Correlation of end-tidal CO2 with transcranial Doppler flow velocity is decreased during chemoregulation in delayed cerebral vasospasm after subarachnoid haemorrhage--results of a pilot study.
Cerebrovascular responses to variations in blood pressure and CO2 are attenuated during delayed vasospasm after subarachnoid hemorrhage (SAH). Transcranial Doppler sonography (TCD) is routinely used to assess the presence of vasospasm, but cerebral blood flow velocities (CBF-V) measured by TCD do not necessarily reflect cerebral blood flow (CBF) or the severity of vasospasm. We hypothesized that the correlation of end-tidal pCO2 levels with CBF-V and CBF is equally decreased in subjects with cerebral vasospasm during variations in pCO2. Four cynomolgus monkeys were assigned to the vasospasm group and eight animals to the control group. The animals in the vasospasm group underwent placement of an autologous subarachnoid blood clot and vasospasm was confirmed by angiography on day 7. In both groups, CBF and CBF-V were measured simultaneously while end-tidal pCO2 was altered. CBF was measured using a thermal probe placed on the cortical surface and CBF-V was measured using a commercial TCD device. Pearson's correlation coefficient between CBF-V values and pCO2 levels in the control group was strong (r = 0.94, p < 0.001) while it was moderate in the vasospasm group (r = 0.54, p = 0.04). The correlation of CBF values with pCO2 in healthy controls was equally strong (r = 0.87, p = 0.005), while there was no correlation in the vasospasm group (r = -0.09, p = 0.83). In this pilot study, correlations of CBF-V with pCO2 values during chemoregulation testing were lower in animals with vasospasm than in healthy ones. This correlation coefficient based on modifications in pCO2 may potentially facilitate the non-invasive assessment of vasospasm.


A pH-applicative fluorescent probe with long measuring range for monitoring hydrazine in water samples and Arabidopsis thaliana.
In this work, a fluorescent probe, RhodCl-Hz, with pH-applicative capability and long measuring range, was developed to serve the topic on the enrichment process of hydrazine. It was practical due to the clear acid-base boundary and the sectioned linear ranges. With the excitation wavelength of 515 nm and the emission peak at 565 nm, the detecting system was steady. It exhibited a clear cut-off point at pH 7.0 and steady fluorescence signals within the range of 7.0-10.0. As a whole, the linear range of 10.0-500 µM (1.0-50.0 equivalent) was long. The Limit of Detection value was calculated as 0.64 μM. With high selectivity, RhodCl-Hz was applied to suit water samples and biological imaging in both Arabidopsis Thaliana root tips and living MCF-7 cells. The information here might be helpful for revealing the enrichment process of hydrazine.


The feasibility of [18F]EF5-PET/CT to image hypoxia in ovarian tumors: a clinical study.
Evaluation of the feasibility of [18F]EF5-PET/CT scan in identifying hypoxic lesions in ovarian tumors in prospective clinical setting. Fifteen patients with a suspected malignant ovarian tumor were scanned with [18F]EF5 and [18F]FDG-PET/CT preoperatively. The distribution of [18F]EF5-uptake, total intraabdominal metabolic tumor volume (TMTV), and hypoxic subvolume (HSV) were assessed. [18F]EF5-PET/CT suggested hypoxia in 47% (7/15) patients. The median HSV was 87 cm3 (31% of TMTV). The [18F]EF5-uptake was detected in primary tumors and in four patients also in intra-abdominal metastases. The [18F]EF5-uptake in cancer tissue was low compared to physiological excretory pathways, complicating the interpretation of PET/CT images. [18F]EF5-PET/CT is not feasible in ovarian cancer imaging in clinical setting due to physiological intra-abdominal [18F]EF5-accumulation. However, it may be useful when used complementarily to FDG-PET/CT.


Distribution and co-existence of Met-enkephalin-like and mesotocin-like immunoreactivity in the neural lobe of the pituitary of the frog.
Content and distribution of Met-enkephalin (Met-ENK)-like immunoreactivity in the hypothalamo-hypophysial system of bovine, rat and frog were examined using specific radioimmunoassay and immunohistochemistry. Ultrastructural localization and co-existence of Met-ENK-, mesotocin (MT)- and vasotocin (VT)-like immunoreactivity in the neural lobe of the frog pituitary was examined by a method combining pre-embedding peroxidase-antiperoxidase immunostaining for Met-ENK with post-embedding immunocolloidal gold staining for MT or VT. The highest concentrations of immunoassayable Met-ENK were present in the neural lobe of the pituitary of the frog. In addition to nerve fibers showing only MT-like or Met-ENK-like immunoreactivity, nerve fibers containing neurosecretory granules showing both MT- and Met-ENK-like immunoreactivities were very rich. But VT-like and Met-ENK-like immunoreactivity was confirmed separately in different axon terminals.


Candida-bacterial cross-kingdom interactions.
While the fungus Candida albicans is a common colonizer of healthy humans, it is also responsible for mucosal infections and severe invasive disease. Understanding the mechanisms that allow C. albicans to exist as both a benign commensal and as an invasive pathogen have been the focus of numerous studies, and recent findings indicate an important role for cross-kingdom interactions on C. albicans biology. This review highlights how C. albicans-bacteria interactions influence healthy polymicrobial community structure, host immune responses, microbial pathogenesis, and how dysbiosis may lead to C. albicans infection. Finally, we discuss how cross-kingdom interactions represent an opportunity to identify new antivirulence compounds that target fungal infections.


Cloning of a SEPALLATA4-like gene (IiSEP4) in Isatis indigotica Fortune and characterization of its function in Arabidopsis thaliana.
E-class MADS-box genes, SEPALLATA (SEP), participate in various aspects of plant development together with B-, C- and D-class MADS-box genes. IiSEP4, a homologous gene of SEP4, was cloned from Isatis indigotica. IiSEP4 was highly expressed in sepals, and its mRNA was mildly detected in leaves, inflorescences, flowers, stamens and young silicles. Constitutive expression of IiSEP4 in Arabidopsis thaliana caused early flowering, accompanied by the reduction of flowers and floral organs. Moreover, the sepals in some flowers were transformed into carpelloid structures with stigmatic papillae, and obviously accompanied by ovule formation. Yeast two-hybrid assays demonstrated that IiSEP4 interacts with other woad MADS proteins to determine the identity of floral organs. These findings reveal the important roles of IiSEP4 in floral development of I. indigotica. The results of this study can lay a foundation for further study on biological functions of MADS transcriptional factors in I. indigotica.


JC virus load in cerebrospinal fluid and transcriptional control region rearrangements may predict the clinical course of progressive multifocal leukoencephalopathy.
Progressive multifocal leukoencephalopathy (PML) is a severe disease of the central nervous system (CNS), caused by infection with the Polyomavirus JC virus (JCV). Because there are no known treatments or prognostic factors, we performed a long-term study focusing mainly on cerebrospinal fluid (CSF) samples from PML patients to describe the virological features akin to the different forms of the disease. Twenty-eight PML patients were enrolled: 10 HIV-1+ patients with classical PML (CPML), 9 HIV-1+ patients with slowly progressing or stable neurological symptoms (benign PML), 3 HIV-1+ asymptomatic patients, and 6 HIV-1-negative patients. CSF, urine, and blood samples were collected at the enrollment (baseline) and every 6 months afterwards when possible. The JCV DNA and HIV-1 RNA loads were determined, and the JCV strains were characterized. At baseline, the mean CSF JCV load was log 6.0 ± 1.2 copies/ml for CPML patients, log 4.0 ± 1.0 copies/ml for benign PML patients, log 4.2 ± 0.5 copies/ml for asymptomatic PML patients, and log 5.8 ± 1.3 copies/ml for HIV-1-negative PML patients (CPML vs. benign: P < 0.01; CPML vs. asymptomatic: P < 0.05; HIV-1 negative vs. benign: P < 0.01). Organization of the JCV transcriptional control region (TCR) showed unusual archetype structures in two long-term survival patients; the NF1 sequence was found most commonly, whereas the Sp1 binding site was the most common for both CPML patients and HIV-1 negative patients. Our results suggest that the JCV load in the CSF and the organization of the TCR should be considered as indicators of PML clinical outcome.


A randomized controlled pilot trial to assess the effectiveness of a specially formulated food supplement and pelvic floor muscle training in women with stress-predominant urinary incontinence.
Pelvic floor muscle training (PFMT) is the first-line treatment approach for stress urinary incontinence. Creatine and leucine have been shown to improve muscle function. Our aim was to assess the effectiveness of a food supplement and PFMT in women with stress-predominant urinary incontinence. Women with stress-predominant urinary incontinence were randomized in 1:1 ratio to receive daily oral supplementation for six weeks with either a food supplement (treatment group) or placebo (control group). Both groups were instructed to perform standardized daily PFMT. The primary outcome was the Urogenital Distress Inventory Short Form (UDI-6) score. Secondary outcomes were the Incontinence Impact Questionnaire (IIQ-7) score, Patient's Global Impression of Severity (PGI-S), and Biomechanical Integrity score (BI-score) measured by Vaginal Tactile Imager. To have a power of 80% and a significance level of 5% to detect a decrease of 16 points in the UDI-6 score, a sample size of 32 was needed, with 16 patients in each arm of our trial. Sixteen women in the control group and sixteen in the treatment group completed the trial. Between-group analysis revealed no significant differences between the control and treatment group except for mean change (delta) in vaginal squeeze pressure [(cmH2O, mean ± SD), 5 ± 12 vs. 15 ± 15, P = 0.04] and mean change (delta) in PGI-S score [(mean ± SD), -0.2 ± 0.9 vs. -0.8 ± 0.8, P = 0.04]. Within-group analysis showed that UDI-6 and IIQ-7 scores improved significantly from baseline to six weeks in the treatment group but not in the control group [UDI-6 score (mean ± SD) 45 ± 21 vs. 29 ± 21, P = 0.02; 43 ± 18 vs. 33 ± 26, P = 0.22] [IIQ-7 score (mean ± SD) 50 ± 30 vs. 30 ± 21, P = 0.01; 48 ± 23 vs.40 ± 28, P = 0.36]. PGI-S scores only improved in the treatment group from baseline to six weeks after treatment [PGI-S score (mean ± SD) 3.1 ± 0.8 vs. 2.3 ± 0.8, P = 0.0001]. BI-score, on average, improved significantly in the treatment and control group as well [SD unit, mean, from - 1.06 to -0.58, P = 0.001; from - 0.66 to -0.42, P = 0.04]. Women with stress-predominant urinary incontinence receiving a specially formulated supplement in addition to daily PFMT for six weeks had significantly improved urinary symptoms (decrease in UDI-6 score and IIQ-7) and BI-score compared to their baseline. ClinicalTrials.gov Identifier: NCT05358769. 27/04/2022.


