Low-noise phase imaging by hybrid uniform and structured illumination transport of intensity equation.
We demonstrate a new approach to the transport of intensity equation (TIE) phase retrieval method which uses structured illumination to improve low-frequency noise performance. In the hybrid scheme, two phase images are acquired: one with uniform and one with sinusoidal grating illumination intensity. The former preserves the high spatial frequency features of the phase best, whereas the latter dramatically increase the response at low spatial frequencies (where traditional TIE notoriously suffers). We then theoretically prove the design of a spectral filter that optimally combines the two phase results while suppressing noise. The combination of uniformly and structured illuminated TIE (hybrid TIE) phase imaging is experimentally demonstrated optically with a calibrated pure phase object.


Characteristics of depressive changes and anxiety in patients with essential hypertension.
Hypertension is among the world's most widespread diseases and one of the most frequent causes of mortality in the adult population. Clinical and experimental observations indicate the importance of psychic factors in the pathogenesis of hypertension. The aim of this study was to characterize depressive symptoms as well as to analyze anxiety level in patients with essential hypertension. A group of 38 patients, 17 females and 21 males, aged 20-77, the average age being 53, treated for essential hypertension diagnosed on the basis of the generally established clinical criteria were examined with the use of A.S. Zigmond's and R.P. Snaith's Hospital Anxiety and Depression Scale (HADS) and C.D. Spielberger's, R.L. Gorsuch's and R.E. Lushene's State-Trait Anxiety Inventory (STAI) in an authorized translation by J. Strelau, M. Tyskarczyk and K. Wrześniewski. Examination results received with the use of HADS reveal a moderate occurrence of depressive symptoms in patients with essential hypertension. The application of STAI enabled state and trait anxiety analysis. The examined patients are characterized by an increased level of A-State as well as an increased level of A-Trait. Patients with hypertension exhibit state anxiety in reaction to all kinds of direct threat factors. They also react with an increased level of trait anxiety as an acquired behavioral disposition. This leads to a conclusion that the examined patients' reaction is marked by the anxiety disproportionate in strength to the actual danger.


The demand for elective surgery in a public system: time and money prices in the UK National Health Service.
We construct a model of the admission process for patients from general practices for elective surgery in the UK National Health Service. Public patients face a positive waiting time, but a zero money price. Fundholding practices faced a positive money price for each patient admitted. The model is tested with data on general practice admission rates for cataract procedures in an English Health Authority. Admission rates are negatively related to waiting times and distance to hospital. Practices respond to financial incentives as predicted by the model: fundholding practices have lower admission rates than non-fundholders and respond differently to changes in waiting times and patient characteristics.


Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris.
Previous studies demonstrated that HLA-DR4 was markedly increased among Ashkenazi Jewish patients with pemphigus vulgaris (PV), almost entirely as the common Jewish extended haplotype [HLA-B38, SC21, DR4, DQw8] or as the haplotype HLA-B35, SC31, DR4, DQw8, and that HLA-DR4, DQw8 was distributed among patients in a manner consistent with dominant expression of a class II (D-region or D-region-linked) susceptibility gene. In the present study of major histocompatibility complex (MHC) haplotypes in 25 non-Jewish PV patients, DR4, DQw8 was found in 12 of the patients and DRw6, DQw5 was found in 15. Only 3 patients had neither. Only 1 of the DR4, DQw8 haplotypes was [HLA-B38, SC21, DR4, DQw8] and 2 were HLA-B35, SC31, DR4, DQw8; most were the presumed fragments (SC31, DR4, DQw8) or (SC21, DR4, DQw8) or DR4, DQw8 with some other complotype. Of the patients with DRw6, DQw5, all were DRw14, DQw5, and 6 had a rare Caucasian haplotype, HLA-Bw55, SB45, DRw14, DQw5. Four of 6 of these were found in patients of Italian extraction, as was the 1 normal example. The non-Jewish patients were of more Southern European extraction than our controls. This suggests that there are two major MHC susceptibility alleles in American patients with PV. The more ancient apparently arose on a haplotype in the Jews, HLA-B38(35), SC21(SC31), DR4, DQw8, and spread to other populations largely as D-region segments. The other arose in or near Italy on the haplotype HLA-Bw55, SB45, DRw14, DQw5 and has also partially fragmented so that many patients carry only DRw14, DQw5. The available data do not permit the specific localization of either the DR4, DQw8- or the DRw14, DQw5-linked susceptibility genes.


Continuum mechanical model of leukocytes during protopod formation.
A new continuum mechanical theory for protopod extension in leukocytes is developed. Protopod formation is an active process which is the basis for amoeboid displacement on substrates. Leukocytes may form protopods both when adhering to a substrate and when freely suspended in plasma. Therefore the required energy is derived from the cell itself. Protopods are depleted of granules and other organelles, they have a fine fibrillar ultrastructure, and they are covered by a cell membrane. They grow at about 5 micron/min until they reach a length of 4-5 micron. A period of protopod retraction follows during which granules re-enter via the protopod base by Brownian motion. Micropipette experiments have indicated that the protoplasm in the leukocyte has viscoelastic properties, whereas the protopod is stiffer and shows elastic behavior. We propose a continuum theory based on the polymerization of the actin matrix in the cell which results in gelation with a preferred orientation. It is triggered by influx of Ca++ across local regions of the cell membrane and the polymerization occurs along an interface at the base of the polymerized protopod. As cytoplasm passes through the interface it is subject both to a volumetric strain due to exclusion of granules and a shear strain due to alignment of actin molecules. The polymerization provides an active force leading to projection of the protopod and cell deformation. The base of the protopod rests on the unpolymerized cytoplasm along the interface. As the external plasma medium and the cell membrane, if it is not stretched taut, offer little resistance, the projection of the protopod proceeds outward with simultaneous unfolding of the membrane.(ABSTRACT TRUNCATED AT 250 WORDS)


Risk factors of high-grade anal intraepithelial neoplasia recurrence in HIV-infected MSM.
To assess risk factors of high-grade anal intraepithelial neoplasia (HGAIN) recurrence in a cohort of HIV-infected MSM. Consecutive HIV-infected 100 MSM with a history of successfully treated intra-anal HGAIN with electrocautery were followed with anal cytology, human papillomavirus (HPV) determination, and high-resolution anoscopy (HRA) at 3-6-month intervals. HGAIN recurrence was analyzed using Kaplan-Meier analysis. Risk factors of recurrence were assessed using Cox proportional hazards regression. The value of different tests for detecting recurrence was also assessed. After a mean follow-up of 17.6 months, 39 of the 100 patients [39%, 95% confidence interval (CI): 29-49] developed recurrent HGAIN, 24 at the previously treated site, and 15 at a different site. The probability of recurrence was 23.5% at 12 months (95% CI: 13.9-33.1) and 53.3% at 24 months (95% CI: 34.3-72.7). Risk factors of recurrence were presence of hepatitis C antibodies (hazard ratio 2.79; 95% CI: 1.04-7.53), nadir CD4 cell count less than 200 cells/μl (hazard ratio 2.61; 95% CI: 1.06-6.44), and HGAIN lesions affecting at least two octants of anal circumference (hazard ratio 8.27; 95% CI: 1.1-62). Infection by at least two HPV oncogenic strains increased the risk of recurrence (hazard ratio 2.3; 95% CI: 0.98-5.42). HRA, anal cytology, and oncogenic HPV determination test showed a sensitivity of 100, 79.4, and 86.7%, and a specificity of 57.7, 36.6, and 34.7%, respectively, for detecting HGAIN recurrence. The risk of HGAIN recurrence in HIV-infected MSM is high. Regular posttreatment follow-up of these patients is mandatory, and performing direct HRA appears to be the best strategy.


Intracranial vessels lack vasa vasorum.
A micro-corrosion technique was used to demonstrate an extensive vasa vasorum network in extracranial vessels but did not reveal this system in intracranial vessels of comparable size in three species of animals. The absence of a vasa vasorum network in cerebral vessels may result in a higher level of susceptibility to periarterial abnormalities, such as cerebral vasospasm secondary to subarachnoid hemorrhage.


Laser in situ keratomileusis versus Artisan lens implantation in correcting ametropia after penetrating keratoplasty for keratoconus.
To compare the long-term safety and efficacy of laser in situ keratomileusis (LASIK) with Artisan phakic intraocular lens implantation to correct refractive errors after penetrating keratoplasty (PK) for keratoconus. This retrospective comparative interventional case series included a total of 33 consecutive keratoconus eyes that had previous PK and received subsequent LASIK (n = 16) or Artisan lens implantation (n = 17) were included in this study. Outcome measures were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive error, and complications. Postoperatively, the UDVA of ≥20/40 was achieved in none of the LASIK group compared to 62.5% of eyes in the Artisan group (P < 0.001); the respective values for CDVA of ≥20/40 were 87.5 and 94.1% (P = 0.51). Spherical equivalent refraction decreased from - 6.97 ± 1.50 D preoperatively to - 4.20 ± 2.05 D postoperatively in the LASIK group (P < 0.001) and from - 10.79 ± 2.15 D preoperatively to - 2.13 ± 1.23 D postoperatively in the Artisan group (P < 0.001). There was no significant change in the refractive astigmatism in LASIK group (P = 0.30) or Artisan group (P = 0.11). The efficacy and safety indices were significantly better for Artisan (0.82 ± 0.34 and 1.13 ± 0.30, respectively) than for LASIK (0.22 ± 0.17 and 0.85 ± 0.24, respectively, P ≤ 0.006 for both comparisons). While refractive error changed significantly from postoperative year 3 to the final visit in the LASIK group, it remained stable in the Artisan group through follow-up period. No significant complications were observed in any group. Artisan lens implantation provided superior and stable visual outcomes compared to LASIK for the management of post PK refractive errors in keratoconus eyes.


Alterations in pulmonary mechanics and gas exchange during routine fiberoptic bronchoscopy.
Pulmonary function and arterial blood gases were measured in 35 patients undergoing routine diagnostic flexible fiberoptic bronchoscopy (FFB) either through an 8-mm endotracheal tube (ETT) or transnasally in order to investigate whether FFB changes lung function in a way which may explain why hypoxemia commonly occurs during this procedure. In these patients with moderate airway obstruction, functional residual capacity (FRC) increased significantly after inserting the ETT, after placing the FFB in the airway through the ETT, and after inserting the flexible bronchoscope transnasally. The mean increase in FRC was 30 percent in the intubated group before FFB insertion and 17 percent in the transnasal group. Removal of the FFB and ETT caused FRC to return toward the control value. Insertion of the ETT-FFB combination or transnasal FFB did not change PaO2 substantially, although following the examination, PaO2 was decreased significantly in the transnasal group but not in the intubated group. The PaO2 decreased significantly in both groups following removal of the ETT and transnasal FFB. These results suggest that placement of an FFB or ETT-FFB combination in the airway in spontaneously breathing subjects elevates FRC.


