The global magnetic field of Mercury from MESSENGER orbital observations.
Magnetometer data acquired by the MESSENGER spacecraft in orbit about Mercury permit the separation of internal and external magnetic field contributions. The global planetary field is represented as a southward-directed, spin-aligned, offset dipole centered on the spin axis. Positions where the cylindrical radial magnetic field component vanishes were used to map the magnetic equator and reveal an offset of 484 ± 11 kilometers northward of the geographic equator. The magnetic axis is tilted by less than 3° from the rotation axis. A magnetopause and tail-current model was defined by using 332 magnetopause crossing locations. Residuals of the net external and offset-dipole fields from observations north of 30°N yield a best-fit planetary moment of 195 ± 10 nanotesla-R(M)(3), where R(M) is Mercury's mean radius.


Pre-eclampsia: the role of highly active antiretroviral therapy and immune markers.
This review highlights the role immune cells and markers such as natural killer (NK) cells, cytokines and human leukocyte antigen (HLA-G) play in predisposing HIV-infected women who are on HAART to develop PE, thus contributing to a better understanding and early diagnosis of PE with a subsequent reduction in maternal foetal and neonatal deaths. Pregnant women infected with the Human Immunodeficiency Virus (HIV) have a 25% risk of mother to child transmission. This risk, however, decreases to 2% if the women is on treatment. Highly active antiretroviral therapy (HAART) is the recommended treatment for both pregnant and non-pregnant women infected with HIV. Treatment with HAART is reported to potentiate predisposition to the development of hypertensive disorders of pregnancy such as pre-eclampsia (PE). Pre-eclampsia accounts for 7-10% of abnormal pregnancies worldwide. Studies demonstrate that pregnant women with HIV have PE at lower frequencies than uninfected women, however, the converse is observed upon HAART initiation. HIV-infected women on HAART exhibit a greater tendency to develop PE, emanating from immune reconstitution induced by HAART. There is paucity of information as to the pathogenesis of PE upon HAART initiation and there are, therefore, controversial data as to whether HAART predisposes women to a lower, equal or higher risk of PE development compared to the general population, further investigations on the impact of HIV infection and HAART on the immune response and rate of PE development in HIV infected pregnant women are urgently needed.


mtDNA variability in two Bantu-speaking populations (Shona and Hutu) from Eastern Africa: implications for peopling and migration patterns in sub-Saharan Africa.
In this study, we report novel data on mitochondrial DNA in two of the largest eastern Bantu-speaking populations, the Shona from Zimbabwe and the Hutu from Rwanda. The goal is to evaluate the genetic relationships of these two ethnic groups with other Bantu-speaking populations. Moreover, by comparing our data with those from other Niger-Congo speaking populations, we aim to clarify some aspects of evolutionary and demographic processes accompanying the spread of Bantu languages in sub-Saharan Africa and to test if patterns of genetic variation fit with models of population expansion based on linguistic and archeological data. The results indicate that the Shona and Hutu are closely related to the other Bantu-speaking populations. However, there are some differences in haplogroup composition between the two populations, mainly due to different genetic contributions from neighboring populations. This result is confirmed by estimates of migration rates which show high levels of gene flow not only between pairs of Bantu-speaking populations, but also between Bantu and non-Bantu speakers. The observed pattern of genetic variability (high genetic homogeneity and high levels of gene flow) supports a linguistic model suggesting a gradual spread of Bantu-speakers, with strong interactions between the different lines of Bantu-speaker descent, and is also in agreement with recent archeological findings. In conclusion, our data emphasize the role that population admixture has played at different times and to varying degrees in the dispersal of Bantu languages.


Methylation-dependent Tissue Factor Suppression Contributes to the Reduced Malignancy of IDH1-mutant Gliomas.
Gliomas with isocitrate dehydrogenase 1 mutations (IDH1mut) are less aggressive than IDH1 wild-type (IDH1wt) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1mut phenotype. Previously, we showed that the gene encoding the procoagulant tissue factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1mut gliomas, correlating with greatly reduced thrombosis in patients with IDH1mut glioma. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1mut gliomas.Experimental Design: TF expression was manipulated in patient-derived IDH1mut and IDH1wt glioma cells, followed by evaluation of in vitro and in vivo behavior and analyses of cell signaling pathways. A demethylating agent, decitabine, increased F3 transcription and TF-dependent coagulative activity in IDH1mut cells, but not in IDH1wt cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1mut cells, and increased the intracranial engraftment of IDH1mut GBM164 from 0% to 100% (P = 0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1wt/EGFRvIIIamp GBM6, and caused complete regression of IDH1wt/EGFRamp GBM12 (P = 0.001). In vitro and in vivo effects were linked to activation of receptor tyrosine kinases (RTK) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of β-catenin. These data show that TF suppression is a component of IDH1mut glioma behavior, and that it may therefore be an attractive target against IDH1wt gliomas.


All fiber polarimetric modulation using an electro-optic fiber with internal Pb-Sn electrodes.
All fiber electro-optic modulation using a polarimetric cell based on an electro-optic fiber with internal Pb-Sn electrodes was demonstrated. For the polarimetric cell, the electro-optic fiber with two 149 cm long internal electrodes was fabricated by injection of a molten Pb-Sn alloy into the holes of the fiber. The characteristics of the modulation were explained by the electric field induced phase retardation due to the polarization dependent electro-optic Kerr effect. The difference in the effective second order nonlinearity between TM and TE polarization directions was obtained to be 0.0035 pm/V at the applied DC voltage of 6.5 kV.


Background factors related to and/or influencing occupation in mentally disordered offenders.
Knowledge of background and occupational related factors of mentally disordered offenders are missing. It is essential to understand these issues when planning discharge from forensic psychiatric hospital care to enable community dwelling. One aim was to investigate mentally disordered offenders' background factors, confidence in and how they value occupations. Another aim was to investigate MDOs background factors' in relation to and the influences on Occupational Performance and Social Participation. Data was collected with an explorative, correlative design after informed consent, from 74 mentally disordered offenders (mean age 34,2) cared for in forensic psychiatric hospitals. Assessments were Allen Cognitive Level Screen, Capability to Perform Daily Occupations, Interview Schedule of Social Interaction, Manchester Short Assessment of Quality of Life, Self-efficacy Scale and Importance scale. Eight background factors were assembled from the individual forensic psychiatric investigation. Most of the investigated background factors relate to and half of them influence occupational performance, particular the cognitive aspect of occupational performance. The influences on occupation originate from adulthood, such as suffering from schizophrenia, psycho/social problems, and having performed violent crimes. These findings indicate that staff in forensic hospital care should initiate rehabilitation with knowledge about MDOs' complex daily occupations. For avoiding information bias, information gathering preceding treatment planning should be performed in collaboration between caring staff and mentally disordered offenders.


"It's not like a fat camp" - A focus group study of adolescents' experiences on group-based obesity treatment.
The health burden related to obesity is rising among children and adolescents along with the general population worldwide. For the individual as well as the society this trend is alarming. Several factors are driving the trend, and the solution seems to be multifaceted because long-lasting treatment alternatives are lacking. This study aims to explore adolescents' and young adults' motivation for attending group-based obesity treatment and social and environmental factors that can facilitate or hinder lifestyle change. In this study, we arranged three focus groups with 17 participants from different obesity treatment programs in the west and south of Norway. The content in these programs differed, but they all used Motivational Interviewing as a teaching method. We conducted a data-driven analysis using systematic text condensation. Self-determination theory has been used as an explanatory framework. We identified four major themes: 1) motivation, 2) body experience and self-image, 3) relationships and sense of belonging, and 4) the road ahead. Many of the participants expressed external motivation to participate but experienced increasing inner motivation and enjoyment during the treatment. Several participants reported negative experiences related to being obese and appreciated group affiliation and sharing experiences with other participants. Motivation may shift during a lifestyle course. Facilitating factors include achieving and experiencing positive outcomes as well as gaining autonomy support from other course participants and friends. Obstacles to change were a widespread obesogenic environment as well as feelings of guilt, little trust in personal achievements and non-supporting friends.


Plastic optical touch panels for large-scale flexible display.
A plastic optical touch panel applicable for large-scale flexible display is demonstrated based on a vertical directional coupling between arrayed channel waveguides and a flexible planar waveguide. When a contact force is applied to the surface, the flexible planar waveguide is bent toward the channel waveguide, and then, the guided mode in the channel waveguide is coupled into the flexible planar waveguide, causing an output power drop. An index-matching liquid is used to fill the gap between the channel and the flexible planar waveguide in order to enhance the transparency of the waveguide touch panel. By applying a force of 1.0 N, the output intensity is decreased by 17 dB, which is sufficiently large for producing a contact signal.


A comparative proteomic analysis of blood serum for developmental stages in pigs.
This study aimed to differentiate genes at developmental stages of pigs from 0 to 150 days of age, to build up a protein database and to find candidate genetic markers for growth traits. The analysis of two-dimensional electrophoresis and matrix-assisted laser-desorption/ionization mass spectrometry separated 252 protein segments. After successfully blasting the peptide sequences, the analysis confirmed 37 differentially expressed proteins that increased from birth to 150 days of age (type A), whereas the type B proteins presented the inverse pattern. The type C proteins included proteins that were expressed continuously throughout the developmental periods. A total of 319 primer sets for 33 genes were designed to find genetic variants using pooled DNA samples of Yorkshire pigs. Amplification products for all primer sets produced approximately 20 000 clones that were sequenced, and 48 candidate SNP sites were finalized for genotyping. A total of 475 animals were used for high throughput genotyping analysis. Among these, phenotype data of all 475 animals were collected for average daily gain, backfat thickness and days to 90 kg, whereas feed conversion data were collected for 300 animals and body measurement traits (starting weight, ending weight, body length, wither height and chest depth) were collected for 209 animals. Association analysis found significant statistical differences between the animals having genotypes of 13 SNPs (g.78935883C>T, g.147629986C>T, g.98266037T>C, g.214707340G>A, g.88350299C>T, g.17180956C>T, g.17181024C>T, g.2350283A>G, g.138361311C>T, g.44996379C>T, g.44996247A>C, g.107715245C>T, g.4149631C>T) for the various measured traits. The identified genetic polymorphisms, of which one was novel (g.214707340G>A), may serve as candidate molecular markers to change population means for the targeted growth traits.


