[Spontaneous clearing of the cornea with detachment of Descemets membrane].
Detachment of Descemet's membrane (DM) is a rare complication of cataract and glaucoma surgery. Although permanent corneal edema is the usual outcome of a large detachment, spontaneous clearing of the cornea may occur. A 55-year-old man underwent trabeculectomy in 1991 under local anesthesia. One day later the cornea was edematous, with a large superior DM detachment curling inward in the anterior chamber, limited by a thin blood pigmented line. Two months after cornea had cleared, and remained clear for ten years, with 20/20 visual acuity and intraocular pressure of 14mmHg. Small detachments of DM after surgery are not rare and usually reattach spontaneously. However, extensive detachment results in overlying corneal edema and may require surgical reapposition. In our case, the cornea cleared spontaneously in the absence of DM repositionning, as denuded corneal stroma may be covered by newly regenerated DM. Before any surgical repair of DM detachment, one should consider spontaneous clearing of the cornea as a possible outcome.


Potassium chloride supplementation diminishes platelet reactivity in humans.
The prevalence of occlusive stroke is inversely correlated with potassium intake. We explored the hypothesis that a high potassium intake attenuates platelet reactivity, as expressed in ADP-evoked platelet aggregation. We studied healthy men (n=31) and women (n=42), blacks (n=33) and whites (n=40). In this cohort, we supplemented the habitual intake of 17 men and 21 women with 60 mmol KCl/70 kg body weight per day for 3 days and maintained 14 men and 21 women on their habitual intake. We then compared the change in ADP concentration causing 50% of the maximal initial rate (EC50) of platelet aggregation in the potassium-supplemented versus control groups. Potassium supplementation attenuated platelet reactivity, expressed by an increase in EC50 of platelet aggregation (P=0.0005), which was primarily attributable to an increase in EC50 in whites (P=0.0004). Urinary potassium excretion was significantly lower in blacks than in whites under basal conditions and after potassium supplementation. We conclude that potassium supplementation diminishes platelet reactivity, a phenomenon that provides a link between platelet biology and occlusive stroke.


Synergistic Antiproliferative Activity of the RAD51 Inhibitor IBR2 with Inhibitors of Receptor Tyrosine Kinases and Microtubule Protein.
Although cancer cell genetic instability contributes to characteristics that mediate tumorigenicity, it also contributes to the tumor-selective toxicity of some chemotherapy drugs. This synthetic lethality can be enhanced by inhibitors of DNA repair. To exploit this potential Achilles heel, we tested the ability of a RAD51 inhibitor to potentiate the cytotoxicity of chemotherapy drugs. 2-(Benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) inhibits RAD51-mediated DNA double-strand break repair but also enhances cytotoxicity of the Bcr-Abl inhibitor imatinib. The potential for synergy between IBR2 and more drugs was examined in vitro across a spectrum of cancer cell lines from various tissues. Cells were exposed to IBR2 simultaneously with inhibitors of receptor tyrosine kinases, DNA-damaging agents, or microtubule disruptors. IBR2, at concentrations that inhibited proliferation between 0% and 75%, enhanced toxicity by up to 80% of imatinib and regorafenib (targets RAF and kit); epidermal growth factor receptor inhibitors erlotinib, gefitinib, afatinib, and osimertinib; and vincristine, an inhibitor of microtubule function. However, IBR2 antagonized the action of olaparib, cisplatin, melphalan, and irinotecan. A vincristine-resistant squamous cell line was not cross resistant to imatinib, but IBR2 and another RAD51 inhibitor (B02) enhanced imatinib toxicity in this cell line, its HN-5a parent, and the colon cancer line HT-29 by up to 60% and much better than verapamil, a P-glycoprotein inhibitor (P < 0.05). Given the disparate agents the functions of which are enhanced by IBR2, the mechanisms of enhancement may be multimodal. Whether RAD51 is common to these mechanisms remains to be elucidated, but it provides the potential for selectivity to tumor cells.


Negative reciprocity between angiotensin II type 1 and dopamine D1 receptors in rat renal proximal tubule cells.
Sodium excretion is bidirectionally regulated by dopamine, acting on D1-like receptors (D1R) and angiotensin II, acting on AT1 receptors (AT1R). Since sodium excretion has to be regulated with great precision within a short frame of time, we tested the short-term effects of agonist binding on the function of the reciprocal receptor within the D1R-AT1R complex in renal proximal tubule cells. Exposure of rat renal proximal tubule cells to a D1 agonist was found to result in a rapid partial internalization of AT1R and complete abolishment of AT1R signaling. Similarly, exposure of rat proximal tubule cells and renal tissue to angiotensin II resulted in a rapid partial internalization of D1R and abolishment of D1R signaling. D1R and AT1R were, by use of coimmunoprecipitation studies and glutathione-S-transferase pull-down assays, shown to be partners in a multiprotein complex. Na+-K+-ATPase, the target for both receptors, was included in this complex, and a region in the COOH-terminal tail of D1R (residues 397-416) was found to interact with both AT1R and Na+-K+-ATPase. Results indicate that AT1R and D1R function as a unit of opposites, which should provide a highly versatile and sensitive system for short-term regulation of sodium excretion.


The use of endoscopic argon plasma coagulation in airway complications after solid organ transplantation.
The objective of the study was to describe a safe and effective treatment option for endobronchial complications after solid organ transplantation. A retrospective analysis was performed in a tertiary-care university hospital. The use of bronchoscopic argon plasma coagulation (APC) for the treatment of endobronchial lesions was studied in five solid organ transplant recipients. Four patients presented with variable degrees of endobronchial obstruction, and one patient presented with massive hemoptysis. Two of the patients with endobronchial obstruction were double lung transplant recipients who developed anastomotic strictures. The strictures were opened with endobronchial stents but became obstructed again by inflammatory granulation tissue overgrowth through the stent mesh. APC was used to maintain airway patency. One kidney transplant recipient developed pulmonary zygomycosis with secondary obstruction of the left main bronchus because of granulation tissue growth through endobronchial stents. Airway patency was reestablished with several treatments with APC. Another kidney transplant recipient developed subglottic and tracheal papillomatosis that was effectively removed with APC. A heart transplant recipient was referred with recurrent massive hemoptysis refractory to bronchial artery embolization. The bleeding was caused by hemorrhagic polypoid lesions, which were completely ablated by APC. Bronchoscopic use of the argon plasma coagulator is a safe and simple technique that can be used effectively to treat endobronchial pathology in solid organ transplant patients.


Black race is an adverse prognostic factor for prostate cancer recurrence following radical prostatectomy in an equal access health care setting.
We determined if black men with clinically localized adenocarcinoma of the prostate have the same recurrence-free outcome following radical prostatectomy, and whether they have similar preoperative, operative and pathological characteristics as white men in an equal access health care environment. We studied consecutive single hospital case series of 366 white and 107 black patients who underwent radical prostatectomy between 1975 and February 29, 1995. Evaluation included comprehensive retrospective chart review, prospective data collection and proactive followup. Univariate and multivariate statistical analyses were done of preoperative, operative, pathological and recurrence data by race. Although the incidences of hypertension and diabetes, pretreatment prostate specific antigen (PSA) and serum creatinine measurements, elevated PSA as an indication for biopsy and clinical stage were greater in black men, the operative variables of blood loss, operative time and performance of a nerve sparing procedure were not different. The incidence of margin positivity was greater in black patients but pathological stage, Gleason score and seminal vesicle or nodal involvement were not different. Black race was an adverse prognostic factor for recurrence following radical prostatectomy after multivariate adjustment for pretreatment PSA and acid phosphatase, organ confinement status and tumor grade. The poorer recurrence-free outcome for black patients even after multivariate adjustment suggests a potentially more aggressive variant of prostate cancer in this population, the etiology of which is unknown. Race should be a stratification factor in clinical trials, especially those including radical prostatectomy and using recurrence-free outcome as an end point.


Review of meningitis surveillance data, upper West Region, Ghana 2009-2013.
The Upper West region of Ghana is within the meningitis belt. Analysis of long term surveillance data is necessary for understanding changes in the disease occurrence. We analyzed five years of surveillance data to describe by person, place and time and to determine trends in meningitis. Meningitis surveillance data from Ghana Health Service in the Upper West Region, from 2009 to 2013 were reviewed. Data was obtained from District-Health Information Management System and line list from the Disease Control Unit. Population figures (denominators) and rainfall data were also analyzed. Within the period 980 cases of meningitis were reported in the region, 507(52%) females and 473(48%) males. The mean age of cases was 20.1years and standard deviation 18.8 years with, 77.6 %( 761/980) cases occurring in persons aged under 30 years. Children under five years were 19.3% (190/980). Attack rates ranged from 6.1/100,000 population in the Daffiama-bussei-Issa-district to 47.5/100,000 in Jirapa. Overall case fatality rate of meningitis was 12.2% with 14deaths/100,000 population. Bacterial agents were isolated from 35% (245/702) of CSF. Majority were Streptococcus pneumonia 48.2 % ( 122/258), and N. meningitides Y/W 135 40.3% (102/258). Meningitis was found to be seasonal with peaks in the dry season. Meningitis in the region is seasonal, and showed a decreasing trend. Jirapa, Lawra, Nadowli and Wa West districts had the highest burden. Control effort of the disease should focus on vaccination against streptococcus pneumonia and N. meningitis W135 especially within crowded settlements such as boarding schools.


Langmuir Monolayers from Substituted 5'-Phenyl-m-terphenyl Carboxylic Acids.
A series of 5'-phenyl-m-terphenyl carboxylic acid (PTCA) derivatives with methyl, chloro, and fluoro substituents at both side phenyl rings have been synthesized and characterized as Langmuir monolayers at the air/water interface. A comparative analysis, based on the surface pressure and electric surface potential measurements under a variety of experimental conditions, is complemented with BAM images. Copyright 2001 Academic Press.


[Removal of ocular artifact from EEG based on JADE].
The method of Joint approximate diagonalization (JADE) is used to remove the ocular artifact from Electroencephalogram (EEG). As the JADE algorithm can be used to separate sub-gaussian and super-gaussian sources, it is possible to extract the signals that are statistically independent, and to identify the spatial map that is associated with the artifactual component. Thus the method can remove artifactual component. Satisfactory results illustrate the robust and practicability of the algorithm.