MR Multitasking-based multi-dimensional assessment of cardiovascular system (MT-MACS) with extended spatial coverage and water-fat separation.
To extend the MR MultiTasking-based Multidimensional Assessment of Cardiovascular System (MT-MACS) technique with larger spatial coverage and water-fat separation for comprehensive aortocardiac assessment. MT-MACS adopts a low-rank tensor image model for 7D imaging, with three spatial dimensions for volumetric imaging, one cardiac motion dimension for cine imaging, one respiratory motion dimension for free-breathing imaging, one T2-prepared inversion recovery time dimension for multi-contrast assessment, and one T2*-decay time dimension for water-fat separation. Nine healthy subjects were recruited for the 3T study. Overall image quality was scored on bright-blood (BB), dark-blood (DB), and gray-blood (GB) contrasts using a 4-point scale (0-poor to 3-excellent) by two independent readers, and their interreader agreement was evaluated. Myocardial wall thickness and left ventricular ejection fraction (LVEF) were quantified on DB and BB contrasts, respectively. The agreement in these metrics between MT-MACS and conventional breath-held, electrocardiography-triggered 2D sequences were evaluated. MT-MACS provides both water-only and fat-only images with excellent image quality (average score = 3.725/3.780/3.835/3.890 for BB/DB/GB/fat-only images) and moderate to high interreader agreement (weighted Cohen's kappa value = 0.727/0.668/1.000/1.000 for BB/DB/GB/fat-only images). There were good to excellent agreements in myocardial wall thickness measurements (intraclass correlation coefficients [ICC] = 0.781/0.929/0.680/0.878 for left atria/left ventricle/right atria/right ventricle) and LVEF quantification (ICC = 0.716) between MT-MACS and 2D references. All measurements were within the literature range of healthy subjects. The refined MT-MACS technique provides multi-contrast, phase-resolved, and water-fat imaging of the aortocardiac systems and allows evaluation of anatomy and function. Clinical validation is warranted.


Pre-emptive placement of a presealant for amniotic access.
Amniotic access for fetal diagnosis and therapy can lead to membrane leaks, separation, and preterm premature rupture of membranes. Morbidity limits the beneficial effects of fetal intervention. We propose to examine a novel preventive "presealant" membrane puncture technique and evaluate it in vitro. Fetal membranes from normal term deliveries were fastened to a pressure controlled pump and punctured after presealant placement. Distinct bioadhesives were then compared for sealing efficacy by the measurement of leak pressures. Membranes were also evaluated for changes in tensile rupture strength after treatment. Preemptive sealing by 2 of the presealants achieved significantly higher leak pressures compared with control membranes (85 and 78, respectively, vs 27 cm of water; P < .05). One of the presealants worked effectively in a membrane-sealant-membrane interface (62 vs 30 cm of water; P < .05). All treated membranes, however, demonstrated diminished tensile rupture forces compared with control membranes (124 vs 170 g/cm2; P > .05). The application of a presealant is effective for the prevention of iatrogenic rupture in an in vitro model and may be beneficial for clinical application. Further studies with different bioadhesives are needed, given the limitations of the glues that are described in this study.


Monitoring success of remediation: seven case studies of moisture and mold damaged buildings.
Based on seven case studies of buildings that underwent different degrees of moisture and mold damage remediation, we aimed to develop methodology for assessment of the success of the remediation process. Methods used in gauging the success included technical monitoring of performance of building structures and heating, ventilation and air conditioning (HVAC) systems, microbial monitoring of indoor air quality (IAQ), and health effects studies of building occupants. The assessment was based on measurable change in the situations before and after remediation. Based on technical monitoring, remediation was successful in three cases, with partial improvement noted in three cases, whereas no remediation was conducted in one case. Based on microbial monitoring, improvement was detected in one, partial improvement in two and no improvement in two cases, whereas no follow-up was conducted in two cases. Health effect studies (mainly self-reported health status) showed improvement in one case, partial improvement in two cases, and no improvement in two cases, whereas no follow-up was conducted in one case, and in one case, follow-up failed due to low response rate. The results illustrate that it is possible to monitor the effects of remediation using various metrics. However, in some cases, no improvement could be observed in IAQ or occupant health, even if the remediation was considered technically successful, i.e. the remediation was fully completed as recommended. This could be due to many reasons, including: 1) all damage may not have been addressed adequately; 2) IAQ or health may not have been perceived improved regardless of remediation; and/or 3) the methods used may not have been sensitive/specific enough to detect such improvement within the 6-12 months follow-up periods after completion of the remediation. There is a need to further develop tools for monitoring and assessment of the success of moisture damage remediation in buildings.


Online case-based learning in medical education: a scoping review.
Case-Based Learning (CBL) in medical education is a teaching approach that engages students as learners through active learning in small, collaborative groups to solve cases from clinical patients. Due to the challenges afforded by the COVID-19 pandemic, small group learning such as CBL, transitioned quickly to include technology-enhanced learning to enable distance delivery, with little information on how to apply pedagogical frameworks and use learning theories to design and deliver online content. To extend understanding of online CBL a scoping review protocol following the PRISMA-ScR framework explored the literature that describes the use of online CBL application in medical education and the outcomes, perceptions, and learning theories. A literature search was conducted in January 2022 followed by a subsequent review in October 2022. After peer review using the PRESS guidelines, the CASP appraisal tool was used to assess the rigor of each study design. The scoping review identified literature published between 2010 and 2022 (n = 13 articles), on online CBL in the field of medical education with 11 observational studies describing student and facilitator perceptions and two randomized controlled studies. Positive perceptions of online learning included a flexible work-life balance, connection with learners, and improved accessibility. Negative experiences of online CBL included poor internet access, a distracting learning environment, and loss of communication. In the studies that collected student performance data, results showed equivalent or improved outcomes compared to the control. The CASP appraisal tool highlighted the deficiencies in most study designs, lack of framework or learning theory, and poor reproducibility of the methods to answer the research questions. This scoping review identified literature to describe the academic outcomes, and student and facilitator perceptions of online CBL in medical education. However, the CASP tool uncovered deficiencies in study descriptions and design leading to poor quality evidence in this area. The authors provide recommendations for frameworks and learning theories for the future implementation of online CBL.


Noradrenergic, serotonergic, and cholinergic sprouting in the hippocampus that follows partial or complete transection of the septohippocampal pathway: contributions of spared inputs.
The aminergic and cholinergic fibers innervating the hippocampus reach their target regions via the dorsal (dorsal fornix, fimbria, and cingulum) and ventral routes. The plasticity of this innervation after lesions of the dorsal pathway was investigated in the septal, medial, and temporal regions of the adult rat hippocampus. The extent and time course of sprouting was assessed by determining high-affinity uptake of [3H]noradrenaline and [3H]serotonin, and the activities of cholinergic enzymes 1 week to 6 months after partial or complete transection of the dorsal pathway. The initial decline in these terminal indices resulting from the transection of the medial or lateral half of the dorsal pathway reflected the distribution of their respective terminal sites in the three hippocampal regions. Longer survival after such lesions led to a substantial recovery of cholinergic and noradrenergic markers indicating reinnervation of the hippocampus by spared dorsal and/or by undamaged ventral afferent fibers. Whether the recovery was complete or not, the sprouting of spared dorsal fibers was maximum within a relatively shorter postlesion survival whereas that of the ventral afferents continued for a longer time. In contrast to the extent of noradrenergic and cholinergic restitution, very poor serotonergic recovery was seen in the same animal in spite of the availability of spared serotonergic afferent fibers and regardless of the duration of postlesion survival. The apparently finite capacity of spared axons for postlesion reinnervation was not increased by longer survival. Amplification of this property of central neurons by other interventions may supplement the approach of transplantation for recovery of function following injury.


Association of gene polymorphisms in MYH11 and TGF-β signaling with the susceptibility and clinical outcomes of DeBakey type III aortic dissection.
To investigate the association of myosin heavy chain protein 11 (MYH11) and transforming growth factor β signaling-related gene polymorphisms with the susceptibility of DeBakey type III aortic dissection (AD) and its clinical outcomes. Four single-nucleotide polymorphism (SNPs) (MYH11 rs115364997, rs117593370, TGFB1 rs1800469, and TGFBR1 rs1626340) were analyzed in patients with DeBakey III AD (173) and healthy participants (335). Gene-gene and gene-environment interactions were evaluated using generalized multifactor dimensionality reduction. The patients were followed up for a median of 55.7 months. MYH11 rs115364997 G or TGFBR1 rs1626340 A carriers had an increased risk of DeBakey type III AD. MYH11, TGFB1, TGFBR1, and environment interactions contributed to the risk of DeBakey type III AD (cross-validation consistency = 10/10, P = 0.001). Dominant models of MYH11 rs115364997 AG + GG genotype (HR = 2.443; 95%CI: 1.096-5.445, P = 0.029), TGFB1 rs1800469 AG + GG (HR = 2.303; 95%CI: 1.069-4.96, P = 0.033) were associated with an increased risk of mortality in DeBakey type III AD. The dominant model of TGFB1 rs1800469 AG + GG genotype was associated with an increased risk of recurrence of chest pain in DeBakey type III AD (HR = 1.566; 95%CI: 1.018-2.378, P = 0.041). In conclusions, G carriers of MYH11 rs115364997 or TGFB1 rs1800469 may be the poor prognostic indicators of mortality and recurrent chest pain in DeBakey type III AD. The interactions of gene-gene and gene-environment are associated with the risk of DeBakey type III AD.


New trifluoromethyl quinolone derivatives: synthesis and investigation of antimicrobial properties.
A series of quinolone derivatives, containing different heterocyclic amines were prepared. Synthesized compounds were evaluated for their in vitro antimicrobial activities against two Gram-positive bacteria, three Gram-negative bacteria as well as four fungi. All the derivatives showed good activity towards Gram-positive bacteria and less activity towards Gram-negative bacteria. They also showed moderate to comparable activity against Aspergillus niger and Candida albicans and low to moderate antifungal activity against Aspergillus fumigatus and Aspergillus flavus.


Zwitterionically modified alginates mitigate cellular overgrowth for cell encapsulation.
Foreign body reaction (FBR) to implanted biomaterials and medical devices is common and can compromise the function of implants or cause complications. For example, in cell encapsulation, cellular overgrowth (CO) and fibrosis around the cellular constructs can reduce the mass transfer of oxygen, nutrients and metabolic wastes, undermining cell function and leading to transplant failure. Therefore, materials that mitigate FBR or CO will have broad applications in biomedicine. Here we report a group of zwitterionic, sulfobetaine (SB) and carboxybetaine (CB) modifications of alginates that reproducibly mitigate the CO of implanted alginate microcapsules in mice, dogs and pigs. Using the modified alginates (SB-alginates), we also demonstrate improved outcome of islet encapsulation in a chemically-induced diabetic mouse model. These zwitterion-modified alginates may contribute to the development of cell encapsulation therapies for type 1 diabetes and other hormone-deficient diseases.


