Shear-thinning effects of hemodynamics in patient-specific cerebral aneurysms.
Two different generalized Newtonian mathematical models for blood flow, derived for the same experimental data, are compared, together with the Newtonian model, in three different anatomically realistic geometries of saccular cerebral aneurysms obtained from rotational CTA. The geometries differ in size of the aneurysm and the existence or not of side branches within the aneurysm. Results show that the differences between the two generalized Newtonian mathematical models are smaller than the differences between these and the Newtonian solution, in both steady and unsteady simulations.


Sex and age specific time patterns and long term time trends of pre-hospital delay of patients presenting with acute ST-segment elevation myocardial infarction.
Prompt initiation of treatment after symptom onset of ST-elevation myocardial infarction (STEMI) is a central goal in limiting myocardial damage because of the time-dependent nature of reperfusion therapies. We examined time patterns and long term time trends of pre-hospital delay time (PHDT) of STEMI patients. PHDT from 3093 STEMI patients derived from the Augsburg Myocardial Infarction Registry (1985-2004) surviving >24h after admission was obtained by a standardized bedside interview. Patients with in-hospital MI (n=140) and resuscitation (n=157) were excluded. Linear regression models were used to examine monthly median PHDT and individual PHDT over time. Female sex was associated with longer PHDT (189 (98-542quartiles) min vs. 154 (85-497) min; p<0.0003). Median PHDT in the youngest male subgroup (25-54 years) was 128 (73-458) min and mounted to 205 (107-600) min in the oldest female subgroup (65-74 years). A minority of 12.4% of patients reached hospital within 1h of delay ranging from 8.7% (in oldest women) to 15.9% (in youngest men). The age-adjusted linear regression model for monthly PHDT revealed no significant change over 20-year time in both sexes. The corresponding average annual percentage change estimates were -0.45 (95% CI: -1.40 to 0.54) for men and -0.08 (95% CI: -1.80 to 1.67) for women. Emergency ambulance use increased over time, however transportation time remained stable. PHDT in STEMI patients is constantly high over a 20-year observation period. Room for improvement especially in older women was evidenced. Preventive strategies with focused efforts on this subgroup are warranted.


Predicting the risk of bone metastasis in prostate cancer.
The ability to identify prostate cancer patients at 'high risk' for bone metastasis development could allow early selection of those most likely to benefit from interventions to prevent or delay bone metastasis. This review is aimed to identify potential predictors of risk for bone metastasis in newly diagnosed patients and in those who have already received treatment. At diagnosis, established predictors of prostate cancer aggressiveness (e.g. PSA level, clinical stage, Gleason score) can identify patients at risk for bone metastasis. Following treatment of the disease, increasing evidence suggests that absolute PSA levels and other measures of PSA kinetics are useful to aid prediction of bone metastasis risk in patients both with and without a history of ADT. However, which PSA parameter most accurately predicts risk and the cut-off values that should be employed are unclear. Inclusion of PSA parameters to identify a high risk population may be beneficial in whom bone-modifying treatments are being considered. Other novel (but unvalidated) biomarkers that potentially predict the development of bone metastases have been identified, although it is unclear whether they will have value as independent markers or when combined with other parameters (e.g. measures of PSA kinetics). Further prospective studies of PSA kinetics and other predictive markers are, therefore, required to define the optimal criteria for identifying patients at high risk of bone metastases and those who are most likely to benefit from intensive monitoring and therapeutic intervention.


Integrated FDG PET/CT: Utility and Applications in Clinical Oncology.
Accurate diagnosis and staging are essential for an optimal management of cancer patients. Positron emision tomography with 2-deoxy-2-fluorine-18-fluoro-D-glucose ((18)FDG-PET) and, more recently, (18)FDG-PET/computed tomography ((18)FDG-PET/CT) have emerged as powerful imaging tools in oncology, because of the valuable functional information they provide. The combined acquisition of PET and CT has synergistic advantages over its isolated constituents and minimizes their limitations. It decreases examination times by 25%-40%, leads to a higher patient throughput and unificates two imaging procedures in a single session. There is evidence that (18)FDG-PET/CT is a more accurate test than either of its components for the evaluation of various tumors. It is a particularly valuable tool for detection of recurrence, especially in asymptomatic patients with rising tumor markers and those with negative or equivocal findings on conventional imaging tests. Yet, there are some limitations and areas of uncertainty, mainly regarding the lack of specificity of the (18)FDG uptake and the variable (18)FDG avidity of some cancers. This article reviews the advantages, limitations and main applications of (18)FDG-PET/CT in oncology, with especial emphasis on lung cancer, colorectal cancer, lymphomas, melanoma and head and neck cancers.


Dysregulation of neutrophil death in sepsis.
Sepsis is a prevalent disease that has alarmingly high mortality rates and, for several survivors, long-term morbidity. The modern definition of sepsis is an aberrant host response to infection followed by a life-threatening organ dysfunction. Sepsis has a complicated pathophysiology and involves multiple immune and non-immune mediators. It is now believed that in the initial stages of sepsis, excessive immune system activation and cascading inflammation are usually accompanied by immunosuppression. During the pathophysiology of severe sepsis, neutrophils are crucial. Recent researches have demonstrated a clear link between the process of neutrophil cell death and the emergence of organ dysfunction in sepsis. During sepsis, spontaneous apoptosis of neutrophils is inhibited and neutrophils may undergo some other types of cell death. In this review, we describe various types of neutrophil cell death, including necrosis, apoptosis, necroptosis, pyroptosis, NETosis, and autophagy, to reveal their known effects in the development and progression of sepsis. However, the exact role and mechanisms of neutrophil cell death in sepsis have not been fully elucidated, and this remains a major challenge for future neutrophil research. We hope that this review will provide hints for researches regarding neutrophil cell death in sepsis and provide insights for clinical practitioners.


[3-dimensional model of transcription and the mechanism of RNA elongation].
The spatial aspects of template-dependent synthesis of RNA have been considered. It has been concluded that the idea of helical translocation on DNA double helix does not correspond to the literary experimental data. An alternative model given here proposes that the growing end of an RNA molecule is capable of transient disconnection from its template without dissociation of the whole transcriptional complex and the steric hindrances imposed by DNA helical turns are relaxed via this disconnection. This supposition explains the way of RNA release, the template properties of nucleosome chains and also some features of interrelations between RNA and DNA during transcription.


