The nearly invisible intraneural cyst: a new and emerging part of the spectrum.
OBJECTIVE The authors have observed that a subset of patients referred for evaluation of peroneal neuropathy with "negative" findings on MRI of the knee have subtle evidence of a peroneal intraneural ganglion cyst on subsequent closer inspection. The objective of this study was to introduce the nearly invisible peroneal intraneural ganglion cyst and provide illustrative cases. The authors further wanted to identify clues to the presence of a nearly invisible cyst. METHODS Illustrative cases demonstrating nearly invisible peroneal intraneural ganglion cysts were retrospectively reviewed and are presented. Case history and physical examination, imaging, and intraoperative findings were reviewed for each case. The outcomes of interest were the size and configuration of peroneal intraneural ganglion cysts over time, relative to various interventions that were performed, and in relation to physical examination and electrodiagnostic findings. RESULTS The authors present a series of cases that highlight the dynamic nature of peroneal intraneural ganglion cysts and introduce the nearly invisible cyst as a new and emerging part of the spectrum. The cases demonstrate changes in size and morphology over time of both the intraneural and extraneural compartments of these cysts. Despite "negative" MR imaging findings, nearly invisible cysts can be identified in a subset of patients. CONCLUSIONS The authors demonstrate here that peroneal intraneural ganglion cysts ride a roller coaster of change in both size and morphology over time, and they describe the nearly invisible cyst as one end of the spectrum. They identified clues to the presence of a nearly invisible cyst, including deep peroneal predominant symptoms, fluctuating symptoms, denervation changes in the tibialis anterior muscle, and abnormalities of the superior tibiofibular joint, and they correlate the subtle imaging findings to the internal fascicular topography of the common peroneal nerve. The description of the nearly invisible cyst may allow for increased recognition of this pathological entity that occurs with a spectrum of findings.


A Questionnaire to Assess the Challenges Faced by Women Who Quit Working as Full-Time Neurosurgeons.
To analyze why women quit full-time employment as neurosurgeons and to discuss the conditions required for their reinstatement. We asked 94 core hospitals providing training programs in the board certification system adopted by the Japan Neurosurgical Society to indicate the total number and present status of women in their department and to send our anonymous questionnaire to women who had formerly worked as full-time neurosurgeons. The questionnaire consisted of closed and open questions on their reasons for quitting as full-time neurosurgeons. Among 427 women evaluated, 72 (17%) had quit full-time employment as neurosurgeons. Twenty-one women who had quit 3-21 years after starting their neurosurgery careers responded to the questionnaire, including 17 board-certified neurosurgeons, 11 individuals with master's degrees, and 16 mothers. Their main reasons for quitting full-time work were difficulty in balancing their neurosurgical career and motherhood (52%) and the physical burden (38%). At the time of quitting, only 2 units (5%) had a career counseling system for women. Two thirds of participants might resume full-time work as neurosurgeons in the future. Their support system during pregnancy and the child-raising period, and understanding of male bosses and colleagues were identified as the key themes. The Japan Neurosurgical Society could facilitate supportive environments for women in neurosurgery by enhancing adequate childcare services, changing the work style of full-time neurosurgeons to incorporate diverse working styles, shorter working hours, understanding of their bosses and colleagues, and a career counseling system.


Predictors of cognitive decline in Alzheimer's disease and mild cognitive impairment using the CAMCOG: a five-year follow-up.
There are discrepant findings regarding which subscales of the Cambridge Cognitive Examination (CAMCOG) are able to predict cognitive decline. The study aimed to identify the baseline CAMCOG subscales that can discriminate between patients and predict cognitive decline in Alzheimer's disease (AD) and mild cognitive impairment (MCI). This was a five-year case-control study of patients with cognitive impairment and a control group. Participants were grouped into AD (n = 121), MCI converted to dementia (MCI-Ad, n = 43), MCI-stable (MCI-St, n = 66), and controls (CTR, n = 112). Differences in the mean scores obtained by the four groups were examined. Receiver operating characteristic curves were used to compare subscale scores in the AD and MCI-Ad groups with those of controls. The influence of age, gender, schooling, and depression on baseline subscale scores was assessed. Of the CAMCOG subscales, Orientation and Memory (learning and recent) (OR + MEM) showed the highest discriminant capacity in the baseline analysis of the four groups. This baseline analysis indicated that OR + MEM was the best predictor of conversion to AD in the MCI-Ad group (area under the curve, AUC = 0.81), whereas the predictive capacity of the global MMSE and CAMCOG scores was poor (AUC = 0.59 and 0.53, respectively). In the baseline analysis, the Orientation and Memory (learning and recent) subscales showed the highest discriminant and predictive capacity as regards both cognitive decline in the AD group and conversion to AD among MCI-Ad patients. This was not affected by age, gender, schooling, or depression.


Mitochondrial portraits of the Madeira and Açores archipelagos witness different genetic pools of its settlers.
We have studied the matrilineal genetic composition of the Madeira and Açores north Atlantic archipelagos, which were settled by the Portuguese in the 15th century. Both archipelagos, and particularly Madeira, were involved in a complex commercial network established by the Portuguese, which included the trading of slaves across the Atlantic. One hundred and fifty-five mtDNAs sampled from the Madeira and 179 from the Açores archipelagos were analysed for the hypervariable segment I (HVS-I), and for haplogroup-diagnostic coding-region RFLPs. The different settlement histories of both groups of islands are well reflected in their present day mtDNA pool. Although both archipelagos show identical diversity values, they are clearly different in their haplogroup content. Madeira displays a stronger sub-Saharan imprint, with haplogroups L1-L3 constituting about 13% of the lineages. Also, the relative frequencies of L sub-clusters in Madeira and mainland Portugal suggests that, at least in part, African presence in Madeira can be attributed to a direct gene flow from West Africa and not via Portugal. A comparison of the genetic composition of these two archipelagos with the Canary Islands, specially taking into account that their European source population was essentially from the Iberian Peninsula, testifies the stronger impact of the North African U6 cluster in the Canaries. This group is present in Madeira at a moderate frequency, but very reduced in the Açores. Nevertheless the recorded introduction of Canary native Guanches, who are characterized by the presence of particular sub-clade U6b1, has left no detectable imprints in the present day population of Madeira.


The high-resolution X-ray crystal structure of the complex formed between subtilisin Carlsberg and eglin c, an elastase inhibitor from the leech Hirudo medicinalis. Structural analysis, subtilisin structure and interface geometry.
Triclinic crystals of the complex formed by eglin with subtilisin Carlsberg were analyzed by X-ray diffraction. The crystal and molecular structure of this complex was determined with data that extended to 0.12-nm resolution by a combination of Patterson search methods and isomorphous replacement techniques. Its structure was refined to a crystallographic R value of 0.178 (1.0-0.12 nm) using an energy-restraint least-squares procedure. The complete subtilisin molecule could be traced without ambiguity in the refined electron density. The eglin component, from which an amino-terminal segment is cleaved off, is only defined from Lys8I (i.e. the lysine residue 8 of the inhibitor) onwards. Per unit cell, 436 fixed solvent molecules and 2 calcium ions were located. In spite of 84 amino acid replacements and one deletion, subtilisin Carlsberg exhibits a very similar polypeptide fold to subtilisin BPN'. The root-mean-square deviations of all alpha-carbon atoms (excluding those at the deletion site) from models of subtilisin BPN' [Alden, R. A., Birktoft, J. J., Kraut, J., Robertus, J. D. & Wright, C. S. (1971) Biochem. Biophys. Res. Commun. 45, 337-344] and subtilisin Novo [Drenth, J., Hol, W. G. J., Jansonius, J. N. & Kockoek, R. (1972) Eur. J. Biochem. 25, 177-181] are 0.077 nm and 0.103 nm. Most of these deviations result from global shifts rather than changes of the local geometry. The single-residue deletion at position 56 affects only the surrounding conformation. Two sites of high electron density and close distances to surrounding oxygen ligands have been found in the Carlsberg enzyme which are probably occupied by calcium ions. Eglin consists of a twisted four-stranded beta-sheet flanked by an alpha-helix and by an exposed proteinase binding loop on opposite sides. Around the reactive site, Leu45I-Asp46I, this loop is mainly stabilized by electrostatic/hydrogen bond interactions with the side chains of two arginine residues which project from the hydrophobic core [Bode, W., Papamokos, E., Musil, D., Seemüller, W. & Fritz, H. (1986) EMBO J. 5, 813-818]. The reactive site loop conformation resembles that found in other 'small' proteinase inhibitors. The scissile peptide bond is not cleaved but its carbonyl group is slightly distorted from planar geometry. Most of the intermolecular contacts are contributed by the nine residues of the reactive-site loop Gly40I-Arg48I.(ABSTRACT TRUNCATED AT 400 WORDS)


Very low density lipoprotein cholesterol associates with coronary artery calcification in type 2 diabetes beyond circulating levels of triglycerides.
While recent genomic studies have focused attention on triglyceride (TG) rich lipoproteins in cardiovascular disease (CVD), little is known of very low-density lipoprotein cholesterol (VLDL-C) relationship with atherosclerosis and CVD. We examined, in a high-risk type-2 diabetic population, the association of plasma VLDL-C with coronary artery calcification (CAC). The Penn Diabetes Heart Study (PDHS) is a cross-sectional study of CVD risk factors in type-2 diabetics (n = 2118, mean age 59.1 years, 36.5% female, 34.1% Black). Plasma lipids including VLDL-C were calculated (n = 1879) after ultracentrifugation. In Tobit regression, VLDL-C levels were positively associated with increasing CAC after adjusting for age, race, gender, Framingham risk score, body mass index, C-reactive protein, exercise, medication and alcohol use, hemoglobin A1c, and diabetes duration [Tobit ratio (TR) and 95% confidence interval (CI) 0.38 (0.12-0.65), P = 0.005] and even after inclusion of apolipoprotein B data [TR 0.31 (0.03-0.58), P = 0.030]. Approximately 3-fold stronger effect was observed in women [TR 0.75 (0.16-1.34), P = 0.013] than men [TR 0.20 (-0.10-0.50), P = 0.189; gender interaction P = 0.034]. Plasma VLDL-C was related more strongly to CAC scores than TG levels (e.g., Akaike information criteria of 7263.65 vs. 7263.94) and had stronger CAC association in individuals with TGs >150 mg/dl (TR 0.80, P = 0.010) vs. those with TGs <150 mg/dl (TR 0.27, P = 0.185). In PDHS, VLDL-C is associated with CAC independent of established CVD risk factors, particularly in women, and may have value even beyond apolipoprotein B levels and in patients with elevated TGs.


