The timing of neonatal brain damage.
Although neonatal morbidity and mortality are less than in the past, the risk of pre-natal and neonatal brain damage has not been eliminated. In order to optimize pre-natal, perinatal and neonatal care, it is necessary to detect factors responsible for brain damage and obtain information about their timing. Knowledge of the timing of asphyxia, infections and circulatory abnormalities would enable obstetricians and neonatologists to improve prevention in pre-term and full-term neonates. Cardiotocography has been criticized as being too indirect a sign of fetal condition and as having various technical pitfalls, though its reliability seems to be improved by association with pulse oximetry, fetal blood pH and electrocardiography. Neuroimaging is particularly useful to determine the timing of hypoxic-ischemic brain damage. Cranial ultrasound has been used to determine the type and evolution of brain damage. Magnetic resonance has also been used to detect antenatal, perinatal and neonatal abnormalities and timing on the basis of standardized assessment of brain maturation. Advances in the interpretation of neonatal electroencephalograms have also made this technique useful for determining the timing of brain lesions. Nucleated red blood cell count in cord blood has been recognized as an important indication of the timing of pre-natal hypoxia, and even abnormal lymphocyte and thrombocyte counts may be used to establish pre-natal asphyxia. Cord blood pH and base excess are well-known markers of fetal hypoxia, but are best combined with heart rate and blood pressure. Other markers of fetal and neonatal hypoxia useful for determining the timing of brain damage are assays of lactate and markers of oxidative stress in cord blood and neonatal blood. Cytokines in blood and amniotic fluid may indicate chorioamnionitis or post-natal infections. The determination of activin and protein S100 has also been proposed. Obstetricians and neonatologists can therefore now rely on various methods for monitoring the risk of brain damage in the antenatal and post-natal periods.


Genomics-assisted breeding for drought tolerance in chickpea.
Terminal drought is one of the major constraints in chickpea (Cicer arietinum L.), causing more than 50% production losses. With the objective of accelerating genetic understanding and crop improvement through genomics-assisted breeding, a draft genome sequence has been assembled for the CDC Frontier variety. In this context, 544.73Mb of sequence data were assembled, capturing of 73.8% of the genome in scaffolds. In addition, large-scale genomic resources including several thousand simple sequence repeats and several million single nucleotide polymorphisms, high-density diversity array technology (15360 clones) and Illumina GoldenGate assay genotyping platforms, high-density genetic maps and transcriptome assemblies have been developed. In parallel, by using linkage mapping approach, one genomic region harbouring quantitative trait loci for several drought tolerance traits has been identified and successfully introgressed in three leading chickpea varieties (e.g. JG 11, Chefe, KAK 2) by using a marker-assisted backcrossing approach. A multilocation evaluation of these marker-assisted backcrossing lines provided several lines with 10-24% higher yield than the respective recurrent parents.Modern breeding approaches like marker-assisted recurrent selection and genomic selection are being deployed for enhancing drought tolerance in chickpea. Some novel mapping populations such as multiparent advanced generation intercross and nested association mapping populations are also being developed for trait mapping at higher resolution, as well as for enhancing the genetic base of chickpea. Such advances in genomics and genomics-assisted breeding will accelerate precision and efficiency in breeding for stress tolerance in chickpea.


Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer.
While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.


Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort.
To evaluate the role of genetic variation at the DMPK locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial. We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats. We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed t test t = -3.7, p = 0.0019). Careful characterization of the DMPK CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials.


Can workers answer their questions about occupational safety and health: challenges and solutions.
Many workers have questions about occupational safety and health (OSH). Answers to these questions empower them to further improve their knowledge about OSH, make good decisions about OSH matters and improve OSH practice when necessary. Nevertheless, many workers fail to find the answers to their questions. This paper explores the challenges workers may face when seeking answers to their OSH questions. Findings suggest that many workers may lack the skills, experience or motivation to formulate an answerable question, seek and find information, appraise information, compose correct answers and apply information in OSH practice. Simultaneously, OSH knowledge infrastructures often insufficiently support workers in answering their OSH questions. This paper discusses several potentially attractive strategies for developing and improving OSH knowledge infrastructures: 1) providing courses that teach workers to ask answerable questions and to train them to find, appraise and apply information, 2) developing information and communication technology tools or facilities that support workers as they complete one or more stages in the process from question to answer and 3) tailoring information and implementation strategies to the workers' needs and context to ensure that the information can be applied to OSH practice more easily.


Neural basis of emotional decision making in trait anxiety.
Although trait anxiety has been associated with risk decision making, whether it is related to risk per se or to the feeling of the risk, as well as the underlying neurocognitive mechanisms, remains unclear. Using a decision-making task with a manipulation of frame (i.e., written description of options as a potential gain or loss) and functional magnetic resonance imaging, we investigated the neurocognitive relationship between trait anxiety and decision making. The classic framing effect was observed: participants chose the safe option when it was described as a potential gain, but they avoided the same option when it was described as a potential loss. Most importantly, trait anxiety was positively correlated with this behavioral bias. Trait anxiety was also positively correlated with amygdala-based "emotional" system activation and its coupling with the ventromedial prefrontal cortex (vmPFC) when decisions were consistent with the framing effect, but negatively correlated with the dorsal anterior cingulate cortex (dACC)-based "analytic" system activation and its connectivity to the vmPFC when decisions ran counter to the framing effect. Our findings suggest that trait anxiety is not associated with subjective risk preference but an evaluative bias of emotional information in decision making, underpinned by a hyperactive emotional system and a hypoactive analytic system in the brain.


A platinum(II) phenylphenanthroimidazole with an extended side-chain exhibits slow dissociation from a c-Kit G-quadruplex motif.
A series of three platinum(II) phenanthroimidazoles each containing a protonable side-chain appended from the phenyl moiety through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) were evaluated for their capacities to bind to human telomere, c-Myc, and c-Kit derived G-quadruplexes. The side-chain has been optimized to enable a multivalent binding mode to G-quadruplex motifs, which would potentially result in selective targeting. Molecular modeling, high-throughput fluorescence intercalator displacement (HT-FID) assays, and surface plasmon resonance (SPR) studies demonstrate that complex 2 exhibits significantly slower dissociation rates compared to platinum phenanthroimidazoles without side-chains and other reported G-quadruplex binders. Complex 2 showed little cytotoxicity in HeLa and A172 cancer cell lines, consistent with the fact that it does not follow a telomere-targeting pathway. Preliminary mRNA analysis shows that 2 specifically interacts with the ckit promoter region. Overall, this study validates 2 as a useful molecular probe for c-Kit related cancer pathways.


Development, Validation, and Results of a Survey of Personal Electronic Device Use Among 299 Anesthesia Providers From a Single Institution.
The pattern of perioperative use of personal electronic devices (PEDs) among anesthesia providers in the United States is unknown. We developed a 31-question anonymous survey of perioperative PED use that was sent to 813 anesthesiologists, anesthesiology residents, and certified registered nurse anesthetists at 3 sites within one health system. The electronic survey assessed patterns of PED use inside the operating room (OR), outside the OR, and observed in others. Questions were designed to explore the various purposes for PED use, the potential impact of specific hospital policies or awareness of medicolegal risk on PED use, and whether PED was a source of perioperative distraction. The overall survey response rate was 36.8% (n = 299). With regard to often/frequent PED activity inside the OR, 24% reported texting, 5% reported talking on the phone, and 11% reported browsing on the Internet. With regard to often/frequent PED activity outside the OR, 88% reported texting, 26% reported talking on the phone, and 63% reported browsing the Internet. With regard to often/frequent PED activity observed in others, 52% reported others texting, 14% reported others talking on the phone, and 34% reported others browsing the Internet. Two percent of respondents self-reported a distraction compared to 15% who had observed a distraction in others. Eighty percent of respondents recognized PED as a potential distraction for patient safety. Our data reinforce that PED use is prevalent among anesthesia providers.


A Bayesian perspective on tinnitus pitch matching.
New tinnitus therapies are being developed and marketed that target the patient's tinnitus frequency. This frequency is estimated clinically by pitch matching, which has the patient identify the pure tone that is closest to the perceived tinnitus frequency. Though widely used, pitch matching is heavily criticized as unreliable, and the degree of reliability varies among patients. At the very least, it is recommended that multiple pitch matches be used to identify the patient's tinnitus frequency. Even so, it is not clear how many pitch matches to collect, how they should be combined, or how doing so will enhance the audiologist's certainty about the true tinnitus frequency. In this article, we describe a simple Bayesian method of sequentially combining pitch matches until acceptable precision is achieved and illustrate the method in 10 patients with chronic tinnitus. Subjects were recruited from previous study participants and support group attendees at the National Center for Rehabilitative Auditory Research. Thirty tinnitus pitch matches were elicited from 10 patients with chronic, monotonal tinnitus. A Bayesian sequential analysis yielded estimated tinnitus frequencies for 7 patients that were within one-quarter octave of their true value with 90% certainty. Between four and twenty pitch matches were required to achieve acceptable results in these seven patients. Despite criticism, pitch matching is widely used to estimate tinnitus frequency. We address reliability concerns with a Bayesian sequential analysis to jointly estimate tinnitus frequency and reliability. The method is easily applied.


