IL-17A polymorphism (rs2275913) and levels are associated with preeclampsia pathogenesis in Chinese patients.
Preeclampsia (PE) is a pregnancy-related condition that affects both the infant and the mother. Although the role of various inflammatory molecules in PE has been demonstrated, the importance of pro-inflammatory molecules such as IL-17A, IL-23 is not well understood. In the present investigation, a potential association of common genetic variants in the IL-17A and IL-23A genes with PE was investigated. 115 PE clinically diagnosed patients who registered to the International Peace Maternity and Child Health Hospital were enrolled in this research. One hundred two pregnant women and 147 healthy Chinese women were also included. ELISA was used to measure IL-17A and IL-23 serum levels in all enrolled subjects. Common genetic polymorphisms in IL-17A (rs 2,275,913, rs1974226, and rs1974226), IL-23A (rs11171806), and IL-12B (rs3212227) were genotyped using the PCR-RFLP or TaqMan probe-based method. Elevated serum IL-17A levels were found in PE patients compared to pregnant (P < 0.0001) and healthy women (P < 0.0001). However, IL-23 levels were comparable across various clinical groups. In addition, heterozygous (GA) and minor allele (A) for IL-17A (rs2275913) and IL-23A (rs11171806) were more prevalent in PE patients compared to pregnant women indicating an important role in the predisposition to PE growth. Interestingly, IL-17A (r 2,275,913) mutants were associated with elevated IL-17A levels relative to wild type (GG). IL-17A (rs2275913) variants are associated with higher serum levels of cytokine, and predisposed PE development.


A record-retention program can protect group practices.
Group practices can benefit from having a systematic record-retention program that includes a formal record-retention policy. While state and Federal laws require the retention of some types of business records, many other records should be retained in the event of an audit or litigation. Having a record-retention program in place can help group practices respond cost-effectively and efficiently when called upon to produce documentation. The record-retention program should include a policy that stipulates not only which records should be kept but also for how long. Group practices should retain records relating to patient care, taxes, payroll, and contracts.


Walking and mindfulness improve the exercise capacity of patients with chronic obstructive pulmonary disease: A randomised controlled trial.
To evaluate the effects of mindful walking practice on the exercise capacity of patients with chronic obstructive pulmonary disease (COPD). A randomised controlled trial with four repeated measurements. Outpatient departments of a medical centre in northern Taiwan. Patients with mild to severe COPD. The control group received usual care, whereas the mindful walking group received usual care plus undertook a mindful walking practice. The main outcome was the six-minute walk distance. And the Global Initiative for Chronic Obstructive Lung Disease classification, dyspnoea, heart rate variability and interoceptive awareness were control factors. Compared with the control group (n = 40), the mindful walking group (n = 38) achieved a significantly longer six-minute walk distance (longer by 45.57 m; P = 0.04). The interaction effect of the six-minute walk distance significantly increased on Week 4 (P = 0.01), Week 8 (P = 0.002) and Week 12 (P = 0.02). Participants in Global Initiative for Chronic Obstructive Lung Disease class A exhibited significantly improved six-minute walk distance compared with those in class D (P = 0.001). Moreover, scores on the emotional awareness scale of interoceptive awareness were significantly associated with the six-minute walk distance (P = 0.02). The eight-week mindful walking practice improved the exercise capacity of patients with COPD, and its effect was sustained for at least four weeks after the end of the practice. This study suggest that this practice improved COPD symptoms, reduced COPD risk and increased the interoceptive awareness of this population.


BRCA1 and BRCA2 germline mutations screening in Algerian breast/ovarian cancer families.
Breast cancer is the leading cause of cancer death in women in Algeria. The contribution of BRCA1 and BRCA2 mutations to hereditary breast/ovarian cancer in Algerian population is largely unknown. Here, we describe analysis of BRCA1 and BRCA2 genes in 86 individuals from 70 families from an Algerian cohort with a personal and family history suggestive of genetic predisposition to breast cancer. The approach used is based on BRCA1 and BRCA2 mutations screening by High-Resolution Melting (HRM) curve analysis followed by direct sequencing. All samples for which no pathogenic mutation was found were analyzed by MLPA for large deletions or duplications. Three distinct pathogenic mutations c.83_84delTG, c.181T>G, c.798_799delTT and two large rearrangements involving deletion of exon 2 and exon 8 respectively, were detected in BRCA1 gene. Moreover 17 unclassified variants and polymorphisms were detected in BRCA1 gene (6 described for the first time). Two pathogenic mutations, c.1310_1313delAAGA and c.5722_5723delCT and 40 unclassified variants and polymorphisms (14 never described before) were identified in BRCA2 gene. For the first time, we used HRM and MLPA to identify BRCA1 and BRCA2 mutations in Algerian patients with a personal and family history suggestive of genetic predisposition to breast cancer. The implications of these new findings in regard to genetic testing and counseling are substantial for the Algerian population.


Perception and estimation of time in long-term survivors of childhood posterior fossa tumors.
We examined short duration perception (400 ms), long duration estimation (30 and 60 min), and spatiotemporal estimation in long-term survivors of childhood cerebellar tumors with a mean time since diagnosis of 14.2 years. Groups of individuals with tumors treated with surgery only (astrocytoma, N = 20) were compared to those with tumors treated with surgery, focal radiation, and craniospinal radiation (medulloblastoma, N = 20), and to age-matched controls (N = 40). Childhood lesions of the cerebellum produced enduring deficits in short-duration perception, but spared the ability to functionally estimate long durations, regardless of the pathology or treatment of the tumor. Evidence did not support any functional recovery over time of the cerebellar system that underlies short-duration perception. Younger age at treatment was not a protective factor. Although no group differences were present in the functional measures of long-duration estimation, tumor-related prospective memory deficits interfered with the ability to produce long-duration prospective estimates. The utilization of sensory and somatomotor information to refine real-world spatiotemporal estimates was compromised in the medulloblastoma group only.


Rescuing Drugs That are Discontinued in Adult Oncology Development for the Benefit of Children and Adolescents With Cancer - An ACCELERATE Multistakeholder Consensus.
Better therapies for childhood cancer remain an unmet need to improve the dismal prognosis of certain malignancies and to reduce the burden of toxicity. Rescuing discontinued or shelved drugs for children, adolescents, and young adults is a strategy to identify new uses for approved or investigational medicines outside the scope of their original medical indication. Our proposed multistakeholder consensus focuses on the development of innovative, patent-protected targeted agents, sourced from previously shelved or discontinued programs that have the potential to provide significant benefit to underserved patient populations, with unmet medical needs. There are several challenges to continuing/rescuing drugs for pediatric oncology development, which include the lack of information for decision making, corporate strategy considerations underlying the decision to invest in pediatric development, and the contracting and technology transfer complexities required to enable divestment and subsequent development. The multistakeholder approach for drug development has the advantage of conveying a consensus among academia, patient advocates, and importantly industry itself. We propose three areas of action to facilitate rescuing potentially beneficial drugs for children and adolescents with cancer: (i) initiatives to provide information to companies considering developing these drugs and a standards framework; (ii) incentives both in Europe and in the United States to encourage companies to develop pediatric-only drugs, with the reform of the EU Pharmaceutical Legislation posing an important opportunity; and (iii) communication of the issues to all stakeholders. Ultimately, this will benefit children and adolescents with cancer.


What will the future be like for patient accounts managers?
Patient accounts managers should prepare for their professional futures by critically examining their strengths and weaknesses and using the results of this examination to build on the strengths and correct the weaknesses. They then should tailor their career plans to fit their best estimates of the healthcare environment of the future.


Asynchrony enhances uncanniness in human, android, and virtual dynamic facial expressions.
Uncanniness plays a vital role in interactions with humans and artificial agents. Previous studies have shown that uncanniness is caused by a higher sensitivity to deviation or atypicality in specialized categories, such as faces or facial expressions, marked by configural processing. We hypothesized that asynchrony, understood as a temporal deviation in facial expression, could cause uncanniness in the facial expression. We also hypothesized that the effect of asynchrony could be disrupted through inversion. Sixty-four participants rated the uncanniness of synchronous or asynchronous dynamic face emotion expressions of human, android, or computer-generated (CG) actors, presented either upright or inverted. Asynchrony vs. synchrony expressions increased uncanniness for all upright expressions except for CG angry expressions. Inverted compared with upright presentations produced less evident asynchrony effects for human angry and android happy expressions. These results suggest that asynchrony can cause dynamic expressions to appear uncanny, which is related to configural processing but different across agents.


Divalent carbon intermediates: laser photolysis and spectroscopy.
A brief review is given of the structures of an important class of reactive intermediates, divalent carbon species (carbenes). The electronic properties of carbenes force an unusual electronic character upon these species that, in turn, leads to intriguing physical and chemical properties. Because of the fleeting nature of carbenes, which are extraordinarily reactive, direct investigation of their structural and chemical behavior has presented a challenge to the experimentalist. The application of spectroscopic and ultrafast laser techniques has met this challenge. With the use of laser methods, along with conventional techniques, quantitative evaluation of the energetics, dynamics, and reactivities of a variety of carbenes has been possible.


Rapid transcriptional autoregulation of a yeast metalloregulatory transcription factor is essential for high-level copper detoxification.
Copper detoxification in the yeast Candida glabrata is carried out in large part by a family of metallothionein (MT) genes: a unique MT-I gene, a tandemly amplified MT-IIa gene, and a single unlinked MT-IIb gene. In response to elevated environmental copper levels, members of this MT gene family are transcriptionally activated by a copper-dependent, sequence-specific DNA-binding transcription factor, AMT1. AMT1 shares several structural and functional features with the Saccharomyces cerevisiae copper metalloregulatory transcription factor ACE1, which is constitutively expressed and poised for rapid transcriptional responses to the toxic metal copper. In this paper, we demonstrate that AMT1 is subject to positive transcriptional autoregulation, which is exerted through binding of copper-activated AMT1 to a single copper responsive element in the AMT1 promoter. A nonautoregulatory amt1 mutant displayed a marked decrease in both copper tolerance and expression of the MT-II genes, which are critical for high-level copper detoxification in Candida glabrata. Kinetic analysis demonstrated the remarkably rapid AMT1 mRNA accumulation in the presence of copper, which is followed by increased expression of the metallothionein gene products. These results demonstrate that AMT1-positive autoregulation plays a critical role in metal detoxification and suggest that the rapid autoactivation of the AMT1 metalloregulatory transcription factor biosynthesis is essential for C. glabrata to quickly build up a cellular defense line to protect cells upon exposure to high environmental copper levels.


Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome.
We investigated extra-cardiac clinical symptoms and signs in the rare Jervell and Lange-Nielsen Syndrome, characterised by impaired KCNQ1 function, a gene essential for gastric acid secretion. All Swedish Jervell and Lange-Nielsen cases with double KCNQ1 mutations (14 cases) were investigated by medical record review, an interview, and were offered laboratory testing for iron-deficiency anaemia and gastrointestinal markers. A history of iron-deficiency anaemia in 12 of 14 patients and subjective gastrointestinal symptoms in 13 of 14 patients was revealed. Previous endoscopy in five cases had revealed no case of coeliac or inflammatory bowel disease but three cases of mucosal hyperplasia/dysplasia. Current signs of anaemia or iron substitution were present in 9 of 12 tested cases. Elevated levels of gastrin in seven of nine cases, pepsinogen in six of seven cases, and faecal calprotectin in nine of nine cases were present. A significant correlation between elevated gastrin levels and concurrent iron-deficiency and/or anaemia was revealed (p-value 0.039). A high frequency of extra-cardiac clinical symptoms and previous medical investigations was found. We propose that the Jervell and Lange-Nielsen Syndrome phenotypically includes gastrointestinal symptoms/signs and secondary iron-deficiency anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations. The resultant elevated gastrin level is a potential risk factor for later gastrointestinal cancer. Clinical monitoring with regard to developing anaemia and hypergastrinaemia should be considered in the Jervell and Lange-Nielsen Syndrome.


Directed chromosome loss by laser microirradiation.
In this article I have presented data that indicate the feasibility of attaining the five objectives outlined in the introduction. It should be possible to assign genes to specific chromosome regions by (i) selective DNA deletion of a 0.25- to 0.5-micro.m segment of one or both homologous chromosomes, (ii) deletion of one or both entire homologous chromosomes, or (iii) combining cell fusion with selective deletion of whole chromosomes and then deletion of chromosome segments. By laser microirradiation it should be possible to determine which chromosomes and chromosome regions are essential for immediate cell survival by removing from individual cells whole chromosomes, and chromosome segments from each of the chromosomes in the karyotype, and then assessing the cloning efficiency of each cell. For example, we have already determined that removal of one large chromosome No. 1 from PTK(2) cells does not prevent the cell from undergoing a subsequent mitosis. It should also be possible to generate new classes of mutants by damaging small selected areas of DNA with the laser beam and then cloning the irradiated cells-but this has yet to be demonstrated. This procedure might reveal recessive alleles on the nonirradiated homolog, or might result in the direct production of a genetic mutation. Irradiation of identical places on both homologous chromosomes could result in deletion of a genetic locus which ultimately might be detected as a deficiency in a metabolic pathway or some other cellular abnormality. Studies on chromosome stability and DNA constancy can be conducted with laser irradiated cells. For example, the karyotypic analysis of chromosome No. 1 suggests that a cellular mechanism exists to maintain the constancy of this chromosome in both the diploid and tetraploid cell lines. The same approach could be used with each of the chromosomes in the karyotype. Various cytochemical procedures could be used for making quantitative DNA studies of the cells, and chromosome and DNA analyses could be performed at varying times following laser microirradiation. It might also be possible to study the repair of chromosomal damage caused by laser irradiation. The cells could be examined by autoradiographic, cytochemical, and electron microscopy procedures at varying times after irradiation, and because the precise location, time, and nature of the mutational event would be known, subsequent analysis of repair and alteration would be facilitated.


[Biodefense: a new challenge for microbiology and public health].
Bioterrorism and the potential use of biological weapons has become an important concern of governments and responsible authorities. An example of this threat occurred in 2001 in the USA, when letters were sent containing spores of the agent that produces anthrax; this resulted in some deaths, and caused panic and negative effects on the world economy. If this small-scale event was able to cause such a huge impact, the repercussions of a massive attack could be catastrophic. In many countries, these events have resulted in the implementation of measures directed toward preventing and responding to bioterrorist threats and acts. As a whole, these measures are known as biodefense. This article briefly analyzes several aspects related to detecting and identifying acts of bioterrorism, and considers the biological agents that are implicated. The microbiological diagnosis that allows identification of the causal agent, a key point for taking suitable control measures, is also included.


Effect of periodontal treatment on peak serum levels of inflammatory markers.
Some subjects with untreated periodontitis exhibit elevated levels of distinct inflammatory markers in serum. The aim of the study was to assess whether nonsurgical periodontal therapy changes the levels of these markers and lowers these peaks. Forty periodontally diseased subjects received nonsurgical periodontal therapy (full-mouth scaling and root planing within 48 h) with either adjunctive systemic amoxicillin and metronidazole (n = 19) or placebo (n = 21). Serum samples, obtained at baseline (BL) and 3 months after treatment (M3), were evaluated for 15 cytokines and 9 acute-phase proteins using the Bio-Plex bead array multianalyte detection system. For each analyte, peak values were defined as greater than the mean + 2 standard deviations (SD) of measurements found in 40 periodontally healthy persons. Proportions were compared using Fisher's exact test. At M3, a significantly better primary clinical outcome (persisting pockets of >4 mm with bleeding on probing) was obtained in patients treated with scaling and root planing plus antibiotics compared to those receiving placebo (3.3 ± 5.1 vs. 6.8 ± 7.8 pockets per patient, p < 0.05). The levels of cytokines and acute-phase proteins of periodontitis patients were usually below the mean + 2 SD threshold of healthy persons. However, values above threshold were found in some individuals. Eleven patients showed a peak value of one analyte, and seven patients showed two peaks. In the remaining 12 patients, between three and ten analytes showed peak values. Therapy greatly reduced the number of subjects with four or more peaks (BL, 11 subjects; M3, 1 subject, p = 0.003). With regards to the reduction of peaks, no specific benefit of adjunctive antibiotics could be seen. Subjects with untreated periodontitis may show high peaks for several inflammatory markers in serum simultaneously. Nonsurgical periodontal treatment with or without antibiotics reduced most of these peak levels.


Subdivision and direction recognition of lambda/16 of orthogonal fringes for nanometric measurement.
Subdivision is one of the essential methods to improve the measurement resolution of optical instruments. A new method is proposed to solve lambda/16 bidirectional subdivision and direction recognition for orthogonal interference signals by constructing two sets of reference signals and using zero-cross detection. The experimental results prove that the method is efficient for orthogonal signals and has good real-time performance by field-programmable gate array realization. This method is easy to realize by use of electronic design automation tools and can be widely used in the signal processing system of optical measurement instruments such as a moiré fringe measurement system and laser interferometer.


McDonald versus modified Shirodkar rescue cerclage in women with prolapsed fetal membranes.
Purpose: We compared the efficacy of modified Shirodkar and McDonald rescue cerclage techniques in women with singleton pregnancies.Methods: The study sample included 47 women who presented at two tertiary hospitals in Turkey from 2008 to 2017 and underwent rescue cerclage due to cervical incompetence and cervical dilatation with fetal membranes prolapsed into the vagina. The outcomes were compared by cerclage technique used, Shirodkar or McDonald.Results: The McDonald cerclage was applied in 27 cases, and modified Shirodkar cerclage in 20 cases. A longer cerclage-to-birth interval (83.8 ± 37.6 vs. 63.7 ± 38.9 days) and later gestational age at delivery (33 vs. 31 weeks) were observed with the Shirodkar cerclage, although these differences were not statistically significant (p = .08 and .63, respectively). Both groups had similar delivery rates after 28, 32, and 37 weeks (p = .20, .15, and .25, respectively), whereas the modified Shirodkar technique resulted in a higher rate of live births although these differences were not statistically significant (85% vs. 63%, p = .09).Conclusion: The effects of the McDonald and modified Shirodkar cerclage procedures on prolonging pregnancy and improving the live birth rate were similar. Therefore, either technique can be applied to prevent neonatal loss due to advanced prematurity.


Methods used to estimate the size of the owned cat and dog population: a systematic review.
There are a number of different methods that can be used when estimating the size of the owned cat and dog population in a region, leading to varying population estimates. The aim of this study was to conduct a systematic review to evaluate the methods that have been used for estimating the sizes of owned cat and dog populations and to assess the biases associated with those methods.A comprehensive, systematic search of seven electronic bibliographic databases and the Google search engine was carried out using a range of different search terms for cats, dogs and population. The inclusion criteria were that the studies had involved owned or pet domestic dogs and/or cats, provided an estimate of the size of the owned dog or cat population, collected raw data on dog and cat ownership, and analysed primary data. Data relating to study methodology were extracted and assessed for biases. Seven papers were included in the final analysis. Collection methods used to select participants in the included studies were: mailed surveys using a commercial list of contacts, door to door surveys, random digit dialled telephone surveys, and randomised telephone surveys using a commercial list of numbers. Analytical and statistical methods used to estimate the pet population size were: mean number of dogs/cats per household multiplied by the number of households in an area, human density multiplied by number of dogs per human, and calculations using predictors of pet ownership. The main biases of the studies included selection bias, non-response bias, measurement bias and biases associated with length of sampling time. Careful design and planning of studies is a necessity before executing a study to estimate pet populations.


Impact of religiosity on the sexual risk behaviors of young men who have sex with men.
Young men who have sex with men (YMSM), particularly Black YMSM, bear a disproportionate burden of new human immunodeficiency virus (HIV) infections in the United States. Several studies support the positive and protective role of religion in health and the prevention of morbidity and mortality. However, little empirical research has been conducted looking at religion with the context of YMSM and HIV prevention. We examined the impact of religious attendance and faithfulness on sexual risk among a community-based sample of 450 YMSM in Chicago ages 16 to 20. Participants were mostly racial/ethnic minorities, that is, Black (53.4%) and Latino (19.9%). Multivariate logistic regression indicated that faithfulness in combination with frequent formal religious attendance was associated with a decrease in reported number of unprotected anal sex acts, including unprotected receptive anal sex with male partners. These association trends were also found for the Black YMSM in our sample, suggesting that religious involvement and faithfulness is a potential protective factor for the acquisition of HIV among this high-risk population.


