[Limitations of preclinical emergency medicine from the legal viewpoint].
Revised and Annotated Version of the Author's Lecture held at the 13th Annual Meeting on Emergency Care Medicine on 14 March 1998 at Baden-baden, Germany. This article highlights the limitations of preclinical emergency care medicine from a legal viewpoint. Among other problems, focus is also on the problem whether a particular emergency care measure can be expected from the emergency physician. Much attention is devoted to a discussion on treating a patient against his will, this constituting a differentiated borderline case in emergency medicine. Another equally differentiated problem concerns the economic aspects--for example, whether an emergency treatment pays returns in terms of economy. This is no limitation in individual cases where emergency treatment is medically indicated, but it does exercise an influence on pre-planning the security level of emergency care services. There are no limitations for emergency services from a legal point of view imposed by the patient's age or his or her domicile in a home for the aged or infirm.


Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition.
Mutations in TP53 gene play a pivotal role in tumorigenesis and cancer development. Here, we report that gain-of-function mutant p53 proteins inhibit the autophagic pathway favoring antiapoptotic effects as well as proliferation of pancreas and breast cancer cells. We found that mutant p53 significantly counteracts the formation of autophagic vesicles and their fusion with lysosomes throughout the repression of some key autophagy-related proteins and enzymes as BECN1 (and P-BECN1), DRAM1, ATG12, SESN1/2 and P-AMPK with the concomitant stimulation of mTOR signaling. As a paradigm of this mechanism, we show that atg12 gene repression was mediated by the recruitment of the p50 NF-κB/mutant p53 protein complex onto the atg12 promoter. Either mutant p53 or p50 NF-κB depletion downregulates atg12 gene expression. We further correlated the low expression levels of autophagic genes (atg12, becn1, sesn1, and dram1) with a reduced relapse free survival (RFS) and distant metastasis free survival (DMFS) of breast cancer patients carrying TP53 gene mutations conferring a prognostic value to this mutant p53-and autophagy-related signature. Interestingly, the mutant p53-driven mTOR stimulation sensitized cancer cells to the treatment with the mTOR inhibitor everolimus. All these results reveal a novel mechanism through which mutant p53 proteins promote cancer cell proliferation with the concomitant inhibition of autophagy.


Effect of Satureja khuzestanica essential oil on male rat fertility.
This study was undertaken to study the effect of Satureja khuzestanica essential oil (SKEO) in male rat fertility. SKEO was administered orally at doses of 75, 150, and 225 mg/kg/day for 45 days through drinking water. Treated and control rats were mated with female on day 45 of treatment. SKEO significantly improved all the parameters evaluated such as potency, fecundity, fertility index, and litter size. Moreover, concentrations of FSH and testosterone were significantly increased in SKEO-treated groups. Also the weights of testes, seminal vesicles, and ventral prostate weights were increased by SKEO (225 mg/kg). Histopathological analysis showed that in male rats treated with SKEO (150, 225 mg/kg) the number of spermatogonium, spermatid cords, Leydig cells, and spermatozoids was increased. Also in these groups, the Sertoli cells were hypertrophic.


A rise of MMP-2 and MMP-9 in bronchoalveolar lavage fluid is associated with acute lung injury after cardiopulmonary bypass in a swine model.
Postoperative acute lung injury (ALI) contributes to the morbidity and mortality following cardiopulmonary bypass (CPB). To determine whether the presence of matrix metalloproteinases (MMPs) is associated with ALI after CPB, MMP-2 and MMP-9 activities in bronchoalveolar lavage fluid (BALF) were compared with parameters indicating impaired gas exchange. In a prospective study, 17 minipigs were subjected to CPB for 60 min. Before and at five and 180 min after CPB, MMP-2 and MMP-9 were assayed in BALF and the arterial-alveolar gradient of oxygen tension (AaDO2), the pulmonary capillary wedge pressure (PCWP) and the water content of lung tissue samples (Wt) were evaluated and compared with baseline values. MMP-2 and MMP-9 increased significantly 5 minutes (2.1- and 6.2-fold, respectively) and 180 minutes (3.4- and 14.3-fold, respectively) post-CPB. AaDO2 and Wt, but not PCWP, increased significantly 180 minutes after CPB and only AaDO2, but not PCWP or Wt, was significantly correlated with MMP-2 (r = 0.66, p = 0.006) and MMP-9 (r = 0.62, p = 0.01). In conclusion, high levels of MMP-2 and MMP-9 in the pulmonary compartment are associated with ALI after CPB.


Reimbursed Price of Orphan Drugs: Current Strategies and Potential Improvements.
The pricing and reimbursement policies for pharmaceuticals are relevant to balance timely and equitable access for all patients, financial sustainability, and reward for valuable innovation. The proliferation of high-cost specialty medicines is particularly true in rare diseases (RDs) where the pricing mechanism is characterised by a lack of transparency. This work provides an overall picture of current strategies for the definition of the reimbursed prices of orphan drugs (ODs) and highlights some potential improvements. Current strategies and suggestions are presented along 4 dimensions: (1) comprehensive value assessment, (2) early dialogs among relevant stakeholders, (3) innovative reimbursement approaches, and (4) societal participation in producing ODs. Comprehensive value assessment could be achieved by clarifying the approach of distributive justice to adopt, ensuring a representative participation of stakeholders, and with a broad consideration of value-bearing factors. With respect to early dialogs, cross-border cooperation can be determinant to companies and agencies. The cost-benefit ratio of early dialogs needs to be demonstrated and the "regulatory capture" effect should be monitored. Innovative reimbursement approaches were developed to balance the need for evidence-based decisions with the timely access to innovative drugs. The societal participation in producing ODs needs to be recognised in a collaborating framework where adaptive agreements can be developed with mutual satisfaction. Such agreements could also impact on coverage and reimbursement decisions as additional elements for the determination of a comprehensive societal value of ODs. Further research is needed to investigate the highlighted open challenges so that RDs will not remain, in practical terms, orphan diseases.


Speech Perception in Noise and Medial Olivocochlear Reflex: Effects of Age, Speech Stimulus, and Response-Related Variables.
The role of the medial olivocochlear system in speech perception in noise has been debated over the years, with studies showing mixed results. One possible reason for this could be the dependence of this relationship on the parameters used in assessing the speech perception ability (age, stimulus, and response-related variables). The current study assessed the influence of the type of speech stimuli (monosyllables, words, and sentences), the signal-to-noise ratio (+5, 0, -5, and -10 dB), the metric used to quantify the speech perception ability (percent-correct, SNR-50, and slope of the psychometric function) and age (young vs old) on the relationship between medial olivocochlear reflex (quantified by contralateral inhibition of transient evoked otoacoustic emissions) and speech perception in noise. A linear mixed-effects model revealed no significant contributions of the medial olivocochlear reflex to speech perception in noise. The results suggest that there was no evidence of any modulatory influence of the indirectly measured medial olivocochlear reflex strength on speech perception in noise.


Precursor of brain-derived neurotrophic factor (proBDNF) forms a complex with Huntingtin-associated protein-1 (HAP1) and sortilin that modulates proBDNF trafficking, degradation, and processing.
proBDNF, a precursor of brain-derived neurotrophic factor (BDNF), is anterogradely transported and released from nerve terminals, but the mechanism underlying this process remains unclear. In this study, we report that proBDNF forms a complex with Huntingtin associated protein-1 (HAP1) and sortilin, which plays an important role in proBDNF intracellular trafficking and stabilization. The interaction of proBDNF with both HAP1A and sortilin in co-transfected HEK293 cells is confirmed by both fluorescence resonance energy transfer and co-immunoprecipitation. The frequent co-localization (>90%) of endogenous HAP1, sortilin, and proBDNF is also found in cultured cortical neurons. Mapping studies using GST pulldown and competition assays has defined the interacting region of HAP1 with proBDNF within amino acids 371-445 and the binding sequences of proBDNF to HAP1 between amino acids 65 and 90. Fluorescence recovery after photobleaching confirms the defective movement of proBDNF-containing vesicles in neurites of HAP1(-/-) neurons, which can be partially restored by reintroducing HAP1 cDNA into the neurons. However, the effect is significantly increased by simultaneously reintroducing both HAP1 and sortilin. proBDNF and HAP1 are highly co-localized with organelle markers for the Golgi network, microtubules, molecular motor, or endosomes in normal neurons, but this co-localization is reduced in HAP1(-/-) neurons. Co-immunoprecipitation and Western blot showed that sortilin stabilizes the proBDNF·HAP1 complex in co-transfected HEK293 cells, helping to prevent proBDNF degradation. Furthermore, the complex facilitates furin cleavage to release mature BDNF.


[Differential display technique and its progress].
Differential display technique is an important method to isolate differentially expressed gene. Comparing to other methods like representational difference analysis, suppression subtractive hybridization and serial analysis of gene expression, differential display technique is used in higher frequency. Since it was established in 1992, it has overcome many disadvantages and widened its practical fields through improvements and enhancements by global researchers. In this paper the principle and the main advantages and disadvantages of differential display technique were briefly introduced. Meanwhile, the four progressed aspects in designing primer, reducing false positives, identifying differentially expressed gene and techniques derived from DD were introduced in detail.


Amino-terminal pro-B-type natriuretic peptides in stable and unstable ischemic heart disease.
Across the entire spectrum of ischemic heart disease, amino-terminal pro-B-type natriuretic peptides (NT-proBNP) are a strong and independent prognostic indicator, representing a particularly strong predictor of heart failure or death. This risk is independent of all other variables, including renal function or troponin, and is proportional to the magnitude of NT-proBNP release, with higher risk observed among those with a more marked elevation of the marker. Although prospective studies on the effect of NT-proBNP measurement in guiding therapy in ischemic heart disease are lacking, among patients presenting with acute coronary syndromes, it is recommended to measure NT-proBNP on (or near) the time of admission. An elevated initial NT-proBNP concentration should prompt consideration of an early invasive management approach. Consideration should be given to repeating the NT-proBNP measurement after 24-72 hours and again at 3-6 months because these follow-up measurements provide more long-term prognostic information than single measures at presentation. In acute ischemic heart disease, an NT-proBNP value >250 ng/L is associated with an adverse prognosis. In patients with stable coronary artery disease, measurement may be performed for prognostication purposes at 6- to 18-month intervals. In the case of clinical suspicion of disease progression, a new sample may be warranted.