Polymorphism and crystallization behavior of Abbott-79175, a second-generation 5-lipoxygenase inhibitor.
The crystal polymorphism of Abbott-79175, a potent second-generation 5-lipoxygenase inhibitor, has been studied. Crystallization from an ethyl acetate/heptane system in which moisture content was not controlled and from an ethanol/water system produced a crystal form I, which by differential scanning calorimetry, thermogravimetric analysis, and Karl Fischer analysis was likely a hemihydrate. This hemihydrate form of the compound was demonstrated to reversibly dehydrate/hydrate with the use of low heat and vacuum followed by exposure to water vapor (100% relative humidity). The dehydrated version of I was designated IA. However, it was shown that a relative humidity approaching 100% was required for the water to re-enter the crystal structure. X-ray powder diffraction and solid state 13C NMR data on polycrystalline samples crystallized from seven single organic solvents suggested two nonsolvated forms of the compound, II and III. The heptane addition rate to a dry ethyl acetate solution of the drug was shown to greatly affect the crystal habit, the crystallite size, and specific surface area upon its precipitation. Solution calorimetry of forms I, IA, and II showed that I had the most endothermic heat of solution, with IA and II having lower values. Initial dissolution rates of compressed disks of these forms in water showed rates of IA > II approximately I. Considering all data, including evidence of conversion of II to I in aqueous suspension, it is suggested that the relative thermodynamic stability (at least when water was present) in decreasing order is I > II > IA, although I and II are similar energetically. The lower terminal dissolution rate for form IA was due to, in part, conversion to the less soluble Form I.


Iron status of toddlers, nonpregnant females, and pregnant females in the United States.
Background: Total-body iron stores (TBI), which are calculated from serum ferritin and soluble transferrin receptor concentrations, can be used to assess the iron status of populations in the United States.Objective: This analysis, developed to support workshop discussions, describes the distribution of TBI and the prevalence of iron deficiency (ID) and ID anemia (IDA) among toddlers, nonpregnant females, and pregnant females.Design: We analyzed data from NHANES; toddlers aged 12-23 mo (NHANES 2003-2010), nonpregnant females aged 15-49 y (NHANES 2007-2010), and pregnant females aged 12-49 y (NHANES 1999-2010). We used SAS survey procedures to plot distributions of TBI and produce prevalence estimates of ID and IDA for each target population. All analyses were weighted to account for the complex survey design.Results: According to these data, ID prevalences (± SEs) were 15.1% ± 1.7%, 10.4% ± 0.5%, and 16.3% ± 1.3% in toddlers, nonpregnant females, and pregnant females, respectively. ID prevalence in pregnant females increased significantly with each trimester (5.3% ± 1.5%, 12.7% ± 2.3%, and 27.5% ± 3.5% in the first, second, and third trimesters, respectively). Racial disparities in the prevalence of ID among both nonpregnant and pregnant females exist, with Mexican American and non-Hispanic black females at greater risk of ID than non-Hispanic white females. IDA prevalence was 5.0% ± 0.4% and 2.6% ± 0.7% in nonpregnant and pregnant females, respectively.Conclusions: Available nationally representative data suggest that ID and IDA remain a concern in the United States. Estimates of iron-replete status cannot be made at this time in the absence of established cutoffs for iron repletion based on TBI. The study was registered at clinicaltrials.gov as NCT03274726.


Multicomponent adsorption in mesoporous flexible materials with flat-histogram Monte Carlo methods.
We demonstrate an extensible flat-histogram Monte Carlo simulation methodology for studying the adsorption of multicomponent fluids in flexible porous solids. This methodology allows us to easily obtain the complete free energy landscape for the confined fluid-solid system in equilibrium with a bulk fluid of any arbitrary composition. We use this approach to study the adsorption of a prototypical coarse-grained binary fluid in "Hookean" solids, where the free energy of the solid may be described as a simple spring. However, our approach is fully extensible to solids with arbitrarily complex free energy profiles. We demonstrate that by tuning the fluid-solid interaction ranges, the inhomogeneous fluid structure inside the pore can give rise to enhanced selective capture of a larger species through cooperative adsorption with a smaller one. The maximum enhancement in selectivity is observed at low to intermediate pressures and is especially pronounced when the larger species is very dilute in the bulk. This suggest a mechanism by which the selective capture of a minor component from a bulk fluid may be enhanced.


Bone marrow chromosome abnormalities in breast cancer in patients following adjuvant chemotherapy.
Two patients developed acute bone marrow cancer following mastectomy and institution of alkylating agents as adjuvant chemotherapy. An aneuploid condition was observed in both cases, along with involvement of chromosomes 11 and 12 in structural rearrangements. Subsequent studies of 18 patients who had or had not received such therapy showed no evidence of chromosomal aberrations. However, the long-term effect of adjuvant chemotherapy in cancer patients is still of concern until additional information becomes available.


Wiring a plant: genetic networks for phloem formation in Arabidopsis thaliana roots.
In plants, phloem conduits form a specialized vascular network mediating the exchange of nutrients and signaling molecules between distantly separated organs. To become effective transport elements, protophloem cells undergo a rather unique, differentiation program that involves nucleus degradation, organelle rearrangement and cell wall thickening. Yet, protophloem sieve elements remain alive because their essential metabolic functions are supported by their neighboring companion cells. In spite of the importance of the phloem, the molecular mechanisms orchestrating protophloem specification and differentiation remain still poorly understood. In this review, I provide a summary of recent discoveries regarding morphogenetic events that determine phloem formation, and also a discussion of the systemic effects on root architecture derived from impaired protophloem differentiation programs.


A nonmonotonic dependence of standard rate constant on reorganization energy for heterogeneous electron transfer processes on electrode surface.
In the present work a nonmonotonic dependence of standard rate constant (k(0)) on reorganization energy (lambda) was discovered qualitatively from electron transfer (Marcus-Hush-Levich) theory for heterogeneous electron transfer processes on electrode surface. It was found that the nonmonotonic dependence of k(0) on lambda is another result, besides the disappearance of the famous Marcus inverted region, coming from the continuum of electronic states in electrode: with the increase of lambda, the states for both Process I and Process II ET processes all vary from nonadiabatic to adiabatic state continuously, and the lambda dependence of k(0) for Process I is monotonic thoroughly, while for Process II on electrode surface the lambda dependence of k(0) could show a nonmonotonicity.


Mediterranean-Type Dietary Pattern and Physical Activity: The Winning Combination to Counteract the Rising Burden of Non-Communicable Diseases (NCDs).
Non-communicable diseases (NCDs) (mainly cardiovascular diseases, cancers, chronic respiratory diseases and type 2 diabetes) are the main causes of death worldwide. Their burden is expected to rise in the future, especially in less developed economies and among the poor spread across middle- and high-income countries. Indeed, the treatment and prevention of these pathologies constitute a crucial challenge for public health. The major non-communicable diseases share four modifiable behavioral risk factors: unhealthy diet, physical inactivity, tobacco usage and excess of alcohol consumption. Therefore, the adoption of healthy lifestyles, which include not excessive alcohol intake, no smoking, a healthy diet and regular physical activity, represents a crucial and economical strategy to counteract the global NCDs burden. This review summarizes the latest evidence demonstrating that Mediterranean-type dietary pattern and physical activity are, alone and in combination, key interventions to both prevent and control the rise of NCDs.


Extracerebral metastases determine the outcome of patients with brain metastases from renal cell carcinoma.
In the era of cytokines, patients with brain metastases (BM) from renal cell carcinoma had a significantly shorter survival than patients without. Targeted agents (TA) have improved the outcome of patients with metastatic renal cell carcinoma (mRCC) however, their impact on patients with BM is less clear. The aim of this analysis was to compare the outcome of patients with and without BM in the era of targeted agents. Data from 114 consecutive patients who had access to targeted agent were analyzed for response rates (ORR), progression free survival (PFS) and overall survival (OS). All patients diagnosed with BM underwent local, BM-specific treatment before initiation of medical treatment. Data of 114 consecutive patients who had access to at least one type of targeted agents were analyzed. Twelve out of 114 renal cell carcinoma (RCC) patients (10.5%) were diagnosed with BM. Systemic treatment consisted of sunitinib, sorafenib, temsirolimus or bevacizumab. The median PFS was 8.7 months (95% CI 5.1 - 12.3) and 11.4 months (95% CI 8.7 - 14.1) for BM-patients and non-BM-patients, respectively (p = 0.232). The median overall survival for patients with and without BM was 13.4 (95% CI 1- 43.9) and 33.3 months (95% CI 18.6 - 47.0) (p = 0.358), respectively. No patient died from cerebral disease progression. ECOG Performance status and the time from primary tumor to metastases (TDM) were independent risk factors for short survival (HR 2.74, p = 0.001; HR: 0.552, p = 0.034). Although extracerebral metastases determine the outcome of patients with BM, the benefit from targeted agents still appears to be limited when compared to patients without BM.


In vivo modulation of the murine immune response to Francisella tularensis LVS by administration of anticytokine antibodies.
The role(s) of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-4 (IL-4) in establishment and maintenance of protective immunity to Francisella tularensis LVS in mice (C3H/HeN) was examined by selective removal of these cytokines in vivo with neutralizing antibodies. The 50% lethal dose (LD50) for mice infected intradermally with F. tularensis alone was 136,000 CFU; treatment of mice with anti-IFN-gamma or anti-TNF-alpha at the time of infection significantly reduced (P much less than 0.05) the LD50 to 2 and 5 CFU, respectively. Abrogation of protective immunity, however, was effective only when anti-IFN-gamma or anti-TNF-alpha was administered prior to day 3 postinfection. In contrast, the LD50 for mice treated with anti-IL-4 was repeatedly higher (555,000 CFU) than for controls; this difference, however, was not significant (P greater than 0.05). Thus, IL-4 may be detrimental, while IFN-gamma and TNF-alpha were clearly crucial to the establishment of protective immunity to F. tularensis during a primary infection. The importance of IFN-gamma and TNF-alpha during a secondary immune response to F. tularensis was also investigated. Spleen cells from immune mice passively transfer protective immunity to recipient mice in the absence of confounding antibody-mediated immunity. This passive transfer of immunity, however, was abrogated by treatment of recipient mice with anti-IFN-gamma or anti-TNF-alpha at the time of challenge infection. That anticytokines effectively abrogate protective immunity very early in the course of infection with F. tularensis suggests that T-cell-dependent activation of macrophages for microbicidal activity is unlikely. These T-cell-independent events early in the course of infection may suppress bacterial replication until a T-cell-dependent response ultimately clears the bacteria.


