A new season for experimental neuroembryology: The mysterious history of Marian Lydia Shorey.
At the turn of the nineteenth and twentieth centuries, the landscape of emerging experimental embryology in the United States was dominated by the Canadian Frank Rattray Lillie, who combined his qualities as scientist and director with those of teacher at the University of Chicago. In the context of his research on chick development, he encouraged the young Marian Lydia Shorey to investigate the interactions between the central nervous system and the peripheral structures. The results were published in two papers which marked the beginning of a new branch of embryology, namely neuroembryology. These papers inspired ground-breaking enquiry by Viktor Hamburger which opened a new area of the research by Rita Levi-Montalcini, in turn leading to the discovery of the nerve growth factor, NGF.


Frequencies of region of difference 1 antigen-specific but not purified protein derivative-specific gamma interferon-secreting T cells correlate with the presence of tuberculosis disease but do not distinguish recent from remote latent infections.
The majority of individuals infected with Mycobacterium tuberculosis achieve lifelong immune containment of the bacillus. What constitutes this effective host immune response is poorly understood. We compared the frequencies of gamma interferon (IFN-gamma)-secreting T cells specific for five region of difference 1 (RD1)-encoded antigens and one DosR-encoded antigen in 205 individuals either with active disease (n = 167), whose immune responses had failed to contain the bacillus, or with remotely acquired latent infection (n = 38), who had successfully achieved immune control, and a further 149 individuals with recently acquired asymptomatic infection. When subjects with an IFN-gamma enzyme-linked immunospot (ELISpot) assay response to one or more RD1-encoded antigens were analyzed, T cells from subjects with active disease recognized more pools of peptides from these antigens than T cells from subjects with nonrecent latent infection (P = 0.002). The T-cell frequencies for peptide pools were greater for subjects with active infection than for subjects with nonrecent latent infection for summed RD1 peptide pools (P <or= 0.006) and culture filtrate protein 10 (CFP-10) antigen (P = 0.029). Individuals with recently acquired (<6 months) versus remotely acquired (>6 months) latent infection did not differ in numbers of peptide pools recognized, proportions recognizing any individual antigen or peptide pool, or antigen-specific T-cell frequencies (P >or= 0.11). The hierarchy of immunodominance for different antigens was purified protein derivative (PPD) > CFP-10 > early secretory antigenic target 6 > Rv3879c > Rv3878 > Rv3873 > Acr1, and the hierarchies were very similar for active and remotely acquired latent infections. Responses to the DosR antigen alpha-crystallin were not associated with latency (P = 0.373). In contrast to the RD1-specific responses, the responses to PPD were not associated with clinical status (P > 0.17) but were strongly associated with positive tuberculin skin test results (>or=15-mm induration; P <or= 0.01). Our results suggest that RD1-specific IFN-gamma-secreting T-cell frequencies correlate with the presence of disease rather than with protective immunity in M. tuberculosis-infected individuals and do not distinguish recently acquired asymptomatic infection from remotely acquired latent infection.


ICSBP-mediated immune protection against BCR-ABL-induced leukemia requires the CCL6 and CCL9 chemokines.
Interferon (IFN) is effective at inducing complete remissions in patients with chronic myelogenous leukemia (CML), and evidence supports an immune mechanism. Here we show that the type I IFNs (alpha and beta) regulate expression of the IFN consensus sequence-binding protein (ICSBP) in BCR-ABL-transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of BCR-ABL-induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the type I IFNs and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression. Insights into the role of these chemokines in the antileukemic response of IFNs suggest new strategies for immunotherapy of CML.


Role of SIRPα in regulation of mucosal immunity in the intestine.
Mononuclear phagocytes such as dendritic cells (DCs) and macrophages in the lamina propria (LP) are thought to be important for both induction of inflammatory responses and maintenance of immunologic tolerance in the mammalian intestine. The molecular mechanisms by which these cells regulate intestinal immunity have remained poorly understood, however. Signal regulatory protein α (SIRPα) is a transmembrane protein that is specifically expressed in DCs, macrophages and neutrophils. Here, we show that SIRPα is abundant in CD11c(+) CD11b(+) LP cells of the mouse intestine. Whereas SIRPα did not appear to be important for the steady-state homeostasis of mucosal immunity in the intestine, the flagellin-stimulated production of IL-17 or interferon (IFN)-γ by LP cells of SIRPα mutant (MT) mice that lack the cytoplasmic region of the protein was markedly decreased compared with that observed with wild-type cells. Moreover, the flagellin-induced production of IL-6 by LP cells from SIRPα MT mice was also greatly reduced. SIRPα MT mice were also resistant to the development of colitis induced by IL-10 deficiency. Our data thus suggest that SIRPα expressed on CD11c(+) LP cells is important for the production of IL-17 or IFN-γ in the LP as well as for the development of colitis induced by IL-10 deficiency.


Mutagenesis of ribosomal protein S8 from Escherichia coli: expression, stability, and RNA-binding properties of S8 mutants.
Protein S8, a 129 amino acid component of the Escherichia coli ribosome, plays an essential role in the assembly of the 30S ribosomal subunit and in the translational regulation of the spc operon by virtue of its capacity to bind specifically to rRNA and mRNA. To study structure-function relationships within the protein, we have constructed a vector for its high-level expression in vivo and developed efficient methods for its purification. Under our conditions, S8 accumulates to a level of 35% of the cellular protein and can be prepared at a purity of over 98% using either HPLC or a combination of ion-exchange and gel-filtration chromatography. The unique cysteine residue at position 126 was replaced by alanine or serine by oligonucleotide-directed mutagenesis, and the two mutant proteins, CA126 and CS126, were expressed and isolated. The effects of the mutations on the RNA-binding ability, secondary structure, and stability of S8 were assessed. CD spectra indicated that wild-type S8 and the two mutant proteins have very similar secondary structures at 25 degrees C. In addition, both mutants are metabolically stable in vivo as inferred from pulse-chase labeling and immunoprecipitation experiments. However, while CA126 exhibits the same affinity for RNA and the same susceptibility to urea and thermal denaturation as wild-type S8, CS126 is severely impaired in its ability to interact with RNA and displays a dramatic reduction in conformational stability. Our results suggest that Cys126 is unlikely to play a specific role in RNA recognition but that it is an integral part of the RNA-binding domain of protein S8.


A Descriptive Analysis of Occupational Fatalities Due to Felonious Assault Among U.S. Law Enforcement Officers During Tactical Incidents, 1996-2014.
Little is known about occupational fatalities among tactical officers. A greater understanding of such injuries is needed to improve officer safety. The purpose of this study was to provide a descriptive analysis of line-of-duty deaths secondary to felonious assault during tactical incidents. Retrospective analysis was performed of open-source de-identified Federal Bureau of Investigation Uniform Crime Reporting Law Enforcement Officers Killed and Assaulted (LEOKA) data inclusive of the years 1996-2014. Officers were included if the fatal injury occurred during operations by a Special Weapons and Tactics (SWAT) team, fugitive task force, narcotics task force, or if the LEOKA narrative described the event as a tactical situation. Of 1,012 officer deaths during the study period, 57 (5.6%) involved tactical officers. On average (± standard deviation), victim officers were 37.3 ± 7.8 years of age at the time of death, with 11.7 ± 6.6 years of law enforcement experience. High-risk warrant service accounted for 63.2% of fatalities. A single officer was killed in 91.2% of incidents; 49.1% of cases involved injuries to other officers. The majority of officers (59.6%) killed were the first officer(s) to enter the scene. The most commonly identified cause of death was head trauma (n = 28). Chest trauma accounted for 14 deaths; 10 (71.4%) sustained an entry wound via the ballistic vest armhole. Where recorded, 52.0% of officers died within the first hour of injury. The provision or nature of buddy care, tactical emergency medical services (EMS) care, or conventional EMS care was rarely noted. Tactical officer deaths most commonly occur during high-risk warrant service, and most often involve the first officer(s) to enter a scene, suggesting an opportunity for improved operational tactics. The frequency of fatal axillary penetration suggests the opportunity for ballistic protection redesign. Information is lacking regarding on-scene care, limiting the ability to determine optimal medical procedures for downed officers during tactical operations. Nearly 50% of victim officers survived more than 1 hour from time of injury, suggesting opportunities to intervene and potentially affect outcomes.


Pentavalent rotavirus vaccine and prevention of gastroenteritis hospitalizations in Australia.
A publicly funded, universal infant pentavalent rotavirus vaccine (RV5) program was implemented in Queensland, Australia, in mid-2007. We sought to assess vaccine effectiveness (VE) of 3 doses of RV5 at preventing rotavirus and nonrotavirus acute gastroenteritis (AGE) hospitalizations in the first birth cohort and impact on hospitalizations in all age groups. Hospitalization rates for rotavirus and nonrotavirus AGE in all age groups before and after RV5 introduction were compared. Population vaccine coverage, hospitalization data, and individual vaccination status were obtained from routinely collected, publicly funded state- and nationally based data sets. Data linkage was performed to calculate 3-dose VE for preventing hospitalization in the eligible age group. RV5 coverage in the first eligible birth cohort was 89.6% for at least 1 dose and 73.1% for 3 doses. Three-dose VE for preventing nonrotavirus AGE hospitalization was 62.3% to 63.9% (any/primary diagnosis) and 89.3% to 93.9% (any/primary diagnosis) for rotavirus hospitalizations. After program implementation, there were immediate and sustained reductions in rotavirus hospitalizations for those who were younger than 20 years and nonrotavirus AGE-coded hospitalizations for those who were younger than 5 years. RV5 is highly effective at preventing rotavirus hospitalizations in a developed country setting, confirming efficacy figures from the pivotal clinical trial. Additional direct and indirect effects are substantial and include reductions in nonrotavirus AGE hospitalizations in vaccinated age groups and rotavirus and nonrotavirus AGE hospitalization rates in older age groups.