A comparison of conventional surfactant treatment and partial liquid ventilation on the lung volume of injured ventilated small lungs.
As an alternative to surfactant therapy (ST), partial liquid ventilation (PLV) with perfluorocarbons (PFC) has been considered as a treatment for acute lung injury (ALI) in newborns. The instilled PFC is much heavier than the instilled surfactant and the aim of this study was to investigate whether PLV, compared to ST, increases the end-expiratory volume of the lung (VL). Fifteen newborn piglets (age <12 h, mean weight 678 g) underwent saline lung lavage to achieve a surfactant depletion. Thereafter animals were randomized to PLV (n = 8), receiving PFC PF5080 (3M, Germany) at 30 mL kg(-1), and ST (n = 7) receiving 120 mg Curosurf®. Blood gases, hemodynamics and static compliance were measured initially (baseline), immediately after ALI, and after 240 min mechanical ventilation with either technique. Subsequently all piglets were killed; the lungs were removed in toto and frozen in liquid N2. After freeze-drying the lungs were cut into lung cubes (LCs) with edge lengths of 0.7 cm, to calculate VL. All LCs were weighed and the density of the dried lung tissue was calculated. No statistically significant differences between treatment groups PLV and ST (means ± SD) were noted in body weight (676 ± 16 g versus 679 ± 17 g; P = 0.974) or lung dry weight (1.64 ± 0.29 g versus 1.79 ± 0.48 g; P = 0.48). Oxygenation index and ventilatory efficacy index did not differ significantly between both groups at any time. VL (34.28 ± 6.13 mL versus 26.22 ± 8.1 mL; P < 0.05) and the density of the dried lung tissue (48.07 ± 5.02 mg mL(-1) versus 69.07 ± 5.30 mg mL(-1); P < 0.001), however, differed significantly between the PLV and ST groups. A 4 h PLV treatment of injured ventilated small lungs increased VL by 30% and decreased lung density by 31% compared to ST treatment, indicating greater lung distension after PLV compared to ST.


A mathematical model of COVID-19 transmission in a tertiary hospital and assessment of the effects of different intervention strategies.
Novel coronavirus (named SARS-CoV-2) can spread widely in confined settings including hospitals, cruise ships, prisons, and places of worship. In particular, a healthcare-associated outbreak could become the epicenter of coronavirus disease (COVID-19). This study aimed to evaluate the effects of different intervention strategies on the hospital outbreak within a tertiary hospital. A mathematical model was developed for the COVID-19 transmission within a 2500-bed tertiary hospital of South Korea. The SEIR (susceptible-exposed-infectious-recovered) model with a compartment of doctor, nurse, patient, and caregiver was constructed. The effects of different intervention strategies such as front door screening, quarantine unit for newly admitted patients, early testing of suspected infected people, and personal protective equipment for both medical staff and visitors were evaluated. The model suggested that the early testing (within eight hours) of infected cases and monitoring the quarantine ward for newly hospitalized patients are effective measures for decreasing the incidence of COVID-19 within a hospital (81.3% and 70% decrease of number of incident cases, respectively, during 60 days). Front door screening for detecting suspected cases had only 42% effectiveness. Screening for prohibiting the admission of COVID-19 patients was more effective than the measures for patients before emergency room or outpatient clinic. This model suggests that under the assumed conditions, some effective measures have a great influence on the incidence of COVID-19 within a hospital. The implementation of the preventive measures could reduce the size of a hospital outbreak.


Adhesion force of staphylococcus aureus on various biomaterial surfaces.
Staphylococcus comprises of more than half of all pathogens in orthopedic implant infections and they can cause major bone infection which can result in destruction of joint and bone. In the current study, adhesion force of bacteria on the surface of various biomaterial surfaces is measured using atomic force microscope (AFM). Staphylococcus aureus was immobilized on an AFM tipless cantilever as a force probe to measure the adhesion force between bacteria and biomaterials (viz. ultra-high molecular weight poly ethylene (UHMWPE), stainless steel (SS), Ti-6Al-4V alloy, hydroxyapatite (HA)). At the contact time of 10s, UHMWPE shows weak adhesion force (~4nN) whereas SS showed strong adhesion force (~15nN) due to their surface energy and surface roughness. Bacterial retention and viability experiment (3M™ petrifilm test, agar plate) dictates that hydroxyapatite shows the lowest vaibility of bacteria, whereas lowest bacterial retention is observed on UHMWPE surface. Similar results were obtained from live/dead staining test, where HA shows 65% viability, whereas on UHMWPE, SS and Ti-6Al-4V, the bacterial viability is 78%, 94% and 97%, respectively. Lower adhesion forces, constrained pull-off distance (of bacterial) and high antibacterial resistance of bioactive-HA makes it a potential biomaterial for bone-replacement arthroplasty.


Frequent deletions at Xq28 indicate genetic heterogeneity in Hunter syndrome.
Hunter syndrome is a human X-linked disorder caused by deficiency of the lysosomal exohydrolase iduronate-2-sulphatase (IDS). The consequent accumulation of the mucopolysaccharides dermatan sulphate and heparan sulphate, in the brain and other tissues, often results in death before adulthood. There is, however, a broad spectrum of severity that has been attributed to different mutations of the Hunter syndrome gene. We have used an IDS cDNA clone to localise the IDS gene to Xq28, distal to the fragile X mutation (FRAXA). One-third of Hunter syndrome patients had various deletions or rearrangements of their IDS gene, proving that different mutations are common in this condition. Deletions of the IDS gene can include a conserved locus that is tightly linked to FRAXA, suggesting that deletion of nearby genes may contribute to the variable clinical severity noted in Hunter syndrome. The cDNA clone was also shown to span the X chromosome breakpoint in a female Hunter syndrome patient with an X;autosome translocation.


Pediatric emergency medicine point-of-care ultrasound: summary of the evidence.
The utility of point-of-care ultrasound is well supported by the medical literature. Consequently, pediatric emergency medicine providers have embraced this technology in everyday practice. Recently, the American Academy of Pediatrics published a policy statement endorsing the use of point-of-care ultrasound by pediatric emergency medicine providers. To date, there is no standard guideline for the practice of point-of-care ultrasound for this specialty. This document serves as an initial step in the detailed "how to" and description of individual point-of-care ultrasound examinations. Pediatric emergency medicine providers should refer to this paper as reference for published research, objectives for learners, and standardized reporting guidelines.


Fabricated micro-nano devices for in vivo and in vitro biomedical applications.
In recent years, the innovative use of microelectromechanical systems (MEMSs) and nanoelectromechanical systems (NEMSs) in biomedical applications has opened wide opportunities for precise and accurate human diagnostics and therapeutics. The introduction of nanotechnology in biomedical applications has facilitated the exact control and regulation of biological environments. This ability is derived from the small size of the devices and their multifunctional capabilities to operate at specific sites for selected durations of time. Researchers have developed wide varieties of unique and multifunctional MEMS/NEMS devices with micro and nano features for biomedical applications (BioMEMS/NEMS) using the state of the art microfabrication techniques and biocompatible materials. However, the integration of devices with the biological milieu is still a fundamental issue to be addressed. Devices often fail to operate due to loss of functionality, or generate adverse toxic effects inside the body. The in vitro and in vivo performance of implantable BioMEMS such as biosensors, smart stents, drug delivery systems, and actuation systems are researched extensively to understand the interaction of the BioMEMS devices with physiological environments. BioMEMS developed for drug delivery applications include microneedles, microreservoirs, and micropumps to achieve targeted drug delivery. The biocompatibility of BioMEMS is further enhanced through the application of tissue and smart surface engineering. This involves the application of nanotechnology, which includes the modification of surfaces with polymers or the self-assembly of monolayers of molecules. Thereby, the adverse effects of biofouling can be reduced and the performance of devices can be improved in in vivo and in vitro conditions.


