Specific inhibition of fungal sterol biosynthesis by SF 86-327, a new allylamine antimycotic agent.
SF 86-327 is a new antimycotic agent of the allylamine type. Its primary action appears to be the inhibition of ergosterol biosynthesis at the point of squalene epoxidation, as was previously found with the related compound naftifine. Biosynthesis was measured by incorporation of [14C]acetate into sterols in cells of Candida albicans, Candida parapsilosis, Torulopsis glabrata, and the dermatophyte Trichophyton mentagrophytes. There was a positive correlation between the SF 86-327 concentrations needed for inhibition of growth and of sterol synthesis in these four fungi. The greater antifungal efficacy of SF 86-327 in comparison with naftifine was also reflected in the relative activities of the two compounds as sterol synthesis inhibitors. Inhibition was maximal at neutral pH. A similar degree of inhibition was found in cell-free extracts when [14C]mevalonate was used as substrate. In all cases, inhibition of sterol synthesis was accompanied by a parallel accumulation of labeled squalene. SF 86-327 and naftifine had no significant effect on initial enzymes of the ergosterol pathway, measured by incorporation of [14C]acetyl coenzyme A, or on steps distal to squalene epoxidation, measured by conversion of labeled squalene 2,3-epoxide or lanosterol. Both allylamines were highly selective for fungal, as opposed to mammalian, sterol biosynthesis. SF 86-327 caused slight inhibition of squalene epoxidation in a rat liver cell-free system, but at concentrations three to four orders of magnitude greater than those required for inhibition of the fungal pathway.


Retained periorbital and intracranial air-gun pellets causing sclopetaria and visual loss.
Three healthy males presented on separate occasions to the emergency room at the King Khaled Eye Specialist Hospital (KKESH) after sustaining trauma by air-gun pellets. Clinical examination indicated sclopetaria in all the cases. The foreign bodies (air-gun pellets) were imbedded in different locations (subconjunctival, intraorbital, and intracranial). All cases resulted in a profound and permanent visual loss. The management of this traumatic injury is discussed and concurs with the published literature.


Raffinose family of oligosaccharides from lupin seeds as prebiotics: application in dairy products.
The raffinose family of oligosaccharides (RFOs) isolated from lupin seeds (Lupinus albus var. Multolupa) was evaluated for bifidogenic effects during the manufacture of probiotic fermented milk. A mixed starter inoculum was composed of Bifidobacterium lactis Bb-12 and Lactobacillus acidophilus (1:1). Lupins are a rich source of RFOs that can be used as functional food ingredients. The addition of RFOs to milk increased B. lactis Bb-12 and L. acidophilus populations at the final fermentation time compared with controls. Final fermentation products are positively affected by addition of RFOs, and time of fermentation was reduced from 12 to 10 h. When RFOs were added to milk, they were preferentially used as a carbon source (57.7%) compared with lactose (23.7%) at the end of fermentation. These results suggest that the eventual choice of B. lactis Bb-12 and L. acidophilus in a mixed culture at a 1:1 ratio and addition of RFOs to produce a fermented milk product would have the advantages of rapid growth and acidificationrate and would likely increase the probiotic effect of the final functional product.


Greater perceptual sensitivity to happy facial expression.
Perception of subtle facial expressions is essential for social functioning; yet it is unclear if human perceptual sensitivities differ in detecting varying types of facial emotions. Evidence diverges as to whether salient negative versus positive emotions (such as sadness versus happiness) are preferentially processed. Here, we measured perceptual thresholds for the detection of four types of emotion in faces--happiness, fear, anger, and sadness--using psychophysical methods. We also evaluated the association of the perceptual performances with facial morphological changes between neutral and respective emotion types. Human observers were highly sensitive to happiness compared with the other emotional expressions. Further, this heightened perceptual sensitivity to happy expressions can be attributed largely to the emotion-induced morphological change of a particular facial feature (end-lip raise).


Characterization and validation of long noncoding RNAs as new candidates in prostate cancer.
Long noncoding RNAs (lncRNAs) have been proved to be an important regulator in gene expression. In almost all kinds of cancers, lncRNAs participated in the process of pathogenesis, invasion, and metastasis. Meanwhile, compared with the large amounts of patients, there is rare knowledge about the role of lncRNAs in prostate cancer (PCa). In this study, lncRNA expression profiles of prostate cancer were detected by Agilent microarray chip, 5 pairs of case and control specimens were involved in. Differentially expressed lncRNAs were screened out by volcano plot for constructing lncRNA-miRNA-mRNA central network. Then, the top ten up-regulated and down-regulated lncRNAs were validated by qRT-PCR in another 5 tumor specimens and 7 para-cancerous/benign contrasts. Furthermore, we searched for the survival curve of the top 10 upregulated and downregulated lncRNAs. A total of 817 differentially expressed lncRNAs were filtered out by the criteria of fold change (FC) and t-test p < 0.05. Among them, 422 were upregulated, whereas 395 were downregulated in PCa tissues. Gene ontology and KEGG pathway analyses showed that many lncRNAs were implicated in carcinogenesis. lnc-MYL2-4:1 (FC = 0.00141, p = 0.01909) and NR_125857 (FC = 59.27658, p = 0.00128) had the highest magnitude of change. The subsequent qPCR confirmed the expression of NR_125857 was in accordance with the clinical samples. High expression of PCA3, PCAT14 and AP001610.9 led to high hazard ratio while low expression of RP11-279F6.2 led to high hazard ratio. Our study detected a relatively novel complicated map of lncRNAs in PCa, which may have the potential to investigate for diagnosis, treatment and follow-up in PCa. Our study revealed the expression of NR_125857 in human PCa tissues was most up-regulated. Further studies are needed to investigate to figure out the mechanisms in PCa.


Are There Lipid Membrane-Domain Subtypes in Neurons with Different Roles in Calcium Signaling?
Lipid membrane nanodomains or lipid rafts are 10-200 nm diameter size cholesterol- and sphingolipid-enriched domains of the plasma membrane, gathering many proteins with different roles. Isolation and characterization of plasma membrane proteins by differential centrifugation and proteomic studies have revealed a remarkable diversity of proteins in these domains. The limited size of the lipid membrane nanodomain challenges the simple possibility that all of them can coexist within the same lipid membrane domain. As caveolin-1, flotillin isoforms and gangliosides are currently used as neuronal lipid membrane nanodomain markers, we first analyzed the structural features of these components forming nanodomains at the plasma membrane since they are relevant for building supramolecular complexes constituted by these molecular signatures. Among the proteins associated with neuronal lipid membrane nanodomains, there are a large number of proteins that play major roles in calcium signaling, such as ionotropic and metabotropic receptors for neurotransmitters, calcium channels, and calcium pumps. This review highlights a large variation between the calcium signaling proteins that have been reported to be associated with isolated caveolin-1 and flotillin-lipid membrane nanodomains. Since these calcium signaling proteins are scattered in different locations of the neuronal plasma membrane, i.e., in presynapses, postsynapses, axonal or dendritic trees, or in the neuronal soma, our analysis suggests that different lipid membrane-domain subtypes should exist in neurons. Furthermore, we conclude that classification of lipid membrane domains by their content in calcium signaling proteins sheds light on the roles of these domains for neuronal activities that are dependent upon the intracellular calcium concentration. Some examples described in this review include the synaptic and metabolic activity, secretion of neurotransmitters and neuromodulators, neuronal excitability (long-term potentiation and long-term depression), axonal and dendritic growth but also neuronal cell survival and death.


Methy-Pipe: an integrated bioinformatics pipeline for whole genome bisulfite sequencing data analysis.
DNA methylation, one of the most important epigenetic modifications, plays a crucial role in various biological processes. The level of DNA methylation can be measured using whole-genome bisulfite sequencing at single base resolution. However, until now, there is a paucity of publicly available software for carrying out integrated methylation data analysis. In this study, we implemented Methy-Pipe, which not only fulfills the core data analysis requirements (e.g. sequence alignment, differential methylation analysis, etc.) but also provides useful tools for methylation data annotation and visualization. Specifically, it uses Burrow-Wheeler Transform (BWT) algorithm to directly align bisulfite sequencing reads to a reference genome and implements a novel sliding window based approach with statistical methods for the identification of differentially methylated regions (DMRs). The capability of processing data parallelly allows it to outperform a number of other bisulfite alignment software packages. To demonstrate its utility and performance, we applied it to both real and simulated bisulfite sequencing datasets. The results indicate that Methy-Pipe can accurately estimate methylation densities, identify DMRs and provide a variety of utility programs for downstream methylation data analysis. In summary, Methy-Pipe is a useful pipeline that can process whole genome bisulfite sequencing data in an efficient, accurate, and user-friendly manner. Software and test dataset are available at http://sunlab.lihs.cuhk.edu.hk/methy-pipe/.


Evolutionary variants of simian virus 40 which are impaired in early lytic functions but transform nonpermissive cells.
From an undiluted passaged virus stock, two size classes of defective simian virus 40 (SV40) DNA were isolated from which two evolutionary variants were cloned. By means of restriction enzyme and heteroduplex analysis, physical maps of the mutants have been constructed. Both mutants contained the region of SV40 DNA coding for the early proteins plus some adjacent sequences (the region from 0.120 to 0.685 map unit, clockwise, on the standard SV40 DNA map). Furthermore, each mutant contained, in the form of two inverted repeats, four times the sequences from the region 0.625 to 0.685 map unit, clockwise. Some biological properties of the mutant DNA were examined, and we found that the mutant DNA (i) has, as compared with SV40 DNA, an impaired ability to induce T antigen in permissive and nonpermissive cells; (ii) does not complement a thermosensitive A mutant of SV40; (iii) replicates very inefficiently without a helper; and (iv), as an apparent contradiction, transforms nonpermissive baby rat kidney cells as well as SV40 DNA. A hypothetical mechanism for the expression of the mutant DNA that might explain the observed biological properties is presented.


