Membrane hydrophone measurement and numerical simulation of HIFU fields up to developed shock regimes.
For the characterization of high-intensity focused ultrasound (HIFU) fields, hydrophone measurements should be performed in water in the whole range of the radiated power; however, cavitation occurs at high output, leading to the destruction of the hydrophone. To avoid this problem, a new hydrophone with additional protective layers covering the electrodes was developed and tested in the experiments. A single-element 1-MHz focusing ultrasound source was used for detailed measurements of the acoustic field in the axial and lateral planes. Measurements were performed with a new membrane hydrophone up to the focal peak compressional and rarefactional pressures of 55.6 and of 12.8 MPa, respectively, when the shock front had already formed in the waveform. Numerical modeling for the beams of periodic waves with an initially uniform amplitude distribution was performed, based on the Khokhlov-Zabolotskaya-Kuznetsov equation. Numerical solutions were compared with the experimental data and found to be in good agreement (within 10%). The influences of the limited bandwidth and the spatial averaging effect of the hydrophone on the accurate measurements of the acoustic field parameters were also investigated.


[Sporotrichosis in patients attending a reference center in Abancay, Peru].
A descriptive study was conducted between the months of May and August 2008 in Santa Teresa Medical Center, Abancay. Of 33 patients clinically suspected with Sporotrichosis: 20 patients were identified with Sporothrix schenckii. 11 (55%) of patients were males. Children between 0 and 14 years were most affected. 60% of the lesions were fixed cutaneous being more frequent in the head and neck (40%). 55% had lessions for less than one month. In pediatric population with involvement of head and neck, Sporotrichosis should be considered in the differential diagnosis of skin lesions of patients from endemic areas.


Genomics, nutrition, obesity, and diabetes.
To present evidence of genetic and environmental interactions as they relate to nutrition, diabetes, and obesity. A review of seminal literature related to genetics, obesity, and diabetes. Multifactorial interactions are important in the development of nutrition-related disorders, but the challenge remains to explain how these interactions are expressed. Treating subpopulations of people might be important and useful to some extent at present, but in the future treating people of given genetic predispositions and other personal and environmental factors will have greater effects on quality-of-life indicators and life expectancies. Individualization coupled with multifactorial interactions will lead to new and more effective preventive and treatment modalities of nutrition-related disorders. With obesity and diabetes, genomics will bridge the traditional use of diet, exercise, and weight reduction with other environmental factors, ultimately leading to healthier lives.


Developing Equitable Primary Health Care in Conflict-Affected Settings: Expert Perspectives From the Frontlines.
Health systems are frequently among the casualties of conflict. Within these settings, increased knowledge is needed on how to rebuild and strengthen health infrastructure resilience, such as primary health care (PHC) systems, in context-specific ways that promote health equity. Therefore, this study aimed to explore perspectives of experts with experience working on frontlines of social crises to contribute to understandings of pathways toward equitable PHC in conflict-affected settings. Semistructured qualitative interviews with 18 expert participants were completed. Through engaging elements of grounded theory situational analysis, three themes emerged iteratively, including (a) Building Blocks, (b) Intermediating Factors, and (c) a Roadmap. These emergent themes contribute to conceptual frameworks explaining key contextually specific priorities, challenges, and facilitating factors for developing resilient health infrastructures under social crises. Findings inform policy and practical guidelines that address complexities of conflict conditions and underscore the importance of PHC development toward promoting health as a human right.


Animal models in chronic obstructive pulmonary disease-an overview.
ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction resultant from an augmented inflammatory response of the respiratory tract to noxious particles and gases. Previous reports present a number of different hypotheses about the etiology and pathophysiology of COPD. The generating mechanisms of the disease are subject of much speculation, and a series of questions and controversies among experts still remain. In this context, several experimental models have been proposed in order to broaden the knowledge on the pathophysiological characteristics of the disease, as well as the search for new therapeutic approaches for acute or chronically injured lung tissue. This review aims to present the main experimental models of COPD, more specifically emphysema, as well as to describe the main characteristics, advantages, disadvantages, possibilities of application, and potential contribution of each of these models for the knowledge on the pathophysiological aspects and to test new treatment options for obstructive lung diseases.


Calprotectin induces cell death in human prostate cancer cell (LNCaP) through survivin protein alteration.
Calprotectin (CP), an abundant heterodimeric cytosolic protein of neutrophils, conveys a variety of functions such as tumor cell growth arrest and antimicrobial activity. We investigated CP activity and its possible apoptosis-inducing mechanism of action against an antiandrogen therapy-resistance prostate cancer cell line LNCaP. Cell viability and Annexin V FITC assays were performed in order to investigate its cell death activity and apoptosis, respectively. In order to address cell death inducing mechanism(s), immunocytochemistry and immunobloting analysis, reactive oxygen species (ROS) and nitric oxide (NO) measurements were performed. The effective concentration of CP against LNCaP promoting LNCaP cell death was 200 µg/mL. ROS and NO levels of cells remarkably were enhanced following treatment with 50 and 100 µg/mL of CP, respectively. Protein expression of anti-apoptotic protein survivin was significantly decreased after administration of tumor cells with CP. Our data indicate that CP regulates the LNCaP cells viability via survivin-mediated pathway and ROS and NO enhancement. Thus, inhibition of survivin expression, enhancement of ROS and NO level by CP or other similar pharmaceutical agents might be effective in lowering the malignant proliferation of human prostate cancer cells.


Role of Areal Capacity in Determining Short Circuiting of Sulfide-Based Solid-State Batteries.
Solid-state batteries (SSBs) with lithium metal anodes offer higher specific energy than conventional lithium-ion batteries, but they must utilize areal capacities >3 mAh cm-2 and cycle at current densities >3 mA cm-2 to achieve commercial viability. Substantial research effort has focused on increasing the rate capabilities of SSBs by mitigating detrimental processes such as lithium filament penetration and short circuiting. Less attention has been paid to understanding how areal capacity impacts lithium plating/stripping behavior in SSBs, despite the importance of areal capacity for achieving high specific energy. Here, we investigate and quantify the relationships among areal capacity, current density, and plating/stripping stability using both symmetric and full-cell configurations with a sulfide solid-state electrolyte (Li6PS5Cl). We show that unstable deposition and short circuiting readily occur at rates much lower than the measured critical current density when a sufficient areal capacity is passed. A systematic study of continuous plating under different electrochemical conditions reveals average "threshold capacity" values at different current densities, beyond which short circuiting occurs. Cycling cells below this threshold capacity significantly enhances cell lifetime, enabling stable symmetric cell cycling at 2.2 mA cm-2 without short circuiting. Finally, we show that full cells with LiNi0.8Mn0.1Co0.1O2 also exhibit threshold capacity behavior, but they tend to short circuit at lower current densities and areal capacities. Our results quantify the effects of transferred capacity and demonstrate the importance of using realistic areal capacities in experiments to develop viable solid-state batteries.


Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is determined by T cells.
Following Mycobacterium tuberculosis infection, alveolar macrophages are initially infected but ineffectively restrict bacterial replication. The distribution of M. tuberculosis among different cell types in the lung changes with the onset of T cell immunity when the dominant infected cellular niche shifts from alveolar to monocyte-derived macrophages (MDM). We hypothesize that changes in bacterial distribution among different cell types is driven by differences in T cell recognition of infected cells and their subsequent activation of antimicrobial effector mechanisms. We show that CD4 and CD8 T cells efficiently eliminate M. tuberculosis infection in alveolar macrophages, but they have less impact on suppressing infection in MDM, which may be a bacterial niche. Importantly, CD4 T cell responses enhance MDM recruitment to the lung. Thus, the outcome of infection depends on the interaction between the T cell subset and the infected cell; both contribute to the resolution and persistence of the infection.


Quantitative evaluation of diffusion-weighted MRI for differentiating benign and malignant thyroid nodules larger than 4 cm.
Our study aimed to diagnose benign or malignant thyroid nodules larger than 4 cm using quantitative diffusion-weighted imaging (DWI) analysis. Eighty-two thyroid nodules were investigated retrospectively and divided them into benign (n = 62) and malignant groups (n = 20). We calculated quantitative features DWI and apparent diffusion coefficient (ADC) signal intensity standard deviation (DWISD and ADCSD), DWI and ADC signal intensity ratio (DWISIR and ADCSIR), mean ADC and minimum ADC value (ADCmean and ADCmin) and ADC value standard deviation (ADCVSD). Univariate and multivariate logistic regression were conducted to identify independent predictors, and develop a prediction model. We performed receiver operating characteristic (ROC) analysis to determine the optimal threshold of risk factors, and constructed combined threshold models. Our study calculated diagnostic performance including area under the ROC curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and unnecessary biopsy rate of all models were calculated and compared them with the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) result. Two independent predictors of malignant nodules were identified by multivariate analysis: DWISIR (P = 0.007) and ADCmin (P < 0.001). The AUCs for multivariate prediction model, combined DWISIR and ADCmin thresholds model, combined DWISIR and ADCSIR thresholds model and ACR-TIRADS were 0.946 (0.896-0.996), 0.875 (0.759-0.991), 0.777 (0.648-0.907) and 0.722 (0.588-0.857). The combined DWISIR and ADCmin threshold model had the lowest unnecessary biopsy rate of 0%, compared with 56.3% for ACR-TIRADS. Quantitative DWI demonstrated favorable malignant thyroid nodule diagnostic efficacy. The combined DWISIR and ADCmin thresholds model significantly reduced the unnecessary biopsy rate.


Long-term compliance with continous positive airway pressure in patients with obstructive sleep apnea syndrome.
A ten-year retrospective analysis of the clinical features and survival of 60 Saudi children with systemic lupus erythematosus (SLE) was made. All the patients fulfilled the 1982 American College of Rheumatologyâs revised criteria for SLE and had had the disease at or before the age of 16 years. The female to male ratio was 5:1, the mean age of onset was 12.1 years (range 1.6-16 years), and the mean duration of follow-up was 4.7 years (range 2.2-11). Thirty-eight patients (63%) were diagnosed correctly before referral to KFSH&RC or KKUH. The mode of presentation was as follows: 55 patients had musculoskeletal involvement (91.6%), 49 patients had skin involvement (81.6%), 40 patients had hematological abnormalities (66.6%), 39 patients had renal disease (65%), 10 patients had pulmonary involvement (16%), 23 patients had cardiovascular disease (38%) and 18 patients had central nervous system involvement. During the study period four patients died (6.6%)âtwo of renal failure, one from meningitis and one from severe sepsis. This is the largest collection of childhood systemic lupus erythematosus from the Middle East and it shows that SLE is more common in Saudis than was hitherto believed, and that it has a high rate of organ involvement.