The Neuropsychology of Adolescent Sexual Offending: Testing an Executive Dysfunction Hypothesis.
Although executive dysfunctions are commonly hypothesized to contribute to sexual deviance or aggression, evidence of this relationship is scarce and its specificity is unproven, especially among adolescents. The objective of this study was to compare the executive functioning (EF) of adolescents with sexual offense convictions (ASOC) to that of non-sex-delinquents (NSD). A secondary goal was to assess the relationship among specific sexual offense characteristics (i.e., victim age), history of childhood sexual abuse (CSA), and EF. It was hypothesized that as a group, ASOC would present similar EF profiles as NSD. It was further hypothesized that ASOC with child victims would present significantly higher rates of CSA and more severe impairment of EF than ASOC with peer-aged or older victims and NSD. A total of 183 male adolescents (127 ASOC and 56 NSD) were interviewed to collect demographic information, sexual development history, history of CSA, an assessment of living conditions, and history of delinquency and sexual offending. Participants were administered the Delis-Kaplan Executive Functioning System and the Hare Psychopathy Checklist-Youth Version. In accord with the first hypothesis, ASOC and NSD presented similar EF scores, well below normative values. Thus, EF deficits may not characterize the profiles of adolescents with sexual behavior problems. Contrarily to our second hypothesis, however, offending against children and or experiencing CSA were not associated with poorer EF performance. On the contrary, ASOC with child victims obtained significantly higher scores on measures of higher order EF than both ASOC with peer-aged or older victims and NSD. Implications of these results and future directions are discussed.


Assimilation and health service utilization of Korean immigrant women.
In this case study, I present descriptive findings with regard to immigrant incorporation and health service utilization. Using focus groups and survey of Korean immigrant women in Wisconsin, I examine whether the ways in which they adapt to the U.S. society is relevant to their health services utilization and the alternatives they seek when available health services are less than satisfactory. The findings suggest that adherence to Korean identity appears to be associated with health service utilization. This is evident in the immigrants' evaluation of the U.S. health services as compared to those of Korea, and the consideration given by these immigrants to seeking health services in Korea instead of the United States. Such concerns on the part of these immigrants have important implications for health researchers, as they highlight the significance of immigrants' transnational experiences and their sense of personal agency in the use of health care.


Efficient and Effective Use of Peer Teaching for Medical Student Simulation.
Simulation is increasingly used in medical education, promoting active learning and retention; however, increasing use also requires considerable instructor resources. Simulation may provide a safe environment for students to teach each other, which many will need to do when they enter residency. Along with reinforcing learning and increasing retention, peer teaching could decrease instructor demands. Our objective was to determine the effectiveness of peer-taught simulation compared to physician-led simulation. We hypothesized that peer-taught simulation would lead to equivalent knowledge acquisition when compared to physician-taught sessions and would be viewed positively by participants. This was a quasi-experimental study in an emergency medicine clerkship. The control group was faculty taught. In the peer-taught intervention group, students were assigned to teach one of the three simulation-based medical emergency cases. Each student was instructed to master their topic and teach it to their peers using the provided objectives and resource materials. The students were assigned to groups of three, with all three cases represented; students took turns leading their case. Three groups ran simultaneously. During the intervention sessions, one physician was present to monitor the accuracy of learning and to answer questions, while three physicians were required for the control groups. Outcomes compared pre-test and post-test knowledge and student reaction between control and intervention groups. Both methods led to equally improved knowledge; mean score for the post-test was 75% for both groups (p=0.6) and were viewed positively. Students in the intervention group agreed that peer-directed learning was an effective way to learn. However, students in the control group scored their simulation experience more favorably. In general, students' response to peer teaching was positive, students learned equally well, and found peer-taught sessions to be interactive and beneficial.


Hospital Variation and Patient Characteristics Associated With Vena Cava Filter Utilization.
There is a wide variation in the use of vena cava filter (VCF). This study assessed the hospital and patient characteristics associated with VCF use in deep vein thrombosis (DVT) and pulmonary embolism (PE). Inpatient discharge data from all acute care hospitals with DVT/PE during 2008-2014 in Kentucky were used. Hierarchical logistic regression models were used to evaluate the relationships of study variables with VCF use. During the study period, 81,922 discharges for DVT/PE were observed and 10.5% of these received a VCF. This included 12,083 cases of PE+DVT, 18,571 cases of PE only, and 51,268 cases of DVT only. VCF use among these groups was 22.7%, 6.0%, and 7.8%, respectively. In adjusted analyses, VCF use was associated with increasing age, indicating that those over age 65 were twice as likely to receive a filter compared with the reference (21-25 y old) group. Significant comorbidities associated with VCF use included cancer, liver disease, cerebrovascular disease, atrial fibrillation, anemia, and concurrent bleeding. Lower extremity, proximal DVTs, and patients receiving thrombolytic therapy or embolectomy, those having surgery, and those who were unstable or had trauma, were also more likely to receive a filter. Among cancer types, brain and metastatic tumors were significantly associated with VCF use. Between-hospital variation after controlling for all covariates was 7.1%. There was high variation in the use of VCFs. Several high-risk subgroups were more likely to use VCFs including older adults and those with cancer and concurrent bleeding.


Cannabis Use in Individuals With Spinal Cord Injury or Moderate to Severe Traumatic Brain Injury in Colorado.
To describe the prevalence of cannabis use in an adult sample with spinal cord injury (SCI) or traumatic brain injury (TBI) in Colorado, and to describe the self-reported reasons and side effects of cannabis use in this sample. Mixed-methods observational study, using focus group data and telephone survey. Community. Colorado adults who sustained SCI or moderate to severe TBI and received services through Craig Hospital. None. Survey. Focus group participants identified issues that were then included in the survey development. Seventy percent of the 116 participants surveyed reported cannabis use before their injury (67% SCI, 74% TBI) and 48% reported use after their injury (53% SCI, 45% TBI). Overall, the most common reason for use was recreational (67%), followed by reducing stress/anxiety (62.5%) and improving sleep (59%). Among the respondents with SCI, the most common reasons for use were to reduce spasticity (70%), recreation (63%), and to improve sleep (63%). Among those with TBI, reasons endorsed were recreational (72%), reducing stress/anxiety (62%), and improving sleep (55%). Smoking was the most common method of use. A majority of this sample reported using cannabis before injury, and approximately half reported using cannabis after injury. Both groups reported recreational use, whereas the group with SCI also highly endorsed using cannabis to address chronic medical conditions. Clinicians should be aware of the high prevalence of cannabis use in these populations and the impact such use may have on the individual's medical management. Further research in this area is needed.


The functions of exogenous and endogenous laminin-5 on corneal epithelial cells.
Recent evidence suggests that the basement membrane not only separates basal cells from Bowman's layer, but also has a crucial role in the proliferation, differentiation and migration of corneal epithelial cells. The basement membrane is composed of a mixture of matrix components including collagens, laminins and heparan sulfate proteoglycans. In these extracellular matrixes, laminin is a major component of the basement membrane. Of 11 laminin isoformes, laminin-5 is a variant, composed of three nonidentical subunits alpha3, beta3, gamma2 and is a major component of the corneal basement membrane. However, little is known about the interactions of laminin-5 with corneal epithelial cells. In this study, we investigated the functions of laminin-5 on SV-40 transfected human corneal epithelial cells (HCE cells). We also revealed different functions between exogenous and endogenous laminin-5 on HCE cells. Laminin-5 is synthesized initially as a 490 kDa molecule that undergoes specific processing to cleavaged isoforms after being secreted. The alpha3 subunit is processed from 200-190 kDa to 160 kDa/145 kDa. The gamma2 subunit is processed from 150 kDa to 105 kDa/80 kDa. The beta3 subunit (140 kDa) is not processed. Exogenously added laminin-5 (soluble form) in this study was purified from a serum-free, conditioned medium of a human gastric carcinoma cell line STKM-I. This soluble laminin is a processed isoform containing alpha3 (160 kDa), beta3 (140 kDa) and gamma2 (105 kDa) chains. On the other hand, immunocytochemical analysis showed that HCE cells themselves secreted laminin-5 endogenously. Western blotting analysis revealed that HCE cells initially produced unprocessed isoform containing 190 kDa alpha3, 140 kDa beta3 and 150 kDa gamma2 chains and that after being secreted, the alpha3 chain was processed to 160 kDa/145 kDa and the gamma2 chain was processed to 105 kDa. Initially we investigated the functions of exogenous (processed) laminin-5 on HCE cells. Exogenously added laminin-5 strongly promoted cell adhesion via alpha3beta1 integrin, cell spreading, assembly of hemidesmosomes and mildly inhibited cell migration. Next we estimated the effect of endogenous (unprocessed) laminin-5 on HCE cells. Using an anti laminin-5 monoclonal antibody (mAb) or anti integrin alpha3beta1 mAbs, the blocking of the interaction between endogenously secreted laminin-5 and HCE cells caused strong inhibition of cell migration. Integrin alpha3beta1 and alpha6beta4 were expressed in HCE cells. These integrins are receptors of laminin-5. But, anti integrin alpha6beta4 mAbs did not have any blocking ability against cell migration. These results indicated that endogenous (unprocessed) laminin-5 has a crucial role in cell migration on HCE cells via alpha3beta1 integrin. In conclusion, structural differences between exogenous (processed) and endogenous (unprocessed) laminin-5 regulated their functions on HCE cells. Exogenously added laminin-5 strongly promoted cell adhesion, cell spreading and assembly of hemidesmosomes. Endogenously secreted laminin-5 had a crucial role in cell migration. In the future, processed soluble laminin-5 could be a useful drug for the prevention of recurrent corneal erosion, and unprocessed soluble laminin-5 could be applied for the treatment of prolonged corneal epithelial defects.


Advances in liquid phase soft-x-ray photoemission spectroscopy: A new experimental setup at BESSY II.
A state-of-the-art experimental setup for soft X-ray photo- and Auger-electron spectroscopy from liquid phase has been built for operation at the synchrotron-light facility BESSY II, Berlin. The experimental station is named SOL3, which is derived from solid, solution, and solar, and refers to the aim of studying solid-liquid interfaces, optionally irradiated by photons in the solar spectrum. SOL3 is equipped with a high-transmission hemispherical electron analyzer for detecting electrons emitted from small molecular aggregates, nanoparticles, or biochemical molecules and their components in (aqueous) solutions, either in vacuum or in an ambient pressure environment. In addition to conventional energy-resolved electron detection, SOL3 enables detection of electron angular distributions by the combination of a ±11° acceptance angle of the electron analyzer and a rotation of the analyzer in the polarization plane of the incoming synchrotron-light beam. The present manuscript describes the technical features of SOL3, and we also report the very first measurements of soft-X-ray photoemission spectra from a liquid microjet of neat liquid water and of TiO2-nanoparticle aqueous solution obtained with this new setup, highlighting the necessity for state-of-the-art electron detection.


