Neurofibromatosis type 1 association with moyamoya disease.
The neurofibromatoses are genetic disorders of the nervous system that primarily affect the development and growth of neural (nerve) cell tissues. The neurofibromatoses are classified as neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). NF1 is the more common type of the neurofibromatoses. The gene responsible for NF1 is located on the chromosome region 17q11.2 and for familial moyamoya disease on chromosome 17q25. This article reports on a 20-year-old female with neurofibromatosis-1 who developed moyamoya syndrome. More extensive reports and further investigations of such families having this combination will certainly provide a better understanding of this link in the near future.


Variation between mouse major urinary protein genes isolated from a single inbred line.
We describe ten Charon 4A genomic DNA clones from BALB/c mice which include at least seven different major urinary protein (MUP) genes. We have established the orientation of all seven sequences, and have placed six of them in precise register by means of restriction site maps and Southern blot hybridization with cloned cDNA sequences. Four of the seven genomic sequences (family I sequences) form hybrids with six independent cDNA clones that have a high thermal stability and hybridize more strongly with mRNA from three inbred mouse lines. Hybrids between the remaining three genomic sequences and the cDNA clones have a lower thermal stability and hybridize less strongly with mRNA from the three inbred lines. Homologies between different cloned sequences extend over as much as 15 kb. No clone contains parts of two MUP genes, and no homology has been detected between the 3' flanking region of one MUP gene and the 5' flanking region of another.


Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target.
Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression. Cancer Res; 77(23); 6679-91. ©2017 AACR.


The AMF-R tubule is a smooth ilimaquinone-sensitive subdomain of the endoplasmic reticulum.
Autocrine motility factor receptor (AMF-R) is a marker for a distinct smooth membranous tubule. Ilimaquinone (IQ) is a sea sponge metabolite which induces the complete vesiculation of the Golgi apparatus and we show here that the addition of IQ to MDCK cells also results in the disruption of the AMF-R tubule. By immunofluorescence microscopy, the resultant punctate AMF-R label resembles the products of IQ-mediated vesiculation of the trans-Golgi network, however, the two labels can be distinguished by confocal microscopy. AMF-R tubule fragmentation occurs after nocodazole or taxol treatment of the cells demonstrating that the action of IQ on AMF-R tubules is not related to the ability of IQ to depolymerize microtubules. IQ activity is therefore not Golgi-specific. Electron microscopy of IQ-treated cells reveals that AMF-R is distributed to fenestrated networks of narrow interconnected tubules which are distinguishable from the uniform Golgi-derived vesicles and morphologically equivalent to smooth ER. Distinct fenestrations are visible in incompletely fragmented tubules which may represent intermediates in the fragmentation process. Smooth AMF-R labeled tubules exhibit continuity with rough ER cisternae and IQ selectively targets smooth and not rough ER. AMF-R tubules can be distinguished from the intermediate compartment labeled for ERGIC-53 by confocal microscopy and thus constitute a distinct IQ-sensitive subdomain of the smooth ER.


Keeping the archives at the University of Nottingham.
The role of the department of Manuscripts and Special Collections at the University of Nottingham is described, with reference to its early development, growth of collections across all disciplines, and current collection strengths. The professional activities of acquisition, cataloguing and providing access are set in the wider perspective of national standards and expectations of delivery. The recent establishment of the W.M.S. (Bill) and Claire Russell Archive is discussed in this context, with some account of the challenges and opportunities which the archive offers for both curators and researchers.


How to achieve trustworthy artificial intelligence for health.
Artificial intelligence holds great promise in terms of beneficial, accurate and effective preventive and curative interventions. At the same time, there is also awareness of potential risks and harm that may be caused by unregulated developments of artificial intelligence. Guiding principles are being developed around the world to foster trustworthy development and application of artificial intelligence systems. These guidelines can support developers and governing authorities when making decisions about the use of artificial intelligence. The High-Level Expert Group on Artificial Intelligence set up by the European Commission launched the report Ethical guidelines for trustworthy artificial intelligence in2019. The report aims to contribute to reflections and the discussion on the ethics of artificial intelligence technologies also beyond the countries of the European Union (EU). In this paper, we use the global health sector as a case and argue that the EU's guidance leaves too much room for local, contextualized discretion for it to foster trustworthy artificial intelligence globally. We point to the urgency of shared globalized efforts to safeguard against the potential harms of artificial intelligence technologies in health care.


Primary human herpesvirus 8 infection generates a broadly specific CD8(+) T-cell response to viral lytic cycle proteins.
Human herpesvirus 8 (HHV-8) is a recently discovered gammaherpesvirus that is the etiologic agent of Kaposi sarcoma (KS). The natural history of primary HHV-8 infection, including clinical outcome and host immune responses that may be important in preventing disease related to HHV-8, has not been elucidated. The present study characterized the clinical, immunologic, and virologic parameters of primary HHV-8 infection in 5 cases detected during a 15-year longitudinal study of 108 human immunodeficiency virus type 1 seronegative men in the Multicenter AIDS Cohort Study. Primary HHV-8 infection was associated with mild, nonspecific signs and symptoms of diarrhea, fatigue, localized rash, and lymphadenopathy. There were no alterations in numbers of CD4(+) or CD8(+) T cells or CD8(+) T-cell interferon gamma (IFN-gamma) production to mitogen or nominal antigen. CD8(+) cytotoxic T-lymphocyte precursor (CTLp) and IFN-gamma reactivity were detected during primary HHV-8 infection, with broad specificity to 5 lytic cycle proteins of HHV-8 encoded by open reading frame 8 (ORF 8; glycoprotein B homolog of Epstein-Barr virus), ORF 22 (gH homolog), ORF 25 (major capsid protein homolog), ORF 26 (a minor capsid protein homolog), or ORF 57 (an early protein homolog), in association with increases in serum antibody titers and appearance of HHV-8 DNA in blood mononuclear cells. CD8(+) T-cell responses to HHV-8 decreased by 2 to 3 years after primary infection. This antiviral T-cell response may control initial HHV-8 infection and prevent development of disease.


Exact time-dependent density functional theory for impurity models.
We employ the density matrix renormalization group to construct the exact time-dependent exchange-correlation potential for an impurity model with an applied transport voltage. Even for short-ranged interaction we find an infinitely long-ranged exchange-correlation potential which is built up instantly after switching on the voltage. Our result demonstrates the fundamental difficulties of transport calculations based on time-dependent density functional theory. While formally the approach works, important information can be missing in the ground-state functionals and may be hidden in the usually unknown non-equilibrium functionals.


Role of STAT3 in inflammatory bowel disease.
Signal transducers and activators of transcription 3 (STAT3) play an important role in various autoimmune disorders including inflammatory bowel disease (IBD). Recent studies have revealed that STAT3 activation plays distinctly different roles between innate immune responses and acquired immune responses in colitis. STAT3-mediated activation of acquired immune responses plays a pathogenic role in colitis by enhancing the survival of pathogenic T cells. In contrast, STAT3-mediated activation of innate responses contributes to the suppression of colitis. This review will summarize the current understanding of the roles of STAT3 in IBD and the potential of targeting STAT3 for the treatment of IBD, emphasizing recent observations.


Abnormal differentiation of human papillomavirus-induced laryngeal papillomas.
We studied the proliferation and differentiation of human laryngeal papillomas, which are benign tumors induced by human papillomaviruses. Immunofluorescent stains of tissues for a number of differentiation-specific proteins showed abnormal differentiation. Papilloma tissue fragments in vitro showed a slightly decreased fraction of proliferating cells that incorporated tritiated thymidine and a markedly reduced incorporation of tritiated uridine when compared with normal tissue. We propose that papillomavirus infection results in normal basal cell proliferation but abnormal terminal differentiation and that this abnormality significantly contributes to the hyperplasia of the papillomas.


Transsexualism in two male triplets.
The authors present clinical and case material on two male triplets with aberrant gender identity. Their findings coincide with those of the few family studies reported in which there were two or more transsexual members; they also reveal patterns generally in keeping with the psychological determinants of transsexualism suggested by Stoller.


An androgen-independent mechanism maintains photorefractoriness in male tree sparrows (Spizella arborea).
A series of experiments was performed to clarify whether photorefractoriness in male tree sparrows is maintained by an androgen-dependent mechanism. Castration did not raise plasma LH in photorefractory males held under a daily photoperiod of 20 h light:4 h darkness (20L:4D). Castrated photorefractory males were implanted with the antiandrogen cyproterone or injected s.c. with the antiandrogen flutamide to determine whether androgens which may be resistant to castration inhibit LH secretion. Neither cyproterone nor flutamide raised plasma LH above values found in castrated control birds. Castrated photorefractory males were treated with testosterone to determine whether plasma LH in photorefractory males is androgen-suppressible. Concentrations of plasma LH were independent of plasma testosterone over a wide range of concentrations. The lack of LH response to castration, to castration coupled with antiandrogen therapy, and to castration coupled with testosterone replacement argues that photorefractoriness in male tree sparrows is maintained by an androgen-independent mechanism.


Consensus evidence-based guidelines for management of hyperglycaemia in patients undergoing coronary artery bypass grafting in patients with diabetes in India.
Diabetes is associated with a significant risk of cardiovascular diseases (CVDs). Patients with diabetes are known to suffer from a disproportionately large burden of CVDs, in terms of higher risk, worse prognosis and more adverse outcomes. Acute coronary syndromes, including coronary artery disease, represent a large proportion of this burden and conventionally coronary artery bypass grafting (CABG) has been the mainstay of facilitating reperfusion in patients with diabetes. However, hyperglycaemia is an important factor which affects the outcomes of CABG and shows a grave impact on patients' well-being. Thus, it is important to appropriately manage hyperglycaemia in the peri-and intra-operative periods to assure the best possible outcomes in patients with diabetes. There is scant evidence to show that oral antidiabetic drugs (OADs) or non-insulin based therapies show considerable benefit in patients undergoing CABG. Even with the use of insulin-based therapies, appropriate glycaemic targets, accurately designed algorithm to achieve such targets and specific recommendations to facilitate the appropriate use of such algorithm are important considerations. However, current international guidelines are either country-specific or fail to address context-specific needs in individual countries. In view of the growing incidence of cardiovascular diseases and diabetes in India, as a result of changing lifestyles, it is imperative upon clinicians to formulate India-specific guidelines for effective management of (CVDs). It is the endeavour of the current guideline to present recommendations based on a firm evidentiary foundation coupled with context-specific inputs from experts' consensus opinion. These recommendations represent an effort to address the urgent need for such an exercise both in the academic as well as the clinical realm.