IGF-I protects porcine granulosa cells from hypoxia-induced apoptosis by promoting homologous recombination repair through the PI3K/AKT/E2F8/RAD51 pathway.
Severe hypoxia induced by vascular compromise (ovarian torsion, surgery), obliteration of vessels (aging, chemotherapy, particularly platinum drugs) can cause massive follicle atresia. On the other hand, hypoxia increases the occurrence of DNA double-strand breaks (DSBs) and triggers cellular damage repair mechanisms; however, if the damage is not promptly repaired, it can also induce the apoptosis program. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that plays essential roles in stimulating mammalian follicular development. Here, we report a novel role for IGF-I in protecting hypoxic GCs from apoptosis by promoting DNA repair through the homologous recombination (HR) process. Indeed, the hypoxic environment within follicles significantly inhibited the efficiency of HR-directed DNA repair. The presence of IGF-I-induced HR pathway to alleviate hypoxia-induced DNA damage and apoptosis primarily through upregulating the expression of the RAD51 recombinase. Importantly, we identified a new transcriptional regulator of RAD51, namely E2F8, which mediates the protective effects of IGF-I on hypoxic GCs by facilitating the transcriptional activation of RAD51. Furthermore, we demonstrated that the PI3K/AKT pathway is crucial for IGF-I-induced E2F8 expression, resulting in increased RAD51 expression and enhanced HR activity, which mitigates hypoxia-induced DNA damage and thereby protects against GCs apoptosis. Together, these findings define a novel mechanism of IGF-I-mediated GCs protection by activating the HR repair through the PI3K/AKT/E2F8/RAD51 pathway under hypoxia.


Maternal and Neonatal Outcomes Associated with Amniotomy among Nulliparous Women Undergoing Labor Induction at Term.
The aim of the study is to evaluate the association between amniotomy at various time points during labor induction and maternal and neonatal outcomes among term, nulliparous women. Secondary analysis of a randomized trial of term labor induction versus expectant management in low-risk, nulliparous women (2014-2017) was conducted. Women met inclusion criteria if they underwent induction ≥38 weeks' gestation using oxytocin with documented time and type of membrane rupture. Women with antepartum stillbirth or fetal anomaly were excluded. The primary outcome was cesarean delivery. Secondary outcomes included maternal and neonatal complications. Maternal and neonatal outcomes were compared among women with amniotomy versus women with intact membranes and no amniotomy at six 2-hour time intervals: before oxytocin initiation, 0 to <2 hours after oxytocin, 2 to <4 hours after, 4 to <6 hours after, 6 to <8 hours after, and 8 to <10 hours after. Multivariable logistic regression adjusted for maternal age, body mass index, race/ethnicity, modified Bishop score on admission, treatment group, and hospital (as a random effect). Of 6,106 women in the parent trial, 2,854 (46.7%) women met inclusion criteria. Of these 2,340 (82.0%) underwent amniotomy, and majority of the women had amniotomy performed between 2 and <6 hours after oxytocin. Cesarean delivery was less frequent among women with amniotomy 6 to <8 hours after oxytocin compared with women without amniotomy (21.9 vs. 29.7%; adjusted odds ratio 0.61, 95% confidence interval 0.42-0.89). Amniotomy at time intervals ≥4 hours after oxytocin was associated with lower odds of labor duration >24 hours. Amniotomy at time intervals ≥2 hours and <8 hours after oxytocin was associated with lower odds of maternal hospitalization >3 days. Amniotomy was not associated with postpartum or neonatal complications. Among a contemporary cohort of nulliparous women undergoing term labor induction, amniotomy was associated with either lower or similar odds of cesarean delivery and other adverse outcomes, compared with no amniotomy.


An Exploration of the Experiences of Physical Therapists Who Identify as LGBTQIA+: Navigating Sexual Orientation and Gender Identity in Clinical, Academic, and Professional Roles.
The purpose of this study was to explore physical therapy through the stories of physical therapists who identify as lesbian, gay, bisexual, transgender, queer, intersex, asexual, and other related identities (LGBTQIA+) to consider how the profession enacts and constructs gender and sexual orientation. Physical therapists with clinical, academic, and professional roles who identify as LGBTQIA+ were recruited from Australia, the United Kingdom, Canada, and the United States. In-depth data were collected via narrative interviews. An iterative group discourse analysis was used to examine key discourses underpinning interview narratives and how these relate to the physical therapy profession. Twenty-two physical therapists were interviewed. Participants had between 1.5 and 40 years of experience across various clinical areas and settings. Participants identified with varying sexual orientations and gender identities. Analysis identified discourses discussed under the following headings: (1) normativity, which related to hetero-normative assumptions about sexual orientation and cisnormative assumptions about gender identity and the intersectionality among sexual orientation, gender identity, and other forms of marginalization; (2) stress and labor, which explored the stress experienced by physical therapists who are LGBTQIA+ (due to fear of discrimination or actual discrimination) and additional emotional and other types of labor or work done in the workplace to hide aspects of their lives to feel safe, educate colleagues, and be a role model; and (3) professionalism, which related to the heterosexual/cisnormative (and other) "norms" that comprised participants' ideas of presenting as "professional" and positioning physical therapists who are LGBTQIA+ as "unprofessional." Findings suggest that cultural norms may need to be reconceptualized in physical therapy to promote inclusion and belonging of individuals who identify as LGBTQIA+. Approaches to upskill new and existing physical therapists may include elements such as individual and institutional reflexivity, learning and implementing appropriate terminology, displaying indicators of inclusivity, and cultural safety training. These elements may provide the first steps to promote inclusive and culturally safe environments for individuals who identify as LGBTQIA+ within the profession. This is the first known study to explore the lived experiences of those who identify as LGBTQIA+ in the physical therapy profession. The findings highlight how prevailing normative discourses in Western society are also present in physical therapy and impact those who identify as LGBTQIA+.


Russell-Silver syndrome.
In comparison to Prader-Willi or Angelman syndrome, Russell-Silver syndrome (RSS) is a relatively "young" imprinting disorder. This congenital disease is characterized by intrauterine and postnatal growth retardation, relative macrocephaly, a typical triangular face, asymmetry, and further less constant characteristic features. Genetic and epigenetic disturbances can meanwhile be detected in approximately 50% of patients with typical RSS features. Up to 5% of patients carry a maternal uniparental disomy of chromosome 7 (UPD(7)mat), at least 44% show hypomethylation in the chromosome 11p15 imprinting center 1 (IC). In 1-2% of RSS patients, (sub)microscopic chromosomal aberrations can be observed. The diagnostic workup should therefore include methylation/genomic testing for chromosome 11p15, UPD(7)mat analysis and molecular karyotyping. The recurrence risk is generally low in RSS but it can be strongly increased in cases of familial epimutations or a chromosomal rearrangement. Interestingly, in approximately 7% of cases with chromosome 11p15 hypomethylation, hypomethylation of additional imprinted loci can be detected. Clinically, patients with hypomethylation at multiple loci do not differ from those with isolated 11p15 hypomethylation whereas the UPD(7)mat patients generally show a milder phenotype. Nevertheless, (epi)genotype-phenotype correlations are still evolving. Furthermore, the pathophysiological mechanisms resulting in the RSS phenotype still remain unknown despite the recent progress in deciphering the molecular defects associated with this condition.


[DNA-dependent RNA polymerase from the nuclei of the spleen of white rats].
DNA-dependent RNA polymerase was isolated from rat spleen cell nuclei and was identified as A and B RNA polymerases by data on DEAE- and P-cellulose ionic exchange chromatography and on concentration dependency on bivalent ions and (NH4)2SO4. Two forms of the enzyme differed from each other in the activity in RNA synthesizing system, and their activity was completely inhibited by actinomycin, DNase and RNase.


Show them what they can't see! An evaluation of the use of customized 3D printed models in head and neck anatomy.
Difficulty in visualizing anatomical structures has been identified as a challenge in anatomy learning and the emergence of three-dimensional printed models (3DPMs) offers a potential solution. This study evaluated the effectiveness of 3DPMs for learning the arterial supply of the head and neck region. 184 undergraduate medical students were randomly assigned to one of four learning modalities including wet specimen, digital model, 3DPM, and textbook image. Posttest scores indicated that all four modalities supported participants' knowledge acquisition, most significantly in the wet specimen group. While the participants rated 3DPMs lower for helping correct identification of structures than wet specimens, they praised 3DPMs for their ability to demonstrate topographical relationships between the arterial supply and adjacent structures. The data further suggested that the biggest limitation of the 3DPMs was their simplicity, thus making it more difficult for users to recognize the equivalent structures on the wet specimens. It was concluded that future designs of 3DPMs will need to consider the balance between the ease of visualization of anatomical structures and the degree of complexity required for successful transfer of learning. Overall, this study presented some conflicting evidence of the favorable outcomes of 3DPMs reported in other similar studies. While effective for anatomy learning as a standalone modality, educators must identify the position 3DPM models hold relative to other modalities in the continuum of undergraduate anatomy education in order to maximize their advantages for students.


Free surface flow between two horizontal concentric cylinders.
Results are reported on a combined experimental and numerical investigation of a free surface flow at small Reynolds numbers. The flow is driven by the rotation of the inner of two horizontal concentric cylinders, with an inner to outer radius ratio of 0.43. The outer cylinder is stationary. The annular gap is partially filled, from 0.5 to 0.95 full, with a viscous liquid leaving a free surface. When the fraction of the annular volume filled by liquid is 0.5, a thin liquid film covers the rotating inner cylinder and reenters the liquid pool. For relatively low rotation speeds, the evolution of the film thickness is consistent with the theory for a plate being withdrawn from an infinite liquid pool. The overall liquid flow pattern at this condition consists of two counter-rotating cells: one is around the inner cylinder and the other with weaker circulation rate is in the bottom part of the annulus and nearly symmetric about the vertical axis. With increasing rotation rate, the free surface becomes more deformed, and the dynamics of the stagnation line and the cusp line dividing the cells are tracked as quantitative measures of the interface shape. In addition, the recirculating flow cells lose symmetry and the cusp deforms the free surface severely. A comparison of numerically computed flow which describes the interface by a phase-field method confirms the dynamics of the two cells and the interface deformation. For filling fraction 0.75, the liquid level is slightly above the inner cylinder and a significant decrease in size of the bottom cell with increasing rotation rate is found. For filling fractions approaching unity, the liquid flow consists of one single cell and the surface deformation remains small.