Genome-Wide Identification of the Transcription Factors Involved in Citrus Fruit Ripening from the Transcriptomes of a Late-Ripening Sweet Orange Mutant and Its Wild Type.
Fruit ripening is a genetically programmed process. Transcription factors (TFs) play key roles in plant development and ripening by temporarily and spatially regulating the transcription of their target genes. In this study, a total of 159 TFs were identified from a spontaneous late-ripening mutant 'Fengwan' (C. sinensis L. Osbeck) sweet orange (MT) and its wild-type counterpart ('Fengjie 72-1', WT) along the ripening period via the Transcription Factor Prediction of PlantTFDB 3.0. Fifty-two differentially expressed TFs were identified between MT and WT; 92 and 120 differentially expressed TFs were identified in WT and MT, respectively. The Venn diagram analysis showed that 16 differentially expressed TFs were identified between MT and WT and during the ripening of WT and MT. These TFs were primarily assigned to the families of C2H2, Dof, bHLH, ERF, MYB, NAC and LBD. Particularly, the number of TFs of the ERF family was the greatest between MT and WT. According to the results of the WGCNA analysis, a weighted correlation network analysis tool, several important TFs correlated to abscisic acid (ABA), citric acid, fructose, glucose and sucrose were identified, such as RD26, NTT, GATA7 and MYB21/62/77. Hierarchical cluster analysis and the expression analysis conducted at five fruit ripening stages further validated the pivotal TFs that potentially function during orange fruit development and ripening.


[Suppression of the human immunodeficiency virus in cultured cells by 5'-phosphites of 3'-azido-2',3'-dideoxynucleosides].
5'-Phosphites (5'-hydrogenphosphonates) of 3'-azido-2'-, 3'-dideoxynucleosides are shown to be effective inhibitors of the human immunodeficiency virus (HIV-1) in MT4 cell culture. 5'-Phosphite of 3'-azido-2', 3'-dideoxythymidine was the most active among these compounds and even a little more active as compared to the well-known anti-AIDS drug 3'-azido-2',3'-dideoxythymidine; at the same time 5'-phosphites of 3'-azido-2',3' -dideoxynucleosides with adenine, guanine and cytosine bases were more active than the corresponding nucleosides. The toxicity of all four phosphites was comparatively low and the equimolar mixture of all four phosphites was 2-3 fold less toxic than each of them separately. Data on the decreased toxicity of the phosphite mixture are explained from the viewpoint of a decreased pool disbalance of natural 2'-deoxynucleoside 5'-triphosphates in cells; a significant pool disbalance is developed in the case of 3'-azido-2',3'-dideoxythymidine action.


Neuropsychological profile associated to PKAN in its initial phase: a case series report.
Pantothenase kinase-associated neurodegeneration (PKAN) is characterized by an abnormal accumulation of iron in basal ganglia and progressing varied extrapyramidal clinical symptoms. There are few studies on the cognitive symptoms and their development. The aim of this study is to explore the neuropsychological profile of PKAN patients in the initial stages of the disorder, when there are relatively fewer motor limitations. we present a full neuropsychological examination of three female cases (two early and one late onset). perception and spatial cognition were within normal range. Performance on other tasks were mixed, except for primary impairments in inhibition, flexibility, and cognitive fluency, which were consistent across cases. unlike most previous studies which report adults with major motor impairment, we present cases of young participants with minor motor difficulties. The results of the neuropsychological assessment - potentially less confounded by poor motor functioning during examination - are compatible with impairments in the fronto-subcortical circuits in the early phases of the disease. This could explain frequent misdiagnoses (e.g., with attention deficit hyperactivity disorder) in initial referrals.


Zinc Finger Nuclease: A New Approach to Overcome Beta-Lactam Antibiotic Resistance.
The evolution of antibiotic-resistant bacteria (ARB) and antibiotic-resistance genes (ARGs) has been accelerated recently by the indiscriminate application of antibiotics. Antibiotic resistance has challenged the success of medical interventions and therefore is considered a hazardous threat to human health. The present study aimed to describe the use of zinc finger nuclease (ZFN) technology to target and disrupt a plasmid-encoded β-lactamase, which prevents horizontal gene transfer-mediated evolution of ARBs. An engineered ZFN was designed to target a specific sequence in the ampicillin resistance gene (amp(R)) of the pTZ57R plasmid. The Escherichia coli bacteria already contained the pZFN kanamycin-resistant (kana(R)) plasmid as the case or the pP15A, kana(R) empty vector as the control, were transformed with the pTZ57R; the ability of the designed ZFN to disrupt the β-lactamase gene was evaluated with the subsequent disturbed ability of the bacteria to grow on ampicillin (amp) and ampicillin-kanamycin (amp-kana)-containing media. The effect of mild hypothermia on the ZFN gene targeting efficiency was also evaluated. The growth of bacteria in the case group on the amp and amp-kana-containing media was significantly lower compared with the control group at 37°C (P < 0.001). Despite being more efficient in hypothermic conditions at 30°C (P < 0.001), there were no significant associations between the incubation temperature and the ZFN gene targeting efficiency. Our findings revealed that the ZFN technology could be employed to overcome ampicillin resistance by the targeted disruption of the ampicillin resistance gene, which leads to inactivation of β-lactam synthesis. Therefore, ZFN technology could be engaged to decrease the antibiotic resistance issue with the construction of a ZFN archive against different ARGs. To tackle the resistance issue at the environmental level, recombinant phages expressing ZFNs against different ARGs could be constructed and released into both hospital and urban wastewater systems.


Synthesis and biological evaluation of analogues of the peptaibol ampullosporin A.
A series of analogues of the fungal peptaibol type metabolite ampullosporin A containing modifications in the C and N terminus as well as alpha-aminoisobutyric acid (Aib) substitutions in different positions of the peptide were synthesized by solid phase synthesis using the 9-fluorenylmethyloxycarbonyl strategy. Depending on the sequence position, couplings were performed with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/1-hydroxybenzotriazole and tetramethylfluoroformamidinium hexafluorophosphate, respectively. The structures of the target peptides were analyzed by electrospray ionization mass spectrometry and chromatographic methods (high-performance liquid chromatography, thin-layer chromatography). The biological activities of these compounds have been evaluated by assaying their potencies for the induction of pigment formation on the fungus Phoma destructiva as well as for the induction of hypothermia and inhibition of locomotoric activity in mice and were compared to the naturally occurring ampullosporins. Native ampullosporin A and analogues with C-terminal Leu or Leu-NH(2) showed comparable activity in the pigmentation assay. Similarly, the ampullosporin A analogues with N-terminal aromatic amino acid residues, such as D-Trp and Tic, also have high potency for pigment formation. The peptides containing structural modifications of ampullosporin A by systematic replacement of Aib by Ala (Ala scan) displayed moderate or high activity in the pigmentation assay, whereas simultaneous substitution of all Aib residues by Ala and Ile, respectively, or by insertion of nonaromatic residues into position 1 resulted in a loss of the effect on P. destructiva. Most of the compounds with no or weak activity in the microbial assay were not active in the hypothermic test, too, except the compound with 1-amino-1-cyclohexane carboxylic acid in position 4 instead of Aib. However, only a few compounds with high potency for pigmentation induction were found to produce strong hypothermia in mice. Thus, in contrast to the native ampullosporins, we succeeded to a certain degree in differentiation of the bioactivities with our synthetic analogues.


A double prodrug system for colon targeting of benzenesulfonamide COX-2 inhibitors.
The design, synthesis and delivery potential of a new type of benzenesulfonamide cyclo-oxygenase-2 (COX-2) inhibitor prodrug is investigated using celecoxib. The approach involves a double prodrug that is activated first by azoreductases and then by cyclization triggering drug release. We studied the intramolecular aminolysis of the acylsulfonamide. The cyclization was surprisingly rapid at physiological pH and very fast at pH 5. The prodrug is activated specifically under conditions found in the colon but highly stable in the presence of human and rodent intestinal extracts. Finally, the prototype with celecoxib was transported much more slowly in the Caco-2 transepithelial model than the parent. The design therefore shows significant promise for the site specific delivery of benzenesulfonamide COX-2 inhibitors to the colon.


Possible Action of Olaparib for Preventing Invasion of Oral Squamous Cell Carcinoma In Vitro and In Vivo.
Despite recent advances in treatment, the prognosis of oral cancer remains poor, and prevention of recurrence and metastasis is critical. Olaparib is a PARP1 inhibitor that blocks polyADP-ribosylation, which is involved in the epithelial-mesenchymal transition (EMT) characteristic of tumor recurrence. We explored the potential of olaparib in inhibiting cancer invasion in oral carcinoma using three oral cancer cell lines, HSC-2, Ca9-22, and SAS. Olaparib treatment markedly reduced their proliferation, migration, invasion, and adhesion. Furthermore, qRT-PCR revealed that olaparib inhibited the mRNA expression of markers associated with tumorigenesis and EMT, notably Ki67, Vimentin, β-catenin, MMP2, MMP9, p53, and integrin α2 and β1, while E-Cadherin was upregulated. In vivo analysis of tumor xenografts generated by injection of HSC-2 cells into the masseter muscles of mice demonstrated significant inhibition of tumorigenesis and bone invasion by olaparib compared with the control. This was associated with reduced expression of proteins involved in osteoclastogenesis, RANK and RANKL. Moreover, SNAIL and PARP1 were downregulated, while E-cadherin was increased, indicating the effect of olaparib on proteins associated with EMT in this model. Taken together, these findings confirm the effects of olaparib on EMT and bone invasion in oral carcinoma and suggest a new therapeutic strategy for this disease.


Separation and determination of anthraquinones in Cassia obtusifolia (Leguminosae) by micellar electrokinetic capillary electrophoresis.
An MEKC method was developed for the determination of the five pharmaceutically important anthraquinones: chrysophanol (1), physcion (2), emodin (3), aloe-emodinin (4), and rhein (5) in Cassia obtusifolia (Leguminosae). A buffer solution (pH 9.00) composed of 20 mM sodium borate, 20 mM sodium deoxycholate (DOC), and 15% ACN was found to be the most suitable electrolyte for this separation. Regression equations revealed linear relationships (correlation coefficients: 0.9993, 0.9992, 0.9996, 0.9989, and 0.9991) between the peak area of each compound (1, 2, 3, 4, and 5) and its concentration. The RSDs of migration times and peak areas were <1.23 and 2.72% within 1 day, respectively. The effects of pH value, surfactant (DOC) concentration, and organic modifier on the migration were also studied. By this way, the contents of five anthraquinones in the extracts of the seed of C. obtusifolia (Leguminosae) from different sources were successfully determined within 14 min.