Correction To: Sex-Specific Incidence Rates and Risk Factors for Hypertension During 13 Years of Follow-up: The Tehran Lipid and Glucose Study.
[This corrects the article DOI: 10.5334/gh.780.].


Correlation of lung parenchymal MR signal intensity with pulmonary function tests and quantitative computed tomography (CT) evaluation: a pilot study.
To evaluate the effect of ventilatory impairment on MR signal intensity of the lung parenchyma. Subjects were five normal volunteers (age = 30 +/- 7.9 years, mean +/- SD) and 19 male patients with chronic obstructive lung disease (COPD) (mean age = 70.4 +/- 6.5 years). Coronal MR images were obtained over entire lung fields at full inspiration and full expiration with cardiac triggering on a 1.5T system. Changes in the mean lung intensity between the two respiratory states were normalized by each intercept of the linear regression lines of the signal changes, and the slope of the relationship was calculated. Computed tomography (CT) images were also obtained in COPD patients at full inspiration using a multidetector row CT scanner. Attenuation values less than -950 Hounsfield units (HU) (RA-950) represented the percentage of relative lung area on the CT. The mean slope of COPD patients (0.365 +/- 0.074) was less steep than that of the normal subjects (0.570 +/- 0.124, P < 0.001). In COPD patients, the slope correlated significantly with forced expiratory volume in one second (FEV1, r = 0.508, P = 0.026), but not with RA-950. In COPD patients, lung signal change measured by MRI correlates with airflow obstruction, but not with volume of the emphysema measured by lung CT.


Quality of life assessment in obesity: physical, psychological, and social function.
This article examines the value of including patients' well being in the clinical assessment of obesity. It also deals with health status measures and the current state of so-called quality-of-life research. The few and limited studies of quality of life in obesity are reviewed and preliminary results of our own work are presented.


Prenatal diagnosis of Wolf-Hirschhorn syndrome confirmed by comparative genomic hybridization array: report of two cases and review of the literature.
Wolf-Hirschhorn syndrome (WHS) is a well known genetic condition caused by a partial deletion of the short arm of chromosome 4. The great variability in the extent of the 4p deletion and the possible contribution of additional genetic rearrangements lead to a wide spectrum of clinical manifestations. The majority of the reports of prenatally diagnosed WHS cases are associated with large 4p deletions identified by conventional chromosome analysis; however, the widespread clinical use of novel molecular techniques such as array comparative genomic hybridization (a-CGH) has increased the detection rate of submicroscopic chromosomal aberrations associated with WHS phenotype. We provide a report of two fetuses with WHS presenting with intrauterine growth restriction as an isolated finding or combined with oligohydramnios and abnormal Doppler waveform in umbilical artery and uterine arteries. Standard karyotyping demonstrated a deletion on chromosome 4 in both cases [del(4)(p15.33) and del(4)(p15.31), respectively] and further application of a-CGH confirmed the diagnosis and offered a precise characterization of the genetic defect. A detailed review of the currently available literature on the prenatal diagnostic approach of WHS in terms of fetal sonographic assessment and molecular cytogenetic investigation is also provided.


Multi-method evaluation of a paediatric ambulatory care unit (PACU): impact on families and staff.
To assess the impact of a purpose-built, short stay paediatric ambulatory care unit (PACU) on the patient journey and perceptions of parents, staff and referrers. Multi-method evaluation, including a parent survey (n = 104), patient journey mapping (n = 10), staff interviews (n = 10), a referrer survey (n = 16), routine activity analysis, and a comparison with the A&E service (A&E parent survey: n = 41). Almost all parents attending PACU (94%) were satisfied with the service and significantly more likely to feel "very" satisfied than parents attending A&E (PACU: 51%, A&E: 31%; p = 0.03). Further, over three quarters (77%) of PACU parents preferred the new model to traditional A&E services. They reported receiving sufficient information (93%), reduced anxiety (55% anxious before service, 13% anxious after; p<0.001), "quick" waiting times (median: 35 min), and enhanced confidence (87%) and understanding (89%) in dealing with their ill child. The number of stages in the patient journey was reduced from six ("traditional" A&E pathway) to four (PACU pathway). Staff and referrers reported this was a "superior" model to A&E, but that improvements were required around appropriate referrals and the need for more multi-disciplinary protocols and liaison. Our study suggests that the PACU model is perceived to be an effective alternative to standard A&E services for the assessment and early management of acutely ill children and their families attending a hospital. It is highly valued by users, staff and referrers and enhances the patient journey. Lessons learnt include the need to enhance multi-disciplinary processes and clarify the role of this form of acute care provision in the wider healthcare system.


Formation, metabolism, and action of hepoxilin A3 in the rat pineal gland.
The present study was undertaken to investigate the possible formation of hepoxilin A3 in the rat pineal gland and to study the potential physiological role for this compound in this tissue. Incubation of homogenates of rat pineal glands with arachidonic acid (66 microM) led to the appearance of hepoxilin A3 (HxA3) analyzed as its stable trihydroxy derivative, trioxilin A3 by gas chromatography in both the electron impact and negative ion chemical ionization modes. Endogenous formation of HxA3 is estimated to be 1.43 +/- 0.66 ng/micrograms of protein. This amount is not modified when the tissue is boiled (2.07 +/- 0.66 ng/micrograms of protein). However, the formation of this compound was stimulated to 21.26 +/- 5.82 ng/micrograms of protein when exogenous arachidonic acid was added to the homogenate. Addition of the dual cyclooxygenase/lipoxygenase inhibitor BW 755C (10 micrograms) resulted in a partial blockade of hepoxilin formation. Using [1-14C]HxA3, we demonstrated that the pineal gland contained hepoxilin epoxide hydrolase, which hydrolyzed HxA3 into trioxilin A3. This hydrolysis was inhibited by 1 mumol/L of 3,3,3-trichloropropene-1,2-oxide. In a separate study, HxA3 in the presence of 3,3,3-trichloropropene-1,2-oxide to block the hydrolysis of HxA3 decreased the production of cyclic AMP in cultured organ rat pineals after stimulation with 5'-N-ethylcarboxamidoadenosine, an A1/A2 adenosine receptor agonist. This effect is stereospecific because the (8S)-enantiomer is more active in decreasing cyclic AMP production (-88.7%) than the (8R)-enantiomer. This is the first demonstration of the presence, metabolism, and action of HxA3 in the rat pineal gland.


A Chinese randomized prospective trial of floppy Nissen and Toupet fundoplication for gastroesophageal disease.
To evaluate the clinical outcomes of laparoscopic floppy Nissen fundoplication (LNF) and laparoscopic Toupet fundoplication (LTF) for the treatment of gastroesophageal disease (GERD). A total of 84 patients with GERD were randomized to either LNF (n = 43) or LTF (n = 41) between January 2010 and January 2013. The primary endpoint measures were the DeMeester score, distal esophageal amplitude (DEA), peristaltic frequency, lower esophageal sphincter pressure (LESP), short-term and long-term postoperative dysphagia and recurrence rate. The secondary endpoints were improvements in symptom scores and quality of life (QoL), and perioperative complications. LNF group had a lower DeMeester score and a higher LESP compared to LTF group after surgery (DeMeester score: P = 0.007; LESP: P = 0.027). The mean DEA and peristaltic frequency both improved significantly after surgery in 2 groups. There was no difference in the incidence of short-term adverse events (including dysphagia, heartburn, regurgitation et al.) between the two groups (P = 0.157). At the time of the latest follow-up, there was no difference in the incidence of symptomatic reflux symptom (heartburn and regurgitation) between the two groups (heartburn: P = 0.363; regurgitation: P = 1.000). A higher frequency of dysphagia was present in the LNF group compared with the LTF group (P = 0.023). LNF is associated with an excessive elevation of LESP which may lead to further persistent dysphagia. Partial fundoplication may provide adequate reflux control, improve esophageal body motility and minimize complications associated with an 'over-tight' fundal wrap. LTF seems to be as safe and effective on the long-term as LNF, but with a lower incidence of postoperative dysphagia (ChiCTR-TRC-13003945).


Friend or foe? The elusive role of hepatic stellate cells in liver cancer.
Liver fibrosis is a substantial risk factor for the development and progression of liver cancer, which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Studies utilizing cell fate mapping and single-cell transcriptomics techniques have identified quiescent perisinusoidal hepatic stellate cells (HSCs) as the primary source of activated collagen-producing HSCs and liver cancer-associated fibroblasts (CAFs) in HCC and liver metastasis, complemented in iCCA by contributions from portal fibroblasts. At the same time, integrative computational analysis of single-cell, single-nucleus and spatial RNA sequencing data have revealed marked heterogeneity among HSCs and CAFs, with distinct subpopulations displaying unique gene expression signatures and functions. Some of these subpopulations have divergent roles in promoting or inhibiting liver fibrogenesis and carcinogenesis. In this Review, we discuss the dual roles of HSC subpopulations in liver fibrogenesis and their contribution to liver cancer promotion, progression and metastasis. We review the transcriptomic and functional similarities between HSC and CAF subpopulations, highlighting the pathways that either promote or prevent fibrosis and cancer, and the immunological landscape from which these pathways emerge. Insights from ongoing studies will yield novel strategies for developing biomarkers, assessing prognosis and generating new therapies for both HCC and iCCA prevention and treatment.


Expression of lymphocyte, macrophage and class I and II major histocompatibility complex antigens in normal human dorsal root ganglia.
We analyzed the expression of lymphocyte, macrophage and class I and II (HLA-DR) major histocompatibility complex (MHC) antigens in normal dorsal root ganglia (DRG) from 19 patients without neurological disease by using an avidin-biotin immunoperoxidase technique. Satellite cells expressed class I and II MHC antigens. The intensity of HLA-DR staining varied among the DRG and was not related to age, history of cancer or infection, or number of T lymphocytes in the DRG. Monoclonal antibodies EBM11 and Leu-M3, that recognize cells of monocyte/macrophage lineage, stained a population of cells in all DRG. Positive cells had an elongated shape and were in the interstitial tissue between the satellite cells. These findings may be relevant to the understanding of the immune mechanisms involved in the neuronal damage of sensory neuropathies of presumably autoimmune origin such as those associated with small-cell lung cancer or Sjögren's syndrome.