Hepatitis C is a risk factor for death after liver retransplantation.
Retransplantation for liver allograft failure associated with hepatitis C virus (HCV) has been increasing due to nearly universal posttransplant HCV recurrence and has been demonstrated to be associated with poor outcomes. We report on the risk factors for death after retransplantation among liver recipients with HCV. A retrospective cohort of liver transplant recipients who underwent retransplantation between January 1997 and December 2002 was identified in the Scientific Registry of Transplant Recipients database. Cox regression was used to assess the relative effect of HCV diagnosis on mortality risk after retransplantation and was adjusted for multiple covariates. Of 1,718 liver retransplantations during the study period, 464 (27%) were associated with a diagnosis of HCV infection. Based on Cox regression, retransplant recipients with HCV had a 30% higher covariate-adjusted mortality risk than those without HCV diagnosis (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.10-1.54; P = 0.002). Other covariates associated with significant relative risk of death after retransplantation included older recipient age, presence in an intensive care unit (ICU), serum creatinine, and donor age. Additional regression analysis revealed that the increase in mortality risk associated with HCV was concentrated between 3 and 24 months postretransplantation, among patients age 18 to 39 at retransplant, and in patients retransplanted during the years 2000 to 2002. In conclusion, HCV liver recipients account for a considerable proportion of all retransplantations performed. Surprisingly, younger age predicted a higher mortality for recipients with HCV undergoing liver retransplantation. This may reflect a willingness to retransplant younger patients with an increased severity of illness or a more virulent HCV infection in this population. Although HCV was predictive of an increased risk of death, consideration of other characteristics of HCV patients, including donor and recipient age and need for preoperative ICU care may identify those at significantly higher risk.


Spectrin tetramer-dimer equilibrium in hereditary elliptocytosis.
The proportion of spectrin tetramers and dimers in 4 degrees C low ionic strength extracts of red cell membranes of 9 subjects with 4 different variants of hereditary elliptocytosis (HE) and 2 subjects with hereditary spherocytosis (HS) was determined by nondenaturing gel electrophoresis. Such extracts reflect the native oligomeric state of spectrin in the red cell membrane. In two hemolytic HE variants (an unclassified adult with increased thermal sensitivity of red cells and an infant also showing increased thermal sensitivity of red cells), the proportion of dimers was increased, whereas the remaining subjects had values within the control range. Conversion of spectrin tetramers to dimers under isotonic conditions at 37 degrees C, or spectrin dimers to tetramers at 30 degrees C, resulted in a high proportion of dimers in the above two HE variants, as well as in a third variant with probable mild HE and sporadic hemolysis. The mother of the infant with elliptocytosis and increased thermal sensitivity of red cells, although hematologically normal, had an increased proportion of dimers in 4 degrees C low ionic strength extracts of her red cell membranes. These findings reflect an underlying primary or secondary abnormality of spectrin in these subjects that affects the association state of spectrin in the red cell membrane. Their exact relationship to the pathogenesis of the elliptical shape of the red cell, or to the presence of hemolysis, is at present unclear.


Comparison of laser interferometry and ultrasound A-scan in the measurement of axial length.
Laser interferometry is a new, non-contact technique for the measurement of axial length. In this study we compared measurements of axial length obtained with this technique with those obtained with ultrasound (A-scan). The reproducibility and examiner-dependency of the two methods were also analysed. Patients presenting at the cataract assessment clinic were invited to participate in the study. Axial length measurements were obtained both by contact ultrasound (A-scan) and by non-contact laser interferometry (IOLMasterTM V1.1, Carl Zeiss, Jena, Germany). Intraocular lens powers were calculated using both sets of measurements. The coefficient of variation served as a measure of reproducibility. A total of 100 eyes in 100 patients were evaluated after informed consent had been obtained. Although estimates of axial length obtained with the two techniques were highly correlated, axial lengths obtained with the contact method (mean 23.35 mm, SD 1.81 mm) were consistently lower than those obtained with the non-contact method (mean 23.55 mm, SD 1.76 mm) and the difference was statistically significant (p < 0.001). The coefficient of variation was lower with laser interferometry (0.1%) than with the ultrasound technique (0.49%). Different estimates of axial length are obtained using contact and non-contact techniques, with the latter producing consistently higher measurements than the former. Laser interferometry provides more reproducible results that should improve the accuracy of measurements of axial length in the clinical setting.


Gene editing of the ABC Transporter/White locus using CRISPR/Cas9-mediated mutagenesis in the Indian Meal Moth.
ATP binding cassette (ABC) proteins are involved in transport of substrates across membranes including eye pigments. Mutations of ABC transporter white, brown and scarlet genes of Drosophila and other insects result in visible eye color phenotypes. White locus was identified in a genome assembly of Plodia interpunctella and was found to extend for 16,670 bp comprising 13 exons. We report here recovery of heritable mutants in white in the Indian meal moth, P. interpunctella, using CRISPR/Cas9-mediated mutagenesis. A white eye strain of P. interpunctella c.737delC (Piw-/-) was previously isolated in 1986. Guide RNA (sgRNA) was designed for exon 1 (sgRNA242). Microinjection of Cas9/sgRNA242 complex into Plodia wild type eggs (≤20 min post oviposition) produced 156 viable larvae of which 81 eclosed as adults. Forty-five (56 %) adults displayed wild type phenotype, while 26 females (32 %) and 10 males (12 %) showed full or partial white eye phenotype. The 26 white eye females were mated with Piw-/- males and 21 matings resulted in F1 white eye progeny. Thirteen of the Piw-242 lines were established and sequencing showed indels at the CRISPR/Cas9 242AM site. Based on RT-PCR analysis, most white mutations resulted in suppressed levels of transcript. These results demonstrate the utility of CRISPR/Cas9 gene editing in Plodia which suggests this technology can be used to characterize the role of various genetic elements including those that encode novel targets or confer insecticide resistance mechanisms.


Complications of Camey-Le Duck ureteral reimplantation technique in modified ureterosigmoidostomy (Mainz pouch II) urinary diversion.
to analyze complications and clinical outcome of Camey-Le Duck ureteral reimplantation technique in modified Mainz pouch II urinary diversion. this retrospective study included a total of 110 patients (101 male and 9 female, mean age 59.2 years, SD = 10.2), who had underwent a modified Mainz pouch II urinary diversion with Camey-Le Duck ureteral reimplantation technique, following total cystectomy, during the period 1995-2014. The mean follow-up, available for 90 (82%) patients period was 19 (1-74) months. Early and late postoperative complications were analyzed. early complications developed in 22 (20%) patients as follow: unilateral ureterohydronephrosis in 8 (7%) patients, bilateral ureterohydronephrosis in one (1%)-two RU (renoureteral units), urinary leakage in 8 (7%), and pyelonephritis in 5 (5%) patients. Late complications developed in 28 (25%) patients: pyelonephritis in 17 (15%), and ureteral reimplantation site stenosis in 11 (10%) patients with 12 RU. Balloon dilatation procedure was applied in all 12 RU, with additional metallic Strecker stent insertion in 5 RU. At 24-month follow-up, all patients with metallic Strecker stent had normal results of serum biochemistry, blood gas analysis and renal ultrasound. In the rest of six patients with 7RU, balloon dilatation has failed and restenosis of ureteral reimplantation site with consequent ipsilateral hydronephrosis was verified. In these patients, permanent percutaneous nephrostomy catheter was applied. Camey-Le Duck ureteral reimplantation technique following Mainz pouch II urinary diversion is simple, reliable and durable. It enables well upper urinary tract protection and is associated with relatively low major complication rates.


Uptake-sequence-independent DNA transformation exists in Neisseria gonorrhoeae.
A DNA transformation dose-response curve of piliated (P+) gonococci with the use of cloned DNA containing a pilE2-cat fusion showed saturation at high and low levels of transforming DNA. At low DNA concentrations, transformation of the P+ strain MS11-A was effectively inhibited by a 1000-fold molar excess of the gonococcal transformation uptake sequence (GCUS). The same molar excess of the GCUS did not inhibit transformation of MS11-A at high DNA concentrations. In MS11-B2, a nonpiliated (P-), pilin-nonproducing, isogenic variant of MS11-A, the GCUS did not inhibit transformation at any level of transforming DNA. These data suggest that two mechanisms of transformation exist in P+ cells: one which utilizes the GCUS and one which does not. In MS11-B2 P- cells, no evidence was found for the presence of the GCUS-dependent mechanism, suggesting that transformation in this background occurs solely by the GCUS-independent mechanism.


Current Perspectives on Augmented Reality in Medical Education: Applications, Affordances and Limitations.
This systematic review has been developed against a background of rapid developments in augmented reality (AR) technology and its application in medical education. The objectives are to provide a critical synthesis of current trends in the field and to highlight areas for further research. The data sources used for the study were the PubMed, Web of Science and Discover databases. Sources included in the study comprised peer reviewed journal articles published between 2015 and 2020. Inclusion criteria included empirical research findings related to learning outcomes and the populations for the selected studies were medical students. Studies were appraised in terms of to what extent the use of AR contributed to learning gains in knowledge and/or skill. Twenty-one studies were included in the analysis, and the dates of these suggested an increasing trend of publications in this area. The uses of AR in each selected study were analyzed through a lens of affordance, to identify which specific affordances of AR appear to be most effective in this domain. Results of the study indicated that AR seems to be more effective in supporting skill development rather than knowledge gain when compared to other techniques. Some key affordances of AR in medical education are identified as developing practical skills in a spatial context, device portability across locations and situated learning in context. It is suggested that a focus on relevant affordances when designing AR systems for medical education may lead to better learning outcomes. It is noted that the majority of AR systems reported in the selected studies are concentrated in the areas of anatomy and surgery, but that are also other areas of practice being explored, and these may provide opportunities for new types of AR learning systems to be developed for medical education.


