Retrospective Cues Mitigate Information Loss in Human Cortex during Working Memory Storage.
Working memory (WM) enables the flexible representation of information over short intervals. It is well established that WM performance can be enhanced by a retrospective cue presented during storage, yet the neural mechanisms responsible for this benefit are unclear. Here, we tested several explanations for retrospective cue benefits by quantifying changes in spatial WM representations reconstructed from alpha-band (8-12 Hz) EEG activity recorded from human participants (both sexes) before and after the presentation of a retrospective cue. This allowed us to track cue-related changes in WM representations with high temporal resolution (tens of milliseconds). Participants encoded the locations of two colored discs for subsequent report. During neutral trials, an uninformative cue instructed participants to remember the locations of both discs across a blank delay, and we observed a monotonic decrease in the fidelity of reconstructed spatial WM representations with time. During valid trials, a 100% reliable cue indicated that the color of the disc participants would be probed to report. Critically, valid cues were presented immediately after the termination of the encoding display ["valid early" (VE) trials] or midway through the delay period ["valid late" (VL) trials]. During VE trials, the gradual loss of location-specific information observed during neutral trials was eliminated, while during VL trials it was partially reversed. Our findings suggest that retrospective cues engage several different mechanisms that together serve to mitigate information loss during WM storage.SIGNIFICANCE STATEMENT Working memory (WM) performance can be improved by a cue presented during storage. This effect, termed a retrospective cue benefit, has been used to explore the limitations of attentional prioritization in WM. However, the mechanisms responsible for retrospective cue benefits are unclear. Here we tested several explanations for retrospective cue benefits by examining how they influence WM representations reconstructed from human EEG activity. This approach allowed us to visualize, quantify, and track the effects of retrospective cues with high temporal resolution (on the order of tens of milliseconds). We show that under different circumstances retrospective cues can both eliminate and even partially reverse information loss during WM storage, suggesting that retrospective cue benefits have manifold origins.


[Therapeutic efficacy of laser and electropuncture reflexotherapy in correcting the initial manifestations of cerebral circulatory insufficiency].
Electrical and laser acupuncture was used in 2 groups of 50 patients each who presented initial manifestations of cerebral circulation insufficiency (CCI). It was shown that stimulating an experimentally selected combination of acupuncture points on the affected side in initial manifestations of CCI, it was possible to achieve a regionally localized action correcting the cerebral hemodynamics. Changes in the tone of the regional vessels of the brain were objectively documented with the help of echopulsography of the cerebral vessels. The findings obtained included prolongation of the blood clotting time, a decreased index of thrombin inactivation and a reduction in the spontaneous fibrinolytic activity of the blood.


[The intoxication with cyclizin in infancy and adult age (Experiences of a contamination-information-central office) (author's transl)].
Epidemiological, clinical and therapeutic aspects obtained from 38 cases of intoxication with the antiemetic drug "cyclizine" in children and adults are discussed. The relative frequency of accidentally or purposely performed overdosage shows a decreasing tendency. The introduction of regulations after the prescription of cyclizine compounds, leaving a limited dose available without prescription and the introduction of a safety package to prohibit misuse by children are reported in their relationship with the epidemiologic data. A toxic dose of 5 mg/kg body weight, a minimal lethal dose (MLD) of about 80 mg/kg are evaluated and compared with previous published data. Differences of age in the development of the clinical picture of the cyclizine-intoxication with a disposition for the evolvement of convulsions in children compared to the total lack of convulsions in adults have to be pointed out. The management of overdoses follows general principles of treatment like gastric lavage, supporting care and includes the specific treatment with the antidote "physostigmin-salicylate", which causes a shortening of the time of recovery.


Diagnosis of thyroid carcinoma.
Despite being one of the most frequent neoplasms occurring in the endocrine system, thyroid carcinoma is, nevertheless, a relatively rare event (0.5-1.5% of all malignant tumours in man); the differentiated forms are the most prevalent and are characterized by a high mean survival rate, whereas the very aggressive forms are rare and prognosis is unfavourable. Diagnostic evaluation of carcinomatous lesions, particularly in the early stages, may give rise to considerable difficulties at a clinical level due to the differentiation of the benign lesions, which are a frequent finding. The traditional clinico-semeiological and instrumental parameters, which, in the past, were used in the assessment of suspected malignancy, should not be considered as markers of malignancy; however, exposure to ionizing radiations during childhood may have a well defined role of risk. Following the recent progress in genetic and molecular studies, it is now possible to exploit genetic-molecular tumor markers and, at present, thyroid medullary carcinoma may be identified also in the absence of clinical evidence, particularly the familial form, thus allowing suitable prophylaxis in those subjects with specific genetic impairment (e.g. preventive thyroidectomy in infancy). Since no discriminating clinico-semeiological parameters are available, considering the aspecificity of scintigraphic findings and the lack of reliability of echographic imaging in providing data which enable us to distinguish a rare neoplastic pattern from the more frequent finding of a benign thyroid mass, fine-needle aspiration (FNA) cytology may today be considered the technique of choice in the screening of the thyroid nodule. Our experience in over 12,000 nodular lesions since 1982, has confirmed that the cytological examination is the most discriminating investigation, diagnostic reliability being far greater than that of traditional techniques. Considering the high frequency of thyroid nodule disease which rarely harbours a carcinomatous lesion, a very scrupulous diagnostic algorithm is mandatory. The FNA cytology, together with morphofunctional and immunological examinations, as well as dynamic exploration of the thyroid hypothalamo-pituitary axis, which allows a nosographic picture of the thyroid nodule disease, provides a more discriminating appraisal for the surgical approach to a single, solitary or prominent nodule.


Roles of Aryl Hydrocarbon Receptor in Aromatase-Dependent Cell Proliferation in Human Osteoblasts.
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and its expression is influenced by environmental compounds, such as 3-methylcholanthrene (3-MC) and β-naphthoflavone (β-NF). AhR and its downstream genes, such as CYP1A1, are considered to play a pivotal role in xenobiotic responses. AhR signaling has also been proposed to mediate osteogenesis in experimental animals, but its details have remained unclear. Therefore, in this study, we examined the possible roles of AhR in human bone. Immunohistochemical analysis revealed that AhR was detected in both osteoblasts and osteoclasts. We then screened AhR-target genes using a microarray analysis in human osteoblastic hFOB cells. Results of microarray and subsequent PCR analysis did reveal that estrogen metabolizing and synthesizing enzymes, such as CYP1B1 and aromatase, were increased by 3-MC in hFOB and osteosarcoma cell line, MG-63. The subsequent antibody cytokine analysis also demonstrated that interleukin-1β and -6 expression was increased by 3-MC and β-NF in hFOB cells and these interleukins were well known to induce aromatase. We then examined the cell proliferation rate of hFOB and MG-63 cells co-treated with 3-MC and testosterone as an aromatase substrate. The status of cell proliferation in both hFOB and MG-63 cells was stimulated by 3-MC and testosterone treatment, which was also inhibited by an estrogen blocker, aromatase inhibitor, or AhR antagonist. These findings indicated that AhR could regulate estrogen synthesis and metabolism in bone tissues through cytokine/aromatase signaling.


[Pharmacology of the venom from the scorpion, Buthus eupeus].
Reactions induced by venom from the scorpion Buthus eupeus and by toxin of the venom have been studied on isolated organs and tissues as well as on intact body. It has been shown that substances interfering with the conduction of nerve excitation, with the mediator storage and interaction of the latter with synaptic receptors prevent the reactions induced by the venom and toxin, whereas ganglion-blocking agents do not affect these reactions. The catecholamine content in rat blood plasma has been found to be increased. It is assumed that the venom and toxin that affect the postganglionic nerve terminals release mediator acetylcholine and noradrenaline.


pH dependence of a mammalian polyamine oxidase: insights into substrate specificity and the role of lysine 315.
Mammalian polyamine oxidases (PAOs) catalyze the oxidation of N1-acetylspermine and N1-acetylspermidine to produce N-acetyl-3-aminopropanaldehyde and spermidine or putrescine. Structurally, PAO is a member of the monoamine oxidase family of flavoproteins. The effects of pH on the kinetic parameters of mouse PAO have been determined to provide insight into the protonation state of the polyamine required for catalysis and the roles of ionizable residues in the active site in amine oxidation. For N1-acetylspermine, N1-acetylspermidine, and spermine, the k(cat)/K(amine)-pH profiles are bell-shaped. In each case, the profile agrees with that expected if the productive form of the substrate has a single positively charged nitrogen. The pK(i)-pH profiles for a series of polyamine analogues are most consistent with the nitrogen at the site of oxidation being neutral and one other nitrogen being positively charged in the reactive form of the substrate. With N1-acetylspermine as the substrate, the value of k(red), the limiting rate constant for flavin reduction, is pH-dependent, decreasing below a pK(a) value of 7.3, again consistent with the requirement for an uncharged nitrogen for substrate oxidation. Lys315 in PAO corresponds to a conserved active site residue found throughout the monoamine oxidase family. Mutation of Lys315 to methionine has no effect on the k(cat)/K(amine) profile for spermine; the k(red) value with N1-acetylspermine is only 1.8-fold lower in the mutant protein, and the pK(a) in the k(red)-pH profile with N1-acetylspermine shifts to 7.8. These results rule out Lys315 as a source of a pK(a) in the k(cat)/K(amine) or k(cat)/k(red) profiles. They also establish that this residue does not play a critical role in amine oxidation by PAO.


Corticosteroid avoidance ameliorates lymphocele formation and wound healing complications associated with sirolimus therapy.
Sirolimus (RAPA) and corticosteroids (CS) both inhibit wound healing. To evaluate the possibility that RAPA and CS have additive effects on wound healing, we evaluated the effects of corticosteroid avoidance (CSAV) on wound healing complications in patients treated with RAPA. One hundred nine patients treated with a CSAV regimen (no pretransplantation or posttransplantation CS) were compared with a historical control group (n = 72) that received cyclosporine (CsA), mycophenolate mofetil (MMF), and CS. The CSAV group received low-dose CsA, MMF, RAPA, and thymoglobulin induction. Complications were classified as follows: wound healing complications (WHC) or infectious wound complications (IWC). WHC included lymphocele, hernia, dehiscence, diastasis, and skin edge separation. IWC included wound abscess and empiric antibiotic therapy for wound erythema. The CSAV group was largely CS-free: 11% of patients received CS for rejection, 12% of patients received CS for recurrent disease, and 85% of patients are currently off CS. The CSAV group had a significantly lower incidence of WHC (13.7% vs 28%; P = .03) and lymphoceles (5.5% vs 16%; P = .02) than the control group. There was no difference in the incidence of IWC between the 2 groups. Patients who received CSAV were 18% less likely (P = .57) to develop any type of complication, 41% less likely (P = .20) to develop a WHC, and 71% less likely (P = .018) to develop a lymphocele. CSAV in a RAPA-based regimen results in a marked reduction in WHC and lymphoceles. Therefore, CSAV provides a promising approach for addressing WHC associated with RAPA therapy.