Transformations to regenerative food systems-An outline of the FixOurFood project.
This paper provides an outline of a new interdisciplinary project called FixOurFood, funded through UKRI's 'Transforming UK food systems' programme. FixOurFood aims to transform the Yorkshire food system to a regenerative food system and will work to answer two main questions: (1) What do regenerative food systems look like? (2) How can transformations be enabled so that we can achieve a regenerative food system? To answer these questions, FixOurFood will work with diverse stakeholders to change the Yorkshire food system and use the learning to inform change efforts in other parts of the UK and beyond. Our work will focus on shifting trajectories towards regenerative dynamics in three inter-related systems of: healthy eating for young children, hybrid food economies and regenerative farming. We do this by a set of action-orientated interventions in schools and the food economy, metrics, policies and deliverables that can be applied in Yorkshire and across the UK. This article introduces the FixOurFood project and concludes by assessing the potential impact of these interventions and the importance we attach to working with stakeholders in government, business, third sector and civil society.


BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells.
The effects of BMP2 on bone marrow stromal cell differentiation and bone formation after bone marrow ablation were determined using C57 BL/6J (B6) mice. Inhibition of BMP2 expression with lentiviral BMP2 shRNA prevented both mineralized nodule formation in vitro and bone formation in vivo, and blocked the expression of Runx2 and osterix, transcriptional determinants of terminal osteogenic differentiation. No effect was observed on the expression of Sox9, a transcription factor, which is the one of the first transcriptional determinant to be expressed in committed chondroprogenitor and osteoprogenitor cells. In vitro studies showed that exogenously added BMP7 rescued the expression of osterix and enhanced the expression of Sox9, but had no effect on the expression of Runx2, while it only partially recovered the development of mineral deposition in the cultures. On the other hand, the exogenous addition of BMP2 rescued both Runx2 and osterix expression, did not enhance the expression of Sox9, but fully recovered the inhibition of mineral deposition in the cultures. Using antibodies against CD146 and Sox9, immunohistological examination of the cell populations found in the medullary space three days after bone marrow ablation, showed qualitatively equal numbers of cells expressing these skeletal progenitor and stem cell markers in control and BMP2 shRNA treated animals. Fluorescence Activated Cell Sorting (FACS) analysis of the cells found with the marrow cavities at three days after marrow ablation using CD146 antibody showed near equal numbers of immunopositive cells in both control and shRNA treated animals. In summary, the differences observed in vitro for BMP2 and BMP7 on osteogenic gene expression and mineralization suggest that they have differing effects on bone cell differentiation. These results further demonstrate that in vivo BMP2 is a central morphogenetic regulator of post natal osteoprogenitor differentiation, but does not affect recruitment of progenitors to the osteoblastic lineage.


The Neurobehavioral Rating Scale: reliability in patients with dementia.
Precise measurement of cognitive, psychiatric, and behavioral symptoms is essential to understanding clinical, pathophysiologic, and treatment aspects of Alzheimer's disease and other dementing illnesses. The Neurobehavioral Rating Scale (NRS) is a 28-item observer-rated instrument that measures a broad range of cognitive and noncognitive symptoms. The interrater reliability of the NRS was examined in 15 patients with dementia. The correlation coefficient for the NRS total scores was .93. Coefficients for NRS factor scores and individual item scores were also satisfactory. Correlations for measures of subjectively experienced symptoms were acceptable, but less robust than measures of cognition and observable behavior. These results support the reliability of the NRS for multidimensional assessment of patients with dementia.


Gastrulation dynamics: cells move into focus.
During vertebrate gastrulation, a relatively limited number of blastodermal cells undergoes a stereotypical set of cellular movements that leads to formation of the three germ layers: ectoderm, mesoderm and endoderm. Gastrulation, therefore, provides a unique developmental system in which to study cell movements in vivo in a fairly simple cellular context. Recent advances have been made in elucidating the cellular and molecular mechanisms that underlie cell movements during zebrafish gastrulation. These findings can be compared with observations made in other model systems to identify potential general mechanisms of cell migration during development.


Implication of Non-electrostatic Contribution to Deionization in Flow-Electrode CDI: Case Study of Nitrate Removal From Contaminated Source Waters.
While flow-electrode capacitive deionization (FCDI) operated in short-circuited closed cycle (SCC) mode appears to hold promise for removal of salt from brackish source waters, there has been limited investigation on the removal of other water constituents such as nitrate, fluoride or bromide in combination with salt removal. Of particular concern is the effectiveness of FCDI when ions, such as nitrate, are recognized to non-electrostatically adsorb strongly to activated carbon particles thereby potentially rendering it difficult to regenerate these particles. In this study, SCC FCDI was used to desalt source waters containing nitrate at different concentrations. Results indicate that nitrate can be removed from source waters using FCDI to concentrations <1 mg NO3-N L-1 though a lower quality target such as 10 mg L-1 would be more cost-effective, particularly where the influent nitrate concentration is high (50 mg NO3-N L-1). Although studies of the fate of nitrate in the FCDI system show that physico-chemical adsorption of nitrate to the carbon initially plays a vital role in nitrate removal, the ongoing process of nitrate removal is not significantly affected by this phenomenon with this lack of effect most likely due to the continued formation of electrical double layers enabling capacitive nitrate removal. In contrast to conventional CDI systems, constant voltage mode is shown to be more favorable in maintaining stable effluent quality in SCC FCDI because the decrease in electrical potential that occurs in constant current operation leads to a reduction in the extent of salt removal from the brackish source waters. Through periodic replacement of the electrolyte at a water recovery of 91.4%, we show that the FCDI system can achieve a continuous desalting performance with the effluent NO3-N concentration below 1 mg NO3-N L-1 at low energy consumption (~0.5 kWh m-3) but high productivity.


Omega-3 Fatty Acid Intake during Pregnancy and Child Neuropsychological Development: A Multi-Centre Population-Based Birth Cohort Study in Spain.
Background: There are few studies that look at the intake of all types of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during the different stages of pregnancy along with a long-term neuropsychological follow-up of the child. This study aims to explore the association between maternal n-3 PUFA intake during two periods of pregnancy and the child's neuropsychological scores at different ages. Methods: Prospective data were obtained for 2644 pregnant women recruited between 2004 and 2008 in population-based birth cohorts in Spain. Maternal n-3 PUFA intake during the first and third trimester of pregnancy was estimated using validated food frequency questionnaires. Child neuropsychological functions were assessed using Bayley Scales of Infant Development version one (BSID) at 1 year old, the McCarthy Scale of Children's Abilities (MSCA) at 4 years old, and the Attention Network Test (ANT) at 7 years old. Data were analysed using multivariate linear regression models and adjusted for potential covariates, such as maternal social class, education, cohort location, alcohol consumption, smoking, breastfeeding duration, and energy intake. Results: Compared to participants in the lowest quartile (<1.262 g/day) of n-3 PUFA consumption during the first trimester, those in the highest quartile (>1.657 g/day) had a 2.26 points (95% confidence interval (CI): 0.41, 4.11) higher MSCA general cognitive score, a 2.48 points (95% CI: 0.53, 4.43) higher MSCA verbal score, and a 2.06 points (95% CI: 0.166, 3.95) higher MSCA executive function score, and a 11.52 milliseconds (95% CI: −22.95, −0.09) lower ANT hit reaction time standard error. In the third pregnancy trimester, the associations were weaker. Conclusions: Positive associations between n-3 PUFA intake during early pregnancy and child neuropsychological functions at 4 and 7 years of age were found, and further clinical research is needed to confirm these findings.


Whence Resistance?
Antimicrobial resistance results from a complex interaction between pathogenic and non-pathogenic bacteria, antimicrobial pressure, and genes, which together comprise the total body of potential resistance elements. The purpose of this study is to review and evaluate the importance of antimicrobial pressure on the development of resistance in a single surgical intensive care unit. We reviewed a prospectively collected dataset of all intensive care unit (ICU)-acquired infections in surgical and trauma patients over a 6-y period at a single hospital. Resistant gram-negative pathogens (rGNR) included those resistant to all aminoglycosides, quinolones, penicillins, cephalosporins, or carbapenems; resistant gram-positive infections (rGPC) included methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE). Each resistant infection was evaluated for prior or concomitant antibiotic use, previous treatment for the same (non-resistant) organism, and concurrent infection with the same organism (genus and species, although not necessarily resistant) in another ICU patient. Three hundred and thirty resistant infections were identified: 237 rGNR and 93 rGPC. Infections with rGNR occurred frequently while receiving antibiotic therapy (65%), including the sensitive form of the subsequent resistant pathogen (42.2%). Infections with rGPC were also likely to occur on antimicrobial therapy (50.6%). Treatment of a different patient for an infection with the same resistant pathogen in the ICU at the time of diagnosis, implying potential patient-to-patient transmission occurred more frequently with rGNR infections (38.8%). Antimicrobial pressure exerts a substantial effect on the development of subsequent infection. Our data demonstrate a high estimated rate of de novo emergence of resistance after treatment, which appears to be more common than patient-to-patient transmission. These data support the concept that efforts to limit antimicrobial usage will be more efficacious than enhanced isolation procedures when trying to reduce antimicrobial resistance.


Association of glutathione S-transferase, EPHX, and p53 codon 72 gene polymorphisms with adult acute myeloid leukemia.
Polymorphisms in genes encoding detoxification enzymes have been suggested as susceptibility factors for many solid tumors. However, their association with hematological malignancies is controversial. A case-control study was done to determine the association between glutathione S-transferase M1 (GSTM1), GSTT1, GSTP1, EPHX1, and p53 codon 72 polymorphisms as risk factors in 120 adult acute myeloid leukemia (AML) cases and 202 healthy controls by polymerase chain reaction-restriction fragment length polymorphism techniques. Data were analyzed using χ(2) and conditional logistic regression model. None of the polymorphisms studied alone was associated with increased risk for AML. However, the frequency of GSTT1 null genotype was higher among controls (28.7%) than AML cases (21.6%), which showed a protective effect of the null genotype (odds ratio = 0.58, 95% confidence interval: 0.33-1.05, p = 0.07). In a combined analysis, both EPHX1 (His113His) and GSTP1 (Ile/Val) genes imparted a fourfold risk for adult AML but did not reach statistical significance (odds ratio = 4.22, 95% confidence interval: 0.992-17.99, p = 0.05). These findings suggest that the etiology of adult AML cannot be explained by polymorphism at a single locus, perhaps because of complexity involved in the metabolism of diverse xenobiotic compounds, and therefore, multiple gene-gene interactions should be investigated to predict the risk of AML.


