification (RT-LAMP) to identify Hantaan virus (HTNV) and Seoul virus (SEOV), members of the Hantavirus genus that cause hemorrhagic fever with renal syndrome (HFRS). Our results showed that these assays can be conducted within 30min under isothermal conditions. The detection limit for HTNV was around 10 copies per reaction, similar to detection levels for quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. The detection limit for SEOV was 100 copies per reaction, a sensitivity that was 10-fold lower than that for qRT-PCR assays but 10-fold higher than that for RT-PCR assays. The method we developed was specific for both HTNV and SEOV without any cross-reaction with other pathogens. We conclude that RT-LAMP assays could be useful for the rapid and direct detection of HTNV and SEOV clinically, and for the epidemiological investigation of HFRS.


The effect of metformin on cardiovascular markers in female mice consuming a high fat diet.
Metformin, widely used to treat diabetes, is now considered a candidate therapeutic for treatment of cardiovascular disease. This study aimed to assess whether metformin's non-glycaemic effects could mitigate cardiovascular disease indices in female mice consuming a high fat diet (HFD). Four-week old female Arc:Arc(S) mice were placed on a standard (std) chow diet or Western-style HFD (22% fat, 0.15% cholesterol). At ∼8 months, the mice were administered 150 mg/kg metformin or vehicle (control) via intraperitoneal injection for 11 days. Blood pressure was measured (tail cuff plethysmography) at Day 9 and 11 of treatment. On Day 11, mice were weighed and culled. The mesenteric arcade and kidneys were collected for assessment of vascular reactivity (wire myography), and assessment of expression of cardiometabolic markers (qPCR), respectively. The HFD fed female mice were significantly heavier than those receiving the std diet at 1-12 weeks on diet, and at cull. Mice on a std diet with metformin treatment were significantly heavier at cull than the mice on a std diet administered the control treatment. Metformin treatment did not alter the weight of the mice receiving the HFD. Neither the HFD (compared to the std diet), nor metformin treatment (compared to control treatment) altered blood pressure, vascular reactivity, or expression of cardiometabolic markers in the kidney. Consumption of a Western-style HFD (without high salt/sugar levels) did not alter the cardiovascular markers measured. Further studies are required to establish the non-glycaemic, cardio-protective effects of metformin in high-risk cohorts.


Dynamics of postmarital residence among the Hadza: a kin investment model.
When we have asked Hadza whether married couples should live with the family of the wife (uxorilocally) or the family of the husband (virilocally), we are often told that young couples should spend the first years of a marriage living with the wife's family, and then later, after a few children have been born, the couple has more freedom--they can continue to reside with the wife's kin, or else they could join the husband's kin, or perhaps live in a camp where there are no close kin. In this paper, we address why shifts in kin coresidence patterns may arise in the later years of a marriage, after the birth of children. To do so, we model the inclusive fitness costs that wives might experience from leaving their own kin and joining their husband's kin as a function of the number of children in their nuclear family. Our model suggests that such shifts should become less costly to wives as their families grow. This simple model may help explain some of the dynamics of postmarital residence among the Hadza and offer insight into the dynamics of multilocal residence, the most prevalent form of postmarital residence among foragers.


Evaluation of the good tumor response of embryonal tumor with abundant neuropil and true rosettes (ETANTR).
The embryonal tumor with abundant neuropil and true rosettes is a rare and highly malignant variant of embryonal brain tumors. It usually affects infants and young children under the age of 4 years and exhibits a very aggressive course with a dismal prognosis. For the 68 cases reported to date the mean age at diagnosis was 25.42 months (range 3-57 months). Survival data are available for 48 children (including our case): the median overall survival is 13.0 months, though 6 (9%) of the children have had a relative long survival (>30 months). The aggressive combined treatment, involving primary surgical tumor removal, adjuvant polychemotherapy, including high-dose chemotherapy with stem cell transplantation, radiotherapy and radiochemotherapy, might play an important role in the longer survival. We have performed a literature review and we present here a multimodal-treated case of a 2- year-old girl with a long survival, who was reoperated when recurrence occurred. The residual tumor demonstrated a good response to temozolomide radiochemotherapy (craniospinal axis + boost) and followed by maintenance temozolomide. The described complex aggressive treatment option might be considered for future cases of this tumor entity.


