Pain assessment by patients and nurses in the early phase of acute myocardial infarction.
In 47 patients admitted to the coronary care unit (CCU) at Sahlgren's Hospital in Göteborg, Sweden, due to acute myocardial infarction (MI) the intensity of pain independently assessed by the patient and by the nurse on duty was evaluated during the first 24 hours in CCU. Pain was assessed according to a modified numerical rating scale graded from 0-10, where 0 meant no pain and 10 meant the most severe pain. A positive correlation between the patients' and nurses' assessments was found (r = 0.76; P less than 0.001). However, the nurses under-estimated the patients' pain in 23% of the situations and over-estimated it in 20%. Over-estimation was particularly found when heart rate and blood pressure increased. Many patients scoring their pain to fairly high degrees were not given pain-relieving treatment. Treatment with morphine did not cause substantial pain relief in a substantial number of patients. A significantly positive correlation was found between the patients' and nurses' assessments of pain, although under-estimation as well as over-estimation occurred. A few patients with severe pain were not treated and when treatment was given it was often ineffective.


Evaluating the evidence: statistical methods in randomized controlled trials in the urological literature.
Randomized controlled trials potentially provide the highest level of evidence to inform clinical decision making. Appropriate use of statistical methods is a critical aspect of all clinical research, including randomized controlled trials. We report the first formal evaluation to our knowledge of the statistical methods of randomized controlled trials published in the urological literature in 1996 and 2004. All human subjects randomized controlled trials published in 4 leading urology journals in 1996 and 2004 were identified for formal review. A standardized evaluation form was developed based on the Consolidated Standards of Reporting Trials statement. Each article was evaluated by 2 independent reviewers with formal training in research design and biostatistics who were blinded to study authors and institution. Discrepancies were settled by consensus. A total of 152 randomized controlled trials were reviewed (65 in 1996, 87 in 2004). The median sample size (IQR) per arm of parallel design randomized controlled trials published in 1996 and 2004 was 36 (11, 96) and 50 (26, 134) study subjects, respectively (p = 0.157). Sample size justifications were provided by 19% of studies in 1996 and 47% of studies in 2004 (p = 0.001). Of randomized controlled trials 16 (25%) vs 32 (37%) identified a single primary outcome variable (p = 0.110). Effect size estimates for primary or secondary outcome variables were provided by 5% vs 13% (p = 0.090) and the precision of the effect was detailed by 5% vs 10% of randomized controlled trials (p = 0.195). This formal review suggests that statistical analysis in urological randomized controlled trials has improved. However, considerable deficiencies remain. Ongoing education in applied statistics may further improve urological randomized controlled trial reporting.


Comparison of different metrics for analysis and visualization in spectroscopic optical coherence tomography.
Spectroscopic Optical Coherence Tomography (S-OCT) extracts depth resolved spectra that are inherently available from OCT signals. The back scattered spectra contain useful functional information regarding the sample, since the light is altered by wavelength dependent absorption and scattering caused by chromophores and structures of the sample. Two aspects dominate the performance of S-OCT: (1) the spectral analysis processing method used to obtain the spatially-resolved spectroscopic information and (2) the metrics used to visualize and interpret relevant sample features. In this work, we focus on the second aspect, where we will compare established and novel metrics for S-OCT. These concepts include the adaptation of methods known from multispectral imaging and modern signal processing approaches such as pattern recognition. To compare the performance of the metrics in a quantitative manner, we use phantoms with microsphere scatterers of different sizes that are below the system's resolution and therefore cannot be differentiated using intensity based OCT images. We show that the analysis of the spectral features can clearly separate areas with different scattering properties in multi-layer phantoms. Finally, we demonstrate the performance of our approach for contrast enhancement in bovine articular cartilage.


Human small intestinal maltase-glucoamylase cDNA cloning. Homology to sucrase-isomaltase.
It has been hypothesized that human mucosal glucoamylase (EC 3.2.1. 20 and 126.96.36.199) activity serves as an alternate pathway for starch digestion when luminal alpha-amylase activity is reduced because of immaturity or malnutrition and that maltase-glucoamylase plays a unique role in the digestion of malted dietary oligosaccharides used in food manufacturing. As a first step toward the testing of this hypothesis, we have cloned human small intestinal maltase-glucoamylase cDNA to permit study of the individual catalytic and binding sites for maltose and starch enzyme hydrolase activities in subsequent expression experiments. Human maltase-glucoamylase was purified by immunoisolation and partially sequenced. Maltase-glucoamylase cDNA was amplified from human intestinal RNA using degenerate and gene-specific primers with the reverse transcription-polymerase chain reaction. The 6,513-base pair cDNA contains an open reading frame that encodes a 1,857-amino acid protein (molecular mass 209,702 Da). Maltase-glucoamylase has two catalytic sites identical to those of sucrase-isomaltase, but the proteins are only 59% homologous. Both are members of glycosyl hydrolase family 31, which has a variety of substrate specificities. Our findings suggest that divergences in the carbohydrate binding sequences must determine the substrate specificities for the four different enzyme activities that share a conserved catalytic site.


A Laboratory Investigation of the Suspension, Transport, and Settling of Silver Carp Eggs Using Synthetic Surrogates.
Asian carp eggs are semi-buoyant and must remain suspended in the water to survive, supported by the turbulence of the flow, until they hatch and develop the ability to swim. Analysis of the transport and dispersal patterns of Asian carp eggs will facilitate the development and implementation of control strategies to target the early life stages. Experimenting with Asian carp eggs is complicated due to practical issues of obtaining eggs in close proximity to experimental facilities and extensive handling of eggs tends to damage them. Herein, we describe laboratory experiments using styrene beads (4.85 mm diameter) as synthetic surrogate eggs to mimic the physical properties of water-hardened silver carp eggs. The first set of experiments was completed in a rectangular vertical column filled with salt water. The salinity of the water was adjusted in an iterative fashion to obtain a close approximation of the fall velocity of the styrene beads to the mean fall velocity of silver carp water-hardened eggs. The terminal fall velocity of synthetic eggs was measured using an image processing method. The second set of experiments was performed in a temperature-controlled recirculatory flume with a sediment bed. The flume was filled with salt water, and synthetic eggs were allowed to drift under different flow conditions. Drifting behavior, suspension conditions, and settling characteristics of synthetic eggs were observed. At high velocities, eggs were suspended and distributed through the water column. Eggs that touched the sediment bed were re-entrained by the flow. Eggs saltated when they touched the bed, especially at moderate velocities and with a relatively flat bed. At lower velocities, some settling of the eggs was observed. With lower velocities and a flat bed, eggs were trapped near the walls of the flume. When bedforms were present, eggs were trapped in the lee of the bedforms in addition to being trapped near the flume walls. Results of this research study provide insights about transport, suspension, and dispersion of silver carp eggs. The knowledge gained from this study is useful to characterize the critical hydrodynamic conditions of the flow at which surrogates for silver carp water-hardened eggs settle out of suspension, and provides insight into how eggs may interact with riverbed sediments and morphology.


Activation of an alfalfa cyclin-dependent kinase inhibitor by calmodulin-like domain protein kinase.
Kip-related proteins (KRPs) play a central role in the regulation of the cell cycle and differentiation through modulation of cyclin-dependent kinase (CDK) functions. We have identified a CDK inhibitor gene from Medicago truncatula (Mt) by a yeast two-hybrid screen. The KRPMt gene was expressed in all plant organs and cultured cells, and its transcripts accumulated after abscisic acid and NaCl treatment. The KRPMt protein exhibits seven conserved sequence domains and a PEST motif that is also detected in various Arabidopsis KRPs. In the yeast two-hybrid test, the KRPMt protein interacted with CDK (Medsa;CDKA;1) and D-type cyclins. However, in the pull-down assays, B-type CDK complexes were also detectable. Recombinant KRPMt differentially inhibited various alfalfa CDK complexes in phosphorylation assays. The immunoprecipitated Medsa;CDKA;1/A;2 complex was strongly inhibited, whereas the mitotic Medsa;CDKB2;1 complex was the most sensitive to inhibition. Function of Medsa;CDKB1;1 complex was not inhibited by the KRPMt protein. The mitotic Medsa;CYCB2 and Medsa;CYCA2;1 complexes responded weakly to this inhibitor protein. Kinase complexes from G2/M cells showed increased sensitivity towards the inhibitor compared with those isolated from G1/S-phase cells. In vitro phosphorylation of Medicago retinoblastoma-related protein was also reduced in the presence of KRPMt. Phosphorylation of this inhibitor protein by the recombinant calmodulin-like domain protein kinase (MsCPK3) resulted in enhanced inhibition of CDK function. The data presented emphasize the selective sensitivity of various cyclin-dependent kinase complexes to this inhibitor protein, and suggest a role for CDK inhibitors and CPKs in cross-talk between Ca2+ signalling and regulation of cell-cycle progression in plants.


Kinematic and postural characteristics of sprint running on sloping surfaces.
The aim of this study was to identify the kinematic and postural characteristics associated with sprint running on uphill and downhill slopes of 3 degrees and on a horizontal surface. Eight male physical education students were filmed while sprinting maximally on an uphill-downhill platform under each of three conditions: (a) uphill at 3 degrees, (b) downhill at 3 degrees and (c) horizontal. Running speed, step rate, step length, step time, contact time, flight time and selected postural characteristics of the step cycle were analysed. Running speed was 9.2% faster (P < 0.05) during downhill and 3.0% slower (P < 0.05) during uphill compared with horizontal sprint running. During downhill and uphill sprint running, step length was the main contributor to the observed changes in running speed. It increased by 7.1% (P < 0.05) for downhill sprint running and was associated with significant changes in posture at touchdown and take-off. During uphill sprint running, step length decreased by 5.2% (P < 0.05), which was associated with significant changes in posture and reduced flight distance. Given the interaction between the acute changes in step length and posture when sprinting on a sloping surface, our findings suggest that such changes in posture may detract from the specificity of training on such surfaces. The chronic effects of training on such slopes on the kinematics and posture of horizontal sprint running are currently unclear.


Association of microfilament bundles with lysosomes in polymorphonuclear leukocytes.
The juxtaposition of microfilament bundles and lysosomes seen both in thin-sectioned cells in the transmission electron microscope and in cryofractured cells in the scanning electron microscope, and the presence of short filamentous structures between lysosomes and microfilament bundles, suggest that microfilaments may be attached to lysosomal membranes and that these filaments may be involved in lysosomal movements. Further work is in progress to test these hypotheses.