Differences in midwives' approaches to pain relief in labour.
To examine the influence of midwives' approaches on the care given to women for pain relief during labour. Non-participant observation was used to collect data on midwives' behaviours during interactions with women in labour. A large teaching hospital in Northern Ireland. Observations focused on interactions that were related to pain relief and involved 11 midwives caring for 15 women throughout the first stage of labour. Midwives' approaches to pain relief differed; at one extreme the midwife acted as 'a cold professional' whilst at the other extreme she was observed to be 'a disorganised carer'. In the middle of these two extremes was the 'warm professional'; her approach had a positive influence on the women's experience of labour pain. IMPLICATION FOR RESEARCH: Further research is needed to develop a profile of the factors that 'make' for a warm professional. The information gained could be used to teach midwives the skills of being 'a warm professional', in particular, the value of effective communication for sensitive care such as pain relief in labour.


Restless legs syndrome in children with chronic kidney disease.
Restless legs syndrome (RLS) is considerably more common among adults with chronic kidney disease (CKD) than in the general population and is associated with increased morbidity and mortality. There is limited information on RLS in children with CKD. Failure to account for conditions that might mimic RLS can lead to overdiagnosis of this syndrome. In a prospective, cross-sectional study, RLS prevalence was compared between pediatric CKD patients and healthy children. RLS was assessed via a questionnaire that included exclusion of mimics. Sleep characteristics and health-related quality of life (HRQoL) were also assessed. Restless legs syndrome was more prevalent in CKD patients (n = 124) than in 85 normal children (15.3 vs. 5.9 %; p = 0.04). There was no significant association between RLS and CKD stage, CKD etiology, CKD duration, and dialysis or transplant status. Children with RLS were more likely to rate their sleep quality as fairly bad or very bad (41.2 vs. 8.8 %; p = 0.003) and report using sleep medications (42.1 vs. 14.7 %; p = 0.01). RLS was associated with lower HRQoL by parent report (p = 0.03). Only five of the 19 patients (26.3 %) with CKD and RLS had discussed RLS symptoms with a healthcare provider, and only one of these patients had been diagnosed with RLS prior to this study. The prevalence of RLS is increased in children with CKD and appears to be underdiagnosed. Systematic screening for RLS and sleep problems would therefore appear to be warranted in children with CKD.


The Activating Receptors of Natural Killer Cells and Their Inter-Switching Potentials.
The global incidence of cancer is on the increase and researchers are prospecting for specific and non-selective therapies derived from the immune system. The killer activating receptors of NK cells are known to be involved in immunosurveillance against tumor and virally-infected cells. These receptors belong to two main categories, namely the immunoglobulin like and C-lectin like families. Though they have different signal pathways, all the killer activating receptors have similar effector functions which include direct cytotoxicity and the release of inflammatory cytokines such as IFN-gamma and TNF-alpha. To transduce signals that exceed the activation threshold for cytotoxicity, most of these receptors require synergistic effort. This review profiles 21 receptors: 13 immunoglobulin-like, 5 lectin-like, and 3 others. It critically explores their structural uniqueness, role in disease, respective transduction signal pathways and their status as current and prospective targets for cancer immunotherapy. While the native ligands of most of these receptors are known, much work is required to prospect for specific antibodies, peptides and multi-target small molecules with high binding affinities.


Myocardial injury, troponin release, and cardiomyocyte death in brief ischemia, failure, and ventricular remodeling.
Troponin released from irreversibly injured myocytes is the gold standard biomarker for the rapid identification of an acute coronary syndrome. In acute myocardial infarction, necrotic cell death is characterized by sarcolemmal disruption in response to a critical level of energy depletion after more than 15 min of ischemia. Although troponin I and T are highly specific for cardiomyocyte death, high-sensitivity assays have demonstrated that measurable circulating levels of troponin are present in many normal subjects. In addition, transient as well as chronic elevations have been demonstrated in many disease states not clearly associated with myocardial ischemia. The latter observations have given rise to the clinical concept of myocardial injury. This review will summarize evidence supporting the notion that circulating troponin levels parallel the extent of myocyte apoptosis in normal ventricular remodeling and in pathophysiological conditions not associated with infarction or necrosis. It will review the evidence that myocyte apoptosis can be accelerated by diastolic strain from elevated ventricular preload and systolic strain from dyskinesis after brief episodes of ischemia too short to cause a critical level of myocyte energy depletion. We then show how chronic, low rates of myocyte apoptosis from endogenous myocyte turnover, repetitive ischemia, or repetitive elevations in left ventricular diastolic pressure can lead to significant myocyte loss in the absence of neurohormonal stimulation. Finally, we posit that the differential response to strain-induced injury in heart failure may determine whether progressive myocyte loss and heart failure with reduced ejection fraction or interstitial fibrosis and heart failure with preserved ejection fraction become the heart failure phenotype.


Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures.
On-demand optogenetic inhibition of glutamatergic neurons in the fastigial nucleus of the cerebellum does not alter hippocampal seizures in a mouse model of temporal lobe epilepsy. In contrast, on-demand optogenetic excitation of glutamatergic neurons in the fastigial nucleus successfully inhibits hippocampal seizures. With this approach, even a single 50 ms pulse of light is able to significantly inhibit seizures. On-demand optogenetic excitation of glutamatergic fastigial neurons either ipsilateral or contralateral to the seizure focus is able to inhibit seizures. Selective excitation of glutamatergic nuclear neurons provides greater seizure inhibition than broadly exciting nuclear neurons without cell-type specificity. Temporal lobe epilepsy is the most common form of epilepsy in adults, but current treatment options provide limited efficacy, leaving as many as one-third of patients with uncontrolled seizures. Recently, attention has shifted towards more closed-loop therapies for seizure control, and on-demand optogenetic modulation of the cerebellar cortex was shown to be highly effective at attenuating hippocampal seizures. Intriguingly, both optogenetic excitation and inhibition of cerebellar cortical output neurons, Purkinje cells, attenuated seizures. The mechanisms by which the cerebellum impacts seizures, however, are unknown. In the present study, we targeted the immediate downstream projection of vermal Purkinje cells - the fastigial nucleus - in order to determine whether increases and/or decreases in fastigial output can underlie seizure cessation. Though Purkinje cell input to fastigial neurons is inhibitory, direct optogenetic inhibition of the fastigial nucleus had no effect on seizure duration. Conversely, however, fastigial excitation robustly attenuated hippocampal seizures. Seizure cessation was achieved at multiple stimulation frequencies, regardless of laterality relative to seizure focus, and even with single light pulses. Seizure inhibition was greater when selectively targeting glutamatergic fastigial neurons than when an approach that lacked cell-type specificity was used. Together, these results suggest that stimulating excitatory neurons in the fastigial nucleus may be a promising approach for therapeutic intervention in temporal lobe epilepsy.


Fluid evolution and related fluid-rock interactions of the Oligocene Zhuhai sandstones in the Baiyun Sag, northern margin of the South China Sea.
Pore fluids control the diagenetic processes and storage spaces of deep clastic rock reservoirs and have become a major area of interest within the fields of sedimentology and petroleum geology. This paper aims to relate the diagenetic processes of the Oligocene Zhuhai sandstones in the Baiyun Sag to pore fluids varying with burial depth. The types and distribution patterns of authigenic minerals are investigated through analysis of petrographic, mineralogical, and geochemical features to illustrate the origin and flow patterns of pore fluids and their influences on reservoir diagenesis. Strong cementation of eogenetic carbonate cement near the sandstone-mudstone interface was a consequence of material migration from adjacent mudstones on a large scale. The pore fluids were mainly affected by microbial methanogenesis and carbonate mineral dissolution in adjacent mudstones during eogenesis. The pore fluids were diffusively transported in a relatively open geochemical system within a local range. Support for this model is provided by the heavier stable isotopic values present in eogenetic calcite and dolomite. Feldspar dissolution during early mesogenesis was spatially accompanied by the precipitation of authigenic quartz and ferroan carbonate cement. Pore fluids in this period were rich in organic acids and CO2, and their migration mechanism was diffusive transport. The obviously lighter carbon and oxygen isotopic compositions of the ferroan calcite support this inference. During late mesogenesis, the input of deep hydrothermal fluid might have been partly responsible for the precipitation of ankerite, barite and authigenic albite. Oil charging may have inhibited carbonate cementation and compaction, accordingly preserving porosity, and together with authigenic kaolinite, might have promoted the transition of the reservoir from water wet to oil wet to the benefit of oil entrapment. The findings reported here shed new light on the evaluation and prediction of sandstone reservoirs that have experienced multiple periods of fluid flow.


Redo sphincteroplasty: are the results sustainable?
This study aimed to investigate the long-term outcomes of patients who undergo redo sphincteroplasty (RS). Patients with fecal incontinence (FI) who underwent RS between November 1988 and December 2011 were retrospectively identified from a prospective database. A questionnaire and telephone survey assessed current Cleveland Clinic Fecal Incontinence Score (CCFFIS; best 0, worst 20) and Fecal Incontinence Quality of Life (FIQoL; best 4.1, worst 1) scale. Success was defined as no further continence surgery, no stoma and CCFFIS <9 at completion of follow-up. The Wilcoxon and Mann-Whitney U tests were used for comparing quantitative variables. Bivariate logistic regression analysis was done to identify predictive factors for success. Fifty-six (66.7%) of 84 patients who underwent RS were available for evaluation at a median follow-up of 74 (range: 12-283) months. The mean CCFFIS decreased from 16.5 ± 3.7 to 11.9 ± 6.6 (P < 0.001) at last follow-up. Twelve patients (21.4%) underwent further continence surgery for failed sphincteroplasty, three (5.4%) of whom had a permanent stoma. Eighteen patients (32.1%) had a CCFFIS <9 at the completion of follow-up, and 16 (28.6%) had long-term success. Twenty-four patients evaluated for FIQoL had a mean value of 2.6 (range: 1.0-4.1). Postoperative CCFFIS was correlated with FIQoL (Spearman's correlation coefficient = -0.854, P < 0.001). Logistic regression analysis did not reveal any significant predictive variables for success of RS. Based on our criteria for success, the long-term success rate for RS over a median of 74 months is poor.


Quantitative EEG correlates of crack cocaine dependence.
Evidence for a distinctive syndrome of neuroadaptation in cocaine dependence has accumulated from behavioral, neurophysiological, and preclinical and clinical pharmacological studies. The authors report on the results of a preliminary investigation of the quantitative electroencephalographic (QEEG) correlates of severe DSM-III-R crack cocaine dependence in seven patients abstinent from cocaine for 1 to 68 days. The major QEEG finding was increased absolute and relative alpha power. Increased alpha power has also been reported in multiple previous studies of depressed patients. This series of crack-dependent patients showed significant depressive morbidity; four patients attempted suicide subsequent to initiating their use of crack and the group mean (+/- SD) Beck Depression Scale score was 18.9 (+/- 6.5). These results complement other studies that support the concept of neuroadaptation to chronic cocaine exposure. Prospective studies correlating QEEG measures with subsequent response to pharmacological interventions for cocaine dependence should be considered.