[Worker's health in nursing undergraduates' conception].
In this paper, which uses a qualitative approach, we try to understand the conception undergraduate Nursing students at the Federal University of Santa Catarina have regarding worker's health. Three questions were asked to twenty students: What does he/she understand as worker's health? How can Nursing help to improve worker's health? Which is the relation between work and lifestyle? The results were grouped in the following themes: conceptions of worker's health; the role of Nursing in the context of worker's health; and relation between work and lifestyle. We highlighted the interrelation between work and lifestyle, and between work and worker's health. Our reflections reinforce the need to discuss these themes in the universities so that students are stimulated to think about their own health since the beginning of their academic life. That way, we believe that they will be able to incorporate protective actions to their own health in their daily's work.


High connectivity of the crocodile shark between the Atlantic and Southwest Indian Oceans: highlights for conservation.
Among the various shark species that are captured as bycatch in commercial fishing operations, the group of pelagic sharks is still one of the least studied and known. Within those, the crocodile shark, Pseudocarcharias kamoharai, a small-sized lamnid shark, is occasionally caught by longline vessels in certain regions of the tropical oceans worldwide. However, the population dynamics of this species, as well as the impact of fishing mortality on its stocks, are still unknown, with the crocodile shark currently one of the least studied of all pelagic sharks. Given this, the present study aimed to assess the population structure of P. kamoharai in several regions of the Atlantic and Indian Oceans using genetic molecular markers. The nucleotide composition of the mitochondrial DNA control region of 255 individuals was analyzed, and 31 haplotypes were found, with an estimated diversity Hd = 0.627, and a nucleotide diversity π = 0.00167. An analysis of molecular variance (AMOVA) revealed a fixation index ΦST = -0.01118, representing an absence of population structure among the sampled regions of the Atlantic Ocean, and between the Atlantic and Indian Oceans. These results show a high degree of gene flow between the studied areas, with a single genetic stock and reduced population variability. In panmictic populations, conservation efforts can be concentrated in more restricted areas, being these representative of the total biodiversity of the species. When necessary, this strategy could be applied to the genetic maintenance of P. kamoharai.


Are physicians prepared for whole genome sequencing? a qualitative analysis.
Although the integration of whole genome sequencing (WGS) into standard medical practice is rapidly becoming feasible, physicians may be unprepared to use it. Primary care physicians (PCPs) and cardiologists enrolled in a randomized clinical trial of WGS received genomics education before completing semi-structured interviews. Themes about preparedness were identified in transcripts through team-based consensus-coding. Data from 11 PCPs and 9 cardiologists suggested that physicians enrolled in the trial primarily to prepare themselves for widespread use of WGS in the future. PCPs were concerned about their general genomic knowledge, while cardiologists were concerned about how to interpret specific types of results and secondary findings. Both cohorts anticipated preparing extensively before disclosing results to patients by using educational resources with which they were already familiar, and both cohorts anticipated making referrals to genetics specialists as needed. A lack of laboratory guidance, time pressures, and a lack of standards contributed to feeling unprepared. Physicians had specialty-specific concerns about their preparedness to use WGS. Findings identify specific policy changes that could help physicians feel more prepared, and highlight how providers of all types will need to become familiar with interpreting WGS results.


Efficacy of Green Tea Extract for Treatment of Dry Eye and Meibomian Gland Dysfunction; A Double-blind Randomized Controlled Clinical Trial Study.
With an incidence rate of 9%, dry eye is a common problem of the ocular surface, especially in patients more than 40-year-old. Green tea extract has anti-oxidative, anti-bacterial, anti-androgen, and immunomodulatory properties. To evaluate the efficacy of green tea extract for treatment of patients with dry eye and Meibomian Gland Dysfunction (MGD). In a double-blind randomized controlled clinical trial, 60 patients were selected within the age range of 30 to 70 years, and divided into two groups by blocked randomization method. Standard treatment included artificial tear eye drops, three times a day for a month for all patients. Topical green tea extract was prescribed three times a day for one month in one of the groups. All patients were evaluated at the beginning and end of the study for clinical symptoms based on the Ocular Surface Disease Index (OSDI) score, Schirmer's test, Tear Breakup Time (TBUT), corneal and conjunctival staining and meibum score. The mean age of participants in the green tea and control group was 61 and 64 years respectively. In the green tea group, the mean score of clinical symptoms was 9±0.86 that improved to 4.86±0.55 after one month (p=0.002). Scores suggesting improvement of TBUTs and the health of meibomian glands were significantly higher in the green tea group (p=0.002). Furthermore, no side effects of the treatment were observed. Green tea extract is an effective, safe, and well-tolerated topical treatment for mild and moderate evaporative dry eyes and MGD.


Monocyte chemoattractant protein 1 causes differential signalling mediated by proline-rich tyrosine kinase 2 in THP-1 cells.
Monocyte chemoattractant protein 1 (MCP-1) has a crucial role in atherogenesis and inflammation. However, MCP-1-mediated signalling pathways in monocytes have not been fully elucidated. In the present study we investigated the role of tyrosine kinases such as proline-rich tyrosine kinase 2 (Pyk2) in MCP-1-mediated signal transduction in the monocytic cell line THP-1. Pyk2 was tyrosine phosphorylated very quickly after stimulation with MCP-1. We found that Lyn, Shc and paxillin were also tyrosine phosphorylated by MCP-1. We examined the association of these molecules by immunoprecipitation and immunoblot analysis. The association of Pyk2 with Lyn was dependent on stimulation with MCP-1 and on tyrosine phosphorylation of Pyk2. Phosphorylation of p38 was also dependent on tyrosine phosphorylation of Pyk2. However, the association of Pyk2 with paxillin and Grb2 was not affected by stimulation with MCP-1. Phosphorylation of ERK (extracellular-signal-regulated protein kinase) was not affected by overexpression of kinase-negative Pyk2. Our results indicate that Pyk2 forms a complex with paxillin, Grb2 and Lyn in THP-1 cells. However, Pyk2 is not always involved in MCP-1-mediated signalling pathways.


Single-particle measurements of phase partitioning between primary and secondary organic aerosols.
Organic aerosols provide a measure of complexity in the urban atmosphere. This is because the aerosols start as an external mixture, with many populations from varied local sources, that all interact with each other, with background aerosols, and with condensing vapors from secondary organic aerosol formation. The externally mixed particle populations start to evolve immediately after emission because the organic molecules constituting the particles also form thermodynamic mixtures - solutions - in which a large fraction of the constituents are semi-volatile. The external mixtures are thus well out of thermodynamic equilibrium, with very different activities for many constituents, and yet also have the capacity to relax toward equilibrium via gas-phase exchange of semi-volatile vapors. Here we describe experiments employing quantitative single-particle mass spectrometry designed to explore the extent to which various primary organic aerosol particle populations can interact with each other or with secondary organic aerosols representative of background aerosol populations. These methods allow us to determine when these populations will and when they will not mix with each other, and then to constrain the timescales for that mixing.


Zinc status alters growth and oxidative stress responses in rat hepatoma cells.
Zinc deficiency and excess influence cellular homeostasis and are believed to modulate apoptosis. Zinc also regulates cell growth and proliferation. Understanding of the role of zinc in the mechanisms associated with these changes is limited because of its diverse, complex, and cell-specific effects. Therefore, we investigated the oxidative stress responses and the underlying molecular mechanisms associated with the disruption of intracellular zinc homeostasis in H4IIE rat hepatoma cells. We found that zinc excess (100 μM) and DTPA (diethylenetriaminepentaacetic acid; 50-100 μM) induced zinc deficiency both generate reactive oxygen species (ROS) and decrease viability in H4IIE cells. However, cotreatment with the antioxidant, N-acetyl-L-cysteine (NAC) both reduced ROS production and protected cells from death. We additionally observed an increase in Bax mRNA and cytochrome c release from the mitochondria in DTPA-treated cells and an elevated expression of Fas/Fas ligand mRNA with zinc treatment. Both treatments increased p53 and MdM2 protein concentrations along with caspase 3/7 activity. These results suggest that zinc deficiency stimulates mitochondrial-dependent apoptosis whereas zinc activates the extrinsic-apoptotic pathway. Both decreasing and increasing cellular zinc concentrations modulate ROS mediated apoptosis and warrant further research on zinc mediated cancer chemoprevention in this and other cancer cell lines.


Sensory neural processing in work-related upper limb disorders.
Pain in the upper limb is a common complaint in adults, and is often attributed to or exacerbated by occupational activities. In many patients there is no demonstrable pathology in the neck or arm to account for the symptom, and this has prompted the hypothesis that such cases might arise through abnormal neural processing of sensory information with a lowering of pain thresholds. In this paper we review the evidence in support of this theory and suggest directions for future research.


Multiple micronutrient deficiencies as a long-term complication of bariatric surgery.
Micronutrient deficiencies may develop as a long-term complication of bariatric surgery due to alteration of gut anatomy and disruption of normal gut absorption. Inadequate repletion of essential vitamin and mineral deficiencies can lead to multisystem dysfunction. We present a case of a woman in her 50s, with a history of Roux-en-Y gastric bypass over 10 years ago, who presented with generalised weakness and a diffuse desquamating rash. A punch biopsy performed was compatible with nutritional deficiency. Labs revealed low levels of micronutrients A, B1, B6, C, E, zinc and copper. The patient received intravenous micronutrients and an oral regimen, which improved her symptoms. Unfortunately, the patient died from cardiac arrest secondary to pulmonary oedema. This report highlights the importance of high suspicion of micronutrient deficiency in patients with a history of bariatric surgery and maintaining lifelong nutritional follow-up.


Robust acoustic trapping and perturbation of single-cell microswimmers illuminate three-dimensional swimming and ciliary coordination.
We report a label-free acoustic microfluidic method to confine single, cilia-driven swimming cells in space without limiting their rotational degrees of freedom. Our platform integrates a surface acoustic wave (SAW) actuator and bulk acoustic wave (BAW) trapping array to enable multiplexed analysis with high spatial resolution and trapping forces that are strong enough to hold individual microswimmers. The hybrid BAW/SAW acoustic tweezers employ high-efficiency mode conversion to achieve submicron image resolution while compensating for parasitic system losses to immersion oil in contact with the microfluidic chip. We use the platform to quantify cilia and cell body motion for wildtype biciliate cells, investigating effects of environmental variables like temperature and viscosity on ciliary beating, synchronization, and three-dimensional helical swimming. We confirm and expand upon the existing understanding of these phenomena, for example determining that increasing viscosity promotes asynchronous beating. Motile cilia are subcellular organelles that propel microorganisms or direct fluid and particulate flow. Thus, cilia are critical to cell survival and human health. The unicellular alga Chlamydomonas reinhardtii is widely used to investigate the mechanisms underlying ciliary beating and coordination. However, freely swimming cells are difficult to image with sufficient resolution to capture cilia motion, necessitating that the cell body be held during experiments. Acoustic confinement is a compelling alternative to use of a micropipette, or to magnetic, electrical, and optical trapping that may modify the cells and affect their behavior. Beyond establishing our approach to studying microswimmers, we demonstrate a unique ability to mechanically perturb cells via rapid acoustic positioning.