[Review of defects of anaesthesia and intensive care (based on fee of forensic medical examinations)].
The article deals with extremely topical problem of the patient safety in anaesthesiology and intensive care. The medical aid complications and defects issue in anaesthesiologist practice is not only specifically medical, but also social significant. The analysis of frequency and nature of defects in anaesthesiology and intensive care was conducted. It was based on 280 forensic medical examinations with anaesthesiologist as an expert. The acquired data showed that treatment defects were found in 63.7% of cases. Special attention was paid to airway management defects. Results helped to determine at which stage and procedure the critical incidents had occurred, as well as their frequency and causes. Considering the discovered causes of defects in anaesthesiology and intensive care, measures aimed at preventing complications and increasing the anaesthesiology and intensive care quality were proposed.


Stability of drugs in stored postmortem femoral blood and vitreous humor.
The stability of 46 drugs in postmortem femoral blood stored for one year at -20 degrees C was investigated. The drugs included benzodiazepines, antidepressants, analgetics and hypnotics. For seven drugs we found a significant change in the concentration between the first and second analysis. Five substances; ethanol, desmethylmianserin, 7-amino-nitrazepam, THC and zopiclone showed a decrease in the concentration whereas the concentrations of two substances; ketobemidone and thioridazine increased. However, the changes observed were not of such an order that it would affect the interpretation in normal forensic casework. We also investigated the possible influence of potassium fluoride on the concentrations of the 46 drugs in vitreous humor after storage for one year. For two substances, ethanol and zopiclone, there were significantly lower concentrations in the samples without potassium fluoride. Furthermore, we also studied the correlation between the concentrations in femoral blood and vitreous humor. For 23 substances there was a significant difference between the concentrations in the vitreous humor and femoral blood. Significant correlations between the concentrations in these two specimens were found for 23 substances, indicating that vitreous humor can be an alternative specimen when blood samples are not available, provided that such correlation exists for the particular substance. Statistical analysis also revealed a correlation between the degree of protein binding of the different drugs and percentage of vitreous/femoral blood concentrations.


Transcriptional regulation of corticotropin-releasing hormone-binding protein gene expression in astrocyte cultures.
The molecular mechanisms involved in regulation of CRH-binding protein (CRH-BP) gene expression were examined using primary rat astrocyte cultures. The cells were treated with various regulators, and CRH-BP messenger RNA (mRNA) levels were determined using ribonuclease protection assays. Forskolin (Fsk, 10 microM) or 12-O-tetradecanoyl-phorbol 13-acetate (TPA, 100 nM) increases CRH-BP mRNA levels up to 30 times control level, and together they act synergistically to increase CRH-BP gene expression up to 100 times control levels. CRH can also positively regulate CRH-BP gene expression to 6.1 times control levels. All of these increases in steady-state CRH-BP mRNA levels can be repressed by dexamethasone, a synthetic glucocorticoid. To determine whether these changes in steady-state CRH-BP mRNA levels are caused by altered transcription or RNA stability, heteronuclear (hn) CRH-BP species were examined using ribonuclease protection assays. CRH-BP hnRNA transcripts can be detected transiently after the addition of Fsk or TPA, and dexamethasone can repress Fsk- or TPA-induced CRH-BP hnRNA levels in this assay. These results demonstrate that CRH, glucocorticoids, and the protein kinase A and protein kinase C signaling pathways are involved in regulation of CRH-BP gene expression in astrocyte cultures, and that this regulation is caused, at least in part, by altered transcription of the gene.


Hepatocellular Carcinoma Subtyping and Prognostic Model Construction Based on Chemokine-Related Genes.
Chemokines not only regulate immune cells but also play significant roles in development and treatment of tumors and patient prognoses. However, these effects have not been fully explained in hepatocellular carcinoma (HCC). We conducted a clustering analysis of chemokine-related genes. We then examined the differences in survival rates and analyzed immune levels using single sample gene set enrichment analysis (ssGSEA) for each subtype. Based on chemokine-related genes of different subtypes, we built a prognostic model in The Cancer Genome Atlas (TCGA) dataset using the survival package and glmnet package and validated it in the Gene Expression Omnibus (GEO) dataset. We used univariate and multivariate regression analyses to select independent prognostic factors and used R package rms to draw a nomogram reflecting patient survival rates at 1, 3, and 5 years. We identified two chemokine subtypes, and after screening, found that Cluster1 had higher survival rates than Cluster2. In addition, in terms of immune evaluation, stromal evaluation, ESTIMATE evaluation, immune abundance, immune function, and expressions of various immune checkpoints, immune levels of Cluster1 were significantly better than those of Cluster2. The immunophenoscore (IPS) of HCC patients in Cluster1 was significantly higher than that in Cluster2. Furthermore, we established a prognostic model consisting of 9 genes, which correlated with chemokines. Through testing, RiskScore was revealed as an independent prognostic factor, and the model could effectively predict HCC patients' prognoses in both TCGA and GEO datasets. This study resulted in the development of a novel prognostic model related to chemokine genes, providing new targets and theoretical support for HCC patients.


Male dimorphism in three sympatric species of Onthophagus (Coleoptera: Scarabaeidae).
Onthophagus trituber, O. taurinus, and O. proletarius, three sympatric dung beetle species native to southern Taiwan, exhibit normally distributed body size (pronotum width) but non-normally distributed horn length due to the presence of horned and hornless morphs. The scaling relationships between horn length and body size were established by using sigmoidal and segmented linear estimation, and the horned/hornless ratio in each of the species was estimated. The ratios estimated by sigmoidal curves showed that all three species were biased toward the hornless morph, whereas the ratios from segmented lines showed that only one species (O. taurinus) was biased toward the hornless morph. Nevertheless, the results of the two methods of estimation were concordant in ranking the horned morph proportions among the three species; O. proletarius had the largest proportion of horned morphs, whereas O. taurinus had the smallest, suggesting that the fewer horned morph in O. taurinus likely resulted from both intra- and inter-specific competition.


Identification of anti-flaviviral drugs with mosquitocidal and anti-Zika virus activity in Aedes aegypti.
Zika virus (ZIKV), an emerging arbovirus belonging to the genus Flavivirus, is transmitted by Aedes mosquitoes. ZIKV infection can cause microcephaly of newborn babies and Guillain-Barré syndrome in adults. Because no licensed vaccine or specific antiviral treatment is available for ZIKV infection, the most commonly used approach to control the spread of ZIKV is suppression of the mosquito vector population. A novel proposed strategy to block arthropod virus (arbovirus) transmission is based on the chemical inhibition of virus infection in mosquitoes. However, only a few drugs and compounds have been tested with such properties. Here we present a comprehensive screen of 55 FDA-approved anti-flaviviral drugs for potential anti-ZIKV and mosquitocidal activity. Four drugs (auranofin, actinomycin D (Act-D), bortezomib and gemcitabine) were toxic to C6/36 cells, and two drugs (5-fluorouracil and mycophenolic acid (MPA)) significantly reduced ZIKV production in C6/36 cells at 2 μM and 0.5 μM, respectively. Three drugs (Act-D, cyclosporin A, ivermectin) exhibited a strong adulticidal activity, and six drugs (U18666A, retinoic acid p-hydroxyanilide (4-HPR), clotrimazole, bortezomib, MPA, imatinib mesylate) significantly suppressed ZIKV infection in mosquito midguts. Some of these FDA-approved drugs may have potential for use for the development of ZIKV transmission-blocking strategies.


[Megadosage of 6-methylprednisolone in systemic vasculitis with renal involvement. A prospective study].
A prospective, open and uncontrolled study of effectiveness and side effects of intravenous 6-methylprednisolone megadoses was carried out in 20 patients with systemic vasculitis with rapidly progressive renal failure. The results showed a favorable response of renal function in 80% of patients and a control of pulmonary hemorrhage in the patients in which it was present. Oliguria and the need for hemodialysis during the acute phase of the disease significantly reduced the response to treatment. Extracapillary proliferation in more than 80% of glomeruli resulted in a lesser degree of recovery of renal function. Severe side effects developed in 2 patients (10%), but they could be exclusively attributed to the 6-methylprednisolone megadose in 1 (5%). It was concluded that 6-methylprednisolone megadoses may be an effective therapeutic alternative for the treatment of these patients.


Correlation between hemolytic profile and phylotype of Cutibacterium acnes (formerly Propionibacterium acnes) and orthopedic implant infection.
Cutibacterium acnes is a recognized culprit for implant-associated infections, but positive cultures do not always indicate clinically relevant infection. Studies have shown a correlation between the β-hemolytic phenotype of C. acnes and its infectious capacity, but correlation with genetic phylotype has not been performed in literature. The purpose of this study is to evaluate β-hemolysis phenotype, genetic phylotype, and mid-term clinical outcomes of C. acnes isolated from orthopedic surgical sites. Fifty-four C. acnes isolates previously obtained from surgical wounds of patients undergoing hip, knee, shoulder, or spine implant removal were re-cultured. There were 21 females and 33 males with an average age of 59 years (range, 18-84). Twenty-four were from clinically infected sites whereas 30 were considered contaminants. De novo β-hemolysis was analyzed and a retrospective chart review was performed to evaluate clinical outcomes at 7.1 years (range, 0.1-12.8). On Brucella agar with 5% rabbit blood, 46% of contaminant and 43% of infectious isolates were hemolytic. Type II phylotype was significantly more nonhemolytic regardless of infectious or contaminant status (p < 0.05). Type 1B correlated with a hemolytic-infectious phenotype and Type 1A with a hemolytic-contaminant phenotype but was not statistically significant. The β-hemolytic profile of C. acnes did not correlate with phylotype or clinically relevant orthopedic infection.


An Indian hospital study of viral causes of acute respiratory infection in children.
From Sept. 1986 to Jan. 1989, a hospital-based study was conducted on 736 children, under 5 years of age, with acute respiratory infection. Nasopharyngeal secretions were examined for viruses by culture and by immunofluorescence. Viruses were detected in 22% of specimens: respiratory syncytial (5%), parainfluenza (5%), influenza A (4%), influenza B (2%), adenovirus (3%), measles (3%). The highest rates of detection were with patients diagnosed clinically as pneumonia or upper respiratory tract infection. The case fatality rate was very high (43%) in children with measles virus infection.