The role of quantitative cultures of non-bronchoscopic samples in ventilator associated pneumonia.
The objective of this study is to determine the role of quantitative cultures of non-bronchoscopic samples such as blinded bronchial sampling (BBS) and endotracheal aspirates (ETA) in the management of ventilator associated pneumonia (VAP). The study also evaluates the clinical diagnosis of VAP based on the inclusion of Gram stain results of BBS/ETA samples into modified clinical pulmonary infection score (CPIS). Fifteen out of the 120 patients admitted to respiratory intensive care unit under mechanical ventilation for more than 48 hours with a clinical suspicion of VAP, were included in this study. Quantitative cultures of BBS and ETA were performed from all the 15 patients. VAP was confirmed in 11 out of 15 cases by quantitative cultures of either the BBS or ETA samples. The condition of 8/11 VAP confirmed patients improved significantly with the change in antibiotic therapy. The overall mortality rate was found to be 18%. The agreement between BBS and ETA results was found to be 83.3%. Modified-clinical pulmonary infection score (CPIS) increased significantly when Gram stain results of BBS/ETA samples were included, thereby strengthening the clinical diagnosis of VAP. Quantitative culture of lower respiratory tract samples obtained by non-bronchoscopic methods may be a useful alternative to bronchoscopy, in the diagnosis of VAP. Inclusion of Gram stain results of BBS/ETA into modified-CPIS may augment the diagnostic evaluation of VAP.


Meta-analysis of the association between adiponectin SNP 45, SNP 276, and type 2 diabetes mellitus.
The present study aimed to determine whether the polymorphisms at rs2241766 and rs1501299 on the ADIPOQ gene were related to the susceptibility of type 2 diabetes mellitus (T2DM). Eight databases, PubMed, GWAS, Embase, Lochrane, Ebsco, CNKI (Chinese National Knowledge Infrastructure), VIP (Viper Database) and ChinaInfo were searched, and a meta-analysis of susceptibility was conducted between SNP45, SNP276 polymorphisms and T2DM. Furthermore, HWE test was conducted to assess the genetic balance of the study, evaluate the quality of Newcastle-Ottawa quality assessment scale (NOS), and establishing allelic, dominant, recessive, heterozygous, and homozygous gene models. This meta-analysis included 53 articles, encompassing 9285 cases with rs2241766 and 14156 controls and 7747 cases with rs1501299 and 10607 controls. For the rs2241766 locus, a significant correlation was found in the three models by the subgroup analysis. Western Asians: dominant gene model (TT + TG vs. GG, P = 0.01); heterozygous gene model (TG vs. GG, P = 0.02); homozygous gene model (TT vs. GG, P = 0.01). South Asians: dominant gene model (TT + TG vs. GG, P = 0.004); heterozygous gene model (TG vs. GG, P = 0.009); homozygous gene model (TT vs. GG, P = 0.005). However, no statistically significant correlation was established among the five genetic models for rs1501299 locus. The findings of the present study indicated that the T allele of rs2241766 polymorphism is the susceptibility locus of T2DM in the West Asian population, but has a protective effect in the South Asian population, albeit further studies are needed in other populations. Also, no association was found between the ADIPOQ rs1501299 polymorphism and T2DM.


Screening and evaluation of study subjects in patient-oriented research.
This article describes practical aspects of screening and evaluation of potential study subjects for patient-oriented research. Screening and evaluation comprise the crucial initial steps in the process of any patient-oriented research study. Appropriate infrastructure, operations, and documentation of the procedures needed to efficiently and effectively conduct screening and evaluation are described. A stepwise approach for screening and evaluating potential study subjects for determination of study eligibility is described. The design and conduct of screening and evaluation procedures should be protocol driven and compliant with regulatory requirements.


Pushing Stoichiometries of Lithium-Rich Layered Oxides Beyond Their Limits.
Lithium-rich layered oxides (LRLOs) are opening unexplored frontiers for high-capacity/high-voltage positive electrodes in Li-ion batteries (LIBs) to meet the challenges of green and safe transportation as well as cheap and sustainable stationary energy storage from renewable sources. LRLOs exploit the extra lithiation provided by the Li1.2TM0.8O2 stoichiometries (TM = a blend of transition metals with a moderate cobalt content) achievable by a layered structure to disclose specific capacities beyond 200-250 mA h g-1 and working potentials in the 3.4-3.8 V range versus Li. Here, we demonstrate an innovative paradigm to extend the LRLO concept. We have balanced the substitution of cobalt in the transition-metal layer of the lattice with aluminum and lithium, pushing the composition of LRLO to unexplored stoichiometries, that is, Li1.2+x (Mn,Ni,Co,Al)0.8-x O2-δ. The fine tuning of the composition of the metal blend results in an optimized layered material, that is, Li1.28Mn0.54Ni0.13Co0.02Al0.03O2-δ, with outstanding electrochemical performance in full LIBs, improved environmental benignity, and reduced manufacturing costs compared to the state-of-the-art.


Nocturnal sleep organization in infants "at risk" for sudden infant death syndrome.
Nocturnal sleep organization was compared in normal infants and those "at risk" for sudden infant death syndrome (SIDS) (siblings and near-miss infants). Before 12 weeks of age, sleep modifications were observed in "at risk" infants. During their sleep they had a smaller percentage of intervening wakefulness with a higher amount of active sleep. Quiet and active sleep episodes had longer durations resulting in a longer sleep cycle. After 12 weeks, sleep organization tended to normalize. This fact is discussed as a possible factor for a SIDS event: a higher arousal threshold could play a critical role if homeostasy is disturbed during sleep, mainly at an age when the homeostatic control is not fully established.