STING-activating nanoparticles normalize the vascular-immune interface to potentiate cancer immunotherapy.
The tumor-associated vasculature imposes major structural and biochemical barriers to the infiltration of effector T cells and effective tumor control. Correlations between stimulator of interferon genes (STING) pathway activation and spontaneous T cell infiltration in human cancers led us to evaluate the effect of STING-activating nanoparticles (STANs), which are a polymersome-based platform for the delivery of a cyclic dinucleotide STING agonist, on the tumor vasculature and attendant effects on T cell infiltration and antitumor function. In multiple mouse tumor models, intravenous administration of STANs promoted vascular normalization, evidenced by improved vascular integrity, reduced tumor hypoxia, and increased endothelial cell expression of T cell adhesion molecules. STAN-mediated vascular reprogramming enhanced the infiltration, proliferation, and function of antitumor T cells and potentiated the response to immune checkpoint inhibitors and adoptive T cell therapy. We present STANs as a multimodal platform that activates and normalizes the tumor microenvironment to enhance T cell infiltration and function and augments responses to immunotherapy.


A qualitative study on the expectations and experiences of mothers during the childbirth process in Western Anatolia, Turkey.
The structure of the delivery room, the protection of privacy, the distance of the hospital and institution policies are important factors affecting women's birth experiences. This study aimed to give voice mothers' expectations of midwives during the birth process, the care received by them, and their views about the delivery environment. The research was conducted with primipara mothers in a public hospital through in-depth interviews in a qualitative pattern based on the interpretive content analysis approach. In-depth interviews were conducted with mothers who had a healthy baby within 8-24 hours after birth. This study was carried out with 15 mothers. Data were collected through semi-structured interview form, tape recorder, and questionnaires including socio-demographic characteristics. Three main themes and eight sub-themes were obtained in the research. Main themes described are "delivery room environment", "views related to midwives", and "experiences during the birth process". Women stated that they found the delivery room hygienically inadequate, their privacy was not protected, and they felt lonely and scared. Women expect more information, support, patience, and friendliness from the midwives. The results obtained from the research will be important in the education of midwives and the regulation of the physical environment of delivery rooms.


Computed tomographic studies of the basis pedunculi in chronic hemiplegic patients: topographic correlation between cerebral lesion and midbrain shrinkage.
A computed tomographic method for analyzing the shrinkage of the basis pedunculi (BP) due to the secondary degeneration of the descending fibers was applied in correlation to the site of cerebral lesions in 89 chronic hemiplegic patients. Cerebral lesions in the anterior corona radiata or the anterior limb of the capsula interna caused shrinkage of the medial BP. Lesions in the central corona radiata or the genu and posterior limb of the capsula interna caused shrinkage of the central BP, while lesions of the posterior corona radiata or the posterior limb of the capsula interna caused shrinkage of the lateral BP. These results suggested that CT images are able to reveal the principle sites of atrophy of the descending fiber tracts in chronic hemiplegia.


Factors associated with physicians' decision to discontinue or down-titrate sulfonylureas for type 2 diabetes patients.
Sulfonylureas (SUs) can help manage type 2 diabetes mellitus, but often have side effects. The objective of this study was to identify factors impacting physicians' decisions to discontinue (DC) or down-titrate (DT) SU therapy. 1,026 physicians from the All Global panel were asked to rate level of concern regarding potential reasons for DC or DT on a 7-point Likert scale (1 = not concerned, 7 = extremely concerned). Physicians also provided information regarding treatment decisions from one DC patient, one DT patient, and two current SU users. When asked to report what factors might lead them to DC or DT an SU, physicians reported that hypoglycemic events requiring medical assistance (DC = 6.0, DT = 5.9), hypoglycemic events requiring nonmedical assistance (DC = 5.9, DT = 5.9), other hypoglycemic events not requiring assistance (DT = 5.7), and treatment goals not being met (DC = 5.6) were most concerning. DC and DT patients were more likely to have experienced ≥ 1 hypoglycemic events in the previous year vs. current users (DC = 41.0%, DT = 43.1%, current = 8.8%; p < .05). Results highlight the strong influence of hypoglycemia on physicians' decisions to DC or DT SU therapy.


CD4+ T lymphocyte responses to viruses and virus-relevant stimuli in teleost fish.
Fish diseases caused by viruses are a major threat to aquaculture. Development of disease protection strategies for sustainable fish aquaculture requires a better understanding of the immune mechanisms involved in antiviral defence. The innate and adaptive arms of the vertebrate immune system collaborate to mount an effective defence against viral pathogens. The T lymphocyte components of the adaptive immune system, comprising two major classes (helper T, Th or CD4+ and cytotoxic T lymphocytes, CTLs or CD8+ T cells), are responsible for cell-mediated immune responses. In particular, CD4+ T cells and their different subsets orchestrate the actions of various other immune cells during immune responses, making CD4+ T cells central drivers of responses to pathogens and vaccines. CD4+ T cells are also present in teleost fish. Here we review the literature that reported the use of antibodies against CD4 in a few teleost fish species and transcription profiling of Th cell-relevant genes in the context of viral infections and virus-relevant immunomodulation. Studies reveal massive CD4+ T cell proliferation and expression of key cytokines, transcription factors, and effector molecules that evoke mammalian Th cell responses. We also discuss gaps in the current understanding and evaluation of teleost CD4+ T cell responses and how development and application of novel tools and approaches to interrogate such responses could bridge these gaps. A greater understanding of fish Th cell responses will further illuminate the evolution of vertebrate adaptive immunity, inform strategies to address viral infections in aquaculture, and could further foster fish as model organisms.


The neurotoxicity of 5,7-dihydroxytryptamine in the mouse atrium: protection by 1-phenyl-3-(2-thiazolyl)-2-thiourea and by ethanol.
1-Phenyl-3-(2-thiazolyl)-2-thiourea (200 mg/kg, 1 h) protected the adrenergic nerve plexus in the mouse atrium against the destructive action of i.v. 5,7-dihydroxytryptamine. Protection was also observed with ethanol (4 g/kg, 1 h) and with nialamide (50 mg/kg, 2 h).


[Tracheal rupture from blunt chest injury in a child].
Tracheobronchial lesions after blunt chest injury are rare. Diagnosis and therapy can prove to be challenging for the attending physician. Nonrecognition of this injury may entail severe complications. Herein we report the case of a 9-year-old girl with rupture of the trachea due to a fall against the handlebar of her kickboard. The clinical, radiological, and features of the therapy performed are discussed.


Decreased fasting free fatty acids with L-carnitine in children with carnitine deficiency.
At the time of acute presentation, children with carnitine deficiency may have increased free fatty acid concentrations and hypoglycemia. However, whether carnitine replacement affects the plasma concentration of these substrates remains to be determined. Therefore, to evaluate the effect of carnitine replacement on plasma substrate and hormone concentrations, five children with carnitine deficiency (two idiopathic, two secondary to long-chain acyl coenzyme A dehydrogenase deficiency, one secondary to isovaleric acidemia) were fasted overnight before and after treatment with oral carnitine (80 +/- 7 mg.kg-1.day-1). During carnitine supplementation, plasma total carnitine (19 +/- 4 versus 45 +/- 6 nmol/ml, pretreatment versus treatment, respectively) and free carnitine (11 +/- 3 versus 31 +/- 6 nmol/ml), as well as red blood cell total carnitine (0.057 +/- 0.019 versus 0.130 +/- 0.019 nmol/mg of hemoglobin) increased (p less than 0.05). Fasting plasma glucose (83 +/- 4 versus 85 +/- 3 mg/dl) and ketone body (0.54 +/- 0.18 and 0.56 +/- 0.20 mM) concentrations did not change with carnitine supplementation, but plasma free fatty acids (1.28 +/- 0.32 versus 0.77 +/- 0.07 mM) decreased (p less than 0.05). No differences in fasting insulin, growth hormone, or cortisol concentrations were observed. Urinary excretion of free carnitine (0.1 +/- 0.0 versus 2.4 +/- 0.7 mumol/mg creatinine), total carnitine (0.3 +/- 0.1 versus 3.4 +/- 0.9 mumol/mg creatinine) and acyl carnitine (0.2 +/- 0.1 versus 0.9 +/- 0.3 mumol/mg creatinine) increased (p less than 0.05) with carnitine supplementation. The decreased plasma free fatty acid concentrations with carnitine supplementation may be due to more efficient fatty acid oxidation and/or increased urinary excretion of fatty acids as acylcarnitines.


Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part III, saturated and unsaturated fatty acid profiles.
The purpose of the third part of this study is to construct a basic lipid model (this includes information regarding total and free saturated, monounsaturated and polyunsaturated fatty acid contents, as well as total and free fatty acid saturation and double bond indexes, and comparisons of total and free n-3, n-6, n-7 and n-9 fatty acids in normal epithelial tissue, and intraepithelial and infiltrating lesions of the cervix) which, together with the individual total and free fatty acid profiles given in parts I and II of this study, should provide an understanding of the turnover of total and free acids, especially essential fatty acids, during cervical carcinogenesis. Such information can serve as a sound basis for further studies in an attempt to access this disease process. We observed an increase in monounsaturated fatty acid values in cancer tissue compared with normal tissue and a decrease of saturated fatty acid values in cancer tissue compared with normal tissue. Based on our observations, we speculate that because of the depletion of polyunsaturated fatty acids, monounsaturated fatty acid are synthesized to compensate for this loss; a possible source for the monounsaturated fatty acids are the saturated fatty acids via elongation and/or desaturation. Of particular interest is the n-3 fatty acid docosahexaenoic acid, the most unsaturated lipid in the biological systems, detected in very small amounts only in cancer cells of the cervix.