Exosomal Circ-XIAP Promotes Docetaxel Resistance in Prostate Cancer by Regulating miR-1182/TPD52 Axis.
Exosomal circular RNAs (circRNAs) are involved in the pathogenesis of prostate cancer (PCa) and chemotherapy resistance. This research aimed to explore the function and molecular mechanism of circRNA X-linked inhibitor of apoptosis (circ-XIAP) in docetaxel (DTX) resistance of PCa. The expression of circ-XIAP, microRNA-1182 (miR-1182), tumor protein D52 (TPD52) was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Exosomes were detected with transmission electron microscopy (TEM). Cluster of differentiation 63 (CD63), cluster of differentiation 9 (CD9) and TPD52 protein levels were detected by Western blot (WB). FIfty percent inhibitory concentration (IC50) of DTX and cell viability were determined using Cell Counting Kit-8 (CCK-8) assay. Colony formation assay was applied to assess colony-forming ability. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Transwell assay was used for measuring cell migration and invasion. Dual-reporter luciferase assay was performed to confirm the interaction between miR-1182 and circ-XIAP or TPD52. The role of circ-XIAP in vivo was confirmed via the mice xenograft model. Circ-XIAP and TPD52 were upregulated and miR-1182 was downregulated in DTX-resistant PCa tissue specimens and cell lines. Circ-XIAP was also overexpressed in exosomes from DTX-resistant cells and could be transmitted via exosomes. Circ-XIAP knockdown enhanced DTX sensitivity by suppressing DTX-resistant cell proliferation, migration and invasion and inducing cell cycle arrest and apoptosis. Circ-XIAP directly targeted miR-1182, and the effects of circ-XIAP knockdown were reversed by downregulating miR-1182 in DTX-resistant cells. TPD52 was the target of miR-1182, and its upregulation weakened the promotive effect of miR-1182 on DTX sensitivity. Importantly, circ-XIAP depletion inhibited tumor growth and increased DTX sensitivity in vivo. Exosomal circ-XIAP promoted DTX resistance of PCa by regulating miR-1182/TPD52 axis, providing a promising therapeutic target for PCa chemotherapy.


Using EHR audit trail logs to analyze clinical workflow: A case study from community-based ambulatory clinics.
To develop a workflow-supported clinical documentation system, it is a critical first step to understand clinical workflow. While Time and Motion studies has been regarded as the gold standard of workflow analysis, this method can be resource consuming and its data may be biased due to the cognitive limitation of human observers. In this study, we aimed to evaluate the feasibility and validity of using EHR audit trail logs to analyze clinical workflow. Specifically, we compared three known workflow changes from our previous study with the corresponding EHR audit trail logs of the study participants. The results showed that EHR audit trail logs can be a valid source for clinical workflow analysis, and can provide an objective view of clinicians' behaviors, multi-dimensional comparisons, and a highly extensible analysis framework.


Damage to the corneal endothelium by Q-switched Nd:YAG laser posterior capsulotomy.
Clinical specular microscopy of the corneal endothelium of eyes immediately before and after Nd:YAG laser posterior capsulotomy revealed apparent endothelial damage. Comparative specular and scanning electron microscopical studies in rabbits showed extensive cell destruction, and clinical observations indicated 'healing' of the lesions by extensions from neighbouring cells. Possible causes of the damage are discussed.


Caregivers' voices: The experiences of caregivers of children who sustained serious accidental and non-accidental head injury in early childhood.
Head injury is a leading cause of mortality and acquired neurological impairment in children. Head-injured children may have neurobehavioural deficits that persist for years following injury. Head injury can result in significant and persistent caregiver burden, including mental health issues, family stress and disorganisation, and unmet social and healthcare service needs. Few studies have examined the healthcare and social service needs of children and their families following head injury sustained at an early age. This qualitative study aims to describe the experiences of caregivers of children who sustained a serious head injury (particularly non-accidental head injury) before the age of 2 years. Caregivers were interviewed up to 15 years following the initial injury. Semi-structured interviews with 21 caregivers of 15 children (aged 3-15 years at the time of interview) were completed. Thematic analysis of interview data generated three key themes: impact, support and information. The study's findings reveal the broad impact of serious childhood head injury on caregivers, specifically the significant distress and burden brought about through lack of information, challenges in accessing support and inconsistent care. Recommendations for developing a quality 'model of care' and improving ease of access to supports for caregivers are provided.


A regurgitant jet and echocardiographic abnormalities in aortic regurgitation: an experimental study.
Acute aortic regurgitation was created experimentally in 21 mongrel dogs to examine the relationship of the regurgitant jet to observed echocardiographic findings. The direction of the regurgitant jet was studied by echo contrast injections in the aortic root. Diastolic fluttering of the anterior mitral leaflet (AML) was noted in all 21 dogs irrespective of direction of the jet. Diastolic fluttering of the interventricular septum (IVS) was noted in six of the seven dogs with a tear of the noncoronary cusp and in one of seven dogs with lesions in the left coronary cusp. In all seven dogs with echocardiographically demonstrated IVS fluttering, a regurgitant jet impinged on the anterior part of the IVS. Amplitude of the AML excursion was not significantly different from control when the lesions involved the noncoronary or the left coronary cusps. However, all seven dogs that had a lesion in the right coronary cusp demonstrated a significant reduction in the amplitude of the AML excursion. The regurgitant jet in these dogs impinged uniformly on the AML. We conclude that diastolic fluttering of the AML is uniformly observed and unrelated to the direction of the regurgitant jet, diastolic fluttering of the IVS is caused by the regurgitant jet impinging upon the IVS, and amplitude of the AML may be reduced as a result of a jet impingement of the AML.


[The current objective criteria for the adequacy of general anesthesia in children].
Auditory evoked potentials (AEP) were recorded and analyzed in 12 children during general halothane and ketamine anesthesia. Ketamine suppressed the amplitude of primary negative component and eliminated secondary AEP components with latencies more than 60 ms, including N-200 and P-300 waves. By contrast, halothane did not affect primary components with less than 95 ms latencies and suppressed the latest components. Hence, ketamine suppresses the nonspecific afferent pathways and the brain structures responsible for memory and emotional functions, while halothane does not affect the afferent pulsation and partially suppresses emotional and mnemonic functions.


Stimulation of cardiac cardiolipin biosynthesis by PPARalpha activation.
The role of peroxisome proliferator-activated receptor alpha (PPARalpha)-stimulated phospholipase A2 (PLA2) in cardiac mitochondrial cardiolipin (CL) biosynthesis was examined in both in vivo and in vitro models. Treatment of rat heart H9c2 cells with clofibrate increased the expression and activity of 14 kDa PLA2 but did not affect the pool size of CL. Clofibrate treatment stimulated de novo CL biosynthesis via an increase in phosphatidylglycerolphosphate (PGP) synthase activity, accounting for the unaltered CL content. Cardiac PLA2, PGP synthase, and CDP-1,2-diacyl-sn-glycerol synthase (CDS-2) activities and CDS-2 mRNA levels were elevated in mice fed clofibrate for 14 days compared with controls. In PPARalpha-null mice, clofibrate feeding did not alter cardiac PLA2, PGP synthase activities, or CDS-2 activity and mRNA level, confirming that these enzymes are regulated by PPARalpha activation. In contrast to mouse heart, clofibrate treatment did not affect the activity or mRNA levels of CDS-2 in H9c2 cells, indicating that CDS-2 is regulated differently in rat heart H9c2 cells in vitro and in mouse heart in vivo. These results clearly indicate that cardiac CL de novo biosynthesis is stimulated by PPARalpha activation in responsive rodent models and that CDS-2 is an example of an enzyme that exhibits alternative regulation in vivo and in cultured cell lines. This study is the first to demonstrate that CL de novo biosynthesis is regulated by PPARalpha activation.


[Recovery of consciousness: process-oriented approach].
Traditionally psychological neurorehabilitation of neurosurgical patients is provided subject to availability of clear consciousness and minimal potential to communicate verbally. Cognitive and emotional disorders, problems in social adaptation, neurotic syndromes are normally targets in such cases. We work with patients having survived severe brain damage being in different states of consciousness: vegetative state, minimal state of consciousness, mutism, confusion, posttraumatic Korsaroff syndrom. Psychologist considers recovery of consciousness as the target besides traditional tasks. Construction of communication with patient is central part of such job, where the patient remains unable to contact verbally, yet it is impossible to consider potential aphasia. This is a non-verbal "dialogue" with patient created by psychologist with gradual development and involving other people and objects of environment. Inline with modern neuroscientific achievements demonstrating ability to recognize by patients with severe brain injury (A. Owen, S. Laureys, M. Monti, M. Coleman, A. Soddu, M. Boly and others) we base upon psychological science, on psychotherapeutic approaches containing instruments inevitable to work with patients in altered states of consciousness and creation of non-verbal communication with patient (Jung, Reich, Alexander, Lowen, Keleman, Arnold and Amy Mindell, S. Tomandl, D. Boadella, A. Längle, P. Levin etc). This article will include 15 years of experience to apply Process-oriented approach by A. Mindell to recovery of consciousness of neurosurgical patients based on work with "minimal signals" (micro moves, breath, mimic reactions etc.), principle of feedback, psychosomatic resonance, empathy.


Reproducibility of blood pressure responses to dietary sodium and potassium interventions: the GenSalt study.
Blood pressure responses to dietary sodium and potassium interventions vary among individuals. We studied the long-term reproducibility of blood pressure responses to dietary sodium and potassium intake. We repeated the dietary sodium and potassium interventions among 487 Chinese adults 4.5 years after the original dietary intervention. The identical dietary intervention protocol, which included a 7-day low-sodium feeding (51.3 mmol/d), a 7-day high-sodium feeding (307.8 mmol/d), and a 7-day high-sodium feeding with oral potassium supplementation (60.0 mmol/d), was applied in both the initial and repeated studies. Three blood pressure measurements were obtained during each of the 3 days of baseline observation and on days 5, 6, and 7 of each intervention period. The results from the 24-hour urinary excretion of sodium and potassium showed excellent compliance with the study diet. Blood pressure responses to dietary intervention in the original and repeated studies were highly correlated. For example, the correlation coefficients (95% confidence interval) for systolic blood pressure levels were 0.77 (0.73-0.80) at baseline, 0.79 (0.75-0.82) during low sodium, 0.80 (0.77-0.83) during high sodium, and 0.82 (0.79-0.85) during high sodium and potassium supplementation interventions (all P<0.0001). The correlation coefficients for systolic blood pressure changes were 0.37 (0.29-0.44) from baseline to low sodium, 0.37 (0.29-0.44) from low to high sodium, and 0.28 (0.20-0.36) from high sodium to high sodium plus potassium supplementation (all P<0.0001). These data indicate that blood pressure responses to dietary sodium and potassium interventions have long-term reproducibility and stable characteristics in the general population.