Establishment and Validation of GV-SAPS II Scoring System for Non-Diabetic Critically Ill Patients.
Recently, glucose variability (GV) has been reported as an independent risk factor for mortality in non-diabetic critically ill patients. However, GV is not incorporated in any severity scoring system for critically ill patients currently. The aim of this study was to establish and validate a modified Simplified Acute Physiology Score II scoring system (SAPS II), integrated with GV parameters and named GV-SAPS II, specifically for non-diabetic critically ill patients to predict short-term and long-term mortality. Training and validation cohorts were exacted from the Multiparameter Intelligent Monitoring in Intensive Care database III version 1.3 (MIMIC-III v1.3). The GV-SAPS II score was constructed by Cox proportional hazard regression analysis and compared with the original SAPS II, Sepsis-related Organ Failure Assessment Score (SOFA) and Elixhauser scoring systems using area under the curve of the receiver operator characteristic (auROC) curve. 4,895 and 5,048 eligible individuals were included in the training and validation cohorts, respectively. The GV-SAPS II score was established with four independent risk factors, including hyperglycemia, hypoglycemia, standard deviation of blood glucose levels (GluSD), and SAPS II score. In the validation cohort, the auROC values of the new scoring system were 0.824 (95% CI: 0.813-0.834, P< 0.001) and 0.738 (95% CI: 0.725-0.750, P< 0.001), respectively for 30 days and 9 months, which were significantly higher than other models used in our study (all P < 0.001). Moreover, Kaplan-Meier plots demonstrated significantly worse outcomes in higher GV-SAPS II score groups both for 30-day and 9-month mortality endpoints (all P< 0.001). We established and validated a modified prognostic scoring system that integrated glucose variability for non-diabetic critically ill patients, named GV-SAPS II. It demonstrated a superior prognostic capability and may be an optimal scoring system for prognostic evaluation in this patient group.


In-Transit Metastasis From Squamous Cell Carcinoma.
In-transit metastasis from cutaneous squamous cell carcinoma (SCC) is an uncommon form of metastasis through lymphatics and occurs more commonly in immunosuppressed patients. To identify cases of in-transit SCC and determine patient characteristics, tumor features, management, and prognosis. A multicenter case series treated by Australian and New Zealand clinicians. In 31 patients, median age was 72 years (range 52-99) and 68% were immunocompetent. Tumors occurred on the head and neck in 94% of cases, with 71% of all tumors occurring on the scalp, forehead, or temple. The median time to presentation with in-transit SCC from treatment of the initial tumor was 5 months. Management included surgery (94%), radiotherapy (77%), chemotherapy (10%), and reduction of immunosuppression (3%). Median follow-up was 12 months. Overall survival at 3 and 5 years were 27% and 13%, respectively. In-transit metastases are described in 31 patients, of whom the majority was immunocompetent. The scalp, forehead, and temple were the most common sites. New clinical and histological diagnostic criteria are proposed. Prognosis was poor with 5-year survival of 13%. Recommended management is a combination of surgery and adjuvant radiotherapy. Reduction of any iatrogenic immunosuppression should be considered.


A p1 aneurysm and diabetes insipidus caused by traumatic brain injury.
We describe a patient with a P1 aneurysm of the posterior cerebral artery (PCA) with diabetes insipidus (DI) caused by traumatic brain injury. A 21-year-old woman presented with epidural hematoma, left temporal contusion and subarachnoid hemorrhage caused by head trauma. DI occurred with normal anterior hypophyseal function on the second day after admission and cerebral angiography demonstrated an aneurysm at the right P1 portion after one month. DI was treated with administration of desmopressin and the aneurysm and P1 portion of the right PCA were occluded completely. After three months, her DI recovered and decompressin was discontinued. The six month follow-up angiogram confirmed cure of the P1 aneurysm. P1 aneurysm and DI can be caused by traumatic brain injury. Cranial DI caused by head injury with perturbations in water balance may be transitory and resolve.


A statistical strategy to identify recombinant viral ribonucleoprotein of avian, human, and swine influenza A viruses with elevated polymerase activity.
Reassortment of influenza A viruses can give rise to viral ribonucleoproteins (vRNPs) with elevated polymerase activity and the previous three pandemic influenza viruses contained reassorted vRNPs of different origins. These suggest that reassorted vRNP may be one of the factors leading to a pandemic virus. In this study, we reconstituted chimeric vRNPs with three different viral strains isolated from avian, human and swine hosts. We applied a statistical strategy to identify the effect that the origin of a single vRNP protein subunit or the interactions between these subunits on polymerase activity. Eighty one chimeric vRNPs were reconstituted in 293T cells at different temperatures. Polymerase activity was determined by luciferase reporter assay and the results were analysed by multiway anova and other statistical methods. It was found that PB2, PB1, NP, PB2-PB1 interaction, PB2-PA interaction and PB1-NP interaction had significant effect on polymerase activity at 37°C and several single subunits and interactions were identified to lead to elevation of polymerase activity. Furthermore, we studied 27 out of these 81 different chimieric vRNPs in different combinations via fractional factorial design approach. Our results suggested that the approach can identify the major single subunit or interaction factors that affect the polymerase activity without the need to experimentally reproduce all possible vRNP combinations. Statistical approach and fractional factorial design are useful to identify the major single subunit or interaction factors that can modulate viral polymerase activity.


Poria cocos water extract (PCW) protects PC12 neuronal cells from beta-amyloid-induced cell death through antioxidant and antiapoptotic functions.
Beta-amyloid (Abeta)-induced neurotoxicity is considered to be mediated through the formation of reactive oxygen species (ROS). In this study, the protective effects of Poria cocos water extract (PCW) against Abeta1-42-induced cell death were investigated using rat pheochromocytoma (PC12) cells. Exposure of PC12 cells to the Abeta1-42 (20 microM) for 48h resulted in neuronal cell death, whereas pretreatment with PCW at the concentration range of 5-125 microg/ml reduced Abeta1-42-induced cell death. In addition, PC12 cells treated with Abeta1-42 exhibited increased accumulation of intracellular oxidative damages and underwent apoptotic death as determined by characteristic morphological alterations and positive in situ terminal end-labeling (TUNEL staining). However, PCW attenuated Abeta1-42-induced cytotoxicity, apoptotic features, and accumulation of intracellular oxidative damage. Moreover, PCW (5 to 125 microg/ml) decreased expression of apoptotic protein Bax and activity of caspase-3, but enhanced expression of anti-apoptotic protein Bcl-2. These results suggest that PCW may protect cells through suppressing the oxidative stress and the apoptosis induced by Abeta1-42, implying that PCW may be potential natural agents for Alzheimer's diseases.


Physical mapping by STS hybridization: algorithmic strategies and the challenge of software evaluation.
An important tool in the analysis of genomic sequences is the physical map. In this paper we examine the construction of physical maps from hybridization data between sequence tag sites (STS) probes and clones of genomic fragments. An algorithmic theory of the mapping process, a proposed performance evaluation procedure, and several new algorithmic strategies for mapping are given. A unifying theme for these developments is the idea of a "conservative extension." An algorithm, measure of algorithm quality, or description of physical map is a conservative extension if it is a generalization for data with errors of a corresponding concept in the error-free case. In our algorithmic theory we show that the nature of hybridization experiments imposes inherent limitations on the mapping information recorded in the experimental data. We prove that only certain types of mapping information can be reliably calculated by any algorithm. A test generator is then presented along with quantitative measures for determining how much of the possible information is being computed by a given algorithm. Weaknesses and strengths of these measures are discussed. Each of the new algorithms presented in this paper is based on combinatorial optimizations. Despite the fact that all the optimizations are NP-complete, we have developed algorithmic tools for the design of competitive approximation algorithms. We apply our performance evaluation program to our algorithms and obtain solid evidence that the algorithms are capable of retrieving high-level reliable mapping information.