Beta3 tyrosine phosphorylation and alphavbeta3-mediated adhesion are required for Vav1 association and Rho activation in leukocytes.
Integrin alpha(v)beta(3)-mediated adhesion of hematopoietic cells to vitronectin results in activation of the Rho GTPases. Mutation of beta(3) tyrosine residue 747, previously shown to disrupt cell adhesion, results in sustained activation of Cdc42 and diminished Rac and Rho activity. We investigated the role of the hematopoietically restricted guanine nucleotide exchange factor Vav1 in alpha(v)beta(3)-mediated adhesion. We find that Vav1, a guanine nucleotide exchange factor for Rac and Rho, associates with alpha(v)beta(3) upon cell adhesion to vitronectin and that this association requires beta(3) tyrosine phosphorylation. Expression of exogenous Vav1 demonstrates that Y160F, but not wild type or the Vav1Y174F mutant, inhibits Rac and Rho activation during alpha(v)beta(3)-mediated cell adhesion to vitronectin. Cells expressing Vav1Y160F exhibit a sustained Cdc42 activation similar to nonphosphorylatable beta(3) mutants. In addition, cytoskeletal reorganization and cell adhesion are severely suppressed in Vav1Y160F-transfected cells, and Vav1Y160F fails to associate with beta(3) integrins. Furthermore, Vav1 itself is selectively phosphorylated upon tyrosine 160 after alpha(v)beta(3)-mediated adhesion, and the association between Vav1 and beta(3) occurs in specific response to adhesion to substrate. These studies describe a phosphorylation-dependent association between beta(3) integrin and Vav1 which is essential for cell progression to a Rho-dominant phenotype during cell adhesion.


Comparison of B-type natriuretic peptide levels in patients with heart failure with versus without mitral regurgitation.
Functional mitral regurgitation (MR) occurs most often in patients with heart failure (HF) and is associated with an adverse prognosis. Recently, B-type natriuretic peptide (BNP) has been validated as a marker of cardiac function and prognosis. We sought to assess the relation between functional MR and BNP levels in patients with HF, and hypothesized that MR is associated with higher BNP levels. In all, 201 patients admitted with the diagnosis of HF had a transthoracic echocardiogram and measurement of BNP levels within 48 hours. MR was graded as none/trace, mild, moderate, or severe using recently published guidelines of the American Society of Echocardiography. BNP was measured by a commercially available instrument (Biosite). The relation of MR to BNP was assessed using multivariable linear regression methods with a Tobin estimation to account for the truncation of BNP values at an upper limit of 1,300 pg/ml. Mean age of the patients was 67 +/- 11 years. The median BNP level was 826 pg/ml. The etiology of HF was predominantly diastolic in 64 patients (32%); 137 patients (68%) had significant left ventricular (LV) systolic dysfunction. Mean LV ejection fraction was 37 +/- 17%. MR was present in 112 patients (56%). After adjusting for clinical, hemodynamic, and echocardiographic variables, only LV ejection fraction (p = 0.016) and moderate or severe MR (p = 0.023) were significantly associated with BNP. When MR was grouped as any MR versus no MR, only LV ejection fraction (p = 0.017) and any degree of MR (p = 0.029) were significantly associated with BNP.


Explosive eruption of coal and basalt and the end-Permian mass extinction.
The end-Permian extinction decimated up to 95% of carbonate shell-bearing marine species and 80% of land animals. Isotopic excursions, dissolution of shallow marine carbonates, and the demise of carbonate shell-bearing organisms suggest global warming and ocean acidification. The temporal association of the extinction with the Siberia flood basalts at approximately 250 Ma is well known, and recent evidence suggests these flood basalts may have mobilized carbon in thick deposits of organic-rich sediments. Large isotopic excursions recorded in this period are potentially explained by rapid venting of coal-derived methane, which has primarily been attributed to metamorphism of coal by basaltic intrusion. However, recently discovered contemporaneous deposits of fly ash in northern Canada suggest large-scale combustion of coal as an additional mechanism for rapid release of carbon. This massive coal combustion may have resulted from explosive interaction with basalt sills of the Siberian Traps. Here we present physical analysis of explosive eruption of coal and basalt, demonstrating that it is a viable mechanism for global extinction. We describe and constrain the physics of this process including necessary magnitudes of basaltic intrusion, mixing and mobilization of coal and basalt, ascent to the surface, explosive combustion, and the atmospheric rise necessary for global distribution.


Biomarkers of Toxic Exposure and Oxidative Stress Among U.S. Adult Users of Premium Cigar Versus Other Cigar Subtypes: 2013-2019.
Cigars are currently the second-highest-used combustible tobacco product among U.S. adults, but knowledge about health effects of premium cigars versus other cigar subtype use is limited. This study analyzed the biospecimen data (n = 31 875) from Waves 1-5 of the Population Assessment of Tobacco and Health Study, collected during 2013-2019. Multivariable generalized estimation equations, accounting for within-person clustering, were conducted to examine differences in urine biomarkers of exposure (BOE) from five classes of harmful and potentially harmful constituents along with a biomarker of oxidative stress (urine 8-isoprostane) among exclusive users of premium cigars versus other exclusive cigar subtypes (ie, non-premium large cigars, cigarillos, and filtered cigars), cigarettes, and non-tobacco users. In comparison to non-tobacco users, exclusive premium cigar users had higher geometric mean concentrations of the nicotine metabolite cotinine (5.8 vs. 0.5ng/mg, p < .0001), tobacco-specific nitrosamine (TSNA) (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL): 7.8 vs. 1.3pg/mg, p < .0001), and volatile organic compound (VOC) (N-Acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA, acrylonitrile): 4.7 vs. 1.6ng/mg, p < .0001). Exclusive premium cigar users were less likely to be daily users than other tobacco user groups and had comparable BOEs with exclusive non-premium large cigar users but generally lower BOEs than exclusive cigarillo, filtered cigar, and cigarette smokers. Daily exclusive premium cigar users had similar nicotine and TSNA exposure but lower exposure to polycyclic aromatic hydrocarbons and volatile organic compounds than exclusive cigarillo and filtered cigar users. Premium cigar use exhibits different exposure to toxicants from other cigar subtype users. Regulations of premium cigars need to formalize product definition and take the population's health effects into consideration. This population study provides important information on BOE and potential harm with premium cigar use and its potential health effects. At present, premium cigars appear to pose a relatively low overall population health risk due to low frequency of use. However, future regulation of other tobacco products might change the landscape of premium cigar use and alter the overall health impact.


Prospective study of three major dietary patterns and risk of gastric cancer in Japan.
Dietary pattern analysis is an alternative and complementary approach to identify the relationship between diet and the risk of chronic disease. This study was aimed at investigating the associations between dietary patterns and the risk of gastric cancer in Japan. Using baseline data from a prospective study of 20,300 men and 21,812 women, we conducted factor analysis and identified 3 major dietary patterns, healthy, traditional and Western, and calculated the factor scores of each pattern for individuals. During 10 years of follow-up, 400 cases of gastric cancer were identified. We found an inverse association between the healthy pattern and gastric cancer risk in women [rate ratio for highest quartile (RR) = 0.56; 95% CI = 0.32-0.96; p for trend = 0.03], but not in men. In contrast, the traditional pattern was significantly associated with the increased risk of gastric cancer in both genders (for men, RR = 2.88, 95% CI = 1.76-4.72; for women, RR = 2.40, 95% CI = 1.32-4.35). The Western pattern was not associated with risk. These associations persisted in histologic subtypes. Our findings support the idea that the healthy pattern decreased the risk of gastric cancer among females, while the traditional pattern increased the risk in both genders.


Insomnia in epilepsy is associated with continuing seizures and worse quality of life.
To evaluate how insomnia is associated with seizure control and quality of life in patients with epilepsy. Consecutive patients with epilepsy attending clinical visits were surveyed with the Insomnia Severity Index (ISI). Patients had to be treated with at least one anticonvulsant and could not have had documented psychogenic pseudoseizure. The presence or absence of seizures and quality of life (QOLIE-P-10) within the past 4 weeks was recorded. Other variables included demographic and clinical data, sleep-wake timing, the Hörne-Östberg Morningness-Eveningness Questionnaire (MEQ), sleepiness (Epworth Sleepiness Scale (ESS), and mood (Center for Epidemiologic Studies Depression Scale, CES-D). 207 patients completed surveys. 43% had clinically significant insomnia, and 51% had at least mild insomnia. 58% were seizure free. Mean ISI scores were significantly worse for those with continuing seizures, and more severe ISI scores correlated strongly with worse QOL. Younger age, shorter duration of epilepsy, use of sedative/hypnotics, medical and sleep comorbidities, delayed sleep timing and chronotype, excessive sleepiness, and depression were all associated with more severe insomnia. Those with unexpected health care visits over the most recent 4 weeks had worse insomnia. After adjustment for these covariates, more severe insomnia remained significantly associated with lack of seizure freedom and with worse QOL. Insomnia is common in epilepsy, and is associated with short term poor seizure control and worse QOL. Future studies must evaluate cause-and-effect relationships. Assessment of insomnia may be important in the comprehensive care of epilepsy and may influence control of epileptic seizures.


Microbiological degradation of bile acids. The conjugation of a certain cholic acid metabolite with amino acids in Corynebacterium equi.
1. (4R)-4[4alpha-(2-Carboxyethyl)-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-1beta-yl]valeric acid (II) could not be utilized by Arthrobacter simplex, even though the acid was one of the metabolites formed from cholic acid (I) by this organism. Therefore the further degradation of the acid (II) by Corynebacterium equi was investigated to identify the intermediates involved in the cholic acid degradation. 2. The organism, cultured in a medium containing the acid (II) as the sole source of carbon, produced unexpected metabolites, the conjugates of this original acid (II) with amino acids or their derivatives, although the yield was very low. These new metabolites were isolated and identified by chemical synthesis as the Na-((4R)-4-[4alpha-(2-carboxyethyl)-3a alpha-hexahydro-7a beta-methyl-5-oxoindan-1 beta-yl]-valeryl) derivatives of L-alanine, glutamic acid, O-acetylhomoserine and glutamine, i.e. compounds (IIIa), (IIIb), (IIId) respectively. 3. The possibility that the bacterial synthetic reaction observed in the acid (II) metabolism with C. equi is analogous to peptide conjugation known in both animals and higher plants is discussed. A possible mechanism for this bacterial conjugation is also considered.