Computer-Mediated Assessment of Intelligibility in Aphasia and Apraxia of Speech.
BACKGROUND: Previous work indicates that single word intelligibility tests developed for dysarthria are sensitive to segmental production errors in aphasic individuals with and without apraxia of speech. However, potential listener learning effects and difficulties adapting elicitation procedures to coexisting language impairments limit their applicability to left hemisphere stroke survivors. AIMS: The main purpose of this study was to examine basic psychometric properties for a new monosyllabic intelligibility test developed for individuals with aphasia and/or AOS. A related purpose was to examine clinical feasibility and potential to standardize a computer-mediated administration approach. METHODS #ENTITYSTARTX00026; PROCEDURES: A 600-item monosyllabic single word intelligibility test was constructed by assembling sets of phonetically similar words. Custom software was used to select 50 target words from this test in a pseudo-random fashion and to elicit and record production of these words by 23 speakers with aphasia and 20 neurologically healthy participants. To evaluate test-retest reliability, two identical sets of 50-word lists were elicited by requesting repetition after a live speaker model. To examine the effect of a different word set and auditory model, an additional set of 50 different words was elicited with a pre-recorded model. The recorded words were presented to normal-hearing listeners for identification via orthographic and multiple-choice response formats. To examine construct validity, production accuracy for each speaker was estimated via phonetic transcription and rating of overall articulation. OUTCOMES #ENTITYSTARTX00026; RESULTS: Recording and listening tasks were completed in less than six minutes for all speakers and listeners. Aphasic speakers were significantly less intelligible than neurologically healthy speakers and displayed a wide range of intelligibility scores. Test-retest and inter-listener reliability estimates were strong. No significant difference was found in scores based on recordings from a live model versus a pre-recorded model, but some individual speakers favored the live model. Intelligibility test scores correlated highly with segmental accuracy derived from broad phonetic transcription of the same speech sample and a motor speech evaluation. Scores correlated moderately with rated articulation difficulty. CONCLUSIONS: We describe a computerized, single-word intelligibility test that yields clinically feasible, reliable, and valid measures of segmental speech production in adults with aphasia. This tool can be used in clinical research to facilitate appropriate participant selection and to establish matching across comparison groups. For a majority of speakers, elicitation procedures can be standardized by using a pre-recorded auditory model for repetition. This assessment tool has potential utility for both clinical assessment and outcomes research.


Multichannel pulse dynamics in a stabilized Ginzburg-Landau system.
We study the stability and interactions of chirped solitary pulses in a system of nonlinearly coupled cubic Ginzburg-Landau (CGL) equations with a group-velocity mismatch between them, where each CGL equation is stabilized by linearly coupling it to an additional linear dissipative equation. In the context of nonlinear fiber optics, the model describes transmission and collisions of pulses at different wavelengths in a dual-core fiber, in which the active core is furnished with bandwidth-limited gain, while the other, passive (lossy) one is necessary for stabilization of the solitary pulses. Complete and incomplete collisions of pulses in two channels in the cases of anomalous and normal dispersion in the active core are analyzed by means of perturbation theory and direct numerical simulations. It is demonstrated that the model may readily support fully stable pulses whose collisions are quasielastic, provided that the group-velocity difference between the two channels exceeds a critical value. In the case of quasielastic collisions, the temporal shift of pulses, predicted by the analytical approach, is in semiquantitative agreement with direct numerical results in the case of anomalous dispersion (in the opposite case, the perturbation theory does not apply). We also consider a simultaneous collision between pulses in three channels, concluding that this collision remains quasielastic, and the pulses remain completely stable. Thus, the model may be a starting point for the design of a stabilized wavelength-division-multiplexed transmission system.


Functional genomics analysis of Singapore grouper iridovirus: complete sequence determination and proteomic analysis.
Here we report the complete genome sequence of Singapore grouper iridovirus (SGIV). Sequencing of the random shotgun and restriction endonuclease genomic libraries showed that the entire SGIV genome consists of 140,131 nucleotide bp. One hundred sixty-two open reading frames (ORFs) from the sense and antisense DNA strands, coding for lengths varying from 41 to 1,268 amino acids, were identified. Computer-assisted analyses of the deduced amino acid sequences revealed that 77 of the ORFs exhibited homologies to known virus genes, 23 of which matched functional iridovirus proteins. Forty-two putative conserved domains or signatures were detected in the National Center for Biotechnology Information CD-Search database and PROSITE database. An assortment of enzyme activities involved in DNA replication, transcription, nucleotide metabolism, cell signaling, etc., were identified. Viruses were cultured on a cell line derived from the embryonated egg of the grouper Epinephelus tauvina, isolated, and purified by sucrose gradient ultracentrifugation. The protein extract from the purified virions was analyzed by polyacrylamide gel electrophoresis followed by in-gel digestion of protein bands. Matrix-assisted laser desorption ionization-time of flight mass spectrometry and database searching led to identification of 26 proteins. Twenty of these represented novel or previously unidentified genes, which were further confirmed by reverse transcription-PCR (RT-PCR) and DNA sequencing of their respective RT-PCR products.


Surgery within multimodal therapy concepts for esophageal squamous cell carcinoma (ESCC): the MRI approach and review of the literature.
Radical esophagectomy with lymphadenectomy remains the only curative therapy for patients with resectable esophageal squamous cell cancer (ESCC), however, combined treatment modalities may improve survival. Based upon more than 1300 consecutive esophageal resections, we present our current multidisciplinary ESCC approach with analysis in the context of recently published RCTs. Subject to tumor staging, patients with resectable ESCC receive either a neoadjuvant radiochemotherapy (uT3N+) or are referred to primary surgery (uT1/2N0). By Medline searches (1997-2009), all published RCTs containing multimodal ESCC therapy concepts were identified and a systematic review was generated. From July 2007 to June 2009, 62 patients with ESCC were treated in our department (40 multimodal treatment concept, 21 primary surgery, 1 definite radiochemotherapy). The R0 resection rate was 78%, in hospital mortality 4.8%. 60% of patients showed a good response to neoadjuvant treatment. 18-month follow-up data revealed absence of tumor recurrence in 7 patients (18%). Our approach is aligned to the current published literature including 12 studies in this review. In line with our institutional experience, neodjuvant radiochemotherapy tends to improve overall survival and increases the likelihood of R0 resection. However, postoperative morbidity and mortality rates are increased. Adjuvant treatment failed to demonstrate any improvement in prognosis. For palliation, concurrent radiochemotherapy is the treatment of choice. The MRI approach can be aligned to the most recent published data. Surgical resection remains the principle treatment for patients with resectable ESCC. Although multimodal therapy concepts tend to improve survival rates, postoperative morbidity and mortality rates are increased.


Efficacy of Hyperthermia in Treatment of Recurrent Metastatic Breast Cancer After Long-Term Chemotherapy: A Report of 2 Cases.
BACKGROUND Breast cancer has a long-term prognosis with various multimodality treatments. This report introduces the effectiveness of radiofrequency (RF) hyperthermia in the long-term treatment for recurrent/metastatic breast cancer. CASE REPORT In the first case, the patient had bone and liver metastases during the course of chemotherapy, hormone therapy, and radiotherapy for 27 years after curative resection of breast cancer. Finally, she received RF hyperthermia alone for liver metastasis and showed a decrease in tumor markers and reduction in liver metastasis on computed tomography (CT). In the second case, the patient underwent curative resection for multiple occurrences on the left side of the breast. She received postoperative chemotherapy combined with hormone therapy but had metachronous local recurrences. She continued hormone therapy after 2 local recurrence resections; unfortunately, she had bone, liver, and lung metastases and pleural dissemination. Eventually, the patient received RF hyperthermia combined with oral chemotherapy. Her tumor markers decreased, and CT showed disappearance of lung metastasis and improved pleural dissemination. Furthermore, the reduction of chemotherapy adverse events due to hyperthermia allowed the patient to continue chemotherapy and improved her quality of life. CONCLUSIONS We present 2 cases in which RF hyperthermia had a positive effect despite the presence of a recurrent tumor after various types of surgery, chemotherapy, and radiotherapy. This report suggests that the addition of RF hyperthermia to conventional multidisciplinary therapies may enhance the therapeutic effect of these treatments and improve the quality of life in patients with recurrent breast cancer.


Successful treatment of chemotherapy-refractory angioimmunoblastic T cell lymphoma with cyclosporin A.
Angioimmunoblastic T cell lymphoma (AITL) is a rare subtype of T cell non-Hodgkin lymphoma. The standard therapeutic strategy for AITL has not yet been established, and its prognosis remains poor. This report concerns the effect of cyclosporin A (CsA) on chemotherapy-refractory AITL. A 68-year-old female with AITL with systemic symptoms, such as high fever, skin rash and generalized lymphadenopathy, was initially treated with conventional cytotoxic chemotherapies using alkylators, anthracyclines and corticosteroids, which failed to induce remission. However, CsA (4 mg/kg/day) plus dexamethasone treatment resulted in a dramatic regression of the tumors and amelioration of systemic symptoms and induced complete remission (CR) within 2 weeks. Currently, the patient's CR has continued for more than 18 months with CsA maintenance therapy. Our experience and previously reported findings suggest that CsA may constitute an alternative treatment option for AITL, even though the use of conventional cytotoxic chemotherapy continues to be the first-line therapy on an empirical basis.


Thoracoabdominal Aortic Aneurysm - The Branch First Technique.
Surgical management of thoracoabdominal aortic aneurysms is complex. In particular, maintaining adequate spinal cord and reno-visceral protection during the operation can be challenging. We describe here a branch-first technique developed at our institution, endeavoring to minimized renal and visceral organ ischemic time, decrease risk of spinal cord injury, and provide a controlled and uncluttered field in which the surgeon can operate.


[Erectile dysfunction, and risk factors of cardiovascular disease].
The paper is a review of the reports presenting the essential aspects of erectile dysfunctions being a serious challenge for the clinicians of various specializations because of increasing number of the diagnosed cases of sexual impairments caused by atherosclerotic background. The authors present the results of the most crucial studies concerning epidemiology of the said condition, an effect of the various demographic factors on its occurrence, with the focus laid on the significant correlation between classic risk factors of atherosclerotic cardiovascular disease and reasons leading to erectile dysfunctions. The work presents also the diagnostic and therapeutic obstacles, the physicians struggling with this more and more often disease, encounter in their every day practice.