Bioeconomic modeling of lactational antimicrobial treatment of new bovine subclinical intramammary infections caused by contagious pathogens.
This study determined the direct and indirect epidemiologic and economic effects of lactational treatment of new bovine subclinical intramammary infections (IMI) caused by contagious pathogens using an existing bioeconomic model. The dynamic and stochastic model simulated the dynamics of Staphylococcus aureus, Streptococcus uberis, Streptococcus dysgalactiae, and Escherichia coli during lactation and the dry period in a 100-cow dairy herd during 1 quota year. Input parameters on cure were obtained from recent Dutch field data. The costs of clinical IMI, subclinical IMI, and intervention were calculated into the combined total annual net costs of IMI per herd. The cost effectiveness of 4 scenarios with lactational intervention was determined; scenarios included no intervention, treatment after 1 mo of infection, treatment after 2 mo of infection, and treatment after 1 mo of infection and culling of uncured cows after 2 mo of infection. Model behavior was observed for variation in parameter input values. Compared with no lactational intervention, lactational intervention of new subclinical IMI resulted in fewer clinical flare ups, less transmission within the herd, and much lower combined total annual net costs of IMI in dairy herds. Antimicrobial treatment of IMI after 1 mo of infection and culling of uncured cows after 2 mo of infection resulted in the lowest costs, whereas treatment after 2 mo of infection was associated with the highest costs between the scenarios with intervention. Changing the probability of cure resulted in a nonlinear change in the cumulative incidence of IMI cases and associated costs. Lactational treatment was able to prevent IMI epidemics in dairy herds at high transmission rates of Strep. uberis, Strep. dysgalactiae, and E. coli. Lactational treatment did not limit the spread of Staph. aureus at high transmission rates, although the associated costs were lower compared with no intervention. To improve udder health in a dairy herd, lactational treatment of contagious subclinical IMI must therefore be preceded by management measures that lower the transmission rate. Lactational treatment of environmental subclinical IMI seemed less cost effective. Detection of subclinical IMI needs improvement to be able to most effectively treat subclinical IMI caused by contagious pathogens during lactation.


Pathogenesis of IgA nephropathy.
Immunoglobulin A (IgA) nephropathy is an immune-complex-mediated glomerulonephritis characterized by the presence of immunoglobulin A deposits in mesangial and paramesangial regions. The patients with IgA nephropathy present with varying clinical symptoms (eg, microhematuria with preserved renal function or progressive deterioration of renal functions resulting in end-stage renal disease). The factors involved in the pathogenetic mechanisms of IgA nephropathy include (1). environmental factors, (2). genetic factors, (3). abnormality of the IgA1 molecule, and (4). various inflammatory mediators. The gene polymorphism studies for human leukocyte antigen (HLA), renin-angiotensin-aldosterone system, and selectin gene clusters, suggest a certain degree of genetic predisposition in patients for IgA nephropathy. Also, the genome-wide screening in familial IgA nephropathy showed linkage of IgA nephropathy to the 6q22-23 chromosome. Besides genetic influence in its pathogenesis, aberrant galactosylation in serum IgA and IgA1 eluted from kidneys with IgA nephropathy has been observed, and conceivably such abnormalities induce the expression of various cytokines, interleukin (IL)-6, platelet-derived growth factor (PDGF), tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta1 in the renal cells, which contributes to further glomerular injury. Despite an enormous amount of information available in the literature, further studies are needed to delineate the precise pathogenetic mechanisms involved in primary IgA nephropathy and also to facilitate the development of newer therapeutic interventions.


Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses.
Pancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelin-redirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-α and IL-2 (Ad5/3-E2F-D24-TNFa-IRES-IL2, or OAd-TNFa-IL2) would improve efficacy. OAd-TNFa-IL2 enhanced the antitumor efficacy of meso-CAR T cells in human-PDA-xenograft immunodeficient mice and efficacy was associated with robustly increased tumor-infiltrating lymphocytes (TILs), enhanced and prolonged T cell function. Mice treated with parental OAd combined with meso-CAR T developed tumor metastasis to the lungs even if primary tumors were controlled. However, no mice treated with combined OAd-TNFa-IL2 and meso-CAR T died of tumor metastasis. We also evaluated this approach in a syngeneic mouse tumor model by combining adenovirus expressing murine TNF-α and IL-2 (Ad-mTNFa-mIL2) and mouse CAR T cells. This approach induced significant tumor regression in mice engrafted with highly aggressive and immunosuppressive PDA tumors. Ad-mTNFa-mIL2 increased both CAR T cell and host T cell infiltration to the tumor and altered host tumor immune status with M1 polarization of macrophages and increased dendritic cell maturation. These findings indicate that combining cytokine-armed oncolytic adenovirus to enhance the efficacy of CAR T cell therapy is a promising approach to overcome the immunosuppressive TME for the treatment of PDA.


Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions.
The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis-eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying >4.1 million significant eQTL for >18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for >10,000 genes). We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. Additionally, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a resource for use by the research community. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalization with lncRNA RP11-677M14.2 (posterior probability of colocalization 0.975).


Pediatric Renal Transplantation: Focus on Current Transition Care and Proposal of the "RISE to Transition" Protocol.
The transition from pediatric to adult medical services is an important time in the life of an adolescent or young adult with a renal transplant. Failure of proper transition can lead to medical non-adherence and subsequent loss of graft and/or return to dialysis. The aim of this study was to conduct a systematic review and survey to assess the challenges and existing practices in transition of renal transplant recipient children to adult services, and to develop a transition protocol. We conducted a literature review and performed a survey of pediatric nephrologists across the United States to examine the current state of transition care. A structured transition protocol was developed based on these results. Our literature review revealed that a transition program has a positive impact on decline in renal function and acute rejection episodes, and may improve long-term graft outcomes in pediatric kidney transplant patients. With a response rate of 40% (60/150) from nephrologists in 56% (49/87) of centers, our survey shows inconsistent use of validated tools despite their availability, inefficient communication between teams, and lack of use of dedicated clinics. To address these issues, we developed the "RISE to Transition" protocol, which relies on 4 competency areas: Recognition, Insight, Self-reliance, and Establishment of healthy habits. The transition program decreases acute graft rejection episodes, and the main challenges in transition care are the communication gap between health care providers and inconsistent use of transition tools. Our RISE to transition protocol incorporates transition tools, defines personnel, and aims to improve communication between teams.


Sanders stage 7b: Using the appearance of the ulnar physis improves decision-making for brace weaning in patients with adolescent idiopathic scoliosis.
The aim of this study was to investigate whether including the stages of ulnar physeal closure in Sanders stage 7 aids in a more accurate assessment for brace weaning in patients with adolescent idiopathic scoliosis (AIS). This was a retrospective analysis of patients who were weaned from their brace and reviewed between June 2016 and December 2018. Patients who weaned from their brace at Risser stage ≥ 4, had static standing height and arm span for at least six months, and were ≥ two years post-menarche were included. Skeletal maturity at weaning was assessed using Sanders staging with stage 7 subclassified into 7a, in which all phalangeal physes are fused and only the distal radial physis is open, with narrowing of the medial physeal plate of the distal ulna, and 7b, in which fusion of > 50% of the medial growth plate of distal ulna exists, as well as the distal radius and ulna (DRU) classification, an established skeletal maturity index which assesses skeletal maturation using finer stages of the distal radial and ulnar physes, from open to complete fusion. The grade of maturity at the time of weaning and any progression of the curve were analyzed using Fisher's exact test, with Cramer's V, and Goodman and Kruskal's tau. We studied a total of 179 patients with AIS, of whom 149 (83.2%) were female. Their mean age was 14.8 years (SD 1.1) and the mean Cobb angle was 34.6° (SD 7.7°) at the time of weaning. The mean follow-up was 3.4 years (SD 1.8). At six months after weaning, the rates of progression of the curve for patients weaning at Sanders stage 7a and 7b were 11.4% and 0%, respectively for those with curves of < 40°. Similarly, the rates of progression of the curve for those being weaned at ulnar grade 7 and 8 using the DRU classification were 13.5% and 0%, respectively. The use of Sanders stages 6, 7a, 7b, and 8 for the assessment of maturity at the time of weaning were strongly and significantly associated (Cramer's V 0.326; p = 0.016) with whether the curve progressed at six months after weaning. Weaning at Sanders stage 7 with subclassification allowed 10.6% reduction of error in predicting the progression of the curve. The use of Sanders stages 7a and 7b allows the accurate assessment of skeletal maturity for guiding brace weaning in patients with AIS. Weaning at Sanders stage 7b, or at ulnar grade 8 with the DRU classification, is more appropriate as the curve did not progress in any patient with a curve of < 40° immediately post-weaning. Thus, reaching full fusion in both distal radial and ulnar physes (as at Sanders stage 8) is not necessary and this allows weaning from a brace to be initiated about nine months earlier. Cite this article: Bone Joint J 2021;103-B(1):141-147.