HIFU treatment time reduction in superficial tumours through focal zone path selection.
This study evaluates the hypothesis that optimising the path of a high intensity focused ultrasound (HIFU) treatment's N focal zone heating pulses can significantly reduce treatment time, and identifies the underlying bio-thermal principles. Thirty-one scanning paths were investigated using 3D simulations, with a minimum thermal dose delivered to every tumour position. Treatment time was calculated as the sum of the N, individually optimised heating and cooling periods. Tumours were superficial (skin to tumour distance ranging from 1.3 to 2.5 cm), but always deep enough so that the pre-tumour normal tissue was routinely heated to its constraint temperature (range: 42-45°C). Properties were uniform and constant, and a range of blood perfusion and phased array powers were studied. The best paths significantly reduced treatment times, with the largest gains occurring when (1) temperature superposition inside the tumour was maximised by successively heating the focal zone positions located in a 'stack' along the transducer's axis, and (2) the focal zone was moved laterally to an optimised location and another stack was applied. Stacking takes advantage of the focal zone's elongated shape, which produces axial temperature superposition within the tumour. Reduced tumour heating times also reduced energy deposition in the normal tissues, thus reducing or eliminating the need for inter-pulse cooling. HIFU treatment times can be significantly reduced by taking advantage of axial temperature superposition in tumours. Further reductions are obtained by correct choice of the transverse scan path.


[Construction of co-expression plasmid containing tPA and VEGF165 genes and its expression in VSMCs].
To construct the eukaryotic co-expression plasmid of tissue-plasminogen activator (tPA) genes and vascular endothelia growth factor165 (VEGF165) and observe its expression in vascular smooth muscle cells (VSMCs). The tPA and VEGF165 genes were cloned from hominal heart tissue with RT-PCR, and then the tPA and VEGF165 genes were cloned into eukaryotic expression plasmid pBudCE4.1 to construct the eukaryotic co-expression plasmid pBudCE4.1/tPA-VEGF165. The pBudCE4.1/tPA-VEGF165 was transfected into VSMCs via lipofection mediation. The expression levels of tPA and VEGF165 mRNAs in the transformed VSMCs were detected by RT-PCR and the expression levels of tPA and VEGF165 proteins were detected by ELISA. The size of RT-PCR product of tPA and VEGF165 genes was 1.9 kb and 576 bp respectively. Restrictive enzyme digestion analysis showed that recombinant co-expression plasmid pBudCE4.1/tPA-VEGF165 had been constructed successfully. The expression of tPA and VEGF165 at mRNA and protein levels in the transformed VSMCs and cells culture supernatant were detected respectively by RT-PCR and ELISA. The recombinant eukaryotic co-expression plasmid pBudCE4.1/tPA-VEGF165 has been successfully constructed. The tPA and VEGF165 are expressed in transformed VSMCs.


Pulmonary Hemorrhage following Edge-to-Edge Mitral Valve Repair.
Mitral valve repair with the MitraClip device has emerged as an effective treatment option for patients with severe mitral regurgitation and contraindications for surgical interventions. While the procedure is not known to cause pulmonary complications, we describe two cases of pulmonary hemorrhage following percutaneous mitral valve repair. The patients did well with supportive care and reinitiation of anticlotting agents was well tolerated after resolution of bleeding.


Fluoride content in bottled waters, juices and carbonated soft drinks in Mexico City, Mexico.
The objective of this study was to analyse 283 samples of soft drinks available in the metropolitan market of Mexico City, Mexico: 105 juices, 101 nectars, 57 carbonated drinks and 20 bottled waters. Samples of the beverages were analysed using an Orion 720A potentiometer and an Orion 9609BN F ion-specific electrode. Fluoride concentration in the above-mentioned products ranged from 0.07 to 1.42 p.p.m. It was found that fluoride concentrations varied according to the brand, flavour and presentation of the product. The highest mean concentration of fluoride was found in the juices and cola drinks (0.67 +/- 0.38 and 0.49 +/- 0.41 p.p.m., respectively). The mean fluoride concentration for carbonated drinks was 0.43 +/- 0.36 p.p.m. Bottled waters had a fluoride concentration of 0.21 +/- 0.08 p.p.m. The findings suggest that fluoride ingested through bottled drinks represents an important part of the total fluoride ingested by the population. In view of the wide variation of fluoride concentration in the tested products, it is necessary to implement regulatory guidelines for controlling its concentration in order to prevent dental fluorosis.


Effect of feeding a diet comprised of various corn silages inclusion with peanut vine or wheat straw on performance, digestion, serum parameters and meat nutrients in finishing beef cattle.
The objective of this study was to compare the feeding value, meat nutrients and associative effects of a diet comprised of various corn silages inclusion with peanut vine or wheat straw in finishing beef cattle. One hundred and eighty Simmental crossbred beef steers were blocked and assigned to the follow treatments: i) whole plant corn silage-based diet (control, WPCS), ii) mixed forages-based diet (replacing a portion of corn silage with wheat straw, WPCSW), iii) corn stalklage-based diet (CS), and iv) sweet corn stalklage-based diet (SCS). Each group consisted of 5 repeated pens with 9 steers/pen. The diets were formulated to be isonitrogenous and isoenergetic with same forage to concentrate ratio. Experimental diets were fed for 90 d. The effective ruminal degradability of dry matter and crude protein were highest for WPCS diet (p<0.05), for neutral detergent fiber was highest in SCS diet (p<0.05). The average daily gain was greater for cattle offered the WPCS diet, intermediate with WPCSW and SCS and lowest with CS (p<0.001). The concentration of non-esterified fatty acid in serum was higher for steers fed with CS and SCS diets than those offered WPCS and WPCSW steers (p<0.001). The treatments did not affect the general nutritional contents and amino acids composition of Longissimus dorsi of steers (p>0.05). The corn silage-based diet exhibited the highest feeding value. The sweet corn stalklage and wheat straw as an alternative to corn silage offered to beef cattle had limited influence on feeding value and meat nutrients. However, the value of a corn stalklage-based diet was relatively poor. To sum up, when the high quality forage resources, such as corn silage, are in short supply, or the growth rate of beef cattle decreases in the later finishing period, the sweet stalklage and wheat straw could be used as a cheaper alternative in feedlot cattle diet without sharp reducing economic benefits.


Directed Autonomic Flow: Functional Motility Fluidics.
Unidirectional coherent motion of a self-moving droplet is achieved and combined in a functional motility fluidic chip for chemical reactions via a novel and straightforward approach. The droplet shows both increased movement speeds and displacement distances without any input of energy. Nanoparticle synthesis is performed using the autonomous movement in a fluidic chip that induces transport, mixing, and collection.


In vivo gum arabic-coated tetrahydrobiopterin protects against myocardial ischemia reperfusion injury by preserving eNOS coupling.
Exogenous tetrahydrobiopterin (BH4), an indispensable cofactor of endothelial nitric oxide synthase (eNOS), supplementation has been proved to be of advantage to improve cardiovascular function. Nevertheless, due to its highly redox-sensitive and easy to be oxidized, there is an urgent need to develop an appropriate BH4 formulation for clinical therapy. Gum Arabic (GA) has been considered as an alternative biopolymer for the stabilization and coating of drugs. The effects of GA on protecting BH4 from being oxidized were investigated in a rat model of myocardial ischemia-reperfusion (I/R). Rats were subjected to 60-min of in vivo left coronary artery occlusion and varying periods of reperfusion with or without pre-ischemic GA-coated BH4 supplementation (10 mg/kg, oral). Myocardial infarction, fibrotic area and left ventricle ejection fraction were correlated with cardiac BH4 content, eNOS protein, NOS enzyme activity, and ROS/NO generation. Pretreatment of rats with GA-coated 6R-BH4, 24 h before myocardial ischemia, resulted in smaller myocardial infarction, improved left ventricular function and inhibited fibrosis, correlated with maintained high levels of cardiac BH4 content, preserved eNOS activation and dimerization, and decreased ROS generation. However in uncoated group, 6R-BH4 treatment did not reduce acute and chronic myocardial I/R injury compared with control I/R rats, which was closely related with the marked loss of myocardial BH4 levels during I/R. These findings provide evidence that in vivo pre-ischemic oral GA-coated BH4 administration preserves eNOS function secondary to maintaining cardiac BH4 content, and confers cardioprotection after I/R.


Conservation of inter-protein binding sites in RUSH and RFBP, an ATP11B isoform.
Isoforms of RUSH interact with a RING-finger binding protein (RFBP), which is a splice variant of the Type IV P-type ATPase, ATP11B. Splice arrays and RT-PCR showed that although most splice variants in RUSH and ATP11B are conserved in human and rabbit, the RFBP isoform is specific to rabbit. Interactions between the discontinuous PVITHC-HAKCPL sequence in the RING-domain of RUSH and the KVIRLIKIS sequence in the catalytic loop of RFBP were first identified with pull-down assays. Fine mapping involved probing CLIPS-constrained RING peptides with GST-tagged KVIRLIKIS. When the companion site in RFBP was fine mapped by replacement analysis with MBP-tagged RING, a four-fold increase in binding was noted for the KVIRLDKIS mutant. Direct comparison of splicing events in the RUSH and ATP11B genes between human and rabbit shows high structural stability in these protein interactions sites, which are 100% conserved in all mammalian orthologs.


Basis and new developments in the field of oxazaphosphorines.
All the research results summarized herein were gained in the attempt to improve selectivity in cancer chemotherapy: "Chemotherapeutic agents are not only ends in themselves, they are also beginnings,. . . Selectivity must be our goal and understanding its basis our guide to the future" (138). The development of the OAP cytostatics CP, IFO, TRO, and SUFO derives from the idea of applying the principle of transport form/active form to the highly reactive nitrogen mustard compounds. The desired conversion of the reactive nitrogen mustard into an inactive transport form (latentiation) was performed by chemical synthesis. The requirement for an enzymatic activation of the transport form to give the active form in the target organ cancer cell was met and has been shown to occur in a sequence of various metabolic reactions. The goal of a substantial increase in the therapeutic range of alkylating agents has been achieved with the development of the OAP cytostatics. The higher cancerotoxic selectivity is closely correlated with the cytotoxic specificity of their activated primary metabolites. A further increase in the cancerotoxic selectivity in OAPs was achieved by the development of mesna as a regional uroprotector. Mesna eliminates the danger of therapy-limiting urotoxic side effects of OAPs, allowing administration of higher dosages and more safely optimizing their therapeutic efficacy and partly overcoming resistance phenomena. The stabilization of the primary OAP metabolites (MAFO), opens up new possibilities in clinical therapy and in preclinical tests, for examination in the clonogenic stem cell test, for in vitro purging in ABMT, and for the regional therapy of tumors. A completely new type of therapy is emerging for OAP, specifically for low-dosage MAFO, as an immunomodulator, under certain circumstances, in combination with further substances, from the biological response modifier group.