Optimising the management of choroidal neovascularisation in Asian patients: consensus on treatment recommendations for anti-VEGF therapy.
In Asian countries, age-related macular degeneration (AMD), specifically wet AMD or choroidal neovascularisation (CNV), is an important cause of blindness and visual handicap. Vascular endothelial growth factors (VEGF) play an integral role in the development of CNV and thus provide an important therapeutic target. Current treatment paradigms for neovascular AMD recognise the place of photodynamic therapy (PDT) in the management of this condition. However, combination therapy targeting different pathways to produce a synergistic effect may result in improved visual outcomes and reduced duration of treatment. Anti-VEGF therapy has greatly improved treatment outcomes in patients with CNV, and a growing body of evidence supports the role of these agents as monotherapy or in combination with PDT. In particular, anti-VEGF may be a first-line treatment option in certain types of subfoveal myopic CNV as well as for classic and occult juxtafoveal and subfoveal CNV. The implementation of evidence-based medicine into current clinical practice is paramount to improving patient care. The authors, who are also members of the Singapore Medical Retina Advisory Board, outline the consensus points and recommended treatment algorithms based on currently available knowledge to provide a structured management approach to the treatment of Asian patients with CNV.


Development and Validation of an Instrument to Measure Staff Perceptions of Recovery Climate and Culture in Mental Health Programs.
Few existing instruments measure recovery-oriented organizational climate and culture. This study developed, psychometrically assessed, and validated an instrument to measure recovery climate and culture. Organizational theory and an evidence-based conceptualization of mental health recovery guided instrument development. Items from existing instruments were reviewed and adapted, and new items were developed as needed. All items were rated by recovery experts. A 35-item instrument was pilot-tested and administered to a national sample of mental health staff in U.S. Department of Veterans Affairs Psychosocial Rehabilitation and Recovery Centers (PRRCs). Analysis entailed an exploratory factor analysis (EFA) and inter-item reliability and scale correlation assessment. Blinded site visits to four PRRCs were performed to validate the instrument. The EFA determined a seven-factor solution for the data. The factors identified were staff expectations, values, leadership, rewards, policies, education and training, and quality improvement. Seven items did not meet retention criteria and were dropped from the final instrument. The instrument exhibited good internal consistency (Cronbach's α=0.81; subscales, α=0.84-0.88). Scale correlations were between 0.16 and 0.61, well below the threshold (α=0.9) for indicating overlapping constructs. Site visitors validated the instrument by correctly identifying high-scoring and low-scoring centers. These findings provide a psychometrically tested and validated instrument for measuring recovery climate and culture in mental health programs. This instrument can be used in evaluation of mental health services to determine the extent to which programs possess the organizational precursors that drive recovery-oriented service delivery.


[Features of the sleep pattern during pregnancy].
To evaluate the qualitative characteristics of a sleep in pregnant women in the 3rd term of the physiological pregnancy by a questionnaire survey. We have demonstrated questionnaire survey data of 400 pregnant women (mean age 27.5 +/- 8.2 years) in the 3rd term of pregnancy. Questioning conducted using the scale PSQI (PITTSBURGH SLEEP QUALITY INDEX--Pittsburgh Sleep Quality Assessment Questionnaire), EPWORTH SLEEPINESS SCALE (sleepiness questionnaire Epfort's) and screening questionnaire to identify obstructive sleep apnea. We have determined that 78% of pregnant women to complain about sleep disorders, namely obstructive sleep disordered breathing, insomnia, "restless legs" syndrome, and combinations thereof. The frequency of sleep disorders increases as pregnancy progresses. Obstructive sleep disordered breathing increases with 10.12% in the 1st term to 31.7% in the 3rd term, insomnia--from 14.3% in the 1st term to 37.6% in the 3rd term. In pregnancy increases of sleep latency (from 14.3 to 44.9 minutes), and reduced the duration of a sleep (from 8.7 to 7.8 hours). high frequency of sleep disorders in pregnancy requires early pathogenetic prevention of pathological conditions, both in the mother and in the fetus.


Electron-microscopic study of the serological affinity between the antigenic components of phages T4 and DDVI.
In an investigation of the antigenic fine structure of phages T4 and DDVI with the use of the neutralization reaction and electron-microscopic observation of the phage-antibody complexes, it has been possible to establish that the head of phage T4 consists of proteins which have antigenic determinants of two types: The first type is identical to the antigens of the head of phage DDVI, and the second type is apparently absent in phage DDVI. The phage DDVI head contains mostly determinants which are common to the phage T4 head, since it was not possible to detect antigenically specific components in the phage DDVI head. The tail sheaths of phage T4 and DDVI appear to be identical in the antigenic respect. A difference has been observed in the fibers and the base plates of the phages investigated. The presence of the following three types of antigens has been established: 1) common to phages T2, T4, and DDVI, 2) common to phages T4 and DDVI, and 3) specific for each phage investigated.


Comparison of basal gastric acid and pepsin output in controls vs. active peptic ulcer disease (PUD).
Quantitative basal and pentagastrin stimulated acid and pepsin outputs were determined in a group of 15 patients without peptic ulcer disease (PUD) and in 11 patients admitted to hospital with endoscopically proven PUD (two gastric and nine duodenal). While there were statistically significant differences in both acid and pepsin outputs in both the basal and maximally stimulated states, only the basal pepsin output clearly separated the groups in this small preliminary study. No patient produced more than 100,000 pU./hr. in the basal state unless an active peptic ulcer was present; no patient with an active ulcer produced less than 100,000 pU./hr.


The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland.
A task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland (APM) was convened to produce some up-to-date, evidence-based, practical, clinical guidelines on the management of cancer-related breakthrough pain in adults. On the basis of a review of the literature, the task group was unable to make recommendations about any individual interventions, but was able to make a series of 12 recommendations about certain generic strategies. However, most of the aforementioned recommendations are based on limited evidence (i.e., case series, expert opinion). The task group also proposed a definition of breakthrough pain, and some diagnostic criteria for breakthrough pain.


Guidelines for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 13: injection therapies, low-back pain, and lumbar fusion.
In summary, there is no meaningful evidence in the medical literature that the use of epidural injections is of any long-term value in the treatment of patients with chronic low-back pain. The literature does indicate that the use of lumbar epidural injections can provide short-term relief in selected patients with chronic low-back pain. There is evidence that suggests that facet joint injections can be used to predict outcome after RF ablation of a facet joint. The predictive ability of facet joint injections does not appear to apply to lumbar fusion surgery. No evidence exists to support the effectiveness of facet injections in the treatment of patients with chronic low-back pain. There is conflicting evidence suggesting that the use of local TPIs can be effective for the short-term relief of low-back pain. There are no data to suggest that TPIs with either steroids or anesthetics alone provide lasting benefit for patients suffering from chronic low-back pain.


Opioids for chronic noncancer pain: prediction and identification of aberrant drug-related behaviors: a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline.
Optimal methods to predict risk of aberrant drug-related behaviors before initiation of opioids for chronic noncancer pain and to identify aberrant behaviors after therapy is initiated are uncertain. We systematically reviewed published literature identified through searches of Ovid MEDLINE and the Cochrane databases through July 2008. Diagnostic test characteristics and accompanying confidence intervals were calculated with data extracted from the studies. Four prospective studies evaluated diagnostic accuracy of risk prediction instruments. Two higher-quality derivation studies found that high scores on the Screener and Opioid Assessment for Patients with Pain (SOAPP) Version 1 and the Revised SOAPP (SOAPP-R) instruments weakly increased the likelihood for future aberrant drug-related behaviors (positive likelihood ratios [PLR], 2.90 [95% CI, 1.91 to 4.39] and 2.50 [95% CI, 1.93 to 3.24], respectively). Low scores on the SOAPP Version 1 moderately decreased the likelihood for aberrant drug-related behaviors (negative likelihood ratio [NLR], 0.13 [95% CI, 0.05 to 0.34]) and low scores on the SOAPP-R weakly decreased the likelihood (NLR, 0.29 [95% CI, 0.18 to 0.46]), but estimates are too imprecise to determine if there is a difference between these instruments. One lower-quality study found that categorization as high risk using the Opioid Risk Tool strongly increased the likelihood for future aberrant drug-related behaviors (PLR, 14.3 [95% CI, 5.35 to 38.4]) and classification as low risk strongly decreased the likelihood (PLR, 0.08 [95% CI, 0.01 to 0.62]). Nine studies evaluated monitoring instruments for identification of aberrant drug-related behaviors in patients on opioid therapy. One higher-quality derivation study found higher scores on the Current Opioid Misuse Measure (COMM) weakly increased the likelihood of current aberrant drug-related behaviors (PLR, 2.77 [95% CI, 2.06 to 3.72]) and lower scores weakly decreased the likelihood (NLR, 0.35 [95% CI, 0.24 to 0.52]). In 8 studies of other monitoring instruments, diagnostic accuracy was poor, results were difficult to interpret due to methodological shortcomings, or standard diagnostic test characteristics were not reported. Definitions for aberrant drug-related behaviors were not standardized across studies and did not account for seriousness of identified behaviors. No reliable evidence exists on accuracy of urine drug screening, pill counts, or prescription drug monitoring programs; or clinical outcomes associated with different assessment or monitoring strategies. Evidence on prediction and identification of aberrant drug-related behaviors is limited. Although several screening instruments may be useful, evidence is sparse and primarily based on derivation studies, and methodological shortcomings exist in all studies. Research that performs external validation, uses standardized definitions for clinically relevant aberrant drug-related behaviors, and evaluates clinical outcomes associated with different assessment and monitoring strategies is needed.