Tissue culture protocols for gene transfer and editing in maize (Zea mays L.).
Efficient methods for gene transfer to maize were developed in the 1990s, first mediated by particle bombardment and then by Agrobacterium tumefaciens. Both methods can efficiently create high-quality events. Genetically modified varieties were commercialized in 1996 and are now planted in more than 90% of the US corn field. Tissue culture protocols for both methods have been well developed and widely employed. Thus, various factors, including handling before gene delivery, techniques to protect cells during gene delivery, and culture media, have been well optimized for various genotypes. Typical protocols for both methods are herein presented to show major outputs from the studies conducted since the early 1990s. As the bombardment protocols tended to be optimized specifically for limited genotypes, the one for B104, a new public inbred with favorable agronomic characteristics, is shown. The Agrobacterium protocol is suitable for various inbred lines, including B104. These protocols are also useful starting points in the optimization of tissue culture for gene editing. The rate-limiting step in both transformation and gene editing is in tissue culture and plant regeneration from modified cells in elite germplasm. Despite the prolonged efforts, large varietal differences in tissue culture responses remain a serious issue in maize. Recently, protocols using morphogenic regulator genes, such as Bbm and Wus2, have been developed that show a strong potential of efficiently transforming recalcitrant varieties.


The Efficacy of Acupuncture Treatment for Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis.
This study aimed to assess the efficacy of acupuncture for treating attention deficit hyperactivity disorder (ADHD) in children and adolescents. Systematic review and meta-analysis including randomized controlled trials that compared the effects of acupuncture treatment (AT) with pharmacotherapy (methylphenidate hydrochloride, MPH) among patients with ADHD. A total of 12 electronic databases were searched from inception until February 3, 2020. The main outcomes were the effective rate and post-treatment hyperactivity scores. We also assessed the incidence of adverse events and follow-up course. A total of 10 studies involving 876 patients were included in this study. The meta-analysis revealed that AT yielded a significantly higher effective rate than MPH (odds ratio 2.239, 95% CI 1.438-3.487, p < 0.001, 8 studies), and that AT can reduce the hyperactivity scores to a lesser degree than MPH (standardized mean difference = -0.882, 95% CI -1.295 to -0.469, p < 0.001, 3 studies). Two studies reported no adverse events in the AT group, while one study suggested that AT can reduce adverse drug reactions. Furthermore, 3 studies concluded that the effects of AT were maintained, even after completion of treatment. This study suggests that AT may be more beneficial than MPH therapy for ADHD patients. However, the evidence may be highly limited, especially considering the outcome of hyperactivity scores with the high risk of bias, very low GRADE, and small number of studies. Thus, further studies of rigorous design and high quality are needed to confirm and strengthen the results, especially in the Western part of the world. Additionally, well-designed randomized controlled trials that evaluate adverse events and include a long-term follow-up should be conducted to determine the efficacy, safety, and side effects of AT for ADHD in children and adolescents.


Multiple health risk behaviors and mental health from a life course perspective: The Dutch TRAILS study.
We examined trajectories of multiple health risk behavior (MHRB) patterns throughout adolescence, and changes in mental health from childhood to young adulthood. Further, we assessed how continuity or onset of MHRBs overall were associated with subsequent changes in mental health, and whether this varied by type of MHRBs. We used six waves of the prospective Dutch TRAILS study (2001-2016; n = 2229), covering ages 11 until 23. We measured MHRBs (substance use: alcohol misuse, cannabis use, smoking; and obesity-related: overweight, physical inactivity, irregular breakfast intake) at three time points during adolescence. We assessed mental health as Youth/Adult Self-report total problems at ages 11 and 23. Latent class growth analyses and ANOVA were used to examine longitudinal trajectories and associations. We identified six developmental trajectories for the total of MHRBs and mental health. Trajectories varied regarding likelihood of MHRBs throughout adolescence, mental health at baseline, and changes in mental health problems in young adulthood. We found no associations for the continuity of overall MHRBs throughout adolescence, and neither for early, mid- or late onset, with changes in mental health problems in young adulthood. However, continuity of MHRBs in the obesity-related subgroup was significantly associated with an increase in mental health problems. Adolescents with the same MHRB patterns may, when reaching adulthood, have different levels of mental health problems, with mental health at age 11 being an important predictor. Further, involvement with obesity-related MHRBs continuously throughout adolescence is associated with increased mental health problems in young adulthood.


DNMT1 and DNMT3b silencing sensitizes human hepatoma cells to TRAIL-mediated apoptosis via up-regulation of TRAIL-R2/DR5 and caspase-8.
DNA methylation plays a critical role in chromatin remodeling and gene expression. DNA methyltransferases (DNMTs) are hypothesized to mediate cellular DNA methylation status and gene expression during mammalian development and in malignant diseases. In this study, we examined the role of DNA methyltransferase 1 (DNMT1) and DNMT3b in cell proliferation and survival of hepatocellular carcinoma (HCC) cells. Gene silencing of both DNMT1 and DNMT3b by targeted siRNA knockdown reduces cell proliferation and sensitizes the cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cell death. The proapoptotic protein caspase-8 demonstrated promoter hypermethylation in HCC cells and was up-regulated by knockdown of DNMT1 and DNMT3b both at mRNA and protein levels. In addition, death receptor TRAIL-R2/DR5 (TRAIL receptor 2/death receptor 5) did not exhibit promoter hypermethylation in HCC cells but was also up-regulated by knockdown of DNMT1 and DNMT3b both at mRNA and protein levels. Consistent with this observation, the combined transfection of DNMT1-siRNA plus DNMT3b-siRNA enhanced formation of the TRAIL-death-inducing signaling complex formation in HCC cells. In conclusion, our data suggest that DNA methylation of specific genomic regions maintained by DNMT1 and DNMT3b plays a critical role in survival of HCC cells, and a simultaneous knockdown of both DNMT1 and DNMT3b may be a novel anticancer strategy for the treatment of HCC.


[The problem of determining the affinity of bivalent antibodies using ELISA and its mathematical solution].
A new approach for the determination of the affinity of monovalent receptors in direct coordinates could be obtained without using Klotz or Scatchard equations. The mathematical solution of the problem of the determination of the affinity of bivalent antibodies by ELISA gives the following relation between absorbance, measured in ELISA. and antigen concentration: omega + square root of omega 2 + omega = liK, where omega = (Ao-Ai)/Ai, Ai is the absorbance, if Ag concentration is equal li; Ao is the absorbance, if Ag concentration is equal zero, K is an equilibrium constant.


Effect of losartan on microalbuminuria in normotensive patients with type 2 diabetes mellitus. A randomized clinical trial.
Angiotensin-converting enzyme inhibitors have shown antiproteinuric effects in normotensive and hypertensive diabetic patients. Angiotensin-receptor antagonists reduce urinary albumin excretion and the risk for renal and cardiovascular complications in hypertensive patients with type 2 diabetes mellitus. The effect of angiotensin-receptor antagonists in normotensive diabetic patients with microalbuminuria has not yet been reported. To assess the antiproteinuric effects of losartan in normotensive patients with type 2 diabetes and microalbuminuria. Multicenter randomized, double-blind, placebo-controlled clinical trial. 19 outpatient clinics in the Netherlands. 147 normotensive patients with type 2 diabetes mellitus and microalbuminuria. 74 patients were randomly assigned to receive losartan and 73 patients were assigned to receive placebo for 10 weeks; 71 patients in each group completed the study. The losartan dose was 50 mg during the first 5 weeks and 100 mg during the subsequent 5 weeks. Change in urinary albumin excretion rate after 5 and 10 weeks, change in creatinine clearance and blood pressure, and safety and tolerability of losartan. A significant 25% relative reduction in the albumin excretion rate occurred after 5 weeks of the 50-mg losartan dose, with further improvement over the subsequent 5 weeks with the 100-mg dose (relative reduction, 34%). In the losartan group, creatinine clearance did not improve and blood pressure decreased slightly. Side effects did not differ between treatment groups. The angiotensin-receptor antagonist losartan reduces urinary albumin excretion in normotensive patients with type 2 diabetes and microalbuminuria. In multivariate analysis, the antiproteinuric effect of losartan was independent of the associated reduction in blood pressure. Losartan was safe and well tolerated in these normotensive patients.


The microbiome and obesity-an established risk for certain types of cancer.
Obesity is a major modifiable risk factor for the development of numerous types of cancer. Although many factors contribute to obesity-driven tumorigenesis, this review focuses on the functioning of the gut microbiota (the microbiome) as an environmental risk factor for certain types of cancers, and presents possible biological mediators. Obesity is a well-studied condition that is associated with microbiotal dysbiosis, which could result in several physiologic changes that may contribute to the relationship between obesity and cancer risk. These include altered microbial metabolism, which contributes to the generation of procarcinogenic toxic metabolites; increased extraction of energy and nutrient availability leading to metabolic dysregulation that contributes to tumor growth; and/or the induction of subclinical inflammation initiating tumorigenesis. Thus, the gut microbiota may serve as a key link between obesity and cancer and, therefore, viable strategies to alter the microbiota may provide novel therapeutics to reduce obesity-associated cancer risk.


Herpes simplex virus type 2 inhibition of Fas ligand expression.
Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are common human pathogens. In this report we demonstrate the capacity of HSV-2, but not HSV-1, to inhibit the activity and cell surface expression of Fas ligand, an important molecule involved in T-cell apoptosis and cell-mediated cytotoxicity. Cells infected with HSV-2 retained Fas ligand intracellularly instead of expressing it on the cell surface. Addition of anti-Fas antibodies markedly inhibited HSV-2 viral production, suggesting that the capacity of the virus to regulate Fas ligand expression, and thereby programmed cell death, may represent a powerful mechanism for the virus to enhance viral replication.