The prevalence of young carers - a standardised survey amongst school students (KiFam-study).
Children and adolescents who provide care, assistance or support for a chronically ill family member are called young carers. While there is a growing body of research about their specific situation, needs and impact of caring, only very few studies provide information on prevalence rates. The aim was to provide prevalence data for young carers in Germany, and to describe and quantify the nature and extent of their help. A cross-sectional study. Data collection took place between 2016 and 2017 in 44 secondary schools (fifth to 13th grade) in North Rhine-Westphalia, Germany. A total of 6313 students aged from 10 to 22 years participated in this study. They represent 0.5% of the basic population. Based on the results of a preliminary qualitative study, a standardised electronic questionnaire was developed, which comprised four subject areas: socio-demographic information, general daily aids, health-related quality of life and chronic illness within the family. Statistical analyses included chi-square tests for nominal data and univariate analyses of variance for metrical data together with 95% confidence intervals. 19.6% (n = 1238) of all respondents state that someone in their family needs help due to a chronic illness. Nevertheless, not all of them are involved in caring activities. The prevalence of those defined as young carers in this study is 6.1% (n = 383), 64% are girls. They take on a wide range of activities. In addition to domestic work, they help their ill relatives with mobility, dressing and undressing, medication, feeding, personal hygiene and with intimate care. The data provide a good insight into the situation of young carers. The prevalence rate is higher than expected. It refers to the social relevance of this topic and the need for further investigations.


Oral zinc therapy in the treatment of alpha-mannosidosis.
Human alpha-mannosidosis is a lysosomal storage disorder characterized by mental retardation, dysostosis multiplex, and hepatosplenomegaly. Deficiency of the enzyme leads to accumulation of mannose-rich glycoconjugates in tissues. Zinc sulphate has been shown to stimulate alpha-mannosidase activity in vitro. Oral zinc therapy was attempted on a 4-year-old boy with alpha-mannosidosis for 3 years. After almost 10 years of follow-up on and off zinc therapy, we must conclude that oral zinc does not substantially affect the clinical course of alpha-mannosidosis.


Incidence of Active Tuberculosis and Cohort Retention Among Adolescents in Western Kenya.
Siaya County, with the highest tuberculosis notification rates in Kenya. To determine the incidence of active tuberculosis and 1-year cohort retention in 12-18-year-old adolescents, in preparation for phase III tuberculosis vaccine trials. Adolescents were enrolled and followed up for 1-2 years to determine tuberculosis incidence. Adolescents with a positive tuberculin skin test, history of cohabitation with a tuberculosis case or at least 1 tuberculosis symptom received clinical and sputum examination and a chest radiograph. Definite tuberculosis cases were bacteriologically confirmed and clinical cases diagnosed by a clinician based on a suggestive chest radiograph and having clinical symptoms. Risk factors were explored using Poisson regression. Among 4934 adolescents without tuberculosis at baseline, 26 tuberculosis cases were identified during follow-up with a corresponding incidence density of 4.4 [95% confidence interval (CI): 3.0-6.4] events per 1000 person-years of observation, 12 definite tuberculosis cases; incidence density of 2.0 (95% CI: 0.9-3.1). Having previous tuberculosis (rate ratio: 12.5; CI: 1.8-100) and presence of tuberculin skin test conversion (rate ratio: 3.4; CI: 1.5-7.7) were significantly associated with higher risk of tuberculosis. Overall (4086/4925), 83.0% of adolescents were retained in the study after 1 year of follow-up. Being female, older, out of school and being orphaned were significant risk factors for loss to follow-up. The tuberculosis incidence in adolescents will help inform future tuberculosis vaccine trial sample size calculations for this setting. The predictive factors for tuberculosis and retention can be further explored in future trials.


Evaluation of phenotypic and genotypic methods for subtyping Campylobacter jejuni isolates from humans, poultry, and cattle.
Six methods for subtyping of Campylobacter jejuni were compared and evaluated with a collection of 90 isolates from poultry, cattle, and sporadic human clinical cases as well as from a waterborne outbreak. The applied methods were Penner heat-stable serotyping; automated ribotyping (RiboPrinting); random amplified polymorphic DNA typing (RAPD); pulsed-field gel electrophoresis (PFGE); restriction fragment length polymorphisms of the flagellin gene, flaA (fla-RFLP); and denaturing gradient gel electrophoresis of flaA (fla-DGGE). The methods were evaluated and compared on the basis of their abilities to identify isolates from one outbreak and discriminate between unrelated isolates and the agreement between methods in identifying clonal lines. All methods identified the outbreak strain. For a collection of 80 supposedly unrelated isolates, RAPD and PFGE were the most discriminatory methods, followed by fla-RFLP and RiboPrinting. fla-DGGE and serotyping were the least discriminative. All isolates included in this study were found to be typeable by each of the methods. Thirteen groups of potentially related isolates could be identified using a criterion that at least four of the methods agreed on clustering of isolates. None of the subtypes could be related to only one source; rather, these groups represented isolates from different sources. Furthermore, in two cases isolates from cattle and human patients were found to be identical according to all six methods.


[Homocysteine--CRP--lipoprotein (a). When do you evaluate the "new" risk factors].
Homocysteine, inflammatory markers (e.g. CRP), hemostatic factors (fibrinogen, PAI-1, factor VII and factor VIII) and lipoprotein (a) are independent risk factors for atherosclerotic disease. Although the association between these factors and atherosclerosis is clear, it is uncertain whether this signals a causal relationship, or whether the parameters simply represent markers of atherosclerosis. Currently, there are no reports on interventional studies demonstrating a benefit from correcting these risk factors. The determination of homocysteine, fibrinogen and lipoprotein should therefore be restricted to certain situations, such as atherosclerosis or a family history of the disease without classical risk factors, or uncertainty about the need for primary pharmacological prevention. An increase in these parameters should prompt the early use of lipid-lowering drugs or aspirin. In exceptional cases only (homocysteine), correction of the risk factors should be considered.


Drosophila integrin-linked kinase is required at sites of integrin adhesion to link the cytoskeleton to the plasma membrane.
Integrin-linked kinase (ILK) was identified by its interaction with the cytoplasmic tail of human beta1 integrin and previous data suggest that ILK is a component of diverse signaling pathways, including integrin, Wnt, and protein kinase B. Here we show that the absence of ILK function in Drosophila causes defects similar to loss of integrin adhesion, but not similar to loss of these signaling pathways. ILK mutations cause embryonic lethality and defects in muscle attachment, and clones of cells lacking ILK in the adult wing fail to adhere, forming wing blisters. Consistent with this, an ILK-green fluorescent protein fusion protein colocalizes with the position-specific integrins at sites of integrin function: muscle attachment sites and the basal junctions of the wing epithelium. Surprisingly, mutations in the kinase domain shown to inactivate the kinase activity of human ILK do not show any phenotype in Drosophila, suggesting a kinase-independent function for ILK. The muscle detachment in ILK mutants is associated with detachment of the actin filaments from the muscle ends, unlike integrin mutants, in which the primary defect is detachment of the plasma membrane from the extracellular matrix. Our data suggest that ILK is a component of the structure linking the cytoskeleton and the plasma membrane at sites of integrin-mediated adhesion.


Characterization of the transcriptional repressive element of the human cytomegalovirus immediate-early US3 gene.
Transcriptional repression is utilized by human cytomegalovirus to regulate expression of the immediate-early US3 gene. Sequences located 3' of the US3 TATA box are required for down regulation of expression. Mutagenesis of US3 sequences identified a 10-nucleotide region that is essential for transcriptional repression. In addition to the 10-nucleotide element, an additional region, which includes the US3 initiator element, was needed to confer repression on a heterologous promoter. Thus, a 19-nucleotide element (-18 to +1 relative to the transcription start site) functioned as a transcriptional repressive element (tre). The tre repressed transcription in a position-dependent but orientation-independent manner. In vivo footprinting experiments demonstrated that transcriptional repression is associated with a decrease in protein interactions with the US3 promoter and surrounding sequences. The data presented here suggest that the association of an as yet unidentified repressor protein with the tre represses transcription by inhibiting assembly of the transcription initiation complex on the US3 promoter.


A comparative proteomic analysis of skin secretions of the tammar wallaby (Macropus eugenii) and the wombat (Vombatus ursinus).
The secretome of the pouch skin of the model marsupial the tammar wallaby, Macropus eugenii has been investigated using techniques of two-dimensional gel electrophoresis, in-gel trypsin digestion followed by nanoliquid chromatography coupled tandem mass spectrometry (LC-MS/MS). Differences in the patterns of secreted proteins were observed in the female pouch at three stages of maturity - reproductively immature; reproductively mature and active and mature, postreproductively active. Skin from the underarm area of mature females had a markedly different secreted protein profile. The greatest diversity of proteins was seen in the mature reproductive pouch and from an opportunistic sample collected from the pouch another mature female marsupial, the common wombat, Vombatus ursinus. A total of 20 proteins were confidently identified from the pouch skin secretions of the tammar wallaby and wombats, whilst 20 proteins were tentatively identified. In all skin secretomes, globins were the most abundant proteins whilst the antimicrobial, dermcidin was detected in the wombat sample. Some proteins such as keratin and actin could be sourced to sloughed and degraded skin cells. A number of proteins were present at such low concentrations that confident identification was not possible. This was compounded by the lack of a comprehensive database of marsupial proteins which constrains the reliability of automated identification protocols.


