Palliative treatment of malignant gastroduodenal obstruction: Applications of self-expandable metal stent.
The aim of this study was to evaluate the efficacy, effects on survival and complications of self-expandable metal stent applications in patients with malignant gastroduodenal obstruction. Twenty-five patients undergoing metal stent insertion due to malignant gastroduodenal obstruction between February 2005 and July 2009 were included in the present study. In all patients, self-expandable metal stent 22 mm in diameter was inserted under scopic guidance. The patients were evaluated regarding age, gender, etiology, efficacy of stent insertion, complications, and duration of patency of the stent. Of the 25 patients included in the study, 15 were female and 10 were male. Their mean age was 65.9 years (57-81 years). The most common etiological causes were duodenal tumor (n=10, 40%) and pancreatic tumor (n=8, 32%). Duodenal stent was inserted successfully in all patients. In 4 patients, percutaneous biliary metal stent was inserted at the same time due to concomitant obstructive jaundice. No mortality occurred during the procedure. A second stent was inserted in 4 patients due to stent migration. The patients were followed for a mean of 92 days (7 to 258 days) after the procedure. The stents remained clinically patent in all patients during the follow-up period until death. Insertion of duodenal metal stent is an effective and safe therapeutic approach in the palliative treatment of malignant gastric outlet obstruction.


A qualitative study about how families coped with managing their well-being, children's physical activity and education during the COVID-19 school closures in England.
In 2020, schools in England closed for six months due to COVID-19, resulting in children being home-schooled. There is limited understanding about the impacts of this on children's mental and physical health and their education. Therefore, we explored how families coped with managing these issues during the school closures. We conducted 30 qualitative interviews with parents of children aged 18 years and under (who would usually be in school) between 16 and 21 April 2020. We identified three themes and eight sub-themes that impacted how families coped whilst schools were closed. We found that family dynamics, circumstances, and resources (Theme 1), changes in entertainment activities and physical movement (Theme 2) and worries about the COVID-19 pandemic (Theme 3) impacted how well families were able to cope. A key barrier to coping was struggles with home-schooling (e.g., lack of resources and support from the school). However, parents being more involved in their children's personal development and education were considered a benefit to home-schooling. Managing the lack of entertainment activities and in-person interactions, and additional health worries about loved ones catching COVID-19 were challenges for families. Parents reported adverse behaviour changes in their children, although overall, they reported they were coping well. However, pre-existing social and educational inequalities are at risk of exacerbation. Families with more resources (e.g., parental supervision, access to green space, technology to facilitate home-schooling and no special educational needs) were better able to cope when schools were closed. On balance, however, families appeared to be able to adapt to the schools being closed. We suggest that policy should focus on supporting families to mitigate the widening health and educational gap between families with more and less resources.


Growth Hormone Induces Transforming Growth Factor-Beta-Induced Protein in Podocytes: Implications for Podocyte Depletion and Proteinuria.
The glomerular podocytes form a major size selective barrier for the filtration of serum proteins and reduced podocyte number is a critical event in the pathogenesis of proteinuria during diabetic nephropathy (DN). An elevated level of growth hormone (GH) is implicated as a causative factor in the development of nephropathy in patients with type 1 diabetes mellitus. We have previously shown that podocytes express GH receptor and are a target for GH action. To elucidate the molecular basis for the effects of GH on podocyte depletion, we conducted PCR-array analyses for extracellular matrix and adhesion molecules in podocytes. Our studies reveal that GH increases expression of a gene that encodes transforming growth factor-beta-induced protein (TGFBIp) expression. Similarly, microarray data retrieved from the Nephromine database revealed elevation of TGFBIp in patients with DN. Treatment with GH results in increased secretion of extracellular TGFBIp by podocytes. Both GH and TGFBIp induced apoptosis and epithelial mesenchymal transition (EMT) of podocytes. Exposure of podocytes to GH and TGFBIp resulted in increased migration of cells and altered podocyte permeability to albumin across podocyte monolayer. Administration of GH to rats induced EMT and apoptosis in the glomerular fraction of the kidney. Therefore, we conclude that the GH-dependent increase in TGFBIp in the podocyte is one of the mechanisms responsible for podocyte depletion in DN.


Total quality management: lessons learned from the medical practice environment.
Experience in dealing with the application of total quality management (TQM) to the medical practice environment suggests some generic lessons that can be helpful in applying TQM in other health care settings. These lessons focus on the need to address the motivation for TQM and its potential value; understanding the barriers created by the organizational and industry culture; identifying the structural barriers within the organization; clearly stating the guiding principles of the TQM effort; implementing the correct management tools for implementation; and allowing users of TQM to create new ideas for the application of TQM in their organizations.


[Topographic and dosimetric considerations in different methods of proton irradiation].
Two techniques are employed for proton irradiation: one--to pass a proton beam through a target, the other one--to stop in it. The advantage of the first technique is a very small angular divergence of the beam penetrating tissues or, consequently, a very high lateral edge field gradient. The second technique has two additional advantages: the absence of radiation lesions behind the target and an increase in the stopping power (dose) at the end of the beam range localized in the target. The authors present their considerations concerning the applicability of each technique and certain characteristic problems of the second technique. Dose field deformations as a result of topometric uncertainties are also estimated. A method of dose design aimed at minimizing the above mentioned effect is proposed.


Hyaluronic acid on the urokinase sustained release with a hydrogel system composed of poloxamer 407: HA/P407 hydrogel system for drug delivery.
Pleural empyema is an inflammatory condition characterized by accumulation of pus inside the pleural cavity, which is usually followed by bacterial pneumonia. During the disease process, the pro-inflammatory and pro-fibrotic cytokines in the purulent pleural effusion cause proliferation of fibroblasts and deposition of extracellular matrix, which lead to fibrin deposition and fibrothorax. Urokinase instillation therapy through a chest drainage tube is frequently used for fibrinolysis in patients with empyema. However, urokinase treatment requires multiple instillation (2-3 times per day, for 4-8 days) and easily flows out from the chest drainage tube due to its high water solubility. In this in vitro study, we developed a thermo-responsive hydrogel based on poloxamer 407 (P407) combined with hyaluronic acid (HA) for optimal loading and release of urokinase. Our results show that the addition of HA to poloxamer gels provides a significantly more compact microstructure, with smaller pore sizes (**p < 0.001). The differential scanning calorimetry (DSC) profile revealed no influence on the micellization intensity of poloxamer gel by HA. The 25% poloxamer-based gel was significantly superior to the 23% poloxamer-based gel, with slower gel erosion when comparing the 16th hour residual gel weight of both gels (*p < 0.05; **p < 0.001). The 25% poloxamer-HA gel also exhibited a superior urokinase release profile and longer release time. A Fourier-transform infrared spectroscopy (FT-IR) study of the P407/HA hydrogel showed no chemical interactions between P407 and HA in the hydrogel system. The thermoresponsive P407/HA hydrogel may have a promising potential in the loading and delivery of hydrophilic drugs. On top of that, in vitro toxicity test of this combination demonstrates a lower toxicity.


Relationship of flight and reproduction in beet armyworm, Spodoptera exigua (Lepidoptera: Noctuidae), a migrant lacking the oogenesis-flight syndrome.
The beet armyworm, Spodoptera exigua, undertakes long-distance migration. We used flight mills to investigate the interaction between flight and reproduction in this species given the apparent absence of the oogenesis-flight syndrome. This syndrome, common in many migratory insects, is characterized by a suite of traits including migration during the pre-oviposition period followed by a switch to oogenesis. No negative effects of inter-ovipositional flight on lifetime fecundity were observed. Instead, adult reproductive output suffered when female flight was initiated the first day after eclosion and before oviposition, suggesting that migratory flight overlaps with the oviposition period rather than being confined to the pre-oviposition period. Mating status of both females and males had no negative influence on their flight performance except that flight distance and flight duration of 7-day-old mated females were significantly less than in unmated females. Furthermore, the number of eggs produced and mating frequency of females less than 7 days of age were not significantly correlated with flight performance, suggesting reproductive development paralleled and was independent of migratory behavior. This independent relationship between flight and reproduction of adults is consistent with the very short pre-oviposition period in this species, and suggests that resources are partitioned between these activities during pupal development. Together, our results uncovered neither obvious trade-offs nor mutual suppression between flight and reproduction in S. exigua, which indicates the lack of an oogenesis-flight syndrome for coordination of these two energy-intensive processes. We propose a conceptual model of migration for this species based on the current and previous studies.


Identification of an RNA-silencing suppressor in the genome of Grapevine virus A.
Higher plants use post-transcriptional gene silencing (PTGS), an RNA-degradation system, as a defence mechanism against viral infections. To counteract this, plant viruses encode and express PTGS suppressor proteins. Four of the five proteins encoded by the Grapevine virus A (GVA) genome were screened using a green fluorescent protein (GFP)-based transient expression assay, and the expression product of ORF5 (protein p10) was identified as a suppressor of silencing. ORF5 p10 suppressed local and systemic silencing induced by a transiently expressed single-stranded sense RNA. This protein was active towards both a transgene and exogenous GFP mRNAs. Ectopic expression of GVA-ORF5 by a Potato virus X vector enhanced symptom severity. The findings that p10 markedly reduces the levels of small interfering RNAs (siRNAs) and that the recombinant protein is able to bind single-stranded and double-stranded forms of siRNAs and microRNAs, suggest the existence of a potential mechanism of suppression based on RNA sequestering.


Assessment and management of hypertension in transplant patients.
Hypertension in renal transplant recipients is common and ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. Cardiovascular morbidity and mortality and shortened allograft survival are important consequences of inadequate control of hypertension. In this review, we examine the epidemiology, pathophysiology, and management considerations of post-transplant hypertension. Donor and recipient factors, acute and chronic allograft injury, and immunosuppressive medications may each explain some of the pathophysiology of post-transplant hypertension. As observed in other patient cohorts, renal artery stenosis and adrenal causes of hypertension may be important contributing factors. Notably, BP treatment goals for renal transplant recipients remain an enigma because there are no adequate randomized controlled trials to support a benefit from targeting lower BP levels on graft and patient survival. The potential for drug-drug interactions and altered pharmacokinetics and pharmacodynamics of the different antihypertensive medications need to be carefully considered. To date, no specific antihypertensive medications have been shown to be more effective than others at improving either patient or graft survival. Identifying the underlying pathophysiology and subsequent individualization of treatment goals are important for improving long-term patient and graft outcomes in these patients.