Empirical Modeling of Zn/ZnO Nanoparticles Decorated/Conjugated with Fotolon (Chlorine e6) Based Photodynamic Therapy towards Liver Cancer Treatment.
The current study is based on Zn/ZnO nanoparticles photodynamic therapy (PDT) mediated effects on healthy liver cells and cancerous cells. The synthesis of Zn/ZnO nanoparticles was accomplished using chemical and hydrothermal methods. The characterization of the synthesized nanoparticles was carried out using manifold techniques (e.g., transmission electron microscopy (TEM), X-ray diffraction (XRD), and energy dispersive X-ray spectroscopy (EDS)). In order to study the biotoxicity of the grown nanoparticles, they were applied individually and in conjunction with the third generation photosensitiser Fotolon (Chlorine e6) in the in vivo model of the normal liver of the Wister rat, and in the in vitro cancerous liver (HepG2) model both in the dark and under a variety of laser exposures (630 nm, Ultraviolet (UV) light). The localization of ZnO nanoparticles was observed by applying fluorescence spectroscopy on a 1 cm² selected area of normal liver, whereas the in vitro cytotoxicity and reactive oxygen species (ROS) detection were carried out by calculating the loss in the cell viability of the hepatocellular model by applying a neutral red assay (NRA). Furthermore, a statistical analysis is carried out and it is ensured that the p value is less than 0.05. Thus, the current study has highlighted the potential for applying Zn/ZnO nanoparticles in photodynamic therapy that would lead to wider medical applications to improve the efficiency of cancer treatment and its biological aspect study.


Angina Leading to Metal in the Heart: An Interesting Case of Saphenous Vein Graft Coiling.
This is an interesting coronary angiography and interventional cardiology case of a 75-year-old Caucasian male with a prior history of coronary artery bypass surgery who presented with non-ST elevation myocardial infarction (NSTEMI) thought to be secondary to distal embolization from thrombus in large right coronary artery (RCA) vein graft aneurysms. This subsequently resulted in percutaneous intervention with coiling of the aneurysmal vein graft segments.


[In vitro activity of a combination of amoxicillin-clavulanic acid on anaerobic bacteria].
One hundred and one anaerobes isolated from clinical specimen were examined for their susceptibility to amoxicillin, alone or in combination with clavulanic acid, cefoxitin, cefotetan, cefotaxime, piperacillin and metronidazole. Tested strains were as follow: 90 Bacteroides fragilis group, 16 Bacteroides bivius and 5 Clostridium difficile. For 54 strains combination amoxicillin-sulbactam were also studied. Minimal inhibitory concentrations (MICs) were determined by agar dilution method on Wilkins-Chalgren agar. All the strains were susceptible to the combination amoxicillin-clavulanic acid. The mode MIC was 0.5 microgram/ml and 16 micrograms/ml for amoxicillin alone.


Metal-Organic Framework as a Chemosensor Based on Luminescence Properties for Monitoring Cetyltrimethylammonium Bromide and Its Application in Smartphones.
Rapid and sensitive detection of surfactants has attracted more and more attention since surfactants not only cause water pollution but also affect the health of human beings. Luminescent metal-organic frameworks combining unique optical property and inherent permanent porosity for guest-host encapsulation are widely used in fluorescence detection. Here we report a ratiometric fluorescent probe (denoted as UiO-66-NH2@PB) based on a Zr-based metal-organic framework (UiO-66-NH2) and a fluorescent dye, phloxine B (PB), for visual and fluorescent determination of cationic surfactants (cetyltrimethylammonium bromide; CTAB). The intensity ratio of dual-emission sensor exhibits a linear response to the CTAB concentrations of 0.1-17 μM and obtains a low detection limit (0.074 μM). Moreover, this method has been successfully utilized to monitor CTAB in the environmental water samples with satisfied recoveries. Importantly, this work provides a new insight into developing smartphone-based sensor to realize a rapid, on-site visual and quantification-based detection of CTAB.


Calcium levels correlate with cell cycle phase and affect the level of the cyclin B transcript in Dictyostelium discoideum.
In pre-aggregation amoebae of Dictyostelium discoideum, phenotypic differences with respect to cellular Ca2+ and cell cycle phases are known to bias post-aggregative cell-type choice. Using chlortetracycline fluorescence as an indicator, we found that cellular Ca2+ is highest at the S phase of the cell cycle. Upon increasing the level of Ca2+ with the help of the calcium ionophore A23187, there is a significant decrease in the cyclin B (clb1) mRNA level; the cdc2 mRNA level shows a marginal decrease. These results suggest that the effect of Ca2+ and the cell cycle on cell fate could be exerted at the level of transcription, or message stability, of specific genes.


Interleukin-2 killer cells: in vitro evaluation of combination with prothymosin alpha.
Interleukin-2 (IL-2) is a potent inducer of lymphokine-activated killer (LAK) activity against both NK-sensitive and NK-resistant tumor cell lines. IL-2 therapy has been associated with clinical responses, but these responses have occurred only with high, toxic doses of the cytokine. Since prothymosin alpha (ProT alpha) is able to enhance the spontaneous NK activity of cells from normal donors, we studied the effect of ProT alpha on LAK activity by IL-2. The lysis of K562 and Daudi cells by effector cells cultured with IL-2 was increased time dependently when cultures also contained ProT alpha. PBLC was separated by discontinuous density centrifugation in the LGL-enriched fractions. Within the CD16+ population, all effector cell precursors were CD2+, but the effector population after IL-2 or IL-2 + ProT alpha activation also contained CD16+CD2- cells; the CD2 molecule is thus indispensable for induction of LAK activity by IL-2 or IL-2 + ProT alpha but not for the action of activated LAK cells (or for the enhancing effect of ProT alpha). Within the CD3- CD16+ LGL population, 5 micrograms/ml ProT alpha plus 50 U/ml IL-2 was able to induce p70 IL-2R expression to a similar extent to 100 U/ml of IL-2. The use of ProT alpha to enhance the induction of LAK activity by IL-2 may be able to improve immunotherapy of cancer.


Future directions for EPA Superfund research.
The EPA Office of Research and Development (ORD) identifies and prioritizes future research areas through a Waste Research Coordination Team. The team works together to plan the ORD Superfund research program, and it has members from each of the ORD laboratories as well as representatives from the Superfund office. Superfund scientists have identified several research topics in applied research areas to improve risk assessment methods and reduce uncertainty in site-specific risk assessments. Research areas include: dermal exposure models and toxicity values, improved methods for exposure factors, pharmaco-kinetic dose-response models, bioavailability and statistical methods. This paper presents ORD future research plans in response to these identified research areas.


A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2 H,3 H-pyrrolo[3,2- b]pyridin-1-yl)-2-[(2 R,5 R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660).
Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP-XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate 27 (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423).


Double transition scenario for anomalous diffusion in glass-forming mixtures.
We study by molecular dynamics computer simulation a binary soft-sphere mixture that shows a pronounced difference in the species' long-time dynamics. Anomalous, power-law-like diffusion of small particles arises that can be understood as a precursor of a double-transition scenario, combining a glass transition and a separate small-particle localization transition. Switching off small-particle excluded-volume constraints slows down, rather than enhances, small-particle transport.


Sac I Restriction Fragment Length Polymorphism (RFLP) related to the human CST2 gene.
Restriction Fragment Length Polymorphism (RFLP) related to cystatin gene (CST) family was detected in the Japanese population by using restriction enzyme Sac I. A polymorphic site, located at 0.9 kb from the 3' end of the CST2 gene, revealed a two allele polymorphism with band sizes of 3.5 kb and 8.3 kb by hybridization with probe including exon 2 of the CST1 gene. The gene frequencies in the Japanese population were 0.326 for 3.5 kb allele and 0.674 for 8.3 kb allele (n = 86). The phenotypes of the polymorphism showed no association with the previously reported electrophoretic cystatin SA protein phenotypes.


Massive haemorrhage from the vallecula: a diagnostic difficulty. Case report.
A case is presented of massive bleeding from a vessel in the vallecula. This was confused with haemoptysis and haematemesis. The bleeding may have resulted from trauma to the vessel during intubation for emergency surgery. 25 units of blood were transfused before the site of the bleeding was identified and controlled by diathermy coagulation.


The characteristics and training of professionals in cancer prevention and control: a survey of theAmerican Society for Preventive Oncology.
To secure continuous stewardship in the field of cancer prevention requires in part training the next generation of scientists and practitioners effectively. We characterized members and meeting registrants of the American Society for Preventive Oncology and assessed their career needs using an electronic survey. From 380 valid email addresses, 233 respondents (61%) included 143 physicians and 81 respondents with other doctorates. More than one third worked at cancer centers (36%), while others worked at schools of medicine (25%) and public health (17%) and other institutions and businesses (22%). Among all respondents, 52% reported having at least one mentor but time spent advising by mentors was generally low. Many were less than satisfied with the amount of mentoring received (44%) and 52% reported interest in matching with an American Society for Preventive Oncology mentor. All were interested in grantsmanship training but junior and senior respondents differed in their preference for other topics, reflecting needs that change with career advancement. Other analyses focused on aspects of institutional commitment, which did not differ by type of degree, even after age adjustment. However, by gender and degree, men were completely supported by institutional funds more often than women among non-medical doctorates [age-adjusted odds ratio (OR) = 3.3, 95% confidence interval (CI) = 1.1-9.8] but not among physicians (age-adjusted OR = 1.3, 95% CI = 0.5-3.1). Men were also more often in tenure-track positions than women (age-adjusted OR = 1.9, 95% CI = 1.1-3.3). In sum, addressing the career development needs of future leaders in the field by providing career and mentoring sessions at annual meetings may help individuals in the field and enrich the discipline overall.