Comparing grazing on lake seston by Dreissena and Daphnia: lessons for biomanipulation.
Biomanipulation measures in lakes, taken to diminish algal blooms, have mainly been restricted to the reduction of zooplanktivorous fish with the aim to stimulate the grazing pressure by native filter feeders such as Daphnia. However, larger filter feeders like the exotic zebra mussel, Dreissena polymorpha, have been suggested as an optional tool because of their high filtering capacity. We compared grazing by two filter feeders, D. polymorpha and Daphnia galeata, offered seston from Lake IJsselmeer, the Netherlands in two consecutive years: 2002 and 2003. The seston in both years was dominated by the colony-forming cyanobacterium Microcystis aeruginosa. The grazing studies were performed under controlled conditions in the laboratory and samples were analyzed on a flow cytometer, making it possible to quantify grazing on different seston components and size fractions, including cyanobacteria, other phytoplankton (green algae, diatoms, etc.), and detritus. No differences in clearance rates, on a per weight basis, were found between the two grazer species. The clearance rate on cyanobacteria (especially <20 microm) was lower in 2003 than in 2002. In 2003, the microcystin concentration of cyanobacteria was higher than in 2002, suggesting that the observed lower clearance rate in 2003 was due to the enhanced toxin content of the cyanobacteria. Zebra mussels, although indiscriminately filtering all seston groups out of the water, positively selected for phytoplankton in their mantle cavity, irrespective of its toxicity, and rejected detritus. Since no differences in clearance rates were found between the two grazer species, we conclude that for biomanipulation purposes of shallow lakes, native species like the daphnids should be preferred over exotic species like zebra mussels. When the seston is dominated by phytoplankton that cannot be filtered out of the water column by Daphnia, however, the use of zebra mussels may be considered. Care should be taken, however, in the choice of the lakes since the mussels may have severe ecological and economic impacts.


Pregnancy-associated osteoporosis presenting severe vertebral fractures.
The syndrome of pregnancy-associated osteoporosis (PAO) is a rare disorder which occurs either in late pregnancy or early post-partum period leading to fragility fracture(s), most commonly in the vertebral bodies. We presented two cases with PAO who had compression fractures at multiple levels involving five vertebrae in one case and 10 vertebrae in the other. Their spinal bone mineral density values were below -2.5 standard deviations. Anti-osteoporotic treatments with nasal calcitonin 400 IU/day, vitamin D 300.000 IU single dose, calcium 1000 mg/day, vitamin D 880 IU/day were initiated. In one case, kyphoplasty was performed by a spinal surgeon. In addition to a thoracolumbosacral orthosis, a rehabilitation program including muscle strengthening, range of motion, relaxation and weight-bearing exercises was started for both cases. These cases emphasize that all pregnant women with complaints of back/lumbar pain should be carefully evaluated.


Does activity affect the outcome of the Oxford unicompartmental knee replacement?
High levels of activity are considered to be a contraindication to unicompartmental knee replacement (UKR) and are not recommended after UKR. To determine if these recommendations should apply to the mobile-bearing Oxford UKR, this study assessed the effect of post-operative activity level on the outcome of this device. The outcome of the first 1000 Phase 3 cemented Oxford UKRs implanted between 1998 and 2010 was assessed using survival analysis, the Oxford Knee Score (OKS) and the American Knee Society Objective (KSS-O) and Functional (KSS-F) Scores. Patients were grouped according to the maximum post-operative Tegner Activity Score. The mean follow-up was 6.1 years (range 1 to 14). Overall, increasing activity was associated with superior survival (p=0.025). In the high activity group, with Tegner≥5 (n=115) 2.6% were revised and the 12-year survival was 97.3% (confidence interval (CI): 92.0% to 99.1%). In the low activity group, with Tegner≤4, (n=885) 4.3% were revised and the 12-year survival was 94.0% (CI: 91.4 to 95.8). The difference between the two groups was not significant (p=0.44). Although the final OKS and KSS-F were significantly better in the high activity group compared to the low activity group (OKS 45v40, KSS-F 95v78), there was no difference in the change in OKS or KSS-O. High activity does not compromise the outcome of the Oxford UKR and may improve it. Activity should not be restricted nor considered to be a contraindication.


Elder Mistreatment Perpetrators with Substance Abuse and/or Mental Health Conditions: Results from the National Elder Mistreatment Study.
A large portion of persons who commit elder mistreatment have long been known to have indicators of substance abuse and/or mental health conditions (SAMHC). However, few studies have specifically examined elder mistreatment by persons with SAMHC, preventing the development of specialized intervention strategies. Using results from the National Elder Mistreatment Study, the current article examines victim, perpetrator, and interaction characteristics between cases of emotional and physical elder mistreatment in which the perpetrator is reported to have vs. not have SAMHC. Chi square tests and Mann-Whitney-Wilcoxon non-parametric tests were performed. 210 perpetrators of emotional elder mistreatment were reported to have SAMHC with 412 perpetrators of emotional mistreatment reported to not have SAMHC. 57 perpetrators of physical elder mistreatment were reported to have SAMHC with 38 perpetrators of physical mistreatment not having SAMHC. Emotional elder mistreatment committed by persons with SAMHC was associated with the following characteristics: perpetrator-unemployment, history of involvement with police, and fewer friendships; victim-female gender, greater emotional problems, and greater occurrences of lifetime emotional mistreatment; interaction-co-residence, and reporting of mistreatment to authorities. Physical elder mistreatment committed by persons with SAMHC was associated with police involvement of the perpetrator and greater occurrences of lifetime physical mistreatment experienced by the victim. These findings indicate that victims of elder mistreatment by persons with SAMHC are in particular need of intervention services as they have greater histories of mistreatment and experience greater emotional problems. Implications for effectively intervening in cases of elder mistreatment by persons with SAMHC are discussed.


Laparoscopic anterior spinal arthrodesis with rhBMP-2 in a titanium interbody threaded cage.
Anterior lumbar interbody arthrodesis is commonly performed for conditions involving infection, deformity, and instability. The purpose of this investigation was to determine the effective dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone graft substitute inside a titanium threaded interbody fusion cage using a nonhuman primate model of laparoscopic anterior lumbar interbody arthrodesis. Eight adult rhesus monkeys underwent laparoscopic exposure of the lumbosacral spine followed by insertion of a hollow titanium threaded cylindrical cage (Sofamor-Danek, Memphis, TN, U.S.A.). Before insertion, the chamber of the cage was filled with a collagen sponge delivery vehicle soaked with either 0 mg/ml (sham, buffer only), 0.75 mg/ml (low dose), or 1.5 mg/ml (high dose) of rhBMP-2 (Genetics Institute, Cambridge, MA, U.S.A.). Fusions were evaluated in a blinded fashion with plain radiographs and computed tomography (CT) scans 12 and 24 weeks after surgery, and by manual palpation and histology after euthanasia 24 weeks after surgery. All five monkeys treated with a cage filled with rhBMP-2 obtained a solid fusion as assessed by manual palpation. The two monkeys that received no growth factor did not achieve solid fusions. Plain radiographs were of limited value, with fusions best assessed on sagittally reconstructed CT scans. Scans from the two animals treated without growth factor showed ingrowth of bone only into the outer edges of the cage, but not through the center. Scans from the rhBMP-2-treated animals demonstrated arthrodesis with continuous bone growth through the cage. Histologic analysis demonstrated normal mature trabecular bone surrounding and growing through the cages, which correlated with the CT scan findings. We conclude that rhBMP-2 delivered in a threaded titanium interbody cage can serve as a bone graft substitute in a nonhuman primate model. Sagittal reconstructed CT may be a better method to assess for fusion with this device.


A major genome region underlying artemisinin resistance in malaria.
Evolving resistance to artemisinin-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia and has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CRs) after treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6969 polymorphic single-nucleotide polymorphisms (SNPs) in 91 parasites from Cambodia, Thailand, and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chromosome 13 that shows strong association (P = 10(-6) to 10(-12)) with slow CRs, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits.


Genomic comparison of chitinolytic enzyme systems from terrestrial and aquatic bacteria.
Chitin degradation ability is known for many aquatic and terrestrial bacterial species. However, differences in the composition of chitin resources between aquatic (mainly exoskeletons of crustaceans) and terrestrial (mainly fungal cell walls) habitats may have resulted in adaptation of chitinolytic enzyme systems to the prevalent resources. We screened publicly available terrestrial and aquatic chitinase-containing bacterial genomes for possible differences in the composition of their chitinolytic enzyme systems. The results show significant differences between terrestrial and aquatic bacterial genomes in the modular composition of chitinases (i.e. presence of different types of carbohydrate binding modules). Terrestrial Actinobacteria appear to be best adapted to use a wide variety of chitin resources as they have the highest number of chitinase genes, the highest diversity of associated carbohydrate-binding modules and the highest number of CBM33-type lytic polysaccharide monooxygenases. Actinobacteria do also have the highest fraction of genomes containing β-1, 3-glucanases, enzymes that may reinforce the potential for degrading fungal cell walls. The fraction of bacterial chitinase-containing genomes encoding polyketide synthases was much higher for terrestrial bacteria than for aquatic ones supporting the idea that the combined production of antibiotics and cell-wall degrading chitinases can be an important strategy in antagonistic interactions with fungi.


