GIMSAN: a Gibbs motif finder with significance analysis.
We present GIMSAN (GIbbsMarkov with Significance ANalysis): a novel tool for de novo motif finding. GIMSAN combines GibbsMarkov, our variant of the Gibbs Sampler, described here for the first time, with our recently introduced significance analysis. GIMSAN is currently available as a web application and a stand-alone application on Unix and PBS (Portable Batch System) cluster through links from http://www.cs.cornell.edu/~keich.


Charge pumping with finger capacitance for body sensor energy harvesting.
Sensors are becoming ubiquitous and increasingly integrated with and on the human body; powering such "body network" devices remains an outstanding problem. In this paper, we demonstrate a touch interrogation powered energy harvesting system. This system transforms the kinetic energy of a human finger to electric energy, with each tap producing approximately 1 nJ of energy at a storage capacitor. As is well known for touch display devices, the proximity of a finger can alter the effective value of small capacitances; we demonstrate that these capacitance changes can drive a current which is rectified to charge a capacitor. As a demonstration, an untethered circuit charged this way can deliver enough instantaneous power to light a red LED every ~ 10 seconds. This technology illustrates the ability to communicate with and operate low-power sensors with motions already used for interfacing to devices.


Analysis of the willow root system by electrical impedance spectroscopy.
Information on plant roots is increasingly needed for understanding and managing plants under various environmental conditions, including climate change. Several methods have been developed to study fine roots but they are either destructive or cumbersome, or may not be suitable for studies of fine root functionality. Electrical impedance, resistance, and capacitance have been proposed as possible non-destructive measures for studying roots. Their use is limited by a lack of knowledge concerning the electrical circuit of the system. Electrical impedance spectroscopy (EIS) was used for hydroponically raised willows (Salix schwerinii) to estimate the root system size. The impedance spectra were investigated in three experimental set-ups and the corresponding appropriate lumped models were formulated. The fit of the proposed lumped models with the measured impedance spectra data was good. The model parameters were correlated with the contact area of the roots and/or stems raised in the hydroponic solution. The EIS method proved a useful non-destructive method for assessing root surface area. This work may be considered to be a new methodological contribution to understanding root systems and their functions in a non-destructive manner.


Function of Escherichia coli biotin carboxylase requires catalytic activity of both subunits of the homodimer.
Biotin carboxylase catalyzes the ATP-dependent carboxylation of biotin and is one component of the multienzyme complex acetyl-CoA carboxylase that catalyzes the first committed step in fatty acid synthesis. The Escherichia coli biotin carboxylase is readily isolated from the other components of the acetyl-CoA carboxylase complex such that enzymatic activity is retained. The three-dimensional structure of biotin carboxylase, determined by x-ray crystallography, demonstrated that the enzyme is a homodimer consisting of two active sites in which each subunit contains a complete active site. To understand how each subunit contributes to the overall function of biotin carboxylase, we made hybrid molecules in which one subunit had a wild-type active site, and the other subunit contained an active site mutation known to significantly affect the activity of the enzyme. One of the two genes encoded a poly-histidine tag at its N terminus, whereas the other gene had an N-terminal FLAG epitope tag. The two genes were assembled into a mini-operon that was induced to give high level expression of both enzymes. "Hybrid" dimers composed of one subunit with a wild-type active site and a second subunit having a mutant active site were obtained by sequential chromatographic steps on columns of immobilized nickel chelate and anti-FLAG affinity matrices. In vitro kinetic studies of biotin carboxylase dimers in which both subunits were wild type revealed that the presence of the N-terminal tags did not alter the activity of the enzyme. However, kinetic assays of hybrid dimer biotin carboxylase molecules in which one subunit had an active site mutation (R292A, N290A, K238Q, or E288K) and the other subunit had a wild-type active site resulted in 39-, 28-, 94-, and 285-fold decreases in the activity of these enzymes, respectively. The dominant negative effects of these mutant subunits were also detected in vivo by monitoring the rate of fatty acid biosynthesis by [(14)C]acetate labeling of cellular lipids. Expression of the mutant biotin carboxylase genes from an inducible arabinose promoter resulted in a significantly reduced rate of fatty acid synthesis relative to the same strain that expressed the wild type gene. Thus, both the in vitro and in vivo data indicate that both subunits of biotin carboxylase are required for activity and that the two subunits must be in communication during enzyme function.


Relationships between carcinogenesis in vivo and alkylation and solvolysis in vitro.
Carcinogenic bromomethyl- and chloromethylanthracenes and benz(a)anthracenes were found to react rapidly in vitro with DNA under physiological conditions and to varying degrees with nucleotides and nucleosides. The compounds were assayed for production of lung adenomas in strain A mice and relative carcinogenic potencies were compared with in vitro alkylation and with in vitro solvolysis rates. Success at quantitative correlation with carcinogenic potency was not obtained with either in vitro parameter. However, comparable noncarcinogenic compounds lacked their marked in vitro reactivity with DNA. Some potential polynuclear electrophiles, including chloromethyl derivatives of acridine and benz(c)acridine, a hydroxymethyl and an acetoxymethyl derivative of benz(a)anthracene, an acetoxymethylanthracene, and an acridinylglycine ester, were found not to be carcinogenic in the lung adenoma test.


Exercise-thermoregulatory stress and increased plasma beta-endorphin/beta-lipotropin in humans.
Six adult male volunteers of similar body composition and physical fitness were tested to determine plasma immunoreactive beta-endorphin/beta-lipotropin (beta-EN/beta-LPH) response under three exercise-thermoregulatory stress conditions. The experimental protocol consisted of 120 min of stationary upright cycling at 50% VO2max under neutral (24 degrees C, 50% rh)-euhydration (NE), hot (35 degrees C, 50% RH)-euhydration (HE), and hot-dehydration (HD) environmental conditions. beta-EN/beta-LPH was calculated by radioimmunoassay at -30-min, 0-min, and 15-min intervals thereafter. Change in plasma volume (delta PV) was measured to determine its effect on beta-EN/beta-LPH concentration. Preexercise beta-EN/beta-LPH levels averaged 23.7 +/- 2.6 pg X ml-1 in all conditions. The greatest beta-EN/beta-LPH response occurred at 105 min in HD conditions when levels rose to 43.2 +/- 6.9 pg X ml-1. Exercise in HD and HE conditions resulted in significantly (P less than 0.05) elevated beta-EN/beta-LPH above levels observed in NE. delta PV did not account for more than 10% of beta-EN/beta-LPH changes at any time interval. The beta-EN/beta-LPH response pattern closely paralleled rectal temperature changes in all conditions. These data suggest that conditions of increasing exercise thermoregulatory stress are associated with increasing peripheral beta-endorphin concentration.


What Are the Key Elements of Educational Interventions for Lay Carers of Patients With Advanced Disease? A Systematic Literature Search and Narrative Review of Structural Components, Processes and Modes of Delivery.
Educating carers about symptom management may help meet patient and carer needs in relation to distressing symptoms in advanced disease. Reviews of the effectiveness of carer interventions exist, but few have focused on educational interventions and none on the key elements that comprise them but which could inform evidence-based design. To identify the key elements (structural components, processes, and delivery modes) of educational interventions for carers of patients with advanced disease. We systematically searched seven databases, applied inclusion and exclusion criteria, conducted quality appraisal, extracted data, and performed a narrative analysis. We included 62 articles related to 49 interventions. Two main delivery modes were identified: personnel-delivered interventions and stand-alone resources. Personnel-delivered interventions targeted individuals or groups, the former conducted at single or multiple time points, and the latter delivered as series. Just more than half targeted carers rather than patient-carer dyads. Most were developed for cancer; few focused purely on symptom management. Stand-alone resources were rare. Methods to evaluate interventions ranged from postintervention evaluations to fully powered randomized controlled trials but of variable quality. Published evaluations of educational interventions for carers in advanced disease are limited, particularly for non-cancer conditions. Key elements for consideration in developing such interventions were identified; however, lack of reporting of reasons for nonparticipation or dropout from interventions limits understanding of the contribution of these elements to interventions' effectiveness. When developing personnel-delivered interventions for carers in advanced disease, consideration of the disease (and, therefore, caring) trajectory, intervention accessibility (timing, location, and transport), and respite provision may be helpful.


Visualizing Pure Quantum Turbulence in Superfluid 3He: Andreev Reflection and its Spectral Properties.
Superfluid 3He-B in the zero-temperature limit offers a unique means of studying quantum turbulence by the Andreev reflection of quasiparticle excitations by the vortex flow fields. We validate the experimental visualization of turbulence in 3He-B by showing the relation between the vortex-line density and the Andreev reflectance of the vortex tangle in the first simulations of the Andreev reflectance by a realistic 3D vortex tangle, and comparing the results with the first experimental measurements able to probe quantum turbulence on length scales smaller than the intervortex separation.


Imbalanced Data Classification via Cooperative Interaction Between Classifier and Generator.
Learning classifiers with imbalanced data can be strongly biased toward the majority class. To address this issue, several methods have been proposed using generative adversarial networks (GANs). Existing GAN-based methods, however, do not effectively utilize the relationship between a classifier and a generator. This article proposes a novel three-player structure consisting of a discriminator, a generator, and a classifier, along with decision boundary regularization. Our method is distinctive in which the generator is trained in cooperation with the classifier to provide minority samples that gradually expand the minority decision region, improving performance for imbalanced data classification. The proposed method outperforms the existing methods on real data sets as well as synthetic imbalanced data sets.


Traumatic brain injury by a firearm projectile: a 16 years experience of the neurosurgery service of Santa Casa de São Paulo.
To evaluate the epidemiology and prognostic factors associated with traumatic brain injury by a firearm projectile (FAP). We reviewed the medical records of 181 patients in the Department of Neurosurgery of Santa Casa de São Paulo (São Paulo Holy House) diagnosed with traumatic brain injury (TBI) resulting from FAP from January 1991 to December 2005. Were evaluated: age, sex, Glasgow Coma Scale (GCS) on admission, brain region affected by the FAP, type of injury (penetrating or tangential), type of treatment and outcome, based on GCS. The relationship between therapeutic strategy and outcome was analyzed using the Chi-square test with Yates correction. The Fisher test was used to verify the same correlation individually for each group stratified by GCS on admission. Of the 181 patients, 85% were male (n = 154) and 15% female (n = 27). Mean age was 31.04 years (± 10.98). The mostly affected brain region was the frontal lobe (27.6%), followed by temporal (24.86%) and occipital (16.57%) ones. Of the TBIs evaluated, 16% were tangential and 84%, penetrating. Patients undergoing surgical treatment had better outcome than those submitted to conservative treatment, and patients who were more severe at admission (GCS 3-8) have better results with the neurosurgical procedure.