Coating formation during drying of β-lactoglobulin: gradual and sudden changes.
The drying dynamics of protein coatings is of importance for many applications. The main focus of research so far was to investigate macroscopic properties of protein coatings, leaving drying dynamics virtually unexplored. A unique combination of techniques is used to monitor drying of a coating containing the protein β-lactoglobulin. The techniques used cover both macroscopic and microscopic aspects of the drying process. For all water fractions amenable to diffusing wave spectroscopy analysis (xw > 0.2 w/w), the tracer particles diffuse in the coating as in a Newtonian viscous medium. Magnetic resonance imaging shows both protein and water are distributed homogeneously over the coating during drying, up to water fractions above 0.2 w/w. When drying continues to lower water fractions, sudden transitions in drying behavior are observed by both dynamic vapor sorption and IR spectroscopy, which we suggest are due to changes in molecular interactions caused by dehydration of the protein backbone.


The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation.
The age-associated decrease in the efficiency of CNS remyelination has clear implications for recovery from demyelinating diseases such as multiple sclerosis (MS) that may last for several decades. Developing strategies to reverse the age-associated decline requires the identification of how the regenerative process is impaired. We addressed whether remyelination becomes slower because of an impairment of recruitment of oligodendrocyte progenitors (OPs) or, as is the case in some MS lesions, an impairment of OP differentiation into remyelinating oligodendrocytes. The OP response during remyelination of focal, toxin-induced CNS demyelination in young and old rats was compared by in situ hybridization using probes to two OP-expressed mRNA species: platelet-derived growth factor-alpha receptor and the OP transcription factor myelin transcription factor 1 (MyT1). We found that the expression patterns for the two OP markers are very similar and reveal a delay in the colonization of the demyelinated focus with OPs in the old animals compared with the young animals. By comparing the mRNA expression pattern of MyT1 with that of the myelin proteins myelin basic protein and Gtx, we found that in the old animals there is also a delay in OP differentiation that increases with longer survival times. These results indicate that the age-associated decrease in remyelination efficiency occurs because of an impairment of OP recruitment and the subsequent differentiation of the OPs into remyelinating oligodendrocytes, and that strategies aimed at ameliorating the age-associated decline in remyelination efficiency will therefore need to promote both components of the regenerative process.


odd skipped related1 reveals a novel role for endoderm in regulating kidney versus vascular cell fate.
The kidney and vasculature are intimately linked both functionally and during development, when nephric and blood/vascular progenitor cells occupy adjacent bands of mesoderm in zebrafish and frog embryos. Developmental mechanisms that underlie the differentiation of kidney versus blood/vascular lineages remain unknown. The odd skipped related1 (osr1) gene encodes a zinc-finger transcription factor that is expressed in the germ ring mesendoderm and subsequently in the endoderm and intermediate mesoderm, prior to the expression of definitive kidney or blood/vascular markers. Knockdown of osr1 in zebrafish embryos resulted in a complete, segment-specific loss of anterior kidney progenitors and a compensatory increase in the number of angioblast cells in the same trunk region. Histology revealed a subsequent absence of kidney tubules, an enlarged cardinal vein and expansion of the posterior venous plexus. Altered kidney versus vascular development correlated with expanded endoderm development in osr1 knockdowns. Combined osr1 loss of function and blockade of endoderm development by knockdown of sox32/casanova rescued anterior kidney development. The results indicate that osr1 activity is required to limit endoderm differentiation from mesendoderm; in the absence of osr1, excess endoderm alters mesoderm differentiation, shifting the balance from kidney towards vascular development.


In-season monitoring of hip and groin strength, health and function in elite youth soccer: Implementing an early detection and management strategy over two consecutive seasons.
The primary purpose of this study was to describe an early detection and management strategy when monitoring in-season hip and groin strength, health and function in soccer. Secondly to compare pre-season to in-season test results. Longitudinal cohort study. Twenty-seven elite male youth soccer players (age: 15.07±0.73years) volunteered to participate in the study. Monitoring tests included: adductor strength, adductor/abductor strength ratio and hip and groin outcome scores (HAGOS). Data were recorded at pre-season and at 22 monthly intervals in-season. Thresholds for alerts to initiate further investigations were defined as any of the following: adductor strength reductions >15%, adductor/abductor strength ratio <0.90, and HAGOS subscale scores <75 out of 100 in any of the six subscales. Overall, 105 alerts were detected involving 70% of players. Strength related alerts comprised 40% and remaining 60% of alerts were related to HAGOS. Hip adductor strength and adductor/abductor strength ratio were lowest at pre-season testing and had increased significantly by month two (p<0.01, mean difference 0.26, CI95%: 0.12, 0.41N/kg and p<0.01, mean difference 0.09, CI95%: 0.04, 0.13 respectively). HAGOS subscale scores were lowest at baseline with all, except Physical Activity, showing significant improvements at time-point one (p<0.01). Most (87%) time-loss were classified minimal or mild. In-season monitoring aimed at early detection and management of hip and groin strength, health and function appears promising. Hip and groin strength, health and function improved quickly from pre-season to in-season in a high-risk population for ongoing hip and groin problems.


Supplementation with Pycnogenol® improves signs and symptoms of menopausal transition.
The aim of this study was to evaluate the efficacy of Pycnogenol® standardized pine bark extract for alleviation of signs and symptoms associated with menopausal transition. Pycnogenol® was used by 38 women as daily supplement in a dosage of 100 mg over an eight week period and menopausal symptoms were evaluated by means of a scoring system, based on a total number of 33 common signs and symptoms. A parallel control group of 32 comparable women was also followed up for the same period. Pycnogenol® was well tolerated, no side effects were reported and the compliance was very good with 98.6% of tablets used as prescribed. A range of 33 menopausal symptoms were evaluated using a scoring system with values ranging from zero (absent) to maximum 4 (very serious). A subset of six most common symptoms comprising hot flushes, night sweats, mood swings, irregular periods, loss of libido and vaginal dryness showed a decrease from average 2.67/4 to 1.45/4 after 8 weeks supplementation with Pycnogenol®. The control group of women showed no change from initial average 2.72/4 to 2.73/4 after eight weeks. The improvement of symptoms was statistical significant compared to the control group. Further symptoms related to fatigue, sleeping disorders, concentration and memory problems, dizziness, depression and irritability all improved significantly with Pycnogenol® compared to baseline values but did not reach statistical significance compared to the control group of women. The sensation of pain related to headaches, breast pain, the feeling of "electric shocks", tingling extremities, burning tongue and itchy skin all improved significantly after intake of Pycnogenol® for eight weeks compared to baseline. Specifically the sensation of "electric shocks" and digestive problems improved significantly with Pycnogenol® as compared to women in the control group. The presence of elevated oxidative stress in women was investigated measuring capillary blood plasma free radicals. Oxidative stress was significantly lowered after four weeks (P<0.05) and eight weeks (P<0.022) in the Pycnogenol® group while no significant changes were observed in the control group at any time. Pycnogenol® significantly contributed to reduce signs and symptoms associated with menopausal transitions in women investigated in this study. Furthermore, Pycnogenol® improved the quality of life of most women and these benefits may be at least in part attributed to decreased oxidative stress levels.


Private and Non-Private Disc Herniation Patients: Do they Differ?
In the 2006 yearly report from the Swedish National Register for Lumbar Spine Surgery it was claimed that international studies show obvious differences between private and non-private patients with regard to results from back surgery. Therefore our aim was to reveal such possible differences by comparing the two categories of patients at a private clinic. The material comprises 1184 patients operated on for lumbar disc herniation during the period of 1987 to 2007. Basic pre-operative data were obtained from the medical records and follow-up was performed by a questionnaire around 5 years post-operatively. Small but statistically significant differences between private and non-private patients were seen pre-operatively regarding the proportions of a/ men and women in the samples, b/ those with physically demanding jobs, c/ those on sick leave and d/ those with lumbar pain. Over the years the admitted private patients had a decreasing mean duration of symptoms which was not seen in the non-private patients. No apparent differences (n.s.) were seen between the two categories of patients pre-operatively regarding age, presence and level of leg pain or the proportion who smoked. Post-operative improvement in leg and lumbar pain was very similar in private and non-private patients as was satisfaction with the results and the proportion of patients returning to work. Despite small pre-operative differences concerning some variables and a significant difference in symptom duration between private and non-private disc herniation patients, the final clinical results were very similar.


Infections Caused by Mycobacterium tuberculosis in Recipients of Hematopoietic Stem Cell Transplantation.
Mycobacterium tuberculosis (M. tuberculosis) infections are uncommon in recipients of hematopoietic stem cell transplantation. These infections are 10-40 times commoner in recipients of stem cell transplantation than in the general population but they are 10 times less in stem cell transplantation recipients compared to solid organ transplant recipients. The incidence of M. tuberculosis infections in recipients of allogeneic stem cell transplantation ranges between <1 and 16% and varies considerably according to the type of transplant and the geographical location. Approximately 80% of M. tuberculosis infections in stem cell transplant recipients have been reported in patients receiving allografts. Several risk factors predispose to M. tuberculosis infections in recipients of hematopoietic stem cell transplantation and these are related to the underlying medical condition and its treatment, the pre-transplant conditioning therapies in addition to the transplant procedure and its own complications. These infections can develop as early as day 11 and as late as day 3337 post-transplant. The course may become rapidly progressive and the patient may develop life-threatening complications. The diagnosis of M. tuberculosis infections in stem cell transplant recipients is usually made on clinical grounds, cultures obtained from clinical specimens, tissues biopsies in addition to serology and molecular tests. Unfortunately, a definitive diagnosis of M. tuberculosis infections in these patients may occasionally be difficult to be established. However, M. tuberculosis infections in transplant recipients usually respond well to treatment with anti-tuberculosis agents provided the diagnosis is made early. A high index of suspicion should be maintained in recipients of stem cell transplantation living in endemic areas and presenting with compatible clinical and radiological manifestations. High mortality rates are associated with infections caused by multidrug-resistant strains, miliary or disseminated infections, and delayed initiation of therapy. In recipients of hematopoietic stem cell transplantation, isoniazid prophylaxis has specific indications and bacillus Calmette-Guerin vaccination is contraindicated as it may lead to disseminated infection. The finding that M. tuberculosis may maintain long-term intracellular viability in human bone marrow-derived mesenchymal stem cells complicates the development of effective vaccines and strategies to eliminate tuberculosis. However, the introduction of linezolid, cellular immunotherapy, and immunomodulation in addition to autologous mesenchymal stem cell transplantation will ultimately have a positive impact on the overall management of infections caused by M. tuberculosis.