Comparison of scales for evaluating premenstrual symptoms in women using oral contraceptives.
To compare two scales used in research to evaluate daily premenstrual mood symptoms during use of a monophasic oral contraceptive. Subanalysis of data from a prospective study. University-affiliated medical center. SUBJECTS; One hundred two reproductive-aged (18-48 yrs) women taking a monophasic oral contraceptive containing ethinyl estradiol and drospirenone in the standard 21-7 fashion (21 days of hormones followed by 7 days of placebo), and who had self-identified premenstrual symptoms of headache, mood changes, or pelvic pain. Subjects completed a single-item questionnaire, the Scott & White Daily Diary of Symptoms, and a multiple-item questionnaire, the Penn State Daily Symptom Report (DSR), to assess their premenstrual symptoms. The Scott & White diary used a visual analog scale of 0-10 to assess pelvic pain, headache, and mood (a composite of anxiety, depression, and irritability). The Penn State DSR contained 17 items: 10 behavioral and seven physical components, each rated on a scale of 0-4, with one item that specifically rated mood swings. Scores from the two scales were compared by using Spearman correlation coefficients, the Kendall W for concordance, and linear regression of ranked sums for study cycles. The Scott & White mood score significantly correlated with the total of the 17 items on the Penn State DSR, as well as the 10 behavioral items, the seven physical items, and the single mood-swing item (p<0.0001); specific coefficients of concordance were 0.44, 0.23, 0.10, and 0.28, respectively, and R2 values were 0.39, 0.39, 0.30, and 0.34, respectively. The daily Scott & White mood score was positively correlated with all 17 elements of the Penn State DSR (0.25-0.57). The greatest correlation was seen with the mood-swing element. Both instruments demonstrated the same patterns during the 21-7 oral contraceptive cycle, with symptoms increasing immediately before and peaking during the 7-day hormone-free interval. A single-item daily mood score using a rating scale of 0-10 was concordant with a relatively complex 17-element symptom index and demonstrated the same pattern of change during cycles of oral contraception. The simple scoring system offers an advantage, especially in clinical studies of long duration.


Intravenous versus super-selected intra-arterial chemotherapy in children with advanced unilateral retinoblastoma: an open-label, multicentre, randomised trial.
Super-selected intra-arterial chemotherapy has increasingly been used as conservative management for retinoblastoma during the past decade. However, the absence of evidence from randomised controlled trials engendered controversy in the administration route of chemotherapy. We aimed to assess the efficacy and safety of intra-arterial chemotherapy compared with intravenous chemotherapy. This open-label, multicentre, randomised trial was done at six hospitals in China. Patients with new-onset unilateral group D or E retinoblastoma (poorly defined, large, or very large tumours, according to the International Intraocular Retinoblastoma Classification) without high-risk clinical factors were included. Patients were randomly assigned (1:1) to receive intra-arterial chemotherapy (injections of 0·5 mg/kg [or depending on age] melphalan with 20 mg carboplatin [first and third cycles] or with 1 mg topotecan [second and fourth cycles]) or intravenous chemotherapy (0·05 mg/kg [or 1·5 mg/m2] vincristine, 5 mg/kg [or 150 mg/m2] etoposide, and 18·6 mg/kg [or 560 mg/m2] carboplatin for six cycles). After intra-arterial chemotherapy, patients received a subcutaneous injection of 0·1 mL nadroparin calcium twice at a 12 h interval. Both intra-arterial and intravenous chemotherapy cycles were completed every 4 weeks. No masking was done, except of independent statisticians, who were masked to the allocation information. The primary outcome was 2-year progression-free globe salvage rate, defined as the time from randomisation to tumour progression or enucleation, whichever occurred first, and was analysed by intention to treat. We also recorded predefined safety outcomes (myelosuppression and ophthalmic arterial stenosis or occlusion) and severe adverse events likely to be related to study treatment. The study is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-15006469, and is complete. Between June 1, 2015, and June 1, 2018, 234 patients with newly diagnosed retinoblastoma were screened and 143 eligible patients (median age 23·6 months [IQR 14·0-31·9]) were enrolled and randomly assigned to the intra-arterial chemotherapy group (n=72) or the intravenous chemotherapy group (n=71). At a median follow-up of 35·8 months (IQR 28·4-43·0), the 2-year progression-free globe salvage rate was 53% (38 of 72 patients) in the intra-arterial chemotherapy group and 27% (19 of 71 patients) in the intravenous chemotherapy group (risk ratio 1·97, 95% CI 1·27-3·07, p=0·0020). Myelosuppression was less common in the intra-arterial chemotherapy group than in the intravenous chemotherapy group (37 [51%] of 72 patients vs 50 [70%] of 71 patients; 0·73, 95% CI 0·56-0·96, p=0·021) and less severe (ptrend=0·0070). In the intra-arterial chemotherapy group, two (3%) of 72 patients had ophthalmic artery occlusion and 13 (18%) patients had ophthalmic artery stenosis. Our findings show that intra-arterial chemotherapy could significantly improve the globe salvage rate in children with advanced unilateral retinoblastoma compared with intravenous chemotherapy, with mild systemic complications and no difference in overall survival rate. Intra-arterial chemotherapy could be an acceptable first-line treatment in children with advanced unilateral retinoblastoma. Scientific Research Program of the National Health and Family Planning Commission of China, the Clinical Research Plan of Shanghai Hospital Development Center, the National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality.