Propofol suppresses invasion and induces apoptosis of osteosarcoma cell in vitro via downregulation of TGF-β1 expression.
Osteosarcoma (OS) is the most common malignant tumor of the bone, with a high mortality rate and poor prognosis. Propofol has been proposed to play a role of antitumor in various cancers. However, the functions and mechanisms of propofol in OS is still not clear. The different concentrations of propofol were co-incubated with osteosarcoma MG-63 lines for 72 hrs. Cell proliferation, apoptosis, and invasion were detected by MTT assay, Flow cytometry analysis, and Matrigel invasion assay. Western blot was used to detect the TGF-β1 protein levels. MG-63 cells were treated with human recombinant TGF-β1 (rh TGF-β1) to assess the role of TGF-β1 in propofol-induced anti-tumor activity. Propofol significantly inhibited cell proliferation and invasion and promoted apoptosis of MG-63 lines cells. Propofol also efficiently reduced TGF-β1 expression. Moreover, restoration of TGF-β1 by rhTGF-β1 treatment reversed the effects of propofol on the biological behavior of OS cells. Propofol can effectively inhibit proliferation and invasion and induce apoptosis of OS cells through, at least partly, downregulation of TGF-β1 expression.


Eye trauma in the workplace: about 110 cases.
To evaluate the epidemiological and clinical characteristics of occupational ocular trauma in order to determine prognostic factors of these eye accidents. This is a cross-sectional study of 110 patients who were victims of occupational accidents that caused eye trauma. They were treated in Department A, Hédi Rais Ophthalmology Institute in Tunis, between March 2018 and March 2019. We collected information from the patients' files according to a standard form. The data collected were: patient demographics, circumstances of the accident, consultation time, clinical examination data and temporary disability. The data were entered and statistically analysed using SPSS 20.0 software. We used the "t-student" and the "chi-deux" as statistical tests. The significance level was set at 5%. We collected 120 eyes from 110 patients. The average age was 37 years with a male predominance. Almost half of the patients (45.4%) were construction workers. In 34% of the cases, a metal object was responsible for the trauma. Projection of superficial foreign bodies was noted in 44.3% of cases and contusion in 34% of cases. The average visual acuity of the traumatised eye was 8/10 and depended on the nature of the trauma. Palpebral ecchymosis (30.9%) and conjunctival hyperhaemia (48.5%) were the most common bio microscopic signs found. Eight cases of corneal wounds were noted, three cases of corneo-scleral wounds associated in 2 cases with an intra-ocular foreign body as well as three cases of bursting of the globe were noted. The risk factors of poor prognosis found were: male sex (p=0.042), the mechanism of the trauma: projection of a foreign body (p=0.0052) and the following occupations: bricklayer, mechanic and construction worker (p<0.0001). The average temporary disability caused by eye trauma was 5 days with a standard deviation of 6 days. Our study described the severity of eye injuries related to work-related accidents. The most important prognostic factors will be the male gender, the mechanism of the trauma and the occupation. These traumas represent a major public health problem. Prevention is the only way to improve the final prognosis.


Digital camera system to perform infrared photography of iris transillumination.
The authors modified a standard digital camera by replacing an internal infrared-blocking filter that allowed photography of iris transillumination defects. Visible and infrared light was produced with a halogen fiberoptic light source that was placed against the inferior eyelid and directed perpendicular to the globe. To obtain images, the camera was mounted to a tabletop tripod placed 3 to 5 in from a chin/headrest apparatus. Images were downloaded onto a personal computer via software and accessories provided by the camera manufacturer. This technique, which is convenient and produces high quality, color images, can highlight details of the normal and pathologic iris. It may have significant utility in clinical research as well as routine clinical care.


Elevated tissue factor levels in leukemic cell homogenate.
Tissue factor (TF) antigen and activity were measured in leukemic cell homogenates. In leukemic cell homogenate, especially that of acute promyelocytic leukemia (APL), both TF antigen and activity were significantly higher than these levels in the mononuclear cells obtained from healthy volunteers. Both TF antigen and activity were significantly higher in myelocytic leukemia than in lymphocytic leukemia cells. In leukemic cell homogenates, there was a close correlation between TF antigen and TF activity. The TF activity/TF antigen ratio was significantly higher in myelocytic leukemia than in lymphocytic leukemia cells. As the TF activity was not increased in lymphocytic leukemia cell homogenates to which were added phospholipids, the decrease in TF activity in lymphocytic leukemia might not be due to phospholipid in the leukemic cell membrane. Values for TF activity, TF antigen, and the TF activity/TF antigen ratio in leukemic cell homogenate from patients with disseminated intravascular coagulation (DIC) were significantly higher than those in patients without DIC. Therefore, the measurement of TF antigen and activity in leukemic cells could be useful for the prediction of DIC.


Readmission After Surgical Resection for Colon and Rectal Cancers: A Retrospective Cohort Study.
Colorectal adenocarcinoma is a leading cause of cancer mortality worldwide, often requiring patients to undergo anatomy-altering surgical interventions leading to increased postoperative readmission. Hospital readmission rates have been correlated with increased mortality. Therefore, it is important to understand the association between 30-day readmission rates and mortality as well as the factors associated with increased readmission rates. This is a retrospective review utilizing data from the National Cancer Database. Our primary outcomes of interest were 30- and 90-day mortality rates. Our primary independent variable of interest was 30-day readmission. Between 2010 and 2016, 207 299 patients underwent surgery for rectal cancer and 754 895 for colon cancer. The readmission rates within 30 days of discharge were 5.4% and 5.5% for patients after surgery for rectal or colon cancer, respectively. 30-day readmission was not associated with 30-day mortality, but it was independently associated with increased 90-day mortality and inferior long-term survival for both cohorts (P = .001). Independent risk factors significantly associated with increased readmission included race, non-private insurance, and low income. This study provides a large, up-to-date, and comprehensive analysis of readmission rates for colon and rectal cancers. We demonstrate that socioeconomic factors are associated with increased 30-day readmission. 30-day readmission is also independently associated with increased 90-day mortality as well as lower overall survival rates. Our study supports the need for implementation of programs that support patients of lower socioeconomic status undergoing surgery to further decrease readmission rates and mortality.


The surgical first assistant: are you compliant?
It is over a century now since the importance of the knowledge and skills of the surgeon's assistant were first considered (Brickner 1907). More recently both the Royal College of Surgeons of England (RCSE 1999, 2011) and the Perioperative Care Collaborative (PCC 2007) have reviewed the role of the non-medically qualified surgical assistant. In 2012, the PCC published their review of the surgical first assistant (SFA) role in response to a call by the RCSE for greater clarity in relation to the plethora of titles afforded to non-medical surgical assistants (RCSE 2011).


Prevalence and treatment of necrotizing ulcerative gingivitis (NUG) in the British Armed Forces: a case-control study.
Necrotizing ulcerative gingivitis (NUG) has been seen in military populations throughout history. This study aims to determine the prevalence, treatment modality and risk factors associated with NUG in the British Armed Forces. A whole population dataset of the British Armed Forces was searched to determine cases of NUG during the period 1 January to 31 December 2012. Individual case records were identified, and a case-control study undertaken with data gathered and analysed against a randomised control group, matched for age, sex and service. A prevalence rate for NUG of 0.11 % was determined against the whole military population. The majority of cases received (alone or in combination) the following: oral hygiene instruction (66.5 %), antibiotics (64.4 %) and a mouthwash (58.1 %). Of the cases, 48.7 % received debridement. Analgesics were only prescribed in 8.4 % of the cases, and smoking cessation advice was only given in 10.7 % of the cases. Analysis of risk factors against the control group showed an increase in odds ratios for diagnosis of NUG of 3.4 (95 % CI 2.0-5.7) for current smokers and 7.3 (95 % CI 1.9-28.0) for individuals with an overall Basic Periodontal Examination (BPE) score of 3. Whilst NUG is a rare disease, it is evident from this study that it still occurs within the British Armed Forces. A strong association was shown between NUG and current smokers and those cases with an overall BPE score of 3. This study provides prevalence data for NUG in the British Armed Forces and description of its treatment and associated risk factors. Oral hygiene and smoking must be addressed in patients with NUG and prescribing protocols should be carefully followed.


[Organization of urgent surgical treatment for complicated colonic cancers in a large industrial city].
The study was concerned with evaluating the results of follow-up of 756 cases of complications of colorectal cancers urgently admitted for surgery to four hospitals of St. Petersburg. Most patients were hospitalized late when complications diagnosed as an acute disease of organs of the abdominal cavity were apparent. Frequent postoperative complications and poor results of treatment were due to advanced age of patients, their grave general condition, concommitant pathologies, frequent errors of diagnosis made before and during hospitalization and lack of a single strategy of therapy. No improvement in the results of treatment of these grave cases can be expected unless the quality of diagnosis and the standards of urgent surgical aid organization are improved and an efficient therapeutic strategy is developed.


Toward a Listening Training Paradigm: Evaluation in Normal-Hearing Young and Middle-Aged Adults.
Adults' most common complaint relates to understanding speech in noisy environments. Hearing aids can compensate for sensory loss but do not restore hearing to normal. Listening training has the potential to partially remediate these problems. In this study, we propose and evaluate a Flemish version of a listening training paradigm, which involves the use of cognitive control as well as auditory perception. The paradigm entails a discrimination task where participants are cued to attend to one of two concurrent talkers with target speakers randomly varying between a female and a male voice. We evaluate learning effects, different scenarios, and masking types. In total, 70 young and 54 middle-aged adults participated in this study. Each adult performed one or more conditions. Participants' hearing was screened before participation, all middle-aged adults passed a cognitive screening task. Analyses indicated learning effects across scenarios that were similar in terms of speech intelligibility. Our results indicated better speech intelligibility when the female speaker was the target, but speech intelligibility did not differ when the target was the male speaker. An unintelligible masker noise results in worse speech intelligibility than a competing talker masker. Our results suggest that listeners could use an intensity cue to identify and/or select the target speaker when presented at a lower signal to noise ratio (SNR). Error analysis suggested higher cognitive control demands when the target and masker were presented at similar levels (i.e., around 0 dB SNR). The addition of independent trials with the intensity of target and masker reversed improved speech intelligibility. Inhibitory control, but not task switching, was reliably correlated with listening performance. The proposed paradigm turned out to be feasible and practicable, demonstrating its potential for training speech intelligibility in noise. We believe that this training paradigm can generate real-life benefits including for persons with hearing loss. This latter application awaits future evaluation.