Distinct roles of arginases 1 and 2 in diabetic nephropathy.
Diabetes is the leading cause of end-stage renal disease, resulting in a significant health care burden and loss of economic productivity by affected individuals. Because current therapies for progression of diabetic nephropathy (DN) are only moderately successful, identification of underlying mechanisms of disease is essential to develop more effective therapies. We showed previously that inhibition of arginase using S-(2-boronoethyl)-l-cysteine (BEC) or genetic deficiency of the arginase-2 isozyme was protective against key features of nephropathy in diabetic mouse models. However, those studies did not determine whether all markers of DN were dependent only on arginase-2 expression. The objective of this study was to identify features of DN that are associated specifically with expression of arginase-1 or -2. Elevated urinary albumin excretion rate and plasma urea levels, increases in renal fibronectin mRNA levels, and decreased renal medullary blood flow were associated almost completely and specifically with arginase-2 expression, indicating that arginase-2 selectively mediates major aspects of diabetic renal injury. However, increases in renal macrophage infiltration and renal TNF-α mRNA levels occurred independent of arginase-2 expression but were almost entirely abolished by treatment with BEC, indicating a distinct role for arginase-1. We therefore generated mice with a macrophage-specific deletion of arginase-1 (CD11bCre /Arg1fl/fl ). CD11bCre /Arg1fl/fl mice had significantly reduced macrophage infiltration but had no effect on albuminuria compared with Arg1fl/fl mice after 12 wk of streptozotocin-induced diabetes. These results indicate that selective inhibition of arginase-2 would be effective in preventing or ameliorating major features of diabetic renal injury.


Better models by discarding data?
In macromolecular X-ray crystallography, typical data sets have substantial multiplicity. This can be used to calculate the consistency of repeated measurements and thereby assess data quality. Recently, the properties of a correlation coefficient, CC1/2, that can be used for this purpose were characterized and it was shown that CC1/2 has superior properties compared with `merging' R values. A derived quantity, CC*, links data and model quality. Using experimental data sets, the behaviour of CC1/2 and the more conventional indicators were compared in two situations of practical importance: merging data sets from different crystals and selectively rejecting weak observations or (merged) unique reflections from a data set. In these situations controlled `paired-refinement' tests show that even though discarding the weaker data leads to improvements in the merging R values, the refined models based on these data are of lower quality. These results show the folly of such data-filtering practices aimed at improving the merging R values. Interestingly, in all of these tests CC1/2 is the one data-quality indicator for which the behaviour accurately reflects which of the alternative data-handling strategies results in the best-quality refined model. Its properties in the presence of systematic error are documented and discussed.


Treatment with a new barbituric acid derivative suppresses diet-induced metabolic dysfunction and non-alcoholic fatty liver disease in mice.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, often accompanied by obesity, diabetes, and increased risks of depression and anxiety. Currently, there are no FDA-approved drugs to treat NAFLD and its related systemic symptoms. Previously, we identified a new barbituric acid derivative (BA-5) that expressed effectiveness against fibrosis and drug-resistant hepatocellular carcinoma. This study investigated the potential of BA-5 against high-fat diet (HFD)-induced NAFLD and mood disorders in mice. Six-weeks-old male C57BL/6 mice were fed with a 45 % HFD for 8 weeks to induce NAFLD and associated metabolic disorders. Mice were treated with a BA-5 and the therapeutic effects and the underlying molecular mechanisms were investigated. Administration of BA-5 significantly reduced serum levels of alanine aminotransferase (ALT), low-density lipoprotein (LDL), fatty acids (FA), and triglycerides (TG) in HFD-fed mice. BA-5 treatment decreased expressions of hepatic lipogenesis-related markers (acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and ATP-citrate lyase (ACLY)), increased fatty acid oxidation markers (carnitine palmitoyltransferase 1A (CPT1A) and acyl-CoA oxidase 1 (ACOX1)), and attenuated hepatic fat accumulation in HFD-fed mice. Moreover, HFD-induced adipocyte size enlargement and activation of lipolysis markers such as phosphorylated (p)-hormone-sensitive lipase (HSL) 565, p-HSL 660, and perilipin were inhibited in BA-5-treated mice. Notably, HFD-induced anxiety- and depression-like behaviors significantly improved in the BA-5 treated group through enhanced anti-inflammatory responses in the hippocampus. This study provides new insights into clinical therapeutic strategies of barbituric acid derivatives for HFD-induced NAFLD and associated mood disturbances.


Dephosphorylation and quantification of organic phosphorus in poultry litter by purified phytic-acid high affinity Aspergillus phosphohydrolases.
Extracellular phosphohydrolases mediate the dephosphorylation of phosphoesters and influence bioavailability and loss of agricultural P to the environment to pose risks of impairment of sensitive aquatic ecosystems. Induction and culture of five strains of Aspergillus were conducted to develop a source of high-affinity and robust phosphohydrolases for detecting environmental P and quantifying bioactive P pools in heterogeneous environmental specimens. Enzyme stability and activity against organic P in poultry litter were evaluated in 71 samples collected across poultry producing regions of Arkansas, Maryland, and Oklahoma of the US Differences existed in strains' adaptability to fermentation medium as they showed a wide range of phytate-degrading activity. Phosphohydrolases from Aspergillus ficuum had highest activity when the strain was cultured on a primarily chemical medium, compared to Aspergillus oryzae which preferred a wheat bran-based organic medium. Kinetics parameters of A. ficuum enzymes (K(m)=210 microM; V(max) of 407 nmol s(-1)) indicated phytic acid-degrading potential equivalent to that of commercial preparations. Purified A. ficuum phosphohydrolases effectively quantified litter bioactive P pools, showing that organic P occurred at an average of 54 (+/-14)% of total P, compared to inorganic phosphates, which averaged 41 (+/-12)%. Litter management and land application options must consider the high water-extractable and organic P concentrations and the biological availability of the organic enzyme-labile P pool. Robustness of A. ficuum enzymes and simplicity of the in situ ligand-based enzyme assay may thus increase routine assessment of litter bioactive P composition to sense for on-farm accumulation of such environmentally-sensitive P forms.


Use of a combined retroperitoneoscopic and transperitoneal laparoscopic technique for the management of renal cell carcinoma with level I tumor thrombi.
To report our initial experiences using a combined retroperitoneoscopic and transperitoneal laparoscopic technique for the management of renal cell carcinoma with level I tumor thrombi. Two patients underwent this technique for tumors 11- and 13-cm in diameter. After transection of the renal artery with limited mobilization of the kidney using a retroperitoneoscopic approach, additional ports were placed, and the management of the tumor thrombus was performed in the large working space provided by the transperitoneoscopic approach. The technique was feasible in the present 2 cases. The total operative times were 170 and 200 min, respectively. The estimated blood loss was 450 cc in the first case and 200 cc in the second case. No complications were observed in either of the patients. Based on the initial clinical experience, we have presented a feasible surgical option for the laparoscopic management of renal cell carcinoma with level I thrombi.


[Modification of recombinant human augmenter of liver regeneration with urea studied by maldi-tof mass spectrometry].
To investigate the modification of recombinant human augmenter of liver regeneration (rhALR) by the urea in purification processes and the biological activity of rhALR and modified rhALR, the molecular weight of proteins and tryptic peptides were determined by matrix-assisted laser desorption time of flight mass spectrometry (MALDI-TOF-MS), and the biological activity of rhALR and modified rhALR was also observed by in vivo experiments. A 30 kD homodimer of rhALR was purified under denaturing conditions. The molecular weight of rhALR is 30 780 if urea was used to denature the inclusion bodies; when the denaturant was guanidine hydrochloride, the molecular weight of rhALR was 30 087. The results of MALDI-TOF-MS of digested rhALR that have been modified by urea showed that peptides that contained lysyl were 43 larger than the theoretical value. Proteins purified by different processes were all able to promote the survival rate of CCl(4)-intoxicated mice. It could be concluded that cyanate, the cleavage product of urea, could react with the epsilon-amino group of lysyl in rhALR, and the modified rhALR had the same biological activity as natural rhALR.


Acquisition and loss of CTX-M plasmids in Shigella species associated with MSM transmission in the UK.
Shigellosis in men who have sex with men (MSM) is caused by multidrug resistant Shigellae, exhibiting resistance to antimicrobials including azithromycin, ciprofloxacin and more recently the third-generation cephalosporins. We sequenced four blaCTX-M-27-positive MSM Shigella isolates (2018-20) using Oxford Nanopore Technologies; three S. sonnei (identified as two MSM clade 2, one MSM clade 5) and one S. flexneri 3a, to explore AMR context. All S. sonnei isolates harboured Tn7/Int2 chromosomal integrons, whereas S. flexneri 3a contained the Shigella Resistance Locus. All strains harboured IncFII pKSR100-like plasmids (67-83kbp); where present blaCTX-M-27 was located on these plasmids flanked by IS26 and IS903B, however blaCTX-M-27 was lost in S. flexneri 3a during storage between Illumina and Nanopore sequencing. IncFII AMR regions were mosaic and likely reorganised by IS26; three of the four plasmids contained azithromycin-resistance genes erm(B) and mph(A) and one harboured the pKSR100 integron. Additionally, all S. sonnei isolates possessed a large IncB/O/K/Z plasmid, two of which carried aph(3')-Ib/aph(6)-Id/sul2 and tet(A). Monitoring the transmission of mobile genetic elements with co-located AMR determinants is necessary to inform empirical treatment guidance and clinical management of MSM-associated shigellosis.


Incorporating prior knowledge to facilitate discoveries in a genome-wide association study on age-related macular degeneration.
Substantial genotyping data produced by current high-throughput technologies have brought opportunities and difficulties. With the number of single-nucleotide polymorphisms (SNPs) going into millions comes the harsh challenge of multiple-testing adjustment. However, even with the false discovery rate (FDR) control approach, a genome-wide association study (GWAS) may still fall short of discovering any true positive gene, particularly when it has a relatively small sample size. To counteract such a harsh multiple-testing penalty, in this report, we incorporate findings from previous linkage and association studies to re-analyze a GWAS on age-related macular degeneration. While previous Bonferroni correction and the traditional FDR approach detected only one significant SNP (rs380390), here we have been able to detect seven significant SNPs with an easy-to-implement prioritized subset analysis (PSA) with the overall FDR controlled at 0.05. These include SNPs within three genes: CFH, CFHR4, and SGCD. Based on the success of this example, we advocate using the simple method of PSA to facilitate discoveries in future GWASs.


High-efficiency ligation and recombination of DNA fragments by vertebrate cells.
DNA-mediated gene transfer (transfection) is used to introduce specific genes into vertebrate cells. Events soon after transfection were quantitatively analyzed by determining the infectivity of the DNA from an avian retrovirus and of mixtures of subgenomic fragments of this DNA. The limiting step of transfection with two DNA molecules is the uptake by a single cell of both DNA's in a biologically active state. Transfected cells mediate ligation and recombination of physically unlinked DNA's at nearly 100 percent efficiency.