Association between measures of spinal mobility and low back pain. An analysis of new attenders in primary care.
Comparison of spinal movements in new attenders to primary care with an episode of low back pain with a sample with no recalled history of ever having had low back pain. To examine the association between restriction of spinal movement and the presence of low back pain in primary care. The presence of restriction in spinal mobility has frequently been investigated by specialists in the clinical setting. What is not known, however, is whether an association exists between pain and restriction in those newly presenting to primary care and whether these measurements can be used to discriminate between those with and without back pain. The study participants consisted of 344 consulters to two general practices, prospectively ascertained in the South Manchester Back Pain Study, who were compared with 118 individuals from the same practices who denied ever having back pain. The two groups were compared for right and left lateral flexion, standing extension, modified Schober's test, finger-to-floor distance, and right and left knee extension. There was a statistically significant reduction in all planes in those with low back pain. Modified Schober's, standing extension, and left knee extension were the most discriminatory, with likelihood ratios of approximately 5 for the optimal cutoff. Restriction of three or more of these seven movements was observed in 50% of the low back pain cases and in less than 5% of the pain-free participants. Stratification by presence or absence of radiation of pain to the legs did not alter these findings. Measures of spinal mobility are restricted to varying extents in a community-based sample of subjects with low back pain. Maximal discrimination was observed when restriction was present in three or more planes. The utility of these measures in predicting outcome remains to be assessed.


Samarium-146 in the early solar system: evidence from neodymium in the allende meteorite.
A carbon-chromite fraction from the Allende C3V chondrite shows strikingly large isotopic enrichments of neodymium-142 (0.47 percent) and neodymium- 143 (36 percent). Both apparently formed by alpha decay of samarium-146 and samarium-147 (half-lives 1.03 x 10(8) and 1.06 x 10(11) years), but the isotopic enrichment was greatly magnified by recoil of residual nuclei into a carbon film surrounding the samarium-bearing grains. These data provide an improved estimate of the original abundance of extinct samarium-146 in the early solar system [(146)Sm/(144)Sm = (4.5 +/- 0.5) x 10(-3)], higher than predicted by some models of pprocess nucleosynthesis. It may be possible to use this isotopic pair as a chronometer of the early solar system.


Evolving mechanism of organotemplate-free hierarchical FAU zeolites with house-of-card-like structures.
Hierarchical FAU zeolites with house-of-card-like (HCL) structures were synthesized through a one-pot organotemplate-free route in the Na2O-Al2O3-SiO2-H2O system. The structure details and formation mechanism of HCL zeolites were determined by the combination of electron crystallography and synthesis chemistry. The results revealed that the unique HCL morphology was attributed to large solution viscosity, and the evolution process obeyed a skeleton crystal growth model due to the limited vortexing effect, which was different from those of the HCL zeolites obtained using organic templates.


[Dialysis-associated amyloid osteopathy--the radiological aspects].
Amongst the complications of dialysis, amyloid osteopathy is getting increasingly significant. It is due to deposition of beta 2-microglobulin. To determine the incidence and time of development of this complication, the skeletal radiographs of 185 patients undergoing dialysis, some for up to ten years, were analysed retrospectively. In about 10% of patients, the presence of beta 2-microglobulin osteopathy may be expected. The radiological features, sites of predilection and differential diagnosis of amyloid osteopathy and of other skeletal changes due to dialysis are discussed.


TIPS Is Not Associated with a Higher Risk of Developing HCC in Cirrhotic Patients: A Systematic Review and Meta-analysis.
Background and Aims: The association between portal-systemic shunt and hepatocellular carcinoma (HCC) development in patients who have cirrhosis is still controversial. This systematic review with meta-analysis was performed to systematically clarify the potential role of portal-systemic shunt in the development of HCC. Methods: The PubMed, Embase, and Cochrane Library databases were searched for potentially eligible literature. Meta-analysis with random-effects model was performed to combine the incidence rates of HCC after portal-systemic shunt. Finally, seven studies were included. In the present review, we mainly focused on 859 patients (365 in the transjugular intrahepatic portal-systemic shunt (TIPS) group and 494 in the non-TIPS group) from five studies to analyze incidence rates after TIPS. Results: At the end of follow-up, there were 66 (18%, 66/365) patients who developed HCC after TIPS intervention and 63 (13%, 63/494) patients who developed HCC after non-TIPS treatments. Pooled estimates with random-effects model did not demonstrate a significant increase of incidence of HCC after TIPS (risk ratio: 1.37 [confidence interval (CI): 0.96 to 1.97]; p = 0.08) compared with non-TIPS treatments. Subgroup analyses for those patients with transplanted liver also did not detect a significant difference between the TIPS group and non-TIPS group (risk ratio: 1.10 [CI: 0.59 to 2.07]; p = 0.75). Conclusions: Current evidence suggests that portal-systemic shunt is not associated with a higher risk of HCC development in cirrhotic patients.


Efficacy of Urtoxazumab (TMA-15 Humanized Monoclonal Antibody Specific for Shiga Toxin 2) Against Post-Diarrheal Neurological Sequelae Caused by Escherichia coli O157:H7 Infection in the Neonatal Gnotobiotic Piglet Model.
Enterohemorrhagic Escherichia coli (EHEC) is the most common cause of hemorrhagic colitis and hemolytic uremic syndrome in human patients, with brain damage and dysfunction the main cause of acute death. We evaluated the efficacy of urtoxazumab (TMA-15, Teijin Pharma Limited), a humanized monoclonal antibody against Shiga toxin (Stx) 2 for the prevention of brain damage, dysfunction, and death in a piglet EHEC infection model. Forty-five neonatal gnotobiotic piglets were inoculated orally with 3 × 10⁸ colony-forming units of EHEC O157:H7 strain EDL933 (Stx1⁺, Stx2⁺) when 22-24 h old. At 24 h post-inoculation, piglets were intraperitoneally administered placebo or TMA-15 (0.3, 1.0 or 3.0 mg/kg body weight). Compared to placebo (n = 10), TMA-15 (n = 35) yielded a significantly greater probability of survival, length of survival, and weight gain (p <0.05). The efficacy of TMA-15 against brain lesions and death was 62.9% (p = 0.0004) and 71.4% (p = 0.0004), respectively. These results suggest that TMA-15 may potentially prevent or reduce vascular necrosis and infarction of the brain attributable to Stx2 in human patients acutely infected with EHEC. However, we do not infer that TMA-15 treatment will completely protect human patients infected with EHEC O157:H7 strains that produce both Stx1 and Stx2.


High-temperature piezoelectric crystals ReCa4O(BO3)3: a review.
High-temperature sensors are desirable for structural health monitoring and/or nondestructive evaluation of next-generation turbines, more efficient jet engines, and the furnace components of electrical power plants. Of all the investigated high-temperature piezoelectric materials, rare-earth calcium oxyborate crystals ReCa4O(BO3)3 (ReCOB, Re: rare-earth) exhibit attractive advantages for high-temperature piezoelectric sensing. In this paper, the electroelastic properties of different ReCOB piezoelectric crystals are investigated. The crosstalk between various vibration modes are discussed, from which the optimized crystal cuts are achieved. Furthermore, temperature dependences of the electrical resistivity, dielectric, elastic, piezoelectric, and electromechanical properties of ReCOB crystals are studied. Finally, the thermal properties, including thermal expansion, specific heat, and thermal conductivity at elevated temperatures are studied and compared with commercially available high-temperature piezoelectric crystals.


Principles of rehabilitation and reactivation: pulmonary hypertension.
Most recently, a specialized and carefully monitored exercise training and rehabilitation program has been recommended as add-on to medical treatment in patients with pulmonary arterial hypertension (class I, level of evidence A). Three prospective randomized, controlled trials, 10 prospective uncontrolled trials, 2 retrospective studies and 2 case series in more than 470 patients with severe pulmonary hypertension (PH) and right heart failure reported beneficial effects of a specialized exercise training and rehabilitation program, i.e. significant improvement in symptoms, exercise capacity, cardiorespiratory function and quality of life, compared with untrained controls. All training studies reported an acceptable safety profile, and some uncontrolled studies showed excellent 1- and 2-year survival rates. However, most studies had a quite small sample size (ranging from 2 to 183 patients) and an uncontrolled design, and they were not designed to assess hemodynamic changes, time to clinical worsening and survival. Nevertheless, there is large evidence that exercise training programs should be performed by centers experienced in both PH patient care and rehabilitation. The best method and duration of the training, characteristics of supervision, and the mechanisms resulting in symptom improvement and increased functional capacity are unclear. In this review, we summarize data of molecular and clinical effects of exercise training in PH patients. Furthermore, we discuss safety data and the role of a self-care management of exercise training in these patients.


Amnesia is a deficit in relational memory.
Eye movements were monitored to assess memory for scenes indirectly (implicitly). Two eye movement-based memory phenomena were observed: (a) the repetition effect, a decrease in sampling of previously viewed scenes compared with new scenes, reflecting memory for those scenes, and (b) the relational manipulation effect, an increase in viewing of the regions where manipulations of relations among scene elements had occurred. In normal control subjects, the relational manipulation effect was expressed only in the absence of explicit awareness of the scene manipulations. Thus, memory representations of scenes contain information about relations among elements of the scenes, at least some of which is not accessible to verbal report. But amnesic patients with severe memory impairment failed to show the relational manipulation effect. Their failure to show any demonstrable memory for relations among the constituent elements of scenes suggests that amnesia involves a fundamental deficit in relational (declarative) memory processing.


Physical, mechanical and degradation properties, and schwann cell affinity of cross-linked chitosan films.
Three kinds of cross-linked chitosan films were prepared with hexamethylene diisocyanate (HDI), epichlorohydrin (ECH) and glutaraldehyde (GA) as cross-linking agents, respectively. The physical and mechanical properties, biodegradability and Schwann cell affinity of the cross-linked films were investigated. A significant decrease in the degradation rate in lysozyme solution and a large change in the mechanical properties were observed compared with non-cross-linked chitosan films. The protein adsorption on chitosan films was determined by means of enzyme-linked immunosorbent assay (ELISA). In comparison with the non-cross-linked films, the chitosan films cross-linked with HDI showed a significant increase (up to 40-50%) in both fibronectin and laminin adsorption, while the protein adsorption on the other two kinds of cross-linked films was similar to that on non-crosslinked films. In addition, cell culture revealed that the HDI cross-linked chitosan films enhanced the spread and proliferation of Schwann cells while the other cross-linked films delayed the cell proliferation. These results suggest that HDI cross-linking of chitosan films provides a combination of physical properties, biodegradability and Schwann cell affinity suitable for peripheral nerve regeneration.


