Combining the FLT3 inhibitor PKC412 and the triterpenoid CDDO-Me synergistically induces apoptosis in acute myeloid leukemia with the internal tandem duplication mutation.
Mutations of the FLT3 receptor tyrosine kinase consisting of internal tandem duplications (ITD) have been detected in blasts from 20% to 30% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. FLT3/ITD results in constitutive autophosphorylation of the receptor and factor-independent survival in leukemia cell lines. The C-28 methyl ester of the oleane triterpenoid (CDDO-Me) is a multifunctional molecule that induces apoptosis of human myeloid leukemia cells. Here, we report that CDDO-Me blocks targeting of NFkappaB to the nucleus by inhibiting IkappaB kinase beta-mediated phosphorylation of IkappaBalpha. Moreover, CDDO-Me blocked constitutive activation of the signal transducer and activator of transcription 3. We report the potent and selective antiproliferative effects of CDDO-Me on FLT3/ITD-positive myeloid leukemia cell lines and primary AML cells. The present studies show that CDDO-Me treatment results in caspase-3-mediated induction of apoptosis of FLT3/ITD-expressing cells and its antiproliferative effects are synergistic with PKC412, a FLT3-tyrosine kinase inhibitor currently in clinical trials. Taken together, our studies indicate that CDDO-Me greatly enhanced the efficacy of the FLT3 inhibitor PKC412, suggesting that combining two separate pathway inhibitors might be a viable therapeutic strategy for AML associated with a FLT3/ITD mutation.


Evaluation of activity of hypothalamo-pituitary-gonadal axis in postmenopausal women suffering from severe acute illness.
Postmenopausal women constitute an ideal model for studying the extent of hypothalamo-pituitary gonadal (HPG) axis suppression in critical illness as the gonadotropins are normally high and non-cyclical in them. The objective was to assess the impact of acute severe illness in postmenopausal women on the HPG axis and the activities of the hypothalamo-pituitary-adrenal (HPA), the hypothalamo- pituitary-thyroid (HPT) axes; and levels of serum prolactin, by comparison between critically ill postmenopausal women and otherwise healthy postmenopausal women. Thirty five consecutive postmenopausal women older than 60 yr admitted to medical intensive care with a s0 implified a0 cute p0 hysiology s0 core II (SAPS II) more than 30 were included. On day five of their in-hospital stay, blood samples were collected for oestradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), cortisol, androstenedione, prolactin and thyroid profile. Thirty five apparently healthy postmenopausal women were selected as controls. Levels of LH, FSH, thyrotropin, free thyroxin (fT 4 ) and free tri-iodothyronine (fT 3 ) were lower while oestradiol, cortisol and dehydroepiandrosterone were higher among patients in comparison to healthy controls. Prolactin levels were similar in patients and controls. Among sick patients both FSH and fT 4 showed a negative correlation ( P<0.05) with the SAPS II score. In critically ill postmenopausal women, paradoxically elevated oestrogen levels despite gonadotropin suppression suggests a non-ovarian origin. Prolactin remained unaltered in patients despite their illness, possibly reflecting atrophy of lactotrophs in menopause.


Anesthetic protocol for videolaparoscopic surgery in rabbits.
To describe the anesthetic protocol and the intubation technique without visualizing the trachea in rabbits, in order to enable the videolaparoscopic surgical procedure. The experiment was performed on 33 female rabbits (Oryctolagus cuniculus), aged from 5 to 7 months. It consisted of general anesthesia and endotracheal intubation by manual palpation of the trachea of the rabbits, without using the laryngoscope, orally, for later videolaparoscopic surgical access to the abdominal cavity. The mean values and standard deviation of vital parameters of the animals were 223.8 + or - 15.61 beats per minute for heart rate; 35 + or - 9 movements per minute for respiratory rate; 96.94 + or - 0.99% of oxymetry and 42.82 + or - 4.02 mmHg for capnometry; 16.7 + or - 4.3 minutes for pneumoperitoneum (duration of surgery) and 1 hour and 14 + or - 8.52 minutes for time of observation (from induction to recovery from anesthesia). All animals were intubated in at most three attempts. No animals were lost after the introduction of this anesthetic technique. This protocol proved adequate, safe and easy to perform, on rabbits submitted to videolaparoscopic surgery.


YscM1 and YscM2, two Yersinia enterocolitica proteins causing downregulation of yop transcription.
Synthesis of the Yop proteins by yersiniae is downregulated when secretion is prevented by closure or destruction of the contact (type III) secretion channel. In Yersinia pseudotuberculosis, a mutation in the IcrQ gene, encoding a secreted protein, reduces this feedback inhibition mechanism. Surprisingly, mutation in the yscM gene, the IcrQ homologue in Y. enterocolitica, does not lead to the same deregulated phenotype. In this paper, we addressed the question of this discrepancy. We found a new gene on the Y. enterocolitica pYV plasmid that encodes a protein with 57% identity to YscM (now called YscM1). Overexpression of this gene, called yscM2, like overexpression of IcrQ and yscM1, blocked Yop secretion. A double yscM1, yscM2 mutant had the same phenotype as that of the IcrQ mutant. The discrepancy can thus be explained by the existence of two functionally equivalent copies of yscM in Y. enterocolitica. Overexpression of yscM1 drastically reduced the expression of a yopH-cat reporter gene when tested in a pYV+ background. However, no effect could be observed in the absence of a pYV plasmid, indicating that YscM1 does not act directly as a transcriptional repressor or as an anti-VirF factor. We have also ruled out that YscM acts by obstructing the secretion channel.


Effects of biphasic positive airway pressure in patients with chronic obstructive pulmonary disease.
Biphasic positive airway pressure (BiPAP) is a ventilatory mode in which two pressure levels (higher (Phigh) and lower (Plow)) acting as continuous positive airway pressure (CPAP) alternate at preset time intervals. BiPAP combines pressure-controlled ventilation with unrestricted spontaneous breathing. BiPAP has not yet been evaluated in patients with chronic obstructive pulmonary disease (COPD). Therefore, the effects of BiPAP (15 cmH2O Phigh and 5 cmH2O Plow) pressure support (PS; 15 cmH2O and positive end-expiratory pressure (PEEP) 5 cmH2O) and CPAP (5 cmH2O) on respiratory mechanics in COPD patients were compared. Twenty-one COPD patients were supported in randomized order with BiPAP, PS and CPAP. Pressure-time product (PTP), work of breathing (WOB), change in oesophageal pressure (deltaPoes), mouth occlusion pressure (P0.1), intrinsic PEEP (PEEPi), tension time index (TTI), respiratory frequency, and tidal volume (VT) were measured. During BiPAP, the COPD patients showed a significantly higher PTP, WOB, deltaPoes, P0.1, TTI and PEEPi than during PS. Comparing the Plow phases of BiPAP and CPAP, the breaths during the Plow phases of BiPAP had a lower VT and a greater WOB and PTP due to a higher PEEPi than on CPAP alone. In conclusion, biphasic positive airway pressure carries the risk of increased work of breathing in spontaneously breathing chronic obstructive pulmonary disease patients. Pressure support is superior for reducing their respiratory muscle effort.


Thanking Cell & Bioscience reviewers.
The editors of Cell & Bioscience would like to thank all the reviewers who contributed to the journal in Volume 3 (2013).


Lymph node recurrence following stage IA vulvar carcinoma: two cases and a short overview of literature.
Stage IA vulvar carcinoma is not supposed to metastasize to the lymph nodes. Therefore, it is assumed that these lesions can be safely treated by less aggressive methods than macroinvasive carcinomas. However, in this case report, two patients are described who had vulvar lesions with a depth of invasion of less than 1 mm and developed lymph node metastases in the groin despite radical wide local excision of their lesions. Both the patients underwent lymphadenectomy and received postoperative radiation therapy on the groins. Neither of the two patients died of vulvar carcinoma. Thus, we conclude that vigilance for the occurrence of lymph node metastases remains necessary after radical, local excision in stage IA vulvar cancer. However, this case report also shows that adequate treatment of groin node metastases can result in a very good long-term survival.


Accuracy of endoscopic staging and targeted biopsies for routine gastric intestinal metaplasia and gastric atrophy evaluation study protocol of a prospective, cohort study: the estimate study.
Patients with chronic atrophic gastritis (CAG) and intestinal metaplasia (IM) are at risk of developing gastric adenocarcinoma. Their diagnosis and management currently rely on histopathological guidance after random endoscopic biopsy sampling (Sydney biopsy strategy). This approach has significant flaws such as under-diagnosis, poor reproducibility and poor correlation between endoscopy and histology. This prospective, international multicentre study aims to establish whether endoscopy-led risk stratification accurately and reproducibly predicts CAG and IM extent and disease stage. Patients with CAG and/or IM on standard white light endoscopy (WLE) will be prospectively identified and invited to undergo a second endoscopy performed by an expert endoscopist using enhanced endoscopic imaging techniques with virtual chromoendoscopy. Extent of CAG/IM will be endoscopically staged with enhanced imaging and compared with standard WLE. Histopathological risk stratification through targeted biopsies will be compared with endoscopic disease staging and to random biopsy staging on WLE as a reference. At least 234 patients are required to show a 10 % difference in sensitivity and accuracy between enhanced imaging endoscopy-led staging and the current biopsy-led staging protocol of gastric atrophy with a power (beta) of 80 % and a 0.05 probability of a type I error (alpha). The study was approved by the respective Institutional Review Boards (Netherlands: MEC-2018-078; UK: 19/LO/0089). The findings will be published in peer-reviewed journals and presented at scientific meetings. NTR7661; Pre-results.


Suckling in the guinea-pig: the simultaneous release of oxytocin and neurophysin.
The release of oxytocin and neurophysin during suckling has been studied in conscious unrestrained guinea-pigs. After prior separation, mothers and litters were allowed to suckle for a period of 10 min, and the weight gain of the litter recorded as an index of milk transfer. Maternal blood samples were obtained without disturbance through previously implanted intravenous cannulae and neurophysin and oxytocin determined on unextracted plasma by specific and sensitive radioimmunoassays. In 82 out of 118 experiments the young gained weight during suckling (1.6 +/- 0.1 (S.E.M.) g/pup) and this was associated with large rises in both oxytocin and neurophysin concentrations in plasma (mean concentrations: oxytocin 65.4 fmol/ml, neurophysin 360 fmol/ml). Where serial samples were taken, oxytocin and neurophysin showed a rapid rise and fall in concentration closely associated with the occurrence of milk ejection as judged by the behaviour of the litter. The present results provide the first direct evidence of a spurt release of both oxytocin and neurophysin measured simultaneously during milk ejection. The conscious lactating guinea-pig thus provides a useful laboratory model in which to study hormone release during milk ejection.