[Risk assessment of bronchial cancer surgery using quantitative lung perfusion scintigraphy].
28 patients with bronchogenic carcinoma were studied to predict lung function after thoracic resectional surgery, i.e. the functional operability, employing preoperative vital capacity (VC), forced expiratory volume (FEV1) and perfusion lung imaging. The perfusion scan was divided into 12 regions of interest which were semiquantitated to determine the relative distribution of perfusion as a fraction of the total perfusion. The planned reduction of lung parenchyma was expressed as percent of total perfusion, and the expected decrease in VC and FEV1, i.e. the predicted postoperative function of the lung, was calculated. The comparison of the predicted functional lung capacity with the re-estimated lung function (VC and FEF1) 6 months after surgery showed high correlation coefficients for both VC and FEV1. Semiquantitative perfusion scintigraphy of the lung helps to determine the extent of surgery possible in the individual therapy of lung cancer and is especially important in patients with a high operative risk.


Fucoxanthin modulates cecal and fecal microbiota differently based on diet.
Obesity is a major health concern worldwide and is considered to be associated with disruption of host-microbial homeostasis, especially microbiota composition in the gastrointestinal tract. Use of microbiota-directed foods or nutraceuticals therefore represents a promising approach for the control of obesity. Fucoxanthin, a marine carotenoid, has been proven to be one of the most effective anti-obesity natural products. However, its action mechanism is yet to be unraveled, especially with respect to its role in the modulation of gut microbiota composition. In the present study, profiles of microbiota in both the cecal and fecal samples from BALB/c mice given respectively the following treatments were examined: normal chow diet (NCD), NCD + fucoxanthin (NCDF), high-fat-diet (HFD), and HFD + fucoxanthin (HFDF). The results showed that fucoxanthin supplementation for 4 weeks significantly changed the composition of both cecal and fecal microbiota. In addition, a differential effect was observed between the supplementation to NCD and to HFD. The changes in the Firmicutes/Bacteroidetes ratio and the abundance of S24-7 and Akkermansia were identified to be among the major gut microbiota modulating events associated with the anti-obesity bioactivity of fucoxanthin. Hence, our results suggested that fucoxanthin could be a promising microbiota-targeted functional-food ingredient.


Effect of pore diameter on the elution behavior of analytes from thermoresponsive polymer grafted beads packed columns.
Temperature-responsive chromatography using thermoresponsive polymers is innovative and can control analyte retention via column temperature. Analyte elution behavior in this type of chromatography depends on the modified thermoresponsive polymer and the structure of the base materials. In the present study, we examine the effect of the pore diameter of silica beads on analyte elution behavior in temperature-responsive chromatography. Poly(N-isopropylacrylamide-co-n-butyl methacrylate) hydrogel was applied to beads of various pore sizes: 7, 12, and 30 nm. Almost the same amount of copolymer hydrogel was applied to all beads, indicating that the efficiency of copolymer modification was independent of pore size. Analyte retention on prepared beads in a packed column was observed using steroids, benzodiazepines, and barbiturates as analytes. Analyte retention times increased with temperature on packed columns of 12- and 30-nm beads, whereas the column packed with 7-nm beads exhibited decreased retention times with increasing temperature. The difference in analyte elution behavior among the various pore sizes was attributed to analyte diffusion into the bead pores. These results demonstrate that bead pore diameter determines temperature-dependent elution behavior.


The theory of S-curve discontinuity in the medical care field.
Confusion reigns supreme in the health are field today. In a previous paper, I described my thoughts about the reasons for this chaos. This article reviews the gradual escalation of health care costs and many of the unsuccessful methods to control them, reiterates the theory of S-Curve discontinuity in health care and develops a "tool" that will enable physician executives to determine whether or not a product or process in health care will succeed in the near and distant future. This new tool can be of value to all health care providers, investors, health planners, politicians involved in evolving health care legislation, and any others who have an investment in the future of health care.


NSAIDs and gastrointestinal cancer prevention.
Numerous studies report the relationship between aspirin and other nonsteroidal anti-inflammatories (NSAIDs) and cancer incidence, in particular for colorectal cancer. This paper systematically reviews the evidence of the effect of aspirin and other NSAIDs on the primary prevention of colorectal and other gastrointestinal cancers in the general population. In 25 investigations of NSAIDs and colorectal cancer, 23 observational studies reported a relative risk reduction but estimates vary widely. Cohort studies generally indicate lesser reductions than case-control studies suggesting possible biases in the latter. Clear evidence of a dose relationship generally appears lacking but data do not indicate useful effects of aspirin in cardioprophylactic doses. Differences have otherwise not been detected between aspirin and other NSAIDs, nor between non-aspirin NSAIDs. There is some evidence that the risk of colorectal cancer reduces with increased duration of NSAID use. The lower incidence of oesophageal and gastric cancers results in smaller numbers of cases in the studies reporting these cancers, particularly in the cohort studies. The trend is for a risk reduction for oesophageal and gastric cancers in people taking NSAIDs, which is more likely to be statistically significant in the case-control studies. A very small number of observational studies have reported the relationship between NSAIDs and the incidence of pancreatic, gallbladder and liver cancers. These show no consistent relationship. In view of the inadequate information about optimal dose and duration of NSAIDs for colorectal cancer reduction, and the adverse effects of NSAIDs, we are not yet in a position to recommend NSAIDs for the primary prevention of colorectal cancer in the general population.


A Mixed-Methods Analysis of Barriers to and Facilitators of Human Papillomavirus Vaccination Among Adolescents in Montana.
Human papillomavirus (HPV) vaccination rates among adolescents are lower in rural areas than in urban areas of the United States. The objective of this study was to identify barriers to and facilitators of adolescent HPV vaccination in Montana, a large, primarily rural state. Using a mixed-methods design, we integrated quantitative analyses of Montana's National Immunization Survey-Teen (NIS-Teen) data from 2013-2017 with qualitative data collected at a statewide meeting in October 2018 and from stakeholder interviews conducted from October 2018 through June 2019. Using NIS-Teen data, we identified trends and estimated adjusted prevalence ratios (aPRs) to identify factors associated with vaccine uptake. Using directed content analysis of qualitative data, we identified themes related to vaccine uptake. In Montana, initiation of the HPV vaccine series among adolescents aged 13-17 increased from 34.4% in 2013 to 65.5% in 2017. We identified 6 themes related to HPV vaccination from qualitative analyses, including medical providers' recommendation style as a facilitator of vaccination and parental vaccine hesitancy as a barrier to vaccination. In NIS-Teen 2017 data (n = 326 adolescents), receiving a medical provider recommendation was significantly associated with series initiation (aPR = 2.3; 95% CI, 1.5-3.6). Among parents who did not intend to initiate the vaccine series for their adolescent within 12 months (n = 71), vaccine safety was the top concern (aPR = 24.5%; 95% CI, 12.1%-36.9%). HPV vaccination rates have increased in Montana but remain lower than rates for other adolescent vaccines. Future work should focus on reducing missed opportunities, increasing parents' knowledge of and confidence in vaccination, and training medical providers on addressing common vaccine concerns.


Perceptually motivated time-frequency analysis.
This paper describes the design of a bilinear time-frequency distribution which is a joint model of temporal and spectral masking. The distribution is used to generate temporally evolving excitation patterns of nonstationary signals and systems and is conceived as a tool for acousticians and engineers for perceptual time-frequency analysis. Distribution time and frequency resolutions are controlled by a separable kernel consisting of a set of low-pass time and frequency smoothing windows. These windows are designed by adapting existing psychoacoustic models of auditory resolution, rather than using mathematical window functions. Cross-term interference and windowing clutter are highly suppressed for the distribution, ensuring resolution accuracy over a dynamic range sufficient to encompass that of the auditory system (in excess of 100 dB). Application to the analysis of a synthetic and two real signals are included to demonstrate the approach.


Avascular necrosis in sickle cell (homozygous S) patients: predictive clinical and laboratory indices.
Pathogenetic mechanism as well as laboratory and clinical correlates of osteonecrosis in sickle cell have not been fully investigated. The aim of this study is to investigate the predictive value of the steady state white cell and platelet count as well as the frequency of bone pain crisis per annum to detect sickle cell patients who will eventually develop avascular necrosis (AVN). A 5 year retrospective analysis of 122 homozygous S (HbSS) patients, aged 6-49 years (mean age 24.7 ± 7 years), out of which 16 patients (13.1%) had developed AVN within the years under review. The prevalence of AVN in sickle cell patients was determined to be 13.1 per 1000. The steady state white cell count, platelet count, frequency of bone pain crisis and hematocrit, was compared in patients that develop AVN and those who had not over the period. Only the steady state platelet count was found to differ significantly ( P = 0.011) between these two patient groups and to correlate positively (Pearson correlation coefficient = -0.251) with development of AVN. The hematocrit, white cell count, and frequency of bone pain crisis were found neither to differ significantly nor correlate with the development of AVN. In conclusion, patients with a raised steady state platelet count may have a higher tendency to develop AVN and may require closer orthopedic review and prophylactic intervention.


[APPLICATION OF LASER TECHNOLOGIES FOR TREATMENT OF URINARY STRESS INCONTINENCE IN WOMEN OF REPRODUCTIVE AGE].
Urinary incontinence is a significant health problem with considerable social impact. Prospective study was carried out to assess the efficacy and safety of erbium laser (Er:Yag 2940 nm) for treatment urinary stress incontinence in women of reproductive age and its influence on quality of life in the area of sexuality. 37 women (mean age 36,2 years) with mild and moderate urinary stress incontinence were enrolled in the study. The control group consisted of 20 women of similar age. Treatment was delivered in outpatient settings without anesthesia and sedation. Laser system Dermablate MCL 31 (Asclepion Laser Technologies, Germany) with a set of vaginal heads V-Asclepion was employed. All patients underwent examination including Q-tip test and Valsalva maneuver and completed ICIQ-SF H FSFI forms. Within 1 month postoperatively all 37 patients noted significant reduction ofurinarystress incontinence symptoms and favorable changes in quality of sexual life. Positive trend was found in urethrovesical junction angle changes. No postoperative complications were registered. The findings from this prospective study confirmed high efficacy and an acceptable safety profile of the new treatment of urinary stress incontinence.