The obesity paradox in stroke: lower mortality and lower risk of readmission for recurrent stroke in obese stroke patients.
Although associated with excess mortality and morbidity, obesity is associated with lower mortality after stroke. The association between obesity and risk of recurrent stroke is unclear. The study aims to investigate the association in stroke patients between body mass index and risk of death and readmission for recurrent stroke. An administrative Danish quality-control registry designed to collect a predefined dataset on all hospitalized stroke patients in Denmark 2000–2010 includes 45 615 acute first-ever stroke patients with information on body mass index in 29 326. Data include age, gender, civil status, stroke severity, computed tomography, and cardiovascular risk factors. Patients were followed up to 9·8 years (median 2·6 years). We used Cox regression models to compare risk of death and readmission for recurrent stroke in the four body mass index groups: underweight (body mass index < 18·5), normal weight (body mass index 18·5–24·9), overweight (body mass index 25·0–29·9), obese (body mass index ≥ 30·0). Mean age 72·3 years, 48% women. Mean body mass index 23·0. Within follow-up, 7902 (26·9%) patients had died; 2437 (8·3%) were readmitted because of recurrent stroke. Mortality was significantly lower in overweight (hazard ratio 0·72; confidence interval 0·68–0·78) and obese (hazard ratio 0·80; confidence interval 0·73–0·88) patients while significantly higher in underweight patients (hazard ratio 1·66; confidence interval 1·49–1·84) compared with normal weight patients. Risk of readmission for recurrent stroke was significantly lower in obese than in normal weight patients (hazard ratio 0·84; confidence interval 0·72–0·92). Obesity was not only associated with reduced mortality relative to normal weight patients. Compared with normal weight, risk of readmission for recurrent stroke was also lower in obese stroke patients.


The abdominal region of the bithorax complex.
The homeotic mutations in the right half of the bithorax complex of Drosophila cause segmental transformations in the second through the eighth segments of the fly. A chromosomal walk in the bithorax complex has now been extended 215 kb through the right half of the complex, and lesions for over 40 mutations have been located on the DNA map. The mutations can be grouped in a series of phenotypic classes, one for each abdominal segment, although each mutation typically affects more than one segment. The mutant lesions of each class are clustered, and they are aligned on the chromosome in the order of the body segments that they affect. Complementation tests suggest interactions between widely spaced DNA regions; indeed, the right half cannot be split anywhere without some loss of function.


Diagnostic Performance of MRI Versus Galactography in Women With Pathologic Nipple Discharge: A Systematic Review and Meta-Analysis.
The objective of our study was to perform a systematic review of the literature of the diagnostic accuracy of MRI compared with galactography in women with pathologic nipple discharge. A systematic literature search was performed (MEDLINE, Embase, Web of Science) for articles evaluating the diagnostic performance of MRI and galactography in patients with pathologic nipple discharge and with histologic verification or clinical follow-up. Distinction between any abnormality and cancer was made. Two independent readers selected eligible articles published until December 2015. The quality of the studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Data analyses were performed using the bivariate model. Ten articles were analyzed for a total of 921 patients. The study quality was high, with a low risk of bias and low concerns regarding applicability. The pooled sensitivity for any abnormality was significantly higher for MRI, with 92% (95% CI, 85-96%), than for galactography, with 69% (95% CI, 59-78%) (p < 0.001). The pooled specificity was 76% (95% CI, 49-92%) for MRI versus 39% (95% CI, 16-69%) for galactography (p < 0.001). The pooled sensitivity and specificity for cancer detection were calculated for MRI only and were 92% (95% CI, 74-98%) and 97% (95% CI, 80-100%), respectively. This meta-analysis shows a higher diagnostic performance of MRI compared with that of galactography in the detection of any kind of lesion in patients with pathologic nipple discharge. Moreover, high sensitivity and very high specificity for cancer by MRI could be confirmed in this clinical setting. If mammography and ultrasound are negative, MRI should be preferred over galactography for further evaluation.


Dose-response relationship between exercise and cognitive function in older adults with and without cognitive impairment: A systematic review and meta-analysis.
This systematic review and meta-analysis examined the dose-response relationship between exercise and cognitive function in older adults with and without cognitive impairments. We included single-modality randomized controlled aerobic, anaerobic, multicomponent or psychomotor exercise trials that quantified training frequency, session and program duration and specified intensity quantitatively or qualitatively. We defined total exercise duration in minutes as the product of program duration, session duration, and frequency. For each study, we grouped test-specific Hedges' d (n = 163) and Cohen's d (n = 23) effect sizes in the domains Global cognition, Executive function and Memory. We used multilevel mixed-effects models to investigate dose-related predictors of exercise effects. In healthy older adults (n = 23 studies), there was a small positive effect of exercise on executive function (d = 0.27) and memory (d = 0.24), but dose-parameters did not predict the magnitude of effect sizes. In older adults with cognitive impairments (n = 13 studies), exercise had a moderate positive effect on global cognition (d = 0.37). For older adults with cognitive impairments, we found evidence for exercise programs with a short session duration and high frequency to predict higher effect sizes (d = 0.43-0.50). In healthy older adults, dose-parameters did not predict the magnitude of exercise effects on cognition. For older adults with cognitive impairments, exercise programs with shorter session duration and higher frequency may generate the best cognitive results. Studies are needed in which different exercise doses are directly compared among randomized subjects or conditions.


Selecting for Disabilities: Selection Versus Modification.
This essay considers one argument used to defend parents who use preimplantation genetic diagnosis (PGD) to select for deafness and other disabilities. Some bioethicists have argued that a distinction should be drawn between genetically modifying embryos to possess disabilities and using PGD to select embryos that already present markers of them, and that the former is unethical because it inflicts avoidable harms onto the resulting children, whereas the latter is permissible because it allows children with potentially impaired abilities to exist. This essay raises doubts about whether a meaningful moral distinction can be drawn between modification and selection. Arguments which distinguish modification from selection can be understood in two ways. One is to read them as presenting a No Harm, No Foul argument. Another is to read them as presenting a Harming Versus Letting Be argument. Neither succeeds, however, either in establishing a meaningful moral distinction between modification and selection, or in showing that the second is morally permissible in contradistinction to the first.


Hydration and glycogen affect T1 relaxation times of liver tissue.
T1 mapping is a useful tool for the assessment of patients with nonalcoholic fatty liver disease but still suffers from a large unexplained variance in healthy subjects. This study aims to characterize the potential effects of liver glycogen concentration and body hydration status on liver shortened modified Look-Locker inversion recovery (shMOLLI) T1 measurements. Eleven glycogen phantoms and 12 healthy volunteers (mean age: 31 years, three females) were scanned at 3 T using inversion recovery spin echo, multiple contrast spin echo (in phantoms), shMOLLI T1 mapping, multiple-echo spoiled gradient recalled echo and 13 C spectroscopy (in healthy volunteers). Phantom r1 and r2 relaxivities were determined from measured T1 and T2 values. Participants underwent a series of five metabolic experiments to vary their glycogen concentration and hydration levels: feeding, food fasting, exercising, underhydration, and rehydration. Descriptive statistics were calculated for shMOLLI T1 , inferior vena cava to aorta cross-sectional area ratio (IVC/Ao) as a marker of body hydration status, glycogen concentration, T2 * and proton density fat fraction values. A linear mixed model for shMOLLI R1 was constructed to determine the effects of glycogen concentration and IVC/Ao ratio. The mean shMOLLI T1 after fasting was 737 ± 67 ms. The mean within-subject change was 80 ± 45 ms. The linear mixed model revealed a glycogen r1 relaxivity in volunteers (0.18 M-1 s-1 , p = 0.03) close to that determined in phantoms (0.28 M-1 s-1 ). A unit change in IVC/Ao ratio was associated with a drop of -0.113 s-1 in R1 (p < 0.001). This study demonstrated a dependence of liver shMOLLI T1 values on liver glycogen concentration and overall body hydration status. Interparticipant variation of hydration status should be minimized in future liver MRI studies. Additionally, caution is advised when interpreting liver T1 measurements in participants with excess liver glycogen.


Endocytosis of human IgG:Fc receptor complexes by transfected BHK cells.
We have analyzed the mode of uptake of human beta FcRII molecules expressed in BHK cells (clone 2/14). When challenged with aggregated human IgG (ahIgG), these cells bind the ligand at 4 degrees C and endocytose the IgG: receptor complexes rapidly upon warming to 37 degrees C, as seen by fluorescence microscopy with antibodies directed against human IgG. Using 125I-labeled ahIgG, we found that 40% of the bound ligand was internalized within 15 min, and approximately 60% within 2 h. Surface replication and thin sectioning combined with immunogold labeling revealed that the ligand was taken up by coated vesicles and was transferred to the endosomal/lysosomal compartment. This was confirmed by confocal laser microscopy of cells double labeled for clathrin and ahIgG. After modulation of the coated vesicle pattern by hypertonic medium, ahIgG transport was impaired. These data show that a single isoform of human FcRII, expressed in an animal cell negative for Fc receptors, can use the coated vesicle based endocytic pathway of the host cell. Reincubation of cycloheximide-treated cells with a second batch of ligand showed that approximately 20% of the beta FcRII was recycled. This finding is in apparent contrast to the fate of the endogenous Fc receptors expressed on mouse macrophages.


Marginal quantile regression for longitudinal data analysis in the presence of time-dependent covariates.
When observations are correlated, modeling the within-subject correlation structure using quantile regression for longitudinal data can be difficult unless a working independence structure is utilized. Although this approach ensures consistent estimators of the regression coefficients, it may result in less efficient regression parameter estimation when data are highly correlated. Therefore, several marginal quantile regression methods have been proposed to improve parameter estimation. In a longitudinal study some of the covariates may change their values over time, and the topic of time-dependent covariate has not been explored in the marginal quantile literature. As a result, we propose an approach for marginal quantile regression in the presence of time-dependent covariates, which includes a strategy to select a working type of time-dependency. In this manuscript, we demonstrate that our proposed method has the potential to improve power relative to the independence estimating equations approach due to the reduction of mean squared error.