Risk of second primary cancers after testicular cancer in East and West Germany: a focus on contralateral testicular cancers.
Testicular cancer survival rates improved dramatically after cisplatin-based therapy was introduced in the 1970s. However, chemotherapy and radiation therapy are potentially carcinogenic. The purpose of this study was to estimate the risk of developing second primary cancers including the risk associated with primary histologic type (seminoma and non-seminoma) among testicular cancer survivors in Germany. We identified 16 990 and 1401 cases of testicular cancer in population-based cancer registries of East Germany (1961-1989 and 1996-2008) and Saarland (a federal state in West Germany; 1970-2008), respectively. We estimated the risk of a second primary cancer using standardized incidence ratios (SIRs) with 95% confidence intervals (95% CIs). To determine trends, we plotted model-based estimated annual SIRs. In East Germany, a total of 301 second primary cancers of any location were observed between 1961 and 1989 (SIR: 1.9; 95% CI: 1.7-2.1), and 159 cancers (any location) were observed between 1996 and 2008 (SIR: 1.7; 95% CI: 1.4-2.0). The SIRs for contralateral testicular cancer were increased in the registries with a range from 6.0 in Saarland to 13.9 in East Germany. The SIR for seminoma, in particular, was higher in East Germany compared to the other registries. We observed constant trends in the model-based SIRs for contralateral testicular cancers. The majority of reported SIRs of other cancer sites including histology-specific risks showed low precisions of estimated effects, likely due to small sample sizes. Testicular cancer patients are at increased risk especially for cancers of the contralateral testis and should receive intensive follow-ups.


Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease.
Amyloid beta-peptide (Abeta)(1-42) oligomers have recently been discussed as intermediate toxic species in Alzheimer's disease (AD) pathology. Here we describe a new and highly stable Abeta(1-42) oligomer species which can easily be prepared in vitro and is present in the brains of patients with AD and Abeta(1-42)-overproducing transgenic mice. Physicochemical characterization reveals a pure, highly water-soluble globular 60-kDa oligomer which we named 'Abeta(1-42) globulomer'. Our data indicate that Abeta(1-42) globulomer is a persistent structural entity formed independently of the fibrillar aggregation pathway. It is a potent antigen in mice and rabbits eliciting generation of Abeta(1-42) globulomer-specific antibodies that do not cross-react with amyloid precursor protein, Abeta(1-40) and Abeta(1-42) monomers and Abeta fibrils. Abeta(1-42) globulomer binds specifically to dendritic processes of neurons but not glia in hippocampal cell cultures and completely blocks long-term potentiation in rat hippocampal slices. Our data suggest that Abeta(1-42) globulomer represents a basic pathogenic structural principle also present to a minor extent in previously described oligomer preparations and that its formation is an early pathological event in AD. Selective neutralization of the Abeta globulomer structure epitope is expected to have a high potential for treatment of AD.


The species composition, richness and diversity studies of fruit flies captured from the orchard of Nagpur mandarin.
The present experiment was conducted to study the diversity of fruit flies in Nagpur mandarin orchard from different agro-ecological zones of Vidarbha region of Maharashtra, India. The fruit flies samples were collected from 18 places falling under 9 agro-ecological zone using methyl eugenol traps. Out of the total collected catches of fruit flies from each zones, Bactrocera dorsalis was found to be the most prominent species followed by Bactrocera zonata. The Z. cucurbitae and B. correcta which occupied third and fourth rank in species composition, respectively. The species viz., Zeugodacus duplicatus and Zeugodacus gavisus recorded very less abundance at all locations. Shannons index of diversity was maximum in Morshi followed by Katol. Simpson index was more at Tiwasa and Achalpur locations which indicated minimum diversity in the population of fruit flies. Higher diversity of fruit flies were recorded in Morshi and Katol followed by Amravati.


Randomised clinical trial: mucosal protection combined with acid suppression in the treatment of non-erosive reflux disease - efficacy of Esoxx, a hyaluronic acid-chondroitin sulphate based bioadhesive formulation.
Several studies have shown that patients with non-erosive reflux disease (NERD) are less responsive to proton pump inhibitors (PPIs) than those with erosive disease as they belong to different subgroups, in whom factors other than acid can trigger symptoms. To evaluate whether combined therapy (mucosal protection plus acid suppression) would improve symptom relief compared to PPI treatment alone. In a multicenter, randomised, double-blind trial, 154 patients with NERD were randomised to receive Esoxx (Alfa Wassermann, Bologna, Italy), a hyaluronic acid-chondroitin sulphate based bioadhesive formulation, or placebo, in addition to acid suppression with standard dose PPIs for 2 weeks. Symptoms (heartburn, acid regurgitation, retrosternal pain and acid taste in the mouth) and health-related quality of life (HRQL) were evaluated before and after treatment. The primary endpoint was the proportion of patients with at least a 3-point reduction in the total symptom score. At the end of treatment, the primary endpoint was reached by 52.6% of patients taking Esoxx compared to 32.1% of those given placebo (P < 0.01). The same was true also for HRQL, evaluated by means of the Short Form-36 questionnaire, which improved with both treatments, but some items were significantly better after Esoxx plus PPI therapy. The synergistic effect of Essox with PPI treatment suggests that mucosal protection added to acid suppression could improve symptoms and HRQL in NERD patients.


Thalassaemia in pregnancy.
Thalassaemia is the most common monogenetic disease worldwide. Antenatal screening is effective and simple, and accurate genetic prenatal diagnosis can be achieved in early gestation. Less invasive methods are feasible with ultrasound fetal assessment for alpha-thalassaemia, analysis of circulating fetal nucleic acid in maternal plasma, and pre-implantation genetic diagnosis. Women with thalassaemia major and intermedia are at risk of various maternal complications, such as cardiac failure, alloimmunisation, viral infection, thrombosis, endocrine and bone disturbances. Therefore, it is prudent to adhere to a standard management plan in this group of pregnant women. Close monitoring of the maternal and fetal condition during pregnancy is essential, and various treatments, such as blood transfusion or postpartum prophylaxis for thromboembolism, may be indicated. After birth, resumption of iron chelation and bisphosphonates treatment is needed, and counselling on breast feeding and contraception should be given.


An open-source automated magnetic optical density meter for analysis of suspensions of magnetic cells and particles.
We present a spectrophotometer (optical density meter) combined with electromagnets dedicated to the analysis of suspensions of magnetotactic bacteria. The instrument can also be applied to suspensions of other magnetic cells and magnetic particles. We have ensured that our system, called MagOD, can be easily reproduced by providing the source of the 3D prints for the housing, electronic designs, circuit board layouts, and microcontroller software. We compare the performance of our system to existing adapted commercial spectrophotometers. In addition, we demonstrate its use by analyzing the absorbance of magnetotactic bacteria as a function of their orientation with respect to the light path and their speed of reorientation after the field has been rotated by 90°. We continuously monitored the development of a culture of magnetotactic bacteria over a period of 5 days and measured the development of their velocity distribution over a period of one hour. Even though this dedicated spectrophotometer is relatively simple to construct and cost-effective, a range of magnetic field-dependent parameters can be extracted from suspensions of magnetotactic bacteria. Therefore, this instrument will help the magnetotactic research community to understand and apply this intriguing micro-organism.


[The late results of deportalization of the pancreatic blood flow in patients with type-1 diabetes mellitus].
Late follow-up result of the pancreatic blood flow deportalization using distal splenorenal anastomosis conduction in 16 patients with type-I diabetes mellitus was studied up. The diabetes mellitus course stabilization was promoted by performance of operation.


Prolonged Grief in Times of Lockdown During the COVID-19 Pandemic.
This study aimed to estimate the prevalence of prolonged grief (PG) during the COVID-19 pandemic and to analyze associated variables. 142 family members of patients who died during the lockdown at a hospital were surveyed 6 months after the death. Prolonged grief, depression and anxiety, grief rumination, and loss-related variables were captured. Logistic regression analyses were conducted to detect the associated variables of PG symptoms. Prolonged grief was present in 44.4% of the bereaved. 76.2% of the relatives reported feeling distressed due to visitor restrictions, and the majority of them were unable to bid farewell to their family member at the time of death. Pastoral or psychological care was also lacking. Low education (p < 0.001), emotional closeness (p = 0.007), loss of a spouse (p < 0.001), inability to bid farewell after death (p = 0.024), feeling of threat due to the pandemic (p < 0.001), depression (p = 0.014), and anxiety (p = 0.028) were significantly associated with prolonged grief.


Comprehensive comparing percutaneous endoscopic lumbar discectomy with posterior lumbar internal fixation for treatment of adjacent segment lumbar disc prolapse with stable retrolisthesis: A retrospective case-control study.
The study was to comprehensively compare the postoperative outcome and imaging parameter characters in a short/middle period between the percutaneous endoscopic lumbar discectomy (PELD) and the internal fixation of bone graft fusion (the most common form is posterior lumbar interbody fusion [PLIF]) for the treatment of adjacent segment lumbar disc prolapse with stable retrolisthesis after a previous lumbar internal fixation surgery.In this retrospective case-control study, we collected the medical records from 11 patients who received PELD operation (defined as PELD group) for and from 13 patients who received the internal fixation of bone graft fusion of lumbar posterior vertebral lamina decompression (defined as control group) for the treatment of the lumbar disc prolapse combined with stable retrolisthesis at Department of Spine Surgery, the Third Hospital of Hebei Medical University (Shijiazhuang, China) from May 2010 to December 2015. The operation time, the bleeding volume of perioperation, and the rehabilitation days of postoperation were compared between 2 groups. Before and after surgery at different time points, ODI, VAS index, and imaging parameters (including Taillard index, inter-vertebral height, sagittal dislocation, and forward bending angle of lumbar vertebrae) were compared.The average operation time, the blooding volume, and the rehabilitation days of postoperation were significantly less in PELD than in control group. The ODI and VAS index in PELD group showed a significantly immediate improving on the same day after the surgery. However, Taillard index, intervertebral height, sagittal dislocation in control group showed an immediate improving after surgery, but no changes in PELD group till 12-month after surgery. The forward bending angle of lumbar vertebrae was significantly increased and decreased in PELD and in control group, respectively.PELD operation was superior in terms of operation time, bleeding volume, recovery period, and financial support, if compared with lumbar internal fixation operation. Radiographic parameters reflect lumber structure changes, which could be observed immediately after surgery in both methods; however, the recoveries on nerve function and pain relief required a longer time, especially after PLIF operation.