Long-term sulfamethoxazole-trimethoprim in Wegener's granulomatosis.
Since 1985, a number of reports have highlighted the effectiveness of a short course of sulfamethoxazole-trimethoprim as an adjuvant to immunosuppressive drugs in the treatment of Wegener's granulomatosis. We report our experience with long-term sulfamethoxazole-trimethoprim therapy in patients with Wegener's granulomatosis. We describe recent advances in the pathogenesis of Wegener's granulomatosis, suggest a complementary mechanism of action of sulfamethoxazole-trimethoprim, and advocate long-term sulfamethoxazole-trimethoprim therapy as a treatment option in Wegener's granulomatosis.


Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study.
To investigate in the prospective Helsinki Heart Study, whether chronic Chlamydia pneumoniae infection, indicated by elevated antibody titers against the pathogen, chlamydial lipopolysaccharide-containing immune complexes, or both, is a risk factor for coronary heart disease. The Helsinki Heart Study was a randomized, double-blind, 5-year clinical trial to test the efficacy of gemfibrozil in reducing the risk for coronary heart disease. Participants were randomized to receive either gemfibrozil (2046 patients) or placebo (2035 patients). Fatal and nonfatal myocardial infarction and sudden cardiac death were the main study end points. Serum samples were collected at 3-month intervals from all patients. One hundred forty cardiac events occurred during the follow-up period. Serum samples from 103 case patients obtained 3 to 6 months before a cardiac end point were matched with those from controls for time point, locality, and treatment. Samples were tested for markers of chronic chlamydial infection. Immunoglobulin A (IgA) and G (IgG) antibodies to C. pneumoniae were measured using the microimmunofluorescence method. Lipopolysaccharide-containing immune complexes were measured using two antigen-specific enzyme immunoassays, the lipopolysaccharide-capture and immunoglobulin M (IgM)-capture methods. Using a conditional logistic regression model, odds ratios for the development of coronary heart disease were 2.7 (95% CI, 1.1 to 6.5) for elevated IgA titers, 2.1 (CI, 1.1 to 3.9) for the presence of immune complexes, and 2.9 (CI, 1.5 to 5.4) for the presence of both factors. If we adjusted for other coronary heart disease risk factors such as age, hypertension, and smoking, the corresponding values would be 2.3 (CI, 0.9 to 6.2), 1.8 (CI, 0.9 to 3.6), and 2.6 (CI, 1.3 to 5.2), respectively. The results suggest that chronic C. pneumoniae infection may be a significant risk factor for the development of coronary heart disease.


Interleukin-27 prevents LPS-induced inflammatory osteolysis by inhibiting osteoclast formation and function.
Osteolysis is a serious complication of several chronic inflammatory diseases and is closely associated with a local chronic inflammatory reaction with a variety of causes. Inflammatory factors and osteoclastogenesis can enhance bone erosion. Interleukin-27 (IL-27) is speculated to play an important role in the physiological immune response. However, there are few studies on its effects on osteoclastogenesis. In this study, IL-27 was shown to inhibit receptor activator nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. The gene expression levels of osteoclast (OC)-specific genes, such as nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and C-FOS, which are essential for OC differentiation and bone resorption, were significantly reduced. Further investigating the underlying mechanism, we found that IL-27 significantly reduced RANKL-induced osteoclastogenesis by inhibiting the phosphorylation of IκB and phosphorylation of nuclear factor κB (NF-κB) p65. Furthermore, IL-27 was shown to inhibit lipopolysaccharide (LPS)-induced osteolysis in vivo. Collectively, these results indicate that IL-27 may be a potential candidate for the treatment of osteolytic diseases.


Online Care Versus In-Person Care for Improving Quality of Life in Psoriasis: A Randomized Controlled Equivalency Trial.
This 12-month, pragmatic, randomized controlled equivalency trial evaluated whether an online, collaborative connected-health model results in equivalent improvements in quality of life compared with in-person care for psoriasis. Overall, 296 adults with physician-diagnosed psoriasis from ambulatory clinics were randomly assigned to either online or in-person care; all were analyzed for outcomes. In the online group, patients and primary care providers sought dermatologists' care directly and asynchronously online. The in-person group sought care face to face. Interventions did not allow blinding of participants; investigators were blinded during analysis. Across 12 months, for the online group, the mean ± standard deviation decline in Skindex-16 from baseline across follow-up visits was 9.02 ± 20.67 compared with 10.55 ± 23.50 for the in-person group. The difference in Skindex-16 between the two groups was -0.83 (95% confidence interval = -5.18 to 3.51), and this was within the equivalence margin (±7.0). For the online group, the mean ± standard deviation decline in Dermatology Life Quality Index was 1.64 ± 4.34 compared with 1.18 ± 4.77 for the in-person group. The difference in Dermatology Life Quality Index between the two groups was -0.45 (95% confidence interval = -1.29 to 0.38) and was within the equivalence margin (±2.5). In conclusion, the online model was as effective as in-person care in improving quality of life among psoriasis patients. This study was funded by the Patient-Centered Outcomes Research Institute and is registered on clinicaltrials.gov (NCT02358135).


Differential expression of angiogenesis-related miRNAs and VEGFA in cirrhosis and hepatocellular carcinoma.
Liver cirrhosis (LC) is a heterogeneous liver disease, the last stage of liver fibrosis, and the major risk factor for hepatocellular carcinoma (HCC). Our study aimed to evaluate the expression of microRNAs and the endothelial vascular growth factor (VEGFA) gene in LC and HCC. The sample group consisted of 46 tissue samples: 21 of LC, 15 of HCC, and 10 of non-tumoural and non-cirrhotic liver tissue (control group). MiRNAs were chosen based on a mirDIP prediction database as regulators of the VEGFA gene. Gene expression of VEGF and miRNAs was quantified by real-time quantitative polymerase chain reaction. VEGFA protein expression was evaluated by ELISA. VEGFA gene expression was significantly overexpressed in LC compared to the control group (p < 0.0001). Hsa-miR-206 (p = 0.0313) and hsa-miR-637 (p = 0.0156) were down-expressed in LC. In HCC, hsa-miR-15b (p = 0.0010), hsa-miR-125b (p = 0.0010), hsa-miR-423-3p (p = 0.0010), hsa-miR-424 (p = 0.0313), hsa-miR-494 (p < 0.0001), hsa-miR-497 (p < 0.0001), hsa-miR-612 (p = 0.0078), hsa-miR-637 (p < 0.0001), and hsa-miR-1255b (p = 0.0156) presented down-expression. Overexpression of VEGFA in LC suggests impairment of angiogenesis in this tissue. The differential expression of microRNAs in LC and HCC observed in our study can lead to the evaluation of possible biomarkers for these diseases.


[Prevalence of antiphospholipid syndrome in patients under 65 years of age with acute myocardial infarction].
The antiphospholipid antibody syndrome (AAS), which is characterized by thromboembolic events and/or fetal loss and/or low platelet count associated with antiphospholipid antibodies, may evolve with acute myocardial infarction (AMI). The presence of AAS among young patients with AMI ranges from 14% to 21%, and this condition implies specific therapeutic attitudes as new thrombotic events may occur, according to some authors. A prospective study was undertaken with 25 patients aged > or = 65 years with AMI that were admitted to our institution during one year who were compared with control patients with similar risk factors. IgG and IgM anticardiolipin antibodies (ACA) were measured in the first 24 hours since the onset of AMI symptoms and three months later. The follow-up ranged from three months to one year. Among patients, ACA positivity in the two measurements was higher (12%) than that observed in the control group (5%) (p = 0.36). ACA positivity on two occasions was not a risk factor for new thrombotic events. ACA positivity is higher among AMI patients (measured early and at three months) than among the general population although the presence of such antibodies does not increase the risk for new post-infarction thrombotic events.


Transient tachypnea of the newborn: what is new?
An infant born by cesarean delivery is at risk of having excessive pulmonary fluid which makes predisposition to transient tachypnea of the newborn (TTN), because fetal thorax compression during labor leads to the loss of large volumes liquid from the lungs. At birth, the pulmonary epithelium switches from predominantly facilitated Cl⁻ secretion to predominantly active Na+ reabsorption with the increase expression epithelial Na+ -channels (ENaC). Diminished activity or immaturity of this process may contribute to the development of TTN. Familial clustering of some TTN cases shows a genetic predisposition in the developing of this disorder. Antenatal glucocorticoids induce lung Na+ reabsorption by increasing the number and activity of channels even in hypoxia. Since a large release of fetal adrenaline occurs late in labor stimulating ENaC to start reabsorbing lung fluids, aerolized ß-agonists may be used in the treatment. Genetic predisposition for ß-adrenergic hyporesponsiveness may cause TTN in newborn period, and asthma/wheezing in older age groups. Although furosemide accelerates lung fluid resorption and cause pulmonary vasodilatation, oral or aerosolized furosemide cannot be recommended as treatment for TTN unless additional data become available.


Influence of nearest neighbor sequence on the stability of base pair mismatches in long DNA; determination by temperature-gradient gel electrophoresis.
Temperature-gradient gel electrophoresis (TGGE) was employed to determine the thermal stabilities of 48 DNA fragments that differ by single base pair mismatches. The approach provides a rapid way for studying how specific base mismatches effect the stability of a long DNA fragment. Homologous 373 bp DNA fragments differing by single base pair substitutions in their first melting domain were employed. Heteroduplexes were formed by melting and reannealing pairs of DNAs, one of which was 32P-labeled on its 5'-end. Product DNAs were separated based on their thermal stability by parallel and perpendicular temperature-gradient gel electrophoresis. The order of stability was determined for all common base pairs and mismatched bases in four different nearest neighbor environments; d(GXT).d(AYC), d(GXG).d(CYC), d(CXA).d(TYG), and d(TXT).d(AYA) with X,Y = A, T, C, or G. DNA fragments containing a single mismatch were destabilized by 1 to 5 degrees C with respect to homologous DNAs with complete Watson-Crick base pairing. Both the bases at the mismatch site and neighboring stacking interactions influence the destabilization caused by a mismatch. G.T, G.G and G.A mismatches were always among the most stable mismatches for all nearest neighbor environments examined. Purine.purine mismatches were generally more stable than pyrimidine.pyrimidine mispairs. Our results are in very good agreement with data where available from solution studies of short DNA oligomers.