Cortical and subcortical anatomy of chronic spatial neglect following vascular damage.
The role of the inferior parietal lobule (IPL) and superior temporal gyrus (STG) or subcortical pathways as possible anatomical correlates of spatial neglect is currently intensely discussed. Some of the conflicting results might have arisen because patients were examined in the acute stage of disease. We examined the anatomical basis of spatial neglect in a sample of patients examined in the post-acute stage following right-hemispheric vascular brain damage. Lesions of 28 patients with chronic spatial neglect were contrasted to lesions of 22 control patients without neglect using lesion subtraction techniques and voxel-wise comparisons. The comparisons identified the temporo-parietal junction (TPJ) with underlying white matter, the supramarginal gyrus, the posterior STG, and the insula as brain regions damaged significantly more often in neglect compared to non-neglect patients. In a subgroup of neglect patients showing particularly large cancellation bias together with small errors on line bisection damage was prevalent deep in the frontal lobe while damage of patients with the reverse pattern was located in the white matter of the TPJ. Considering our results and the findings of previous studies, spatial neglect appears to be associated with a network of regions involving the TPJ, inferior IPL, posterior STG, the insular cortex, and posterior-frontal projections. Frontal structures or projections may be of particular relevance for spatial exploration, while the IPL may be important for object-based attention as required for line bisection.


Determination of cell fate in skeletal muscle following BMP gene transfer by in vivo electroporation.
We previously developed a novel method for gene transfer, which combined a non-viral gene expression vector with transcutaneous in vivo electroporation. We applied this method to transfer the bone morphogenetic protein (BMP) gene and induce ectopic bone formation in rat skeletal muscles. At present, it remains unclear which types of cells can differentiate into osteogenic cells after BMP gene transfer by in vivo electroporation. Two types of stem cells in skeletal muscle can differentiate into osteogenic cells: muscle-derived stem cells, and bone marrow-derived stem cells in the blood. In the present study, we transferred the BMP gene into rat skeletal muscles. We then stained tissues for several muscle-derived stem cell markers (e.g., Pax7, M-cadherin), muscle regeneration-related markers (e.g., Myod1, myogenin), and an inflammatory cell marker (CD68) to follow cell differentiation over time. Our results indicate that, in the absence of BMP, the cell population undergoes muscle regeneration, whereas in its presence, it can differentiate into osteogenic cells. Commitment towards either muscle regeneration or induction of ectopic bone formation appears to occur five to seven days after BMP gene transfer.


Peripheral quantitative computed tomography at the distal radius: cross-calibration between two scanners.
Peripheral quantitative computed tomography (pQCT) is an important technique to study the interaction between the muscle and bone systems. We have recently established pQCT reference ranges for children, adolescents and young adults using a recent version (XCT 2000) of the Stratec scanners (Stratec Inc., Pforzheim, Germany). However, the previous version of this type of scanner (XCT 900) is still widely used and cross-calibration is needed to use these reference data. Therefore, both distal radii of 19 healthy subjects (age 21 to 59 years; 11 women) were analyzed at the "4% site" using both the XCT 900 and the XCT 2000. Cross-sectional area, total and trabecular bone mineral density (BMD), total bone mineral content (BMC) and polar Strength-Strain Index (SSI) results from the two scanners were compared using linear regression analysis. To achieve scanner calibration we used the intercept and slope of the correlations. The correlation coefficients between the two devices were 0.82 for the cross-sectional area, 0.81 for total BMD, 0.97 for trabecular BMD, 0.99 for total BMC and 0.86 for polar SSI. In conclusion, these data allow for the conversion of XCT 900 results at the distal radius to XCT 2000 values and vice versa.


[Image diagnosis of aortic valve disease: an update].
Aortic valve disease is the most common acquired valvular disease and most often requiring surgical valve replacement in our environment. In this chapter the latest scientific contributions in the field of cardiac imaging in this disease (echocardiography, magnetic resonance imaging and cardiac computed tomography) are reviewed. Some of them have aroused large and lively debates in forums in recent years. These contributions have forced us to rethink some diagnostic criteria, and the management of this disease as well.


[Use of new biochemical markers in diagnosis of aseptic hip endoprosthesis loosening].
Aseptic loosening of endoprosthesis is the most important problem in total hip arthroplasty. The diagnosis of aseptic loosening is based on anamnesis, the clinical findings, the radiography and scintigraphy. Despite the multitude of diagnostic possibilities it is still a problem to get an exact and early diagnosis. The process of loosening in the bone interface always leads to a change of bone structure of the surrounding bone tissue. In a prospective study we measured biochemical markers of bone metabolism in serum and urine to evaluate a possible change occurring parallel to endoprotheic loosening. 37 patients with severe signs of loosening (later intraoperatively confirmed) and 30 patients without any clinical or radiological signs of loosening (control group) were induced. Gender, age and model of endoprosthesis were similar in both groups. Parameters of bone formation (osteocalcin, alkaline phosphatase, procollagen I C-terminal extension peptide) and bone resorption (Cross-linked n-terminal telopetide) were measured. The cross-linked n-terminal telopetide (NTX) was significant increased in the loosening group (p < 0.001). Of the measured bone formation markers only osteocalcin showed a significantly higher level in patients with endoprosthetic loosening (p < 0.002). All other measured parameters of the bone metabolism showed no significant differences between the both groups. Our results show, that biochemical markers can provide relevant information of endoprosthesic loosening. We are now analysing in a prospective longitudinal study whether these parameters are also suitable to detect early endoprosthetic loosening.


Psychotic disorders in urban areas: an overview of the Study on Low Prevalence Disorders.
This paper reports on a study designed within the framework of the National Survey of Mental Health and Wellbeing to: estimate the prevalence of psychoses in urban areas of Australia; identify profiles of symptomatology, impairments and disabilities; collect information on services received and needed; and explore quality of life issues in a broadly representative sample of people with psychotic illnesses. The study was conducted over four areas in the Australian Capital Territory, Queensland, Victoria and Western Australia, as a two-phase survey: (i) a census and screening for psychosis of all individuals who made contacts with mental health services during a period of 1 month in 1997; and (ii) interviews with a stratified random sample (n=980) of the screen-positive individuals (n=3800) using a standardised instrument. The point prevalence (1 month) of psychotic disorders in the urban population aged 18-64 is in the range of 4-7 per 1000 with a weighted mean of 4.7 per 1000. People with psychotic disorders experience high rates of functional impairments and disability, decreased quality of life, persistent symptoms, substance-use comorbidity and frequent side effects of medication. Although the utilisation of hospital-based and community mental health services, as well as of public and non-governmental helping agencies, is high, the majority live in extreme social isolation and adverse socioeconomic circumstances. Among the many unmet needs, the limited availability of community-based rehabilitation, supported accommodation and employment opportunities is particularly prominent. The so-called 'low-prevalence' psychotic disorders represent a major and complex public health problem, associated with heavy personal and social costs. There is a need for a broad programmatic approach, involving various sectors of the community, to tackle the multiple dimensions of clinical disorder, personal functioning and socioeconomic environment that influence the course and outcome of psychosis and ultimately determine the effectiveness of service-based intervention.


Comparative proteomic analysis to identify the novel target gene of angiotensin II in adrenocortical H295R cells.
Angiotensin II (Ang II) is a well-known peptide that maintains the balance of electrolytes in the higher vertebrates. Ang II stimulation in the adrenal gland induces the synthesis of mineralocorticoids, mainly aldosterone, through the up-regulation of aldosterone synthase (CYP11B2) gene expression. Additionally, it has been reported that Ang II activates multiple signaling pathways such as mitogen-activated protein kinase (MAPK) and Ca2+ signaling. Although Ang II has various effects on the cellular signaling in the adrenal cells, its biological significance, except for the aldosterone synthesis, is still unclear. In this study, we attempted to search the novel target gene(s) of Ang II in the human adrenal H295R cells using a proteomic approach combined with stable isotopic labeling using amino acid in cell culture (SILAC). Interestingly, we found that Ang II stimulation elevated the expression of phosphofructokinase type platelet (PFKP) in both protein and mRNA levels. Moreover, transactivation of PFKP by Ang II was dependent on extracellular-signal-regulated kinase (ERK) 1/2 activation. Finally, we observed that Ang II treatment facilitated glucose uptake in the H295R cells. Taken together, we here identified PFKP as a novel target gene of Ang II, indicating that Ang II not only stimulates steroidogenesis but also affects glucose metabolism.


An insertion peptide in yeast glycyl-tRNA synthetase facilitates both productive docking and catalysis of cognate tRNAs.
The yeast Saccharomyces cerevisiae possesses two distinct glycyl-tRNA synthetase (GlyRS) genes: GRS1 and GRS2. GRS1 is dually functional, encoding both cytoplasmic and mitochondrial activities, while GRS2 is dysfunctional and not required for growth. The protein products of these two genes, GlyRS1 and GlyRS2, are much alike but are distinguished by an insertion peptide of GlyRS1, which is absent from GlyRS2 and other eukaryotic homologues. We show that deletion or mutation of the insertion peptide modestly impaired the enzyme's catalytic efficiency in vitro (with a 2- to 3-fold increase in Km and a 5- to 8-fold decrease in kcat). Consistently, GRS2 can be conveniently converted to a functional gene via codon optimization, and the insertion peptide is dispensable for protein stability and the rescue activity of GRS1 at 30°C in vivo. A phylogenetic analysis further showed that GRS1 and GRS2 are paralogues that arose from a gene duplication event relatively recently, with GRS1 being the predecessor. These results indicate that GlyRS2 is an active enzyme essentially resembling the insertion peptide-deleted form of GlyRS1. Our study suggests that the insertion peptide represents a novel auxiliary domain, which facilitates both productive docking and catalysis of cognate tRNAs.