Aberrantly Glycosylated IgA1 in IgA Nephropathy: What We Know and What We Don't Know.
IgA nephropathy (IgAN), the most common primary glomerular disease worldwide, is characterized by glomerular deposition of IgA1-containing immune complexes. The IgA1 hinge region (HR) has up to six clustered O-glycans consisting of Ser/Thr-linked N-acetylgalactosamine usually with β1,3-linked galactose and variable sialylation. Circulating levels of IgA1 with abnormally O-glycosylated HR, termed galactose-deficient IgA1 (Gd-IgA1), are increased in patients with IgAN. Current evidence suggests that IgAN is induced by multiple sequential pathogenic steps, and production of aberrantly glycosylated IgA1 is considered the initial step. Thus, the mechanisms of biosynthesis of aberrantly glycosylated IgA1 and the involvement of aberrant glycoforms of IgA1 in disease development have been studied. Furthermore, Gd-IgA1 represents an attractive biomarker for IgAN, and its clinical significance is still being evaluated. To elucidate the pathogenesis of IgAN, it is important to deconvolute the biosynthetic origins of Gd-IgA1 and characterize the pathogenic IgA1 HR O-glycoform(s), including the glycan structures and their sites of attachment. These efforts will likely lead to development of new biomarkers. Here, we review the IgA1 HR O-glycosylation in general and the role of aberrantly glycosylated IgA1 in the pathogenesis of IgAN in particular.


Observation of Ethanol-Induced Condensation and Decondensation Processes at a Single-DNA Molecular Level in Microfluidic Devices Equipped with a Rapid Solution Exchange System.
Conformational transitions from secondary (e.g., B- to A-form DNA) to higher-order (e.g., coil to globule) transitions play important roles in genome expression and maintenance. Several single-molecule approaches using microfluidic devices have been used to determine the kinetics of DNA chromatin assembly because microfluidic devices can afford stretched DNA molecules through laminar flow and rapid solution exchange. However, some issues, particularly the uncertainty of time 0 in the solution exchange process, are encountered. In such kinetic experiments, it is critical to determine when the target solution front approaches the target DNA molecules. Therefore, a new design for a microfluidic device is developed that enables the instantaneous exchange of solutions in the observation channel, allowing accurate measurements of DNA conformational transitions; stepwise, ethanol-induced conformational transitions are revealed. Although full DNA contraction from coil to globule is observed with >50% ethanol, no outstanding change is observed at concentrations <40% in 10 min. With 50% ethanol solution, the DNA conformational transition passes through two steps: (i) fast and constant-velocity contraction and (ii) relatively slow contraction from the free end. The first process is attributed to the B to A conformational transition by gradual dehydration. The second process is due to the coil-globule transition as the free end of DNA starts the contraction. This globular structure formation counteracts the shear force from the microfluids and decelerates the contraction velocity. This real-time observation system can be applied to the kinetic analysis of DNA conformational transitions such as kinetics of chromatin assembly and gene expression.


A fluorescent probe based on aggregation-induced emission for hydrogen sulfide-specific assaying in food and biological systems.
A fluorescent probe based on a triphenylamine benzopyridine platform for hydrogen sulfide (H2S) assaying has been designed and synthesized. As a result of the H2S-triggered cleavage reaction, the disappearance of the quenching effect of dinitrophenyl and the increased hydrophobicity in a poor solvent lead to the aggregation-induced emission (AIE) effect; consequently an obvious 'turn-on' fluorescence signal can be observed in this process. The probe TPANF features high selectivity towards H2S, low detection limit (0.17 μM), and good photostability and biocompatibility. Moreover, it has been successfully utilized to monitor H2S in food samples to distinguish the extent of food deterioration and to identify the H2S concentration variation in living cells. In addition, endogenous H2S in HCT-116 xenograft tumor tissues was imaged by using this probe. The approach could provide useful insight for the development of other activatable AIE-based probes that are potentially helpful for specific assaying in food chemistry and biological systems.


Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity.
To migrate efficiently to target locations, cells must integrate receptor inputs while maintaining polarity: a distinct front that leads and a rear that follows. Here we investigate what is necessary to overwrite pre-existing front-rear polarity in neutrophil-like HL60 cells migrating inside straight microfluidic channels. Using subcellular optogenetic receptor activation, we show that receptor inputs can reorient weakly polarized cells, but the rear of strongly polarized cells is refractory to new inputs. Transient stimulation reveals a multi-step repolarization process, confirming that cell rear sensitivity to receptor input is the primary determinant of large-scale directional reversal. We demonstrate that the RhoA/ROCK/myosin II pathway limits the ability of receptor inputs to signal to Cdc42 and reorient migrating neutrophils. We discover that by tuning the phosphorylation of myosin regulatory light chain we can modulate the activity and localization of myosin II and thus the amenability of the cell rear to 'listen' to receptor inputs and respond to directional reprogramming.


Dynamic hip kinematics during recreational classical ballet and hula dance after total hip arthroplasty: two case reports.
The in vivo assessment of the three-dimensional kinematics of the hip during dance activities in patients after total hip arthroplasty has not been previously reported. We evaluated the replaced hip kinematics during recreational classical ballet and hula dance using radiographic-based image-matching techniques. A 58-year-old Japanese woman (patient 1; height, 157 cm; weight, 74.5 kg) and a 73-year-old Japanese woman (patient 2; height, 153 cm; weight, 48 kg) were still doing classical ballet and hula dance, respectively, after primary total hip arthroplasty. For ballet, there were gradual three-dimensional hip movements with 48° flexion, 36° abduction, and 49° external rotation in développé and 34° flexion, 29° abduction, and 43° external rotation in plié. For hula, there were small three-dimensional hip movements with 31° flexion, 15° adduction, and 11° external rotation in kao and 17° flexion, 11° adduction, and 11° external rotation in kaholo. No liner-to-neck contact was found in any dance activities. Both classical ballet and hula dance produced complex ranges of hip movements and activity-dependent kinematics. These kinematic data could be useful for recommending each patient with total hip arthroplasty to continue recreational dance activities.


The Addition of High-Load Resistance Exercises to a High-Intensity Functional Training Program Elicits Further Improvements in Body Composition and Strength: A Randomized Trial.
The current study aimed to examine the effects of adding specific high-load resistance exercises to a high-intensity functional training (HIFT) program on healthy adults' physical fitness and body composition. Twenty recreationally active volunteers (30 ± 4 y, 12 females, 8 males) were randomly assigned to either a HIFT-control (HIFT-C, n = 10) or HIFT-power (HIFT-P, n = 10) group and trained three times per week for eight weeks. The HIFT-C protocol included four rounds of an 8-exercise circuit (30:15 s work: rest, 2 min rest after the second round). The exercises used were clean-and-press, box jump, TRX chest press, wall ball throws, burpees, repeated 10 m sprints, sumo squat-and-upright row, and abdominal crunches. The HIFT-P-group replaced TRX chest press with bench press and squat-and-upright row with squat, both at an intensity of 80% 1 RM. Before and after the intervention, participants underwent an evaluation of body composition, cardiorespiratory fitness, vertical jump, 1 RM bench press, and the maximum number of abdominal crunches in 1 min. In both groups, cardiorespiratory fitness, squat jump, countermovement jump, bench press 1 RM, and percent body fat improved significantly after the intervention (p < 0.050), while a trend towards significant time x group interaction was found for bench press 1 RM (p = 0.076), indicating a superiority of HIFT-P over HIFT-C. Muscle mass significantly increased by 3.3% in the HIFT-P group, while abdominal muscle endurance improved by 16.2% in the HIFT-C group (p < 0.050). Short-term HIFT resulted in improvements in whole-body cardiorespiratory and neuromuscular fitness and reduction of body fat. The addition of high-load resistance exercises was well tolerated and resulted in increased muscle mass and upper body maximal strength. HIFT-P programs can be suitable for individuals seeking to enhance muscle mass and physical fitness in a short time.


Dietary antioxidant capacity is inversely associated with diabetes biomarkers: the ATTICA study.
Elevated dietary antioxidant activity has been regarded as providing potential benefits to health. The present work aimed at evaluating the association of glycemic indices with total dietary antioxidant capacity in healthy adults. The ATTICA study consisted of men and women, randomly selected from all areas of Attica region in Greece. In this work, a random sub-sample from the ATTICA study's database was studied, consisting of 551 men (41 ± 11 years) and 467 women (38 ± 11 years), with complete nutritional and biochemical information. Dietary habits were evaluated using a validated food-frequency questionnaire. The dietary antioxidant capacity was based on published values for Italian foods measured by three different assays: ferric-reducing antioxidant power (FRAP), total radical-trapping antioxidant parameter (TRAP) and Trolox equivalent antioxidant capacity (TEAC). Inverse, age-energy adjusted correlations were observed between FRAP and log-glucose (r = -0.149, p = 0.001), log-insulin (r = -0.221, p = 0.001) and log-HOMA-IR (r = -0.186, p = 0.001) concentration, as well as with TRAP and TEAC. After controlling for age, gender, body mass index, physical activity status, smoking habits and energy intake, multi-adjusted analysis confirmed the previous relationships only among participants who were not on the Mediterranean dietary pattern. Although more prospective studies are required, the data presented support the view that dietary modification towards higher consumption of antioxidants should be implemented in public health strategies, in order to better control glycemic markers in individuals, and prevent the development of diabetes at the population level.


Lateral hypothalamic kindling induces manic-like behavior in rats: a novel animal model.
The lateral hypothalamus integrates critical physiological functions such as the sleep-wake cycle, energy expenditure, and sexual behaviors. These functions are severely dysregulated during mania. In this study, we successfully induced manic-like behavioral phenotypes in adult, male Wistar rats through bilateral lateral hypothalamic area kindling (LHK). To test the validity of the model, we studied the effect of standard antimanic medications lithium (47.5 mg/kg) or valproic acid (200 mg/kg) twice/day for 15 days in attenuating manic-like behaviors in the LHK rat. Compared with pre-kindling behaviors, LHK rats displayed significantly increased sexual self-stimulation (P = 0.034), excessive rearing (P = 0.0005), feeding (P = 0.013), and grooming (P = 0.007) during the kindling interval. LHK rats also drank more alcohol during the mania-induction days compared with baseline ethanol consumption levels (P = 0.01). Moreover, LHK rat exhibited increased total locomotor activity (P = 0.02) with reduced rest interval (P < 0.001) during the mania induction and post-mania days compared with baseline activity levels and rest intervals. Chronic administration of lithium or valproic acid significantly attenuated manic-like behaviors in the LHK rat model. Given the behavioral phenotype and the response to standard antimanic medications, the LHK rats may provide a model for studying manic psychopathology in humans.