The evaluation and monitoring of volume status in congestive heart failure.
The increasing prevalence of heart failure dictates that physicians effectively assess and treat congestion. The evaluation of volume status in the complex group of patients with heart failure is very challenging. Physical examination is at best challenging and not always helpful, confounded by body habitus and comorbidities. Weight monitoring has been shown to be helpful, especially in combination with remote monitoring or telephonic checks. Invasive methods such as pulmonary artery catheters provide significant information but have not been proven to be clinically effective. Noninvasive measures such as impedance cardiography and echocardiography provide additional information. The future of heart failure management may reside in implantable monitors, either alone or in combination with other intracardiac devices. These monitors can provide surrogates of pulmonary capillary wedge pressure and volume. They can also be followed remotely and provide information on the patient's status more frequently than office visits. This manuscript will review volume assessment including past, current, and future methods.


Hand therapist management of the lateral epicondylosis: a survey of expert opinion and practice patterns.
Lateral epicondylosis (LE) is a common condition. Knowledge on practice patterns underlies identification of knowledge to practice gaps. The purpose was to determine the practice patterns and beliefs of hand therapists in managing LE. The study design used was a descriptive survey. A survey of Certified Hand Therapists and members of the American Society of Hand Therapists was conducted (n=693). Questions were framed around frequency and perceived effectiveness of interventions, examination techniques, outcome measures, and prognostic factors. More than 80% of therapists use education/activity modification, home exercise, LE orthoses, and stretching for both the acute and chronic LE. Therapists perceive education, orthoses and home exercise are the most effective for acute cases, whereas in chronic cases, orthoses dropped to ninth in ranked perceived effectiveness. Grip strength (80%) and numeric pain rating (71%) were the most commonly used outcome measures. Most (>70%) therapists perceived occupation and duration of symptoms are prognostic in terms of resolution of symptoms, whereas compliance with exercise (78%) and work factors are important for return to work. Therapists rely on impairment measures to evaluate hand therapy outcomes in patients with LE. Hand therapists are aligned with a number of recommendations from the available systematic reviews, although the use of outcome measures and optimal definition of education and exercise exhibit evidence to practice gaps. Level 5.


Isolation of vaccine-derived measles viruses from children with acute respiratory infection.
The measles elimination project led by the World Health Organization (WHO) has been moving toward the target of eliminating measles in the WHO Western Pacific Region. In Japan, prefectural public health institutes play a key role for the laboratory diagnosis of measles virus (MV) infection, which is based on PCR, virus isolation, and genotyping. Microscopic examination of viral-sensitive cell lines during routine virus isolation from nasopharyngeal specimens has been used to detect the morphological changes typical for the growth of respiratory viruses. Here, we describe the unexpected isolation of vaccine-derived MVs from the two unrelated 1-year-old boys with acute respiratory infection. The nasopharyngeal specimens were obtained from one patient in February 2007 and from another in December 2012. Incidentally, the two children had received measles-rubella vaccination 9 or 11 days before the sampling. The isolates from two children induced morphological changes of the viral-sensitive cell lines, such as syncythia formation (cell fusion). We finally identified the isolates as vaccine-derived MVs by sequence analysis and immunological methods with anti-measles nucleoprotein antibodies. As no typical symptoms of MV infection were observed in either patient, the vaccine-derived MVs were isolated not as causative pathogens but by chance. In fact, there was no suspected case of secondary MV infection in either patient, thereby excluding the possibility that vaccine-derived MVs spread from human to human. Our experiences suggest the possibility of vaccine-derived MV isolation by cell cultures and the difficulty in identifying MVs in specimens from patients other than clinically suspected measles cases.


Grieving a loss from AIDS.
The determinants of the nature of an AIDS death and their likely effects on the survivors are identified. Specifically discussed with illustrative case examples are stigma, lack of social support, contagion, untimely death, protracted illness and disfigurement, and neurological complications. Strategies for intervention are suggested.


Mobilization of F-actin and clathrin during redistribution of Chlamydia trachomatis to an intracellular site in eucaryotic cells.
Immunofluorescence was used to examine the distribution of Chlamydia trachomatis serovars L2 and E, F-actin, and clathrin in infected McCoy and HeLa cells. After incubation at 4 degrees C, C. trachomatis serovar L2 was randomly distributed on the McCoy cell surface. After a temperature shift to 37 degrees C, chlamydiae redistributed, within 30 min, to one local aggregate in the central or perinuclear region of individual cells. About 90% of these aggregated chlamydiae were intracellularly localized, but some remained randomly distributed on the cell surface. Similar results were obtained with HeLa cells and C. trachomatis serovar E, except that the redistribution was slower in HeLa cells than in McCoy cells and fewer cells infected with serovar E exhibited a local aggregate than those infected with serovar L2. Cytochalasin D inhibited more than 90% of this local aggregation. Instead, in cytochalasin D-treated cells, the entry of chlamydiae was inhibited and the organisms became localized on the cell surface in a peripheral local aggregate that distributed in a manner similar to that of phalloidin-stained actin. In a double immunofluorescence assay, F-actin and clathrin aggregated correspondingly in time and position with central or perinuclear aggregation of chlamydiae. These results indicate that polymerized actin and clathrin participate in a rapid redistribution of chlamydiae to an intracellular aggregate.


Panel of prototypical recombinant infectious molecular clones resistant to nevirapine, efavirenz, etravirine, and rilpivirine.
We created a panel of 10 representative multi-nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant recombinant infectious molecular HIV-1 clones to assist researchers studying NNRTI resistance or developing novel NNRTIs. The cloned viruses contain most of the major NNRTI resistance mutations and most of the significantly associated mutation pairs that we identified in two network analyses. Each virus in the panel has intermediate- or high-level resistance to all or three of the four most commonly used NNRTIs.


Future perspectives of the pharmacological management of diabetic dyslipidemia.
Diabetic dyslipidemia is frequent among patients with type 2 diabetes mellitus (T2DM) and is characterized by an increase in triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and small-dense (atherogenic) particles, and by a decrease in low high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 that are strongly related to insulin resistance. The increased flux of free fatty acids from adipose tissue to the liver aggravates hepatic insulin resistance and promotes all of aspects of the dyslipidemic state. Areas covered: Statins are the first-line agents for treatment while other lipid-lowering drugs (ezetimibe, fibrate and proprotein convertase subtilisin/kexin type 9) or novel anti-diabetic agents (dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon like peptide-1 receptor agonist (GLP-1RA), sodium/glucose cotransporter 2 inhibitors (SGLT2is)) or nutraceuticals (berberine, omega 3 fatty acid, red yeast rice) can be used alone or in combination. Expert commentary: In patients with T2DM, lipid abnormalities should be identified and treated as part of the overall diabetic treatment, in order to prevent cardiovascular disease. The choice of drugs to be used is mainly based on the lipid profile and on the characteristic lipoprotein abnormalities; the use of new drugs for the treatment of hyperglycemia and lipids alteration in these patients can improve diabetic dyslipidemia.


Comparison of 33P with 45Ca distribution in developing rat molar enamel in vivo and in vitro.
The distribution of 45Ca and 33P in developing rat molar enamel has been studied using freeze sectioning and autoradiographic methods. The distribution patterns of the two tracers in vivo were dissimilar. The use of in vitro methods showed that flux of 33P into enamel is not influenced by the cells of the enamel organ. It is suggested that the factors controlling movement of calcium and phosphorus into mineralizing enamel may be similar to those proposed for bone.


Vibration-controlled transient elastography: a practical approach to the noninvasive assessment of liver fibrosis.
Therapeutic advances for hepatitis C and the increasing prevalence on nonalcoholic fatty liver disease are reshaping the diagnostic approach to disease staging in clinical hepatology. Well tolerated, inexpensive and reliable alternatives to liver biopsy are a critical need for clinicians and patients alike. Vibration-controlled transient elastography (VCTE, also known as 'transient elastography') is a robust, point-of-care tool for the noninvasive assessment of liver fibrosis. This tool efficiently prioritizes the treatment for patients with viral hepatitis at risk for advanced liver disease and identifies the subgroups with metabolic or cholestatic liver disease who are at the highest risk. Rather than staging fibrosis, VCTE provides an accurate risk estimate of advanced fibrosis. In addition, it is increasingly recognized that elastography can predict outcomes including hepatic decompensation and mortality. The ideal use of this tool is to perform it in conjunction with a serologic marker of fibrosis to confirm its findings. When combined with serologic markers of fibrosis, VCTE allows the vast majority of patients to avoid a liver biopsy.


Impact of APOE in mild cognitive impairment.
The authors aimed to use baseline data of an ongoing large, prospective study in subjects with mild cognitive impairment (MCI) to investigate the impact of APOE genotype on the symptom profile of the condition. Cognitive assessments included the AD Assessment Scale cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and a cognitive battery for assessment of memory, attention, and executive function. Behavioral assessments included the Neuropsychiatric Inventory and Beck Depression Inventory. Activities of daily living were assessed by the AD Cooperative Study Activities of Daily Living (ADCS-ADL) scale. Hippocampal volumes were measured with MRI. A total of 494 of 1,018 study subjects provided APOE data. Approximately 40% of the subjects were APOE epsilon4 carriers. APOE epsilon4 carriers had lower MMSE (p = 0.01) and higher ADAS-cog (p < 0.0001) scores than noncarriers, indicating worse cognitive impairment. APOE epsilon4 carriers also had greater deficits on New York University delayed paragraph recall and Buschke free and cued selective reminding tests, and on the ADCS-ADL scale (p < 0.001). They also had smaller hippocampal volumes (p = 0.002). Behavioral scores were similar across the subgroups. MCI subjects carrying the APOE epsilon4 allele showed distinct cognitive and imaging profiles, which appeared to resemble those of early Alzheimer patients. APOE epsilon4 genotype was associated with greater impairments in memory and functional activities as well as hippocampal atrophy.