HLA-DRB1 motifs and heat shock proteins in rheumatoid arthritis.
Susceptibility to develop Rheumatoid arthritis (RA) maps to a highly conserved amino acid motif expressed in the third hypervariable region of different HLA-DRB1 alleles. This motif, namely QKRAA, QRRAA or RRRAA helps the development of RA by an unknown mechanism. In the past ten years, we have extensively studied the unique properties of the QKRAA motif of HLA-DRB1*0401 and have found: (1) That it can constitute B and T cell epitopes on many infectious agents; (2) That it can shape the T cell repertoire; (3) That it is overrepresented in protein databases; (4) That it constitutes a binding motif for the highly conserved family of 70 kD heat shock proteins. This may cause abnormal trafficking of HLA-DRB1*0401 in B cells and/or abnormal T cell responses to bacterial and human 70 kD heat shock proteins in people who express HLA-DRB1*0401.


Amino Acids Content in Germinating Seeds and Seedlings from Castanea sativa L.
During germination the chestnut (Castanea sativa L.) var ecotype 33 accumulates a large amount of asparagine in the cotyledons. This compound also accumulates in the growing axis:shoots and roots. In the cotyledons, gamma-aminobutyrate (GABA) represents a major amino compound during germination and early seedling growth. In young seedlings, 35 days old, arginine predominates over the other soluble amino acids, particularly in roots. Five enzymic activities involved in arginine and GABA have been measured in the storage organ of the seed: arginase and ornithine carbamyltransferase decrease during germination indicating the slowing down of the urea cycle. In contrast, ornithine aminotransferase increases. Glutamate decarboxylase is particularly active about 21 days after imbibition and GABA aminotransferase activity decreases during germination. These two activities are in good agreement with the likely transport of GABA from cotyledons to growing axis. Asparagine, arginine, and GABA are the three amino compounds obviously involved in the mobilization of nitrogen reserves in the germinating chestnut seeds Castanea sativa.


Tibial post wear in posterior-stabilized knee replacements is design-dependent.
Polyethylene tibial post wear in posterior-stabilized knee designs is a major problem. The Insall-Burstein II (IB PS II) reportedly has severe anterior wear of the post in retrieved implants. We hypothesized the more anterior placement in the IB PS II would be reflected in greater wear at the anterior face than the IB PS I. We examined 234 retrieved inserts using subjective scales to grade post damage and wear. Of the IB PS II inserts, 38% demonstrated severe wear compared with only 25% of IB PS I inserts. The most prevalent damage location for the IB PS II was the anterior face, whereas the IB PS I sustained wear mainly on the medial face. While the IB PS post was not designed to constrain posterior femoral displacement, our observations confirm contact in hyperextension or other paradoxic anterior tibial translation is common and design-dependent. Minimizing wear and damage through proper post placement and changes in implant design to anticipate contact on the anterior post should be considered for future posterior stabilized knee replacements. These changes cannot occur in isolation, however, because changes in post placement and design also depend on their relation to the shape and location of the tibial bearing surfaces.


Molecular insights into the Patched1 drug efflux inhibitory activity of panicein A hydroquinone: a computational study.
Human Hedgehog receptor Patched1 (PTCH1) is able to efflux chemotherapeutics of different chemical structure out of cancer cells thus contributing to multidrug resistance phenomena in tumor treatment. A screening of natural compounds purified from marine sponges led to the identification of the first PTCH1 efflux inhibitor, panicein A hydroquinone (PAH), demonstrated to increase doxorubicin toxicity in vitro and vemurafenib toxicity in vitro and in vivo. In this work we combined different computational techniques to gain molecular insights of the inhibitory activity of PAH and some of its active and inactive analogues. We first performed a thorough characterization and druggability analysis of the main putative substrate binding pockets known from available cryo-electron microscopy structures. Further, dynamical descriptors of the active and inactive PAH analogues were extracted from microsecond-long all-atom molecular dynamics simulations in water solution. Finally, a blind ensemble docking methodology coupled with the conformational analysis of compounds enabled rationalization of the interaction between PTCH1 and PAH and derivatives in terms of their intrinsic physico-chemical properties. Our results suggest that the Neck pocket is the preferential binding site for PAH analogues on PTCH1, and that compounds assuming an open cylindric-like shape in solution are most likely to be good binders for PTCH1.


Changes in dynamic embryonic heart wall motion in response to outflow tract banding measured using video densitometry.
Abnormal blood flow during early cardiovascular development has been identified as a key factor in the pathogenesis of congenital heart disease; however, the mechanisms by which altered hemodynamics induce cardiac malformations are poorly understood. This study used outflow tract (OFT) banding to model increased afterload, pressure, and blood flow velocities at tubular stages of heart development and characterized the immediate changes in cardiac wall motion due to banding in chicken embryo models with light microscopy-based video densitometry. Optical videos were used to acquire two-dimensional heart image sequences over the cardiac cycle, from which intensity data were extracted along the heart centerline at several locations in the heart ventricle and OFT. While no changes were observed in the synchronous contraction of the ventricle with banding, the peristaltic-like wall motion in the OFT was significantly affected. Our data provide valuable insight into early cardiac biomechanics and its characterization using a simple light microscopy-based imaging modality.


Stenting of a renal artery stenosis achieves better relief of the obstructive lesion than balloon angioplasty.
A balloon-expandable (Palmaz-Schatz) stainless steel stent was utilized following balloon angioplasty (PTRA) to determine if the obstructive lesion, using quantitative methods (automated measuring the diameter stenosis, and transstenotic peak systolic and mean pressure gradients), was significantly further reduced or abolished. Hemodynamic transstenotic gradient and stenoses measurements were made during 21 renal artery stenting procedures; prior and following PTRA, and subsequent to stent deployment. The stent sizes placed in the renal arteries were 5 mm (19%), 6 mm (67%), and 7 mm (14%). The results were as follows: [table: see text] The balloon-expandable (Palmaz-Schatz) stent significantly further reduced, and in fact effectively abolished, the obstructive renal artery lesion in comparison to balloon angioplasty (PTRA). The stent's effectiveness with regard lesion recurrence, maintenance, and preservation of renal function; cure or improved management of hypertension; and survival will be determined by careful clinic follow-up.