[Creativity and innovation: competences on nursing management].
This article presents the importance of the creativity and innovation on health services, distinguishing those concepts. Creative behavior is the improvement of an element or known actions: whereas innovation means finding new alternatives. Considering competences like knowledge, skill and attitude--KSA, it is understood that by stimulating creativity and innovation, the performance of the health professional will be optimized. Therefore, creativity and innovation are key elements for improvement and organization, and, more specifically, for Nursing to find alternatives for solving problems related to the occupation as a whole. In this way, this approach brings a strategic tool on the process of management and a differential for the nurse, which by innovating and creating will amaze herself with her potential.


Large-scale expression profiling and physiological characterization of jasmonic acid-mediated adaptation of barley to salinity stress.
Barley (Hordeum vulgare L.) is a salt-tolerant member of the Triticeae. Recent transcriptome studies on salinity stress response in barley revealed regulation of jasmonic acid (JA) biosynthesis and JA-responsive genes by salt stress. From that observation and several other physiological reports, it was hypothesized that JA is involved in the adaptation of barley to salt stress. Here we tested that hypothesis by applying JA to barley plants and observing the physiological responses and transcriptome changes. Photosynthetic and sodium ion accumulation responses were compared after (1) salinity stress, (2) JA treatment and (3) JA pre-treatment followed by salinity stress. The JA-pre-treated salt-stressed plants accumulated strikingly low levels of Na(+) in the shoot tissue compared with untreated salt-stressed plants after several days of exposure to stress. In addition, pre-treatment with JA partially alleviated photosynthetic inhibition caused by salinity stress. Expression profiling after a short-term exposure to salinity stress indicated a considerable overlap between genes regulated by salinity stress and JA application. Three JA-regulated genes, arginine decarboxylase, ribulose 1.5-bisphosphate carboxylase/oxygenase (Rubisco) activase and apoplastic invertase are possibly involved in salinity tolerance mediated by JA. This work provides a reference data set for further study of the role of JA in salinity tolerance in barley and other plants species.


The role of chemotherapy in unresectable or metastatic adenocarcinoma of the stomach and gastroesophageal junction.
Gastric cancer including gastroesophageal junction adenocarcinomas are most challenging and deadly cancers of the gastrointestinal tract. Gastric cancer has a fatality-to-case ratio of 0.66, translating that nearly two thirds of newly diagnosed patients will have disseminated disease and in need of systemic therapy. Advanced gastric adenocarcinoma (AGC) is a heterogenous disease with differences in geographical distribution, histopathology, and molecular subtypes. Fluoropyrimidines (5-FU, S-1, and capecitabine), platinum compounds (cisplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), and the topoisomerase inhibitory irinotecan are active drugs against AGC. The combination of fluoropyrimidines with a platinum compound is the optimal first-line treatment. Trastuzumab (given in combination with chemotherapy for HER2 positive tumors) and ramucirumab are the only targeted agents approved by the food and drug administration for the treatment in AGC for first and second line respectively. Efforts are being directed to harness the immune system with checkpoint inhibitors and to combining these drugs with chemotherapy in clinical trials. Genomic technology advancements might provide us with the tools to create personalized treatment for AGC in the near future with the goal to improve outcomes. In this article we aimed to review current therapeutic regimens for AGC with an update of ongoing clinical trials.


Defining standard of care in the developing world: the intersection of international research ethics and health systems analysis.
In recent years there has been intense debate regarding the level of medical care provided to 'standard care' control groups in clinical trials in developing countries, particularly when the research sponsors come from wealthier countries. The debate revolves around the issue of how to define a standard of medical care in a country in which many people are not receiving the best methods of medical care available in other settings. In this paper, we argue that additional dimensions of the standard of care have been hitherto neglected, namely, the structure and efficiency of the national health system. The health system affects locally available medical care in two important ways: first, the system may be structured to provide different levels of care at different sites with referral mechanisms to direct patients to the appropriate level of care. Second, inefficiencies in this system may influence what care is available in a particular locale. As a result of these two factors locally available care cannot be equated with a national 'standard'. A reasonable approach is to define the national standard of care as the level of care that ought to be delivered under conditions of appropriate and efficient referral in a national system. This standard is the minimum level of care that ought to be provided to a control group. There may be additional moral arguments for higher levels of care in some circumstances. This health system analysis may be helpful to researchers and ethics committees in designing and reviewing research involving standard care control groups in developing country research.


Transcranial magnetic stimulation for the treatment of obsessive-compulsive disorder.
Transcranial magnetic stimulation (TMS) was introduced as a neurophysiological technique in 1985 when Anthony Barker and his team developed a compact machine that permitted non-invasive stimulation of the cerebral cortex (Barker 1985). Since its introduction, TMS has been used to evaluate the motor system, to study the function of several cerebral regions, and for the pathophysiology of several neuropsychiatric illnesses. In addition, it has been suggested that TMS might have therapeutic potential. Some controlled studies have evaluated the effects of repetitive TMS (rTMS) in patients with obsessive-compulsive disorder (OCD). Greenberg (Greenberg 1997) observed that a single session of right prefrontal cortex stimulation produced a significant decrease in compulsive urges in OCD patients lasting over eight hours. Other studies have reported transitory improvements in mood but there are no observations for changes in anxiety or obsessions. To develop a systematic review on the clinical efficacy and safety of transcranial magnetic stimulation from randomised controlled trials in the treatment of obsessive-compulsive disorder. An electronic search was performed including the Cochrane Collaboration Depression, Anxiety and Neurosis Review Group trials register (last searched June, 2002), the Cochrane Controlled Trials Register (Issue 2, 2002), MEDLINE (1966-2002), EMBASE (1974-2002), PsycLIT (1980-2002), and bibliographies from reviewed articles. Randomised controlled trials assessing the therapeutic efficacy and safety of transcranial magnetic stimulation for obsessive-compulsive disorder. All reviewers independently extracted the information and verified it by cross-checking. Disagreements were resolved through discussion. Three trials were included in the review and only two contained data in a suitable form for quantitative analysis. It was not possible to pool any results for a meta-analysis. No difference was seen between rTMS and sham TMS using the Yale-Brown Obsessive-Compulsive Scale or the Hamilton Depression Rating Scale for all time periods analysed. There are currently insufficient data from randomised controlled trials to draw any conclusions about the efficacy of transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder.


Beyond Cervical Length: Association between Postcerclage Transvaginal Ultrasound Parameters and Preterm Birth.
To assess the value of transvaginal ultrasound parameters after cerclage placement in estimating the risk of spontaneous preterm birth. This is a retrospective cohort at a single tertiary care center from 2013 to 2016. Women carrying a singleton, nonanomalous fetus with cerclage in situ and at least one postcerclage transvaginal ultrasound from 160/7 to 256/7 weeks' gestation were included. In addition to abstracting maternal demographic and obstetric characteristics, two study investigators separately reviewed each of the images from the first transvaginal ultrasound after cerclage placement, masked to pregnancy outcomes. We measured the angle between the anterior uterine wall and cervical canal at the internal os and external os, closed canal length above and below the stitch, width of the anterior and posterior cervix at the level of the cerclage, and stitch distance from the cervical canal. The presence of additional ultrasound findings such as sludge and cervical funneling was also noted. The main outcomes were preterm birth < 34 weeks and preterm birth < 37 weeks. Transvaginal ultrasound parameters were compared between women with preterm birth and those without preterm birth using chi-square, Fisher's exact, and Wilcoxon's rank-sum tests, as appropriate. Log binomial regression was used to estimate the relative risk of preterm birth for all significant obstetric and ultrasound characteristics. A total of 102 women met inclusion criteria: 58% had history-indicated, 20% ultrasound-indicated, and 23% exam-indicated cerclages. Of these, 28 (27.5%) women delivered at < 34 weeks' gestation, and 48 (47.0%) women delivered at < 37 weeks' gestation. Preterm birth did not vary by race, maternal age, insurance, smoking, or gestational age of the earliest prior preterm birth (for multiparous women), but women who had preterm birth were more likely to have exam-indicated cerclage. There were several transvaginal ultrasound parameters associated with preterm birth < 34 weeks and preterm birth < 37 weeks. Of these, cervical length below the stitch, stitch distance from the cervical canal, straight cervical canal, funneling to or past the stitch, and presence of sludge had the greatest effect sizes. Rates of preterm birth are high postcerclage. In addition to measuring cervical length, utilization of postcerclage transvaginal ultrasound to evaluate the location of the cerclage within the cervix, the curvature of the cervical canal, and the presence of funneling and sludge may help identify women who are at the highest risk for preterm birth.


Vitronectin-binding staphylococci enhance surface-associated complement activation.
Coagulase-negative staphylococci are well recognized in medical device-associated infections. Complement activation is known to occur at the biomaterial surface, resulting in unspecific inflammation around the biomaterial. The human serum protein vitronectin (Vn), a potent inhibitor of complement activation by formation of an inactive terminal complement complex, adsorbs to biomaterial surfaces in contact with blood. In this report, we discuss the possibility that surface-immobilized Vn inhibits complement activation and the effect of Vn-binding staphylococci on complement activation on surfaces precoated with Vn. The extent of complement activation was measured with a rabbit anti-human C3c antibody and a mouse anti-human C9 antibody, raised against the neoepitope of C9. Our data show that Vn immobilized on a biomaterial surface retains its ability to inhibit complement activation. The additive complement activation-inhibitory effect of Vn on a heparinized surface is very small. In the presence of Vn-binding strain, Staphylococcus hemolyticus SM131, complement activation on a surface precoated with Vn occurred as it did in the absence of Vn precoating. For S. epidermidis 3380, which does not express binding of Vn, complement activation on a Vn-precoated surface was significantly decreased. The results could be repeated on heparinized surfaces. These data suggest that Vn adsorbed to a biomaterial surface may serve to protect against surface-associated complement activation. Furthermore, Vn-binding staphylococcal cells may enhance surface-associated complement activation by blocking the inhibitory effect of preadsorbed Vn.