Enhanced bioavailability and anthelmintic efficacy of mebendazole in redispersible microparticles with low-substituted hydroxypropylcellulose.
Mebendazole (MBZ) is an extremely insoluble and therefore poorly absorbed drug and the variable clinical results may correlate with blood concentrations. The necessity of a prolonged high dose treatment of this drug increases the risk of adverse effects. In the present study we prepared redispersible microparticles (RDM) containing MBZ, an oral, poorly water-soluble drug, in different proportions of low-substituted hydroxypropylcellulose (L-HPC). We investigated the microparticulate structures that emerge spontaneously upon dispersion of an RDM in aqueous medium and elucidated their influence on dissolution, and also on their oral bioavailability and therapeutic efficiency using a murine model of infection with the nematode parasite Trichinella spiralis. Elevated percentages of dissolved drug were obtained with RDM at 1:2.5 and 1:5 ratios of MBZ: L-HPC. Thermal analysis showed an amorphization of MBZ in the RDM by the absence of a clear MBZ melting peak in formulations. The rapid dissolution behavior could be due to the decreased drug crystallinity, the fast dissolution time of carriers as L-HPC, together with its superior dispersibility and excellent wetting properties. RDM-1:2.5 and RDM-1:5 resulted in increased maximum plasma concentration and area(s) under the curve (AUC)0-∞ values. Likewise, after oral administration of the RDM-1:2.5 and RDM-1:5 the AUC0-∞ were 2.67- and 2.97-fold higher, respectively, compared to those of pure MBZ. Therapeutic activity, assessed on the Trichinella spiralis life cycle, showed that RDM-1:5 was the most effective in reducing the number of parasites (4.56-fold) as compared to pure MBZ, on the encysted stage. THE MBZ: L-HPC RDM might be an effective way of improving oral bioavailability and therapeutic activity using low doses of MBZ (5 mg/kg), which implies a low degree of toxicity for humans.


The first virally encoded cytochrome p450.
The genome sequence of the giant virus Acanthamoeba polyphaga mimivirus revealed the presence of two putative cytochrome P450 (CYP) genes. The product of one of the two predicted CYP genes (YP_143162) showed low-level homology to sterol 14-demethylase (CYP51) and contained a C-terminal polypeptide domain of unknown function. YP_143162 expression (without an N-terminal membrane binding domain) in Escherichia coli yields a CYP protein which gives a reduced CO difference maximum at 448 nm and was formally demonstrated as the first viral cytochrome P450. Analysis of binding of lipid and sterol substrates indicated no perturbation in CYP heme environment, and an absence of activity was seen when 14-methyl sterols were used as a substrate. The function of the CYP protein and its C-terminal domain remain unknown.


Technical notes on endothelial progenitor cells: ways to escape from the knowledge plateau.
In the last 10 years an increasing interest has been devoted to the study of endothelial progenitor cells (EPCs), a subtype of immature cells involved in endothelial repair and neoangiogenesis. EPCs have been discovered as a novel integrated part of the cardiovascular system, which plays a comprehensive role in tissue homeostasis. Consistently, alterations and/or reduction of the circulating EPC pool have been associated with different manifestations of cardiovascular disorders and atherosclerosis. This is why, the extent of the EPC pool is now considered a mirror of vascular health, while EPC reduction has become a surrogate biomarker of cardiovascular risk and of the ongoing vascular damage. Unfortunately, the methods used to study EPCs still lack standardization, and this is significantly decelerating progress in the field. In this review, we focus on some aspects related to the two methods used to assess circulating EPCs: flow cytometry and cell culture. We uncover the many traps hidden in the choice of the right protocol, and suggest the best solutions on the basis of evidence and background theories.


Simulated elliptical bioprosthetic valve deformation: implications for asymmetric transcatheter valve deployment.
The asymmetric, elliptical shape of a transcatheter aortic valve (TAV), after implantation into a calcified aortic root, has been clinically observed. However, the impact of elliptical TAV configuration on TAV leaflet stress and strain distribution and valve regurgitation is largely unknown. In this study, we developed computational models of elliptical TAVs based on a thin pericardial bioprosthetic valve model recently developed. Finite element and computational fluid dynamics simulations were performed to investigate TAV leaflet structural deformation and central backflow leakage, and compared with those of a nominal symmetric TAV. From the results, we found that for a distorted TAV with an elliptical eccentricity of 0.68, the peak stress increased significantly by 143% compared with the nominal circular TAV. When the eccentricity of an elliptical TAV was larger than 0.5, a central backflow leakage was likely to occur. Also, deployment of a TAV with a major calcified region perpendicular to leaflet coaptation line was likely to cause a larger valve leakage. In conclusion, the computational models of elliptical TAVs developed in this study could improve our understanding of the biomechanics involved in a TAV with an elliptical configuration and facilitate optimal design of next-generation TAV devices.


[The relationship between osteoporosis, osteopenia and periodontitis].
A review of the literature on the reciprocal influence of osteoporosis and periodontitis. The imbalance in coupling of bone remodeling causes skeletal osteopenia and osteoporosis. Does the remodeling imbalance influence the oral bone? Both diseases are chronic, multifactorial and result at bone loss. In addition, the diseases share common risk factors such genetics, dietary, environmental and systemic factors. Different studies indicate that the skeletal bone loss in osteoporosis accelerate the decrease in bone density in oral bone. Although the differences in etiology between the two diseases some studies showed that treatment of osteoporosis improved the periodontal health. Further investigation of the mechanisms behind the relationship between osteoporosis and periodontitis may lead to common treatment strategies.


Identifying elements of ICU care that families report as important but unsatisfactory: decision-making, control, and ICU atmosphere.
One in fi ve deaths in the United States occurs in the ICU, and many of these deaths are experienced as less than optimal by families of dying people. The current study investigated the relationship between family satisfaction with ICU care and overall ratings of the quality of dying as a means of identifying targets for improving end-of-life experiences for patients and families. This multisite cross-sectional study surveyed families of patients who died in the ICU in one of 15 hospitals in western Washington State. Measures included the Family Satisfaction in the ICU (FS-ICU) and the Single-Item Quality of Dying (QOD-1) questionnaires. Associations between FS-ICU items and the QOD-1 were examined using multivariate linear regression controlling for patient and family demographics and hospital site. Questionnaires were returned for 1,290 of 2,850 decedents (45%). Higher QOD-1 scores were significantly associated (all P < .05) with (1) perceived nursing skill and competence (β= 0.15), (2) support for family as decision-makers ( β= 0.10), (3) family control over the patient's care( β= 0.18), and (4) ICU atmosphere (β= 0.12). FS-ICU items that received low ratings and correlated with higher QOD-1 scores (ie, important items with room for improvement) were (1) support of family as decision-maker, (2) family control over patient's care, and (3) ICU atmosphere. Increased support for families as decision-makers and for their desired level of control over patient care along with improvements in the ICU atmosphere were identified as aspects of the ICU experience that may be important targets for quality improvement. ClinicalTrials.gov; No.: NCT00685893; URL: www.clinicaltrials.gov.


The disparity in access to new medication by type of health insurance: lessons from Germany.
Drug provision within the German statutory health insurance system has undergone several reforms, including the introduction of drug macrobudgets in 1993. The objective of this study was to investigate the extent to which statutorily (SHI) and fully privately (PHI) health-insured patients were provided with new medication recommended by professional bodies in an equitable fashion using the example of migraine patients. We conducted a retrospective cohort study. A total of 367 primary-care practices (MediPlus, IMS Health) in Germany in the second year of the HealthCare Structural Reform Act were studied. Subjected consisted of 7703 SHI and 470 PHI migraineurs (International Classification of Diseases, 10th edition G43) aged 18 to 65 years at their first migraine prescription visit in 1994. We compared prescription of oral or subcutaneous serotonin 5HT1B/1D receptor agonist sumatriptan with nonserotoninergic migraine therapy. In multiplicative risk regression with variance estimation accounting for clustering of patients within practices, PHI patients were 2.3 times (95% confidence interval [CI], 1.6-3.3) more likely to receive sumatriptan than their SHI counterparts at the mean age of the cohorts (43 years) adjusted for incident versus prevalent migraine treatment, the gender of the patient, the age, gender, and primary care specialist group of the physician, and the type and the community size class of the practice. This disparity widened by 38% (95% CI, 1-88%) every 10 years of patient age. Even though virtually everyone in Germany has health insurance and drug coverage, use of new and recommended migraine medicines was less common among those with SHI compared with their privately insured counterparts. Systematic studies of access to health care recommended by professional bodies will be critically important to ensure delivery of high-quality health care for all patients.


Nutrient removal as a function of benzene supply within vertical-flow constructed wetlands.
The role of benzene, macrophytes and temperature in terms of nutrient removal within constructed wetlands is unknown. Therefore, a research study over approximately 30 months was conducted to assess the potential of vertical-flow constructed wetlands to treat nutrients and to examine the effect of benzene concentration, presence of Phragmites australis (Cav.) Trin. ex Steud (common reed), and temperature control on nutrient removal. Experimental wetlands removed between 72% and 90% of benzene at an influent concentration of 1000 mg L(-1). A statistical analysis indicated that benzene is linked to increased effluent chemical oxygen demand and biochemical oxygen demand concentrations. However, there was no significant relationship between benzene treatment and both nitrogen and phosphorus removal. Phragmites australis played a negligible role in organic matter (chemical oxygen demand, biochemical oxygen demand, nitrogen and phosphorus) removal. Control of temperature favoured biochemical oxygen demand removal. However, no significant difference in chemical oxygen demand, and nitrogen and phosphorus removal was detected. Only the combination of the benzene and temperature variables had a significant impact on biochemical oxygen demand removal. The effluent biochemical oxygen demand concentrations in temperature-controlled benzene treatment wetlands were much lower than those located in the natural environment. However, any other combination between benzene, P. australis and the environmental control variables had no significant effect on biochemical oxygen demand, chemical oxygen demand, or nitrogen and phosphorus removal.


