Heat-inducible transgenic expression in the silkmoth Bombyx mori.
Germline transformation with new transposon vectors now enables causal tests of gene function via ectopic protein expression or RNA interference in non-drosophilid insects. The problem remains of how to drive the transgene expression in vivo. We employed germline transformation using the piggyBac 3xP3-EGFP vector to test whether the Drosophila heat shock hsp70 promoter will be active in the live silkworm. We modified the original vector by cloning the coding sequence for Bombyx nuclear receptor Ftz-F1 between the hsp70 promoter and the terminator. Three independent transgenic lines expressing the Pax-6-driven EGFP marker in larval and adult photoreceptors were obtained with efficiencies of up to 1.7% of fertile G0 adults that gave GFP-positive progeny. Chromosomal integration of the transposon was confirmed with inverse PCR. Heat induction of the transgenic BmFtz-F1 was proven at both the mRNA and protein levels. RT-PCR data showed that the Drosophila heat shock promoter was functional in all three transgenic lines. Although basal activity was apparent at 25 degrees C, 1 h at 42 degrees C induced BmFtz-F1 mRNA at different stages of development and in diverse tissues. The relative levels of induction differed among the transgenic lines. Northern blot hybridization detected transgenic BmFtz-F1 only after heat shock and low levels of the mRNA were still present 6 h after the heat treatment. Immunostaining of epidermis using anti-BmFtz-F1 antibody showed a clear increase of nuclear signal 90 min after a heat shock.


Prevalence of Fecal Incontinence in Normal Pressure Hydrocephalus: A Prospective Evaluation of 100 Patients.
Normal pressure hydrocephalus (NPH) is a frequent disease in elderly patients. The main symptoms are gait disturbance, urine incontinence, and cognitive decline. Fecal urgency and incontinence are described as rare additional symptoms; however, no exact numbers are known. The aim of this study was to investigate the prevalence of fecal disturbances in NPH patients. Patients who presented to our department with confirmed diagnosis of NPH between January and December 2021 were interviewed prospectively about fecal function. Additionally, the extent of gait disturbance, cognitive decline, ventriculomegaly (EvansIndex), disproportionate enlarged subarachnoid space hydrocephalus (DESH presence), age, gender, and length of history were documented. In those who were operated with a hydrocephalus shunt postoperative development of stool incontinence was followed up. One hundred patients were evaluated (67 males, 33 females, medium age 77.5 years, medium Evans Index: 0.37; 87 with disproportionate enlarged subarachnoid space hydrocephalus). 97 patients showed gait disturbance, 84 cognitive decline, and 87 bladder dysfunctions. 78 patients had the complete Hakim triad. 32 patients complained about fecal incontinence (20 with urge incontinence, 12 with complete incontinence). Twenty nine patients were shunted, of which 17 (57%) recovered completely, 9 (31%) partially, and 3 (10%) did not show any change. Fecal urgency and incontinence is a frequent finding in NPH (32%) and is essential for the quality of life. In the general population, fecal incontinence in elderly is found in up to 15%. The more than two-fold higher prevalence in NPH patients and the high percentage of postshunted improvement suggests that NPH causes often directly fecal disturbance.


Biosynthesis of 2-acetyl-1-pyrroline in rice calli cultures: Demonstration of 1-pyrroline as a limiting substrate.
The role of 1-pyrroline was studied via feeding experiments using rice calli cultures to gain further insight into the key steps of 2-acetyl-1-pyrroline (2AP) biosynthesis in rice. The origin of the acetyl donor was also studied through stable isotope labelled substrates. Incubation of fresh calli from a fragrant rice variety (Aychade) and a non-fragrant variety (Gladio×Fidji K2) with 1-pyrroline led to a significant increase in 2AP in both varieties. Importantly, the amount of 2AP in the non-fragrant variety could be greatly enhanced by this supplementation. When rice calli were fed with increasing levels of 1-pyrroline, 2AP levels increased accordingly. Our data show that 1-pyrroline is a limiting factor for 2AP synthesis in rice. Heat treatment of calli suggested that 1-pyrroline might be enzymatically acetylated. The presence of labelled 2AP in calli supplemented with [U-(13)C]glucose, sodium acetate (1,2-(13)C2) and sodium octanoate (1,2,3,4-(13)C4) suggested that these compounds are possible candidates for acetyl group-donors of 2AP, predominately in the form of intact labelled (13)C2-units.


Surgical treatment of bronchial asthma by resection of the laryngeal nerve.
Management of asthma in chronically affected patients is a serious health problem. Our aim was to show that surgical treatment of chronic bronchial asthma by unilateral resection of the internal branch of the superior laryngeal nerve (ib-SLN) is an adequateand lasting remedial response. In a retrospective study, 41 (26 male and 15 female) patients with bronchial chronic asthma were treated surgically during the period between 2005 and 2013. It consisted of a unilateral resection of the ib-SLN under optical zoom, on patients placed in supinator position. 35 patients (24 male and 11 female) who were un-operated were included as a control. In all patients, medication was reduced progressively. When the results were compared with the control group, it was seen that in 26% of the patients, both forced expiratory volume (FEV) and peak expiratory flow (PEF) increased significantly (p <05) and only modestly in 53.6% of patients (FEV, p <05 and PEF, p <05). In the remaining 20% of patients, these parameters remained however unchanged. Overall, in 80% of patients unilateral resection of the ib-SLN gave satisfactory results because it shortened the intervals and duration of asthmatic attacks, rendering thereby a reduction in medication. This minimal-invasive method helped prevent/cure asphyxias in chronic bronchial asthma without affecting cough reflex,respiratory control and phonation and it helped patients avoid severe crisis. This approach is of interest for patients with severe and/or uncontrolled bronchial asthma in settings with limited access to drug treatment.


[Clinical efficacy and achievement of a complete remission in depression: increasing interest in treatment with escitalopram].
Such a prevalent disease as Major Depressive Disorder (MDD), associated with prominent impairment in physical and social functioning, implies as well an increased morbidity and mortality. Long-term treatments are required due to the frequent occurrence of relapses. Patient compliance is a core factor in both acute and continuation treatment, closely related to tolerability issues. We have partially reviewed the literature published on PubMed since 2004 which assess the relative antidepressant efficacy of escitalopram and comparator antidepressants in adult patients who met DSM-IV criteria for major depressive disorder (MDD). Clinically important differences exist between commonly prescribed antidepressants. These analyses are in favor of a superior efficacy and tolerability of long-term escitalopram treatment (10 to 20mg/day) compared with active controls, including selective serotonin re-uptake inhibitors (SSRIs) (paroxetine, citalopram, bupropion, fluoxetine, fluvoxamine, sertraline), serotonin/noradrenaline reuptake inhibitors (SNRIs) (venlafaxine, milnacipran and duloxetine) and noradrenergic and specific serotonergic antidepressants (NaSSAs) (mirtazapine). Cipriani et al. (2009) have performed a network meta-analysis of 12 new generation antidepressants. They have shown that clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favor of escitalopram and sertraline in acute treatment, defined as 8-week treatment. Kasper et al. (2009) conducted a post-hoc pooled analysis of data from two 6-month randomized controlled trials that revealed superior efficacy and tolerability of escitalopram when compared with paroxetine. The pooled analysis of four randomized, double-blind, active comparator, 6-month trials in MDD, by Wade et al. (2009), showed that short-term outcomes may predict long-term treatment compliance and outcomes. A higher probability of achieving remission was associated with responding after 8 weeks and with completing 6 months of treatment. Furthermore, Week 24 complete remission (MADRS≤5) was significantly (P<0,01) higher for escitalopram (51.7%) than for the pooled comparators (45.6%). And after 6 months, fewer patients discontinued treatment with escitalopram (15.9%) than with the pooled comparators (23.9%) (P<0.001). This fragmentary review of the literature shows that it is necessary to adopt a stringent definition of remission in depression, especially in clinical trials; a MADRS total score less or equal to 10 to define remission, a MADRS total score less or equal to 5 to define complete remission, and moreover no MADRS single item greater than 1 to define symptom-free remission. In all these meta-analyses, the superiority of escitalopram compared with other antidepressants was confirmed for both acute and long-term treatment of MDD, especially in harshly depressed patients.


Repeated application of first-layer antiserum improves immunofluorescence staining: a modification of the indirect immunofluorescence staining procedure.
Repeated application of the first-layer antiserum in the indirect immunofluorescence technique considerably improves the immunostaining. The modified method reveals more antigenic sites and increases the contrast between specific and background stainings, particularly where sparsely distributed antigenic areas are to be investigated. The effect of this novel immunostaining procedure is compared with that of the routine procedure and of other modifications. Possible mechanisms for the improving effect are discussed. A procedure of combined modifications is recommended for exploration of non-abundant antigens or for achieving a high-quality photograph.


Polycyclic aromatic compounds (PACs) in the Canadian environment: Sources and emissions.
Twenty-five years after the first look at polycyclic aromatic compounds (PACs) in Canada, this article presents current knowledge on Canadian PAC emission sources. The analysis is based on national inventories (the National Pollutant Release Inventory (NPRI) and the Air Pollutant Emissions Inventory (APEI)), an analysis of Canadian forest fires, and several air quality model-ready emissions inventories. Nationally, forest fires continue to dominate PAC emissions in Canada, however there is uncertainty in these estimates. Though forest fire data show a steady average in the total annual area burned historically, an upward trend has developed recently. Non-industrial sources (home firewood burning, mobile sources) are estimated to be the second largest contributor (∼6-8 times lower than forest fires) and show moderate decreases (25%-65%) in the last decades. Industrial point sources (aluminum production, iron/steel manufacturing) are yet a smaller contributor and have seen considerable reductions (90% +) in recent decades. Fugitive emissions from other industrial sources (e.g. disposals by the non-conventional oil extraction and wastewater sectors, respectively) remain a gap in our understanding of total PAC emissions in Canada. Emerging concerns about previously unrecognized sources such as coal tar-sealed pavement run-off, climate change are discussed elsewhere in this special issue. Results affirm that observations at the annual/national scale are not always reflective of regional/local or finer temporal scales. When determining which sources contribute most to human and ecosystem exposure in various contexts, examination at regional and local scales is needed. There is uncertainty overall in emissions data stemming in part from various accuracy issues, limitations in the scope of the various inventories, and inventory gaps, among others.