[Clinical characteristics and etiology of children with hypereosinophilia].
To analyze the clinical characteristics and etiology of hypereosinophilia in children. Clinical data of 88 children with hypereosinophilia admitted in Children's Hospital of Zhejiang University School of Medicine during April 2009 and May 2015 were retrospectively reviewed. The clinical manifestations, etiologies, and the correlation of disease severity with different etiologies were analyzed. The main clinical manifestations were fever, abdominal pain, cough and/or tachypnea, skin rash, hemafecia and diarrhea, which were observed in 19 (21.6%), 15 (17.0%), 14 (15.9%), 13 (14.8%), 11 (12.5%) and 6 (6.8%) cases, respectively. For etiologies, there were 28 cases (31.8%) induced by infections, including 11 cases of acute bronchial pneumonia, 9 cases of parasite infection, 4 cases of septicemia, 2 cases of urinary system infection, 1 case of cellulitis and 1 case of cholecystitis complicated with pancreatitis. The etiologies for the rest cases were allergic diseases (25 cases, 28.4%), eosinophilic gastroenteritis (20 cases, 22.7%), immunodeficiency (3 cases, 3.4%, all were moderate to severe eosinophilia), ABO hemolysis (2 cases, 2.3%), hematologic neoplasms (2 cases, 2.3%), eosinophilic cystitis (1 case, 1.1%), eosinophilic granulomatosis with polyangitis (1 case, 1.1%), nephrotic syndrome (1 case, 1.1%), and 5 cases (5.7%) were of unknown causes. Fever, abdominal pain, cough and/or tachypnea are the most common clinical manifestations in children with hypereosinophilia. Infection, allergic diseases and eosinophilic gastroenteritis are the most common etiologies, and parasites are the most common pathogen identified. Differential diagnosis of primary immunodeficiency should be considered in children with moderate to severe eosinophilia.


CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure.
CYP2D6, a member of the cytochrome P450 superfamily, is responsible for the metabolism of about 25% of the commonly prescribed drugs. Its activity ranges from complete deficiency to excessive activity, potentially causing toxicity of medication or therapeutic failure with recommended drug dosages. This study aimed to describe the CYP2D6 diversity at the global level. A total of 1060 individuals belonging to 52 worldwide-distributed populations were genotyped at 12 highly informative variable sites, as well as for gene deletion and duplications. Phenotypes were predicted on the basis of haplotype combinations. Our study shows that (i) CYP2D6 diversity is far greater within than between populations and groups thereof, (ii) null or low-activity variants occur at high frequencies in various areas of the world, (iii) linkage disequilibrium is lowest in Africa and highest in the Americas. Patterns of variation, within and among populations, are similar to those observed for other autosomal markers (e.g. microsatellites and protein polymorphisms), suggesting that the diversity observed at the CYP2D6 locus reflects the same factors affecting variation at random genome markers.


[Comparison of dobutamine under different fluids resuscitation for shock induced by ischemia/reperfusion].
To compare the effects of dobutamine under different fluids resuscitation for shock induced by intestinal ischemia/reperfusion (I/R) injury in rabbits. Thirty-two anesthetized rabbits were randomized into four groups of eight animals each. The groups were followed as: (1) lactated Ringer's solution (LRS) resuscitation; (2) LRS+hydroxyethyl starch solution (HES) resuscitation; (3) LRS resuscitation+dobutamine treatment; (4) LRS+HES resuscitation+dobutamine treatment. All these rabbits underwent the intestinal I/R injury developed by occluding superior mesenteric artery (SMA) with a non-crushing vascular clamp for 60 minutes and then loosing the clamp for 300 minutes. The fluid resuscitation and drug treatment began at the same time of reperfusion. Hemodynamic parameters including mean artery pressure (MAP), heart rate (HR), aortic velocity (AoV, as cardiac output) and SMA blood flow (Qsma) were measured. Tissue oxygenation was assessed indirectly by measuring the tonometric parameters of the gut, including difference between partial pressure of carbon dioxide in intestinal intramucosal and partial pressure of carbon dioxide in arterial blood (Pt-a CO2 gap), intestinal intramucosal pH (pHi), arterial blood lactate acid concentration and oxygen delivery (DO2). HR, AoV and Qsma as measured in two dobutamine groups were significantly higher in values than LRS and LRS+HES groups (all P<0.05). But MAP as measured in two dobutamine groups were significantly higher in values than only LRS (P<0.05), and in LRS+HES resuscitation+dobutamine treatment group was also significantly higher in values than LRS resuscitation+dobutamine treatment group (P<0.05). Dobutamine in LRS resuscitation+dobutamine treatment and LRS+HES resuscitation+dobutamine treatment group could greatly decrease lactate and Pt-aCO2 gap, significantly improve pHi and DO2 compared with other two resuscitation groups (all P<0.05). Dobutamine in LRS+HES resuscitation+dobutamine treatment group could also greatly decrease lactate and Pt-aCO2 gap, significantly improve pHi compared with LRS resuscitation+dobutamine treatment group (all P<0.05). Dobutamine could improve hemodynamic parameters and tissue oxygenation in shock induced by intestinal I/R injury in rabbits, being better used under the LRS+HES resuscitation.


How bio-questionable are the different recombinant human erythropoietin copy products in Thailand?
The high prevalence of pure red cell aplasia in Thailand has been associated with the sharp increase in number of recombinant human erythropoietin (rhEPO) copy products, based on a classical generic regulatory pathway, which have entered the market. This study aims to assess the quality of rhEPO copy products being used in Thailand. Twelve rhEPO copy products were purchased from pharmacies in Thailand, shipped under controlled cold chain conditions to the Netherlands and characterized using (1) high performance size-exclusion chromatography, (2) asymmetrical flow field-flow fractionation, (3) sodium dodecyl sulfate polyacrylamide gel electrophoresis in combination with (4) Western blotting and additionally tested for (5) host cell protein impurities as well as (6) endotoxin contamination. Some of the tested rhEPO copy products showed high aggregate levels and contained a substantial amount of protein fragments. Also, one of rhEPO copy products had a high endotoxin level, exceeding the FDA limit. Our observations show that some of the tested copy products on the Thai market differ significantly from the originator rhEPO product, Epogen®. This comparison study supports a link between the quality attributes of copy rhEPO products and their immunogenicity.


Distribution and prevalence of reflux in the superficial and deep venous system in the general population--results from the Bonn Vein Study, Germany.
Venous diseases are among the most frequent diseases in the general population of industrialized countries. The aim of this article is to investigate the population-based prevalence of pathologic reflux in superficial and deep leg veins, taking into account factors as gender, age, and clinical classification of venous disease. In a population-based cross-sectional study, 3072 subjects aged 18 to 79 years (1350 male, 1722 female, response 59%) were enrolled from October 2000 through November 2001. A standardized interview was conducted to document phlebological history and clinical examinations including duplex sonography of selected superficial and deep leg veins. Pathological reflux was defined as being >500 ms. All participants where classified according to the CEAP classification. Using the highest clinical stage per participant, 9.6% where classified C0, 59.0% C1, 14.3% C2, 13.5% C3, 2.9% C4, and 0.7% C5-C6. A pathological reflux (>500 ms) was found in 35.3% (95% confidence interval [CI] 33.6-37.1) of subjects with 21.0% (95% CI 19.5-22.5) showing reflux in at least one superficial vein and 20.0% (95% CI 18.6-21.5) showing reflux in at least one deep vein. We observed significantly higher reflux prevalence for the superficial veins in women while for the deep veins reflux prevalence were significantly higher in men. Prevalence of reflux in the superficial veins markedly increases with age. In the deep venous system, no clear changes in reflux prevalence with age can be observed. For superficial veins, reflux prevalence is markedly higher with higher C-stages. For the deep veins, the proportion of refluxes is relatively constant in stages C0-C3 with a distinct increase of prevalence from stage C4 onward. Our results show a high prevalence of reflux both for the superficial and the deep venous system. Reflux prevalence is associated with gender, age, and the clinical stage as measured by the CEAP classification. Further longitudinal studies are needed to clarify the relevance of pathological reflux in subjects with otherwise healthy veins.


The End of Life Accompanied by COVID-19: A Qualitative Study on Changes in Behavior and Stigmatization of the Grieving Families in Peru (Part II).
The rapid spread of SARS-CoV-2 has led to changes in every aspect of life and death. In Peru, where the longest quarantine has occurred with suboptimal results, the rituals have been turned around, impacting the relatives in multiple aspects. Here, we used a qualitative approach to analyze unresolved grief, hygiene changes, and stigma through semi-structured, online (Google Meet) interviews with 15 participants aged 20-72, who had lost family members to COVID-19. The recorded and transcribed interviews were analyzed using reflexive thematic analysis. Most participants had unresolved grief due to the blocking of funeral rituals, which could predispose them to prolonged mourning. After the loss of relatives, hygiene measures will be improved to avoid infections and new deaths in every family, while most participants felt no stigma in their milieu, since their relatives accompanied them during the funeral, supporting them from afar. It is important that interventions are implemented to prevent the progression of grief by providing mental health opportunities for the bereaved.


Spinalization unmasks clonidine's alpha 1-adrenergic mediated excitation of the flexor reflex in rats.
Clonidine exerts alpha 2-adrenergic mediated depressant effects on most behaviors measured in a normal animal. However, in the spinal-transected (spinalized) animal, clonidine apparently facilitates the flexor reflex through a stimulation of spinal alpha 1-adrenoceptors. The purpose of the present study was to determine if spinalization per se causes the shift in clonidine's profile from an alpha 2- to an alpha 1-adrenergic agonist. The hindlimb flexor reflex was elicited by electrical pulses delivered through electrodes implanted subcutaneously in the hindpaw and was measured with a force transducer and polygraph. In contrast to an alpha 2-adrenergic mediated inhibition of the flexor reflex in intact rats, clonidine produced an alpha 1-adrenergic mediated increase in flexor reflex amplitude in spinalized rats. Because decerebration did not alter the depression due to clonidine, and intraventricular (but not intrathecal) administration of oxymetazoline mimicked the effect of clonidine, the depressant effects of alpha 2-adrenergic agonists are mediated through alpha 2-adrenergic receptors localized in the brainstem. Alternate methods for inducing a functional spinal transection (spinal block with intrathecal procaine; spinal ligation) indicated that the shift in clonidine's effect from inhibition of the flexor reflex to excitation occurred immediately following spinalization. Spinal ligation did not produce alpha 1-adrenergic supersensitivity at 15 min or 2 hr after transection, as measured by alterations in [3H]prazosin receptor binding or behavioral responses to clonidine. Thus, the shift in clonidine's effects from alpha 2-adrenergic mediated inhibition of the flexor reflex in intact rats to alpha 1-adrenergic mediated excitation in spinalized rats results because spinal transection unmasks clonidine's alpha 1-adrenergic stimulatory effect. Other conditions under which clonidine exerts alpha 1-adrenoceptor mediated excitatory effects on behavior are discussed.