Feasibility of total body irradiation in chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphomas.
Combined total body irradiation (TBI) and Prednimustine were prospectively evaluated in 30 patients affected either with chronic lymphocytic leukemia (CLL) or with low-grade non-Hodgkin's lymphoma (NHL) eleven patients were previously treated. Between January 1984 and May 1987, 20 evaluable patients with CLL, median age 66 years (range 43-82), classified according to Rai (4 in stage I, 10 in stage II, 4 in stage III, 2 in stage IV) and 10 evaluable patients with NHL low-grade malignancy according to the Working Formulation, Stages III and IV, median age 54 years (range 32-71) were treated using a 6 MeV Linear Accelerator, applying two opposite alternating fields including total body, with a fraction of 15 cGy, 2 fractions weekly (3-day interval) for a total dose of 150 cGy given over 5 weeks. Prednimustine (100 mg/m2, orally, for 5 consecutive days, every 3-4 weeks, for 6-9 courses) was administered 2 months after TBI treatment, as consolidation therapy. By May 1989, a total of 85% hematological responses (defined as normalization of the differential white cell count, of the total blood cell count and of bone marrow infiltration) were obtained after combined treatment in CLL patients; moreover 3 CR (according to the WHO criteria), 75% with splenomegaly reduction and 40% with lymphadenopathy reduction were seen. Ninety percent objective responses (5 CR and 4 PR) were observed in the NHL patients, with 50% having splenomegaly reduction and 67% lymphadenopathy reduction. The median response time in the two groups was, respectively, 14 and 23 months. The overall toxicity (WHO grades 1,2,3,4) after combined treatment was 65% and 70% in the two patient groups. WHO grade III toxicity, completely reversible, was verified in only 16.6% of the cases; all cases, except one, were previously treated. Additionally, 1 toxic death (grade IV thrombocytopenia and leukopenia) was observed in a heavily pretreated patient affected with CLL after TBI alone. Prednimustine regimen was generally well tolerated. The high response rate and acceptable toxicity, confirms the feasibility and the usefulness of TBI in the context of a combined treatment for CLL and low-grade NHL patients. However in order to further reduce the severe toxic side effects, observed in one patient, white blood cells and platelet count should be plotted and monitored carefully, particularly in pretreated patients.


Female breast cancer management and survival: The experience of major public hospitals in South Australia over 3 decades-trends by age and in the elderly.
Clinical registry data from major South Australian public hospitals were used to investigate trends in invasive breast-cancer treatment and survival by age. Disease-specific survival was calculated for the 1980 to 2013 diagnostic period using Kaplan-Meier product-limit estimates, with a censoring of live cases on December 31, 2014. Cox proportional hazards regression was used to examine differences in survival by age and tumour characteristic. First-round treatments following diagnosis were analysed, using multiple logistic regression to adjust for confounding. Five-year survival increased from 75% in the 1980s to 87% in 2000 to 2013, consistent with national trends, and with increases occurring irrespective of age. There was an increased use of breast conserving surgery, radiotherapy, chemotherapy, and hormone treatments. Five-year survival was lower for women aged 80+ years, increasing from 65% in the 1980s to 74% in 2000 to 2013. Lower survival in these older women persisted after adjusting for TNM stage, other clinical variables, and diagnostic year, without evidence of a reduced disparity over time. Older women were less likely to have surgery, radiotherapy, and chemotherapy throughout 1980 to 2013. By comparison, their use of hormone therapy was elevated. The adjusted relative odds of mastectomy (as opposed to breast conserving surgery) were lower for the 80+ year age range. Breast-cancer survival increases applied to all ages, including 80+ years, but poorer outcomes persisted in this older group and the gap did not reduce. A key question is whether the best trade-off now exists between optimally therapeutic cancer treatment and accommodations for frailty and co-morbidity in the aged, or whether opportunities exist for better trade-offs and better survival. Local registry data are important for describing local service activity and outcomes by age for local service providers, health administrations and consumer groups; monitoring disparities; and indicating effects of local initiatives.


GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders.
γ-Aminobutyric acid-B receptor antibodies (GABA(B)R-ab) were recently described in 15 patients with limbic encephalitis (LE), associated with small-cell lung cancer (SCLC) or with concurrent glutamic acid decarboxylase (GAD) antibodies. We analyzed the frequency of GABA(B)R-ab in 147 patients with LE or neurologic syndromes associated with GAD-ab. We examined the presence of GABA(B)R-ab in 70 patients with LE (33 paraneoplastic with onconeural antibodies, 18 paraneoplastic without onconeural antibodies [5 with Gad-ab], and 19 idiopathic with either GAD-ab [5 patients] or seronegative) and 77 patients with GAD-ab-associated neurologic syndromes other than LE (29 stiff-person syndrome, 28 cerebellar ataxia, 14 epilepsy, and 6 with diverse paraneoplastic neurologic syndromes). GABA(B)R-ab were analyzed in serum or CSF by indirect immunofluorescence on HEK293 cells transfected with GABA(B1) and GABA(B2) receptor subunits. GABA(B)R-ab were detected in 10 of the 70 patients with LE (14%). Eight had SCLC and 2 were idiopathic. One of the 8 patients with LE with SCLC had an additional onconeural antibody (Hu) and 2 GAD-ab. GABA(B)R-ab were identified in 7 (70%) of the 10 patients with LE and SCLC without onconeural antibodies. GABA(B)R-ab antibodies were not found in patients with GAD-ab and stiff-person syndrome, idiopathic cerebellar ataxia, or epilepsy. However, one patient with GAD-ab, paraneoplastic cerebellar ataxia, and anaplastic carcinoid of the thymus also presented GABA(B)R-ab. GABA(B)R-ab are the most common antibodies found in LE associated with SCLC previously considered "seronegative." In patients with GAD-ab, the frequency of GABA(B)R-ab is low and only observed in the context of cancer.


[Catamenial pneumothorax due to diaphragmatic endometriosis confirmed by histological examination; report of a case].
We reported a case of catamenial pneumothorax caused by diaphragmatic endometriosis that was histologically confirmed. A 49-year-old female who had recurrent chest pain and cough appearing on the day preceding each menstruation from 5 years ago. These episode suggested catamenial pneumothorax. Thoracotomy revealed the characteristic appearances of catamenial pneumothorax such as blueberry spots and multiple small holes on the central tendon of the right diaphragm. But there were no lesions on the visceral pleura of the lung. Partial resection of the diaphragm including these lesions were performed. Histological examination showing positive for estrogen receptor and progesterone receptor confirmed the presence of endometrial tissue on the diaphragm. The patient has been well controlled by therapy with gonadotropin releasing hormone, without recurrence of catamenial pneumothorax.


Cytotoxic and anti-oxidant activities of lanostane-type triterpenes isolated from Poria cocos.
A new lanostane-type triterpene, 29-hydroxypolyporenic acid C (8), was isolated from the dried sclerotia of Poria cocos together with eight other known compounds pachymic acid (1), dehydropachymic acid (2), 3-acetyloxy-16alpha-hydroxytrametenolic acid (3), polyporenic acid C (4), 3-epi-dehydropachymic acid (5), 3-epi-dehydrotumulosic acid (6), tumulosic acid (7), and dehydrotumulosic acid (9). The compounds were identified by spectral analysis and comparison with spectroscopic data reported in the literatures. Although none of the nine (1 to 9) compounds showed promising antioxidant activity, 1 through 6 and 8 showed good cytotoxicity against human lung cancer cell line A549 and human prostate cancer cell line DU145. Interestingly, all these compounds exhibited better cytotoxicity towards A549 than DU145 cells.


UV light-induced cyclobutane pyrimidine dimers are mutagenic in mammalian cells.
We used a simian virus 40-based shuttle vector plasmid, pZ189, to determine the role of pyrimidine cyclobutane dimers in UV light-induced mutagenesis in monkey cells. The vector DNA was UV irradiated and then introduced into monkey cells by transfection. After replication, vector DNA was recovered from the cells and tested for mutations in its supF suppressor tRNA marker gene by transformation of Escherichia coli carrying a nonsense mutation in the beta-galactosidase gene. When the irradiated vector was treated with E. coli photolyase prior to transfection, pyrimidine cyclobutane dimers were removed selectively. Removal of approximately 90% of the pyrimidine cyclobutane dimers increased the biological activity of the vector by 75% and reduced its mutation frequency by 80%. Sequence analysis of 72 mutants recovered indicated that there were significantly fewer tandem double-base changes and G X C----A X T transitions (particularly at CC sites) after photoreactivation of the DNA. UV-induced photoproducts remained (although at greatly reduced levels) at all pyr-pyr sites after photoreactivation, but there was a relative increase in photoproducts at CC and TC sites and a relative decrease at TT and CT sites, presumably due to a persistence of (6-4) photoproducts at some CC and TC sites. These observations are consistent with the fact that mutations were found after photoreactivation at many sites at which only cyclobutane dimers would be expected to occur. From these results we conclude that UV-induced pyrimidine cyclobutane dimers are mutagenic in DNA replicated in monkey cells.


Agmatine Modulates the Phenotype of Macrophage Acute Phase after Spinal Cord Injury in Rats.
Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages. M1 macrophage induces a pro-inflammatory response, but M2 inspires an anti-inflammatory response. In this study, it was clarified whether the neuroprotective effect of agmatine is related with the modulation of macrophage subdivision after spinal cord injury. Spinal cord injury was induced in rats with contusion using MASCIS. Animals received agmatine (100 mg/kg, IP) daily for 6 days beginning the day after spinal cord injury. The proportion of M1 and M2 macrophages are confirmed with immunohistochemistry and FACS. CD206+ & ED1+ cells were counted as M2 macrophages. The systemic treatment of agmatine increased M2 macrophages caudal side to epicenter 1 week after spinal cord injury in immunohistochemistry. M2 macrophage related markers, Arginase-1 and CD206 mRNA, were increased in the agmatine treatment group and M2 macrophage expressing and stimulated cytokine, IL-10 mRNA, also was significantly overexpressed by agmatine injection. Among BMPs, BMP2/4/7, agmatine significantly increased only the expression of BMP2 known to reduce M1 macrophage under inflammatory status. These results suggest that agmatine reduces impairment after spinal cord injury through modulating the macrophage phenotype.