Pancreas acinar cell differentiation. VII. Autoradiographic demonstration of intracellular radioactivity with with S-adenosyl-L-(C 3 H 3 ) methionine.
After rat pancreas anlagen were grown in an organ culture medium for 9 days and further incubated for 15, 30 or 60 minutes in media to which C(3)H(3)-Sadenosyl-L-methionine (C(3)H(3)-SAM) was added, autoradiography demonstrated radioactivity in the nucleolus, nucleus and cytoplasm of the acinar cell. Under similar circumstances, except that the anlagen were grown in a methionine-deficient (CD-MD) medium prior to incubation with C(3)H(3)-SAM, much greater concentrations of radioactivity were present in the nucleolus, nucleus and cytoplasm of the acinar cell than in the respective compartments of anlagen grown in control medium. The nucleolus showed the highest concentration of radioactivity in anlagen grown in either control or methionine-deficient medium. The nucleolus of the acinar cell of anlagen grown in CD-MD medium appeared to be the most undermethylated cellular compartment and was larger than the nucleolus of the acinar cell grown in the control CD medium, so it is possible that a deficient methylation of ribosomal RNA precursors led to a piling up of RNA in the nucleolus and a decrease in the flow of ribosomal precursors to the cytoplasm. Other substance might have been undermethylated and thereby have inhibited differentiation.


Release of inhibitory neurotransmitters in response to anoxia in turtle brain.
In mammals a massive release of the excitatory neurotransmitter glutamate, occurring within a few minutes of anoxia/ischemia, is thought to be a major mediator of anoxic brain damage. In contrast to the mammalian brain, the turtle brain is exceptionally anoxia tolerant. Using intracerebral microdialysis in turtle brain striatum, we have found a large increase in the extracellular level of the inhibitory neurotransmitter gamma-aminobutyric acid during anoxia, reaching 90 times the normoxic level after 240 min, whereas no substantial release of glutamate occurred. Moreover, the inhibitory neurotransmitters/neuromodulators glycine and taurine also displayed increased extracellular levels during anoxia. Increased extracellular levels of inhibitory amino acids may be one of the hitherto elusive mechanisms that underlie the decreased activity and energy consumption characterizing the anoxic turtle brain.


Relaxation anisotropy in cartilage by NMR microscopy (muMRI) at 14-microm resolution.
To study the structural anisotropy and the magic-angle effect in articular cartilage, T1 and T2 images were constructed at a series of orientations of cartilage specimens in the magnetic field by using NMR microscopy (muMRI). An isotropic T1 and a strong anisotropic T2 were observed across the cartilage tissue thickness. Three distinct regions in the microscopic MR images corresponded approximately to the superficial, transitional, and radial histological zones in the cartilage. The percentage decrease of T2 follows the pattern of the curve of (3cos2theta - 1)2 at the radial zone, where the collagen fibrils are perpendicular to the articular surface. In contrast, little orientational dependence of T2 was observed at the transitional zone, where the collagen fibrils are more randomly oriented. The result suggests that the interactions between water molecules and proteoglycans have a directional nature, which is somehow influenced by collagen fibril orientation. Hence, T2 anisotropy could serve as a sensitive and noninvasive marker for molecular-level orientations in articular cartilage.


Intracellular homocysteine metabolites in SLE: plasma S-adenosylhomocysteine correlates with coronary plaque burden.
We hypothesised that intracellular homocysteine and homocysteine metabolite levels in patients with SLE are disproportionately elevated compared with the levels seen in healthy subjects and that they are independently associated with coronary plaque in SLE. A liquid chromatography-tandem mass spectrometry absolute quantification assay was used for the determination of six analytes in both plasma and peripheral blood mononuclear cells (PBMCs): homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), methionine (Met), cystathionine (Cysta) and 5-methyltetrahydrofolate (5m-THF). We then compared intracellular (PBMC) and extracellular (plasma) Hcy and Hcy metabolite (SAM, SAH, Met, Cysta and 5m-THF) concentrations in 10 patients with SLE and in 10 age, sex and ethnicity matched controls. Subjects with a history of diabetes mellitus, cardiovascular disease, hypertension, alcohol consumption in excess of 3 units per day, anaemia, renal insufficiency (serum creatinine >1.5 mg/dL) and pregnancy were excluded. All patients with SLE had two coronary CT angiography studies as screening for occult coronary atherosclerotic disease. Plasma from patients with SLE had higher levels of Hcy (p<0.0001), SAH (p<0.05), SAM (p<0.001) and lower levels of Met (p<0.05) and Cysta (p<0.001) compared with controls. PBMC intracellular concentrations from patients with SLE had higher levels of Cysta (p<0.05), SAH (p<0.05), SAM (p<0.001) and lower levels of 5m-THF (p<0.001). Plasma SAH showed a positive correlation with total coronary plaque, calcified plaque and non-calcified plaque (p<0.05). Intracellular concentrations of Hcy metabolites were significantly different between patients with SLE and controls, despite similar intracellular Hcy levels. Plasma SAH was positively correlated with total coronary plaque, calcified plaque and non-calcified plaque.


Optimization of the Post-Process Heat Treatment Strategy for a Near-α Titanium Base Alloy Produced by Laser Powder Bed Fusion.
During the last decades, titanium alloys have been of great interest for lightweight applications due to their high strength in combination with a low material density. Current research activities focus on the investigation of near-α titanium alloys produced by laser powder bed fusion (LPBF). These alloys are known for their superior tensile strength and high creep resistance. This study focuses on the optimization of post-process heat treatments and the impact on tensile and creep strength of a LPBF produced Ti6242S alloy. Therefore, a variety of annealing steps were conducted to gain knowledge about the decomposition process of the non-equilibrium as-built microstructure and the arising influence on the mechanical properties. Components made of Ti6242S and produced by LPBF reveal an extraordinarily high ultimate tensile strength of about 1530 MPa at room temperature, but show a low elongation at fracture (A5 = 4.3%). Based on microstructure-property relationships, this study recommends precise heat treatments on how to improve the desired mechanical properties in terms of strength, ductility as well as creep resistance. Moreover, this study shows a triplex heat treatment, which enhances the elongation at fracture (A5) to 16.5%, while the ultimate tensile strength is still at 1100 MPa.


Benefits and risks of tight glucose control in critically ill adults: a meta-analysis.
The American Diabetes Association and Surviving Sepsis Campaign recommend tight glucose control in critically ill patients based largely on 1 trial that shows decreased mortality in a surgical intensive care unit. Because similar studies report conflicting results and tight glucose control can cause dangerous hypoglycemia, the data underlying this recommendation should be critically evaluated. To evaluate benefits and risks of tight glucose control vs usual care in critically ill adult patients. MEDLINE (1950-2008), the Cochrane Library, clinical trial registries, reference lists, and abstracts from conferences from both the American Thoracic Society (2001-2008) and the Society of Critical Care Medicine (2004-2008). We searched for studies in any language in which adult intensive care patients were randomly assigned to tight vs usual glucose control. Of 1358 identified studies, 34 randomized trials (23 full publications, 9 abstracts, 2 unpublished studies) met inclusion criteria. Two reviewers independently extracted information using a prespecified protocol and evaluated methodological quality with a standardized scale. Study investigators were contacted for missing details. We used both random- and fixed-effects models to estimate relative risks (RRs). Twenty-nine randomized controlled trials totaling 8432 patients contributed data for this meta-analysis. Hospital mortality did not differ between tight glucose control and usual care overall (21.6% vs 23.3%; RR, 0.93; 95% confidence interval [CI], 0.85-1.03). There was also no significant difference in mortality when stratified by glucose goal ([1] very tight: < or = 110 mg/dL; 23% vs 25.2%; RR, 0.90; 95% CI, 0.77-1.04; or [2] moderately tight: < 150 mg/dL; 17.3% vs 18.0%; RR, 0.99; 95% CI, 0.83-1.18) or intensive care unit setting ([1] surgical: 8.8% vs 10.8%; RR, 0.88; 95% CI, 0.63-1.22; [2] medical: 26.9% vs 29.7%; RR, 0.92; 95% CI, 0.82-1.04; or [3] medical-surgical: 26.1% vs 27.0%; RR, 0.95; 95% CI, 0.80-1.13). Tight glucose control was not associated with significantly decreased risk for new need for dialysis (11.2% vs 12.1%; RR, 0.96; 95% CI, 0.76-1.20), but was associated with significantly decreased risk of septicemia (10.9% vs 13.4%; RR, 0.76; 95% CI, 0.59-0.97), and significantly increased risk of hypoglycemia (glucose < or= 40 mg/dL; 13.7% vs 2.5%; RR, 5.13; 95% CI, 4.09-6.43). In critically ill adult patients, tight glucose control is not associated with significantly reduced hospital mortality but is associated with an increased risk of hypoglycemia.


Autocrine induction of major histocompatibility complex class I antigen expression results from induction of beta interferon in oncogene-transformed BALB/c-3T3 cells.
By varying growth conditions, we identified a novel mechanism of autocrine regulation of major histocompatibility complex (MHC) class I gene expression by induction of beta interferon gene expression in transformed BALB/c-3T3 cells. Low-serum conditions enhanced MHC class I antigen expression in v-rasKi- and v-mos-transformed BALB/c-3T3 cells but not in untransformed BALB/c-3T3 cells. Transformed and untransformed cells grown under standard serum conditions (10% bovine calf serum) expressed similar cell surface levels of MHC class I antigens. However, low-serum conditions (0.5% bovine calf serum) induced four- to ninefold increases in cell surface levels of MHC class I antigens in both v-rasKi- and v-mos-transformed cells but not in untransformed cells. These increases in MHC class I gene expression were seen at both the mRNA and cell surface protein levels and involved not only the heavy-chain component of the class I antigens but also beta 2 microglobulin. Beta 1 interferon mRNA and beta interferon-inducible 2',5'-oligoadenylate synthetase mRNA were induced by growth under low-serum conditions in transformed BALB/c-3T3 cells, and antibodies to beta interferon blocked the induction of MHC class I antigen expression by serum deprivation in these cells. These results demonstrate that growth under low-serum conditions leads to induction of beta interferon expression in oncogene-transformed cells which then directly mediates autocrine enhancement of MHC class I gene expression.