Capacity building for assessing new technologies: approaches to examining personalized medicine in practice.
This article focuses on the overarching question: how can we use existing data to develop the capacity to improve the evidence base on personalized medicine technologies and particularly regarding their utilization and clinical utility? We focus on data from health payers who are key stakeholders in capacity building, as they need data to guide decisions and they develop data as part of operations. Broadly defined, health payers include insurance carriers, third party payers, health-plan sponsors and organized delivery systems. Data from health payers have not yet been widely used to assess personalized medicine. Now, with an increasing number of personalized technologies covered and reimbursed by health payers, and an increasing number of emerging technologies that will require policy decisions, there is a great opportunity to develop the evidence base using payer data and by engaging with these stakeholders. Here, we describe data that are available from, and are being developed by, health payers and assess how these data can be further developed to increase the capacity for future research, using three examples. The examples suggest that payer data can be used to examine clinical utility and approaches can be developed that simultaneously address the characteristics of personalized medicine, real world data and organizations. These examples can now help us to elucidate how to best examine clinical utility in actual practice and build evaluation approaches that can be applied to future technologies.


Temporal association of CD40 antigen expression with discrete stages of human B-cell ontogeny and the efficacy of anti-CD40 immunotoxins against clonogenic B-lineage acute lymphoblastic leukemia as well as B-lineage non-Hodgkin's lymphoma cells.
Detailed immunophenotypic analyses of immunologically classified leukemias and lymphomas showed that CD40 displays an exquisite B-lineage specificity within the human lymphopoietic system. Notably, 82% of B-lineage chronic lymphocytic leukemias (CLLs), 82% of B-lineage hairy cell leukemias (HCLs), 86% of B-lineage non-Hodgkin's lymphomas (NHLs), and 29% of B-lineage acute lymphoblastic leukemias (ALLs) were CD40+. Quantitative analyses of the correlated expression of CD40 and other B-lineage differentiation antigens on fetal lymphoid precursor cells by multiparameter two-color/three-color flow cytometry, combined with analyses of sequential antigen expression on fluorescence-activated cell fluorescence activated cell sorter (FACS) isolated immunologically distinct fetal B-cell precursor subpopulations during in vitro proliferation and differentiation, provided evidence that the acquisition of CD40 antigen in human B-cell ontogeny occurs subsequent to the expression of CD10 and CD19 antigens but before the surface expression of CD20, CD21, CD22, CD24, and surface immunoglobulin M (sIgM). Some leukemic pro-B cells from ALL patients as well as normal pro-B cell clones from fetal livers displaying germline Ig heavy chain genes were CD40+, indicating that the acquisition of CD40 antigen likely precedes the rearrangement of Ig heavy chain genes. CD40+ FACS-sorted malignant cells from B-lineage ALL as well as B-lineage NHL patients were capable of in vitro clonogenic growth, indicating the CD40 antigen is expressed on clonogenic leukemia and lymphoma cells. This hypothesis was confirmed by the ability of an anti-CD40 immunotoxin that we used as an antigen-specific cytotoxic probe to effectively kill clonogenic B-lineage ALL and NHL cells.


AG 205, a progesterone receptor membrane component 1 antagonist, ablates progesterone's ability to block oxidative stress-induced apoptosis of human granulosa/luteal cells†.
The present studies were designed to determine whether progesterone (P4)-progesterone receptor membrane component 1 (PGRMC1) signaling is able to attenuate the apoptotic effects of oxidative stress induced by hydrogen peroxide (H2O2). To achieve this goal, freshly isolated human granulosa/luteal cells were maintained in culture. After several passages, the cells were treated with H2O2, which induced apoptosis within 2.5 h, while simultaneous treatment with P4 attenuated the apoptotic action of H2O2. AG 205, a PGRMC1 antagonist, eliminated P4's ability to prevent H2O2-induced apoptosis. AG 205 neither affected PGRMC1's cytoplasmic localization nor its interaction with PGRMC2, but appeared to reduce its presence within the nucleus. AG 205 also (1) increased the monomeric and decreased the higher molecular weight forms of PGRMC1 (i.e., dimers/oligomers) and (2) altered the expression of several genes involved in apoptosis. The most dramatic change was an approximate 8-fold increase in Harakiri (Hrk) mRNA. However, AG 205 did not induce apoptosis in the absence of H2O2. Taken together, these observations suggest that the higher molecular weight forms of PGRMC1 likely account in part for PGRMC1's ability to suppress the expression of Hrk. Harakiri is a BH-3 only member of the B-cell lymphoma 2 (BCL2) family that promotes apoptosis by binding to and antagonizing the antiapoptotic action of BCL2- and BCL2-like proteins. It is likely then that PGRMC1's ability to suppress Hrk is part of the mechanism through which P4-PGRMC1 signaling preserves the viability of human granulosa/luteal cells.


Leucine Supplementation Does Not Restore Diminished Skeletal Muscle Satellite Cell Abundance and Myonuclear Accretion When Protein Intake Is Limiting in Neonatal Pigs.
Rapid growth of skeletal muscle in the neonate requires the coordination of protein deposition and myonuclear accretion. During this developmental stage, muscle protein synthesis is highly sensitive to amino acid supply, especially Leu, but we do not know if this is true for satellite cells, the source of muscle fiber myonuclei. We examined whether dietary protein restriction reduces myonuclear accretion in the neonatal pig, and if any reduction in myonuclear accretion is mitigated by restoring Leu intake. Neonatal pigs (1.53 ± 0.2 kg) were fitted with jugular vein and gastric catheters and fed 1 of 3 isoenergetic milk replacers every 4 h for 21 d: high protein [HP; 22.5 g protein/(kg/d); n= 8]; restricted protein [RP; 11.2 g protein/(kg/d); n= 10]; or restricted protein with Leu [RPL; 12.0 g protein/(kg/d); n= 10]. Pigs were administered 5-bromo-2'-deoxyuridine (BrdU; 15 mg/kg) intravenously every 12 h from days 6 to 8. Blood was sampled on days 6 and 21 to measure plasma Leu concentrations. On day 21, pigs were killed and the longissimus dorsi (LD) muscle was collected to measure cell morphometry, satellite cell abundance, myonuclear accretion, and insulin-like growth factor (IGF) system expression. Compared with HP pigs, postprandial plasma Leu concentration in RP pigs was 37% and 47% lower on days 6 and 21, respectively (P < 0.05); Leu supplementation in RPL pigs restored postprandial Leu to HP concentrations. Dietary protein restriction reduced LD myofiber cross-sectional area by 21%, satellite cell abundance by 35%, and BrdU+ myonuclear abundance by 25% (P < 0.05); Leu did not reverse these outcomes. Dietary protein restriction reduced LD muscle IGF2 expression by 60%, but not IGF1 or IGF1R expression (P < 0.05); Leu did not rescue IGF2 expression. Satellite cell abundance and myonuclear accretion in neonatal pigs are compromised when dietary protein intake is restricted and are not restored with Leu supplementation.


A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging.
To investigate the effect of age on global and regional brain volumes and rates of atrophy, and to compare directly results based on cross-sectional and longitudinal data. Thirty-nine healthy control subjects (age range, 31-84 years) underwent serial magnetic resonance imaging assessments. Measurements included the whole-brain, temporal lobe, hippocampal, and ventricular volumes at baseline and for repeat scans. We found significant decreases in cross-sectional whole-brain (P<.001), temporal lobe (P<.001), and hippocampal (P =.003) volumes and a significant increase in ventricular volume (P<.001) with increasing age. Cross-sectional and longitudinal estimates of atrophy rates were similar. We also found directional evidence of acceleration in atrophy rates with increasing age in all analyses, with the most marked changes occurring after 70 years of age. This increase in rates after 70 years of age was particularly marked in the ventricles (P<.001) and the hippocampi (P =.01). We found a significant age-associated decrease in global and regional brain volumes. Some evidence indicates that this decline in brain volumes may be due to a nonlinear acceleration in rates of atrophy with increasing age. A better understanding of this process may help to discriminate normal age-related changes from neurodegenerative diseases.


Attractant and repellent induce opposing changes in the four-helix bundle ligand-binding domain of a bacterial chemoreceptor.
Motile bacteria navigate toward favorable conditions and away from unfavorable environments using chemotaxis. Mechanisms of sensing attractants are well understood; however, molecular aspects of how bacteria sense repellents have not been established. Here, we identified malate as a repellent recognized by the MCP2201 chemoreceptor in a bacterium Comamonas testosteroni and showed that it binds to the same site as an attractant citrate. Binding determinants for a repellent and an attractant had only minor differences, and a single amino acid substitution in the binding site inverted the response to malate from a repellent to an attractant. We found that malate and citrate affect the oligomerization state of the ligand-binding domain in opposing way. We also observed opposing effects of repellent and attractant binding on the orientation of an alpha helix connecting the sensory domain to the transmembrane helix. We propose a model to illustrate how positive and negative signals might be generated.


An assessment of the performance and requirements for "adiabatic" engines.
A review of research on low heat rejection engines, on cooperative efforts in the United States and abroad to incorporate ceramics in intermittent combustion engines, and on the use of ceramics in these engines is presented. The reduction of heat loss from the combustion chamber of diesel engines improves fuel efficiency only 3 or 4 percent. Some other gains may be possible from a smaller cooling system, recovery of exhaust energy, and improvements in aerodynamics. It is judged that designs of low heat rejection engines will have the greatest initial impact on armored combat vehicles. Organization, coordination, planning, and cooperation on R&D for the use of ceramics in intermittent combustion engines appear to be greater abroad than in the United States.