The influence of toxicity constraints in models of chemotherapeutic protocol escalation.
The prospect of exploiting mathematical and computational models to gain insight into the influence of scheduling on cancer chemotherapeutic effectiveness is increasingly being considered. However, the question of whether such models are robust to the inclusion of additional tumour biology is relatively unexplored. In this paper, we consider a common strategy for improving protocol scheduling that has foundations in mathematical modelling, namely the concept of dose densification, whereby rest phases between drug administrations are reduced. To maintain a manageable scope in our studies, we focus on a single cell cycle phase-specific agent with uncomplicated pharmacokinetics, as motivated by 5-Fluorouracil-based adjuvant treatments of liver micrometastases. In particular, we explore predictions of the effectiveness of dose densification and other escalations of the protocol scheduling when the influence of toxicity constraints, cell cycle phase specificity and the evolution of drug resistance are all represented within the modelling. For our specific focus, we observe that the cell cycle and toxicity should not simply be neglected in modelling studies. Our explorations also reveal the prediction that dose densification is often, but not universally, effective. Furthermore, adjustments in the duration of drug administrations are predicted to be important, especially when dose densification in isolation does not yield improvements in protocol outcomes.


Mastication of almonds: effects of lipid bioaccessibility, appetite, and hormone response.
Epidemiologic and clinical data indicate that nuts can be incorporated into the diet without compromising body weight. This has been attributed to strong satiety properties, increased resting energy expenditure, and limited lipid bioaccessibility. The role of mastication was explored because of evidence that the availability of nut lipids is largely dependent on the mechanical fracture of their cell walls. In a randomized, 3-arm, crossover study, 13 healthy adults (body mass index, in kg/m(2): 23.1 +/- 0.4) chewed 55 g almonds 10, 25, or 40 times. Blood was collected and appetite was monitored during the following 3 h. Over the next 4 d, all foods were provided, including 55 g almonds, which were consumed under the same chewing conditions. Complete fecal samples were collected. Hunger was acutely suppressed below baseline (P < 0.05), and fullness was elevated above baseline longer (P < 0.05) after 40 chews than after 25 chews. Two hours after consumption, fullness levels were significantly lower and hunger levels were significantly higher after 25 chews than after 10 and 40 chews (P < 0.05). Initial postingestive glucagon-like peptide-1 concentrations were significantly lower after 25 chews than after 40 chews (P < 0.05), and insulin concentrations declined more rapidly after 25 and 40 chews than after 10 chews (both P < 0.05). Fecal fat excretion was significantly higher after 10 chews than after 25 and 40 chews (both P < 0.05). All participants had higher fecal energy losses after 10 and 25 chews than after 40 chews (P < 0.005). The results indicate important differences in appetitive and physiologic responses to masticating nuts and likely other foods and nutrients. This trial was registered at clinicaltrials.gov as NCT00768417.


Nontraumatic skull base defects with spontaneous CSF rhinorrhea and arachnoid herniation: imaging findings and correlation with endoscopic sinus surgery in 27 patients.
Defects at the skull base leading to spontaneous CSF rhinorrhea are rare lesions. The purpose of our study was to correlate CT and MR findings regarding the location and content of CSF leaks in 27 patients with endoscopic sinus surgery observations. Imaging studies in 27 patients with intermittent CSF rhinorrhea (CT in every patient including 10 examinations with intrathecal contrast, plain CT in 2 patients, and MR in 15 patients) were analyzed and were retrospectively blinded to intraoperative findings. CT depicted a small endoscopy-confirmed osseous defect in 3 different locations: 1) within the ethmoid in 15 instances (53.6% of defects) most commonly at the level of the anterior ethmoid artery (8/15); 2) adjacent to the inferolateral recess of the sphenoid sinus in 7 patients including one patient with bilateral lesions (8/28 defects, 28.6%); 3) within the midline sphenoid sinus in 5 of 28 instances (17.9%). Lateral sphenoid defects (3.5 +/- 0.80 mm) were larger than those in ethmoid (2.7 +/- 0.77 mm, P < or = 0.029) or midsphenoid location (2.4 +/- 0.65 mm, P < or = 0.026). With endoscopy proven arachnoid herniation in 24 instances as reference, MR was correct in 14 of 15 instances (93.3%), CT cisternography in 5 of 8 instances (62.5%). Plain CT in 1 patient was negative. In patients with a history of spontaneous CSF rhinorrhea, CT was required to detect osseous defects at specific sites of predilection. MR enabled differentiating the contents of herniated tissue and allowed identification of arachnoid tissue as a previously hardly recognized imaging finding.


Adult adherent stromal cells in the management of graft-versus-host disease.
Early reports demonstrated the safety of adherent mesenchymal stromal cell (MSC) infusions in the hematopoietic stem cell transplantation (HCT) setting, as well as clinical efficacy for treatment of steroid refractory acute graft-versus-host disease (GVHD); however, two large, Phase III randomized, placebo-controlled trials of MSC for initial therapy or steroid refractory GVHD failed to meet their primary endpoints of durable complete response. Subset analyses demonstrated efficacy in selected patient populations, contributing to recent approvals of MSC for pediatric patients in Canada and New Zealand. In this review, we discuss the biologic and immunomodulatory properties of MSC and potential mechanisms involved. We review the results of prior clinical trials incorporating MSC for GVHD treatment or prophylaxis, the recent approvals in Canada and New Zealand, as well as future directions in the field. The role of MSC infusions, in the prophylaxis and/or treatment of GVHD after HCT, continues to be under active investigation. Whether, and how, to incorporate MSC infusions is unclear, and ongoing questions include the source tissue type and culture methods, the timing and dosage of MSC product infusions, as well as the optimal clinical trial design and endpoints for assessment of clinical response.


Distinct CED-10/Rac1 domains confer context-specific functions in development.
Rac GTPases act as master switches to coordinate multiple interweaved signaling pathways. A major function for Rac GTPases is to control neurite development by influencing downstream effector molecules and pathways. In Caenorhabditis elegans, the Rac proteins CED-10, RAC-2 and MIG-2 act in parallel to control axon outgrowth and guidance. Here, we have identified a single glycine residue in the CED-10/Rac1 Switch 1 region that confers a non-redundant function in axon outgrowth but not guidance. Mutation of this glycine to glutamic acid (G30E) reduces GTP binding and inhibits axon outgrowth but does not affect other canonical CED-10 functions. This demonstrates previously unappreciated domain-specific functions within the CED-10 protein. Further, we reveal that when CED-10 function is diminished, the adaptor protein NAB-1 (Neurabin) and its interacting partner SYD-1 (Rho-GAP-like protein) can act as inhibitors of axon outgrowth. Together, we reveal that specific domains and residues within Rac GTPases can confer context-dependent functions during animal development.


Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes.
We analyzed the outcomes of patients who survived disease-free for 1 year or more after a second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant after disease relapse; among these, 325 were relapse free at 1 year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplantation in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least 1 year was 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status before second HCT was significantly associated with higher risk for overall mortality (hazard ratio, 1.71 for patients with disease not in complete remission before second HCT, P < .01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults after second transplantation. Chronic GVHD was the leading cause of nonrelapse mortality, followed by organ failure and infection. The cumulative incidence of developing at least 1 of the studied late effects within 10 years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence, 22%) and cataracts (20%); in adults they were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease free for at least 1 year, many can be expected to survive long term. However, they continue to be at risk for relapse and nonrelapse morbidity and mortality. Novel approaches are needed to minimize relapse risk and long-term transplantation morbidity in this population.


Use of Acticoat dressings in burns: what is the evidence?
The virtues of silver as an antimicrobial agent have been known for some time. Various silver containing dressings are currently used for the treatment of wounds. Introduced in the late 1990s, Acticoat is a nanocrystalline silver dressing developed to overcome some shortcomings of the older dressings by providing sustained release of silver up to 7 days. We aim to determine the level of evidence available in the literature in view of recent increased usage of Acticoat. A Medline search was conducted to identify articles evaluating the use of Acticoat in burn wounds. A level of evidence adapted from the Oxford Centre for Evidence-Based-Medicine was assigned to each of these articles. Only one study was considered to be LOE 1, which is a multicentre randomised controlled trial comparing Acticoat against Silver Sulfadiazine. One further randomised control trial was downgraded to LOE 2 due to a wide confidence interval. Twenty studies (66%) were LOE 5 of which 6 were case reports and 14 were in vitro/animal studies. The available LOE 1 study demonstrates that Acticoat has better antimicrobial activity compared to another available silver dressing. Other studies suggest Acticoat has fewer adverse effects and reduces healing times. Its ease of application and low frequency of change makes it an ideal dressing in burn wounds. More well designed and properly reported randomised controlled trials are essential for informed clinical decision-making.


Symptom control, functioning and satisfaction among Swiss patients treated with risperidone long-acting injectable.
To investigate antipsychotic efficacy and tolerability of risperidone long-acting injectable (RLAI) in Swiss patients with schizophrenia or other psychotic disorders, changed directly from their previous antipsychotic medication. Patients symptomatically stable for ≥1 month on their previous medication and considered to require a treatment change, received 25 mg RLAI (increased to 37.5 or 50 mg, if required) every 2 weeks for 6 months. Of 60 patients enrolled (68.3% male, average age 40.4 years), most (81.7%) had DSM-IV schizophrenia (mainly paranoid). Previous treatments were with atypical antipsychotics (58.3% of patients), depot (38.3%) and conventional oral (13.3%) neuroleptics. Mean total PANSS scores were significantly reduced from baseline to treatment endpoint (76.1 vs. 64.4, P<0.001), as were all PANSS subscale and symptom factor scores. The CGI, GAF, and patient satisfaction with treatment were also significantly improved at endpoint (P<0.001). At endpoint, 37.0% of patients rated their satisfaction as "very good" compared with only 4.3% at baseline. Mean scores for total ESRS and Parkinsonism subscales were significantly reduced at endpoint (P<0.001). Treatment with RLAI significantly improved disease symptoms, functioning, patient satisfaction, and reduced movement disorders. It provides an important option for long-term treatment of patients with psychotic disorders.