Ensuring basic competency in chest tube insertion using a simulated scenario: an international validation study.
Chest tube insertion can be associated with serious complications. A structured training programme is needed to minimise complications and enhance patient safety. Novices should pass a reliable test with solid evidence of validity before performing the procedure supervised on patients. The aim of this study was to establish a credible pass/fail standard. We used an established assessment tool the Chest Tube Insertion Competency Test (TUBE-iCOMPT). Validity evidence was explored according to Messick's five sources of validity. Two methods were used to establish a credible pass/fail standard. Contrasting groups' method: 34 doctors (23 novices and 11 experienced surgeons) performed the procedure twice and all procedures were video recorded, edited, blinded and rated by two independent, international raters. Modified Angoff method: seven thoracic surgeons individually determined the scores that defined the pass/fail criteria. The data was gathered in Copenhagen, Denmark and Riyadh, Saudi Arabia. Internal consistency reliability was calculated as Cronbach's alpha to 0.94. The generalisability coefficient with two raters and two procedures was 0.91. Mean scores were 50.7 (SD±13.2) and 74.7 (SD±4.8) for novices and experienced surgeons, respectively (p<0.001). The pass/fail score of 62 points resulted in zero false negatives and only three false positives. We have gathered valuable additional validity evidence for the assessment tool TUBE-iCOMPT including establishment of a credible pass/fail score. The TUBE-iCOMPT can now be integrated in mastery learning programmes to ensure competency before independent practice.


Ligand-stabilized and atomically precise gold nanocluster catalysis: a case study for correlating fundamental electronic properties with catalysis.
We present results from our investigations into correlating the styrene-oxidation catalysis of atomically precise mixed-ligand biicosahedral-structure [Au25(PPh3)10(SC12H25)5Cl2](2+) (Au25-bi) and thiol-stabilized icosahedral core-shell-structure [Au25(SCH2CH2Ph)18](-) (Au25-i) clusters with their electronic and atomic structure by using a combination of synchrotron radiation-based X-ray absorption fine-structure spectroscopy (XAFS) and ultraviolet photoemission spectroscopy (UPS). Compared to bulk Au, XAFS revealed low Au-Au coordination, Au-Au bond contraction and higher d-band vacancies in both the ligand-stabilized Au clusters. The ligands were found not only to act as colloidal stabilizers, but also as d-band electron acceptor for Au atoms. Au25-bi clusters have a higher first-shell Au coordination number than Au25-i, whereas Au25-bi and Au25-i clusters have the same number of Au atoms. The UPS revealed a trend of narrower d-band width, with apparent d-band spin-orbit splitting and higher binding energy of d-band center position for Au25-bi and Au25-i. We propose that the differences in their d-band unoccupied state population are likely to be responsible for differences in their catalytic activity and selectivity. The findings reported herein help to understand the catalysis of atomically precise ligand-stabilized metal clusters by correlating their atomic or electronic properties with catalytic activity.


Evolution not Revolution: Nutrition and Obesity.
The increasing prevalence of obesity over the course of life is a global health challenge because of its strong and positive association with significant health problems such as type 2 diabetes, cardiovascular disease, stroke, and some cancers. The complex causes and drivers of obesity include genetic factors, social, ecological and political influences, food production and supply, and dietary patterns. Public health messages and government food and activity guidelines have little impact; the retail food environment has many low-priced, nutrient-poor, but energy-dense products and there is a gap between what an individual knows and what they do. Public health and education services need legislation to mandate supportive environments and promote food literacy. Two New Zealand case studies of proof-of-principle of positive change are described: Project Energize and Under 5 Energize as exemplars of school environment change, and the development of the Nothing Else™ healthier snack bar as an example of working with the food industry. Changes in food literacy alongside food supply will contribute in the long term to positive effects on the future prevalence of obesity and the onset of non-communicable disease. More cross-disciplinary translational research to inform how to improve the food supply and food literacy will improve the health and wellbeing of the economy and the population.


Combined analyses of 20 common obesity susceptibility variants.
Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes. In this study we investigate the combined effect of these variants and their ability to discriminate between normal weight and overweight/obese individuals. We applied receiver operating characteristics (ROC) curves, and estimated the area under the ROC curve (AUC) as a measure of the discriminatory ability. The analyses were performed cross-sectionally in the population-based Inter99 cohort where 1,725 normal weight, 1,519 overweight, and 681 obese individuals were successfully genotyped for all 20 variants. When combining all variants, the 10% of the study participants who carried more than 22 risk-alleles showed a significant increase in probability of being both overweight with an odds ratio of 2.00 (1.47-2.72), P = 4.0 x 10(-5), and obese with an OR of 2.62 (1.76-3.92), P = 6.4 x 10(-7), compared with the 10% of the study participants who carried less than 14 risk-alleles. Discrimination ability for overweight and obesity, using the 20 single nucleotide polymorphisms (SNPs), was determined to AUCs of 0.53 and 0.58, respectively. When combining SNP data with conventional nongenetic risk factors of obesity, the discrimination ability increased to 0.64 for overweight and 0.69 for obesity. The latter is significantly higher (P < 0.001) than for the nongenetic factors alone (AUC = 0.67). The discriminative value of the 20 validated common obesity variants is at present time sparse and too weak for clinical utility, however, they add to increase the discrimination ability of conventional nongenetic risk factors.


[Study of lysozyme by a spin-label method in the 2-mm range].
Two millimeter range ESR-spectroscopy was used to measure the values of magnetic resonance parameters of egg lysozyme samples modified with nitroxyl label 4-(iodine-acetamide)-2,2,6,6-tetramethylpiperidine-1-oxyl by hist-15 residue. It has been shown that in a lyophilic sample the spin label forms a hydrogen bond with the protein group and when the sample is moistened--with water molecules. Temperature changes of the pattern of ESR line are analysed. It is concluded that in the moistened samples within 230-320 K the nitroxyl fragment of the label gets engaged in anisotropic movement with preferable rotation around Z-axis of N-O. fragment with anisotropy coefficient 5 and mean correlation time tau congruent to 5 X 10(-7) divided by 5 X 10(-8) c.


The intermodality relationship of auditory and vision perception.
A review of the literature reemphasizes the importance of the intermodality relationship of auditory and vision perception in assisting children learning to read. Following a description of the neuro-pathways, hemispheric dominance theories and the developmental sequences, suggestions are provided for the application of the knowledge about auditory and vision perception in the prevention of the ever increasing number of children experiencing learning disabilities.


Actomyosin regulatory properties of yeast tropomyosin are dependent upon N-terminal modification.
The yeast tropomyosin 1 gene (TPM1) encodes the major isoform of the two tropomyosins (Tm) found in yeast. The gene has been expressed in E. coli and the protein purified. The gene product (yTm1) is a 199-amino acid protein that has a low affinity for actin compared to the native yTm1 purified from yeast. Mass spectrometry shows that the native protein is acetylated while the recombinant protein is not. A series of yTm1 N-terminal constructs were made with either an Ala-Ser dipeptide extension previously shown to restore actin binding to skeletal muscle Tm or the natural extension found in fibroblast Tm 5a/b. All constructs bound actin tightly and showed similar CD spectra and thermal stability. All constructs induced cooperativity in the equilibrium binding of myosin subfragment 1, to actin but the binding curves differed significantly between the constructs. The apparent cooperative unit size (n) and closed/open equilibrium (K(T)) were determined using a fluorescence titration technique [Maytum et al. (1998) Biophys. J. 74, A347]. The data could be accounted for by changes in K(T) (0.1-1) with no change in n. Values of n were approximately twice the structural unit size (5 actin sites). The presence of yTm on actin had little effect upon the overall affinity of S1 for actin despite showing an ability to regulate the acto-myosin interaction. These results show that the short yTm can aid our understanding of actomyosin regulation and that the N-terminus of Tm has a major influence upon its regulatory properties.


Injury-related predictors of symptom severity following sports-related concussion.
Decisions regarding return to play after sports-related concussion partially revolve around athletes' self-reported symptoms. Given this emphasis on symptoms, it would be beneficial to be able to identify characteristics that could predict which athletes may be susceptible to developing an increase in postconcussion symptoms following head injury. The purpose of this study was to describe the symptoms that athletes endorse immediately following concussion and to determine what impact injury-related characteristics have on the development of postconcussion symptoms within the first week following concussion. Participants included 54 collegiate athletes who sustained concussions and were referred to our concussion management program for postconcussion testing. The main outcome measures included the Post-Concussion Symptom Scale and an interview querying athletes' retrospective symptoms over time, starting immediately postinjury. Descriptive statistics revealed that the most common immediate symptoms following concussion include dizziness (endorsed by 83.6% of the sample), headache (65.5%), feeling in a fog (61.8%), and visual disturbance (60.0%). Logistic regression analyses indicated that retrograde and anterograde amnesia, as well as loss of consciousness, were not significantly predictive of postconcussion symptoms within one week following concussion (p > .05). However, the total symptom score assessed immediately postinjury, in addition to endorsing immediate headache symptoms following concussion, reliably predicted a higher level of symptom reporting in the first week following concussion (p < .05). Finally, receiver-operating characteristic (ROC) curve analysis, using 80% sensitivity to predict the high postconcussion symptom group, established cutoff scores of 7.5 for the immediate total symptom score and 0.5 for immediate headache. These findings demonstrate the importance of evaluating symptoms immediately following concussion. Athletes who endorse more immediate postconcussion symptoms, especially headache symptoms, may be at risk for greater and more severe postconcussion symptoms within the first week following concussion. The present findings have implications for the management and treatment of sports-related concussions.


Effect of O6-benzylguanine on the sensitivity of human tumor xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea and on DNA interstrand cross-link formation.
We have previously shown that O6-benzylguanine can be used to deplete cells of the DNA repair protein O6-alkylguanine-DNA alkyltransferase and to enhance the sensitivity of human glioma (SF767) and colon tumor (HT29) cells to the cytotoxic effects of alkylnitrosoureas. In the present study, the combination of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was evaluated in vitro to determine the number of DNA interstrand cross-links formed and in vivo to compare the therapeutic index with that of BCNU alone. The number of DNA interstrand cross-links, as measured by alkaline elution, was increased in HT29 cells treated with 10 microM O6-benzylguanine for 2 h prior to BCNU exposure compared to cells treated with BCNU only. The number of single strand breaks was not increased by prior exposure to O6-benzylguanine. To evaluate the therapeutic index, HT29 and SF767 cells were grown as xenografts in nude mice and the tumor growth rate after treatment with BCNU alone was compared with the rate after treatment with O6-benzylguanine and BCNU. Treatment was administered i.p. when tumors reached 100-200 mm3. For animals bearing HT29 xenografts that were treated with 60 mg/kg O6-benzylguanine 1 h prior to 20 mg/kg BCNU, the average time for tumor volume to increase by 200% was 25 days, compared to 10 days for animals treated with 20 mg/kg BCNU alone. For animals bearing SF767 xenografts, the tumor growth of controls was not significantly different from that of animals treated with O6-benzylguanine alone or BCNU alone up to the maximally tolerated dose (50 mg/kg). For these 3 groups, the average time for tumors to reach 300 mm3 was 9-12 days. However, when animals were treated with 80 mg/kg O6-benzylguanine 1 h prior to receiving 20 mg/kg BCNU tumor size did not increase for at least 21 days. Our studies demonstrate that the therapeutic index of BCNU can be increased when given in combination with O6-benzylguanine.