Fluorimetric determination of oenanthotoxin.
Oenanthotoxin as crude yellow crystals was obtained, after the extraction and treatment from Oenanthe crocata L. fresh roots. The fluorescence response of oenanthotoxin solutions undergo changes, depending on the solvent used. Chloroformic solutions of oenanthotoxin showed a maximum fluorescent emission at 425 nm when the exciting wavelength was at 370 nm; in methanol it was displaced (lambda ex 375 nm, lambda em 435 nm), and in benzene showed a lambda em at 450 nm when the lambda ex was 395 nm. There was a linear relationship shown between the oenantotoxin concentration and fluorimetric response while within suitable experimental limits, the minimum concentration detected was 9.02 micrograms/ml. Using these properties, a fluorimetric method has been developed for the identifications and evaluation of oenanthotoxin.


Do Treatment Differences between Arms Affect the Main Outcome of ERSPC Rotterdam?
We assessed differences in treatment between the screening and control arms of ERSPC Rotterdam and studied whether possible treatment differences could explain the positive study outcome. In ERSPC Rotterdam men 55 to 74 years old were randomized to a screening arm of 21,210 and a control arm of 21,166. Treatment after diagnosis was at the discretion of the care provider chosen by the patient. Initial treatment was compared in 4 risk groups. The relation between prostate cancer incidence and prostate cancer mortality was assessed by risk group by correlating the incidence RR and the mortality RR. A direct relation would have supported a stage shift as the main cause of changes in prostate cancer mortality. Initial treatment differed between the arms in the low, intermediate and high risk groups but not in the metastatic group. The RRs of prostate cancer incidence and mortality per risk group were related 1:1 (regression line slope 1.00, 95% CI 0.30-1.74). Of changes in prostate cancer mortality 94% could be explained by changes in prostate cancer incidence. This made treatment differences unlikely as the reason for the observed decrease in prostate cancer mortality. Differences in treatment between the ERSPC Rotterdam screening and control arms were unlikely to explain the differences in prostate cancer mortality. Results are instead consistent with a decrease in prostate cancer mortality as the result of a favorable stage through screening.


[Agreement between guidelines for pharmaco-economic research and never-before-published health-economics evaluations].
To investigate whether the health-economics research published in Dutch journals is in agreement with the guidelines for pharmaco-economic research as published in 1999 by the Dutch 'College voor zorgverzekeringen' [Healthcare Insurance Board]. Descriptive. A literature search was performed for health-economic evaluations published during 1990-1999 in Dutch journals such as Nederlands Tijdschrift voor Geneeskunde (NTvG), Pharmaceutisch Weekblad and Tijdschrift voor Gezondheidswetenschappen. The resulting 19 studies, primarily published in the NTvG, were compared with the pharmaco-economic guidelines, summarised in 9 criteria. The social perspective was taken in 5 studies (26%), non-related medical costs were excluded in 19 (100%), relevant subgroup analyses were performed in 16 (84%), effectiveness was explicitly differentiated from efficacy in 15 (79%), incremental analysis was performed in 18 (95%), an adequate period of analysis was chosen in 16 (84%), costs, benefits and health gains were discounted in 13 (68%), sensitivity analysis was included in the investigation in 10 (53%), and estimated cost prices were used in 9 (47%). The methodology in recently published Dutch health-economics research was partly in agreement with the later official guidelines for pharmaco-economic studies in the Netherlands.


Effects of formalin, methacarn, and fineFIX fixatives on RNA preservation.
Formalin-fixed tissues represent the most abundant clinical material for retrospective studies. However, formalin highly affects macromolecules, impairing their extraction and analysis. In this study, the suitability of some potential substitutes of formalin for RNA-based applications has been considered. Conventional formalin was compared with methacarn and the commercial FineFIX. Their impact on overall RNA preservation was investigated in a cell line-based model fixed during a time course treatment and in a series of fixed human tissues. RNA yield was detected by Nanodrop; ribosomal RNA (rRNA) integrity by electrophoresis and the Agilent Bioanalyzer; messenger RNA (mRNA) integrity by Northern blot and endpoint reverse transcription-polymerase chain reaction; and mRNA amount by real-time polymerase chain reaction. In the cell line model, formalin fixation showed time-dependent detrimental effects on overall RNA preservation. Methacarn and FineFIX were more conservative on both rRNA and mRNA preservation and their impact was time-independent. In tissues, high rRNA degradation levels were found in all fixed specimens, contrasting with the results found in the cells. Conversely, the effects of the fixatives on mRNA integrity reflected the observations shown in the cell line model. In methacarn-fixed samples mRNA amount was also preserved, whereas in formalin and FineFIX-fixed samples it was notably lower when compared with the fresh frozen control. Alcohol-based fixatives are a good solution for long-term fixation of both cytologic and tissue samples by virtue of their time-independent effects on mRNA preservation. In fixed tissue samples, however, the potential effects of preanalytical tissue-related factors should be considered when performing mRNA quantitative analysis.


[Work accidents in Brazil. A study in São Paulo state, Brazil, the Botucatu region, using the causal tree method].
This paper discusses, within the prevailing Brazilian situation, the possibility of applying "causal tree" (CT) method in investigating occupational accidents by safety personnel in the public health services and workers' unions. The method was developed during the seventies in France, for use by plant safety personnel. The authors used this method in Botucatu, state of São Paulo, Brazil, in order to investigate 40 serious occupational accidents that occurred in industrial plants during the second half of 1993, that had been registered by social security. In these cases, the predominance of situations in which the lack of safety measures were identified by inspection indicates that in most instances, the use of CT is unnecessary. However, the authors discuss its use by safety personnel from the public health services and workers' unions to investigate certain accidents to contribute to the knowledge base and help overcome the cultural based guilt which, in Brazil, has turned the victim into the person responsible for the accident.


Sourdough authentication: quantitative PCR to detect the lactic acid bacterial microbiota in breads.
No national legislation anywhere in the world regulates and protects traditional/typical sourdough breads. Sourdough fermentation is firmly associated with a century-old tradition, and with sensory and nutritional quality of breads. A well-defined cell density of lactic acid bacteria has to be reached at the end of fermentation, and be indirectly detectable in baked breads. A Quantitative PCR (qPCR) method was developed to discriminate between breads made with and without sourdoughs. Universal primers targeting an approximately 178-bp fragment of the 16S rRNA-encoding gene of lactic acid bacteria were designed, covering the known diversity of sourdough lactic acid bacteria and excluding commonly encountered flour bacterial contaminants. A total of 191 breads either made with traditional type I and dried sourdough and baker's yeast, or by a chemical leavening method were shown to be accurately discriminated by means of qPCR. Discriminating values of gene copy number were only weakly correlated with pH values, and with lactate and acetate concentration, thus questioning the validity of these latter indirect indices. The use of sourdough has to be guaranteed to meet both bakery and consumer expectations, and to fulfil legal requirements; our work presents a reliable authentication method providing a suitable tool to satisfy such requirements.


Osteoarthritis year in review 2015: soluble biomarkers and the BIPED criteria.
To review and summarize biomarker data published from April 2014 to May 2015 to provide insight to the ongoing work in the field of osteoarthritis (OA). Furthermore, to summarize the BIPED criteria and set it in context of the medical needs of 2015. PubMed was used as searching machine: Time period 2014/04/01-2015/05/01, MeSH term [Biomarker] AND [Osteoarthritis], Language; English, Full text available. Reviews were excluded. Only papers describing protein based biomarkers measured in human body fluids from OA patients were included. Biomarkers of joint tissue turnover, cytokines, chemokines and peptide arrays were measured in different cohorts and studies. Amongst those were previously tested biomarkers such as osteocalcin, Carboxy-terminal cross-linked fragment of type II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP). A majority of the biomarker were classified as I, B or B biomarkers according to the BIPED criteria. Work is continuing on testing biomarkers in OA. There is still a huge, unmet medical need to identify, test, validate and qualify novel and well-known biomarkers. A pre-requisite for this is better characterization and classification of biomarkers to their needs, which may not be reached before higher understanding of OA phenotypes has been gained. In addition, we provide some references to some recent guidelines from Food and Drug Administration (FDA) and European Medicines Agency (EMA) on qualification and usage of biomarkers for drug development and personalized medicine, which may provide value to the field.


Electroplasticization of Liquid Crystal Polymer Networks.
Shape-shifting liquid crystal networks (LCNs) can transform their morphology and properties in response to external stimuli. These active and adaptive polymer materials can have impact in a diversity of fields, including haptic displays, energy harvesting, biomedicine, and soft robotics. Electrically driven transformations in LCN coatings are particularly promising for application in electronic devices, in which electrodes are easily integrated and allow for patterning of the functional response. The morphing of these coatings, which are glassy in the absence of an electric field, relies on a complex interplay between polymer viscoelasticity, liquid crystal order, and electric field properties. Morphological transformations require the material to undergo a glass transition that plasticizes the polymer sufficiently to enable volumetric and shape changes. Understanding how an alternating current can plasticize very stiff, densely cross-linked networks remains an unresolved challenge. Here, we use a nanoscale strain detection method to elucidate this electric-field-induced devitrification of LCNs. We find how a high-frequency alternating field gives rise to pronounced nanomechanical changes at a critical frequency, which signals the electrical glass transition. Across this transition, collective motion of the liquid crystal molecules causes the network to yield from within, leading to network weakening and subsequent nonlinear expansion. These results unambiguously prove the existence of electroplasticization. Fine-tuning the induced emergence of plasticity will not only enhance the surface functionality but also enable more efficient conversion of electrical energy into mechanical work.


Time to face it! Facebook intrusion and the implications for romantic jealousy and relationship satisfaction.
Young people's exposure to social network sites such as Facebook is increasing, along with the potential for such use to complicate romantic relationships. Yet, little is known about the overlaps between the online and offline worlds. We extended previous research by investigating the links between Facebook intrusion, jealousy in romantic relationships, and relationship outcomes in a sample of undergraduates currently in a romantic relationship. A Facebook Intrusion Questionnaire was developed based on key features of technological (behavioral) addictions. An eight-item Facebook Intrusion Questionnaire with a single-factor structure was supported; internal consistency was high. Facebook intrusion was linked to relationship dissatisfaction, via jealous cognitions and surveillance behaviors. The results highlight the possibility of high levels of Facebook intrusion spilling over into romantic relationships, resulting in problems such as jealousy and dissatisfaction. The results have implications for romantic relationships and for Facebook users in general.