Chemical Additives Enable Native Mass Spectrometry Measurement of Membrane Protein Oligomeric State within Intact Nanodiscs.
Membrane proteins play critical biochemical roles but remain challenging to study. Recently, native or nondenaturing mass spectrometry (MS) has made great strides in characterizing membrane protein interactions. However, conventional native MS relies on detergent micelles, which may disrupt natural interactions. Lipoprotein nanodiscs provide a platform to present membrane proteins for native MS within a lipid bilayer environment, but previous native MS of membrane proteins in nanodiscs has been limited by the intermediate stability of nanodiscs. It is difficult to eject membrane proteins from nanodiscs for native MS but also difficult to retain intact nanodisc complexes with membrane proteins inside. Here, we employed chemical reagents that modulate the charge acquired during electrospray ionization (ESI). By modulating ESI conditions, we could either eject the membrane protein complex with few bound lipids or capture the intact membrane protein nanodisc complex-allowing measurement of the membrane protein oligomeric state within an intact lipid bilayer environment. The dramatic differences in the stability of nanodiscs under different ESI conditions opens new applications for native MS of nanodiscs.


Management of subluxation injury in a thumb-sucking child: a case report.
This case report presents use of a custom trauma splint that was fabricated to prevent excessive thumb-sucking trauma to a previously-subluxated permanent incisor. A 10-year-old boy was referred to the clinic 10 days after falling in the schoolyard that resulted in a trauma to his maxillary left central incisor. The extent of clinical mobility stipulated fabrication of a custom trauma splint that would prevent further trauma to the incisor caused by excessive pressure of the thumb. A light-cured resin composite splint, covering the incisal edges of the central incisors and labial surfaces of the lateral incisors was made, and approximately 1-mm composite within the impressions of central incisors were trimmed off. The splint was bonded to the neighboring lateral incisors with flowable resin composite and root canal therapy was initiated on the subluxated incisor. After one week, the patient stopped his sucking habit completely. The treatment not only allowed for complete healing of the subluxated incisor without being exposed to further trauma, but also for spontaneous eruption of the tooth and closure of the existing open-bite.


Implementation of a Community-Partnered Research Suicide-Risk Management Protocol: Case Study From Community Partners in Care.
Suicidality is common among participants in clinical trials and health services research, but approaches to suicide risk assessment and mitigation vary widely. Studies involving vulnerable populations with limited access to care raise additional ethical concerns. The authors applied a community-partnered approach to develop and implement a suicide-risk management protocol (SRMP) in a depression study in an underresourced setting in Los Angeles. Using a community-partnered participatory research framework, the authors designed and adapted the SRMP. Qualitative data regarding SRMP implementation included notes from SRMP development meetings and from study clinicians conducting outreach calls to study participants. Analyses included baseline and 6- and 12-month telephone survey data from 1,018 enrolled adults with moderate to severe depressive symptoms (8-item Patient Health Questionnaire score ≥10), of whom 48% were Black and 40% Latino. Community stakeholders prioritized a robust SRMP to ensure participant safety. Features included rapid telephone outreach by study clinicians in all cases of reported recent suicidality and expedited treatment access. Using a suicidality timeframe prompt of "in the past 2 weeks," endorsement of suicidality was common (15% at baseline, 32% cumulative). Midway through the study, the SRMP was modified to assess for present suicidality, which reduced the frequency of clinician involvement. Overall, 318 outreach calls were placed, with none requiring an emergency response. Treatment referrals were provided in 157 calls, and outreach was well received. SRMP implementation in research involving underresourced and vulnerable communities merits additional considerations. Partnering with community stakeholders can facilitate the development of acceptable and feasible SRMP procedures.


Functional role of M-type (KCNQ) K⁺ channels in adrenergic control of cardiomyocyte contraction rate by sympathetic neurons.
M-type (KCNQ) K⁺ channels are known to regulate excitability and firing properties of sympathetic neurons (SNs), but their role in regulating neurotransmitter release is unclear, requiring further study. We sought to use a physiological preparation in which SNs innervate primary cardiomyocytes to evaluate the direct role of M-channels in the release of noradrenaline (NA) from SNs. Co-cultures of rat SNs and mouse cardiomyocytes were prepared, and the contraction rate (CR) of the cardiomyocyte syncytium monitored by video microscopy. We excited the SNs with nicotine, acting on nicotinic acetylcholine receptors, and monitored the increase in CR in the presence or absence of the specific M-channel opener retigabine, or agonists of bradykinin B2 or purinergic P2Y receptors on the SNs. The maximal adrenergic effect on the CR was determined by application of isoproterenol (isoprenaline). To isolate the actions of B2 or P2Y receptor stimulation to the neurons, we prepared cardiomyocytes from B2 receptor or P2Y2 receptor knock-out mice, respectively. We found that co-application of retigabine strongly decreased the nicotine-induced increase in CR. Conversely, co-application of bradykinin or the P2Y-receptor agonist UTP augmented the nicotine-induced increase in CR to about half of the level produced by isoproterenol. All effects on the CR were wholly blocked by propranolol. Our data support the role of M-type K⁺ channels in the control of NA release by SNs at functional adrenergic synapses on cardiomyocytes.We conclude that physiological receptor agonists control the heart rate via the regulation of M-current in SNs.


Fatty acid regulation of fatty acid-binding protein expression in the small intestine.
The effects of dietary oil intake and fatty acid infusions on the expression of intestinal and liver fatty acid-binding proteins (I-FABP and L-FABP, respectively) were investigated in the small intestine of mice. A daily force-feeding for 7 days with 0.2 ml sunflower oil specifically increased L-FABP mRNA and protein levels in duodenum and proximal jejunum. This upregulation was mediated in time- and dose-dependent manners by a minute quantity of linoleic acid, the main fatty acid found in sunflower oil. The L-FABP induction was only found with long-chain fatty acids, with the nonmetabolizable, substituted fatty acid alpha-bromopalmitate being far more active. A hormonally mediated effect is unlikely because long-chain fatty acids induced L-FABP mRNA in the Caco-2 cell line cultured in serum-free medium. Therefore, long-chain fatty acids are strong inducers of L-FABP gene expression in the small intestine. In contrast to data found in the rat, I-FABP gene expression appears to be unaffected by a lipid-enriched diet in the mouse.


Risk factors leading to Cryptosporidium infection in men who have sex with men.
Cryptosporidiosis is a devastating illness in people with HIV/AIDS yet there have been no analytical epidemiological studies measuring risk factors leading to cryptosporidiosis in men who have sex with men (MSM). The objective of this study was to measure the risk factors for exposure to Cryptosporidium among MSM. The study was a case-control design. It recruited MSM who had laboratory confirmed Cryptosporidium infection between 1997 and 2000. Participants answered a questionnaire about potential risk factors leading to exposure to Cryptosporidium. 10 cases and 24 controls were recruited. Men having more than one sexual partner in the past month were more likely to have had Cryptosporidium diarrhoea p=0.034 (OR 6.67, CI (1.15 to 38.60). Insertive anal sex (p=0.059) and attending a sex venue one or more times (p=0.059) also increased the odds of having cryptosporidiosis. The study results suggest that sexual behaviour is a significant risk factor for cryptosporidial diarrhoea in MSM. The results will be used to inform risk groups about behaviours that may put them at increased risk of cryptosporidial diarrhoea.


Osteoinduction by biomaterials--physicochemical and structural influences.
Osteoinduction by biomaterials has been shown to be a real phenomenon by many investigators in the last decade. The exact mechanism of this phenomenon is, however, still largely unknown. This in vivo study in goats was performed to get insight into processes governing the phenomenon of osteoinduction by biomaterials and had four main goals: (i) to further investigate the influence of physicochemical properties and structure on biomaterial osteoinductive potential, (ii) to investigate the influence of implant size on the amount of induced bone, (iii) to investigate implantation site dependence, and (iv) to investigate changes occurring on the surface of the material after implantation. Intramuscular implantations of four different biphasic calcium phosphate ceramics, consisting of hydroxyapatite and beta-tricalcium phosphate and a carbonated apatite ceramic, indicated that, for a maximal osteoinductive potential, there is an optimal specific surface area for each material type. It was further shown that a decrease of the implant size with a half significantly decreased the relative amount of induced bone. In addition, subcutaneous implantation did not give rise to ectopic bone formation in any of the animals, while bone was induced in most animals intramuscularly. Analysis of the surfaces of the materials after subcutaneous implantation inside diffusion chambers indicated that the increased specific surface area leads to more surface reactivity, which is hypothesized to be essential for osteoinductivity by biomaterials.


Alveolar distraction osteogenesis for dental implant treatments of the vertical bone atrophy: A systematic review.
To determine if alveolar vertical distraction osteogenesis obtains better results compared to other bone regeneration treatments (guided bone regeneration with membranes and / or filling material, or autogenous bone graft) in terms of bone gain, complications, and implant survival and success rates. An electronic search was performed in Pubmed (MEDLINE), Cochrane Library and Scopus databases in March 2017. Besides, a manual search was carried out. Inclusion criteria were randomized controlled trials published within the last 10 years with at least 1 year of follow-up after implant placement. No language restriction was applied. Exclusion criteria were studies in patients with bone defects produced by trauma, congenital malformation or oncologic surgical treatment. The methodological quality of the selected studies was evaluated by means of the Cochrane Collaboration's Tool for assessing risk of bias. The reports were classified into different levels of recommendation according to the "Strength of Recommendation Taxonomy ". Out of 221 articles, two randomized controlled trials were finally selected for the inclusion in the systematic review. Bone gain and complications were higher with the alveolar vertical distraction osteogenesis compared to the autologous bone graft. There was higher bone resorption with the autologous bone graft. Implant survival and success rates were similar between studies, despite of the used technique. Both alveolar distraction osteogenesis and autogenous bone graft are effective bone regeneration techniques for the treatment of mandibular vertical bone atrophy. A level B recommendation can be established for the use of alveolar vertical distraction osteogenesis for the treatment of the mandibular vertical bone atrophy.


Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26.
To examine the defect in side-chain oxidation during the formation of bile acids in cerebrotendinous xanthomatosis, we measured in vitro hepatic microsomal hydroxylations at C-12 and C-25 and mitochondrial hydroxylation at C-26 and related them to the pool size and synthesis rates of cholic acid and chenodeoxycholic acid as determined by the isotope dilution technique. Hepatic microsomes and mitochondria were prepared from seven subjects with cerebrotendinous xanthomatosis and five controls. Primary bile acid synthesis was markedly reduced in cerebrotendinous xanthomatosis as follows: cholic acid, 133 +/- 30 vs. 260 +/- 60 mg/d in controls; and chenodeoxycholic acid, 22 +/- 10 vs. 150 +/- 30 mg/d in controls. As postulated for chenodeoxycholic acid synthesis, mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha-diol was present in all specimens and was 30-fold more active than the corresponding microsomal 25-hydroxylation. However, mean mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha-diol was less active in cerebrotendinous xanthomatosis than in controls: 59 +/- 17 compared with 126 +/- 21 pmol/mg protein per min. As for cholic acid synthesis, microsomal 25-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was substantially higher in cerebrotendinous xanthomatosis and control preparations (620 +/- 103 and 515 +/- 64 pmol/mg protein per min, respectively) than the corresponding control mitochondrial 26-hydroxylation of the same substrate (165 +/- 25 pmol/mg protein per min). Moreover in cerebrotendinous xanthomatosis, mitochondrial 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol-26-hydroxylase activity was one-seventh as great as in controls. Hepatic microsomal 12 alpha-hydroxylation, which may be rate-controlling for the cholic acid pathway, was three times more active in cerebrotendinous xanthomatosis than in controls: 1,600 vs. 500 pmol/mg protein per min. These results demonstrate severely depressed primary bile acid synthesis in cerebrotendinous xanthomatosis with a reduction in chenodeoxycholic acid formation and pool size disproportionately greater than that for cholic acid. The deficiency of chenodeoxycholic acid can be accounted for by hyperactive microsomal 12 alpha-hydroxylation that diverts precursors into the cholic acid pathway combined with decreased side-chain oxidation (mitochondrial 26-hydroxylation). However, side-chain oxidation in cholic acid biosynthesis may be initiated via microsomal 25-hydroxylation of 5beta-cholestane-3alpha,7alpha,12alpha-triol was substantially lower in control and cerebrotendinous xanthomatosis liver. Thus, separate mechanisms may exist for the cleavage of the cholesterol side chain in cholic acid and chenodeoxycholic acid biosynthesis.


Emerging trends in free-living amebic infections of the brain: implications for organ transplantation.
This epidemiological review analyzed cases of Naegleria fowleri primary amebic meningoencephalitis (PAM) and Balamuthia mandrillaris granulomatous amebic encephalitis (GAE) for behavioral and demographic risk factors for pathogen exposures and potential transmission by organ transplantation. The Centers for Disease Control and Prevention (CDC) Naegleria Workgroup Registry provided 121 cases of laboratory-confirmed PAM over the period, 1937-2007. The CDC and the California Encephalitis Project provided 28 cases of GAE over the period, 1994-2010. There was a statistically significant increase in clusters of PAM cases between the periods, 1937-1996 and 1997-2007. Risk factors for PAM included male gender, freshwater exposures, summer exposures, and exposures in southern-tier US (United States) states. Risk factors for GAE included male gender, exposures in southern-tier US states, Hispanic ethnicity in California, occupational or recreational contacts with soil, and recent organ transplantation. Fatal free-living amebic infections of the brain are increasing today due to more frequent environmental, recreational, and occupational exposures; organ transplantation; and unanticipated clusters of PAM due to N. fowleri inoculations following nasal sinus irrigation using neti pots filled with municipal tap water. Potential organ donors dying from meningoencephalitis of unexplained causes should be screened for free-living amebic infections of the brain capable of hematogenous dissemination in organ recipients.


ADME-guided design and synthesis of aryloxanyl pyrazolone derivatives to block mutant superoxide dismutase 1 (SOD1) cytotoxicity and protein aggregation: potential application for the treatment of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. The arylsulfanyl pyrazolone (ASP) scaffold was one of the active scaffolds identified in a cell-based high throughput screening assay targeting mutant Cu/Zn superoxide dismutase 1 (SOD1) induced toxicity and aggregation as a marker for ALS. The initial ASP hit compounds were potent and had favorable ADME properties but had poor microsomal and plasma stability. Here, we identify the microsomal metabolite and describe synthesized analogues of these ASP compounds to address the rapid metabolism. Both in vitro potency and pharmacological properties of the ASP scaffold have been dramatically improved via chemical modification to the corresponding sulfone and ether derivatives. One of the ether analogues (13), with superior potency and in vitro pharmacokinetic properties, was tested in vivo for its pharmacokinetic profile, brain penetration, and efficacy in an ALS mouse model. The analogue showed sustained blood and brain levels in vivo and significant activity in the mouse model of ALS, thus validating the new aryloxanyl pyrazolone scaffold as an important novel therapeutic lead for the treatment of this neurodegenerative disorder.


An unusual overrepresentation of genetic factors related to iron homeostasis in the genome of the fluorescent Pseudomonas sp. ABC1.
Members of the genus Pseudomonas inhabit diverse environments, such as soil, water, plants and humans. The variability of habitats is reflected in the diversity of the structure and composition of their genomes. This cosmopolitan bacterial genus includes species of biotechnological, medical and environmental importance. In this study, we report on the most relevant genomic characteristics of Pseudomonas sp. strain ABC1, a siderophore-producing fluorescent strain recently isolated from soil. Phylogenomic analyses revealed that this strain corresponds to a novel species forming a sister clade of the recently proposed Pseudomonas kirkiae. The genomic information reveals an overrepresented repertoire of mechanisms to hoard iron when compared to related strains, including a high representation of fecI-fecR family genes related to iron regulation and acquisition. The genome of the Pseudomonas sp. ABC1 contains the genes for non-ribosomal peptide synthetases (NRPSs) of a novel putative Azotobacter-related pyoverdine-type siderophore, a yersiniabactin-type siderophore and an antimicrobial betalactone; the last two are found only in a limited number of Pseudomonas genomes. Strain ABC1 can produce siderophores in a low-cost medium, and the supernatants from cultures of this strain promote plant growth, highlighting their biotechnological potential as a sustainable industrial microorganism.


Animal models of pulmonary emphysema.
Chronic obstructive pulmonary disease is a major cause of morbidity and mortality worldwide. The mechanisms by which cigarette smoke leads to the irreversible dilatation and destruction of terminal airspaces of the lung are being unravelled largely as a result of the explosion of studies in animals. At the forefront of this has been the use of genetically manipulated mice, and the evolution and understanding of different models of emphysema. This review will summarise the current models of emphysema.


Widespread recurrence 7 years after radical abdominal trachelectomy for early cervical adenocarcinoma.
Cervical cancer is the third most common female cancer worldwide and the use of routine screening resulted in earlier stage and younger age at diagnosis. Fertility preservation via radical trachelectomy comes up as an option in such patients. Recent literature reviews confirm the safety of this operation with excellent oncologic outcomes in appropriately chosen patients. However, recurrent disease is likely and a strict follow-up is recommended to detect recurrences at an early stage following radical trachelectomy. In this report, a case who underwent radical trachelectomy and developed widespread recurrences 7 years after initial surgery possibly due to the lack of oncologic follow-up is discussed.


Analysis of CD40 expression in breast cancer and its relation to clinicopathological characteristics.
Breast cancer is currently the most common cancer in women worldwide. For this reason, new biomarkers for better predicting response to treatment are needed. CD40, described as expressed in haematological and epithelial tumors, is linked to apoptosis and offers promise as a new predictive/ prognostic marker. We evaluated CD40 expression in formalin-fixed, paraffin-embedded samples from 181 breast carcinomas using immunohistochemical staining with CD40 antibody. Samples were divided according to hormone (oestrogen receptor /ER/, progesterone receptor /PR/) and her-2/neu status into groups: 1.Luminal A (ER+PR+her-2/neu-), 2. Luminal B (ER+PR+her-2/neu+), 3.Triple-negative (ER-PR-her-2/neu-) and 4. Her-2/neu (ER-PR-her-2/neu+). The results of CD40 staining were correlated with clinicopathological data. CD40 was found to be expressed in membrane, cytoplasm and nucleus. Normal ducts expressed cytoplasmic CD40 in 30% of cases, in breast tumor ducts in 53% of cases. CD40 was evaluated as an independent marker and significant positive correlation was found with Bcl-2 (p =0.002), early stage (p =0.016) and preoperative chemotherapy (p =0.043). There was higher overall survival for patients with cytoplasmic CD40 expression (0.05). Differences in expression of cytoplasmic CD40 between groups with different hormonal and her-2/neu status were statistically highly significant (p=0.00003). In groups with different hormonal status, a positive statistical correlation was found for the luminal A group with relapse (p=0.024) and stage (p=0.006). No correlation was found with age, disease onset, family history of cancer/ breast cancer, patient history, hormonal replacement therapy, menopausal status at onset of disease, adjuvant chemotherapeutic treatment or disease free survival. Nuclear expression of CD40 was found to be unrelated to any clinicopathological data. However, there was higher ratio of positive cases in cancer cases (83%) than in normal tissue (30%). In conclusion, cytoplasmic expression of CD40 is related to factors connected to better prognosis and suggest that CD40 may have potential as a new prognostic factor in breast cancer.


Geomicrobiology: how molecular-scale interactions underpin biogeochemical systems.
Microorganisms populate every habitable environment on Earth and, through their metabolic activity, affect the chemistry and physical properties of their surroundings. They have done this for billions of years. Over the past decade, genetic, biochemical, and genomic approaches have allowed us to document the diversity of microbial life in geologic systems without cultivation, as well as to begin to elucidate their function. With expansion of culture-independent analyses of microbial communities, it will be possible to quantify gene activity at the species level. Genome-enabled biogeochemical modeling may provide an opportunity to determine how communities function, and how they shape and are shaped by their environments.