EDTA-dominated hollow tube-like porous graphitic carbon nitride towards enhanced photocatalytic hydrogen evolution.
Graphite carbon nitride (g-C3N4) as metal-free photocatalyst has been widely studied recently in photocatalytic water reduction, which is considered as one of the promising routes to realizing the hydrogen energy-based society in the future. The generally used preparation process based on thermal polymerization of precursors easily brought the formation of aggregated nanosheets morphology, severely limiting its photocatalytic activity. Herein, the hollow tube-like morphology with porous surface was elaborately obtained by ethylene diamine tetraacetic acid (EDTA)-involved hydrothermal treatment of melamine precursor. The hollow and porous features shortened the migration distance of photo-generated carriers, trapped the incident lights, and provided more photocatalytic reactive sites, then realizing the enhanced photocatalytic H2-evolution activity up to 7.1 times that of pristine g-C3N4. The presence of EDTA acted as the pivotal role to control the recrystallization process of melamine and its derivative, cyanuric acid, and thus to determine the framework formation of the hollow tube-like microstructure. Moreover, complete thermal decomposition of cyanuric acid during the thermal polymerization of precursors was responsible for the hollow and porous features. This work extends the morphology regulation cognition of g-C3N4 based on hydrothermal treatment of precursors, and is expected to bring deep understanding and feasible strategies to design morphology-dominated highly-efficient g-C3N4 photocatalysts.


Combined use of municipal solid waste biochar and bacterial biosorbent synergistically decreases Cd(II) and Pb(II) concentration in edible tissue of forage maize irrigated with heavy metal-spiked water.
A pot experiment was carried out to evaluate the effect of a municipal solid waste (MSW) biochar and a bacterial strain on the forage maize growth and the concentration of lead (Pb) and cadmium (Cd) in the edible tissue of maize irrigated with water contaminated with Cd (5 mg L-1) and Pb (100 mg L-1). Experimental treatments included (i) bacterial strain at two levels: no bacterial strain and Enterobacter cloacae R7; (ii) MSW biochar at three levels: 0, 1, and 3% (w/w); and (iii) irrigation water quality at five levels: plants irrigated with 100% freshwater (FW), plants irrigated with 75%FW + 25% contaminated water (CW), plants irrigated with 50%FW + 50% CW, plants irrigated with 25%FW + 75% CW, and plants irrigated with 100% CW. The effect of various treatments on maize growth indices and concentration of Pb(II) and Cd(II) in the plant was significant at 5% level. The concentration of these metals in the shoot of plants irrigated with 75 and 100% CW was higher than the permissible limits for Cd(II) and Pb(II) in livestock feed. However, the concentration of these metals in the shoot of the plants irrigated with 25 and 50% CW was lower than the permissible limit for this use. In this study, the combined application of 3%biochar and E. cloacae R7 had a significant effect on increased root dry weight (ranging from 29 to 33%), shoot dry weight (ranging from 32 to 43%) and bacterial root colonization (ranging from 33 to 53%) and on reduced concentration of Pb (ranging from 78 to 80%) and Cd (ranging from 72 to 76%) of the shoot of maize plant (edible tissues used by livestock), which was below the permissible limits for livestock feed, compared to corresponding controls. According to the results of this study, to reduce the concentration of the heavy metals in forage maize shoot (below the permissible limits for livestock feed), it is suggested using heavy metal-contaminated water either in combination with freshwater (50 or 75% FW) or in combination with biochar and bacterial biosorbent, averting human/animal health risk.


Prolactin, vasoactive intestinal peptide, and peptide histidine methionine elicit selective increases in REM sleep in rabbits.
The purpose of these experiments was to determine whether (1) vasoactive intestinal peptide (VIP) produces effects on rabbit sleep similar to those reported for rats and cats; (2) peptide histidine methionine (PHM), a peptide closely related to VIP, mimics the sleep effects of VIP; and (3) pituitary prolactin (PRL), a pituitary hormone that has a sleep-related secretory pattern and for which VIP and PHM act as releasing factors, has similar effects on sleep. VIP or PHM (0.01, 0.1 and 1.0 nmol/kg) was intracerebroventricularly (i.c.v.) injected; PRL (ovine PRL, 45 and 200 IU/kg) was subcutaneously (s.c.) administered. Sleep-wake activity and brain temperature were recorded for 6 h. For controls, rabbits received artificial cerebrospinal fluid i.c.v. or PRL-vehicle s.c. VIP and PHM promoted rapid eye movement sleep (REMS), although these effects were not dose-dependent. In addition, the high dose of VIP and PHM transiently increased wakefulness. Increases in REMS occurred only during hours 2-6 after i.c.v. injection of VIP and peptide histidine leucine (PHI). After s.c. injection of PRL, REMS started to increase in postinjection hour 3. The effect of the high dose was significantly more pronounced than that of the small dose. Each substance enhanced the frequency of REMS episodes, and the high dose of PRL also increased the duration of REMS bouts. These results are consistent with the hypothesis that VIP is involved in physiological regulation of REMS, and that the VIP- and PHM-induced increases in REMS may be mediated via release of PRL.


Immediate delivery versus expectant management in women with chronic hypertension: a meta-analysis of randomized controlled trials.
The current guidelines regarding chronic hypertension during pregnancy recommend induction of labor at term. The only previous meta-analysis on this topic found two randomized controlled trials but failed to pool together their results. We aimed to find the best literature-based evidence regarding delivery timing in chronic hypertension during pregnancy. We searched the following electronic databases: MEDLINE, EMBASE, Scopus, ClinicalTrials.gov, the PROSPERO International Prospective Register of Systematic Reviews, and the Cochrane Central Register of Controlled Trials, Google Scholar. We selected randomized controlled trials comparing expectant management versus immediate delivery. The search was performed by two authors and the conflicts resolved in meetings. we collected maternal and neonatal outcomes in a metanalysis following the random-effects model. Two studies were found. The summary effect measure was 1.1 (C.I. 0.51-2.1) regarding the maternal outcomes, 2.6 (C.I. 0.91-7.44) regarding the neonatal outcomes, and 1.5 (C.I. 0.8-2.79) combined. There was no statistically significant difference between maternal and neonatal outcomes (P=0.2). The results of our meta-analysis pointed towards a non-difference between immediate delivery and expectant management, in women with chronic hypertension.


Seasonal variations in outcomes after kidney transplantation: UNOS review of 336,330 transplants.
The "July effect" is a widely discussed phenomenon of worse patient outcomes at teaching hospitals in July due to inexperienced house staff. We conducted a retrospective review of Organ Procurement and Transplantation Network data from Oct 1, 1987 to June 30, 2011, including longitudinal censored data of 360,330 transplantations. Demographic and comorbid variables for donors and recipients were collected. Primary outcomes were graft loss, patient death, and delayed graft function. Secondary outcomes were surgical complications, length of stay, and graft rejection. We compared survival indicators (1-month, 1-, 3-, and 5-year survival and median survival times) for both grafts and patients. We also analyzed death-censored graft survival. There were fewer July donors with diabetes (p = 0.003), hypertension (p = 0.000), and extended criteria (p<0.0001). Graft survival (p = 0.000), death-censored graft survival (p = 0.001), and patient survival (p = 0.002) were statistically higher in July. After adjusting the Cox model for extended criteria donors, there was no difference in outcomes (p>0.05 for graft, death-censored graft survival, and patient survival). We conclude that there is no July effect. Initially identified, superior outcomes in July may be attributed to more conservative allografts selection in the beginning of the academic year.


Therapeutic effects of Shenfu Injection on post-cardiac arrest syndrome.
Survival rates after cardiac arrest have not changed substantially over the past 5 decades. Postcardiac arrest (CA) syndrome (PCAS) is the primary reason for the high mortality rate after successful restoration of spontaneous circulation (ROSC). Intravenous administration of Shenfu Injection (, SFI) may attenuate post-CA myocardial dysfunction and cerebral injury, inhibit systemic ischemia/reperfusion responses, and treat underlying diseases. In this article, we reviewed the therapeutic effects of SFI in PCAS. SFI might be useful in the treatment of PCAS, incorporating the multi-link and multi-target advantages of Chinese medicine into PCAS management. Further experimental and clinical research to verify the therapeutic effects of SFI in PCAS is required.


The role of JrLACs in the lignification of walnut endocarp.
The walnut shell, which is composed of a large number of sclereids originating from the lignified parenchyma of the endocarp, plays an important role in fruit development and during harvesting and storage. The physical and chemical properties of walnut shells are closely related to the lignin content. Laccase is the key enzyme responsible for lignin biosynthesis by the polymerization of monolignols and plays crucial roles in secondary cell wall formation in plants. In this study, we screened and identified laccase family genes from the walnut genome and investigated the expression of laccase during endocarp lignification in walnut. A total of 37 laccase genes were screened from the walnut genome and distributed on nine chromosomes and classified into 6 subfamilies, among which subfamily IV showed distinct expansion. We observed that endocarp lignification started 44 days after flowering (DAF), and at later periods, the lignin content increased rapidly, with growth peaks at 44-50 DAF and 100-115 DAF. The lignification of the endocarp proceeded from the outside to the inside, as demonstrated by section staining in combination with endocarp staining. Furthermore, the changes in the expression of laccase family genes in the endocarp at different developmental stages were studied, and JrLACs showed different expression trends. The expression of nine genes showed significant increase after 44 DAF, and among these, JrLAC12-1, JrLAC12-2 and JrLAC16 showed a significant change in expression at the lignification stage. A study of the expression of JrLACs in different tissues and at various endocarp developmental stages revealed, that most JrLACs were expressed at low levels in mature tissues and at high levels in young tissues, in particular, JrLAC12-1 showed high expression in the young stems. A significant positive correlation was found between the expression of JrLAC12-1 and the variation in the lignin content in the endocarp. Laccase genes play an important role in the lignification of the walnut endocarp, and JrLACs play different roles during fruit development. This study shows that JrLAC12-1 may play a key role in the lignification of endocarp.


Ectopic bone formation by 3D porous calcium phosphate-Ti6Al4V hybrids produced by perfusion electrodeposition.
Successful clinical repair of non-healing skeletal defects requires the use of bone substitutes with robust bone inductivity and excellent biomechanical stability. Thus, three-dimensionally functionalised porous calcium phosphate-Ti6Al4V (CaP-Ti) hybrids were produced by perfusion electrodeposition, and the in vitro and in vivo biological performances were evaluated using human periosteum derived cells (hPDCs). By applying various current densities at the optimised deposition conditions, CaP coatings with sub-micrometer to nano-scale porous crystalline structures and different ion dissolution kinetics were deposited on the porous Ti6Al4V scaffolds. These distinctive physicochemical properties caused a significant impact on in vitro proliferation, osteogenic differentiation, and matrix mineralisation of hPDCs. This includes a potential role of hPDCs in mediating osteoclastogenesis for the resorption of CaP coatings, as indicated by a significant down-regulation of osteoprotegerin (OPG) gene expression and by the histological observation of abundant multi-nucleated giant cells near to the coatings. By subcutaneous implantation, the produced hybrids induced ectopic bone formation, which was highly dependent on the physicochemical properties of the CaP coating (including the Ca(2+) dissolution kinetics and coating surface topography), in a cell density-dependent manner. This study provided further insight on stem cell-CaP biomaterial interactions, and the feasibility to produced bone reparative units that are predictively osteoinductive in vivo by perfusion electrodeposition technology.