Central role of mitochondria in drug-induced liver injury.
A frequent mechanism for drug-induced liver injury (DILI) is the formation of reactive metabolites that trigger hepatitis through direct toxicity or immune reactions. Both events cause mitochondrial membrane disruption. Genetic or acquired factors predispose to metabolite-mediated hepatitis by increasing the formation of the reactive metabolite, decreasing its detoxification, or by the presence of critical human leukocyte antigen molecule(s). In other instances, the parent drug itself triggers mitochondrial membrane disruption or inhibits mitochondrial function through different mechanisms. Drugs can sequester coenzyme A or can inhibit mitochondrial β-oxidation enzymes, the transfer of electrons along the respiratory chain, or adenosine triphosphate (ATP) synthase. Drugs can also destroy mitochondrial DNA, inhibit its replication, decrease mitochondrial transcripts, or hamper mitochondrial protein synthesis. Quite often, a single drug has many different effects on mitochondrial function. A severe impairment of oxidative phosphorylation decreases hepatic ATP, leading to cell dysfunction or necrosis; it can also secondarily inhibit ß-oxidation, thus causing steatosis, and can also inhibit pyruvate catabolism, leading to lactic acidosis. A severe impairment of β-oxidation can cause a fatty liver; further, decreased gluconeogenesis and increased utilization of glucose to compensate for the inability to oxidize fatty acids, together with the mitochondrial toxicity of accumulated free fatty acids and lipid peroxidation products, may impair energy production, possibly leading to coma and death. Susceptibility to parent drug-mediated mitochondrial dysfunction can be increased by factors impairing the removal of the toxic parent compound or by the presence of other medical condition(s) impairing mitochondrial function. New drug molecules should be screened for possible mitochondrial effects.


Extracardiac contributions to chest pain perception in patients 6 months after acute myocardial infarction.
The amount of perceived anginal pain in patients after infarction deserves the attention of the physician. This study sought to identify the modulating influence of extracardiac factors on persistent angina pectoris after myocardial infarction. A total of 552 male survivors of acute myocardial infarction (age 29 to 65 years, median 54 years) were followed for a period of 6 months; the affective state was assessed immediately after the acute event. The prognostic importance of postinfarction depression on chest pain perception was evaluated 6 months after the cardiac event in 376 patients. After the 6-month follow-up period, 199 (53%) of the patients with myocardial infarction had angina pectoris. Somatic risk factors and electrocardiographic data at initial testing did not contribute to the risk of having chest pain. However, patients with high levels of depression at initial testing had an almost 3-fold risk of having angina pectoris 6 months after the index event. Older age, lower social class status, and preinfarction angina were also significantly related to angina pectoris at the end of the study. Patients who were pain free before the index infarction reported significantly more symptoms of chest pain at the study end point (P </=.02), when they had moderate to high degrees of postinfarction depression. In the logistic regression model, depression, then followed by preinfarction angina pectoris and low social class index, contributed significantly to the prediction of follow-up angina pectoris. The results of this study add evidence to the hypothesis that the perception of chest pain may be triggered not only by the nociceptive stimulation of the ischemic heart but also by extracardiac sources. Depressive mood state, when concomitant with cardiac disease, is shown to intensify perceived chest pain.


Alternative medicine among college students.
The use of "alternative" medicine has become increasingly popular in the United States. Books devoted to alternative medicine, e.g., Spontaneous Healing and 8 Weeks to Optimum Health, have become best sellers. Nevertheless, relatively few research studies have focused on the subject. This study examined the role of alternative medicine among college students. Issues addressed included students' familiarity with, use of, and perceptions regarding unconventional health therapies. The study substantiated a phenomenon health care providers across the country are discovering: a growing number of Americans with interest and financial resources support the development of "mainstream" alternative medicine programs. Results of the study also suggest that well-respected traditional health care organizations would not suffer reputation damage if they were to offer such programs.


Prior immunologic experience potentiates the subsequent antibody response when Salmonella strains are used as vaccine carriers.
Prior immunologic experience with homologous and heterologous serotype Salmonella strains potentiated the subsequent antibody response when the same strains were used as vaccine carriers of foreign antigens. This potentiation was positively correlated with the appearance of antibody directed against the lipopolysaccharide of the carrier strain. Both serum and mucosal antibody responses against the foreign antigen increased over time. Antibody responses in sera of animals primed with either the homologous or heterologous serotype strain were not statistically significantly different, while animals primed with the homologous serotype strain developed significantly better mucosal antibody responses against the foreign antigen.


Gut microbiome of mothers delivering prematurely shows reduced diversity and lower relative abundance of Bifidobacterium and Streptococcus.
Preterm birth is the main reason for neonatal deaths worldwide. We investigate whether maternal gut microbiota may play a previously overlooked role. The Norwegian Microbiota Study (NoMIC) is a case control study on preterm birth (<259 days of gestation, calculated primarily based on the last menstrual period), including two consecutively born term infants per infant born prematurely. Eligible mothers were fluent in Norwegian and recruited from the maternity ward at a county hospital in Eastern Norway in the period 2002-2005. Fecal samples were collected at day 4 postpartum, and analyzed using 16S ribosomal RNA gene sequencing. We used samples from 121 mothers giving birth vaginally. Measures of alpha diversity (Shannon, Phylogenetic Diversity and Observed Operational Taxonomic Units) and microbiome composition were combined with information from the Medical Birth Registry, pregnancy journals, and questionnaires. The association between maternal gut diversity and preterm delivery was examined using logistic regression. One IQR increase in Shannon diversity was significantly associated with 38% lower odds of spontaneous preterm birth, (95% confident interval (CI): 1%, 61%), and the association was stronger when adjusting for maternal age, marital status, ethnicity, parity, BMI, education, antibiotic use, pets in the household, income and smoking (48% lower odds, 95% CI: 4.2%, 72%). Mothers delivering prematurely also had lower abundance of OTUs belonging to Bifidobacterium and Streptococcus, and of the Clostridiales order. Analysis of maternal gut microbiota using next-generation sequencing shows that low gut diversity, with a distinct microbial composition, is associated with spontaneous preterm delivery.


