Extreme elevation of placental alkaline phosphatase as a marker of preterm delivery, placental insufficiency and low birth weight.
Clinical case of extremely elevated levels of alkaline phosphatase (ALP) enzyme detected in the 3rd trimester of gestation, the diagnostic and therapeutic procedures, delivery and puerperium are presented. The paper also offers a review of the currently available bibliographical data of the issue. The case presents a 23-year-old secundipara with clinical problems in her 3rd trimester, namely a generalized pruritus. The gestation had signs of asymmetrical fetal hypotrophy induced by placental insufficiency. Laboratory tests showed elevated (as much as a 10.5-fold increase) values of alkaline phosphatase enzyme, 94.05% of which was placental isoenzyme. The patient also had clinical symptoms of a preterm delivery. The spontaneous delivery occurred in 36 week of gestation. The postpuerperium values of alkaline phosphatase returned to normal. The authors point out the potential relationship between elevated placental isoenzyme of alkaline phosphatase levels and placental insufficiency and the onset of a preterm delivery.


An open study to assess the efficacy and safety of topical 3% diclofenac in a 2.5% hyaluronic acid gel for the treatment of actinic keratoses.
Actinic keratoses are potential precursors of invasive squamous cell carcinoma; therefore, treatment is often recommended. Current topical treatments may cause considerable discomfort, pain, or skin irritation. This study was established to explore the role, if any, of topical 3% diclofenac in 2.5% hyaluronic acid gel in the management of actinic keratoses. An open-label study was conducted of topical 3% diclofenac in 2.5% hyaluronic acid gel applied to 1 or more actinic keratoses. Patients were instructed to apply 1.0 g of the gel twice daily for as many as 180 days. Treatment was stopped earlier than 180 days if lesions were assessed as cleared. Twenty-nine adults were treated for periods of 33 to 176 days (median, 62 days). Of the 29 subjects, 27 were reevaluated 30 days after drug therapy discontinuation. Of the 27 patients, 22 (81%) had a complete response and another 4 (15%) showed marked clinical improvement. The preparation was generally well tolerated, although in 7 patients (24%) an irritant-type contact dermatitis developed, which was confined to the treatment site. Topical 3% diclofenac in 2.5% hyaluronic acid gel may be a clinically useful topical agent for the treatment of actinic keratoses.


Diet modification and metformin have a beneficial effect in a fly model of obesity and mucormycosis.
In an experimental model of obesity and hyperglycemia in Drosophila melanogaster we studied the effect of diet modification and administration of metformin on systemic infection with Rhizopus, a common cause of mucormycosis in diabetic patients. Female Wt-type Drosophila flies were fed regular (RF) or high-fat diet (HFD; 30% coconut oil) food with or without metformin for 48 h and then injected with R. oryzae. Survival rates, glucose and triglyceride levels were compared between 1) normal-weight flies (RF), 2) obese flies (HFD), 3) obese flies fed with RF, 4) flies continuously fed on HFD + metformin, 5) flies fed on HFD + metformin, then transferred to RF, and 6) obese flies administered metformin after infection [corrected].Glucose levels were compared across groups of non-infected flies and across groups of infected flies. Survival was significantly decreased (P = 0.003) in obese flies, while post-infection glucose levels were significantly increased (P = 0.0001), compared to normal-weight flies. Diet and administration of metformin led to weight loss, normalized glucose levels during infection, and were associated with decreased mortality and tissue fungal burden. In conclusion, diet and metformin help control infection-associated hyperglycemia and improve survival in Drosophila flies with mucormycosis. Fly models of obesity bear intriguing similarities to the pathophysiology of insulin resistance and diabetes in humans, and can provide new insights into the pathogenesis and treatment of infections in obese and diabetic patients.


A sequential Cox approach for estimating the causal effect of treatment in the presence of time-dependent confounding applied to data from the Swiss HIV Cohort Study.
When estimating the effect of treatment on HIV using data from observational studies, standard methods may produce biased estimates due to the presence of time-dependent confounders. Such confounding can be present when a covariate, affected by past exposure, is both a predictor of the future exposure and the outcome. One example is the CD4 cell count, being a marker for disease progression for HIV patients, but also a marker for treatment initiation and influenced by treatment. Fitting a marginal structural model (MSM) using inverse probability weights is one way to give appropriate adjustment for this type of confounding. In this paper we study a simple and intuitive approach to estimate similar treatment effects, using observational data to mimic several randomized controlled trials. Each 'trial' is constructed based on individuals starting treatment in a certain time interval. An overall effect estimate for all such trials is found using composite likelihood inference. The method offers an alternative to the use of inverse probability of treatment weights, which is unstable in certain situations. The estimated parameter is not identical to the one of an MSM, it is conditioned on covariate values at the start of each mimicked trial. This allows the study of questions that are not that easily addressed fitting an MSM. The analysis can be performed as a stratified weighted Cox analysis on the joint data set of all the constructed trials, where each trial is one stratum. The model is applied to data from the Swiss HIV cohort study.


Hyperbaric oxygenation prevents delayed neuronal death following transient ischaemia in the gerbil hippocampus.
The mechanism of the neuroprotective effect of hyperbaric oxygenation remains unclear although its clinical benefits have been well recognized for human ischaemic neuronal disease. The preventive effect of hyperbaric oxygenation against delayed neuronal death was investigated in the gerbil following transient forebrain ischaemia. Delayed neuronal death in the gerbil was produced by clips on both the common carotid arteries (10 min). Morphological examination was carried out after several protocols of hyperbaric oxygenation, modified from the protocols for human ischaemic neuronal disease. Neurons in the hippocampal CA1 were well preserved in the gerbils treated with hyperbaric oxygenation, more so than in the gerbils with no hyperbaric oxygenation. Moreover, more neurons were preserved in the CA1 treated with hyperbaric oxygenation within 6 h of the ischaemia, than when the hyperbaric oxygenation was started 24 h after the ischaemia. The induction of heat shock proteins (HSP72 and HSP27) became weaker in the gerbils with hyperbaric oxygenation than in those without hyperbaric oxygenation, as seen immunohistochemically. We also observed an increase in dense bodies, that were shown to be lysosomes and myelinoid structures in the cytoplasm of the neurons ultrastructurally, in the hippocampus with hyperbaric oxygenation. However, no oxygen toxicity to the neurons was detected, up to at least two atmospheres absolute. This experimental system was useful to investigate the preventive mechanism of hyperbaric oxygenation against delayed neuronal death in the gerbil, and to determine the clinical indications and the most effective protocol for hyperbaric oxygenation for ischaemic neuronal damage in the human brain.


Transplanted Umbilical Cord Mesenchymal Stem Cells Modify the In Vivo Microenvironment Enhancing Angiogenesis and Leading to Bone Regeneration.
Umbilical cord mesenchymal stem cells (UC-MSCs) show properties similar to bone marrow mesenchymal stem cells (BM-MSCs), although controversial data exist regarding their osteogenic potential. We prepared clinical-grade UC-MSCs from Wharton's Jelly and we investigated if UC-MSCs could be used as substitutes for BM-MSCs in muscoloskeletal regeneration as a more readily available and functional source of MSCs. UC-MSCs were loaded onto scaffolds and implanted subcutaneously (ectopically) and in critical-sized calvarial defects (orthotopically) in mice. For live cell-tracking experiments, UC-MSCs were first transduced with the luciferase gene. Angiogenic properties of UC-MSCs were tested using the mouse metatarsal angiogenesis assay. Cell secretomes were screened for the presence of various cytokines using an array assay. Analysis of implanted scaffolds showed that UC-MSCs, contrary to BM-MSCs, remained detectable in the implants for 3 weeks at most and did not induce bone formation in an ectopic location. Instead, they induced a significant increase of blood vessel ingrowth. In agreement with these observations, UC-MSC-conditioned medium presented a distinct and stronger proinflammatory/chemotactic cytokine profile than BM-MSCs and a significantly enhanced angiogenic activity. When UC-MSCs were orthotopically transplanted in a calvarial defect, they promoted increased bone formation as well as BM-MSCs. However, at variance with BM-MSCs, the new bone was deposited through the activity of stimulated host cells, highlighting the importance of the microenvironment on determining cell commitment and response. Therefore, we propose, as therapy for bone lesions, the use of allogeneic UC-MSCs by not depositing bone matrix directly, but acting through the activation of endogenous repair mechanisms.


Laboratory testing in newly treated elderly hypertensive patients without co-morbidities: a population-based cohort study.
Although a purported advantage of newer antihypertensive drug classes is a reduced need for laboratory testing, little is known about the frequency of laboratory monitoring of hypertensive patients in clinical practice and whether this differs across drug classes. This population-based cohort study used linked administrative databases in Ontario, Canada. All elderly residents of Ontario (age 66 and over) who were newly treated for uncomplicated hypertension between 1994 and 2002 were followed for 24 months or until they were admitted to hospital, died, or were no longer on their initially prescribed monotherapy. We examined the frequency and type of laboratory tests performed while patients were treated with antihypertensive monotherapy. In a cohort of 164,413 patients, 39% were treated with thiazides and 46% were prescribed "newer" drug classes as initial therapy. At baseline, 96,534 patients (59%) did not have any laboratory testing done, and during 1,701,520 months of monotherapy (mean time on initial agent 10.3 months) only 79,985 (49%) had any tests done. Laboratory testing was significantly less frequent in patients prescribed newer drug classes than thiazides: the adjusted rate ratios for laboratory testing were 0.94 (95% confidence interval [CI] 0.93-0.95) with angiotensin-converting enzyme inhibitors, 0.80 (95% CI 0.79-0.81) with calcium-channel blockers, and 0.79 (95% CI 0.76-0.82) with angiotensin-receptor blockers. However, the absolute increase in testing was small (16 extra electrolyte tests, 6 extra renal function tests, 4 extra glucose tests, and 6 fewer serum cholesterol tests per 100 patients every 6 months), such that the extra laboratory testing observed with thiazides resulted in an additional cost of only C$0.63 per patient every 6 months in comparison with the cost of the newer drug classes. Laboratory testing in clinical practice was significantly less frequent among patients prescribed newer drug classes than among those prescribed thiazides; however, laboratory monitoring was infrequent in this cohort of elderly patients with hypertension but without comorbidities, and the magnitude of differences between drug classes was small.