Comparison of endogenous and exogenous sources of ATP in fueling Ca2+ uptake in smooth muscle plasma membrane vesicles.
A smooth muscle plasma membrane vesicular fraction (PMV) purified for the (Ca2+/Mg2+)-ATPase has endogenous glycolytic enzyme activity. In the presence of glycolytic substrate (fructose 1,6-diphosphate) and cofactors, PMV produced ATP and lactate and supported calcium uptake. The endogenous glycolytic cascade supports calcium uptake independent of bath [ATP]. A 10-fold dilution of PMV, with the resultant 10-fold dilution of glycolytically produced bath [ATP] did not change glycolytically fueled calcium uptake (nanomoles per milligram protein). Furthermore, the calcium uptake fueled by the endogenous glycolytic cascade persisted in the presence of a hexokinase-based ATP trap which eliminated calcium uptake fueled by exogenously added ATP. Thus, it appears that the endogenous glycolytic cascade fuels calcium uptake in PMV via a membrane-associated pool of ATP and not via an exchange of ATP with the bulk solution. To determine whether ATP produced endogenously was utilized preferentially by the calcium pump, the ATP production rates of the endogenous creatine kinase and pyruvate kinase were matched to that of glycolysis and the calcium uptake fueled by the endogenous sources was compared with that fueled by exogenous ATP added at the same rate. The rate of calcium uptake fueled by endogenous sources of ATP was approximately twice that supported by exogenously added ATP, indicating that the calcium pump preferentially utilizes ATP produced by membrane-bound enzymes.


Vibrational frequency analysis, FT-IR and Laser-Raman spectra, DFT studies on ethyl (2E)-2-cyano-3-(4-methoxyphenyl)-acrylate.
The experimental FT-IR (4000-400 cm(-1)) and Laser-Raman spectra (4000-100 cm(-1)) of ethyl (2E)-2-cyano-3-(4-methoxyphenyl)-acrylate in solid phase have been recorded. Its theoretical vibrational frequencies, IR intensities, Raman activities and optimized geometric parameters (bond lengths and bond angles) have been calculated using density functional theory (DFT/B3LYP: Becke, 3-parameter, Lee-Yang-Parr and DFT/M06-2X: the highly parameterized empirical exchange correlation function) with 6-311++G(d, p) basis set by Gaussian 03 software, for the first time. The assignments of the vibrational frequencies have been done by potential energy distribution (PED) analysis using VEDA4 software. The optimized geometric parameters and vibrational frequencies have been seen to be in good agreement with the corresponding experimental data and results in the literature. In addition, the highest occupied molecular orbital (HOMO) energy, the lowest unoccupied molecular orbital (LUMO) energy and the other related molecular energy values of the compound have been investigated by using the same theoretical calculations.


The occurrence of actinlike filaments in association with migrating pigment granules in frog retinal pigment epithelium.
In the retina of the frog and certain other animals, melanin pigment granules move in response to light so as to shield photoreceptor outer segments. The granules are contained within the cells of the pigment epithelium (PE) which lie as a continuous sheet between the neural retina and the choroid. Moderate illumination of the eye causes the melanin granules to move from a region within a PE cell body into numerous fingerlike extensions of the cell which interdigitate with the receptor outer segments. This migration takes many minutes and is reversed when the light falling on the eye increases in intensity. Several reviews are concerned with the early descriptions of this phenomenon (6,30) and with more recent experiments (1,5,19). The mechanism of the pigment granule motion is undetermined although there are studies concerning PE ultrastructure (8, 23, 31), scanning electron microscopy of the fingerlike extensions of the PE cells (27), the role of the PE in photoreceptor phagocytosis (32), the nature of the pigment granules (19), and the action spectrum of the light which induces the migration (16). This study reports the presence of a system of microfilaments associated with the pigment granules in the fingerlike extensions processes of the PE cells. We demonstrate by heavy meromyosin (HMM) labeling that the filaments are actinlike in character and suggest that these filaments could be responsible for the migration of the melanin pigment granules.


The Alice in Wonderland Syndrome: A Case of Aura Accompanying Cluster Headache.
Cluster headache (CH) is a primary headache which has highly specific and sensitive criteria, and notpresence of an aura. It has been recently reported that CH may not presence with aura more than ever and this condition will be identified by headache specialists as a new form of CH. As there is no report to our knowledge on Alice in Wonderland syndrome (AIWS) manifested as CH aura in the literature, we present a case of a 35-year-old man having AIWS as CH aura. Clinically, AIWS is not uncommon and is likely to be underestimated as a diagnostic entity. Valproate may be preferred for treatment in CH patients with AIWS aura.


Water simulation model with explicit three-molecule interactions.
Much effort has been directed at developing models for the computer simulation of liquid water. The simplest models involve effective two-molecule interactions, parametrized from experiment, for use in classical molecular dynamics simulations. These models have been very successful in describing the structure and dynamics of liquid water at room temperature and one atmosphere pressure. A completely successful model, however, should be robust enough to describe the properties of liquid water at other thermodynamic points, water's complicated phase diagram, heterogeneous situations like the liquid/vapor interface, ionic, and other aqueous solutions, and confined and biological water. In this paper, we develop a new classical simulation model with explicit three-molecule interactions. These interactions presumably make the model more robust in the senses described above, and since they are short-ranged, the model is efficient to simulate. The model is formulated as a perturbation from a classical two-molecule interaction model, where the forms of the correction to the two-molecule term and the three-molecule terms result from electronic structure calculations on dimers and trimers. The magnitudes of these perturbations, however, are determined empirically. The resulting model improves upon the well-known two-molecule interaction models for both static and dynamic properties.


Using long-read CAGE sequencing to profile cryptic-promoter-derived transcripts and their contribution to the immunopeptidome.
Recent studies have shown that the noncoding genome can produce unannotated proteins as antigens that induce immune response. One major source of this activity is the aberrant epigenetic reactivation of transposable elements (TEs). In tumors, TEs often provide cryptic or alternate promoters, which can generate transcripts that encode tumor-specific unannotated proteins. Thus, TE-derived transcripts (TE transcripts) have the potential to produce tumor-specific, but recurrent, antigens shared among many tumors. Identification of TE-derived tumor antigens holds the promise to improve cancer immunotherapy approaches; however, current genomics and computational tools are not optimized for their detection. Here we combined CAGE technology with full-length long-read transcriptome sequencing (long-read CAGE, or LRCAGE) and developed a suite of computational tools to significantly improve immunopeptidome detection by incorporating TE and other tumor transcripts into the proteome database. By applying our methods to human lung cancer cell line H1299 data, we show that long-read technology significantly improves mapping of promoters with low mappability scores and that LRCAGE guarantees accurate construction of uncharacterized 5' transcript structure. Augmenting a reference proteome database with newly characterized transcripts enabled us to detect noncanonical antigens from HLA-pulldown LC-MS/MS data. Lastly, we show that epigenetic treatment increased the number of noncanonical antigens, particularly those encoded by TE transcripts, which might expand the pool of targetable antigens for cancers with low mutational burden.


Effects of obesity on the biomechanics of stair-walking in children.
Anthropometric characteristics, particularly body mass, are important factors in the development and progression of varus/valgus angular deformities of the knee and have long-term implications including increased risk of osteoarthritis. However, information on how excessive body weight affects the biomechanics of dynamic activities in children is limited. The purpose of this study was to test the hypothesis that during stair-walking lower extremity joint moments normalized to body mass in obese children are greater than those in normal-weight children. Eighteen obese children (10.5±1.5 years, 148±10cm, 56.6±8.4kg) and 17 normal-weight children (10.4±1.3 years, 143±9cm, 36.7±7.5kg) were recruited. A Vicon system and two AMTI force plates were used to record and analyze the kinematics and kinetics of ascending and descending stairs. Significant differences in spatio-temporal, kinematic and kinetic parameters during ascending and descending stairs between obese and normal-weight children were detected. For stair ascent, greater hip abduction moments (+23%; p=0.001) and greater knee extension moments (+20%; p=0.008) were observed. For stair descent, smaller hip extension moment (-52%; p=0.031), and greater hip flexion moments (+25%; p=0.016) and knee extension moments (+15%, p=0.008) were observed for obese subjects. To date, it is unclear if and how the body may adapt to greater joint moments in obese children. Nevertheless, these differences in joint moments may contribute to a cumulative overloading of the joint through adolescence into adulthood, and potentially result in a greater risk of developing knee and hip osteoarthritis.


Genome of 'Charleston Gray', the principal American watermelon cultivar, and genetic characterization of 1,365 accessions in the U.S. National Plant Germplasm System watermelon collection.
Years of selection for desirable fruit quality traits in dessert watermelon (Citrullus lanatus) has resulted in a narrow genetic base in modern cultivars. Development of novel genomic and genetic resources offers great potential to expand genetic diversity and improve important traits in watermelon. Here, we report a high-quality genome sequence of watermelon cultivar 'Charleston Gray', a principal American dessert watermelon, to complement the existing reference genome from '97103', an East Asian cultivar. Comparative analyses between genomes of 'Charleston Gray' and '97103' revealed genomic variants that may underlie phenotypic differences between the two cultivars. We then genotyped 1365 watermelon plant introduction (PI) lines maintained at the U.S. National Plant Germplasm System using genotyping-by-sequencing (GBS). These PI lines were collected throughout the world and belong to three Citrullus species, C. lanatus, C. mucosospermus and C. amarus. Approximately 25 000 high-quality single nucleotide polymorphisms (SNPs) were derived from the GBS data using the 'Charleston Gray' genome as the reference. Population genomic analyses using these SNPs discovered a close relationship between C. lanatus and C. mucosospermus and identified four major groups in these two species correlated to their geographic locations. Citrullus amarus was found to have a distinct genetic makeup compared to C. lanatus and C. mucosospermus. The SNPs also enabled identification of genomic regions associated with important fruit quality and disease resistance traits through genome-wide association studies. The high-quality 'Charleston Gray' genome and the genotyping data of this large collection of watermelon accessions provide valuable resources for facilitating watermelon research, breeding and improvement.