The Seed Biotinylated Protein of Soybean (Glycine max): A Boiling-Resistant New Allergen (Gly m 7) with the Capacity To Induce IgE-Mediated Allergic Responses.
Soybean is a common allergenic food; thus, a comprehensive characterization of all the proteins that cause allergy is crucial to the development of effective diagnostic and immunotherapeutic strategies. A cDNA library was constructed from seven stages of developing soybean seeds to investigate candidate allergens. We searched the library for cDNAs encoding a seed-specific biotinylated protein (SBP) based on its allergenicity in boiled lentils. A full-length cDNA clone was retrieved and expressed as a 75.6-kDa His-tagged recombinant protein (rSBP) in Escherichia coli. Western immunoblotting of boiled bacterial extracts demonstrated specific IgE binding to rSBP, which was further purified by metal affinity and anion exchange chromatographies. Of the 23 allergic sera screened by ELISA, 12 contained IgEs specific to the purified rSBP. Circular dichroism spectroscopy revealed a predominantly unordered structure consistent with SBP's heat stability. The natural homologues (nSBP) were the main proteins isolated from soybean and peanut embryos after streptavidin affinity purification, yet they remained low-abundance proteins in the seed as confirmed by LC-MS/MS. Using capture ELISAs, the soybean and peanut nSBPs were bound by IgEs in 78 and 87% of the allergic sera tested. The soybean nSBP was purified to homogeneity and treatments with different denaturing agents before immunoblotting highlighted the diversity of its IgE epitopes. In vitro activation of basophils was assessed by flow cytometry in a cohort of peanut-allergic children sensitized to soybean. Stronger and more frequent (38%) activations were induced by nSBP-soy compared to the major soybean allergen, Gly m 5. SBPs may represent a novel class of biologically active legume allergens with the structural resilience to withstand many food-manufacturing processes.


Transdermal estrogen reduces vascular resistance and serum cholesterol in postmenopausal women.
Our aim was to compare the effects of transdermal versus oral estrogens on vascular resistance index, mean arterial pressure, serum lipid concentrations, norepinephrine, and left ventricular structure. Ten postmenopausal women received transdermal estradiol (0.05 mg/d) plus cyclic oral progesterone for 6 months. Responses were compared with those of 23 women receiving oral conjugated estrogens (0.625 mg/d) plus cyclic progesterone and with those of 9 subjects receiving placebo in a concurrent randomized trial. We assessed the vascular resistance index and the mean arterial pressure at rest and during behavioral stressors. Oral and transdermal estrogen significantly decreased the vascular resistance index, mean arterial pressure, norepinephrine, and total and low-density lipoprotein cholesterol to a similar extent. Changes in the vascular resistance index and mean arterial pressure were equally evident at rest and during stress. Although both treatments reduced left ventricular mass (-4% to -6%) and relative wall thickness (-3% to -5%), these changes were not statistically significant. Equivalent reductions in vascular resistance index, norepinephrine, mean arterial pressure, and cholesterol were observed with transdermal and oral estrogens. Future studies comparing novel hormone regimens with oral hormone replacement therapy should include multiple risk markers to allow better assessment of their potential impact on coronary artery health.


Levels and Determinants of Fine Particulate Matter and Carbon Monoxide in Kitchens Using Biomass and Non-Biomass Fuel for Cooking.
To assist interpretation of a study in rural Pakistan on the use of biomass for cooking and the risk of coronary heart disease, we continuously monitored airborne concentrations of fine particulate matter (PM2.5) and carbon monoxide (CO) for up to 48 h in the kitchens of households randomly selected from the parent study. Satisfactory data on PM2.5 and CO respectively were obtained for 16 and 17 households using biomass, and 19 and 17 using natural gas. Linear regression analysis indicated that in comparison with kitchens using natural gas, daily average PM2.5 concentrations were substantially higher in kitchens that used biomass in either a chimney stove (mean difference 611, 95% CI: 359, 863 µg/m3) or traditional three-stone stove (mean difference 389, 95% CI: 231, 548 µg/m3). Daily average concentrations of CO were significantly increased when biomass was used in a traditional stove (mean difference from natural gas 3.7, 95% CI: 0.8, 6.7 ppm), but not when it was used in a chimney stove (mean difference -0.8, 95% CI: -4.8, 3.2 ppm). Any impact of smoking by household members was smaller than that of using biomass, and not clearly discernible. In the population studied, cooking with biomass as compared with natural gas should serve as a good proxy for higher personal exposure to PM2.5.


Production of common antigen by enteric bacteria grown in a synthetic culture medium.
Enterobacteriaceae share a common antigen (CA). The present investigation was carried out to determine whether this antigen is produced by representative strains of Escherichia, Salmonella, and Serratia grown in a completely synthetic medium. For comparative purposes, antigen production by the same strains grown in infusion broth was determined. CA, as assayed by indirect hemagglutination and immunogenicity studies in the rabbit, was produced by the microorganisms cultured in both media. The amount of CA produced by the strains varied according to the size of microbial population and to the length of culture. With the exception of E. coli O14, the strains studied, on day 7, produced 1.4 to 8 times more CA in infusion broth than in the synthetic medium; with E. coli O14, the ratio of CA in the respective media was 96:1. E. coli O14, but not E. coli O111 or S. typhimurium, when grown in the synthetic medium, engendered CA antibodies upon intravenous injection into rabbits. Ethanol extraction of the latter two strains yielded an immunogenic ethanol-soluble antigen preparation. The ethanol-soluble fraction of E. coli O111 also induced a secondary response in animals primed with E. coli O111 or S. typhimurium cultures grown in the synthetic medium. It is concluded that CA produced in a completely synthetic culture medium has the same attributes as CA produced in infusion broth.


Laser light scattering in biomedical diagnostics and therapy.
The description of special features of laser light interaction with biotissues, such as the skin, eye and dental tissues etc., with respect to laser diagnostics and therapy methods development is done. Optical models of transparent and turbid biotissues are analyzed. The role of static and dynamic light scattering in the light dosimetry, tissue heating, and receiving information of biotissue optical parameters, its structure, movements, and vibrations is considered.


Postprocessing of imagery from active optics: some pitfalls.
There may be pitfalls to watch for when recording imagery from active phase compensation devices located in the exit pupil of the system. At least three of these pitfalls are identified, and each is manifested as a degradation in the imagery. Both nearby and high altitude atmospheric disturbances contribute to the degradation. The first pitfall is identified as residual phase errors caused by measurement and hardware limitations. The second pitfall is identified as nonisoplanatism, and it occurs because wavefronts from different source points experience different high altitude disturbances. The third pitfall is identified as amplitude fluctuations in the exit pupil of the system, and it is also caused by the high altitude atmospheric disturbances. The two pitfalls caused by the high altitude disturbances are reduced by applying additional phase compensation in a plane that is the image of the high altitude disturbances. But even this may not be sufficient to eliminate the need for postprocessing of the image ry of extended sources.


Acute effects of summer air pollution on respiratory function in primary school children in southern England.
There is growing concern about health effects of air pollution in the UK. Studies in the USA have reported adverse effects on lung function among children but no comparable studies have been published in the UK. This study investigates the relationship between daily changes in ambient air pollution and short term variations in lung function in a panel of school children. One hundred and fifty four children aged 7-11 attending a primary school adjacent to a major motorway in Surrey, south-east England, were studied. Bellows spirometry was performed daily on 31 schooldays between 6 June and 21 July 1994. Levels of ozone, nitrogen dioxide, and particulates of less than 10 microns in diameter (PM10) were measured continuously at the school and the pollen count was measured six miles away. Relationships between daily changes in forced expiratory volume in 0.75 seconds (FEV0.75), forced vital capacity (FVC), the FEV0.75/FVC ratio and pollutants were analysed using separate autoregressive models for each child. A weighted average of the resulting slopes was then calculated. There was a significant inverse relationship between daily mean PM10 levels lagged one day and FVC, with a reduction in lung function of 1% (95% CI 0.3% to 2%) across the whole range of PM10 levels (20-150 micrograms/m3). The effect on FEV0.75 was similar (-0.5%) but was not significant when weighted by 1/SE2 (95% CI -1.2% to 0.2%). There was no effect of PM10 levels on the FEV0.75/FVC ratio. No significant association was seen between FEV0.75, FVC, or the FEV0.75/FVC ratio and either ozone or nitrogen dioxide levels. There was no evidence that wheezy children were more affected than healthy children. Pollen levels on the previous day had no effect on lung function and did not change the air pollution results. There is a very small, but statistically significant, adverse effect of airborne respirable particulate matter, measured as PM10, on lung function in this study group. There is no evidence for an inverse association of lung function with levels of ozone or NO2 measured on the previous day.


Assessment of collagen quality associated with non-enzymatic cross-links in human bone using Fourier-transform infrared imaging.
Aging and many disease conditions, most notably diabetes, are associated with the accumulation of non-enzymatic cross-links in the bone matrix. The non-enzymatic cross-links, also known as advanced glycation end products (AGEs), occur at the collagen tissue level, where they are associated with reduced plasticity and increased fracture risk. In this study, Fourier-transform infrared (FTIR) imaging was used to detect spectroscopic changes associated with the formation of non-enzymatic cross-links in human bone collagen. Here, the non-enzymatic cross-link profile was investigated in one cohort with an in vitro ribose treatment as well as another cohort with an in vivo bisphosphonate treatment. With FTIR imaging, the two-dimensional (2D) spatial distribution of collagen quality associated with non-enzymatic cross-links was measured through the area ratio of the 1678/1692cm-1 subbands within the amide I peak, termed the non-enzymatic crosslink-ratio (NE-xLR). The NE-xLR increased by 35% in the ribation treatment group in comparison to controls (p<0.005), with interstitial bone tissue being more susceptible to the formation of non-enzymatic cross-links. Ultra high-performance liquid chromatography, fluorescence microscopy, and fluorometric assay confirm a correlation between the non-enzymatic cross-link content and the NE-xLR ratio in the control and ribated groups. High resolution FTIR imaging of the 2D bone microstructure revealed enhanced accumulation of non-enzymatic cross-links in bone regions with higher tissue age (i.e., interstitial bone). This non-enzymatic cross-link ratio (NE-xLR) enables researchers to study not only the overall content of AGEs in the bone but also its spatial distribution, which varies with skeletal aging and diabetes mellitus and provides an additional measure of bone's propensity to fracture.


Isolation and Characterization of 2,4-D Butyl Ester Degrading Acinetobacter sp. ZX02 from a Chinese Ginger Cultivated Soil.
Strain ZX02 was isolated from Chinese ginger cultivated soil contaminated with various pesticides, which could utilize 2,4-dichlorophenoxyacetic acid butyl ester (2,4-D butyl ester) as the sole carbon source. On the basis of the sequence analysis of 16S rRNA gene as well as the morphological, biochemical, and physiological characteristics of strain ZX02, the organism belonged to Gram-negative bacterium and was identified as Acinetobacter sp. ZX02. The strain ZX02 showed a remarkable performance in 2,4-D butyl ester degradation (100% removal in <96 h) in pure culture. Strain ZX02 was sensitive to tetracycline and resistant to amoxicillin and chloramphenicol in an antibiotic sensitivity test. The curing study indicates that the gene for degradation of 2,4-D butyl ester was encoded on a single plasmid of 23 kb. The gene encoding resistance to polymixin B sulfate was also located on this plasmid. On the basis of its greater biodegradation activity, this bacterium is a potential candidate as a bioremediation agent in soils contaminated with 2,4-D butyl ester.