Prodrug-Type Phosphotriester Oligonucleotides with Linear Disulfide Promoieties Responsive to Reducing Environment.
Various chemical modifications have been developed to create new antisense oligonucleotides (AONs) for clinical applications. Our previously designed prodrug-type phosphotriester-modified oligonucleotide with cyclic disulfides (cyclic SS PTE ON) can be converted into unmodified ON in an intracellular-mimetic reducing environment. However, the conversion rate of the cyclic SS PTE ON was very low, and the AON with cyclic SS PTE modifications showed much weaker antisense activity than corresponding to the fully phosphorothioate-modified AON. In this study, we synthesized several types of PTE ONs containing linear disulfides (linear SS PTE ONs) and evaluated their conversion rates under reducing conditions. From the results, the structural requirements for the conversion of the synthesized linear SS PTE ONs were elucidated. Linear SS PTE ON with promising promoieties showed a nuclease resistance up to 4.8-fold compared to unmodified ON and a cellular uptake by endocytosis without any transfection reagent. In addition, although the knockdown activity of the linear SS PTE gapmer AON is weaker than that of the fully phosphorothioate-modified gapmer AON, the knockdown activity is slightly stronger than that of the cyclic SS PTE gapmer AON. These results suggest that the conversion rates may be related to the expression of the antisense activity.


On the correlation between hydrogen bonding and melting points in the inositols.
Inositol, 1,2,3,4,5,6-hexahydroxycyclohexane, exists in nine stereoisomers with different crystal structures and melting points. In a previous paper on the relationship between the melting points of the inositols and the hydrogen-bonding patterns in their crystal structures [Simperler et al. (2006 ▶). CrystEngComm 8, 589], it was noted that although all inositol crystal structures known at that time contained 12 hydrogen bonds per molecule, their melting points span a large range of about 170 °C. Our preliminary investigations suggested that the highest melting point must be corrected for the effect of molecular symmetry, and that the three lowest melting points may need to be revised. This prompted a full investigation, with additional experiments on six of the nine inositols. Thirteen new phases were discovered; for all of these their crystal structures were examined. The crystal structures of eight ordered phases could be determined, of which seven were obtained from laboratory X-ray powder diffraction data. Five additional phases turned out to be rotator phases and only their unit cells could be determined. Two previously unknown melting points were measured, as well as most enthalpies of melting. Several previously reported melting points were shown to be solid-to-solid phase transitions or decomposition points. Our experiments have revealed a complex picture of phases, rotator phases and phase transitions, in which a simple correlation between melting points and hydrogen-bonding patterns is not feasible.


Inter-residue interactions in alpha-helical transmembrane proteins.
The number of available membrane protein structures has markedly increased in the last years and, in parallel, the reliability of the methods to detect transmembrane (TM) segments. In the present report, we characterized inter-residue interactions in α-helical membrane proteins using a dataset of 3462 TM helices from 430 proteins. This is by far the largest analysis published to date. Our analysis of residue-residue interactions in TM segments of membrane proteins shows that almost all interactions involve aliphatic residues and Phe. There is lack of polar-polar, polar-charged and charged-charged interactions except for those between Thr or Ser sidechains and the backbone carbonyl of aliphatic and Phe residues. The results are discussed in the context of the preferences of amino acids to be in the protein core or exposed to the lipid bilayer and to occupy specific positions along the TM segment. Comparison to datasets of β-barrel membrane proteins and of α-helical globular proteins unveils the specific patterns of interactions and residue composition characteristic of α-helical membrane proteins that are the clue to understanding their structure. Results data and datasets used are available at http://lmc.uab.cat/TMalphaDB/interactions.php. Supplementary data are available at Bioinformatics online.


Perceptions of falls risk and falls prevention among people with osteoarthritis.
To understand the perceptions of falls risk and falls prevention, and the perceived enablers and barriers to engaging in falls prevention strategies/activities among people with doctor-diagnosed hip and/or knee osteoarthritis. A qualitative study utilising semi-structured telephone interviews. Researchers independently analysed qualitative data using an inductive method guided by the COM-B framework. Interviews were analysed thematically using open, axial, and selective coding. Recruitment ceased at 20 interviews, once data saturation was evident. Participants were 18 women and two men aged 52-84 years and half had fallen in the last 12 months. Main themes were the absence of recommendations to access activities after having a fall, inconsistencies between perceptions of the relationship between OA and falls, and individual beliefs of not being at risk of falling because of taking precautions. Knowledge about falls prevention programs was limited, the term "falls prevention" was considered stigmatising and only applicable to older frail people. Home modifications were perceived as broadcasting negativity; participants felt falls terminology should be changed from a negative to a positive focus. Falls were often seen as inevitable consequence of keeping active. Re-framing the language used to discuss falls is recommended to promote uptake of falls prevention activities.Implications for rehabilitationDespite growing evidence that osteoarthritis (OA) is an independent risk factor for falls, people with OA do not perceive themselves to be at risk and falls prevention is for those who are "old and frail".Re-framing the language used to discuss falls and falls prevention to focus on positive messages may promote the uptake of falls prevention activities in this population.Improving the awareness of falls and falls risk among people with OA through effective health education is needed in order to foster the uptake of, and engagement with, falls prevention activities.


Two Year Visual Acuity and Structural Outcomes in Patients with Diabetic Macular Oedema Treated with Intravitreal Aflibercept - A Retrospective Cohort Study.
To assess visual and anatomical outcomes of intravitreal aflibercept for clinically significant diabetic macular oedema (DME). For this retrospective single-center cohort study at a tertiary referral center, we performed a data warehouse query to identify 117 treatment-naive patients (139 eyes) undergoing intravitreal treatment with aflibercept for DME between January 2014 and May 2018. Changes in best-corrected visual acuity (BCVA) values (as measured with ETDRS letters), central retinal thickness (CRT) and total macular volume (TVOL) are reported over a two-year period at various time-points. The total number of injections per study eye was 5.5 ± 1.4 after one and 8.7 ± 2.2 injections after two years. Baseline visual acuity (VA) was 60.1 ± 14.5 letters. A gain of 4.8 and 9.2 letters from baseline was observed after one and two years, respectively (both p ≤ 0.01). In comparison to the mean CRT at baseline (419 ± 174 µm), a CRT decrease was observed after one and two years of treatment (298 ± 115 µm and 319 ± 119 µm, respectively; both p ≤ 0.01). Similarly, TVOL decreased from 10.12 ± 2.05 mm3 to 8.96 ± 0.96 mm3 and 9.01 ± 1.29 mm3 (both p ≤ 0.01). This study demonstrates that treating DME with intravitreal aflibercept yields positive functional and structural outcomes over a two-year period. However, we observed fewer injection numbers, along with inferior VA and structural outcomes than has been reported in randomized clinical trials. Our results show similar results as in patients treated with ranibizumab due to DME in real-life settings.


Conformational movements and cooperativity upon amino acid, ATP and tRNA binding in threonyl-tRNA synthetase.
The crystal structures of threonyl-tRNA synthetase (ThrRS) from Staphylococcus aureus, with ATP and an analogue of threonyl adenylate, are described. Together with the previously determined structures of Escherichia coli ThrRS with different substrates, they allow a comprehensive analysis of the effect of binding of all the substrates: threonine, ATP and tRNA. The tRNA, by inserting its acceptor arm between the N-terminal domain and the catalytic domain, causes a large rotation of the former. Within the catalytic domain, four regions surrounding the active site display significant conformational changes upon binding of the different substrates. The binding of threonine induces the movement of as much as 50 consecutive amino acid residues. The binding of ATP triggers a displacement, as large as 8A at some C(alpha) positions, of a strand-loop-strand region of the core beta-sheet. Two other regions move in a cooperative way upon binding of threonine or ATP: the motif 2 loop, which plays an essential role in the first step of the aminoacylation reaction, and the ordering loop, which closes on the active site cavity when the substrates are in place. The tRNA interacts with all four mobile regions, several residues initially bound to threonine or ATP switching to a position in which they can contact the tRNA. Three such conformational switches could be identified, each of them in a different mobile region. The structural analysis suggests that, while the small substrates can bind in any order, they must be in place before productive tRNA binding can occur.


[Spasticity treated with selective posterior rhizotomy].
Spasticity is often seen in patients with central nervous lesions. Some patients with severe spasticity are not optimally treated with physiotherapy and medication. We present a case history of a 41-year-old woman with multiple sclerosis and severe painful spasticity in her lower limbs. Her spasticity did not respond to treatment with physiotherapy, spasmolytic medication, botulinum toxin A, intrathecal baclofen or epidural spinal cord stimulation. The patient was treated with selective posterior rhizotomy S1-L1. Section of 60% of the rootlets on the right side and 40% on left the side resulted in a good outcome with less spasticity and pain. Finally her contractures were treated with tenotomy and myotomy, also with good functional result. Patients suffering from severe painful spasticity and who do not respond to physiotherapy in combination with other spasmolytic medication should be considered for surgical treatment. In some patients posterior rhizotomy is the treatment of choice.


Evidence of Early Diabetic Nephropathy in Pediatric Type 1 Diabetes.
Diabetic nephropathy (DN) is one of the most common microvascular complications in type 1 diabetes Mellitus (T1D). Urinary markers of renal damage or oxidative stress may signal early stages of DN. The association of these markers with blood pressure (BP) patterns and glycemic variability (GV) in children is yet to be explored. Subjects between the ages of 10 and 21 years with T1D were enrolled. Continuous glucose monitoring (CGM) and ambulatory blood pressure monitoring (ABPM) were performed on each subject. Urine samples were collected and analyzed for albumin, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) and pentosidine. The study included 21 subjects (62% female) with median age of 16.8 (IQR: 14.5, 18.9). Median HbA1C was 8.4 (IQR: 7.5, 9.3). While microalbuminuria was negative in all but one case (4.8%), urinary NGAL/Cr and pentosidine/Cr ratios were significantly elevated (P<0.001) in diabetic patients despite having normal microalbuminuria, and they correlated significantly with level of microalbumin/Cr (r=0.56 [CI: 0.17, 0.8] and r=0.79 [CI: 0.54, 0.91], respectively). Using ABPM, none had hypertension, however, poor nocturnal systolic BP dipping was found in 48% of cases (95% CI: 28-68%). Urinary NGAL/Cr negatively correlated with nocturnal SBP dipping (r=-0.47, CI: -0.76, -0.03). Urine NGAL/Cr also showed a significant negative correlation with HbA1c measurements, mean blood glucose, and high blood glucose index (r=-0.51 [CI: -0.78, -0.09], r=-0.45 [CI: -0.74, -0.03], and r=-0.51 [CI: -0.77, -0.1], respectively). Median urinary NGAL/Cr and pentosidine/Cr ratios were higher in the high GV group but were not significantly different. This pilot study explores the role of ABPM and urinary markers of tubular health and oxidative stress in early detection of diabetic nephropathy. GV may play a role in the process of this diabetic complication.