Structural alterations of pathologically or physiologically modified DNA.
We have studied the alterations of DNA conformation in in vitro depurinated or methylated topological isomers of the plasmid pAT 153. Depurination by heat/acid treatment or alkylation by methyl methanesulfonate (pathological modifications) result in DNA unwinding detected as a reduction in the degree of supercoiling of DNA topoisomers as measured by the alteration of electrophoretic mobility on agarose gel. On the contrary, in vitro enzymic methylation at the C-5 position of cytosine (physiological modification) does not measurably alter the tertiary structure of the circular substrates. From the average number of modified sites needed to remove one superhelical twist from each single topoisomer of a population of partially relaxed DNA molecules, we have calculated an unwinding angle smaller than -3.4 degree per methylated purine and of approximately -12.0 degree per apurinic site. These results, together with previously reported values of unwinding by pyrimidine dimers, suggest a possible mechanism of recognition of damaged sites by repair mechanisms that are not single-damage specific.


Macular thickness measurements in normal eyes using spectral domain optical coherence tomography.
Knowledge of the macular thickness in a normal population is important for the evaluation of pathological macular change. The purpose of this study was to define and measure macular thickness in normal eyes using spectral domain optical coherence tomography (OCT). Fifty eyes from 50 normal subjects (29 men and 21 women, aged 22 to 68 years) were scanned with a prototype Cirrus HD-OCT system (5 microm axial resolution) (Carl Zeiss Meditec, Inc.). The proprietary Cirrus segmentation algorithm was used to produce retinal thickness maps, which were then averaged over 9 regions defined by a circular target centered at the true fovea location. The macular thickness of 13 subjects scanned with both HD-OCT and StratusOCT were compared. After centering the fovea, the mean and standard deviation values for retinal thickness measurements were calculated point wise and averaged on standard regions. For patients scanned with both systems, the thickness measurements from HD-OCT were approximately 50 microm larger than those from StratusOCT. The difference between the two measurements decreased somewhat with eccentricity. Using HD-OCT, it is possible to acquire retinal data sets containing an unprecedented number of data points. Furthermore, it is possible to use OCT fundus images to evaluate the scan quality and to center the measurement at the fovea. These advantages, together with good automated segmentation, can produce more accurate retinal thickness measurements. Incorporation of the photoreceptor layer in the measurements is anatomically meaningful and may be significant in evaluating various retinal pathologies and visual acuity outcomes.


A role for galectin-3 in the development of early molecular alterations in short-term aortic stenosis.
Aortic stenosis (AS) is characterized by pressure overload and causes left ventricular (LV) fibrosis and inflammation, two mechanisms that eventually lead to cardiac dysfunction. Galectin-3 (Gal-3), a β-galactoside-binding lectin, promotes cardiac remodelling. In the present study, we investigated the role of Gal-3 in LV remodelling in patients with AS and the effects of Gal-3 blockade in rats subjected to short-term (6-week) supravalvular aortic banding (AS group). Myocardial biopsies were obtained from 25 patients with severe AS referred for aortic valve replacement and from necropsies of 11 cardiovascular disease-free control individuals. Gal-3 was up-regulated in myocardial biopsies from AS patients compared with controls. Gal-3 directly correlated with parameters assessing myocardial fibrosis and inflammation in AS patients. Normotensive AS animals presented decreased LV diastolic diameter compared with controls. At the histological level, AS rats exhibited a slight increase in LV cross-sectional area and LV wall thickness, and augmented cardiomyocyte width and cross-sectional area. AS animals presented enhanced cardiac Gal-3 expression, which paralleled higher myocardial fibrosis and inflammation. Cardiac Gal-3 was associated with fibrosis and inflammatory markers. Gal-3 pharmacological inhibition prevented the increase in cardiac Gal-3 and normalized histological and molecular alterations in AS rats. In short-term AS, the increase in myocardial Gal-3 expression was associated with cardiac fibrosis and inflammation, alterations that were prevented by Gal-3 blockade. These data suggest that Gal-3 inhibition could be a novel therapeutic approach in the prevention of AS-associated early pathological cardiac remodelling.


Comparison of parent and child reports of emotional trauma symptoms in pediatric outpatient settings.
Exposure to emotionally traumatic events is common among children who are treated in pediatric medical care settings, and it is important to recognize the emotional reactions that children might develop as a response to the trauma. Practitioners sometimes rely on parental reports of the child's emotional reactions, but these reports may be biased by the parent's own posttraumatic symptoms. Understanding the differences between parent and child reports of the child's emotional symptoms is essential to guide proper diagnosis and care. This study evaluated discrepancies in parental versus child reports of the child's emotional trauma symptoms in pediatric medical care settings. We enrolled children and adolescents (age: 8-19) who had not previously received a diagnosis of a psychiatric disorder and were treated in pediatric specialty care clinics at Mount Sinai Medical Center in New York. We used the UCLA posttraumatic stress reaction index, child, adolescent, and parent versions, to evaluate child and parent reports of symptoms of posttraumatic stress disorder (PTSD) in the child. The Impact of Event Scale was used to evaluate the parents' own posttraumatic symptoms. We conducted a "best estimate" psychiatric diagnostic procedure to determine whether the child met diagnostic criteria for PTSD and evaluated the association between the diagnostic status (as determined by the "best estimate" procedure) and the results of the questionnaires. A total of 115 patients and parents consented to the study, and 76 completed the evaluation. Sixty-four percent of the parents identified the child's traumatic experience as their own most traumatic experience, too. The child's self-report of PTSD symptoms was significantly correlated with the diagnosis of PTSD in the child. In contrast, parents' reports of their child's PTSD symptoms were not significantly associated with the child's diagnosis. Parents' own posttraumatic symptoms were associated with parental reports of the child's overall PTSD symptoms (correlation coefficient: 0.283). When a child is emotionally traumatized, the parent's own posttraumatic stress may influence his or her report and interpretation of the child's symptoms. Clinicians who evaluate children and adolescents for PTSD in medical care settings should directly seek the child's report and should not rely exclusively on parental reports. Parental reports of a child's PTSD symptoms can offer insights into the parent's own level of posttraumatic stress.


The work activity as an interface among different logics: The case of distributing food in a university restaurant.
Work activity integrates the tasks to be performed, the means of work available, the instructions, the rules to be observed, the particular factors related to the individuals (skills, inner state), and the effects both on the task and on the operator. By analyzing the activity, the different logics and conflicts in the design of production systems are revealed. To show how the work activity can support the transformation of the working conditions, when revealed by an ergonomic intervention, by integrating the different design standpoints, which are always present in the project's work situations. For this case study, the Ergonomic Work Analysis (EWA) was used on the staff that serves meals at a new university restaurant in Rio de Janeiro (Brazil) with a focus on the portioning of the transported ready-cooked meals and the variability related thereto. The results of observations, verbalizations, self-confrontations and strategy analysis, collected through field notes and audio and photographic records, became a final report submitted to the directors of the university restaurant. This research showed that the work activity of the serving maids helped to reveal the different logics of the heterogeneous actors in the design of the work situation under analysis. The work activity, when revealed by an ergonomic intervention, can be an interface during the design process to articulate these different logics and to support the dialog among different design standpoints. Thus, the concept of fixed portioning became a concept of flexible portioning, which provided the serving maids with an increased autonomy level at the counter, thus improving both the quality of services and the working conditions of those involved therewith. The activity-focused design can be understood as an ongoing, multiple logical process whereby workers bring the design into their workplaces, which reveals aspects of their own activity, thus helping to change the initial concepts. The ergonomic intervention, based on the revealed activity, helps to highlight the existence of different logics and also to support the actors in articulating their own logics during the design process.


Zinc changes after renal allotransplantation.
In 72 patients the plasma zinc concentration and the urinary zinc excretion were studied immediately after renal allotransplantation and during a 7 1/2-year follow-up period. The plasma zinc concentration was below that of healthy control subjects during the first three weeks after transplantation (mean 39 microgram/dl) and returned to the control level within the subsequent four weeks. The urinary zinc excretion and correspondingly the urinary zinc/creatinine ratio (> 1.0 microgram/mg) were increased during the first week after transplantation. During the remainder of the observation period, both plasma and urinary zinc were within the control range. The observed changes parallel those reported after major operations. We could not detect any influence exerted by acute or chronic rejection, serious infection, or corticosteroid therapy.


Confocal microscopy and optical coherence tomography imaging of hereditary granular dystrophy.
This case report examines the clinical characteristics of hereditary granular dystrophy through the use of slit lamp digital photography, confocal microscopy (CM) and optical coherence tomography (OCT). A review of the literature describing the histopathological and genetic associations of stromal dystrophies, suggest it may be possible to differentiate dystrophies based on their clinical manifestations, and appearances of CM and OCT images, with or without the use of genetic testing. Two sisters, previously diagnosed with Granular (Groenouw I) Dystrophy, were examined. Examination included the use of digital slit lamp photography, CM and OCT imaging. "Breadcrumb" opacities were visualized in the anterior two-thirds of the stroma with all three imaging techniques. Opacities were demonstrated in the posterior third of the stroma with the digital photography and OCT techniques. The digital photography, CM and OCT images support the sister's diagnosis of Granular (Groenouw I) Dystrophy. Currently, genetic and histopathological testing are the only techniques available to determine exactly which corneal dystrophy and gene mutation are present. The results of this case report demonstrate that slit lamp digital photography, combined with CM and OCT may be capable of providing sufficient diagnostic information to diagnose corneal granular dystrophies in a clinical setting.