Comparing the use of differentiated adipose-derived stem cells and mature adipocytes to model adipose tissue in vitro.
In vitro models of human adipose tissue may serve as beneficial alternatives to animal models to study basic biological processes, identify new drug targets, and as soft tissue implants. With this approach, we aimed to evaluate adipose-derived stem cells (ASC) and mature adipocytes (MA) comparatively for the application in the in vitro setup of adipose tissue constructs to imitate native adipose tissue physiology. We used human primary MAs and human ASCs, differentiated for 14 days, and encapsulated them in collagen type I hydrogels to build up a three-dimensional (3D) adipose tissue model. The maintenance of the models was analyzed after seven days based on a viability staining. Further, the expression of the adipocyte specific protein perilipin A and the release of leptin and glycerol were evaluated. Gene transcription profiles of models based on dASCs and MAs were analyzed with regard to native adipose tissue. Compared to MAs, dASCs showed an immature differentiation state. Further, gene transcription of MAs suggests a behavior closer to native tissue in terms of angiogenesis, which supports MAs as preferred cell type. In contrast to native adipose tissue, genes of de novo lipogenesis and tissue remodeling were upregulated in the in vitro attempts.


Sugar feeding in adult stable flies.
Adult stable flies (Stomoxys calcitrans L.) are known to feed readily on sugars in the laboratory. However, little is known concerning the extent of stable fly sugar feeding in wild populations. We examined the frequency of sugar feeding in stable flies collected on Alsynite sticky traps in rural and urban environments. In addition, stable flies were visually examined to determine whether blood was present in the gut. In laboratory studies, sugars were detectable with the anthrone technique in stable flies for approximately 3 d after being imbibed, and blood could be visually detected in the gut for 24-48 h after feeding. Twelve percent of the field-collected flies had detectable sugar with a higher percentage of the urban flies having sugar fed than the rural flies, 21 and 8%, respectively. Female flies sugar fed at a slightly higher rate than males, 13 versus 11%, respectively. Less than 1% of the field-collected flies had blood in their guts. The frequency of observable blood was slightly higher in flies collected in an urban environment compared with those collected in a rural environment and did not differ between male and female flies. The number of flies with both blood and sugar was slightly higher than would be expected based on the frequencies of each alone. Seasonal patterns of both sugar feeding and blood feeding were similar in the rural and urban environments; both peaked in the early summer, May to mid-June, and dropped through the summer and fall. Sugar feeding in the urban environment increased again in October.


International and Geographic Trends in Gender Authorship within Plastic Surgery.
Professional advancement in academic plastic surgery may depend on scholarly activity. The authors evaluate gender-based publishing characteristics in three international plastic surgery journals. A retrospective review of all articles published in 2016 in the following journals was undertaken: Plastic and Reconstructive Surgery, Journal of Plastic, Reconstructive and Aesthetic Surgery, European Journal of Plastic Surgery, Annals of Surgery, and New England Journal of Medicine. Data were collected on lead author gender (first or senior author) and differences in author gender proportions, by journal, by article topic, and by geographic location were evaluated. Overall, 2610 articles were retrieved: 34.1 percent were from plastic surgery journals, 12.8 percent were from the Annals of Surgery, and 53.1 percent were from the New England Journal of Medicine. There was a lower proportion of female lead authors among plastic surgery journals compared with the Annals of Surgery and the New England Journal of Medicine (31 percent versus 39 percent versus 39 percent; p = 0.001). There were no differences in female lead author geographic location in the Annals of Surgery or the New England Journal of Medicine; within the plastic surgery journals, there were differences (p = 0.005), including a lower proportion arising from East Asia (15 percent) and a higher proportion arising from Canada (48 percent). Within plastic surgery, Plastic and Reconstructive Surgery had the lowest proportion of female lead author (p < 0.001). The proportion of female lead author varied by article topic (p < 0.001) and was notably higher in breast (45.6 percent) and lower in head and neck/craniofacial-orientated articles (25.0 percent). There are gender disparities in three mainstream plastic surgery journals-Plastic and Reconstructive Surgery, the Journal of Plastic, Reconstructive and Aesthetic Surgery, the European Journal of Plastic Surgery-and there are lower proportions of lead female authorship compared with the Annals of Surgery and the New England Journal of Medicine. Further research should focus on understanding any geographic disparities that may exist.


A Spanish Sign Language (LSE) Adaptation of the Communicative Development Inventories.
This article presents the adaptation of the MacArthur Communicative Development Inventory (CDI; Fenson et al., 1993, Guide and technical manual for the MacArthur Communicative Development Inventories. San Diego, CA: Singular Press; Fenson et al. 1994, Variability in early communicative development. Monographs of the Society for Research in Child Development, 59, 1-173) to Spanish Sign Language (LSE). Data were collected from 55 participants (32 boys and 23 girls; 17 deaf signers, 38 hearing signers) who, evaluated by their caregivers every 4 months, presented a total of 170 records. The parents reported the signs that the children could understand or produce between 8 and 36 months. Results suggested that the CDI adapted to LSE is a valid and reliable instrument. Signing children could understand more signs than they produced at this early developmental stage. There were no significant differences between boys and girls, or between deaf and hearing children. The development of LSE is similar to other sign languages, although with a lower production of signs in the early stages, perhaps due to the bilingualism of most of the children of our study.


Antiviral activity of hop constituents against a series of DNA and RNA viruses.
We investigated whether crude hop extracts and purified hop components representing every major chemical class of hop compound have antiviral activity. These hop constituents were tested for antiviral activity against bovine viral diarrhea virus (BVDV) as a surrogate model of hepatitis C virus (HCV), human immunodeficiency virus (HIV), influenza A virus (FLU-A), influenza B virus (FLU-B), rhinovirus (Rhino), respiratory syncytial virus (RSV), yellow fever virus (YFV), cytomegalovirus (CMV), hepatitis B virus (HBV), and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The extracts all failed to prevent the replication of HIV, FLU-A, FLU-B, RSV and YFV. A xanthohumol-enriched hop extract displayed a weak to moderate antiviral activity against BVDV (therapeutic index (TI)=6.0), HSV-2 (TI=>5.3), Rhino (TI=4.0) and HSV-1 (TI=>1.9) with IC(50) values in the low microg/ml range. Pure iso-alpha-acids demonstrated low to moderate antiviral activity against both BVDV (TI=9.1) and CMV (TI=4.2) with IC(50) values in the low microg/ml range. No antiviral activity was detected using beta-acids or a hop oil extract. Ultra-pure preparations (>99% pure) were used to show that xanthohumol accounted for the antiviral activity observed in the xanthohumol-enriched hop extract against BVDV, HSV-1 and HSV-2. Xanthohumol was found to be a more potent antiviral agent against these viruses than the isomer iso-xanthohumol. With Rhino, the opposite trend was observed with iso-xanthohumol showing superior antiviral activity to that observed with xanthohumol. Xanthohumol also showed antiviral activity against CMV, suggesting that it might have a generalized anti-herpesvirus antiviral activity. Again, superior antiviral activity was observed with the xanthohumol isomer against CMV. In summary, iso-alpha-acids and xanthohumol were shown to have a low-to-moderate antiviral activity against several viruses. These hop constituents might serve as interesting lead compounds from which more active anti-HCV, anti-Rhino and anti-herpesvirus antiviral agents could be synthesized.


Emotional arousal impairs association-memory: Roles of amygdala and hippocampus.
Emotional arousal is well-known to enhance memory for individual items or events, whereas it can impair association memory. The neural mechanism of this association memory impairment by emotion is not known: In response to emotionally arousing information, amygdala activity may interfere with hippocampal associative encoding (e.g., via prefrontal cortex). Alternatively, emotional information may be harder to unitize, resulting in reduced availability of extra-hippocampal medial temporal lobe support for emotional than neutral associations. To test these opposing hypotheses, we compared neural processes underlying successful and unsuccessful encoding of emotional and neutral associations. Participants intentionally studied pairs of neutral and negative pictures (Experiments 1-3). We found reduced association-memory for negative pictures in all experiments, accompanied by item-memory increases in Experiment 2. High-resolution fMRI (Experiment 3) indicated that reductions in associative encoding of emotional information are localizable to an area in ventral-lateral amygdala, driven by attentional/salience effects in the central amygdala. Hippocampal activity was similar during both pair types, but a left hippocampal cluster related to successful encoding was observed only for negative pairs. Extra-hippocampal associative memory processes (e.g., unitization) were more effective for neutral than emotional materials. Our findings suggest that reduced emotional association memory is accompanied by increases in activity and functional coupling within the amygdala. This did not disrupt hippocampal association-memory processes, which indeed were critical for successful emotional association memory formation.


Epigenotype-phenotype correlations in Silver-Russell syndrome.
Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition. A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken. The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.


Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer.
The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables. The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements. ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects. A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor. Interaction of PTEN and ERG pathways warrants further studies.