[Effect of calcium and vitamin D in the reduction of falls in the elderly: a randomized trial versus placebo].
Supplements of calcium and vitamin D (Ca/VitD) could help prevent falls, although it is unknown whether the effect differs according to the level of physical activity or baseline 25-OH-vitamin D3. The objective is to determine the effect of Ca/VitD supplements in reducing falls and the musculoskeletal function in elderly over 65 years living in the community, who do not have osteoporosis or vitamin D deficiency. Randomized double-blinded clinical trial. A total of 508 patients were selected from 35 Family Medicine consultations. The treatment was administered to 398 subjects (Ca/VitD 188 and placebo 210). The efficacy parameters were: incidence of falls, changes in muscle strength in dominant hand and changes in musculoskeletal function. The cumulative incidence of falls in the group Ca/VitD was 27.7% (95% confidence interval [95% CI]: 21.0 to 34.3) and 30.5% in the placebo group (95% CI: 24.0 to 36.9) (P=.537). The difference was not significant in the subgroup analysis: male/female, active/inactive physically and level of 25-OH-vitamin D3 higher/less than 32 ng/ml. There was no difference in muscle strength in subjects of both groups. The proportion of adverse effects was higher in the Ca/VitD group (14.4 versus 7.1%, P=.019). The results contradict the recommendation to provide supplements, and it is not an effective and well tolerated strategy. Although they may reduce the risk of falls when there are very low levels of vitamin D, the results are unsatisfactory when elders do not have this deficiency, and it is necessary to consider the possibility of adverse effects.


Altering in vivo macrophage responses with modified polymer properties.
Macrophage reprogramming has long been the focus of research in disease therapeutics and biomaterial implantation. With different chemical and physical properties of materials playing a role in macrophage polarization, it is important to investigate and categorize the activation effects of material parameters both in vitro and in vivo. In this study, we have investigated the effects of material surface chemistry on in vivo polarization of macrophages. The library of materials used here include poly(N-isopropylacrylamide-co-acrylic acid) (p(NIPAm-co-AAc)) nanoparticles (∼600 nm) modified with various functional groups. This study also focuses on the development of a quantitative structure-activity relationship method (QSAR) as a predictive tool for determining the macrophage polarization in response to particular biomaterial surface chemistries. Here, we successfully use in vivo imaging and histological analysis to identify the macrophage response and activation. We demonstrate the ability to induce a spectrum of macrophage phenotypes with a change in material functionality as well as identify certain material parameters that seem to correlate with each phenotype. This suggests the potential to develop materials for a variety of applications and predict the outcome of macrophage activation in response to new surface chemistries.


Numbers of mutations to different types of colorectal cancer.
The numbers of oncogenic mutations required for transformation are uncertain but may be inferred from how cancer frequencies increase with aging. Cancers requiring more mutations will tend to appear later in life. This type of approach may be confounded by biologic heterogeneity because different cancer subtypes may require different numbers of mutations. For example, a sporadic cancer should require at least one more somatic mutation relative to its hereditary counterpart. To better estimate numbers of mutations before transformation, 1,022 colorectal cancers were classified with respect to microsatellite instability (MSI) and germline DNA mismatch repair mutations characteristic of hereditary nonpolyposis colorectal cancer (HNPCC). MSI- cancers were also classified with respect to clinical stage. Ages at cancer and a Bayesian algorithm were used to estimate the numbers of oncogenic mutations required for transformation for each cancer subtype. Ages at MSI+ cancers were consistent with five or six oncogenic mutations for hereditary (HNPCC) cancers, and seven or eight mutations for its sporadic counterpart. Ages at cancer were consistent with seven mutations for sporadic MSI- cancers, and were similar (six to eight mutations) regardless of clinical cancer stage. Different biologic subtypes of colorectal cancer appear to require different numbers of oncogenic mutations before transformation. Sporadic MSI+ cancers may require more than a single additional somatic alteration compared to hereditary MSI+ cancers because the epigenetic inactivation of MLH1 commonly observed in sporadic MSI+ cancers may be a multistep process. Interestingly, estimated numbers of MSI- cancer mutations were similar (six to eight mutations) regardless of clinical cancer stage, suggesting a propensity to spread or metastasize does not require additional mutations after transformation. Estimates of oncogenic mutation numbers may help explain some of the biology underlying different cancer subtypes.


One-pot superhydrophilic surface modification of waste polyurethane foams for high-efficiency oil/water separation.
Despite of the fact that polymers have brought tremendous convenience to human life, they have also inevitably caused considerable environmental pollution after their service life. Therefore, a feasible strategy that can effectively recycle waste polymers and endow them with high added value is much desired. Superwetting materials have shown great promise in oily wastewater treatment because of their high oil/water separation efficiency. However, most of these materials present some limitations, such as complex preparation procedures and poor salt tolerance, which hamper their practical applications. In this study, an iron hydroxide@polydopamine@waste polyurethane foam (Fe(OH)3@PDA@WPU) was synthesized via a facile and mild "one-pot" reaction. During this process, polymerization of dopamine and in situ growth of Fe(OH)3 were simultaneously realized, and the resultant PDA and Fe(OH)3 nanoparticles were firmly attached to the surface of WPU. Due to the abundant hydrophilic groups from PDA and Fe(OH)3 coupled with the surface roughness created by Fe(OH)3 nanoparticles, the surface properties of the foam could be changed from hydrophobic to superhydrophilic. Remarkably, the Fe(OH)3@PDA@WPU was capable of separating various oil/water mixtures even under some severe conditions (e.g. erosion in a saturated sodium chloride solution and longtime sonication), demonstrating high potential in marine oily sewage treatment. Moreover, this work also paved a new path for reducing the negative impact of waste polymer foams on our environment, and in the meantime realizing their high value utilization.


Peptidyl dipeptidase in rabbit brain microvessels.
The activity of peptidyl dipeptidase (peptidyldipeptide hydrolase, EC 220.127.116.11), also known as angiotensin-converting enzyme, was studied in small blood vessel preparations isolated from rabbit brain. The vascular preparation contained arterioles and capillaries and was essentially free of extravascular material. Enzymatic activity was demonstrated in microvessel homogenates using both hippuryl-histidyl-leucine and tritium-labeled angiotensin I as substrates. Activity in the microvessels was dependent on the presence of chloride ion and was sensitive to inhibition by converting enzyme inhibitors previously shown to be effective in both vivo and in vitro. Specific activity in the micro-vessels was approximately 20 times that in homogenates of brain, and was almost 60% of that found in rat lung homogenates. The data were consistent with an endothelial localication for peptidyl dipeptidase in the cerebral vasculature and supports the proposal that this enzyme has a physiological role in extrapulmonary vascular beds.


Impact of loss to follow-up on survival estimation for cystic fibrosis.
Deaths among those lost to follow-up (LTFU) in the Cystic Fibrosis Foundation Patient Registry (CFFPR) are critically important to the epidemiology of cystic fibrosis (CF). Unreported deaths could impact estimates of survival if LTFU is associated with disease trajectory. We characterized the LTFU population (1986-2017) from the CFFPR and identified deaths via linkage with the National Death Index (NDI). Median predicted survival age and conditional survival were estimated with and without additional deaths and person-time from the NDI. Of the 10,582 individuals LTFU in the CFFPR, 2,460 (23.2%) matched to an NDI death record. Individuals who died after LTFU with a CF diagnosis were 43% female, 91% White/non-Hispanic, 59% had advanced CF lung disease based on last CFFPR recorded forced expiratory volume in one second (FEV1) %predicted <40 and 18% were post-lung transplant. Median predicted survival age during the most recent period available, 2013-2017, increased from 44.3 years (95% CI: 43.2, 45.7) to 45.8 years (95% CI 44.5, 47.1) with the inclusion of NDI data. Inclusion of deaths and additional person-time among those LTFU changed the point estimate of median predicted survival for most time periods and increased the point estimate from 2009 onwards.


Coronary flow and resistance reserve in patients with chronic aortic regurgitation, angina pectoris and normal coronary arteries.
Left ventricular hypertrophy has been found to be associated with a reduction of coronary vascular reserve, which could be responsible for episodes of myocardial ischemia. To evaluate coronary flow and resistance reserve in patients with chronic aortic regurgitation, coronary sinus blood flow and coronary resistance were measured before and after an intravenous dipyridamole infusion (0.14 mg/kg per min X 4 min) in eight control subjects and eight patients with aortic regurgitation, exertional angina pectoris and normal coronary arteriograms. Coronary flow reserve, evaluated by the dipyridamole/basal coronary sinus blood flow ratio, and coronary resistance reserve, evaluated by the basal/dipyridamole coronary resistance ratio, were both significantly reduced in patients with aortic regurgitation (1.67 +/- 0.40 versus 4.03 +/- 0.52 in control subjects, p less than 0.001 and 1.71 +/- 0.50 versus 4.38 +/- 0.88 in control subjects, p less than 0.001, respectively). In patients with aortic regurgitation, basal coronary sinus blood flow was higher than in control subjects (276 +/- 81 versus 105 +/- 24 ml/min, respectively, p less than 0.001) and basal coronary resistance was lower (0.31 +/- 0.13 versus 0.95 +/- 0.17 mm Hg/ml per min, respectively, p less than 0.001), but coronary blood flow and resistance after dipyridamole were not significantly different in the two groups (461 +/- 159 versus 418 +/- 98 ml/min in control subjects, 0.19 +/- 0.11 versus 0.22 +/- 0.04 mm Hg/ml per min in control subjects, respectively). These data demonstrate that coronary reserve is severely reduced in patients with chronic aortic regurgitation and exertional angina.(ABSTRACT TRUNCATED AT 250 WORDS)


Influencing mechanisms of lifestyle and dietary factors on chronic diseases among community residents: updated evidence in Shanghai, China.
This study aimed to determine the risk factors for chronic diseases and to identify the potential influencing mechanisms from the perspectives of lifestyle and dietary factors. The findings could provide updated and innovative evidence for the prevention and control of chronic diseases. A cross-sectional study. Shanghai, China. 1005 adults from Yangpu district of Shanghai participated in the study, and responded to questions on dietary habits, lifestyle and health status. Residents suffering from chronic diseases accounted for about 34·99 % of the respondents. Logistic regression analysis showed that age, diet quality, amount of exercise and tea drinking were related to chronic diseases. Age > 60 and overeating (Diet Balance Index total score > 0) had negative additive interaction on the occurrence of chronic disease, while overexercise (Physical Activity Index > 17·1) and tea drinking had negative multiplicative interaction and negative additive interaction on the occurrence of chronic disease. Diet quality, physical activity and tea drinking were incomplete mediators of the relationship between types of medical insurance residents participating in and chronic diseases. The residents in Yangpu District of Shanghai have a high prevalence of chronic diseases. Strengthening access of residents to health education and interventions to prevent chronic diseases and cultivating healthy eating and exercise habits of residents are crucial. The nutritional environment of the elderly population should be considered, and the reimbursement level of different types of medical insurance should be designed reasonably to improve the accessibility of medical and health services and reduce the risk of chronic diseases.