Maintaining adequate anticoagulation on extracorporeal membrane oxygenation therapy: Hemochron Junior Low Range versus Hemochron 400.
Extracorporeal membrane oxygenation (ECMO) therapy requires that patients be anticoagulated to prevent clotting and thrombotic complications. There are several bedside whole blood microcoagulation systems available to determine activated clotting time (ACT) levels. Many ECMO centers use Hemochron (International Technidyne, Edison, NJ) products to determine ACT levels. During the study period, we used the Hemochron 400 and then changed to the Hemochron Junior Low Range. There were two specific aims of this study. First, to determine if there was a difference in ACT levels measured by these two distinct Hemochron products both marketed for the use in ECMO therapy. Second, to determine if the differing ACT levels produced by these two devices affected clinical outcomes. We compared ACT levels between two devices on 70 paired blood specimens obtained from four neonatal ECMO patients receiving heparin. A retrospective review of 77 ECMO patients was performed to analyze frequency of circuit emergencies and length of ECMO circuit life while using the two products. In lower ACT ranges, the Hemochron Jr. LR consistently yielded higher ACT values than the Hemochron 400. In higher ACT ranges, the Hemochron Jr. LR consistently yielded lower ACT values than the Hemochron 400. Without calibration, after changing devices, this discrepancy led to shorter circuit life and more circuit clotting complications. After calibration and adjustment in target ACT values, there was a trend toward longer circuit life, and there were fewer clotting complications. There is a difference in the ACT values produced by Hemochron 400 and Hemochron Jr. LR. Failure to calibrate target ACT levels after changing machines may lead to shorter circuit life and more clotting complications.


Comparative analysis of crystallins and lipids from the lens of Antarctic toothfish and cow.
Animal model systems of senile cataract and lens crystallin stability are essential to understand the complex nature of lens transparency. Our aim in this study was to assess the long-lived Antarctic toothfish Dissostichus mawsoni (Norman) as a model system to understand long-term lens clarity in terms of solubility changes that occur to crystallins. We compared the toothfish with the mammalian model cow lens, dissecting each species' lens into a cortex and nuclear region. In addition to crystallin distribution, we also assayed fatty acid (FA) composition by negative ion electrospray ionization mass spectrometry (ESI-MS). The majority of toothfish lens crystallins from cortex (90.4%) were soluble, whereas only a third (31.8%) from the nucleus was soluble. Crystallin solubility analysis by SDS-PAGE and immunoblots revealed that relative proportions of crystallins in both soluble and urea-soluble fractions were similar within each species examined and in agreement with previous reports for bovine lens. From our data, we found that both toothfish and cow crystallins follow patterns of insolubility that mirror each animals lens composition with more γ crystallin aggregation seen in the toothfish lens nucleus than in cow. Toothfish lens lipids had a large amount of polyunsaturated fatty acids that were absent in cow resulting in an unsaturation index (I(U)) four-fold higher than that of cow. We identified a novel FA with a molecular mass of 267 mass units in the lens epithelial layer of the toothfish that accounted for well over 50% of the FA abundance. The unidentified lipid in the toothfish lens epithelia corresponds to either an odd-chain (17 carbons) FA or a furanoid. We conclude that long-lived fishes are likely good animal models of lens crystallin solubility and may model post-translational modifications and solubility changes better than short-lived animal models.


Cost-effectiveness of acupuncture treatment in patients with chronic neck pain.
Acupuncture is increasingly used in patients with chronic pain, but there is a lack of evidence on the cost-benefit relationship of this treatment strategy. The objective of this study was to assess costs and cost-effectiveness of additional acupuncture treatment in patients with chronic neck pain compared to patients receiving routine care alone. A randomized controlled trial including patients (18 years of age) with chronic neck pain (>6 months) was carried out. We assessed the resource use and health related quality of life (SF-36) at baseline and after 3 months using complete social health insurance funds and standardized questionnaires, respectively. The main outcome parameters were direct and indirect cost differences during the 3 months study period and the incremental cost-effectiveness ratio (ICER) of acupuncture treatment. A total of 3,451 patients (1,753 acupuncture-group, 1,698 control-group) were randomized (31% men, age 53.5+/-12.9 years; 69% women, 49.2+/-12.7 years). Acupuncture treatment was associated with significantly higher costs over the 3 months study duration compared to routine care (925.53+/-1,551.06 euros vs. 648.06+/-1,459.13 euros; mean difference: 277.47 euros [95% CI: 175.71 euros-379.23 euros]). This cost increase was mainly due to costs of acupuncture (361.76+/-90.16 euros). The ICER was 12,469 euros per QALY gained and proved robust in additional sensitivity analyses. Since health insurance databases were used, private medical expenses such as over the counter medication were not included. Beyond the 3 months study duration, acupuncture might be associated with further health economic effects. According to international cost-effectiveness threshold values, acupuncture is a cost-effective treatment strategy in patients with chronic neck pain.


Real-time computation of diffraction fields for pixelated spatial light modulators.
Fast calculation of diffraction field from a three-dimensional object is an important problem in holographic three-dimensional television. As a result of this, several fast algorithms can be found in the literature, but most them omit pixelated structure of the display device used in the reconstruction process. We propose a fast algorithm for diffraction field calculation from a three-dimensional object for a pixelated display device. Real-time calculations can also be achieved when the proposed algorithm is run on a graphical processing unit. Performance assessment of the algorithm is obtained by the computation time of the diffraction field and the error on the reconstructed object. The proposed algorithm employs a precomputed look-up-table which is formed by one-dimensional kernels. Each kernel in the look-up-table denotes a diffraction field on the display device from a point light source at a specific depth along longitudinal axis. Allocated memory space by the precomputed look-up-table is optimized according to the sampling policy of the depth parameter. Look-up-table formed by uniformly sampled depth parameter provides the same error on the reconstructed object with less number of kernels. Also, optical experiments are conducted and successful results are obtained.


Survivin and escaping in therapy-induced cellular senescence.
Therapy-induced accelerated cellular senescence (ACS) is a reversible tumor response to chemotherapy that is likely detrimental to the overall therapeutic efficacy of cancer treatment. To further understand the mechanism by which cancer cells can escape the sustained cell cycle arrest in ACS, we established a tissue culture model, in which the p53-null NCI-H1299 cells can be induced into senescence by an abbreviated exposure to a chemotherapeutic agent. Previously, we have reported that senescent cells overexpress Cdc2/Cdk1 when they bypassed the prolonged arrest and their viability is dependent on Cdc2/Cdk1 kinase activity. In our study, we show that human survivin is the immediate downstream effector of the Cdc2/Cdk1 mediated survival signal. Survivin cooperates with Cdc2/Cdk1 to inhibit apoptosis following chemotherapy and promote senescence escape. Using HIV-1 TAT peptides to disrupt survivin phosphorylation by Cdc2/Cdk1, we also found that phosphorylated survivin is necessary both for the escape of senescent cells and for maintenance of subsequent viability after bypassing senescence. These results further propose survivin as an important determinant of senescence reversibility and as a putative molecular target to enforce cell death in ACS.


Alloreactive T cells that do not require TCR and CD8 coengagement are present in naive mice and contribute to graft rejection.
Class I alloreactive CTL populations have been defined as either CD8 dependent or CD8 independent, based upon their ability to kill target cells in the presence of Ab to CD8. The CD8-dependent population uses CD8 in a coreceptor role with the TCR, and mutations in the class I molecule that destroy the CD8 binding site abrogate CTL killing, even if the target cell expresses other allelic forms of class I molecules with an intact binding site for CD8. The CD8-independent population apparently does not require CD8, as Ab to CD8 has no effect on the ability of these cells to kill appropriate target cells. We have isolated a third population of CTL that is inhibited by the addition of CD8 Ab yet can kill target cells that express the alloantigenic molecule incapable of binding CD8, provided that the target cells also express non antigenic class I molecules that contain an intact binding site for CD8. We refer to these cells as CD8 bystander-dependent CTL. Many (10 of 12) of these CTL were able to kill H-2Kb-expressing transfectants of T2 cells, consistent with the idea that they recognize a peptide-independent determinant that may be expressed at a high density on the cell surface. These CD8 bystander-dependent CTL are only readily detectable in vitro when spleen cells from mice primed in vivo with a skin graft are used.


Impact of Test Instructions on 6-min Walk Distance in Adults With Chronic Respiratory Disease: A RANDOMIZED CONTROLLED TRIAL.
The 6-min walk test (6MWT) is commonly used to assess functional exercise capacity in people with chronic respiratory disease in both clinical and research settings. However, two tests are required to achieve accurate results, due to a well-documented learning effect for the 6-min walk distance (6MWD). Whether it is possible to reduce or eliminate the learning effect by optimizing 6MWT instructions is not known. People with chronic respiratory disease referred to pulmonary rehabilitation undertook two 6MWT with random allocation to modified instructions (fast-walk as fast as possible; n = 46) or usual instructions (far-walk as far as possible; n = 49). The primary outcome was the learning effect, defined as the difference in the 6MWD between test one and test two. Subgroup analyses investigated whether effects varied in those who were naïve to the 6MWT or according to diagnosis (chronic obstructive pulmonary disease, interstitial lung disease, and bronchiectasis). A learning effect was present in both groups, with a mean improvement in the 6MWD on the second test of 14 m in the fast (modified) group (95% CI, 6-22) and 11 m in the far (usual) group (95% CI, 4-19). There was no statistically or clinically significant difference between groups in the magnitude of the learning effect (between-group difference -3 m, 95% CI, -14 to 8). There was no significant effect of naivety to the 6MWT or diagnosis. The current recommended procedures for the 6MWT, including standardized instructions and performance of two tests on each occasion, should be retained.