The NCI's AIDS antiviral drug screening program.
The Developmental Therapeutics Program (DTP) in the National Cancer Institute has an unique mission by serving as a resource for all academic and private research institutions, the National Institutes of Health in the USA, and the global scientific community in the quest for effective therapeutic agents for treating patients with Acquired Immune Deficiency Syndrome (AIDS) as well as for cancer patients. This communication will concentrate on the developmental therapeutic program on anti-AIDS drug discovery.


Redefining smoking and the self as a nonsmoker.
A grounded theory approach was used to develop a substantive theory answering the question, What are older adults' experiences who have quit smoking? Interviews were conducted with 21 elders with a mean age of 67 years who had quit smoking for a minimum of 3 months and a maximum of 5 years. Data analysis yielded a core variable redefining smoking and the self as a nonsmoker, which was indicated by the major theoretical categories of recognizing the need to quit, making the decision, learning to be a nonsmoker, and sustaining as a nonsmoker. Participants actually changed their views about smoking and themselves as smokers. They believed that they were vulnerable because of their ages and that age and smoking were a problematic combination. Findings support that nurses and other health care providers can assist older adults in the process of quitting smoking.


Consanguinity in patients with mesial temporal lobe epilepsy due to hippocampal sclerosis in a Saudi population.
To investigate if there is an association between consanguinity and hippocampal sclerosis (HS) in the Saudi population. A retrospective case-control study was conducted by assessing the prevalence of consanguinity in patients with pathologically proven HS, who underwent epilepsy surgery at King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia, between January 2004 and December 2015. We reviewed the medical records to extract data, which included; age, gender, duration of epilepsy, history of febrile seizure, family history of epilepsy in a first or second-degree relative, and pathology reports. A total of 120 patients, out of which 40 patients (65% male) having mesial temporal lobe epilepsy due to HS, and 80 controls (56% male) with cryptogenic epilepsy, were identified. Twenty-two patients (53.5%) in the HS group had a history of consanguinity. In the control group, 30 patients (37.5%) had a history of consanguinity. The odds ratio was 2.04 (95% confidence interval = 0.94 - 4.4, p=0.052). A family history of epilepsy was found in 28% of the patients with HS and 32.5% cryptogenic epilepsy. Only 8 patients (19.5%) with HS reported a history of febrile seizure. Our retrospective case-control study suggests that consanguinity might increase the likelihood of developing HS.


Research on the Participation of Chinese Sports Cultural Elite in Ice and Snow Sports.
Governments have a responsibility to provide equal opportunities for sport and physical activity to all people of population. Chinese governments have issued many policies, such as "exhibition in the south, expansion in the West and East" of ice and snow sports to promote and stimulate the participation of the broad masses of the people. As a high-cost sport, the participants of ice and snow sports are usually socially elite groups. This study investigated the participation of cultural elite groups in ice and snow sports and investigated the social mobilization effect of ice and snow sports participation promotion policies by using binary regression and sequential regression models. The research shows that there are two different stages of one-time and continuous participation in the development of ice and snow sports in China. The one-time participation of ordinary people in ice and snow sports is mainly in response to the social mobilization of government policies. At the same time, it is positively correlated with site restrictions and knowledge of ice and snow sports. In the continuous participation group, gender, income, perception of ice and snow culture, and convenience near the site were highly positively correlated with consumption level. According to the results, low- and middle income people are less likely to participate in these activities because of their income. Therefore, this policy can increase inequalities.


Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases.
Analyses of the urinary concentration relative to creatinine of the collagen crosslinks, pyridinoline (Pyd) and deoxy-pyridinoline (Dpd) were made in 47 patients with metabolic bone diseases to assess the validity of these assays as indicators of bone resorption. The mean values for patients with Paget's disease of bone, primary hyperparathyroidism and osteomalacia were significantly higher (P less than 0.001) than those for age-matched healthy individuals. During treatment of Paget's disease with bisphosphonates, there was a steady decline in the urinary concentration of the crosslinks to the normal range; this change occurred earlier than for serum alkaline phosphatase. There were significant correlations (P less than 0.01) between the concentrations of both crosslinks and the corresponding values for hydroxyproline. At lower crosslink concentrations, however, these relationships were less marked due to large variations in hydroxyproline values. The results show that measurements of urinary Pyd and Dpd provide clinically applicable indices of bone resorption that are more specific than other markers.


Molecular and cell biology of cystic fibrosis.
The questions emerged in better focus: we need to know, definitively, what CFTR is and what it does. We need to know how mutant CFTR expression leads to the relentless lung disease that takes the lives of the patients. We need to know how the different mutations in CFTR behave functionally. Much more information is needed on the pathways for ion transport in the airways in order for us to consider therapeutic alternatives. Better information on CFTR expression, particularly in the lung, would greatly facilitate consideration of pathophysiology as well as gene therapy. Many of these questions can be attacked by imaginative use of the tools already in hand. The need is urgent. The wondrous scientific advancements of the last five years and the additional money being spent on CF research have bought no dramatic increase in life expectancy for the patients. Every day, three more succumb.


The oomycete microbe-associated molecular pattern Pep-13 triggers SERK3/BAK1-independent plant immunity.
Oomycetes MAMP Pep-13 can trigger SERK3/BAK1-independent PTI. Silencing of SERK3/BAK1 in solanaceous plants resulted in reduced expression of brassinosteroid marker genes and enhanced PTI transcriptional responses to Pep-13 treatment. To prevent disease, pattern recognition receptors (PRRs) are responsible for detecting microbe-associated molecular patterns (MAMPs) to switch on plant innate immunity. SOMATIC EMBROYOGENESIS KINASE 3 (SERK3)/BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1 (BAK1) is a well-characterized receptor-like kinase (RLK) that serves as a pivotal co-receptor with PRRs to activate immunity following recognition of MAMPs including flg22, EF-Tu, INF1 and XEG1. However, the requirement for SERK3/BAK1 in many pattern-triggered immune (PTI) signaling pathways is not yet known. Pep-13 is an oomycete MAMP that consists of a highly conserved motif (an oligopeptide of 13 amino acids) shared in Phytophthora transglutaminases. Quantitative RT-PCR analysis reveals that the transcripts of three PTI marker genes (WRKY7, WRKY8 and ACRE31) rapidly accumulate in response to three different MAMPs: flg22, chitin and Pep-13. Whereas silencing of SERK3/BAK1 in Nicotiana benthamiana or potato compromised transcript accumulation in response to flg22, it did not attenuate WRKY7, WRKY8 and ACRE31 up-regulation in response to chitin or Pep-13. This indicates that Pep-13 triggers immunity in a SERK3/BAK1-independent manner, similar to chitin. Surprisingly, silencing of SERK3/BAK1 led to significantly increased accumulation of PTI marker gene transcripts following Pep-13 or chitin treatment, compared to controls. This was accompanied by reduced expression of brassinosteroid (BR) marker genes StSTDH, StEXP8 and StCAB50 and StCHL1, which is a negative regulator of PTI, supporting previous reports that SERK3/BAK1-dependent BR signaling attenuates plant immunity. We provide Pep-13 as an alternative to chitin as a trigger of SERK3/BAK1-independent immunity.


Perineal approaches to rectal prolapse.
The management of full-thickness rectal prolapse involves surgical intervention in the majority of cases. Many procedures have been described. Perineal procedures are generally reserved for patients with multiple comorbid conditions or those considered too elderly or frail to withstand an abdominal surgical approach. They also play an important role in the management of rectal mucosal prolapse. The techniques, advantages, and complications of perineal approaches to rectal prolapse in use today are the focus of this chapter.


Metoprolol ameliorates cyclosporine a-induced hypertension and nephrotoxicity in rats.
Despite their clinical relevance as important cardiovascular modulators, there are few studies regarding the potential protective effect of β-blockers against immunosuppressive-induced cardiovascular side effects. This study investigated the possible ameliorating effect of β1-blocker, metoprolol (MTP), against both hypertensive and nephrotoxic effects of cyclosporine A (CSA). Compared with vehicle (olive oil)-treated rats, chronic treatment with CSA (20 mg·kg·d subcutaneous, for 14 days) increased systolic blood pressure, elevated renal function indices and plasma renin activity, impaired renovascular responsiveness of isolated perfused rat kidneys to endothelium-dependent vasodilations induced by carbachol. These effects were abolished upon concurrent administration of MTP (5 mg·kg·d for 14 days, intraperitoneal). The possibility that alterations in the antioxidant and/or circulating cytokine levels contributed to the CSA-MTP interaction was also investigated. MTP abrogated the oxidative (superoxide dismutase, catalase), lipid peroxidation (malondialdyde), and elevated the cytokine (TNF-α and TGF-β) effects of CSA. Histologically, CSA caused tubular brush border loss and isometric vacuolization clustered in the proximal tubule; this effect disappeared in rats cotreated with MTP. The use of a nonhypotensive dose of MTP (1.25 mg/kg) countered in part endothelium dysfunction altered oxidative stress parameters and cytokine levels in CSA-treated rats. Collectively, MTP abrogates both the hypertensive and the nephrotoxic effects of CSA via ameliorating endothelium dysfunction, oxidative stress, and upregulated cytokine levels caused by CSA. The demonstration of nephroprotection by the low dose of MTP suggests that its renal effect may be partially unrelated to its hemodynamic activity.


Care of the growth-restricted newborn.
With the first 1,000 days of life proving to be a critical window of opportunity for physical and cognitive growth and development, an optimal intrauterine environment is vital. If fetus needs are compromised prenatally, there is an increased risk of intrauterine growth restriction (IUGR), and infants being born premature, low birth weight (LBW), or small-for-gestational age (SGA). Specialized care of these high-risk infants is necessary in terms of preconception interventions, resuscitation, thermoregulation, nutritional support and kangaroo mother care. Significant evidence supports exclusive breastfeeding as the standard of care for feeding SGA, preterm, LBW and very low birth weight infants. Expressed milk or donor milk may also require fortification, to meet higher nutrient needs of these newborns. Future research should address the gap in the literature on specific care of term and preterm IUGR and or SGA infants, and strengthening evidence for human milk bank models and emollient care.


Games for Health: Past, Present, and Future?
This article provides a review of selected past and present games for health. This will highlight some existing games for health and examine the relationship between health content and game technology. Because of this relationship, new technology trends may suggest future approaches to the application of videogame-based health interventions.