Acquisition of texture-cued fasting-anticipatory meal-size change in rats with adequate energy intake.
To determine if an increase in intake at a meal before a long fast can be conditioned to food texture cues, male Sprague-Dawley rats were given a high- or low-fat diet in one texture (powder or pellet) for 1 h prior to a 12.5-h fast and in the other texture before a 3-h fast. Each group (N = 9) went through a pseudorandom sequence of four duplicates of each texture-fast pairing over 4 experimental days in each of three training trials, followed by one 4-day trial under extinction, i.e. without the difference in fast lengths between textures. Neither the high-fat group nor the low-fat group as a whole gave a clear indication of a learnt texture-cued increase in meal size before the longer fast relative to the shorter fast. However, the rats trained on the high-fat diet that had the highest intakes on the first 4 days of training showed a relative increase in the amount eaten of the texture predicting the longer fast during the third training trial, and this effect also approached statistical significance in the extinction test. These results provide some support for the conclusion that anticipatory hunger/satiety can be differentially conditioned to dietary texture cues, but only if sufficient food is eaten before a short fast to prevent the rise in hunger during longer fasts that reinforces the discriminative increase in meal size.


Input impedance of the systemic circulation in man.
To determine the systemic input impedance, pulsatile pressure and flow were measured in the ascending aorta in 16 human subjects who were undergoing diagnostic cardiac catheterization. Blood flow was measured with a catheter-tip electromagnetic velocity meter, and pressure with an external transducer connected with the fluid-filled lumen of the catheter. Five subjects were found to have no evidence of cardiovascular disease (group A, mean age 32 +/- 2 years, mean aortic pressure 97 +/- 4 mm Hg). Seven had clinical and angiographic signs of coronary arterial disease, and mean pressures less than 100 mm Hg (group B, mean age 48 +/- 2 years). Four subjects had signs of coronary disease and mean pressures greater than 100 mm Hg (group C, mean age 48 +/- 3 years). The frequency spectra of impedance were qualitatively similar in all three groups and resembled those previously observed in the canine aorta. Characteristic impedance was lower in the normal subjects (group A, average 53 dyn sec cm-5) than in the subjects with coronary artery disease (groups B and C, average 129 dyn sec cm-5). Among the subjects with coronary disease, characteristic impedance was higher in the hypertensive subjects (group C, average 202 dyn sec cm-5) than in those with lower mean pressures (group B, average 95 dyn sec cm-5). External left ventricular work per unit time (hydraulic power) averaged 1715 milliwatts (mW) in group A, 1120 mW in group B, and 2372 mW in group C. Cardiac outputs were within normal limits in all subjects, but tended to be lower in group B than in group C. These results suggest that the subjects of group C were better able to meet the increased energy demands imposed by an abnormally high aortic input impedance. Further investigation is needed to learn whether the high impedances in subjects with coronary disease represent an increase with age and transmural pressure alone, or whether some additional factor is involved. The data on relatively normal subjects permit a tentative definition of the normal limits for aortic input impedance in man: 26-80 dyn sec cm-5.


Selection of human single domain antibodies recognizing the CMYC protein using enhanced intracellular antibody capture.
Protein functions that are mediated by interaction with other proteins (protein-protein interactions, PPI) are important for normal cell biology and also in disease. Molecules that can interfere with PPI are required as laboratory tools to dissect function, as lead drug surrogates for target validation and as templates for drug discovery. We describe enhanced developments to Intracellular Antibody Capture (IAC) technology that can select antibody fragments able to interact with targets in cells. This is illustrated by the isolation of single heavy chain variable region domains binding to the basic-helix-loop-helix and leucine zipper region of the CMYC oncogenic protein. The enhanced IAC (eIAC) methodology deploys screening in yeast cells of a single diverse library initially with randomization only of CDR3. Further sequential randomization of CDR2 and CDR1 of three independently selected anti-CMYC clones illustrates an in vivo affinity maturation process. This concise eIAC approach facilitates the rapid selection of antibody fragments to explore the proteome interaction spectrum of mammalian cells and disease targeting.


Targeting Metabolic Remodeling in Triple Negative Breast Cancer in a Murine Model.
Background: Chemotherapy is the backbone of systemic treatment for triple negative breast cancer (TNBC), which is one of the most relevant breast cancers molecular types due to the ability of tumor cells to develop drug resistance, highlighting the urgent need to design newer and safer drug combinations for treatment. In this context, to overcome tumor cell drug resistance, we employed a novel combinatorial treatment including Doxorubicin, Metformin, and Sodium Oxamate (DoxMetOx). Such pharmacological combination targets indispensable hallmarks of cancer-related to aerobic glycolysis and DNA synthesis. Materials and Methods: Thirty-five female nude mice were transplanted subcutaneously with MDA-MB-231 triple negative human cancer cell line. Once tumors were visible, mice were treated with doxorubicin, metformin, oxamate or all possible pharmacologic combinations. Treatments were administered daily for 15 days and tumors were measured by calipers every day. MicroPET images were taken in three different occasions, basal state, in the middle of the treatment, and at the end of treatment. Western blot analyses, qRT-PCR, flow cytometry, and cytotoxicity assays were performed to elucidate the mechanism of cell death promoted by the drugs in vitro. Results: In this work we assessed the proof of concept of metabolic correction in solid tumors as an effective drug treatment; hence, mice bearing tumors treated with the DoxMetOx therapy showed a complete inhibition of the tumor mass growing in 15 days of treatment depicted by the micro PET images. In vitro studies displayed that the three drugs together act by inhibiting both, mTOR-phosphorylation and expression of LDH-A gene, promoting apoptosis via dependent on the caspase-3 pathway, accompanied by cleavage of PARP. Moreover, induction of autophagy process was observed by the accumulation of LC3-II, a primordial protein implicated in the conformation and elongation of the autophagolysosome. Conclusions: The lack of effective drugs to inhibit TNBC growth is the main cause of therapy failure and tumor relapse. We have showed that targeting crucial molecular pathways in cancer by the combination of Doxorubicin, Metformin, and Oxamate resulted as an efficient and rapid tumor growth inhibitor in a triple negative xenograft model. Our findings are promising for patients diagnosed with TNBC tumors, for which unfortunately there are no reliable drug therapies.


Rubella among crew members of commercial cruise ships--Florida, 1997.
During April-July 1997, two different commercial cruise lines notified CDC of rubella outbreaks among crew members. In July 1997, CDC initiated an investigation on one cruise ship to determine the extent of and risk factors for rubella infection among crew members and to assess the potential risk for rubella transmission to passengers-particularly rubella-susceptible pregnant women at risk for giving birth to an infant with congenital rubella syndrome (CRS). This report summarizes rubella outbreaks involving two cruise ships and the results of the CDC investigation on one cruise ship, which demonstrate that crew members can serve as a susceptible population for rubella infection and should be vaccinated with measles-mumps-rubella vaccine (MMR) if they are not immune. Although the outbreaks were limited to crew members, cruise ship travel provides an environment conducive to the potential spread of rubella and other infectious diseases among crew and passengers; therefore, women of childbearing age, particularly pregnant women, should be immune to rubella before traveling on cruise ships to reduce the risks for rubella infection and CRS.


Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer's-like impairment in mice.
Accumulation of amyloid-β (Aβ) protein may cause synapse degeneration and cognitive impairment in Alzheimer's disease (AD) by reactivating expression of the developmental synapse repressor protein Ephexin5 (also known as ARHGEF15). Here, we have reported that Aβ is sufficient to acutely promote the production of Ephexin5 in mature hippocampal neurons and in mice expressing human amyloid precursor protein (hAPP mice), a model for familial AD that produces high brain levels of Aβ. Ephexin5 expression was highly elevated in the hippocampi of human AD patients, indicating its potential relevance to AD. We also observed elevated Ephexin5 expression in the hippocampi of hAPP mice. Removal of Ephexin5 expression eliminated hippocampal dendritic spine loss and rescued AD-associated behavioral deficits in the hAPP mice. Furthermore, selective reduction of Ephexin5 expression using shRNA in the dentate gyrus of presymptomatic adolescent hAPP mice was sufficient to protect these mice from developing cognitive impairment. Thus, pathological elevation of Ephexin5 expression critically drives Aβ-induced memory impairment, and strategies aimed at reducing Ephexin5 levels may represent an effective approach to treating AD.


Nutrition Assessment of B-Vitamins in Highly Active and Sedentary Women.
Female athletes and active women require adequate nutrition for optimal health and performance. Nutrition assessments are needed to identify potential nutrients of concern. Folate, vitamin B6, and vitamin B12 function in important pathways used during physical activity and female athletes may be at risk for poor status of these micronutrients. This cross-sectional study described a comprehensive nutrition assessment of the B-vitamins (folate, vitamin B6, and vitamin B12) using both dietary (food and dietary supplements) and biochemical assessments among highly active and sedentary women. Highly active (n = 29; age 20 ± 2 years; body mass index (BMI) 23.8 ± 3.5 kg/m²) and sedentary (n = 29; age 24 ± 3 years; BMI 22.6 ± 3.0 kg/m²) women were recruited for this study. Participants completed 7-day weighed food records and a fasting blood draw. Although the highly active women reported higher intakes of energy (p < 0.01), folate (p < 0.01), vitamin B6 (p < 0.01), and vitamin B12 (p < 0.01), no significant differences were found between the groups for biomarkers of folate, vitamin B6, and vitamin B12. All of the highly active women had biomarkers within the desired reference ranges, suggesting good status. In general, most participants were able to meet the 1998 Recommended Daily Allowance (RDA) from food alone. For the women that reported using dietary supplements, micronutrient intakes met the 1998 RDA and in some cases, exceeded the Tolerable Upper Intake Level. This nutrition assessment documented good status for folate, vitamin B6, and vitamin B12 in the highly active women. Similar assessment approaches (food, dietary supplements, and biomarkers) should to completed with other nutrients of concern for the female athlete.