Effects of lidocaine infiltration on cost of rhinoplasty made under general anesthesia.
This study aimed to compare the effects of combined and noncombined lidocaine with adrenaline infiltration in general anesthesia (GA) procedures, in which the standard anesthesia depth is monitored by Bispectral Index monitoring, on minimum alveolar concentration (MAC) levels and the costs. Following approval by the local ethics committee, an American Society of Anesthesiologists physical status I–II group of 40 adult patients for whom elective rhinoplasties under GA were planned was divided into 2 double-blind randomized groups. In group 1, GA and lidocaine + adrenaline were administered, whereas in group 2, only GA and adrenaline were administered. All the patients who had been taken to the operation room underwent electrocardiography and measurements of the peripheral oxygen saturation, end-tidal carbon dioxide, heart rate, mean blood pressure, and Bispectral Index monitoring. Using the operation time and the MAC% values, the total consumed inhalation agent amounts were calculated, and the cost difference was determined. The mean blood pressure values were lower in group 1 (P < 0.05). In group 1, the MAC% was 20.83% lower than that of group 2; the consumed desflurane amount was 20.29%, and the cost was 20.29% lower than that of group 2 (P < 0.05). In rhinoplasties under GA, the lidocaine + adrenaline combination infiltration not only decreased inhaled anesthetic requirement and cost but also supported the hemodynamic stability. In addition, surgical satisfaction increased in the lidocaine + adrenaline group because of small number of agitated patients during the recovery period.


Evaluating a unique, specialist psychiatric genetic counseling clinic: uptake and impact.
People with psychiatric disorders and their family members have expressed interest in receiving genetic counseling (GC). In February 2012, we opened the first (to our knowledge) specialist psychiatric GC clinic of its kind, for individuals with non-syndromic psychiatric disorders and their families. Prior to GC and at a standard 1-month follow-up session, clinical assessment tools are completed, specifically, the GC outcomes scale (GCOS, which measures empowerment, completed by all clients) and the Illness Management Self Efficacy scale (IMSES, completed by those with mental illness). Consecutive English-speaking clients attending the clinic between 1 February 2012 and 31 January 2013 who were capable of consenting were asked for permission to use their de-identified clinical data for research purposes. Descriptive analyses were conducted to ascertain demographic details of attendees, and paired sample t-tests were conducted to assess changes in GCOS and IMSES scores from pre- to post-GC. Of 143 clients, seven were unable to consent, and 75/136 (55.1%) consented. Most were female (85.3%), self-referred (76%), and had personal experience of mental illness (65.3%). Mean GCOS and IMSES scores increased significantly after GC (p < 0.0001 and p = 0.011, respectively). In a naturalistic setting, GC increases empowerment and self-efficacy in this population.


Vandetanib for the treatment of medullary thyroid carcinoma.
To review the place in therapy of vandetanib for medullary thyroid carcinoma (MTC). Literature searches were performed in Ovid MEDLINE, EMBASE, and Google Scholar using the search terms ZD6474 OR vandetanib OR Caprelsa combined with medullary thyroid carcinoma. Two phase 2 trials and 1 phase 3 trial were identified. Vandetanib is approved for the treatment of unresectable, locally advanced or metastatic MTC in patients with symptomatic or progressive disease. In the phase 3 randomized, double-blind, placebo-controlled trial, vandetanib 300 mg daily (n = 231) was compared with placebo (n = 100). Vandetanib-treated patients experienced a significant improvement in progression-free survival (PFS; hazard ratio [HR] = 0.46; 95% CI = 0.31-0.69; P < .001). No difference in overall survival (OS) was seen at the time of publication. Most adverse effects were grade 1 or 2 and managed by dose interruptions or reductions. The most common grade 3/4 adverse effects were diarrhea, hypertension, QT prolongation, fatigue, and rash. Because of the potential for QT prolongation, torsades de pointes, and sudden death, vandetanib is restricted via a Risk Evaluations and Mitigation Strategy program. Vandetanib prolongs PFS but has not been shown to improve OS. Vandetanib can be considered for patients with unresectable locoregional disease. It is a first-line option for patients with unresectable symptomatic distant metastases as well as an option for advanced disseminated symptomatic metastatic disease. Vandetanib is expected to be an important addition to the formulary of health plans that provide prescription drug benefits.


The effect of oxygen on the frequency of somatic recombination in Drosophila melanogaster.
The influence of oxygen on the frequency of somatic recombination in the yellow singed system on the X chromosome of Drosophila melanogaster was studied under a variety of experimental conditions. Flies raised from egg to adult in atmospheres containing 70-90% oxygen were found to have significantly more mosaic spots on their abdominal tergites than were observed in flies which developed in air. First instar larvae X-rayed in from 0 to 100% oxygen demonstrated the existence of an oxygen effect for somatic recombination in the cells which form the abdominal hypoderm. The mosaic spot counts, beginning with the lowest numbers which were found in flies X-rayed in nitrogen, increased rapidly with rising oxygen tensions until the percentage in air was reached, then leveled off at the higher concentrations. Post-treatment with nitrogen of larvae X-rayed in air or oxygen created a substantially higher number of mosaic spots than were found when larvae, after being similarly irradiated, were instead placed into air or oxygen.


Evaluation of academic scientists' responses to situations that pose a conflict of interest.
The industry-academy relationship has many benefits, but it also has potential drawbacks, including potential conflicts of interest (e.g., when the profit motives of a private company unduly influence academic responsibilities). To date, policies intended to regulate or manage financial conflicts of interest appear to be unsatisfying and inadequate. The present study examined predictors of the responses of academic scientists and clinicians to hypothetical situations in which financial and other conflicts of interest may arise. Academic scientists and clinicians at five medical schools completed an anonymous survey that included vignettes that posed a potential conflict of interest. Participants indicated the likelihood that they would engage in specific actions to avoid conflicts of interest. Findings indicated that junior faculty and those whose departments received more federal grant money were more likely to respond in ways that could create conflicts of interest (ps < .05). These results suggest that various sub-groups of faculty may require different approaches to appropriately avoid or manage financial conflicts of interest. These findings may contribute to the development of new policies that deal more effectively with conflicts of interest.


Comparative Toxicity of DDT Isomers and Related Compounds to Mosquito Larvae and Fish.
The p, p'-DDT isomer is several times as toxic as the o,p'-DDT isomer to both goldfish and mosquito larvae. The methoxy analogue equals DDT in toxicity to fish, but is less toxic to mosquito larvae. On the other hand, the DDD analogue ranks about as high as DDT in toxicity to mosquito larvae, but appears to be less toxic to goldfish.


Inositol 1,4,5-trisphosphate-induced release of sequestered Ca2+ from highly purified human platelet intracellular membranes.
Evidence has accumulated in support of a role for intracellularly generated inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in raising cytosol [Ca2+] when various hormones, neurotransmitters, growth factors and other stimulants act on cell surfaces. The increase in [Ca2+] that follows stimulant-receptor interaction is accompanied by rapid hydrolysis of phosphoinositides. One product, Ins(1,4,5)P3, arising from the breakdown of phosphatidylinositol 4,5-bisphosphate was shown to promote the release of Ca2+ from non-mitochondrial stores in a variety of cells. Although platelet intracellular membranes have been implicated in the control of cytosol [Ca2+] and we previously characterized a Ca2+-sequestering mechanism associated with them, we have as yet no knowledge of how this Ca2+ store is mobilized after a stimulus-receptor interaction at the platelet surface. Using free-flow electrophoresis, we isolated and purified human platelet intracellular membranes. They show high enrichment and exclusive localization of the endoplasmic-reticulum marker NADH:cytochrome c reductase, and they sequester Ca2+ by an ATP-dependent process, reaching steady-state values in 10-12 min. Saturation with Ca2+ occurs at around 10-30 microM external Ca2+. When Ins(1,4,5)P3 is added to the 45Ca-loaded vesicles, a rapid release of Ca2+ occurs (approx. 35% in 15-30s). The magnitude of the release depends upon external [Ca2+], being maximum in the range 0.3-0.8 microM and low at external [Ca2+] greater than 1 microM. After release there is a rapid re-uptake of Ca2+, with restoration of the former steady-state values within 1 min. Half-maximal release occurs at approx. 0.25 microM-Ins(1,4,5)P3. This release and re-uptake pattern is not observed with ionophore A23187 or arachidonic acid, both of which liberate Ca2+ irreversibly. Inositol 1,4-bisphosphate was ineffective in releasing Ca2+ from these intracellular membranes. The results support the role of Ins(1,4,5)P3 as a specific intracellular mediator, transducing the action of excitatory agonists acting on the platelet surface into metabolic, mechanochemical and other functional events, known to occur during platelet activation.


An evaluation of the fixed-dose combination sacubitril/valsartan for the treatment of arterial hypertension.
Essential hypertension is a significant risk factor for cardiovascular disease, renal disease, and mortality with increasing prevalence. Despite the availability of various antihypertensive agents, hypertension is still poorly controlled. Therefore, new chemical compounds with antihypertensive efficacy need to be developed. The dual angiotensin II receptor-neprilysin inhibitor LCZ696 is a single molecule synthesized by co-crystallization of valsartan and the neprilysin inhibitor prodrug sacubitril (1:1 molar ratio). This review includes an overview of hypertension and the current pharmacotherapy. The authors summarize the LCZ696 drug chemistry, pharmacodynamics, pharmacokinetics, metabolism, randomized control trials (RCTs), and safety concerns. Databases searched included PubMed, Google Scholar, Embase, and ClinicalTrials.gov. LCZ696 is effective in hypertension treatment. Short-term RCTs have shown that the highest doses of LCZ696 (200 and 400 mg [q.d.]) were more effective at lowering office and ambulatory blood pressure than angiotensin II receptor blockers (ARB) alone while having a similar tolerability profile. The effects of LCZ696 on hypertensive organ damage are only sparsely investigated and so far no studies have established the impact of LCZ696 on cardiovascular event rates. Future studies should focus on the comparison of LCZ696 and combination therapies already in use such as ARB and calcium channel blockers.