[Meta-analysis of studies on cut-off value of serum ferritin for identifying iron deficiency].
To synthesize evidence to discuss the appropriate cut-off value of serum ferritin (SF) for identifying iron deficiency. A comprehensive electronic search and manual tracking were performed to collect potential studies on cut-off value of SF for identifying iron deficiency. Most relevant studies were identified according to the inclusion and exclusion criteria and data were extracted. All included studies were divided into three groups according to the cutoff value of SF: 12 -20 microg/L group, 25 microg/ L or 30 microg/L group and 36 - 60 microg/L group. Heterogeneity of the included studies was tested to select proper efficacy model for calculating pooled weighted diagnostic indicators and their 95% CI. Summary receiver operating characteristic (SROC) curve was made and the area under the curve (AUC) and Q * index were calculated respectively for the three groups. Finally, sensitivity analysis were performed. A total of 14 studies were included and were divided into three groups. After the pooled efficacy analysis, we found that the 12 - 20 microg/L group showed the lowest pooled sensitivity (0.767, 95 CI 0.705 -0.821) but highest specificity (0.959, 95 CI 0.934 -0.976). Compared with the other two groups, the pooled sensitivity of 25, 30 microg/L group (0.877, 95 CI 0.799 - 0.933) was highest, its pooled specificity was (0.944, 95 CI 0.888 - 0.977), the pooled sensitivity and pooled specificity of 36 - 60 microg/L group (0.836, 95 CI 0.797 - 0.870), (0.876, 95 CI 0.846 - 0.901)] were both relatively low. In terms of the integrated diagnostic capabilities, the 25, 30 microg/L group showed the highest diagnostic odds ratio (101.42, 95 CI 36.137 - 284.64), the largest AUC (0.9497 +/- 0.039) and the Q * index nearest 1 (0.8901 +/- 0.052) among the three groups. After we removed the studies with samples less than 50 and the studies from Chinese authors, the 25, 30 microg/L group still showed the best diagnostic efficiency. 25 or 30 microg/L of SF as the cut-off value of identifying iron deficiency shows high accuracy and good integrated diagnostic capability.


Whole-genome sequencing of Atacama skeleton shows novel mutations linked with dysplasia.
Over a decade ago, the Atacama humanoid skeleton (Ata) was discovered in the Atacama region of Chile. The Ata specimen carried a strange phenotype-6-in stature, fewer than expected ribs, elongated cranium, and accelerated bone age-leading to speculation that this was a preserved nonhuman primate, human fetus harboring genetic mutations, or even an extraterrestrial. We previously reported that it was human by DNA analysis with an estimated bone age of about 6-8 yr at the time of demise. To determine the possible genetic drivers of the observed morphology, DNA from the specimen was subjected to whole-genome sequencing using the Illumina HiSeq platform with an average 11.5× coverage of 101-bp, paired-end reads. In total, 3,356,569 single nucleotide variations (SNVs) were found as compared to the human reference genome, 518,365 insertions and deletions (indels), and 1047 structural variations (SVs) were detected. Here, we present the detailed whole-genome analysis showing that Ata is a female of human origin, likely of Chilean descent, and its genome harbors mutations in genes (COL1A1, COL2A1, KMT2D, FLNB, ATR, TRIP11, PCNT) previously linked with diseases of small stature, rib anomalies, cranial malformations, premature joint fusion, and osteochondrodysplasia (also known as skeletal dysplasia). Together, these findings provide a molecular characterization of Ata's peculiar phenotype, which likely results from multiple known and novel putative gene mutations affecting bone development and ossification.


Epidemiology of Human Bocavirus in the Middle East and North Africa: Systematic Review.
The emergence of the COVID-19 pandemic highlighted the importance of studying newly emerging viruses that cause respiratory illnesses. Human bocavirus (HBoV) is one of the relatively newly discovered viruses that has been detected worldwide and causes respiratory and gastrointestinal infections, mainly in pediatric patients. However, little is known about the pathogenicity and evolution of HBoV. This systematic review was initiated to clarify the prevalence and circulating genotypes of HBoV in both respiratory and stool samples from patients of all age groups in the Middle East and North Africa (MENA) from 2005 to February 2021. We performed an electronic search through Science Direct, Scopus, PubMed, Mendeley and Cochrane Library databases. We included all studies reporting the detection rate of HBoV in the MENA region. Data were extracted, and the quality of the included articles was assessed. We included articles containing data on HBoV only or with other respiratory or gastrointestinal viral infections. Review articles, case studies, and animal and environmental studies were excluded. The final number of articles included in this study was 65 articles. The results showed that the HBoV prevalence in children was the lowest in Iran (0%) and the highest in Egypt (56.8%). In adults, the lowest and the highest prevalence were reported in Iran, with values of 0% and 6.6%, respectively. Regarding the respiratory cases, our findings revealed no significant difference between HBoV prevalence among the tested categories (p-value = 0.998). The present study has shown that HBoV is common in children and adults in the MENA region. This systematic review highlights the need for more data on the role of coinfection of HBoV and other viruses, for instance, SARS-CoV-2 in children with acute bronchiolitis.


Mixed-Weight Neural Bagging for Detecting m6A Modifications in SARS-CoV-2 RNA Sequencing.
The m6A modification is the most common ribonucleic acid (RNA) modification, playing a role in prompting the virus's gene mutation and protein structure changes in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Nanopore single-molecule direct RNA sequencing (DRS) provides data support for RNA modification detection, which can preserve the potential m6A signature compared to second-generation sequencing. However, due to insufficient DRS data, there is a lack of methods to find m6A RNA modifications in DRS. Our purpose is to identify m6A modifications in DRS precisely. We present a methodology for identifying m6A modifications that incorporated mapping and extracted features from DRS data. To detect m6A modifications, we introduce an ensemble method called mixed-weight neural bagging (MWNB), trained with 5-base RNA synthetic DRS containing modified and unmodified m6A. Our MWNB model achieved the highest classification accuracy of 97.85% and AUC of 0.9968. Additionally, we applied the MWNB model to the COVID-19 dataset; the experiment results reveal a strong association with biomedical experiments. Our strategy enables the prediction of m6A modifications using DRS data and completes the identification of m6A modifications on the SARS-CoV-2. The Corona Virus Disease 2019 (COVID-19) outbreak has significantly influence, caused by the SARS-CoV-2. An RNA modification called m6A is connected with viral infections. The appearance of m6A modifications related to several essential proteins affects proteins' structure and function. Therefore, finding the location and number of m6A RNA modifications is crucial for subsequent analysis of the protein expression profile.


Nurses, midwives and health research.
Despite the wealth of researchable topics in maternal and child health, it is rare for studies in this field to be carried out by nurse-midwives. This article explores the historical origins of nursing, its educational characteristics and its dominance by women, identifying obstacles to independent research and pointing to ways of overcoming them.