[Research approaches in the behavioral genetics of psychiatric disorders].
Multi-factorial inheritance combines genetic and environmental effects. Each factor contributes a relatively small part to the overall phenotype. Multi-factorial multi-genetic illnesses are usually divided into two categories: 1. Continuous variation of the normal distribution--phenotypes that can be measured within the normal scale (i.e. blood pressure). A normal distribution is obtained and the mean is in the middle. 2. Multi-factorial threshold trait--a threshold separates between the existence or absence of the phenotype. The curve of distribution obtained only predicts sensitivity for the illness rather than it's existence, since the illness appears only beyond a specific threshold, which represents a specific combination of defected genes. Mental illnesses (psychoses, affective disorders and neuroses) are multi-factorial illnesses, affected at a level of approximately 50% by inheritance. These diseases are not inherited in a simple Mendelian way, and, most probably, many genes are involved. Today, there is still no biochemical or molecular marker for any of the mental illnesses, and diagnosis of patients is obtained according to behavioral accepted scales. The aim of behavioral genetics is to understand the interaction between genes and behavioral variability among individuals. Most behaviors are complex, and when a genetic influence is observed, we can not point at a single responsible gene. Behavioral genetics targets to identify multiple genes and to understand the contribution of each of them to a specific behavioral trait. Methods to study multi-gene diseases include linkage analysis, family studies, twin and adoption studies, search for candidate genes affected by drug therapy of the patients, analysis of candidate genes using knockout mice and SNP's, methods that identify the effect of specific genes on behavior by QTL, and gene expression using DNA differential display and DNA microarray chips. The present review summarizes and exemplifies these issues.


[Hypothermia during chemotherapy for lymphomas].
There are only few reports in the literature on the occurrence of hypothermia after chemotherapy. It occurred after various cytostatics and lasted for few hours to several days. Our material consisted of 11 patients with malignant lymphoma who were given chemotherapy protocols including cisplatin. In 5 patients (2 with Hodgkin's disease and 3 with non-Hodgkin's lymphoma) who had high fever, after treatment the temperature decreased down to 34.3 degrees C. Hypothermia disappeared spontaneously after few days. The drug responsible for this effect in our patients was cisplatin.


Papillary Tumor of Pineal Region in a 5-Year-Old Male Child: A Rare Entity.
Papillary tumor of the pineal region (PTPR) is a rare grade II to III pineal lesion. These tumors mostly occur in adults, only rarely in children, with six cases in children under the age of 16 years (10.2%) up to now. We report the case of a 5-year-old male child presenting with worsening headaches, abnormally enlarged head since birth and visual disturbances. Imaging reveals a mass in the region of the pineal gland. The third and lateral ventricles were enlarged. The patient underwent a gross-total surgical resection of pineal mass through a suboccipital supracerebellar approach and tissue sent for histopathological examination and an available immunohistochemical workup has been done which confirmed the diagnosis of papillary tumor pineal region. This case highlights the histopathological features, imaging along clinical presentation similar to those in the original description of this rare entity PTPR. More studies are required to determine the prognosis and standard treatment protocol of this rare entity.


Frontoethmoidal giant cell reparative granuloma.
We present a case of a giant cell reparative granuloma of the frontoethmoidal region that had a large intracranial extraaxial component and was studied with MR. Although rare, giant cell reparative granuloma can be suggested in the correct clinical setting and when MR features suggest a fibrous lesion.


Prevalence of color vision deficiency among school children in Wolkite, Southern Ethiopia.
Colour vision deficiency is the commonest disorders of vision and undiagnosed colour vision defect could pose a handicap to the performance of an affected student. The prevalence of colour blindness varies in different geographical area and ethnicity. Hence, a cross sectional study was conducted among school children in Gurage Zone, Southern Ethiopia from April 15 to June 20, 2018. Socio-demographic data was collected on a face to face interview using structured questionnaire. All study participants underwent color vision evaluation using Ishihara's pseudo isochromatic test 38 plate editions. Data analysis was done using SPSS version 23. A total of 844 (471 boys and 373 girls) school children were screened for colour vision. The overall prevalence of colour vision deficiency was 4.1%, comprised of 3.6% in boys and 0.6% in girls. Out of 35 color blind subjects, 15 (42.9%) and 20 (57.1%) were the victims of protan and deutan defects respectively. Majority of the colour blind subjects were not aware of their colour vision status. Hence, the study concluded that the prevalence of colour vision deficiency in our study is significant and colour vision screening among school should be performed.


The isolation and identification of pathogenic fungi from Tessaratoma papillosa Drury (Hemiptera: Tessaratomidae).
Litchi stink-bug, Tessaratoma papillosa Drury (Hemiptera: Tessaratomidae), is one of the most widespread and destructive pest species on Litchi chinensis Sonn and Dimocarpus longan Lour in Southern China. Inappropriate use of chemical pesticides has resulted in serious environmental problems and food pollution. Generating an improved Integrated Pest Management (IPM) strategy for litchi stink-bug in orchard farming requires development of an effective biological control agent. Entomopathogenic fungi are regarded as a vital ecological factor in the suppression of pest populations under field conditions. With few effective fungi and pathogenic strains available to control litchi stink-bug, exploration of natural resources for promising entomopathogenic fungi is warranted. In this study, two pathogenic fungi were isolated from cadavers of adult T. papillosa. They were identified as Paecilomyces lilacinus and Beauveria bassiana by morphological identification and rDNA-ITS homogeneous analysis. Infection of T. papillosa with B. bassiana and P. lilacinus occurred initially from the antennae, metameres, and inter-segmental membranes. Biological tests showed that the two entomopathogenic fungi induced high mortality in 2nd and 5th instar nymphs of T. papillosa. B. bassiana was highly virulent on 2nd instar nymphs of T. papillosa, with values for cadaver rate, LC50 and LT50 of 88.89%, 1.92 × 107 conidia/mL and 4.34 days respectively. This study provides two valuable entomopathogenic fungi from T. papillosa. This finding suggests that the highly virulent P. lilacinus and B. bassiana play an important role in the biocontrol of T. papillosa in China. These pathogenic fungi had no pollution or residue risk, and could provide an alternative option for IPM of litchi stink-bug.


Reduction of the current of injury leaving the amputation inhibits limb regeneration in the red spotted newt.
Immediately following amputation of the limb in salamanders, a strong, steady, and polarized flow of ionic current is produced by the injury. Current flows in a proximodistal direction within the limb stump and is associated with a fall in electrical potential of about 50 mV/mm near the stump's end. This current is electrogenically driven by the Na(+)-dependent, internally positive transcutaneous voltage of the intact skin of the limb stump. Reduction of this EMF, the skin's battery, by topical application of Na+ blocking agents leads to inhibition or disruption of normal limb regeneration. This suggests electrical factors are a critical control of limb regeneration. Here we test another means to reduce the injury current and its associated electrical field within the forelimb stump of red spotted newts. A fine (40 gauge), insulated, multistrand wire was inserted beneath the skin of the animal's back, with the uninsulated portion terminating either at the shoulder region or at the base of the tail. When this cathodal (negative) electrode is connected to a regulated current source, sufficient current was pulled into the stump end from an external anode (placed in the water the animal was immersed in) to markedly reduce or null the endogenous current for the first 8 days following amputation. The extent of limb regeneration in sham-treated and experimentally treated animals was determined 1 month following amputation at the elbow. Sham-treated animals regenerated normally, with most producing digits within this time. Limb regeneration was completely arrested, or caused to be strikingly hypomorphic, in half of the experimentally treated animals. This effect was independent of where the subcutaneous electrode was placed and suggests that electrical (physiological) factors are indeed a critical control of limb regeneration in urodeles.


Heterologous sensitization of adenylate cyclase is protein kinase A-dependent in Cath.a differentiated (CAD)-D2L cells.
Persistent activation of Galphai/o-coupled receptors results in a paradoxical enhancement of subsequent drug-stimulated adenylate cyclase activity. The exact mechanism of this up-regulation in the cyclic AMP signaling pathway, known as heterologous sensitization, remains undefined. The present study was designed to investigate the involvement of cyclic AMP-dependent protein kinase in D2L receptor-mediated sensitization in a neuronal cellular environment. The current studies were conducted in the Cath.a differentiated (CAD) cell line transfected stably with the D2L dopamine receptor (CAD-D2L). Long-term 18 h treatment with the D2 receptor agonist, quinpirole, resulted in a two-fold enhancement of forskolin-stimulated cyclic AMP accumulation. Similarly, long-term treatment with the PKA inhibitors, H89 or Rp-8Br-cAMP, also enhanced adenylate cyclase activity. In contrast, long-term activation of protein kinase A (PKA) by forskolin, isobutylmethylxanthine (IBMX), or dibutyryl cyclic AMP caused a significant reduction in subsequent forskolin-stimulated cyclic AMP accumulation and reduced both quinpirole- and H89-induced heterologous sensitization. The effects of PKA inhibitors and activators did not involve changes in PKA subunit expression. RT-PCR analysis of adenylate cyclase isoform expression patterns revealed the expression of mRNA for ACVI and ACIX in CAD-D2L cells. The ability of ACVI to be negatively regulated by PKA is consistent with the observation that inhibition of PKA results in heterologous sensitization of adenylate cyclase activity in CAD-D2L cells.


Cloning and characterization of cDNA of the GPI-anchored purple acid phosphatase and its root tissue distribution in Spirodela oligorrhiza.
A cDNA clone of the glycosylphosphatidylinositol (GPI)-anchored purple acid phosphatase (PAP) has been obtained by a combination of cDNA library screening and 5' rapid amplification of cDNA ends from Spirodela oligorrhiza plants grown under phosphate-deficient (-P) conditions. The open reading frame of the S. oligorrhiza PAP cDNA consists of 1 365 bp encoding a 455 amino acid protein. Its deduced amino acid sequence shows 82 and 80% similarity to Arabidopsis thaliana and Phaseolus vulgaris PAP, respectively. The amino acid residue, Ala439, followed by two more small amino acid residues, Asp and Ser, is predicted to be the GPI-anchoring (omega) site. The absence of a dibasic motif upstream of the putative omega site suggests that the PAP is a cell wall protein. This presumption is supported by the finding that PAP was released by digestion of the cell wall fraction with cellulase. The GPI anchor is speculated to be a signal for transporting PAP to the cell wall. Immunohistochemical results using -P plant roots demonstrate that PAP is preferentially distributed in the outermost cortical cells of roots but not in the epidermis, suggesting its role in acquiring inorganic phosphate under phosphate-deficient conditions. Northern blot analysis using the S. oligorrhiza PAP cDNA as a probe demonstrates that expression of the PAP gene increased during growth of -P plants and this time-dependent occurrence in mRNA levels of the PAP in -P plants was also observed in their protein and activity levels.