Opportunities for improving medication use and monitoring in gout.
To study patterns and predictors of medication use and laboratory monitoring in gout. In a cohort of veterans with a diagnosis of gout prescribed allopurinol, colchicine or probenecid, quality of care was assessed by examining adherence to the following evidence-based recommendations: (1) whether patients starting a new allopurinol prescription (a) received continuous allopurinol, (b) received colchicine prophylaxis, (c) achieved the target uric acid level of <or=6 mg/dl; and (2) whether doses were adjusted for renal insufficiency. The association of sociodemographic characteristics, healthcare utilisation and comorbidity with the recommendations was examined by logistic/Poisson regression. Of the 643 patients with gout receiving a new allopurinol prescription, 297 (46%) received continuous allopurinol, 66 (10%) received colchicine prophylaxis and 126 (20%) reached the target uric acid level of <or=6 mg/dl. During episodes of renal insufficiency, appropriate dose reduction/discontinuation of probenecid was done in 24/31 episodes (77%) and of colchicine in 36/52 episodes (69%). Multivariable regression showed that higher outpatient utilisation, more rheumatology care and lower comorbidity were associated with better quality of care; more rheumatology clinic or primary care visits were associated with less frequent allopurinol discontinuation; more total outpatient visit days or most frequent visits to a rheumatology clinic were associated with a higher likelihood of receiving colchicine prophylaxis; and a lower Charlson Comorbidity Index or more outpatient visit days were associated with higher odds of reaching the target uric acid level of <or=6 mg/dl. Important variations were found in patterns of medication use and monitoring in patients with gout with suboptimal care. A concerted effort is needed to improve the overall care of gout.


Vitamin A status and metabolism of cutaneous polyamines in the hairless mouse after UV irradiation: action of beta-carotene and astaxanthin.
Solar radiations (UV A and B) can cause epidermis photoaging and skin cancers. These frequently irreversible effects result from the in situ generation of free radicals. However, it has been noted that nutritional factors can modulate photochemical damage, in particular the common carotenoids present in food, which can be considered as potential prophylactic agents against carcinogenesis. We investigated the effect of UV A and B radiations on the skin of the SKH1 hairless mouse fed a diet either lacking in vitamin A or supplemented with retinol, beta-carotene or astaxanthin. The latter is an oxygenated carotenoid (like canthaxanthin) without provitamin A activity and with strong singlet oxygen quenching ability. After analysing of vitamin status of each group (plasma retinol concentrations and hepatic reserves), we searched for UV-induced modifications of polyamine metabolism by measuring epidermal ornithine decarboxylase (ODC) activity and free polyamines concentration (putrescine, spermidine and spermine). In the basal state without irradiation, differences in ODC activity between groups were nonsignificant; but after UV stimulation, ODC increased markedly in the skin of vitamin A-deficient animals, much more than in other groups. Curiously, the addition of astaxanthin or beta-carotene to the regimen containing retinol reduced the protective effect of retinol alone. Regarding polyamines after irradiation, putrescine was significantly increased in the skin of deficient animals, in parallel with ODC activity. However, astaxanthin had a stronger inhibitory effect on putrescine accumulation than retinol, and decreased spermidine and spermine concentrations: this suggests a specific action on transglutaminases.


Microanatomical and immunohistochemical study of the human anterior branch of the medial antebrachial cutaneous nerve of forearm at the antecubital fossa and its clinical implications.
Poor prognosis of nerve repair in patients may be due to changes in intraneural anatomy with age. Also, chances of Complex Regional Pain Syndrome-Type I (CRPS-I) secondary to peripheral nerve injury are comparatively high. The present study is to find the fascicular pattern of the anterior branch of the medial antebrachial cutaneous nerve of forearm (MACN) (at antecubital fossa), microanatomic morphometric characteristics of its connective tissue components (adipose tissue) and changes with age and study of intraneural sympathetic fiber content. Sixty six human (37-88-year-old) cadaveric anterior branch of MACN have been collected from antecubital fossa and the study has been performed at magnifications (5x, 10x, 20x, and 40x objective) after routine histological (Hematoxylin & Eosin stain, Masson's trichrome stain) processing was done for morphometric analysis (total cross-sectional, fascicular and non-fascicular area) and immunohistochemical (tyrosine hydroxylase) processing for sympathetic fibers. The anterior branch of the MACN's average total cross section area was 1.150 mm(2) on right side and 1.156 mm(2) on left side. There was significant increase in non-fascicular connective tissue area. In non-fascicular area, there was very less amount of adipose tissue in 86.37% of cases and more adipose tissue in 13.63% (elderly) cases. The average sympathetic fiber area is 0.0109 mm(2) without definite relationship with age. Our study makes an attempt to build a normal data base for MACN which might be helpful during the application of diagnostic and surgical nerve graft procedures.


Sociocognitive self-regulatory mechanisms governing judgments of the acceptability and likelihood of sport cheating.
This study extends previous psychosocial literature (Bandura et al., 2001, 2003) by examining a structural model of the self-regulatory mechanisms governing the acceptability and likelihood of cheating in a sport context. Male and female adolescents (N = 804), aged 15-20 years, took part in this study. Negative affective self-regulatory efficacy influenced the acceptability and likelihood of cheating through the mediating role of moral disengagement, in females and males. Affective efficacy positively influenced prosocial behavior through moral disengagement or through resistive self-regulatory efficacy and social efficacy, in both groups. The direct effects of affective efficacy on beliefs about cheating were only evident in females. These results extend the findings of Bandura et al. (2001, 2003) to the sport context and suggest that affective and resistive self-regulatory efficacy operate in concert in governing adolescents' moral disengagement and transgressive behaviors in sport.


Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: an international inception cohort study.
To describe the prevalence, characteristics, attribution, and clinical significance of neuropsychiatric (NP) events in an international inception cohort of systemic lupus erythematosus (SLE) patients. The study was conducted by the Systemic Lupus International Collaborating Clinics (SLICC). Patients were enrolled within 15 months of fulfilling the American College of Rheumatology (ACR) SLE classification criteria. All NP events within a predefined enrollment window were identified using the ACR case definitions of 19 NP syndromes. Decision rules were derived to determine the proportion of NP disease attributable to SLE. Clinical significance was determined using the Short Form 36 (SF-36) Health Survey and the SLICC/ACR Damage Index (SDI). A total of 572 patients (88% female) were recruited, with a mean +/- SD age of 35 +/- 14 years. The mean +/- SD disease duration was 5.2 +/- 4.2 months. Within the enrollment window, 158 of 572 patients (28%) had at least 1 NP event. In total, there were 242 NP events that encompassed 15 of 19 NP syndromes. The proportion of NP events attributed to SLE varied from 19% to 38% using alternate attribution models and occurred in 6.1-11.7% of patients. Those with NP events, regardless of attribution, had lower scores on the SF-36 and higher SDI scores compared with patients with no NP events. Twenty-eight percent of SLE patients experienced at least 1 NP event around the time of diagnosis of SLE, of which only a minority were attributed to SLE. Regardless of attribution, the occurrence of NP events was associated with reduced quality of life and increased organ damage.


An alternative approach for estimating the accuracy of colposcopy in detecting cervical precancer.
Since colposcopy helps to detect cervical cancer in its precancerous stages, as new strategies and technologies are developed for the clinical management of cervical neoplasia, precisely determining the accuracy of colposcopy is important for characterizing its continued role. Our objective was to employ a more precise methodology to estimate of the accuracy of colposcopy to better reflect clinical practice. For each patient, we compared the worst histology result among colposcopically positive sites to the worst histology result among all sites biopsied, thereby more accurately determining the number of patients that would have been underdiagnosed by colposcopy than previously estimated. We utilized data from a clinical trial in which 850 diagnostic patients had been enrolled. Seven hundred and ninety-eight of the 850 patients had been examined by colposcopy, and biopsy samples were taken at colposcopically normal and abnormal sites. Our endpoints of interest were the percentages of patients underdiagnosed, and sensitivity and specificity of colposcopy. With the threshold of low-grade squamous intraepithelial lesions for positive colposcopy and histology diagnoses, the sensitivity of colposcopy decreased from our previous assessment of 87.0% to 74.0%, while specificity remained the same. The drop in sensitivity was the result of histologically positive sites that were diagnosed as negative by colposcopy. Thus, 28.4% of the 798 patients in this diagnostic group would have had their condition underdiagnosed by colposcopy in the clinic. In utilizing biopsies at multiple sites of the cervix, we present a more precise methodology for determining the accuracy of colposcopy. The true accuracy of colposcopy is lower than previously estimated. Nevertheless, our results reinforce previous conclusions that colposcopy has an important role in the diagnosis of cervical precancer.


Functional characterization of nine Norway Spruce TPS genes and evolution of gymnosperm terpene synthases of the TPS-d subfamily.
Constitutive and induced terpenoids are important defense compounds for many plants against potential herbivores and pathogens. In Norway spruce (Picea abies L. Karst), treatment with methyl jasmonate induces complex chemical and biochemical terpenoid defense responses associated with traumatic resin duct development in stems and volatile terpenoid emissions in needles. The cloning of (+)-3-carene synthase was the first step in characterizing this system at the molecular genetic level. Here we report the isolation and functional characterization of nine additional terpene synthase (TPS) cDNAs from Norway spruce. These cDNAs encode four monoterpene synthases, myrcene synthase, (-)-limonene synthase, (-)-alpha/beta-pinene synthase, and (-)-linalool synthase; three sesquiterpene synthases, longifolene synthase, E,E-alpha-farnesene synthase, and E-alpha-bisabolene synthase; and two diterpene synthases, isopimara-7,15-diene synthase and levopimaradiene/abietadiene synthase, each with a unique product profile. To our knowledge, genes encoding isopimara-7,15-diene synthase and longifolene synthase have not been previously described, and this linalool synthase is the first described from a gymnosperm. These functionally diverse TPS account for much of the structural diversity of constitutive and methyl jasmonate-induced terpenoids in foliage, xylem, bark, and volatile emissions from needles of Norway spruce. Phylogenetic analyses based on the inclusion of these TPS into the TPS-d subfamily revealed that functional specialization of conifer TPS occurred before speciation of Pinaceae. Furthermore, based on TPS enclaves created by distinct branching patterns, the TPS-d subfamily is divided into three groups according to sequence similarities and functional assessment. Similarities of TPS evolution in angiosperms and modeling of TPS protein structures are discussed.