Symptomatological Variants and Related Clinical Features in Adult Attention Deficit Hyperactive Disorder.
A large amount of the current literature has focused on the characteristic symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents. In contrast, less attention has been devoted to ADHD clinical subtypes in adult patients. We evaluated 164 consecutive adult ADHD (A-ADHD) outpatients using DSM-5 criteria and many specific rating scales and questionnaires. A principal component factor analysis was performed on clinical and symptomatological variables to describe potential clinical variants. We sought to determine different A-ADHD variants focusing on demographic and clinical features. A four-factor solution was identified, and patients were clustered, according to their z-score, in 4 subgroups. The first was marked out by Emotional Dysregulation (ED), the second by Substance Use (SU), the third by Core-ADHD Symptoms (Co-ADHD) and the fourth by Positive Emotionality (PE). Predominantly ED patients showed worse overall function, early treatment with antidepressants and a greater presence of borderline personality disorder than predominantly Co-ADHD patients. Predominantly SU patients reported high rates of bipolar disorder and severe general psychopathology. The PE factor was related to hyperthymic temperament and hypomania and showed a higher level of functioning. Females with A-ADHD showed a lower risk of being included in SU, and A-ADHD patients with co-occurring delayed sleep phase had less risk of being included in the SU factor than the prevailing Co-ADHD group. Our empirically based description of four clinical A-ADHD variants shows several aspects beyond the definition given by the DSM-5 diagnostic criteria.


Hydroxyapatite coated with heaptocyte growth factor (HGF) stimulates human osteoblasts in vitro.
We have studied in vitro the effect of a hydroxyapatite (HA) tricalcium phosphate material coated with hepatocyte growth factor (HA-HGF) on cell growth, collagen synthesis and secretion of metalloproteinases (MMPs) by human osteoblasts. Cell proliferation was stimulated when osteoblasts were incubated with untreated HA and was further increased after exposure to HA-HGF. The uptake of [3H]-proline was increased after treatment with HA. When osteoblasts were exposed to HA-HGF, collagen synthesis was increased with respect to HA. The secretion of MMPs in control cells was undetectable, but in HA and HA-HGF cells MMP 2 and MMP 9 were clearly synthesised. Our results suggest that HA can promote osteoblast activity and that HGF can further increase its bioactivity.


[Rapid determination of 137Cs in environmental samples--purification of 137Cs by ammonium molybdophosphate column separation].
A rapid method for the determination of 137Cs in environmental samples was proposed. The principal technic employed in this study is based on column separation of 137Cs using ammonium molybdophosphate mixed with glass fiber to eliminate contribution of natural radionuclides such as 40K and 87Rb. The separation of cesium from potassium and rubidium was performed by the elution with 0.5m ammonium nitrate solution. The time required for separation of cesium was five hours as compared with the conventional cation exchange separation which required thirteen hours. The chemical yield of cesium carrier was normally more than 90 percent. The results obtained were compared with that by the conventional methods using Bio-Rex cation exchange separation and the good agreement between the two methods was obtained.


Dual Inhibition of PI3K/Akt/mTOR Pathway and Role of Autophagy in Non-Small Cell Lung Cancer Cells.
The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling axis has emerged as a novel target for cancer therapy. Agents that inhibit this pathway are currently under development for lung cancer treatment. In the present study, we have tested whether dual inhibition of PI3K/Akt/mTOR signaling can lead to enahnced antitumor effects. We have also examined the role of autophagy during this process. We analyzed the combination effect of the mTOR inhibitor, temsirolimus, and the Akt inhibitor, GSK690693, on the survival of NCI-H460 and A549 non-small cell lung cancer cells. Cell proliferation was determined by MTT assay and apoptosis induction was evaluated by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Autophagy induction was also evaluated by acridine orange staining. Changes of apoptosis or autophagy-related proteins were evaluated by western blot analysis. Combination treatment with temsirolimus and GSK690693 caused synergistically increased cell death in NCI-H460 and A549 cells. This was attributable to increased induction of apoptosis. Caspase 3 activation and poly(ADP-ribose) polymerase cleavage accompanied these findings. Autophagy also increased and inhibition of autophagy resulted in increased cell death, suggesting its cytoprotective role during this process. Taken together, our results suggest that the combination of temsirolimus and GSK690693 could be a novel strategy for lung cancer therapy. Inhibition of autophagy could also be a promising method of enhancing the combination effect of these drugs.


A Neuro-Influence Experiment to Evaluate the Persuasiveness of Pre-Exposure Prophylaxis Promotion Messages Among Men Who Have Sex With Men: Protocol for a Randomized Controlled Trial.
Pre-exposure prophylaxis (PrEP) is recommended by the US Centers for Disease Control and Prevention, but behavioral factors limit uptake, especially among men who have sex with men. A better understanding of how humans cognitively process information may inform health message development to promote PrEP uptake. This paper is informed by the neuroscience of persuasion and influence and describes the protocol of a neuro-influence experiment using functional near-infrared spectroscopy (fNIRS) to evaluate the persuasiveness of PrEP promotion messages among men who have sex with men in Baltimore, Maryland. We will conduct a randomized controlled trial using fNIRS to measure brain activation among 60 participants viewing PrEP promotion messages either developed through a crowdsourcing open contest implemented by the study team or developed with a traditional social marketing approach. We will evaluate the effectiveness of PrEP promotion messages by assessing brain activation in the regions associated with persuasion and changes in PrEP willingness, behavioral intention, initiation, and action between the 2 groups. This study is funded by the National Institutes of Health (National Institute of Mental Health: R34MH116725). Participant recruitment and data collection were completed in October 2023. The first results are expected to be submitted for publication in 2024. In addition to providing insight into the effectiveness of PrEP promotion messages, this study will examine the feasibility, acceptability, and utility of neuroimaging techniques to evaluate PrEP promotion messages for high-risk men who have sex with men. The findings can also demonstrate the utility of fNIRS as a tool for preproduct testing of health campaigns and enable the public health community to deliver more effective messages to improve health outcomes. DERR1-10.2196/52546.


Sunscreen dermatitis due to glyceryl PABA: significance of cross-reactions to this PABA Ester.
Glyceryl PABA (Escalol 106), present in many popular sunscreens, is a common sensitizer which invariably cross-reacts with benzocaine; it is present in over 400 over-the-counter products. Glyceryl PABA does not appear to cross-react with the sunscreening agents amyl (Escalol 506) and octyl (Escalol 507) dimethyl PABA. Glyceryl PABA, may, on occasion, cross-react with para-aminobenzoic acid (PABA), paraphenylenediamine, aniline, and sulfa drugs. Ironically, the sunscreening agent glyceryl PABA may, itself, act as a photosensitizing agent.


Feature-based representations of emotional facial expressions in the human amygdala.
The amygdala plays a central role in processing facial affect, responding to diverse expressions and features shared between expressions. Although speculation exists regarding the nature of relationships between expression- and feature-specific amygdala reactivity, this matter has not been fully explored. We used functional magnetic resonance imaging and principal component analysis (PCA) in a sample of 300 young adults, to investigate patterns related to expression- and feature-specific amygdala reactivity to faces displaying neutral, fearful, angry or surprised expressions. The PCA revealed a two-dimensional correlation structure that distinguished emotional categories. The first principal component separated neutral and surprised from fearful and angry expressions, whereas the second principal component separated neutral and angry from fearful and surprised expressions. This two-dimensional correlation structure of amygdala reactivity may represent specific feature-based cues conserved across discrete expressions. To delineate which feature-based cues characterized this pattern, face stimuli were averaged and then subtracted according to their principal component loadings. The first principal component corresponded to displacement of the eyebrows, whereas the second principal component corresponded to increased exposure of eye whites together with movement of the brow. Our results suggest a convergent representation of facial affect in the amygdala reflecting feature-based processing of discrete expressions.


Adjunct ablation strategies for persistent atrial fibrillation-beyond pulmonary vein isolation.
Atrial fibrillation (AF) is the most common sustained arrhythmia. Recent guidelines recommend pulmonary vein isolation (PVI) as the main procedural endpoint to control recurrent AF in symptomatic patients resistant to antiarrhythmic drugs. The efficacy of such procedure is higher in paroxysmal AF while is still unsatisfactory in persistent and long-standing persistent AF. This review will summarize the state-of-the-art of AF ablation techniques in patients with persistent AF, discussing the evidence underlying different approaches with a particular focus on adjunctive ablation strategies beyond PVI including linear ablation, ablation of complex fractionated atrial electrograms (CFAE), ablation of ganglionated plexi, dominant frequency, rotors and other anatomical sites frequently involved in AF triggers.


Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets.
Biliary tract cancers (BTCs) are a heterogeneous group of aggressive, rare malignancies with limited standard chemotherapeutic options for advanced disease. Recent studies have demonstrated potential novel biliary cancer targets and a possible role for immunotherapy in the treatment of patients with this disease. Intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and gallbladder carcinoma (GBC) are frequently grouped together in clinical trials despite differences in tumor biology. To further investigate tumor biology differences, we profiled 1,502 BTCs using next-generation sequencing (NGS), immunohistochemistry, in situ hybridization, and RNA sequencing. IHCCs had higher rates of IDH1, BAP1, and PBRM1 mutations and FGFR2 fusions; EHCCs had higher rates of KRAS, CDKN2A, and BRCA1 mutations; and GBCs had higher rates of homologous recombination repair deficiency and Her2/neu overexpression and amplification. IHCCs and GBCs had higher rates of potential positive predictive biomarkers for immune checkpoint inhibition (PD-L1 expression, high microsatellite instability, and high tumor mutational burden) than EHCCs. These findings support clinical molecular profiling of BTCs to inform potential therapeutic selection and clinical trial design based on the primary tumor's site of origin within the biliary tree.