Voiding efficiency in children is significantly impaired by the presence of the urethral catheter during pressure-flow studies.
Little is known about the effect of catheterization during pressure-flow studies (PFS) on voiding efficiency in children. Our objective was to determine the effect of urethral catheterization on Qmax and flow index (FI) during PFS compared to the free flow of uroflowmetry (UF). We retrospectively reviewed 63 consecutive children who underwent UF and PFS at our center on the same day (2019-2022). Voiding data was available for 46 patients. Patients first underwent a UF with full bladder, then PFS after urethral catheter insertion. Patients with urethral pathologies (n = 6), on clean intermittent catheterization (CIC) (n = 2) and with major comorbidities (n = 2) were excluded. Indications for UF/PFS were LUTS, recurrent UTIs, incontinence or neurosurgical pre-operative evaluation. Data was collected from the UF and the PFS and compared using paired t-test. The idealized Qmax and flow index (FI) were calculated for UF and PFS using the formulas described by Franco et al.: Male Qmax = 11.26 + 0.0701(TBC [total bladder capacity]) - 0.0000513(TBC); Female Qmax = 10.723 + 0.073(TBC) - 0.0000423(TBC), FI = Actual Qmax/Expected Qmax (Franco and et al., 2016; Franco et al., 2018; Franco and et al., 2016). Median age was 7 years old (IQR 5-11). Twenty-one (40%) patients were male and 32 (60%) patients were female. Of the 53 patients, 3 boys and 4 girls (n = 7; 13%) were unable to void with the catheter in place during PFS but able to void after its removal. Of the remaining 46 cases, the Qmax during PFS was 5 mL/s slower than the Qmax recorded on the UF without catheter, representing a decrease of 29% (12.3 vs 17.3 mL/s; p < 0.0001). The impact of urethral catheter during PFS was more important in males vs females (Qmax decreased by 7.7 vs 3.3 mL/s, or 45 vs 19%). The mean FI during PFS was 44%, which was a 30% reduction compared to the 74% FI obtained with UF (p < 0.00001). In males, the FI decreased by 37% on PFS, whereas it decreased 26% in females, similar to the Qmax decrease. Voiding efficiency, as assessed by Qmax and FI, is decreased during PFS compared to uroflow studies. Our data documents for the first time the impact of urethral catheterization on pediatric voiding efficiency. Abnormal flow rates and elevated PVRs should be used to guide patient management only if obtained by uroflow. Prospective validation comparing free flow with PFS studies will help characterize the impact of urethral catheter relative to bladder pathology, age, gender and catheter size used.


Protozoan hemoglobin from Tetrahymena pyriformis. Isolation, characterization, and amino acid sequence.
A hemoprotein that can be defined as hemoglobin based on oxygen binding was isolated from Tetrahymena pyriformis. The protein exists in monomeric form and is separated into four fractions (Ia, Ib, IIa, and IIb) on a CM-cellulose column. From examinations of the absorption spectra and the N-terminal sequence, fractions Ia and Ib were assigned to the oxy-form and its met-form, respectively, of the one protein, while IIa and IIb corresponded to those of the other one. The complete amino acid sequence was therefore determined of fractions I and II. The I was composed of 121 amino acid residues, with the N-terminal serine being blocked. The II, on the other hand, consisted of 119 amino acid residues, its sequence being exactly identical to that of the third residue, lysine, to the C-terminal lysine of the fraction I. Although the genomic multiplicity cannot be ruled out completely, we have concluded that fraction II is a degradation product of the fraction I by endogeneous proteases. The amino acid sequence of T. pyriformis hemoglobin is very unique and showed no notable degree of similarity with the other hemoglobins sequenced so far, but it was found to be 33.9% identical with Paramecium caudatum hemoglobin by a maximal alignment.