Racial Disparities in Modifiable Risk Factors and Statin Usage in Black Patients With Familial Hypercholesterolemia.
Background Black men and women are at higher risk for, and suffer greater morbidity and mortality from, atherosclerotic cardiovascular disease (ASCVD) compared with adults of European Ancestry (EA). Black patients with familial hypercholesterolemia are at particularly high risk for ASCVD complications because of lifelong exposure to elevated levels of low-density-lipoprotein cholesterol. Methods and Results This retrospective study analyzed ASCVD prevalence and risk factors in 808 adults with heterozygous familial hypercholesterolemia from 5 US-based lipid clinics, and compared findings in Black versus EA patients. Multivariate logistic regression models were used to determine the strongest predictors of ASCVD as a function of race. No significant difference was noted in the prevalence of ASCVD in Black versus EA patients with familial hypercholesterolemia (39% versus 32%, respectively; P=0.15). However, Black versus EA patients had significantly greater prevalence of modifiable risk factors, including body mass index (mean, 32±7 kg/m2 versus 29±6 kg/m2; P<0.001), hypertension (82% versus 50%; P<0.001), diabetes (39% versus 15%; P<0.001), and current smoking (16% versus 8%; P=0.006). Black versus EA patients also had significantly lower usage of statins (61% versus 73%; P=0.004) and other lipid-lowering agents. In a fully adjusted multivariate model, race was not independently associated with ASCVD (odds ratio, 0.92; 95% CI, 0.60-1.49; P=0.72). Conclusions The strongest predictors of ASCVD in Black patients with familial hypercholesterolemia were hypertension and cigarette smoking. These data support wider usage of statins and other lipid-lowering therapies and greater attention to modifiable risk, specifically blood pressure management and smoking cessation.


Work related stress and European policy--a comparative exploration of contextual stressors in the rehabilitation sector in five European countries.
Dealing with work related stress is a declared priority of European Union mental health policy. A particularly under-researched sector in this regard is the community vocational support sector for people with mental health and intellectual disability problems. To report on the organisational profile of the vocational support and rehabilitation sector for people with mental health and intellectual disabilities as this relates to occupational stress, in five European countries (Austria, Ireland, Italy, Romania and UK). A sector profile questionnaire was distributed to representative organisations in five countries and a short face-to-face survey was conducted with 25 local managers (five from each country) to draw up a profile and facilitate a comparative description and analysis. It was found that there is no national and European data collected at any level in this sector upon which to base effective policy interventions to combat occupational stress specific to professionals working in this sector. Results indicate that the sector in a number of the countries sampled does not have effective mechanisms in place to deal with occupational stress. Developing effective transnational occupational stress management policy that supports staff working in this sector and measuring its success is greatly impaired by a failure to effectively define the purpose of the sector and collect and collate national data to support it.


Treatment of Behçet's disease--an update.
To report the experience of the investigators and review the major treatment trials conducted for Behçet's disease (BD). A MEDLINE literature review from 1970 to date was performed on the drugs prescribed for the treatment of BD. Open and controlled clinical studies and indications for the treatment of affected organs are analyzed. Glucocorticoids are indicated for the treatment of BD, although no controlled studies have been reported. The combination of corticosteroids and immunosuppressant drugs is used when vital organs are involved. Nonsteroidal anti-inflammatory drugs are of little value in arthritis. In controlled trials, colchicine was efficacious for erythema nodosum and arthritis, particularly in women. Cyclosporine A has a rapid action and when combined with azathioprine is effective in patients with severe uveitis and extraocular manifestations. Chlorambucil is indicated for uveitis and meningoencephalitis. In controlled studies, azathioprine prevented unilateral uveitis from becoming bilateral and improved extraocular symptoms. Pulse cyclophosphamide combined with corticosteroids improves severe systemic vasculitis. Interferon alpha benefits ocular and extraocular manifestations, but controlled studies are lacking. Methotrexate is indicated for uveitis and arthritis, and sulfasalazine improves gastrointestinal vasculitis. In controlled trials, thalidomide was effective for mucocutaneous manifestations, but on its discontinuation the disease exacerbated. Orogenital manifestations are treated with local application of corticosteroids or other medications. Combination therapy is not always efficacious in controlling inflammation. The goal of management is to treat early to avoid recurrences and irreversible damage to the vital organs. With proper management of BD, loss of useful vision was reduced from 75% to 20% of the affected eyes. However, less favorable results are seen for central nervous system and large artery and vein involvement.


Mutation by DNA shuffling of 5-enolpyruvylshikimate-3-phosphate synthase from Malus domestica for improved glyphosate resistance.
A new 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene from Malus domestica (MdEPSPS) was cloned and characterized by rapid amplification of cDNA ends to identify an EPSPS gene appropriate for the development of transgenic glyphosate-tolerant plants. However, wild-type MdEPSPS is not suitable for the development of transgenic glyphosate-tolerant plants because of its poor glyphosate resistance. Thus, we performed DNA shuffling on MdEPSPS, and one highly glyphosate-resistant mutant with mutations in eight amino acids (N63D, N86S, T101A, A187T, D230G, H317R, Y399R and C413A.) was identified after five rounds of DNA shuffling and screening. Among the eight amino acid substitutions on this mutant, only two residue changes (T101A and A187T) were identified by site-directed mutagenesis as essential and additive in altering glyphosate resistance, which was further confirmed by kinetic analyses. The single-site A187T mutation has also never been previously reported as an important residue for glyphosate resistance. Furthermore, transgenic rice was used to confirm the potential of MdEPSPS mutant in developing glyphosate-resistant crops.


Polarization insensitive phase modulator for quantum cryptosystems.
In this paper, we propose a polarization-insensitive phase modulation scheme based on frequency modulation of light waves using either one or a pair of acousto-optic modulators. A stable Sagnac quantum key distribution (QKD) system employing this technique is also proposed. The interference visibility for a 40km and a 10km fiber loop is 96% and 99% respectively, at single-photon level. We ran standard BB84 QKD protocol in a simplified Sagnac setup (40km fiber loop) continuously for one hour and the measured quantum bit error rate stayed within 2%-5% range.


Chloroquine diphosphate: a risk factor for herpes zoster in patients with dermatomyositis/polymyositis.
Herpes zoster has been widely described in the context of different systemic autoimmune diseases but not dermatomyositis/polymyositis. Therefore, we analyzed the prevalence, risk factors and herpes zoster outcomes in this population. A retrospective cohort study of herpes zoster infections in dermatomyositis/polymyositis patients was performed. The patients were followed at a tertiary center from 1991 to 2012. For the control group, each patient with herpes zoster was paired with two patients without herpes zoster. Patients were matched by gender and the type of myositis, age at myositis onset and disease duration. Of 230 patients, 24 (10.4%) had a histories of herpes zoster (19 with dermatomyositis and five with polymyositis, two-thirds female). The mean age of the patients with herpes zoster was 44.6±16.8 years. No difference between the groups was found regarding cumulative clinical manifestations. Disease activity, autoantibody, muscle and leukogram parameters were also comparable between the groups. No differences in immunosuppressive (alone or in association with other immunosuppressive therapies) or glucocorticoid (current use, medium dose and cumulative dose in the last two months) therapies were found between patients with and without herpes zoster. However, a higher proportion of patients in the herpes zoster group received chloroquine diphosphate compared to the control group. All of the patients received acyclovir; 58.3% of patients had postherpetic neuralgia and no cases of recurrence were reported. Furthermore, individuals who were taking high prednisone doses at the time of the herpes zoster diagnosis had reduced levels of postherpetic neuralgia. These data suggest that chloroquine diphosphate could predispose patients with dermatomyositis/polymyositis to developing herpes zoster, particularly women and dermatomyositis patients.


Genetic parameters for testes size and sperm number in Hereford bulls.
Paternal half-sib heritability and genetic correlation estimates were obtained utilizing data from 578 Hereford bulls from 66 sires. Bulls were maintained in three lines (weaning weight, postweaning gain and control) of an ongoing selection project. Growth performance traits studied were adjusted 205-d weaning weight, 365-d weight, individual feed efficiency, sonoray fat thickness and postweaning gain. Heritability estimates for these traits were .15 +/- .17, .33 +/- .19, .46 +/- .21, .28 +/- .18 and .52 +/- .21, respectively. Scrotal measurements taken were circumference of both testes and length and diameter of right testis at 205 and 365 d of age. Heritability estimates were .08 +/- .20, .07 +/- .20 and .28 +/- .24 at 205 d, and .44 +/- .24, .16 +/- .21 and .40 +/- .24 at 365 d, respectively. Excised testes traits, circumference, right testis length, diameter and weight, total sperm in the testes and sperm/gram of testes had heritability estimates of .21 +/- .26, .19 +/- .26, .02 +/- .24, .63 +/- .27, .14 +/- .21 and -.13 +/- .18, respectively. Genetic correlations of scrotal measurements at 205 d with scrotal measurements at 365 d and excised testes traits were negative. Scrotal measurements at 365 d had high positive genetic correlations with excised testes size, weight and total sperm. These relationships suggest that selection for increase of scrotal size at 365 d should increase testes size and weight and sperm numbers. Genetic correlations of weights and gain with scrotal measurements at 365 d and excised testes characteristics were moderate to high, in a favorable direction. Genetic correlations of testes traits with feed efficiency were essentially zero, while those with fat thickness were moderately positive. These results suggest that increasing testes size should not adversely affect growth performance traits except through the reduction in selection intensity.


The properties of an HBV surface antigen protein carrying the binding site for the receptor of hepatocytes--its formation of surface antigen particles and secretion from discrete cell lines.
A human hepatitis B virus (HBV) gene, which encodes the major surface antigen protein (S protein) carrying the hepatocyte receptor-binding site, was constructed with site-directed mutagenesis and in vitro recombination. When expressed in monkey kidney cell line COS-M6, this gene product (S309 protein) formed surface antigen (HBsAg) particles and secreted from the cells. It was stable within the cells and in the culture medium and could be immunoprecipitated with antisera directed against plasma-derived HBsAg or synthetic preS1 polypeptide. Isopycnic CsCl gradient centrifugation showed that the density of S309 protein particles (1.25 g/ml) was slightly higher than that of S protein particles. The S309 protein was readily secretable from hepatoma cell lines, and the amount secreted was comparable to that of the S protein. By contrast, only about 10% of the S309 protein was secreted from COS-M6 cells, and its appearance in culture medium was delayed. The efficiency of the secretion of the S309 protein can be improved when it is coexpressed with the S protein.