Alphaherpesvirus Major Tegument Protein VP22: Its Precise Function in the Viral Life Cycle.
Alphaherpesviruses are zoonotic pathogens that can cause a variety of diseases in humans and animals and severely damage health. Alphaherpesvirus infection is a slow and orderly process that can lie dormant for the lifetime of the host but may be reactivated when the immune system is compromised. All alphaherpesviruses feature a protein layer called the tegument that lies between the capsid and the envelope. Virus protein (VP) 22 is one of the most highly expressed tegument proteins; there are more than 2,000 copies of this protein in each viral particle. VP22 can interact with viral proteins, cellular proteins, and chromatin, and these interactions play important roles. This review summarizes the latest literature and discusses the roles of VP22 in viral gene transcription, protein synthesis, virion assembly, and viral cell-to-cell spread with the purpose of enhancing understanding of the life cycle of herpesviruses and other pathogens in host cells. The molecular interaction information herein provides important reference data.


Selective screening of a large phage display library of plasminogen activator inhibitor 1 mutants to localize interaction sites with either thrombin or the variable region 1 of tissue-type plasminogen activator.
Phage display technology has been exploited to study in detail the interaction between plasminogen activator inhibitor 1 (PAI-1) and either thrombin or an essential positively charged "loop" of tissue-type plasminogen activator (t-PA), denoted variable region 1 (VR1). For this purpose, a PAI-1 mutant phage library was used that served as a reservoir of PAI-1 proteins potentially deficient in the interaction with either VR1 or thrombin. A stringent two-step selection procedure was developed. (i) A negative selection was performed by incubating the pComb3/PAI-1 mutant library with an excess of a thrombin mutant with its VR1 domain substituted with that of t-PA (thrombin-VR1). (ii) The remaining phages were complexed with t-PA (positive selection) and selected by panning with an immobilized anti-t-PA monoclonal antibody. Four consecutive panning rounds yielded an enrichment of pComb3/PAI-1 mutant phages of approximately 50-fold. Sequence analysis of 16 different cDNAs, encoding PAI-1 mutants that are hampered in the binding to thrombin-VR1, revealed the following mutations. Four independent variants share a mutation of the P4' residue (Glu350 --> Lys). Nine independent PAI-1 variants share a substitution of P1' (Met347 --> Lys), whereas three others share a P2 substitution (Ala345 --> Asp). Kinetic analysis of representative PAI-1 mutants provides evidence that the P4' residue is essential for the interaction with the VR1 domain, consistent with the data of Madison et al. (Madison, E.L., Goldsmith, E.J., Gething, M.J., Sambrook, J.F., and Gerard, R.D. (1990) J. Biol. Chem. 265, 21423-21426), whereas the P1' and P2 residues confer thrombin specificity. Concordant with the design of the selection procedure, mutants were obtained that inhibit thrombin-VR1 at least 100-fold slower than wild-type PAI-1, identifying residues that are central to the interaction with either thrombin or VR1. This study demonstrates that phage technology can be used to analyze large numbers of mutants defective in their interaction with other (domains of) proteins, provided an adequate selection scheme is devised.


Vestibular autorotation test asymmetry analysis of acoustic neuromas.
The vestibular autorotation test (VAT) measures the vestibulo-ocular reflex (VOR) response from 2 to 6 Hz, during 18 seconds of active head movements, while the patient attempts to fixate on a wall-mounted target. A new method of measuring eye velocity asymmetry from VAT data is presented, based on computer estimation of the 0th harmonics of discrete Fourier spectra over short segments of digital eye and head velocity records. Eye asymmetries greater than a 3% normal range are shown to be directionally correlated with the side of the lesions in patients with unilateral labyrinthectomies. Among patients with a diagnosis of acoustic neuroma, who were tested preoperatively with the VAT, nine of nine patients showed eye asymmetries greater than 3% toward the side of the neuroma. Those patients with acoustic neuromas who have sufficiently vigorous high-frequency head responses showed mean percentages of eye asymmetry that were linearly correlated with the size of the acoustic neuroma. These results suggest that VAT high-frequency asymmetry provides a useful method of diagnostic evaluation of the side and extent of unilateral peripheral lesions.


beta-Cell function: a key pathological determinant in polycystic ovary syndrome.
We report data from 60 patients with polycystic ovary syndrome (PCOS) who had undergone assessment of insulin resistance, pancreatic beta-cell function, obesity, and androgen levels to elucidate the complex relationships among these traits. Homeostasis model assessment was used to quantify insulin resistance and beta-cell function. A reference population was derived from the National Health and Nutrition Examination Study (NHANES III, 1988-1994). Indices of insulin resistance, insulin secretion, bioavailable testosterone, and body mass index all exhibited significant pairwise correlations. Multiple regression analysis clarified the phenotypic relationships, demonstrating that insulin resistance and bioavailable testosterone were independent predictors of beta-cell function; beta-cell function and obesity were independent predictors of insulin resistance; and beta-cell function was an independent predictor of bioavailable testosterone. Of note, comparison with normal women from NHANES revealed a significantly stronger relationship between beta-cell function and insulin resistance in PCOS, raising the possibility of an intrinsic defect in beta-cell function whereby increasing insulin resistance leads to a greater insulin response in PCOS than normal. The altered relationship of beta-cell function and insulin resistance coupled with the fact that beta-cell function, not insulin resistance, was a predictor of hyperandrogenemia suggests that beta-cell dysfunction may be a key pathogenic determinant in PCOS.


Healthcare value of implementing hepatitis C screening in the adult general population in Spain.
Elimination of hepatitis C virus (HCV) infection requires high diagnostic rates and universal access to treatment. Around 40% of infected individuals are unaware of their infection, which indicates that effective screening strategies are needed. We analyzed the efficiency (incremental cost-utility ratio, ICUR) of 3 HCV screening strategies: a) general population of adults, b) high-risk groups, and c) population with the highest anti-HCV prevalence plus high-risk groups. An analytical decision model, projecting progression of the disease over a lifetime, was used to establish the candidate population for HCV screening. HCV data were obtained from the literature: anti-HCV prevalence (0.56%-1.54%), viremic patients (31.5%), and percentage of undiagnosed persons among those with viremia (35%). It was assumed that most patients would be treated and have HCV therapy response (98% SVR); transition probabilities, utilities, and disease management annual costs were obtained from the literature. Efficiency over the life of patients under the National Health System perspective was measured as quality-adjusted life years (QALY) and total cost (screening, diagnosis, pharmacological and disease management). A discount rate of 3% was applied to costs and outcomes. Screening of the adult population would identify a larger number of additional chronic hepatitis C cases (N = 52,694) than screening the highest anti-HCV prevalence population plus high-risk groups (N = 42,027) or screening high-risk groups (N = 26,128). ICUR for the general population vs. high-risk groups was €8914/QALY gained per patient (€18,157 incremental cost and 2.037 QALY). ICUR for the general population vs. population with highest anti-HCV prevalence plus high-risk groups was €7,448/QALY gained per patient (€7,733 incremental cost and 1.038 QALY). These ICUR values are below the accepted efficiency threshold (€22,000-€30,000). HCV screening and treatment of the general adult population is cost-effective compared to screening of high-risk groups or the population with the highest anti-HCV prevalence plus high-risk groups.


Early Complications and Secondary Procedures in Transfibular Total Ankle Replacement.
A new transfibular total ankle arthroplasty (TAA) system has not been assessed for potential early complications. We retrospectively assessed prospectively collected data on the initial cohort of patients undergoing TAA with this implant. We evaluated visual analog scale (VAS) pain and function, range of motion, and early radiographic outcomes. Twenty consecutive TAAs (19 patients) were treated with the implant from January 2013 through June 2014. Average patient age was 63.7 (range, 41-80) years, with an average follow-up of 18 (range, 12-27) months. No fibular nonunion or implant failure was found at 12 months postoperatively. One patient had asymptomatic mild tibial lucency. Four of 20 TAAs underwent additional surgery for anterior impingement (1 ankle), deep infection and symptomatic fibular hardware (1 ankle), and symptomatic fibular hardware (2 ankles). Of 20 ankles treated with a new transfibular arthroplasty system, no fibular nonunion, delayed union, or implant failure was noted at 12 months postoperatively. Two complications were resolved with secondary treatment, and 2 other ankles underwent secondary surgery for symptomatic fibular hardware with good outcome. The findings suggest that this total ankle system is safe and effective at short-term follow-up. Level IV, retrospective case series.


The Advantages and Challenges of Anticancer Dendritic Cell Vaccines and NK Cells in Adoptive Cell Immunotherapy.
In the last decade, an impressive advance was achieved in adoptive cell therapy (ACT), which has improved therapeutic potential and significant value in promising cancer treatment for patients. The ACT is based on the cell transfer of dendritic cells (DCs) and/or immune effector cells. DCs are often used as vaccine carriers or antigen-presenting cells (APCs) to prime naive T cells ex vivo or in vivo. Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are used as major tool effector cells for ACT. Despite the fact that NK cell immunotherapy is highly effective and promising against many cancer types, there are still some limitations, including insignificant infiltration, adverse conditions of the microenvironment, the immunosuppressive cellular populations, and the low cytotoxic activity in solid tumors. To overcome these difficulties, novel methods of NK cell isolation, expansion, and stimulation of cytotoxic activity should be designed. In this review, we discuss the basic characteristics of DC vaccines and NK cells as potential adoptive cell preparations in cancer therapy.


Why is [Ca2+]i increased in blood cells in primary hypertension?
In order to explore a previously observed association between raised blood cell cytosolic calcium [Ca2+]i and primary hypertension, resting levels of [Ca2+]i in the Milan hypertensive rat strain (MHS) were measured. The [Ca2+]i was increased significantly at 7 weeks in MHS (116 +/- 8 versus 93 +/- 6 mumol/l, P < 0.005, n = 7) and non-significantly at 5 weeks (109 +/- 7 versus 85 +/- 9 mumol/l, n = 5). In Okamoto-Aoki spontaneous hypertensive rats (SHR), calcium fluxes were measured with Quin 2 in platelets and lymphocytes. Calcium influx was measured during calcium-pump inhibition either with vanadate or ATP-depletion. Influx was increased in vanadate-treated (but not in ATP-depleted) cells of SHR. This suggests an ATP dependence of calcium influx in blood cells which is more pronounced in SHR. Calcium efflux was determined when the influx was stopped by external EGTA. Calcium efflux was [Ca2+]i-dependent and was moderately increased in SHR. The faster efflux in SHR was due to higher [Ca2+]i. The [Ca2+]i-dependency of calcium efflux was comparable in SHR and Wistar-Kyoto (WKY) rats. These results suggest that a slight but significant rise of cytosolic calcium occurs in blood cells in primary hypertension. In Okamoto-Aoki SHR this rise was due to a higher calcium entry rate.