Presentation of Novel Hybrid Algorithm for Detection and Classification of Breast Cancer Using Growth Region Method and Probabilistic Neural Network.
Mammography is a significant screening test for early detection of breast cancer, which increases the patient's chances of complete recovery. In this paper, a clustering method is presented for the detection of breast cancer tumor locations and areas. To implement the clustering method, we used the growth region approach. This method detects similar pixels nearby. To find the best initial point for detection, it is essential to remove human interaction in clustering. Therefore, in this paper, the FCM-GA algorithm is used to find the best point for starting growth. Their results are compared with the manual selection method and Gaussian Mixture Model method for verification. The classification is performed to diagnose breast cancer type in two primary datasets of MIAS and BI-RADS using features of GLCM and probabilistic neural network (PNN). Results of clustering show that the presented FCM-GA method outperforms other methods. Moreover, the accuracy of the clustering method for FCM-GA is 94%, as the best approach used in this paper. Furthermore, the result shows that the PNN methods have high accuracy and sensitivity with the MIAS dataset.


Efficacy of Complementary Therapies in the Quality of Life of Breast Cancer Survivors.
Breast cancer (BC) is the most common cancer diagnosed in women and the second most common cancer overall, ranking as the fifth cause of death from cancer. The chronicity of the disease produces long-term physiological and psychological manifestations, which adversely affect the quality of life of the individual. The primary treatment while managing cancer presents with various debilitating side effects. With the recent advances in treatment techniques that have improved the survival rate, patients suffer from continuing posttreatment complications. Patients seem to cope well with the stress of treatment of BC and sustain a normal life; however, the deterioration in physical well-being makes the patient functionally inefficient. Exercise has been proven to be an effective, safe, and feasible tool in combating the adverse effects of treatment, prevents complications and decreases the risk of BC-specific mortality. This review briefly presents an overview of the burden of the disease and its management strategies. Owing to the heterogeneity of the population and the multitude of therapies they receive, the response of each patient to treatment is different and so is the magnitude of adverse effects. The review discusses the late sequelae following treatment and evidence supporting the role of physical activity in their management. In conclusion, there is a need for personalized physical activity plans to be developed to suit the individual and their circumstances.


Switch to unusual amino acids at codon 215 of the human immunodeficiency virus type 1 reverse transcriptase gene in seroconvertors infected with zidovudine-resistant variants.
Sequences of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) domain were determined by direct sequencing of HIV-1 RNA in successive plasma samples from eight seroconverting patients infected with virus bearing the T215Y/F amino acid substitution associated with zidovudine (ZDV) resistance. At baseline, additional mutations associated with ZDV resistance were detected. Three patients had the M41L amino acid change, which persisted. Two patients had both the D67N and the K70R amino acid substitutions; reversion to the wild type was seen at both positions in one of these patients and at codon 70 in the other one. Reversion to the wild type at codon 215 was observed in only one of eight patients. Unusual amino acids, such as aspartic acid (D) and cysteine (C), appeared at position 215 in four patients during follow-up. These variants isolated by coculturing were sensitive to ZDV. Overgrowth of these variants suggests that they have better fitness than the original T215Y variant. Intraindividual nucleoside substitutions over time were 10 times more frequent in codons associated with ZDV resistance (41, 67, 70, 215, and 219) than in other codons of the RT domain. The predominance of nonsynonymous substitutions observed over time suggests that most changes reflect adaptation of the RT function. The variance in sequence evolution observed among patients, in particular at codon 215, supports a role for chance in the evolution of the RT domain.


DEVELOPMENTAL QUANTITATIVE GENETICS AND THE EVOLUTION OF ONTOGENIES.
A model is presented which permits integration of developmental information into genetic discussions about evolutionary change in morphology. Development of a trait is described in terms of an ontogenetic trajectory whose properties are defined by a small number of parameters. Some evolutionary aspects of development are examined from the perspective of this quantitative genetic model. Particular attention is given to the developmental origin of pleiotropic effects, developmental constraints, heterochrony, and the growth and morphogenesis of complex morphologies. The role of genetic maternal effects in mammalian development is briefly examined, particularly as it relates to selection on developmental traits.


Inductively coupled wireless RF coil arrays.
As the number of coils increases in multi-channel MRI receiver-coil arrays, RF cables and connectors become increasingly bulky and heavy, degrading patient comfort and slowing workflow. Inductive coupling of signals provides an attractive "wireless" approach, with the potential to reduce coil weight and cost while simplifying patient setup. In this work, multi-channel inductively coupled anterior arrays were developed and characterized for 1.5T imaging. These comprised MR receiver coils inductively (or "wirelessly") linked to secondary or "sniffer" coils whose outputs were transmitted via preamps to the MR system cabinet. The induced currents in the imaging coils were blocked by passive diode circuits during RF transmit. The imaging arrays were totally passive, obviating the need to deliver power to the coils, and providing lightweight, untethered signal reception with easily positioned coils. Single-shot fast spin echo images were acquired from 5 volunteers using a 7-element inductively coupled coil array and a conventionally cabled 7-element coil array of identical geometry, with the inductively-coupled array showing a relative signal-to-noise ratio of 0.86 +/- 0.07. The concept was extended to a larger 9-element coil array to demonstrate the effect of coil element size on signal transfer and RF-transmit blocking.


Submicro-pillars and holes from the depth-wise Talbot images of a conical phase mask.
We construct two-dimensional arrays of submicro-pillars and holes from the depth-wise Talbot images of a conical phase mask in a photoactive layer prepared on a quartz substrate. In contrast to the conventional Talbot lithography employing only one image in the photoactive layer, two images of the phase mask are produced in a depth-wise manner such that the pillar patterns are in the primary image plane while the hole patterns in the secondary image plane according to the penetration depth of the exposure energy. The conical symmetry plays a critical role in producing the covariant patterns of the phase mask in the photoactive layer through the suppression of higher orders of diffraction. Our two image-type approach is simple and versatile for producing different kinds of periodic structures for photonic applications and surface engineering on a micrometer-to-nanometer scale.


Insights into Antibonding Induced Energy Density Enhancement and Exotic Electronic Properties for Germanium Nitrides at Modest Pressures.
Here, the electronic and bonding features in ground-state structures of germanium nitrides under different components that not accessible at ambient conditions have been systematically studied. The forming essence of weak covalent bonds between the Ge and N atom in high-pressure ionic crystal Fd-3 m-Ge3N4 is induced by the binding effect of electronic clouds originated from the Ge_ p orbitals. Hence, it helps us to understand the essence of covalent bond under high pressure, profoundly. As an excellent reducing agent, germanium transfer electrons to the antibonding state of the N2 dimer in Pa-3-GeN2 phase at 20 GPa, abnormally, weakening the bonding strength considerably than nitrogen gap (N≡N) at ambient pressure. Furthermore, the common cognition that the atomic distance will be shortened under the high pressures has been broken. Amazingly, with a lower range of synthetic pressure (∼15 GPa) and nitrogen contents (28%), its energy density is up to 2.32 kJ·g-1, with a similar order of magnitude than polymeric LiN5 (nonmolecular compound, 2.72 kJ·g-1). It breaks the universal recognition once again that nitrides just containing polymeric nitrogen were regarded as high energy density materials. Hence, antibonding induced energy density enhancement mechanism for low nitrogen content and pressure has been exposed in view of electrons. Both the highest occupied molecular orbitals (HOMO) and the lowest unoccupied molecular orbitals (LUMO) are usually the separated orbitals of N_π* and N_σ*, which are the key to stabilization. Besides, the sp2 hybridizations that exist in N4 units are responsible for the stability of the R-3 c-GeN4 structure and restrict the delocalization of electrons, exhibiting nonmetallic properties.


Accelerated sequence divergence of conserved genomic elements in Drosophila melanogaster.
Recent genomic sequencing of 10 additional Drosophila genomes provides a rich resource for comparative genomics analyses aimed at understanding the similarities and differences between species and between Drosophila and mammals. Using a phylogenetic approach, we identified 64 genomic elements that have been highly conserved over most of the Drosophila tree, but that have experienced a recent burst of evolution along the Drosophila melanogaster lineage. Compared to similarly defined elements in humans, these regions of rapid lineage-specific evolution in Drosophila differ dramatically in location, mechanism of evolution, and functional properties of associated genes. Notably, the majority reside in protein-coding regions and primarily result from rapid adaptive synonymous site evolution. In fact, adaptive evolution appears to be driving substitutions to unpreferred codons. Our analysis also highlights interesting noncoding genomic regions, such as regulatory regions in the gene gooseberry-neuro and a putative novel miRNA.


Characterization and extinction measurement of potassium terbium fluoride single crystal for high laser power applications.
High optical quality of potassium terbium fluoride, KTb3F10 (KTF), crystals are characterized and tested for extinction at high laser powers up to 400 W. The measured Verdet constant of the crystal is comparable with that of terbium gallium garnet (TGG) crystal. KTF crystals show high extinction at high incident power and an order of magnitude smaller absorption with respect to TGG, making it a superior crystal for high laser power applications.


[Molecular actors in Alzheimer's disease: which diagnostic and therapeutic consequences?].
Alzheimer's disease is a neurodegenerative disorder characterized by neuropathological lesions: amyloid deposits and neurofibrillary degeneration. However, the links between these two brain hallmarks are still poorly understood. Until now, mainly amyloid pathology has been targeted un many clinical trials without any success. Both new therapeutic strategies and diagnosis improvement are needed.


Proteomic Differences between Listeria monocytogenes Isolates from Food and Clinical Environments.
Listeria monocytogenes is an organism associated with a wide range of foods. It causes listeriosis, a severe illness that mainly affects people with weakened immune systems. Proteomic profiles of three different L. monocytogenes isolates were studied using 1D SDS PAGE, 2DE and mass spectrometry. The protein banding patterns generated by 1D SDS PAGE of three strains of L. monocytogenes were found to be similar. Visual observations from 2DE gel maps revealed that certain spots appeared to have intensity differences. Key differences in proteins synthesis of three strains of L. monocytogenes were found using the PDQest TM 2DE Analysis software. Comparison showed that the clinical isolate (strain SB92/844) had 53.4% and 53.9% protein profile similarity with dairy isolate (strain V7) and seafood isolate (SB92/870), respectively. The identity of selected protein spots was achieved using MALDI-TOF and ion trap mass spectrometry. It was found that certain identified proteins (i.e., a major cold shock protein and superoxide dismutase) were expressed differently between two local strains of L. monocytogenes (SB92/844, SB92/870) and one strain from overseas (V7).