CD133+CD44+ population efficiently enriches colon cancer initiating cells.
Previous reports have demonstrated that CD133(+) cells or CD44(+) cells might be cancer initiating cells (CIC) of colon cancer. However, the association between the two cell types is unclear. In this study, we evaluated the tumorigenicity of each population of human colon cancer divided by CD133 and CD44 using non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. Using the colon cancer cell lines HT29 and Caco2 we evaluated the change of expression status of CD133 or CD44 by a treatment with sodium butyrate (NaBT) that can induce cellular differentiation. Next, we prepared ten clinical samples of colon cancer and analyzed the expression and tumorigenicity of CD133 and CD44. With NaBT treatment, CD44 expression was greatly downregulated in both HT29 and Caco2 (HT29: nontreatment versus treatment; 77.8% versus 0.6%, Caco2: 14.0% versus 0.4%, respectively), more than CD133 expression (HT29: nontreatment versus treatment; 90.1% versus 67.7%, Caco2: 98.9% versus 76.3%, respectively). In clinical samples, the percentages of CD133(+) cells and CD44(+) cells varied from 0.3% to 82.0% (mean 35.5%), and from 11.5% to 58.4% (mean 30.0%), respectively. Subcutaneous injection of CD133(+) or CD44(+) cells made a tumor in all mice (3/3 and 4/4, respectively). The combined analysis of CD133 and CD44 revealed that only the CD133(+)CD44(+) population had the ability to produce a tumor (3/3). The findings demonstrate that, at present, the CD133(+)CD44(+ ) population may be the best to identify tumor initiating cells of human colon cancer.


Antiviral amphipathic oligo- and polyribonucleotides: analogue development and biological studies.
A series of novel N1 alkylated purine nucleic acids were polymerized either enzymatically or by automated synthesis to further establish the SAR requirements for HIV, RT, and HCMV activity. Out of the series, two constructs, 2'-O-methyl-1-allylinosinic acid phosphorothioate 33-mer (16) and an oligomer incorporating 1-propyl-6-thioinosinic acid residues (20), were found to be highly active under all three assay conditions. SAR studies indicate that sulfur incorporation, high molecular weight, and low steric bulk at N1 all can be important for activity.


Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella.
The mammalian intestine is host to a microbial community that prevents pathogen expansion through unknown mechanisms, while antibiotic treatment can increase susceptibility to enteric pathogens. Here we show that streptomycin treatment depleted commensal, butyrate-producing Clostridia from the mouse intestinal lumen, leading to decreased butyrate levels, increased epithelial oxygenation, and aerobic expansion of Salmonella enterica serovar Typhimurium. Epithelial hypoxia and Salmonella restriction could be restored by tributyrin treatment. Clostridia depletion and aerobic Salmonella expansion were also observed in the absence of streptomycin treatment in genetically resistant mice but proceeded with slower kinetics and required the presence of functional Salmonella type III secretion systems. The Salmonella cytochrome bd-II oxidase synergized with nitrate reductases to drive luminal expansion, and both were required for fecal-oral transmission. We conclude that Salmonella virulence factors and antibiotic treatment promote pathogen expansion through the same mechanism: depletion of butyrate-producing Clostridia to elevate epithelial oxygenation, allowing aerobic Salmonella growth.


In vitro antimalarial susceptibility and molecular markers of drug resistance in Franceville, Gabon.
Malaria remains a major public health problem, due largely to emergence and widespread P. falciparum drug resistance. WHO recommends artemisinine combination based therapy (ACT) to overcome P. falciparum drug resistance, but reports of declining ACT efficacy have been published. A thorough understanding of the molecular bases of P. falciparum resistance to existing drugs is therefore needed. The aims of this study were to analyze the in vitro sensitivity of P. falciparum field isolates from Franceville, Gabon, to chloroquine (CQ), mefloquine (MF), dihydroartemisinine (DHA) and monodesethylamodiaquine (MDAQ), and to investigate polymorphisms associated with drug resistance. We conducted a cross-sectional study of 53 field isolates. Field isolates sensitivity to CQ, MF, DHA and MDAQ was assessed using the colorimetric DELI test. The Pfmdr1 codons 86 and 1246, Pfcrt (haplotype codon 72 to 76) and the PfATPAse6 codons 110 and 2694 were analysed by PCR-RFLP. Associations between drug sensitivity and parasite gene polymorphisms were evaluated with the Chi square test, and routine hematological parameters were analyzed with Fisher's exact test implemented with Epinfo software. In all statistical tests, significance was assumed at p<0.05. A total of 46 P. falciparum isolates were successfully cultured in vitro and their sensitivity was tested. The proportions of isolates resistant to CQ, MF and MDAQ were 43.5%, 23.4% and 56.5%, respectively. Some isolates (23.9%) had DHA IC50 values higher than 10 nM. The median IC50 values were 71.67 (interquartile range (IQR, 1-438.2), 6.59 (IQR, 0.08-96), 64.79 (IQR, 0.09-448) and 6.45 nM (IQR, 0.09-23) for CQ, MF, MDAQ and DHA, respectively. The strongest correlation between diminished DHA sensitivity and MF resistance was observed (r2=0.73), followed by correlation between diminished DHA sensitivity and CQ resistance. Cross-resistance between CQ and MF was also observed. The prevalence of the 86Y and 1246Y mutations in Pfmdr1, 76T in Pfcrt, and 110A and 2694T in PfATPase6 was respectively 42% and 17.1%, 97.8%, and 0% and 22.2%. These high levels of antimalarial drug resistance in Franceville, Gabon, call for reinforced surveillance of drug efficacy.


Hail the impossible: p-values, evidence, and likelihood.
Significance testing based on p-values is standard in psychological research and teaching. Typically, research articles and textbooks present and use p as a measure of statistical evidence against the null hypothesis (the Fisherian interpretation), although using concepts and tools based on a completely different usage of p as a tool for controlling long-term decision errors (the Neyman-Pearson interpretation). There are four major problems with using p as a measure of evidence and these problems are often overlooked in the domain of psychology. First, p is uniformly distributed under the null hypothesis and can therefore never indicate evidence for the null. Second, p is conditioned solely on the null hypothesis and is therefore unsuited to quantify evidence, because evidence is always relative in the sense of being evidence for or against a hypothesis relative to another hypothesis. Third, p designates probability of obtaining evidence (given the null), rather than strength of evidence. Fourth, p depends on unobserved data and subjective intentions and therefore implies, given the evidential interpretation, that the evidential strength of observed data depends on things that did not happen and subjective intentions. In sum, using p in the Fisherian sense as a measure of statistical evidence is deeply problematic, both statistically and conceptually, while the Neyman-Pearson interpretation is not about evidence at all. In contrast, the likelihood ratio escapes the above problems and is recommended as a tool for psychologists to represent the statistical evidence conveyed by obtained data relative to two hypotheses.


CD163 Expression in Neurons After Experimental Intracerebral Hemorrhage.
CD163, a receptor for hemoglobin, is involved in hemoglobin clearance after intracerebral hemorrhage (ICH). In contrast to microglial/macrophage CD163, neuronal CD163 hemoglobin has not been well studied. This study examined the expression of neuronal CD163 in a pig model of ICH and in vitro rat cortical neurons and the impact of deferoxamine on that expression. There were 2 parts to this study. In the in vivo part, piglets had injection of autologous blood into the right frontal lobe. The time course of CD163 expression and the effect of deferoxamine on the expression of CD163 after ICH were determined in the grey matter. In the in vitro part, the levels of CD163 and neuronal death and the effect of deferoxamine were examined in rat cortical neurons culture treated with hemoglobin. CD163-positive cells were found, and the CD163 protein levels were upregulated in the ipsilateral grey matter after ICH. The CD163 levels peaked at days 1 and 3. The CD163-positive cells were colocated with NeuN-positive, heme oxygenase-2-positive, and terminal deoxynucleatidyl transferase dUTP nick end labeling-positive cells. Deferoxamine treatment attenuated ICH-induced CD163 upregulation and significantly reduced both brain CD163 and hemoglobin levels at day 3. Treating neuronal cultures with hemoglobin for 24 hours resulted in CD163 upregulation and increased cell death. Deferoxamine significantly attenuated the hemoglobin-induced neuronal death and CD163 upregulation. CD163 is expressed in neurons and upregulated after ICH. Deferoxamine reduced ICH-induced CD163 upregulation and brain cell death in vivo and hemoglobin-induced CD163 upregulation and neuronal death in vitro.