Convex Regression with Interpretable Sharp Partitions.
We consider the problem of predicting an outcome variable on the basis of a small number of covariates, using an interpretable yet non-additive model. We propose convex regression with interpretable sharp partitions (CRISP) for this task. CRISP partitions the covariate space into blocks in a data-adaptive way, and fits a mean model within each block. Unlike other partitioning methods, CRISP is fit using a non-greedy approach by solving a convex optimization problem, resulting in low-variance fits. We explore the properties of CRISP, and evaluate its performance in a simulation study and on a housing price data set.


Instrumental variables when evaluating screening trials: estimating the benefit of detecting cancer by screening.
When evaluating the benefit of detecting cancer by screening we try to answer the question, 'what would a screen detected subject's outcome have been if his/her cancer had progressed to clinical detection'. By 'outcome' we mean survival time, cancer size and stage, lead time effects and more. Because only an unethical study can answer it directly, researchers have attempted to answer the question indirectly using data from randomized cancer screening studies (subjects randomized to study (screened) or control (not screened)). Inferences are made by first selecting the cancer cohort (those subjects who are found to have cancer), then comparing subjects having screen detected cancers to subjects having clinically detected cancers. However, there are two difficulties with this approach: (i) because screening (intends to) detect cancers early, at the trial's end the study group contains more cancer cases than the control group and so the cancer cohort has some unidentified control subjects missing (that is, subjects having cancer during the screening period that have not yet been clinically detected); (ii) because screen detected cancers (may) differ from clinically detected cancers, the comparison group should include only a (non-identified) subset of the cancer cohort's control subjects (that is, only those control subjects having cancers that would have been screen detected). Statistical literature acknowledges these difficulties and attempts to solve them separately, but without success; those methods do not yield meaningful causal inferences and admit substantial bias. Recently, Angrist, Imbens and Rubin and Imbens and Rubin provide a framework for instrumental variable methods that we interpret as allowing us to make causal inferences with incompletely identified comparison groups. We apply their framework to evaluating cancer screening trials and find that we may simultaneously accommodate both difficulties while giving a meaningful answer to the question posed above. Using data from a breast cancer screening trial we demonstrate the general method with a variety of outcome measures and extensions.


Nomogram for prediction of portal vein system thrombosis after splenectomy for hypersplenism in patients with Wilson disease.
The occurrence of portal vein system thrombosis (PVST) after splenectomy in patients with Wilson disease (WD) can lead to serious complications. The early identification of high-risk patients can help improve patient prognosis. This study aimed to establish and validate a personalized nomogram for assessing the risk of PVST after splenectomy in patients with WD and hypersplenism. We retrospectively collected the data from 81 patients with WD and hypersplenism who underwent splenectomy. Based on whether PVST occurred within a month after the operation, they were divided into the PVST group and the non-PVST group. The clinical data of the 2 groups were compared, and univariate analysis was used to select the statistically significant features and incorporated into the least absolute shrinkage and selection operator (LASSO) regression model for optimization. Multivariate logistic regression analysis was used to determine the independent risk factors for PVST after splenectomy, which were then applied to establish a personalized nomogram. We calculated the concordance (C)-index and drew the receiver operating characteristic (ROC) curve, the model calibration curve, and the clinical decision analysis (DCA) curve to evaluate the accuracy, calibration, and clinical applicability of the model, respectively. We used bootstrapping for internal validation of the model. Univariate analysis showed that the differences in preoperative portal vein diameter and velocity of portal blood flow, postoperative mean platelet volume (MPV), mean platelet distribution width (PDW), D-dimer, prothrombin time (PT), and the increase of platelet count (PLT) were of statistical significance (P<0.05). According to the results of the LASSO and multivariate logistic regression analyses, a model including preoperative portal vein diameter, preoperative portal blood flow velocity, postoperative D-dimer, and the increase of PLT was established to predict the risk of PVST after splenectomy. The model showed good accuracy with a C-index of 0.838 (95% CI: 0.750-0.926) and had a well-fitted calibration curve. Furthermore, internal validation showed it achieved a moderate C-index of 0.805. The DCA curve indicated that the model has clinical applicability when patients are treated at thresholds of 2-100%. Establishing a predictive model for the risk of PVST in patients with WD and hypersplenism after splenectomy can help clinicians identify patients at high risk of PVST who require intervention measures.


Differential Alcohol Use Disparities by Sexual Identity and Behavior Among High School Students.
Sexual minority youth (SMY) use alcohol at disproportionate rates compared to their heterosexual peers. However, sexual orientation is multidimensional. Analyzing alcohol use disparities only by one dimension of sexual orientation may result in critical disparities being obscured. Data from state and local versions of the Youth Risk Behavior Survey were pooled (2009-2017), resulting in a large, diverse sample (n = 201,671). Multivariable logistic regression models were used to analyze associations between sexual identity/sexual behavior and three alcohol use outcomes among sexually active youth: age at first drink, binge drinking and current drinking. SMY, when categorized by sexual identity and sexual behavior, reported greater alcohol use than their heterosexual peers, though the magnitude of these disparities varied by subgroup. Both those who identified as bisexual and those who reported sexual behavior with both males and females reported the greatest levels of alcohol use. Decomposition analysis revealed that youth whose reported sexual behavior was not aligned with stereotypical behavioral expectations based on their sexual identity had higher odds of current drinking and drinking before 13 years as compared to other youth. Results highlight the need to incorporate multiple methods of sexual orientation measurement into substance use research. Interventions based solely on identity, rather than both identity and behavior, may not be sufficient; targeted research into the causes of alcohol use disparities is needed, especially for bisexual youth, youth whose sexual behavior and sexual identity are not stereotypically aligned, and youth who report a sexual identity of 'not sure.'


LH responses to LHRH, DBcAMP, and 17 beta-estradiol in cultures derived from aged rats.
Effects of luteinizing hormone-releasing hormone (LHRH), N6,O2'-dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAmP), and 17 beta-estradiol (E2) on LH responses were compared in 4-day-old pituitary cultures derived from female rats (Fischer 344) of 9 and 31 mo of age. Pituitary LH contents were similar in 5 X 10(5) freshly dispersed cells prepared from the two groups of rats. LH release in response to a 4-h incubation with 10 nM LHRH was virtually the same in cultures derived from 9- and 31-mo-old rats, 140 +/- 2 ng and 138 +/- 18 ng/4 h, respectively. In cultures derived from 9-mo-old rats, incubation with 8 mM DBcAMP for 4 h significantly stimulated LH release (286% of control level), and treatment with 10 nM E2 for 3 days significantly increased both basal LH release and LH accumulation (sum of LH contents in cells and medium) to 162 and 125% of control level, respectively. Neither DBcAMP nor E2 affected cultures derived from the 31-mo-old rats. These results indicate that there is a difference in the LH response to DBcAMP and E2 between cultures derived from 9- and 31-mo-old rats. The loss of pituitary responsiveness to DBcAMP and E2 and the loss of pituitary cyclicity in the aged female rat may be causally related.


Electrophysiological and morphological evaluation of the acute ototoxicity of sodium nitroprusside.
Nitric oxide (NO) is a messenger molecule that mediates several physiological functions and pathological processes. Sodium nitroprusside (SNP), a potent vasodilator, when given clinically as an anti-hypertension agent, exerts its function by releasing NO. It was reported recently that SNP causes a loss of auditory nerve compound action potential (CAP) after topical application of SNP on guinea pig round window membrane (RWM). The current study was designed to investigate the ototoxic target of SNP through both electrophysiological and morphological approaches. The CAP threshold at frequencies ranging from 2 to 36 kHz, the cochlear microphonic quadratic distortion product (cmQDP, F2-F1, where F1 = 17.1 kHz; F2 = 18 kHz), and the cochlear microphonic (CM) at the frequency of F1 were recorded via a round window electrode before and up to 2 h after RWM application of 1 microliter of drug solution. Cochlear blood flow (CBF) and arterial blood pressure were monitored. The cochleae were then processed for morphological examination. The effect of SNP on endocochlear potential (EP) was also studied. Results showed that cmQDP, CM, and CAP, as well as EP, were suppressed in varying amounts, while CBF was substantially increased following drug application. Morphological evaluations showed swelling of the afferent inner radial dendrites within the basal cochlear turn in the higher concentration groups of SNP, while the hair cells presented no evidence of damage at the light microscopic level. The results indicate that SNP has an acute ototoxic effect in a concentration- and time-dependent manner. The targets of SNP ototoxicity are at least the afferent dendrites and stria vascularis.


Recovery of motor function after lesions in motor cortex of monkey.
This behavioural study concerns the contribution of active retraining to motor recovery after a standard lesion in the motor cortex, and includes an evaluation of various retraining procedures. These problems have not previously been experimentally analysed in man or animal. Rhesus monkeys (27) were initially trained on two motor tasks which consisted of a pulling task, involving the proximal muscles of the upper limb, and a hand-grip task for the distal musculature. Strength of pulling and hand-grip were measured quantitatively. For brevity, only the hand grip data are described. After a plateau of proficient performance was achieved in both hands (usually 6-8 months), the cortical precentral forelimb area was surgically ablated on one side. Each animal was then randomly assigned to one of four experimental groups or to a sham operative control group. The groups differed with respect to the use of the contralateral and/or ipsilateral forelimb(s) in post-operative motor training on the same task. In addition, to evaluate the contribution of spontaneous post-operative recovery independent of retraining, we started to train two groups immediately after surgery; in the other two experimental groups the weak forelimb remained idle for the first four post-operative months. Combined training of the weak and normal limb, which resulted in 85% recovery in the weak limb, did not differ statistically from training the weak limb alone (79% recovery). This suggests that the critical factor in promoting recovery is training of the weak forelimb, presumably by 'activation' of the damaged hemisphere. The role of the ipsilateral (strong) limb appears negligible. When post-operative training in the weak limb was delayed four months, spontaneous recovery noted one week after the start of delayed training was about 50% compared with 9% recovery after one week in the groups retrained immediately after surgery (P less than 0.001). The 'immediate' groups, however, continued to improve over a six-month period to about 82% of their pre-operative performance. The 'delay' groups, by contrast, exhibited only slight further improvement, reaching a plateau of 67% recovery six months after the start of retraining (10 months post-operatively). This difference in recovery between the immediate and delay groups was significant at the 0.05 level. This confirms that active physical retraining facilitates motor recovery, although the mechanism remains obscure. The data also suggest that, to be most effective, the training should begin as soon as possible after the insult to the brain has occurred.