TRPM8 and RAAS-mediated hypertension is critical for cold-induced immunosuppression in mice.
Mechanisms underlying cold-induced immunosuppression remain unclear. Here we found that cold exposure leads to transient receptor potential melastatin 8 (TRPM8)-dependent, renin-angiotensin-aldosterone system (RAAS)-mediated hypertension, which subsequently induces small molecule and fluid extravasation, increases plasma Ig levels, and elicits immunosuppression. An effect is similar to the clinically-used immunosuppressive treatments of intravenous immunoglobulin (IVIg) against various inflammatory diseases, such as immune thrombocytopenia (ITP). Essential roles of TRPM8 and Ig in cold-induced immunosuppression are supported by the cold-mediated amelioration of ITP and the cold-mediated suppression of bacterial clearance, which were observed in wild-type mice but not in Ig- and TRPM8-deficient mutants. Treatment with antihypertensive drugs aliskiren and losartan drastically reversed high plasma Ig levels and ameliorated cold-induced immunosuppression, indicating the involvement of the RAAS and hypertension. These results indicated that the natively increased plasma Ig level is associated with immunosuppression during periods of cold exposure, and antihypertensive drugs can be useful to manage cold-induced immunosuppression.


Preterm birth and visual development.
Visual impairment, oculomotor abnormalities, and refractive error are prevalent among children with a history of preterm birth. These conditions may result from exposure of the immature visual system to early visual stimulation, from nutritional deficits that occur following the abrupt loss of placental maternal-to-fetal transfer of essential nutrients, and as secondary effects of systemic disease or complications associated with preterm birth. This chapter provides an overview of the structural and functional maturation of the visual system of the healthy preterm infant and of several forms of visual impairment that are prevalent in the low birth weight population.


A new triterpenoid saponin from Ardisia gigantifolia.
A new triterpenoid saponin, named 3-O-β-d-glucopyranosyl-(1 → 3)-β-d-xylopyranosyl-(1 → 2)-[α-l-rhamnopyranosyl-(1 → 3)]-β-d-glucopyranosyl-(1 → 4)-[β-d-glucopyranosyl-(1 → 2)]-α-l-arabinopyranosyl-3β,16α,28,30-tetrahydroxy-olean-12-ene (1), along with four known triterpenoids (2-5), was isolated from the rhizomes of Ardisia gigantifolia. Their structures were elucidated by spectroscopic methods. Compounds 1-4 showed cytotoxic activity against Hela, EJ, BCG, and HepG-2 cell lines. The percentage of early apoptotic cells after treatment with 1 was significantly increased compared with control cells (p < 0.05).


Stability of an ion channel in lipid bilayers: implicit solvent model calculations with gramicidin.
Gramicidin is a helical peptide, 15 residues in length, which dimerizes to form ion-conducting channels in lipid bilayers. Here we report calculations of its free energy of transfer from the aqueous phase into bilayers of different widths. The electrostatic and nonpolar contributions to the desolvation free energy were calculated using implicit solvent models, in which gramicidin was described in atomic detail and the hydrocarbon region of the membrane was described as a slab of hydrophobic medium embedded in water. The free energy penalties from the lipid perturbation and membrane deformation effects, and the entropy loss associated with gramicidin immobilization in the bilayer, were estimated from a statistical thermodynamic model of the bilayer. The calculations were carried out using two classes of experimentally observed conformations: a head-to-head dimer of two single-stranded (SS) beta-helices and a double-stranded (DS) intertwined double helix. The calculations showed that gramicidin is likely to partition into the bilayer in all of these conformations. However, the SS conformation was found to be significantly more stable than the DS in the bilayer, in agreement with most of the experimental data. We tested numerous transmembrane and surface orientations of gramicidin in bilayers of various widths. Our calculations indicate that the most favorable orientation is transmembrane, which is indeed to be expected from a channel-forming peptide. The calculations demonstrate that gramicidin insertion into the membrane is likely to involve a significant deformation of the bilayer to match the hydrophobic width of the peptide (22 A), again in good agreement with experimental data. Interestingly, deformation of the bilayer was induced by all of the gramicidin conformations.


Body image in middle-aged HIV-infected and uninfected women.
We assessed factors associated with negative body image among 225 HIV-infected and 207 uninfected women. Standardized interviews obtained sociodemographic data and elicited agreement with the statement: 'Overall I am satisfied with my body shape'. Height and weight were measured. Overall, 39% of the women were obese and 47% had a negative body image. Factors independently associated with negative body image were HIV-infection, BMI, and depression. Given the high prevalence of obesity and negative body image, interventions aimed at assisting women with weight loss are warranted.


Analytical and Clinical Evaluation of Chemiluminescent Carcinoembryonic Antigen (CEA) by HISCL-5000 Immunoanalyzer.
The carcinoembryonic antigen (CEA) is coupled with a diagnosis and prognosis for cancers METHODS: The analytical performance of CEA by chemiluminescent immunoassay (HISCL-5000, Sysmex, Kobe, Japan) was evaluated on the basis of precision, linearity, trueness, and method comparison. Clinical evaluation was performed by area under the receiver operating characteristic curve (AU-ROC) curve analysis for lung, stomach and colorectal cancers. Total coefficient of variation (CV) (5.039% to 5.632%), linearity (0.5 to 982 ng/mL) and the percentage bias by trueness verification were less than desirable specifications for imprecision (6.4%) and bias (14.3%). The regression equation was y=0.354+0.957x(r=0.968) from method comparison. AUROC for lung, stomach, and colorectal cancers compared with normal healthy control ranged from 0.908 to 0.967 (cut-off 4.50 to 4.71 ng/mL), and compared with non-malignant benign disease, ranged from 0.578 to 0.721 (cut-off 8 to 20.70 ng/mL). CEA by HISCL-5000 immunoassay provided reliable performance. Comorbidities should be considered for interpretation of CEA.


Detrimental effect of dietary sodium and beneficial effect of dietary magnesium on glomerular changes in cyclosporin-A-treated spontaneously hypertensive rats.
Cyclosporin A (CsA) causes renal magnesium wasting, hypertension, and occasionally irreversible renal damage. We examined the effect of dietary sodium and magnesium on renal histology in spontaneously hypertensive rats (SHR) receiving CsA. Forty-six 8-week-old SHR were divided into six groups and given different dietary levels of sodium (low 0.3%, high 2.6%) and magnesium (low 0.2%, high 0.6%). Low-dose CsA (5 mg/kg/d) was given subcutaneously for 6 weeks in four groups. Systolic blood pressure, serum creatinine, degree of proteinuria, and renal tissue CsA and calcium concentrations were determined. Kidney wet weight to total body-weight ratio was calculated as an index of renal hypertrophy. Renal histological alterations were scored according to glomerular changes: 100 glomeruli were assigned for severity of change a score from 0 to 3. The number of affected glomeruli was multiplied by the damage score to obtain a damage index. In the CsA-treated high-sodium diet group systolic blood pressure and glomerular damage index were increased, and renal hypertrophy was the most common. These changes were prevented by oral magnesium supplementation. The glomerular damage index correlated positively with increases in systolic blood pressure, serum creatinine, proteinuria, and renal calcium concentration. Dietary sodium enhanced CsA-induced functional and morphological renal changes in SHR and aggravated hypertensive renal arteriolar and glomerular lesions. Dietary magnesium supplementation protected against the deleterious effects of sodium and CsA.


Clinical evaluation of a small-volume infusion system in surgical intensive care patients.
This study evaluated flow-rate accuracy, safety, and dependability of an infusion system manufactured by the 3M Company. The Small Volume Infusion (SVI) system is portable and consists of a mechanically powered infuser, calibrated flow-regulating set, and syringe. Intravenous fluids and drugs were administered to six surgical intensive care patients. Forty-one trials were carried out at infusion rates of 1, 10, or 30 ml/h. Flow rate varied less than or equal to 10 percent from the intended infusion rate in the majority of trials. One patient experienced pain at the injection site and one malfunction occurred. The SVI system is a safe, dependable alternative method for the administration of intravenous fluids and drugs. The device may prove to be particularly useful for the administration of drugs not requiring changes in flow rate during infusion or in situations where fluid restriction is desirable.


Diagnosis of malignant catarrhal fever by polymerase chain reaction amplification of alcelaphine herpesvirus 1 sequence.
We derived sequence information from cloned HindIII fragment "D" of alcelaphine herpesvirus 1 strain WC11, an agent of malignant catarrhal fever (MCF). Based on this sequence, oligonucleotide primers were selected and synthesized for use in a polymerase chain reaction amplification assay. These primers were used to test samples of total nucleic acids isolated from multiple tissues taken from an Indian gaur (Bos guarus gaurus) at the San Diego Wild Animal Park in San Diego, California (USA) which had clinical signs of a natural infection of MCF. Six of eight tissue samples examined had amplifiable sequences present. A nucleic acid probe complementary to the sequence of the original clone between the primer sites also was synthesized and used to confirm the identity of the amplified viral sequences, thus providing a diagnosis of MCF at the molecular level.


CdO/ZnO core/shell nanostructures grown from single molecular precursors.
Quadrilateral CdO nanoparticles were grown from cadmium cupferronate complex by injecting the precursor dissolved in octylamine into trioctylamine at 220 and 250 degrees C. CdO/ZnO core/shell structures were synthesized with a method similar to that of growing CdO cores by injecting the shell precursor following the growth of cores. The shell growth temperature was adjusted from 160 to 130 degrees C, and the shell precursor supply speed was adjusted from 4 to 8 ml/h. The obtained nanostructures were characterized by X-ray diffraction, high resolution transmission electron microscope, and ultraviolet-visible spectrophotometer. No core/shell structures formed if the shell precursor injection speed was as high as 8 ml/h. A very thin layer of ZnO shells would form on CdO cores if the shell precursor was injected at a speed of 4 ml/h at temperature of 160 degrees C, and the shells had good crystal quality. CdO/ZnO core/shell nanostructures were inclined to be spherical, and no homogeneous formation of ZnO nanoparticles was observed if the shell precursor injection temperature was lowered to 130 degrees C.


Revisiting N-to-O acyl shift for synthesis of natural product-like cyclic depsipeptides.
Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored in synthetic cyclic peptides. Herein we investigate a cyclic peptide scaffold able to undergo an N-O acyl rearrangement. Upon acylation of the amine with diverse carboxylic acids, the resulting cyclic depsipeptides displayed favorable cellular permeability and a conformation similar to the parent peptide. The rearrangement was found to be scaffold and conformation dependent as evidenced by molecular dynamics experiments.