Faint electric treatment-induced rapid and efficient delivery of extraneous hydrophilic molecules into the cytoplasm.
Effective delivery of extraneous molecules into the cytoplasm of the target cells is important for several drug therapies. Previously, we showed effective in vivo transdermal delivery of naked siRNA into skin cells induced by faint electric treatment (ET) iontophoresis, and significant suppression of target mRNA levels (Kigasawa et al., Int. J. Pharm., 2010). This result indicates that electricity promoted the delivery of siRNA into cytoplasm. In the present study, we analyzed the intracellular delivery of naked anti-luciferase siRNA by faint ET, and found that the luciferase activity of cells expressing luciferase was reduced by in vitro ET like in vivo iontophoresis. Cellular uptake of fluorescent-label siRNA was increased by ET, while low temperature exposure, macropinocytosis inhibitor amiloride and caveolae-mediated endocytosis inhibitor filipin significantly prevented siRNA uptake. These results indicate that the cellular uptake mechanism involved endocytosis. In addition, voltage sensitive fluorescent dye DiBAC4 (3) penetration was increased by ET, and the transient receptor potential channel inhibitor SKF96365 reduced siRNA uptake, suggesting that faint ET reduced membrane potentials by changing intracellular ion levels. Moreover, to analyze cytoplasmic delivery, we used in-stem molecular beacon (ISMB), which fluoresces upon binding to target mRNA in the cytoplasm. Surprisingly, cytoplasmic ISMB fluorescence appeared rapidly and homogeneously after ET, indicating that cytoplasmic delivery is markedly enhanced by ET. In conclusion, we demonstrated for the first time that faint ET can enhance cellular uptake and cytoplasmic delivery of extraneous molecules.


Dose effects of tricyclic antidepressants in the treatment of acute depression - A systematic review and meta-analysis of randomized trials.
Tricyclic antidepressants (TCA) continue to be an important group of drugs, but it is unclear whether a dose-response relationship is supported by high-level evidence. Systematic review in the Cochrane Collaboration's Central Register of Controlled Trials (CENTRAL) of studies randomizing patients to at least two doses of one TCA, complemented by searches in Medline, Embase, and PsycInfo. In multilevel regression, we calculated the standardized mean difference (SMD) in antidepressant efficacy per mg TCA dose increase, and we analyzed drop-outs due to adverse events. Finally, we computed random effects meta-analyses of all dose comparisons investigated in a minimum of two studies. Out of 5365 studies screened, we included 15 randomized trials on 24 comparisons of 14 different dose contrasts. We found a statistically non-significant positive effect of increasing the dose: 0.34 SMD with 100 mg/d dose increase ([-0.03; 0.70] p = 0.073). While several comparisons showed no clear signal of a dose gradient, 300 mg of imipramine/desipramine is statistically significantly superior to 150 mg (SMD: 0.80 [0.28; 1.33], p = 0.003, I2: 0%). Drop-outs increased with higher doses, albeit not statistically significantly: Odds ratio (OR) of 1.44 with 100 mg dose increase [0.54; 3.86]. Overall, risk of bias was high. Limited number of studies with mainly high risk of bias. So far, data on a dose-response relationship in TCAs from direct dose comparisons are inconclusive. Clinically, escalation to high doses may be justified if side effects are bearable.


Long-term Care of the Adult Liver Transplant Recipient.
While outcomes after liver transplantation have increased over the last two decades, this is primarily as a consequence of a reduction in early deaths and survival of those who survive the first 6 months has not significantly changed. Causes of premature death and graft loss include cardiovascular disease, renal impairment, malignancy and some infections. As the number of transplant recipients increase, care is being given by primary and secondary care clinicians. Management of the well patient is crucially dependent on careful assessment and where appropriate intervention, especially of cardiovascular risk - such as advice about avoidance of weight gain; management of hypertension, hyperlipidaemia and diabetes; and provision of appropriate lifestyle advice. Other interventions include surveillance for de novo malignancies, active management of immunosuppressive regimen with the need to tailor immunosuppression to the individual. Prompt investigation of abnormalities of liver function is essential. Immune-mediated graft damage still occurs but is less common as a cause for graft loss. Adherence is sometimes an issue, especially in teenagers and young adults, and should be considered and support given where needed. Immunisations (avoiding live and attenuated vaccines) should be encouraged. Recurrence of disease remains an issue, and some interventions (such as appropriate use of antiviral therapy for those grafted with viral hepatitis, use of ursodeoxycholic acid for those grafted for primary biliary cholangitis or long-term steroids for those grafted for autoimmune disease) may improve and maintain graft function. Close collaboration between recipient and the attending clinicians in primary, secondary and tertiary care and close attention to modifiable conditions will lead to improved outcomes.


HLA-A*24:244, a variant of HLA-A*24:02:01:01, detected in a Taiwanese individual.
One nucleotide substitution in codon 51 of HLA-A*24:02:01:01 results in the novel allele, HLA-A*24:244.


A computer simulation study of normal and abnormal hip joint contact pressure.
The contact pressure on 112 normal hip joints and 66 acetabular dysplastic hip joints was analysed using a three-dimensional rigid body spring model. Geometric models were made from conventional anteroposterior radiographs, with the assumption that the acetabular surface was spherical. In normal hips, the distribution of contact pressure was almost even over the joint surface, and the maximum contact pressure was relatively low. However, in a dysplastic hip joint, the pressure was concentrated on the anterolateral edge of the acetabulum and increased enormously not only with the reduction in lateral coverage but also with the reduction in the anterior coverage of the acetabulum. This result indicates that a three-dimensional analysis is indispensable for estimating the mechanical effect on acetabular cartilage.


Gas-liquid chromatography of triazine herbicides as heptafluorobutyryl derivatives and some applications to analysis in foods.
The heptafluorobutyryl (HFB) derivatives of ten triazine herbicides were prepared by reacting the pesticides with heptafluorobutyric anhydride in benzene, in the presence of trimethylamine or pyridine as catalyst. The reactions produced mainly the mono-HFB products while some of the herbicides had small quantities of the di-HFB derivatives present. The derivatives were 300 fold to several thousand fold more sensitive to electron-capture detection than the underivatized triazines. They also were 5-10 fold more sensitive than the parents by electrolytic conductivity detection in the halogen mode while they were of similar sensitivity with the same detector in the nitrogen mode. The derivatives eluted in the same general order as the parent triazines on stationary phases of OV-1, OV-101, OV-101/QF-1, and OV-210. This method was successfully applied to the analysis of potatoes, peas and tomatoes spiked with various triazines at levels of 0.13-0.86 ppm.


The mechanical principles behind the golden ratio distribution of veins in plant leaves.
Tree leaves are commonly composed of thin mesophyll, carrying out photosynthesis under sunlight, and thick veins. Although the role of leaf veins in water transportation has been known for a long time, their role in providing structural support and guaranteeing large sunlighted area was rarely studied and remains elusive. Here, with use of a novel inverse optimization approach, we aim for uncovering the material design principle behind the unique pattern of venation. It is intriguing to observe that an almost Golden Ratio (GR) distribution of leaf veins always provides optimized structural behavior. Specifically, our research reveals, for the first time, that this unique GR distribution of relatively strong vein material is helpful for maximizing the bending stiffness and leading to a large sunlighted area which is vital for the photosynthesis process of a leaf. Moreover, the GR distribution of leaf veins is also observed in a wide class of plant leaf geometries (i.e., shape, thickness), where experimental evidence is provided for the optimized results. Therefore, our findings can not only serve to explain the mystery of veins GR distribution but also provide widely applicable guidelines on designing soft structures with exceptional mechanical performances.


Whole-genome identification and expression profiling of growth-regulating factor (GRF) and GRF-interacting factor (GIF) gene families in Panax ginseng.
Panax ginseng is a perennial herb and one of the most widely used traditional medicines in China. During its long growth period, it is affected by various environmental factors. Past studies have shown that growth-regulating factors (GRFs) and GRF-interacting factors (GIFs) are involved in regulating plant growth and development, responding to environmental stress, and responding to the induction of exogenous hormones. However, GRF and GIF transcription factors in ginseng have not been reported. In this study, 20 GRF gene members of ginseng were systematically identified and found to be distributed on 13 chromosomes. The ginseng GIF gene family has only ten members, which are distributed on ten chromosomes. Phylogenetic analysis divided these PgGRFs into six clades and PgGIFs into two clades. In total, 18 of the 20 PgGRFs and eight of the ten PgGIFs are segmental duplications. Most PgGRF and PgGIF gene promoters contain some hormone- and stress- related cis-regulatory elements. Based on the available public RNA-Seq data, the expression patterns of PgGRF and PgGIF genes were analysed from 14 different tissues. The responses of the PgGRF gene to different hormones (6-BA, ABA, GA3, IAA) and abiotic stresses (cold, heat, drought, and salt) were studied. The expression of the PgGRF gene was significantly upregulated under GA3 induction and three weeks of heat treatment. The expression level of the PgGIF gene changed only slightly after one week of heat treatment. The results of this study may be helpful for further study of the function of PgGRF and PgGIF genes and lay a foundation for further study of their role in the growth and development of Panax ginseng.