Do Non-participants at Screening have a Different Threshold for an Acceptable Benefit-Harm Ratio than Participants? Results of a Discrete Choice Experiment.
The objective of the study was to investigate non-participants' preferences for cardiovascular disease screening programme characteristics and whether non-participation can be rationally explained by differences in preferences, decision-making styles and informational needs between non-participants and participants. We conducted a discrete choice experiment at three screening sites between June and December 2017 among 371 male non-participants and 830 male participants who were asked to trade different levels of five key programme characteristics (chance of health benefit, risk of overtreatment, risk of later regret, screening duration and screening location). Data were analysed using a multinomial mixed-logit model. Health benefit was used as a payment vehicle for estimation of marginal substitution rates. Non-participants were willing to accept that 0.127 (95% confidence interval 0.103-0.154) fewer lives would be saved to avoid overtreatment of one individual, whilst participants were willing to accept 0.085 (95% confidence interval 0.077-0.094) fewer lives saved. This translates into non-participants valuing health benefits 7.9 times higher than overtreatment. The corresponding value of participants is 11.8. Similarly, non-participants had higher requirements than participants for advanced technology and a quicker screening duration. With regard to their participation decision, 64% of the non-participants felt certain about their choice compared with 89% among participants. This study shows that non-participants have different preferences than participants at screening as they express relatively more concern about overtreatment and have higher requirements for a high-tech screening programme. Non-participants also report to be more uncertain about their participation decision and more often seek additional information to the standard information provided in the invitation letter. Further studies on informational needs and effective communication strategies are warranted to ensure that non-participation is a fully informed choice.


Pathologic characteristics of NUT midline carcinoma arising in the mediastinum.
NUT midline carcinomas (NMCs) comprise a group of highly aggressive tumors that have been reported primarily in the head, neck, and mediastinum of younger individuals. These tumors overexpress the nuclear protein in the testis (NUT), most commonly due to a chromosomal translocation that fuses the NUT gene on chromosome 15 with the BRD4 gene on chromosome 19. Although the earliest recognized cases were described in the thymus or mediastinum, an extensive survey for NMCs among malignant thymic or other mediastinal neoplasms has not been reported. We examined NUT expression in 114 cases of poorly differentiated carcinomas or unclassified mediastinal malignancies using a clinically validated NUT-specific monoclonal antibody. Four of 114 (3.5%) cases showed nuclear NUT expression. A NUT translocation was confirmed by fluorescence in situ hybridization in 3 of these cases. These tumors arose in 2 men and 2 women with a median age of 50 years (range, 28 to 68 y). Three of the tumors were originally diagnosed as undifferentiated epithelioid or round cell malignant neoplasms; 1 tumor contained focal squamous differentiation and was originally diagnosed as a poorly differentiated squamous carcinoma of probable thymic origin. We find that the incidence of NMC within the mediastinum, particularly among undifferentiated tumors, is similar to that reported at other anatomic sites. NMC should be considered in the differential diagnosis of any poorly differentiated epithelioid mediastinal tumor, regardless of age.


A critical analysis of low molecular weight heparin use during pregnancy in a tertiary referral centre.
The aim of this study was to analyse low molecular weight heparin (LMWH) use during pregnancy in terms of patient evaluation, treatment indication and social and financial costs. This was a retrospective analysis of patients using LMWH in their pregnancies. A total of 147 women were included in the study. The most common indications were thrombophilia (55/147, 37.4%); recurrent pregnancy loss (RPL); (47/147, 32.0%) and previous single pregnancy loss (18/147, 12.2%). In the RPL group, 53.1% of patients were not evaluated with standard tests; 31.9% of women were incompletely evaluated and 15% were properly evaluated. Out of 104 women screened for thrombophilia, 32 (32/104, 30.8%) were tested during pregnancy. Despite published guidelines and increasing scientific evidence against their use in some indications, LMWHs are prescribed widely during pregnancy for a variety of indications. Public and healthcare providers' education to change this attitude should be implemented.


A three-parameter mechanical property reconstruction method for MR-based elastic property imaging.
A reconstruction process featuring full parameterization of the three dimensional, time-harmonic equations of linear elasticity is developed and reconstructed property images are presented from simulation-based investigation. While interesting in its own right through the potential for increased adaptability of these reconstructive elastic imaging techniques, this study also presents a set of analysis tools used to study the poor convergence behavior found in the case of tissue like conditions (i.e. nearly incompressible materials). The choice of elastic properties for imaging in elastography research remains an open question at this point; the use of the stability and sensitivity-based analytical methods described here will help to predict and understand the value and reliability of different parameterizations of elasticity imaging. Additionally, though results indicate significant work needs to be done to achieve effective multiparameter reconstructive imaging, the methods detailed here offer the promise of increased flexibility and sophistication in elastographic imaging techniques.


Carbon nanotubes induce secondary structure changes of bovine albumin in aqueous phase.
Interaction of nanomaterials to protein molecules is one of the most important issues to deeply understand the influences of the nanomaterials upon physiological processes and protein functions. So far most of investigations focused on the protein molecules adsorbed on the nanomaterials surface, less is known about those in the aqueous phase (not absorbed). In this work, luminescent spectroscopy analysis, circular dichroism measurement, atomic force microscopy, matrix-assisted laser desorption/ionization time of flight mass spectrometry, isoelectric focusing and sulfate polyacrylamide gel electrophoresis were used to investigate the influence of oxidized water-soluble multiwalled carbon nanotubes (CNT) dispersing in aqueous solution upon the structures of bovine serum albumin (BSA) through co-incubation. We focused on BSA molecules that stayed in the aqueous phase instead of those adsorbed by CNT. Experimental results show that the fractions of beta-sheet decreased from 33.3% to 29.8% and beta-turn increased from 2% to 5% in reference with native BSA. There was a slight increase of alpha-helix and a slight reduction of random coil. BSA molecules that had been encountered with CNT and were left in the solution formed a loose and flatten morphology on graphite substrates instead of their native tight and round morphology observed by AFM. The value of isoelectric point for BSA after exposed to CNT moved towards to a higher pH position compared with native BSA. All together, it was concluded that the oxidized water-soluble multiwalled carbon nanotubes not only adsorb bovine serum albumin molecules to their surface, but also induces albumin molecules in the aqueous solution undergo secondary structure changes, which lead to a conformation change.


Higher aggrecan 1-F21 epitope concentration in synovial fluid early after anterior cruciate ligament injury is associated with worse knee cartilage quality assessed by gadolinium enhanced magnetic resonance imaging 20 years later.
To investigate if cartilage related biomarkers in synovial fluid are associated with knee cartilage status 20 years after an anterior cruciate ligament (ACL) injury. We studied 25 patients with a complete ACL rupture without subsequent ACL reconstruction or radiographic knee OA. All had a delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) 20 years after the ACL injury, using the T1 transverse relaxation time in the presence of gadolinium (T1Gd) which estimates the concentration of glycosaminoglycans in hyaline cartilage. Synovial fluid samples were aspirated acutely (between 0 and 18 days) and during 1 to 5 follow up visits between 0.5 and 7.5 years after injury. We quantified synovial fluid concentrations of aggrecan (epitopes 1-F21 and ARGS), cartilage oligomeric matrix protein, matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by immunoassays, and sulfated glycosaminoglycans by Alcian blue precipitation. Western blot was used for qualitative analyses of aggrecan fragments in synovial fluid and cartilage samples. Western blot indicated that the 1-F21 epitope was located within the chondroitin sulfate 2 region of aggrecan. Linear regression analyses (adjusted for age, sex, body mass index and time between injury and sampling) showed that acute higher synovial fluid 1-F21-aggrecan concentrations were associated with shorter T1Gd values 20 years after injury, i.e. inferior cartilage quality (standardized effects between - 0.67 and - 1.0). No other statistically significant association was found between molecular biomarkers and T1Gd values. Higher acute synovial fluid 1-F21-aggrecan concentrations in ACL injured patients, who managed to cope without ACL reconstruction and were without radiographic knee OA, were associated with inferior knee cartilage quality assessed by dGEMRIC 20 years after injury.


Strategies for mutational analysis of the large multiexon ATM gene using high-density oligonucleotide arrays.
Mutational analysis of large genes with complex genomic structures plays an important role in medical genetics. Technical limitations associated with current mutation screening protocols have placed increased emphasis on the development of new technologies to simplify these procedures. High-density arrays of >90,000-oligonucleotide probes, 25 nucleotides in length, were designed to screen for all possible heterozygous germ-line mutations in the 9.17-kb coding region of the ATM gene. A strategy for rapidly developing multiexon PCR amplification protocols in DNA chip-based hybridization analysis was devised and implemented in preparing target for the 62 ATM coding exons. Improved algorithms for interpreting data from two-color experiments, where reference and test samples are cohybridized to the arrays, were developed. In a blinded study, 17 of 18 distinct heterozygous and 8 of 8 distinct homozygous sequence variants in the assayed region were detected accurately along with five false-positive calls while scanning >200 kb in 22 genomic DNA samples. Of eight heterozygous sequence changes found in more than one sample, six were detected in all cases. Five previously unreported sequence changes, not found by other mutational scanning methodologies on these same samples, were detected that led to either amino acid changes or premature truncation of the ATM protein. DNA chip-based assays should play a valuable role in high throughput sequence analysis of complex genes.


Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1.
Targeted genome editing in hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematological diseases. However, the limited efficiency of homology-directed editing in primitive HSPCs constrains the yield of corrected cells and might affect the feasibility and safety of clinical translation. These concerns need to be addressed in stringent preclinical models and overcome by developing more efficient editing methods. We generated a humanized X-linked severe combined immunodeficiency (SCID-X1) mouse model and evaluated the efficacy and safety of hematopoietic reconstitution from limited input of functional HSPCs, establishing thresholds for full correction upon different types of conditioning. Unexpectedly, conditioning before HSPC infusion was required to protect the mice from lymphoma developing when transplanting small numbers of progenitors. We then designed a one-size-fits-all IL2RG (interleukin-2 receptor common γ-chain) gene correction strategy and, using the same reagents suitable for correction of human HSPC, validated the edited human gene in the disease model in vivo, providing evidence of targeted gene editing in mouse HSPCs and demonstrating the functionality of the IL2RG-edited lymphoid progeny. Finally, we optimized editing reagents and protocol for human HSPCs and attained the threshold of IL2RG editing in long-term repopulating cells predicted to safely rescue the disease, using clinically relevant HSPC sources and highly specific zinc finger nucleases or CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9). Overall, our work establishes the rationale and guiding principles for clinical translation of SCID-X1 gene editing and provides a framework for developing gene correction for other diseases.


Comparison of Machine Learning Techniques for Prediction of Hospitalization in Heart Failure Patients.
The present study aims to compare the performance of eight Machine Learning Techniques (MLTs) in the prediction of hospitalization among patients with heart failure, using data from the Gestione Integrata dello Scompenso Cardiaco (GISC) study. The GISC project is an ongoing study that takes place in the region of Puglia, Southern Italy. Patients with a diagnosis of heart failure are enrolled in a long-term assistance program that includes the adoption of an online platform for data sharing between general practitioners and cardiologists working in hospitals and community health districts. Logistic regression, generalized linear model net (GLMN), classification and regression tree, random forest, adaboost, logitboost, support vector machine, and neural networks were applied to evaluate the feasibility of such techniques in predicting hospitalization of 380 patients enrolled in the GISC study, using data about demographic characteristics, medical history, and clinical characteristics of each patient. The MLTs were compared both without and with missing data imputation. Overall, models trained without missing data imputation showed higher predictive performances. The GLMN showed better performance in predicting hospitalization than the other MLTs, with an average accuracy, positive predictive value and negative predictive value of 81.2%, 87.5%, and 75%, respectively. Present findings suggest that MLTs may represent a promising opportunity to predict hospital admission of heart failure patients by exploiting health care information generated by the contact of such patients with the health care system.


Effect of vector on infectivity of Trypanosoma cruzi.
A comparative study was carried out on the interaction between Triatoma infestans and bloodstream forms (BSF) of Trypanosoma cruzi isolates RA and UP, both lethal for mouse, and CA-I nonlethal for this host. Parasite duplication was readily detected in triatomes fed with CA-I, metacyclic (Mtc) differentiation reaching a maximum at an optimum ingestion level of 250 BSF/insect. Progress and differentiation proved much lower for RA, but reached intermediate values for the UP isolate. Assays for infectivity for each isolate after bug passage revealed a drop for the RA and UP, whereas for CA-I an increase was observed indicating that virulence of BSF and Mtc differs. Our results suggest that parasite selection by insect passage modulates infectivity of a given parasite population; however, virulence was independent of the absolute number of Mtc in the insect's feces.


Predictors of Essential Health and Nutrition Service Delivery in Bihar, India: Results From Household and Frontline Worker Surveys.
In Bihar, India, coverage of essential health and nutrition interventions is low. These interventions are provided by 2 national programs--the Integrated Child Development Services (ICDS) and Health/National Rural Health Mission (NRHM)--through Anganwadi workers (AWWs) and Accredited Social Health Activists (ASHAs), respectively. Little is known, however, about factors that predict effective service delivery by these frontline workers (FLWs) or receipt of services by households. This study examined the predictors of use of 4 services: (1) immunization information and services, (2) food supplements, (3) pregnancy care information, and (4) general nutrition information. Data are from a 2012 cross-sectional survey of 6,002 households in 400 randomly selected villages in 1 district of Bihar state, as well as an integrated survey of 377 AWWs and 382 ASHAs from the same villages. For each of the 4 service delivery outcomes, logistic regression models were specified using a combination of variables hypothesized to be supply- and demand-side drivers of service utilization. About 35% of households reported receiving any of the 4 services. Monetary immunization incentives for AWWs (OR = 1.55, CI = 1.02-2.36) and above-median household head education (OR = 1.39, CI = 1.05-1.82) were statistically significant predictors of household receipt of immunization services. Higher household socioeconomic status was associated with significantly lower odds of receiving food supplements (OR = 0.87, CI = 0.79-0.96). ASHAs receiving incentives for institutional delivery (OR = 1.52, CI = 0.99-2.33) was marginally associated with higher odds of receiving pregnancy care information, and ASHAs who maintained records of pregnant women was significantly associated with households receiving such information (OR = 2.25, CI = 1.07-4.74). AWWs receiving immunization incentives was associated with significantly higher odds of households receiving general nutrition information (OR = 1.92, CI = 1.08-3.41), suggesting a large spillover effect of incentives from product- to information-oriented services. Product-oriented incentives affect delivery of both product- and information-oriented services, although household factors are also important. In India, existing government programs can mitigate supply- and demand-side constraints to receiving essential interventions by optimizing existing incentives for FLWs in national programs, helping FLWs better organize their work, and raising awareness among groups who are less likely to access services.


Endoscopic iliopsoas tenotomy for iliopsoas impingement on a collared femoral prosthesis.
Groin pain after total hip replacement is an uncommon event and may be the result of several causes, including iliopsoas impingement. We describe the case of a 51-year-old woman who was diagnosed with iliopsoas impingement after total hip replacement with a collared femoral stem. She did not improve despite extensive conservative treatment. She was treated by endoscopic iliopsoas tenotomy, and the surgical technique is described herein. Her preoperative groin pain and popping disappeared completely at 3 months postoperatively.


Racial differences in clinical use of cinacalcet in a large population of hemodialysis patients.
African-Americans with end-stage renal disease receiving dialysis have more severe secondary hyperparathyroidism than Whites. We aimed to assess racial differences in clinical use of cinacalcet. This retrospective cohort study used data from DaVita, Inc., for 45,589 prevalent hemodialysis patients, August 2004, linked to Centers for Medicare & Medicaid Services data, with follow-up through July 2007. Patients with Medicare as primary payer, intravenous vitamin D use, or weighted mean parathyroid hormone (PTH) level >150 pg/ml at baseline (August 1-October 31, 2004) were included. Cox proportional hazard modeling was used to evaluate race and other demographic and clinical characteristics as predictors of cinacalcet initiation, titration, and discontinuation. Of 16,897 included patients, 7,674 (45.4%) were African-American and 9,223 (54.6%) were white; 53.2% of cinacalcet users were African-American. Cinacalcet was prescribed for 47.7% of African-Americans and 34.5% of Whites, and for a greater percentage of African-Americans at higher doses at each PTH strata. After covariate adjustment, African-Americans were more likely than Whites to receive cinacalcet prescriptions (hazard ratio 1.17, p < 0.001). The direction and magnitude of this effect appeared to vary by age, baseline PTH, and calcium, and by elemental calcium use. African-Americans were less likely than Whites to have prescriptions discontinued and slightly more likely to undergo uptitration (hazard ratio 1.09, 95% confidence interval 0.995-1.188), but this relationship lacked statistical significance. Cinacalcet is prescribed more commonly and at higher initial doses for African-Americans than for Whites to manage secondary hyperparathyroidism.


Sentinel e-health network on grid: developments and challenges.
Grid technologies have proven their capabilities to settle challenging problems of medical data access. The grid ability to access distributed databases in a secure and reliable way while preserving data ownership opened new perspectives in medical data sharing and disease surveillance. This paper focuses on the implementation challenges of grid-powered sentinel networks within the e-sentinelle project. This initiative aims to create a lightweight grid dedicated to cancer data exchange and enable automatic disease surveillance according to definition of epidemiological alarms. Particularly, issues related to security, patient identification, databases integration, data representation and medical record linkage are discussed.


The buffering of calcium with quin2 reversibly forestalls anaphase onset in stamen hair cells of Tradescantia.
Cells from immature stamen hairs of the spiderwort plant Tradescantia virginiana cv. Zwanenburg Blue exhibit remarkable precision in the timing of their mitotic events: anaphase onset occurs 33 +/- 4 min after nuclear envelope breakdown, and cell plate vesicle aggregation occurs approximately 19 +/- 4 min after anaphase onset. To test the hypothesis that altered calcium levels might affect mitotic events, we incubated stamen hairs with the acetoxymethyl ester of the Ca-chelator, quin2 (quin2AM), or the K+-salt of quin2 free acid, and found that mitotic progression was blocked in metaphase and late anaphase. The inhibition of mitotic progression was dependent upon the quin2AM or quin2 concentration and the duration of incubation with the probe. Metaphase arrest could be reversed within several min by the addition of 100 microM CaCl2 to the extracellular medium, while lower concentrations of Ca2+ or the presence of Mg2+ in the buffer were insufficient to reverse the block. A second perfusion of 100 microM CaCl2 was usually necessary to promote cell plate vesicle aggregation. The effective concentration of quin2AM for reversible mitotic arrest was 50 microM (30 min) or 500 microM (12 min); a 30-min incubation in 50 microM quin2 acted similarly. The similarity of dose responses of Ca2+-reversal of quin2AM- and quin2-induced metaphase arrest suggests that the active species is the free acid and that the mode of inhibition is through Ca2+-chelation. Because the free acid is not permeant, and because extracellular esterase activity exists in the cell wall, the site of quin2 activity is probably outside the plasma membrane, in the wall space.(ABSTRACT TRUNCATED AT 250 WORDS)