Biological Impact of Organic Extracts from Urban-Air Particulate Matter: An In Vitro Study of Cytotoxic and Metabolic Effects in Lung Cells.
Atmospheric particulate matter (PM) with diameters below 10 µm (PM10) may enter the lungs through inhalation and are linked to various negative health consequences. Emergent evidence emphasizes the significance of cell metabolism as a sensitive target of PM exposure. However, the current understanding of the relationship between PM composition, conventional toxicity measures, and the rewiring of intracellular metabolic processes remains limited. In this work, PM10 sampled at a residential area (urban background, UB) and a traffic-impacted location (roadside, RS) of a Portuguese city was comprehensively characterized in terms of polycyclic aromatic hydrocarbons and plasticizers. Epithelial lung cells (A549) were then exposed for 72 h to PM10 organic extracts and different biological outcomes were assessed. UB and RS PM10 extracts dose-dependently decreased cell viability, induced reactive oxygen species (ROS), decreased mitochondrial membrane potential, caused cell cycle arrest at the G0/G1 phase, and modulated the intracellular metabolic profile. Interestingly, the RS sample, richer in particularly toxic PAHs and plasticizers, had a greater metabolic impact than the UB extract. Changes comprised significant increases in glutathione, reflecting activation of antioxidant defences to counterbalance ROS production, together with increases in lactate, NAD+, and ATP, which suggest stimulation of glycolytic energy production, possibly to compensate for reduced mitochondrial activity. Furthermore, a number of other metabolic variations hinted at changes in membrane turnover and TCA cycle dynamics, which represent novel clues on potential PM10 biological effects.


The ratio of N-terminal pro-B-type natriuretic peptide to troponin I for differentiating acute coronary syndrome.
It is difficult to differentiate whether coronary or non-coronary causes in patients with elevated troponin I (TnI) in emergency department (ED). The aim of this study was to develop a clinical decision tool for differentiating a coronary cause in the patients with elevated TnI. This was a retrospective observational study that enrolled consecutive ED patients. Patients were included in the study if they were ≥16 years of age, had admitted through ED with a medical illness, and TnI levels at initial evaluation in the ED were ≥0.2 ng/mL. Patients diagnosed with ST elevation myocardial infarction or congestive heart failure were excluded. Coronary angiography, electrocardiogram, laboratory results, echocardiography, and clinical characteristics were analyzed. Among the included 1441 patients, 603 and 838 patients were categorized into an acute coronary syndrome (ACS) group and non-acute coronary syndrome (non-ACS) group, respectively. The ratio of N-terminal pro-Btype natriuretic peptide (NT-proBNP) to TnI was significantly higher in the non-ACS group compared to the ACS group. The AUC of NT-proBNP/TnI (0.805, 95% CI, 0.784-0.826) was significantly superior to that of NT-proBNP/creatinine kinase-MB, TnI, and NT-proBNP. The patients of the non-ACS group with high levels of TnI and BNP showed more critically ill manifestation at the time of presentation and higher mortality. NT-proBNP/TnI may help to distinguish medical patients with elevated TnI whether the elevated TnIs were caused from ACSs or from conditions other than ACS.


Mimicry in plant-parasitic fungi.
Mimicry is the close resemblance of one living organism (the mimic) to another (the model), leading to misidentification by a third organism (the operator). Similar to other organism groups, certain species of plant-parasitic fungi are known to engage in mimetic relationships, thereby increasing their fitness. In some cases, fungal infection can lead to the formation of flower mimics (pseudo flowers) that attract insect pollinators via visual and/or olfactory cues; these insects then either transmit fungal gametes to accomplish outcrossing (e.g. in some heterothallic rust fungi belonging to the genera Puccinia and Uromyces) or vector infectious spores to healthy plants, thereby spreading disease (e.g. in the anther smut fungus Microbotryum violaceum and the mummy berry pathogen Monilinia vaccinii-corymbosi). In what is termed aggressive mimicry, some specialized plant-parasitic fungi are able to mimic host structures or host molecules to gain access to resources. An example is M. vaccinii-corymbosi, whose conidia and germ tubes, respectively, mimic host pollen grains and pollen tubes anatomically and physiologically, allowing the pathogen to gain entry into the host's ovary via stigma and style. We review these and other examples of mimicry by plant-parasitic fungi and some of the mechanisms, signals, and evolutionary implications.


Aspects of the stereochemistry of torularhodin biosynthesis.
1. The incorporation of [2-(14)C]acetate, [2-(14)C]mevalonic acid and [2-(14)C,2-(3)H(2)]-mevalonic acid into torulene and torularhodin by Rhodotorula rubra and Rhodotorula glutinis was studied. 2. A recovery of 14.3% of the label was obtained on decarboxylation of the torularhodin biosynthesized from [2-(14)C]mevalonic acid. 3. An analysis of the (3)H/(14)C ratio in torularhodin gave a value of 9.44:8. 4. These results, obtained by different experimental techniques, show that the reactions in the conversion of the dimethyl group of isopentenyl pyrophosphate into the 16',17'-position of torularhodin must be free from randomization. A mechanism for the isomerization of isopentenyl pyrophosphate to dimethylallyl pyrophosphate is suggested.


Diastereo- and Enantioselective Synthesis of Tetracyclic Cycloheptanols through (4+3) Annulation via C-C/C-H Activation Cascade.
Transition metal-catalyzed annulations of four-membered rings via C-C activation are powerful tools to construct complex fused and bridged ring systems. Despite significant progress in (4+1), (4+2) and (4+4) annulations, the (4+3) annulation remains unexplored. Herein, we develop an asymmetric Rh-catalyzed intramolecular (4+3) annulation of α-arylalkene-tethered benzocyclobutenols for the synthesis of dihydrofuran-annulated dibenzocycloheptanols with two discontinuous chiral carbon centers via a C-C and C-H activation cascade. The reaction features excellent diastereo- and enantioselectivities and 100% atom economy, and is applicable to late-stage modification of complex molecules.


Biogenic amine content of shalgam (salgam): a traditional lactic acid fermented Turkish beverage.
Shalgam is a traditional Turkish fermented beverage. The biogenic amine contents of 20 shalgam samples from different manufacturers in Turkey were analyzed for the first time, using HPLC after derivatization with benzoyl chloride. Of the 10 biogenic amines under study, putrescine, cadaverine, histamine, and tyramine were detected in all shalgam samples. Putrescine was the prevailing biogenic amine. Putrescine concentrations were between 5.0 and 42.3 mg/L. Total biogenic amine contents were between 26.7 and 134.3 mg/L. Concentrations of biogenic amines were below the maximum permissible limits. pH values of shalgam samples were in the range from 3.15 to 4.25; acidities of shalgam samples were from 0.530% to 1.028% (w/v); total dry matter values were from 2.33% to 3.67% (w/w); total free amino acid contents were from 0.0074% to 0.0318% (w/v). Significant correlations were detected between biogenic amine concentrations and pH values, acidities, total dry matter contents, and total free amino acid contents.


The relationship between social risk factors and latent tuberculosis infection among individuals residing in England: a cross-sectional study.
To investigate the relationship between social risk factors and latent tuberculosis infection (LTBI) among individuals who are eligible for LTBI screening in the United Kingdom (UK). This cross-sectional study used data collected in the UK Prognostic Evaluation of Diagnostic Interferon-Gamma Release Assays (IGRAs) Consortium Study which enrolled 9176 recent tuberculosis (TB) contacts and migrants at National Health Service (NHS) facilities and community settings in the UK. The study outcome was LTBI (positive IGRA test (QuantiFERON-TB Gold In-Tube or T-SPOT.TB)). The main exposures were history of smoking, history of substance misuse, homelessness, prison stay and socioeconomic deprivation. 4914 (56.2%) individuals resided in the most deprived areas and 2536 (27.6%) had LTBI. In the multivariable analysis (adjusting for age, gender, place of birth, ethnicity, HIV status, BCG vaccination and recent TB contact) living in the least deprived areas compared with living in the most deprived areas was associated with reduced odds of LTBI (odds ratio (OR)=0.68, 95% CI: 0.51 to 0.90) while ever been homeless (OR=1.50, 95% CI: 1.02 to 2.21) was associated with increased odds of LTBI. Smoking, homelessness and substance misuse were not associated with LTBI. Social deprivation could be an important risk factor for LTBI, highlighting the social inequality in the burden of TB infection in the UK. Migrants and TB contacts who were socially deprived or homeless were at a significantly higher risk for LTBI, thus tailored intense public health interventions to these groups may help to reduce the risk of future TB disease. ClinicalTrials.gov Registry (NCT01162265).


Structure-Activity Relationships of Triphenylethylene Derivatives and Their Evaluation as Anticancer and Antiviral Agents.
Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) that is used in the treatment of breast cancer, yet with the risk of developing uterine cancer. A perfect SERM would act as an estrogen activator on bones, the cardiovascular system, and the central nervous system while providing neutral or estrogen blocking effects on the breast and the uterus. Herein, we report on the design, synthesis, and evaluation of new rigid and flexible TAM analogues. Mainly, a chloro substituent is introduced at the para position of the TAM ring C blocking the CYP2D6 hydroxylation site. Most compounds showed estrogenic activity higher than TAM using the yeast estrogen screen assays, indicating the determinant role of the chloro substituent upon functional activity. Despite being estrogenic, compound 2B showed potent antiproliferative activity in the NCI 60 cell lines with mean GI50 = 3.67 μM, GI50 = 1.05 μM on MCF-7 cell lines, and GI50 = 1.30 μM on MDA-MB-231. The estrogenic activity of compound 2B was further confirmed by stimulating alkaline phosphatase in Ishikawa cells, and it showed no increase in relative uterine wet weight in ovariectomized rats. Compound 2F showed EC90 = 0.31 μg/mL and SI90 = 60 against Ebola virus; this is 200-fold more potent than the positive control favipiravir. This is the first time to report estrogenic triphenylethylenes as anti-EBOV agents. The anti-EBOV activity reported is a function of the substitution pattern of the scaffold rather than the functional activity. Moreover, compound 3D showed excellent PO pharmacokinetic properties in mice. In conclusion, for this class of TAM-like compounds, the blockage of the p-position of ring C is decisive for the functional activity; meanwhile, the triarylethylene substitution pattern is detrimental for the antiviral activity.