The effect of epsilon-aminocaproic acid on biochemical changes in the development of the cellular slime mould Dictyostelium discoideum.
epsilon-Aminocaproic acid (EACA) inhibited the development of Dictyostelium discoideum strain AX2 after the aggregation stage. Biochemical changes that occurred early in development (loss of cellular protein, RNA and carbohydrate; increase in the specific activity of N-acetylglucosaminidase, alpha-mannosidase, threonine deaminase and leucine aminopeptidase) were not affected by concentrations of EACA which blocked development; but biochemical changes that occurred later (synthesis of carbohydrate, increase in the specific activity of UDP-glucose pyrophosphorylase) were inhibited. Spores from fruiting bodies formed in the presence of low concentrations of EACA were larger, more spherical and less able to survive heat treatment than spores from fruiting bodies of control (no EACA) cells.


Using in-cell SHAPE-Seq and simulations to probe structure-function design principles of RNA transcriptional regulators.
Antisense RNA-mediated transcriptional regulators are powerful tools for controlling gene expression and creating synthetic gene networks. RNA transcriptional repressors derived from natural mechanisms called attenuators are particularly versatile, though their mechanistic complexity has made them difficult to engineer. Here we identify a new structure-function design principle for attenuators that enables the forward engineering of new RNA transcriptional repressors. Using in-cell SHAPE-Seq to characterize the structures of attenuator variants within Escherichia coli, we show that attenuator hairpins that facilitate interaction with antisense RNAs require interior loops for proper function. Molecular dynamics simulations of these attenuator variants suggest these interior loops impart structural flexibility. We further observe hairpin flexibility in the cellular structures of natural RNA mechanisms that use antisense RNA interactions to repress translation, confirming earlier results from in vitro studies. Finally, we design new transcriptional attenuators in silico using an interior loop as a structural requirement and show that they function as desired in vivo. This work establishes interior loops as an important structural element for designing synthetic RNA gene regulators. We anticipate that the coupling of experimental measurement of cellular RNA structure and function with computational modeling will enable rapid discovery of structure-function design principles for a diverse array of natural and synthetic RNA regulators.


[The medicalization of childbirth in Brazil through the study of obstetrics handbooks].
In this research note, I present a preliminary account of doctoral research in women's and children's health at the Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira/Fiocruz. The aim is to study the spread of knowledge and practices relating to childbirth by analyzing obstetrics handbooks published in Brazil between 1980 and 2011, contributing to the development of childbirth care in which the woman and her needs are at the center of the decision-making process about which care, interventions, and procedures are to be dispensed during labor and childbirth.


On-line coordination in complex goal-directed movements: a matter of interactions between several loops.
Motor flexibility is the ability to rapidly modify behavior when unexpected perturbations occur. In goal directed movements, this process may be involved during the motor execution itself, by using on-line motor corrections, or off-line, on a trial-by-trial basis. A consensus has emerged to describe and unify these two dependant processes within the framework of the internal models theory in which the cerebellum is involved in error processing. However, this general framework may be incomplete to describe on-line motor corrections when complex motor coordination is involved in the task. In particular, interaction torques existing between different effectors limit the independence between different controllers that could be considered to control various body parts. In addition, recent findings suggest that different (sub)-cortical loops may be involved during orienting responses to visual stimuli but also during on-line motor corrections following visual perturbations. The way these different loops with different dynamics interact but achieve the same motor goal is an important problem in motor control. The simplest organization may be sequential, as in the well-known stretch reflex. This implies that during on-line corrections, the nervous system may be involved in a distributed fashion and that motor plans and synergies depend both on anatomical and temporal constraints. More particularly, motor plans and synergies may be stored and may differ according to the (sub)-cortical loops involved during the whole on-line correction process. Finally, questions concerning the independence (or not) of these loops remain unanswered. The case of strict independence would mean that between the various corrective loops, (i) error processing and (ii) motor plans/synergies would be different. By contrast, in a situation of dependency, it would probably mean that interactions would link lower (and faster) to upper (and longer) loops by informing these latter of the motor corrections sent by the former, similarly to an efference copy.


Alpha 1-antichymotrypsin inhibits A beta degradation in vitro and in vivo.
The neuropathology of Alzheimer's disease (AD) is characterized by extensive deposition of the toxic amyloid beta peptide (A beta) in selected regions of the brain and brain vasculature (Selkoe, 1999). Thus, lowering the levels of A beta may be beneficial for AD patients. A beta is a proteolytic fragment derived from the amyloid precursor protein (APP). The mechanisms of A beta formation from its precursor have been studied extensively; however, considerably less effort has been invested into studying A beta clearance. We find that the degradation of A beta in our system is dependent upon the presence of a metallopeptidase E.C.22.214.171.124 (MP24.15) (Yamin et al., 1999). We have previously purified MP24.15 to homogeneity from AD brain and identified it as an APP-processing protease in vitro (Papastoitsis, 1994). To confirm its role in cell culture, we transfected SKNMC neuroblastoma cells with sense and antisense cDNAs of MP24.15 and with a mock construct. Compared to mock conditioned media (CM), CM of MP24.15-overexpressing cells had very high A beta-degrading activity. Conversely, CM of antisense-expressing cells lacked A beta-degrading activity. These results suggested that MP24.15 is involved in A beta degradation. Characterization of the proteolytic activity directly responsible for A beta degradation using a spectrum of protease inhibitors revealed that only serine protease inhibitors completely blocked A beta degradation. Therefore, MP24.15 appears to activate a serine protease, which then cleaves A beta. Interestingly, alpha 1-antichymotrypsin (ACT) which we discovered to be highly elevated in AD brain (Abraham, et al., 1988) also inhibited A beta degradation. To our delight, ACT proved to be an inhibitor of A beta degradation in vivo as well. When we crossed transgenic mice expressing human ACT with plaque-producing mice expressing human APP, the doubly transgenic mice had twice as many plaques at 20 months of age as the APP mice (Mucke et al., 2000). Successful completion of this study could lead to the design of reagents that would reduce the amyloid load in AD patients.


Impact of transamination reactions and protein turnover on labeling dynamics in (13)C-labeling experiments.
A dynamic model describing carbon atom transitions in the central metabolism of Saccharomyces cerevisiae is used to investigate the influence of transamination reactions and protein turnover on the transient behavior of (13)C-labeling chemostat experiments. The simulations performed suggest that carbon exchange due to transamination and protein turnover can significantly increase the required time needed for metabolites in the TCA cycle to reach isotopic steady state, which is in agreement with published experimental observations. On the other hand, transamination and protein turnover will speed-up the net rate of incorporation of labeled carbon into some free and protein-bound amino acids. The simulation results indicate that the pattern of labeled carbon incorporation into amino acids obtained from biomass hydrolysate shows significant deviation from the commonly assumed first-order kinetics behavior until after three residence times. These observations suggest that greater caution should be used while also pointing to new opportunities in the design and interpretation of (13)C-labeling experiments.


Global assessment instrument for quality of nursing doctoral education with a research focus: Validity and reliability study.
This study was designed to assess the content and construct validity and reliability of the Quality of Nursing Doctoral Education (QNDE) instrument for nursing doctoral programmes with a research focus. A cross-sectional, survey study. Using Qualtrics survey, the research team sent emails to potential participants providing a link to the study and the QNDE instrument. A total of 234 faculty and doctoral students participated: 17 faculty from 14 countries in the first stage; 111 faculty and 106 doctoral students from 20 countries in the second stage. The content validity, internal consistency reliability, and construct validity of the four domains (program, faculty, resources, and evaluation) of the QNDE were examined in two stages. Data were collected from purposive samples of faculty and students between June 2018 and March 2019. Confirmatory factor analysis was conducted in ordinal scale using robust weighted least square mean and variance (WLSMV) adjusted estimator in MPlus 8. Content validity of the items in the four domains was accepted when the item showed content validity (I-CVI > 0.78). Internal consistency reliability in four domains was computed using Cronbach's alpha, α = 0.88 to 0.97. Construct validity of the QNDE was established by confirmatory factor analysis based on model fit statistics. Factor loading coefficients for all items in each domain were statistically significant (>0.5; p < .001). Participation of 234 faculty and doctoral students from 20 countries on four continents confirmed content validity, internal consistency reliability, and construct validity of the QNDE instrument. These findings support the credibility of this revised QNDE instrument for assessing the quality of nursing doctoral education with a research focus. This is a significant step forward in enhancing the capability for evaluating doctoral programmes.


Gait cycle spectrogram analysis using a torso-attached inertial sensor.
Measurement of gait parameters can provide important information about a person's health and safety. Automatic analysis of gait using kinematic sensors is a newly emerging area of research. We describe a new way to detect walking, and measure gait cadence, by using time-frequency signal processing together with spectrogram analysis of signals from a chest-worn inertial measurement unit (IMU). A pilot study of 11 participants suggests that this method is able to distinguish between walk and non-walk activities with up to 88.70% sensitivity and 97.70% specificity. Limitations of the method include instability associated with manual fine-tuning of local and global threshold levels.