Purification of a Crenarchaeal ATP Synthase in the Light of the Unique Bioenergetics of Ignicoccus Species.
In this study, the ATP synthase of Ignicoccus hospitalis was purified, characterized, and structurally compared to the respective enzymes of the other Ignicoccus species, to shed light on energy conservation in this unique group of archaea. The crenarchaeal genus Ignicoccus comprises three described species, i.e., I. hospitalis and Ignicoccus islandicus from hot marine sediments near Iceland and Ignicoccus pacificus from a hydrothermal vent system in the Pacific Ocean. This genus is unique among all archaea due to the unusual cell envelope, consisting of two membranes that enclose a large intermembrane compartment (IMC). I. hospitalis is the best studied member of this genus, mainly because it is the only known host for the potentially parasitic archaeon Nanoarchaeum equitansI. hospitalis grows chemolithoautotrophically, and its sole energy-yielding reaction is the reduction of elemental sulfur with molecular hydrogen, forming large amounts of hydrogen sulfide. This reaction generates an electrochemical gradient, which is used by the ATP synthase, located in the outer cellular membrane, to generate ATP inside the IMC. The genome of I. hospitalis encodes nine subunits of an A-type ATP synthase, which we could identify in the purified complex. Although the maximal in vitro activity of the I. hospitalis enzyme was measured around pH 6, the optimal stability of the A1AO complex seemed to be at pH 9. Interestingly, the soluble A1 subcomplexes of the different Ignicoccus species exhibited significant differences in their apparent molecular masses in native electrophoresis, although their behaviors in gel filtration and chromatography-mass spectrometry were very similar.IMPORTANCE The Crenarchaeota represent one of the major phyla within the Archaea domain. This study describes the successful purification of a crenarchaeal ATP synthase. To date, all information about A-type ATP synthases is from euryarchaeal enzymes. The fact that it has not been possible to purify this enzyme complex from a member of the Crenarchaeota until now points to significant differences in stability, possibly caused by structural alterations. Furthermore, the study subject I. hospitalis has a particular importance among crenarchaeotes, since it is the only known host of N. equitans The energy metabolism in this system is still poorly understood, and our results can help elucidate the unique relationship between these two microbes.


The injustice of unsafe motherhood.
This paper presents an overview of the dimensions of unsafe motherhood, contrasting data from economically developed countries with some from developing countries. It addresses many common factors that shape unsafe motherhood, identifying medical, health system and societal causes, including women's powerlessness over their reproductive lives in particular as a feature of their dependent status in general. Drawing on perceptions of Jonathan Mann, it focuses on public health dimensions of maternity risks, and equates the role of bioethics in conscientious medical care to that of human rights in public health care. The microethics of medical care translate into the macroethics of public health, but the transition compels some compromise of personal autonomy, a key feature of Western bioethics, in favour of societal analysis. Religiously-based morality is seen to have shaped laws that contribute to unsafe motherhood. Now reformed in former colonizing countries of Europe, many such laws remain in effect in countries that emerged from colonial domination. UN conferences have defined the concept of 'reproductive health' as one that supports women's reproductive self-determination, but restrictive abortion laws and practices epitomize the unjust constraints to which many women remain subject, resulting in their unsafe motherhood. Pregnant women can be legally compelled to give the resources of their bodies to the support of others, while fathers are not legally compellable to provide, for instance, bone-marrow or blood donations for their children's survival. Women's unjust legal, political, economic and social powerlessness explains much unsafe motherhood and maternal mortality and morbidity.


Gene conversion (recombination) mediates expansions of CTG[middle dot]CAG repeats.
Genetic recombination is a robust mechanism for expanding CTG.CAG triplet repeats involved in the etiology of hereditary neurological diseases (Jakupciak, J. P., and Wells, R. D. (1999) J. Biol. Chem. 274, 23468-23479). This two-plasmid recombination system in Escherichia coli with derivatives of pUC19 and pACYC184 was used to investigate the effect of triplet repeat orientation on recombination and extent of expansions; tracts of 36, 50, 80, and 36, 100, and 175 repeats in length, respectively, in all possible permutations of length and in both orientations (relative to the unidirectional replication origins) revealed little or no effect of orientation of expansions. The extent of expansions was generally severalfold the length of the progenitor tract and frequently exceeded the combined length of the two tracts in the cotransformed plasmids. Expansions were much more frequent than deletions. Repeat tracts bearing two G-to-A interruptions (polymorphisms) within either 171- or 219-base pair tracts substantially reduced the expansions compared with uninterrupted repeat tracts of similar lengths. Gene conversion, rather than crossing over, was the recombination mechanism. Prior studies showed that DNA replication, repair, and tandem duplication also mediated genetic instabilities of the triplet repeat sequence. However, gene conversion (recombinational repair) is by far the most powerful expansion mechanism. Thus, we propose that gene conversion is the likely expansion mechanism for myotonic dystrophy, spinocerebellar ataxia type 8, and fragile X syndrome.


Involvement of extracellular signal regulated kinases in traumatic brain injury-induced depression in rodents.
Traumatic brain injury (TBI) is the most common cause of death and acquired disability among children and young adults in the developed countries. In clinical studies, the incidence of depression is high after TBI, and the mechanisms behind TBI-induced depression remain unclear. In the present study, we subjected rats to a moderate fluid percussion into the closed cranial cavity to induce TBI. After 3 days of recovery, injured rats were given a forced swim test (FST) and novelty-suppressed feeding tests. We found that TBI rats exhibited increased duration of immobility and longer latency to begin chewing food in a new environment compared with sham-operated rats. Western blot analysis showed that TBI led to a decrease in the phosphorylated levels of extracellular signal regulated kinases (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK). Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), significantly reduced the duration of immobility when administered once per day for 14 days. Consistent with behavioral tests, fluoxetine treatment reversed TBI-induced decrease in p-ERK1/2 and p-p38 MAPK levels. Pre-treatment with a selective tryptophan hydroxylase inhibitor para-chlorophenylalanine (PCPA) blocked the antidepressant effect of fluoxetine. PCPA also prevented the effect of fluoxetine on ERK1/2 phosphorylation without affecting p38 MAPK phosphorylation. Pre-treatment with ERK inhibitor SL327 but not p38 MAPK inhibitor SB203580 prevented the antidepressant effect of fluoxetine. These results suggest that ERK1/2 plays a critical role in TBI-induced depression.


alpha and beta spectrin distribution during the differentiation of pyriform cells in follicles of lizard Podarcis sicula.
Using alpha and beta spectrin mammalian antibodies on Western blotting, we demonstrated that lizard ovarian follicles contain two isoforms of alpha spectrin, Mr 94 and 134 kDa, and a 230 kDa beta spectrin, and that their pattern modifies in relation to pyriform cell differentiation. In fact, a positive immunoreaction is firstly evident within follicular epithelium of previtellogenic follicles when small cells differentiate into pyriform cells via intermediate cells. Later on, immunostain is present in pyriform cells and in the oocyte cortex that previously appears unstained. It is noteworthy that immunostain is also present on small cells located in contact with the oocyte membrane, but not on those located under the basal lamina and among pyriform cells, not engaged in pyriform cell differentiation. During the subsequent stages of previtellogenic phase, spectrin immunostain over the follicular epithelium and in the oocyte cortex does not change. By contrast, in vitellogenic follicles, when the follicular epithelium is constituted only by small cells, immunostain is evident at the level of the oocyte cortex and the cytoplasm of regressing pyriform cells. The present data strongly suggest that the alpha and beta spectrin pattern put in evidence during the different phases of lizard oocyte growth is related to the differentiation of small into pyriform cells, where such protein may guarantee a relationship between surface glycoproteins (Andreuccetti et al., 2001: Anat Rec 263:1-9), and the cytoskeleton distribution (Maurizii et al., 2000: Raf Mol Reprod Dev 57:159-166). Furthermore, the distribution of spectrin mRNA, similar to that observed for the protein, demonstrates that spectrin, once synthesized within pyriform cells, is transferred through intercellular bridges in the oocyte cortex, thus confirming that pyriform cells are nurse that significantly are involved in the oocyte growth. Finally, the present data demonstrate that alpha spectrin of lizard ovarian follicles has Mr quite different from those so far reported and may constitute a new group of isoforms. This important result will be the focus of future experiments. Mol. Reprod. Dev. 67: 101-107, 2004.


The incidence of complications associated with lip and/or tongue piercings: a systematic review.
This review determines the incidence of complications associated with lip and/or tongue piercings based on a systematic evaluation of the available literature. MEDLINE-PubMed, Cochrane-CENTRAL and EMBASE databases were comprehensively searched through June 2014 to identify appropriate studies. The incidence of complications, as established by a dental professional associated with oral and peri-oral piercings, was evaluated in populations with lip and/or tongue piercings. The quality of the case-control studies was assessed using the Newcastle-Ottawa Scale. For case series studies, the risk of bias was assessed using the National Institute for Health and Clinical Excellence scale. An independent screening of 1580 unique titles and abstracts revealed 15 publications that met the eligibility criteria. The incidence of gingival recessions appeared to be 50% in subjects with lip piercings and 44% in subjects with a tongue piercing. Tooth injuries were observed in 26% individuals with lip piercings and in up to 37% of individuals with tongue piercings. Subjects with a lip piercing were 4.14 times (P = 0.005) more likely to develop gingival recession than those without a lip piercing. Subjects with a tongue piercing were more likely than non-pierced subjects to experience gingival recession (relative risk (RR) 2.77; P = 0.00001) and tooth injuries (RR 2.44; P = 0.003). Both lip and tongue piercings are highly associated with the risk of gingival recession, and tongue piercings are also associated with tooth injuries.