Retroviral transduction of hematopoietic cells differentiated from human embryonic stem cell-derived CD45(neg)PFV hemogenic precursors.
Human embryonic stem cells (hESCs) provide a unique opportunity to study molecular mechanisms that regulate specification of the hematopoietic lineage in the human. Exploitation of this model using transgenic strategies depends on the ability to target cells of the hematopoietic lineage effectively and establish stable transgene expression. Here, a recently defined subpopulation of endothelial-like precursors derived from hESCs that is exclusively responsible for hematopoietic cell fate (CD45(neg)PFV) is shown to express GALVR-1 receptor and be efficiently transduced with GALV-pseudotyped retrovirus. Retroviral transduction, measured by enhanced green fluorescent protein, of hESC-derived CD45(+) cells differentiated from isolated CD45(neg)PFV precursors was 26.5 +/- 13% with 5.6 +/- 4% of these cells coexpressing CD34. An average of 17.5% of clonogenic hematopoietic progenitors derived from CD45(neg)PFV precursors expressed the retroviral transgene. Addition of serum to cultures after retroviral exposure supported transgene expression in resulting hematopoietic cells derived from hemogenic CD45(neg)PFV precursors. Our study represents the first report to demonstrate that retroviral transduction systems, similar to those used currently in clinical gene therapy protocols, are capable of efficient transduction of hematopoietic progenitors derived from hESCs.


Distinct patterns of genetic differentiation among annelids of eastern Pacific hydrothermal vents.
Population genetic and phylogenetic analyses of mitochondrial COI from five deep-sea hydrothermal vent annelids provided insights into their dispersal modes and barriers to gene flow. These polychaetes inhabit vent fields located along the East Pacific Rise (EPR) and Galapagos Rift (GAR), where hundreds to thousands of kilometers can separate island-like populations. Long-distance dispersal occurs via larval stages, but larval life histories differ among these taxa. Mitochondrial gene flow between populations of Riftia pachyptila, a siboglinid worm with neutrally buoyant lecithothrophic larvae, is diminished across the Easter Microplate region, which lies at the boundary of Indo-Pacific and Antarctic deep-sea provinces. Populations of the siboglinid Tevnia jerichonana are similarly subdivided. Oasisia alvinae is not found on the southern EPR, but northern EPR populations of this siboglinid are subdivided across the Rivera Fracture Zone. Mitochondrial gene flow of Alvinella pompejana, an alvinellid with large negatively buoyant lecithotrophic eggs and arrested embryonic development, is unimpeded across the Easter Microplate region. Gene flow in the polynoid Branchipolynoe symmytilida also is unimpeded across the Easter Microplate region. However, A. pompejana populations are subdivided across the equator, whereas B. symmitilida populations are subdivided between the EPR and GAR axes. The present findings are compared with similar evidence from codistributed species of annelids, molluscs and crustaceans to identify potential dispersal filters in these eastern Pacific ridge systems.


A prospective evaluation of the clinical utility of the lower-extremity injury-severity scores.
High-energy trauma to the lower extremity presents challenges with regard to reconstruction and rehabilitation. Failed efforts at limb salvage are associated with increased patient mortality and high hospital costs. Lower-extremity injury-severity scoring systems were developed to assist the surgical team with the initial decision to amputate or salvage a limb. The purpose of the present study was to prospectively evaluate the clinical utility of five lower-extremity injury-severity scoring systems. Five hundred and fifty-six high-energy lower-extremity injuries were prospectively evaluated with use of five injury-severity scoring systems for lower-extremity trauma designed to assist in the decision-making process for the care of patients with such injuries. Four hundred and seven limbs remained in the salvage pathway six months after the injury. The sensitivity, specificity, and area under the receiver operating characteristic curve were calculated for the Mangled Extremity Severity Score (MESS); the Limb Salvage Index (LSI); the Predictive Salvage Index (PSI); the Nerve Injury, Ischemia, Soft-Tissue Injury, Skeletal Injury, Shock, and Age of Patient Score (NISSSA); and the Hannover Fracture Scale-97 (HFS-97) for ischemic and nonischemic limbs. The scores were analyzed in two ways: including and excluding limbs that required immediate amputation. The analysis did not validate the clinical utility of any of the lower-extremity injury-severity scores. The high specificity of the scores in all of the patient subgroups did confirm that low scores could be used to predict limb-salvage potential. The converse, however, was not true. The low sensitivity of the indices failed to support the validity of the scores as predictors of amputation. Lower-extremity injury-severity scores at or above the amputation threshold should be cautiously used by a surgeon who must decide the fate of a lower extremity with a high-energy injury.


Shotgun ion mobility mass spectrometry sequencing of heparan sulfate saccharides.
Despite evident regulatory roles of heparan sulfate (HS) saccharides in numerous biological processes, definitive information on the bioactive sequences of these polymers is lacking, with only a handful of natural structures sequenced to date. Here, we develop a "Shotgun" Ion Mobility Mass Spectrometry Sequencing (SIMMS2) method in which intact HS saccharides are dissociated in an ion mobility mass spectrometer and collision cross section values of fragments measured. Matching of data for intact and fragment ions against known values for 36 fully defined HS saccharide structures (from di- to decasaccharides) permits unambiguous sequence determination of validated standards and unknown natural saccharides, notably including variants with 3O-sulfate groups. SIMMS2 analysis of two fibroblast growth factor-inhibiting hexasaccharides identified from a HS oligosaccharide library screen demonstrates that the approach allows elucidation of structure-activity relationships. SIMMS2 thus overcomes the bottleneck for decoding the informational content of functional HS motifs which is crucial for their future biomedical exploitation.


Cerebrovascular Disease in Patients with COVID-19: A Review of the Literature and Case Series.
COVID-19 has been associated with a hypercoagulable state causing cardiovascular and neurovascular complications. To further characterize cerebrovascular disease (CVD) in COVID-19, we review the current literature of published cases and additionally report the clinical presentation, laboratory and diagnostic testing results of 12 cases with COVID-19 infection and concurrent CVD from two academic medical centers in Houston, TX, USA, between March 1 and May 10, 2020. To date, there are 12 case studies reporting 47 cases of CVD in COVID-19. However, only 4 small case series have described the clinical and laboratory findings in patients with COVID-19 and concurrent stroke. Viral neurotropism, endothelial dysfunction, coagulopathy and inflammation are plausible proposed mechanisms of CVD in COVID-19 patients. In our case series of 12 patients, 10 patients had an ischemic stroke, of which 1 suffered hemorrhagic transformation and two had intracerebral hemorrhage. Etiology was determined to be embolic without a clear cause identified in 6 ischemic stroke patients, while the remaining had an identifiable source of stroke. The majority of the patients had elevated inflammatory markers such as D-dimer and interleukin-6. In patients with embolic stroke of unclear etiology, COVID-19 may have played a direct or indirect role in the processes that eventually led to the strokes while in the remaining cases, it is unclear if infection contributed partially or was an incidental finding.


Genetics of congenital anomalies of the kidney and urinary tract.
Congenital anomalies of the kidney and urinary tract (CAKUT) occur in 1 in 500 births and are a major cause of morbidity in children. Notably, CAKUT account for the most cases of pediatric end-stage renal disease and predispose the individual to hypertension and cardiovascular disease throughout life. Although some forms of CAKUT are a part of a syndrome or are associated with a positive family history, most cases of renal system anomalies are sporadic and isolated to the urinary tract. Broad phenotypic spectrum of CAKUT and variability in genotype-phenotype correlation indicate that pathogenesis of CAKUT is a complex process that depends on interplay of many factors. This review focuses on the genetic mechanisms (single-gene mutations, modifier genes) leading to renal system anomalies in humans and discusses emerging insights into the role of epigenetics, in utero environmental factors, and micro-RNAs (miRNAs) in the pathogenesis of CAKUT. Common gene networks that function in defined temporospatial fashion to orchestrate renal system morphogenesis are highlighted. Derangements in cellular, molecular, and morphogenetic mechanisms that direct normal renal system development are emphasized as a major cause of CAKUT. Integrated understanding of how morphogenetic process disruptions are linked to CAKUT will enable improved diagnosis, treatment, and prevention of congenital renal system anomalies and their consequences.


Patterns of breast recurrence in a pilot study of brachytherapy confined to the lumpectomy site for early breast cancer with six years' minimum follow-up.
In this pilot study of high-dose-rate brachytherapy to the lumpectomy site as the sole radiation, ipsilateral and contralateral breast recurrences are documented with specific attention to the location of recurrence relative to the lumpectomy site. Between March 1992 and January 1996, 39 patients with T1 (32 patients) and T2 breast cancers received 37.2 Gy in 10 fractions (b.i.d.) over 1 week prescribed to a volume encompassing the surgical clips. Thirteen received adjuvant tamoxifen, and 4 received chemotherapy. Follow-up included annual bilateral mammograms and clinical breast examination every 3 to 6 months. Whereas 13 patients had intraoperative implantation of the lumpectomy site, 26 had postoperative implantation. The latter group and 7 of the former group had surgical clips marking the lumpectomy site, which allowed estimates of the distance of any ipsilateral breast recurrence from the lumpectomy site, using the mediolateral and cranio-caudad mammographic views. At a median follow-up of 91 months, 33 women are alive, 4 have died of disease, and 2 have died of other causes. The 5-year actuarial rate of ipsilateral breast recurrence was 16.2%. Of 6 ipsilateral recurrences, 2 occurred within the lumpectomy site (in-field recurrences). One of the 2 patients had a 1-mm microscopic margin at initial diagnosis; the recurrence was a 3.5-mm microscopic focus of duct carcinoma in situ. The other patient had a 1.5-cm, high-grade infiltrating mammary carcinoma with no residual at wider resection at first diagnosis; the 5-mm invasive recurrence was also of high grade. Four women developed invasive recurrences at least 1.6 cm or more from the lumpectomy site (out-of-field recurrences). Two of these women had gross multifocal recurrences with two cancers in each patient; 1 of the 2 patients had an extensive intraductal component at initial diagnosis. The estimated nearest distances between the out-of-field recurrences and the surgical clips were 1.6, 5.5, 7.7, and 12.0 cm. All ipsilateral breast recurrences were salvaged by mastectomy (4 patients) or by repeat lumpectomy (2 patients) and whole-breast radiation. The interval postdiagnosis to ipsilateral recurrence ranged from 20 months to 58 months. There were two contralateral breast recurrences at intervals of 34 and 36 months; 1 of these patients also had a multifocal, ipsilateral recurrence at 58 months, as previously described. Among patients with any breast recurrence, 1 patient had a family history of prostate cancer; there was no family history of breast or ovarian cancer. Of 17 patients who received adjuvant systemic therapy, only 1 had a breast recurrence. In this pilot study, breast recurrences outside of the lumpectomy site were the predominant pattern of recurrence.