Effects of arousal modulation via resonance breathing on craving and affect in women with substance use disorder.
Craving for alcohol and other drugs is a complex in-the-moment experience that involves within-person changes in physiological arousal and affect. We evaluated the utility of a just-in-time, self-administered resonance breathing smartphone application (app) to reduce craving and improve affect in women during outpatient treatment for substance use disorders (SUD). Women (N = 57) receiving outpatient addiction treatment were randomized to practice either cardiovascular resonance breathing (0.1 Hz/6 breaths per minute) or a sham (∼0.23 Hz/14 breaths per minute) in the face of urges over an 8-week intervention. Craving (Penn Alcohol Craving Scale) and affect (Positive and Negative Affect Scale) were collected weekly throughout the intervention. App data were uploaded weekly to assess frequency of use. Generalized Estimated Equations modeled craving and affect as a function of group randomization and app use frequency across the 8-week intervention. Higher levels of craving were associated with more frequent app use. The group X app use interaction was significant for craving. Frequent app use during the intervention phase was associated with lower craving levels in the resonance breathing group relative to the sham group over the 8-week intervention. There was no effect of app use frequency on affect measures. Women assigned to practice sham breathing who used the intervention frequently experienced elevations in craving that are commonly reported during outpatient SUD treatment. Women assigned to resonance breathing who used the intervention frequently did not experience such increases. Resonance breathing may be protective against triggers in outpatient treatment. Physiological mechanisms are discussed.


Study of the synergistic effects of salinity, pH, and temperature on the surface-active properties of biosurfactants produced by Lactobacillus pentosus.
Many studies have investigated the effects of pH, temperature, and salinity on the surface-active properties of various surfactants, although in most cases the variables have been studied separately, without considering the effects of any interactions between them. In the present study, a Box-Behnken factorial design was applied to study the effects of pH, temperature, and salinity on the surface-active properties of a biosurfactant produced by Lactobacillus pentosus. The data obtained enabled development of a second-order model describing the interrelationships between operational and experimental variables, by equations including linear, interaction, and quadratic terms. The variable that had the greatest effect on the surface-active properties of the biosurfactant was pH. Moreover, at pH 3-5.5, decreases in salinity and temperature acted synergistically, reducing the surface tension of the biosurfactant; at pH 8, the same effect was observed with increasing salinity and temperature.


Two Arabidopsis orthologs of the transcriptional coactivator ADA2 have distinct biological functions.
Histone acetylation is an example of covalent modification of chromatin structure that has the potential to regulate gene expression. Gcn5 is a prototypical histone acetyltransferase that associates with the transcriptional coactivator Ada2. In Arabidopsis, two genes encode proteins that resemble yeast ADA2 and share approximately 45% amino acid sequence identity. We previously reported that plants harboring a T-DNA insertion in the ADA2b gene display a dwarf phenotype with developmental defects in several organs. Here we describe T-DNA insertion alleles in the ADA2a gene, which result in no dramatic growth or developmental phenotype. Both ADA2a and ADA2b are expressed in a variety of plant tissues; moreover, expression of ADA2a from a constitutive promoter fails to complement the ada2b-1 mutant phenotype, consistent with the hypothesis that the two proteins have distinct biochemical roles. To further probe the cellular roles of ADA2a and ADA2b, we studied the response of the transcriptional coactivator mutants to abiotic stress. Although ada2b seedlings display hypersensitivity to salt and abscisic acid and altered responses to low temperature stress, the responses of ada2a seedlings to abiotic stress generally parallel those of wildtype plants. Intriguingly, ada2a;ada2b double mutant plants display an intermediate, gcn5-like phenotype, suggesting that ADA2a and ADA2b each work independently with GCN5 to affect genome function in Arabidopsis.


Rituximab administration in pediatric patients with newly diagnosed acute lymphoblastic leukemia.
Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience allergic reactions. We hypothesized that by decreasing antibody-producing CD20-positive B cells, rituximab may reduce these reactions. Children and adolescents (aged 1-18 years) with newly diagnosed B-ALL treated on the St. Jude Total XVII study were randomized to induction therapy with or without rituximab on day 3 (cohort 1) or on days 6 and 24 (cohort 2). Patient clinical demographics, CD20 expression, minimal residual disease (MRD), rituximab reactions, pegaspargase allergy, anti-pegaspargase antibodies, and pancreatitis were evaluated. Thirty-five patients received rituximab and 37 did not. Among the 35 recipients, 16 (45.7%) experienced a grade 2 or higher reaction to rituximab. There were no differences between recipients and non-recipients in the incidence of pegaspargase reactions (P > 0.999), anti-pegaspargase antibodies (P = 0.327), or pancreatitis (P = 0.480). CD20 expression on day 8 was significantly lower in rituximab recipients (P < 0.001), but there were no differences in MRD levels on day 8, 15, or at the end of induction. Rituximab administration during induction in pediatric patients with B-ALL was associated with a high incidence of infusion reactions with no significant decrease in pegaspargase allergies, anti-pegaspargase antibodies, or MRD.


A pre-formulation study of tetracaine loaded in optimized nanostructured lipid carriers.
Tetracaine (TTC) is a local anesthetic broadly used for topical and spinal blockade, despite its systemic toxicity. Encapsulation in nanostructured lipid carriers (NLC) may prolong TTC delivery at the site of injection, reducing such toxicity. This work reports the development of NLC loading 4% TTC. Structural properties and encapsulation efficiency (%EE > 63%) guided the selection of three pre-formulations of different lipid composition, through a 23 factorial design of experiments (DOE). DLS and TEM analyses revealed average sizes (193-220 nm), polydispersity (< 0.2), zeta potential |- 21.8 to - 30.1 mV| and spherical shape of the nanoparticles, while FTIR-ATR, NTA, DSC, XRD and SANS provided details on their structure and physicochemical stability over time. Interestingly, one optimized pre-formulation (CP-TRANS/TTC) showed phase-separation after 4 months, as predicted by Raman imaging that detected lack of miscibility between its solid (cetyl palmitate) and liquid (Transcutol) lipids. SANS analyses identified lamellar arrangements inside such nanoparticles, the thickness of the lamellae been decreased by TTC. As a result of this combined approach (DOE and biophysical techniques) two optimized pre-formulations were rationally selected, both with great potential as drug delivery systems, extending the release of the anesthetic (> 48 h) and reducing TTC cytotoxicity against Balb/c 3T3 cells.


Room temperature preparation of cellulose nanocrystals with high yield via a new ZnCl2 solvent system.
Here, a facile method to fabricate cellulose nanocrystals (CNCs) with high yield from microcrystalline cellulose (MCC) at room temperature (RT) is achieved by using a new solvent system of zinc chloride (ZnCl2) and a little amount of hydrochloric acid (HCl). Compared with sulphuric acid hydrolysis process, about one-fifth mole of acid is used for per gram of CNCs in our protocol. CNCs with rod-like morphology are regenerated with a maximum yield of 35.2% and high crystallinity of 73.8%. Moreover, with an additional 2 h of ball-milling, the yield of CNCs could significantly increase to 66.9% at RT. The possible formation mechanism for CNCs prepared by the solvent system of ZnCl2/HCl is proposed. As the first example of isolation of CNCs with high yield at RT using ZnCl2, this work provides a facile, energy-saving, and practical strategy for the preparation of cellulose nanomaterials.


Tenth revision U.S. mortality rates for use with the NIOSH Life Table Analysis System.
The objective of this study was to update rate files for the NIOSH Life Table Analysis System for Personal Computers (PC LTAS) reflecting the newly adopted tenth revision changes to the International Classification of Diseases. PC LTAS allows researchers to conduct comparative mortality and morbidity analyses for the purpose of identifying disease-exposure associations using person-time-at-risk for age, race, sex, and calendar time-specific reference rates from 1940. Previously available through 1998, files for the United States and individual states were updated through 2004 using uncensored population data. Tenth revision causes were added if compatible with earlier NIOSH death categories, based on revisions 5 through 9. A few new cause categories were added. The resulting NIOSH categories are described for two new U.S. rate files: 1960 through 2004 and 1940 through 2004. The new U.S. rate files are available online or on request.


Epithelial morphogenesis of germline-derived pluripotent stem cells on organotypic skin equivalents in vitro.
For tissue engineering, cultivation of pluripotent stem cells on three-dimensional scaffolds allows the generation of organ-like structures. Previously, we have established an organotypic culture system of skin to induce epidermal differentiation in adult stem cells. Multipotent stem cells are not able to differentiate across germinal boundaries. In contrast, pluripotent stem cells readily differentiate into tissues of all three germ layers. Germline-derived pluripotent stem cells (gPS cells) can be generated by induction of pluripotency in mouse unipotent germline stem cells without the introduction of exogenous transcription factors. In the current study, we analyzed the influence of organotypic culture conditions of skin on the epithelial differentiation of gPS cells in comparison to the well-established HM1 ES cell line. Quantitative RT-PCR data of the pluripotency gene Oct4 showed that gPS cells are characterized by an accelerated Oct4-downregulation compared to HM1 ES cells. When subjected to the organotypic culture conditions of skin, gPS cells formed tubulocystic structures lined by stratified (CK5/6(+), CK14(+), CK8/18(-)) epithelia. HM1 ES cells formed only small tubulocystic structures lined by simple, CK8/18(+) epithelia. BMP-4, an epidermal morphogen, significantly enhanced the expression of epithelial markers in HM1 ES cells, but did not significantly affect the formation of complex (squamous) epithelia in gPS cells. In HM1 ES cells the differentiation into squamous epithelium was only inducible in the presence of mature dermal fibroblasts. Both pluripotent stem cell types spontaneously differentiated into mesodermal, endodermal and into neuroectodermal cells at low frequency, underlining their pluripotent differentiation capacity. Concluding, the organotypic culture conditions of skin induce a multilayered, stratified epithelium in gPS cells, in HM1 ES cells only in the presence of dermal fibroblasts. Thus, our data show that differentiation protocols strongly depend on the stem cell type and have to be modified for each specific stem cell type.