Putting it all together: managing pain in autologous and implant-based breast reconstruction.
Appropriate pain management in breast reconstruction improves outcomes and patient satisfaction. The purpose of this study is to review the current methodology and paradigms in pain management following breast reconstruction. A review of the scientific literature was performed. The protocols used at our institution were further examined and contrasted in the context of this published literature. Pain following breast reconstruction is multifactorial and patient specific. Pain can originate from the mastectomy alone, from the donor site, or from tissue expansion. Counseling a patient is of upmost importance. The armamentarium to address pain includes narcotic analgesics, nonnarcotic analgesics, local anesthesia, and other nontraditional regimens. Each of these methods has an evidence-based efficacy and patient selection factors for application. The data contained herein provide a review of perioperative pain management following autologous and implant-based breast reconstruction.


Metabolic and cellular analysis of alopecia in vitamin D receptor knockout mice.
Targeted ablation of the vitamin D receptor (VDR) results in hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, osteomalacia, and alopecia--the last a consequence of defective anagen initiation. To investigate whether the markedly elevated levels of 1,25-dihydroxyvitamin D led to the alopecia, we raised VDR-null mice in a ultraviolet light-free environment and fed them chow lacking vitamin D for five generations. Despite undetectable circulating levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, alopecia persisted in the VDR-null mice, demonstrating that the alopecia was not secondary to toxic levels of 1,25-dihydroxyvitamin D interacting with an alternative receptor. Furthermore, alopecia was not seen in control littermates, suggesting that absence of ligand and absence of receptor cause different phenotypes. To identify the cell population responsible for the alopecia, we performed hair-reconstitution assays in nude mice and observed normal hair follicle morphogenesis, regardless of the VDR status of the keratinocytes and dermal papilla cells. However, follicles reconstituted with VDR-null keratinocytes demonstrated a defective response to anagen initiation. Hence, alopecia in the VDR-null mice is due to a defect in epithelial-mesenchymal communication that is required for normal hair cycling. Our results also identify the keratinocyte as the cell of origin of the defect and suggest that this form of alopecia is due to absence of ligand-independent receptor function.


Psychosis Biotypes: Replication and Validation from the B-SNIP Consortium.
Current clinical phenomenological diagnosis in psychiatry neither captures biologically homologous disease entities nor allows for individualized treatment prescriptions based on neurobiology. In this report, we studied two large samples of cases with schizophrenia, schizoaffective, and bipolar I disorder with psychosis, presentations with clinical features of hallucinations, delusions, thought disorder, affective, or negative symptoms. A biomarker approach to subtyping psychosis cases (called psychosis Biotypes) captured neurobiological homology that was missed by conventional clinical diagnoses. Two samples (called "B-SNIP1" with 711 psychosis and 274 healthy persons, and the "replication sample" with 717 psychosis and 198 healthy persons) showed that 44 individual biomarkers, drawn from general cognition (BACS), motor inhibitory (stop signal), saccadic system (pro- and anti-saccades), and auditory EEG/ERP (paired-stimuli and oddball) tasks of psychosis-relevant brain functions were replicable (r's from .96-.99) and temporally stable (r's from .76-.95). Using numerical taxonomy (k-means clustering) with nine groups of integrated biomarker characteristics (called bio-factors) yielded three Biotypes that were virtually identical between the two samples and showed highly similar case assignments to subgroups based on cross-validations (88.5%-89%). Biotypes-1 and -2 shared poor cognition. Biotype-1 was further characterized by low neural response magnitudes, while Biotype-2 was further characterized by overactive neural responses and poor sensory motor inhibition. Biotype-3 was nearly normal on all bio-factors. Construct validation of Biotype EEG/ERP neurophysiology using measures of intrinsic neural activity and auditory steady state stimulation highlighted the robustness of these outcomes. Psychosis Biotypes may yield meaningful neurobiological targets for treatments and etiological investigations.


Increased myocardial beta-receptors and adrenergic responses in hyperthyroid pigs.
Controversy exists presently as to whether thyroid hormone potentiates the action of catecholamines on the heart. Therefore, the relationships between adrenergic sensitivity, myocardial beta-receptor number, and the cardiovascular responses associated with excess thyroid hormone were investigated in pigs (Sus scrofa). A hyperthyroid state was induced by the administration of triiodothyronine (T3; 1 mg/kg iv). After 7 days there was a significant increase in resting heart rate, systolic blood pressure, rate-pressure product, and O2 consumption in the hyperthyroid state. At this time echocardiography showed a substantial increase in myocardial cross-sectional size. Pharmacological tests showed an increased intrinsic heart rate (127 +/- 29 to 205 +/- 25 beats/min; P less than 0.001) and an increased chronotropic sensitivity to isoproterenol. The concentration of isoproterenol required for a 50% of maximal response (ED50) was reduced by 33 +/- 30% (2.1 +/- 1.0 to 1.2 +/- 0.3 micrograms/l; P less than 0.025). The slope of the line relating isoproterenol concentration and change in heart rate was increased by 29 +/- 33% (61 +/- 10 to 78 +/- 10; P less than 0.025). Radioligand studies demonstrated an increase in the number of beta-receptors in right atrial membranes from hyperthyroid animals (41 +/- 7 vs. 75 +/- 18 fmol/mg; P less than 0.02). The apparent dissociation constant (KD) of the receptor for l-isoproterenol was similar in membranes from euthyroid and hyperthyroid animals (157 +/- 57 vs. 219 +/- 59 nM, respectively; P = NS). This study demonstrates that hyperthyroidism is associated with an increased chronotropic sensitivity to isoproterenol, consequent to an up-regulation of beta-adrenergic receptors in the right atrium.


Nuclear factor of activated T cells and serum response factor cooperatively regulate the activity of an alpha-actin intronic enhancer.
Expression of alpha-actin in smooth muscle cells (SMCs) is regulated, in part, by an intronic serum response factor (SRF)-binding CArG element. We have identified a conserved nuclear factor of activated T cells (NFAT) binding site that overlaps this CArG box and tested the hypothesis that this site plays a previously unrecognized role in regulating alpha-actin expression. A reporter construct prepared using a 56-bp region of the mouse alpha-actin first intron containing SRF, NFAT, and AP-1 sites (SNAP) acted as an enhancer element in the context of a minimal thymidine kinase promoter. Basal reporter activity following expression in SMCs was robust and sensitive to the calcineurin-NFAT pathway inhibitors cyclosporin A and FK506. Mutating either the NFAT or SRF binding site essentially abolished reporter activity, suggesting that both NFAT and SRF binding are required. Basal activity in non-smooth muscle HEK293 cells was SRF-dependent but NFAT-independent and approximately 8-fold lower than that in SMCs. Activation of NFAT in HEK293 cells induced an approximately 4-fold increase in activity that was dependent on the integrity of both NFAT and SRF binding sites. NFATc3.SRF complex formation, demonstrated by co-immunoprecipitation, was facilitated by the presence of SNAP oligonucleotide. Inhibition of the calcineurin-NFAT pathway decreased alpha-actin expression in cultured SMCs, suggesting that the molecular interaction of NFAT and SRF at SNAP may be physiologically relevant. These data provide the first evidence that NFAT and SRF may interact to cooperatively regulate SMC-specific gene expression and support a role for NFAT in the phenotypic maintenance of smooth muscle.


High quantities of multidrug-resistant Escherichia coli are present in the Machángara urban river in Quito, Ecuador.
Urban river pollution by multidrug-resistant (MDR) bacteria constitutes an important public health concern. Epidemiologically important strains of MDR Escherichia coli transmissible at the human-animal-environment interfaces are especially worrying. Quantifying and characterizing MDR E. coli at a molecular level is thus imperative for understanding its epidemiology in natural environments and its role in the spread of resistance in precise geographical areas. Cefotaxime-resistant E. coli was characterized along the watercourse of the major urban river in Quito. Our results showed high quantities of cefotaxime-resistant E. coli (2.7 × 103-5.4 × 105 CFU/100 mL). The antimicrobial resistance index (ARI) revealed the exposure of the river to antibiotic contamination, and the multiple antibiotic resistance index indicated a high risk of contamination. The blaCTX-M-15 gene was the most prevalent in our samples. Isolates also had class 1 integrons carrying aminoglycoside-modifying enzymes and folate pathway inhibitors. The isolates belonged to phylogroups A, B1 and D. Clonal complex 10 was found to be the most prevalent (ST10, ST44 and ST 167), followed by ST162, ST394 and ST46. Our study provides a warning about the high potential of the major urban river in Quito for spreading the epidemiologically important MDR E. coli.


Alpha[11C] methyl-L-typtophan positron emission tomography in patients with alternating hemiplegia of childhood.
Based on previous reports suggesting a role of the neurotransmitter serotonin in the pathomechanism of alternating hemiplegia of childhood and speculation that it may be a migraine variant, we measured brain serotonin synthesis in children with alternating hemiplegia of childhood. Clinical and neurodevelopmental data, as well as standard uptake values in 25 brain regions and whole-brain serotonin synthesis capacity (unidirectional uptake rate constant or K-complex), were assessed in six patients with alternating hemiplegia of childhood (three girls and three boys; mean age = 7 6/12 years) using alpha[11C]methyl-L-tryptophan positron emission tomography (PET). The PET studies were performed interictally in three patients, during the ictal state in two patients, and postictally in one patient. The PET data were compared to those obtained interictally from six age-matched patients with focal epilepsy (two girls and four boys; mean age = 7 8/12 years) and six non-age-matched apparently normal siblings of autistic children (two girls and four boys; mean age = 9 11/12 years). Patients with alternating hemiplegia of childhood studied in the ictal or postictal state showed increased serotonin synthesis capacity in the frontoparietal cortex, lateral and medial temporal structures, striatum, and thalamus when compared to controls, and subjects with alternating hemiplegia of childhood studied interictally. The involvement of these brain regions was consistent with the semiology of the hemiplegic attacks. In patients with interictal studies and in the controls, the PET scans revealed similar and bilaterally symmetric regional patterns of serotonin synthesis capacity. Increased whole-brain serotonin synthesis capacity (reported in migraine subjects without aura) was not found in the alternating hemiplegia of childhood group. There was no correlation between the neurodevelopmental scores and regional standard uptake values; however, patients with a larger estimated lifetime attack number showed greater delay in communication (P = .005) and daily living skills (P = .042). These studies suggest increased regional serotonergic activity associated with attacks in alternating hemiplegia of childhood. Furthermore, the attack number may have an effect on neurodevelopmental delay, thus supporting the notion that alternating hemiplegia of childhood may be a progressive disorder.