Comparison of "silent" clustered and sparse temporal fMRI acquisitions in tonal and speech perception tasks.
In the functional imaging of auditory cortical functions, long silent periods between the data acquisitions prevent interferences between scanner noise and the auditory stimulus processing. Recent fMRI studies have shown that sparse temporal acquisition designs are advantageous over continuous scanning protocols on physiological, perceptual, and cognitive levels. Sparse temporal acquisition schemes (STA) which use a single volume acquisition after each trial imply the advantage of auditory stimulation devoid of ambient scanner noise but have the drawback of a reduced statistical power. To alleviate this effect, STA schemes have been extended to clustered-sparse temporal acquisition (CTA) designs which record several subsequent BOLD contrast images in rapid succession. In the present study, we collected data from 13 healthy volunteers performing a speech and a tonal discrimination task using both a CTA and STA scheme to carry out a systematic evaluation of these acquisition protocols. By statistical modeling of the fMRI data sets, we revealed stronger effect sizes for the STA protocol regardless of the task, reflecting the better signal-to-noise-ratio of MR images acquired with this scheme. In contrast, we demonstrate higher statistical power for the use of a CTA protocol. Accordingly, in the context of standard fMRI analysis, the CTA protocol clearly outperformed the STA scheme at the level of single-subject analysis and fixed-effects group analysis. Our results clearly suggest that it is advantageous to acquire several sample points per trial if one wants to use the benefit of "silent" fMRI. Furthermore, our data demonstrate the feasibility of the clustered acquisition of subsequent imaging volumes along the T1-decay.


Triage score for severity of illness.
To evolve a triage scoring system for severity of illness based on clinical variables related to systemic inflammatory response syndrome (SIRS). Prospective study in a tertiary-care hospital. Consecutive pediatric patients admitted to the ward or pediatric intensive care unit (PICU) were studied. The respiratory rate, heart rate, capillary refill time, oxygen saturation (SpO2), systolic blood pressure and temperature were noted, Sensorium level was assessed on AVPU score. Variables were based on SIRS criteria and criteria mentioned in Advanced Pediatric Life Support (APLS). Each study variable was scored as 0 or 1 (normal or abnormal) and total score for each child obtained. The survival at discharge was correlated with the study variables and the total score. Another score based on the magnitudes of the coefficients in multiple logistic regression analysis was computed and the correlation between this score and mortality was also studied. ROC curve analysis was performed to see the overall predictive ability of the score as well as a cut off at which maximum discrimination occurred. Of 1099 children studied, 44 died. Of the seven variables, only five variables were abnormal in the study subjects. Except heart rate and respiratory rate, all other variables and age showed significant association with survival status (P < 0.01). The mortality increased with increase in the number of abnormal variables: 0.4% 2.2% 6.1% 15.3% 19.4% and 29.4%for scores of 0,1,2,3,4 and 5 respectively and the linear trend was significant (P < 0.01). Mortality also increased with a decrease in age (P < 0.01). Children with a score of 2 or more (2 or more abnormal clinical variables) had significantly higher mortality as compared to those with no abnormal clinical variables (score = 0). Based on the regression coefficients, the maximum possible score was 9.8. Regression based score was found to predict survival status well. The area under the ROC curve was 0.887, indicating that overall 88.7% of the subjects could be predicted correctly. Maximum discrimination was observed at a score of 2.5 (sensitivity 84.1% specificity 82.2%). For triage scoring, any child with 2 or more abnormal clinical variables should be taken as serious that might lead to death. With a more detailed scoring, score of 2.5 can be taken as cut-off to select children who possibly need admission and closer observation.


The Effects of Exoskeleton Assisted Knee Extension on Lower-Extremity Gait Kinematics, Kinetics, and Muscle Activity in Children with Cerebral Palsy.
Individuals with cerebral palsy often exhibit crouch gait, a debilitating and inefficient walking pattern marked by excessive knee flexion that worsens with age. To address the need for improved treatment, we sought to evaluate if providing external knee extension assistance could reduce the excessive burden placed on the knee extensor muscles as measured by knee moments. We evaluated a novel pediatric exoskeleton designed to provide appropriately-timed extensor torque to the knee joint during walking in a multi-week exploratory clinical study. Seven individuals (5-19 years) with mild-moderate crouch gait from cerebral palsy (GMFCS I-II) completed the study. For six participants, powered knee extension assistance favorably reduced the excessive stance-phase knee extensor moment present during crouch gait by a mean of 35% in early stance and 76% in late stance. Peak stance-phase knee and hip extension increased by 12° and 8°, respectively. Knee extensor muscle activity decreased slightly during exoskeleton-assisted walking compared to baseline, while knee flexor activity was elevated in some participants. These findings support the use of wearable exoskeletons for the management of crouch gait and provide insights into their future implementation.


Qualitative assessment of a challenge-based learning and teamwork applied in electronics program.
Every student of industrial technology engineering must develop and acquire specific electronic competencies and skills, such as those pertaining to the design, analysis, and assembly of basic circuits in the context of both analogue and digital electronics, including the corresponding instrumentation. Additionally, as is the case for practically all university degrees but has not always been addressed adequately in the field of engineering, generic competencies such as oral communication and teamwork must be acquired. The experience discussed in the article focuses on the design, implementation, and assessment of a hybrid (face-to-face and virtual) educational activity that facilitates the acquisition of specific engineering skills through a teamwork-based approach and enhances communication among students in the context of experimentation. The students, who are divided into teams, must develop a series of embedded systems with the aim of providing a solution to a problem derived from Sustainable Development Goal 11: Sustainable Cities and Communities. This approach entails the challenge of working with a heterogeneous sample of students studying for a dual degree in design and mechanics, whose motivations are also highly varied. The innovative objective of the educational proposal focuses on adapting the practice to the roles and profiles of the students and tailoring project phases to the competency needs of each student. The results highlight the need to design real practices that foster the motivation of engineering students; they also emphasize the fact that in the context of teamwork, roles pertaining to the specific competencies required by dual-degree students should be defined. The evaluation of such an experiment using the Bipolar Laddering Assessment has exhibited utility and reliability regarding small samples of users and has been shown to be valid regarding identifying the strengths and weaknesses of educational experiments.


Combined fibrinogen concentration and neutrophil-lymphocyte ratio as a prognostic marker of gastric cancer.
Certain patients with early gastric cancer succumb to recurrent disease and cancer-associated complications. The key cause of recurrence is challenging to determine, since clinical blood markers that are able to predict the tumor properties of gastric cancer are limited. The present study investigated the fibrinogen concentration and neutrophil-lymphocyte ratio (NLR) in blood specimens from patients with gastric cancer, and assessed the clinical applicability of combining the fibrinogen concentration with the NLR (CFS-NLR) as a prognostic marker of gastric cancer. The present study consisted of 275 patients with gastric cancer, who were divided into three groups: Those possessing hyperfibrinogenemia (≥305 mg/dl) and a high NLR (≥2.34; CFS-NLR 2 group); those possessing either hyperfibrinogenemia or a high NLR (CFS-NLR 1 group); or those that possessed neither abnormality (CFS-NLR 0 group). The CFS-NLR was significantly associated with the depth of tumor invasion, lymph node metastasis, lymphovascular invasion and tumor stage (P<0.0001). The prognostic differences among the three groups were significant (P=0.0016). Therefore, the CFS-NLR may be a potentially useful blood marker for predicting tumor progression and the prognosis of patients with gastric cancer.


In vitro activity of kaempferol isolated from the Impatiens balsamina alone and in combination with erythromycin or clindamycin against Propionibacterium acnes.
The in vitro antibacterial activity against antibiotic-resistant Propionibacterium acnes of kaempferol isolated from the Impatiens balsamina alone and in combination with erythromycin or clindamycin antibiotics was investigated. The antibiotic combination effect against antibiotic-resistant P. acnes was studied by checkerboard test. Kaempferol and quercetin demonstrated antibacterial activities against P. acnes. Minimum inhibitory concentrations (MICs) for both compounds were < or =32 ug/ml and < or =64 ug/ml for clindamycin-sensitive and-resistant P. acnes, respectively. The four combination formulations (kaempferol and either erythromycin or clindamycin; quercetin and either erythromycin or clindamycin) exhibited a synergic inhibition of P. acnes growth. The combination of kaempferol with quercetin showed an indifferent effect. The combination of clindamycin with kaempferol or quercetin showed a greater synergic effect than that of erythromycin with kaempferol or quercetin. Thus, these combinations demonstrated the potential to treat acne.


Valence norms for 3,600 English words collected during the COVID-19 pandemic: Effects of age and the pandemic.
The topic of affective development over the lifespan is at the forefront of psychological science. One of the intriguing findings in this area is superior emotion regulation and increased positivity in older rather than younger adults. This paper aims to contribute to the empirical base of studies on the role of affect in cognition. We report a new dataset of valence (positivity) ratings to 3,600 English words collected from North American and British English-speaking younger (below 65 years of age) and older adults (65 years of age and older) during the COVID-19 pandemic. This dataset represents a broad range of valence and a rich selection of semantic categories. Our analyses of the new data pitted against comparable pre-pandemic (2013) data from younger counterparts reveal differences in the overall distribution of valence related both to age and the psychological fallout of the pandemic. Thus, we found at the group level that older participants produced higher valence ratings overall than their younger counterparts before and especially during the pandemic. Moreover, valence ratings saw a super-linear increase after the age of 65. Together, these findings provide new evidence for emotion regulation throughout adulthood, including a novel demonstration of greater emotional resilience in older adults to the stressors of the pandemic.