New mechanism for methicillin resistance in Staphylococcus aureus: clinical isolates that lack the PBP 2a gene and contain normal penicillin-binding proteins with modified penicillin-binding capacity.
Seventeen clinical isolates of Staphylococcus aureus (from the United States and Europe) selected for low (borderline)-level methicillin resistance (MIC of methicillin, 2 to 4 micrograms/ml; MIC of oxacillin, 0.5 to 8 micrograms/ml) were examined for their mechanisms of resistance. Five strains were typical of heterogeneous S. aureus: they gave positive reactions with a DNA probe specific for mec and contained a small fraction (10(-6] of highly resistant cells (MIC, greater than 100 micrograms/ml). The rest of the 12 strains were homogeneous with respect to their methicillin resistance: the MIC of methicillin for all cells was 2 to 4 micrograms/ml, and no cells for which MICs were 50 micrograms/ml or higher were detectable (less than 10(-9]. None of these strains reacted with the mec-specific DNA probe. One representative strain of each group was characterized in more detail. Strain CDC-1, prototype of heterogeneous methicillin-resistant S. aureus, contained penicillin-binding protein (PBP) 2a; its DNA could transform a methicillin-susceptible and novobiocin-resistant recipient to methicillin resistance with ca. 35% linkage to Novr. Introduction of the "factor X" determinant (K. Murakami and A. Tomasz, J. Bacteriol. 171:874-879, 1989) converted strain CDC-1 to high, homogeneous resistance. Strain CDC-6, prototype of the second group of isolates, showed completely homogeneous MICs of methicillin, oxacillin, and cefotaxime. The strain contained modified "normal" PBPs: PBPs 1 and 2 showed low drug reactivity (and/or cellular amounts), and PBP 4 was present in elevated amounts. No PBP 2a could be detected. DNA isolated from strain CDC-6 could transform the methicillin-susceptible and novobiocin-resistant strain to methicillin resistance in a multistep fashion, but this resistance showed no genetic linkage to the Nov marker. We suggest that staphylococci with borderline resistance may contain at least three different classes of mechanism: heterogeneous, methicillin-resistant S. aureus, PBPs of modified drug reactivities, and the previously reported hyperproduction of beta-lactamase (L.K. McDougal and C. Thornsberry, J. Clin Microbiol. 23:832-839, 1986).


Biologic Treatment Options for Pediatric Psoriasis and Atopic Dermatitis-A Review.
Background and Objectives: Severe, recalcitrant cases of pediatric psoriasis or atopic dermatitis may necessitate treatment with biological agents; however, this may be difficult due to lack of treatment options and standardized treatment guidelines. This review evaluates the biological treatment options available, including off-label uses, and provides a basic therapeutic guideline for pediatric psoriasis and atopic dermatitis. Materials and Methods: A PubMed review of biological treatments for pediatric psoriasis and atopic dermatitis with information regarding age, efficacy, dosing, contra-indications, adverse events, and off-label treatments. Results: Currently there are three European Medicines Agency (EMA)-approved biological treatment options for pediatric psoriasis: etanercept, ustekinumab, and adalimumab. While dupilumab was recently Food and Drug Administration (FDA)- and EMA-approved for adult atopic dermatitis, it is still not yet approved for pediatric atopic dermatitis. Conclusion: Given the high morbidity associated with pediatric atopic dermatitis and psoriasis, there is a need for more treatment options. Further research and post-marketing registries are needed to extend the use of biologics into pediatric patients.


New surface forces apparatus using two-beam interferometry.
We designed a new surface forces apparatus for measuring the interactions between two nontransparent substrates and/or in nontransparent liquids. The small displacement of a surface, the bottom one in this study, was measured by the two-beam (twin path) interferometry technique using the phase difference between the laser light reflected by the fixed mirror and that by the mirror on the back of the bottom surface unit. It is possible to determine the distance with a resolution of 1 nm in the working range of 5 microm. This apparatus was successfully applied to measure the forces between mica surfaces in pure water and aqueous KBr solutions.


Review of Mammarenavirus Biology and Replication.
The family Arenaviridae is divided into three genera: Mammarenavirus, Reptarenavirus, and Hartmanivirus. The Mammarenaviruses contain viruses responsible for causing human hemorrhagic fever diseases including New World viruses Junin, Machupo, Guanarito, Sabia, and Chapare virus and Old World viruses Lassa, and Lujo virus. These two groups of arenaviruses share the same genome organization composed of two ambisense RNA segments. These segments contain four open reading frames that encode for four proteins: the nucleoprotein, glycoprotein precursor, L protein, and Z. Despite their genome similarities, these groups exhibit marked differences in their replication life cycles. This includes differences in attachment, entry, and immune evasion. By understanding the intricacy of replication in each of these viral species we can work to develop counter measures against human diseases. This includes the development of vaccines and antivirals for these emerging viral threats. Currently only the vaccine against Junin virus, Candid#1, is in use as well as Ribavirin for treatment of Lassa Fever. In addition, small molecule inhibitors can be developed to target various aspects of the virus life cycle. In these ways an understanding of the arenavirus replication cycle can be used to alleviate the mortality and morbidity of these infections worldwide.


DY-9760e inhibits endothelin-1-induced cardiomyocyte hypertrophy through inhibition of CaMKII and ERK activities.
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) have pivotal roles in endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. We here tested whether a novel CaM antagonist, DY-9760e inhibits ET-1-induced hypertrophy through inhibition of CaMKII and ERK activities. We first confirmed that Ca(2+) oscillation induced by ET-1 treatment elicits transient activation of CaMKII and ERK in cultured cardiomyocytes. DY-9760e treatment with 3 microM totally and partially inhibited the ET-1-induced CaMKII and ERK activation, respectively. The ET-1-induced ERK activation was also partially blocked by a CaMKII inhibitor, KN93. To confirm involvement of CaMKII activity in the ERK activation by ET-1 and A23187, cultured cardiomyocytes were transfected with a constitutively active CaMKII. The transfection with the active CaMKII elicited ERK activation in cultured cardiomyocytes and cotransfection with dominant negative CaMKII eliminated its ERK activation. Consistent with inhibitory actions of DY-9760e on the ET-1-induced CaMKII and ERK activation, induction of hypertrophy-related genes including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was significantly inhibited by DY-9760e treatment. Combination treatment with DY-9760e and U0126, a MEK inhibitor, totally blocked the ET-1-induced ANP and BNP expression. DY-9760e treatment (3 microM) significantly inhibited the ET-1-induced hypertrophy and combination treatment with DY-9760e and U0126 totally blocked the ET-1-induced hypertrophy in cultured cardiomyocytes. These results suggest that DY-9760e elicits antihypertrophic action on ET-1-induced cardiac hypertrophy through inhibition of CaMKII and ERK activation and that CaMKII activity in part mediates ET-1-induced ERK activation.


Multiscale Mesh Deformation Component Analysis With Attention-Based Autoencoders.
Deformation component analysis is a fundamental problem in geometry processing and shape understanding. Existing approaches mainly extract deformation components in local regions at a similar scale while deformations of real-world objects are usually distributed in a multi-scale manner. In this article, we propose a novel method to exact multiscale deformation components automatically with a stacked attention-based autoencoder. The attention mechanism is designed to learn to softly weight multi-scale deformation components in active deformation regions, and the stacked attention-based autoencoder is learned to represent the deformation components at different scales. Quantitative and qualitative evaluations show that our method outperforms state-of-the-art methods. Furthermore, with the multiscale deformation components extracted by our method, the user can edit shapes in a coarse-to-fine fashion which facilitates effective modeling of new shapes.


Non-coding RNAs in DNA damage response.
Genome-wide studies have revealed that human and other mammalian genomes are pervasively transcribed and produce thousands of regulatory non-protein-coding RNAs (ncRNAs), including miRNAs, siRNAs, piRNAs and long non-coding RNAs (lncRNAs). Emerging evidences suggest that these ncRNAs also play a pivotal role in genome integrity and stability via the regulation of DNA damage response (DDR). In this review, we discuss the recent finding on the interplay of ncRNAs with the canonical DDR signaling pathway, with a particular emphasis on miRNAs and lncRNAs. While the expression of ncRNAs is regulated in the DDR, the DDR is also subjected to regulation by those DNA damage-responsive ncRNAs. In addition, the roles of those Dicer- and Drosha-dependent small RNAs produced in the vicinity of double-strand breaks sites are also described.


TRPS1 gene alterations in human subependymoma.
Subependymoma is a rare primary brain tumor, constituting 0.07-0.51% of brain tumors. Genetic alterations in subependymoma are largely unknown, but familial occurrences have been reported. Trichorhinophalangeal syndrome type 1 (TRPS1) is a rare hereditary malformation complex caused by mutations in a gene identified in the year 2000 on 8q24.12. We report two patients with TRPS I and surgically treated subependymomas, one of whom has a first degree relative, now deceased, who was affected and also had a subependymoma. We therefore sought a role for the TRPS1 gene in the molecular oncogenesis of subependymoma. Formalin fixed tumor specimens and saliva samples were obtained from the two index patients as well as tumor samples from six sporadic subependymoma surgical specimens. A heterozygous TRPS1 germ line mutation predicted to cause a frame shift leading to a premature stop codon was found in the first index patient and also present in the associated tumor. No germline mutation was found in the second index patient, but his tumor displayed copy number neutral loss of heterozygosity in TRPS1. TRPS1 mutation analysis of the sporadic subependymomas revealed genetic, mostly loss of function alterations in one-third (two of six) of samples. Genetic alterations in TRPS1 likely play a role in at least a subgroup of subependymomas. Confirmation and further (epi)genetic investigations, ideally in newly acquired, fresh-frozen tumor samples, are warranted.


Resistance of Haemophilus influenzae to trimethoprim.
Out of 210 isolates of Haemophilus influenzae obtained from the sputum of 63 patients with chronic respiratory infections 109 (52%) were resistant to trimethoprim-sulphamethoxazole by the disc test. The minimal inhibitory concentrations of trimethoprim for 17 out of 18 strains recorded as resistant were 10 mug/ml or higher. Resistant strains were isolated from time to time from 32 (82%) out of 39 patients known to have been treated with trimethoprim-sulphamethoxazole, compared with only 1 (12.5%) out of 8 patients known not to have been treated with this drug combination. Resistant strains were isolated most frequently from patients who had received long-term treatment. Since sulphamethoxazole penetrates from the blood into the bronchial secretions less readily than does trimethoprim it seems likely that the ratio of the two drugs in the bronchial tree is far from ideal. This may be an important factor in the use of these drugs for chest infections.