Biochemical analysis of triggering signals induced by bridging of IgE receptors.
Bridging of IgE receptors on rat mast cell plasma membranes induces phospholipid methylation and a monophasic increase in cyclic AMP. The stimulation of phospholipid methylation in the plasma membrane appears to be intrinsic to the processes leading to Ca2+ influx and histamine release. Evidence was obtained that IgE receptors are closely associated with methyltransferases and adenylate cyclase in the plasma membranes. The activation of one enzyme is regulated by the other. An increase in the cyclic AMP level before receptor bridging suppressed phospholipid methylation. On the other hand, inhibition of phospholipid methylation may affect the initial rise in cyclic AMP. Our experiments also indicated that bridging the receptor activates a membrane-associated proteolytic enzyme. Inasmuch as the inhibition of the enzyme activation results in the suppression of both phospholipid methylation and initial rise in cyclic AMP induced by receptor bridging, the proteolytic enzyme may be involved in the activation of methyltransferases and adenylate cyclase.


[Infectious complications of polytraumas: microbiological and epidemiological aspects].
The authors discuss problems of terminology and definition of terms associated with surgery of injuries, polytrauma and a conception of wound dystrophy. Great statistical material (about 5000 casualties with polytrauma) was used to show the structure and frequency of infectious complications of severe associated injuries systematized according to the original classification of this pathology. The classification is based on a universal pathophysiological process developing in response to any extraordinary influence--a systemic inflammatory response. The mechanisms of the appearance of infectious complications of severe injuries are described. The authors propose new organizational and epidemiological accesses to prophylactics of infectious complications of polytraumas.


Spatial segregation and aging of metabolic processes underlie phenotypic heterogeneity in mycobacteria.
Individual cells within clonal populations of mycobacteria vary in size, growth rate, and antibiotic susceptibility. Heterogeneity is, in part, determined by LamA, a protein found exclusively in mycobacteria. LamA localizes to sites of new cell wall synthesis where it recruits proteins important for polar growth and establishing asymmetry. Here, we report that in addition to this function, LamA interacts with complexes involved in oxidative phosphorylation (OXPHOS) at a subcellular location distinct from cell wall synthesis. Importantly, heterogeneity depends on a unique extension of the mycobacterial ATP synthase, and LamA mediates the coupling between ATP production and cell growth in single cells. Strikingly, as single cells age, concentrations of proteins important for oxidative phosphorylation become less abundant, and older cells rely less on oxidative phosphorylation for growth. Together, our data reveal that central metabolism is spatially organized within a single mycobacterium and varies within a genetically identical population of mycobacteria. Designing therapeutic regimens to account for this heterogeneity may help to treat mycobacterial infections faster and more completely.


HeTDR: Drug repositioning based on heterogeneous networks and text mining.
Using existing knowledge to carry out drug-disease associations prediction is a vital method for drug repositioning. However, effectively fusing the biomedical text and biological network information is one of the great challenges for most current drug repositioning methods. In this study, we propose a drug repositioning method based on heterogeneous networks and text mining (HeTDR). This model can combine drug features from multiple drug-related networks, disease features from biomedical corpora with the known drug-disease associations network to predict the correlation scores between drug and disease. Experiments demonstrate that HeTDR has excellent performance that is superior to that of state-of-the-art models. We present the top 10 novel HeTDR-predicted approved drugs for five diseases and prove our model is capable of discovering potential candidate drugs for disease indications.


[Postural synergy disorders in local brain lesions].
The electrical activity of the muscles of the legs and trunk was examined in 84 patients with verified (primarily neoplastic) affections of the brain. The patients were in the standing posture and were asked to make a voluntary movement (to raise an arm). The examinations showed that in patients with one hemisphere affected the posture synergy of the muscles was disturbed in both halves of the body. This was regarded as a consequence of a dysfunction in the so-called secondary, higher motor zones of the brain. The disturbances of the premovement activation of the muscles in both halves of the body were found to be significant only in cases of frontal lobe affections. This was confirmed by restoration of the posture synergy after successful ablation of the tumour.


Prostate radiotherapy in newly diagnosed metastatic prostate cancer.
The aim of this article is to review the role of prostate radiotherapy in the multimodal management of newly diagnosed metastatic hormone naïve prostate cancer. Two randomized controlled trials have evaluated the role of prostate radiotherapy with systemic therapy (androgen deprivation therapy ± docetaxel) in newly diagnosed metastatic hormone-naive prostate cancer. In a combined cohort of over 2000 patients, prostate radiotherapy with systemic therapy improved survival over systemic therapy alone in patients with low metastatic burden but not in high-burden patients. Prostate radiotherapy with systemic therapy is now a recommended first-line option for newly diagnosed men with low metastatic burden prostate cancer. The current recommended definition for low metastatic burden is based on conventional imaging (Tc bone scans and CT/MRI). Cross-correlative studies are required to pick an appropriate threshold for sensitive-imaging modalities such as PSMA PET or whole-body MRI. Ongoing trials are evaluating prostate radiotherapy in this setting combined with abiraterone/docetaxel and metastasis-directed therapy. Prostate radiotherapy with systemic therapy improves survival in patients with newly diagnosed, low metastatic burden prostate cancer and is a recommended first-line treatment option. Ongoing trials are evaluating combination with metastasis-directed therapy and other systemic treatments.


Ki67 expression and the effect of neo-adjuvant chemotherapy on luminal HER2-negative breast cancer.
Patients with luminal HER2-negative tumours have a favourable prognosis. However, there is a subpopulation in which poorer outcomes are obtained with endocrine therapy alone. This subpopulation is considered to benefit from chemotherapy. However, the significance of chemotherapy for those with luminal tumours has decreased due to recent changes in treatment strategies. Thus, it is often difficult to determine whether we should recommend chemotherapy to such patients in clinical practice. We investigated Ki67 expression, as a means of predicting the responses of luminal HER2-negative breast cancer patients to neo-adjuvant chemotherapy (NAC), in order to identify a subpopulation that would benefit from these treatments. We enrolled 114 luminal HER2-negative breast cancer patients undergoing surgery after NAC. Biomarkers were examined using biopsy specimens obtained prior to treatment, to avoid any chemotherapy-related effects. Chemotherapy effects were determined employing operative specimens and we defined pathological complete response (pCR) as invasive nest disappearance, based only on the primary breast tumour. We applied receiver operating characteristic curve analysis to data from our 114 patients, to investigate Ki67 expression as a predictor of pCR. The pCR rate was significantly higher for tumours with high Ki67 expression (p < 0.01) and all patients who obtained pCR remained recurrence-free during the median 58-month observation period. We identified 35% as the Ki67 cut-off value which distinguishes those with a pCR from other cases. Another dataset, comprised of 196 patients with a median 29-month observation period, was recruited for validation. Disease-free survival was found to be significantly (p < 0.01) lower in the patients with tumours in which Ki67 expression was higher than 35%. Our results raise the possibility of the luminal HER2-negative subpopulation with Ki67 expression higher than 35% benefiting from chemotherapy, as evidenced by improved survival.


The polyproline region of p53 is required to activate apoptosis but not growth arrest.
p53 is a pivotal regulator of apoptosis but its mechanism of action is obscure. We report that the polyproline (PP) region located between p53's transactivation and DNA binding domains is necessary to induce apoptosis but not cell growth arrest. The PP region was dispensable for DNA binding, inhibition of SAOS-2 tumor cell growth, suppression of E1A + RAS cell transformation, and cell cycle inhibition. A temperature-sensitive dominant inhibitory p53 mutant lacking PP (p53ts deltaPP) retained its ability to cooperate with adenovirus E1A in transformation of primary BRK cells. However, while activation of wt p53 induced apoptosis in E1A + p53ts-transformed cells, activation of p53 deltaPP induced cell cycle arrest but not apoptosis in E1A + p53ts deltaPP-transformed cells. Similarly, PP deletion abolished apoptosis in LoVo colon carcinoma cells, which are killed by wt p53 overexpression. Transactivation was largely unaffected by PP deletion. Significantly, BAX induction was intact, indicating that additional events are required for p53 to induce apoptosis. As a recently described site for familial mutation in at least one breast cancer family, the PP region represents a domain that may be altered in human tumors. We concluded that p53's ability to induce apoptosis is dispensable for inhibiting cell growth and transformation and that the PP region plays a crucial role in apoptotic signaling.


Mitochondria can import artificial precursor proteins containing a branched polypeptide chain or a carboxy-terminal stilbene disulfonate.
A purified, artificial precursor protein was used as a transport vehicle to test the tolerance of the mitochondrial protein import system. The precursor was a fusion protein consisting of mouse dihydrofolate reductase linked to a yeast mitochondrial presequence; it contained a unique cysteine as its COOH-terminal residue. This COOH-terminal cysteine was covalently coupled to either a stilbene disulfonate derivative or, with the aid of a bifunctional cross-linker, to one of the free amino groups of horse heart cytochrome c. Coupling to horse heart cytochrome c generated a mixture of branched polypeptide chains since this cytochrome lacks a free alpha-amino group. Both adducts were imported and cleaved by isolated yeast mitochondria. The mitochondrial protein import machinery can thus transport more complex structures and even highly charged "membrane-impermeant" organic molecules. This suggests that transport occurs through a hydrophilic environment.