Health behaviors and quality of life among colorectal cancer survivors.
To examine, at the population level, health behaviors, comorbidities, and health-related quality of life among colorectal cancer (CRC) survivors compared with other cancer survivors and persons without cancer. We used data from the 2009 and 2010 Behavioral Risk Factor Surveillance System cancer survivor modules. We calculated descriptive statistics, conducted chi-square tests for comparisons, and used multivariable logistic regression analysis to compare CRC survivors with other cancer survivors and persons without cancer. Of the 52,788 cancer survivors included in this analysis, 4001 reported being CRC survivors. When compared with other cancer survivors, CRC survivors reported higher percentages of obesity and lack of physical activity; however, they had lower levels of current smoking. Adjusted results show that CRC survivors were significantly more likely to report lack of physical activity, fair/poor health, and other chronic health conditions compared with persons without a cancer diagnosis. Conversely, CRC survivors reported lower levels of current smoking than persons without cancer. CRC survivors have a higher proportion of heath conditions and behaviors that may significantly increase their risks for recurrence or development of a second cancer. Targeted interventions to address these health issues should be considered.


Members of the KpnI family of long interspersed repeated sequences join and interrupt alpha-satellite in the monkey genome.
Three different members of a family (KpnI-family) of interspersed repeated DNA sequences were found linked to alpha-satellite sequences in cloned segments of the African green monkey genome. In two of these segments the KpnI-family member is over 6 kbp in length and one of them is flanked by alpha-satellite on both sides indicating that it was inserted into a satellite array. Hybridization of subcloned portions of the family members to restriction endonuclease digests of monkey and human DNA and to a genomic library of African green monkey DNA indicate that 1) family members are interspersed in both the monkey and human genomes, 2) some family members may include sequences in addition to those in the three characterized here, 3) some family members may contain only parts of the sequences characterized here and 4) while the overall organization of the family is similar in the human and monkey genome the majority of the family members in each of the two genomes are distinctly identified by the variant position of certain restriction endonuclease sites. This last observation suggests that within each genome there is a tendency to maintain particular versions of the sequence. Observations 2) and 3) suggest that the KpnI family is complex and includes a variety of subfamilies.


Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery.
This observational study sought to identify the off-label use pattern of recombinant activated factor VII (rFVIIa) in cardiac surgery and to identify predictors of its effectiveness and risk. At 18 Canadian centers, 522 nonhemophiliac cardiac surgical patients received rFVIIa during the period 2003 through 2006; data were available, and retrospectively collected, on 503 patients. The median (quartile 1, quartile 3) units of red blood cells transfused from surgery to therapy and in the 24 hours after therapy were 8 (5, 12) and 2 (1, 5), respectively (P<0.0001). Mortality rate was 32%, and mortality or major morbidity rate was 44%. These rates were within expected ranges (mortality, 27% to 35%; mortality or morbidity, 39% to 48%), which were calculated with a separate cohort of cardiac surgical patients who did not receive rFVIIa used as reference. Independent predictors of complications included instability before therapy (multiple inotropes or intra-aortic balloon pump) and increasing red blood cell units transfused before and after therapy. Variables independently associated with nonresponse included abnormal coagulation parameters and >15 red blood cell units transfused before therapy. In Canada, rFVIIa is used primarily when standard interventions have failed to control bleeding. In this setting, rFVIIa is associated with reduced blood product transfusions and, after risk adjustment, does not appear to be associated with increased or decreased complication rates. The effectiveness of the drug may be enhanced if it is given early in the course of refractory blood loss in the setting of adequate amounts of circulating coagulation factors.


An rbcL mRNA-binding protein is associated with C3 to C4 evolution and light-induced production of Rubisco in Flaveria.
Nuclear-encoded RLSB protein binds chloroplastic rbcL mRNA encoding the Rubisco large subunit. RLSB is highly conserved across all groups of land plants and is associated with positive post-transcriptional regulation of rbcL expression. In C3 leaves, RLSB and Rubisco occur in all chlorenchyma cell chloroplasts, while in C4 leaves these accumulate only within bundle sheath (BS) chloroplasts. RLSB's role in rbcL expression makes modification of its localization a likely prerequisite for the evolutionary restriction of Rubisco to BS cells. Taking advantage of evolutionarily conserved RLSB orthologs in several C3, C3-C4, C4-like, and C4 photosynthetic types within the genus Flaveria, we show that low level RLSB sequence divergence and modification to BS specificity coincided with ontogeny of Rubisco specificity and Kranz anatomy during C3 to C4 evolution. In both C3 and C4 species, Rubisco production reflected RLSB production in all cell types, tissues, and conditions examined. Co-localization occurred only in photosynthetic tissues, and both proteins were co-ordinately induced by light at post-transcriptional levels. RLSB is currently the only mRNA-binding protein to be associated with rbcL gene regulation in any plant, with variations in sequence and acquisition of cell type specificity reflecting the progression of C4 evolution within the genus Flaveria.


StrainIQ: A Novel n-Gram-Based Method for Taxonomic Profiling of Human Microbiota at the Strain Level.
The emergence of next-generation sequencing (NGS) technology has greatly influenced microbiome research and led to the development of novel bioinformatics tools to deeply analyze metagenomics datasets. Identifying strain-level variations in microbial communities is important to understanding the onset and progression of diseases, host-pathogen interrelationships, and drug resistance, in addition to designing new therapeutic regimens. In this study, we developed a novel tool called StrainIQ (strain identification and quantification) based on a new n-gram-based (series of n number of adjacent nucleotides in the DNA sequence) algorithm for predicting and quantifying strain-level taxa from whole-genome metagenomic sequencing data. We thoroughly evaluated our method using simulated and mock metagenomic datasets and compared its performance with existing methods. On average, it showed 85.8% sensitivity and 78.2% specificity on simulated datasets. It also showed higher specificity and sensitivity using n-gram models built from reduced reference genomes and on models with lower coverage sequencing data. It outperforms alternative approaches in genus- and strain-level prediction and strain abundance estimation. Overall, the results show that StrainIQ achieves high accuracy by implementing customized model-building and is an efficient tool for site-specific microbial community profiling.


Three-Dimensional Bioprinting of Human iPSC-Derived Neuron-Astrocyte Cocultures for Screening Applications.
For a cell model to be viable for drug screening, the system must meet throughput and homogeneity requirements alongside having an efficient development time. However, many published 3D models do not satisfy these criteria. This therefore, limits their usefulness in early drug discovery applications. Three-dimensional (3D) bioprinting is a novel technology that can be applied to the development of 3D models to expedite development time, increase standardization, and increase throughput. Here, we present a protocol to develop 3D bioprinted coculture models of human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons and astrocytes. These cocultures are embedded within a hydrogel matrix of bioactive peptides, full-length extracellular matrix (ECM) proteins, and with a physiological stiffness of 1.1 kPa. The model can be rapidly established in 96-well and 384-well formats and produces an average post-print viability of 72%. The astrocyte-to-neuron ratio in this model is shown to be 1:1.5, which is within the physiological range for the human brain. These 3D bioprinted cell populations also show expression of mature neural cell type markers and growth of neurite and astrocyte projections within 7 days of culture. As a result, this model is suitable for analysis using cell dyes and immunostaining techniques alongside neurite outgrowth assays. The ability to produce these physiologically representative models at scale makes them ideal for use in medium-to-high throughput screening assays for neuroscience targets.


Oat agriculture, cultivation and breeding targets: implications for human nutrition and health.
Oats are undervalued in comparison with wheat, rice and barley, despite their unique composition that includes many of the nutrients required for health and a reduced risk of degenerative disease incidence. Furthermore, oats as whole grain and some of their associated products also contain β-glucan, a complex polysaccharide that has an approved health claim to reduce blood cholesterol levels and reduce the risk of CHD incidence if consumed at ≥ 3 g/d. At the agronomic level, oats exhibit optimal growth in regions of moderate temperature and long day length. In addition, they can tolerate wet weather and acidic soils more effectively than other cereals, such as wheat. Studies have shown that there is diversity in the content and composition of nutrients and health-beneficial components within the available wild and cultivated germplasm and that these are amenable to be enhanced by different agronomic practices as well as are susceptible to climatic variation. The advances in modern plant genetics, developed in sister cereals such as wheat, rice and barley, mean that oat development and exploitation should see an acceleration in the coming decade as they are adopted and applied. These advances include approaches such as genome sequencing, genotyping by sequencing and the allied next-level analytical approaches of RNA sequencing, transcriptome profiling and metabolomics. The collation and coordination of these approaches should lead to the generation of new, tailored oat varieties that are nutritionally enhanced and contain a greater proportion of health-beneficial components that can be translated through into a wide(r) range of consumer products with the ultimate hope of associated benefits to human health and nutrition.


Bacterial Infections in Hematopoietic Stem Cell Transplant Recipients.
Bacterial infections are major complications after Hematopoietic Stem Cell Transplant (HSCT). They consist mainly of bloodstream infections (BSI), followed by pneumonia and gastrointestinal infections, including typhlitis and Clostridium difficile infection. Microbiological data come mostly from BSI. Coagulase negative staphylococci and Enterobacteriaceae are the most frequent pathogens causing approximately 25% of BSI each, followed by enterococci, P. aeruginosa and viridans streptococci. Bacterial pneumonia is frequent after HSCT, and Gram-negatives are predominant. Clostridium difficile infection affects approximately 15% of HSCT recipients, being more frequent in case of allogeneic than autologous HSCT. The epidemiology and the prevalence of resistant strains vary significantly between transplant centres. In some regions, multi-drug resistant (MDR) Gram-negative rods are increasingly frequent. In others, vancomycin-resistant enterococci are predominant. In the era of increasing resistance to antibiotics, the efficacy of fluoroquinolone prophylaxis and standard treatment of febrile neutropenia have been questioned. Therefore, a thorough evaluation of local epidemiology is mandatory to decide the need for prophylaxis and the choice of the best regimen for empirical treatment of febrile neutropenia. For the latter, individualised approach has been proposed, consisting of either escalation or de-escalation strategy. De-escalation strategy is recommended since resistant bacteria should be covered upfront, mainly in patients with severe clinical presentation and previous infection or colonisation with a resistant pathogen. Non-pharmacological interventions, such as screening for resistant bacteria, applying isolation and contact precautions should be put in place to limit the spread of MDR bacteria. Antimicrobial stewardship program should be implemented in transplant centres.