Melanoma incidence and frequency modulation (FM) broadcasting.
The incidence of melanoma has been increasing steadily in many countries since 1960, but the underlying mechanism causing this increase remains elusive. The incidence of melanoma has been linked to the distance to frequency modulation (FM) broadcasting towers. In the current study, the authors sought to determine if there was also a related link on a larger scale for entire countries. Exposure-time-specific incidence was extracted from exposure and incidence data from 4 different countries, and this was compared with reported age-specific incidence of melanoma. Geographic differences in melanoma incidence were compared with the magnitude of this environmental stress. The exposure-time-specific incidence from all 4 countries became almost identical, and they were approximately equal to the reported age-specific incidence of melanoma. A correlation between melanoma incidence and the number of locally receivable FM transmitters was found. The authors concluded that melanoma is associated with exposure to FM broadcasting.


Auxin biosynthesis by the YUCCA flavin monooxygenases controls the formation of floral organs and vascular tissues in Arabidopsis.
Auxin biosynthesis in plants has remained obscure although auxin has been known for decades as a key regulator for plant growth and development. Here we define the YUC gene family and show unequivocally that four of the 11 predicted YUC flavin monooxygenases (YUC1, YUC2, YUC4, and YUC6) play essential roles in auxin biosynthesis and plant development. The YUC genes are mainly expressed in meristems, young primordia, vascular tissues, and reproductive organs. Overexpression of each YUC gene leads to auxin overproduction, whereas disruption of a single YUC gene causes no obvious developmental defects. However, yuc1yuc4, yuc2yuc6, all of the triple and quadruple mutants of the four YUC genes, display severe defects in floral patterning, vascular formation, and other developmental processes. Furthermore, inactivation of the YUC genes leads to dramatically reduced expression of the auxin reporter DR5-GUS in tissues where the YUC genes are expressed. Moreover, the developmental defects of yuc1yuc4 and yuc1yuc2yuc6 are rescued by tissue-specific expression of the bacterial auxin biosynthesis gene iaaM, but not by exogenous auxin, demonstrating that spatially and temporally regulated auxin biosynthesis by the YUC genes is essential for the formation of floral organs and vascular tissues.


Proteomic interrogation of human chromatin.
Chromatin proteins provide a scaffold for DNA packaging and a basis for epigenetic regulation and genomic maintenance. Despite understanding its functional roles, mapping the chromatin proteome (i.e. the "Chromatome") is still a continuing process. Here, we assess the biological specificity and proteomic extent of three distinct chromatin preparations by identifying proteins in selected chromatin-enriched fractions using mass spectrometry-based proteomics. These experiments allowed us to produce a chromatin catalog, including several proteins ranging from highly abundant histone proteins to less abundant members of different chromatin machinery complexes. Using a Normalized Spectral Abundance Factor approach, we quantified relative abundances of the proteins across the chromatin enriched fractions giving a glimpse into their chromosomal abundance. The large-scale data sets also allowed for the discovery of a variety of novel post-translational modifications on the identified chromatin proteins. With these comparisons, we find one of the probed methods to be qualitatively superior in specificity for chromatin proteins, but inferior in proteomic extent, evidencing a compromise that must be made between biological specificity and broadness of characterization. Additionally, we attempt to identify proteins in eu- and heterochromatin, verifying the enrichments by characterizing the post-translational modifications detected on histone proteins from these chromatin regions. In summary, our results provide insights into the value of different methods to extract chromatin-associated proteins and provide starting points to study the factors that may be involved in directing gene expression and other chromatin-related processes.


Understanding drug targets: no such thing as bad news.
How can small-to-medium pharma and biotech companies enhance the chances of running a successful drug project and maximise the return on a limited number of assets? Having a full appreciation of the safety risks associated with proposed drug targets is a crucial element in understanding the unwanted side-effects that might stop a project in its tracks. Having this information is necessary to complement knowledge about the probable efficacy of a future drug. However, the lack of data-rich insight into drug-target safety is one of the major causes of drug-project failure today. Conducting comprehensive target-safety reviews early in the drug discovery process enables project teams to make the right decisions about which drug targets to take forward.


Factor structure and concurrent validity of the Cognitive Fusion Questionnaire (CFQ) in a sample of Somali immigrants living in North America.
The process of resettlement in a new country and culture is commonly one of intense stress. Somali immigrants and refugees living in North America represent a large ethnocultural group navigating the complexities of forced displacement and resettlement. Despite the immense resilience exhibited by Somali communities in resettlement, the behavioral health needs of these communities require effective and culturally appropriate psychological assessment tools that can be used across service and research sectors. Given this need, we sought to examine the psychometric properties and concurrent validity of the Cognitive Fusion Questionnaire (CFQ), a transdiagnostic measure of cognitive fusion, in a sample of 233 (M age = 25.35; female = 45%) Somali young adults living in North America. Results using confirmatory factor analysis demonstrated that the one-factor structure of the CFQ previously found in other diverse populations held in the present sample. The structure and related item loadings were invariant across three key variables: gender, age, and location of resettlement in North America. Importantly, cognitive fusion was meaningfully associated with aspects of clinical and psychosocial functioning thought to be highly relevant to this population, including posttraumatic stress, anxiety, and depression symptoms, thwarted belongingness and perceived burdensomeness, and experiences of discrimination. Building upon the growing body of evidence supporting the CFQ's strong psychometric properties across cultural groups, researchers, and clinicians should have an added degree of confidence and enthusiasm in utilizing this measure to support immigrant and refugee communities. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Towards generation of mJ-level ultrashort THz pulses by optical rectification.
Optical rectification of ultrashort laser pulses in LiNbO3 by tilted-pulse-front excitation is a powerful way to generate near single-cycle terahertz (THz) pulses. Calculations were carried out to optimize the output THz peak electric field strength. The results predict peak electric field strengths on the MV/cm level in the 0.3-1.5 THz frequency range by using optimal pump pulse duration of about 500 fs, optimal crystal length, and cryogenic temperatures for reducing THz absorption in LiNbO3. The THz electric field strength can be increased further to tens of MV/cm by focusing. Using optimal conditions together with the contact grating technique THz pulses with 100 MV/cm focused electric field strength and energies on the tens-of-mJ scale are feasible.


Amycolatopsis albispora sp. nov., isolated from deep-sea sediment.
A novel Gram-stain-positive, aerobic, non-motile actinobacterium, designated strain WP1T, was isolated from a deep-sea sediment sample collected from the Indian Ocean, and examined in a taxonomic study using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain WP1T formed a distinct phyletic lineage in the genus Amycolatopsis and was closely related to A. magusensis KT2025T (97.8 % 16S rRNA gene sequence similarity), A. palatopharyngis 1BDZT (97.3 %) and A. marinaMs392AT (97.2 %). The isolate grew at 4-45 °C, pH 5-11 and in the presence of 0-8 % (w/v) NaCl. The cell wall of the novel strain contained meso-diaminopimelic acid and arabinose and galactose as the diagnostic sugars. Major fatty acids identified were iso-C16 : 0, C17 : 1ω8c and C17 : 1ω6c. The predominant menaquinones were MK-9(H4) and MK-7. The polar lipids detected were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylmethylethanolamine, four unknown phospholipids and one unknown glycolipid. The genomic DNA G+C content was 72.2 mol%. Strain WP1T displayed low DNA-DNA reassociation with A. magusensis DSM 45510T (mean value 36.2 %), A. palatopharyngis JCM 12460T (31.5 %) and A. marina JCM 16121T (29.7 %). Based on the data reported here, strain WP1T represents a novel species within the genus Amycolatopsis, for which the name Amycolatopsis albisporasp. nov. is proposed. The type strain is WP1T (=KCTC 39642T=MCCC 1A10745T).


Vulnerability to heat-related mortality in Latin America: a case-crossover study in Sao Paulo, Brazil, Santiago, Chile and Mexico City, Mexico.
Factors affecting vulnerability to heat-related mortality are not well understood. Identifying susceptible populations is of particular importance given anticipated rising temperatures from climatic change. We investigated heat-related mortality for three Latin American cities (Mexico City, Mexico; São Paulo, Brazil; Santiago, Chile) using a case-crossover approach for 754 291 deaths from 1998 to 2002. We considered lagged exposures, confounding by air pollution, cause of death and susceptibilities by educational attainment, age and sex. Same and previous day apparent temperature were most strongly associated with mortality risk. Effect estimates remained positive though lowered after adjustment for ozone or PM(10). Susceptibility increased with age in all cities. The increase in mortality risk for those >or=65 comparing the 95th and 75th percentiles of same-day apparent temperature was 2.69% (95% CI: -2.06 to 7.88%) for Santiago, 6.51% (95% CI: 3.57-9.52%) for São Paulo and 3.22% (95% CI: 0.93-5.57%) for Mexico City. Patterns of vulnerability by education and sex differed across communities. Effect estimates were higher for women than men in Mexico City, and higher for men elsewhere, although results by sex were not appreciably different for any city. In São Paulo, those with less education were more susceptible, whereas no distinct patterns by education were observed in the other cities. Elevated temperatures are associated with mortality risk in these Latin American cities, with the strongest associations in São Paulo, the hottest city. The elderly are an important population for targeted prevention measures, but vulnerability by sex and education differed by city.