Neuropsychological development in a child with early-treated congenital hypothyroidism as compared with her unaffected identical twin.
Neonatal screening for congenital hypothyroidism (CH) prevents the serious neuropsychological features of CH, but the question remains whether intelligence and motor skills of CH children treated early are completely normal. In this report we describe the rare case of two genetically identical twins, only one of whom was affected by CH due to thyroid agenesis. L-Thyroxine (9 microg/kg body weight/day) therapy was initiated at 27 days of age and was adequate throughout the follow-up. Neuropsychological evaluation was performed on the twins in parallel from 3 months to 8 years of age. The CH twin (NB) did not show major neuromotor impairments but, compared with the unaffected twin (EB), she had a slight delay in postural/motor achievements and in language development that completely disappeared at 8 years of age. On standardised tests of intelligence, NB was indistinguishable from control children but, compared with her twin, she had lower IQ scores in most testing occasions up to 7 years of age (NB = 108 vs EB = 115). School achievements of NB did not significantly differ from those of her classmates but, compared with her twin, she scored worse in writing, mechanical reading, verbal memory, and possibly in arithmetic. Because the twins were genetically and phenotypically identical, were raised in the same environment, and received a similar education, it is concluded that hypothyroidism in utero and in the first neonatal month was responsible for the lower neuropsychological achievements of the CH twin. While foetal hypothyroidism is at present unavoidable, earlier diagnosis and initiation of treatment in neonates with CH are important and highly recommended.


Cyclic 3-deaza-adenosine diphosphoribose: a potent and stable analog of cyclic ADP-ribose.
Cyclic 3-deaza-adenosine diphosphoribose (3-deaza-cADPR), an analog of cyclic adenosine diphosphoribose (cADPR) was synthesized. 3-deaza-cADPR differs from cADPR by only the substitution of carbon for nitrogen at the 3-position of the purine ring. Similar to cADPR, the analog has potent calcium releasing activity in sea urchin egg homogenates and was able to induce calcium release at concentrations as low as 0.3 nM. The EC(50) value for 3-deaza-cADPR-induced calcium release was 1 nM, which is about 70 times more potent than cADPR. The properties of calcium release induced by 3-deaza-cADPR in all other respects were similar to those of cADPR. Thus, 3-deaza-cADPR and cADPR were capable of cross-desensitizing each other and their calcium releasing activities were potentiated by Sr(2+) as well as caffeine. 8-amino-cADPR, a selective antagonist of cADPR, was also able to inhibit 3-deaza-cADPR induced calcium release. Taken together, these data suggest that 3-deaza-cADPR releases calcium through the same mechanism as cADPR. 3-deaza-cADPR was found to be resistant to both heat and enzymatic hydrolysis. Only 15% of 3-deaza-cADPR was destroyed after boiling this compound for 2 h. No loss of 3-deaza-cADPR was observed when treated with CD38 under conditions where cADPR was completely hydrolyzed. Thus, 3-deaza-cADPR is a potent and stable analog of cADPR. These properties should make 3-deaza-cADPR a useful probe in studies focused on the mechanism of cADPR action.


Magnetic resonance imaging of childhood Guillain-Barre syndrome.
To describe the spinal magnetic resonance imaging (MRI) features in children with Guillain-Barre syndrome (GBS) and to investigate the correlation with the clinical/laboratory findings. Clinical/laboratory findings of 40 children (mean age 5.7 years; range, 3 months-15 years) who had a final diagnosis of GBS were retrospectively reviewed. Clinical severity was graded according to Hughes classification. Electromyogram and cerebrospinal fluid analysis of the patients were recorded. All patients had a contrast-enhanced spinal MRI. The contrast enhancement pattern was determined, and the diameters of anterior and posterior spinal nerve roots were measured. The clinical/laboratory findings were correlated with the MRI findings. Twenty-eight patients had an electromyogram examination, and 25 of them revealed findings consistent with GBS. Cerebrospinal fluid analysis of 37 out of 40 patients showed albumino-cytologic dissociation. All but two patients had thickening and contrast enhancement of the nerve roots and cauda equina on spinal MRI. The most common MRI finding was enhancement of both the anterior and the posterior nerve roots of cauda equina which was prominent anteriorly. The mean anteroposterior diameter of the anterior nerve roots was 2.19 mm (range, 1.38-3.30 mm) and the posterior nerve root was 1.80 mm (range, 1.07-2.97 mm). Spinal MRI is a reliable imaging method for the diagnosis of GBS as it was positive in 38 of 40 patients. The severity on MRI does not correlate with severity of the clinical condition. MRI can be used as a supplementary diagnostic modality to clinical and laboratory findings of GBS.


Feasibility of 3D harmonic contrast imaging.
Improved endocardial border delineation with the application of contrast agents should allow for less complex and faster tracing algorithms for left ventricular volume analysis. We developed a fast rotating phased array transducer for 3D imaging of the heart with harmonic capabilities making it suitable for contrast imaging. In this study the feasibility of 3D harmonic contrast imaging is evaluated in vitro. A commercially available tissue mimicking flow phantom was used in combination with Sonovue. Backscatter power spectra from a tissue and contrast region of interest were calculated from recorded radio frequency data. The spectra and the extracted contrast to tissue ratio from these spectra were used to optimize the excitation frequency, the pulse length and the receive filter settings of the transducer. Frequencies ranging from 1.66 to 2.35 MHz and pulse lengths of 1.5, 2 and 2.5 cycles were explored. An increase of more than 15 dB in the contrast to tissue ratio was found around the second harmonic compared with the fundamental level at an optimal excitation frequency of 1.74 MHz and a pulse length of 2.5 cycles. Using the optimal settings for 3D harmonic contrast recordings volume measurements of a left ventricular shaped agar phantom were performed. Without contrast the extracted volume data resulted in a volume error of 1.5%, with contrast an accuracy of 3.8% was achieved. The results show the feasibility of accurate volume measurements from 3D harmonic contrast images. Further investigations will include the clinical evaluation of the presented technique for improved assessment of the heart.


Metabolite marker discovery for the detection of bladder cancer by comparative metabolomics.
Bladder cancer is one of the most common urinary tract carcinomas in the world. Urine metabolomics is a promising approach for bladder cancer detection and marker discovery since urine is in direct contact with bladder epithelia cells; metabolites released from bladder cancer cells may be enriched in urine samples. In this study, we applied ultra-performance liquid chromatography time-of-flight mass spectrometry to profile metabolite profiles of 87 samples from bladder cancer patients and 65 samples from hernia patients. An OPLS-DA classification revealed that bladder cancer samples can be discriminated from hernia samples based on the profiles. A marker discovery pipeline selected six putative markers from the metabolomic profiles. An LLE clustering demonstrated the discriminative power of the chosen marker candidates. Two of the six markers were identified as imidazoleacetic acid whose relation to bladder cancer has certain degree of supporting evidence. A machine learning model, decision trees, was built based on the metabolomic profiles and the six marker candidates. The decision tree obtained an accuracy of 76.60%, a sensitivity of 71.88%, and a specificity of 86.67% from an independent test.


How Significant Are Differences Obtained by Neglecting Correlations When Testing for Deformation: A Real Case Study Using Bootstrapping with Terrestrial Laser Scanner Observations Approximated by B-Spline Surfaces.
B-spline surfaces possess attractive properties such as a high degree of continuity or the local support of their basis functions. One of the major applications of B-spline surfaces in engineering geodesy is the least-square (LS) fitting of surfaces from, e.g., 3D point clouds obtained from terrestrial laser scanners (TLS). Such mathematical approximations allow one to test rigorously with a given significance level the deformation magnitude between point clouds taken at different epochs. Indeed, statistical tests cannot be applied when point clouds are processed in commonly used software such as CloudCompare, which restrict the analysis of deformation to simple deformation maps based on distance computation. For a trustworthy test decision and a resulting risk management, the stochastic model of the underlying observations needs, however, to be optimally specified. Since B-spline surface approximations necessitate Cartesian coordinates of the TLS observations, the diagonal variance covariance matrix (VCM) of the raw TLS measurements has to be transformed by means of the error propagation law. Unfortunately, this procedure induces mathematical correlations, which can strongly affect the chosen test statistics to analyse deformation, if neglected. This may lead potentially to rejecting wrongly the null hypothesis of no-deformation, with risky and expensive consequences. In this contribution, we propose to investigate the impact of mathematical correlations on test statistics, using real TLS observations from a bridge under load. As besides TLS, a highly precise laser tracker (LT) was used, the significance of the difference of the test statistics when the stochastic model is misspecified can be assessed. However, the underlying test distribution is hardly tractable so that only an adapted bootstrapping allows the computation of trustworthy p-values. Consecutively, the extent to which heteroscedasticity and mathematical correlations can be neglected or simplified without impacting the test decision is shown in a rigorous way, paving the way for a simplification based on the intensity model.


Socio-environmental factors in relation to leprosy at Jaipur.
In a house to house study of leprosy cases at Jaipur (148) a majority (91) had NL leprosy, 50 had LL leprosy and remaining 7 had indeterminate leprosy. More cases (84.5%) had a poor housing, overcrowding, low socioeconomic status. Out of 59 persons giving history of contact a majority had it at home and others at work places. The period of contact was more than five years in 74.6% cases. Most of the cases had lesions on exposed or easily accessible parts of the body.


Identifying contributing factors to fatal and serious injury motorcycle collisions involving children in Malaysia.
In Malaysia, motorcycle crashes constitute approximately 60 percent of all road trauma, and a substantial proportion involve children 16 years and younger. There are, however, many gaps in our knowledge on contributing factors to crashes and injury patterns amongst children killed and seriously injured in motorcycle crashes. The aim of this study was to examine fatal and serious injury motorcycle-related collisions to identify contributing factors and injury patterns amongst child motorcyclists. All identified motorcyclist fatal crashes between 2007 and 2011 (inclusive) were extracted from the national Police-reported crash database (M-ROADS) and a range of variables were selected for examination. A total of 17,677 crashes were extracted where a rider or pillion was killed and of these crashes 2,038 involved children, equating to 12 percent. Examination of crashes involving children revealed that some crashes involved more than two children on the motorcycle, therefore, overall children constituted 9.5% of fatal and 18.4% of serious injury collisions. A high proportion of child fatal or serious injury collisions involved the child as the rider (62%), and this was most common for children aged between 10 and 16 years. The majority of collisions occurred on rural roads, in speed limit zones of 50-70km/h, and approximately one-third occurred at an intersection. Collisions involving another motorcycle or a passenger vehicle contributed to 41% and 53% of the total fatalities and severe injuries, respectively. A high proportion (43.9%) of the children (25.5% riders and 18.8% pillion) sustained head injuries with 37.7% being in the 10-16 age group. Furthermore, 52.4% of the children sustaining head injuries did not wear a helmet. The implications of these findings for countermeasures within a Safe System framework, particularly interventions aimed at reducing the rate of unlicensed riding and helmet wearing, and infrastructure countermeasures are discussed.