Experiences of an Emergency Department Visit Among Older Adults and Their Families: Qualitative Findings From a Mixed-Methods Study.
Emergency department (ED) visits are critical events for older adults, but little is known regarding their experiences, particularly about their physical needs, the involvement of accompanying family members, and the transition back to the community. To explore experiences of an ED visit among patients aged 75 and older. In a mixed-methods study, a cohort of patients aged 75 and older (or a family member) discharged from the ED back to the community was recruited from 4 urban EDs. A week following discharge, structured telephone interviews supplemented with open-ended questions were conducted. A subsample (76 patients, 32 family members) was purposefully selected. Verbatim transcripts of responses to the open-ended questions were thematically analyzed. Experiences related to physical needs included comfort, equipment supporting mobility and autonomy, help when needed, and access to drink and food. Family members required opportunities to provide patient support and greater involvement in their care. At discharge, patients/families required adequate discharge education, resolution of their health problem, information on medications, and greater certainty about planned follow-up medical and home care services. Our findings suggest several areas that could be targeted to improve patient and family perceptions of the care at an ED visit.


Metanephric adenoma: a rare differential diagnosis of renal tumor in children.
Metanephric adenoma is an extremely rare tumor of the kidney. The clinical and anatomic characteristics are not yet well defined, but it is currently considered to be a benign tumor with a good prognosis, although recently two metastatic cases have been reported. Around 50% of cases are incidental findings, and symptoms include polycythemia, abdominal pain, hematuria and palpable mass. The morphological characteristics are similar to those of Wilms' tumor, suggesting a common embryological precursor. We present here the youngest girl yet to be reported with a diagnosis of metanephric adenoma.


Behaviors of Water Intake, Hydration Status, and Related Hydration Biomarkers among Physically Active Male Young Adults in Beijing, China: A Cross-Sectional Study.
Studies on the water intake of athletes in daily life are insufficient. The objective was to determine the water intake and hydration status among physically active male young adults. In this cross-sectional studies study, 111 physically active male young adults were recruited. The amount of daily total drinking fluid intake (TDF) among participants was recorded and evaluated in real time over 7 days using the "7-day 24-hour fluid intake questionnaire" (liq. In 7). The daily water intake from food (WFF) was calculated using the weighing, duplicate portion, and direct-drying method over 3 days. All urine samples over 3 days were collected, and urine biomarkers were determined. According to 24 h urine osmolality, the participants were divided into three groups with euhydration status, middle hydration, and hypo hydration statuses. Finally, 109 participants completed the study. The median daily total water intake (TWI), TDF, and WFF were 2701, ik1789, and 955 mL, respectively. Among participants, 17 participants (16%) were in euhydration status, 47 participants (43%) were in hypohydration, and 45 participants (41%) were in middle hydration. There were statistical significances in the 24 h urine volume, osmolality, urine specific gravity, and concentrations of K, Na, and Cl in different hydration statuses (χ 2 = 28.212, P < 0.01; χ 2 = 91.341, P < 0.01; χ 2 = 47.721, P < 0.01; χ 2 = 41.548, P < 0.01; χ 2 = 46.863, P < 0.01; and χ 2 = 40.839, P < 0.01). Moderate-intensity correlations were found between the TDF and 24 h urine volume, 24 h urine osmolality, 24 h urine Na concentration, morning urine osmolality, and morning urine Na concentration (r = 0.408, P < 0.01; r = -0.378, P < 0.01; r = -0.325, P < 0.01; r = -0.344, P < 0.01; and r = -0.329, P < 0.01). There were also moderate-intensity correlations between the TDF and 24 h urine osmolality, morning urine osmolality, and morning urine Na concentration (r = -0.365, P < 0.01; r = -0.371, P < 0.01; and r = -0.322, P = 0.01). Increased and higher moderate-intensity correlations were found between plain water and 24 h urine volume, 24 h urine osmolality, 24 h urine K and Na concentration, morning urine osmolality, and morning urine Na concentration (r = 0.374, P < 0.01; r = -0.520, P < 0.01; r = -0.312,P < 0.01; r = -0.355, P < 0.01; r = -0.446, P < 0.01; and r = -0.378, P < 0.01). Insufficient water intake and hypohydration were common among physically active male young adults. The amount and type of water intake were correlated with hydration status and urine biomarkers. The results could provide scientific and accurate references for the development of recommendations on water intake for athletes.


Deficiency of the corpus callosum: incomplete penetrance and substrain differentiation in BALB/c mice.
In a foundation population of BALB/c mice used to establish a colony at Waterloo in 1977, about 11% of adults showed either total absence or gross deficiency of the corpus callosum. Comparisons between parents and offspring, between progenies of different males, and between 13 separate lines established by full-sib inbreeding showed that variation in the adult corpus callosum reflected a genuine incomplete penetrance in a genetically uniform population. However, after seven generations of inbreeding, a spontaneous change occurred in one line (BALB/cWah 1), resulting in more than 50% of adults with deficient corpus callosum, among which about 20% have complete absence of callosal axons traversing the hemispheres.


Internal border zone injury predicts the functional outcome of acute MCA stroke patients.
Classification of deep (D), superficial (S) MCA territories and their junctional vascular area (the internal border zone, IBZ) can help to identify patients most likely to benefit from aggressive reperfusion therapy after stroke. We tested the prognostic value of an IBZ injury compared to DWI-ASPECTS and infarct volume. DW lesions of 168 patients with acute (4.2±6.5 h) MCA strokes were retrospectively examined and manually delineated. Patients with haemorrhagic transformation or other neurological diseases were excluded. Clinical data were recorded within 24 h following symptom onset and 48 h for patients who benefited from reperfusion therapy. The occurrence of an IBZ injury was determined using a standardized stereotaxic atlas. Performance to predict a good outcome (mRS<3 at 3 months) was estimated through ROC curves for DWI-ASPECTS≤6, lesion volume≥100 mL and IBZ injury. Logistic regression models were performed to estimate independent outcomes for infarct volume and IBZ injury. Infarcts involving the IBZ were larger (94.9±98.8 mL vs. 30.2±31.3 mL), had higher NIHSS (13.8±7.2 vs. 7.2±5.7), more frequent MCA occlusions (64.9% vs. 28.3%), and worse outcomes (mRS 3.0±1.8 vs. 1.9±1.7), and were less responsive to IVtPA (34±47% vs. 55±48% of NIHSS improvement). The area under the ROC curves was comparable between the occurrence of IBZ injury (0.651), ASPECTS≤6 (0.657) and volume≥100 mL (0.629). Logistic regression analyses showed an independent effect of an IBZ injury, especially for superficial MCA strokes and for patients who benefited from reperfusion therapy. An IBZ injury is an early and independent marker of stroke severity, functional prognosis and treatment responsiveness.


Endometrioid adenocarcinoma of the ovary and endometriosis.
We present a retrospective analysis of 22 cases of endometrioid ovarian carcinoma, reviewed to identify endometriosis and its malignant transformation. Twenty-two patients with endometrioid ovarian cancer were included in the review. Their clinical and histological data were retrospectively reviewed. The origin of the tumours was considered endometriosis-related when the presence of malignant changes in endometriosis glands leading to endometrioid carcinoma were found. Endometriosis was detected in three cases (3/22=14%). One of them presented a clearly benign to malignant transformation area. In another patient, the transition zone was abrupt and present in both ovaries. In the third, a pre-menopausal woman, ovarian endometriosis with only focal endometrioid carcinoma was observed. The three of them had a clear-cell carcinoma component. The presence of a clear-cell component was significantly greater in patients with endometriosis than in patients without endometriosis Each patient had a different clinical presentation: increase in abdominal perimeter, post-menopausal vaginal haemorrhage and hypermenorrhea. Preoperative CA 125 levels were avalaible in 15 of the patients (15/22=68%). Endometriosis was found in two of these 15 patients, both with the highest CA 125 measured levels, exceeding 1700 U/ml. In the remaining of the patients, CA 125 value did not exceed 35 U/ml. Although this association is not very frequent, patients with ovarian endometriosis and a high CA 125 serum level should be managed with special care, regardless of their pre-menopausal or post-menopausal status.


Relationship between carbon pool changes and environmental changes in arid and semi-arid steppe-A two decades study in Inner Mongolia, China.
As the arid and semi-arid grassland with the most extensive distribution area in northern China, the carbon stored in Inner Mongolia (IM) grassland is highly susceptible to environmental changes. With the global warming and drastic climate changes, exploring the relationship between carbon pool changes and environmental changes and their spatiotemporal heterogeneity is necessary. This study estimates the carbon pool distribution of IM grassland during 2003-2020 by combining the measured below ground biomass (BGB) dataset, measured soil organic carbon (SOC) dataset, multi-source satellite remote sensing data products, and random forest regression modeling method. It also discusses the variation trend of BGB/SOC and its correlation with critical environmental factors, vegetation condition factors and drought index. The results show that the BGB/SOC in IM grassland was stable during 2003-2020, with a weak upward trend. The correlation analysis reveals that high temperature and drought environment were unfavorable for developing vegetation roots and would lead to a decrease in BGB. Furthermore, temperature rise, soil moisture decrease, and drought adversely effected grassland biomass and SOC in areas with low altitude, high SOC density, suitable temperature and humidity. However, in areas with relatively poor natural environments and relatively low SOC content, SOC was not significantly affected by environmental deterioration and even showed an accumulation trend. These conclusions provide directions for SOC treatment and protection. In areas where SOC is abundant, it is important to reduce carbon loss caused by environmental changes. However, in areas with poor SOC, due to the high carbon storage potential of grasslands, carbon storage can be improved through scientifically managing grazing and protecting vulnerable grasslands.


[Neurooncology].
The central and peripheral nervous systems give rise to a variety of tumors which differ markedly in their incidence, age preference, and prognosis. The nervous system is also frequently affected by metastatic cancer. The major therapeutic options for tumors of the nervous system include surgical resection, radiotherapy using various strategies of fractionation, total dose, and target volume, and different approaches of chemotherapy such as systemic, intrathecal, and interstitial chemotherapy as well as high-dose chemotherapy with stem cell rescue. An increasing number of therapeutic options in neurooncology are no more merely palliative treatments, but may be curative, indicating that neurooncology is experiencing an era both of controversies regarding previous standards of care and of innovative strategies to combat tumors of the nervous system.