Acute phase effects of ATP-MgCl2 on experimental spinal cord injury.
The purpose of this study was to study the acute phase effects of adenosine triphosphate (ATP)-MgCl2 on experimental spinal cord clip compression injury. Spinal cord clip compression injury was performed on 36 albino Wistar rats. The rats were divided into five groups. T4-T8 total laminectomy was performed on all rats. Group 1: sham-operated group. Group 2: clip compression group. In group 3, ATP-MgCl2 (100 micro mol/kg) was given 2 min before the "clip compression injury." In group 4, ATP-MgCl2 (100 micro mol/kg) was given 5 min after the clip compression injury. In group 5, ATP MgCl2 (100 micro mol/kg) was administered 8 h after the injury. The spinal cords were excised for a length of 2 cm and deep frozen at -76 degrees C. Tissue malondialdehyde (MDA) levels were used to determine the effects of ATP-MgCl2 on spinal cord lipid peroxidation. In the groups in which ATP MgCl2 was administered after the clip compression injury (groups 4 and 5), the decrease in spinal cord MDA levels was statistically significant when compared with those of the injury group (group 2). Although MDA levels of group 4 were lower than those of group 5, this difference was not statistically significant. Administration of the ATP-MgCl2 before the clip compression injury (in group 3) did not have a statistically significant effect on lipid peroxidation when compared with the injury group (group 2). In this study, we found that ATP-MgCl2 has decreased lipid peroxidation in spinal cord injury and protected the spinal cord from secondary injury after the trauma. We concluded that ATP-MgCl2 may be used in the treatment of spinal cord injuries in conjunction with the other treatment modalities, but further investigations are mandatory.


Effect of thiol-activated toxins (streptolysin O, alveolysin, and theta toxin) on the generation of leukotrienes and leukotriene-inducing and -metabolizing enzymes from human polymorphonuclear granulocytes.
The generation of leukotrienes (LTC4, LTD4, LTE4, and LTB4; 12-epi-LTB4 isomer) from human granulocytes by thiol-activated toxins (streptolysin O, alveolysin from Bacillus alvei, and theta toxin from Clostridium perfringens) is described. The release occurs under noncytolytic conditions. Although LTB4 is the major component after calcium ionophore stimulation, more LTC4 as compared with LTB4 is released with the toxins. The 5-lipoxygenase pathway of toxin-mediated activation can effectively be inhibited by caffeic acid, a lipoxygenase inhibitor. The toxins also induce the release of leukotriene-metabolizing enzymes such as gamma-glutamyltranspeptidase, which transfers LTC4 into LTD4, and dipeptidase, which metabolizes LTD4, into LTE4. Dipeptidase activity is more pronounced than the gamma-glutamyltranspeptidase activity but still does not reach the levels obtained when cells were triggered with opsonized zymosan.


Integrated single-walled carbon nanotube/microfluidic devices for the study of the sensing mechanism of nanotube sensors.
A method to fabricate integrated single-walled carbon nanotube/microfluidic devices was developed. This simple process could be used to directly prepare nanotube thin film transistors within the microfluidic channel and to register SWNT devices with the microfludic channel without the need of an additional alignment step. The microfluidic device was designed to have several inlets that deliver multiple liquid flows to a single main channel. The location and width of each flow in the main channel could be controlled by the relative flow rates. This capability enabled us to study the effect of the location and the coverage area of the liquid flow that contained charged molecules on the conduction of the nanotube devices, providing important information on the sensing mechanism of carbon nanotube sensors. The results showed that in a sensor based on a nanotube thin film field effect transistor, the sensing signal came from target molecules absorbed on or around the nanotubes. The effect from adsorption on metal electrodes was weak.


Pancreatic panniculitis.
Pancreatic panniculitis (PP) is a rare variant of panniculitis characterized by subcutaneous fat necrosis, that affects 0.3-3% of patients across a range of different pancreatic disorders. It presents with painful, tender, erythematous to violaceous nodules that may undergo spontaneous ulceration and discharge of an oily brown, viscous material, resulting from liquefactive necrosis of adipocytes. These lesions usually involve the lower extremities, although may also spread over the buttocks, trunk, arms and scalp. In addition to the skin, fat necrosis may involve periarticular, abdominal and intramedullary adipose tissue. In 40% of cases, skin manifestations can precede by 1 to 7 months the abdominal symptoms of pancreatic disease, which include mostly acute and chronic pancreatitis, pancreatic carcinoma, more frequently of acinar cell type, and pancreatic abnormalities. Histopathologically, PP shows characteristic features of mostly lobular panniculitis with marked necrosis of adipocytes. The necrotic adipocytes with finely granular and basophilic material in the cytoplasm due to calcium deposits are known as "ghost adipocytes". The treatment of pancreatic panniculitis is directed to the underlying pancreatic disease. The prognosis is poor in cases associated with pancreatic carcinoma. When there is widespread and persistent disease, frequent relapses, or ulceration, the possibility of an occult carcinoma of the pancreas should be always considered. While describing three patients seen at the Dermatology Section of the University of Genova from 1990 to 2012, we highlight that, in addition to the rarity of the disease, the precise diagnosis requires adequate samples consisting in large-scalpel incisional biopsies of fully developed lesions.


Antimicrobial resistance genes in multidrug-resistant Salmonella enterica isolated from animals, retail meats, and humans in the United States and Canada.
Salmonella enterica is a prevalent foodborne pathogen that can carry multidrug resistance (MDR) and pose a threat to human health. Identifying the genetics associated with MDR in Salmonella isolated from animals, foods, and humans can help determine sources of MDR in food animals and their impact on humans. S. enterica serovars most frequently carrying MDR from healthy animals, retail meats, and human infections in the United States and Canada were identified and isolates resistant to the largest number of antimicrobials were chosen. Isolates were from U.S. slaughter (n=12), retail (9), and humans (9), and Canadian slaughter (9), retail (9), and humans (8; total n=56). These isolates were assayed by microarray for antimicrobial resistance and MDR plasmid genes. Genes detected encoded resistance to aminoglycosides (alleles of aac, aad, aph, strA/B); beta-lactams (bla(TEM), bla(CMY), bla(PSE-1)); chloramphenicol (cat, flo, cmlA); sulfamethoxazole (sulI); tetracycline (tet(A, B, C, D) and tetR); and trimethoprim (dfrA). Hybridization with IncA/C plasmid gene probes indicated that 27/56 isolates carried one of these plasmids; however, they differed in several variable regions. Cluster analysis based on genes detected separated most of the isolates into two groups, one with IncA/C plasmids and one without IncA/C plasmids. Other plasmid replicons were detected in all but one isolate, and included I1 (25/56), N (23/56), and FIB (10/56). The presence of different mobile elements along with similar resistance genes suggest that these genetic elements may acquire similar resistance cassettes, and serve as multiple sources for MDR in Salmonella from food animals, retail meats, and human infections.


Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder.
Contiguous gene syndromes affecting the mitochondrial oxidative phosphorylation system have been rarely reported. Here, we describe a patient with apparent mitochondrial encephalomyopathy accompanied by several unusual features, including dysmorphism and hepatopathy, caused by a homozygous triple gene deletion on chromosome 5. The deletion encompassed the NDUFAF2, ERCC8 and ELOVL7 genes, encoding complex I assembly factor 2 (also known as human B17.2L), a protein of the transcription-coupled nucleotide excision repair (TC-NER) machinery, and a putative elongase of very long-chain fatty acid synthesis, respectively. Detailed evaluation of cultured skin fibroblasts revealed disturbed complex I assembly, depolarization of the mitochondrial membrane, elevated cellular NAD(P)H level, increased superoxide production and defective TC-NER. ELOVL7 mRNA was not detectable in these cells and no alterations in fatty acid synthesis were found. By means of baculoviral complementation we were able to restore the aberrations, thereby establishing causative links between genotype and cell-physiological phenotype. This first chromosomal microdeletion illustrates that beside primary defects in mitochondrial genes also additional genes possibly contribute to the disease phenotype, providing an additional explanation for the broad clinical symptoms associated with these disorders.


SUSCEPTIBILITY ARTIFACTS ON T2*-WEIGHTED MAGNETIC RESONANCE IMAGING OF THE CANINE AND FELINE SPINE.
The T2*-weighted gradient recalled echo sequence is a sensitive means to detect blood degradation products. While not a routine sequence in magnetic resonance imaging of the spine in small animals, it can provide additional valuable information in select cases. The goal of this retrospective, cross-sectional study was to describe findings when acquiring this sequence during magnetic resonance imaging examination of the spine in small animals. The University of Tennessee's veterinary radiology database was searched for dogs and cats that underwent magnetic resonance imaging for suspect spinal disease in which a T2*-weighted gradient recalled echo sequence was acquired and susceptibility artifact was identified. The following information was recorded: signalment, clinical signs, location and appearance of susceptibility artifact, and final diagnosis. Thirty-nine cases were included in the study. Extradural susceptibility artifacts were observed in cases of intervertebral disc herniation with or without associated hemorrhage (n = 28), extradural hemorrhage associated with spinal trauma (n = 2), hemophilia (n = 1), and in a cystic extradural mass (n = 1). Remaining lesions displaying susceptibility artifact were intramedullary and included presumptive acute noncompressive nucleus pulposus extrusion (n = 2), hematoma (n = 1), hemangiosarcoma metastasis (n = 1), intramedullary disc extrusion (n = 1), presumptive meningomyelitis (n = 1), and a mass of undetermined etiology (n = 1). Inclusion of a T2*-weighted gradient recalled echo sequence may be helpful in spinal magnetic resonance imaging when standard imaging sequences are ambiguous or intramedullary lesions are observed.