Evaluation of Extended-Wear Hearing Aids as a Solution for Intermittently Noise-Exposed Listeners With Hearing Loss.
Many individuals with noise-related hearing loss continue working in environments where they are periodically exposed to high levels of noise, which increases their risk for further hearing loss. These individuals often must remove their hearing aids in operational environments because of incompatibility with the mandated personal protective equipment, thus reducing situational awareness. Extended-wear hearing aids might provide a solution for these individuals because they can be worn for weeks or months at a time, protect users from high-level noise exposures, and are compatible with communication headsets, earmuffs, and other types of personal protective equipment. The purpose of this study was to evaluate localization ability and speech understanding, feasibility of fitting and use, and acceptability in terms of comfort in a population of noise-exposed, active duty Service members. Participants in the study were active duty Service members who were experienced hearing aid users and were currently using standard hearing aids bilaterally. Participants were fitted with extended-wear hearing aids for up to 14 weeks. Laboratory measures included functional gain, sound localization, and speech recognition (in quiet and in noise). Performance was compared between unaided, standard hearing aids, extended-wear hearing aids, and extended-wear hearing aids combined with a tactical communication device (3M Peltor ComTac). In addition, self-perceived benefit between extended-wear hearing aids and standard hearing aids was compared. The extended-wear hearing aids provided more attenuation of external sound when turned off compared to standard hearing aids. Speech understanding in quiet and in noise was comparable between extended-wear hearing aids and standard hearing aids and was better when a tactical communication device was worn in addition to extended-wear hearing aids. Localization with extended-wear hearing aids was the worst, intermediate with the standard hearing aids, and the best when the ears were unaided. The extended-wear hearing aids and standard hearing aids provided similar self-perceived communication benefits relative to unaided ears. Device failure and issues with extended-wear hearing aids fit and comfort contributed to a high participant withdrawal rate. Overall, the hearing benefits of extended-wear hearing aids for Service members with hearing loss were comparable to those obtained with standard hearing aids, except for sound localization, which was poorer with extended-wear hearing aids. Extended-wear hearing aids provide the additional benefits of protecting the ears from high-level impulsive noise and being compatible with tactical communication and protection systems and other existing personal protective equipment and communication gear. The withdrawal rate in this study, however, suggests that extended-wear hearing aids may not be suitable for active duty Service members in locations where properly trained hearing professionals are not available to replace or re-insert extended-wear hearing aids when needed due to discomfort or device failure.


Oncogenic Ras/ERK signaling activates CDCP1 to promote tumor invasion and metastasis.
Involvement of Ras in cancer initiation is known, but recent evidence indicates a role in cancer progression, including metastasis and invasion; however, the mechanism is still unknown. In this study, it was determined that human lung cancer cells with Ras mutations, among other popular mutations, showed significantly higher expression of CUB domain-containing protein 1 (CDCP1) than those without. Furthermore, activated Ras clearly induced CDCP1, whereas CDCP1 knockdown or inhibition of CDCP1 phosphorylation by Src-directed therapy abrogated anoikis resistance, migration, and invasion induced by activated-Ras. Activation of MMP2 and secretion of MMP9, in a model of Ras-induced invasion, was found to be regulated through induction of phosphorylated CDCP1. Thus, CDCP1 is required for the functional link between Ras and Src signaling during the multistage development of human malignant tumors, highlighting CDCP1 as a potent target for treatment in the broad spectrum of human cancers associated with these oncogenes. CDCP1 protein induced by oncogenic Ras/Erk signaling is essential for Ras-mediated metastatic potential of cancer cells.


Heparin-coated shunts for lesions of the descending thoracic aorta. Experimental and clinical observations.
Heparin sodium-coated shunts are employed frequently to maintain trunk and lower extremity perfusion during temporary occlusion of the descending thoracic aorta. In the past five years, this shunt has been used in a series of 39 patients ranging in age from 19 to 72 years old, with 34 survivors (87%). The proximal end of the shunt was placed in the subclavian artery in 17 patients, the left ventricle in ten, and in the ascending or transverse aortic arch in 12. The distal end of the shunt was placed either in the lower thoracic aorta or in the femoral artery. For further evaluation of effectiveness, paired observations were made in dogs to determine the physiological consequences with the proximal end of the shunt inserted at two different sites. Although neither shunt decompressed the left ventricle fully, the subclavian-femoral shunt was significantly more effective than was the left ventricle-femoral artery bypass. If a choice exists for sites of insertion of the shunt, it appears that it should be placed distal to the aortic valve, since this position provides the least increase in systolic blood pressure and is associated with a lower demand for myocardial blood flow.


Meta-analysis comparing Mediterranean to low-fat diets for modification of cardiovascular risk factors.
Evidence from individual trials comparing Mediterranean to low-fat diets to modify cardiovascular risk factors remains preliminary. We systematically searched MEDLINE, EMBASE, Biosis, Web of Science, and the Cochrane Central Register of Controlled Trials from their inception until January 2011, as well as contacted experts in the field, to identify randomized controlled trials comparing Mediterranean to low-fat diets in overweight/obese individuals, with a minimum follow-up of 6 months, reporting intention-to-treat data on cardiovascular risk factors. Two authors independently assessed trial eligibility and quality. We identified 6 trials, including 2650 individuals (50% women) fulfilling our inclusion criteria. Mean age of enrolled patients ranged from 35 to 68 years, mean body mass index from 29 to 35 kg/m(2). After 2 years of follow-up, individuals assigned to a Mediterranean diet had more favorable changes in weighted mean differences of body weight (-2.2 kg; 95% confidence interval [CI], -3.9 to -0.6), body mass index (-0.6 kg/m(2); 95% CI, -1 to -0.1), systolic blood pressure (-1.7 mm Hg; 95% CI, -3.3 to -0.05), diastolic blood pressure (-1.5 mm Hg; 95% CI, -2.1 to -0.8), fasting plasma glucose (-3.8 mg/dL, 95% CI, -7 to -0.6), total cholesterol (-7.4 mg/dL; 95% CI, -10.3 to -4.4), and high-sensitivity C-reactive protein (-1.0 mg/L; 95% CI, -1.5 to -0.5). The observed heterogeneity across individual trials could, by and large, be eliminated by restricting analyses to trials with balanced co-interventions or trials with restriction of daily calorie intake in both diet groups. Mediterranean diets appear to be more effective than low-fat diets in inducing clinically relevant long-term changes in cardiovascular risk factors and inflammatory markers.


A homozygote novel L451W mutation in CECR1 gene causes deficiency of adenosine deaminase 2 in a pediatric patient representing with chronic lymphoproliferation and cytopenia.
Deficiency of Adenosine Deaminase 2 (DADA2) is a monogenic autoinflammatory disorder characterized by livedo reticularis, skin ulcers, subcutaneous rash, aphthous ulcers, and leukocytoclastic vasculitis, neurological signs such as early onset stroke and polyneuropathy. A minority of DADA2 patients suffer from severe cytopenia and lymphoproliferation. Herein, we report an adolescent patient, followed up as having a hematological disorder for many years, eventually diagnosed as having DADA2. In view of the presence of elevated acute phase reactants, hepatosplenomegaly, low IgM level, lymphopenia, anemia, and neutropenia, and a subtle neurological involvement we considered DADA2 diagnosis. The diagnosis was confirmed by identification of a novel L451W mutation in CECR1 gene. The patient has been successfully treated with etanercept, monthly intravenous immunoglobulin replacement, and low-dose methylprednisolone. In conclusion, although the absence of skin and neurological findings, low IgM levels, and persistent lymphopenia should lead the physicians to consider DADA2 in patients with particularly complicated hematological abnormalities.


DNA polymerase epsilon is required for coordinated and efficient chromosomal DNA replication in Xenopus egg extracts.
DNA polymerase epsilon (Pol epsilon) is thought to be involved in DNA replication, repair, and cell-cycle checkpoint control in eukaryotic cells. Although the requirement of other replicative DNA polymerases, DNA polymerases alpha and delta (Pol alpha and delta), for chromosomal DNA replication has been well documented by genetic and biochemical studies, the precise role, if any, of Pol epsilon in chromosomal DNA replication is still obscure. Here we show, with the use of a cell-free replication system with Xenopus egg extracts, that Xenopus Pol epsilon is indeed required for chromosomal DNA replication. In Pol epsilon-depleted extracts, the elongation step of chromosomal DNA replication is markedly impaired, resulting in significant reduction of the overall DNA synthesis as well as accumulation of small replication intermediates. Moreover, despite the decreased DNA synthesis, excess amounts of Pol alpha are loaded onto the chromatin template in Pol epsilon-depleted extracts, indicative of the failure of proper assembly of DNA synthesis machinery at the fork. These findings strongly suggest that Pol epsilon, along with Pol alpha and Pol delta, is necessary for coordinated chromosomal DNA replication in eukaryotic cells.


Poly (ADP-ribose) polymerase (PARP) inhibitor regimens for ovarian cancer in phase III randomized controlled trials: a network meta-analysis.
We aimed to evaluate poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) regimens in BRCA-mutated ovarian cancer for patients responsive to front-line platinum (bevacizumab and olaparib, veliparib and chemotherapy, olaparib) or platinum-sensitive relapsed (olaparib, rucaprib, niraparib) patients in phase III randomized controlled trials. A network meta-analysis was utilized to generate the direct and indirect comparisons. The primary outcomes for network meta-analysis were efficacy (hazard ratios for progression-free survival in BRCA mutation cohort) and toxicity (odds ratios for all grade 3-4 adverse events). The American Society of Clinical Oncology (ASCO) value framework was used to assess the cost-effectiveness of the PARPi regimens. Network meta-analysis indicated no statistically significant differences in efficacy and toxicity among the assessed upfront or relapsed PARPi regimens (95% CI included 1). The ASCO value framework indicated that current PARPi regimens were similar in clinical benefits, toxicity, and net health benefit in the upfront (bevacizumab and olaparib, veliparib and chemotherapy, olaparib) and relapsed setting (olaparib, rucaprib, niraparib). The addition of bevacizumab to olaparib ($353.72) increased the cost per unit net health benefit for patients compared with olaparib monotherapy ($260.57). The upfront PARPi regimens had lower toxic scores than the regimens used at relapse. The choice of PARPi regimens both in the upfront and relapsed setting should consider not only efficacy and toxicity but also costs in BRCA mutation patients. Current combining PARPi regimens are not recommended for such patients in the upfront setting from the cost-effective perspective. Upfront PARPi regimens are less toxic than those used at relapse.