Approach to developmental disabilities in newcomer families.
To provide a framework for primary care providers to approach developmental disabilities in both refugee and nonrefugee immigrant populations. Ovid MEDLINE was searched from January 2005 to February 2017 using subject headings developmental disability, developmental delay, refugee, and immigrant for relevant English-language articles. Most of the content and recommendations in this review are derived from the Canadian Paediatric Society's Caring for Kids New to Canada website. As family physicians, it can be daunting to care for newcomer families who arrive without previous developmental disability or delay screening and diagnoses. Disruption to families and education, decreased health literacy, witnessed traumatic events, and culturally specific barriers can affect the presentation of developmental concerns among refugees and immigrants. Surveillance and screening for developmental concerns in a culturally sensitive manner using evidence-based tools are cornerstones of early intervention. For refugees in particular, in light of the inequities they have faced before migration and during their migration trajectory, screening for developmental disabilities and intervening provides an opportunity to help achieve equitable outcomes for refugee children and optimize their health and well-being.


Impact of measurement and feedback on chlorhexidine gluconate bathing among intensive care unit patients: A multicenter study.
To assess whether measurement and feedback of chlorhexidine gluconate (CHG) skin concentrations can improve CHG bathing practice across multiple intensive care units (ICUs). A before-and-after quality improvement study measuring patient CHG skin concentrations during 6 point-prevalence surveys (3 surveys each during baseline and intervention periods). The study was conducted across 7 geographically diverse ICUs with routine CHG bathing. Adult patients in the medical ICU. CHG skin concentrations were measured at the neck, axilla, and inguinal region using a semiquantitative colorimetric assay. Aggregate unit-level CHG skin concentration measurements from the baseline period and each intervention period survey were reported back to ICU leadership, which then used routine education and quality improvement activities to improve CHG bathing practice. We used multilevel linear models to assess the impact of intervention on CHG skin concentrations. We enrolled 681 (93%) of 736 eligible patients; 92% received a CHG bath prior to survey. At baseline, CHG skin concentrations were lowest on the neck, compared to axillary or inguinal regions (P < .001). CHG was not detected on 33% of necks, 19% of axillae, and 18% of inguinal regions (P < .001 for differences in body sites). During the intervention period, ICUs that used CHG-impregnated cloths had a 3-fold increase in patient CHG skin concentrations as compared to baseline (P < .001). Routine CHG bathing performance in the ICU varied across multiple hospitals. Measurement and feedback of CHG skin concentrations can be an important tool to improve CHG bathing practice.


[Histochemical investigations on human bladder cancer (author's transl)].
The histochemical enzyme activity of alkaline phosphatase, nonspecific esterase, 5-nucleotidase, beta-glucuronidase, glucose-6-phosphatase, succinate dehydrogenase, and glucose-6-phosphate dehydrogenase in human bladder cancer was investigated. Tumors of 84 patients, classified into grades I-III according to the WHO classification, were compared with 12 normal and 16 inflamed bladder epithelia. As a rule, loss of alkaline phosphatase activity and a decrease of nonspecific esterase activity was found in most of these tumors. The activity of beta-glucuronidase was decreased and compared with normal tissue, also the activity of 5-nucleotidase. The succinate dehydrogenase activity in tumor tissue was frequently increased, whereas glucose-6-phosphate dehydrogenase did not show any significant reaction.


Osteopontin expression correlates with clinical outcome in patients with mycobacterial infection.
Osteopontin (OPN) is a protein that is expressed in chronic inflammatory diseases including tuberculosis, and its deficiency predisposes to more severe mycobacterial infections in mice. However, no reports have identified altered OPN expression in, or correlated these alterations to, infections in humans. The data presented herein identify alterations in the tissue expression of OPN protein and describe an inverse correlation between these levels and disease progression after inoculation of Mycobacterium bovis bacillus Calmette-Guérin vaccine in humans. Patients with regional adenitis and good clinical outcomes had abundant OPN in infected lymph nodes. This pattern of OPN accumulation was also observed in patients infected by M. avium-intracellulare. In contrast, patients with disseminated infection and histologically ill-defined granulomas had no significant osteopontin accumulation in infected lymph nodes; these patients had either deficiencies in the interferon-gamma receptor 1 or idiopathic immune defects. The level of OPN protein expression was inversely correlated with disseminated infection and, of particular interest, with death of the patient. We conclude that osteopontin expression correlates with an effective immune and inflammatory response when humans are challenged by a mycobacterial infection and that osteopontin contributes to human resistance against mycobacteria.


Antiepileptic drugs: a consideration of clinical and biochemical outcome in patients with epilepsy.
The challenge of antiepileptic drugs (AEDs) management is to attain the best compromise between the desire to maximize seizure control and the need to keep side-effects within tolerable limits for the individual patient. To reduce devastation in Iranian epileptic patients, the aim of this study was to explore the overall outcome following AEDs prescription. A cross-sectional study of 36 patients located at the epilepsy ward, conducted to Isfahan Neurosciences Research Centre was carried out during the year 2011. Female (n = 17) and male subjects (n = 19) with a mean age of 27 years (range; 7-74 years) were studied. Variables including, sex, age, age of seizure onset, type, and number of AEDs, biochemical and hematological data were recorded in d-Base and statistical analyses were performed using SPSS (version 18) for windows. The main drug to control seizure attack was carbamazepine and valproic-acid. The following tests were the most frequently influenced; alkaline phosphatase (AP), lymphocyte (Lymph), white blood cell (WBC) counts and hemoglobin (Hgb). There was a significant increase in (AP) (mean; 534.6 u/l(↑); [P = 0.02] in three patients and (Lymph) (55%(↑); [43-84] %(↑); [P = 0.04] in seven patients. WBC was lower than 4400 mm(3↓) (P = 0.02) in six patients. Hgb was significantly lower in 70.6% of women (11.8(↓); [10-14.2] g/dl(↓); [P = 0.04] and 68.4% of men population (12.3(↓); [9.7-13.8] g/dl(↓); [P = 0.01]. Mean age of epilepsy onset was 15.6 years (range: Birth-74 years). Analysis of drug prescriptions showed that the incidence of monotherapy and polypharmacy (2 up to six AEDs simultaneously) was 19.4% plus 80.6% respectively. In Iranian epileptic population, effectiveness of treatment should be attributed by the close supervising of AEDs in relation to clinical circumstance, laboratory data, and therapeutic drug monitoring. Any significant change in patients' biochemical and hematological data may require close verifying for the rapid detection of severe anemia, leukopenia, lymphocytosis, osteomalacia, or liver failure.


A randomized, double-blind trial of transcranial electrostimulation in early Parkinson's disease.
We studied the effects of noninvasive transcranial electrical stimulation on the motor and psychological symptoms of early Parkinson's disease. Twenty-three subjects were treated with 10 days of placebo versus active treatment and then followed for 14 weeks. Baseline off medication Unified Parkinson's Disease Rating Scale parts I-III was 29.4 ± 10.0. The primary end point, Unified Parkinson's Disease Rating Scale in week 2 following treatment, reduced by 5.3 ± 9.7 for those in active treatment and 7.7 ± 4.8 for those receiving placebo (not significant). Similarly, no significant differences were seen in the Hamilton Anxiety Scale, Geriatric Depression Scale, and Epworth Sleepiness Scale over the duration of the study. The treatment was well tolerated without device-related adverse events. Despite the negative study, nonpharmacological approaches should continue to be pursued in Parkinson's disease, as they are generally well received by patients.


Cancer Therapy-associated Lymphoproliferative Disorders: An Under-recognized Type of Immunodeficiency-associated Lymphoproliferative Disorder.
We describe the clinicopathologic features of 17 patients who had a hematologic malignancy of various types, were treated, and subsequently developed a lymphoproliferative disorder (LPD). There were 10 men and 7 women with a median age of 59 years (range, 36 to 83 y). The primary hematologic neoplasms included: 5 chronic lymphocytic leukemia/small lymphocytic lymphoma, 3 plasma cell myeloma, 2 acute monoblastic leukemia, and 1 case each of mixed-phenotype acute leukemia, chronic myeloid leukemia, splenic marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, T-cell prolymphocytic leukemia, and peripheral T-cell lymphoma. All patients were treated with chemotherapy with or without therapeutic antibodies; 3 also underwent autologous stem cell transplantation. The mean interval from initiation of therapy for initial hematologic malignancy to onset of LPD was 66 months (range, 3 to 299 mo). Ten (59%) LPDs were extranodal and 7 (41%) involved nodal tissues. The histologic diagnoses included: 8 diffuse large B-cell lymphoma, 4 classical Hodgkin lymphoma, 3 polymorphic LPD, 1 lymphomatoid granulomatosis, and 1 Epstein-Barr virus (EBV) mucocutaneous ulcer. Fourteen cases were EBV. Following the onset of LPD, chemotherapy was administered to 10 (59%) patients. With a median follow-up of 100 months (range, 5 to 328 mo), 8 (47%) patients are alive and 9 (53%) died. One (6%) patient with lymphomatoid granulomatosis underwent spontaneous remission. On the basis of the clinicopathologic features and high prevalence of EBV infection in this cohort, we believe that these LPDs show similarities with other types of immunodeficiency-associated LPDs. We suggest that cancer therapy-associated LPD be included in future classification systems for immunodeficiency-associated LPDs.


The two-component signal transduction protein Chk1p regulates quorum sensing in Candida albicans.
Regulation of hyphal morphogenesis in Candida albicans can occur through quorum sensing (QS). A QS signal, farnesol, is produced during high-density growth and inhibits morphogenesis. However, the signal transduction pathway that regulates QS is unknown. Here, we show that a C. albicans mutant lacking Chk1p but not either the Sln1p or the Nik1p histidine kinase is refractory to the inhibitory effect of farnesol both in cell suspension and during the formation of a biofilm. This study is the first to demonstrate a role for a two-component signal transduction protein in QS by a eukaryotic organism.