Suicide Risk in Personality Disorders: A Systematic Review.
This systematic review aimed to distil recent literature investigating psychosocial factors which may account for the association between personality disorder (PD) and suicide attempt or suicide death. Suicide risk is particularly elevated in people with PD compared to those with no, or many other, mental health diagnoses. Despite this, suicide prevention strategies for PD populations have not progressed markedly in recent years. It is critical, therefore, to identify additional factors associated with suicide in PD populations. Of the 34 studies included in this review, most identified a relationship between personality disorder and suicide attempt and/or death. Historical interpersonal factors (e.g., childhood trauma), drug and alcohol use, and ideation-to-enaction factors were commonly associated with suicide-related outcomes. Interventions that provide interpersonal support may reduce suicide attempts. Limitations of the review include the heterogeneity of studies and small sample sizes.


Ethanol fermentation driven by elevated expression of the G1 cyclin gene CLN3 in sake yeast.
Cellular and subcellular morphology reflects the physiological state of a cell. To determine the physiological nature of sake yeast with superior fermentation properties, we quantitatively analyzed the morphology of sake yeast cells by using the CalMorph system. All the sake strains examined here exhibited common morphological traits that are typically observed in the well-characterized whiskey (whi) mutants that show accelerated G(1)/S transition. In agreement with this finding, the sake strain showed less efficient G(0)/G(1) arrest and elevated expression of the G(1) cyclin gene CLN3 throughout the fermentation period. Furthermore, deletion of CLN3 remarkably impaired the fermentation rate in both sake and laboratory strains. Disruption of the SWI6 gene, a transcriptional coactivator responsible for Cln3p-mediated G(1)/S transition, also resulted in a decreased fermentation rate, whereas whi mutants exhibited significant improvement in the fermentation rate, demonstrating positive roles of Cln3p and its downstream signalling pathway in facilitating ethanol fermentation. The combined results indicate that enhanced induction of CLN3 contributes to the high fermentation rate of sake yeast, which are natural whi mutants.


Disability perception in Menière's disease: when, how much and why?
The purpose of the study was to evaluate self-perceived handicap in patients with definite Menière's disease (MD). A cross-sectional study was conducted. To examine the self-perception of disability, participants completed a DHI (Dizziness Handicap Inventory). Parameters compared with DHI scores: sex, age, unilateral/bilateral affectation, time elapsed since the onset of symptoms, pure-tone average (PTA), stages of MD, audiometric change (last 6 months), PTA in low frequencies (PTAl) and audiometric change in PTAl, subjective perception of fluctuating hearing threshold, tinnitus between attacks, number of vertiginous episodes (last 6 months), time elapsed since last attack, subjective perception of instability intercrises and Tumarkin attacks. 90 patients were included; they completed a total of 104 questionnaires. DHI scores ranged from 2 to 100 (average: 47.08, SD 24.45). In 29 cases (27.9 %) the disability perception was mild, in 43 (41.3 %) moderate, and in 32 (30.8 %) severe. Correlation between disability perception and some vestibular symptoms was found: number of typical attacks (last 6 months), time elapsed since last attack, instability intercrises and Tumarkin attacks. No relationship was found with the rest of variables. Disability perception in patients with MD depends primarily on vestibular symptoms (particularly, instability and frequency of attacks). So, we suggest to design a new staging system of MD taking into account both auditory criteria and also vestibular symptoms.


Quantitative determination of S-alk(en)ylcysteine-S-oxides by micellar electrokinetic capillary chromatography.
A novel method for determination of S-alk(en)ylcysteine-S-oxides by capillary electrophoresis has been developed and validated. The method is based on extraction of these sulfur amino acids by methanol, their derivatization by fluorenylmethyl chloroformate and subsequent separation by micellar electrokinetic capillary chromatography. Main advantages of the new method are simplicity, sensitivity, high specificity and very low running costs, making it suitable for routine analysis of a large number of samples. Employing this method, the content of S-alk(en)ylcysteine-S-oxides was determined in 12 commonly consumed alliaceous and cruciferous vegetables (e.g. garlic, onion, leek, chive, cabbage, radish, cauliflower and broccoli). The total content of these amino acids in the Allium species evaluated varied between 0.59 and 12.3mg g(-1) fresh weight. Whereas alliin was found only in garlic, isoalliin was the major S-alk(en)ylcysteine-S-oxide in onion, leek, chive and shallot. On the other hand, the cruciferous species analyzed contained only methiin in the range of 0.06-2.45mg g(-1) fresh weight.


Differential regulation of Na+/H+ exchange and H(+)-ATPase by pH and HCO3- in kidney proximal tubules.
This study examines the effects of acute in vitro acid-base disorders on Na+/H+ and H(+)-ATPase transporters in rabbit kidney proximal tubules (PT). PT suspensions were incubated in solutions with varying acid base conditions for 45 min and utilized for brush border membrane (BBM) vesicles preparation. BBM vesicles were studied for Na+/H+ exchange activity (assayed by 22Na+ influx) or abundance (using NHE-3 specific antibody) and H(+)-ATPase transporter abundance (using antibody against the 31 kDa subunit). The Na+/H+ exchanger activity increased by 55% in metabolic acidosis (pH 6.5, HCO3- 3 mM) and decreased by 41% in metabolic alkalosis (pH 8.0, HCO3- 90 mM). The abundance of NHE-3 remained constant in acidic, control, and alkalotic groups. H(+)-ATPase abundance, however, decreased in metabolic acidosis and increased in metabolic alkalosis by 57% and 42%, respectively. In PT suspensions incubated in isohydric conditions (pH 7.4), Na+/H+ exchanger activity increased by 29% in high HCO3- group (HCO3- 96 mM) and decreased by 16% in the low HCO3- groups (HCO3- 7 mM. The NHE-3 abundance remained constant in high, normal, and low [HCO3-] tubules. The abundance of H(+)-ATPase, however, increased by 82% in high [HCO3-] and decreased by 77% in the low [HCO3-] tubules. In PT suspensions incubated in varying pCO2 and constant [HCO3-], Na+/H+ exchanger activity increased by 35% in high pCO2 (20% pCO2, respiratory acidosis) and decreased by 32% in low pCO2 (1.5% pCO2, respiratory alkalosis) tubules. The NHE-3 abundance remained unchanged in high, normal, and low pCO2 tubules.(ABSTRACT TRUNCATED AT 250 WORDS)


Monetary valuation of unsorted waste: A shadow price approach.
Improving the management of municipal solid waste (MSW) is fundamental to promote circular economy and sustainability. Unsorted waste involves negative environmental impacts which often are ignored in economic feasibility studies due to its difficult valuation. In this study the shadow price of unsorted waste using the directional distance function was estimated. This methodological approach also allowed us to compute eco-efficiency scores of a set of municipalities in the provision of MSW services. The empirical application focused on a sample of 119 Chilean municipalities. The results showed that the average shadow price of unsorted waste was 297.66 €/ton which means that the environmental cost of left waste as unsorted was 297.66 € per ton. A regression tree model illustrated that population density, tourism intensity and the generation of waste per capita significantly influenced the shadow price of unsorted waste. Moreover, it was illustrated that Chilean municipalities were very inefficient in the management of MSW since the average eco-efficiency score was 0.272. The findings from this study reveal that additional and alternative policies should be adopted to improve the management of MSW and increase its recycling rate.


Physical basis of the rheologic properties of F-actin.
The viscoelastic properties of purified rabbit skeletal muscle actin filaments (F-actin) were measured at physiologic ionic strength and pH over a range of concentrations and filament lengths. Although F-actin demonstrated transitory elastic behavior, viscous flow was observed at longer times consistent with a high degree of filament overlap. The compliance was independent of stress over a 4-fold range, implying that the measurement did not disrupt any interfilament "bonds". The dynamic storage modulus increased monotonically with frequency over the range measured, whereas the dynamic loss modulus had a relative minimum and was always less than the dynamic storage modulus. These observations are typical of topologically constrained behavior. The absolute value of the complex dynamic viscosity of F-actin, varied as the -0.8 power of the frequency and at a frequency of 0.1 radians/s was proportional to the product of the weight average filament length raised to the 0.7 power and the concentration. The experimental data agreed well with the predictions of a theory of the rheologic behavior of stiff rods in semidilute solutions. We conclude that the mechanical behavior of pure F-action solutions can be explained on the basis of the mutual topologic constraints to diffusion of long stiff rods which do not otherwise interact.


Making sense of trying not to teach: an interview study of tutors' ideas of problem-based learning.
To explore how a cohort of first-ever "foundation" tutors in a new problem-based curriculum characterized and made sense of problem-based learning (PBL). The sample consisted of all foundation tutors (n = 34) from The University of Liverpool's undergraduate medical curriculum, 1996-97, the first semester of the first year that PBL became a main vehicle for knowledge acquisition. The cross-sectional study design involved semistructured telephone interviews with the tutors about PBL and problem solving. The author taped and transcribed the interviews and conducted an inductive analysis of these qualitative data. All tutors responded, with interviews lasting about 20 minutes: 26/34 (76%) were men and 23 (68%) were medically qualified. Twenty-nine (85%) facilitated 19-21 of the 21 PBL sessions. Most tutors conceptualized PBL as being student-centered (68%), involving small-group work (53%), but ignored its reflective component. They conceptualized good PBL tutors diversely, but mostly as "knowing" when and how to intervene (41%) and empathizing with students (29%). Few tutors characterized PBL in terms of problem solving, yet over half agreed, cursorily, that they were intimately related. The tutors were generally unclear about this relationship. These tutors mostly characterized PBL positively as a philosophy, yet missed its reflective elements and were particularly challenged by their own fallibility in knowing when and how to intervene without teaching. Internal motivation and direct experience of PBL helped balance some of the tutors' confusion with the educational rationale, highlighting possibilities for future staff development.