Vitamin E and paraquat poisoning.
Whether vitamin E treatment might have a protective effect in paraquat poisoning was examined in male rats which received single ip paraquat injections in the LD50 dose range (14.8 mg cation/kg body weight). Vitamin E (d, alpha-tocopherol acetate in soybean oil) was administered either 30 minutes after paraquat (923 IU/kg ip) followed by a second injection 24 hours later (462 IU/kg im), or 2 hours before paraquat (1,000 IU/kg im) followed by a second injection 26 hours later (500 IU/kg im). In neither experimental arrangement did the vitamin E therapy alter the acute (7 day) mortality nor reduce the characteristic pathological lung changes observed at death or in 30-day survivors examined by light microscopy when compared with an equal number of non-treated control animals.


Bilateral ovarian steroid cell tumor in congenital adrenal hyperplasia due to classic 11beta-hydroxylase deficiency.
An 8.7 year-old patient, raised as a boy, presented with premature appearance of pubic hair and accelerated growth since 2 years of age and ambiguous genitalia noted at birth. There was first degree consanguinity between his parents. A similar problem was reported in a cousin. Examination of the external genitalia revealed complete scrotal fusion, a 5 cm long phallus, urogenital sinus at base of phallus with no gonads palpable. Pigmentation was increased. His blood pressure was 150/100 mm Hg. Pubic and axillary hair were at stage 3. Bone age was 17 years. Adrenal ultrasound was normal. Pelvic ultrasound showed relatively enlarged uterus and ovaries with normal echogenicity. Karyotype was 46,XX. Hormone profile was compatible with congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency (11-deoxycortisol: 11.5 nmol/l [400 ng/dl] [normal: 0.6-4.5 nmol/l [20-155 ng/ml]], androstenedione: 17.4 nmol/l [5 ng/ml] [normal: 0.1-1.2 nmol/l [0.03-0.35 ng/ml]]). Prednisolone and antihypertensive drugs were started. The patient underwent bilateral salpingo-oophorectomy and hysterectomy at 9.1 years. Histopathological examination of both ovaries revealed steroid cell tumor. The type of the tumor was "not otherwise specified" (NOS). Basal hormone levels and ACTH test performed 10 months after the operation and 7 days off treatment reconfirmed the diagnosis of 11beta-hydroxylase deficiency. Steroid cell tumors are extremely rare forms of steroid hormone-reducing ovarian neoplasms in childhood and may coexist with or imitate virilizing CAH.


The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey.
We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.


Human leukocyte antigen-G polymorphisms in periodontitis.
Objective: This study evaluated human leucocyte antigen-G gene polymorphisms in patients with periodontitis and healthy controls.Material and methods: The insertion/deletion polymorphism of 14 bp and a single nucleotide polymorphism (SNP) C > G on the position +3142 of the 3' untranslated region of the gene were analyzed in chronic periodontitis (n = 62), aggressive periodontitis (n = 24) patients and healthy individuals (n = 47).Results: Considering the 14 bp insertion/deletion, a significant deviation from Hardy-Weinberg expectations in the chronic periodontitis group was observed, but not in the other groups. No significant deviations were observed in patients and control groups considering the +3142 C > G SNP. A significant increased frequency of homozygotes for the 14 bp deletion allele was observed in the chronic periodontitis group as compared to controls. This group also presented a higher frequency of the deletion allele, which was marginally not significant. Concerning this polymorphism, no significant differences were observed between the aggressive periodontitis and healthy control groups. In addition, no significant differences were seen amongst patients and controls when considering the +3142 C > G frequencies.Conclusion: No differences were found amongst patients and controls when considering the +3142 C > G SNP haplotypes frequencies, but a significant increased frequency of homozygotes for the 14 bp deletion allele was observed in chronic periodontitis patients compared to healthy controls, suggesting a susceptibility role of this polymorphism in the pathogenesis of this condition.


Polymorphic expression of glutathione transferases A1, M1, P1 and T1 in epithelial ovarian cancer: a Serbian case-control study.
Since several studies have proposed that epithelial ovarian cancer should not be considered as a single disease entity and that it results from an accumulation of genetic changes, we aimed to assess the polymorphic expression of major cytosolic glutathione S-transferases (GSTM1, T1, A1 and P1) with respect to ovarian cancer susceptibility and aggressiveness. This case-control study was conducted on 93 newly diagnosed epithelial ovarian cancer patients and 178 healthy matched controls. The multiplex polymerase chain reaction (PCR) was used to detect homozygous deletions of GSTM1 and GSTT1 genes. Analysis of the single nucleotide polymorphism (SNP) GSTA1 C69T was performed using PCR-restriction fragment length polymorphism (RFLP), while for SNP GSTP1 Ile105Val real-time PCR was used. No significant association to ovarian cancer risk was found for individual GSTM1, GSTA1 and GSTP1 genotypes (p>0.05). However, the carriers of GSTT1-active genotype were at 2-fold higher risk of ovarian cancer development (95%CI: 1.00-4.01, p=0.049), which was even more elevated in the subgroup of patients with positive family history of cancer. Moreover, the frequency of all three GST genotypes that might be associated to ovarian cancer risk (GSTT1-active, GSTA1-active and GSTP1-referent) was significantly higher in patients than in the control group (p=0.042). Even more, patients who were carriers of combination of these three genotypes represented over 64% of the total number of patients within any of the International Federation of Gynecology and Obstetrics (FIGO) stages of ovarian cancer. This study provides supportive evidence that GSTs might affect both susceptibility and progression of ovarian cancer.


[Preparation and quality control of soybean isoflavone dropping pills].
To establish the optimized preparation procedure and study the method to determine the content for soybean isoflavone(SIF) Dropping Pills. The preparation conditions, such as the proportion between SIF and PEGs, the temperature of mixture of SIF and PEGs, dropping distance, etc., were studied with Uniform Design and One-way ANOVA. SIF was identified by TLC and the content of SIF was determined by UV spectrometry at 262 nm detection wavelength. Three batches of the prepared products meet the standards of the Chinese pharmacopoeia on dropping pills. SIF can be identified by TLC. Using UV spectrometry, the linear range of SIF was 0. 407 2 to 4. 072 g x mL(-1) and the correlation coefficient was 0. 999 8. In high, middle and low concentration, average recovery were 96. 54%, 97.27% and 97.21%, respectively (RSD were 1.3%, 0.78% and 0.71%). The preparation procedure is feasible, simple and suitable, the method established in this paper can be adopted for the quality control of SIF dropping pills, and the determination method is simple, relatively fast and accurate.


Evaluation of in vivo selective binding of [11C]doxepin to histamine H1 receptors in five animal species.
The specific binding of [(11)C]doxepin, which has been used as a radioligand for mapping histamine H(1) receptors in human brain by positron emission tomography, was evaluated in five animal species. In mice the [(11)C]doxepin uptake was reduced by treatment with cold doxepin and two H(1) receptor antagonists, but not with H(2)/H(3) antagonists. The specific binding evaluated with treatment with (+)-chlorpheniramine (H(1) antagonist) was in the range of 10-30% in mouse, rat, rabbit, and monkey, but was not detected in guinea pig.


Video coding scheme using DCT-pyramid vector quantization.
A new and effective video coding scheme for contribution quality is proposed. The CMTT/2, a joint committee of CCIR and CCITT, has proposed a video coding scheme (already approved at European level by ETS) working at 34-45 Mbit/s. Basically this proposal includes a DCT transform for spatial correlation removal and motion compensation for temporal correlation removal. The individual transform coefficients are then scalar quantized with a non uniform bit assignment. Starting from the CMTT/2 proposal, the study presents a new video coding scheme designed using a vector quantizer solution instead of the scalar one. Specifically, the pyramid vector quantization (PVQ) has been chosen as the vector quantization method as it is able to reduce the DCT coefficients Laplacian distribution. Simulation results show that the proposed video coding scheme gives the same contribution quality at 22 Mbit/s as the one obtained with the CMTT/2 proposal at 45 Mbit/s.


Currarino syndrome presenting as a cerebrospinal fluid leak from the dermal sinus tract: case report.
Currarino syndrome is an autosomal dominant condition with variable expressivity and penetrance that is associated with several classic features: sacral dysgenesis, presacral mass, and/or anorectal anomalies. The authors present a unique case in which the patient's initial presentation was a CSF leak from a sinus tract. The sinus tract was identified and disconnected from the thecal sac, obliterating the anterior sacral meningocele. This case represents a unique scenario in which Currarino syndrome manifested as a CSF leak from a dermal sinus tract.


From plants to animals; the role of plant cell death in ruminant herbivores.
Plant cell death occurring as a result of adverse environmental conditions is known to limit crop production. It is less well recognized that plant cell death processes can also contribute to the poor environmental footprint of ruminant livestock production. Although the forage cells ingested by grazing ruminant herbivores will ultimately die, the lack of oxygen, elevated temperature, and challenge by microflora experienced in the rumen induce regulated plant stress responses resulting in DNA fragmentation and autolytic protein breakdown during the cell death process. Excessive ruminal proteolysis contributes to the inefficient conversion of plant to microbial and animal protein which results in up to 70% of the ingested nitrogen being returned to the land as the nitrogenous pollutants ammonia and urea. This constitutes a significant challenge for sustainable livestock production. As it is estimated that 25% of cultivated land worldwide is assigned to livestock production, it is clear that understanding the fundamental biology underlying cell death in ingested forage will have a highly significant role in minimizing the impact of human activities. This review examines our current understanding of plant metabolism in the rumen and explores opportunities for exploitation of plant genetics to advance sustainable land use.


An overview of venus geology.
The Magellan spacecraft is producing comprehensive image and altimetry data for the planet Venus. Initial geologic mapping of the planet reveals a surface dominated by volcanic plains and characterized by extensive volcanism and tectonic deformation. Geologic and geomorphologic units include plains terrains, tectonic terrains, and surficial material units. Understanding the origin of these units and the relation between them is an ongoing task of the Magellan team.


Early deaths in newly diagnosed cases of pediatric acute leukemia: a Southwest Oncology Group Study.
A reanalysis of all ten clinical trials conducted by the Southwest Oncology Group from 1958 thorugh 1976 in newly diagnosed pediatric acute leukemia was carried out to quantify the "early death" rate (i.e., rate of deaths during the first four weeks of remission induction) and to determine factors related to these deaths. Out of 1,964 patients registered, there were 126 (6.4%) early deaths. For the 1,375 acute lymphocytic leukemia (ALL) patients only, there were 75 (5.5%) early deaths. During the last eleven years on this study (1965 through 1976), the death rate for ALL patients appears to have remained stable at five deaths per 100 patients, despite the general improvement in overall survival. The most important prognostic factor was the initial platelet count: patients with a platelet count below 25,000 had a death rate over three times higher than that of patients with a platelet count over 75,000. Infants under one year of age also had a very high early death rate (6 of 41, 15%).