The Role of Serine-Glyoxylate Aminotransferase and Malyl-CoA Lyase in the Metabolism of Methylococcus capsulatus Bath.
The genome of aerobic methanotroph Methylococcus capsulatus Bath possesses genes of three biochemical pathways of C1-carbon assimilation: the ribulose monophosphate cycle, the Calvin-Benson-Bassham cycle, and the partial serine cycle. Numerous studies have demonstrated that during methanotrophic growth cells of Methylococcus capsulatus Bath express key enzymes of these routes. In this study, the role of the serine cycle key enzymes, serine-glyoxylate aminotransferase (Sga) and malyl-CoA lyase (Mcl) in metabolism of Methylococcus capsulatus Bath was investigated by gene inactivation. The Δsga mutant obtained by double homologous recombination showed a prolonged lag phase, and after the lag period, the growth rate became similar to that of the wild type strain. The elevated intracellular levels of glutamate, serine, glycine, alanine, methionine, leucine, and succinate suggested significant metabolic changes in the mutant cells. Deletion of the mcl gene resulted in very poor growth and glycine only partially improved growth of the mutant strain. Cells of Δmcl mutant possess lower content of histidine, but enhanced level of alanine, leucine, and lysine than those of the wild type strain. Our data imply the importance of the serine cycle enzymes in metabolism of the methanotroph as well as relationships of the three C1 assimilation pathways in the gammaproteobacterial methanotrophs.


Multisite Randomized Controlled Trial of Bladder Management in Labor With Epidural Analgesia/Anesthesia.
To compare the effects of continuous indwelling catheterization with those of intermittent catheterization during labor with epidural analgesia/anesthesia on mode of birth and incidence of urinary tract infection (UTI) symptoms in the postpartum period. Randomized clinical trial. Labor and delivery units at three metropolitan hospitals in the Western United States. Women (N = 252) who were nulliparous with term, singleton pregnancies in labor with epidural analgesia/anesthesia. Participants were randomized to indwelling or intermittent (every 2 hours) catheterization groups after the administration of epidural analgesia/anesthesia during labor. One to 2 weeks after discharge, participants were contacted and questioned about symptoms of UTI. A total of 252 participants were enrolled in the study: 81% (n = 202) gave birth vaginally, and 19% (n = 50) gave birth via cesarean. Between the indwelling and intermittent catheterization groups, demographic characteristics were similar. We found no significant difference in the incidence of cesarean birth between groups (15.6% vs. 22.5%, p = .172). Overall, 3% of participants reported and sought treatment for symptoms of UTI within 2 weeks with no significant difference between groups (p = .929). We found no differences in mode of birth or symptoms of UTI in women who received indwelling or intermittent catheterization during epidural analgesia/anesthesia. We recommend additional research with objective data for UTI diagnosis and larger samples to study the multiple potential confounding variables associated with cesarean birth after catheterization during epidural analgesia/anesthesia.


Comparative study on heterogeneous activation of peroxydisulfate and peroxymonosulfate with black carbon derived from coal tar residues: Contribution of free radical, 1O2 and surface-bound radicals.
Carbon materials draw increasing attention as metal-free catalysts for persulfates activation. Herein, the potential of black carbon (BC) derived from coal tar residues on heterogeneous activation of peroxydisulfate (PDS) and peroxymonosulfate (PMS) to eliminate organic pollutants was investigated. Compared with UV/persulfates systems, persulfates/BC systems degraded 3 selected phenolic compounds (i.e. phenol, 4-chlorophenol (4-CP) and bisphenol A (BPA)) with an order of magnitude higher oxidation rates, and removed dissolved organics (DOC) with over 27% higher efficiency. In the PDS/BC system, 1O2 and surface-bound radicals were proved to be the dominant active species, while free radicals, 1O2, and surface-bound radicals were responsible for organics oxidation in the PMS/BC system. Relative contribution of different reactive species in persulfates/BC systems was pH-dependent. Surface oxygen functionalities of BC were involved in 1O2 generation, and its structural defects played a critical role in forming free radicals and surface-bound radicals. This study provided an in-depth insight into carbon-driven persulfates activation processes.


Kinetics and efficacy of theophylline in the treatment of apnea in the premature newborn.
Aminophylline (theophylline-ethylenediamine) was administered to 27 premature newborns to prevent apneic spells. Of the 22 patients monitored for theophylline concentration, a therapeutic blood level was reached in 19 in 1--2 days, and 3 stayed below it. "Toxic" blood levels (less than or equal to 20 microgram/ml) were reached in 3 cases, one of whom showed signs of toxicity. Theophylline treatment was not efficient in the prevention of apnea when a serious underlying disease was present. Theophylline blood half-life (mean:27.0 h) and clearance (mean 12.9 ml/h/kg) confirmed the slow elimination pattern of the drug in the premature infant.