Microclimate environment model construction and control strategy of enclosed laying brooder house.
The growth performance and health of chicks can be significantly improved by a suitable microclimate in brooder houses. However, the microclimate of the chicken house is affected by factors such as its structure and the heat dissipation of chickens, making it is difficult to establish an accurate mathematical model and achieve effective regulation. In this paper, the environmental data acquisition system of enclosed chick brooder house was established by analyzing various environmental factors in brooder houses. According to the structural characteristics of brooder houses and the growth environment of chicks and other parameters, the microclimate simulation model of brooder houses was established using the physical law of energy balance. The coefficient of determination R2 (R-square) between simulated temperature and humidity output value and measured value was 0.7634 and 0.9740, respectively, and Root Mean Square Error (RMSE) was 1.55°C and 2.61%, respectively. The correctness of the simulation model was verified. On the basis of established microclimate models, a simulation model of fuzzy decoupling Proportion Integration Differentiation (PID) control in chicken house environments was established for the strong coupling between temperature control and general risk control system in chicken houses. Different control strategies were generated by fuzzy and logical reasoning about multiple environmental factors. The compensation coefficient was added to optimize the environmental regulation system of brooder houses. The temperature maximum deviation between the set value and the fuzzy decoupling PID controller was 0.5°C, the maximum relative error was 2.7%, the maximum deviation of relative humidity between the set value and the fuzzy decoupling PID controller was 4.93%, the maximum relative error was 10.49%.The simulation results show the control strategy meets the temperature and humidity control requirements, verify the effectiveness of the control strategy and model. The experimental results can guide the actual environmental control of brooder houses.


Molecular and Pharmacological Bladder Cancer Therapy Screening: Discovery of Clofarabine as a Highly Active Compound.
The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.


Central 5-HT2B/2C and 5-HT3 receptor stimulation decreases salt intake in sodium-depleted rats.
In the present study, we investigated the participation of central 5-HT(2B/2C) and 5-HT(3) receptors in the salt intake induced by sodium depletion in Wistar male rats. Sodium depletion was produced by the administration of furosemide associated with a low salt diet. Third ventricle injections of mCPP, a 5-HT(2B/2C) agonist, at doses of 80, 160 and 240 nmol, promoted a dose-dependent reduction in salt intake in sodium-depleted rats. The inhibitory effect produced by central administration of mCPP was abolished by the central pretreatment with SDZ SER 082, a 5-HT(2B/2C) antagonist. Similar results were obtained with third ventricle injections of m-CPBG (80, 160 and 240 nmol), a selective 5-HT(3) agonist that also induced a dose-related decrease in salt intake in sodium-depleted rats. The central pretreatment with LY-278,584, a selective 5-HT(3) receptor antagonist, was able to impair the salt intake inhibition elicited by third ventricle injections of m-CPBG. Central administration of each one of the antagonists alone or a combination of both antagonists together did not significantly change salt intake after sodium depletion. On the other hand, the central administration of both mCPP and m-CPBG, in the highest dose used to test their effect on salt intake (240 nmol), was unable to modify blood pressure in sodium-depleted rats. It is concluded that: (1) pharmacological activation of central 5-HT(2B/2C) and 5-HT(3) receptors diminishes salt intake during sodium depletion, (2) an inhibitory endogenous drive exerted by central 5-HT(2B/2C) and 5-HT(3) receptors does not seem to exist and (3) the reduction in salt intake generated by the pharmacological activation of these central receptors is not produced by an acute hypertensive response.


Preparation and application of polystyrene-divinylbenzene sorbent with weak cation-exchange character for the selective extraction of illicit drugs in environmental water.
A novel mixed-mode weak cation-exchange sorbent (PS-DVB-WCX-II) was prepared by the modification of polystyrene-divinylbenzene with mercaptosuccinic acid for the selective extraction of illicit drugs in environmental water. The PS-DVB-WCX-II was synthesized through the Friedel-Crafts acylation reaction on the surface of polystyrene-divinylbenzene, followed by nucleophilic substitution reaction and thiol-ene click reaction. The sorbent can selectively absorb illicit drugs through the reverse-phase interactions provided by benzene ring on the polymer backbone and the ion-exchange interactions provided by functional group (-COOH). As compared with the extraction performance of three commercial SPE cartridges, it was found that the prepared sorbent had better adsorption performance with the recovery values between 84.1% and 106.0% for the selected 11 illicit drugs under the optimized SPE conditions. Illicit drugs in environmental water were extracted by the sorbent, prior to the detection of UHPLC-MS/MS. Two quantitative methods were established respectively for the detection of 11 illicit drugs in different matrices of river water and wastewater. Both methods had good determination coefficient (r2>0.992) in the range of 0.5-50 ng/L, 2.5-250 ng/L, 5-500 ng/L, and low limits of detection (S/N = 3) of 0.17-1.67 ng/L. In the real wastewater samples, the concentration of morphine was 18.3-126.3 ng/L, and the methamphetamine was 12.7-27.4 ng/L. Meanwhile, PS-DVB-WCX-II was compared with Oasis MCX and Oasis HLB in the detection of real wastewater samples. The results revealed that PS-DVB-WCX-II and Oasis MCX had better performance in absorbing methamphetamine than Oasis HLB, and PS-DVB-WCX-II had better ability to remove the matrix. The results suggested that the prepared weak cation-exchange sorbent had the potential in the application of illicit drug detection in environmental water.


Evidence for two promoters upstream of the pts operon: regulation by the cAMP receptor protein regulatory complex.
Several potential target sites for multiple regulatory mechanisms were previously identified in the 5' flanking region of the pts operon. We have investigated the in vitro interactions of the cAMP receptor protein (CRP).cAMP regulatory complex with two DNA binding sites, by gel mobility-shift assays, and report the analysis of the functional role of each of the binding sites in vivo. Promoter-reporter gene fusion studies identified two CRP.cAMP-dependent promoters (the previously identified P1 and another promoter, P0) upstream of ptsH. The crr promoters (P2) within ptsI may be negatively regulated by CRP.cAMP.


Analyses of circRNA and mRNA profiles in the submandibular gland in hypertension.
The aim of this study was to elucidate the roles played by circular RNAs (circRNAs) in the mechanism underlying submandibular gland (SMG) dysfunction in hypertension. We employed RNA-seq to analyze the circRNA and mRNA expression profiles of SMGs. Seventy-five differentially expressed (DE) circRNAs and 691 DE mRNAs were determined to be significantly altered in spontaneously hypertensive rats. Altered mRNAs were primarily related to the immune system and immune response. Eight circRNAs were selected for further analysis. Cell adhesion molecules were determined to be the most strongly enriched pathway through analysis of DE mRNAs, the coding noncoding gene co-expression (CNC) network and the competitive endogenous RNA (ceRNA) network. The salivary secretion pathway was observed to be notably enriched through analysis of the ceRNA network. These results suggest that the crosstalk among circRNAs may play a crucial role in the development of SMG dysfunction in hypertension.


Incidence of biofilms among the multidrug resistant E. coli, isolated from urinary tract infections in the Nilgiris district, South India.
Multidrug resistant uropathogenic Escherichia coli (MDRUPEC) significantly correlates with recurrent, complicated, and persistent urinary tract infection (UTI). The leading cause of multidrug resistance is the ability of E. coli to form biofilms. The physiological heterogeneity, genetic incontinency, and putative events in gene expression of biofilms render them resistant to antimicrobials and the host immune system. Understanding the determinants of antimicrobial resistance and its correlation with biofilm formations will, therefore, help the development of a better strategy for treating biofilm-associated UTIs. The present study reports on the in vitro detection of biofilm formation among multidrug resistant E. coli strains isolated from urine, the major cause of communal, nosocomial, and food-borne uropathogenic UTI. This is a cross-sectional study conducted in and around Ooty, Nilgiris, India. From the 869 urine samples analyzed for UTI, 29.34% were found to be caused by E. coli. Among this about 23.92% were found to be multidrug resistant. Among the multidrug resistant E. coli isolates, 36.06% of them were potent biofilm producers. E. coli biofilms (n = 22) were resistant to the antibiotics used to treat UTI, namely, amikacin, amoxicillin, ampicillin, cefepime, cefoperazone, cefotaxime, ceftriaxone, cefuroxime, cephalotin, ciprofloxacin, co-trimoxazole, gentamicin, levofloxacin, and nalidixic acid, but sensitive to imipenem and meropenem. All the biofilm producers exhibited motility and hemaggultination but none were positive for hemolysin production. The isolated E. coli biofilms were confirmed by VITEK R2 Compact (bioMerieux, France) and 16S rRNA gene sequencing.


Vasoproliferative process resembling pulmonary capillary hemangiomatosis in a cat.
Pulmonary capillary hemangiomatosis is a rare, vascular obstructive disorder that uniformly causes pulmonary arterial hypertension. Clinically, pulmonary capillary hemangiomatosis is indistinguishable from primary pulmonary arterial hypertension and histology is required for definitive diagnosis. The distinctive histologic feature of pulmonary capillary hemangiomatosis is non-malignant extensive proliferation of capillaries in the alveolar septae. Vasodilator treatment of humans with primary arterial hypertension due to pulmonary capillary hemangiomatosis can result in fatal acute pulmonary edema. Computed tomography is thus critical to discern pulmonary capillary hemangiomatosis from other causes of pulmonary arterial hypertension prior to vasodilator therapy. This is the first report of a vasoproliferative process resembling pulmonary capillary hemangiomatosis in the feline species. A 15-year-old, male castrated, domestic shorthair cat presented for persistent labored breathing presumptively due to congestive heart failure despite treatment with diuretics for 7 days. Echocardiography showed evidence of hypertrophic cardiomyopathy with severe pulmonary hypertension; however, a normal sized left atrium was not consistent with congestive heart failure. Thoracic computed tomography was performed and showed evidence of diffuse ill-defined nodular ground glass opacities, enlarged pulmonary arteries, and filling defects consistent with pulmonary thromboembolism. The cat acutely decompensated after a single dose of sildenafil and was euthanized. Histopathology of the lungs showed severe multifocal alveolar capillary proliferation with respiratory bronchiolar infiltration, marked type II pneumocyte hyperplasia and multifocal pulmonary arterial thrombosis. This is the first description in a cat of a vasoproliferative disorder resembling pulmonary capillary hemangiomatosis complicated by multifocal pulmonary arterial thrombosis. Inspiratory and expiratory ventilator-driven breath holds with angiography revealed lesions predominantly characterized by ground glass opacification and vascular filling defects with absence of air trapping. The results from this report suggest that, as in humans, the cat can develop a pulmonary capillary hemangiomatosis-like disease in which vasodilator therapy to address pulmonary hypertension may lead to fatal pulmonary edema.