Predicting drug-drug interactions based on multi-view and multichannel attention deep learning.
Predicting drug-drug interactions (DDIs) has become a major concern in the drug research field because it helps explore the pharmacological function of drugs and enables the development of new therapeutic drugs. Existing prediction methods simply integrate multiple drug attributes or perform tasks on a biomedical knowledge graph (KG). Though effective, few methods can fully utilize multi-source drug data information. In this paper, a multi-view and multichannel attention deep learning (MMADL) model is proposed, which not only extracts rich drug features containing both drug attributes and drug-related entity information from multi-source databases, but also considers the consistency and complementarity of different drug feature representation learning approaches to improve the effectiveness and accuracy of DDI prediction. A single-layer perceptron encoder is applied to encode multi-source drug information to obtain multi-view drug representation vectors in the same linear space. Then, the multichannel attention mechanism is introduced to obtain the attention weight by adaptively learning the importance of drug features according to their contributions to DDI prediction. Further, the representation vectors of multi-view drug pairs with attention weights are used as inputs of the deep neural network to predict potential DDI. The accuracy and precision-recall curves of MMADL are 93.05 and 95.94, respectively. The results indicate that the proposed method outperforms other state-of-the-art methods.


Effects of hepatic glycogen content on hepatic insulin action in humans: alteration in the relative contributions of glycogenolysis and gluconeogenesis to endogenous glucose production.
Hepatic glycogen content varies by almost 2-fold during the day, generally increasing from a nadir before breakfast to a peak 4-5 h after supper. To determine whether differences in hepatic glycogen content of this magnitude alter hepatic insulin action, nine subjects were studied on two occasions. On one occasion saline was infused, whereas on the other occasion an infusion of glucose [16.4 micromol/kg lean body mass (-lbm) x min] was started immediately after supper and continued throughout the night so as to spare hepatic glycogen. The nocturnal glucose infusion resulted in higher (P < 0.05) plasma glucose (6.0 +/- 0.1 vs. 5.1 +/- 0.1 mmol/L) and insulin (127 +/- 38 vs. 49 +/- 9 pmol/L) concentrations, and lower (P < 0.05) plasma glucagon concentrations (74 +/- 11 vs. 97 +/- 20 pg/mL) than did saline infusion. As anticipated, endogenous glucose production (EGP) was substantially lower (P < 0.001) during the glucose than during the saline infusion (7.0 +/- 0.9 vs. 19.4 +/- 1.3 micromol/kg-lbm x min). After discontinuation of the glucose infusion, glucose and insulin concentrations fell to levels that no longer differed from those observed during the saline infusion. In contrast, EGP increased to rates that were higher (P < 0.05) than those observed over the same interval after overnight saline infusion (19.2 +/- 1.2 vs. 16.5 +/- 0.7 micromol/kg-lbm x min). Despite higher EGP, the rate of incorporation of 14CO2 into glucose was lower (P < 0.001) after glucose than that after saline infusion (9.8 +/- 1.2% vs. 24.4 +/- 3.0%), implying a reciprocal relationship between hepatic glycogen content and gluconeogenesis. On the other hand, when differences in basal rates were taken into account, insulin-induced suppression of both EGP and incorporation of 14CO2 into glucose did not differ on the two occasions. Thus, whereas hepatic glycogen content influences both the absolute rate of EGP and the percent contribution of gluconeogenesis to EGP, it does not alter hepatic insulin action.


Raman Spectroscopy Combined with Principal Component Analysis for Screening Nasopharyngeal Cancer in Human Blood Sera.
This study demonstrates the analysis of nasopharyngeal cancer (NPC) in human blood sera using Raman spectroscopy combined with the multivariate analysis technique. Blood samples of confirmed NPC patients and healthy individuals have been used in this study. The Raman spectra from all these samples were recorded using 785 nm laser for excitation. Important Raman bands at 760, 800, 815, 834, 855, 1003, 1220-1275, and 1524 cm-1, have been observed in both normal and NPC samples. A decrease in the lipids content, phenylalanine, and β-carotene, whereas increases in amide III, tyrosine, and tryptophan have been observed in the NPC samples. The two data sets were well separated using principal component analysis (PCA) based on Raman spectral data. The spectral variations between the healthy and cancerous samples have been further highlighted by plotting loading vectors PC1 and PC2, which shows only those spectral regions where the differences are obvious.


Relationship of speed of slaughter on infected premises and intensity of culling of other premises to the rate of spread of the foot-and-mouth disease epidemic in Great Britain, 2001.
During the foot-and-mouth disease epidemic in the UK in 2001, two major control policies were the rapid identification of cases and the culling of animals on infected premises and on dangerous contact premises. Dangerous contact premises were divided into two groups, premises contiguous to an infected premises and non-contiguous premises. In England, the largest numbers of geographically clustered infected premises were in Cumbria, the South West (Somerset, Devon and Cornwall) and the Settle/Clitheroe area straddling the Yorkshire-Lancashire border. In each of these clusters, the rate of spread of the disease, the average time from the first lesion to slaughter on infected premises, and the intensity of culling of contiguous premises and non-contiguous premises were calculated for seven-day periods. Linear regression analysis was used to look for relationships between these factors and the rate of spread of the disease. The average time from the first lesion to slaughter had a statistically significant relationship in two of the three clusters and the intensity of culling of non-contiguous premises had a significant relationship in one. The intensity of culling of contiguous premises had no significant relationship in any of the three clusters.


Managing postmenopausal women with hormone receptor-positive advanced breast cancer who progress on endocrine therapies with inhibitors of the PI3K pathway.
Although endocrine therapies that interfere with estrogen receptor (ER)-mediated signaling have revolutionized the management of postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC), long-term management of these patients is suboptimal because of the eventual emergence of endocrine resistance. Intense research has elucidated a number of targets that act downstream or upstream of the ER, as well as those that crosstalk with the ER; however, clinical validation of inhibiting specific targets to overcome endocrine resistance has been lacking. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been implicated to mediate endocrine resistance, and a number of novel agents that target this pathway are in early- and late-stage clinical trials. Recently, everolimus, an inhibitor of mTOR, a critical component of the PI3K/AKT/mTOR pathway, in combination with endocrine therapy, was shown to prolong progression-free survival with a manageable adverse-event profile in postmenopausal patients with HR+ BC. Bolstered by the safety and efficacy observed with concomitant inhibition of the ER and the PI3K/mTOR pathway and the validation of dual inhibition approach in managing postmenopausal patients with HR+ BC, a number of novel agents that inhibit PI3K (pan-PI3K inhibitors) or PI3K and mTOR (dual PI3K/mTOR) are being evaluated in clinical trials. Thus, mTOR inhibitors have provided the much-needed ammunition to oncologists who manage postmenopausal women with BC and have paved the way for the development of novel therapies that target the PI3K/mTOR pathway. Use of these novel therapies in managing postmenopausal women with BC, in combination with endocrine therapies, is expected to improve overall outcomes by overcoming endocrine resistance.


The New Zealand Blood Donors' Health Study: baseline findings of a large prospective cohort study of injury.
Cohort studies have contributed important scientific knowledge regarding the determinants of chronic diseases. Despite the need for etiologic investigations, this design has been infrequently used in injury prevention research. To describe the baseline findings of the New Zealand Blood Donors' Health Study, a large prospective study designed to investigate relationships between lifestyle, psychosocial factors, and serious injury due to road crashes, falls, self harm, assault, work, sport, and recreation. Participants were recruited from fixed and mobile collection sites of a voluntary non-profit blood donor program. Baseline exposure data (for example risk taking behaviors, alcohol and marijuana use, sleep habits, and depression) were collected using a self administered questionnaire. Outcome data regarding serious injury will be collected prospectively through computerized record linkage of participants' unique identifiers to national morbidity and mortality databases. In total, 22 389 participants enrolled in the study (81% response rate). The diverse study population included 36% aged 16-24 years, 20% rural residents, and large variability in exposures of interest. For example, in the 12 months before recruitment, 21% had driven a motor vehicle when they considered themselves over the legal limit for alcohol, and 11% had been convicted of traffic violations (excluding parking infringements). Twelve per cent had seriously considered attempting suicide sometime in their life. This is the first, large scale cohort study investigating determinants of serious injury in New Zealand and among the largest worldwide. Preliminary findings from prospective analyses that can inform injury prevention policy are expected within five years.


[Neurologic disorders in chronic venous insufficiency of the lower extremities (clinico-electroneuromyographic study)].
Using combined clinical-electroneuromyographic examinations of 161 patients with varicose or postthrombotic veins, the changes in the nervous system related to chronic venous insufficiency of the lower extremities were studied. The following neurologic syndromes secondary to regional hemodynamic disorders were identified: polyneuropathic, mononeuropathic, lumbar-sacral radiculitis. Neurologic disorders were found to be correlated with the degree of the chronic venous insufficiency decompensation. The results of clinical observations are supported by the electroneuromyographic evidence. The authors discuss the pathogenetic significance of peripheral nervous system impairments in the development and the course of the syndrome of chronic venous insufficiency as well as therapeutic measures aimed at the prevention and management of neurologic disorders.


Characterization and efficacy of PKH26 as a probe to study the replication history of the human hematopoietic KG1a progenitor cell line.
The PKH26 dye can, in principle, be used for the study of asymmetric cell divisions (ASDs). A requirement for the identification of ASDs based on fluorescence intensity is that the PKH26 dye is distributed equally between daughter cells at each division, but this has not been demonstrated at a single-cell level. The efficacy of PKH26 as a probe for the study of ASDs was examined using the human hematopoietic KG1a cell. An automated time-lapse fluorescent microscope system was used to determine changes in cell size and fluorescence intensity during culture, and track cell divisions. The images of daughter cells were analyzed using the Isee software to determine the distribution of PKH26 dye between daughter cells. Ratios of cell size, mean fluorescence intensity, and total fluorescence intensity were calculated by dividing the values for one daughter cell by the value of the other daughter cell. The ratios for cell size, mean intensity, and total intensity were 1.13 +/- 0.12, 1.08 +/- 0.07, and 1.15 +/- 0.14 (mean +/- SD), respectively. Thus, PKH26 is not distributed equally to both daughter cells upon cell division. However, the replication history of individual KG1a cells can be reliably deduced for up to three divisions based solely on the mean and total fluorescence intensity of the PKH26 dye, using PKH26 concentrations below the chemical and phototoxic limits (2 microM).