Did RNA editing in plant organellar genomes originate under natural selection or through genetic drift?
The C<-->U substitution types of RNA editing have been observed frequently in organellar genomes of land plants. Although various attempts have been made to explain why such a seemingly inefficient genetic mechanism would have evolved, no satisfactory explanation exists in our view. In this study, we examined editing patterns in chloroplast genomes of the hornwort Anthoceros formosae and the fern Adiantum capillus-veneris and in mitochondrial genomes of the angiosperms Arabidopsis thaliana, Beta vulgaris and Oryza sativa, to gain an understanding of the question of how RNA editing originated. We found that 1) most editing sites were distributed at the 2nd and 1st codon positions, 2) editing affected codons that resulted in larger hydrophobicity and molecular size changes much more frequently than those with little change involved, 3) editing uniformly increased protein hydrophobicity, 4) editing occurred more frequently in ancestrally T-rich sequences, which were more abundant in genes encoding membrane-bound proteins with many hydrophobic amino acids than in genes encoding soluble proteins, and 5) editing occurred most often in genes found to be under strong selective constraint. These analyses show that editing mostly affects functionally important and evolutionarily conserved codon positions, codons and genes encoding membrane-bound proteins. In particular, abundance of RNA editing in plant organellar genomes may be associated with disproportionately large percentages of genes in these two genomes that encode membrane-bound proteins, which are rich in hydrophobic amino acids and selectively constrained. These data support a hypothesis that natural selection imposed by protein functional constraints has contributed to selective fixation of certain editing sites and maintenance of the editing activity in plant organelles over a period of more than four hundred millions years. The retention of genes encoding RNA editing activity may be driven by forces that shape nucleotide composition equilibrium in two organellar genomes of these plants. Nevertheless, the causes of lineage-specific occurrence of a large portion of RNA editing sites remain to be determined.


Assessment of the role of hepatitis C, Helicobacter pylori and autoimmunity in MALT lymphoma of the ocular adnexa in 45 Austrian patients.
A recent series from Italy has suggested a pathogenic link between hepatitis C virus and MALT lymphoma of the ocular adnexa. The hypothesis of our study was to prove this concept in Austrian patients with MALT lymphoma of the ocular adnexa. A total of 45 patients presenting with MALT lymphoma of the ocular adnexa were assessed for the presence of infection with hepatitis A, B and C. Furthermore, extensive staging to evaluate the extent of disease along with analysis of Helicobacter pylori-infection, the presence or absence of autoimmune diseases (AD) and assessment of MALT-lymphoma specific genetic changes was performed. Only 2/45 (4%) patients were tested positive for hepatitis C, while 10/45 (22%) had an underlying AD and 15/39 (38%) had HP infection. Chromosomal aberrations were detected in 19 (54%) of 35 patients analyzed. Disseminated disease was a significant risk factor for relapse (p=0.014). Our series suggests that infection with hepatitis C is not a significant contributor to the pathogenesis of ocular adnexal MALT lymphoma in the Austrian population, while a substantial proportion of these patients suffer from autoimmune conditions.


Purpose in life and reduced incidence of stroke in older adults: 'The Health and Retirement Study'.
To determine whether purpose in life is associated with reduced stroke incidence among older adults after adjusting for relevant sociodemographic, behavioral, biological, and psychosocial factors. We used prospective data from the Health and Retirement Study, a nationally representative panel study of American adults over the age of 50. 6739 adults who were stroke-free at baseline were examined. A multiple imputation technique was used to account for missing data. Purpose in life was measured using a validated adaptation of Ryff and Keyes' Scales of Psychological Well-Being. After controlling for a comprehensive list of covariates, we assessed the odds of stroke incidence over a four-year period. We used psychological and covariate data collected in 2006, along with occurrences of stroke reported in 2008, 2010, and during exit interviews. Covariates included sociodemographic factors (age, gender, race/ethnicity, marital status, education level, total wealth, functional status), health behaviors (smoking, exercise, alcohol use), biological factors (hypertension, diabetes, systolic blood pressure, diastolic blood pressure, BMI, heart disease), negative psychological factors (depression, anxiety, cynical hostility, negative affect), and positive psychological factors (optimism, positive affect, and social participation). Greater baseline purpose in life was associated with a reduced likelihood of stroke during the four-year follow-up. In a model that adjusted for age, gender, race/ethnicity, marital status, education level, total wealth, and functional status, each standard deviation increase in purpose was associated with a multivariate-adjusted odds ratio of 0.78 for stroke (95% CI, 0.67-0.91, p=.002). Purpose remained significantly associated with a reduced likelihood of stroke after adjusting for several additional covariates including: health behaviors, biological factors, and psychological factors. Among older American adults, greater purpose in life is linked with a lower risk of stroke.