Comparison of Allergenicity at Gly m 4 and Gly m Bd 30K of Soybean after Genetic Modification.
Despite rapid growth of genetically modified (GM) crops, effective evaluations of genetic modification on allergenicity are still lacking. Gly m Bd 30K is cross-reactive with cow's milk protein casein, Gly m 4, and with birch pollen allergen Bet v 1. Here we compared the allergenicity between GM and non-GM soybeans with respect to the foci Gly m 4 and Gly m Bd 30K. Recombinant allergens of Gly m Bd 30K and Gly m 4 were generated and polyclonal antibodies raised to identify these two allergenic components in soybeans. GM soybean was first PCR-confirmed using 35S promoter. A total of 20 soybeans (half GM, half non-GM) obtained from a food market were used to assess their allergenicity based on IgE-binding and histamine release. The concentrations of Gly m Bd 30K and Gly m 4 in soybeans were then determined. Most soybean-allergic patients (9 of 10) showed IgE-positive reactions to the allergen of 30 kDa in molecular weight. That allergen turned out to be Glycine max Gly m Bd 30K based on LC-MS/MS analyses. Gly m Bd 30K is therefore the major allergen in the soybean. An increase in the transcription of both the Gly m 4 (stress-induced protein SAM22) and Gly m Bd 28K (soybean allergen precursor) was found after genetic modification. The protein concentrations of Gly m 4 and Gly m Bd 30K were not statistically significant different between non-GM and GM soybeans. There were also no statistical significances between them in the tests of IgE binding and histamine release. In conclusion, soybeans showed similar concentrations of Gly m Bd 30K and Gly m 4 regardless of genetic modification or absence thereof. The allergenicity of both Gly m Bd 30K and Gly m 4 was therefore not altered after genetic modification. Patients showing hypersensitivity to soybeans and who had pre-existing allergy to birch pollen and cow's milk casein might not further increase their allergic reactions following exposures to the GM soybeans.


Epimerase active domain of Pseudomonas aeruginosa AlgG, a protein that contains a right-handed beta-helix.
The polysaccharide alginate forms a protective capsule for Pseudomonas aeruginosa during chronic pulmonary infections. The structure of alginate, a linear polymer of beta1-4-linked O-acetylated d-mannuronate (M) and l-guluronate (G), is important for its activity as a virulence factor. Alginate structure is mediated by AlgG, a periplasmic C-5 mannuronan epimerase. AlgG also plays a role in protecting alginate from degradation by the periplasmic alginate lyase AlgL. Here, we show that the C-terminal region of AlgG contains a right-handed beta-helix (RHbetaH) fold, characteristic of proteins with the carbohydrate-binding and sugar hydrolase (CASH) domain. When modeled based on pectate lyase C of Erwinia chrysanthemi, the RHbetaH of AlgG has a long shallow groove that may accommodate alginate, similar to protein/polysaccharide interactions of other CASH domain proteins. The shallow groove contains a 324-DPHD motif that is conserved among AlgG and the extracellular mannuronan epimerases of Azotobacter vinelandii. Point mutations in this motif disrupt mannuronan epimerase activity but have no effect on alginate secretion. The D324A mutation has a dominant negative phenotype, suggesting that the shallow groove in AlgG contains the catalytic face for epimerization. Other conserved motifs of the epimerases, 361-NNRSYEN and 381-NLVAYN, are predicted to lie on the opposite side of the RHbetaH from the catalytic center. Point mutations N362A, N367A, and V383A result in proteins that do not protect alginate from AlgL, suggesting that these mutant proteins are not properly folded or not inserted into the alginate biosynthetic scaffold. These motifs are likely involved in asparagine and hydrophobic stacking, required for structural integrity of RHbetaH proteins, rather than for mannuronan catalysis. The results suggest that the AlgG RHbetaH protects alginate from degradation by AlgL by channeling the alginate polymer through the proposed alginate biosynthetic scaffold while epimerizing approximately every second d-mannuronate residue to l-guluronate along the epimerase catalytic face.


[Infectious endocarditis of gyneco-obstetric origin. Apropos of 15 cases].
With the object of analyzing current characteristics of post-partum and post-abortum infective endocarditis (IE), authors carried out a retrospective study of 15 cases between september 1985 and may 1992. Mean age was 22.2 +/- 4.0 years. Origin of sepsis was delivery (1 case), abortion (14 cases). There was no underlying cardiac lesion in 9 cases, rheumatic heart disease in 6 cases. Infecting organisms were Staphylococcus aureus (n = 6), streptococcus D (n = 3), Clostridium perfringens (n = 2). There were 10 acute and 5 subacute IE, 7 right-sided, 7 left-sided, and 1 right and left-sided IE. Vegetations were determined by transthoracic echocardiography in 12 cases (80%). The main complications were heart failure (15 cases), and pulmonary or arterial embolism (7 cases). Lethality was 53.3% and was not different in tricuspid acute IE and left-sided IE. Treatment was the more difficult as cardiac surgery is expensive or even inaccessible. Accordingly, prevention is primordial. It consist of antibiotic prophylaxis and fight against illicit abortion.


[Standard structures in protein molecules. II. Beta-alpha hairpins].
Standard conformations of polypeptide chains folded into beta-alpha-hairpins are considered in the paper. It is shown that there is a limited number of standard beta-alpha-hairpins having relatively short connections in the proteins and each beta-alpha-hairpin has a strictly definite order of hydrophobic, hydrophilic and glycine residues in the amino acid sequence coding for it.


Overexpression and amplification of five genes in a multidrug-resistant Chinese hamster ovary cell line.
Multidrug-resistant cells are cross-resistant to a wide range of unrelated drugs, many of which are used in cancer chemotherapy. We constructed a cDNA library from RNA of the multidrug-resistant Chinese hamster ovary cell line CHRC5. By differential screening we isolated cDNAs derived from mRNAs that are overexpressed in this cell line. The cDNAs could be grouped in five classes on the basis of transcript lengths detected in RNA blots. We infer that each class codes for a separate protein. The corresponding genes are amplified 10 or 30 times in CHRC5 DNA, providing an explanation for the constitutive overexpression found in this cell line. Despite differential amplification, the genes may be linked in one large amplicon as indicated by the hybridization analysis of large fragments of CHRC5 DNA separated by pulsed field gradient gel electrophoresis. Therefore, some of these genes might be fortuitously coamplified and not contribute functionally to the resistant phenotype. It is also possible, however, that genes involved in drug resistance are clustered. One of our clones cross-hybridized with the recently described cDNA pCHP1 (J. R. Riordan, K. Deuchars, N. Kartner, N. Alon, J. Trent, and V. Ling, Nature [London] 316:817-819, 1985) encoding part of the 170-kilodalton P-glycoprotein, a protein which is frequently overproduced in multidrug-resistant cells. The nature of the four other genes is still unknown. Sequences of four of the five classes of cDNAs are conserved in mouse and human DNA.


Evaluation of quantitative polymerase chain reaction assays targeting Mycobacterium avium, M. intracellulare, and M. avium subspecies paratuberculosis in drinking water biofilms.
Mycobacterium avium (MA), Mycobacterium intracellulare (MI), and Mycobacterium avium subsp. paratuberculosis (MAP) are difficult to culture due to their slow growing nature. A quantitative polymerase chain reaction (qPCR) method for the rapid detection of MA, MI, and MAP can be used to provide data supporting drinking water biofilms as potential sources of human exposure. The aim of this study was to characterize two qPCR assays targeting partial 16S rRNA gene sequences of MA and MI and use these assays, along with two previously reported MAP qPCR assays (IS900 and Target 251), to investigate Mycobacterium occurrence in kitchen faucet biofilms. MA and MI qPCR assays demonstrated 100% specificity and sensitivity when evaluated against 18 non-MA complex, 76 MA, and 17 MI isolates. Both assays detected approximately 1,000 cells from a diluted cell stock inoculated on a sampling swab 100% of the time. DNA analysis by qPCR indicated that 35.3, 56.9 and 11.8% of the 51 kitchen faucet biofilm samples collected contained MA, MI, and MAP, respectively. This study introduces novel qPCR assays designed to specifically detect MA and MI in biofilm. Results support the use of qPCR as an alternative to culture for detection and enumeration of MA, MI, and MAP in microbiologically complex samples.


Melatonin Ameliorates Neuropsychiatric Behaviors, Gut Microbiome, and Microbiota-Derived Metabolites in Rats with Chronic Sleep Deprivation.
With the increasing prevalence of sleep deprivation (SD)-related disorders, the effective treatment of sleep disorders has become a critical health research topic. Thus, we hypothesized and investigated the effectiveness of a 3-week melatonin intervention on neuropsychiatric behavioral responses mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD. Eighteen 6-week-old Wistar rats were used and divided into the control grup (C, n = 6), SD group (n = 6), and melatonin-supplemented group (SDM, n = 6). During weeks 0 to 6, animals were provided with the AIN-93M diet and free access to water. Four-week chronic SD was conducted from weeks 7 to 10. Exogenous melatonin administration (10 mg/kg BW) was injected intraperitoneally 1 h before the daily administration of SD for 3 weeks in the SDM group. SD rats exhibited anxiety-like behavior, depression-like behavior, and cognitive impairment. Exogenous melatonin administration ameliorated neuropsychiatric behaviors induced by chronic SD. Analysis of fecal metabolites indicated that melatonin may influence brain messaging through the microbiota-gut-brain axis by increasing the production of short-chain fatty acids (SCFA) and decreasing the production of secondary bile acids (SBA). Four-week SD reduced the cerebral cortex expression of MT1, but not in the colon. Chronic SD led to anxiety and depression-like behaviors and cognitive decline, as well as the reduced intestinal level of SCFAs and the enhanced intestinal level of SBAs in rats. In this work, we confirmed our hypothesis that a 3-week melatonin intervention on neuropsychiatric behavioral response mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD.


Modeling the forest transition: forest scarcity and ecosystem service hypotheses.
An historical generalization about forest cover change in which rapid deforestation gives way over time to forest restoration is called "the forest transition." Prior research on the forest transition leaves three important questions unanswered: (1) How does forest loss influence an individual landowner's incentives to reforest? (2) How does the forest recovery rate affect the likelihood of forest transition? (3) What happens after the forest transition occurs? The purpose of this paper is to develop a minimum model of the forest transition to answer these questions. We assume that deforestation caused by landowners' decisions and forest regeneration initiated by agricultural abandonment have aggregated effects that characterize entire landscapes. These effects include feedback mechanisms called the "forest scarcity" and "ecosystem service" hypotheses. In the forest scarcity hypothesis, forest losses make forest products scarcer, which increases the economic value of forests. In the ecosystem service hypothesis, the environmental degradation that accompanies the loss of forests causes the value of ecosystem services provided by forests to decline. We examined the impact of each mechanism on the likelihood of forest transition through an investigation of the equilibrium and stability of landscape dynamics. We found that the forest transition occurs only when landowners employ a low rate of future discounting. After the forest transition, regenerated forests are protected in a sustainable way if forests regenerate slowly. When forests regenerate rapidly, the forest scarcity hypothesis expects instability in which cycles of large-scale deforestation followed by forest regeneration repeatedly characterize the landscape. In contrast, the ecosystem service hypothesis predicts a catastrophic shift from a forested to an abandoned landscape when the amount of deforestation exceeds the critical level, which can lead to a resource degrading poverty trap. These findings imply that incentives for forest conservation seem stronger in settings where forests regenerate slowly as well as when decision makers value the future.