[Intraarterial therapy of maxillary adenoid cystic carcinoma using cis-platinum (author's transl)].
A woman suffering from extended maxillary adenoid cystic carcinoma of mixed cribriform solid type was treated by selective intraarterial infusion of Cisplatinum using a new intraarterial infusion technique. Within four weeks--the entire dosage of Cisplatinum was 400 mg--the patient came into complete remission, clinically and histologically, suggesting that the adenoid cystic carcinoma may be more susceptible to chemotherapy than thought up to the present day. However, primary chemotherapy should be followed by radiotherapy or surgical treatment.


The Implication of Coronary Artery Calcium Testing for Cardiovascular Disease Prevention and Diabetes.
Over the last two decades coronary artery calcium (CAC) scanning has emerged as a quick, safe, and inexpensive method to detect the presence of coronary atherosclerosis. Data from multiple studies has shown that compared to individuals who do not have any coronary calcifications, those with severe calcifications (i.e., CAC score >300) have a 10-fold increase in their risk of coronary heart disease events and cardiovascular disease. Conversely, those that have a CAC of 0 have a very low event rate (~0.1%/year), with data that now extends to 15 years in some studies. Thus, the most notable implication of identifying CAC in individuals who do not have known cardiovascular disease is that it allows targeting of more aggressive therapies to those who have the highest risk of having future events. Such identification of risk is especially important for individuals who are not on any therapies for coronary heart disease, or when intensification of treatment is being considered but has an uncertain role. This review will highlight some of the recent data on CAC testing, while focusing on the implications of those findings on patient management. The evolving role of CAC in patients with diabetes will also be highlighted.


Glycemic control in patients with diabetes mellitus upon admission to a dental clinic: considerations for dental management.
The purpose of this study was to determine the level of glycemic control in dental patients with diabetes upon admission to a dental school clinic. One hundred patients (mean age: 57.7 years) of the Oral Diagnosis-Admissions Clinic at the University of Minnesota School of Dentistry, Minneapolis, Minnesota, with diabetes mellitus were chosen as subjects. Fasting blood glucose was measured using a portable blood glucose monitoring device as a part of their initial dental examination. Twenty-eight of the 100 patients were found to be hyperglycemic (> or = 126 mg/dl; 174.8 +/- 40.8 mg/dl; mean +/- SEM); 2 patients were found to be hypoglycemic (< 70 mg/dl). Of the 8 patients with type 1 diabetes in the cohort, 3 (37.5%) were very hyperglycemic, with fasting blood glucose levels > 250 mg/dl. This is important information for dental practitioners because patients with diabetes may not be under good glycemic control, and dentists may have to take special precautions before, during, and after treatment. This paper reviews the pathogenesis of diabetes, the detection of patients with undiagnosed or poorly controlled diabetes, and the management of patients with diabetes during dental treatment.


Prevalence of sexually transmitted infections and performance of STI syndromes against aetiological diagnosis, in female sex workers of red light area in Surat, India.
To measure prevalence of selected sexually transmitted infections (STI) and HIV among female sex workers (SWs) in the red light area of Surat, India, and to evaluate the performance of STI syndrome guidelines (for general population women in India) in this group against the standard aetiological diagnosis of STIs by laboratory methods. In a cross sectional study, 124 out of an estimated total of 500 SWs were mobilised to a health camp near the red light area during 2000. After obtaining consent, a behavioural questionnaire was administered, followed by clinical examination and specimen collection for different STIs. 118 SWs completed all aspects of the survey. HIV testing was unlinked and anonymous. The mean number of different sexual partners of SWs per day was five. 94.9% reported consistent condom use with the clients. 58.5% of SWs had no symptoms related to STDs at the time of examination. Reported symptoms included lower abdominal pain (19.5%), abnormal vaginal discharge (12.7%), painful sexual intercourse (12.7%), painful micturition (11.0%), itching around the genital area (10.2%), and genital ulcer (5.9%). The prevalence of STI "syndromes" were vaginal discharge syndrome 51.7%, pain in lower abdomen 19.5%, enlarged inguinal lymph nodes 11.9%, and genital ulcer 5.9%. Based on the laboratory reports (excluding HIV tests), 62 (52.5%) SWs did not have any of the four tested STIs. Prevalence of laboratory confirmed STIs were syphilis 22.7% (based on reactive syphilis serology tests), gonorrhoea 16.9%, genital chlamydial infection 8.5%, and trichomoniasis 14.4%. HIV prevalence was 43.2%. The performance of Indian recommended treatment guidelines for vaginal discharge syndrome (VDS) and genital ulcer syndrome (GUS) against aetiological diagnosis was poor. Prevalence of different STIs and HIV among the FSWs in the Surat red light area is high despite high reported condom use with clients. Syndromic case management is missing a large number of asymptomatic cases and providing treatment in the absence of disease. Therefore, it is necessary to explore alternative strategies for control of STIs in female sex workers. STI services need to be improved.


Local adaptations in bryophytes revisited: the genetic structure of the calcium-tolerant peatmoss Sphagnum warnstorfii along geographic and pH gradients.
Bryophytes dominate some ecosystems despite their extraordinary sensitivity to habitat quality. Nevertheless, some species behave differently across various regions. The existence of local adaptations is questioned by a high dispersal ability, which is thought to redistribute genetic variability among populations. Although Sphagnum warnstorfii is an important ecosystem engineer in fen peatlands, the causes of its rather wide niche along the pH/calcium gradient are poorly understood. Here, we studied the genetic variability of its global populations, with a detailed focus on the wide pH/calcium gradient in Central Europe. Principal coordinates analysis of 12 polymorphic microsatellite loci revealed a significant gradient coinciding with water pH, but independent of geography; even samples from the same fens were clearly separated along this gradient. However, most of the genetic variations remained unexplained, possibly because of the introgression from phylogenetically allied species. This explanation is supported by the small heterogeneous cluster of samples that appeared when populations morphologically transitional to S. subnites, S. rubellum, or S. russowii were included into the analysis. Alternatively, this unexplained variation might be attributed to a legacy of glacial refugia with recently dissolved ecological and biogeographic consequences. Isolation by distance appeared at the smallest scale only (up to 43 km). Negative spatial correlations occurred more frequently, mainly at long distances (up to 950 km), implying a genetic similarity among samples which are very distant geographically. Our results confirm the high dispersal ability of peatmosses, but simultaneously suggested that their ability to cope with a high pH/calcium level is at least partially determined genetically, perhaps via specific physiological mechanisms or a hummock-forming ability.


Efficacy of two non-antibiotic therapies, oxytocin and topical liniment, against bovine staphylococcal mastitis.
Eight cows were challenged by a single quarter intramammary infusion of a relatively low-virulence strain of Staphylococcus aureus on four occasions five weeks apart and, after each challenge, each cow received one of four treatments, according to a duplicated Latin-square design. The treatments were massage alone (negative control), massage with a proprietary liniment, oxytocin, and a single course of a proprietary intramammary antibiotic. The massage treatments were applied at every milking for three weeks, oxytocin was given for one week, and the antibiotic was given after three successive milkings. Milk samples were collected immediately before and for three weeks after each challenge, and a scoring system was used to quantify the presence of bacteria during the whole of the period. None of the treatments completely eliminated bacteria from all the cows. Relative to the negative control, the liniment had no significant effect, but both oxytocin and the antibiotic reduced the numbers of bacteria significantly and did not differ significantly in efficacy.


[A derivative of the X(Z) chromosome causes a change in the mutability properties of genes in homologous chromosomes from unstable lines of Drosophila melanogaster].
The impact of an XZ chromosome derivative, the In(1)T2,ymosWYIsnmYI strain, on mutation and reversion frequencies in strains with the unstable yellow gene is analyzed. These strains were isolated during a yellow mutation outbreak observed in the natural population of Drosophila melanogaster in Uman' (Ukraine) from 1982 to 1991. The In(1)T2,YmosWYIsnmYI chromosome was shown to suppress yellow gene mutability and activate singed gene mutability. A possible mechanism of homologous suppression and destabilization is considered.


Proliferative capacity of murine hematopoietic stem cells in vitro.
Large numbers of granulocytes can be collected repeatedly from the supernatant medium of long-term cultures of mouse bone marrow cells. A constant relationship was found between the number of adherent hematopoietic stem cells and the lifetime cell production per culture. The data indicate that there is a limit to the proliferative capacity of normal and of irradiated stem cells. A similar limitation was found in the production of marked granulocytes from clonal cultures of "beige" C57 (bg/bgJ) stem cells placed in limiting dilutions into stromal culture layers.