BDNF boosts spike fidelity in chaotic neural oscillations.
Oscillatory activity and its nonlinear dynamics are of fundamental importance for information processing in the central nervous system. Here we show that in aperiodic oscillations, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, enhances the accuracy of action potentials in terms of spike reliability and temporal precision. Cultured hippocampal neurons displayed irregular oscillations of membrane potential in response to sinusoidal 20-Hz somatic current injection, yielding wobbly orbits in the phase space, i.e., a strange attractor. Brief application of BDNF suppressed this unpredictable dynamics and stabilized membrane potential fluctuations, leading to rhythmical firing. Even in complex oscillations induced by external stimuli of 40 Hz (gamma) on a 5-Hz (theta) carrier, BDNF-treated neurons generated more precisely timed spikes, i.e., phase-locked firing, coupled with theta-phase precession. These phenomena were sensitive to K252a, an inhibitor of tyrosine receptor kinases and appeared attributable to BDNF-evoked Na(+) current. The data are the first indication of pharmacological control of endogenous chaos. BDNF diminishes the ambiguity of spike time jitter and thereby might assure neural encoding, such as spike timing-dependent synaptic plasticity.


Disentangling the concept of "the complex older patient" in general practice: a qualitative study.
The rising life expectancy in the developed world leads to an increase in the number of older patients and the complexity of their complaints in general practice. Although interventions and support for general practitioners are available, implementation lags. Knowledge on what determines a complex older patient, the problems of which general practitioners encounter and the situations they actually need support for, is necessary for better implementation. To provide support to general practitioners in their struggle with complex older patients, the aim of this research was to disentangle the concept of the complex older patient in general practice. A qualitative approach was used consisting of 15 semi-structured interviews with general practitioners. The general practitioner was asked to prepare a case of a complex older patient out of their own practice that could be discussed during the interview. Transcripts of the interview were analysed using inductive thematic analysis. Analysis of the interviews resulted in twelve themes that could be categorised into five factors that contribute to the complexity of cases of older patients. The five factors are: not being in charge, different views on necessary care, encountering the boundaries of medicine, limits to providing social care, ill-equipped. The factors that were found imply that a better organisational structure for elderly care and consulting elderly care physicians could support general practitioners in providing care for older complex patients. Furthermore, understanding the current concept of patient autonomy seems unjustified in cases of complex older patients.


Competitive, substrate-dependent reductive debromination/dehydrobromination of 1,2-dibromides with triethylamine.
The interaction of various 1,2-dibromides with NEt3 under various conditions (THF and DMF, respectively) at different temperatures was investigated. Our results from these reactions show that substrate dependent dehydrobrominations compete with reductive debrominations. A comprehensive discussion of these competitive pathways is offered.


Sport-related differences in biomarkers of bone resorption and cartilage degradation in endurance athletes.
By measuring urinary cross-linked N-telopeptide (NTx) as a bone resorption marker and urinary C-telopeptide of type II collagen (CTx-II) as a cartilage degradation marker, we asked whether differences in skeletal stresses in college athletes undergoing high-intensity training for diverse types of aerobic sports affect their skeletal metabolism and, if so, differentially or in unison. The study was cross-sectional at a Division 1 college campus with 60 student athletes representing crew, cross-country running and swimming. Controls were 16 non-athlete undergraduates. Urine samples were collected for NTx and CTx-II analysis by enzyme-linked immunosorbent assay, normalizing results to creatinine. Two-way analysis of variance models and pair-wise comparisons were used to test whether biomarker levels differed by sport and the significance when adjusted for body mass index (BMI). NTx and CTx-II showed significant differences between groups before and after adjusting for BMI. NTx was highest in the rowers, and higher in rowers and runners than in swimmers or controls. CTx-II was significantly higher in runners than in crew, swimmers or controls, when unadjusted for BMI. After adjusting for BMI, these group differences remained significant except for runners over crew. Athletes in-training in the three sports show significant differences in these markers of bone resorption and cartilage collagen degradation. The results suggest that crew undergo the highest bone remodeling and runners the highest cartilage degradation. The results also show how these markers can vary physiologically between individuals, at extremes of skeletal exercise.


Interactions of chaperonin with a weakly active anthranilate synthase from the aphid endosymbiont Buchnera aphidicola.
The endosymbiotic bacterium Buchnera provides its aphid host with essential amino acids. Buchnera is typical of intracellular symbiotic and parasitic microorganisms in having a small effective population size, which is believed to accelerate genetic drift and reduce the stability of gene products. It is hypothesized that Buchnera mitigates protein instability with an increased production of the chaperonins GroESL. In this paper, we report the expression and functional analysis of trpE, a plasmid-borne fast-evolving gene encoding the tryptophan biosynthesis enzyme anthranilate synthase. We overcame the problem of low enzyme stability by using an anthranilate synthase-deficient mutant of E. coli as the expression host and the method of genetic complementation for detection of the enzyme activity. We showed that the Buchnera anthranilate synthase was only weakly active at the temperature of 26 degrees C but became inactive at the higher temperatures of 32 degrees C and 37 degrees C and that the coexpression with chaperonin genes groESL of E. coli enhanced the function of the Buchnera enzyme. These findings are consistent with the proposed role of groESL in the Buchnera-aphid symbiosis.


Two kinds of ocular trauma score for paediatric traumatic cataract in penetrating eye injuries.
To compare the ocular trauma score (OTS) and the paediatric penetrating ocular trauma score (POTS) as prognostic model for visual outcome in paediatric traumatic cataract cases after penetrating eye injuries. All children younger than 16 years with unilateral traumatic cataract following penetrating trauma between 2007 and 2012 were retrospectively reviewed. Univariate chi-square analysis was conducted to identify the variables associated with profound visual loss. The area under the receiver-operating characteristic curves (AUROC) was used to assess the predictive ability of the two models. The study group comprised 65 boys and 37 girls. The variables associated with profound visual loss were: a relative afferent papillary defect (RAPD) (P<0.001), poor initial vision (P=0.01), vitreous haemorrhage (P<0.001), retinal detachment (P<0.001), posterior penetrating site (P<0.001), hyphema (P<0.001), no intraocular len implantation (P<0.001) and endophthalmitis (P=0.001). OTS could not be calculated in 21 patients (20.6%) without clinical data on initial visual acuity and RAPD. For the patients with complete clinical data, POTS was similar to OTS in predicting poor vision (AUROC 0.904 vs 0.924) and in predicting good vision (AUROC 0.766 vs 0.736). For all the samples, POTS was a robust predictor of poor vision (AUROC 0.910) and had a moderate ability to predict good vision (AUROC 0.764). OTS has high ability to predict visual outcome for paediatric traumatic cataract following penetrating ocular trauma. POTS is also a reliable prognostic model for very young child without initial vision or RAPD, but is only for penetrating eye injuries.


The density of dystopic neurons in the white matter of the gyrus frontalis inferior in epilepsies.
It has been suspected for a long time that developmental disturbances of the brain could be a factor in the causation of epilepsies. The diagnostic term "microdysgenesis" indicates the morphological correlate for this hypothesis. An increase in the number of nerve cells in the white matter belongs to this microdysgenesis. Its diagnosis, judged purely qualitatively, is very uncertain and cannot be clearly be differentiated from normal findings. In this study, the nerve cell density in the white matter of the gyrus frontalis inferior was determined morphometrically. There was a significantly increased cell count in the group with primary generalized epilepsy compared to the control group. However, even in the group with traumatic epilepsy there still a significantly higher cell count than in the control group, although clearly lower than in the group with primary generalized epilepsy. The study supports the hypothesis that disturbed maturation could be an aetiological factor in epilepsy.


Association of transferrin G258A and transferrin receptor A82G polymorphisms with the risk of Parkinson disease in certain area.
It has been reported that polymorphisms of transferrin (TF) G258A and transferrin receptor (TFR) A82G might be associated with susceptibility to Parkinson disease (PD). Owing to limitation of sample size and inconclusive results, we conducted a meta-analysis to clarify the association. By searching PubMed, Embase, Chinese National Knowledge Infrastructure, China Biological Medicine Database, and Wanfang Databases, the published articles about studies of the association of the TF G258A, TFR A82G gene polymorphisms with the risk of PD were collected. Q-statistics and I statistics were calculated to examine heterogeneity and summary odds ratios (ORs) and 95% confidence intervals (95%CI) were evaluated the association. Five studies assessed the relationship between TF G258A and risk of PD. A significant increased protective of A allele and AA genotype was observed in allele model and recessive model (the allele model A vs G: OR = 0.54, 95%CI 0.40-0.72, P < .001; the recessive model AA vs GA + GG: OR = 0.32, 95%CI 0.20-0.52, P < .001). The remaining models of the TF G258A genotype showed no significant association with PD risk, while the protective tendency were increased (the heterozygote model GA vs GG: OR = 0.93, 95%CI 0.61-1.43, P = .75; the homozygous model AA vs GG: OR = 0.47, 95%CI 0.21-1.04, P = .06; the dominant model GA + AA vs GG: OR = 0.75, 95%CI 0.50-1.11, P = .15). There was also a lack of association between TFR A82G polymorphism and PD (the allele model G vs A: OR = 0.92, 95%CI 0.75-1.13, P = .43; the heterozygote model AG vs AA: OR = 1.17, 95%CI 0.79-1.71, P = .43; the homozygous model GG vs AA: OR = 0.91, 95%CI 0.60-139, P = .66; the dominant model AG + GG vs AA: OR = 1.05, 95%CI 0.73-1.49, P = .81; the recessive model GG vs AG +AA: OR = 0.80, 95%CI 0.59-1.09, P = .16). Our study suggests that TF G258A polymorphism may be associated with PD, while TFR A82G polymorphism may not contribute to PD based on the current evidence.


Effect of coxsackievirus b3 on ion channel currents in rat ventricular myocytes.
To investigate the effects of coxsackievirus B3(CVB3) on ion channel currents in rat ventricular myocytes. Rat hearts were isolated with collagenase to acquire single ventricular myocytes, L-type voltage-dependent calcium channel (VDCC) current (I(Ca)), Na+ current (I(Na)), outward potassium current (I(out)), inwardly rectifying potassium current(I(KI)) were recorded using whole cell patch clamp techniques. CVB3 infection increased I(Ca) and I(out), while decreased I(KI); but it had no obvious effect on I(Na). The effects of CVB3 an I(Ca), I(out), I(KI) may be one of the mechanisms of myocytes damage and the occurrence of abnormal electroactivities induced by CVB3 infection.