HBEGF: an EGF-like growth factor with FGF23-like activity?
Renal signaling networks downstream of FGF23 are not well delineated, but elucidating them may offer an opportunity to control target genes independent of FGF23 in states of dysregulated mineral metabolism. Ni et al. identify HBEGF as a paracrine/autocrine factor in the proximal tubules of mice that mimics the inductive effect of FGF23 on the vitamin D-catabolizing enzyme 24-hydroxylase through a common mitogen-activated protein kinase-dependent pathway. An understanding of how these findings relate to human disease is eagerly anticipated.


Polyhydroxyalkanoate/carbon nanotube nanocomposites: flexible electrically conducting elastomers for neural applications.
Medium chain length-polyhydroxyalkanoate/multi-walled carbon nanotube (MWCNTs) nanocomposites with a range of mechanical and electrochemical properties were fabricated via assisted dispersion and solvent casting, and their suitability as neural interface biomaterials was investigated. Mechanical and electrical properties of medium chain length-polyhydroxyalkanoate/MWCNTs nanocomposite films were evaluated by tensile test and electrical impedance spectroscopy, respectively. Primary rat mesencephalic cells were seeded on the composites and quantitative immunostaining of relevant neural biomarkers, and electrical stimulation studies were performed. Incorporation of MWCNTs to the polymeric matrix modulated the mechanical and electrical properties of resulting composites, and promoted differential cell viability, morphology and function as a function of MWCNT concentration. This study demonstrates the feasibility of a green thermoplastic MWCNTs nanocomposite for potential use in neural interfacing applications.


Biogenesis of iron-sulfur clusters in photosystem I: holo-NfuA from the cyanobacterium Synechococcus sp. PCC 7002 rapidly and efficiently transfers [4Fe-4S] clusters to apo-PsaC in vitro.
The NfuA protein has been postulated to act as a scaffolding protein in the biogenesis of photosystem (PS) I and other iron-sulfur (Fe/S) proteins in cyanobacteria and chloroplasts. To determine the properties of NfuA, recombinant NfuA from Synechococcus sp. PCC 7002 was overproduced and purified. In vitro reconstituted NfuA contained oxygen- and EDTA-labile Fe/S cluster(s), which had EPR properties consistent with [4Fe-4S] clusters. After reconstitution with 57Fe2+, Mössbauer studies of NfuA showed a broad quadrupole doublet that confirmed the presence of [4Fe-4S]2+ clusters. Native gel electrophoresis under anoxic conditions and chemical cross-linking showed that holo-NfuA forms dimers and tetramers harboring Fe/S cluster(s). Combined with iron and sulfide analyses, the results indicated that one [4Fe-4S] cluster was bound per NfuA dimer. Fe/S cluster transfer from holo-NfuA to apo-PsaC of PS I was studied by reconstitution of PS I complexes using P700-F(X) core complexes, PsaD, apo-PsaC, and holo-NfuA. Electron transfer measurements by time-resolved optical spectroscopy showed that holo-NfuA rapidly and efficiently transferred [4Fe-4S] clusters to PsaC in a reaction that required contact between the two proteins. The NfuA-reconstituted PS I complexes had typical charge recombination kinetics from [F(A)/F(B)](-) to P700+ and light-induced low-temperature EPR spectra. These results establish that cyanobacterial NfuA can act as a scaffolding protein for the insertion of [4Fe-4S] clusters into PsaC of PS I in vitro.


Candidate mechanisms underlying effects of contractile activity on muscle morphology and energetics in cancer cachexia.
Skeletal muscle wasting is a prominent pathophysiological feature of cancer cachexia. Recent evidence suggests the manifestation of mitochondrial dysfunction along with a diminished oxidative capacity. These abnormalities have been concurrently observed with impaired muscle force production and the accelerated onset of fatigue in both tumour-bearing animals and cancer patients exhibiting wasting. To address the burden imposed by cachexia, nutritional and pharmacological interventions have been investigated extensively; in contrast, contractile activity-based countermeasures (i.e. exercise training) have been less frequently explored. Although limited, several preclinical studies that implemented contractile activity have reported favourable outcomes such as the retention of muscle mass and the restoration of energetic homeostasis. Even fewer investigations have examined the mechanisms accounting for these protective effects. An experimental approach addressing contractile activity-dependent expression of muscle mass and energy metabolism regulators may yield information that provides mechanistic support for exercise countermeasures. In this review, we present several candidate mechanisms underlying the protective effects of contractile activity as support for exercise countermeasure strategies. Given the limited quantity of data in this area, insights will be derived from studies on contractile activity-dependent modulation of common cellular and molecular events regulating muscle morphology and energetics during other muscle wasting conditions (e.g. sarcopenia).


Computer simulation study of irreversible adsorption: coverage fluctuations.
In this paper, we develop a cellular automata model to study the coverage fluctuations in monolayers of irreversible adsorbed particles. The effect of bulk diffusion and excluded volume interactions between adsorbed and incoming particles on coverage fluctuations is analyzed by simulations and analytically. We also show that the macroscopic boundary and initial conditions imposed at the system (open or closed cell) determine the effect of these factors on coverage fluctuations. In fact, under certain conditions, the excluded volume interactions only influence fluctuations near the jamming limit.


Footprinting of yeast DNA topoisomerase II lysyl side chains involved in substrate binding and interdomainal interactions.
Footprinting of yeast DNA topoisomerase II and its NH2- and COOH-terminal truncation derivatives was carried out to map the locations of lysyl side chains that are involved in enzyme-DNA interaction, in the binding of ATP, or in interaction between domains of the same enzyme molecule. Several conclusions were drawn based on these measurements and the crystal structures of a 92-kDa fragment of the yeast enzyme and a 43-kDa fragment of Escherichia coli gyrase B-subunit. First, the footprinting results support the model previously inferred from the 92-kDa fragment crystal structure that the main site of DNA binding is comprised of a pair of semicircular grooves. Second, the binding of a nonhydrolyzable ATP analog to the yeast enzyme appears to affect citraconylation at a minimum of six lysines in the ATPase domain of each polypeptide. Two of these lysines are probably involved in contacting the nucleotide directly, and one probably becomes buried when the two ATPase domains of a dimeric enzyme come into contact upon ATP binding; for the others, changes in lysine reactivity appear to reflect allosteric changes following ATP binding. Third, from a comparison of the footprint of the intact enzyme and those of the truncated polypeptides comprised of either the NH2- or the COOH-terminal half of the intact polypeptide, it appears that there are few contacts between the NH2- and COOH-terminal half of yeast DNA topoisomerase II.


Macular pigment density measured by autofluorescence spectrometry: comparison with reflectometry and heterochromatic flicker photometry.
We present a technique for estimating the density of the human macular pigment noninvasively that takes advantage of the autofluorescence of lipofuscin, which is normally present in the human retinal pigment epithelium. By measuring the intensity of fluorescence at 710 nm, where macular pigment has essentially zero absorption, and stimulating the fluorescence with two wavelengths, one well absorbed by macular pigment and the other minimally absorbed by macular pigment, we can make accurate single-pass measurements of the macular pigment density. We used the technique to measure macular pigment density in a group of 159 subjects with normal retinal status ranging in age between 15 and 80 years. Average macular pigment density was 0.48 +/- 0.16 density unit (D.U.) for a 2 degrees -diameter test field. We show that these estimates are highly correlated with reflectometric (mean: 0.23 +/- 0.07 D.U.) and psychophysical (mean: 0.37 +/- 0.26 D.U.; obtained by heterochromatic flicker photometry) estimates of macular pigment in the same subjects, despite the fact that systematic differences in the estimated density exist between techniques. Repeat measurements over both short- and long-time intervals indicate that the autofluorescence technique is reproducible: The mean absolute difference between estimates was less than 0.05 D.U., superior to the reproducibility obtained by reflectometry and flicker photometry. To understand the systematic differences between density estimates obtained from the different methods, we analyzed the underlying assumptions of each technique. Specifically, we looked at the effect of self-screening by visual pigment, the effect of changes in optical property of the deeper retinal layers, including the role of retinal pigmented epithelium melanin, and the role of secondary fluorophores and reflectors in the anterior layers of the retina.


Role of dopachrome conversion enzyme in the melanization of filarial worms in mosquitoes.
Melanization is an effective defence reaction of mosquito hosts against invading parasites. In mosquitoes, the biosynthesis of melanin is initiated by the hydroxylation of tyrosine to DOPA by phenoloxidase (PO). DOPA is a branch point of the melanization reaction; it may be oxidized to dopaquinone by PO or be decarboxylated to dopamine by dopa decarboxylase. Further oxidation of dopaquinone by PO produces dopachrome. Dopachrome is then converted to 5, 6-dihydroxyindole by dopachrome conversion enzyme (DCE) to produce melanin. The conversion of dopachrome is a rate-limiting step of the melanization reaction, and the presence of PO and DCE significantly accelerates melanization reactions. In this study, a cDNA encoding DCE was cloned from the mosquito Armigeres subalbatus. Real-time PCR analysis revealed increased transcripts from haemocytes in microfilariae (mf)-inoculated mosquitoes. Gene silencing using double-stranded RNA was used to elucidate the role of DCE in the melanization reaction of parasites in Ar. subalbatus. The levels of both DCE transcripts and protein in gene knockdown mosquitoes were dramatically reduced. Compared with controls, the degree of melanization of mf in DCE-knockdown mosquitoes was significantly decreased. These results suggest that DCE is a critical enzyme that is required for effective melanization immune responses.


Influence of a triblock copolymer on phase behavior and shear-induced topologies of a surfactant lamellar phase.
The influence of a triblock copolymer, poly(ethylene oxide)20-b-poly(propylene oxide)70-b-poly(ethylene oxide)20 (Pluronic P123) on the phase behavior and on the shear-induced multilamellar vesicle (MLV, also called Onion) formation in the lyotropic lamellar phase of the nonionic surfactant C10E3 was investigated by means of rheology, small-angle neutron scattering (SANS), and microscopy. Added triblock copolymer shifted the Lalpha-L3 phase transition to lower temperatures. In the presence of triblock copolymer, MLV structure was not stable and easily transformed back into the lamellar phase with increasing polymer concentration and temperature. In the study of the shear-induced MLV formation, we found an increase of the critical shear rate for the onset of the shear-thickening, which also indicates the instability of MLV in the presence of the triblock copolymer. No MLV formation was observed at high polymer concentration. Suppression of the shear-induced MLV formation might be attributed to the enhancement of the effective surface tension originating from the excluded volume effect between polymers adsorbed onto the membranes.