Implementation of PT symmetric devices using plasmonics: principle and applications.
The so-called PT symmetric devices, which feature ε((-x)) = ε((x))* associated with parity-time symmetry, incorporate both gain and loss and can present a singular eigenvalue behaviour around a critical transition point. The scheme, typically based on co-directional coupled waveguides, is here transposed to the case of variable gain on one arm with fixed losses on the other arm. In this configuration, the scheme exploits the full potential of plasmonics by making a beneficial use of their losses to attain a critical regime that makes switching possible with much lowered gain excursions. Practical implementations are discussed based on existing attempts to elaborate coupled waveguide in plasmonics, and based also on the recently proposed hybrid plasmonics waveguide structure with a small low-index gap, the PIROW (Plasmonic Inverse-Rib Optical Waveguide).


Liver disease in a district hospital remote from a transplant centre: a study of admissions and deaths.
The profile of liver disease admissions and associated deaths in a district general hospital was studied to determine whether patients with end stage liver disease are appropriately referred for consideration of liver transplantation. Admission details were provided by the Office of Population Censuses and Surveys (OPCS) and their accuracy was assessed by case note analysis. According to OPCS, 77 patients with liver disease were admitted on 113 occasions between 1 January 1987 and 31 December 1989. The case notes of 74 (96%) were retrieved and examined. Only 64 (86%) had primary liver disease. Twenty four (31%) died of liver failure. Alcohol was the aetiological agent in two thirds. According to accepted criteria, 11 patients were suitable for liver transplant assessment but only three had been referred to a transplant centre. Of the remaining eight, five died during the study period. Two of the three patients referred died without transplantation; one underwent transplant and survived. There is discrepancy between OPCS data and true disease aetiologies, with approximately 40% under reporting of alcoholic liver disease. If this population is representative of the situation nationally, substantial numbers of patients with end stage liver disease might benefit from liver transplantation, but are not referred to a centre.


Comparisons of surgical outcomes, complications, and costs between laparotomy and laparoscopy in early-stage ovarian cancer.
The purpose of this study was to compare the surgical outcomes, complications, and costs between laparoscopic staging and laparotomic staging for early-stage ovarian cancer. We evaluated 113 patients who underwent laparoscopy (n = 26) or laparotomy (n = 87) for staging. We retrospectively analyzed patients' demographics and operative variables, including operative time, estimated blood loss, lymph node count, hospital stay, complications, postoperative pain, and return to normal activity. In addition, costs for laparoscopy and laparotomy groups were also compared. The mean operation time was longer in laparoscopy group compared to laparotomy group (227.6 minutes vs 184.6 minutes, P = 0.016). The laparoscopy group had less intraoperative blood loss, less transfusion requirement, shorter postoperative hospital stay, earlier general diet intake, shorter time to adjuvant chemotherapy, and lower postoperative pain score after 6, 24, and 48 hours compared with the laparotomy group. The mean number of lymph node retrievals was comparable between the groups. The incidence of operative complications was lower in the laparoscopy group (7.7%) relative to the laparotomy group (23.0%). The total average cost for staging completed via laparotomy was $1237 and that via laparoscopy was $1998, with significant difference. Complete surgical staging by laparoscopy was achieved in all cases with comparable operative time and less operative complications compared with laparotomy for selected patients with early-stage ovarian cancer. However, the operation costs for laparoscopy were significantly higher than the operation costs for laparotomic staging surgery.


Validation of a short version of the glaucoma medication self-efficacy questionnaire.
The aims of this study were: (1) to examine whether the original glaucoma medication adherence and eye drop technique self-efficacy scales could be shortened for easier use in practice settings; and (2) to validate these scales against objective medication adherence measures. Prospective study conducted at a single private practice site. We measured subjects' adherence to glaucoma medications through Medication Event Monitoring System (MEMS) devices and assessed eye drop instillation technique by video-recording. Principal components factor analysis and logistic and linear regression were used to analyse the data. Our results yielded a 10-item Glaucoma Medication Adherence Self-Efficacy Scale that was strongly associated with subject adherence measured using MEMS (β coefficient 8.52, 95% CI 1.94 to 15.1). In addition, the six-item Eye Drop Technique Self-Efficacy Scale was strongly associated with video-recorded subject eye drop installation technique (OR 10.47, 95% CI 1.78 to 61.63). Eye care providers and researchers could use these shorter scales to identify subjects with either poor glaucoma medication adherence and/or eye drop instillation technique. This could help to identify those who may benefit most from education and training on both adherence and eye drop instillation.


Triptolide induces growth inhibition and apoptosis of human laryngocarcinoma cells by enhancing p53 activities and suppressing E6-mediated p53 degradation.
Triptolide, an active compound extracted from Chinese herb Leigongteng (Tripterygium wilfordii Hook F.), shows a broad-spectrum of anticancer activity through its cytotoxicity. However, the efficacy of triptolide on laryngocarcinoma rarely been evaluated, and the mechanism by which triptolide-induced cellular apoptosis is still not well understood. In this study, we found that triptolide significantly inhibited the laryngocarcinoma HEp-2 cells proliferation, migration and survivability. Triptolide induces HEp-2 cell cycle arrest at the G1 phase and apoptosis through intrinsic and extrinsic pathways since both caspase-8 and -9 are activated. Moreover, triptolide enhances p53 expression by increasing its stability via down-regulation of E6 and E6AP. Increased p53 transactivates down-stream target genes to initiate apoptosis. In addition, we found that short time treatment with triptolide induced DNA damage, which was consistent with the increase in p53. Furthermore, the cytotoxicity of triptolide is decreased by p53 knockdown or use of caspases inhibitor. In conclusion, our results demonstrated that triptolide inhibits cell proliferation and induces apoptosis in laryngocarcinoma cells by enhancing p53 expression and activating p53 functions through induction of DNA damage and suppression of E6 mediated p53 degradation. These studies indicate that triptolide is a potential anti-laryngocarcinoma drug.


Vitamin D deficiency in patients with liver cirrhosis.
There is ongoing evidence that vitamin D is related to the pathophysiology of cirrhosis. Although the incidence of vitamin D deficiency in chronic liver diseases and cirrhosis is strongly documented, its pathogenic association with advanced liver fibrosis remains controversial. There is evidence of a significant relation of 25(OH)D levels with the degree of liver dysfunction, considering that an inverse correlation of 25(OH)D levels with both Child-Pugh score and Model for End-Stage Liver Disease has been reported. In addition, vitamin D deficiency has been shown to increase the risk for overall mortality and infections in patients with cirrhosis. Vitamin D deficiency has been also associated with advanced stages of hepatocellular carcinoma and poor prognosis. Finally, there are studies suggesting that patients with chronic hepatitis C and normal vitamin D levels have higher virological response to treatment. However, there are not enough studies conducted in cirrhotic-only populations. The association between vitamin D and cirrhosis demonstrates a great potential for clinical application. The relation between vitamin D deficiency and the degree of liver function, degree of fibrosis and infectious complications could support its use as a prognostic index and a diagnostic tool.


Quality of life and pain in patients with facioscapulohumeral muscular dystrophy.
The aim of this study was to assess quality of life (QoL) and evaluate the occurrence and characteristics of pain in facioscapulohumeral muscular dystrophy (FSHD) patients. No study has yet assessed QoL in a large group of FSHD patients and, overall, few studies have assessed pain in neuromuscular diseases. We performed a prospective study using a multidimensional protocol including: clinical (according to the Clinical Severity Scale Rev1); genetic (p13E-11 EcoRI fragments Rev1); QoL (Short Form-36); pain (Visual Analog Scale and Portenoy-6 questions); and depression (Beck Depression Inventory) assessment. QoL measures of FSHD were compared with those of Italian norms. Moreover, we correlated QoL and pain measurements with clinical findings. Sixty-five patients were enrolled in the study. QoL was statistically significantly reduced with respect to the Italian normative sample, mainly in physical domains. Our study demonstrated that pain is frequent in FSHD patients. More than half of the patients complained of at least moderate pain. Women complained of slightly higher levels of deterioration in the emotional aspects of QoL than men. Clinical pattern (as assessed by Clinical Severity Scale) was closely related to physical QoL domains: the higher the clinical involvement, the more severe the QoL deterioration. This study provided information that may be crucial in clinical practice: pain may be a relevant aspect in FSHD patients, and prevention strategies or relevant therapies should be considered as appropriate. Moreover, we must pay more attention to gender differences: women can suffer far greater deterioration in the emotional aspects of QoL. Further multidimensional observations are needed. Muscle Nerve 40: 200-205, 2009.