Effectiveness of culturally focused interventions in increasing the satisfaction of hospitalized Asian patients: a systematic review.
Patient satisfaction is a driving force for healthcare organizations to enhance patient services. As the Asian population in the United States is increasing at a significant rate, it is important to understand the needs of this population to implement culturally focused services that will lead to increased Asian in-patient satisfaction. The objective of the systematic review was to identify the best available evidence on the effectiveness of culturally focused interventions in increasing satisfaction of hospitalized adult Asian patients. This review considered studies that included Asian adults, 18 years of age and older, who were admitted to acute-care hospitals in countries where Asians are a minority culture. This review considered studies that included any intervention or sets of interventions implemented by hospitals for the purpose of making the hospital experience consistent with the cultural preferences of adult Asian in-patients. Satisfaction of adult Asian hospitalized patients as measured by self-report satisfaction scales or tools considered by accrediting and/or governing bodies to be acceptable sources of evidence of patients' perceptions of their care. This review first considered randomized controlled trials (RCTs), non-RCTs and quasi-experimental studies. As no RCTs or quasi-experimental studies were found, the reviewers also considered before and after studies, cohort studies and case-control studies for inclusion. This review also considered for inclusion descriptive study designs including case series, individual case reports and descriptive cross-sectional studies related to the adult Asian population in acute-care hospital settings. Three descriptive studies were selected in the review. The search strategy aimed to find both published and unpublished studies in English and Chinese (Mandarin and Cantonese) languages. A search of MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Educational Research Information Clearinghouse (ERIC), the Cochrane Library, the Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, Scopus, Excerpta Medical Databases (Embase) and Academic Search Premier was conducted, followed by a reference search of relevant studies and a gray literature search of the Virginia Henderson Library, Google Scholar, Mednar, conference proceedings and websites. The initial key words searched were patient satisfaction, culturally focused, hospitals, Asian-American and adult. Data were extracted using a standardized critical appraisal checklist and data extraction instrument from the Joanna Briggs Institute. Due to the statistical and methodological heterogeneity between included studies, statistical meta-analysis was not possible. Results are presented in a narrative summary. Three descriptive studies were reviewed with sample sizes ranging from 107 to 19,583 and a total of 386 Asian participants. Two of the studies reported on nine measures of patient satisfaction, whereas the third provided data on four measures. The interventions identified were: communication between physician/registered nurse and patient, cultural services, Asian social workers, interpreters, and cultural food. The first study included intervention groups that were exposed to inpatient information on hospitalized Chinese cultural services compared to the "usual care" control. The percentage of patients' satisfaction in the group who knew about the services (95%) was significantly higher (p < 0.01). In the same study, patients' satisfaction with nurses was higher (95%) in patients with nurses who were aware of Chinese cultural services, compared to patients with nurses who were unaware (83%) (p < 0.01). The second study developed a survey measuring 'Level of Top Box' satisfaction of Chinese patients in Chinese unit ('Informed of Chinese Culture Service') and non-Chinese unit ('Usual Care') with the outcome measure for patient satisfaction without p value. The two studies showed an increase in Asian inpatient satisfaction with communication between the physician/registered nurse and patient, as well as with pain control and quietness of the room. Also, two studies used the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) questions as patient satisfaction surveys. The third study was a descriptive/comparative secondary analysis of HCAHPS and Cultural Competency Assessment Tool for Hospitals (CCATH) surveys. There was also no p value for patient satisfaction measurement. The design and analysis of this study was more complex, using hospital wide-cultural competency and addressing factors such as race and language ability (English and non-English speakers). The surveys completed in Chinese were less than 0.1% of the sample size and the Asian data were eliminated. This study also showed that a greater degree of cultural competence in hospitals was positively associated with patient satisfaction with doctors' communication (P < 0.05). Evidence was insufficient to demonstrate cause and effect. Results suggest that culturally competent communication with patients by physicians and registered nurses, quietness of the room, information about treatments and procedures, and cultural foods are associated with increased satisfaction among hospitalized adult Asian patients.


[Electron microscopy of alpha-latrotoxin from the venom of the black widow spider Latrodectus mactans tredecimguttatus].
Two-dimensional crystals of alpha-latrotoxin from the venom of black widow spider (Latrodectus mactans tredecimguttatus) were studied by the negative staining electron microscopy. Two-dimensional crystals were obtained by adsorption of the protein solution with a high Mg2+ concentration on carbon-coated electron microscopy grids. The crystals were about 0.4 mkm in size, had the unit cell parameters: a = b = 15.55 nm, gamma = 90 degrees, p4 plane group symmetry. The contour map of a stain-excluding region of such crystals was calculated by the Fourier-filtering procedure at about 4 nm resolution. The calculation of molecular weight of the unit cell, with the symmetry p4 taken into account, showed that alpha-latrotoxin particles, revealed by negative staining, consisted of 4 or 8 protomers.


Metastability and paramagnetism in superconducting mesoscopic disks
A projected order parameter is used to calculate not only local minima of the Ginzburg-Landau energy functional but also saddle points or energy barriers responsible for the metastabilities observed in superconducting mesoscopic disks [A. K. Geim et al., Nature (London) 396, 144 (1998)]. We calculate the local minima magnetization and find the energetic instability points between vortex configurations with different vorticity. We also find that, for any vorticity, the supercurrent can reverse its flow direction on decreasing the magnetic field before one vortex can escape.


Volume regulation initiated by Na(+)-nutrient cotransport in isolated mammalian villus enterocytes.
We assessed ion transport during regulatory volume decrease (RVD) in jejunal villus enterocytes, isolated in suspension from guinea pig jejunum and swollen by exposure to L-alanine (L-Ala) or D-glucose (D-Glc) in the presence of Na+. Cell volume was measured electronically. Relative volume of cells (rel vol: cell vol/isotonic vol) within 1 min of L-Ala (20 mM) addition increased (1.10 +/- 0.03, P less than 0.005), but by 5 min there was no difference between cells in L-Ala or 20 mM D-Ala (0.95 +/- 0.02). Cell shrinkage after maximal swelling was greater with L-Ala than with D-Ala (14 +/- 4 vs. 2 +/- 1%, P less than 0.01). Initial swelling generated by L-Ala required extracellular Na+ (P less than 0.02). Volume increased 30 s after D-Glc (20 mM), and cells were larger than cells treated with L-Glc (1.04 +/- 0.01 vs. 0.95 +/- 0.01, P less than 0.001); subsequent cell shrinkage was complete in 2 min (8 +/- 2%, P less than 0.05). Swelling generated by methyl alpha-D-glucoside was prevented by 0.1 mM phloridzin (P less than 0.05). RVD after D-Glc swelling was prevented by inhibitors of K+ channels, 5 mM Ba2+ (P less than 0.001), 100 microM quinine (P less than 0.005), or 25 mM TEA (P less than 0.02), but the same inhibitors completely prevented L-Ala swelling. All inhibitors had no effect on L-Ala uptake into brush-border membrane vesicles in presence of Na+ gradient.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of sacrificed healthy aorta during thoracoabdominal aortic aneurysm repair using off-the-shelf endovascular branched devices and open surgery.
Off-the-shelf devices for branched endovascular aortic repair of thoracoabdominal aortic aneurysm (TAAA) have been developed to overcome the manufacturing- and logistics-related delays characteristic of device customization. Nonetheless, the structural requirements of branched endovascular aortic repair, together with the need for additional thoracic components to suit different anatomies, might lead to a large sacrifice of healthy aorta. We enrolled 18 consecutive TAAA patients treated between 2010 and 2016 in two centers employing the off-the-shelf t-Branch (Cook Medical, Bloomington, Ind) device (TB group). We matched these 18 patients one-to-one with another 18 patients of the 464 consecutive TAAAs treated in the same period by means of open repair (O group) in one of the two centers. The patients were matched on the basis of t-Branch feasibility, distance from the left subclavian artery to the beginning of the aneurysm, and diameter of proximal landing zone evaluated at preoperative computed tomography angiography. We compared the overall length of sacrificed healthy native aorta (the sealing zone in the TB group) in the two groups according to postoperative computed tomography angiography, and we investigated the number of intercostal arteries lost from that healthy aortic segment. We calculated also the real unnecessary sacrificed aorta by subtracting the compulsory minimum neck coverage requested to obtain the proximal sealing (25 mm). We matched one-to-one six extent II, seven extent III, and five extent IV TAAAs. Overall, the length of sacrificed healthy aorta was longer (P < .001) in the TB group (median length: TB group, 49 mm [interquartile range (IQR), 31-60 mm]; O group, 14 mm [IQR, 10-20 mm]), and consequently the number of intercostal arteries lost (median number of pairs lost: TB group, four [IQR, three-four]; O group, two [IQR, one-three]) was higher (P = .004). Stratifying the results according to TAAA extent and after having subtracted from the TB group the length of aorta required for proximal sealing (25 mm), the length of sacrificed healthy aorta was longer (P = .008) only in the extent IV TAAA, 125 mm (IQR, 56-155 mm). The number of intercostal artery pairs sacrificed was longer only in extent III TAAA (P = .043) and extent IV TAAA (P = .024). No significant 30-day clinical outcomes difference was observed between the matched groups. The use of the t-Branch device compared with open repair is associated with a greater sacrifice of healthy aorta in extent IV TAAA and with an increased loss of intercostal arteries arising from healthy aortic proximal neck. The theoretical possible increased risk of spinal cord ischemia secondary to the routine use of this off-the-shelf device should thus be analyzed further.


Hemodialysis and chloroquine poisoning.
The use of hemodialysis in the treatment of chloroquine intoxication was investigated. The in vitro and in vivo clearances of chloroquine were adequate (in vitro 53.4 ml. per minute, in vivo 57 ml. per minute). However, dialysis did not reduce the mortality in dogs. Eight milligrams per kilogram were uniformly fatal with or without dialysis whereas 5 mg. per kilogram were not fatal in any dog. Less than 5 per cent of administered chloroquine was removed during 6 hours of dialysis. Red cell chloroquine averaged 4 times serum values. Hemodialysis is ineffective in the treatment of chloroquine intoxication probably because chloroquine rapidly becomes intracellular after administration.


Wwp2, an E3 ubiquitin ligase that targets transcription factor Oct-4 for ubiquitination.
The POU transcription factor Oct-4 is a master regulator affecting the fate of pluripotent embryonic stem cells. However, the precise mechanisms by which the activation and expression of Oct-4 are regulated still remain to be elucidated. We describe here a novel murine ubiquitin ligase, Wwp2, that specifically interacts with Oct-4 and promotes its ubiquitination both in vivo and in vitro. Remarkably, the expression of a catalytically inactive point mutant of Wwp2 abolishes Oct-4 ubiquitination. Moreover, Wwp2 promotes Oct-4 degradation in the presence of overexpressed ubiquitin. The degradation is blocked by treatment with proteasome inhibitor. Fusion of a single ubiquitin to Oct-4 inactivates its transcriptional activity in a heterologous Oct-4-driven reporter system. Furthermore, overexpression of Wwp2 in embryonic stem cells significantly reduces the Oct-4-transcriptional activities. Collectively, we demonstrate for the first time that Oct-4 can be post-translationally modified by ubiquitination and that this modification dramatically suppresses its transcriptional activity. These results reveal that the functional status of Oct-4, in addition to its expression level, dictates its transcriptional activity, and the results open up a new avenue to understand how Oct-4 defines the fate of embryonic stem cells.


A Century of Board Directors.
The selection of directors of the American Board of Ophthalmology (ABO) initially was carried out by the 3 founding organizations of the ABO: the American Medical Association, the American Ophthalmological Society, and the American Academy of Ophthalmology and Otolaryngology. Since 1982, the ABO has chosen its own directors and, in 2001, began adding public directors. It is only in recent years that women comprise an increasing proportion of ABO directors.