Recent advances in antiarrhythmic drug treatment of atrial fibrillation.
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia in clinical practice associated with significant morbidity and mortality. With the growing number of the affected individuals, the development of safe and effective treatment options for AF has become a worldwide priority. Currently available antiarrhythmic medications for the restoration and maintenance of sinus rhythm have limitations due to the modest efficacy and a potential for adverseeffects. Although substantial progress has been made in AF-ablation techniques, broad application of these nonpharmacological treatment modalities is limited and antiarrhythmic drug treatment is still the cornerstone and the first-line therapy for the majority of AF patients. Improvements in the understanding of the principal pathophysiological mechanisms of AF obtained in the last several years have provided promising treatment opportunities. New therapeutic options are based on the more selective targeting of ion channels and intercellular connection proteins predominantly expressed in the atria, the restoration of intracellular Ca(2+) homeostasis and the prevention of AF-associated electrical and structural remodeling. In this review, we provide a highlight of the most important pathophysiological mechanisms in AF with a relation to the potential therapeutic interventions, and discuss novel findings regarding the current and future pharmacological AF management and recent patents.


Developmental plasticity of auditory cortical inhibitory synapses.
Functional inhibitory synapses form in auditory cortex well before the onset of normal hearing. However, their properties change dramatically during normal development, and many of these maturational events are delayed by hearing loss. Here, we review recent findings on the developmental plasticity of inhibitory synapse strength, kinetics, and GABAA receptor localization in auditory cortex. Although hearing loss generally leads to a reduction of inhibitory strength, this depends on the type of presynaptic interneuron. Furthermore, plasticity of inhibitory synapses also depends on the postsynaptic target. Hearing loss leads reduced GABAA receptor localization to the membrane of excitatory, but not inhibitory neurons. A reduction in normal activity in development can also affect the use-dependent plasticity of inhibitory synapses. Even moderate hearing loss can disrupt inhibitory short- and long-term synaptic plasticity. Thus, the cortex did not compensate for the loss of inhibition in the brainstem, but rather exacerbated the response to hearing loss by further reducing inhibitory drive. Together, these results demonstrate that inhibitory synapses are exceptionally dynamic during development, and deafness-induced perturbation of inhibitory properties may have a profound impact on auditory processing.


Nucleic acid-protein interactions in turnip yellow mosaic virus.
Mild alkaline treatment induces the formation of a specific RNA complex inside turnip yellow mosaic virus. Dialysis at pH 4.5 destroys this complex inside the capsid, but does not destroy complexes that have been removed from their capsids. These facts were interpreted in terms of a breakage and subsequent re-formation of RNA-protein links. In combination with supporting potentiometric data, they suggest histidinyl-phosphate salt links or carboxylate-amino hydrogen bonds, or both, as the principal means of association of turnip yellow mosaic virus protein and RNA.


Phenolation of cyclodextrin polymers controls their lead and organic micropollutant adsorption.
Porous β-cyclodextrin polymers linked with tetrafluoroterephthalonitrile (TFN-CDPs) have shown promise for adsorbing organic micropollutants (MPs) more quickly and effectively than conventional adsorbents. Prior to their discovery, the nucleophilic aromatic substitution (SNAr) reaction used to prepare TFN-CDP was nearly unknown for the aliphatic alcohol nucleophiles, and the low isolated yields of TFN-CDP motivated model studies of the reaction between TFN and n-butanol. These experiments reveal a previously undescribed substitution reaction of TFN in which a fluorine is substituted by a hydroxyl group. This process is responsible for the low yields of the polymerization and incorporates phenolate groups into the polymer network. Phenolation and polymerization (etherification) are competing processes, and the level of phenolate incorporation was controlled by varying the rate of base addition and initial monomer concentrations. TFN-CDPs with varying phenolate content were prepared and evaluated as adsorbents for both Pb2+ ions and 83 MPs. More heavily phenolated polymers showed increased capacity to bind Pb2+ ions. Phenolation was also correlated with increased binding affinity for almost all of the 83 MPs tested, including neutral, cationic, and anionic substances. These results leverage a newly discovered side reaction during SNAr reactions of electron-poor aryl fluorides to improve both the yield and the uptake affinity for both lead and organic MPs of TFN-CDPs.


99mTc MIBI scintimammography with a high resolution single tube gamma camera: preliminary study.
99mTc MIBI scintimammography is a sensitive and specific diagnostic technique for breast cancer detection when cancers more than 1 cm sized are considered. However the sensitivity falls in the case of submillimetric lesions. We developed a new Small Field of View, High Resolution Detector, able to image the breast in similar conditions of x-ray mammography: it allows the performance of Single Photon Emission Mammography (SPEM) studies. Seven patients with suspicion of malignant lesions were comparatively submitted to a Prone Scintimammography (PSM) by Anger camera and to a cranio-caudal view SPEM. The final diagnosis was reached by histopathology. Four malignant lesions were identified by SPEM but not by PSM, which that failed to image two submillimetric cancers. Both the cameras gave normal findings for benign lesions, confirming the high sensitivity of this technique. The results allow us to consider the SPEM camera as promising to improve scintimammographic sensitivity, even when small-sized tumors are examined.


Lack of association between falciparum malaria parasitemia and acute diarrhea in Nigerian children.
It is widely believed that malaria causes diarrhea. Yet, national and international diarrheal diseases control programs are silent about the overlap between these two major public health problems that coexist in most tropical countries. To test the hypothesis that malaria is associated with diarrhea and to define the role of malaria in morbidity due to diarrhea, 522 children 6-60 months of age presenting with acute diarrhea to the Children's Emergency Ward of the University College Hospital in Ibadan, Nigeria were routinely screened by means of thin and thick blood films for malaria parasitemia. Controls, without diarrhea, were studied in parallel. Detailed clinical features were recorded for every patient. Sixty-eight (13%) of the 522 diarrhea patients screened had malaria parasitemia. Among the controls (who had similar distributions of admission temperature, hemoglobin types, glucose-6-phosphate dehydrogenase deficiency, and prior treatment with antimalarial drugs), parasitemia was not significantly different, occurring in 56 (17.9%) of 313. In the dry season, however, a significantly higher prevalence of parasitemia was observed among the control group (15.5%) than in the diarrhea group (7.0%) (P = 0.004). Parasitemia was significantly more common in the dehydrated diarrhea patients than their well-hydrated counterparts (25% of 56 versus 11% of 466; P < 0.005). There were no significant differences in admission temperature, the presence of vomiting, or the home use of oral rehydration fluids between the dehydrated and the well-hydrated subsets of diarrhea patients. Consideration of parasite densities did not alter any of the foregoing relationships. These data contradict the widely held view that diarrhea is a symptom of malaria or that malaria causes diarrhea. They do, however, provide support for examining blood smears at least in dehydrated children with diarrhea in malaria-endemic areas and giving immediate antimalarial therapy to those who have malaria parasitemia.


Physiotherapist-led programmes and interventions for rehabilitation of anterior cruciate ligament, medial collateral ligament and meniscal injuries of the knee in adults.
Soft-tissue injuries of the knee, mainly involving the anterior cruciate ligament (ACL), the medial collateral ligament (MCL) and menisci, are common and their rehabilitation after non-surgical or surgical treatment often involves intensive and prolonged physiotherapy. To examine the evidence for effectiveness of various physiotherapist-led (or 'directed') rehabilitation programmes, and of various interventions used within these programmes, for rehabilitation of acute or chronic ACL, MCL or meniscal injuries of the knee in adults. We searched the Cochrane Musculoskeletal Injuries Group's specialised register (to June 2001), MEDLINE (from 1966 to August 1999), EMBASE (from 1980 to February 1997), CINAHL (1982 to April 1999), CURRENT CONTENTS (up to March 1999) and reference lists of relevant articles, and consulted colleagues. Date of the most recent search: June 2001. Randomised or quasi-randomised clinical trials evaluating physiotherapist-led rehabilitation programmes, or components of rehabilitation programmes, for the treatment or post-surgical rehabilitation of ACL, MCL or knee meniscal injuries. Excluded were trials investigating electrical stimulation, or various interventions such as cryotherapy, immobilisation braces and continuous passive motion when used in initial or early treatment. Laboratory based trials reporting intermediate outcomes were also excluded. All trials, judged as fitting the selection criteria by two reviewers, were independently assessed by two reviewers for methodological quality by use of an 11 item checklist. Data were independently extracted by two reviewers. Any disagreement was resolved by discussion. Although quantitative data from most trials are presented, using relative risks or mean differences together with 95 per cent confidence intervals, trial heterogeneity and lack of outcome data prevented meaningful pooling of results from comparable trials. Thirty-one trials, involving 1545 mainly young and male patients, met the inclusion criteria of the review. Methodological quality was highly variable: allocation concealment and / or assessor blinding were rare, and assessment of outcome was often incomplete and short-term. ACL injury and /or deficiency was the main focus of 18 trials, MCL injury of two trials, meniscal injury of nine trials and a mixture of soft-tissue injuries in the other two trials. The trial comparisons fell into five main categories: rehabilitation programme versus control (6 trials); one rehabilitation programme versus another (6 trials); different timing of rehabilitation (4 trials); one component of a programme versus another (6 trials); supplementary interventions to a programme versus none (9 trials). No trial provided sufficient evidence to establish the relative effectiveness of the intervention(s) under investigation. The available evidence for physiotherapist-led rehabilitation of ACL, MCL and meniscal injuries is wide ranging in terms of scope but insufficient to establish the relative effectiveness of the various approaches and methods in current use. There is a need for further research involving good quality, large scale randomised trials with sufficiently long follow-up to fully assess knee function and recovery.


Correlation of Immune Responses Mediated by T Helper 1 and 2 in Children with Viral Encephalitises.
This work deals with the problem concerning the mechanisms of triggering the demyelinating process by viruses as the consequence of molecular mimicry between viral antigens and the immunodominant region of the myelin basic protein with the subsequent involvement of reactions, mediated by T helper cells 1 and 2. Special emphasis is made on the new data indicating that reagin mechanisms play an active role in the development of neuropathology, corresponding to the results obtained by the authors in the study of humoral response in multiple sclerosis patients. Thus, the presence of pronounced total and specific IgE response was established to myelin basic protein, correlating with more severe clinical manifestations of the disease. Taking into account the viral nature of the demyelinization, the authors studied a number of humoral characteristics of immune response, indicating the degree of the involvement of T helper cells 1 and 2 into the pathogenesis of acute viral encephalitises. The determination of these characteristics was carried out with the use of original methods developed by the authors. The analysis of the results obtained in this study revealed the obvious presence of relationship between the involvement of autoimmune and atopic response in children with acute viral encephalitises and the manifestation of molecular mimicry of corresponding viruses with the immunodominant region of myelin basic protein. The most prognostically unfavorable group was the group of children having rubella, adenovirus and herpetic encephalitises.