Adenosine-induced bronchoconstriction and contraction of airway smooth muscle from allergic rabbits with late-phase airway obstruction: evidence for an inducible adenosine A1 receptor.
Recently, there has been an increasing interest in adenosine as a potential mediator of allergic asthma. In the present study, we used the allergic rabbit model developed in our laboratory to study the airway responses to adenosine and receptor binding in allergic lung vs. normal. Neonatal, pathogen-free rabbit litter mates were injected intraperitoneally within 24 hr of birth with ragweed pollen extract (1 mg/ml) to produce preferentially allergen-specific immunoglobulin E. Immunization produced bronchial airway hyperresponsiveness. Aerosolized adenosine (0.156-10 mg/ml) caused a dose-dependent bronchoconstriction (PC50 adenosine = 1.64 +/- 0.84 mg/ml). 9-Chloro-2-(2-furyl)[1,2,4]triazole[1,5- c]quinazolin-5-amine (CGS-15943), a nonxanthine adenosine receptor antagonist, significantly inhibited the adenosine-induced airway obstruction in term of dynamic compliance (P < .05). Adenosine also increased the lung resistance in a dose-dependent manner which was significantly inhibited by CGS-15943 (P < .05). Nonimmunized, pathogen-free, age-matched rabbits (control) did not respond to adenosine at these same concentrations. Adenosine also produced a concentration-dependent (10(-9)-10(-4) M) contraction of isolated tracheal and bronchial airway rings in vitro from allergic rabbits but had no detectable effect on normal rabbit airway smooth muscle. Peripheral airway smooth muscles (secondary and tertiary) were more responsive to adenosine than central (tracheal) airways. The contraction produced by 10(-4) M adenosine in primary, secondary and tertiary airways was 90, 135 and 265% of the contraction produced by 50 mM KCl, respectively. CGS-15943 (10(-7) M) significantly inhibited the adenosine-induced contraction (P < .05) shifting the dose-response curve to the right.(ABSTRACT TRUNCATED AT 250 WORDS)


Primary and submovement control of aiming in C6 tetraplegics following posterior deltoid transfer.
Upper limb motor control in fast, goal-directed aiming is altered in tetraplegics following posterior-deltoid musculotendinous transfer. Specifically, movements have similar end-point accuracy but longer duration and lower peak velocity than those of age-matched, neurotypical controls. Here, we examine in detail the interplay between primary movement and submovement phases in five C6 tetraplegic and five control participants. Aiming movements were performed in two directions (20 cm away or toward), with or without vision. Trials that contained a submovement phase (i.e., discontinuity in velocity, acceleration or jerk) were identified. Discrete kinematic variables were then extracted on the primary and submovements phases. The presence of submovements did not differ between the tetraplegic (68%) and control (57%) groups, and almost all submovements resulted from acceleration and jerk discontinuities. Tetraplegics tended to make a smaller amplitude primary movement, which had lower peak velocity and greater spatial variability at peak velocity. This was followed by a larger amplitude and longer duration secondary submovement. Peak velocity of primary movement was not related to submovement incidence. Together, the primary and submovement phases of both groups were equally effective in reducing end-point error. C6 tetraplegic participants exhibit some subtle differences in measures of motor behaviour compared to control participants, but importantly feedforward and feedback processes work effectively in combination to achieve accurate goal-directed aiming.


Geographic distribution of schistosomiasis and soil-transmitted helminths in Western Kenya: implications for anthelminthic mass treatment.
A survey of 1,246 children 10-12 years old in 32 primary schools in Kenya near Lake Victoria was conducted to determine prevalence and distribution of schistosome and geohelminth infections. Stool and urine samples were collected and examined for eggs of Schistosoma mansoni, S. haematobium, and intestinal helminths. A questionnaire was used to obtain demographic information and to quantify exposure to surface waters. Houses, schools, and water sources were mapped using a geographic information system. The mean school prevalence of S. mansoni infection was 16.3% (range = 0-80%). Proximity to the lake (r = 0.89, P < 0.001) and contact with lake water were associated with infection, as were specific water-related activities including swimming, fishing, and collecting water. Sixty-three percent of students were infected with one or more other geohelminths and these infections were more homogenously distributed. The separate distributions of schistosome and geohelminth infections have important implications for combined mass-treatment programs.


The modification of attentional bias to emotional information: A review of the techniques, mechanisms, and relevance to emotional disorders.
A negative bias in the deployment of attention to emotional stimuli is commonly found in both anxiety and depression. Recent work has highlighted that such biases are causally related to emotional vulnerability, suggesting that interventions that ameliorate them may be therapeutic. Here, we review the evidence that attentional bias can be modified using both pharmacological and psychological interventions. We highlight the behavioral and neuroimaging studies that suggest that these interventions impact upon attention via alteration of distinct neural mechanisms. Specifically, pharmacological interventions appear to influence the initial deployment of attention via an effect on the amygdala-based stimulus appraisal system, whereas psychological interventions influence attention at later time points and may alter activity in the lateral prefrontal cortex. Finally, we suggest a conceptual framework that embraces both pharmacological and psychological approaches and consider the possible implications of this work for future research and treatment development.


Bioavailability of zinc in Wistar rats fed with rice fortified with zinc oxide.
The study of zinc bioavailability in foods is important because this mineral intake does not meet the recommended doses for some population groups. Also, the presence of dietary factors that reduce zinc absorption contributes to its deficiency. Rice fortified with micronutrients (Ultra Rice®) is a viable alternative for fortification since this cereal is already inserted into the population habit. The aim of this study was to evaluate the bioavailability of zinc (Zn) in rice fortified with zinc oxide. During 42 days, rats were divided into four groups and fed with diets containing two different sources of Zn (test diet: UR® fortified with zinc oxide, or control diet: zinc carbonate (ZnCO3)), supplying 50% or 100%, respectively, of the recommendations of this mineral for animals. Weight gain, food intake, feed efficiency ratio, weight, thickness and length of femur; retention of zinc, calcium (Ca) and magnesium (Mg) in the femur and the concentrations of Zn in femur, plasma and erythrocytes were evaluated. Control diet showed higher weight gain, feed efficiency ratio, retention of Zn and Zn concentration in the femur (p < 0.05). However, no differences were observed (p > 0.05) for dietary intake, length and thickness of the femur, erythrocyte and plasmatic Zn between groups. Although rice fortified with zinc oxide showed a lower bioavailability compared to ZnCO3, this food can be a viable alternative to be used as a vehicle for fortification.


Thearubigins protect against acetaminophen-induced hepatic and renal injury in mice: biochemical, histopathological, immunohistochemical, and flow cytometry study.
Acetaminophen toxicity is used as a model for studying chemical toxicity. N-acetylcysteine (NAC) is used for the treatment of hepatotoxicity; however, there is no specific therapy for nephrotoxicity. This study was designed to investigate the potential protective effect of black tea extract (BTE) and its main phenolic pigment, thearubigins (TRs), against acetaminophen (APAP)-induced hepatic and renal injury in mice. Besides control groups, six groups (n = 8) were given intraperitoneally APAP (300 mg/kg) and then after 1.5 hours were treated intraperitoneally as follows: NAC (318 mg/kg), BTE (3%, 4.5%), and TRs (50, 60, and 70 mg/kg). Six hours post-APAP injection, blood was collected for biochemical measurements. Later, liver and kidneys were removed for histopathological, immunohistochemical, and flow cytometry studies. APAP increased alanine aminotransferase and malondialdehyde and decreased glutathione levels in blood. Treatments significantly reversed these changes mostly with NAC and TRs70. TRs showed dose-dependent significant differences. The APAP-induced central lobular hepatic necrosis and increased TUNEL positivity were mild with co-administration of NAC and TRs (60, 70) while moderate with co-administration of BTE (3, 4.5) and TRs50. The APAP-increased serum creatinine level was significantly reversed by treatments (mostly TRs60, 70). The APAP-induced renal tubular epithelial degeneration and necrosis were mild with co-administration of TRs (60, 70) while moderate with co-administration of NAC, BTE (3, 4.5), and TRs50. The APAP-accumulated apoptotic cells in sub-G1 phase were significantly decreased by treatments, mostly by NAC and TRs70 in the liver and TRs (60, 70) in kidneys. Thearubigins protected against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice possibly through their antioxidant activity.


Formation and Dynamics of Waves in a Cortical Model of Cholinergic Modulation.
Acetylcholine (ACh) is a regulator of neural excitability and one of the neurochemical substrates of sleep. Amongst the cellular effects induced by cholinergic modulation are a reduction in spike-frequency adaptation (SFA) and a shift in the phase response curve (PRC). We demonstrate in a biophysical model how changes in neural excitability and network structure interact to create three distinct functional regimes: localized asynchronous, traveling asynchronous, and traveling synchronous. Our results qualitatively match those observed experimentally. Cortical activity during slow wave sleep (SWS) differs from that during REM sleep or waking states. During SWS there are traveling patterns of activity in the cortex; in other states stationary patterns occur. Our model is a network composed of Hodgkin-Huxley type neurons with a M-current regulated by ACh. Regulation of ACh level can account for dynamical changes between functional regimes. Reduction of the magnitude of this current recreates the reduction in SFA the shift from a type 2 to a type 1 PRC observed in the presence of ACh. When SFA is minimal (in waking or REM sleep state, high ACh) patterns of activity are localized and easily pinned by network inhomogeneities. When SFA is present (decreasing ACh), traveling waves of activity naturally arise. A further decrease in ACh leads to a high degree of synchrony within traveling waves. We also show that the level of ACh determines how sensitive network activity is to synaptic heterogeneity. These regimes may have a profound functional significance as stationary patterns may play a role in the proper encoding of external input as memory and traveling waves could lead to synaptic regularization, giving unique insights into the role and significance of ACh in determining patterns of cortical activity and functional differences arising from the patterns.


Estimating view parameters from random projections for Tomography using spherical MDS.
During the past decade, the computed tomography has been successfully applied to various fields especially in medicine. The estimation of view angles for projections is necessary in some special applications of tomography, for example, the structuring of viruses using electron microscopy and the compensation of the patient's motion over long scanning period. This work introduces a novel approach, based on the spherical multidimensional scaling (sMDS), which transforms the problem of the angle estimation to a sphere constrained embedding problem. The proposed approach views each projection as a high dimensional vector with dimensionality equal to the number of sampling points on the projection. By using SMDS, then each projection vector is embedded onto a 1D sphere which parameterizes the projection with respect to view angles in a globally consistent manner. The parameterized projections are used for the final reconstruction of the image through the inverse radon transform. The entire reconstruction process is non-iterative and computationally efficient. The effectiveness of the sMDS is verified with various experiments, including the evaluation of the reconstruction quality from different number of projections and resistance to different noise levels. The experimental results demonstrate the efficiency of the proposed method. Our study provides an effective technique for the solution of 2D tomography with unknown acquisition view angles. The proposed method will be extended to three dimensional reconstructions in our future work. All materials, including source code and demos, are available on https://engineering.purdue.edu/PRECISE/SMDS.