Near-infrared grating-assisted SPR optical fiber sensors: design rules for ultimate refractometric sensitivity.
Plasmonic optical fiber sensors are continuously developed for (bio)chemical sensing purposes. Recently, surface plasmon resonance (SPR) generation was achieved in gold-coated tilted fiber Bragg gratings (TFBGs). These sensors probe the surrounding medium with near-infrared narrowband resonances, which enhances both the penetration depth of the evanescent field in the external medium and the wavelength resolution of the interrogation. They constitute a unique configuration to probe all the fiber cladding modes individually. We use them to analyze the modal distribution of gold-coated telecommunication-grade optical fibers immersed in aqueous solutions. Theoretical investigations with a finite-difference complex mode solver are confirmed by experimental data obtained on TFBGs. We show that the refractometric sensitivity varies with the mode order and that the global SPR envelope shift in response to surrounding refractive index (SRI) changes higher than 1e-2 RIU (refractive index unit) can be ~25% bigger than the local SPR mode shift arising from SRI changes limited to 1e-4 RIU. We bring clear evidence that the optimum gold thickness for SPR generation lies in the range between 50 and 70 nm while a cladding diameter decrease from 125 µm to 80 µm enhances the refractometric sensitivity by ~20%. Finally, we demonstrate that the ultimate refractometric sensitivity of cladding modes is ~550 nm/RIU when they are probed by gold-coated TFBGs.


Cost-effectiveness of transcatheter aortic valve replacement compared with standard care among inoperable patients with severe aortic stenosis: results from the placement of aortic transcatheter valves (PARTNER) trial (Cohort B).
In patients with severe aortic stenosis who cannot have surgery, transcatheter aortic valve replacement (TAVR) has been shown to improve survival and quality of life compared with standard therapy, but the costs and cost-effectiveness of this strategy are not yet known. The PARTNER trial randomized patients with symptomatic, severe aortic stenosis who were not candidates for surgery to TAVR (n=179) or standard therapy (n=179). Empirical data regarding survival, quality of life, medical resource use, and hospital costs were collected during the trial and used to project life expectancy, quality-adjusted life expectancy, and lifetime medical care costs to estimate the incremental cost-effectiveness of TAVR from a US perspective. For patients treated with TAVR, mean costs for the initial procedure and hospitalization were $42 806 and $78 542, respectively. Follow-up costs through 12 months were lower with TAVR ($29 289 versus $53 621) because of reduced hospitalization rates, but cumulative 1-year costs remained higher ($106 076 versus $53 621). We projected that over a patient's lifetime, TAVR would increase discounted life expectancy by 1.6 years (1.3 quality-adjusted life-years) at an incremental cost of $79 837. The incremental cost-effectiveness ratio for TAVR was thus estimated at $50 200 per year of life gained or $61 889 per quality-adjusted life-year gained. These results were stable across a broad range of uncertainty and sensitivity analyses. For patients with severe aortic stenosis who are not candidates for surgery, TAVR increases life expectancy at an incremental cost per life-year gained well within accepted values for commonly used cardiovascular technologies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894.


Astigmatic Results of a Diffractive Trifocal Toric IOL Following Intraoperative Aberrometry Guidance.
To determine if intraoperative aberrometry (IA) improves astigmatic outcomes for trifocal toric IOL (TTI) cases. This was a retrospective study examining 137 eyes that underwent cataract extraction and TTI implantation using femtosecond laser, digital registration, and IA. Final cylinder power and axis of placement were determined by IA. Monocular uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA), uncorrected near visual acuity (UNVA), and refractive data were collected at 3 months. Postoperative residual astigmatism (PRA) determined by manifest refraction was compared to back-calculated residual astigmatism (BRA) using the cylinder power calculated preoperatively. Postoperatively, 97.8% of eyes had IA PRA ≤ 0.50D and 80.3% had BRA ≤ 0.50 D, a difference of 17.5%. Mean PRA for IA was 0.07 D ± 0.19 (range 0.00-1.00 D) compared to BRA 0.31 D ± 0.33 (range 0.00-1.34 D) (P < 0.001). Cylinder power was changed in 50.4% of cases based upon IA. Postoperative mean UDVA (LogMAR) was 0.04 ± 0.09 (range -0.12-0.30 logMAR), and 65% of eyes were ≤ 0.0, 85% ≤ 0.1, and 99% ≤ 0.18. The proportion of eyes with PRA ≤ 0.50 D and mean PRA was significantly lower using IA versus the preoperative planned cylinder power.


DNA barcoding exposes a case of mistaken identity in the fern horticultural trade.
Using cheilanthoid ferns, we provide an example of how DNA barcoding approaches can be useful to the horticultural community for keeping plants in the trade accurately identified. We use plastid rbcL, atpA, and trnG-R sequence data to demonstrate that a fern marketed as Cheilanthes wrightii (endemic to the southwestern USA and northern Mexico) in the horticultural trade is, in fact, Cheilanthes distans (endemic to Australia and adjacent islands). Public and private (accessible with permission) databases contain a wealth of DNA sequence data that are linked to vouchered plant material. These data have uses beyond those for which they were originally generated, and they provide an important resource for fostering collaborations between the academic and horticultural communities. We strongly advocate the barcoding approach as a valuable new technology available to the horticulture industry to help correct plant identification errors in the international trade.


Impact of Antibiotics Associated with the Development of Toxic Epidermal Necrolysis on Early and Late-Onset Infectious Complications.
Toxic epidermal necrolysis (TEN) is a rare disease, which predominantly manifests as damage to the skin and mucosa. Antibiotics count among the most common triggers of this hypersensitive reaction. Patients with TEN are highly susceptible to infectious complications due to the loss of protective barriers and immunosuppressant therapy. The aim of this study was to investigate the potential relationship between antibiotics used before the development of TEN and early and late-onset infectious complications in TEN patients. In this European multicentric retrospective study (Central European Lyell syndrome: therapeutic evaluation (CELESTE)), records showed that 18 patients with TEN used antibiotics (mostly aminopenicillins) before the disease development (group 1), while in 21 patients, TEN was triggered by another factor (group 2). The incidence of late-onset infectious complications (5 or more days after the transfer to the hospital) caused by Gram-positive bacteria (especially by Enterococcus faecalis/faecium) was significantly higher in group 1 than in group 2 (82.4% vs. 35.0%, p = 0.007/p corr = 0.014) while no statistically significant difference was observed between groups of patients with infection caused by Gram-negative bacteria, yeasts, and filamentous fungi (p > 0.05). Patients with post-antibiotic development of TEN are critically predisposed to late-onset infectious complications caused by Gram-positive bacteria, which may result from the dissemination of these bacteria from the primary focus.


Associations of Resistance Exercise with Cardiovascular Disease Morbidity and Mortality.
Resistance exercise (RE) can improve many cardiovascular disease (CVD) risk factors, but specific data on the effects on CVD events and mortality are lacking. We investigated the associations of RE with CVD and all-cause mortality and further examined the mediation effect of body mass index (BMI) between RE and CVD outcomes. We included 12,591 participants (mean age, 47 yr) who received at least two clinical examinations 1987-2006. RE was assessed by a self-reported medical history questionnaire. During a mean follow-up of 5.4 and 10.5 yr, 205 total CVD events (morbidity and mortality combined) and 276 all-cause deaths occurred, respectively. Compared with no RE, weekly RE frequencies of one, two, three times or total amount of 1-59 min were associated with approximately 40%-70% decreased risk of total CVD events, independent of aerobic exercise (AE) (all P values <0.05). However, there was no significant risk reduction for higher weekly RE of more than four times or ≥60 min. Similar results were observed for CVD morbidity and all-cause mortality. In the stratified analyses by AE, weekly RE of one time or 1-59 min was associated with lower risks of total CVD events and CVD morbidity regardless of meeting the AE guidelines. Our mediation analysis showed that RE was associated with the risk of total CVD events in two ways: RE had a direct U-shaped association with CVD risk (P value for quadratic trend <0.001) and RE indirectly lowered CVD risk by decreasing BMI. Even one time or less than 1 h·wk of RE, independent of AE, is associated with reduced risks of CVD and all-cause mortality. BMI mediates the association of RE with total CVD events.


Pteropods make thinner shells in the upwelling region of the California Current Ecosystem.
Shelled pteropods are widely regarded as bioindicators for ocean acidification, because their fragile aragonite shells are susceptible to increasing ocean acidity. While short-term incubations have demonstrated that pteropod calcification is negatively impacted by ocean acidification, we know little about net calcification in response to varying ocean conditions in natural populations. Here, we examine in situ calcification of Limacina helicina pteropods collected from the California Current Ecosystem, a coastal upwelling system with strong spatial gradients in ocean carbonate chemistry, dissolved oxygen and temperature. Depth-averaged pH ranged from 8.03 in warmer offshore waters to 7.77 in cold CO2-rich waters nearshore. Based on high-resolution micro-CT technology, we showed that shell thickness declined by ~ 37% along the upwelling gradient from offshore to nearshore water. Dissolution marks covered only ~ 2% of the shell surface area and were not associated with the observed variation in shell thickness. We thus infer that pteropods make thinner shells where upwelling brings more acidified and colder waters to the surface. Probably the thinner shells do not result from enhanced dissolution, but are due to a decline in calcification. Reduced calcification of pteropods is likely to have major ecological and biogeochemical implications for the cycling of calcium carbonate in the oceans.


A labeled substrate approach to discovery of biocatalytic reactions: a proof of concept transformation with N-methylindole.
Biocatalysis has become an important method in the pharmaceutical industry for the incorporation of new functionality in small molecules. Currently this method is limited in the types of reactions that can be carried out and no strategy exists to systematically screen for new biocatalyzed reactions. This study involves the development of a medium throughput screen to identify and optimize new reactions using a series of marine-derived bacterial cell lines, which were screened against several (13)C labeled organic substrates. The reactions were analyzed using (13)C NMR as the primary screening tool. We describe the discovery of a bacterial catalyzed indole oxidation reaction in which complete conversion of (13)C labeled N-methyl indole to 3-hydroxyindole was observed. In addition, the sensitivity of this reaction to dO(2) levels can be exploited to oxidize to either 3-hydroxyindole or 2-oxoindole. This new platform sets up an important tool for the discovery of new organic transformations using an extensive library of marine bacteria.