Molecular dynamics simulations of nanoscale and sub-nanoscale friction behavior between graphene and a silicon tip: analysis of tip apex motion.
A sliding object on a crystal surface with a nanoscale contact will always experience stick-slip movement. However, investigation of the slip motion itself is rarely performed due to the short slip duration. In this study, we performed molecular dynamics simulation and frictional force microscopy experiments for the precise observation of slip motion between a graphene layer and a crystalline silicon tip. The simulation results revealed a hierarchical structure of stick and slip motion. Nanoscale stick and slip motion is composed of sub-nanoscale stick and slip motion. Sub-nanoscale stick and slip motion occurred on a timescale of a few ps and a force scale of 10(-1) nN. The relationship between the trajectories of the silicon tip and stick-slip peak revealed that in-plane and vertical motions of the tip provide information about stick and slip motion in the sub-nanoscale and nanoscale ranges, respectively. Parametric studies including tip size, scan angle, layer thickness, and flexibility of the substrate were also carried out to compare the simulation results with findings on lateral force microscopy.


Auditory and vestibular dysfunction associated with blast-related traumatic brain injury.
The dramatic escalation of blast exposure in military deployments has created an unprecedented amount of traumatic brain injury (TBI) and associated auditory impairment. Auditory dysfunction has become the most prevalent individual service-connected disability, with compensation totaling more than 1 billion dollars annually. Impairment due to blast can include peripheral hearing loss, central auditory processing deficits, vestibular impairment, and tinnitus. These deficits are particularly challenging in the TBI population, as symptoms can be mistaken for posttraumatic stress disorder, mental-health issues, and cognitive deficits. In addition, comorbid factors such as attention, cognition, neuronal loss, noise toxicity, etc., can confound assessment, causing misdiagnosis. Furthermore, some auditory impairments, such as sensorineural hearing loss, will continue to progress with age, unlike many other injuries. In the TBI population, significant clinical challenges are the accurate differentiation of auditory and vestibular impairments from multiple, many times overlapping, symptoms and the development of multidisciplinary rehabilitation strategies to improve treatment outcomes and quality of life for these patients.


Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy.
Expression of microRNA-652 (miR-652) increases in the diseased heart, decreases in a setting of cardioprotection, and is inversely correlated with heart function. The aim of this study was to assess the therapeutic potential of inhibiting miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Mice were subjected to a sham operation or transverse aortic constriction (TAC) for 4 wk to induce hypertrophy and cardiac dysfunction, followed by administration of a locked nucleic acid (LNA)-antimiR-652 (miR-652 inhibitor) or LNA control. Cardiac function was assessed before and 8 wk post-treatment. Expression of miR-652 increased in hearts subjected to TAC compared to sham surgery (2.9-fold), and this was suppressed by ∼95% in LNA-antimiR-652-treated TAC mice. Inhibition of miR-652 improved cardiac function in TAC mice (fractional shortening:29±1% at 4 wk post-TAC compared to 35±1% post-treatment) and attenuated cardiac hypertrophy. Improvement in heart function was associated with reduced cardiac fibrosis, less apoptosis and B-type natriuretic peptide gene expression, and preserved angiogenesis. Mechanistically, we identified Jagged1 (a Notch1 ligand) as a novel direct target of miR-652. In summary, these studies provide the first evidence that silencing of miR-652 protects the heart against pathological remodeling and improves heart function.


Cancellous structure of tarsal bones.
The internal structure of the tarsal bones has been studied to investigate their cancellous architecture. It is revealed that these bones have fine and coarse meshworks and even a tendency for obliteration of the trabecular pattern in the bones lying distal to this midtarsal joint. Internal structure of the talus does not show an arched pattern of bony lamellae. An increased density of bony lamellae in the internal structure of the navicular bone could result from excessive stress, enforced by its close relationship to the three cuneiform bones.


[Management of nasal meningoencephaloceles and cerebrospinal rhinorrhea].
CSF rhinorrhea constitutes a diagnostic challenge. If unrecognized or incompletely managed, it can result in devastating complications. The physician must e aware to this entity and it's management. The conventional neurosurgical management of meningoencephaloceles and cerebrospinal rhinorrhea has been by the intracranial approach. Otolaryngologists have undertaken extracranial approaches for repair of these problems with fair results. In recent years, functional endoscopic sinus surgery has gained popularity and was advocated for the repair of nasal meningoencephaloceles and CSF fistulae. Between 1998 and 1999, five patients were operated by the senior author (M.P) by means of endoscopic sinus surgery. His success rate and lower morbidity make this approach the treatment of choice. The perioperative use of fluoroscein allows us to locate precisely the defect and to confirm complete sealing of the leak. We present our experience in managing 5 cases, 3 of which presented with meningoencephaloceles.


Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations.
Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and recrystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures by the digested milk lipids. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for coadministration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.


Evaluation of Penalized-Likelihood Estimation Reconstruction on a Digital Time-of-Flight PET/CT Scanner for 18F-FDG Whole-Body Examinations.
The resolution and quantitative accuracy of PET are highly influenced by the reconstruction method. Penalized-likelihood estimation algorithms allow for fully convergent iterative reconstruction, generating a higher image contrast than ordered-subsets expectation maximization (OSEM) while limiting noise. In this study, a type of penalized reconstruction known as block-sequential regularized expectation maximization (BSREM) was compared with time-of-flight OSEM (TOF OSEM). Various strengths of noise penalization factor β were tested along with various acquisition durations and transaxial fields of view (FOVs) with the aim of evaluating the performance and clinical use of BSREM for 18F-FDG PET/CT, both quantitatively and in a qualitative visual evaluation. Methods: Eleven clinical whole-body 18F-FDG PET/CT examinations acquired on a digital TOF PET/CT scanner were included. The data were reconstructed using BSREM with point-spread function recovery and β-factors of 133, 267, 400, and 533-and using TOF OSEM with point-spread function-for various acquisition times per bed position and various FOVs. Noise level, signal-to-noise ratio (SNR), signal-to-background ratio (SBR), and SUV were analyzed. A masked evaluation of visual image quality, rating several aspects, was performed by 2 nuclear medicine physicians to complement the analysis. Results: The lowest levels of noise were reached with the highest β-factor, resulting in the highest SNR, which in turn resulted in the lowest SBR. A β-factor of 400 gave noise equivalent to TOF OSEM but produced a significant increase in SUVmax (11%), SNR (22%), and SBR (12%). BSREM with a β-factor of 533 at a decreased acquisition duration (2 min/bed position) was comparable to TOF OSEM at a full acquisition duration (3 min/bed position). Reconstructed FOV had an impact on BSREM outcome measures; SNR increased and SBR decreased when FOV was shifted from 70 to 50 cm. The evaluation of visual image quality resulted in similar scores for reconstructions, although a β-factor of 400 obtained the highest mean whereas a β-factor of 267 was ranked best in overall image quality, contrast, sharpness, and tumor detectability. Conclusion: In comparison with TOF OSEM, penalized BSREM reconstruction resulted in an increased tumor SUVmax and an improved SNR and SBR at a matched level of noise. BSREM allowed for a shorter acquisition than TOF OSEM, with equal image quality.


Evidence, causes, and consequences of declining nitrogen availability in terrestrial ecosystems.
The productivity of ecosystems and their capacity to support life depends on access to reactive nitrogen (N). Over the past century, humans have more than doubled the global supply of reactive N through industrial and agricultural activities. However, long-term records demonstrate that N availability is declining in many regions of the world. Reactive N inputs are not evenly distributed, and global changes-including elevated atmospheric carbon dioxide (CO2) levels and rising temperatures-are affecting ecosystem N supply relative to demand. Declining N availability is constraining primary productivity, contributing to lower leaf N concentrations, and reducing the quality of herbivore diets in many ecosystems. We outline the current state of knowledge about declining N availability and propose actions aimed at characterizing and responding to this emerging challenge.


Mechanisms of time-dependent potentiation of insulin release: involvement of nitric oxide synthase.
Time-dependent potentiation (TDP) of insulin release is normally absent in mice. However, we recently demonstrated that TDP occurs in mouse islets under conditions of forced decrease of intracellular pH (pH(i)) associated with elevated NADPH+H(+) (NADPH) levels. Hence, TDP in mouse islets may be kept suppressed by neuronal nitric oxide (NO) synthase (nNOS), an NADPH-utilizing enzyme with alkaline pH optimum. To determine the role of nNOS in the suppression of TDP in mouse islets, glucose-induced TDP was monitored in mouse islets in which nNOS activity had been genetically removed or chemically inhibited and compared with the TDP response in wild-type mouse islets with and without forced intracellular acidification. Genetic deletion of nNOS was provided by an nNOS knockout (NOS-KO) mouse model, B6-129S4-Nos1(tm1Plh)/J. To explore how nNOS inhibits TDP, we compared pH(i) and NADPH levels in wild-type and NOS-KO islets and monitored TDP with various components of the nNOS reaction added. Glucose normally does not produce TDP in wild-type mouse islets except under forced intracellular acidification. Remarkably, glucose produced strong TDP in NOS-KO islets and in wild-type islets treated with nNOS inhibitors. TDP in NOS-KO islets was not inhibited by the addition of NO, and NOS-KO islets exhibited a lower pH(i) than wild-type islets. The addition of arginine to wild-type islets also enabled glucose to induce TDP. Our results show that nNOS activity contributes to the absence of TDP in mouse islets putatively through depletion of intracellular arginine.