Changes in the smoking behavior of elderly Mexican Americans in the Southwest from 1982-1984 to 1993-1994.
The aim of this work was to examine changes in the smoking behavior of elderly Mexican Americans in the southwestern United States from the early 1980s to the early 1990s. Data from the 1993-1994 Hispanic EPESE study (n = 2,809) on persons ages 65 to 74 and 75 to 84 residing in the five southwestern states were compared with data from the 1982-1984 Hispanic HANES study (n = 753, persons ages 55 to 74), which included a Mexican American sample from the same five southwestern states. Rates of current smoking in 1993-1994 for persons ages 65 to 74 were approximately half the rates for persons of the same age a decade earlier. Smoking rates for persons ages 75 to 84 in 1993-1994 were significantly lower than rates for persons ages 65 to 74 a decade earlier. Finally, rates for persons ages 65 to 74 in 1993-1994 were significantly lower than those for persons ages 55 to 64 in 1982-1984. Although some of the declines in smoking in recent years represent aging effects (including declines due to greater mortality among smokers), the much lower rates for same-age people (65 to 74) over the 10-year period are more significant in that they represent cohort differences. It appears that the broader public health message that is causing the general population to quit smoking is reaching the elderly Mexican American population of the Southwest.


A role for intermediate filaments in determining and maintaining the shape of nerve cells.
To date, the functions of most neural intermediate filament (IF) proteins have remained elusive. Peripherin is a type III intermediate filament (IF) protein that is expressed in developing and in differentiated neurons of the peripheral and enteric nervous systems. It is also the major IF protein expressed in PC12 cells, a widely used model for studies of peripheral neurons. Dramatic increases in peripherin expression have been shown to coincide with the initiation and outgrowth of axons during development and regeneration, suggesting that peripherin plays an important role in axon formation. Recently, small interfering RNAs (siRNA) have provided efficient ways to deplete specific proteins within mammalian cells. In this study, it has been found that peripherin-siRNA depletes peripherin and inhibits the initiation, extension, and maintenance of neurites in PC12 cells. Furthermore, the results of these experiments demonstrate that peripherin IF are critical determinants of the overall shape and architecture of neurons.


Maternal control behavior and locus of control: examining mechanisms in the relation between maternal anxiety disorders and anxiety symptomatology in children.
This study tested components of a proposed model of child anxiety and examined the mediational roles of (1) maternal control behavior, (2) maternal external locus of control, and (3) child external locus of control in the association between maternal and child anxiety. Thirty-eight clinically anxious mothers and 37 nonanxious mothers participated along with one of their children aged 6 to 14 (52.0% female; 78.7% Caucasian). Path analysis indicated that the overall model fit the data very well. Analyses also indicated that child external locus of control mediated the associations between (1) maternal and child anxiety and (2) maternal control behavior and child anxiety. Maternal anxiety was not related to maternal control behavior and maternal external locus of control was not associated with child anxiety. Findings are discussed in the context of theoretical models (e.g., Chorpita and Barlow 1998) regarding the transmission of maternal anxiety to their children and the specific roles of maternal behavior and child locus of control.


Lower endoscopy reduces colorectal cancer incidence in older individuals.
In older individuals, there are unclear effects of lower endoscopy on incidence of colorectal cancer (CRC) and of colonoscopy on site of CRC. We investigated whether sigmoidoscopy or colonoscopy is associated with a decreased incidence of CRC in older individuals, and whether the effect of colonoscopy differs by anatomic location. We performed a case-control study using linked US Veterans Affairs and Medicare data. Cases were veterans aged 75 years or older diagnosed with CRC in fiscal year 2007. Cases were matched for age and sex to 3 individuals without a CRC diagnosis (controls). We determined the number of cases and controls who received colonoscopies or sigmoidoscopies from fiscal year 1997 to a date 6 months before the diagnosis of CRC (for cases) or to a corresponding index date (for controls). The probability of exposure was modeled using generalized linear mixed equations, adjusted for potential confounders. For the analysis of CRC risk in different anatomic locations, the proximal colon was defined as proximal to the splenic flexure. We identified 623 cases and 1869 controls (mean age, 81 y; 98.7% male, 86.2% Caucasian). Among cases, 243 (39.0%) underwent any lower endoscopy (177 colonoscopies). Among controls, 978 (52.3%) underwent any lower endoscopy (758 colonoscopies). Cases were significantly less likely than controls to have undergone lower endoscopy within the preceding 10 years (adjusted odds ratio [aOR], 0.58; 95% confidence interval [CI], 0.48-0.69). This effect was significant for colonoscopy (aOR, 0.57; 95% CI, 0.47-0.70), but not sigmoidoscopy. Similar results were observed when a 5-year exposure window was applied. Colonoscopy was associated with a reduced risk of distal CRC (aOR, 0.45; 95% CI, 0.32-0.62) and proximal CRC (aOR, 0.65; 95% CI, 0.46-0.92). In a study of the US Veterans Affairs and Medicare databases, lower endoscopy in the preceding 10 years was associated with a significant reduction in CRC incidence among older veterans. Colonoscopy was associated with significant reductions in distal and proximal CRC.


Do-not-resuscitate (DNR) status and major depressive disorder (MDD): Clinical association and hospitalization outcomes.
To understand (1) the association of Major Depressive Disorder (MDD) and do-not-resuscitate (DNR) status among hospitalized patients and (2) the association of MDD and hospitalization outcomes among DNR patients. This was a cross-sectional analysis of United States Healthcare Cost and Utilization Project, Nationwide Inpatient Sample data from 2009 to 2013 for patients >18 years. To address the first objective, we used multivariable logistic regression among all hospitalized patients to compute the adjusted odds ratio (aOR) of having DNR status if patients have active MDD of varying severities after controlling for age, sex, race, suicidal ideation, and Elixhauser Comorbidity Index. To address the second objective, we used multivariable regression among patients with DNR status to compute aOR of having hospitalization outcomes such as increased length of stay, higher total charges, leaving against medical advice, and mortality if patients have MDD. Among all hospitalizations, 2.3% had DNR status. There was an inverse association between severity of MDD and having DNR status. Relative to those without MDD, patients with moderate recurrent MDD episode (aOR 0.74 (95% confidence interval (CI): 0.65-0.85) and severe recurrent MDD episode (aOR of 0.42 (95% CI: 0.37-0.48)) were significantly less likely to have DNR status. Among DNR patients, those with all severities of MDD except mild single episode MDD were >40% less likely to die during hospitalization. Among DNR patients, patients with MDD had 0.7 day longer length of stay, and >$4,500 higher total charges. Patients are less likely to have DNR status if they have active MDD. Among patients with DNR status, those with MDD are less likely to die during hospitalization than those without MDD. With current practice, depression is not associated with increased likelihood of death due to foregoing resuscitation prematurely, though the exact mechanisms of these findings need further investigation.


Antidepressants and the Risk of Cardiovascular Events in Elderly Affected by Cardiovascular Disease: A Real-Life Investigation From Italy.
The purpose of this study was to assess the possible relation between use of antidepressant (AD) drugs, that is, tricyclic ADs, selective serotonin reuptake inhibitors (SSRIs), and atypical ADs (AAs), and the risk of hospitalization for cardiovascular (CV) events among older patients with previous CV diseases. A nested case-control study was carried out among patients aged 65 years and older from 5 Italian health care territorial units who were discharged for CV disease during 2008 to 2010. The cohort was composed by 344,747 individuals, and of these, 97,739 (28%) experienced hospital admission for CV events (myocardial infarction, arrhythmia, stroke, heart failure) during follow-up (until 2014) and were included as cases. Up to 5 controls were randomly selected and matched to each. A conditional logistic regression was fitted to estimate the risk of CV events associated with ADs past or current use. A within-patient comparison was performed by the case-crossover design to account the effect of depression. Current users of SSRIs and AAs were at increased risk of CV events with odds ratios of 1.25 (95% confidence interval, 1.21-1.29) and 1.31 (1.25-1.37), respectively. An increased risk of arrhythmia and stroke was associated with current use of SSRIs and AAs, whereas an increased risk of heart failure was detected with current use of any ADs. The results were confirmed by the case-crossover approach. Evidence that AD use is associated with an increased risk of CV events in accordance with specific mechanisms of action among older people with CV disease was added by this study.


Stable source of high quality telecom-band polarization-entangled photon-pairs based on a single, pulse-pumped, short PPLN waveguide.
We demonstrate a stable source of high quality telecom-band polarization-entangled photon-pairs based on a single, pulse-pumped, short periodically-poled lithium niobate (PPLN) waveguide. Full quantum state tomographic measurement performed on the photon-pairs has revealed a very high state purity of 0.94, and an entanglement fidelity exceeding 0.96 at the low-rate-regime. At higher rates, entanglement quality degrades due to emission of multiple-pairs. Using a new model, we have confirmed that the observed degradation is largely due to double- and triple-pair emissions.


5'-AMP-activated protein kinase activity is elevated early during primary brain tumor development in the rat.
We found that adenosine 5'-monophosphate-activated protein kinase (AMPK), which is considered the "fuel sensor" of mammalian cells because it directly responds to the depletion of the fuel molecule ATP, is strongly activated by tumor-like hypoxia and glucose deprivation. We also observed abundant AMPK activity in tumor cells in vivo, using subcutaneous tumor xenografts prepared from cells transformed with oncogenic H-Ras. Such rapidly growing transplants of tumor cells, however, represent fully developed tumors that naturally contain energetically stressed microenvironments that can activate AMPK. Therefore, to investigate the induction of AMPK activity during experimental tumorigenesis, we used an established model of brain tumor (glioma) development in the offspring of rats exposed prenatally to the mutagen N-ethyl-N-nitrosourea. We observed that immunostaining for a specific readout of AMPK activity (AMPK-dependent phosphorylation of acetyl-CoA carboxylase) was prominent during N-ethyl-N-nitrosourea-initiated neurocarcinogenesis, from the occurrence of early hyperplasia (microtumors) to the emergence of large gliomas. Moreover, we observed that immunostaining for activating phosphorylation of AMPK correlated with the same stages of glioma development, notably in mitotic tumor cells in which the signal showed punctate as well as cytoplasmic patterns associated with spindle formation. Based on these observations, we propose that neurocarcinogenesis requires AMPK-dependent regulation of cellular energy metabolism.