Age-dependent symptomatology of depression in hospitalized patients and its implications for DSM-5.
We investigated effects of current age and age at onset on symptomatology of depression with reference to proposed revisions in DSM-5. The study entailed medical records of 326 inpatients diagnosed with major depressive disorder, including 520 depressive episodes, with 113 first episodes lifetime. Subjects were divided into three groups: young-adults, middle-aged adults and older adults. In young-adults, active suicidal ideation, lifetime suicidal attempts, irritability, anhedonia and persistent depressive symptoms between the episodes were more frequent than in the other groups. Among older adults, depression was associated with insomnia, hypochondriasis, somatization, decreased appetite, weight loss, memory impairment and decreased activity. The older age was not associated with higher number of previous episodes of depression, bigger severity or duration of a single episode or a different degree of remission. Early-onset depression was associated with more suicidal attempts. The study was retrospective and the sample may be treated only as representative for hospitalized depressed patients. Age and age at onset are important factors influencing the course and symptomatology of a depressive episode. Depressive episodes with anxiety and with suicide risk severity are important specifiers that vary with the age at onset and/or age of the patient and should be considered for inclusion in the DSM-5 revision.


Rigid real-time prospective motion-corrected three-dimensional multiparametric mapping of the human brain.
To develop a rigid real-time prospective motion-corrected multiparametric mapping technique and to test the performance of quantitative estimates. Motion tracking and correction were performed by integrating single-shot spiral navigators into a multiparametric imaging technique, three-dimensional quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS). The spiral navigator was optimized, and quantitative measurements were validated using a standard system phantom. The effect of motion correction on whole-brain T1 and T2 mapping under different types of head motion during the scan was evaluated in 10 healthy volunteers. Finally, six patients with Parkinson's disease, which is known to be associated with a high prevalence of motion artifacts, were scanned to evaluate the effectiveness of our method in the real world. The phantom study demonstrated that the proposed motion correction method did not introduce quantitative bias. Improved parametric map quality and repeatability were shown in volunteer experiments with both in-plane and through-plane motions, comparable to the no-motion ground truth. In real-life validation in patients, the approach showed improved parametric map quality compared to images obtained without motion correction. Real-time prospective motion-corrected multiparametric relaxometry based on 3D-QALAS provided robust and repeatable whole-brain multiparametric mapping.


Volume determination of oral cavity tumors by 3-dimensional ultrasonography.
With the help of 3-dimensional (3D) ultrasound, the ultrasonographic determination of tumor volumes offers a new view of tumors in the oral cavity. These are classified according to their maximal diameter in TNM classification whereby the possibility exists in the high T category of overestimating small tumors that have spread into surrounding structures, and in the low T of underestimating large volume tumors that do not extend into surrounding structures. We analyzed a group of 49 patients with tumors of the oral cavity, all of whom underwent surgery. Tumor volumes were determined before surgery with 3D ultrasound aided by 3D View program software. After excision, the tumors were classified in pT categories based on pathologic findings. N stage was determined after neck dissection and correlation to tumor volume were performed. The average volume of T1 tumors was 1.74 cm(3); T2 was 5.21 cm(3); T3 was 23.36 cm(3), and T4 was 13.53 cm(3). There were significant differences in tumor volumes between all T categories except T3 and T4. Tumor volumes in our patients did not correlate with N stage. Volume determination of tumors with the help of 3D View software may categorize small tumors better and perhaps become a new refinement in TNM tumor classification. Results show that although T category in oral cavity tumors is determined by diameter in T1 to T3, the volumes match with T category. By using this method, a successful follow-up can be performed and the effects of radiotherapy or chemotherapy can be evaluated.


Evaluation of Effectiveness and Safety of High-Dose Daptomycin: Results from Patients Included in the European Cubicin(®) Outcomes Registry and Experience.
Daptomycin, a rapid concentration-dependent bactericidal antibiotic, is approved at a dose of 4 mg/kg/day for the treatment of complicated skin and soft tissue infections (cSSTI) and at a dose of 6 mg/kg/day for the treatment of Staphylococcus aureus right-sided infective endocarditis (RIE) and bacteremia associated with cSSTI and RIE. Studies have reported the successful use of high-dose daptomycin (>6 mg/kg/day) in patients with difficult-to-treat infections. The present analysis evaluated the effectiveness and safety of high doses (>6 mg/kg/day) of daptomycin for the treatment of different Gram-positive infections. European Cubicin(®) Outcomes Registry and Experience (EU-CORE) is a non-interventional, multicenter, retrospective, patient registry designed to collect real-world data from patients treated with daptomycin between 2006 and 2012. Clinical outcomes were assessed at the end of daptomycin treatment for three dose groups: ≤6, >6 to <8, and ≥8 mg/kg/day. Safety was assessed for up to 30 days post-daptomycin treatment. Of the 6075 patients enrolled in EU-CORE, 4892 patients received daptomycin doses ≤6 mg/kg/day, while 1097 patients received high doses (>6 mg/kg/day). The primary infections with the largest proportion of patients treated with a high dose (>6 mg/kg/day) were osteomyelitis (37.1%), foreign body/prosthetic infection (31.6%), and endocarditis (27.6%). S. aureus was identified in 42.9% of patients with positive cultures treated with either ≤6 or >6 mg/kg/day. The overall clinical success rate was 82.0% (899/1097) with high doses (>6 mg/kg/day) and 80.3% (3928/4890) with doses ≤6 mg/kg/day. Numerically higher clinical success rate was observed for endocarditis and foreign body/prosthetic infection, as well as for coagulase-negative staphylococcal and enterococcal infections, with high-dose daptomycin treatment. There were no new or unexpected safety findings at doses >6 mg/kg/day. These results suggested that daptomycin at doses >6 mg/kg/day was effective and well tolerated. High-dose daptomycin is a potential therapeutic option in patients with difficult-to-treat Gram-positive infections. This study was funded by Novartis Pharma AG.


Stability-indicating hydrophilic interaction liquid chromatography method for highly polar and basic compounds.
A hydrophilic interaction liquid chromatography (HILIC) method was developed for the analysis of very polar and basic 4-(aminomethyl)pyridine (4-AMP) and its related compounds. Separation parameters such as stationary phase, buffer pH, buffer ionic strength, organic modifier, and column temperature were evaluated. The retention mechanisms were explored through the evaluation of the common chromatographic parameters in the method development. The data indicated the existence of surface adsorption phenomena for 4-AMP and its positional isomers (2-AMP, 3-AMP). For two degradants, different retention mechanisms might be involved when compared to 4-AMP. The selectivity of two critical pairs 3-/4-AMP isomer and Degradant-1/-2 diastereomer changed through isoelution temperature with reversal of elution order. The validation results indicated that the HILIC method is a sensitive, reproducible, and robust method suitable for the analysis of 4-AMP and its related compounds.


A role for leukemia inhibitory factor in melanoma-induced bone metastasis.
Melanoma is commonly associated with multi-organ metastasis, and bone is a frequent metastatic site for melanoma. However, the mechanism responsible for such melanoma-induced bone metastasis is still poorly understood. In the present study, the intracardiac inoculation of leukemia inhibitory factor (LIF)-producing human melanoma-derived cells (SEKI) developed osteolytic bone destruction in male BALB/cA-nu/nu nude mice. To elucidate the role of LIF in melanoma-induced osteolysis, cells were prepared in which the expression of LIF was reduced using a siRNA technique from the parent SEKI cells. Osteoclastogenesis was induced in the co-culture of LIF and/or SEKI cells with osteoblastic stromal cells in vitro, whereas the LIF-reduced SEKI cells did not induce osteoclastogenesis. The intracardiac inoculation of LIF-reduced SEKI cells resulted in a significant reduction in the incidence and number of bone metastasis in comparison to those in the mice inoculated with the parent SEKI cells. The expression of LIF was found in seven of nine human melanoma-derived cell lines, suggesting that LIF expression is a universal event in melanoma. These findings suggest that a potential role for LIF in the melanoma-induced bone metastasis possibly through the stimulation of osteoclastogenesis. LIF might therefore be a potentially effective drug target in the treatment of bone metastasis in melanoma.


Type I and III collagens as a possible target for drug delivery to the injured sites of vascular bed.
Interaction of anti-human collagen types I and III antibodies, as well as human red blood cells conjugated with these antibodies, with the surface of denuded intima of human aorta has been studied. Data on the accessibility of antigenic determinants of collagen types I and III for antibodies and red blood cells conjugated with these antibodies have been obtained in ex vivo experiments in an original model. On the basis of the obtained results it is concluded that antigenic determinants of collagen types I and III exposed as a result of blood vessel wall injury can serve as a target for drug delivery to the injured site(s).


[Therapy of ANCA-associated vasculitis with severe renal manifestation under routine conditions].
In the MEPEX trial the poor prognosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with severe renal manifestation (AAVr) could be significantly improved in the first year by plasmapheresis. How and to what extent is this knowledge of AAVr therapy implemented into routine practice and what effectiveness and adverse events resulted? This was a retrospective cohort study in which all patients who received remission induction therapy for AAVr under routine clinical conditions (RCC) in this hospital from 2009 to 2014 after publication of the MEPEX trial (n = 22) were compared with those in the plasmapheresis arm of the MEPEX trial (n = 70). Endpoints were dialysis-dependent chronic kidney disease and mortality after 3 and 12 months and severe life-threatening adverse events during the first 12 months. All patients with AAVr were treated by plasmapheresis under RCC. The two groups showed no differences with respect to the rate of dialysis dependency (after 3 months RCC 14 % versus MEPEX 16 %, P = 1.00 and after 12 months RCC 23 % versus MEPEX 14 %, P = 0.55) or mortality (after 3 months RCC 18 % versus MEPEX 16 %, P = 0.75 and after 12 months RCC 18 % versus MEPEX 27 %, P = 0.57). The rate of severe life-threatening adverse events was similar under RCC and under controlled study conditions (64 % versus 69 %, P = 0.87). Under RCC there is a high quality of medical treatment for AAVr. All patients received plasmapheresis for remission induction with comparable effectiveness and safety compared to controlled study conditions.