Treatment of postmenopausal osteoporosis with delayed-release risedronate 35 mg weekly for 2 years.
Bone mineral density response to once weekly delayed-release formulation of risedronate, given before or following breakfast, was non-inferior to that seen with traditional immediate-release risedronate given daily before breakfast. Delayed-release risedronate is a convenient dosing regimen for oral bisphosphonate therapy that might avoid poor compliance. This 2-year, randomized, controlled, non-inferiority study assessed the efficacy and safety of a delayed-release (DR) 35-mg weekly oral formulation of risedronate that allows subjects to take their weekly risedronate dose before or immediately after breakfast. Results from the first year of the study were published previously (McClung et al. Osteoporos Int 23(1):267-276, 2012); we now report the final results after 2 years. Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5 mg immediate-release (IR) daily (n = 307) at least 30 min before breakfast, or risedronate 35 mg DR weekly, either immediately following breakfast (FB, n = 307) or at least 30 min before breakfast (BB, n = 308). Bone mineral density (BMD), bone turnover markers (BTMs), fractures, adverse events, and bone histomorphometry were evaluated. A total of 248 subjects (80.8 %) in the IR daily group, 234 subjects (76.2 %) in the DR FB weekly group, and 240 subjects (77.9 %) in the DR BB weekly group completed the 2-year study. After 2 years of treatment, BMD increases at the lumbar spine and total hip with the weekly DR doses similar to or greater than that with the IR daily dose. Decreases in BTMs were similar or significantly lower in the DR groups. Bone histomorphometry results did not differ among the DR weekly and the IR daily formulations. The three regimens were similarly well tolerated. Risedronate 35 mg DR weekly is as effective and as well tolerated as risedronate 5 mg IR daily, and will allow subjects to take their weekly risedronate dose immediately after breakfast.


Motion detection and motion verbs: language affects low-level visual perception.
Recent theories propose that semantic representation and sensorimotor processing have a common substrate via simulation. We tested the prediction that comprehension interacts with perception, using a standard psychophysics methodology. While passively listening to verbs that referred to upward or downward motion, and to control verbs that did not refer to motion, 20 subjects performed a motion-detection task, indicating whether or not they saw motion in visual stimuli containing threshold levels of coherent vertical motion. A signal detection analysis revealed that when verbs were directionally incongruent with the motion signal, perceptual sensitivity was impaired. Word comprehension also affected decision criteria and reaction times, but in different ways. The results are discussed with reference to existing explanations of embodied processing and the potential of psychophysical methods for assessing interactions between language and perception.


Brain region-specific gene expression profiles in freshly isolated rat microglia.
Microglia are important cells in the brain that can acquire different morphological and functional phenotypes dependent on the local situation they encounter. Knowledge on the region-specific gene signature of microglia may hold valuable clues for microglial functioning in health and disease, e.g., Parkinson's disease (PD) in which microglial phenotypes differ between affected brain regions. Therefore, we here investigated whether regional differences exist in gene expression profiles of microglia that are isolated from healthy rat brain regions relevant for PD. We used an optimized isolation protocol based on a rapid isolation of microglia from discrete rat gray matter regions using density gradients and fluorescent-activated cell sorting. Application of the present protocol followed by gene expression analysis enabled us to identify subtle differences in region-specific microglial expression profiles and show that the genetic profile of microglia already differs between different brain regions when studied under control conditions. As such, these novel findings imply that brain region-specific microglial gene expression profiles exist that may contribute to the region-specific differences in microglia responsivity during disease conditions, such as seen in, e.g., PD.


Adjunctive psychotherapy for bipolar disorder: state of the evidence.
Psychotherapy has long been recommended as adjunctive to pharmacotherapy for bipolar disorder, but it is unclear which interventions are effective for which patients, over what intervals, and for what domains of outcome. This article reviews randomized trials of adjunctive psychotherapy for bipolar disorder. Eighteen trials of individual and group psychoeducation, systematic care, family therapy, interpersonal therapy, and cognitive-behavioral therapy are described. Relevant outcome variables include time to recovery, recurrence, duration of episodes, symptom severity, and psychosocial functioning. The effects of the treatment modalities varied according to the clinical condition of patients at the time of random assignment and the polarity of symptoms at follow-up. Family therapy, interpersonal therapy, and systematic care appeared to be most effective in preventing recurrences when initiated after an acute episode, whereas cognitive-behavioral therapy and group psychoeducation appeared to be most effective when initiated during a period of recovery. Individual psychoeducational and systematic care programs were more effective for manic than depressive symptoms, whereas family therapy and cognitive-behavioral therapy were more effective for depressive than manic symptoms. Adjunctive psychotherapy enhances the symptomatic and functional outcomes of bipolar disorder over 2-year periods. The various modalities differ in content, structure, and associated mediating mechanisms. Treatments that emphasize medication adherence and early recognition of mood symptoms have stronger effects on mania, whereas treatments that emphasize cognitive and interpersonal coping strategies have stronger effects on depression. The placement of psychotherapy within chronic care algorithms and its role as a preventative agent in the early stages of the disorder deserve investigation.


Effect of BMI on prediction of accelerometry-based energy expenditure in youth.
The objective of this study is to determine the effect of body mass index (BMI) on level of agreement between six previously established prediction equations for three commonly used accelerometers to predict summary measures of energy expenditure (EE) in youth. One hundred and thirty-one youth between the ages of 10-17 yr and BMI from 15 to 44 kg·m were outfitted with hip-worn ActiGraph GT1M (Pensacola, FL), Actical (MiniMiter/Respironics, Bend, OR), and RT3 (StayHealthy, Monrovia, CA) accelerometers and spent approximately 24 h in a whole-room indirect calorimeter while performing structured and self-selected activities. Five commonly used regression and one propriety equations for each device were used to predict the minute-to-minute EE (normalized to METs), daily physical activity level (PAL), and time spent in sedentary, light, moderate, and vigorous physical activity intensity categories. The calculated values were compared with criterion measurements obtained from the room calorimeter. All predictive equations, except RT3, significantly over- or underpredicted daily PAL (P < 0.001), with large discrepancies observed in the estimate of sedentary and light activity. Discrepancies between actual and estimated PAL ranged from 0.05 to 0.68. In addition, BMI represented a modifier for two ActiGraph predictive equations (AG1 and AG2), affecting the accuracy of physical activity-related EE predictions. ActiGraph (AG3) and the RT3 closely predicted overall PAL (within 4.2% and 6.8%, respectively) as a group. When adjusting for age, sex, and ethnicity, Actical (AC1 and AC2) and ActiGraph (AG3) were not influenced by BMI. However, a gap between some hip-worn accelerometer predictive and regression equations was demonstrated compared with both criterion measurement and each other, which poses a potential difficulty for interstudy (e.g., different accelerometers) and intrastudy (e.g., BMI and adiposity) comparisons.


Molecular and Morphological Characterization of Tylenchus Zeae n. Sp. (Nematoda: Tylenchida) from Corn (Zea Mays) in South Carolina.
Specimens of a tylenchid nematode were recovered in 2019 from soil samples collected from a corn field, located in Pickens County, South Carolina, USA. A moderate number of Tylenchus sp. adults (females and males) were recovered. Extracted nematodes were examined morphologically and molecularly for species identification, which indicated that the specimens of the tylenchid adults were a new species, described herein as Tylenchus zeae n. sp. Morphological examination and the morphometric details of the specimens were very close to the original descriptions of Tylenchus sherianus and T. rex. However, females of the new species can be differentiated from these species by body shape and length, shape of excretory duct, distance between anterior end and esophageal intestinal valve, and a few other characteristics given in the diagnosis. Males of the new species can be differentiated from the two closely related species by tail, spicules, and gubernaculum length. Cryo-scanning electron microscopy confirmed head bearing five or six annules; four to six cephalic sensilla represented by small pits at the rounded corners of the labial plate; a small, round oral plate; and a large, pit-like amphidial opening confined to the labial plate and extending three to four annules beyond it. Phylogenetic analysis of 18S rRNA gene sequences placed Tylenchus zeae n. sp. in a clade with Tylenchus arcuatus and several Filenchus spp., and the mitochondrial cytochrome oxidase c subunit 1 (COI) gene region separated the new species from T. arcuatus and other tylenchid species. In the 28S tree, T. zeae n. sp. showed a high level of sequence divergence and was positioned outside of the main Tylenchus-Filenchus clade.


Dual effects of glucose on the cytosolic Ca2+ activity of mouse pancreatic beta-cells.
The cytosolic Ca2+ activity of mouse pancreatic beta-cells was studied with the intracellular fluorescent indicator quin2 . When the extracellular Ca2+ concentration was 1.20 mM, the basal cytosolic Ca2+ activity was 162 +/- 9 nM. Stimulation with 20 mM glucose increased this Ca2+ activity by 40%. In the presence of only 0.20 mM Ca2+ or after the addition of the voltage-dependent Ca2+ -channel blocker D-600, glucose had an opposite and more prompt effect in reducing cytosolic Ca2+ by about 15%. It is concluded that an early result of glucose exposure is a lowering of the cytosolic Ca2+ activity and that this effect tends to be masked by a subsequent increase of the Ca2+ activity due to influx of Ca2+ through the voltage-dependent Ca2+ channels.