Three-dimensional simulation of the Caenorhabditis elegans body and muscle cells in liquid and gel environments for behavioural analysis.
To better understand how a nervous system controls the movements of an organism, we have created a three-dimensional computational biomechanical model of the Caenorhabditis elegans body based on real anatomical structure. The body model is created with a particle system-based simulation engine known as Sibernetic, which implements the smoothed particle-hydrodynamics algorithm. The model includes an elastic body-wall cuticle subject to hydrostatic pressure. This cuticle is then driven by body-wall muscle cells that contract and relax, whose positions and shape are mapped from C. elegans anatomy, and determined from light microscopy and electron micrograph data. We show that by using different muscle activation patterns, this model is capable of producing C. elegans-like behaviours, including crawling and swimming locomotion in environments with different viscosities, while fitting multiple additional known biomechanical properties of the animal. This article is part of a discussion meeting issue 'Connectome to behaviour: modelling C. elegans at cellular resolution'.


T2-Pseudonormalization and Microstructural Characterization in Advanced Stages of Late-infantile Metachromatic Leukodystrophy.
T2-weighted signal hyperintensities in white matter (WM) are a diagnostic finding in brain magnetic resonance imaging (MRI) of patients with metachromatic leukodystrophy (MLD). In our systematic investigation of the evolution of T2-hyperintensities in patients with the late-infantile form, we describe and characterize T2-pseudonormalization in the advanced stage of the natural disease course. The volume of T2-hyperintensities was quantified in 34 MRIs of 27 children with late-infantile MLD (median age 2.25 years, range 0.5-5.2 years). In three children with the most advanced clinical course (age >4 years) and for whom the T2-pseudonormalization was the most pronounced, WM microstructure was investigated using a multimodal MRI protocol, including diffusion-weighted imaging, MR spectroscopy (MRS), myelin water fraction (MWF), magnetization transfer ratio (MTR), T1-mapping and quantitative susceptibility mapping. T2-hyperintensities in cerebral WM returned to normal in large areas of 3 patients in the advanced disease stage. Multimodal assessment of WM microstructure in areas with T2-pseudonormalization revealed highly decreased values for NAA, neurite density, isotropic water, mean and radial kurtosis, MWF and MTR, as well as increased radial diffusivity. In late-infantile MLD patients, we found T2-pseudonormalization in WM tissue with highly abnormal microstructure characterizing the most advanced disease stage. Pathological hallmarks might be a loss of myelin, but also neuronal loss as well as increased tissue density due to gliosis and accumulated storage material. These results suggest that a multimodal MRI protocol using more specific microstructural parameters than T2-weighted sequences should be used when evaluating the effect of treatment trials in MLD.


A study of co-positivity of three multipuncture techniques with intradermal PPD tuberculin.
One hundred thirty-five patients with a reaction of 10 mm or more of induration to 5 TU of intradermal PPD were simultaneously tested with 3 multipuncture techniques to determine the copositivity of the multiple puncture methods with the Mantoux method. Of the 3 multipuncture preparations used (Tine Test, Aplitest, and Mono-Vacc), the Mono-Vacc had 2 (1.5 per cent) false-negative result after 48 hours with only one remaining negative result after 72 hours; whereas the Tine-Test had 21 (15.5 per cent), and the Aplitest had 13 (9.6 per cent) false-negative reactions after 48 hours. Vesicular eruptions were not a commonly noted reaction to the multipuncture preparations. Of the 3 multipuncture preparations commercially available, Mono-Vacc is the preferred reagent because of its significantly lower incidence of false-negative reactions.


Evidence that Akt mediates platelet-derived growth factor-dependent increases in activity and surface expression of the neuronal glutamate transporter, EAAC1.
Previously we have shown that platelet-derived growth factor (PDGF) rapidly increases the activity of the neuronal glutamate transporter, EAAC1. This increase in activity is associated with a rapid (within minutes) redistribution of transporter from a subcellular compartment to the plasma membrane and is blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K). Similar effects of PI3K inhibitors have been observed for insulin-dependent up-regulation of the GLUT4 subtype of glucose transporter. Although GLUT4 regulation also depends on the serine-threonine kinase (Akt/protein kinase B), a downstream target of PI3K, the downstream effectors responsible of PDGF-dependent regulation of EAAC1 have not been identified. In the present study, PDGF increased the level of Akt phosphorylation (Ser 473) in C6 glioma cells, a cell line that has been used to study regulated trafficking of endogenous EAAC1. Two inhibitors of PI3K blocked this effect. In transient transfection studies, a dominant negative mutant of Akt-1 blocked PDGF-induced redistribution of epitope-tagged EAAC1 (myc-EAAC1). Conversely, constitutively active Akt-1 (CA Akt-1) increased the cell surface expression of myc-EAAC1. A lentiviral vector engineered to express CA Akt-1 increased Akt activation, cell surface expression of endogenous EAAC1, and Na(+)-dependent glutamate transport activity. Together, these studies suggest that Akt is required for PDGF-induced regulation of EAAC1.


Correction: Geospatial modeling of land cover change in the Chocó-Darien global ecoregion of South America; One of most biodiverse and rainy areas in the world.
[This corrects the article DOI: 10.1371/journal.pone.0211324.].


Microcin B17, a novel tool for preparation of maxicells: identification of polypeptides encoded by the IncFII minireplicon pMccB17.
The DNA replication inhibitor peptide microcin B17 is shown to be a useful tool for preparing Escherichia coli maxicells. To illustrate its usefulness, we have identified polypeptides synthesized from pMccB17 and R100 IncFII miniplasmids. After comparing the respective polypeptides and the miniplasmid restriction maps, we concluded that these plasmids share extensive homology in the basic replicon but are different for an adjacent region (parD) that is involved in plasmid stability and maintenance.


Determination of "borderline resectable" pancreatic cancer - A global assessment of 30 shades of grey.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. Accurate preoperative assessment using computed tomography (CT) to determine resectability is crucial in ensuring patients are offered the most appropriate therapeutic strategy. Despite the use of classification guidelines, any interobserver variability between reviewing surgeons and radiologists may confound decisions influencing patient treatment pathways. In this multicentre observational study, an international group of 96 clinicians (42 hepatopancreatobiliary surgeons and 54 radiologists) were surveyed and asked to report 30 pancreatic CT scans of pancreatic cancer deemed borderline at respective multidisciplinary meetings (MDM). The degree of interobserver agreement in resectability among radiologists and surgeons was assessed and subgroup regression analysis was performed. Interobserver variability between reviewers was high with no unanimous agreement. Overall interobserver agreement was fair with a kappa value of 0.32 with a higher rate of agreement among radiologists over surgeons. Interobserver variability among radiologists and surgeons globally is high, calling into question the consistency of clinical decision making for patients with PDAC and suggesting that central review may be required for studies of neoadjuvant or adjuvant approaches in future as well as ongoing quality control initiatives, even amongst experts in the field.


Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy.
Immunopathologic studies over the past two decades have demonstrated that rapidly progressive glomerulonephritis (RPGN) can result from glomerular deposition of anti-GBM antibody, immune complexes, or from some as yet undefined mechanism that does not involve glomerular antibody deposition. The latter process may be cell mediated and resembles a small vessel vasculitis. Most cases of idiopathic RPGN are not accompanied by pathogenic glomerular immunoglobulin deposition. Recent experimental studies of immune mechanisms of glomerular injury have identified several new processes that can induce damage to the capillary wall sufficient to result in crescentic glomerulonephritis (GN). These include direct effects of anti-GBM antibody alone and of the complement C5b-9 (membrane attack) complex, nephritogenic effects of inflammatory effector cells that involve reactive oxygen species and glomerular halogenation, and injury mediated by sensitized lymphocytes independently of antibody deposition. Macrophages have been shown to participate in both intracapillary and extracapillary fibrin deposition and crescent formation as well as to mediate capillary wall damage. The role of resident glomerular cells and cell-cell interactions in glomerulonephritis is still under active investigation. Despite these several advances in understanding immune injury to the glomerulus, therapy for RPGN remains largely empiric. Although the prognosis in RPGN has clearly improved over time, no form of disease-specific therapy has been clearly shown yet to be beneficial in a controlled study. Interpretation of the existing literature on therapy is complicated by the availability of only historical rather than concurrent controls, lack of attention to several variables known to affect disease outcome, and uncertainty regarding bias in favor of reporting positive results. Available data suggests that optimal outcomes may be achieved in anti-GBM nephritis by treatment with steroids, immunosuppression and plasma exchange, particularly when therapy is directed at patients with mild but rapidly progressive disease before oliguria or severe azotemia develop. Pulse steroids are probably the most cost-effective therapy for the idiopathic form of RPGN, but treatment with cytotoxic agents should be considered if clinical or histologic evidence of vasculitis is present.


Neurotropic Enterovirus Infections in the Central Nervous System.
Enteroviruses are a group of positive-sense single stranded viruses that belong to the Picornaviridae family. Most enteroviruses infect humans from the gastrointestinal tract and cause mild symptoms. However, several enteroviruses can invade the central nervous system (CNS) and result in various neurological symptoms that are correlated to mortality associated with enteroviral infections. In recent years, large outbreaks of enteroviruses occurred worldwide. Therefore, these neurotropic enteroviruses have been deemed as re-emerging pathogens. Although these viruses are becoming large threats to public health, our understanding of these viruses, especially for non-polio enteroviruses, is limited. In this article, we review recent advances in the trafficking of these pathogens from the peripheral to the central nervous system, compare their cell tropism, and discuss the effects of viral infections in their host neuronal cells.


Operative vs Nonoperative Treatment of Achilles Tendon Ruptures Using Early Functional Rehabilitation: Critical Analysis of Evidence.
Nonoperative treatment with functional rehabilitation of Achilles tendon ruptures (ATRs) has become more common because of claim of "equivalent" risk of rerupture compared to operative treatment. We investigated how current evidence corroborates the often-claimed "equal" or "nondifferent" complication rates. A search of meta-analyses in PubMed, CENTRAL, and Scopus was performed. Meta-analyses including randomized controlled trials (RCTs) comparing open operative repair of ATR and nonoperative treatment with functional rehabilitation regarding reruptures and other complications were identified. Four separate meta-analyses with 6 pooled treatment comparisons were identified. One of the 6 treatment effects (for risk ratio [RR]) showed a reduced risk of rerupture favoring operative treatment, whereas in the remaining analyses the null hypothesis assuming equal risk or an RR of 1 could not be rejected. The smallest RR (benefit in favor of surgery) that could be rejected based on the 95% CI was 0.28. The smallest risk difference that could be rejected in favor of surgery was 6.4%, indicating that nonoperative may have up to 6.4% higher rerupture rate. Treatment effects for complications other than rerupture had very large variability and imprecision. The literature comparing surgery with nonoperative treatment using functional rehabilitation in ATR have been interpreted in favor of nonoperative treatment as the rerupture rates were falsely considered "equivalent." None of the published meta-analyses excluded a relative risk that is likely to affect the course of treatment in many cases. Increasing incidence of nonoperative treatment in ATRs is not clearly supported by current evidence.