Role of angiotensin subtype 2 receptor in neointima formation after vascular injury.
The role of angiotensin receptor subtypes 1 and 2 was assessed on neointima formation after injury in rat carotid artery. The effects of angiotensin converting enzyme inhibition by perindopril (3 mg.kg-1 x day-1 p.o.) and selective blockade of angiotensin subtype 1 receptors by DuP 753 (5 and 30 mg.kg-1 x day-1 p.o.) were compared on proliferative response to balloon injury. In rats treated 6 days before and for 14 days after injury, perindopril significantly reduced (-76%, p < 0.01) myointimal hyperplasia. In contrast, DuP 753 at 5 mg.kg-1 x day-1 did not modify the hyperplastic response to balloon catheterization. Only at 30 mg.kg-1 x day-1 was DuP 753 able to reduce neointima formation (-47%, p < 0.05). This dose was equipotent to perindopril on the renin-angiotensin system as assessed by the pressor response to angiotensin II and angiotensin I. Therefore, blockade of subtype 1 receptors was a less effective means of suppression of myointimal growth than angiotensin converting enzyme inhibition, suggesting that another angiotensin receptor subtype or converting enzyme substrates are involved in this process. For the determination of whether angiotensin subtype 2 receptors were implicated, the specific subtype 2 receptor antagonist CGP 42112A (1 mg.kg-1 x day-1) was continuously infused perivascularly for 14 days in the vicinity of the injured carotid artery. CGP 42112A was as effective in preventing neointima formation as perindopril (-73%, p < 0.01, versus -76%, p < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


The transglutaminase 2 gene is aberrantly hypermethylated in glioma.
Transglutaminase 2 (TG2) is a ubiquitously expressed protein that catalyzes protein/protein crosslinking. Because extracellular TG2 crosslinks components of the extracellular matrix, TG2 is thought to function as a suppressor of cellular invasion. We have recently uncovered that the TG2 gene (TGM2) is a target for epigenetic silencing in breast cancer, highlighting a molecular mechanism that drives reduced TG2 expression, and this aberrant molecular event may contribute to invasiveness in this tumor type. Because tumor invasiveness is a primary determinant of brain tumor aggressiveness, we sought to determine if TGM2 is targeted for epigenetic silencing in glioma. Analysis of TGM2 gene methylation in a panel of cultured human glioma cells indicated that the 5' flanking region of the TGM2 gene is hypermethylated and that this feature is associated with reduced TG2 expression as judged by immunoblotting. Further, culturing glioma cells in the presence of the global DNA demethylating agent 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor Trichostatin A resulted in re-expression of TG2 in these lines. In primary brain tumors we observed that the TGM2 promoter is commonly hypermethylated and that this feature is a cancer-associated phenomenon. Using publically available databases, TG2 expression in gliomas was found to vary widely, with many tumors showing overexpression or underexpression of this gene. Since overexpression of TG2 leads to resistance to doxorubicin through the ectopic activation of NFκB, we sought to examine the effects of recombinant TG2 expression in glioma cells treated with commonly used brain tumor therapeutics. We observed that in addition to doxorubicin, TG2 expression drove resistance to CCNU; however, TG2 expression did not alter sensitivity to other drugs tested. Finally, a catalytically null mutant of TG2 was also able to support doxorubicin resistance in glioma cells indicating that transglutaminase activity is not necessary for the resistance phenotype.


Online Detection of Multiple Stimulus Changes Based on Single Neuron Interspike Intervals.
Nervous systems need to detect stimulus changes based on their neuronal responses without using any additional information on the number, times, and types of stimulus changes. Here, two relatively simple, biologically realistic change point detection methods are compared with two common analysis methods. The four methods are applied to intra- and extracellularly recorded responses of a single cricket interneuron (AN2) to acoustic simulation. Solely based on these recorded responses, the methods should detect an unknown number of different types of sound intensity in- and decreases shortly after their occurrences. For this task, the methods rely on calculating an adjusting interspike interval (ISI). Both simple methods try to separate responses to intensity in- or decreases from activity during constant stimulation. The Pure-ISI method performs this task based on the distribution of the ISI, while the ISI-Ratio method uses the ratio of actual and previous ISI. These methods are compared to the frequently used Moving-Average method, which calculates mean and standard deviation of the instantaneous spike rate in a moving interval. Additionally, a classification method provides the upper limit of the change point detection performance that can be expected for the cricket interneuron responses. The classification learns the statistical properties of the actual and previous ISI during stimulus changes and constant stimulation from a training data set. The main results are: (1) The Moving-Average method requires a stable activity in a long interval to estimate the previous activity, which was not always given in our data set. (2) The Pure-ISI method can reliably detect stimulus intensity increases when the neuron bursts, but it fails to identify intensity decreases. (3) The ISI-Ratio method detects stimulus in- and decreases well, if the spike train is not too noisy. (4) The classification method shows good performance for the detection of stimulus in- and decreases. But due to the statistical learning, this method tends to confuse responses to constant stimulation with responses triggered by a stimulus change. Our results suggest that stimulus change detection does not require computationally costly mechanisms. Simple nervous systems like the cricket's could effectively apply ISI-Ratios to solve this fundamental task.


Anxiety responses, plasma corticosterone and central monoamine variations elicited by stressors in reactive and nonreactive mice and their reciprocal F1 hybrids.
Stressor-provoked anxiety, plasma corticosterone, and variations of brain monoamine turnover are influenced by genetic factors, but may also be moderated by early life experiences. To evaluate the contribution of maternal influences, behavioral and neurochemical stress responses were assessed in strains of mice that were either stressor-reactive or -resilient (BALB/cByJ and C57BL/6ByJ, respectively) as well as in their reciprocal F(1) hybrids. BALB/cByJ mice demonstrated poorer maternal behaviors than did C57BL/6ByJ dams, irrespective of the pups being raised (inbred or F(1) hybrids). The BALB/cByJ mice appeared more anxious than C57BL/6ByJ mice, exhibiting greater reluctance to step-down from a platform and a greater startle response. Although the F(1) behavior generally resembled that of the C57BL/6ByJ parent strain, in the step-down test the influence of maternal factors were initially evident among the F(1) mice (particularly males) with a BALB/cByJ dam. However, over trials the C57BL/6ByJ-like behavior came to predominate. BALB/cByJ mice also exhibited greater plasma corticosterone elevations, 5-HT utilization in the central amygdala (CeA), and greater NE turnover in the paraventricular nucleus of the hypothalamus (PVN). Interestingly, among the F(1)'s corticosterone and 5-HIAA in the CeA resembled that of the BALB/cByJ parent strain, whereas MHPG accumulation in the PVN was more like that of C57BL/6ByJ mice. It seems that, to some extent, maternal factors influenced anxiety responses in the hybrids, but did not influence the corticosterone or the monoamine variations. The inheritance profiles suggest that anxiety was unrelated to either the corticosterone or monoamine changes.


The long-term effect of group living homes versus regular nursing homes for people with dementia on psychological distress of informal caregivers.
In this follow-up study, the long-term influence of group living homes (GLHs) on informal caregiver distress was compared with modern yet regular nursing homes (NHs). Informal caregivers of GLH (N = 37) and NH residents (N = 49) were studied at the time of admission, 6 months thereafter, and approximately 24 months after admission. Repeated measures of ANOVA were performed to study group-by-time effects on psychopathology, role overload, and feelings of competence. All outcomes of psychological distress in GLH caregivers showed significantly greater decline compared with NH caregivers during the first six months after admission. The course of psychological distress stabilized in both caregiver groups after six months. GLHs may have played a role in reducing caregiver burden during the first six months after the nursing home admission of the care recipient. The stabilization of caregivers' psychological distress between T1 and T2 may indicate that there is no further room for improvement in the GLH and NH groups after six months. The implication would be that both GLHs and NHs succeeded in keeping caregivers' distress relatively low over the long term. More knowledge is needed on whether and how caregivers' psychological distress after institutionalization of the care recipient can be reduced to a greater extent.


Fatal haemorrhage following fine needle aspiration of the thyroid.
Fine needle aspiration is routinely performed as part of the assessment of thyroid nodules. It is generally regarded as a very safe procedure, though rarely significant bleeding can occur in its aftermath. A 79-year-old female was referred for assessment of an incidental thyroid nodule which had been identified on computed tomography of the chest and extended into the retrosternal space. The patient was referred for fine needle aspiration under ultrasound guidance. Three passes were made with a 25 gauge needle into the nodule; a haemorrhagic aspirate was obtained and sent for cytological examination. Several hours later, the patient developed a cough and progressive breathlessness and died at home before she could be taken to hospital. The key finding from the post-mortem was extensive haemorrhage within the capsule of thyroid. In the absence of another identifiable aetiology, the cause of death was considered to be acute haemorrhage into the thyroid gland. Thyroid fine needle aspiration is generally a safe procedure, but it is important to recognise that, rarely, major complications can occur.


Molecular characterization of the Epstein-Barr virus DNA in three new Burkitt's lymphoma-derived cell lines.
Three new Epstein-Barr virus DNA populations have been isolated from the recently established Burkitt's lymphoma-derived cell lines, LY47, LY91 and BL8. Each of these lines carries one of the specific chromosome translocations associated with Burkitt's lymphoma but few if any other chromosomal abnormalities. An outline of their molecular organization, as determined by restriction enzyme analysis, is presented. Two of the isolates, LY47 and BL8, give patterns broadly similar to Epstein-Barr virus DNA molecules studied to date. The third, LY91, shows a highly unusual molecular organization, in particular within BamHI subfragments of the EcoRI A fragment, indicative of the presence of a major defective molecular species within this line. All three cell lines produce virions that are capable of transforming immature B-lymphocytes.


Evaluation of a district growth screening programme: the Oxford Growth Study.
The Oxford district growth screening programme was established in 1988 as a community based survey of the heights of children at 3 and 4.5 years of age in a district of 550,000 people. The current birthrate is 7500 births/year and over the first three years of the study 20,338 children were screened in the community; the ascertainment ranged from 61-73.9% of the total expected. Mean height SD scores were significantly greater than the British standards; mean SD scores for boys and girls were 0.33 and 0.35 respectively at age 3, and 0.20 and 0.26 at 4.5 years. Altogether 260 (1.3%) of the total cohort were found to have heights < or = -2SD scores. The mean growth velocity of 2742 children measured at 3 and 4.5 years of age was similar to that of the national standards, 7.14 cm/year in boys and 7.21 cm/year in girls. Follow up data was available from 149 children whose heights were confirmed to be < or = -2SD scores. Of these 69 were already under the care of paediatricians. Thus far diagnoses in the 149 have included growth hormone deficiency (n = 2), Turner's syndrome (n = 2), Noonan's syndrome (n = 4), and emotional deprivation (n = 1). Ways in which ascertainment and detection of treatable causes of short stature could be improved are discussed and it is concluded that community growth screening is a useful part of the child health surveillance programme.