Ex vivo lipopolysaccharide (LPS)-induced TNF-alpha, IL-1beta, IL-6 and PGE2 secretion in whole blood from Type 1 diabetes mellitus patients with or without aggressive periodontitis.
Several studies have demonstrated that diabetes is a risk factor for developing periodontal disease, increasing its prevalence and severity. Furthermore, periodontitis may impair the metabolic control and adequate treatment of diabetic patients. LPS from Gram-negative bacteria penetrates the periodontal tissues and subsequently recruits and activates immune cells. Progression to severe periodontitis with loss of supporting structures is mediated by several factors, including secretion of a broad spectrum of inflammatory and destructive (PGE2). mediators such as cytokines (TNF-alpha, IL-1b and IL-6), chemokines (IL-8) and prostaglandin E2. The aim of this work is to investigate differences in the TNF-a, IL-1b and IL-6 expression and prostaglandin E2 (PGE2) release in blood from diabetic patients with and without aggressive periodontitis (AP) stimulated with lipopolysaccharide (LPS). For this purpose we recruited 29 Type 1 diabetes mellitus (DM) patients, 14 with AP and 15 without AP. Fourteen healthy individuals formed the control group. For cytokine expression and PGE2 secretion, an ex vivo whole blood culture system was used. Cytokines and PGE2 were detected by commercial immunometric assays. A wide range of inter-individual variability in spontaneous and LPS-induced TNF-alpha, IL-1b and IL-6 levels in patient groups and controls was found. The mean of spontaneous and LPS-induced TNF-alpha and IL-1b levels did not differ significantly (p > 0.5) when patients were compared to control individuals. Although not significant, the spontaneous TNF-alpha, IL-1b and IL-6 levels in the group of Type 1 DM with AP were higher than in controls, while in diabetic patients without AP, these values were depressed in comparison with controls. In both groups of patients, the means of LPS-induced IL-6 levels were higher than the controls but the differences observed were not significant (p = 0.07). However, the LPS-induced PGE2 levels varied significantly when all groups were compared (p = 0.007). The means of LPS-induced PGE2 levels for Type 1 diabetic patients with AP (p = 0.0009) and without AP (p = 0.024) were significantly higher than the levels observed for healthy controls. Finally, we conclude that Type 1 diabetic patients with or without AP did not express higher LPS-induced TNF-a, IL-1b and IL-6 levels than controls. However, the PGE2 levels released were significantly higher than those detected in controls.


Molecular mechanisms of sorafenib action in liver cancer cells.
Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced hepatocellular carcinoma (HCC). However, as the clinical application of sorafenib evolves, there is increasing interest in defining the mechanisms underlying its anti-tumor activity. Considering that this specific inhibitor could target unexpected molecules depending on the biologic context, a precise understanding of its mechanism of action could be critical to maximize its treatment efficacy, while minimizing adverse effects. Two human HCC cell lines (HepG2 and Huh7), carrying different biological and genetic characteristics, were used in this study to examine the intracellular events leading to sorafenib-induced HCC cell-growth inhibition. Sorafenib inhibited cell growth in both cell lines in a dose- and time-dependent manner and significantly altered expression levels of 826 and 2011 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in angiogenesis, apoptosis, transcription regulation, signal transduction, protein biosynthesis and modification were predominantly upregulated, while genes implicated in cell cycle control, DNA replication recombination and repair, cell adhesion, metabolism and transport were mainly downregulated upon treatment. However, each sorafenib-treated HCC cell line displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semiquantitative and quantitative RT-PCR and by western blotting. Many novel genes emerged from our transcriptomics analysis that had not previously been reported to be effected by sorafenib. Further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies.


Osteocyte remodeling of the perilacunar and pericanalicular matrix.
With additional functions of osteocytes being identified, the concept that osteocytes are just "static lacunar-dwelling cells" is no longer accepted. We reviewed most of the relevant literature on osteocyte's function in the direct remodeling of the perilucunar matrix, discussing the advantages and disadvantages. Special attention was paid to how the negative researchers argue about the "osteocytic osteolysis" principle, and how the positive side addressed the arguments. We also discussed the newly found data of osteocytic remodeling function from our group. With more biotechnology in hand, there is increased excitement in the prospect of now being able to answer the two important questions: do osteocytes have the capability to remove mineral from the perilacunar matrix and if so what are the molecular and cellular mechanisms? do osteocytes have the capability to deposit new mineral on the perilacunar matrix and if so what are the cellular and molecular mechanisms?


Postpartum hemorrhage: when uterotonics and sutures fail.
Systemic bleeding at the time of postpartum hemorrhage (PPH) is usually the result of coagulopathy that has developed acutely as a result of massive hemorrhage after uterotonics and sutures have failed. Occasionally, the patient has a preexisting coagulopathy, but more often, coagulopathy arises acutely as the result of massive hemorrhage, which is usually related to obstetrical and less often surgical bleeding. Despite being able to identify risk factors for PPH in the antenatal and intrapartum period, the majority of women who ultimately develop PPH do not have any such factors and every pregnancy is at risk. The coagulopathy associated with massive PPH may be due to hemodilution, failure of liver synthetic function as occurs with acute liver failure of pregnancy, or disseminated intravascular coagulation (DIC). There are no data from clinical trials to help guide management of transfusion in PPH, although the management of blood component therapy in severe PPH is similar to that in other massive hemorrhage. Standard practice is to replace fibrinogen to maintain a level of ≥ 100 mg/dL, yet recent evidence suggests that the level of fibrinogen needed to prevent PPH is at least 400 mg/dL. Recombinant activated factor VIIa (rFVIIa) has been used in the management of severe PPH unresponsive to blood component therapy. Coagulation laboratory evaluation may be useful in guiding hemostatic management during massive PPH, but for the results to be useful, they must be rapidly available and provide information that would not be available from clinical assessment alone. The hematologist or hemostasis expert has the opportunity to make the difference between life and death for the patient experiencing massive PPH.


Towards an improved pain assessment in castrated horses using facial expressions (HGS) and circulating miRNAs.
Pain in horses is an emergent welfare concern, and its assessment represents a challenge for equine clinicians. This study aimed at improving pain assessment in horses through a convergent validation of existing tools: we investigated whether an effective analgesic treatment influences the horse grimace scale (HGS) and the concentration of specific circulating microRNAs (miRNAs). Eleven stallions underwent routine surgical castration under general anaesthesia. They were divided into two analgesic treatment groups: castration with the administration of preoperative flunixin and castration with preoperative flunixin plus a local injection of mepivacaine into the spermatic cords. HGS and levels of seven circulating miRNAs were evaluated pre-, 8 and 20 hours post-procedure. Compared to pre-castration, HGS, miR-126-5p, miR-145 and miR-let7e increased significantly in horses receiving flunixin at 8 hours post-castration (Friedman test, p < 0.05). Both behavioural and molecular changes occurred in horses receiving flunixin only, confirming that the addition of local mepivacaine is an effective analgesic treatment. Combining the use of HGS and circulating miRNAs, particularly miR-145, could be meaningful to monitor acute pain conditions in horses. Our results further validate the HGS as a method to assess acute pain in horses and point out miR-145 as a promising biomarker to identify pain.


Histiocytosis X of the larynx.
The present report is concerned with the observation of histiocytosis X in the larynx in a man aged 57 years. This localisation of the process is quite unusual and we have found only one similar case in the literature. The differential diagnosis and possible etiological factors are briefly discussed.


Age-related sensitive periods influence visual language discrimination in adults.
Adults as well as infants have the capacity to discriminate languages based on visual speech alone. Here, we investigated whether adults' ability to discriminate languages based on visual speech cues is influenced by the age of language acquisition. Adult participants who had all learned English (as a first or second language) but did not speak French were shown faces of bilingual (French/English) speakers silently reciting sentences in either language. Using only visual speech information, adults who had learned English from birth or as a second language before the age of 6 could discriminate between French and English significantly better than chance. However, adults who had learned English as a second language after age 6 failed to discriminate these two languages, suggesting that early childhood exposure is crucial for using relevant visual speech information to separate languages visually. These findings raise the possibility that lowered sensitivity to non-native visual speech cues may contribute to the difficulties encountered when learning a new language in adulthood.


Genetic insights into the microevolutionary dynamics and early introductions of human monkeypox virus in Mexico.
The recent global outbreak of mpox, caused by monkeypox virus (MPV) emerged in Europe in 2022 and rapidly spread to over 40 countries. The Americas are currently facing the highest impact, reporting over 50,000 cases by early 2023. In this study, we analyzed 880 MPV isolates worldwide to gain insights into the evolutionary patterns and initial introduction events of the virus in Mexico. We found that MPV entered Mexico on multiple occasions, from the United Kingdom, Portugal, and Canada, and subsequently spread locally in different regions of Mexico. Additionally, we show that MPV has an open pangenome, highlighting the role of gene turnover in shaping its genomic diversity, rather than single-nucleotide polymorphisms (SNPs), which do not contribute significantly to genome diversity. Although the genome contains multiple SNPs in coding regions, these remain under purifying selection, suggesting their evolutionary conservation. One notable exception is amino acid position 63 of the protein encoded by the Cop-A4L gene, which is intricately related to viral maturity, which we found to be under strong positive selection. Ancestral state reconstruction indicated that the ancestral state at position 63 corresponds to the amino acid valine, which is present only in isolates of clade I. However, the isolates from the current outbreak contained threonine at position 63. Our findings contribute new information about the evolution of monkeypox virus.


Behavioral cues to expand a pain model of the cognitively impaired elderly in long-term care.
The purpose of this study was to determine the relationship between hypothesized pain behaviors in the elderly and a measurement model of pain derived from the Minimum Data Set-Resident Assessment Instrument (MDS-RAI) 2.0 items. This work included a longitudinal cohort recruited from Medicare-certified longterm care facilities across the United States. MDS data were collected from 52,996 residents (mean age 83.7 years). Structural equation modeling was used to build a measurement model of pain to test correlations between indicators and the fit of the model by cognitive status. The model evaluates the theoretical constructs of pain to improve how pain is assessed and detected within cognitive levels. Using pain frequency and intensity as the only indicators of pain, the overall prevalence of pain was 31.2%; however, analysis by cognitive status showed that 47.7% of the intact group was in pain, while only 18.2% of the severely, 29.4% of the moderately, and 39.6% of the mildly cognitively impaired groups were experiencing pain. This finding supports previous research indicating that pain is potentially under-reported in severely cognitively impaired elderly nursing home residents. With adjustments to the measurement model, a revised format containing affective, behavioral, and inferred pain indicates a better fit of the data to include these domains, as a more complete measure of the pain construct. Pain has a significant effect on quality of life and long-term health outcomes in nursing home residents. Patients most at risk are those with mild to severe cognitive decline, or those unable to report pain verbally. Nursing homes are under great scrutiny to maintain standards of care and provide uniform high-quality care outcomes. Existing data from federally required resident surveys can serve as a valuable tool to identify indicators of pain and trends in care. Great responsibility lies in ensuring pain is included and monitored as a quality measure in long-term care, especially for residents unable to communicate their pain verbally.