Deposition and distribution of myclobutanil and tebuconazole in a semidwarf apple orchard by hand-held gun and air-assisted sprayer application.
Sprayers have been shown in numerous reports to influence pesticide deposition and distribution significantly, and public concern for their potential risk has been increasing in recent years. In this study, a hand-held gun sprayer and two air-assisted sprayers (a conventional axial fan air-blast sprayer and a tower sprayer) were used to apply myclobutanil and tebuconazole, and their influence on pesticide distribution and deposition in a semidwarf apple orchard was systematically investigated. The coefficients of variation of different canopy zones associated with the tower sprayers were 38.9-41.9% for leaves and 35.5-36.4% for fruit, generally lower than the coefficients of variation related to the other two sprayers. Tests conducted using the air-assisted sprayers recorded an overall higher drift on the adjacent rows than experiments carried out with the hand-held gun sprayer. The results of drift in soil indicated that pesticide was mainly distributed within 5 m downwind of the treated area, and the distribution pattern was influenced by sprayer design. The total pesticide concentration deposited in soil within 5 m during application by the tower sprayer was 0.28 m mg kg-1 for myclobutanil and 0.90 m mg kg-1 for tebuconazole, much lower than that of the hand-held gun sprayer and the conventional axial fan air-blast sprayer. The results indicate that the tower sprayer gives a more uniform distribution and guarantees better effectiveness for the phytosanitary treatment. The tower sprayer also protected the soil better and reduced environmental pollution due to its scientific structural design. © 2020 Society of Chemical Industry.


Analgesic efficacy of lidocaine and multimodal analgesia for chest tube removal: A randomized trial study.
To assess the analgesic efficacy of subcutaneous lidocaine and multimodal analgesia for chest tube removal following heart surgery. Sixty volunteers were randomly allocated in two groups; 30 participants in the experimental group were given 1% subcutaneous lidocaine, and 30 controls were given a multimodal analgesia regime comprising systemic anti-inflammatory agents and opioids. The intensity and quality of pain and trait and state anxiety were assessed. The association between independent variables and final outcome was assessed by means of the Chi-squared test with Yates' correction and Fisher's exact test. The groups did not exhibit significant difference with respect to the intensity of pain upon chest tube removal (p= 0.47). The most frequent descriptors of pain reported by the participants were pressing, sharp, pricking, burning and unbearable. The present study suggests that the analgesic effect of the subcutaneous administration of 1% lidocaine combined with multimodal analgesia is most efficacious.


Serum irisin levels in patients with myasthenia gravis.
Myasthenia gravis (MG) is an autoimmune disorder whose main symptoms are muscle weakness and fatigue. Irisin is a novel skeletal muscle-derived myokine participating in several physiological and pathological processes. The initial objective of the project was to explore serum levels of irisin in patients with MG, as well as its correlation with disease severity. We retrospectively evaluated serum levels of irisin in 77 MG patients and 57 healthy controls (HCs) by enzyme-linked immunosorbent assay. Further, clinical parameters were measured properly. Serum irisin levels were significantly elevated in MG patients compared with HCs (p < 0.001). Furthermore, serum irisin levels were associated with the myasthenia gravis activities of daily living score in ocular myasthenia gravis (OMG) patients (r = 0.476, p = 0.004), but there was no relationship to be considered of any relevant value in generalized myasthenia gravis (GMG) patients. Acetylcholine receptor antibody-positive MG patients had higher serum irisin levels compared with HCs. Thymoma, endotracheal intubation, or intensive care unit treatments subsequently were not found to have effect on serum levels of irisin, but tendencies of increase were observed in negative ones. Serum irisin levels were elevated in patients with MG, suggesting its possible involvement in MG. And irisin is expected to be a signal to evaluate the activities of daily living of OMG patients, while its effect needs further study.


Religion promotes a love for thy neighbour: But how big is the neighbourhood?
The term prosocial has often been taken to mean nice or neighbourly, but many acts that further in-group interests are hostile and aggressive towards out-groups. According to Norenzayan et al., religion's ability to foster social cohesion within religious groups has been a key factor in the human transition to complex societies. But what are the prospects for nonparochial "religious prosociality"?