Management of variceal haemorrhage.
Variceal bleeding is the most important complication of portal hypertension. Mortality due to the first variceal bleeding is very high (50%) and of those surviving a variceal bleeding episode, up to 80% may rebleed. Proper management of the acute variceal bleeding episode, the prevention of rebleeding and primary prophylaxis for variceal haemorrhage are therefore mandatory in order to improve the morbidity and mortality of cirrhotic patients with variceal bleeding. Injection sclerotherapy would be the treatment of choice for acute variceal bleeding. Drug treatment in the form of either a combined vasopressin-nitroglycerin regimen or somatostatin may be used as an alternative. Patients not responding to these treatments should be referred for surgery. For the prevention of variceal rebleeding, non-selective beta-blockers should be tried first, reserving long-term injection sclerotherapy for patients with contraindications or intolerance to beta-blockers or in whom beta-blocker therapy has failed. Surgical rescue in the form of either shunt surgery or lever transplantation should be considered if either treatment fails. A new technique, transjugular intrahepatic portosystemic stent-shunt (TIPSS) may replace shunt surgery in the future. Beta-blockers is the treatment of choice for primary prophylaxis of variceal haemorrhage and has a role in preventing acute and chronic bleeding from congestive gastropathy. However, the above sequential approach from the least invasive to the more invasive therapeutic options may not be appropriate for all cirrhotic patients with variceal bleeding.


Ca(2+)-induced persistent protein kinase C activation in rat hippocampal homogenates.
Protein kinase C (PKC) is thought to play an important role in neuronal function by mediating changes in synaptic strength. Specifically, it has been argued that persistent PKC activation underlies the maintenance of long-term potentiation (LTP) of synaptic transmission in the hippocampus, a model widely used to study mammalian learning and memory. Because the induction of LTP is known to be dependent upon Ca2+ influx into the postsynaptic neuron, we investigated Ca(2+)-dependent mechanisms that operate to elicit persistent PKC activation in the hippocampus. Hippocampal homogenates were incubated with Ca2+ for a brief period and subsequently assayed for persistent changes in basal (Ca(2+)-independent) PKC activity, using the selective PKC substrate neurogranin(28-43) (NG(28-43)). After Ca2+ incubation, basal PKC phosphorylation of NG(28-43) was increased and expression of the increased activity could be inhibited by PKC(19-36), a selective peptide inhibitor of PKC. These data indicate the presence of a persistently activated form of PKC in Ca(2+)-pretreated hippocampal homogenates. The persistently activated PKC was localized to the soluble fraction of homogenates. Generation of the soluble, persistently activated form of PKC was blocked by the calpain inhibitor, leupeptin, suggesting a proteolytic activation of PKC. Column chromatography and Western blots indicated the presence of PKM, a proteolytic fragment of PKC that is active in the absence of calcium, diacylglycerols, or phospholipid cofactors. Thus, Ca2+ induces proteolytic activation of PKC in hippocampal homogenates. This suggests that proteolytic activation is a plausible candidate as a mechanism underlying the persistent activation of PKC associated with LTP.


[Endomyocardial biopsy in the heart transplant patient: the state of the art].
Data regarding 2176 endomyocardial biopsies (EMB) (Nov. '85-Dec. '89) performed in 164 transplanted hearts (4 etherotopic) from 158 patients (6 retransplants) are herein reported. This study was aimed to evaluate: 1) Incidence and characteristics of early ischemic myocardial damage. 2) The influence of different immunosurveillance protocols on incidence, degree and aggressiveness of acute rejection and the inflammatory infiltrate composition. 3) The immunophenotype of infiltrating cells in moderate acute rejection episodes. 4) HLA-DR antigen expression on myocyte sarcolemma. 5) Characterization of cells expressing immune response mediators. 6) Myocardial localization of opportunistic infections. 7) Useful information on chronic rejection. Our results demonstrate that: a) Mild rejection seldom progresses to moderate degree. b) Different immunosuppressive protocols can influence the incidence of acute rejection: in fact, in OKT3 protocol, the incidence of rejection episodes is higher than in other protocols as well as aggressiveness toward myocytes. c) Infiltrating cells maintain T lymphocyte prevalence with minor amounts of B lymphocytes and macrophages in the 3 different protocols. T cell subset characterization showed a slight prevalence of CD8 bearing cells over CD4 positive cells whereas CD57 cells were few and scattered. d) Class II Major Histocompatibility Complex (HLA-DR) expression never occurs on myocyte sarcolemma. e) TNF alpha is expressed in acute cardiac rejection by immunologically activated T lymphocytes and macrophages and the number of immunoreactive cells increases with progression of the rejection. f) Human cytomegalovirus infections can be primary or recurrent. Myocardial involvement has been observed in primary forms. Virus can affect endothelial cells (with no inflammatory reaction) or myocytes (myocarditis) and its diagnosis requires a combination of immunohistochemical and molecular biology techniques. Diagnosis of Toxoplasma gondii infection can be usually accomplished by routine histopathological study. g) Chronic rejection diagnosis is rarely based on biopsy derived information.


The 'obligate diploid' Candida albicans forms mating-competent haploids.
Candida albicans, the most prevalent human fungal pathogen, is considered to be an obligate diploid that carries recessive lethal mutations throughout the genome. Here we demonstrate that C. albicans has a viable haploid state that can be derived from diploid cells under in vitro and in vivo conditions, and that seems to arise through a concerted chromosome loss mechanism. Haploids undergo morphogenetic changes like those of diploids, including the yeast-hyphal transition, chlamydospore formation and a white-opaque switch that facilitates mating. Haploid opaque cells of opposite mating type mate efficiently to regenerate the diploid form, restoring heterozygosity and fitness. Homozygous diploids arise spontaneously by auto-diploidization, and both haploids and auto-diploids show a similar reduction in fitness, in vitro and in vivo, relative to heterozygous diploids, indicating that homozygous cell types are transient in mixed populations. Finally, we constructed stable haploid strains with multiple auxotrophies that will facilitate molecular and genetic analyses of this important pathogen.


Characterizing infection in anti-neutrophil cytoplasmic antibody-associated vasculitis: results from a longitudinal, matched-cohort data linkage study.
Infection exerts a major burden in ANCA-associated vasculitis (AAV), however, its precise extent and nature remains unclear. In this national study we aimed to longitudinally quantify, characterize and contextualize infection risk in AAV. We conducted a multicentre matched cohort study of AAV. Complementary data on infections were retrieved via data linkage with the population-based Scottish microbiological laboratory, hospitalization and primary care prescribing registries. A total of 379 AAV patients and 1859 controls were followed up for a median of 3.5 years (interquartile range 1.9-5.7). During follow-up, the proportions of AAV patients with at least one laboratory-confirmed infection, severe infection and primary care antibiotic prescription were 55.4%, 35.6% and 74.6%, respectively. The risk of infection was higher in AAV than in matched controls {laboratory-confirmed infections: incidence rate ratio [IRR] 7.3 [95% confidence interval (CI) 5.6, 9.6]; severe infections: IRR 4.4 [95% CI 3.3, 5.7]; antibiotic prescriptions: IRR 2.2 [95% CI 1.9, 2.6]}. Temporal trend analysis showed that AAV patients remained at a higher risk of infections throughout the follow-up period, especially year 1. Although the Escherichia genus was the most commonly identified pathogen (16.6% of AAV, 5.5% of controls; P < 0.0001), AAV patients had the highest risk for Herpes [IRR 12.5 (95% CI 3.7, 42.6)] and Candida [IRR 11.4 (95% CI 2.4, 55.4)]. AAV patients have up to seven times higher risk of infection than the general population and the overall risk remains significant after 8 years of follow-up. The testing of enhanced short- to medium-term prophylactic antibiotic regimes should be considered.


Partial Splenectomy for Splenic Cyst using a Bipolar Radiofrequency Device.
The main goals of spleen preserving surgery are control of peroperative bleeding and maintaining the spleen's function postoperatively. Several techniques of spleen preserving surgery have been described. This report presents a new technique to perform partial splenectomy. We performed this partial splenectomy with a bipolar radiofrequency (RF) device in a 21 years old woman with a splenic cyst, with almost no peroperative blood loss.


Selegiline orally disintegrating tablets in patients with Parkinson disease and "wearing off" symptoms.
Selegiline orally disintegrating tablet (ODT; Zelapar) is a selective monoamine oxidase B inhibitor developed as an adjunct to levodopa (LD) for Parkinson disease. Most patients on long-term LD therapy eventually experience deterioration at the end of the LD dosing interval, with predictable "wearing off" and "on-off" fluctuations. We conducted a 12-week, double-blind, placebo-controlled, parallel-design trial of selegiline ODT. The primary efficacy point was reduction in the percentage of average daily "off" time. Secondary measures included reductions in daily off hours and total daily off time, Clinical Global Impressions-Improvement (CGI-I), and Patient Global Impression-Improvement (PGI-I). Patients on LD received selegiline ODT (1.25 mg/d for 6 weeks, then 2.5 mg/d for 6 weeks) or placebo. Safety and tolerability were measured. The intent-to-treat population included 98 patients receiving selegiline ODT and 50 patients receiving placebo. Combined efficacy results for weeks 10 and 12 revealed an 11.6% reduction in percentage of daily off time for selegiline ODT versus a 9.8% reduction for placebo (NS). PGI-I detected a statistically significant difference between treatment groups in favor of selegiline ODT (P = 0.02), whereas CGI-I detected a strong trend toward improvement (P = 0.06). Selegiline ODT was safe and well tolerated. This study showed no significant difference in improvement in percentage of off time with selegiline ODT versus placebo. Some clinical impressions (e.g., PGI-I, CGI-I) improved. This result contrasts with an identically designed study that showed a significant improvement in off time with selegiline ODT. A combined analysis of both studies suggested overall efficacy.