Y chromosome haplogroups may confer susceptibility to partial AZFc deletions and deletion effect on spermatogenesis impairment.
Partial AZFc deletions related to testis-specific gene families are common mutations of the Y chromosome, but their contribution to spermatogenic impairment is still unresolved, and the risk factors for the formation of the deletions remain unknown. With this in mind, we investigated the possible association between Y chromosome haplogroups and predisposition to partial AZFc deletions and their effect on spermatogenesis in a Chinese population. The haplogrouping was carried out using 12 polymorphic loci on the Y chromosome in 269 non-AZFc-deleted controls with an unknown spermatogenic status and 214 men with a partial AZFc deletion defined by the absence of the sequence-tagged site and sequence family variant loss of the DAZ and CDY1 genes. In the latter group, 57 men had normozoospermia and 157 men had azoo/oligozoospermia. Among these, 122 had a de novo partial AZFc deletion. Y haplogroup distribution differed significantly between men with a de novo partial AZFc deletion and the control group, and between men with a specific subtype of the partial AZFc deletions and the control group. Further, partial AZFc deletions gave rise to spermatogenesis impairment in some Y haplogroups. The findings indicate that some monophyletic Y chromosomes may be associated with predisposition to specific subtypes of partial AZFc deletion and adverse effect on spermatogenesis. Although these deletions were not confirmed with gene dosage analysis, the results suggest that Y chromosome background is an important factor that affects partial AZFc deletion formation and its contribution to spermatogenic failure.


The production of novel root compounds in children with specific language impairment.
This study examined ten children with specific language impairment (SLI), 16 normally developing children, and ten adults for the production of novel root compounds. The participants were asked to invent names for pictures of 24 pairs of contrasting, novel objects. For half of the pictures, the context supported a grammatical novel root compound, 16 contexts supported only an ungrammatical compound, and eight contexts supported a marginally grammatical compound. All participants used novel root compounds in grammatical contexts and relatively few compounds in ungrammatical contexts. The children with SLI used the information presented in the experimental probes less frequently than the normal controls. In addition, the children with SLI made more word-order errors in their production of novel compounds. However, they were as likely as their normal counterparts to resist the use of regular plural markers within compounds. The results of this study support a difficulty associated with processing linguistic information on the part of the children with SLI.


Emissions from single filaments in air triggered by tailored background energy flows.
We investigated emission patterns from single or few filaments in air created by femtosecond laser pulses with spatially modulated wavefronts. For 800 nm filaments, spiral emissions can be obtained in the infrared. Time-resolved analysis of the corresponding dynamics of the energy surrounding the filament reveals stable energy flows with angular momentum that interact with the filament and with each other. Changing this energy distribution by modulation of the wavefront of the initial laser pulse directly affects the emission behavior of the filament.


The emergence of the creative ager - On subject cultures of late-life creativity.
In the last fifteen years, research on aging has seen a new interest in creativity in later life. While late-life creativity has often been described as a method to unpack the potential of older adults in the face of demographic change, this newfound interest is arguably linked to the commodification of late-life creativity itself in terms of innovation and productivity. These new modes of creativity might then also establish new ways to age. Has the homo aestheticus spread into old age? To explore this question, this paper first lays out a praxeology of late-life creativity. In this framework, creativity as well as age is understood as a social practice through which the artwork as well as the (older) artist is continuously produced. Second, this paper draws upon data from thirteen semi-structured interviews with older adults regularly involved in creative practices in their everyday lives. Using the documentary method, data shows how older adults describe the creative practice and what meanings they attach to growing older within these practices. Analyzing subject cultures that emerge from creativity in later life shows how creative practice calls for a specific self-image that is centered around productivity, the preservation of field positions despite growing older and active as well as anti-aging. Studying late-life creativity through a praxeological lens allows for critically evaluating current modes of creativity and the normative positions that are inherent in these practices.


Human milk vacuolating cytotoxin A immunoglobulin A antibodies modify Helicobacter pylori infection in Gambian children.
We collected data, including the weights, urea breath test results, and presence of maternal milk cytotoxin-associated gene-specific and vacuolating cytotoxin A-specific immunoglobulin A monthly from 48 mothers and infants (to 44 weeks of age) in The Gambia. In all, 11 children (23%) had negative urea breath test results, and 37 (77%) had positive results. Weight loss associated with Helicobacter pylori colonization was restricted to children whose mothers did not produce anti-vacuolating cytotoxin A antibodies in their milk (P=.028, by t test).


The pathobiochemistry of nitrogen dioxide.
Nitrogen dioxide (*NO2) is an oxidizing free radical which can initiate a variety of destructive pathways in living systems, and several diseases are suspected to be connected with both exogenously and endogenously formed *NO2. Peroxynitrite (ONOO-/ONOOH) is believed to be an important endogenous source of *NO2 radicals, but other sources, among them enzymatically ones, have been identified recently. It also became clear during the last few years that in vivo formation of 3-nitrotyrosine strictly depends on the availability of *NO2 radicals. Since nitrogen dioxide is a very toxic compound an arsenal of antioxidants (e.g. vitamin C, glutathione, vitamin E, and beta-carotene) must eliminate this harmful radical in vivo. Here the recently identified superoxide (O2*-)-dependent formation of peroxynitrate (O2NOO-) and the central role of vitamin C are of special importance.


Effects of analog and digital filtering on auditory middle latency responses in adults and young children.
Effects of analog high pass (HP) filtering were compared with those of zero phase-shift digital filtering on the auditory middle latency responses (MLR) from nine adults and 16 young children with normal hearing. Analog HP filtering exerted several prominent effects on the MLR waveforms in both adults and young children, such as suppression of Po (ABR), enhancement of Nb, enhancement or emergence of Pb, and latency decrements for Pa and the later components. Analog HP filtering at 20 Hz produced more pronounced waveform distortions in the responses from young children than from adults. Much greater latency decrements for Pa and Nb were observed for young children than for adults in the analog HP-filtered responses at 20 Hz. A large positive peak (Pb) emerged at about 65 ms after the stimulus onset. From these results, the use of digital HP filtering at 20 Hz is strongly recommended for obtaining unbiased and stable MLR in young children.


Poly(vinylidene Fluoride-Hexafluoropropylene) Porous Membrane with Controllable Structure and Applications in Efficient Oil/Water Separation.
Poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP) porous membranes are fabricated via thermally induced phase separation (TIPS) with mixed diluent (dibutyl phthalate (DBP)/dioctyl phthalate (DOP)). The effects of mixed diluent are discussed in detail in term of morphology, mean pore size, selective wettability, etc. The results show that the membrane structure changes from spherulitic to bicontinuous with the change of DBP/DOP ratio. It is also found that the degree of crystallization decreases with the decrease of DBP/DOP ratio in mixed diluent. When liquid-liquid (L-L) phase separation precedes solid-liquid (S-L) phase separation, the obtained membranes have outstanding hydrophobicity and lipophilicity, excellent mechanical property. Additionally, the PVDF-HFP hybrid membranes are prepared with silica (SiO₂) particles and the effect of SiO₂ content on structure and properties is discussed. It is found that the PVDF-HFP hybrid membrane with 2 wt % SiO₂ (M3-S2) has better properties and higher filtration rate and separation efficiency for surfactant-stabilized water-in-oil emulsion separation. Moreover, the membrane M3-S2 also exhibits excellent antifouling performance for long-running.


SILAC for biomarker discovery.
SILAC has been employed in MS-based proteomics for nearly a decade. This method is based on cells in culture metabolically incorporating isotope-coded essential amino acids and allows the quantification of global protein populations to identify characteristic changes. Variations of this technique developed over the years allow the application of SILAC not only to cell culture derived samples but also to tissues and human specimens, making this powerful technique amenable to clinically relevant samples. In this review, we provide an overview of different SILAC-derived methods and their use in the identification and development of biomarkers.


Quality of Life in Hidradenitis Suppurativa: validation of the HSQoL-24.
To date, there are no disease-specific instruments in Spanish to assess quality of life of patients with hidradenitis suppurativa. A multicentre study was previously carried out in Spain between 2016 and 2017 to develop the Hidradenitis Suppurativa Quality of Life-24 (HSQoL-24), a disease-specific questionnaire to assess quality of life in patients with hidradenitis suppurativa. The objectiv-es of this study are to revalidate the HSQoL-24 in Spanish with a larger sample of patients, and to present the English version. In this multi-centre study in Spain, patients with hidradenitis suppurativa completed the HSQoL-24, the Dermatology Life Quality Index and the Skindex-29. The Hurley staging system was used to assess the severity of the disease. Validation of the questionnaire was carried out in 130 patients, of whom 75 (57.7%) were women. This study demonstrates adequate values of reliability and validity of the HSQoL-24, confirming the previous test re-test validation and making this questionnaire one of wide clinical validity in terms of results perceiv-ed by patients.


Prediction of the ablated area by the spread of microbubbles during radiofrequency ablation of hepatocellular carcinoma.
Radiofrequency ablation (RFA) is effective for the treatment of hepatocellular carcinoma (HCC). To prevent the ablation of adjacent organs and vessels, the spread of microbubbles generated by heating during RFA was observed by ultrasonography (US) and used to predict the ablated area; however, several reports documented that discrepancies existed between the spread of microbubbles and the ablated area. The spread of microbubbles during RFA was observed by US in 24 patients with HCC and the areas were compared with the defect of enhancement in contrast enhanced (CE)-US, using Levovist in the same plane. During the ablation, the posterior margin was obscure but the border could be visualized 5 min after the ablation. The size of the area of hyperechogenicity 5 min after ablation and that of the defect observed by CE-US was found to correlate (r(2)=0.91, P<0.0001). The shape of the hyperechogenicity corresponded well to the defect area, even in cases showing irregular spread of the microbubbles. The observation of microbubbles during RFA can predict the ablated area and might be useful to prevent the unfavorable ablation of adjacent organs and vessels.


Targeting pathological B cell receptor signalling in lymphoid malignancies.
Signalling through the B cell receptor (BCR) is central to the development and maintenance of B cells. In light of the numerous proliferative and survival pathways activated downstream of the BCR, it comes as no surprise that malignant B cells would co-opt this receptor to promote their own growth and survival. However, direct evidence for BCR signalling in human lymphoma has only come to light recently. Roles for antigen-dependent and antigen-independent, or tonic, BCR signalling have now been described for several different lymphoma subtypes. Furthermore, correlative data implicate antigen-dependent BCR signalling in many other forms of lymphoma. A host of therapeutic agents targeting effectors of the BCR signalling pathway are now in clinical trials and have shown initial success against multiple forms of lymphoma.