Determinants of ligand binding specificity of the alpha(1)beta(1) and alpha(2)beta(1) integrins.
The alpha(1)beta(1) and alpha(2)beta(1) integrins are cell surface collagen receptors. Cells expressing the alpha(1)beta(1) integrin preferentially adhere to collagen IV, whereas cells expressing the alpha(2)beta(1) integrin preferentially adhere to collagen I. Recombinant alpha(1) and alpha(2) integrin I domains exhibit the same collagen type preferences as the intact integrins. In addition, the alpha(2) integrin I domain binds echovirus 1; the alpha(1) I domain does not. To identify the structural components of the I domains responsible for the varying ligand specificities, we have engineered several alpha(1)/alpha(2) integrin I domain chimeras and evaluated their virus and collagen binding activities. Initially, large secondary structural components of the alpha(2) I domain were replaced with corresponding regions of the alpha(1) I domain. Following analysis in echovirus 1 and collagen binding assays, chimeras with successively smaller regions of alpha(1) I were constructed and analyzed. The chimeras were analyzed by ELISA with several different alpha(2) integrin monoclonal antibodies to assess their proper folding. Three different regions of the alpha(1) I domain, when present in the alpha(2) I domain, conferred enhanced collagen IV binding activity upon the alpha(2) I domain. These include the alpha3 and alpha5 helices and a portion of the alpha6 helix. Echovirus 1 binding was lost in a chimera containing the alphaC-alpha6 loop; higher resolution mapping identified Asn(289) as playing a critical role in echovirus 1 binding. Asn(289) had not been implicated in previous echovirus 1 binding studies. Taken together, these data reveal the existence of multiple determinants of ligand binding specificities within the alpha(1) and alpha(2) integrin I domains.


Magnetic resonance imaging during acute myocardial infarction.
Experimental canine studies have demonstrated the potential of magnetic resonance imaging (MRI) for detecting and characterizing acute myocardial infarction (AMI) in humans. Accordingly, electrocardiographic-gated spin-echo MR images of the left ventricular short axis were obtained in 34 patients a mean of 11 +/- 6 days (range 3 to 30) after AMI. This imaging technique allowed division of the left ventricle into segments corresponding to the left ventricular segments on angiography. Patients were separated into 2 groups; the first 16 patients (group I) were examined using a variety of imaging techniques. Information derived from this experience resulted in a standard imaging protocol and development of criteria for the presence of AMI. The imaging protocol and interpretation criteria were used in the assessment of a subsequent group of 18 patients (group II). Of the 14 patients in group II with satisfactory image quality, all showed an increase in myocardial signal intensity consistent with an AMI. In addition, the anterior or inferior location of the abnormal MR segments corresponded to the electrocardiographic infarct location. MR segments showing increased signal intensity corresponded with severely hypokinetic or akinetic segments on the left ventriculogram in 8 patients having both procedures. In a group of volunteers who underwent imaging and whose images were interpreted in the same manner as those of the patients with AMI, 1 of 9 subjects had regional variation in myocardial signal intensity compatible with an AMI. In summary, AMI is readily detected, located and characterized by electrocardiographic-gated MRI. These findings suggest that MRI techniques may have a role in the evaluation of AMI in humans.


Parallel language activation and inhibitory control in bimodal bilinguals.
Findings from recent studies suggest that spoken-language bilinguals engage nonlinguistic inhibitory control mechanisms to resolve cross-linguistic competition during auditory word recognition. Bilingual advantages in inhibitory control might stem from the need to resolve perceptual competition between similar-sounding words both within and between their two languages. If so, these advantages should be lessened or eliminated when there is no perceptual competition between two languages. The present study investigated the extent of inhibitory control recruitment during bilingual language comprehension by examining associations between language co-activation and nonlinguistic inhibitory control abilities in bimodal bilinguals, whose two languages do not perceptually compete. Cross-linguistic distractor activation was identified in the visual world paradigm, and correlated significantly with performance on a nonlinguistic spatial Stroop task within a group of 27 hearing ASL-English bilinguals. Smaller Stroop effects (indexing more efficient inhibition) were associated with reduced co-activation of ASL signs during the early stages of auditory word recognition. These results suggest that inhibitory control in auditory word recognition is not limited to resolving perceptual linguistic competition in phonological input, but is also used to moderate competition that originates at the lexico-semantic level.


Predictors of human papillomavirus awareness and knowledge in 2013: gaps and opportunities for targeted communication strategies.
Nearly 80 million people in the U.S. are currently infected with at least one of two strains of human papillomavirus (HPV), which is associated with 70% of cervical cancers. Greater cervical cancer mortality has been observed among women of lower SES and those living in rural, versus urban, areas. African American and Hispanic women are significantly more likely to die from cervical cancer than non-Hispanic white women. To assess current population awareness of and knowledge about HPV and the HPV vaccine, as well as the contribution of sociodemographic characteristics to disparities in HPV awareness and knowledge. Cross-sectional data were obtained from the National Cancer Institute's 2013 Health Information National Trends Survey (HINTS; N=3,185). Multivariable logistic regression was employed to identify gaps in awareness and knowledge by sex, education, income, race/ethnicity, geographic area, and other important sociodemographic characteristics. Analyses were conducted in 2014. Sixty-eight percent of Americans had heard of HPV and the HPV vaccine. Consistent with the Knowledge Gap Hypothesis, awareness and knowledge were patterned by sex, age, education, and other important sociodemographic factors. Those in rural areas were less likely than those in urban areas to know that HPV causes cervical cancer. Less than 5% of Americans were aware that HPV often clears on its own without treatment. Although awareness and knowledge of HPV is increasing, there are opportunities to target communication with populations for whom knowledge gaps currently exist, in order to promote dialogue about the vaccine among patients and their providers.


The insulin response to intravenous fructose in maturity-onset diabetes mellitus and in normal subjects.
Insulin responses to intravenous fructose and glucose were measured in 15 patients with maturity-onset diabetes mellitus. In eight patients given fructose first the insulin responses to fructose and glucose were similar. In seven patients given glucose first the insulin response to subsequently infused fructose was significantly greater than to glucose. Multiple regression analysis showed that the ratio of the fructose to glucose insulin response, assessed by area under the insulin serum concentration-time curve (F/G ratio) in individual patients, correlated most closely with prefructose infusion plasma glucose. Similar analysis, applied to results in 27 normal subjects, showed that the most important determinant of the insulin response to fructose in this group also was the immediate prefructose infusion plasma glucose. Thus in diabetics, as in normal controls, the response of the beta cell to intravenous fructose appears to be sensitively set by the ambient plasma glucose concentration at the onset of fructose infusion.


Experimental infection of gnotobiotic mice with Campylobacter jejuni: colonisation of intestine and spread to lymphoid and reticulo-endothelial organs.
Axenic and monoxenic C3H mice were used to develop an animal model for enteroinvasiveness and translocation of Campylobacter jejuni. After oral administration of 10(7)-10(8) viable cells of C. jejuni on day 0 (D0), bacterial colonisation was followed quantitatively during 23 days by counting free luminal bacteria and tissue-associated bacteria in the duodenum, ileum and colon. The kinetics of bacterial colonisation were the same in axenic and monoxenic mice; bacteria were more numerous in distal than in proximal intestinal segments. Electronmicroscope studies of axenic infected mice showed C. jejuni free in the intestinal lumen on D2 and D7, and adhering to microvilli or included in enterocyte vacuoles in the colon on D2 without inflammatory reaction; C. jejuni was isolated from mesenteric lymph nodes until D23, but from blood, spleen, liver and bile until D1 only. In monoxenic infected mice, C. jejuni was found from D1 to D4 in mesenteric lymph nodes and Peyer's patches, whereas the associated bacterium (Clostridium perenne) was never cultured from any organs. On the basis of our observations in this gnotobiotic model, C. jejuni appears to be an enteroinvasive bacterium with a particular affinity for lymphoid organs.


The human membrane cofactor CD46 is a receptor for species B adenovirus serotype 3.
Many human adenovirus (Ad) serotypes use the coxsackie B virus-Ad receptor (CAR). Recently, CD46 was suggested to be a receptor of species B Ad serotype 11 (Ad11), Ad14, Ad16, Ad21, Ad35, and Ad50. Using Sindbis virus-mediated cDNA library expression, we identify here the membrane cofactor protein CD46 as a surface receptor of species B Ad3. All four major CD46 transcripts and one minor CD46 transcript expressed in nucleated human cells were isolated. Rodent BHK cells stably expressing the BC1 form of CD46 bound radiolabeled Ad3 with a dissociation constant of 0.3 nM, identical to that of CD46-positive HeLa cells expressing twice as many Ad3 binding sites. Pull-down experiments with recombinant Ad3 fibers and a soluble form of the CD46 extracellular domain linked to the Fc portion of human immunoglobulin G (CD46ex-Fc) indicated direct interactions of the Ad3 fiber knob with CD46ex-Fc but not CARex-Fc (Fc-linked extracellular domain of CAR). Ad3 colocalized with cell surface CD46 in both rodent and human cells at the light and electron microscopy levels. Anti-CD46 antibodies and CD46ex-Fc inhibited Ad3 binding to CD46-expressing BHK cells more than 10-fold and to human cells 2-fold. In CD46-expressing BHK cells, wild-type Ad3 and a chimeric Ad consisting of the Ad5 capsid and the Ad3 fiber elicited dose-dependent cytopathic effects and transgene expression, albeit less efficiently than in human cells. Together, our results show that all of the major splice forms of CD46 are predominant and functional binding sites of Ad3 on CD46-expressing rodent and human cells but may not be the sole receptor of species B Ads on human cells. These results have implications for understanding viral pathogenesis and therapeutic gene delivery.


Transcriptional mapping of the bacteriophage Mu DNA.
The transcription of temperate phage Mu throughout lytic development was analysed quantitatively by hybridization of pulse-labelled RNA to full-length Mu DNA and to plasmids that define Mu DNA segments covering the whole phage genome. The transcription rate (i.e. binding data corrected for the incorporation rate of the radioactive precursor, for the size of the DNA template, and for the number of phage genomes present in the bacterium at the time of analysis) revealed three defined phases of Mu transcription: early (0 to 9 min), intermediate (between 9 and the interval 14 to 17 min) and late (from the interval 14 to 17 min onward). The analysis also revealed that the region comprising the genes involved in phage morphogenesis was organized into two independent 'late' transcription units.