Low self-compassion in patients with bipolar disorder.
Emerging research suggests that low self-compassion may be linked to psychopathology and in particular depressive symptoms. To further elucidate this topic, the present study investigated self-compassion in patients with Bipolar Disorder (BD). Thirty remitted BD patients were compared to thirty age- and sex matched controls on the Self-Compassion Scale (SCS). The BD patients also completed the Altman Self-Rating Mania Scale (ASRM), the Major Depression Inventory (MDI), the Work and Social Adjustment Scale (WSAS), the Satisfaction With Life Scale (SWLS) and the Internalized Stigma of Mental Illness Scale (ISMI-10) and further reported their illness history on a survey sheet. The BD patients were found to have significantly lower self-compassion than controls. In addition, self-compassion correlated positively and significantly with life-satisfaction but no significant correlations with functional impairment, internalized stigma or frequency of past affective episodes were found. The small sample size entailed reduced statistical power. By suggesting that self-compassion is reduced and possibly linked to life-satisfaction in BD, the findings highlight a potential vulnerability meriting further investigations.


Biphasic increase of apical Cl- conductance by muscarinic stimulation of HT-29cl.19A human colon carcinoma cell line: evidence for activation of different Cl- conductances by carbachol and forskolin.
The modulation of ion transport pathways in filter-grown monolayers of the Cl(-)-secreting subclone (19A) of the human colon carcinoma cell line HT-29 by muscarinic stimulation was studied by combined Ussing chamber and microimpalement experiments. Basolateral addition of 10(-4) M carbachol induced a complex poly-phasic change of the cell potential consisting of (i) a fast and short (30-sec) depolarization of 15 +/- 1 mV from a resting value of -52 +/- 1 mV and an increase of the fractional resistance of the apical membrane (first phase), (ii) a repolarization of 22 +/- 1 mV leading to a hyperpolarization of the cell (second phase), (iii) a depolarization of 11 +/- 1 mV and a decrease of the fractional resistance of the apical membrane (the third phase), (iv) and sometimes, a hyperpolarization of 6 +/- 1 mV and an increase of the fractional resistance of the apical membrane (fourth phase). The transepithelial potential increased with a peak value of 2.4 +/- 0.3 mV (basolateral side positive). The transepithelial PD started to increase (serosa positive), coinciding with the start of the second phase of the intracellular potential change, and continued to increase during the third phase. Ion replacements and electrical circuit analyses indicate that the first phase is caused by increase of the Cl- conductance in the apical and basolateral membrane, the second phase by increased K+ conductance of the basolateral membrane, and the third phase and the fourth phase by increase and decrease, respectively, of an apical Cl- conductance. The first and second phase of the carbachol effect could be elicited also by ionomycin. They were strongly reduced by EGTA. Phorbol dibutyrate (PDB) induced a sustained depolarization of the cell and a decrease of the apical fractional resistance. The results suggest that two different types of Cl- channels are involved in the carbachol response: one Ca2+ dependent and a second which may be PKC sensitive. In the presence of a supramaximal concentration of forskolin, carbachol evoked a further increase of the apical Cl- conductance. It is concluded that the short-lasting carbachol/Ca(2+)-dependent Cl- conductance is different from the forskolin-activated conductance. The increase of the Cl- conductance in the presence of forskolin by carbachol may be due to activation of different Cl- channels or to modulation of the PKA-activated Cl- channels by activated PKC.


Evolutionary dynamics of group fairness.
The emergence and impact of fairness is commonly studied in the context of 2-person games, notably the Ultimatum Game. Often, however, humans face problems of collective action involving more than two individuals where fairness is known to play a very important role, and whose dynamics cannot be inferred from what is known from 2-person games. Here, we propose a generalization of the Ultimatum Game for an arbitrary number of players--the Multiplayer Ultimatum Game. Proposals are made to a group of responders who must individually reject or accept the proposal. If the total number of individual acceptances stands below a given threshold, the offer will be rejected; otherwise, the offer will be accepted, and equally shared by all responders. We investigate the evolution of fairness in populations of individuals by means of evolutionary game theory, providing both analytical insights and results from numerical simulations. We show how imposing stringent consensuses significantly increases the value of the proposals, leading to fairer outcomes and more tolerant players. Furthermore, we show how stochastic effects--such as imitation errors and/or errors when assessing the fitness of others--may further enhance the overall success in reaching fair collective action.