Influence of incidental radiation dose in the subventricular zone on survival in patients with glioblastoma multiforme treated with surgery, radiotherapy, and temozolomide.
To determine if there is an association between the incidental radiation dose to the subventricular zone and survival in patients with glioblastoma multiforme treated with surgery, radiotherapy and temozolomide. Sixty-five patients, treated between 2006 and 2015, were included in this retrospective study. The doses (75th percentile; p75) administered to the ipsilateral, contralateral and bilateral subventricular zone were compared to overall survival and progression-free survival using Cox proportional hazards models. Covariates included: age, sex, surgery, tumor location, and concomitant and adjuvant temozolomide. Median progression-free survival and overall survival were 11.5 ± 9.96 and 18.8 ± 18.5 months, respectively. The p75 doses to the ipsilateral, contralateral and bilateral subventrivular zone were, respectively, 57.30, 48.8, and 52.7 Gy. Patients who received a dose ≥48.8 Gy in the contralateral subventricular zone had better progression-free survival than those who received lower doses (HR 0.46; 95% CI 0.23-0.91 P = 0.028). This association was not found for overall survival (HR 0.60; 95% CI 0.30-1.22 P = 0.16). Administration of adjuvant temozolomide was significantly associated with improved progression-free survival (HR 0.19; 95% CI 0.09-0.41 P < 0.0001) and overall survival (HR 0.11; 95% CI 0.05-0.24 P = 0.001). In the subgroup of 46 patients whose O6-methylguanine-DNA methyltransferase gene promoter status was known, the methylation had no effect on either progression-free survival (P = 0.491) or overall survival (P = 0.203). High-dose radiation in the contralateral subventricular zone was associated with a significant improvement in progression-free survival but not overall survival in patients treated for glioblastoma multiforme.


Validation of a cortisol enzyme immunoassay and characterization of salivary cortisol circadian rhythm in chimpanzees (Pan troglodytes).
Monitoring concentrations of stress hormones is an important tool for behavioral research and conservation for animals both in the wild and captivity. Glucocorticoids can be measured in mammals as an indicator of stress by analyzing blood, feces, urine, hair, feathers, or saliva. The advantages of using saliva for measuring cortisol concentrations are three-fold: it is minimally invasive, multiple samples can be collected from the same individual in a short timeframe, and cortisol has a relatively short response time in saliva as compared with other materials. The purpose of this study was to: (1) conduct an adrenocorticotropic hormone (ACTH) challenge as a physiological validation for an enzyme immunoassay to measure salivary cortisol in chimpanzees and (2) characterize the circadian rhythm of salivary cortisol in chimpanzees. We determined that salivary cortisol concentrations peaked 45 min following the ACTH challenge, which is similar to humans. Also, salivary cortisol concentrations peaked early in the morning and decreased throughout the day. We recommend that saliva collection may be the most effective method of measuring stress reactivity and has the potential to complement behavioral, cognitive, physiological, and welfare studies.


Phosphorylation causes subtle changes in solvent accessibility at the interdomain interface of methylesterase CheB.
The crystal structure of the unphosphorylated state of methylesterase CheB shows that the regulatory domain blocks access of substrate to the active site of the catalytic domain. Phosphorylation of CheB at Asp56 results in a catalytically active transiently phosphorylated enzyme with a lifetime of approximately two seconds. Solvent accessibility changes in this transiently phosphorylated state were probed by MALDI-TOF-detected amide hydrogen/deuterium exchange. No changes in solvent accessibility were seen in the regulatory domain upon phosphorylation of Asp56, but two regions in the catalytic domain (199-203 and 310-317) became more solvent accessible. These two regions flank the active site and contain domain-domain contact residues. Comparison with results from the isolated catalytic domain-containing C-terminal fragment of CheB (residues 147-349) showed that the increased solvent accessibility was less than would have occurred upon detachment of the regulatory domain. Thus, phosphorylation causes subtle changes in solvent accessibility at the interdomain interface of CheB.


Increased renal tubular reabsorption of calcium and magnesium by the offspring of diabetic rat pregnancy.
Diabetic pregnancy has a marked influence on offspring calcium and magnesium homeostasis. Urinary excretion of calcium and magnesium is reduced, yet offspring of diabetic pregnancy exhibit hypomagnesemia and hypocalcemia. The aim of this study was to measure renal hemodynamic and tubular function in the offspring of diabetic (OD) and control, nondiabetic (OC) rats at 4 and 8 wk of age to determine the glomerular and tubular mechanisms through which renal calcium and magnesium handling are programmed in utero. The fraction of filtered calcium that was excreted was significantly lower in OD at both 4 and 8 wk of age [8 wk: OC (n = 6), 11.8 +/- 2.9 versus OD (n = 5), 4.3 +/- 0.6%; p < 0.05] and that of magnesium was lower at 8 wk of age [OC (n = 6), 42.4 +/- 7.5 versus OD (n = 5), 13.0 +/- 1.7%; p < 0.01]. This increased reabsorption occurred despite an elevated GFR in OD. These findings clearly indicate that tubular reabsorptive mechanisms for calcium and magnesium are increased markedly in OD. Serum PTH concentration was reduced in 8-wk-old OD [OC (n = 7), 539.4 +/- 142.1 versus OD (n = 9), 174.3 +/- 69.4 pg/ml; p < 0.05], consistent with previous reports in human infants. Taken together, these observations suggest that the basis for the altered renal magnesium and calcium handling in OD involves increased tubular transport activity and possibly increased sensitivity of these mechanisms to PTH.


Direct comparison of PI-RADS version 2 and version 1 regarding interreader agreement and diagnostic accuracy for the detection of clinically significant prostate cancer.
to simultaneously evaluate interreader agreement and diagnostic accuracy in the of PI-RADS v2 and compare it to v1. A total of 67 patients (median age 65.3 y, range 51.2-78.2 y; PSA 6.8μg/L, 0.2-33μg/L) undergoing MRI of the prostate and subsequent transperineal template biopsy within ≤6 months from MRI were included. Four readers from two institutions evaluated the likelihood of prostate cancer using PI-RADS v1 and v2 in two separate reading sessions ≥3 months apart. Interreader agreement was assessed for each pulse-sequence and for total PI-RADS scores using the intraclass correlation coefficient (ICC). Differences were considered significant for non-overlapping 95%-confidence intervals. Diagnostic accuracy was assessed with the area under the receiver operating characteristic curve (AZ). A p-value <0.05 was considered statistically significant. Interreader agreement for DCE-scores was good in v2 (ICC2=0.70; 95% CI: 0.66-0.74) and slightly lower in v1 (ICC1=0.64, 0.59-0.69). Agreement for DWI scores (ICC1=0.77, ICC2=0.76) as well as final PI-RADS scores per quadrant were nearly identical (ICC1=ICC2=0.71). Diagnostic accuracy showed no significant differences (p=0.09-0.93) between v1 and v2 in any of the readers (range: AZ=0.78-0.88). PI-RADS scores show similar interreader agreement in v2 and v1 at comparable diagnostic performance. The simplification of the DCE interpretation in v2 might slightly improve agreement while not negatively affecting diagnostic performance.


A dialysis medium refreshment cell culture set-up for an osteoblast-osteoclast coculture.
Culture medium exchange leads to loss of valuable auto- and paracrine factors produced by the cells. However, frequent renewal of culture medium is necessary for nutrient supply and to prevent waste product accumulation. Thus it remains the gold standard in cell culture applications. The use of dialysis as a medium refreshment method could provide a solution as low molecular weight molecules such as nutrients and waste products could easily be exchanged, while high molecular weight components such as growth factors, used in cell interactions, could be maintained in the cell culture compartment. This study investigates a dialysis culture approach for an in vitro bone remodeling model. In this model, both the differentiation of human mesenchymal stromal cells (MSCs) into osteoblasts and monocytes (MCs) into osteoclasts is studied. A custom-made simple dialysis culture system with a commercially available cellulose dialysis insert was developed. The data reported here revealed increased osteoblastic and osteoclastic activity in the dialysis groups compared to the standard nondialysis groups, mainly shown by significantly higher alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activity, respectively. This simple culture system has the potential to create a more efficient microenvironment allowing for cell interactions via secreted factors in mono- and cocultures and could be applied for many other tissues.


A mathematical description of miniature postsynaptic current generation at central nervous system synapses.
Variation in the amplitude of miniature postsynaptic currents (mPSCs) generated by individual quanta of neurotransmitter is a major contributor to the variance of evoked synaptic responses. Here we explore the possible origins of this variability by developing a mathematical description of mPSC generation and consider the contribution of "off-center" release to this variability. By "off-center" release we mean variation in the distance between the position where a presynaptic vesicle discharges its content of neurotransmitter into the synaptic cleft and the center of a cluster of postsynaptic receptors (PRCs) that responds to those transmitter molecules by generating an mPSC. We show that when the time course of quantal discharge through a fusion pore (noninstantaneous release) is considered, elementary analytical descriptions of the subsequent diffusion of transmitter within the synaptic cleft (with or without uptake) predict the development of significant gradients of transmitter concentration during the rising phase of mPSCs. This description of diffusion is combined with a description of the pharmacodynamics of receptors in the PRC and of the time dependence of the gradient of transmitter concentration over the area of the PRC to reconstruct the time course and amplitude of an mPSC for a synapse of a given geometry. Within the constraints of known dimensions of presynaptic active zones and postsynaptic receptor clusters at CNS synapses, our analysis suggests that "off-center" release, produced by allowing release to occur anywhere within an anatomically defined presynaptic active zone, can be an important contributor to mPSC variability. Indeed, modulation of the influence of "off-center" release may be a novel way of controlling synaptic efficacy. We also show how noninstantaneous release can serve to focus the action of neurotransmitter within a given synapse and thereby reduce cross-talk between synapses.