Sex differences in acute delta-9-tetrahydrocannabinol (Δ9-THC) response and tolerance as a function of mouse strain.
Cannabinoids are increasingly used to alleviate pain; however, tolerance to their antinociceptive effects, including those of delta-9-tetrahydrocannabinol (Δ9-THC), may limit their therapeutic utility. With more women than men using medical cannabis for pain relief, it is crucial to understand how sex influences cannabinoid-mediated antinociception and tolerance. Though studies in rats consistently find females are more sensitive to the acute antinociceptive effects of cannabinoids, our work with mice consistently finds the converse. The present study examined whether our observed sex differences in Δ9-THC-induced antinociception and tolerance are consistent across multiple mouse strains or are strain-dependent. Male and female C57BL/6J (B6), DBA/2, AKR, and CBA/J mice were assessed for differences in acute Δ9-THC-induced antinociception and hypothermia prior to and following seven days of once-daily Δ9-THC administration. Consistent with our previous findings, male B6 mice were more sensitive to the acute antinociceptive effects of Δ9-THC than female littermates, an effect which dissipated with age. B6 males had decreased cannabinoid expression in the PAG compared to females. While DBA and CBA female mice showed increased Δ9-THC-antinociception compared to male littermates at 30 and 10 mg/kg Δ9-THC, respectively, these differences were less pronounced at higher doses, revealing that dose of Δ9-THC may also be important. Overall, CBA mice were more sensitive to Δ9-THC-induced antinociception while AKR mice were less responsive. These studies highlight the therapeutic potential of Δ9-THC in pain management and underscore the importance of considering not only Δ9-THC dose as a function of sex, but potentially genetic differences when evaluating their clinical utility.


Quantitative analysis of chromatin compaction in living cells using FLIM-FRET.
We present a quantitative Förster resonance energy transfer (FRET)-based assay using multiphoton fluorescence lifetime imaging microscopy (FLIM) to measure chromatin compaction at the scale of nucleosomal arrays in live cells. The assay uses a human cell line coexpressing histone H2B tagged to either enhanced green fluorescent protein (FP) or mCherry FPs (HeLa(H2B-2FP)). FRET occurs between FP-tagged histones on separate nucleosomes and is increased when chromatin compacts. Interphase cells consistently show three populations of chromatin with low, medium, or high FRET efficiency, reflecting spatially distinct regions with different levels of chromatin compaction. Treatment with inhibitors that either increase chromatin compaction (i.e., depletion of adenosine triphosphate) or decrease chromosome compaction (trichostatin A) results in a parallel increase or decrease in the FLIM-FRET signal. In mitosis, the assay showed variation in compaction level, as reflected by different FRET efficiency populations, throughout the length of all chromosomes, increasing to a maximum in late anaphase. These data are consistent with extensive higher order folding of chromatin fibers taking place during anaphase.


The role of patient factors and implant position in squeaking of ceramic-on-ceramic total hip replacements.
We investigated factors that were thought to be associated with an increased incidence of squeaking of ceramic-on-ceramic total hip replacements. Between June 1997 and December 2008 the three senior authors implanted 2406 primary total hip replacements with a ceramic-on-ceramic bearing surface. The mean follow-up was 10.6 years. The diagnosis was primary osteoarthritis in each case, and no patient had undergone previous surgery to the hip. We identified 74 squeaking hips (73 patients) giving an incidence of 3.1% at a mean follow-up of 9.5 years (4.1 to 13.3). Taller, heavier and younger patients were significantly more likely to have hips that squeaked. Squeaking hips had a significantly higher range of post-operative internal (p = 0.001) and external rotation (p = 0.003) compared with silent hips. Patients with squeaking hips had significantly higher activity levels (p = 0.009). A squeaking hip was not associated with a significant difference in patient satisfaction (p = 0.24) or Harris hip score (p = 0.34). Four implant position factors enabled good prediction of squeaking. These were high acetabular component inclination, high femoral offset, lateralisation of the hip centre and either high or low acetabular component anteversion. This is the largest study to date to examine patient factors and implant position factors that predispose to squeaking of a ceramic-on-ceramic hip. The results suggest that factors which increase the mechanical forces across the hip joint and factors which increase the risk of neck-to-rim impingement, and therefore edge-loading, are those that predispose to squeaking.


Transience effect in capture-recapture studies: The importance of its biological meaning.
Capture-recapture (CR) models are an essential tool for estimating demographic parameters in most animal and some plant populations. To avoid drawing incorrect conclusions in any statistical inference, a crucial prerequisite is to assess the goodness of fit of a general model to the data. In CR models, a frequent cause of lack of fit, is the so-called transience effect, which is due to a lower expectation of re-observation of individuals marked for the first time as compared to other individuals. The transience effect may result either from different biological causes or from the sampling procedure. A transience effect is usually treated by distinguishing at least two age-classes in the survival probability, but other approaches may be more suitable. Here we develop a conceptual and analytical framework for including a transience effect in capture-recapture models. We show the implementation of two additional parametrizations that incorporate a transience effect. With these parametrizations, we can directly estimate the "transience probability" defined as the probability that a newly caught individual disappear from the population beyond what is expected based on the behavior of the previously caught individuals in the same sample. Additionally, these parametrizations allow testing biological hypotheses concerning drivers affecting this probability. Results from our case study show differences between parametrizations, with the parametrization most currently used giving different estimates, especially when including covariates. We advocate for a unifying framework for treating a transience effect, that helps clarifying the ideas and terminology, and where the biological reasons should be the rule for choosing the appropriate analytical procedure. This framework will also open new and powerful ways for the detection and exploration of ecological processes such as the costs of the first reproduction or the deleterious effects of some types of marking.


Combined T2-weighted and diffusion-weighted MRI for localization of prostate cancer.
The objective of our study was to compare T2-weighted MRI alone and T2 combined with diffusion-weighted imaging (DWI) for the localization of prostate cancer. T2-weighted imaging and DWI (b value = 600 s/mm2) were performed in 49 patients before radical prostatectomy using an endorectal coil at 1.5 T in this prospective trial. The peripheral zone of the prostate was divided into sextants and the transition zone into left and right halves. T2 images alone and then T2 images combined with apparent diffusion coefficient (ADC) maps (T2 + DWI) were scored for the likelihood of tumor and were compared with whole-mount histology results. Fixed window and level settings were used to display the ADC maps. Only tumors with an area of more than 0.13 cm2 (> 4 mm diameter) and a Gleason score of > or = 6 were considered significant. The area under the receiver operating characteristic curve (A(z)) was used to assess accuracy. In the peripheral zone, the A(z) value was significantly higher (p = 0.004) for T2 plus DWI (A(z) = 0.89) than for T2 imaging alone (A(z) = 0.81). Performance was poorer in the transition zone for both T2 plus DWI (A(z) = 0.78) and T2 (A(z) = 0.79). For the whole prostate, sensitivity was significantly higher (p < 0.001) with T2 plus DWI (81% [120/149]) than with T2 imaging alone (54% [81/149]), with T2 plus DWI showing only a slight loss in specificity compared with T2 imaging alone (84% [204/243] vs 91% [222/243], respectively). Combined T2 and DWI MRI is better than T2 imaging alone in the detection of significant cancer (Gleason score > or = 6 and diameter > 4 mm) within the peripheral zone of the prostate.


[Alphacalcidol in the treatment of osteopenic syndrome in patients with bronchial asthma].
To assess effectiveness of alphacalcidol in the treatment of osteopenic syndrome in patients with bronchial asthma (BA). 65 BA patients with low densitometric parameters of bone tissue density were examined for bone density, basic parameters of Ca-P metabolism and some markers of bone metabolism during 6-month therapy with alphacalcidol (alpha-D3-TEVA) in a dose 0.5-0.75 mcg/day. All the patients after 6 months of therapy experienced pain relief, normalization of calcium-phosphorus metabolism, lower risk of broken bones. Their bone tissue increased its density. Alphacalcidol has analgetic and antiresorptive properties. It effectively prevents and treats osteopenic syndrome in patients with bronchial asthma.


[Diabetogenic tropical pancreatitis].
The tropical calcifying pancreatitis and/or fibrous pancreatitis are responsible for a number of cases of juvenile insulin-dependent diabetes in the Third World countries. World wide distributed in the tropical areas of Asia, Africa and South America, they can also be observed in Europe, in migrants from these countries. Intensive epidemiological and biochemical studies are currently developed in order to shed light on the many obscure points. Classification of the typical calcifying pancreatitis and the related syndromes is a matter of debate. The pathological basis is calcification of the pancreas and echography of the gland may become a cheap convenient relatively specific tool for epidemiology. The clinical syndrome consists of chronic painful pancreatic episodes since childhood, associated with pancreatic exocrine insufficiency, followed by the onset, during adolescence, of diabetes mellitus, which is most of the times insulin dependent. Patients' history is free of chronic alcoholism, but includes constantly chronic caloric and proteic malnutrition. Although insulin dependent this diabetes in not prone to ketosis, due presumably to carnitine deficiency and relative glucagon deficiency (or suppressibility). Insulin resistance is traditionally noted, the pathophysiology of which is unknown. The mechanism of calcification appearance is also undetermined. Either a deficiency in pancreatic stone protein, or the toxic effect of cyanogen glucosides present in cassava and other tropical foodstuffs, or the malnutrition-related deficiency in sulphur-containing aminoacids may be causal factors. No valid experimental model of the disease is available.


Pharmacokinetics and tissue penetration of tazobactam administered alone and with piperacillin.
The pharmacokinetics of tazobactam (500 mg) administered intravenously alone were compared with the pharmacokinetics of tazobactam coadministered with piperacillin (4 g), and the penetration into an inflammatory exudate in six healthy males was studied. Piperacillin influenced the pharmacokinetics of tazobactam. The mean levels of tazobactam in plasma at 4 h were 0.6 microgram/ml when it was given alone and 1.2 micrograms/ml when it was given with piperacillin (P = 0.0003). The mean total clearances of tazobactam were 203.5 and 134.2 ml/min (P = 0.035) when it was given alone and with piperacillin, respectively There were no significant differences in the elimination half lives, areas under the concentration-time curve from 0 h to infinity, or volumes of distribution. Inflammatory exudate penetration was rapid, and the mean maximum levels of tazobactam attained were 6.4 and 11.3 micrograms/ml when it was given alone or with piperacillin, respectively (P less than 0.06). The mean percent penetration of tazobactam and the area under the concentration-time curve from 0 h to infinity in inflammatory exudate were greater when tazobactam was given with piperacillin. The mean 24-h urinary recoveries of tazobactam were 63.7% +/- 7.9% when it was given alone and 56.8% +/- 2.7% when it was given with piperacillin. The explanation for the differences in the pharmacokinetics of tazobactam when it was administered alone compared with those when it was given with piperacillin was unclear.