Evaluation of DGT as a long-term water quality monitoring tool in natural waters; uranium as a case study.
The performance of the diffusive gradient in thin film technique (DGT) was evaluated as a tool for the long-term monitoring of water quality, using uranium as a case study. DGTs with a Metsorb™ (TiO2) sorbent were deployed consecutively at two alkaline freshwater sites, the River Enborne and the River Lambourn, UK for seven-day intervals over a five-month deployment period to obtain time weighted average concentrations. Weekly spot samples were taken to determine physical and chemical properties of the river water. Uranium was measured in these spot samples and after extraction from the DGT devices. The accuracy of the DGT device time weighted average concentrations to averaged spot water samples in both rivers was 86% (27 to 205%). The DGT diffusive boundary layer (DBL) (0.037-0.141 cm - River Enborne and 0.062-0.086 cm - River Lambourn) was affected by both water flow and biofouling of the diffusion surface. DBL thicknesses found at both sites were correlated with flow conditions with an R(2) value of 0.614. Correlations were also observed between the DBL thickness and dissolved organic carbon (R(2) = 0.637) in the River Lambourn, indicating the potential presence of a complex zone of chemical interactions at the surface of the DGT. The range of DBL thicknesses found at the River Lambourn site were also attributed to of the development of macro-flora on the active sampling surface, indicating that the DBL thickness cannot be assumed to be water flow dependant only. Up to a 57% under-estimate of uranium DGT concentration was observed compared to spot sample concentrations if the DBL was neglected. This study has shown that the use of DGT can provide valuable information in environmental monitoring schemes as part of a 'tool-box' approach when used alongside conventional spot sampling methods.


Monitoring of rain events with a submersible UV/VIS spectrophotometer.
A submersible UV/VIS spectrophotometer has been implemented on the pre-treatment unit of a large-scale wastewater treatment plant (350,000 person-equivalent) to monitor the rapid changes in total Suspended Solids and total Chemical Oxygen Demand occurring during rain events as well as injections of reject water from the sludge treatment train or wasted activated sludge. Calibration has been proven to be difficult for fast composition-varying streams but the device is able to monitor qualitatively sudden quality changes, in spite of the noise affecting the signal.


A longitudinal cohort study of adolescent elite footballers and controls investigating the development of cam morphology.
Cam morphology describes an asphericity of the femoral head that develops during adolescence, is highly prevalent in athletes, and predisposes individuals to future osteoarthritis. However, it's aetiology remains poorly understood. The aim of this study was to perform 3-year longitudinal follow-up of a control population and football club academy cohort to compare the change in hip and growth plate anatomy between athletes and controls. MRI and questionnaires were used to characterise change in hip and growth plate anatomy and quantify activity levels. 121 male academy footballers and 107 male and female controls participated at baseline. Footballers experienced significantly greater increases in femoral head asphericity (4.83 degrees (95% CI: 2.84 to 6.82), p < 0.001) than controls. A positive correlation existed between activity levels and change in femoral head morphology (coefficient 0.79, p ≤ 0.001). Greatest morphological change occurred in individuals aged 11-12 years at baseline, with no significant change in individuals aged 14 years and older at baseline. Cam morphology development was secondary to soft tissue hypertrophy and lateral growth plate extension. In conclusion, excessive loading of the hip joint through exercise prior to 14 years of age may result in growth plate adaptations causing cam morphology. Potential interventions may include training type and load modification in young adolescent football players.


A target triggered proximity combination-based fluorescence sensing strategy for adenosine detection.
Adenosine is a potent physiological and pharmacological regulator, and its abnormal level is closely related to disease development. The sensitive and specific detection of adenosine is crucial for health evaluation and disease diagnosis. In this work, a target triggered proximity combination-based fluorescence sensing strategy is developed for the sensitive and specific detection of adenosine. A difunctional probe showing target recognition and signal amplification is designed, by integration of DNA linker-connected split aptamer fragments with a fragment-elongated polymerase/nicking template. The presence of adenosine would glue the split aptamers, which triggers the two distal aptamer fragments to combine with each other into proximity. The approaching aptamer fragment ends then initiate the strand displacement amplification (SDA) reaction, generating numerous DNA primers. The DNA primers further hybridize with a padlock probe and initiate the rolling circle amplification (RCA) reaction, producing numerous G-quadruplex sequences. The G-quadruplex sequences finally bind with Thioflavin T to obtain enhanced fluorescence signals. The method exhibits a linear correlation within the adenosine concentration range from 5.0 × 10-7 M to 2.0 × 10-5 M (R = 0.999) with a detection limit of 8.4 × 10-8 M, and a good selectivity to distinguish adenosine from its analogues. The recoveries of adenosine in human serum are from 91% to 94%, demonstrating that the system works well in biological fluids. The proposed sensing strategy is anticipated to hold promise in biochemical research, clinical diagnosis and disease treatment.


Functional receptors in Xenopus oocytes for U-37883A, a novel ATP-sensitive K+ channel blocker: comparison with rat insulinoma cells.
Follicle-enclosed Xenopus oocytes were used to describe the ATP-sensitive K+ (KATP) channel-blocking properties of U-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl), in comparison with glibenclamide. In follicular oocytes, the KATP channel opener P1060 (30 microM), a pinacidil analog, activated a large outward K+ current that was blocked by glibenclamide (IC50 = 0.33 microM) and U-37883A (IC50 = 0.26 microM). P1060 activation was inhibited by both U-37883A and glibenclamide in a noncompetitive manner. U-37883A also blocked the KATP channel activation by cAMP (300 microM) and adenosine (10 microM). Single-channel studies on isolated follicular cells showed that U-37883A (10 microM) reduced the open probability of the KATP channel by 76%, without significantly modifying the single-channel current amplitude. Receptor binding studies with [3H]U-37883 in membranes from follicle-enclosed oocytes demonstrated a single class of low affinity binding sites, with a Kd of 450 nM and a Bmax of 17 pmol/mg of protein. Studies with analogs of U-37883A showed that U-52090A inhibited KATP current and displaced [3H]U-37883 from its binding site with similar potencies. In contrast, U-42069D neither inhibited KATP current nor competed with [3H]U-37883 binding. In RINm5F cells (an insulinoma cell line), U-37883A, unlike glibenclamide, failed to inhibit KATP current. Furthermore, there was no significant specific binding of [3H]U-37883 in RINm5F cell membranes, which displayed high levels of specific binding of [3H]glibenclamide. These data demonstrate the presence of a receptor for U-37883A-type guanidines that controls the activity of the endogenous KATP channels in follicle-enclosed oocytes. The available data collectively suggest that U-37883A is a more selective blocker of the follicular KATP channel, which is very similar to that in smooth muscle, than of the pancreatic beta cell KATP channel.


Disintegration of Sensorimotor Brain Networks in Schizophrenia.
Schizophrenia is a severe mental disorder associated with derogated function across various domains, including perception, language, motor, emotional, and social behavior. Due to its complex symptomatology, schizophrenia is often regarded a disorder of cognitive processes. Yet due to the frequent involvement of sensory and perceptual symptoms, it has been hypothesized that functional disintegration between sensory and cognitive processes mediates the heterogeneous and comprehensive schizophrenia symptomatology. Here, using resting-state functional magnetic resonance imaging in 71 patients and 196 healthy controls, we characterized the standard deviation in BOLD (blood-oxygen-level-dependent) signal amplitude and the functional connectivity across a range of functional brain networks. We investigated connectivity on the edge and node level using network modeling based on independent component analysis and utilized the brain network features in cross-validated classification procedures. Both amplitude and connectivity were significantly altered in patients, largely involving sensory networks. Reduced standard deviation in amplitude was observed in a range of visual, sensorimotor, and auditory nodes in patients. The strongest differences in connectivity implicated within-sensorimotor and sensorimotor-thalamic connections. Furthermore, sensory nodes displayed widespread alterations in the connectivity with higher-order nodes. We demonstrated robustness of effects across subjects by significantly classifying diagnostic group on the individual level based on cross-validated multivariate connectivity features. Taken together, the findings support the hypothesis of disintegrated sensory and cognitive processes in schizophrenia, and the foci of effects emphasize that targeting the sensory and perceptual domains may be key to enhance our understanding of schizophrenia pathophysiology.


Microglia express gamma-interferon-inducible lysosomal thiol reductase in the brains of Alzheimer's disease and Nasu-Hakola disease.
Gamma-interferon-inducible lysosomal thiol reductase (GILT), expressed in antigen-presenting cells (APCs), facilitates the reduction of disulfide bonds of endocytosed proteins in the endocytic pathway and they are further processed for presentation of immunogenic peptides loaded on major histocompatibility complex (MHC) class II. Although the constitutive and IFNγ-inducible expression of GILT was observed in various APCs, such as dendritic cells, monocytes/macrophages, and B cells, GILT-expressing cell types remain unknown in the human central nervous system (CNS). Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2, both of which are expressed on microglia. A rare heterozygous variant of the TREM2 gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD), suggesting that both NHD and AD are induced by dysfunction of the microglial TREM2 signaling pathway in the brains. We studied by immunohistochemistry GILT expression in NHD and AD brains. GILT was expressed on amoeboid microglia with the highest levels of expression in AD brains, compared with those in non-neurological control (NC) brains and in NHD brains. In AD brains, the clusters of amoeboid microglia surrounding amyloid-beta (Aꞵ) deposition strongly expressed GILT. Furthermore, a human microglial cell line expressed GILT in response to IFNγ. These results indicate that microglia, expressing constitutively high levels of GILT, act as a principal cell type of APCs in AD brains, in contrast to baseline levels of GILT expression in NHD brains.


Unveiling common responses of Medicago truncatula to appropriate and inappropriate rust species.
Little is known about the nature of effective defense mechanisms in legumes to pathogens of remotely related plant species. Some rust species are among pathogens with broad host range causing dramatic losses in various crop plants. To understand and compare the different host and nonhost resistance (NHR) responses of legume species against rusts, we characterized the reaction of the model legume Medicago truncatula to one appropriate (Uromyces striatus) and two inappropriate (U. viciae-fabae and U. lupinicolus) rusts. We found that similar pre and post-haustorial mechanisms of resistance appear to be operative in M. truncatula against appropriate and inappropriate rust fungus. The appropriate U. striatus germinated better on M. truncatula accessions then the inappropriate U. viciae-fabae and U. lupinicolus, but once germinated, germ tubes of the three rusts had a similar level of success in finding stomata and forming an appressoria over a stoma. However, responses to different inappropriate rust species also showed some specificity, suggesting a combination of non-specific and specific responses underlying this legume NHR to rust fungi. Further genetic and expression analysis studies will contribute to the development of the necessary molecular tools to use the present information on host and NHR mechanisms to breed for broad-spectrum resistance to rust in legume species.