Differences between caregiver-perceived and dentist-assessed oral health status of patients among intellectual disabilities.
This study compared the caregiver-perceived and dentist-determined oral health status of patients with intellectual disabilities to determine factors that affect caregiver-perception of patients' oral health. 297 patients [mean (SD) age = 51.9 (12.5) years] and 56 professional caregivers [42.1 (8.2) years] from three institutional facilities took part. Data were acquired via self-administered questionnaires by caregivers and oral examination by dentists. Oral hygiene condition, numbers of decayed and missing teeth, and periodontal disease reported by caregivers and dentists were compared using paired t-test and Pearson correlation. Demographic and dental factors of the patients and caregivers were analyzed using chi square and Fisher's exact tests. Caregivers underestimated decayed and missing teeth compared to dentists (p⟨0.05). Oral hygiene condition and periodontal disease were similarly rated by the two groups. Tooth brushing, diet type, sex, and overall oral health status of the patients were associated with caregiver perception (p⟨0.05). Career length and time since caregivers last received dental care were also related factors (p⟨0.05). Professional caregivers of adult patients with intellectual disabilities had different perceptions of oral health status based on patient and caregiver circumstances.


Testing and evaluation of opiate analgesics and antagonists.
In recent years many advances have been made in our understanding of how opiates function as modulators of pain. These discoveries have in turn led to substantial improvements in the methodology available for the testing of newly synthesized opiates. Preliminary in vitro assays can now define opiate receptor selectivity and also classify a drug as a pure or mixed agonist-antagonist. These results can then be verified by in vivo behavioral or neurochemical studies using laboratory animals. This protocol, which involves tests that are relatively simple and inexpensive to conduct, yields reproducible results which provide insight into the study design required for the clinical evaluation of the new agents. Considering the complexity of the problem involved in modifying the pharmacological profile of an opiate, the progress that has been made in the methodology for evaluating these substances is commendable.


Mechanisms of virus-induced asthma exacerbations: state-of-the-art. A GA2LEN and InterAirways document.
Viral infections of the respiratory tract are the most common precipitants of acute asthma exacerbations. Exacerbations are only poorly responsive to current asthma therapies and new approaches to therapy are needed. Viruses, most frequently human rhinoviruses (RV), infect the airway epithelium, generate local and systemic immune responses, as well as neural responses, inducing inflammation and airway hyperresponsiveness. Using in vitro and in vivo experimental models the role of various proinflammatory or anti-inflammatory mediators, antiviral responses and molecular pathways that lead from infection to symptoms has been partly unravelled. In particular, mechanisms of susceptibility to viral infection have been identified and the bronchial epithelium appeared to be a key player. Nevertheless, additional understanding of the integration between the diverse elements of the antiviral response, especially in the context of allergic airway inflammation, as well as the interactions between viral infections and other stimuli that affect airway inflammation and responsiveness may lead to novel strategies in treating and/or preventing asthma exacerbations. This review presents the current knowledge and highlights areas in need of further research.


Molecular and biochemical aspects of chitin synthesis inhibition.
Chitin, is a beta-1,4-linked aminopolysacharide homopolymer of GlcNAc that occurs as a glycoprotein in the exoskeleton of arthropods, the cell wall of fungi and in various components of diverse invertebrates. It is synthesized in two different ways: in fungi the chitin synthase enzyme occurs as an inactive zymogen in vesicles called chitosomes and requires proteolytic activation; in arthropods this enzyme is membrane-bound and catalyzes the addition of GlcNAc units to a dolichol carrier. Chitin is degraded by three different chitinases, the endochitinase that degrades chitin into oligosaccharides of differing chain lengths, the exochitinase that degrades oligosaccharides into diacetylchitobiose and chitobiase, which degrades diacetylchitobiose into GlcNAc monomers. Inhibition of chitin synthesis as well as degradation can both result in deleterious effects that are often similar. Chitin synthesis can be blocked during the various steps by a variety of antibiotics, metabolic inhibitors, insect growth regulators, alkaloids and hormone analogs. During the molting process in arthropods, genes are sequentially expressed and repressed by developmental hormones. When these hormones or their analogs are administered temporally out of sequence, it can result in the blocking of cuticle formation, including chitin synthesis. With the advent of biotechnology and the availability of both complementary DNA and antibody probes, it is possible to develop high throughput assays for discovering new chemicals that can block chitin formation. Chitin synthesis inhibitors as well as inhibitors of chitin degradation that produce similar effects are promising agents for controlling insect pests, fungal pathogens and helminthic parasites.


New Era: Endoscopic treatment options in obesity-a paradigm shift.
The prevalence of obesity continues to rise, and along with it comes a multitude of health-related consequences. The healthcare community has consistently struggled with providing treatment options to obese patients, in part due to the reluctance of patients in pursuing the more effective (yet invasive) surgical approaches such as sleeve gastrectomy and Rou-en-Y gastric bypass. On the other hand, the less invasive approach such as lifestyle/behavioral interventions and pharmacotherapy (Orlistat, Phenteramine, Phentermine/Topiramate, Locaserin, Naltrexon/Buproprion, and Liraglutide) have very limited efficacy, especially in the morbidly obese patients. Despite our best efforts, the epidemic of obesity continues to rise and pose enormous costs on our healthcare system and society. Bariatric endoscopy is an evolving field generated to combat this epidemic through minimally invasive techniques. These procedures can be performed in an ambulatory setting, are potentially reversible, repeatable, and pose less complications than their invasive surgical counterparts. These modalities are designed to alter gut metabolism by means of space occupation, malabsorption, or restriction. In this review we will discuss different bariatric endoscopic options (such as intragastric balloons, endoscopic sleeve gastroplasty, endoscopic aspiration therapies and gastrointestinal bypass sleeves), their advantages and disadvantages, and suggest a new paradigm where providers may start incorporating this modality in their treatment approach for obese patients.


[Phyllodes tumor in the breast].
In three women aged 51, 37 and 58 years, with a palpable tumour in the breast, excision and pathological examination led to the diagnosis of 'phyllodes tumour'. During 3-5 years after radical excision, in one patient followed by radiotherapy, no recurrences were seen. This rare breast tumour with a variable clinical course usually affects women between the ages of 30 and 50. There is often a large tumour and (or) rapid growth. Mammography and ultrasound are unhelpful diagnostically. Cytology is unreliable as the tumour is heterogeneous. Histologically the tumour can be benign, borderline malignant or malignant. Surgical excision with a margin of > or = 1 cm is the therapy of choice. The risk of recurrence after insufficient excision is considerable and histological deterioration can occur. Multiple samples, examination of resection margins and investigation into atypia, mitotic activity and stromal overgrowth are essential for making a prognosis and a treatment plan. In case of doubt regarding radicality, surgeon and pathologist should compare views; non-radicality necessitates re-excision.


Electronic-health in Saudi Arabia. Just around the corner?
The Saudi health sector has witnessed significant progress in recent decades with some local hospitals receiving international recognition. However, this has not been accompanied by advancement of the electronic-health e-health field, whose applications have become a necessity for hospitals to achieve certain objectives such as enhancing the quality of healthcare, and reducing the time and cost for healthcare delivery. In this paper we investigate the advancement of e-health in the world and in Saudi Arabia. A new model for e-health diffusion in Saudi Arabia is also proposed.


Molecular aspects of age-related cognitive decline: the role of GABA signaling.
Alterations in inhibitory interneurons contribute to cognitive deficits associated with several psychiatric and neurological diseases. Phasic and tonic inhibition imparted by γ-aminobutyric acid (GABA) receptors regulates neural activity and helps to establish the appropriate network dynamics in cortical circuits that support normal cognition. This review highlights basic science demonstrating that inhibitory signaling is altered in aging, and discusses the impact of age-related shifts in inhibition on different forms of memory function, including hippocampus-dependent spatial reference memory and prefrontal cortex (PFC)-dependent working memory. The clinical appropriateness and tractability of select therapeutic candidates for cognitive aging that target receptors mediating inhibition are also discussed.


Expression of plasminogen activator inhibitors type-1 and type-2 in the mouse lung after administration of crystalline silica.
Altered expression of plasminogen activator inhibitors (PAIs) is of potential relevance to the process of lung fibrosis. To clarify the involvement of PAIs in interstitial lung diseases, we examined whether alterations in PAI-1 and PAI-2 were induced in response to a single intratracheal administration of a fibrosing dose of crystalline silica in mice (5 mg x animal(-1)). The time course of changes in PAI activity and PAI-1 protein were characterized in bronchoalveolar lavage fluid (BALF) and changes in PAI-1 and PAI-2 messenger ribonucleic acid (mRNAs) were monitored by reverse transcriptase polymerase chain reaction (RT-PCR) in BALF cells and lung tissue up to the fibrotic stage of the disease. Substantial levels of PAI activity were found in BALF of control animals, whereas no PAI-1 protein was detected. In response to silica treatment, we observed an acute increase of PAI activity and PAI-1 protein levels in BALF (day 1), associated with an induction of PAI-1 and PAI-2 mRNA levels in lung tissue. In alveolar macrophages, silica treatment induced a persistent upregulation of PAI-2 mRNA only. One month after silica treatment, PAI activity was undetectable in BALF while substantial PAI activity was still present in controls. At the same time point, sustained upregulation of PAI-1 and PAI- 2 mRNAs was, however, noted in lung tissue of animals treated with silica. These findings support the possible implication of PAIs in the remodelling process induced by silica in the lung.


CALUX measurements: statistical inferences for the dose-response curve.
Chemical Activated LUciferase gene eXpression [CALUX] is a reporter gene mammalian cell bioassay used for detection and semi-quantitative analyses of dioxin-like compounds. CALUX dose-response curves for 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] are typically smooth and sigmoidal when the dose is portrayed on a logarithmic scale. Non-linear regression models are used to calibrate the CALUX response versus TCDD standards and to convert the sample response into Bioanalytical EQuivalents (BEQs). Several complications may arise in terms of statistical inference, specifically and most important is the uncertainty assessment of the predicted BEQ. This paper presents the use of linear calibration functions based on Box-Cox transformations to overcome the issue of uncertainty assessment. Main issues being addressed are (i) confidence and prediction intervals for the CALUX response, (ii) confidence and prediction intervals for the predicted BEQ-value, and (iii) detection/estimation capabilities for the sigmoid and linearized models. Statistical comparisons between different calculation methods involving inverse prediction, effective concentration ratios (ECR(20-50-80)) and slope ratio were achieved with example datasets in order to provide guidance for optimizing BEQ determinations and expand assay performance with the recombinant mouse hepatoma CALUX cell line H1L6.1c3.