Echocardiographic evaluation of right ventricular function in patients with acute pulmonary embolism: a study using tricuspid annular motion.
Assessment of right ventricular (RV) function is a challenge due to complex anatomy. We studied systolic and diastolic tricuspid annular excursion and longitudinal RV fractional shortening as geometry-independent measures in patients with acute pulmonary embolism (PE). Forty patients with PE were studied within 24 hours after admission and after 3 months, and compared to 23 healthy subjects used as controls. We recorded tricuspid annular plane systolic (TAPSE) and diastolic (TAPDE) excursion from the four-chamber view and calculated RV fractional shortening as TAPSE/RV diastolic length. The diastolic RV function was defined as the ratio of the amplitude of tricuspid annular plane excursion during atrial systole to total tricuspid annular plane diastolic excursion (atrial/total TAPDE). In the acute stage, the TAPSE was decreased in PE compared to healthy subjects (19 +/- 5 vs. 26 +/- 4 mm, P < 0.001), with greater reduction in patients with increased, compared to normal, RV pressure (16.6 +/- 5 vs. 20.5 +/- 5 mm, P < 0.05). The atrial/total TAPDE was increased in patients compared to healthy subjects (47 +/- 13% vs. 38 +/- 7%, P < 0.001) and normalized during the follow-up. Although the patients were asymptomatic after 3 months, the TAPSE recovered incompletely as compared to healthy subjects (21.4 +/- 4 vs. 26 +/- 4 mm, P < 0.001). Both systolic and diastolic RV function are impaired in acute PE. Diastolic function recovers faster than systolic; therefore, the atrial contribution to RV filling may be a useful measure to follow changes in diastolic function in PE.


Lentigo maligna/lentigo maligna melanoma: current state of diagnosis and treatment.
Lentigo maligna (LM) is a subtype of melanoma in situ that typically develops on sun-damaged skin. Presentation may be quite subtle and delayed diagnosis is common. Clinical margins are often ill defined. Histologic evaluation can be difficult due to the widespread atypical melanocytes that are present in the background of long-standing sun damage. Recurrence following standard therapies is common. To review the clinical features, histopathology, and treatment options for LM. Emphasis is placed on recent advances in the treatment of LM. Literature review. The estimated lifetime risk of LM progressing to LM melanoma is 5%. Standard excision of LM with 5 mm margins is insufficient in 50% of cases. The recurrence rate with standard excision ranges from 8 to 20%. Mohs surgery and staged excision may offer better margin control and lower recurrence rates (4-5%). Estimates of recurrence rates following nonsurgical therapies such as cryosurgery, radiotherapy, electrodessication and curettage, laser surgery, and topical medications range from 20 to 100% at 5 years. Adequate treatment of LM requires a comprehensive knowledge of the diagnostic features, histopathology, and treatment options. Surgical modalities with meticulous evaluation of tissue margins appears to offer the lowest rates of disease recurrence.


[A case of HCC with a tumor thrombus in the main portal vein surviving (Vp4) for over three years and six months].
On June 22, 1984, a 69-year-old man was admitted to hospital because of high fever and weight loss. On admission, laboratory data revealed the following: ICG R15 17%, and an AFP of 14 X 10(4) ng/ml. Celiac angiogram revealed a hypervascular tumor, a prominent A-P shunt, and an obstruction of the main portal trunk. After three sessions of one shot chemotherapy using ADM, MMC, and CDDP during the first admission, the AFP serum level decreased to 17,400 ng/ml, and tumor size regressed. Subsequently, the patient has received eighteen sessions of one-shot chemotherapy every two to four months and is still alive as of December 1987.


Thalidomide and prednisolone inhibit growth factor-induced human retinal pigment epithelium cell proliferation in vitro.
Thalidomide and prednisolone were recently introduced as treatment modalities in age-related macular degeneration (AMD). Growth factor-induced activation of retinal pigment epithelial (RPE) cells is a crucial event in this disease. The purpose was to examine the effect of thalidomide and prednisolone on growth factor-preactivated RPE cells. Human RPE cells were stimulated with 10 ng/ml platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), or vascular endothelial growth factor (VEGF) for 24 h. Afterwards, thalidomide (50 microg/ml) or prednisolone (100 ng/ml) were added for 24 h. RPE cell proliferation was determined by [3H]-thymidine incorporation. PDGF and bFGF significantly stimulated human RPE cell proliferation (p < 0.005), the value for VEGF stimulation was not significant (p = 0.3). The effect of the growth factors was diminished after addition of thalidomide and prednisolone (p < 0.005). The current study shows that the inhibitory properties of thalidomide and prednisolone remain even after growth factor activation of the cells.


How Signaling Molecules Regulate Tumor Microenvironment: Parallels to Wound Repair.
It is now suggested that the inhibition of biological programs that are associated with the tumor microenvironment may be critical to the diagnostics, prevention and treatment of cancer. On the other hand, a suitable wound microenvironment would accelerate tissue repair and prevent extensive scar formation. In the present review paper, we define key signaling molecules (growth factors, cytokines, chemokines, and galectins) involved in the formation of the tumor microenvironment that decrease overall survival and increase drug resistance in cancer suffering patients. Additional attention will also be given to show whether targeted modulation of these regulators promote tissue regeneration and wound management. Whole-genome transcriptome profiling, in vitro and animal experiments revealed that interleukin 6, interleukin 8, chemokine (C-X-C motif) ligand 1, galectin-1, and selected proteins of the extracellular matrix (e.g., fibronectin) do have similar regulation during wound healing and tumor growth. Published data demonstrate remarkable similarities between the tumor and wound microenvironments. Therefore, tailor made manipulation of cancer stroma can have important therapeutic consequences. Moreover, better understanding of cancer cell-stroma interaction can help to improve wound healing by supporting granulation tissue formation and process of reepithelization of extensive and chronic wounds as well as prevention of hypertrophic scars and formation of keloids.


The effect of spray drying on the compaction properties of hypromellose acetate succinate.
The aim of this study was to evaluate the compaction behavior of a model two-component amorphous spray-dried dispersion system compared with the unprocessed excipients, using simulated rotary tablet press production conditions. In this study, the stabilizing polymer, hypromellose acetate succinate (HPMCAS), was solubilized and spray dried with and without sodium lauryl sulfate (SLS). The impact of compression force and speed on the tabletting process was quantified by means of tablet tensile strength, compaction energy, and Heckel analysis. Addition of the surfactant SLS, spray dried or as a physical mix, reduced the tablet strength. However, a lesser impact on the unprocessed excipients was observed in comparison with the spray-dried excipients. In the presence of 1% (w/w) SLS, tablets displayed a tendency to cap when compressed at higher speeds, supported by high elastic energy values indicating high uniaxial stress upon decompression. In the presence of 3% (w/w) SLS, tablets could not be produced at high speeds. Heckel analysis revealed a greater strain rate sensitivity of HPMCAS when spray dried in the presence of surfactant. Exposure of samples to a range of relative humidities before compaction had no effect on tablet strength. This study has shown that spray drying of HPMCAS in the presence of a surfactant affects the compressibility of the material, resulting in decreased tablet strength, increased elastic deformation, and capping.


Stress or Strain Does Not Impact Sorption in Stiff Mesoporous Materials.
The present paper investigates strain-induced sorption in mesoporous silicon. Contrarily to a previous report based on indirect evidence, we find that external mechanical strain or stress has no measurable impact on sorption isotherms, down to a relative accuracy of 10-3. This conclusion is in agreement with the analysis of the sorption-induced strain of porous silicon and holds for other stiff mesoporous materials such as porous silicas.


Alterations in the O-linked glycosylation of IgA1 in children with Henoch-Schönlein purpura.
To examine O-linked glycosylation of serum IgA1 in children with acute Henoch-Schönlein purpura (HSP). The O-linked oligosaccharides of serum IgA1 from 28 children with acute HSP and 26 control children were examined by enzyme immunoassay using plant lectins with well defined carbohydrate binding specificities. The lectins included Artocarpus integrifolia (jacalin), Arachis hypogaea (peanut lectin), and Sambucus nigra (elderberry lectin). Jacalin binds to galactose-N-acetylgalactosamine (Gal-GalNAc). Jacalin interaction with this oligosaccharide is not influenced by the presence of sialic acid on the galactose moiety. Peanut lectin also interacts with Gal-GalNAc, but binding is inhibited if the galactose residue is sialylated. Elderberry lectin binds to N-acetylneuraminic acid (sialic acid). There was no difference in the binding of jacalin to IgA1 from patients with HSP compared to controls (p = 0.5). The binding of peanut lectin to IgA1 was significantly higher in HSP compared to controls (p = 0.007). Since peanut lectin binding is inhibited by the presence of sialylated galactose, these results suggest diminished sialic content of the O-linked oligosaccharides of IgA1 in HSP compared to controls. Indeed, the binding of the sialic acid-specific elderberry lectin to IgA1 was significantly lower in HSP compared to controls (p = 0.004). The O-linked oligosaccharides of serum IgA1 from children with acute HSP are deficient in salic acid compared to serum IgA1 from control children.


Induction of Ig light chain gene rearrangement in heavy chain-deficient B cells by activated Ras.
During B cell development, rearrangement and expression of Ig heavy chain (HC) genes promote development and expansion of pre-B cells accompanied by the onset of Ig light chain (LC) variable region gene assembly. To elucidate the signaling pathways that control these events, we have tested the ability of activated Ras expression to promote B cell differentiation to the stage of LC gene rearrangement in the absence of Ig HC gene expression. For this purpose, we introduced an activated Ras expression construct into JH-deleted embryonic stem cells that lack the ability to assemble HC variable region genes and assayed differentiation potential by recombination activating gene (RAG) 2-deficient blastocyst complementation. We found that activated Ras expression induces the progression of B lineage cells beyond the developmental checkpoint ordinarily controlled by mu HC. Such Ras/JH-deleted B cells accumulate in the periphery but continue to express markers associated with precursor B cells including RAG gene products. These peripheral Ras/JH-deleted B cell populations show extensive Ig LC gene rearrangement but maintain an extent of kappa LC gene rearrangement and a preference for kappa over lambda LC gene rearrangement similar to that of wild-type B cells. We discuss these findings in the context of potential mechanisms that may regulate Ig LC gene rearrangement.