Processing-body movement in Arabidopsis depends on an interaction between myosins and DECAPPING PROTEIN1.
Processing (P)-bodies are cytoplasmic RNA protein aggregates responsible for the storage, degradation, and quality control of translationally repressed messenger RNAs in eukaryotic cells. In mammals, P-body-related RNA and protein exchanges are actomyosin dependent, whereas P-body movement requires intact microtubules. In contrast, in plants, P-body motility is actin based. In this study, we show the direct interaction of the P-body core component DECAPPING PROTEIN1 (DCP1) with the tails of different unconventional myosins in Arabidopsis (Arabidopsis thaliana). By performing coexpression studies with AtDCP1, dominant-negative myosin fragments, as well as functional full-length myosin XI-K, the association of P-bodies and myosins was analyzed in detail. Finally, the combination of mutant analyses and characterization of P-body movement patterns showed that myosin XI-K is essential for fast and directed P-body transport. Together, our data indicate that P-body movement in plants is governed by myosin XI members through direct binding to AtDCP1 rather than through an adapter protein, as known for membrane-coated organelles. Interspecies and intraspecies interaction approaches with mammalian and yeast protein homologs suggest that this mechanism is evolutionarily conserved among eukaryotes.


Activated Oxytocin Neurons in the PVN-DVC Pathway in Asthmatic Rats.
Asthma is a heterogeneous disease, and the central nervous system (CNS) also participates in the pathogenesis of asthma. We previously reported the amygdala might regulate asthmatic attacks via projecting to the paraventricular hypothalamic nucleus (PVN). The dorsal vagal complex (DVC) is a crucial region that modulates respiratory. This study aimed to observe the activity in both PVN and DVC and the connection between PVN and DVC in asthmatic rats. Immunohistochemistry was conducted to observe the changes in Fos and oxytocin (OT) expression. Retrograde tracing using wheat germ agglutinin-horseradish peroxidase (WGA-HRP) and double immunohistochemistry for OT and Fos was used to observe the HRP/OT/Fos positive neurons distribution in the PVN. The results showed that during an asthma attack, the Fos positive neurons increased in both PVN and DVC over time. The expression of OT positive neurons in PVN showed a similar trend in parallel to the c-Fos positive neurons in PVN. The HRP retrograde-labeled neurons were densely distributed in the medial and lateral subnucleus in the PVN. OT+/HRP+ and Fos+/OT+/HRP+ accounted for 18.14%, and 2.37% of HRP-labeled neurons, respectively. Our study showed PVN and DVC were activated and the expression of OT positive neurons in PVN were increased over time during an asthma attack. The existence of connection between PVN and DVC suggested the OT neurons in PVN might project to DVC which might be involved in the pathogenesis of asthma.


Effect of resin use in the post-embedding procedure on immunoelectron microscopy of membranous antigens, with special reference to sensitivity.
To investigate quantitatively the effect of resins on the sensitivity of immunoelectron microscopy of membranous antigen, ultra-thin sections of bovine epithelial tissue embedded in five different kinds of resins [JB-4 (JB4), LR Gold (LRG), Lowicryl K4M (K4M), Quetol 812 (Q812), and Spurr's (Spurr) resin] were labeled specifically with anti-desmosomal glycoprotein I(DGI) antibody followed by protein A-gold (PAG) conjugates. When we compared the labeling intensity expressed as the number of PAG particles per 500-nm length of the desmosomal region along the membrane, three hydrophilic resins (JB4, LRG, and K4M) showed much greater levels of labeling intensity than did epoxy resins (Q812 and Spurr), which had a negative value. The three hydrophilic resins showed only minor differences in their levels of labeling intensity. The intensity obtained with JB4, which was the highest of the three, was further increased by pretreatment of the ultra-thin sections with methyl methacrylate monomer (MM) for 5 min. On the basis of these results, wide applicability of this new technique for membranous antigens, which have been difficult to detect positively by any previously employed techniques, is suggested.


Association of aggression with a novel microRNA binding site polymorphism in the wolframin gene.
Rare mutations in the WFS1 gene lead to Wolfram syndrome, a severe multisystem disorder with progressive neurodegeneration and diabetes mellitus causing life-threatening complications and premature death. Only a few association studies using small clinical samples tested the possible effects of common WFS1 gene variants on mood disorders and suicide, the non-clinical spectrum has not been studied yet. Self-report data on Aggression, Impulsiveness, Anxiety, and Depression were collected from a large (N = 801) non-psychiatric sample. Single nucleotide polymorphisms (SNPs) were selected to provide an adequate coverage of the entire WFS1 gene, as well as to include putative microRNA binding site polymorphisms. Molecular analysis of the assumed microRNA binding site variant was performed by an in vitro reporter-gene assay of the cloned 3' untranslated region with coexpression of miR-668. Among the 17 WFS1 SNPs, only the rs1046322, a putative microRNA (miR-668) binding site polymorphism showed significant association with psychological dimensions after correction for multiple testing: those with the homozygous form of the minor allele reported higher aggression on the Buss-Perry Aggression Questionnaire (P = 0.0005). Functional effect of the same SNP was also demonstrated in a luciferase reporter system: the minor A allele showed lower repression compared to the major G allele, if co-expressed with miR-668. To our knowledge, this is the first report describing a microRNA binding site polymorphism of the WFS1 gene and its association with human aggression based on a large, non-clinical sample.


Impact of Sepsis on High-Density Lipoprotein Metabolism.
Background: High-density lipoproteins (HDL) are thought to play a protective role in sepsis through several mechanisms, such as promotion of steroid synthesis, clearing bacterial toxins, protection of the endothelial barrier, and antioxidant/inflammatory activities. However, HDL levels decline rapidly during sepsis, but the contributing mechanisms are poorly understood. Methods/Aim: In the present study, we investigated enzymes involved in lipoprotein metabolism in sepsis and non-sepsis patients admitted to the intensive care unit (ICU). Results: In 53 ICU sepsis and 25 ICU non-sepsis patients, we observed significant differences in several enzymes involved in lipoprotein metabolism. Lecithin-cholesterol acyl transferase (LCAT) activity, LCAT concentration, and cholesteryl transfer protein (CETP) activity were significantly lower, whereas phospholipid transfer activity protein (PLTP) and endothelial lipase (EL) were significantly higher in sepsis patients compared to non-sepsis patients. In addition, serum amyloid A (SAA) levels were increased 10-fold in sepsis patients compared with non-sepsis patients. Furthermore, we found that LCAT activity was significantly associated with ICU and 28-day mortality whereas SAA levels, representing a strong inflammatory marker, did not associate with mortality outcomes. Conclusion: We provide novel data on the rapid and robust changes in HDL metabolism during sepsis. Our results clearly highlight the critical role of specific metabolic pathways and enzymes in sepsis pathophysiology that may lead to novel therapeutics.


Prognosis of Pregnancy-Associated Gastric Cancer: An Age-, Sex-, and Stage-Matched Case-Control Study.
Pregnancy-associated gastric cancer is a rare condition. This case-control study was performed to identify the clinicopathological features and prognostic factors of pregnancy-associated gastric cancer. All consecutive patients who presented to our tertiary referral hospital with pregnancy-associated gastric cancer from 1991 to 2012 were identified. Two age-, sex-, and stagematched controls for each case were also identified from the records. Clinicopathological, gynecological, and oncological outcomes were recorded. Immunohistochemical staining was performed for estrogen receptor, progesterone receptor, epidermal growth factor receptor, human epidermal growth factor receptor, and E-cadherin. Fluorescence in situ hybridization was performed for fibroblast growth factor receptor 2. The median overall survival rates of the pregnancyassociated gastric cancer and control groups were 7.0 months and 15.0 months, respectively (p=0.189). Poor prognostic factors included advanced stage and tumor location in the corpus or the entire stomach but not pregnancy status or loss of E-cadherin. Pregnancy-associated gastric cancer was associated with a longer time from diagnosis to treatment (21 days vs 7 days, p=0.021). The two groups did not differ in the expression of the receptors or E-cadherin. The dismal prognosis of pregnancy-associated gastric cancer may related to the tumor stage and location rather than to pregnancy itself.


[Acute renal failure in premature neonates].
Hemodynamic stress is the leading cause of acute renal failure (ARF) in premature neonates. Incidence of ARF in this population is between 8 and 24%. The aim of this study was to determine the frequence of presence of ARF in premature neonates, as well as its impact on their survival. A retrospective study of 114 premature neonates [(gestational age, GA less than 37 gestation weeks (gw)] admitted to the Intensive Care Unit (ICU) at the Pediatric Clinic, Institute of Child and Youth Healthcare of Vojvodina in 2007 was conducted. Serum creatinine, urea and bilirubine were determined on the 3rd day of life in 65 newborns who met inclusion criteria. ARF was diagnosed in 16 newborns (n = 16/65; 25%). The premature neonates with ARF had significantly lower GA [<28 gw - 8/16 (50%) vs. 5/49 (10%); p < 0.05], birth weight (BW) (1265 g vs. 1615 g; p < 0.05) and systolic blood pressure (43.37 mm Hg vs. 52.7 mmHg; p < 0.05) than ones without ARF. Non-olyguric ARF was diagnosed in 62% of newborns with ARF (n = 10/16), while the rest had the olyguric type (n = 6/16; 38%). Twenty-five percent of premature neonates with ARF (n = 4/16) died in contrast to 10% of premature neonates without ARF (n = 5/49). ARF was treated conservatively in all but 3 cases when peritoneal dialysis was performed. Renal function has recovered completely in all of the survivors. In order to determine their predictivity in relation to ARF, following parameters were analyzed: GA, BW < 1500 g, presence of concomitant sepsis and intracranial hemorrhage grade III/IV. BW < 1500 g demonstrated the highest sensitivity (se 0.75), while GA < 28 gw, sepsis and intracranial hemorrhage grade III/IV showed high specificity (sp = 0.90, 0.89 0.88, respectively). Acute renal failure frequently occurs in population of premature neonates and requires meticulous fluid and electrolyte balance, especially in the case of low birth weight and extreme immaturity.


Abnormal early cleavage events predict early embryo demise: sperm oxidative stress and early abnormal cleavage.
Human embryos resulting from abnormal early cleavage can result in aneuploidy and failure to develop normally to the blastocyst stage. The nature of paternal influence on early embryo development has not been directly demonstrated although many studies have suggested effects from spermatozoal chromatin packaging, DNA damage, centriolar and mitotic spindle integrity, and plasma membrane integrity. The goal of this study was to determine whether early developmental events were affected by oxidative damage to the fertilizing sperm. Survival analysis was used to compare patterns of blastocyst formation based on P2 duration. Kaplan-Meier survival curves demonstrate that relatively few embryos with short (<1 hr) P2 times reached blastocysts, and the two curves diverged beginning on day 4, with nearly all of the embryos with longer P2 times reaching blastocysts by day 6 (p < .01). We determined that duration of the 2nd to 3rd mitoses were sensitive periods in the presence of spermatozoal oxidative stress. Embryos that displayed either too long or too short cytokineses demonstrated an increased failure to reach blastocyst stage and therefore survive for further development. Although paternal-derived gene expression occurs later in development, this study suggests a specific role in early mitosis that is highly influenced by paternal factors.