Proinflammatory cytokine expression by Theileria annulata infected cell lines correlates with the pathology they cause in vivo.
Control of Theileria annulata is currently best achieved by the use of live attenuated cell line vaccines. However, the mechanisms underlying attenuation are unclear and there is a need to rapidly produce new cell line vaccines, which could safely and effectively vaccinate cattle against tropical theileriosis. There is increasing evidence to suggest that proinflammatory cytokines produced by T. annulata infected cells play a central role in both pathology and immune evasion. This study aimed to test this hypothesis and to evaluate cytokine expression as a marker of virulence. The pathogenicity and protective efficacy of cloned T. annulata cell lines that expressed different levels of proinflammatory cytokines were compared. In two independent trials using different stocks of T. annulata, cell lines that expressed higher levels of proinflammatory cytokines induced severe reactions, and in some cases death, when used to vaccinate groups of cattle. In contrast, low cytokine expressing lines induced low post-vaccinal reactions. The results clearly demonstrated that cytokine expression by T. annulata infected cells could be used as a marker of virulence and provided strong evidence to support a role for cytokines in the induction of pathology. Both high and low cytokine expressing cell lines protected cattle against heterologous challenge infection, offering the possibility of using cytokine expression to rapidly select new safe, potent vaccines against tropical theileriosis without the need for culture attenuation.


Genomics Insights into Pseudomonas sp. CG01: An Antarctic Cadmium-Resistant Strain Capable of Biosynthesizing CdS Nanoparticles Using Methionine as S-Source.
Here, we present the draft genome sequence of Pseudomonas sp. GC01, a cadmium-resistant Antarctic bacterium capable of biosynthesizing CdS fluorescent nanoparticles (quantum dots, QDs) employing a unique mechanism involving the production of methanethiol (MeSH) from methionine (Met). To explore the molecular/metabolic components involved in QDs biosynthesis, we conducted a comparative genomic analysis, searching for the genes related to cadmium resistance and sulfur metabolic pathways. The genome of Pseudomonas sp. GC01 has a 4,706,645 bp size with a 58.61% G+C content. Pseudomonas sp. GC01 possesses five genes related to cadmium transport/resistance, with three P-type ATPases (cadA, zntA, and pbrA) involved in Cd-secretion that could contribute to the extracellular biosynthesis of CdS QDs. Furthermore, it exhibits genes involved in sulfate assimilation, cysteine/methionine synthesis, and volatile sulfur compounds catabolic pathways. Regarding MeSH production from Met, Pseudomonas sp. GC01 lacks the genes E18.104.22.168 and megL for MeSH generation. Interestingly, despite the absence of these genes, Pseudomonas sp. GC01 produces high levels of MeSH. This is probably associated with the metC gene that also produces MeSH from Met in bacteria. This work is the first report of the potential genes involved in Cd resistance, sulfur metabolism, and the process of MeSH-dependent CdS QDs bioproduction in Pseudomonas spp. strains.


Role of ampD homologs in overproduction of AmpC in clinical isolates of Pseudomonas aeruginosa.
AmpD indirectly regulates the production of AmpC beta-lactamase via the cell wall recycling pathway. Recent publications have demonstrated the presence of multiple ampD genes in Pseudomonas aeruginosa and Escherichia coli. In the prototype P. aeruginosa strain, PAO1, the three ampD genes (ampD, ampDh2, and ampDh3) contribute to a stepwise regulation of ampC beta-lactamase and help explain the partial versus full derepression of ampC. In the present study, the roles of the three ampD homologs in nine clinical P. aeruginosa isolates with either partial or full derepression of ampC were evaluated. In eight of nine isolates, decreased RNA expression of the ampD genes was not associated with an increase in ampC expression. Sequence analyses revealed that every derepressed isolate carried mutations in ampD, and in two fully derepressed strains, only ampD was mutated. Furthermore, every ampDh2 gene was of the wild type, and in some fully derepressed isolates, ampDh3 was also of the wild type. Mutations in ampD and ampDh3 were tested for their effect on function by using a plasmid model system, and the observed mutations resulted in nonfunctional AmpD proteins. Therefore, although the sequential deletion of the ampD homologs of P. aeruginosa can explain partial and full derepression in PAO1, the same model does not explain the overproduction of AmpC observed in these clinical isolates. Overall, the findings of the present study indicate that there is still an unknown factor(s) that contributes to ampC regulation in P. aeruginosa.


Patient-dentist relationship and dental anxiety among young Sudanese adult patients.
To evaluate the effects of the patient-dentist relationship on dental anxiety among young adult Sudanese patients. In this cross-sectional study, 864 patients attending outpatient dental clinics of the governmental dental hospitals in Khartoum, Sudan were recruited; 51.2% were males and 48.8% were females, with an age range of 18-24 years. The questionnaire used evaluated the socio-demographics, education levels, economic status, patient experience, and also included the Dental Anxiety Scale, Corah (J Dent Res 1969 48: 596). High dental anxiety was reported by 22.2%, 29.5% reported moderate dental anxiety, and 48.3% reported low or no dental anxiety. There were statistically significant associations between dental anxiety and gender, time lapse since the previous dental visit (P < 0.004) and the reason for the previous visit (P < 0.001). In addition, the dental clinic environment (P < 0.002), the time waiting before seeing the dentist (P < 0.001) and the overhearing of pain expressed by other patients (P < 0.001) were also statistically significant. Negative comments by the treating dentist also had a statistically significant impact (P < 0.032). In contrast, a clear explanation of related dental care (P < 0.008), as well as the allowance of adequate time to discuss oral health (P < 0.006), had significantly positive effects. The study showed that the patient-dentist relationship had a significant association with dental anxiety, and may be an important target for improving the delivery and standards of oral health in dentally anxious patients in this region.


Channel estimation and synchronization for polarization-division multiplexed CO-OFDM using subcarrier/polarization interleaved training symbols.
We propose and demonstrate the use of subcarrier/polarization-interleaved training symbols for channel estimation and synchronization in polarization-division multiplexed (PDM) coherent optical orthogonal frequency-division multiplexed (CO-OFDM) transmission. The principle, the computational efficiency, and the frequency-offset tolerance of the proposed method are described. We show that the use of subcarrier/polarization interleaving doubles the tolerance to the frequency offset between the transmit laser and the receiver's optical local oscillator as compared to conventional schemes. Using this method, we demonstrate 43-Gb/s PDM CO-OFDM transmission with 16-QAM subcarrier modulation over 5,200-km of ultra-large-area fiber.


Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis.
Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis. We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate. Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change -1 (range -4 to +8) versus 0 (-4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups. The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no effect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not sufficient to ameliorate SIRS in severe acute pancreatitis


Impact of Atomizer Age and Flavor on In Vitro Toxicity of Aerosols from a Third-Generation Electronic Cigarette against Human Oral Cells.
Electronic cigarettes (ECs) are categorized into generations which differ in terms of design, aerosol production, and customizability. Current and former smokers prefer third-generation devices that satisfy tobacco cravings more effectively than older generations. Recent studies indicate that EC aerosols from first- and second-generation devices contain reactive carbonyls and free radicals and can cause in vitro cytotoxicity. Third-generation ECs have not been adequately studied. Further, previous studies have focused on cells from the respiratory tract, whereas those of the oral cavity, which is exposed to high levels of EC aerosols, have been understudied. We quantified the production of reactive carbonyls and free radicals by a third-generation EC and investigated the induction of cytotoxicity and oxidative stress in normal and cancerous human oral cell lines using a panel of eight commercial EC liquids. We found that EC aerosols produced using a new atomizer contained formaldehyde, acetaldehyde, and acrolein, but did not contain detectable levels of free radicals. We found that EC aerosols generated from only one of the eight liquids tested using a new atomizer induced cytotoxicity against two human oral cells in vitro. Treatment of oral cells with the cytotoxic EC aerosol caused a concomitant increase in intracellular oxidative stress. As atomizer age increased with repeated use of the same atomizer, carbonyl production, radical emissions, and cytotoxicity increased. Overall, our results suggest that third-generation ECs may cause adverse effects in the oral cavity and normal EC use, which involves repeated use of the same atomizer to generate aerosol, may enhance the potential toxic effects of third-generation ECs.


Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.
Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.


Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites.
The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target.


Therapists' experiences and perceptions of teamwork in neurological rehabilitation: reasoning behind the team approach, structure and composition of the team and teamworking processes.
Teamwork and the interdisciplinary team approach have been strongly advocated for use in the provision of neurological rehabilitation services. However, whether teamwork has been adopted, and in what form, has yet to be established. The present study investigated therapists' experiences and perceptions of the reasoning behind the team approach in neurological rehabilitation, the structure and composition of the team within which they worked and the team working process. This article reports part of an exploratory qualitative study. Five occupational therapists and five physiotherapists from three teams: a rehabilitation centre; a community team; and a stroke unit based within the UK. Semi-structured interviews were undertaken with each participant and then transcribed. Content and thematic analysis of the qualitative interview data was carried out, with respondents validating both the transcription and analysis stages. Perceived composition and structure of the neurological rehabilitation team was variable across teams and between individual team members. There was disparity as to whether patients were included within the neurological team; the interdisciplinary team approach had not been consistently adopted and there were sub-teams and other team memberships in existence. Reasoning behind the team approach supported the perceived benefits of teamwork from a number of perspectives, and the activities reported as part of the team process were diverse. Different teams may choose to use different strategies depending on the aims and context of the team effort. In some instances interdisciplinary teamwork and patient-centred approaches were not adopted consistently and the process of teamwork itself is both complex and diverse.