Psychological and perceptual factors associated with arrhythmias and benign palpitations.
Little is known about how patients who seek medical help for benign palpitations can be distinguished from those with clinically significant arrhythmias. This study tested whether patients with arrhythmia can be distinguished from those who are aware of sinus rhythm or extrasystoles on the basis of sex, prevalence of anxiety disorders, and heartbeat perception. A consecutive sample of patients referred to a cardiology clinic participated in the study. Patients were diagnosed as having either arrhythmia (N = 62), extrasystoles (N = 75), or awareness of sinus rhythm (N = 47). They were assessed with use of the anxiety disorders and hypochondriasis modules of the Structured Clinical Interview for DSM-IV. Both patients and control subjects (N = 35) answered questionnaires measuring anxiety, fear of bodily sensations, and depression and underwent a heartbeat perception test. The present report focuses on patients who had palpitations but no comorbid cardiovascular disease. Patients with awareness of sinus rhythm could be distinguished from those with arrhythmia by several variables: female sex, higher prevalence of panic disorder, poor performance on the heartbeat perception test, report of palpitations when doing the test, higher heart rates, lower levels of physical activity, and (as trends) a greater prevalence of panic attacks, fear of bodily sensations, and depression. In contrast, patients with arrhythmias rarely reported palpitations when doing the test but were more likely to perceive their heartbeats accurately than patients with sinus rhythm and control subjects. Performance on the heartbeat perception test was intermediate in patients with extrasystoles; these patients also had an intermediate prevalence of panic disorder and intermediate depression scores. Measures of panic disorder and a simple heartbeat perception test could complement medical assessment in the diagnosis of patients who seek medical help for palpitations. The results also have implications for the treatment of patients with benign palpitations.


Olivocochlear neurons in the chinchilla: a retrograde fluorescent labelling study.
Although the chinchilla is widely used as a model for auditory research, little is known about the distribution and morphology of its olivocochlear neurons. Here, we report on the olivocochlear neurons projecting to one cochlea, as determined by single and double retrograde fluorescent tracer techniques. 10 adult chinchillas were anesthetized and given either unilateral or bilateral injections of a fluorescent tracer (either Fluoro-Gold or Fast Blue) into scala tympani or as a control, a unilateral injection into the middle ear cavity. The results indicate that there are similarities as well as significant differences between the chinchilla and other species of rodents in the distributions of their olivocochlear neurons. Based on three well-labelled cases, there was a mean total of 1168 olivocochlear neurons in the chinchilla. Of these, the majority (mean 787) were small, lateral olivocochlear neurons found almost exclusively within the ipsilateral lateral superior olivary nucleus. The next largest group consisted of a mean of 280 medial olivocochlear neurons virtually all of which were located in the dorsomedial peri-olivary nucleus. Chinchilla medial olivocochlear neurons were more predominantly crossed in their projections (4:1) than in any known species. The smallest group of olivocochlear neurons (mean 101) consisted of larger lateral olivocochlear neurons (shell neurons) which were located on the margins of the superior olivary nucleus and which projected mainly (2.2:1) ipsilaterally. Double retrograde labelling was observed only in medial olivocochlear neurons and occurred in only 1-2% of these cells. The results confirm previous findings which indicated a relative paucity of fibers belonging to the uncrossed as compared to the crossed olivocochlear bundle. This, together with the strong apical bias of the uncrossed projection reported previously, offers possible explanations for the apparent absence of efferent-mediated suppressive effects of contralateral acoustic stimulation in this species. Regarding the lateral olivocochlear system, the chinchilla is shown to possess both intrinsic and shell neurons, as in the rat.


[Elevation of gamma-glutamyltransferase levels in treated epileptic patients].
Plasma levels of gamma-glutamyl transpeptidase were measured prospectively in 75 epileptic patients treated with one of the following drugs: phenobarbitone (n = 20), phenytoin (n = 23), carbamazepine (n = 18) or sodium valproate (n = 14). A significant increase in gamma-glutamyl transpeptidase levels was observed from the 7th day of treatment onward. The increase was particularly pronounced in the phenytoin group, with mean and maximum values of 104.10 and 215 mU/ml respectively, followed by the phenobarbitone group (mean 68.15, max. 124 mU/ml), the carbamazepine group (mean 49.83, max. 100 mU/ml) and the sodium valproate group (mean 35.42, max. 70 mU/ml). This was due to enzyme induction being highest with phenytoin and phenobarbitone which are strongly liposoluble and have prolonged half-life. Any epileptic patient with plasma gamma-glutamyl transpeptidase levels higher than those found in this study may be suspected of having viral or alcoholic hepatitis.


Knowledge Discovery from Biomedical Ontologies in Cross Domains.
In recent years, there is an increasing demand for sharing and integration of medical data in biomedical research. In order to improve a health care system, it is required to support the integration of data by facilitating semantic interoperability systems and practices. Semantic interoperability is difficult to achieve in these systems as the conceptual models underlying datasets are not fully exploited. In this paper, we propose a semantic framework, called Medical Knowledge Discovery and Data Mining (MedKDD), that aims to build a topic hierarchy and serve the semantic interoperability between different ontologies. For the purpose, we fully focus on the discovery of semantic patterns about the association of relations in the heterogeneous information network representing different types of objects and relationships in multiple biological ontologies and the creation of a topic hierarchy through the analysis of the discovered patterns. These patterns are used to cluster heterogeneous information networks into a set of smaller topic graphs in a hierarchical manner and then to conduct cross domain knowledge discovery from the multiple biological ontologies. Thus, patterns made a greater contribution in the knowledge discovery across multiple ontologies. We have demonstrated the cross domain knowledge discovery in the MedKDD framework using a case study with 9 primary biological ontologies from Bio2RDF and compared it with the cross domain query processing approach, namely SLAP. We have confirmed the effectiveness of the MedKDD framework in knowledge discovery from multiple medical ontologies.


Twelve tips for practical clinical skills coaching.
Coaching is rapidly evolving in clinical medicine, including for clinical skills (CS) learning. Yet a schema is needed for how to coach students in the many CS that are pivotal to the practice of medicine. These twelve tips aim to provide practical strategies for teachers and educators to coach students for CS learning. The tips cover many important aspects of CS coaching, including establishing a safe space, ways to prepare to coach, setting goals, guiding a coaching relationship, fostering coaching conversations, and in-person or virtual approaches. Together, the tips align as seven key steps of an overall coaching process. The twelve tips apply equally to coaching struggling students and all students seeking to improve CS and offer a guide for coaching at an individual or program level.


Reproducibility in the cardiometabolic responses to high-intensity interval exercise in adults with type 1 diabetes.
Patients with type 1 diabetes (T1D) often report a rise in their blood glucose level following brief intense exercise. We sought to determine the reproducibility of the cardiometabolic responses to high-intensity interval training (HIIT). Sixteen adults with T1D, using an optimized multiple daily injection with basal insulin glargine 300 U/mL (Gla-300), performed four fasted HIIT sessions over a 4-6-week period. Exercise consisted of high-intensity interval cycling and multimodal training over 25 min. Heart rate and rating of perceived exertion rose similarly in all sessions, as did lactate, catecholamine and growth hormone levels. Plasma glucose increased in response to HIIT in 62 of 64 visits (97%), with an overall increase of 3.7 ± 1.6 mmol/L (Mean ± SD) (P < 0.001). In within-patient comparisons, the change in plasma glucose among the four HIIT sessions was significantly correlated with a composite correlation of 0.58 ([r2 = 0.34]; 95% CI 0.35-0.80; P < 0.01). Intersession observations of four separate HIIT sessions showed high intrasubject reproducibility in the cardiometabolic responses to exercise, including the rise in plasma glucose, when adults with T1D perform the activity in a fasted state.


Pathogenic analysis of suspected COVID-19 patients in a SARS-CoV-2 non-epidemic area of China.
The aim of this study is to find the distributions of pathogens in 164 suspected COVID-19 patients from the outpatient clinic of Shenjing Hospital of China Medical University from 24th January, 2020, to 29th February of 2020. 164 COVID-19 suspected patients were from the Shengjing Hospital of China Medical University. Oropharyngeal swab specimens were acquired by respiratory doctors under standardized conditions. Specific nucleic acids of SARS-CoV-2, influenza A and B, respiratory syncytial virus A and B, adenovirus, parainfluenza virus, along with pneumonic mycoplasma were detected by real-time fluorescence PCR. Symptomatic, epidemiologic, laboratory and radiological data of the patients were obtained from the electronic medical record system of our hospital. Among the 164 patients, 3 were positive for SARS-CoV-2, 15 were positive for other respiratory viruses and 16 were positive for pneumonic mycoplasma. Of the positive patients above, 1 patient was co-infected with SARS-CoV-2 and adenovirus, and 1 was co-infected with influenza B and pneumonic mycoplasma. The 3 SARS-CoV-2 infected patients were clinically diagnosed as COVID-19 because they meet the diagnostic criteria listed in "Chinese Clinical Guidance for COVID-19 Pneumonia diagnosis and treatment", including epidemic history, symptom and pathogenic detection, as well as abnormalities of the laboratory and radiological data. However, the clinical characteristics of COVID-19 patients were non-specific compared to those of the patients infected with other respiratory viruses. The endemic common respiratory pathogens are more prevalent than SARS-CoV-2 in the SARS-CoV-2 non-epidemic areas of this research. Detection of the pathogen is the unique means for definite COVID-19 diagnosis.


Lymphocytic interstitial pneumonia.
Lymphocytic interstitial pneumonia is a common complication of HIV infection in children, but uncommon in adults. It is characterized clinically by the presence of cough and dyspnea, diffuse pulmonary infiltrates on chest x-ray, restrictive pulmonary dysfunction, and hypoxemia. This constellation of findings usually erroneously suggests PCP, and a lung biopsy is necessary to establish the diagnosis. Typical microscopic findings include diffuse infiltration of the pulmonary interstitium with a mixture of lymphocytes and plasma cells; immunohistologic studies reveal that in association with HIV infection, these lymphocytes are T cells. The pathogenesis of LIP in patients with HIV infection is not known. It is believed that it represents a tissue response to EBV infection, HIV infection of the lung, or both. Although patients with LIP may respond dramatically to corticosteroid therapy, others may improve with no treatment. Unfortunately, most patients eventually succumb to other complications of HIV infection.