Referral of children to a general anaesthetic dental service in Tayside.
To determine the adequacy of child referral for dental general anaesthesia (DGA) by local dental practitioners, given the recent guidance document to dentists from the General Dental Council and in addition, to determine the subsequent treatment and factors which influence treatment selection. A prospective study. Department of Paediatric Dentistry, Dundee Dental Hospital, Dundee. Children [n = 84] who were referred for dental extractions under general anaesthetic over a three month period. Non-surgical dental extractions under general anaesthetic were requested in nearly 90% of referrals. In the majority of cases, the referral was deemed inadequate; e.g. the medical history was not mentioned in the majority of cases (85.7%) despite nearly one-fifth of patients having a relevant medical history. In general, referring practitioners under-estimated the extent of disease, requiring treatment plans to be changed in 76% of cases; all changes represented an increase in the number of dental extractions undertaken. The most common reasons for general anaesthetic use were: multiple dental extractions (73.8%); the patient's anxiety (63.1%); and patient's age (41.7%). As an alternative to general anaesthesia, treatment was undertaken successfully using inhalation sedation in nearly 15% of cases. Dental extractions under general anaesthetic are still a common reason for referral. Referring practitioners frequently provide inadequate information, in addition to under-estimating the treatment required. Alternative forms of anxiety management are available and should be considered for children requiring dental extractions.


Pathophysiological aspects of Aspergillus colonization in disease.
Aspergillus colonization of the lower respiratory airways is common in normal people, and of little clinical significance. However, in some patients, colonization is associated with severe disease including poorly controlled asthma, allergic bronchopulmonary aspergillosis (ABPA) with sputum plugs, worse lung function in chronic obstructive pulmonary aspergillosis (COPD), invasive aspergillosis, and active infection in patients with chronic pulmonary aspergillosis (CPA). Therefore, understanding the pathophysiological mechanisms of fungal colonization in disease is essential to develop strategies to avert or minimise disease. Aspergillus cell components promoting fungal adherence to the host surface, extracellular matrix, or basal lamina are indispensable for pathogen persistence. However, our understanding of individual differences in clearance of A. fumigatus from the lung in susceptible patients is close to zero.


Signatures of the Chiral Anomaly in Phonon Dynamics.
Discovered in high-energy physics, the chiral anomaly has recently made way to materials science by virtue of Weyl semimetals (WSM). Thus far, the main efforts to probe the chiral anomaly in WSM have concentrated on electronic phenomena. Here, we show that the chiral anomaly can have a large impact in the A_{1} phonons of enantiomorphic WSM. In these materials, the chiral anomaly produces an unusual magnetic-field-induced resonance in the effective phonon charge, which in turn leads to anomalies in the phonon dispersion, optical reflectivity, and the Raman scattering.


Peripheral axotomy of the rat mandibular trigeminal nerve leads to an increase in VIP and decrease of other primary afferent neuropeptides in the spinal trigeminal nucleus.
In the vasoactive intestinal polypeptide (VIP)-rich lumbosacral spinal cord, VIP increases at the expense of other neuropeptides after primary sensory nerve axotomy. This study was undertaken to ascertain whether similar changes occur in peripherally axotomised cranial sensory nerves. VIP immunoreactivity increased in the terminal region of the mandibular nerve in the trigeminal nucleus caudalis following unilateral section of the sensory root of the mandibular trigeminal nerve at the foramen orale. Other primary afferent neuropeptides (substance P, cholecystokinin and somatostatin) were depleted and fluoride-resistant acid phosphatase activity was abolished in the same circumscribed areas of the nucleus caudalis. The rise in VIP and depletion of other markers began 4 days postoperatively and was maximal by 10 days, these levels remaining unchanged up to 1 year postoperatively. VIP-immunoreactive cell bodies were absent from trigeminal ganglia from the unoperated side but small and medium cells stained intensely in the ganglia of the operated side after axotomy. These observations indicate that increase of VIP in sensory nerve terminals is a general phenomenon occurring in both cranial and spinal sensory terminal areas. The intense VIP immunoreactivity in axotomised trigeminal ganglia suggests that the increased levels of VIP in the nucleus caudalis are of peripheral origin, indicating a change in expression of neuropeptides within primary afferent neurons following peripheral axotomy.


Educating Medical Students for Practice in a Changing Landscape: An Analysis of Public Health Topics within Current Indonesian Medical Programs.
Medical curricula need to prepare doctors for emerging health issues and increased public health roles. With medical schools spread over a vast geographical region of Indonesia, ensuring that all schools meet appropriate standards in the quality of subjects, course delivery, and performance is challenging. This paper explores the inclusion of public health subjects in medical education across the country. A search of all subjects (n = 388) who were taught in 28 representative medical schools was undertaken and categorized by geographical region, accreditation grade, and according to the Indonesian National Standard of Medical Competency. Basic biomedicine subjects had the highest representation in the curricula (49.2 ± 8.7%) and public health was generally well represented (14.3 ± 5.0%). All medical schools complied with the minimum of 144 credits required for the bachelor stage. No statistically significant difference was found between school accreditation grades, or when an overall comparison of programs in Eastern and Western regions was undertaken. The Indonesian medical schools included have relatively good curriculum transparency, and public health is an important feature in their curricula. Further research is critical to identify the materials taught, the relevance and the applicability of the specific public health content, and the assessment of public health competency of graduates.


Revision and Implementation of "Clinical Guideline for Tuberculosis and HIV in Prisons", Great Tehran Prison, Iran.
To evaluate the feasibility of the revised "Clinical Guideline for HIV and TB" in the Great Tehran Prison during October 2013 to June 2014. The guideline includes all aspects of HIV/TB diagnosis based on active case finding (ACF), treatment and care services. Before the implementation, a focus group discussion was conducted, and attended by experts on prison health. The objective was to identify defects and limitations of the guideline. After the discussion, the guideline was revised. The Great Tehran Prison contains three separate units; all prisoners are taken first to "reception and identification unit (quarantine)" and then send to two housing units according to their legal status. An HIV ACF strategy was employed in the quarantine, and two units through a voluntary provider-initiated HIV testing. Three staff of the triangular clinic trained the prisoners about common routes of HIV transmission and the symptoms of TB in the units. In the quarantine, all prisoners were examined for all HIV-risk factors, HIV testing and symptoms of TB. In unit one, healthcare staff continued the ACF process, while in unit two, the peers of prisoners were assigned as the healthcare communicators to proceed with the strategy. At this caring process, when the test result was positive, then the process of care, treatment and follow ups was initiated. Moreover, the use of directly observed therapy (DOT) for antiretroviral therapy (ART) and TB was applied to the sick prisoners. There was also a follow-up caring for released prisoner to refer them to care and treatment services outside the prison. The guideline was implemented in the prison successfully. Regarding feasibility of the guideline, the investigators of this study suggest that the guideline should be implemented in other prisons across the country.


Haemodynamics of renoprival hypertension in man: studies during graded fluid withdrawal.
1. Frequent measurements of arterial pressure, cardiac output, heart rate and body weight were carried out in three hypertensive anephric subjects during the reversal of hypertension by carefully controlled stepwise fluid withdrawal over a period of 24 days. 2. The initial 5% decrease of body weight was associated with decrements of arterial pressure and total peripheral resistance of 15 and 35% respectively, whereas cardiac output had risen by 25%. After a further decrease in body weight by 5%, arterial pressure was lowered another 15% without a change in total peripheral resistance, and cardiac output had returned to base line. 3. These data do not support the concept that whole-body autoregulation is an important factor in the pathogenesis of renoprival hypertension.


Worldwide exploration of the microbiome harbored by the cnidarian model, Exaiptasia pallida (Agassiz in Verrill, 1864) indicates a lack of bacterial association specificity at a lower taxonomic rank.
Examination of host-microbe interactions in early diverging metazoans, such as cnidarians, is of great interest from an evolutionary perspective to understand how host-microbial consortia have evolved. To address this problem, we analyzed whether the bacterial community associated with the cosmopolitan and model sea anemone Exaiptasia pallida shows specific patterns across worldwide populations ranging from the Caribbean Sea, and the Atlantic and Pacific oceans. By comparing sequences of the V1-V3 hypervariable regions of the bacterial 16S rRNA gene, we revealed that anemones host a complex and diverse microbial community. When examined at the phylum level, bacterial diversity and abundance associated with E. pallida are broadly conserved across geographic space with samples, containing largely Proteobacteria and Bacteroides. However, the species-level makeup within these phyla differs drastically across space suggesting a high-level core microbiome with local adaptation of the constituents. Indeed, no bacterial OTU was ubiquitously found in all anemones samples. We also revealed changes in the microbial community structure after rearing anemone specimens in captivity within a period of four months. Furthermore, the variation in bacterial community assemblages across geographical locations did not correlate with the composition of microalgal Symbiodinium symbionts. Our findings contrast with the postulation that cnidarian hosts might actively select and maintain species-specific microbial communities that could have resulted from an intimate co-evolution process. The fact that E. pallida is likely an introduced species in most sampled localities suggests that this microbial turnover is a relatively rapid process. Our findings suggest that environmental settings, not host specificity, seem to dictate bacterial community structure associated with this sea anemone. More than maintaining a specific composition of bacterial species some cnidarians associate with a wide range of bacterial species as long as they provide the same physiological benefits towards the maintenance of a healthy host. The examination of the previously uncharacterized bacterial community associated with the cnidarian sea anemone model E. pallida is the first global-scale study of its kind.