Cyclosporin A followed by the treatment of acute exacerbation of idiopathic pulmonary fibrosis with corticosteroid.
Idiopathic pulmonary fibrosis (IPF) is a slowly progressive disease with a poor prognosis. Acute exacerbation is the worst stage in the clinical course of IPF, as the condition is unresponsive to most conventional therapies. Corticosteroids and other immunosuppressive drugs have been attempted for the treatment of acute exacerbation, but only with very limited effectiveness. This study was performed to examine the effect of cyclosporin A (CsA) on acute exacerbation of IPF. Thirteen patients with acute exacerbation of IPF were retrospectively studied. All 13 patients received pulse-therapy with methylprednisolone (1,000 mg per day for 3 days), followed by oral prednisolone (40-60 mg per day). Seven patients were received CsA (1.0-2.0 mg/kg per day) after the treatment with corticosteroids. We attempted to keep the blood trough level of CsA between 100 and 150 ng/ml. Among the 7 patients treated with CsA, 4 patients have survived for 60, 120, 276 and 208 weeks, respectively; 2 did not respond to pulse-therapy with methylprednisolone and died within 8 weeks after the start of CsA treatment. The other patient experienced re-exacerbation and died 87 weeks after the discontinuation of CsA due to the development of viral encephalitis. In contrast, all 6 patients treated without CsA died within 66 weeks after the onset of acute exacerbation. Four of these patients responded to pulse-therapy with methylprednisolone, but their condition deteriorated again while the subsequent prednisolone was being tapered. CsA seems to prevent re-exacerbation of IPF and improve the patients' chances for long-term survival.


Plasma urokinase antigen and plasminogen activator inhibitor-1 antigen levels predict angiographic coronary restenosis.
The fibrinolytic system is intimately involved in several processes that contribute to restenosis, including clot dissolution, cell migration, and tissue remodeling. However, the role of the individual activators (urokinase [uPA] and tissue plasminogen [tPA] activators) and inhibitors (plasminogen activator inhibitor [PAI-1]) of the fibrinolytic system in maintaining patency after coronary artery angioplasty and stenting is unclear. We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty (n=110) or stenting (n=49) of de novo native coronary artery lesions. Plasma samples were drawn at baseline (before angioplasty) and serially after angioplasty (immediately afterward and 6 hours, 24 hours, 3 days, 7 days, 1 month, 3 months, and 6 months afterward). Antigen and activity assays were performed for uPA, tPA, and PAI-1. Follow-up quantitative coronary angiography was performed in 92% of eligible patients. The overall angiographic restenosis rate (diameter stenosis >50%) was 31% (37% in PTCA patients, 17% in stented patients). At all time periods, including baseline, uPA antigen levels were significantly higher and PAI-1 antigen levels were significantly lower in patients with restenosis. Restenosis rates for patients in the upper tertile of baseline uPA antigen levels were 2-fold higher than for those in the lower 2 tertiles (46% versus 24% and 22%, respectively; P<0.004). In a stepwise regression multivariate analysis, obstruction diameter after the procedure and uPA antigen were significant predictors of follow-up diameter stenosis. Plasma uPA antigen levels and PAI-1 antigen levels identify patients at increased risk for restenosis after percutaneous coronary revascularization.


Aqueous Lyotropic Mesophase Behavior of Gemini Dicarboxylate Surfactants Swollen with n-Decane.
We report detailed small-angle X-ray scattering (SAXS) studies of the impact of variable n-decane loadings on the lyotropic liquid crystalline (LLC) phase behaviors of homologous bis(tetramethylammonium) gemini didecanoate surfactants TMA-7x, which derive from dimerizing decanoic acid through its α-carbon with hydrocarbyl linkers -(CH2)x- where x = 3, 4, 5, and 6. TMA-7x amphiphiles with x = 3 or 5 exhibit a strong propensity to form normal double gyroid (G) LLC network mesophases over wide surfactant hydration ranges, as compared to homologues with x = 4 or 6. On swelling aqueous TMA-7x LLC mesophases with up to 35 wt % n-decane, we demonstrate that odd-carbon linked surfactants (x = 3 or 5) form G and normal double diamond (D) phases over wide water concentration windows with T = 22-100 °C. Complementary studies of decane-swollen TMA-7x (x = 4 or 6) aqueous LLCs instead demonstrate significantly diminished network phase stability, in favor of hexagonally-packed cylinder phases and a zoo of complex quasispherical micelle packings, which include micellar C14 and C15 Laves phases (P63/mmc and Fd3(-)m symmetries, respectively) and high-symmetry hexagonally close packed (HCP) and body-centered cubic (BCC) arrangements. These rich phase behaviors are rationalized in terms of linker length parity-dependent surfactant conformations and the delicate free energy balance that guides the packing of these geometrically anisotropic amphiphiles by minimizing unfavorable water-hydrophobic contacts, maximizing ionic surfactant-headgroup counterion solvation with minimal local variations, and maximizing electrostatic cohesion within these supramolecular assemblies.


Laboratory simulation of Hg0 emissions from a snowpack.
Snow surfaces play an important role in the biogeochemical cycle of mercury in high-latitude regions. Snowpacks act both as sources and sinks for gaseous compounds. Surprisingly, the roles of each environmental parameter that can govern the air-surface exchange over snow are not well understood owing to the lack of systematic studies. A laboratory system called the laboratory flux measurement system was used to study the emission of gaseous elemental mercury from a natural snowpack under controlled conditions. The first results from three snowpacks originating from alpine, urban and polar areas are presented. Consistent with observations in the field, we were able to reproduce gaseous mercury emissions and showed that they are mainly driven by solar radiation and especially UV-B radiation. From these laboratory experiments, we derived kinetic constants which show that divalent mercury can have a short natural lifetime of about 4-6 h in snow.


MGRN1 depletion promotes intercellular adhesion in melanoma by upregulation of E-cadherin and inhibition of CDC42.
Mahogunin Ring Finger 1 is an E3-ubiquitin ligase encoded by the color gene MGRN1. Our previous in vitro and in vivo studies demonstrated that Mgrn1 deletion in mouse melanoma cells induced cell differentiation and adhesion, and decreased cell motility and invasion on collagen I, and lung colonization in an in vivo model. Here, we investigated the role of MGRN1 on human melanoma cell morphology, adhesion and expression of genes/proteins involved in an EMT-like transition. We demonstrated that wild-type BRAF human melanoma cells adopted a clustering-like morphology on collagen I, with permanent MGRN1 abrogation resulting in bigger cell clusters. Enhanced intercellular adhesion was mostly mediated by induction of E-cadherin and higher co-localization with β-catenin. Transcriptional upregulation of E-cadherin likely occurred through downregulation of the ZEB1 repressor. Finally, pulldown assays showed reduced activation of CDC42 in the absence of MGRN1, which was reverted after E-cadherin silencing. Overall, these findings highlight a new MGRN1-dependent pathway regulating melanoma cell shape, motility, and invasion potential.


Novel estrogenic action of the pesticide residue beta-hexachlorocyclohexane in human breast cancer cells.
The estrogenic action of some persistent organochlorine pesticide residues may play a role in the progression of hormonally responsive tumors of the breast and uterus. The prototypical xenoestrogen o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT) acts by binding and activating the estrogen receptor (ER). The present study focuses attention on the mechanisms through which another organochlorine compound, beta-hexachlorocyclohexane (beta-HCH), exerts estrogen-like effects in human breast cancer cells. Both o,p'DDT and beta-HCH stimulated proliferation in a dose-dependent manner in the ER-positive cell lines MCF-7 and T47D but not in the ER-negative lines MDA-MB231, MDA-MB468, and HS578T. Both compounds produced an increase in the steady state level of pS2 mRNA in MCF-7 cells. These responses were equal in magnitude to the maximal effect of estradiol, and they were inhibited by inclusion of the antiestrogen ICI164384. On the other hand, when tested in a competitive binding assay, beta-HCH did not displace 17beta-[3H]estradiol from the ER even at a concentration that was 40,000-fold higher than the tracer steroid. Furthermore, nuclear retention of the ER during homogenization procedures was induced by a 2- or 24-h treatment of MCF-7 cells with o,p'-DDT and 17beta-estradiol but not by treatment with beta-HCH; this indicates that beta-HCH nether activates the ER, nor is it converted intracellularly to an ER ligand. Transcriptional activation by beta-HCH occurs in estrogen-responsive GH3 rat pituitary tumor cells transfected with a luciferase reporter construct driven by a complex 2500-bp portion of the PRL gene promoter; this trans-activation response is inhibited by inclusion of ICI164384. However, beta-HCH is ineffective in stimulating a reporter construct driven only by a consensus estrogen response element and a minimal promoter derived from the herpes simplex virus thymidine kinase gene. Thus, beta-HCH cannot act on a simple, single estrogen response element; rather, it requires the combinatorial regulation found in a complex promoter. These data are consistent with the notion that beta-HCH stimulation of cell proliferation and gene expression is ER dependent, but its action is not through the classic pathway of binding and activating the ER. beta-HCH may represent a new class of xenobiotic that produces estrogen-like effects through nonclassic mechanisms and, therefore, may be of concern with regard to breast and uterine cancer risk.


Efficient method for controlling the spatial coherence of a laser.
An efficient method to tune the spatial coherence of a degenerate laser over a broad range with minimum variation in the total output power is presented. It is based on varying the diameter of a spatial filter inside the laser cavity. The number of lasing modes supported by the degenerate laser can be controlled from 1 to 320,000, with less than a 50% change in the total output power. We show that a degenerate laser designed for low spatial coherence can be used as an illumination source for speckle-free microscopy that is nine orders of magnitude brighter than conventional thermal light.