Evidence for fast signals and later processing in human V1/V2 and V5/MT+: A TMS study of motion perception.
Evidence from human and primate studies suggests that fast visual processing may utilize signals projecting from primary visual cortex (V1) through the dorsal stream, to area V5/MT+ or beyond and subsequently back into V1. This coincides with the arrival of parvocellular signals en route to the ventral pathway and infero-temporal cortex. Such evidence suggests that the dorsal stream region V5/MT+ is activated rapidly through the traditional hierarchical pathway and also via a less-well-established direct signal to V5/MT+ bypassing V1. To test this, 16 healthy humans underwent transcranial magnetic stimulation (TMS) of V1/V2 and V5/MT+ while performing a motion-direction detection task. A three-alternate forced-choice design (left/right motion, stationary) allowed analysis of the quality of errors made, in addition to the more usual performance measures. Transient disruption of V1/V2 and V5/MT+ significantly reduced accuracy when TMS was applied at or near motion onset. Most participants also showed disrupted performance with TMS application over V1/V2 approximately 125 ms post motion onset, and significantly reduced accuracy at 158 ms with V5/MT+ stimulation. The two periods of disruption with V1/V2 TMS are suggestive of feedforward/feedback models, although the earlier period of disruption has not been reported in previous TMS studies. Very early activation of V5/MT+, evidenced by diminished accuracy and reduced perception of motion after TMS may be indicative of a thalamic-extrastriate pathway in addition to the traditionally expected later period of processing. A profound disruption of performance prestimulus onset is more likely to reflect disruption of top-down expectancy than disruption of visual processing.


Lymphomas with follicular and monocytoid B-cell components. Evidence for a common clonal origin from follicle center cells.
We investigated the clonal relationship between follicular center cell and monocytoid B-cell components of non-Hodgkin lymphoma by isolating the components and comparing the nucleotide sequences of the complementarity-determining region (CDR)3 of the rearranged immunoglobulin heavy chain (IgH) gene. Paraffin blocks from 4 cases with amplifiable DNA using the polymerase chain reaction (PCR) were identified. Multiple representative cell clusters of the 2 components were obtained by microdissection, and the IgH CDR3 was amplified using a seminested PCR. Most of the PCR products obtained from both tumor components in each case had identical lengths when analyzed with polyacrylamide gel electrophoresis (PAGE) and identical migratory patterns on denaturing gradient gel electrophoresis (DGGE). These findings indicate sequence identity of the IgH CDR3 of both tumor components. Sequence analysis showed that point mutations were responsible for bands from the same case that had nonidentical migratory patterns by DGGE. The components in each of the 4 cases studied have the same clonal origin. Intraclonal sequence variations in the IgH gene were observed in 2 cases, consistent with the presence of continued somatic hypermutation after establishment of the clone. The expression of CD10 and bcl-2, as well as the detection of bcl-2 rearrangements in 2 cases, indicate that these lymphomas are of follicular center cell origin.


The effect of anti-Z-DNA antibodies on the B-DNA-Z-DNA equilibrium.
Four different preparations of rabbit and goat anti-Z-DNA antibodies were examined to determine the effects of antibody binding on the B-DNA-Z-DNA equilibrium. One of the four antibodies, a goat IgG, caused a marked lowering in the ionic strength required for the B-DNA to Z-DNA transition in poly(dG-dC) X poly(dG-dC), shifting the midpoint from 2.25 to 2.0 M NaCl. This IgG had a more prominent high affinity antibody population than did the other goat IgG, which caused little change in the midpoint of this transition. The presence of anti-Z-DNA antibodies also reduced the degree of negative supercoiling required for the formation of Z-DNA in (dG-dC)n sequences inserted into closed circular plasmid DNA. The goat IgG with the more marked effect on the salt-induced transition also had a greater effect in favoring Z-DNA formation in negatively supercoiled plasmids. A shift toward Z-DNA formation was observed in circular dichroism measurements upon antibody binding to poly(dG-dC) X poly(dG-dC) in very low ionic strength solution as well. We propose that the stabilization of Z-DNA by antibody binding in poly(dG-dC) X poly(dG-dC) occurs cooperatively, several antibody molecules binding to a single polymer molecule and stabilizing the entire molecule in Z-DNA through their combined binding energies. The stabilization of Z-DNA by antibody binding in a supercoiled plasmid can be significant, and failure to consider this effect and to choose appropriate conditions for measurement can lead to errors in estimating when Z-DNA will form in response to negative supercoiling.


Does Perfusion MRI After Closed Reduction of Developmental Dysplasia of the Hip Reduce the Incidence of Avascular Necrosis?
Gadolinium-enhanced perfusion MRI (pMRI) after closed reduction/spica casting for developmental dysplasia of the hip (DDH) has been suggested as a potential means to identify and avoid avascular necrosis (AVN). To date, however, no study has evaluated the effectiveness of pMRI in clinical practice or compared it with other approaches (such as postreduction CT scan) to show a difference in the proportion of AVN. (1) Can a pMRI-based protocol be used immediately post closed reduction to minimize the risk that AVN would develop? (2) What are the overall hip-related outcomes after closed reduction/spica casting using this protocol? (3) Do any patient-specific factors at the time of closed reduction predict future AVN? This was a retrospective cohort study at a large tertiary care children's hospital. Between 2009 and 2013 we treated 43 patients with closed reduction/spica casting for DDH, of whom 33 (77%) received a postreduction pMRI. All patients were indicated for pMRI per treating surgeon preference. A convenience sample totaling 25 hips in 22 patients treated with pMRI was then established using the following exclusion criteria: DDH of neuromuscular/syndromic origin, failed initial closed reduction, less than 1 year of clinical and radiographic followup, and subsequent open reduction. Next, the 40 patients treated with closed reduction between 2004 and 2009 were screened until the chronologically most recent 25 hips (after applying the previously mentioned exclusion criteria) were identified in 21 of the first 34 patients (62%) screened. Although termed the CT group, specific postreduction imaging was not a defined inclusion criterion in this group with the majority (21 of 25 [84%]) receiving postreduction CT and the remainder (four of 25 [16%]) receiving only postreduction radiographs. All hips with globally decreased femoral head perfusion on postreduction pMRI were treated with immediate cast removal followed by repeat closed reduction or open reduction, as per surgeon preference, with two of 33 (6%) requiring such further interventions. Salter criteria were then used to determine the proportion of AVN on radiographs at 1-year and final followup. Secondary outcomes including residual dysplasia and the need for further corrective surgery were ascertained through radiographic and retrospective chart review. At 1-year followup there was no difference in the proportion of AVN in the historical CT group as compared with the pMRI group (six of 25 [24%] versus one of 25 [4%]; odds ratio [OR], 7.6; 95% confidence interval [CI], 0.8-363; p = 0.098). However, by final followup there was a statistically higher proportion of AVN in the CT group (seven of 25 [28%] versus one of 25 [4%]; OR, 9.3; 95% CI, 1.0-438; p = 0.049). No patient with normal perfusion on postreduction pMRI went on to develop AVN. In those pMRI patients in whom a successful reduction was initially obtained, two of 25 (8%) went on to require further corrective surgery and one of 25 (4%) had a redislocation event. With the numbers available, no patient-specific factors at the time of closed reduction were predictive of future AVN, including the patient's age/weight, the presence of an ossific nucleus, history of previous bracing treatment, or the abduction angle in spica cast. A pMRI-based protocol immediately after closed reduction/spica casting may decrease the risk of AVN by helping the surgeon to evaluate femoral head vascularity. Although preliminary in nature, this study could serve to guide further investigation into the potential role of pMRI for the treatment of patients who require closed reduction/spica casting for DDH. Level III, therapeutic study.


Satisfaction with an In-House Nasal Foreign Body Removal Manikin: A Randomized Controlled Trial.
Nasal foreign bodies can lead to life-threatening conditions. Hence, it is a necessity that physicians be well trained in the appropriate procedures for removal of nasal foreign bodies. However, training on real patients is not only unpractical it is also too dangerous, due to risk of foreign body aspiration during the procedure. Therefore, our goal was to construct a manikin, with a specific design, to serve all possible needs for training. We developed an in-house manikin from 2 materials; these being flexible polyurethane foam and silicone. Silicone, which has elasticity similar to nasal alae, was used to develop the detachable nose and nasal cavity, whilst polyurethane foam, which is light and easy to carry, was used to develop the head. The in-house manikin was compared with a commercial manikin for satisfaction after a nasal foreign body removal procedure was performed in both groups, by 37 physicians, after conducting a randomized controlled trial with a crossover design. The satisfaction scores of the in-house manikin were statistically significantly higher than the satisfaction scores of the commercial manikin for 6 dimensions: proper size, ease of use, ease of maintenance, flexibility of nasal alae relative to actual anatomy, similarity of the nasal cavity relative to actual anatomy and confidence that the manikin can upskill the medical students ability to practice on real patients (p value < 0.05). This in-house nasal foreign body removal manikin design had high satisfaction for training and could be used to develop further nasal foreign body removal manikins in the future.


Prenatal administration of morphine to the rat: tolerance to the analgesic effect of morphine in the offspring.
The analgesic activity of morphine was assessed by the hot-plate technique in the offspring of female CFE rats that had received morphine twice daily on days 5 to 12 of pregnancy. A dose of 5.0 mg/kg of morphine was administered for the first 3 injections; 10 mg/kg was used for each of the remaining 13. Morphine dose-response curves were determined in the offspring at 5 weeks of age. The analgesic effect of morphine in the offspring of morphine-treated females (morphine offspring) was attenuated by as much as 50% compared to the offspring of saline-treated females (saline offspring). This same relationship between the morphine and saline offspring was also observed in offspring rendered tolerant to the analgesic effect of morphine. A diminished analgesia in the morphine offspring compared to the saline offspring was also observed after the injection of graded doeses of levorphanol in both nontolerant and morphine-tolerant offspring. The analgesic effect of a single dose of morphine was also attenuated in 3-, 5- and 11-week-old morphine offspring. No differences were found in either brain or plasma concentration of morphine between the morphine and saline offspring. The long-term effect of prenatal morphine administration could not be explained on the basis of maternal influences since cross-fostering procedures failed to abolish it. It is concluded that the administration of moderate doses of morphine to gestating rats can induce a long-lasting tolerance to the analgesic effect of morphine in the offspring.