Tetrodotoxin-sensitive Na+ channels in isolated single cultured rat myocardial cells.
We studied the existence of tetrodotoxin (TTX)-sensitive fast Na+ channels in isolated single (verified by dye injection) myocardial cells compared with small multiple-cell groups from 1- to 3-day-old rat ventricles in cell culture. For single cells, average values were -63 mV maximum membrane potential, 32 mV overshoot, and 65 V/s maximum rate of rise of the action potentials (+Vmax). These values were comparable to values from groups of multiple (2-10) cells. TTX strongly depressed +Vmax dose dependently, with no difference between single and multiple cells. +Vmax was also decreased by lowering extracellular Na+ concentration but not by D 600 or lowering extracellular Ca2+ concentration. These results suggest that 1) isolated single cells possess TTX-sensitive fast Na+ channels, 2) culturing per se does not alter TTX sensitivity, and 3) TTX sensitivity is not modified by cell density.


A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency.
Isolated 17,20 lyase deficiency is commonly defined by apparently normal 17α-hydroxylase activity but severely reduced 17,20 lyase activity of the bifunctional enzyme cytochrome P450 (CYP) enzyme 17A1 (CYP17A1), resulting in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. Cytochrome b5 (CYB5A) is thought to selectively enhance 17,20 lyase activity by facilitating the allosteric interaction of CYP17A1 with its electron donor P450 oxidoreductase (POR). We investigated a large consanguineous family including three siblings with 46,XY disorder of sex development (DSD) presenting with isolated 17,20 lyase deficiency. We investigated the clinical and biochemical phenotype, conducted genetic analyses, and functionally characterized the identified CYB5A mutation in cell-based CYP17A1 coexpression assays. All three siblings presented with 46,XY DSD, sex steroid deficiency, normal mineralocorticoids and glucocorticoids, and a urine steroid metabolome suggestive of isolated 17,20 lyase deficiency. CYP17A1 and POR sequences were normal, but we detected a homozygous CYB5A missense mutation (g.28,400A→T; p.H44L). Functional in vitro analysis revealed normal CYP17A1 17α-hydroxylase activity but severely impaired 17,20 lyase activity. In silico analysis suggested the disruption of CYB5A heme binding by p.H44L. We have identified the first human CYB5A missense mutation as the cause of isolated 17,20 lyase deficiency in three individuals with 46,XY DSD. Detailed review of previously reported cases with apparently isolated 17,20 lyase deficiency due to mutant CYP17A1 and POR reveals impaired 17α-hydroxylase activity as assessed by steroid metabolome analysis and short cosyntropin testing. This suggests that truly isolated 17,20 lyase deficiency is observed only in individuals with inactivating CYB5A mutations.


Preparation for procedures and surgery through play.
The child life therapist utilizes play techniques with hospitalized children for preparation and integration before and after medical procedures and surgery. Unstructured and structured play sessions enable children to anticipate threatening events and mobilize their coping behaviors. Through manipulating appropriate play materials including miniature-size medical equipment, children communicate if facts of preparation have been understood, misinterpreted or denied. Concrete play experiences (e.g., doctor puppet play), enable children to understand hospital routines and sequences of events. Sensory experiences (e.g., needle play), help them dramatize situations and to adopt changes of role from passive to active ones. Opportunities for play after procedures (particularly intrusive ones) and surgery must be made available to clarify any misconceptions and to emphasize the nurturing and healing aspects of treatment. Psychological preparation for necessary procedures and surgery through play results in children enduring and cooperating more readily and have more trust in all medical personnel.


DNA: a programmable force sensor.
Direct quantification of biomolecular interaction by single-molecule force spectroscopy has evolved into a powerful tool for materials and life sciences. We introduce an approach in which the unbinding forces required to break intermolecular bonds are measured in a differential format by comparison with a known reference bond (here, a short DNA duplex). In addition to a marked increase in sensitivity and force resolution, which enabled us to resolve single-base pair mismatches, this concept allows for highly specific parallel assays. This option was exploited to overcome cross-reactions of antibodies in a protein biochip application.


Design of the femoral component for cementless hip replacement: the surgeon's perspective.
Few guidelines are currently available to the surgeon when choosing a specific femoral component for cementless total hip replacement (THR). A survey of the members of the American Association for Hip and Knee Surgeons (AAHKS) was conducted to gain insight into the importance of implant material, stress shielding, and micromotion in the selection of cementless femoral components. A comprehensive survey was distributed to 300 orthopedic surgeons selected from the members of the AAHKS; 169 of the 300 surgeons completed the detailed questionnaire. The results of the survey were analyzed using the SPSS software package to obtain general trends in opinion, and a stepwise regression analysis was used to correlate responses with training and clinical experience. Interestingly, there was little consensus among surgeons with respect to the relative importance of implant material, stress shielding, and micromotion in the selection of prostheses for cementless THR. In general, bone loss secondary to stress shielding was the least important issue, and axial and rotational micromotion were considered progressively more significant problems. Cementless titanium alloy stems were perceived as offering no significant advantage over cobalt chrome alloy stems. Moreover, there was no consensus as to whether a collar was advantageous. Prosthesis stability, restoration of motion, and a proven clinical record were more important to surgeons than were ease of implantation and removal, cost, and availability.


[Ultrastructure of the cell wall in vegetative mycelia of Agaricus bisporus (Lange) Imbach].
A comparative description of the cell wall ultrastructure was made for vegetative mycelia in Agaricus bisporus, other species of Agaricus, and Pleurotus ostreatus. Apart from well known ultrastructural features of cell walls of the examined strains, inclusions of different kinds were observed. The cell wall thickness varied in different Agaricus strains. Maximum differences between the examined strains were 1.4 times. The cell wall thickness in P. ostreatus strains was by 3 to 4 times less than that in Agaricus strains. Using electron micrographs, a brief description of mycelia and A. bisporus basidia ultrastructure was composed.


Targeting DNA damage and repair by curcumin.
Curcumin is a compound with anti-tumor effects in a tolerable dose. A recent paper by Rowe et al described that curcumin induced DNA damage in triple negative breast cancer cells and regulated BRCA1 protein expression and modification.1 Related research and potential use of curcumin will be discussed in this article.


Transcriptional activation of the human rod cGMP-phosphodiesterase beta-subunit gene is mediated by an upstream AP-1 element.
During photoactivation retinal cGMP-phosphodiesterase (PDE) mediates signal transduction in the photoreceptor outer segments. Mutations in the beta-subunit gene of rod-specific PDE (beta-PDE) have been associated with inherited retinal degeneration in a number of species, including human. Here we have investigated the proximal upstream sequences that participate in transcriptional activation of this gene. Transient transfections demonstrated that the sequence from -72 to +53 bp contained sufficient information to direct high levels of gene expression in cells of retinal origin. Deletion or mutagenesis of an AP-1 motif present in this region caused 90-95% reduction in reporter gene expression. By gel mobility shift assay we demonstrated specific interactions between putative nuclear transcription factors and this AP-1 element. These findings indicate that the proximal AP-1 site in the human beta-PDE promoter is functionally relevant and necessary for transcriptional activation of this gene.


Ultrasound prevents renal ischemia-reperfusion injury by stimulating the splenic cholinergic anti-inflammatory pathway.
AKI affects both quality of life and health care costs and is an independent risk factor for mortality. At present, there are few effective treatment options for AKI. Here, we describe a nonpharmacologic, noninvasive, ultrasound-based method to prevent renal ischemia-reperfusion injury in mice, which is a model for human AKI. We exposed anesthetized mice to an ultrasound protocol 24 hours before renal ischemia. After 24 hours of reperfusion, ultrasound-treated mice exhibited preserved kidney morphology and function compared with sham-treated mice. Ultrasound exposure before renal ischemia reduced the accumulation of CD11b(+)Ly6G(high) neutrophils and CD11b(+)F4/80(high) myeloid cells in kidney tissue. Furthermore, splenectomy and adoptive transfer studies revealed that the spleen and CD4(+) T cells mediated the protective effects of ultrasound. Last, blockade or genetic deficiency of the α7 nicotinic acetylcholine receptor abrogated the protective effect of ultrasound, suggesting the involvement of the cholinergic anti-inflammatory pathway. Taken together, these results suggest that an ultrasound-based treatment could have therapeutic potential for the prevention of AKI, possibly by stimulating a splenic anti-inflammatory pathway.


Do children learn from their prediction mistakes? A registered report evaluating error-based theories of language acquisition.
Error-based theories of language acquisition suggest that children, like adults, continuously make and evaluate predictions in order to reach an adult-like state of language use. However, while these theories have become extremely influential, their central claim-that unpredictable input leads to higher rates of lasting change in linguistic representations-has scarcely been tested. We designed a prime surprisal-based intervention study to assess this claim. As predicted, both 5- to 6-year-old children (n = 72) and adults (n = 72) showed a pre- to post-test shift towards producing the dative syntactic structure they were exposed to in surprising sentences. The effect was significant in both age groups together, and in the child group separately when participants with ceiling performance in the pre-test were excluded. Secondary predictions were not upheld: we found no verb-based learning effects and there was only reliable evidence for immediate prime surprisal effects in the adult, but not in the child group. To our knowledge, this is the first published study demonstrating enhanced learning rates for the same syntactic structure when it appeared in surprising as opposed to predictable contexts, thus providing crucial support for error-based theories of language acquisition.


High KLF4 level in normal tissue predicts poor survival in colorectal cancer patients.
Krüppel-like factor 4 (KLF4) is involved in many important cellular processes such as growth, development, differentiation, proliferation, and apoptosis. The purpose of this study was to determine the significance of KLF4 in both tumors and normal tissues of patients with colorectal cancer (CRC). Between January 2003 and June 2005, 125 patients with CRC receiving treatment at the Yonsei Cancer Center were selected. We examined the mRNA level of the KLF4 gene in primary CRC specimens and matched normal colon tissues using real-time RT-PCR. Correlation of survival with clinicopathological parameters, including KLF4 level, was investigated with univariate and multivariate analyses. CRC tissue had a significantly lower KLF4 level when compared with matched normal tissues (KLF4 in tumors: 2007 ± 1531 copies/μl, KLF4 in normal tissues: 6586 ± 2834 copies/μl; P < 0.0001). However, there was a correlation between the KLF4 level in tumors and normal tissues. Patients with a high KLF4 level in matched normal tissues were more likely than those with a low KLF4 level to develop recurrence and had poorer overall survival (P = 0.005). Therefore, the KLF4 level in the normal tissue of individuals was associated with prognosis of individuals. Our data suggest that KLF4 mRNA expression level in normal tissues and tumors may be a useful prognostic marker in patients with CRC.