Application of an antibiotic crescent-shaped polymethylmethacrylate strut in thoracic vertebral tuberculosis.
Spinal tuberculosis accounts for up to 50% of all cases with musculoskeletal tuberculosis. In patients needing surgical treatment, the use of anterior instrumentation offers the theoretical advantage of more complete debridement and decompression, safer mobilization and reliable deformity correction. However, the placement of instrumentation in an infected area remains a matter of debate. We present a patient with thoracic vertebral tuberculosis using an antibiotic crescent-shaped PMMA strut for spinal reconstruction and fusion. The patient recovered satisfactory and no complication was observed in the follow-up. The antibiotic crescent-shaped PMMA strut can be used as a carrier for antibiotic drug and an ideal alternative for anterior spinal reconstruction. However, long-term outcome in this case requires further evaluation.


Closed Continuous Irrigation With Lidocaine and Immediate Mobilization for Treatment of Pyogenic Tenosynovitis.
Pyogenic flexor tenosynovitis treatment consists of either closed continuous irrigation with sterile saline or antibiotic solution, or open debridement and irrigation. These treatment approaches serve to resolve the infection, but are extremely painful and residual stiffness can be devastating to the patient. We describe herein our approach to managing pyogenic flexor tenosynovitis. To provide continuous irrigation, a butterfly catheter with needle removed is utilized with irrigation holes cut into the tubing. The catheter is inserted into the tendon sheath at the level of the Al pulley and brought out at the level of the A5 pulley. A knot is tied in the end of the catheter for retention, eliminating the need for sutures. Immediately postoperative, continuous irrigation with sterile saline mixed with lidocaine is initiated and is titrated to achieve pain-free motion in the finger. Occupational therapy begins an aggressive course of active and passive range of motion exercises immediate postoperatively, which is continued for the remainder of hospitalization. Our approach of continuous infusion of a lidocaine solution allows for pain-free movement immediately postoperatively to mechanically debride tissue, as well as allow for early active range of motion. We have obtained excelleepaknt results with this technique in all of our cases.


Peptide Decoration of Nanovehicles to Achieve Active Targeting and Pathology-Responsive Cellular Uptake for Bone Metastasis Chemotherapy.
To improve bone metastases chemotherapy, a peptide-conjugated diblock copolymer consisting of chimeric peptide, poly(ethylene glycol) and poly(trimethylene carbonate) (Pep-b-PEG-b-PTMC) is fabricated as a drug carrier capable of bone-seeking targeting as well as pathology-responsive charge reversal to ensure effective cellular uptake at the lesion sites. The chimeric peptide CKGHPGGPQAsp8 consists of an osteotropic anionic Asp8, a cathepsin K (CTSK)-cleavable substrate (HPGGPQ) and cationic residue tethered to polymer chain. Pep-b-PEG-b-PTMC can spontaneously self-assemble into negatively charged nanomicelles (~75 nm). As to the model drug of doxorubicin, Pep-b-PEG-b-PTM shows 30.0 ± 1 % and 90.1 ± 2 % for loading content and loading efficiency, respectively. High bone binding capability is demonstrated with that 66 % of Pep-b-PEG-b-PTMC micelles are able to bind to hydroxyl apatite, whereas less than 15 % is for Pep-free micelles. The nanomicelles exhibit a negative-to-positive charge conversion from -18.5 ± 1.9 mV to 15.2 ± 1.8 mV upon exposure to CTSK, an enzyme overexpressed in bone metastatic microenvironments. Such a pathology-responsive transition would lead to remarkably enhanced cellular uptake of the nanomicelles upon reaching lesion sites, thus improving the drug efficacy as verified by the in vitro cytotoxicity assay and the in vivo study in myeloma-bearing 5TGM1 mice model.


Comparison of regional recurrence rates of radical and comprehensive neck dissection type 3 in N0 laryngeal cancer.
To determine whether comprehensive neck dissection (CND) type 3 could accomplish regional tumor control as well as radical neck dissection (RND) in clinically N0 laryngeal cancer patients, we compared the regional recurrence rates of 316 N0 laryngeal cancer patients. In the 316 N0 patients, 486 neck dissections were performed. For 170 patients the dissection was bilateral, and for 146 patients it was unilateral. Of these, 193 were type 3 CNDs, and 293 were RNDs. In 30 (15.5%) of 193 type 3 CNDs and in 53 (18.1%) of 293 RNDs, metastatic lymph nodes were determined histopathologically in neck dissection specimens. The difference in cervical lymph node metastasis rates was not statistically significant (P > 0.05). During follow-up, 3 patients who underwent CND type 3 (1.6%) and 12 who underwent RND (4.1%) had regional recurrences. The difference between recurrence rates was not statistically significant (P > 0. 05). A conclusion was reached that CND type 3 safely provided regional cancer control in N0 laryngeal cancer and that it might be performed to decrease the morbidity of RND.


Pharmacodynamics of beta-blockers in heart failure: lessons from the carvedilol or metoprolol European trial.
Heart failure is a growing public health problem in the United States, and the approach to the treatment of heart failure has undergone a radical transformation in the past decade. The use of beta-blocker therapy in heart failure patients is now widely recommended, based on evidence from large-scale clinical trials demonstrating that bisoprolol, carvedilol, and extended-release metoprolol succinate significantly reduce morbidity and mortality in patients with heart failure. Although these agents appear to provide similar benefits, the question remains whether pharmacologic differences among them could translate to differences in clinical outcomes. The Carvedilol Or Metoprolol European Trial (COMET) compared nonselective blockade of the beta1-/beta2-/alpha1-adrenergic receptors with carvedilol versus selective beta1-blockade with immediate-release metoprolol tartrate in patients with chronic heart failure. The trial found that carvedilol significantly reduced all-cause mortality compared with immediate-release metoprolol tartrate, although there were no differences in hospitalizations. Herein we review the pharmacokinetics and pharmacodynamics of metoprolol and carvedilol. In doing so, several issues regarding the design of COMET are identified that could alter the interpretation of the results of this trial. These include the choice of dose and dosage regimen of immediate-release metoprolol tartrate, a dosage form that has never been shown to reduce mortality in patients with heart failure. Additional studies are needed to fully understand whether there are any advantages of selective versus nonselective adrenergic blockade and whether there are any clinically meaningful differences in effectiveness between beta-blockers with proven benefit in the management of chronic heart failure. The results of COMET demonstrate that all beta-blockers and dosage forms are not interchangeable when prescribed for heart failure. Clinicians should choose only those agents (and dosage forms) that have been proven to reduce mortality in this patient population.


A Prospective Study of Urinary Prostaglandin E2 Metabolite, Helicobacter pylori Antibodies, and Gastric Cancer Risk.
Previous studies suggest that a stable end-product of prostaglandin E2, the urinary metabolite PGE-M, is associated with colorectal cancer, and 1 study of relatively small sample size found an association with gastric cancer among women. In the present study we further investigate the PGE-M, Helicobacter pylori, and gastric cancer association. The present analysis included 359 prospectively ascertained gastric cancer cases and 700 individually matched controls from the Shanghai Women's and Men's Health Studies. Urinary PGE-M was measured by a liquid chromatography/tandem mass spectrometric method. Seropositivity to 15 H. pylori recombinantly expressed fusion proteins was detected by H. pylori multiplex serology. Adjusting for H. pylori, increasing PGE-M was associated with higher risk of gastric cancer (quartile 4 vs 1: odds ratio [OR], 1.76 [95% confidence interval {CI}, 1.17-2.66], Ptrend = .004). This association remained after excluding those diagnosed within 2 years from sample collection (OR, 1.73 [95% CI, 1.12-2.65], Ptrend = .007). However it was no longer present among individuals with 10 or more years of follow-up (2-4.9 years: OR, 3.15 [95% CI, 1.11-8.91]; 5-9.9 years: OR, 2.23 [95% CI, 1.22-4.06]; ≥10 years: OR, 0.73 [95% CI, .31-1.70]). Compared to H. pylori-negative individuals with below-median PGE-M levels, H. pylori-positive individuals with above-median PGE-M levels had a 5-fold increase in the odds of gastric cancer (OR, 5.08 [95% CI, 2.47-10.43]). In China, higher PGE-M levels may indicate an increased risk of gastric cancer independent of the risk conferred by H. pylori infection status, particularly for cancers diagnosed within 10 years of sample collection.


The longitudinal ramifications of stroke caregiving: a systematic review.
Family members assume considerable care responsibilities for relatives suffering from stroke. Although a number of quantitative and qualitative studies examine the emotional and psychological ramifications of stroke caregiving, no recent review has considered the longitudinal implications of family stroke care. The goal of this systematic review was to determine whether duration of family care is a significant predictor of stroke caregiving outcomes and if stroke caregiving outcomes change over time. PsycINFO (1950 to 2009), MEDLINE (1966 to 2009), and CINAHL (1982 to 2009) databases were searched to identify relevant research articles. Reference lists of selected articles were also hand searched. Of 1,188 studies identified, 117 were selected for review based on eligibility criteria. Synthesized results found that duration of care did not emerge as a significant predictor of stroke caregiving outcomes in most cross-sectional quantitative studies. Caregiver stress, depression, and subjective health measures did not tend to demonstrate significant change in longitudinal quantitative studies (although some studies did indicate increases and/or decreases in well-being over time). Qualitative studies describe a more dynamic stroke caregiving process. The results of this review emphasize the need to apply more rigorous research approaches, appropriate theories, and mixed-method designs to advance the state-of-the-art. Such improvements will provide practitioners with stronger evidence to guide the development, targeting, and timing of clinical interventions.


3rd generation poly(ethylene imine)s for gene delivery.
Cationic polymers play a crucial role within the field of gene delivery offering the possibility to circumvent (biological) barriers in an elegant way. However, polymers are accompanied either by a high cytotoxicity or low efficiency. In this study, a series of high molar mass poly(2-oxazoline)-based copolymers was synthesized introducing 2-ethyl-2-oxazoline, ethylene imine, and primary amine bearing monomer units representing a new generation of poly(ethylene imine) (PEI). The potential of these modified PEIs as non-viral gene delivery agents was assessed and compared to linear PEI by studying the cytotoxicity, the polyplex characteristics, the transfection efficiency, and the cellular uptake using plasmid DNA (pDNA) as well as small interfering RNA (siRNA). High transfection efficiencies, even in serum containing media, were achieved using pDNA without revealing any cytotoxic effects on the cell viability at concentrations up to 1 mg mL-1. The delivery potential for siRNA was further investigated showing the importance of polymer composition for different genetic materials. To elucidate the origins for this superior performance, super-resolution and electron microscopy of transfected cells were used, identifying the endosomal release of the polymers as well as a reduced protein interaction as the main difference to PEI-based transfection processes. In this respect, the investigated copolymers represent remarkable alternatives as non-viral gene delivery agents.