Relationship between plasma high-density lipoprotein concentrations and lipoprotein lipase and hepatic lipase activities in children with hyperlipidaemia.
1. Significant positive correlations were found between the lipoprotein lipase and hepatic lipase activities of post-heparin plasma samples and plasma high-density-lipoprotein (HDL) cholesterol concentrations in 21 children with hyperlipidaemia and six normal adult males. 2. A significant positive correlation was also observed between the two lipase activities and the ratio of HDL cholesterol to apoprotein AI (apo AI) concentrations. 3. These findings provide further evidence that a significant proportion of HDL and possibly the HDL, subfraction is formed during the clearance of triglyceride-rich lipoproteins.


The Long-Term Effects of Growth Hormone Replacement on Bone Mineral Density and Trabecular Bone Score: Results of the 10-Year Prospective Follow-up.
There are only few studies concerning about long-term effect of growth hormone (GH) replacement therapy on bone mineral density and bone microstructure. To assess effect of GH replacement therapy on bone mineral density (BMD) and trabecular bone score (TBS) in adult GH deficient (AGHD) subjects over period of 10 years. From 2005 to 2018, a prospective study of AGHD patients was conducted in national referral center for treatment of GHD. All patients received subcutaneous recombinant human GH in an IGF 1-normalizing regimen once a day. Lumbar spine (L-spine) and total hip (TH) BMD using Hologic densitometers were measured at baseline and every two years during treatment with rhGH. TBS was derived from L1-L4 DXA using iNsight® software (Medimaps, France) at each time point. Periods of measurement were baseline, year 2; 4; 6; 8 and 10. In total, 63 patients (38 males, 25 females, mean age 25.1±16 years) were included in the study. After 10 years of GH treatment, IGF-1 significantly increased (~35 %), with greatest increase at year 2. During 10-year follow-up, L-spine BMD increased approximately of 7 % (NS). TH BMD increase of 11 % during follow-up (p=0.0003). The greatest increment of BMD was achieved at year 6 on both sites, L-spine (+6 %) and TH BMD (+13 %) (p<0.05). There was no significant change of TBS during whole follow-up. In this study, sustaining positive effect of GH replacement therapy on bone density in subjects with adult GH deficiency over 10 years of follow-up was observed. The study did not show effect on TBS, as indirect measure of trabecular bone microarchitecture.


[The initial prodrome in schizophrenia--core dimensions of experience and behavior].
In order to identify and possibly prevent psychosis at prodromal stages, it is important to learn how patients and families perceive initial prodromes, particularly the prodromal subjective experiences. We explore prodromal phenomena and identify potential core dimensions in 19 first-episode DSM-IV schizophrenia patients and describe experiences and behaviour that appear to be essential components of initial prodromes. The subjects reported serious difficulties interpreting and talking about prodromal experiences at the time when they occurred; this caused delayed identification, the reasons for which we report. Out of eight groups of prodromal experiences we highlight two as tentative core dimensions: [disturbance of perception of self] and [extreme preoccupation by and withdrawal to overvalued ideas]. Four potential dimensions of prodromal behaviour are also identified: (1) leaving school, university or job, or major school truancy, (2) marked and lasting observable shift of interests, (3) marked and lasting social passivity, withdrawal, or isolation, and (4) marked and lasting change in global appearance or behaviour.


Are serum amyloid A or D-lactate useful to diagnose synovial contamination or sepsis in horses?
Synovial sepsis in horses is life threatening and accurate diagnosis allowing prompt treatment is warranted. This study assessed the diagnostic value of serum amyloid A (SAA) and D-lactate in blood and synovial fluid (SF) as diagnostic markers of synovial sepsis in horses and correlated them with total nucleated cell count (TNCC), percentage of neutrophils (%N) and total protein (TP) in SF. Blood and SF SAA and D-lactate concentrations were determined in a case-control observational study including 112 horses (38 with synovial contamination or sepsis (SCS), 66 with non-septic intra-synovial pathology (NSISP) and 8 controls). Blood and SF SAA were significantly higher in SCS than in NSISP and control horses. SAA values were similar in NSISP and control horses. SF SAA was moderately correlated with synovial TNCC, TP and blood SAA. Blood and SF SAA were 82.4 per cent and 80 per cent sensitive and 88.9 per cent and 73 per cent specific for diagnosis of SCS, with cut-off values of 60.7 and 1.14 µg/ml, respectively. Blood and SF D-lactate concentrations were not significantly different between groups. This study shows that blood and SF SAA concentrations can aid to distinguish SCS from non-septic synovial pathology; however, D-lactate was not useful.


Luminance Contrast Drives Interactions between Perception and Working Memory.
Visual working memory (WM) enables the use of past sensory experience in guiding behavior. Yet, laboratory tasks commonly evaluate WM in a way that separates it from its sensory bottleneck. To understand how perception interacts with visual memory, we used a delayed shape recognition task to probe how WM may differ for stimuli that bias processing toward different visual pathways. Luminance compared with chromatic signals are more efficient in driving the processing of shapes and may thus also lead to better WM encoding, maintenance, and memory recognition. To evaluate this prediction, we conducted two experiments. In the first psychophysical experiment, we measured contrast thresholds for different WM loads. Luminance contrast was encoded into WM more efficiently than chromatic contrast, even when both sets of stimuli were equated for discriminability. In the second experiment, which also equated stimuli for discriminability, early sensory responses in the EEG that are specific to luminance pathways were modulated by WM load and thus likely reflect the neural substrate of the increased efficiency. Our results cannot be accounted for by simple saliency differences between luminance and color. Rather, they provide evidence for a direct connection between low-level perceptual mechanisms and WM by showing a crucial role of luminance for forming WM representations of shape.


Non-uniform recovery of left ventricular transmural mechanics in ST-segment elevation myocardial infarction.
After a transient ischemic episode, the subendocardial region is more severely injured than outer subepicardial layers and may regain a proportionately greater degree of mechanical function in the longitudinal direction. We sought to explore left ventricular (LV) transmural mechanics in patients with ST-segment elevation myocardial infarction (STEMI) for determining the mechanism underlying recovery of global LV function after primary percutaneous coronary intervention (PCI). A total of 42 patients (62 +/- 11 years old, 71% male) with a first STEMI underwent serial assessments of LV longitudinal, circumferential and radial strains (LS, CS and RS) by selective tracking of subendocardial and subepicardial regions within 48 hours and a median of 5 months after PCI. LV mechanical parameters were compared with sixteen age and gender matched normal controls. In comparison with controls, endocardial and epicardial LS were markedly attenuated at 48 hours following PCI (P < 0.001). An improvement in LV ejection fraction (EF > 5%) following PCI was seen in 24 (57%) patients and was associated with improvement in endocardial and epicardial LS (P < 0.001 and P = 0.003, respectively) and endocardial CS (P = 0.01). Radial strain and wall motion score index, however, remained persistently abnormal. The change in endocardial LS (OR 1.2, 95% CI 1.03 to 1.42, P = 0.01) and the change in epicardial LS (OR 1.2, 95% 1.03 to 1.46, P = 0.02) were significantly associated with the improvement in LVEF, independent of the location of STEMI and the presence of underlying multivessel disease. In patients with STEMI treated by PCI, the recovery of LV subendocardial shortening strain seen in the longitudinal direction underlies the improvement in LV global function despite persistent abnormalities in radial mechanics and wall motion score index.


Efficacy and safety of single vs dual antiplatelet therapy in patients on anticoagulation undergoing percutaneous coronary intervention: A systematic review and meta-analysis.
Selection of an appropriate antithrombotic regimen in patients requiring oral anticoagulation (OAC) undergoing percutaneous coronary intervention (PCI) still remains a challenge. An ideal 9-2regimen should balance the risk of bleeding against ischemic benefit. A comprehensive literature search for studies comparing triple antithrombotic therapy (TAT) vs double antithrombotic therapy (DAT) in patients requiring OAC undergoing PCI was performed in clinicalTrials.gov, PubMed, Web of Science, EBSCO Services, Cochrane Central Register of Controlled Trials, Google Scholar, and various scientific conference sessions from inception to May 1st, 2019. A meta-analysis was performed using random-effects model to calculate risk ratio (RR) and 95% confidence interval (CI). Fifteen studies were eligible and included 13 967 patients, of which 7349 received TAT and 6618 received DAT. Compared with DAT, TAT was associated with lower risk of myocardial infarction (RR, 0.82; 95%CI, 0.69-0.98; P = .03) and stent thrombosis (RR, 0.66; 95%CI, 0.46-0.96; P = .03). There was no difference in risk of trial defined major adverse cardiac events, all-cause mortality, and stroke between two groups. Compared with DAT, TAT was associated with higher risk of trial defined major bleeding (RR, 1.67; 95%CI, 1.38-2.01; P < .00001), including thrombolysis in myocardial infarction major bleeding (RR, 1.81; 95%CI, 1.47-2.24; P < .00001) but no significant difference in risk of intracranial bleeding. In patients requiring OAC undergoing PCI, TAT was associated with a lower risk of myocardial infarction but with a significantly higher risk of major bleeding when compared with DAT.


Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics.
The inhibitory effect of a marine-sponge toxin, okadaic acid, was examined on type 1, type 2A, type 2B and type 2C protein phosphatases as well as on a polycation-modulated (PCM) phosphatase. Of the protein phosphatases examined, the catalytic subunit of type 2A phosphatase from rabbit skeletal muscle was most potently inhibited. For the phosphorylated myosin light-chain (PMLC) phosphatase activity of the enzyme, the concentration of okadaic acid required to obtain 50% inhibition (ID50) was about 1 nM. The PMLC phosphatase activities of type 1 and PCM phosphatase were also strongly inhibited (ID50 0.1-0.5 microM). The PMCL phosphatase activity of type 2B phosphatase (calcineurin) was inhibited to a lesser extent (ID50 4-5 microM). Similar results were obtained for the phosphorylase a phosphatase activity of type 1 and PCM phosphatases and for the p-nitrophenyl phosphate phosphatase activity of calcineurin. The following phosphatases were not affected by up to 10 microM-okadaic acid: type 2C phosphatase, phosphotyrosyl phosphatase, inositol 1,4,5-trisphosphate phosphatase, acid phosphatases and alkaline phosphatases. Thus okadaic acid had a relatively high specificity for type 2A, type 1 and PCM phosphatases. Kinetic studies showed that okadaic acid acts as a non-competitive or mixed inhibitor on the okadaic acid-sensitive enzymes.