Cariogenic bacteria and dental health status in adolescents: the role of oral health behaviours.
To evaluate the association between dental health status and levels of cariogenic bacteria in teenagers and the influence of behaviours and socio-demographic background on levels of bacteria. Study design: A cross-sectional population-based sample of 13-year-old adolescents (112 females and 78 males, total 190) was examined. The number of decayed, missing and filled surfaces (DMFS), plaque and hygiene index were recorded according to the WHO criteria. The saliva samples were collected in a sterile container and then analysed by culture on Mitis Salivarius Bacitracin (MSB) agar for mutans Streptococci and on Man Rogosa Sharp (MRS) agar for Lactobacilli. The levels of bacteria were expressed as the number of colonies forming units per millilitre of saliva (CFU/ml). Associations between levels of mutans Streptococci and Lactobacilli and dental health were estimated by odds ratio (OR) and 95% confidence interval (95% CI) using unconditional logistic regression. No mutans Streptococci were detected in 53.2% of the adolescents but 22.6% presented ≥ 10³ CFU/ml. For Lactobacilli, these values were, respectively 43.7% and 34.7%. After adjustment for gender and social class, the OR (95% CI) for DMFS >5 was 8.66 (3.57-21.02) if mutans Streptococci ≥ 10³ CFU and 2.11 (0.96-4.64) if Lactobacilli ≥ 10³ CFU. This data allow us to conclude that hygiene habits and dental visits are not associated with high levels of cariogenic bacteria, but high scores of DMFS were found in adolescents with high levels of mutans Streptococci and lower parents' education.


Intracranial EEG Structure-Function Coupling and Seizure Outcomes After Epilepsy Surgery.
Surgery is an effective treatment for drug-resistant epilepsy, which modifies the brain's structure and networks to regulate seizure activity. Our objective was to examine the relationship between brain structure and function to determine the extent to which this relationship affects the success of the surgery in controlling seizures. We hypothesized that a stronger association between brain structure and function would lead to improved seizure control after surgery. We constructed functional and structural brain networks in patients with drug-resistant focal epilepsy by using presurgery functional data from intracranial EEG (iEEG) recordings, presurgery and postsurgery structural data from T1-weighted MRI, and presurgery diffusion-weighted MRI. We quantified the relationship (coupling) between structural and functional connectivity by using the Spearman rank correlation and analyzed this structure-function coupling at 2 spatial scales: (1) global iEEG network level and (2) individual iEEG electrode contacts using virtual surgeries. We retrospectively predicted postoperative seizure freedom by incorporating the structure-function connectivity coupling metrics and routine clinical variables into a cross-validated predictive model. We conducted a retrospective analysis on data from 39 patients who met our inclusion criteria. Brain areas implanted with iEEG electrodes had stronger structure-function coupling in seizure-free patients compared with those with seizure recurrence (p = 0.002, d = 0.76, area under the receiver operating characteristic curve [AUC] = 0.78 [95% CI 0.62-0.93]). Virtual surgeries on brain areas that resulted in stronger structure-function coupling of the remaining network were associated with seizure-free outcomes (p = 0.007, d = 0.96, AUC = 0.73 [95% CI 0.58-0.89]). The combination of global and local structure-function coupling measures accurately predicted seizure outcomes with a cross-validated AUC of 0.81 (95% CI 0.67-0.94). These measures were complementary to other clinical variables and, when included for prediction, resulted in a cross-validated AUC of 0.91 (95% CI 0.82-1.0), accuracy of 92%, sensitivity of 93%, and specificity of 91%. Our study showed that the strength of structure-function connectivity coupling may play a crucial role in determining the success of epilepsy surgery. By quantitatively incorporating structure-function coupling measures and standard-of-care clinical variables into presurgical evaluations, we may be able to better localize epileptogenic tissue and select patients for epilepsy surgery. This is a Class IV retrospective case series showing that structure-function mapping may help determine the outcome from surgical resection for treatment-resistant focal epilepsy.


Tris(2-Pyridylmethylamine)V(O)2 Complexes as Counter Ions of Diprotonated Decavanadate Anion: Potential Antineoplastic Activity.
The synthesis and theoretical-experimental characterization of a novel diprotanated decavanadate is presented here due to our search for novel anticancer metallodrugs. Tris(2-pyridylmethyl)amine (TPMA), which is also known to have anticancer activity in osteosarcoma cell lines, was introduced as a possible cationic species that could act as a counterpart for the decavanadate anion. However, the isolated compound contains the previously reported vanadium (V) dioxido-tpma moieties, and the decavanadate anion appears to be diprotonated. The structural characterization of the compound was performed by infrared spectroscopy and single-crystal X-ray diffraction. In addition, DFT calculations were used to analyze the reactive sites involved in the donor-acceptor interactions from the molecular electrostatic potential maps. The level of theory mPW1PW91/6-31G(d)-LANL2DZ and ECP = LANL2DZ for the V atom was used. These insights about the compounds' main interactions were supported by analyzing the noncovalent interactions utilizing the AIM and Hirshfeld surfaces approach. Molecular docking studies with small RNA fragments were used to assess the hypothesis that decavanadate's anticancer activity could be attributed to its interaction with lncRNA molecules. Thus, a combination of three potentially beneficial components could be evaluated in various cancer cell lines.


Deceptively normal ventricular fluid in lymphomatous meningitis.
The diagnosis of leptomeningeal cancer ultimately depends on the finding of abnormal cerebrospinal fluid with malignant cytologic study results. We report a case of relapsed leptomeningeal lymphomatosis in which ventricular cerebrospinal fluid was entirely normal while lumbar spinal fluid was diagnostically abnormal. To our knowledge, this is the first such reported case, and it highlights the importance of sampling cerebrospinal fluid close to the site of clinical involvement.


[The influence of socio-demographic and psychological variables on the level of satisfaction of geriatric patients from dental care].
The increasing geriatric population poses unique treatment challenges for the dental practice. Satisfaction from dental treatment is considered to be an important issue that influences the attitude and cooperation of the geriatric patient. It is associated with the quality of treatment and with different variables, such as physical, emotional, social and financial. The objectives of the present study were to perform a preliminary characterization of a group of geriatric patients and to identify possible factors that might be associated with their level of satisfaction from dental treatment. Fifty-one geriatric patients (20 males and 31 females) participated in the study. They were given a questionnaire which included 41 items regarding: socio-demographic variables, social activity, self image, level of apprehension, locus of control and level of satisfaction from dental care. Twenty-two patients reported a high level of satisfaction from dental treatment and twenty-nine reported a low level of satisfaction. No significant association was found between the degree of satisfaction from dental treatment and the examined variables of social activity, self-image and level of apprehension. Good doctor-patient relationships--"the art of care", is considered to have an important impact on the level of satisfaction, especially among the geriatric patients. Therefore, it is suggested that these relationships might determine the level of satisfaction of the geriatric patient from dental treatment.


Genetic identification of the central nucleus and other components of the central extended amygdala in chicken during development.
In mammals, the central extended amygdala shows a highly complex organization, and is essential for animal survival due to its implication in fear responses. However, many aspects of its evolution are still unknown, and this structure is especially poorly understood in birds. The aim of this study was to define the central extended amygdala in chicken, by means of a battery of region-specific transcription factors (Pax6, Islet1, Nkx2.1) and phenotypic markers that characterize these different subdivisions in mammals. Our results allowed the identification of at least six distinct subdivisions in the lateral part of the avian central extended amygdala: (1) capsular central subdivision; (2) a group of intercalated-like cell patches; (3) oval central nucleus; (4) peri-intrapeduncular (peri-INP) island field; (5) perioval zone; and (6) a rostral part of the subpallial extended amygdala. In addition, we identified three subdivisions of the laterodorsal bed nucleus of the stria terminalis (BSTLd) belonging to the medial region of the chicken central extended amygdala complex. Based on their genetic profile, cellular composition and apparent embryonic origin of the cells, we discuss the similarity of these different subdivisions of chicken with different parts of the mouse central amygdala and surrounding cell masses, including the intercalated amygdalar masses and the sublenticular part of the central extended amygdala. Most of the subdivisions include various subpopulations of cells that apparently originate in the dorsal striatal, ventral striatal, pallidal, and preoptic embryonic domains, reaching their final location by either radial or tangential migrations. Similarly to mammals, the central amygdala and BSTLd of chicken project to the hypothalamus, and include different neurons expressing proenkephalin, corticotropin-releasing factor, somatostatin or tyrosine hydroxylase, which may be involved in the control of different aspects of fear/anxiety-related behavior.


On-line and in situ monitoring of oxygen concentration and gas temperature in a reheating furnace utilizing tunable diode-laser spectroscopy.
Increased demands on energy savings and quality control in metallurgical processes have created incentives for new methods to monitor and control the process. In this paper we will present a field trial that shows the potential of tunable diode-laser spectroscopy (TDLS) for simultaneous contact free measuring and monitoring of the oxygen concentration as well as the gas temperature in a reheating furnace during production. The field trials were carried out at an oil-fueled reheating furnace during 7 weeks of production. The tunable diode-laser spectrometer was measuring in situ across the preheating zone and the soaking zone in the furnace. During the campaign the oxygen concentration and the gas temperature in the furnace environment were simultaneously monitored and instantaneous variations in these parameters could easily be recorded and subsequently correlated to actual changes in the process. Furthermore, the much shorter response-time of the TDLS technique compared with conventional measurement methods such as thermocouples and extractive gas analyzers was also demonstrated during the trials. The results show the potential for the TDLS technique to be used for energy savings as well as product quality improvements by controlling the burners in the reheating furnace. The results show that it would be possible to control and optimize the oxygen concentration with TDLS in the control loop of the reheating furnace.