Ultrasonographic blood flow measurement in the carotid arteries in postmenopausal women.
The aim of the present study was to evaluate blood flow in postmenopausal women on hormone replacement therapy (HRT) compared to controls. Blood flow was ultrasonographically measured in the great arteries of the neck instead of in the vessels of the internal genital organs. Fifty healthy women with climacteric complaints, at least 6 months postmenopausal, participated in the study. They were randomly divided into two groups. One group received 2 mg estradiol (E2) for 12 days, continued with 2 mg E2 and 1 mg norethisterone acetate for 10 days, followed by 1 mg E2 for 6 days, cyclically during 6 months. The other group received placebo tablets the first 3 months and the same HRT as the first group for the last 3 months. Blood flow was measured ultrasonographically by color flow pulsed Doppler in the common (CCA), internal (ICA) and external (ECA) carotid arteries, before the start of the study, after 3 and 6 months of therapy. CCA and ICA, both low resistance vessels, and ECA, a high resistance vessel, and their waveforms were identified. Pulsatility index did not decrease statistically significant (p > 0.05) in any of the great vessels during 6 months of HRT in this study. There were no differences in blood flow between the HRT-treated group compared to control group during 3 months of therapy, except for the right ECA (p = 0.04). The difference in blood flow and wave-forms of the major arteries of the neck were clearly shown, but HRT did not have any important impact on the blood flow in this study. No difference was shown concerning blood flow between the two groups of postmenopausal women, on active therapy or placebo.


Ectopic pregnancy.
Ectopic pregnancy is a major gynecologic emergency, which results in significant morbidity for the mother and inevitable loss of the pregnancy. Its presentation can be varied from minor symptoms to sudden collapse. It produces a diagnostic dilemma and a management problem. With advances in medical care, most women survive ectopic pregnancy and many will be diagnosed early enough to allow conservative management with the resulting lower morbidity and possible anatomic conservation. This article covers what is currently known about the etiology of this condition, the best approach to the diagnoses and management and the long-term consequences for the women concerned.


MRI in traumatic spinal cord injury: from clinical assessment to neuroimaging biomarkers.
Traumatic spinal cord injury occurs when an external physical impact damages the spinal cord and leads to permanent neurological dysfunction and disability, and it is associated with a high socioeconomic burden. Conventional MRI plays a crucial role in the diagnostic workup as it reveals extrinsic compression of the spinal cord and disruption of the discoligamentous complex. Additionally, it can reveal macrostructural evidence of primary intramedullary damage such as haemorrhage, oedema, post-traumatic cystic cavities, and tissue bridges. Quantitative MRI, such as magnetisation transfer, magnetic resonance relaxation mapping, and diffusion imaging, enables the tracking of secondary changes across the neuraxis at the microstructural level. Both conventional MRI and quantitative MRI metrics, obtained early after spinal cord injury, are predictive of clinical outcome. Thus, neuroimaging biomarkers could serve as surrogate endpoints for more efficient future trials targeting acute and chronic spinal cord injury. The adoption of neuroimaging biomarkers in centres for spinal cord injury might lead to personalised patient care.


Opinions about euthanasia and advanced dementia: a qualitative study among Dutch physicians and members of the general public.
The Dutch law states that a physician may perform euthanasia according to a written advance euthanasia directive (AED) when a patient is incompetent as long as all legal criteria of due care are met. This may also hold for patients with advanced dementia. We investigated the differing opinions of physicians and members of the general public on the acceptability of euthanasia in patients with advanced dementia. In this qualitative study, 16 medical specialists, 19 general practitioners, 16 elderly physicians and 16 members of the general public were interviewed and asked for their opinions about a vignette on euthanasia based on an AED in a patient with advanced dementia. Members of the general public perceived advanced dementia as a debilitating and degrading disease. Physicians emphasized the need for direct communication with the patient when making decisions about euthanasia. Respondent from both groups acknowledged difficulties in the assessment of patients' autonomous wishes and the unbearableness of their suffering. Legally, an AED may replace direct communication with patients about their request for euthanasia. In practice, physicians are reluctant to forego adequate verbal communication with the patient because they wish to verify the voluntariness of patients' request and the unbearableness of suffering. For this reason, the applicability of AEDs in advanced dementia seems limited.


[The analgesic effect of exercise during labor].
The aim of this study was to test for an analgesic effect of exercise during labor. 50 women in labor exercised continuously with moderate intensity on a bicycle ergometer for 20 minutes. During rest and exercise, they rated their pain on a visual analogue scale (VAS). Venous blood was sampled for beta-endorphin, cortisol and catecholamines during rest and directly after exercise. 84 percent of the women perceived uterine contractions during exercise as less painful than at rest. 76.2 percent objectified the pain relief by a reduction in VAS units 1.67 +/- 1.01. Beta-endorphin levels were much higher after exercise than at rest (P < 0.001). During exercise the fetal heart rate rose slightly within the reference range. Uterine contractions were more frequent during and after exercise than at rest (P < 0.05). Exercising on a bicycle ergometer during labor seems to be safe for the fetus, a stimulus to uterine contractions, and a source of analgesia, possibly due to the release of beta-endorphin.


Photodepletion differentially affects CD4+ Tregs versus CD4+ effector T cells from patients with chronic graft-versus-host disease.
Even the most potent immunosuppressive drugs often fail to control graft-versus-host disease (GVHD), the most frequent and deleterious posttransplantation complication. We previously reported that photodepletion using dibromorhodamine (TH9402) eliminates T cells from healthy donors activated against major histocompatibility complex-incompatible cells and spares resting T cells. In the present study, we identified photodepletion conditions selectively eradicating endogenous proliferating T cells from chronic GVHD patients, with the concomittant sparing and expansion of CD4(+)CD25(+) forkhead box protein 3-positive T cells. The regulatory T-cell (Treg) nature and function of these photodepletion-resistant cells was demonstrated in coculture and depletion/repletion experiments. The mechanism by which Tregs escape photodepletion involves active P-glycoprotein-mediated drug efflux. This Treg-inhibitory activity is attributable to interleukin-10 secretion, requires cell-cell contact, and implies binding with cytotoxic T-lymphocyte antigen 4 (CTLA-4). Preventing CTLA-4 ligation abrogated the in vitro generation of Tregs, thus identifying CTLA-4-mediated cell-cell contact as a crucial priming event for Treg function. Moreover, the frequency of circulating Tregs increased in chronic GVHD patients treated with TH9402 photodepleted cells. In conclusion, these results identify a novel approach to both preserve and expand Tregs while selectively eliminating CD4(+) effector T cells. They also uncover effector pathways that could be used advantageously for the treatment of patients with refractory GVHD.


Report of the third international workshop on molecular blood group genotyping.
The Third International Society of Blood Transfusion Workshop on Molecular Blood Group Genotyping was held in 2008, with a feedback meeting at the International Society of Blood Transfusion Congress in Macao SAR, China. Thirty-three laboratories participated, eight less than in 2006. Six samples were distributed: sample 1 representing DNA from a sample referred because of abnormal serological results in D testing; samples 2 and 3 from transfusion-dependent patients for testing for all clinically important polymorphisms; sample 4 a mixture of two DNA samples designed to simulate a chimera, referred because of abnormal serological results in donor testing; and samples 5 and 6 plasma samples from RhD-negative pregnant women, for fetal RhD testing (only tested by 17 laboratories). For samples 1-3, 24 of 33 laboratories obtained completely correct results. For sample 4, the ability to detect the minority DNA population was partly dependent on method. Of the 17 laboratories that received samples 5 and 6, 13 reported correct results on both samples. Overall a small improvement from previous workshops was noted, but there is still room for improvement. The main conclusion for the 2006 workshop can be reiterated: with greater care and attention to detail, very high standards could be set for molecular blood group genotyping.


Attention alters feature space in motion processing.
Attending to a particular feature modulates the activity of neurons throughout the visual field with the result that relevant features are enhanced while irrelevant features are suppressed. Do these modulatory influences merely lead to a gating of relevant features, or does attention have a direct impact on the representation of feature space, leading to a different percept depending on the content of attention? We observed that direction estimates of the static motion aftereffect drastically change when human observers attend to a stimulus whose motion direction differs from the one of the adaptor. This observation suggests that feature-based attention might operate by local magnifications of feature space between relevant and irrelevant features.


Non-elective caesarean delivery due to ineffective uterine contractility or due to obstructed labour in relation to maternal body mass index.
To assess whether non-elective caesarean section due to obstructed labour and/or ineffective uterine contractility was associated with maternal body mass index (BMI). The prospective dataset from the Swedish Medical Birth Registry consisted of 233,887 nulliparous women with a spontaneous onset of labour categorized in six classes of pre-pregnancy BMI, who delivered in Sweden between, January 1, 1999 and December 31, 2005. The mode of delivery was classified as either vaginal or by caesarean section. The caesarean section was classified as either elective or non-elective. Adjusted risks for non-elective caesarean section due to ineffective uterine contractility, or obstructed labour or fetal distress were determined using Mantel-Haenszel technique. The risk of a non-elective caesarean section due to obstructed labour was not significantly associated with maternal BMI. However, ineffective uterine contractility was significantly associated with maternal BMI and the risk of non-elective caesarean delivery due to labour arrest disorders increased with increasing BMI, reaching a 4-fold increased risk among the morbidly obese women. The risk of non-elective caesarean section due to fetal distress also increased significantly with increasing maternal BMI. It appears that ineffective labour could be a factor leading to the increased risk of non-elective caesarean section among obese and morbidly obese women. These findings challenge obstetricians to learn more about how to manage oxytocin infusions during labour in relation to maternal BMI.