Vitamin D and methylarginines in chronic kidney disease (CKD).
Vitamin D associates with the plasma concentration of the endogenous inhibitor of the nitric oxide system asymmetric dimethyl arginine (ADMA) and cross-sectional studies in CKD patients treated with the vitamin D receptor activator paricalcitol show that plasma ADMA is substantially less than in those not receiving this drug. In the frame of a randomized, double-blind, placebo controlled trial, the Paracalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY), we investigated whether vitamin D receptor activation by paricalcitol (2 μg/day x 12 weeks) affects the plasma concentration of ADMA and symmetric dimethyl arginine (SDMA) in 88 patients with stage 3 to 4 CKD. Paricalcitol produced the expected small rise in serum calcium and phosphate and a marked PTH suppression. However, ADMA [Paricalcitol: baseline 0.75 μMol/L (95%CI: 0.70-0.81), 12 week 0.72 μMol/L (95%CI: 0.66-0.78); Placebo: baseline 0.75 μMol/L (95%CI: 0.70-0.90) 12 weeks 0.70 μMol/L (95%CI: 0.66-0.74)] and SDMA [Paricalcitol: baseline 0.91 μMol/L (95%CI: 0.82-1.00), 12 week 0.94 μMol/L (95%CI: 0.82-0.1.06); Placebo: baseline 0.91 μMol/L (95%CI: 0.82-1.06) 12 weeks 0.99 μMol/L (95%CI: 0.88-1.10)] remained unchanged during the trial and 2 weeks after stopping these treatments. Paricalcitol does not modify plasma ADMA and SDMA in patients with stage 3-4 CKD. The apparent beneficial effects of paricalcitol on ADMA registered in cross-sectional studies is likely attributable to confounding by indication rather than to a true effect of this drug on ADMA metabolism.


Central administration of yohimbine increases free 3-methoxy-4-hydroxyphenylglycol in the cerebrospinal fluid of the rat.
The effect of the alpha2-antagonist, yohimbine, on cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG), dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindolactic acid (5-HIAA) concentrations was studied in vivo. Cerebrospinal fluid was removed at a constant flow rate of 1 microliters/min from the third ventricle of rats and directly analysed by liquid chromatography coupled with electrochemical detection. An intracerebroventricular injection of yohimbine (100 nmol) dramatically increased MHPG levels. These results suggest a functional stimulation of alpha-2 adrenoceptors modulating noradrenergic neurotransmission in vivo.


A Cultural Paradigm--Learning by Observing and Pitching In.
We discuss Learning by Observing and Pitching In (LOPI) as a cultural paradigm that provides an interesting alternative to Assembly-Line Instruction for supporting children's learning. Although LOPI may occur in all communities, it appears to be especially prevalent in many Indigenous and Indigenous-heritage communities of the Americas. We explain key features of this paradigm, previewing the chapters of this volume, which examine LOPI as it occurs in the lives of families and communities. In this introductory chapter, we focus especially on one feature of the paradigm that plays an important role in its uptake and maintenance in families, institutions, and communities-the nature of assessment. We consider the power of the dominant paradigm and the challenges in making paradigm shifts.


Elephant shark sequence reveals unique insights into the evolutionary history of vertebrate genes: A comparative analysis of the protocadherin cluster.
Cartilaginous fishes are the oldest living phylogenetic group of jawed vertebrates. Here, we demonstrate the value of cartilaginous fish sequences in reconstructing the evolutionary history of vertebrate genomes by sequencing the protocadherin cluster in the relatively small genome (910 Mb) of the elephant shark (Callorhinchus milii). Human and coelacanth contain a single protocadherin cluster with 53 and 49 genes, respectively, that are organized in three subclusters, Pcdhalpha, Pcdhbeta, and Pcdhgamma, whereas the duplicated protocadherin clusters in fugu and zebrafish contain >77 and 107 genes, respectively, that are organized in Pcdhalpha and Pcdhgamma subclusters. By contrast, the elephant shark contains a single protocadherin cluster with 47 genes organized in four subclusters (Pcdhdelta, Pcdhepsilon, Pcdhmu, and Pcdhnu). By comparison with elephant shark sequences, we discovered a Pcdhdelta subcluster in teleost fishes, coelacanth, Xenopus, and chicken. Our results suggest that the protocadherin cluster in the ancestral jawed vertebrate contained more subclusters than modern vertebrates, and the evolution of the protocadherin cluster is characterized by lineage-specific differential loss of entire subclusters of genes. In contrast to teleost fish and mammalian protocadherin genes that have undergone gene conversion events, elephant shark protocadherin genes have experienced very little gene conversion. The syntenic block of genes in the elephant shark protocadherin locus is well conserved in human but disrupted in fugu. Thus, the elephant shark genome appears to be less prone to rearrangements compared with teleost fish genomes. The small and "stable" genome of the elephant shark is a valuable reference for understanding the evolution of vertebrate genomes.


Patient perceptions that limit a community-based intervention to promote participation.
A workshop designed to teach seniors to communicate more effectively with their physicians and enhance patient participation in the consultation was held in a community centre. A grounded theory analysis of follow-up telephone interviews provided examples of effectiveness but also revealed six categories of barriers to changing the pattern of established communication, particularly over the short term.