A Re-evaluation of Online Pornography Use in Germany: A Combination of Web Tracking and Survey Data Analysis.
Several researchers have questioned the reliability of pornography research's findings. Following a recent call to use more reliable data sources, we conducted two analyses to investigate patterns and predictors of online pornography use (OPU). Our analyses were based on data from a large-scale German online web tracking panel (N = 3018) gathered from June 2018 to June 2019. The study we present here has two parts: In the first part, we looked at group differences (gender and age) in tracked OPU. Overall, this part's results confirm questionnaire-based research findings regarding sex and age differences. In the second part of our study, we combined the web tracking data with data from an online survey which was answered by a subset of the tracking participants (n = 1315) to assess the relevance of various predictors of OPU that have been identified in previous research. Again, our results mostly echoed previous findings based on self-reports. Online pornography was used more by males and younger individuals, while relationship status, sexist attitudes, and social dominance orientation were not associated with OPU. However, we did find differences in OPU between members of different religious communities. Our study confirms some critical findings on OPU from previous questionnaire-based research while extending existing research by providing a more fine-grained analysis of usage patterns based on web tracking data.


An international survey of pediatric apheresis practice.
Pediatric apheresis (PA) has distinct characteristics compared to adult apheresis, and requires specialized knowledge and experience to perform safely, particularly in low-weight patients. As evidence-based medicine advances the field of therapeutic apheresis, increased attention must be paid to pediatric patients with conditions for which apheresis is indicated. An electronic survey of >5,000 potential participants throughout the world was conducted to ascertain the scope and the current state of practice. The survey elicited 159 responses from 12 countries; 107 of the responses provided sufficient information for analysis. Participants performed an average of 176 PA procedures/year (range: 1-2,000). The types of PA procedures were therapeutic plasma exchange (92% of centers), red cell exchange (86%), leukocyte depletion (87%) and peripheral blood hematopoietic progenitor cell collection (72%). More than 65% of the centers had treated children older than 5 years with PA. Many centers had also performed PA on younger children; 40% have treated patients <12 months of age; 61% had treated patients 1-5 years old. 36% of centers reported that they would perform apheresis regardless of patient weight; 18% used a 5 kg threshold, 11% used 5-10 kg, and 17% used 10 kg as their weight threshold. This report is the largest single survey of centers performing PA. The results provide information about the scope and diversity of PA and identify areas where considerable variability in practice exists. Further exploration of these differences could establish best practices in PA through international research and collaboration.


Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: heterogeneity of function within the temporal lobe.
It is widely believed that declarative memory is mediated by a medial temporal lobe memory system consisting of several distinct structures, including the hippocampus and perirhinal cortex. The strong version of this view assumes a high degree of functional homogeneity and serial organization within the medial temporal lobe, such that double dissociations between individual structures should not be possible. In the present study, we tested for a functional double dissociation between the hippocampus and peri-postrhinal cortex in a single experiment. Rats with bilateral excitotoxic lesions of either the hippocampus or peri-postrhinal cortex were assessed in tests of spatial memory (radial maze) and object recognition memory. For the latter, the spontaneous object recognition task was conducted in a modified apparatus designed to minimize the potentially confounding influence of spatial and contextual factors. A clear functional double dissociation was observed: rats with hippocampal lesions were impaired relative to controls and those with peripostrhinal cortex lesions on the spatial memory task, whereas rats with peri-postrhinal lesions were impaired relative to the hippocampal and control groups in object recognition. These results provide strong evidence in favor of heterogeneity and independence of function within the temporal lobe.


Raloxifene-induced osteonecrosis of the jaw (MRONJ) with no exposure to bisphosphonates: clinical and radiographic findings.
Raloxifene is a selective estrogen receptor modulator (SERM) that is used to manage osteoporosis in women. Because of its tissue selectivity, raloxifene has fewer side effects than estrogen therapy; however, raloxifene-associated osteonecrosis of the jaw (ONJ) has recently been reported. While most of the reported cases were treated with antiresorptive therapy in addition to raloxifene, ONJ can also occur with the isolated use of raloxifene. This report presents a case where there was no prior exposure to bisphosphonates, in which the patient incidentally had florid cemento-osseous dysplasia (FCOD). Raloxifene-associated ONJ has never been reported before in a patient with FCOD. It is unclear whether the presence of FCOD increases the risk of ONJ. Case report: Clinical and radiographic findings regarding an African-American patient with FCOD and raloxifene-induced ONJ are described. The patient underwent a battery of investigations and surgical debridement of the area in question. She has remained disease free in the 2 years following the treatment. Conclusions: The aim of this report is to shed some light on a serious complication of raloxifene, a medication that is increasingly encountered in dental practices. Dental practitioners should use this knowledge to increase their awareness of possible ONJ development after the use of raloxifene. Brief recommendations and guidance in general dental practice for management of patients on raloxifene are also presented.


Characterisation of mobile genetic elements in Mycoplasma hominis with the description of ICEHo-II, a variant mycoplasma integrative and conjugative element.
Mobile genetic elements are found in genomes throughout the microbial world, mediating genome plasticity and important prokaryotic phenotypes. Even the cell wall-less mycoplasmas, which are known to harbour a minimal set of genes, seem to accumulate mobile genetic elements. In Mycoplasma hominis, a facultative pathogen of the human urogenital tract and an inherently very heterogeneous species, four different MGE-classes had been detected until now: insertion sequence ISMhom-1, prophage MHoV-1, a tetracycline resistance mediating transposon, and ICEHo, a species-specific variant of a mycoplasma integrative and conjugative element encoding a T4SS secretion system (termed MICE). To characterize the prevalence of these MGEs, genomes of 23 M. hominis isolates were assembled using whole genome sequencing and bioinformatically analysed for the presence of mobile genetic elements. In addition to the previously described MGEs, a new ICEHo variant was found, which we designate ICEHo-II. Of 15 ICEHo-II genes, five are common MICE genes; eight are unique to ICEHo-II; and two represent a duplication of a gene also present in ICEHo-I. In 150 M. hominis isolates and based on a screening PCR, prevalence of ICEHo-I was 40.7%; of ICEHo-II, 28.7%; and of both elements, 15.3%. Activity of ICEHo-I and -II was demonstrated by detection of circularized extrachromosomal forms of the elements through PCR and subsequent Sanger sequencing. Nanopore sequencing enabled the identification of mobile genetic elements and of ICEHo-II, a novel MICE element of M. hominis, whose phenotypic impact and potential impact on pathogenicity can now be elucidated.


Lithium Salt Diffusion in Diblock Copolymer Electrolyte Using Fourier Transform Infrared Spectroscopy.
The diffusion of a lithium salt through a diblock copolymer electrolyte was studied using vibrational spectroscopy. Lithium bis-trifluoromethylsulfonimide (LiTFSI) was dissolved in a lamellar-structured, high-molecular-weight polystyrene-poly(ethylene oxide) diblock copolymer at various concentrations (0-4.51 molLiTFSI/kgPEO). The diffusion coefficient of LiTFSI was determined from time-resolved Fourier Transform infrared spectroscopy attenuated total reflectance (FTIR-ATR) as a function of the salt concentration. By the application of the Beer-Lambert law, FTIR-ATR was used to detect concentration changes. Mutual diffusion was driven by putting in contact two polymer electrolyte membranes with different salt concentrations. Thus, mutual diffusion coefficients were obtained without the influence of electric fields or electrode interfaces. The accuracy of the simple experimental approach and straightforward analysis was validated by comparison to diffusion coefficients reported from measurements in electrochemical cells. Both methods yield mutual diffusion coefficients of lithium salt that are only weakly (and nonmonotonically) dependent on salt concentration. There is some indication in the spectra that there exist two populations of salt with different dissociation states. This could explain the observed nonmonotonic concentration dependence of the mutual diffusion coefficient of the salt. This hypothesis will be examined quantitatively with complementary measurements in future work.


Comparison of CT and positron emission tomography/CT coregistered images in planning radical radiotherapy in patients with non-small-cell lung cancer.
Imaging with F-18 fluorodeoxyglucose positron emission tomography (PET) significantly improves lung cancer staging, especially when PET and CT information are combined. We describe a method for obtaining CT and PET images at separate acquisitions, which allows coregistration and incorporation of PET information into the radiotherapy (RT) planning process for non-small-cell lung cancer. The influence of PET information on RT planning was analysed for 10 consecutive patients. Computed tomography and PET images were acquired with the patient in an immobilization device, in the treatment position. Using specially written software, PET and CT data were coregistered using fiducial markers and imported into our RT planning system (Cadplan version 6). Treatment plans were prepared with and without access to PET/CT coregistered images and then compared. PET influenced the treatment plan in all cases. In three cases, geographic misses (gross tumour outside planning target volume) would have occurred had PET not been used. In a further three cases, better planning target volume marginal coverage was achieved with PET. In four patients, three with atelectasis, there were significant reductions in V20 (percentage of the total lung volume receiving 20 Gy or more). Use of coregistered PET/CT images significantly altered treatment plans in a majority of cases. This method could be used in routine practice at centres without access to a combined PET/CT scanner .


Application of the major gene index and offspring-between-parents function to dermatoglyphic fingertip variables.
Forty-eight digital dermatoglyphic variables in 192 nuclear families were analyzed to search for evidence of major gene effects, utilizing a pair of recently developed statistics called the major gene index (MGI) and offspring-between-parents (OBP) function. They operate on the principle that under a multifactorial blending inheritance scheme an offspring's phenotypic value approximates the midparental value, whereas under major gene inheritance, the child's value more closely resembles that of one of his parents. Both statistics yielded comparable results. All ridge-count variables showed no strong deviation from a multifactorial model. Pattern-type variables gave values suggesting the presence of major gene effects, but these results were probably the consequence of the variables' relatively discrete distributions, since a departure of a variable from a reasonably continuous phenotypic distribution was shown to interfere significantly with the interpretation of both statistics.