Cancer incidence among workers in soft paper mills: A cohort study.
To elucidate whether occupational exposure to soft paper dust increases the incidence of cancer. We studied 7988 workers in Swedish soft paper mills from 1960 to 2008, of whom 3233 (2 187 men and 1046 women) had more than 10 years of employment. They were divided into high exposure (>5 mg/m3 for >1 year) or lower exposure to soft paper dust based on a validated job-exposure matrix. They were followed from 1960 to 2019, and person-years at risk were stratified according to gender, age, and calendar-year. The expected numbers of incident tumors were calculated using the Swedish population as the reference, and standardized incidence ratios (SIR) with 95% confidence intervals (95% CI) were assessed. Among high-exposure workers with more than 10 years of employment, there was an increased incidence of colon cancer (SIR 1.66, 95% CI 1.20-2.31), small intestine cancer (SIR 3.27, 95% CI 1.36-7.86), and thyroid gland cancer (SIR 2.68, 95% CI 1.11-6.43), as well as lung cancer (SIR 1.56, 95% CI 1.12-2.19). Among the lower-exposed workers there was an increased incidence of connective tissue tumors (sarcomas) (SIR 2.26, 95% CI 1.13-4.51) and pleural mesothelioma (SIR 3.29, 95% CI 1.37-7.91). Workers in soft paper mills with high exposure to soft paper dust have an increased incidence of large and small intestine tumors. Whether the increased risk is caused by paper dust exposure or some unknown associated factors is unclear. The increased incidence of pleural mesothelioma is probably linked to asbestos exposure. The reason for increased incidence of sarcomas is unknown.


The evolution of CD4+ T cell cytometry in perspective: challenges for resource poor settings.
CD4+ T cell cytometry antedated the Human Immunodeficiency Virus (HIV) epidemic. However it was in the wake of the HIV scourge that CD4+ T cell counting technology gradually evolved from a pure cellular research assay technique into a routine clinical diagnostic test. In the more than two and half decades of the HIV/AIDS pandemic, this cell based diagnostic test has undergone several phases of technological improvements in the efforts to produce cheaper and more robust equipment for the monitoring of patients. The evolution however, is still very much in progress. Resource poor countries that remain the worst hit by the scourge of HIV/AIDS are paradoxically usually the last to benefit from the impact of the technological advancements in CD4+ T cell cytometry. This review highlights the progress and the scientific milestones so far attained in the development of improved techniques for CD4+ T cells count as a major cornerstone of patient care, as well as the emerging future directions in the evolution of this important cellular diagnostic test. Some of the challenges for developing economies are highlighted.


Pre-treatment urea breath test results predict the efficacy of Helicobacter pylori eradication therapy in patients with active duodenal ulcers.
To evaluate the association of pre-treatment (13)C-urea breath test (UBT) results with H pylori density and efficacy of eradication therapy in patients with active duodenal ulcers. One hundred and seventeen consecutive outpatients with active duodenal ulcer and H pylori infection were recruited. H pylori density was histologically graded according to the Sydney system. Each patient received lansoprazole (30 mg b.i.d.), clarithromycin (500 mg b.i.d.) and amoxicillin (1 g b.i.d.) for 1 week. According to pre-treatment UBT values, patients were allocated into low (<16 per thousand), intermediate (16-35 per thousand), and high (>35 per thousand) UBT groups. A significant correlation was found between pre-treatment UBT results and H pylori density (P<0.001). H pylori eradication rates were 94.9%, 94.4% and 81.6% in the low, intermediate and high UBT groups, respectively (per protocol analysis, P=0.11). When patients were assigned into two groups (UBT results < or =35 per thousand and >35 per thousand), the eradication rates were 94.7% and 81.6%, respectively (P=0.04). The intragastric bacterial load of H pylori can be evaluated by UBT, and high pre-treatment UBT results can predict an adverse outcome of eradication therapy.


Analysis of a Kalman filter based method for on-line estimation of atmospheric dispersion parameters using radiation monitoring data.
A Kalman filter method is discussed for on-line estimation of radioactive release and atmospheric dispersion from a time series of off-site radiation monitoring data. The method is based on a state space approach, where a stochastic system equation describes the dynamics of the plume model parameters, and the observables are linked to the state variables through a static measurement equation. The method is analysed for three simple state space models using experimental data obtained at a nuclear research reactor. Compared to direct measurements of the atmospheric dispersion, the Kalman filter estimates are found to agree well with the measured parameters, provided that the radiation measurements are spread out in the cross-wind direction. For less optimal detector placement it proves difficult to distinguish variations in the source term and plume height; yet the Kalman filter yields consistent parameter estimates with large associated uncertainties. Improved source term assessment results, when independent estimates of the plume height can be used. Perspectives for using the method in the context of nuclear emergency management are discussed, and possible extensions to the present modelling scheme are outlined, to account for realistic accident scenarios.


Combination iron depletion therapy.
Iron (Fe) depletion with anti-transferrin (Tf) receptor monoclonal antibodies (MAbs), Fe chelators, or gallium (Ga) salts inhibits in vitro and in vivo growth of tumor cells. The present studies examined the cytotoxic effects of an IgA anti-human Tf receptor MAb, 42/6, combined with parabactin, a powerful Fe chelator, or Ga nitrate. Parabactin inhibited in vitro growth of human hematopoietic and solid tumor cells, and the rank order of their sensitivities to the Fe chelator was identical to their relative sensitivity to MAb 42/6 as demonstrated in previous studies. When the most parabactin and MAb 42/6-sensitive (HL60 leukemia) and -resistant (KB carcinoma) cells were incubated with various concentrations of parabactin, cell killing was time and dose dependent over the first 24 hours. Little additional cytotoxicity occurred, however, when cells were exposed to parabactin for 48 hours. HL60 cells were slightly more sensitive than KB cells to parabactin cytotoxicity. Addition of optimally effective concentrations of anti-Tf receptor MAb 42/6 to parabactin increased cytotoxicity to HL60 cells over a narrow parabactin dose range but had little effect on cytotoxicity to KB cells. Cell cycle analysis of cells treated with parabactin for 24 hours showed that doses causing variable cytotoxicity increased the percentage of cells in S phase, but higher parabactin concentrations consistently arrested cells in G1 phase or at the G1/S interface. MAb 42/6 also increased toxicity of parabactin to granulocyte/macrophage colony-stimulating factors and normal marrow granulocyte/macrophage progenitors. When HL60 or KB cells were treated with MAb 42/6 combined with Ga nitrate, MAb 42/6 increased cytotoxicity of Ga for HL60 cells but had little or no effect on Ga cytotoxicity to KB cells. In contrast, MAb 42/6 had minimal effects on cytotoxicity of the ribonucleotide reductase inhibitor, isoquinaldehyde thiosemicarbazone, to either HL60 or KB cells. Both hematopoietic and solid tumors were killed by Fe depletion, but the present studies suggested that hematopoietic cells are more sensitive than solid tumor cells to cytotoxic effects of Fe depletion. Combined Fe depletion therapy by the use of MAb 42/6 with an Fe chelator or Ga salt increased toxicity to MAb 42/6-sensitive cells, such as HL60, but was not more effective against MAb 42/6-resistant solid tumor cells. Combination Fe depletion therapy of hematopoietic cell tumors merits evaluation in experimental in vivo tumor systems.


Rapid administration of high-dose human antibody Fab fragments to dogs: pharmacokinetics and toxicity.
The treatment of drug overdose with drug-specific antibody fragments may require very high antibody doses. To address the feasibility of this therapy, we studied the pharmacokinetics and toxicity of high-dose human nonspecific Fab fragments in beagles. Three dogs received 5.3 g/kg Fab iv over 1 hr. Because nephrotoxicity was observed, three subsequent dogs received 3.2 g/kg. The fraction of the Fab dose excreted in urine (10 +/- 6%) was lower than reported values for either high or low doses of Fab in other species. The terminal serum elimination half-life (42 hr for the higher and 48 hr for the lower dose) was also longer than reported values for other species, due to lower renal and nonrenal Fab clearance. Fab administration was tolerated without adverse hemodynamic effects. One of three dogs at each dose developed transient oliguria. All dogs developed a transient but marked increase in the serum creatinine concentration. At 2 weeks creatinine clearance had returned to normal. Urinary protein and albumin excretion at 2 weeks were within the normal range for dogs but were increased over their baseline values. The histology of all organs was normal at 3 weeks by light microscopy, and renal histology by electron microscopy was also normal. The mechanism of Fab nephrotoxicity, not observed previously with high-dose Fab in rats or lower doses of Fab in other species including dogs, is not clear. These data suggest that further study of the potential toxicity of high-dose Fab, and its reversibility, is needed to assess the feasibility of treating drug overdose with this antibody fragment.(ABSTRACT TRUNCATED AT 250 WORDS)


Perspectives on Technology-Assisted Relaxation Approaches to Support Mind-Body Skills Practice in Children and Teens: Clinical Experience and Commentary.
It has been well-established that a variety of mind-body (MB) techniques, including yoga, mental imagery, hypnosis, biofeedback, and meditation, are effective at addressing symptoms such as pain, anxiety, nausea, and insomnia, as well as helping with a wide variety of medical, emotional, and behavioral issues in pediatric populations. In addition, MB skills can also be health promoting in the long-term, and with regular practice, could potentially contribute to longer attention spans, social skills, emotional regulation, and enhanced immune system functioning. Importantly, the benefits accrued from MB skills are largely dose dependent, meaning that individuals who practice with some consistency tend to benefit the most, both in the short- and long-term. However, clinical experience suggests that for busy patients, the regular practice of MB skills can be challenging and treatment adherence commonly becomes an issue. This commentary reviews the concept of technology assisted relaxation as an engaging and effective option to enhance treatment adherence (i.e., daily practice) for pediatric patients, for whom MB skills have been recommended to address physical and mental health challenges.