Clinical Features and Treatment Outcome of Malignant Pleural Mesothelioma.
Malignant pleural mesothelioma is a problematic condition due to poor prognosis and difficulties in management. We evaluated the treatment and outcome of 378 mesothelioma patients referred to 6 Italian Oncology Departments. Demographic and clinical data were collected. Treatment was assessed in terms of chemotherapy (line of treatment, pemetrexed-based regimen, other therapies), surgery, and radiotherapy. Response to therapy, progression-free survival, and overall survival were evaluated. 36 and 342 patients received best supportive care and active treatment, respectively; 86 patients underwent surgery, and 26 received trimodal therapy. Disease control after first-line chemotherapy was achieved in 74.2% of patients (75.7% in patients treated with pemetrexed combined with other drugs and 69% with pemetrexed as monotherapy). The disease control rate was 82.6% in pemetrexed re-challenged individuals. Median survival time was 11.6 months with supportive care, 16.2 months with chemotherapy only, 32.4 months with surgery plus chemotherapy, and 47.2 months with trimodal therapy. A more favorable prognosis was observed in responders to first-line therapy who were then actively treated with second-line (24.8 vs. 11.8 months in non-responders, p < 0.001) and third-line chemotherapy (28.9 vs. 17.8 months in non-responders, p = 0.005). Mesothelioma patients benefited from chemotherapy alone only when retreated in the second line after response to first-line therapy.


Committee Opinion No. 652 Summary: Magnesium Sulfate Use in Obstetrics.
The U.S. Food and Drug Administration advises against the use of magnesium sulfate injections for more than 5-7 days to stop preterm labor in pregnant women. Based on this, the drug classification was changed from Category A to Category D, and the labeling was changed to include this new warning information. However, the U.S. Food and Drug Administration's change in classification addresses an unindicated and nonstandard use of magnesium sulfate in obstetric care. The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine continue to support the short-term (usually less than 48 hours) use of magnesium sulfate in obstetric care for appropriate conditions and for appropriate durations of treatment, which includes the prevention and treatment of seizures in women with preeclampsia or eclampsia, fetal neuroprotection before anticipated early preterm (less than 32 weeks of gestation) delivery, and short-term prolongation of pregnancy (up to 48 hours) to allow for the administration of antenatal corticosteroids in pregnant women who are at risk of preterm delivery within 7 days.


Pathogenicity of Moraxella osloensis, a bacterium associated with the nematode Phasmarhabditis hermaphrodita, to the slug Deroceras reticulatum.
Moraxella osloensis, a gram-negative bacterium, is associated with Phasmarhabditis hermaphrodita, a nematode parasite of slugs. This bacterium-feeding nematode has potential for the biological control of slugs, especially the grey garden slug, Deroceras reticulatum. Infective juveniles of P. hermaphrodita invade the shell cavity of the slug, develop into self-fertilizing hermaphrodites, and produce progeny, resulting in host death. However, the role of the associated bacterium in the pathogenicity of the nematode to the slug is unknown. We discovered that M. osloensis alone is pathogenic to D. reticulatum after injection into the shell cavity or hemocoel of the slug. The bacteria from 60-h cultures were more pathogenic than the bacteria from 40-h cultures, as indicated by the higher and more rapid mortality of the slugs injected with the former. Coinjection of penicillin and streptomycin with the 60-h bacterial culture reduced its pathogenicity to the slug. Further work suggested that the reduction and loss of pathogenicity of the aged infective juveniles of P. hermaphrodita to D. reticulatum result from the loss of M. osloensis from the aged nematodes. Also, axenic J1/J2 nematodes were nonpathogenic after injection into the shell cavity. Therefore, we conclude that the bacterium is the sole killing agent of D. reticulatum in the nematode-bacterium complex and that P. hermaphrodita acts only as a vector to transport the bacterium into the shell cavity of the slug. The identification of the toxic metabolites produced by M. osloensis is being pursued.


ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.
Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.


Can early life-stages of the marine fish Sparus aurata be useful for the evaluation of the toxicity of linear alkylbenzene sulphonates homologues (LAS C10-C14) and commercial LAS?
Most commercial household cleaning agents and personal care products contain the anionic surfactant linear alkylbenzene sulphonates (LAS) as the active compound. After their use they are discharged, theoretically after adequate wastewater treatment, into receiving waters finally reaching estuaries and coastal waters. Laboratory toxicity tests are useful tools in determining at which concentration a certain wastewater compound becomes hazardous for an existing group of organisms. Early life-stage toxicity tests include exposure during the most sensitive development period of the organism. In fish, this type of assay has shown to predict accurately maximum acceptable toxicant concentration (MATC) values (comprised in the range defined by the NOEC and LOEC) in fish early life-stage tests. For this reason, larvae of the seabream, Sparus aurata, were exposed to increasing concentrations of LAS homologues (C10-C14) and commercial LAS. Obtained LC50 values ranged between 0.1 and 3.0 mg l(-1) and were compared with LC50 values of previous hatching experiments with the same species. Larvae proved to be more sensitive to LAS exposure of individual homologues than eggs, except in the case of commercial LAS. LC50 values can be directly employed to determine their potential risk in a concrete environment with known pollutant concentrations. Dividing the LC50 value with the found homologue concentration and extrapolating with certain security factors proposed by different environmental organisms, potentially hazardous pollutant concentrations may be detected. Average estuarine or coastal LAS concentrations are generally below toxicity limits for this kind of organism, considering that the average alkyl chain length of commercial LAS is 11.6 carbon atoms.


Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features.
GRN, the gene coding for the progranulin (PGRN) protein, was recognized as a gene linked to frontotemporal lobar degeneration (FTLD). The first mutations identified were null mutations giving rise to haploinsufficiency. Missense mutations were subsequently detected, but only a small subset has been functionally investigated. We identified missense mutations (C105Y, A199V, and R298H) in FTLD cases with family history and/or with low plasma PGRN levels. The aim of this study was to determine their pathogenicity. We performed functional studies, analyzing PGRN expression, secretion, and cleavage by elastase. GRN C105Y affected both secretion and elastase cleavage, likely representing a pathogenic mutation. GRN A199V did not alter the physiological properties of PGRN and GRN R298H produced only moderate effects on PGRN secretion, indicating that their pathogenicity is uncertain. In the absence of strong segregation data and neuropathological examinations, genetic, biomarker, and functional studies can be applied to an algorithm to assess the likelihood of pathogenicity for a mutation. This information can improve our understanding of the complex mechanisms by which GRN mutations lead to FTLD.


Correlation of Caveolin-1 Expression with Prognosis in Patients with Gastric Cancer after Gastrectomy.
Upregulation of caveolin-1 (Cav-1) expression is correlated with histopathological grade and poor prognosis in several human cancers. However, in gastric cancer, its clinical utility as a useful prognostic molecular marker remains unclear. The prognostic importance of Cav-1 expression was retrospectively analyzed by immunohistochemistry in 148 patients with gastric cancer who had undergone radical gastrectomy. Cav-1 expression was positive in 23 (15.5%) patients and negative in 125 (84.5%) patients. Tumor location, tumor grade, lymph node involvement, pT stage, pTNM stage, and the presence of recurrence were found to be significantly associated with Cav-1 expression. The median disease-free survival (DFS) of patients with negative Cav-1 expression was significantly better than that of patients with positive Cav-1 expression (not reached vs. 10.2 months, p < 0.001). Moreover, patients with positive Cav-1 expression had a worse median overall survival (OS) compared to patients with negative Cav-1 expression (14.2 vs. 40.3 months, p = 0.004). In the multivariate analysis, Cav-1 expression (positive vs. negative) was an independent prognostic factor for DFS (p < 0.001, hazard ratio (HR) 2.58) and OS (p = 0.031, HR 1.87), as was lymph node metastasis. Our results suggest that positive Cav-1 expression is associated with progression and poor prognosis in gastric cancer patients after radical gastrectomy. Targeting Cav-1 would be a potential option for future gastric cancer treatment.


Localization of nitric oxide synthase-like immunoreactivity in the developing nervous system of the snail Ilyanassa obsoleta.
Production of nitric oxide (NO), an evolutionarily conserved, intercellular signaling molecule, appears to be required for the maintenance of the larval state in the gastropod mollusc Ilyanassa obsoleta. Pharmacological inactivation of endogenous nitric oxide synthase (NOS), the enzyme that generates NO, can trigger metamorphosis in physiologically competent larvae of this species. Neuropils in the brains of these competent larvae display histochemical reactivity for NADPH diaphorase (NADPHd), an indication of neuronal NOS activity. The intensity of NADPHd staining is greatest in the neuropil of the apical ganglion (AG), a region of the brain that contains the apical sensory organ and that innervates the bilobed ciliated velum, the larval swimming and feeding organ. Once metamorphosis is initiated, the intensity of NADPHd staining in the AG and presumably, concomitant NO production, decline. The AG is finally lost by the end of larval metamorphosis, some 4 days after induction. To determine if the neurons of the AG are a source of larval NO, we conducted immunocytochemical studies on larval Ilyanassa with commercially available antibodies to mammalian neuronal NOS. We localized NOS-like immunoreactivity (NOS-IR) to 3 populations of cells in competent larvae: somata of the AG and putative sensory neurons in the edge of the mantle and foot. Immunocytochemistry on pre-competent larvae demonstrated that numbers of NOS-IR cells in the AG increase throughout the planktonic larval stage.


Interaction of depression and bereavement on mental health in the elderly.
Three hundred ninety-three elderly adults aged 55 and older were divided into 1 of 9 subgroups in a 3 (bereavement group: survivors of spouses who died by natural death or by suicide and nonbereaved control Ss) x 3 (depression group: none, mild, and moderate-severe) design over 4 times of measurement--1 month, 6 months, 1 year, and 2.5 years after death of spouse. Significant Bereavement x Depression Group effects were obtained on Brief Symptom Inventory scores. The moderate-severe depression/suicide subgroup had the greatest psychiatric complications with bereavement. Results indicated that elderly persons with significant clinical depression at the time of a spouse's death were at significant risk for psychological complications during the bereavement process, and survivors of spouses who had committed suicide were even more at risk within the greatest depression group.