Effect of nitric oxide synthase inhibitor on cochlear dysfunction induced by transient local anoxia.
To evaluate whether nitric oxide (NO) plays a role in the mechanism of generation of cochlear dysfunction induced by anoxia and reperfusion, the effects of a nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine, were examined using 71 albino guinea pigs. Transient cochlear anoxia of different duration (15, 30 or 60 min) was induced by pressing the labyrinthine artery and compound action potential (CAP) was measured before and 4 h after anoxia. N-nitro-L-arginine (1-30 mg/kg) administered intraperitoneally 1 h before the onset of anoxia alleviated the cochlear dysfunction when the anoxic period was 15 or 30 min. No beneficial effect was observed, however, in the 60-min anoxia. These results indicate that NO contributes to the generation of anoxia-induced cochlear dysfunction and that NOS inhibitor has a protective effect on the cochlear injury induced by anoxia of moderate duration.


GABAergic projections from the hippocampus to the retrosplenial cortex in the rat.
The retrosplenial cortex (RS) in rats has been implicated in a wide range of behaviors, including spatial navigation and memory. Relevant to this, the RS is closely interconnected with the hippocampus by multiple direct and indirect routes. Here, by injecting the retrograde tracer cholera toxin subunit B conjugated with Alexa488 (CTB-Alexa488) in the granular retrosplenial cortex (GRS), we demonstrate a moderately dense non-pyramidal projection from CA1. Neurons are in several layers, but mainly (about 65%) at the border of the stratum radiatum (SR) and stratum lacunosum moleculare (SLM). In particular, by double-labeling with GAD67 or gamma-aminobutyric acid (GABA), we establish that these neurons are GABAergic. Further immunocytochemical screening for calcium-binding proteins, somatostatin (SS) or cholecystokinin (CCK) failed to identify additional neurochemical subgroups; but a small subset (about 14%) is positive for the m2 muscarinic acetylcholine receptor (M2R). Terminations target layer 1 of the GRS, as shown by biotinylated dextran amine (BDA) injections into CA1 and confirmed by a very superficial injection of CTB-Alexa488 in GRS. The superficial injection shows that there is a sparse GABAergic projection from the subiculum to layer 1 of the GRS, in addition to the dense excitatory connections to layer 3. The role of these dual inhibitory-excitatory pathways - within the subiculum, and in parallel from CA1 and the subiculum - remains to be determined, but may be related to synchronized oscillatory activity in the hippocampal complex and GRS, or to the generation of rhythmic activity within the GRS.


The impact of human copy number variation on a new era of genetic testing.
Cytogenetic studies have demonstrated that duplications or deletions of entire chromosomes or microscopically visible aberrations are associated with specific congenital disorders. The subsequent development and application of microarray-based assays have established the importance of copy number variants (CNV) as a substantial source of genetic diversity in the human genome. Pathogenic CNVs are associated not only with birth defects and cancers, but also with neurodevelopmental disorders at birth or neurodegenerative diseases in adulthood. Unfortunately, the limited knowledge of the phenotypic effects of most CNVs has led to the classification of many CNVs as genomic imbalances of unknown clinical significance. This has caused many clinicians to resist the introduction of microarray technologies in detecting CNVs in a genome-wide manner for prenatal applications. This review summarises our current understanding of CNVs, the common detection methods, and the implications for human health and prenatal diagnosis.


Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony-stimulating activity and prostaglandin E2.
Granulocyte-macrophage colony-stimulating activity (GM-CSA) can be produced by a variety of normal cell types including mononuclear phagocytes, activated T lymphocytes, endothelial cells, and fibroblasts. Recent evidence shows that a major role of the monocyte-macrophage is the recruitment of environmental cells, i.e., fibroblasts, to produce GM-CSA. In this study we have identified interleukin 1 (IL-1) as a monokine that stimulates fibroblasts to produce and release GM-CSA and prostaglandin E2 (PGE2). Both purified human monocyte-derived IL-1 and human recombinant IL-1 (10(-10) M) can be substituted for monocyte-conditioned medium in stimulating fibroblast GM-CSA and PGE2 production. Both forms of IL-1 stimulate fibroblasts to produce GM-CSA and PGE2 in a dose-dependent fashion. The fibroblast-stimulating activity found in monocyte-conditioned medium was completely blocked by anti-IL-1. We conclude that monocytes produce IL-1, and that monocyte-derived IL-1 induces fibroblasts to produce GM-CSA and PGE2.


Acute spinal cord compression in hereditary multiple exostoses.
Osteocartilaginous exostoses are benign bone tumors frequently found in the metaphysis of long bones but rarely in the spine. Four patients with acute spinal cord decompensation due to vertebral exostoses spinal cord compression have been previously described in the literature. We report an additional case of rapidly evolving spinal cord compression due to a cervical osteochondroma in a patient with hereditary multiple exostoses (HME), also known as Bessel Hagen disease. Careful analysis of the 5 cases suggested to us that patients with HME should have a systematic spinal imaging screening, in order to prevent rapid neurological decompensation. A minimal risk surgical procedure can be performed at a time of election.


Aberrant Splicing Events and Epigenetics in Viral Oncogenomics: Current Therapeutic Strategies.
Global cancer incidence and mortality are on the rise. Although cancer is fundamentally a non-communicable disease, a large number of cancers are known to have a viral aetiology. A high burden of infectious agents (Human immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis B virus (HBV)) in certain Sub-Saharan African countries drives the rates of certain cancers. About one-third of all cancers in Africa are attributed to infection. Seven viruses have been identified with carcinogenic characteristics, namely the HPV, HBV, Hepatitis C virus (HCV), Epstein-Barr virus (EBV), Human T cell leukaemia virus 1 (HTLV-1), Kaposi's Sarcoma Herpesvirus (KSHV), and HIV-1. The cellular splicing machinery is compromised upon infection, and the virus generates splicing variants that promote cell proliferation, suppress signalling pathways, inhibition of tumour suppressors, alter gene expression through epigenetic modification, and mechanisms to evade an immune response, promoting carcinogenesis. A number of these splice variants are specific to virally-induced cancers. Elucidating mechanisms underlying how the virus utilises these splice variants to maintain its latent and lytic phase will provide insights into novel targets for drug discovery. This review will focus on the splicing genomics, epigenetic modifications induced by and current therapeutic strategies against HPV, HBV, HCV, EBV, HTLV-1, KSHV and HIV-1.


Effect of donor-recipient HLA matching at HLA A, B, C, and DRB1 on outcomes after umbilical-cord blood transplantation for leukaemia and myelodysplastic syndrome: a retrospective analysis.
The importance of matching at the HLA C locus has not been well defined for unrelated umbilical-cord blood transplantation. The selection algorithm for umbilical-cord blood units generally considers intermediate resolution HLA typing at A and B and allele-level typing at DRB1. We aimed to establish the relative importance of additional matching at HLA C. We used Cox regression to assess retrospectively the effect of donor-recipient HLA matching on outcomes of single umbilical-cord blood transplantations for leukaemia and myelodysplastic syndrome. Our primary endpoint was transplant-related mortality. HLA typing was done with molecular techniques with a minimum of intermediate resolution for HLA A, B, and C, and at the allele-level for DRB1. The median age of our study population was 10 years (range <1-62) and 552 (69%) of 803 patients were aged 16 years or younger at transplantation. Compared with transplantations matched at HLA A, B, C, and DRB1 (n=69), transplant-related mortality risk was higher after transplantations matched at HLA A, B, and DRB1 and mismatched at HLA C (n=23; HR 3·97, 95% CI 1·27-12·40; p=0·018). Transplant-related mortality risk was also higher after transplantations with a single mismatch at HLA A, B, or DRB1 and mismatched at HLA C (n=234; 1·70, 1·06-2·74; p=0·029) compared with transplantations matched at HLA C with a single mismatch at HLA A, B, or DRB1 (n=127). Assessing the overall effect of HLA disparity on transplant-related mortality, risks were higher with units mismatched at two (n=259; 3·27, 1·42-7·54; p=0·006), three (n=253; 3·34, 1·45-7·71; p=0·005), or four (n=75; 3·51, 1·44-8·58; p=0·006) loci compared with matched units (n=69). Our data suggest that the present strategy for umbilical-cord blood unit selection should be reassessed; matching at HLA C for units that are matched at HLA A, B, or DRB1 or in the presence of a single locus mismatch at HLA A, B, or DRB1 should be included to minimise mortality risks. National Cancer Institute, National Heart Lung and Blood Institute, National Institute for Allergy and Infectious Diseases, Leukemia and Lymphoma Society, US Department of the Navy, Children's Leukemia Research Association, and INSERM.


Rural women's perceptions of community prenatal care systems: an empowerment strategy.
Rural U.S. women often experience many barriers to prenatal care involving health care provider shortages, distance to health care, and less health insurance coverage as compared to urban women. Fewer community planning and consumer resources as well as less transportation also often decrease opportunities for rural women to participate in community health planning and assessment. The purpose of this article is to describe social work strategies for empowering rural women in their assessment of community prenatal care systems. A case study of a rural demonstration project addressing prenatal care barriers is presented as well as implications for social work practice.


Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?
Heart failure is a devastating clinical syndrome, but current therapies are unable to abolish the disease burden. New strategies to treat or prevent heart failure are urgently needed. Over the past decades, a clear relationship has been established between poor cardiac performance and metabolic perturbations, including deficits in substrate uptake and utilization, reduction in mitochondrial oxidative phosphorylation and excessive reactive oxygen species production. Together, these perturbations result in progressive depletion of cardiac adenosine triphosphate (ATP) and cardiac energy deprivation. Increasing the delivery of energy substrates (e.g., fatty acids, glucose, ketones) to the mitochondria will be worthless if the mitochondria are unable to turn these energy substrates into fuel. Micronutrients (including coenzyme Q10, zinc, copper, selenium and iron) are required to efficiently convert macronutrients to ATP. However, up to 50% of patients with heart failure are deficient in one or more micronutrients in cross-sectional studies. Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation, moving our view of the failing myocardium away from an "an engine out of fuel" to "a defective engine on a path to self-destruction." This summary of evidence suggests that supplementation with micronutrients-preferably as a package rather than singly-might be a potential therapeutic strategy in the treatment of heart failure patients.


Stenotrophomonas maltophilia endocarditis of prosthetic mitral valve.
We present a 78-year-old woman with prosthetic valve endocarditis due to Stenotrophomonas maltophilia (S. maltophilia) 3 years after mitral valve replacement. Administration of sulfamethoxazole-trimethoprim was effective; however, it was discontinued because of side effects, which led to failure of antibiotic therapy. Complications of multiple cerebral infarction and paravalvular abscess developed. Although the prosthetic valve was removed 50 days after admission, she died 4 months after surgery. S. maltophilia has been increasingly being considered as a serious nosocomial pathogen. S. maltophilia endocarditis is rare; however, it should be recognized as a possible life-threatening disease in patients with prosthetic valve.