Abdominal ultrasound with scintigraphic and clinical correlates in infants with sickle cell anemia: baseline data from the BABY HUG trial.
The purpose of this study is to perform and evaluate baseline abdominal ultrasound in infants with sickle cell anemia who participated in the BABY HUG multiinstitutional randomized placebo-controlled trial of hydroxyurea therapy and to examine the potential relationships among ultrasound results and clinical, nuclear medicine, and laboratory data. After local institutional review board approval and with informed guardian consent, 116 girls and 87 boys (age range, 7.5-18 months) with sickle cell anemia underwent standardized abdominal sonography at 14 institutions. Imaging was centrally reviewed by one radiologist who assessed and measured the spleen, kidneys, gallbladder, and common bile duct. Baseline physical assessment of spleen size, serum alanine aminotransferase and bilirubin levels, (99m)Tc sulfur colloid liver-spleen scans, and (99m)Tc diethylenetriaminepentaacetic acid clearance glomerular filtration rates (GFRs) were obtained. Analysis of variance and the Student test were performed to compare sonographic findings to published results in healthy children and to clinical and laboratory findings. The mean (± SD) spleen volume (108 ± 47 mL) was significantly greater than published normal control values (30 ± 14 mL; p < 0.0001). There was no correlation between spleen volume and function assessed by liver-spleen scan. The mean GFR (125 ± 34 mL/min/1.73 m(2)) was elevated compared with control GFRs (92 ± 18 mL/min/1.73 m(2)). Renal volumes (right kidney, 29 ± 8 mL; left kidney, 31 ± 9 mL) were significantly greater than control volumes (right kidney, 27 ± 3 mL; left kidney, 27 ± 3 mL; p < 0.0001) and were positively correlated with GFR (p = 0.0009). Five percent of patients had sonographic biliary abnormalities (sludge, n = 6; dilated common bile duct, n = 2; and cholelithiasis and thickened gallbladder wall, n = 1 each). There was no correlation between biliary sonographic findings and laboratory results. In infants with sickle cell anemia, sonographic spleen volume does not reflect function, but increased renal volume correlates with GFR and is consistent with hyperfiltration. Sonographic biliary abnormalities can occur early in life, while remaining clinically silent.


The value of assessing pulmonary venous flow velocity for predicting severity of mitral regurgitation: A quantitative assessment integrating left ventricular function.
Although alteration in pulmonary venous flow has been reported to relate to mitral regurgitant severity, it is also known to vary with left ventricular (LV) systolic and diastolic dysfunction. There are few data relating pulmonary venous flow to quantitative indexes of mitral regurgitation (MR). The object of this study was to assess quantitatively the accuracy of pulmonary venous flow for predicting MR severity by using transesophageal echocardiographic measurement in patients with variable LV dysfunction. This study consisted of 73 patients undergoing heart surgery with mild to severe MR. Regurgitant orifice area (ROA), regurgitant stroke volume (RSV), and regurgitant fraction (RF) were obtained by quantitative transesophageal echocardiography and proximal isovelocity surface area. Both left and right upper pulmonary venous flow velocities were recorded and their patterns classified by the ratio of systolic to diastolic velocity: normal (>/=1), blunted (<1), and systolic reversal (<0). Twenty-three percent of patients had discordant patterns between the left and right veins. When the most abnormal patterns either in the left or right vein were used for analysis, the ratio of peak systolic to diastolic flow velocity was negatively correlated with ROA (r = -0.74, P <.001), RSV (r = -0.70, P <.001), and RF (r = -0.66, P <.001) calculated by the Doppler thermodilution method; values were r = -0.70, r = -0.67, and r = -0.57, respectively (all P <.001), for indexes calculated by the proximal isovelocity surface area method. The sensitivity, specificity, and predictive values of the reversed pulmonary venous flow pattern for detecting a large ROA (>0.3 cm(2)) were 69%, 98%, and 97%, respectively. The sensitivity, specificity, and predictive values of the normal pulmonary venous flow pattern for detecting a small ROA (<0.3 cm(2)) were 60%, 96%, and 94%, respectively. However, the blunted pattern had low sensitivity (22%), specificity (61%), and predictive values (30%) for detecting ROA of greater than 0.3 cm(2) with significant overlap with the reversed and normal patterns. Among patients with the blunted pattern, the correlation between the systolic to diastolic velocity ratio was worse in those with LV dysfunction (ejection fraction <50%, r = 0.23, P >.05) than in those with normal LV function (r = -0.57, P <.05). Stepwise linear regression analysis showed that the peak systolic to diastolic velocity ratio was independently correlated with RF (P <.001) and effective stroke volume (P <.01), with a multiple correlation coefficient of 0.71 (P <.001). In conclusion, reversed pulmonary venous flow in systole is a highly specific and reliable marker of moderately severe or severe MR with an ROA greater than 0.3 cm(2), whereas the normal pattern accurately predicts mild to moderate MR. Blunted pulmonary venous flow can be seen in all grades of MR with low predictive value for severity of MR, especially in the presence of LV dysfunction. The blunted pulmonary venous flow pattern must therefore be interpreted cautiously in clinical practice as a marker for severity of MR.


Classification of Intrahepatic Cholangiocarcinoma into Perihilar Versus Peripheral Subtype.
Intrahepatic cholangiocarcinoma (ICC) constitutes a group of heterogeneous malignancies within the liver. We sought to subtype ICC based on anatomical origin of tumors, as well as propose modifications of the current classification system. Patients undergoing curative-intent resection for ICC, hilar cholangiocarcinoma (CCA), or hepatocellular carcinoma (HCC) were identified from three international multi-institutional consortia of databases. Clinicopathological characteristics and survival outcomes were assessed. Among 1264 patients with ICC, 1066 (84.3%) were classified as ICC-peripheral subtype, whereas 198 (15.7%) were categorized as ICC-perihilar subtype. Compared with ICC-peripheral subtype, ICC-perihilar subtype was more often associated with aggressive tumor characteristics, including a higher incidence of nodal metastasis, macro- and microvascular invasion, perineural invasion, as well as worse overall survival (OS) (median: ICC-perihilar 19.8 vs. ICC-peripheral 37.1 months; p < 0.001) and disease-free survival (DFS) (median: ICC-perihilar 12.8 vs. ICC-peripheral 15.2 months; p = 0.019). ICC-perihilar subtype and hilar CCA had comparable OS (19.8 vs. 21.4 months; p = 0.581) and DFS (12.8 vs. 16.8 months; p = 0.140). ICC-peripheral subtype tumors were associated with more advanced tumor features, as well as worse survival outcomes versus HCC (OS, median: ICC-peripheral 37.1 vs. HCC 74.3 months; p < 0.001; DFS, median: ICC-peripheral 15.2 vs. HCC 45.5 months; p < 0.001). ICC should be classified as ICC-perihilar and ICC-peripheral subtype based on distinct clinicopathological features and survival outcomes. ICC-perihilar subtype behaved more like carcinoma of the bile duct (i.e., hilar CCA), whereas ICC-peripheral subtype had features and a prognosis more akin to a primary liver malignancy.


Isolated Medial Patellofemoral Ligament Reconstruction with Semitendinosus Tendon Allograft.
Medial patellofemoral ligament (MPFL) reconstruction is recommended to surgically stabilize the patella against excessive lateral patellar translation. It is currently the cornerstone of treatment for recurrent lateral patellar instability. The MPFL is often disrupted during acute patellar dislocations but may also be attenuated in the setting of recurrent lateral instability. Numerous techniques have been developed with the primary goal of restoring the static function of the MPFL in resisting lateral translation of the patella during early flexion of the knee. There are now numerous options for the surgical technique, fixation devices, and graft choice, with equal clinical results as long as key surgical principles are maintained1. This article provides a step-by-step description of our preferred technique as well as offering technical pearls and a review of patient outcomes. The MPFL is reconstructed anatomically using a hamstring allograft or autograft with an ideal width of 4 to 5 mm. The graft is secured to the femur with an interference screw at its anatomic insertion point, which can be defined by radiographic or anatomic landmarks, is passed through the soft tissues between the capsule and the medial retinaculum/vastus medialis oblique muscles, and is secured to the superomedial patellar border. Nonoperative treatment of lateral patellar dislocations is associated with recurrent dislocation rates of 35% to 50%; surgical treatment for recurrent dislocations has afforded improved patient outcomes2,3. In general, there are 3 surgical options to restore the function of the MPFL. Historically, acute repair was thought to offer the MFPL a chance to "heal" and resume its function; however, the literature has failed to support this as a reliable option in the setting of lateral patellar instability4. Similarly, delayed tightening or imbrication of the MPFL in the setting of chronic laxity has not demonstrated worthwhile clinical results5. MPFL reconstruction with a graft, as described here, has provided the most consistent outcomes. Isolated reconstruction of the MPFL is indicated for patients with a history consistent with recurrent lateral patellar instability and a physical examination demonstrating excessive lateral patellar translation. Patients with high-grade trochlear dysplasia and patella alta may be better treated with concomitant osseous procedures such as trochleoplasty or tibial tubercle osteotomy.


Myelin formation following transplantation of normal fetal glia into myelin-deficient rat spinal cord.
Structurally normal myelin sheaths develop in the spinal cord of juvenile myelin-deficient rats (mdr) 11 days after transplantation of normal fetal spinal cord fragments or cultured cells that do not yet express galactocerebroside. Cultures result in more extensive myelin formation, and in both cases the myelin that forms is located primarily at or near the site of transplantation. Myelin formation also occurs after transplantation of postnatal donor tissue, but the extent diminishes with donor age, and none was seen after transplantation of adult donor tissue over the two-week period studied. Injection of killed tissue, tissue derived from mouse donors or an extract of myelin also did not lead to myelin formation. The results imply that myelin formed in the host following transplantation was generated by oligodendrocytes newly differentiated from donor precursor cells rather than by donor oligodendrocytes that were already mature at the time of transplantation or by host oligodendrocytes that took up components of the injected material. We conclude that exogenous fetal glial cell precursors are able to survive, differentiate and form myelin in the environment of the juvenile mdr spinal cord.


Limited reproducibility of MUCH and WUCH: evidence from the ELSA study.
To evaluate the long-term reproducibility of masked (MUCH) and white-coat uncontrolled hypertension (WUCH), an information crucial for determining the long-term prognostic impact of these conditions. Reproducibility of MUCH and WUCH was assessed in 1664 hypertensive patients recruited for the European Lacidipine Study on Atherosclerosis and treated with atenolol or lacidipine (±additional drugs) during a 4-year period. Office and 24 h blood pressure (BP) was measured at baseline and every year during treatment, allowing repeated classification of either condition. After 1 year of treatment 21.1% and 17.8% of the patients were classified as MUCH and WUCH, respectively. For both conditions the prevalence was similar in the following years, although with a large change in patients composition because only about 1/3 of patients classified as MUCH or WUCH at one set of office and ambulatory BP measurements maintained the same classification at a subsequent set of measurements. In only 4.5% and 6.2% MUCH and WUCH persisted throughout the treatment period. MUCH and WUCH reproducibility was worse than that of patients showing control or lack of control of both office and ambulatory BP, i.e. controlled and uncontrolled hypertension, respectively. Both MUCH and WUCH display poor reproducibility over time. This should be taken into account in studies assessing the long-term prognostic value of these conditions based on only one set of BP measurements.