Ovulatory surges of human CG prevent hormone-induced granulosa cell tumor formation leading to the identification of tumor-associated changes in the transcriptome.
Granulosa cell tumors comprise approximately 10% of ovarian tumors and, although rare, are clinically important due to their potential for malignancy and recurrence. Although their morphological features have been carefully described, the global changes in gene expression associated with their formation remain undetermined. To initiate this characterization, we used a transgenic mouse model in which granulosa cell tumors occur with 100% penetrance in CF-1 mice that harbor a novel transgene encoding a chimeric LHbeta subunit. When this transgene is expressed in other strains of mice, including (C57BL/6 female symbol x CF-1 male symbol,Tg) F1 hybrids, luteomas develop even though levels of LH remain high. This dichotomous response permits a longitudinal comparison of global changes in transcriptomes uniquely associated with either granulosa cell tumors or luteomas. Herein we report numerous changes in the transcriptome, including a decrease in LH receptor mRNA and increases in several mRNAs that encode secreted proteins previously associated with granulosa cell tumors. Furthermore, we identified a constellation of mRNAs that encode proteins that may serve as new markers for this tumor phenotype. Additional experiments indicated that periodic treatment with human CG prevented formation of granulosa cell tumors in mice genetically predisposed to tumor development and, instead, led to the appearance of luteomas. More importantly, ovarian transcriptomes from the luteomas induced by ovulatory doses of human CG permitted refined confirmation of gene expression changes that were uniquely associated with either granulosa cell tumors in the permissive CF-1 genetic background or in luteomas in the F1 hybrids. Together, these dynamic changes in the ovarian transcriptome indict various signaling pathways potentially involved in mediating the actions of LH over time and, depending on genetic background, the formation of either a luteoma or a granulosa cell tumor.


Acute and long-term outcomes of rotational atherectomy in small (< 3.0 mm) coronary arteries.
Conventional balloon angioplasty (BA) of small coronary arteries (SCA) is followed by a high rate of restenosis. Rotational atherectomy may be effective as an alternate treatment of stenoses unsuitable for other devices. The purpose of this study was to assess the efficacy of RA in the treatment of SCA. A retrospective analysis was performed of 226 lesions in 159 consecutive patients who underwent RA of SCA (mean diameter = 2.36 +/- 0.49 mm). One hundred forty-eight lesions (65.5%) were type B2 or C of AHA/ACC criteria. Follow-up angiography was performed at 3 and 6 months after the procedure. Procedural success was achieved in 96.9% of patients. The mean burr-to-artery ratio was 0.74 +/- 0.17. Adjunctive BA and stent implantation were needed in 94.2% and 22.6% of lesions, respectively. Minimal lumen diameter (MLD) increased from 0.66 +/- 0.35 mm to 1.97 +/- 0.58 mm (P < 0.01). Angiographic complications consisted of acute reclosure (3.5%), no reflow/slow flow (12.4%), and coronary artery perforation (1.8%). No death, Q-wave myocardial infarction (MI), or coronary artery bypass graft (CABG) occurred during the initial hospitalization. Restenosis rates at 3 and 6 months were 40.6% and 44.2%, respectively, and target lesion revascularization (TLR) rates were 28.5% and 33.0%, respectively. Restenosis and TLR rates during follow-up were comparable among patients who underwent RA + adjunctive BA versus patients who underwent RA + stenting. Long-term clinical follow-up was complete in 143 patients over a mean period of 348 +/- 166 days. The survival free from cardiac death, MI, CABG or repeated BA was 59.6% at 1 year. In conclusion, RA of SCA has relatively high restenosis rates, but may be appropriate for more complex, calcified lesions unsuitable for other devices.


Femoroacetabular impingement: biomechanical and dynamic considerations.
Femoroacetabular impingement (F.A.I.) is a pathologic process caused by an abnormal shape of the acetabulum, of the femoral head, or both. F.A.I., often referred to as idiopathic, may be secondary to slipped capital femoral epiphysis, congenital hypoplasia of the femur, Legg-Calvé Perthes disease, post-traumatic mal-union and protrusio acetabuli. From 2009 to 2012 we studied 21 patients (14 males), with a mean age of 52 (33 y - 75 y), affected by idiopathic F.A.I. Every patient underwent pelvic and hip joint X-rays and CT scan with 3D reconstructions, in order to evaluate the morphology of the pelvis and the hip joint and the torsion of the lower limbs (Femoroacetabular ante-retroversion). Our results show an average femoral ante-version angle of 12,4° (15°-20° physiological range) in patients affected by CAM impingement and an average acetabular ante-version angle of 13,5° (15°-20° physiological range) for those with PINCER impingement. These values, in patients affected by F.A.I., are probably related to morphologic and biomechanical features that may lead to the onset of idiopathic femoroacetabular impingement. In the literature, other studies partially support our findings, suggesting a more critical approach to a patient with idiopathic F.A.I. extending evaluations to nearby articulations.


Steroid-sparing effect of pimecrolimus cream 1% in children with severe atopic dermatitis.
To investigate if pimecrolimus cream 1% reduces the need for steroids in the long-term management of severe pediatric atopic dermatitis (AD). A total of 184 pediatric patients (aged 2-17 years) with a history of severe AD according to Rajka and Langeland were enrolled. Patients were randomized to treatment with pimecrolimus cream or vehicle cream for a 24-week period. Prednicarbate 0.25% was applied as rescue medication. Patients on pimecrolimus required steroids on a mean of 29% of study days, compared with 35% of patients on vehicle (p = 0.1841). On the head and neck only, the respective figures were 10 versus 19% (p = 0.0009). In patients enrolled with acute severe disease (Investigator's Global Assessment > or = 4), steroids were used on 28% of the days in the pimecrolimus group compared to 45% in the control group (p = 0.0024). On the head and neck, steroids were used on 10% of study days with pimecrolimus versus 30% with vehicle (p < 0.0001). The results indicate that the need for topical steroids on the head and neck is reduced with pimecrolimus cream 1% in the management of severe pediatric AD according to the definition of Rajka and Langeland.


Improvement of ocular penetration of amikacin sulphate by association to poly(butylcyanoacrylate) nanoparticles.
The main objective of this paper was to investigate the ability of polycyanoacrylate nanoparticles to improve the corneal penetration of hydrophilic drugs. Three different nanoparticle formulations were prepared by changing the nature of the stabilizer agent (Dextran 70000, Synperonic F 68 and sodium lauryl sulphate). The significant influence of the stabilizer type on the particle size, electrophoretic mobility and on the drug loading efficiency was proved. Moreover, the ocular disposition of amikacin was affected by its association to nanoparticles, displaying the most interesting results when Dextran 70000 was employed for preparation of nanoparticles. The increase of the amikacin concentration in cornea and aqueous humour was statistically significant for this nanoparticle formulation with respect to the other formulations and the control solution. The in-vitro release profiles obtained using a dialysis system were similar for all the nanoparticle formulations and for the control solution, indicating that drug molecules are desorbed from the nanoparticles quickly enough to maintain the equilibrium concentration in the dialysis system.


Methodological concerns related to response bias in migrant and seasonal farmworkers.
The original objective was to measure the impact of kneepads on musculoskeletal pain in migrant and seasonal farmworkers (MSFWs). Secondary analyses were conducted to quantify the extent to which response bias may have skewed the study's results. Surveys were used to collect data on baseline pain and post-intervention pain, the amount of time participants spent wearing kneepads, and their overall ratings of the intervention. Participants did not experience significantly less pain with kneepads, and wore them for considerably less than the prescribed amount of time. However, subjects rated them very favorably. Given the strong suspicion of response bias, no firm conclusions could be drawn regarding the intervention. Unique survey methodologies must be used with MSFWs, who tend to have low research literacy and are particularly susceptible to response bias. Objective study outcomes are particularly favorable in this population in order to minimize dependence on self-reported measures. Am. J. Ind. Med. 59:1112-1119, 2016. © 2016 Wiley Periodicals, Inc.


Tumbling and subsequent aging improves tenderness of beef longissimus lumborum and semitendinosus steaks by disrupting myofibrillar structure and enhancing proteolysis.
Tenderness is an important sensory attribute to the overall eating experience of beef. Identifying novel methods to ensure consistent tenderness, especially in inherently tough cuts, is critical for the industry. This study investigated if tumbling without brine inclusion could be an effective method to improve the quality and palatability attributes of beef longissimus lumborum (LL) and semitendinosus (ST) steaks. Furthermore, interactions with postmortem aging were evaluated to determine how tumbling might affect protein degradation and muscle ultrastructure. At 5 d postmortem, pairs of LL and ST muscles from beef carcasses (n = 16) were bisected, vacuum packaged, and tumbled for 0, 40, 80, or 120 min. Sections were divided and subsequently aged an additional 0 or 10 d at 2 °C. Tumbling for any duration improved instrumental tenderness of LL (P < 0.001) but not ST (P > 0.05) steaks, regardless of aging time. Tumbling exacerbated moisture loss in both muscles shown by greater purge and cooking losses (P < 0.05). Myofibrillar fragmentation was induced through tumbling in both muscles (P < 0.001), which was supported by transmission electron microscopy images. Tumbling for 120 min followed by 10 d of aging resulted in less abundant intact troponin-T in both LL and ST (P < 0.05), as well as less intact desmin in ST (P < 0.05); however, calpain-1 autolysis was not affected by tumbling (P > 0.05). No effects of tumbling, aging, nor the interaction were found for the content and solubility of collagen (P > 0.05). Consumer panelists (n = 120/muscle) rated LL steaks tumbled for any duration higher for tenderness and overall liking compared to control steaks (P < 0.05). For ST, significant interactions were found for consumer liking of tenderness and juiciness. In general, tumbling without subsequent aging resulted in poorer juiciness than non-tumbled (P < 0.05), while at 10 d no differences in juiciness were found between treatments (P > 0.05). For ST steaks that were aged 10 d, 120 min of tumbling resulted in greater tenderness liking than non-tumbled steaks (P < 0.05). These results suggest that tumbling would result in myofibrillar fragmentation and may benefit the degradation of myofibrillar proteins; however, there would be negligible impacts on collagen. Accordingly, tumbling without brine inclusion alone may be sufficient to improve tenderness and overall liking of LL steaks, while combined tumbling with subsequent postmortem aging would be necessary to improve tenderness liking of ST.


Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia cells in vitro, as single agent and in drug combination.
The mammalian target of rapamycin inhibitor rapamycin and its analogues show promising anticancer activity in various experimental tumor models and are presently evaluated in clinical trials. We, here, evaluated the in vitro activity of rapamycin with regard to tumor-type specificity and possible mechanisms of drug resistance in 97 tumor cell samples from patients and in a resistance-based cell line panel, using the fluorometric microculture cytotoxicity assay. Rapamycin was dose-dependently cytotoxic in patient tumor cells and in cell lines. In primary cells, rapamycin was more active in hematological than in solid tumor samples, with chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia being the most sensitive tumor types. Considerable inter-individual differences in sensitivity were apparent among CLL samples, but no difference was observed between IGHV mutated and unmutated CLL samples, whereas a tendency to lower rapamycin sensitivity was indicated for samples displaying poor-prognostic genomic markers. Combination experiments in CLL cells indicated that rapamycin acted synergistically with vincristine, cisplatin, chlorambucil and taxotere. These results and the clinically-experienced good tolerance to rapamycin analogues encourage clinical studies of rapamycin in CLL treatment as single agent but also in combination with, e.g., vincristine and chlorambucil.


Birt-Hogg-Dubé syndrome: report of a new mutation.
Birt-Hogg-Dubé syndrome is an autosomal dominant genodermatosis caused by germline mutations in the folliculin gene and characterized by facial papules, pulmonary cysts, kidney tumours and recurrent pneumothoraces. Several distinct mutations in the folliculin gene resulting in a truncated protein have been described. The present report describes a new mutation, which has not been reported in individuals with Birt-Hogg-Dubé syndrome but is of a type predicted to cause disease.


[Recombinant human TSH stimulation in radioiodine treatment of disseminated differentiated thyroid cancer--update of current and our own experiences].
Traditionally, for diagnostic and therapeutic application of radioiodine in patients with differentiated thyroid cancer (DTC), a 4 to 6 week withdrawal of thyroid hormone was applied. Recombinant human TSH (rhTSH) was developed to provide TSH stimulation without withdrawal of thyroid hormone and associated morbidity. The results of rhTSH administration and endogenous TSH stimulation are equivalent in detecting recurrent DTC. At the present time rhTSH is approved as an adjunct for diagnostic procedures and thyroid ablation in patients with DTC. In addition, rhTSH has potential for use in facilitating the treatment of metastases in patients with DTC. In this review we have summarized our own experiences with rhTSH aided radioiodine therapy in patients with disseminated thyroid cancer. Generally, rhTSH was very well tolerated and treatment results were comparable to those achieved with thyroid hormone withdrawal.


Assessment of molecular events in squamous and non-squamous cell lung carcinoma.
Although considerable knowledge exists on the tumor biology of lung cancer, there is still a need to assess molecular events for the clinical management of the disease. We studied the pattern of chromosomal imbalances in 45 non-small cell lung carcinomas (NSCLC) by comparative genomic hybridization (CGH) and correlated the results with clinicopathological features including immunohistochemical (IHC) expression of the epidermal growth factor receptor (EGFR). Twenty-one tumors were squamous cell carcinomas (SCC) and 24 non-squamous cell lung carcinomas (NSCC) comprising 9 adenocarcinomas (ADC), 9 large cell carcinomas (LCC), 4 sarcomatoid carcinomas and 2 adenosquamous carcinomas. The mean number of individual imbalances was 7.1 for SCC (mean gains, 3.8; mean losses, 3.4) and 6.4 for NSCC (mean gains, 4.5; mean losses, 1.9). Several individual imbalances correlated significantly with increasing number of imbalances, that were +1q, -3p, +3q, -5q, -8p, +8q, +7p, +12p, and +14q. Altogether, the most frequent imbalances were +3q (49%), +5p (49%), -5q (36%), +8q (29%), -8p (24%), -3p (22%), +7p (22%), +12p (22%), +14q (20%), +18p (20%), +1q (18%), and +7q (18%). Among these, +3q and +18p correlated significantly with SCC, and +5p and +14q with NSCC. Remarkably, overlapping imbalances included +3q26, +7p11 in SCC and +1q21, +3q24, +12p11, and +14q12 in NSCC. EGFR expression was higher in SCC than in NSCC and correlated with +3q in the entire series. In addition, +12p correlated significantly with disease progress with the exception of nodal involvement in NSCC as well as with disease progress, regardless of nodal involvement, in the entire series. In conclusion, the present study contributes to the molecular biological characterization of NSCLC histological subtypes and through evaluation of molecular events to the recently emergent focus on novel markers for lung cancer treatment.


HIV antiretroviral agents inhibit protein synthesis and decrease ribosomal protein S6 and 4EBP1 phosphorylation in C2C12 myocytes.
Combined antiretroviral drug regimens have promoted clinical, immunologic, and virologic improvements in AIDS patients. Nevertheless, these therapies are associated with derangements in lipid and carbohydrate metabolism. In this study, we examined the effects of a representative protease inhibitor (nelfinavir), a nonnucleoside reverse transcriptase inhibitor (nevirapine), and a nucleoside reverse transcriptase inhibitor (zidovudine) on protein synthesis in skeletal muscle cells. To examine these processes, C2C12 myocytes were treated with increasing concentrations of nelfinavir, nevirapine, or zidovudine for 1 or 2 days, and rates of protein synthesis were determined by measuring [35S]methionine/cysteine incorporation into cellular proteins. Treatment of myocytes with therapeutic concentrations of nelfinavir, nevirapine, or zidovudine for 48 hr decreased protein synthesis by 14-20%. An approximately 60% decline was observed in cells treated with higher concentrations of nevirapine or nelfinavir. In contrast, the basal rate of protein synthesis was not affected when cells were incubated with these compounds for 24 hr. Therapeutic concentrations of nelfinavir and nevirapine did not impair the anabolic effect of insulin on protein synthesis. However, zidovudine suppressed the stimulatory effect of insulin. The decreased protein synthesis induced by nelfinavir and zidovudine was associated with decreases in the phosphorylation of the S6 ribosomal protein (rpS6) and the repressor binding protein 4EBP1, while the inhibitory effect of nevirapine was mainly associated with a decline in phosphorylated 4EBP1. In conclusion, nelfinavir, nevirapine, and zidovudine treatments decreased protein synthesis in myocytes and this effect was correlated with a reduction in the phosphorylation level of proteins that regulate translation initiation.


Isotopic characterisation of lead deposited 1989-2001 at two upland Scottish locations.
The isotopic composition of lead collected with grass samples taken over the period 1989-2001 from plots at two upland locations (Glensaugh in north east and Hartwood in central Scotland) has been determined using thermal ionisation mass spectrometry. Although marked reductions in lead concentrations in grass were observed at Glensaugh in the initial three years, subsequently concentrations have remained relatively constant (1-3 microg g(-1)) in all plots to the present day. The one exception was a roadside plot at Hartwood which showed a large reduction from 1.0 microg g(-1) in 1999 to 0.2 microg g(-1) in 2000 following the abolition of petrol lead in the UK at the beginning of 2000. The total concentrations at this plot were consistently lower than those found at plots away from road traffic but exposed to the prevailing wind direction. The 206Pb/207Pb ratio increased steadily at all the plots throughout the period of the study indicating the reducing influence of petrol lead but the changes were not as great as might be expected with the decrease in the use of leaded petrol. Assuming the collected lead had only two sources, petrol lead and a diffuse background "industrial" lead, the proportion of petrol lead was only in the range 17-69% for roadside samples and 0-39% in other samples. A substantial proportion of deposited lead, therefore, now has its origin other than in petrol. Mixing curves indicate that whereas the lead deposited at Glensaugh could be defined by only two end members, that at Hartwood needs more than two components in the mixture. The results also suggest that although petrol lead has been eliminated, traffic is still a source of lead and another source defined as "traffic lead" should be considered.


Discovery and characterization of potent thiazoles versus methicillin- and vancomycin-resistant Staphylococcus aureus.
Methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) infections are growing global health concerns. Structure-activity relationships of phenylthiazoles as a new antimicrobial class have been addressed. We present 10 thiazole derivatives that exhibit strong activity against 18 clinical strains of MRSA and VRSA with acceptable PK profile. Three derivatives revealed an advantage over vancomycin by rapidly eliminating MRSA growth within 6 h, and no derivatives are toxic to HeLa cells at 11 μg/mL.


Data-driven prediction of multistable systems from sparse measurements.
We develop a data-driven method, based on semi-supervised classification, to predict the asymptotic state of multistable systems when only sparse spatial measurements of the system are feasible. Our method predicts the asymptotic behavior of an observed state by quantifying its proximity to the states in a precomputed library of data. To quantify this proximity, we introduce a sparsity-promoting metric-learning (SPML) optimization, which learns a metric directly from the precomputed data. The optimization problem is designed so that the resulting optimal metric satisfies two important properties: (i) it is compatible with the precomputed library and (ii) it is computable from sparse measurements. We prove that the proposed SPML optimization is convex, its minimizer is non-degenerate, and it is equivariant with respect to the scaling of the constraints. We demonstrate the application of this method on two multistable systems: a reaction-diffusion equation, arising in pattern formation, which has four asymptotically stable steady states, and a FitzHugh-Nagumo model with two asymptotically stable steady states. Classifications of the multistable reaction-diffusion equation based on SPML predict the asymptotic behavior of initial conditions based on two-point measurements with 95% accuracy when a moderate number of labeled data are used. For the FitzHugh-Nagumo, SPML predicts the asymptotic behavior of initial conditions from one-point measurements with 90% accuracy. The learned optimal metric also determines where the measurements need to be made to ensure accurate predictions.


Alpha-satellite DNA and vector composition influence rates of human artificial chromosome formation.
Human artificial chromosomes (HACs) have been proposed as a new class of potential gene transfer and gene therapy vector. HACs can be formed when bacterial cloning vectors containing alpha-satellite DNA are transfected into cultured human cells. We have compared the HAC-forming potential of different sequences to identify features critical to the efficiency of the process. Chromosome 17 or 21 alpha-satellite arrays are highly competent HAC-forming substrates in this assay. In contrast, a Y-chromosome-derived alpha-satellite sequence is inefficient, suggesting that centromere specification is at least partly dependent on DNA sequence. The length of the input array is also an important determinant, as reduction of the chromosome-17-based array from 80 kb to 35 kb reduced the frequency of HAC formation. In addition to the alpha-satellite component, vector composition also influenced HAC formation rates, size, and copy number. The data presented here have a significant impact on the design of future HAC vectors that have potential to be developed for therapeutic applications and as tools for investigating human chromosome structure and function.