Pharmacotherapy for post-traumatic stress disorder - a systematic review and meta-analysis.
Post-traumatic stress disorder (PTSD) is a prevalent and disabling condition. Evidence that PTSD is characterized by specific psychobiological dysfunctions has contributed to a growing interest in use of medication in its treatment. To assess the effects of medication in the treatment of PTSD. Systematic review of randomised controlled trials (RCTs) following the Cochrane Collaboration guidelines. A more detailed version of the review is published in the Cochrane Database of Systematic Reviews. We searched the Cochrane Depression, Anxiety and Neurosis Group specialised register, the Cochrane Central Register of Controlled Trials (Cochrane Library issue 4, 2004), MEDLINE (January 1966 - December 2004), PsycINFO (1966 - 2004), the National PTSD Center Pilots database, and the meta register module of the Controlled Trials database. Reference lists of retrieved articles were searched for additional studies. Two raters independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. Investigators were contacted to obtain missing data. Summary statistics were stratified by medication class, and by medication agent for the selective serotonin re-uptake inhibitors (SSRIs). Dichotomous and continuous measures were calculated using a random effects model, heterogeneity was assessed, and subgroup/sensitivity analyses were done. Thirty-five short-term (14 weeks or less) RCTs were included in the analysis (4 597 participants). Symptom severity for 17 trials was significantly reduced in the medication groups, relative to placebo (weighted mean difference (WMD) = -5.76, 95% confidence interval (CI)-8.16 - -3.36, N = 2 507). Similarly, summary statistics for responder status from 13 trials demonstrated overall superiority of a variety of medication agents compared with placebo (relative risk (RR) = 1.49, 95% CI: 1.28, 1.73, number needed to treat (NNT) = 4.85, N = 1 272). Medication and placebo response occurred in 59.1% (N = 644) and 38.5% (N = 628) of patients, respectively. Of the medication classes, evidence of treatment efficacy was most convincing for the SSRIs. Medication was also effective in reducing the severity of the PTSD re-experiencing/intrusion, avoidance/numbing, and hyperarousal symptom clusters in 9 trials (N = 1 304). In addition, medication was superior to placebo in reducing comorbid depression and disability. Medication was also less well tolerated than placebo. A narrative review of the 3 maintenance trials suggested that long-term medication may be required in treating PTSD. Medication treatments can be effective in treating PTSD, acting to reduce its core symptoms, as well as associated depression and disability, and should be considered as part of the treatment of this disorder. The findings of this review support the status of SSRIs as first-line agents in the pharmacotherapy of PTSD, as well as their value in longterm treatment. However, there remain important gaps in the evidence base, and there is a continued need for more effective agents in the management of PTSD.


Induction of peptide-specific primary cytotoxic T lymphocyte responses from human peripheral blood.
Various protocols were developed and compared for eliciting specific cytotoxic T lymphocyte (CTL) cell lines from the unselected human peripheral blood mononuclear cells of naive donors. Interleukin-7 and CD4+ T cells primed in vitro by keyhole limpet hemocyanin were shown to act together in the generation of these responses. Primary responses were consistently induced with a variety of different HLA class I-binding malarial peptides. Primary CTL responses could be induced from unselected CD8+ and from CD45RA+CD8+ T cells. The CTL lines derived from these naive donors were CD8+ and demonstrated a high level of HLA class I-restricted killing for > 3 months after priming in vitro. They were also able to recognize and kill targets infected with a recombinant vaccinia virus containing the full-length antigen. In addition, this same protocol enhanced up to fourfold the levels of secondary CTL responses induced. The optimal method presented for naive cytotoxic T cell stimulation is simple, rapid and generally applicable and should provide a useful tool for both basic research and human therapy.


Regulation of intracellular pH by bovine intervertebral disc cells.
Extracellular acidity is an important determinant of intervertebral disc matrix turnover, possibly exerting effects through changes of intracellular pH (pHi). There is, however, little information concerning the ways in which these cells regulate their pHi. Fluorimetric techniques have been used in the present study to measure pH in isolated intervertebral disc cells, and to characterise the membrane transport pathways by which it is regulated. Nucleus pulposus cells were obtained from bovine intervertebral discs by standard enzymatic digestion techniques, and loaded with the PH-sensitive fluoroprobe BCECF. Resting pHi was approximately 6.7 for cells suspended in either HEPES buffered (HBS) or CO2/HCO3--buffered (BBS) media. Intrinsic buffering capacity was approximately 19 mM pH unit(-1) in HBS and was increased when cells were suspended in BBS. A combination of ion substitution and inhibitor studies for cells at steady-state pH or acidified by exposure to NH4Cl revealed that in HBS Na+ x H+ exchange and an H+-ATPase extrude acid from these cells. Only one of these two systems, the Na+ x H+ exchanger, exhibited a sensitivity to pH, identifying it as the regulator of pH under these conditions. In BBS, an additional pathway which was dependent on extracellular Na+, extracellular HCO3- and intracellular Cl- was detected. These properties are consistent with the four ion HCO3--dependent transporter, although the cation-rich, anion-poor extracellular matrix of the intervertebral disc means that such a pathway has only a marginal role in disc cell pHi regulation.


Low expression of SHP-2 is associated with less favorable prostate cancer outcomes.
Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) is an important regulator of cell signaling because of its ability to dephosphorylate receptors of growth factors as well as the cytokines and tyrosine-phosphorylated proteins associated with these receptors. In the current study, we used four different prostate cancer cell lines: PC3, DU145, LNCaP and LNCaP-IL6+. Tumor specimens from 122 patients with prostate cancer were analyzed using a tissue microarray. Our data demonstrate that all four prostate cancer cell lines express the SHP-2 protein. Additionally, low staining intensity and SHP-2 expression in the cytoplasm of cancer cells in prostate tumor specimens was inversely correlated with prostate volume (p = 0.041 and p = 0.042, respectively) whereas nuclear staining was positively correlated with extracapsular extension (p = 0.039). In our post-prostatectomy specimens, we found that patients with low SHP-2 expression had less favorable outcomes with respect to biochemical recurrence and clinical progression (p = 0.005 and p = 0.018, respectively). The loss of cytoplasmic SHP-2 expression is associated with increased growth and prostatic cancer progression.


High rates of stopping or switching biological medications in veterans with rheumatoid arthritis.
To define the characteristics of a population of veterans with rheumatoid arthritis (RA) who have stopped or switched their first biologic agent, and to assess if measures of disease activity are predictors in the decision to alter the regimen. A retrospective analysis of the VA electronic medical record system identified RA patient demographic and disease activity parameters from 1999 to 2007. Demographic data included age, race/ethnicity, sex, and tobacco use. Disease-specific data included date of RA onset, past DMARD therapies, prednisone use, as well as the disease activity score (DAS-28) and the health assessment questionnaire (HAQ) at each clinic visit. The use of six biologicals (infliximab, etanercept, adalimumab, abatacept, rituximab, anakinra) was identified in order to compare those who continued with the medication to those discontinuing or switching to another biological. Descriptive and parametric statistics were applied to define differences between the two groups. Of 454 RA patients identified, 212 have been on a biologic agent at one point in time, and 100 patients (47%) had either stopped or switched their first biologic agent. Among these 100 patients, the most common reasons for stopping or switching a biologic agent were adverse events (in 48%) and inefficacy (43%) Adverse events included malignancies (23% of 48 patients), rash (23%), infections (18.8%), and cardiac complications (18.8%). When comparing the 100 patients versus the 112 that did not stop or switch their first agent, the DAS-28 correlated significantly with a change of regimen with an OR 2.1 (p<0.001). The HAQ score had an OR of 2.0 (p<0.04). RA patients who continue taking their initial biologic medication have similar age, RA disease duration, ethnicity, and smoking status to those requiring switching or discontinuation. The DAS28 and HAQ scores significantly correlated with stopping or switching of a first biologic agent. Adverse event rates were high and their distributions differed in this population compared to previous studies of younger Caucasian females.


Intraoral Microbial Metabolism and Association with Host Taste Perception.
Metabolomics has been identified as a means of functionally assessing the net biological activity of a particular microbial community. Considering the oral microbiome, such an approach remains largely underused. While the current knowledge of the oral microbiome is constantly expanding, there are several deficits in knowledge particularly relating to their interactions with their host. This work uses nuclear magnetic resonance spectroscopy to investigate metabolic differences between oral microbial metabolism of endogenous (i.e., salivary protein) and exogenous (i.e., dietary carbohydrates) substrates. It also investigated whether microbial generation of different metabolites may be associated with host taste perception. This work found that in the absence of exogenous substrate, oral bacteria readily catabolize salivary protein and generate metabolic profiles similar to those seen in vivo. Important metabolites such as acetate, butyrate, and propionate are generated at relatively high concentrations. Higher concentrations of metabolites were generated by tongue biofilm compared to planktonic salivary bacteria. Thus, as has been postulated, metabolite production in proximity to taste receptors could reach relatively high concentrations. In the presence of 0.25 M exogenous sucrose, increased catabolism was observed with increased concentrations of a range of metabolites relating to glycolysis (lactate, pyruvate, succinate). Additional pyruvate-derived molecules such as acetoin and alanine were also increased. Furthermore, there was evidence that individual taste sensitivity to sucrose was related to differences in the metabolic fate of sucrose in the mouth. High-sensitivity perceivers appeared more inclined toward continual citric acid cycle activity postsucrose, whereas low-sensitivity perceivers had a more efficient conversion of pyruvate to lactate. This work collectively indicates that the oral microbiome exists in a complex balance with the host, with fluctuating metabolic activity depending on nutrient availability. There is preliminary evidence of an association between host behavior (sweet taste perception) and oral catabolism of sugar.