From the Editor: An Introduction to the JSLHR Supplement on Implementation Science.
The JSLHR Supplement on Implementation Science is aimed at providing discussion and examples of research in implementation science, the study of methods designed to promote the incorporation of research findings into clinical practice. Practitioners in the language science area were invited to submit articles that address their experience with various aspects of implementation science. Six articles from several research groups comprise this supplement. Implementation science is an aspect of intervention research that merits consideration by communication disorders scientists. More extensive practice of implementation science will improve uptake of evidence-based practice in the clinical community.


Possible congenital dilatation of the pancreatic duct.
The main pancreatic duct can become dilated in a number of conditions. We describe a patient with gross dilatation of the main pancreatic duct without evidence of causative underlying pathology suggesting congenital dilatation of the pancreatic duct. A 36-year-old man presented with signs of intestinal obstruction and a history of surgery for congenital pyloric stenosis. Incidental findings on CT showed a massively dilated main pancreatic duct. On MRI there was no duct irregularity or solid mural nodule, making a main duct intraductal papillary mucinous neoplasm unlikely. Endoscopic ultrasound findings were in keeping with those on MRI. Fine needle aspiration revealed a non-viscous fluid with a low carcinoembryonic antigen and high amylase concentration, consistent with normal pancreatic fluid levels rather than a mucinous collection. After 1 year, the cyst remains unchanged. This patient will be kept under surveillance with yearly MRI.


Site-specific cleavage of natural mRNA sequences by newly designed hairpin catalytic RNAs.
The negative strand of tobacco ringspot virus satellite RNA is a self-cleaving RNA. Its catalytic domain and substrate domain have been identified, and the catalytic domain has been named hairpin catalytic RNA. Here we report the construction of a plasmid containing a modified hairpin catalytic RNA sequence that can be transcribed in vitro. Because this plasmid has two specific restriction enzyme recognition sites at both ends of the substrate binding site in the catalytic RNA sequence, it is possible to construct new plasmids by substituting different sequences in the substrate binding site. Using this plasmid, synthetic DNA, and in vitro transcription, we obtained three ribozymes designed to cleave Escherichia coli prolipoprotein signal peptidase (lsp) mRNA at specific sites. All three ribozymes cleaved the lsp mRNA sequence in vitro at the specific sites, and two of them cleaved it efficiently. Kinetic analyses showed that one had a higher kcat/Km value than that of the well-known hammerhead ribozyme. Problems associated with attaining the goal of expressing these ribozymes in vivo also are discussed.


A new species of Heterochondria (Copepoda: Chondracanthidae) parasitic on many-banded sole, Zebrias fasciatus (Pleuronectiformes: Soleidae) from Korea, with a key to the species of the genus.
A new species of Chondracanthidae (Copepoda: Cyclopoida), Heterochondria orientalis sp. n., is described based on specimens of both sexes collected from the gill rakers and the inner side of the operculum of the many-banded sole, Zebrias fasciatus (Basilewsky), from the Yellow Sea, Korea. The new species resembles most closely H. zebriae (Ho, Kim et Kuman, 2000), but can be distinguished from this species and other congeners by the shape of the trunk and length of the antenna, the number of teeth on the mandible and the terminal process of the maxilla, and the structure of the male antennule and maxilliped. Heterochondria orientalis is the first copepod species reported from Z. fasciatus and the first heterochondrid species reported from sole fishes in the Northwest Pacific. A key to distinguish all 10 nominal species of the genus is provided.


web cellHTS2: a web-application for the analysis of high-throughput screening data.
The analysis of high-throughput screening data sets is an expanding field in bioinformatics. High-throughput screens by RNAi generate large primary data sets which need to be analyzed and annotated to identify relevant phenotypic hits. Large-scale RNAi screens are frequently used to identify novel factors that influence a broad range of cellular processes, including signaling pathway activity, cell proliferation, and host cell infection. Here, we present a web-based application utility for the end-to-end analysis of large cell-based screening experiments by cellHTS2. The software guides the user through the configuration steps that are required for the analysis of single or multi-channel experiments. The web-application provides options for various standardization and normalization methods, annotation of data sets and a comprehensive HTML report of the screening data analysis, including a ranked hit list. Sessions can be saved and restored for later re-analysis. The web frontend for the cellHTS2 R/Bioconductor package interacts with it through an R-server implementation that enables highly parallel analysis of screening data sets. web cellHTS2 further provides a file import and configuration module for common file formats. The implemented web-application facilitates the analysis of high-throughput data sets and provides a user-friendly interface. web cellHTS2 is accessible online at http://web-cellHTS2.dkfz.de. A standalone version as a virtual appliance and source code for platforms supporting Java 1.5.0 can be downloaded from the web cellHTS2 page. web cellHTS2 is freely distributed under GPL.


A risk and economic analysis of dirty bomb attacks on the ports of Los Angeles and Long Beach.
This article analyzes possible terrorist attacks on the ports of Los Angeles and Long Beach using a radiological dispersal device (RDD, also known as a "dirty bomb") to shut down port operations and cause substantial economic and psychological impacts. The analysis is an exploratory investigation of a combination of several risk analysis tools, including scenario generation and pruning, project risk analysis, direct consequence modeling, and indirect economic impact assessment. We examined 36 attack scenarios and reduced them to two plausible or likely scenarios using qualitative judgments. For these two scenarios, we conducted a project risk analysis to understand the tasks terrorists need to perform to carry out the attacks and to determine the likelihood of the project's success. The consequences of a successful attack are described in terms of a radiological plume model and resulting human health and economic impacts. Initial findings suggest that the chances of a successful dirty bomb attack are about 10-40% and that high radiological doses are confined to a relatively small area, limiting health effects to tens or at most hundreds of latent cancers, even with a major release. However, the economic consequences from a shutdown of the harbors due to the contamination could result in significant losses in the tens of billions of dollars, including the decontamination costs and the indirect economic impacts due to the port shutdown. The implications for countering a dirty bomb attack, including the protection of the radiological sources and intercepting an ongoing dirty bomb attack are discussed.


Gender differences in HIV and hepatitis C related vulnerabilities among aboriginal young people who use street drugs in two Canadian cities.
Vulnerability to HIV and Hepatitis C virus (HCV) infection for indigenous populations worldwide must be contextualized in experiences of current and past trauma. Aboriginal women entrenched in poverty face further gender-specific harms which place them at increased risk for HIV infection. This study was cross-sectional and based on a community-based sample of Aboriginal young people (Metis, Aboriginal, First Nations, Inuit, and non-status Indians) between the ages of 14 and 30 years who used injection or non-injection non-cannabis illegal drugs (street drugs) in the previous month. Between October 2003 and July 2005, 543 participants living in either Vancouver or Prince George, Canada, were recruited by word of mouth, posters, and street outreach. Young people in the study completed a questionnaire administered by Aboriginal interviewers. Female participants (n = 262) were compared to male participants (n = 281) with respect to sociodemographics, trauma, sexual risk variables, and drug use patterns. Trained nurses drew blood samples for HIV and HCV antibodies and provided pre- and post-test counseling. Proportions positive for HIV and HCV were significantly higher among young women. HIV was 13.1% [9.5, 17.7] in women compared to 4.3% [2.5, 7.4] in men, and HCV was 43.6% [37.6, 49.8] in women as compared to 25.4% [20.5, 30.9] in men. When the analysis was restricted to young people who reported injection drug use, the proportions positive for HIV and HCV remained significantly higher among young women. Experiences of forced sex were reported by 70% of young women compared to 29% of young men, p < 0.001, while the median age of first forced sex was 6-years-old for both men and women. The results of the final model indicated that HIV had been associated with residing in Vancouver, having injected for longer, and sexual abuse, but not being female. However, this gendered analysis demonstrated that a greater proportion of young women were experiencing sexual abuse, and sexual abuse was associated with HIV positive status. Harm reduction and drug treatment programs are urgently required that target women at a young age and address complex traumatic experiences associated with childhood sexual abuse.


Tetrandrine as a calcium antagonist.
1. The Ca(2+)-antagonism of tetrandrine (TET) on the Ca2+ mobilization in various types of cells were reviewed. Inositol trisphosphate (IP3)-generating drugs were used as Ca(2+)-mobilizing agonists and the effects were compared with those produced by using the microsomal Ca(2+)-ATPase inhibitor thapsigargin (TG), which is a tool for analysing Ca2+ store-regulated Ca2+ entry (capacitative Ca2+ entry). 2. In rat phaeochromocytoma PC12 cells, 100 mumol/L TET abolished high K+ (30 mmol/L)-induced sustained increases in cytoplasmic Ca2+ concentrations ([Ca2+]i) and partially inhibited bradykinin (1 mumol/L)- or TG (100 nmol/L)-induced Ca2+ entry. 3. In NIH/3T3 fibroblasts and rat parotid acinar cells, 100 mumol/L TET abolished Ca2+ entry induced by bombesin (1 mumol/L) and carbachol (100 mumol/L), respectively, or TG (100 nmol/L). However, in the human leukaemia T cell line Jurkat, 100 mumol/L TET did not inhibit Ca2+ entry evoked by either the anti-CD3 antibody OKT3 (10 mg/L) or TG (100 nmol/L). 4. In rat glioma C6 cells, the effects of TET on Ca2+ mobilization were further examined. At a high concentration, TET (300 mumol/L) alone did not affect [Ca2+]i in C6 cells. Tetrandrine inhibited the peak and sustained increases in [Ca2+]i induced by bombesin and TG in a dose-dependent manner. Although TET or TG did not produce increases in IP3, TET did inhibit increases in IP3 produced by bombesin. 5. Our results suggest that the action of TET on Ca2+ entry is dependent on cell types and that TET inhibits both Ca2+ entry from the extracellular medium and Ca2+ release from intracellular stores in rat glioma C6 cells.