Changes in Health-Related Behaviours and Mental Health in a UK Public Sample during the First Set of COVID-19 Public Health Restrictions.
Public health restrictions, in response to the COVID-19 pandemic, have had potentially wide-ranging, unintended effects on health-related behaviours such as diet and physical activity and also affected mental health due to reduced social interactions. This study explored how health-related behaviours and mental health were impacted in a sample of the UK public during the first set of COVID-19 public health restrictions. Two online surveys were administered in the UK, one within the first three months of the restrictions (Timepoints 1 (T1—involving pre-pandemic recall) and 2/T2) and another ten weeks later (Timepoint 3/T3). Moderate−vigorous physical activity (MVPA), outdoor time, sitting time, screen time and sexual activity were self-reported. Diet was assessed using the Dietary Instrument for Nutrition Education questionnaire. Mental health was measured using the short-form Warwick−Edinburgh Mental Wellbeing Scale and Becks' Anxiety and Depression Inventories. Differences between timepoints were explored using the Friedman, Wilcoxon signed-rank, McNemar and McNemar−Bowker tests. Two hundred and ninety-six adults (74% under 65 years old; 65% female) provided data across all timepoints. Between T1 and T2, MVPA, time outdoors and sexual activity decreased while sitting, and screen time increased (p < 0.05). Between T2 and T3, saturated fat intake, MVPA, time outdoors, and mental wellbeing increased while sitting, screen time and anxiety symptoms decreased (p < 0.05). This study found that depending on the level of COVID-19 public health restrictions in place, there appeared to be a varying impact on different health-related behaviours and mental health. As countries emerge from restrictions, it is prudent to direct necessary resources to address these important public health issues.


Phase I study of high-dose thiotepa with busulfan, etoposide, and autologous stem cell support in children with disseminated solid tumors.
The aim of this phase I study was to define the maximum tolerated dose (MTD) of thiotepa (TT), administered with busulfan (BU) 480 mg/m(2) and etoposide 2,400 mg/m(2), followed by autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (APBSCT) support in children with solid tumors either disseminated at diagnosis or after relapse. Nineteen patients, between 2 and 16 years of age, received a high-dose chemotherapy regimen including escalating doses of TT starting from 150 mg/m(2). Subsequent dose escalation was determined by a modified Fibonacci scheme. Whenever one patient at one dosage level showed a grade III or grade IV reversible toxicity, additional patients were admitted (one by one) up to a maximum number of 6. Upon observing grade III or IV reversible toxicity in two or more systems, in 3 of the 6 patients, no further escalation was performed, and the corresponding dosage was taken as the MTD. WHO criteria were adopted to assess grade of toxicity. All patients had hematological recovery; and neutrophils and platelet engraftment were observed after median times of 12 and 29 days from stem cell infusion, respectively. The MTD of TT was determined to be 750 mg/ m(2). At this level, 3 of 6 patients experienced grade III mucositis and/or grade III gastrointestinal toxicity. No patient died of treatment-related toxicity. A dose of 750 mg/m(2) TT is the MTD when it is associated with BU 480 mg/m(2) and etoposide 2, 400 mg/m(2). This ablative regimen represents a feasible and tolerable combination for high-dose chemotherapy followed by hematopoietic stem cell rescue (HSCR). Phase II studies in children with poor-prognosis solid tumors are required to evaluate the effectiveness of this treatment.


Alkali-metal-ion-directed self-assembly of redox-active manganese(III) supramolecular boxes.
The ability to organize functional molecules into higher dimensional arrays with well-defined spatial relationships between the components is one of the major goals in supramolecular chemistry. We report here a new route for the preparation of supramolecular boxes, incorporating two types of metal ions: (i) alkali-metal ions, which induce the supramolecular architecture and essentially play a structural role in the final compounds; (ii) manganese(III) ions, which are redox-active systems and give functionality to the new cages. Our results evidence that the size of the cavity inside the box can be tuned depending on the alkali metal used, a characteristic that gives this new family of compounds the potential to act selectively against different substrates. These compounds behave as active catalysts for disproportionation of H2O2 or for water photolysis, but they catalyze neither catecholase reaction nor peroxidase action upon using bulky organic substrates.


Ovarian tumor expression of an oviductal protein in the hen: a model for human serous ovarian adenocarcinoma.
We hypothesized that ovarian tumors without oviductal involvement would not express the oviductal protein ovalbumin, the major protein found in the magnum of the hen's oviduct. On the basis of gross visual examination, tissues samples were removed from hens determined to have ovarian tumors and were processed, embedded in paraffin, sectioned, mounted on glass slides, and stained with hematoxylin and eosin. Ovarian tumors and other peritoneal lesions were evaluated histologically. Paraffin sections of ovarian and oviductal tissue were deparaffinized and evaluated for the protein expression of ovalbumin, proliferating cell nuclear antigen (PCNA), and progesterone receptor (PR). Hens with ovarian adenocarcinoma without (n = 10) or with (n = 6) oviductal involvement were positive for ovalbumin in the ovary. Ovary sections from normal hens (n = 9) were negative, and oviductal sections from normal hens (n = 3) were positive for ovalbumin. Expression of PCNA protein was abundant in all ovarian tumors (16 of 16). Oviductal epithelial cells strongly expressed PCNA protein. Expression of PR was observed in 9 of 14 ovarian tumors. The presence of ovalbumin in ovarian tumors in the absence of any oviductal involvement suggests that ovarian tumors dedifferentiate during the disease process and thereby resemble serous-type ovarian tumors in women.


Immune response to Escherichia coli.
Chickens from a line artifically selected for lew level of plasma corticosterone (LPC) produced higher antibody titers, produced antibody earlier, continued the production of antibody longer, responded to lower dosages of antigen, and had greater body weight gain than those from a line slected for a high level of plasma corticosterone (hpc). the HPC line resisted Escherichia coli challenge and antigen more effectively than the LPC line. It appears that, although the HPC line is more effective in its defense against bacterial infections, the LPC line can be aided more by vaccines.


Resolving electron injection from singlet fission-borne triplets into mesoporous transparent conducting oxides.
Photoinduced electron transfer into mesoporous oxide substrates is well-known to occur efficiently for both singlet and triplet excited states in conventional metal-to-ligand charge transfer (MLCT) dyes. However, in all-organic dyes that have the potential for producing two triplet states from one absorbed photon, called singlet fission dyes, the dynamics of electron injection from singlet vs. triplet excited states has not been elucidated. Using applied bias transient absorption spectroscopy with an anthradithiophene-based chromophore (ADT-COOH) adsorbed to mesoporous indium tin oxide (nanoITO), we modulate the driving force and observe changes in electron injection dynamics. ADT-COOH is known to undergo fast triplet pair formation in solid-state films. We find that the electronic coupling at the interface is roughly one order of magnitude weaker for triplet vs. singlet electron injection, which is potentially related to the highly localized nature of triplets without significant charge-transfer character. Through the use of applied bias on nanoITO:ADT-COOH films, we map the electron injection rate constant dependence on driving force, finding negligible injection from triplets at zero bias due to competing recombination channels. However, at driving forces greater than -0.6 eV, electron injection from the triplet accelerates and clearly produces a trend with increased applied bias that matches predictions from Marcus theory with a metallic acceptor.


[Analysis of the discrete structure of antibodies by affinity and antigen-binding capacity].
Immune sera are a mixture of different groups of antibodies belonging to the same class of immunoglobulins, but differing in their affinity. The graphic analysis and numerical methods permit the determination of the size and affinity of each group of antibodies. Differences in affinity are manifested as differences in antigen-binding capacity. The antigen-binding capacity index, calculated as the product of the association constant multiplied by the concentration of the active centers of antibodies, is proposed.


Effects of Extracorporeal Shockwave Therapy on Improvements in Lymphedema, Quality of Life, and Fibrous Tissue in Breast Cancer-Related Lymphedema.
To evaluate the effects of extracorporeal shockwave therapy (ESWT) on improving lymphedema, quality of life, and fibrous tissue in patients with stage 2 lymphedema. Breast cancer-related lymphedema patients referred to the rehabilitation center were recruited. We enrolled stage 2 lymphedema patients who had firmness of the skin at their forearm, a circumference difference of more than 2 cm between each arm, or a volume difference between upper extremities greater than 200 mL, confirmed by lymphoscintigraphy. The patients were randomly divided into the ESWT group and the control group. ESWT was performed for 3 weeks (two sessions per week); both groups received complex decongestive physical therapy. All patients were evaluated at baseline and at 3 weeks after treatment. The measurements performed included visual analog scale score, volume, circumference, QuickDASH (Quick Disabilities of the Arm, Shoulder and Hand) score, bioelectrical impedance, and skin thickness. The patients in both groups (n=15 in each group) completed the 3-week therapy experiment. No significant differences were observed in demographic characteristics between groups. After the 3-week treatment period, improvement was noted in the circumference difference below the elbow, volume, ratio of extracellular water to total body water, and skin thickness in the ESWT group. A significant difference was found in all the above-mentioned areas except in circumference below the elbow in the ESWT group. ESWT reduced edema and skin fibrosis without significant complications. Therefore, ESWT can be used together with complex decongestive physical therapy for treating lymphedema.


The importance of risk reduction in critically ill patients.
Intensive care patients are per definition at risk for an unfavourable outcome while at the same time being exposed to the risks of a very complex and invasive process of care. This review addresses this extrinsic risk with respect to causative factors and strategies for risk reduction. A growing amount of evidence shows that the actual risk of an unfavourable outcome in critically ill patients depends on the quality of the process of care. Several domains have been identified in which changes in infrastructure, process, and culture can result in a substantial risk reduction and increased patient safety. Important examples refer to work environment and workload of intensive care professionals, safety climate, information flow, and continuity of care. Recent studies have demonstrated that routine procedures in intensive care are amenable to considerable improvement. This review discusses recent findings related to the reduction of risk in critically ill patients with respect to the process of intensive care medicine and the conditions under which that care is provided.