[The labor migration sending regions in the state of Zacatecas].
"In a preliminary survey in the state of Zacatecas, [Mexico,] we identified those municipalities which contribute most to the migration of Mexican workers to the United States; later, we corroborated our findings in situ and drew up an approximation of the geographic and economic characteristics of those municipalities, which make up 'migration sending zones or regions' in the state." (SUMMARY IN ENG)


Coronavirus-induced membrane fusion requires the cysteine-rich domain in the spike protein.
The spike glycoprotein of mouse hepatitis virus strain A59 mediates the early events leading to infection of cells, including fusion of the viral and cellular membranes. The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail. In this study, we examined the role of these carboxyl-terminal domains in spike-mediated membrane fusion. We show that the cytoplasmic tail is not required for fusion but has the capacity to enhance membrane fusion activity. Chimeric spike protein mutants containing substitutions of the entire transmembrane anchor and cys domain with the herpes simplex virus type 1 glycoprotein D (gD-1) anchor demonstrated that fusion activity requires the presence of the A59 membrane-spanning domain and the portion of the cys domain that lies upstream of the cytoplasmic tail. The cys domain is a required element since its deletion from the wild-type spike protein abrogates fusion activity. However, addition of the cys domain to fusion-defective chimeric proteins was unable to restore fusion activity. Thus, the cys domain is necessary but is not sufficient to complement the gD-1 anchor and allow for membrane fusion. Site-specific mutations of conserved cysteine residues in the cys domain markedly reduce membrane fusion, which further supports the conclusion that this region is crucial for spike function. The results indicate that the carboxyl-terminus of the spike transmembrane anchor contains at least two distinct domains, both of which are necessary for full membrane fusion.


Maxadilan binds to membrane fractions of brain tissue.
Maxadilan is a potent vasodilator peptide isolated from salivary glands extracts of the hematophagous sand fly. Besides effects on the cutaneous vasculature, it has also been shown to relax rabbit aortic rings while elevating levels of cAMP. As a result of the effects on the skin and aorta, it was elected to undertake an examination of the tissue distribution of binding sites for maxadilan. In addition to specific binding in rabbit aorta and spleen, binding was detected in brain from various species including human, bovine, rabbit, rat and mouse with a kD of between 85 and 201 pM. Competitive displacement of [125I] maxadilan by a number of known vasoconstrictor peptides, vasodilator peptides and small molecule receptor ligands did not occur in the rabbit brain preparation. These results suggest the presence of specific binding sites in mammalian tissue for maxadilan whose endogenous ligand remains unknown.


The cost and intermediary cost-effectiveness of oral HIV self-test kit distribution across 11 distribution models in South Africa.
Countries around the world seek innovative ways of closing their remaining gaps towards the target of 95% of people living with HIV (PLHIV) knowing their status by 2030. Offering kits allowing HIV self-testing (HIVST) in private might help close these gaps. We analysed the cost, use and linkage to onward care of 11 HIVST kit distribution models alongside the Self-Testing AfRica Initiative's distribution of 2.2 million HIVST kits in South Africa in 2018/2019. Outcomes were based on telephonic surveys of 4% of recipients; costs on a combination of micro-costing, time-and-motion and expenditure analysis. Costs were calculated from the provider perspective in 2019 US$, as incremental costs in integrated and full costs in standalone models. HIV positivity among kit recipients was 4%-23%, with most models achieving 5%-6%. Linkage to confirmatory testing and antiretroviral therapy (ART) initiation for those screening positive was 19%-78% and 2%-72% across models. Average costs per HIVST kit distributed varied between $4.87 (sex worker model) and $18.07 (mobile integration model), with differences largely driven by kit volumes. HIVST kit costs (at $2.88 per kit) and personnel costs were the largest cost items throughout. Average costs per outcome increased along the care cascade, with the sex worker network model being the most cost-effective model across metrics used (cost per kit distributed/recipient screening positive/confirmed positive/initiating ART). Cost per person confirmed positive for HIVST was higher than standard HIV testing. HIV self-test distribution models in South Africa varied widely along four characteristics: distribution volume, HIV positivity, linkage to care and cost. Volume was highest in models that targeted public spaces with high footfall (flexible community, fixed point and transport hub distribution), followed by workplace models. Transport hub, workplace and sex worker models distributed kits in the least costly way. Distribution via index cases at facility as well as sex worker network distribution identified the highest number of PLHIV at lowest cost.


Mapping of radio frequency electromagnetic field exposure levels in outdoor environment and comparing with reference levels for general public health.
In this study, radio frequency electromagnetic field exposure levels were measured on the main streets in the city center of Diyarbakır, Turkey. Measured electric field levels were plotted on satellite imagery of Diyarbakır and were compared with exposure guidelines published by the International Commission on Non-Ionizing Radiation Protection (ICNIRP). Exposure measurements were performed in dense urban, urban and suburban areas each day for 7 consecutive days. The measurement system consisted of high precision and portable spectrum analyzer, three-axis electric field antenna, connection cable and a laptop which was used to record the measurement samples as a data logger. The highest exposure levels were detected for two places, which are called Diclekent and Batıkent. It was observed that the highest instantaneous electric field strength value for Batıkent was 7.18 V/m and for Diclekent was 5.81 V/m. It was statistically determined that the main contributor band to the total exposure levels was Universal Mobile Telecommunications System band. Finally, it was concluded that all measured exposure levels were lower than the reference levels recommended by ICNIRP for general public health.


Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection?
Anthracycline antibiotics have saved the lives of many cancer victims in the 50 plus years since their discovery. A major limitation of their use is the dose-limiting cardiotoxicity. Efforts focusing on understanding the biochemical basis for anthracycline cardiac effects have provided several strategies currently in clinical use: limit dose exposure, encapsulate anthracyclines in liposomes to reduce myocardial uptake, administer concurrently with the iron chelator dexrazoxane to reduce free iron-catalyzed reactive oxygen species formation; and modify anthracycline structure in an effort to reduce myocardial toxicity. Despite these efforts, anthracycline-induced heart failure continues to occur with consequences for both morbidity and mortality. Our inability to predict and prevent anthracycline cardiotoxicity is, in part, due to the fact that the molecular and cellular mechanisms remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes in vitro and small animals in vivo have demonstrated several forms of cardiac injury, and it remains unclear how these translate to the clinical setting. Given the clinical evidence that myocyte death occurs after anthracycline exposure in the form of elevations in serum troponin, myocyte cell death seems to be a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular "sarcopenia" characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. There is now evidence that erbB2 signaling in response to the ligand neuregulin regulates anthracycline uptake into cells via the multidrug-resistance protein. Therefore, up-regulation of cardiac neuregulin signaling may be one strategy to limit myocardial anthracycline injury. Moreover, assessing an individual's risk for anthracycline injury may be improved by having some measure of endogenous activity of this and other myocardial protective signals.


Birth wantedness reports: a look forward and a look back.
A number of checks can be done to assess reliability of attitudinal data pertaining to fertility. We ascertain how births that would be considered unintended, based on Time 1 reports of fertility intentions, are classified by respondents at a second interview after the birth occurred. The 1988 National Survey of Family Growth and a telephone reinterview allow us to identify respondents who initially intended to postpone or stop childbearing, but who then had a birth, and to analyze the reports they gave of the wantedness of the pregnancy leading to the birth. We also examine wantedness responses of women who claimed in 1988 that they intended to conceive within the next few years. Reports are compared across a range of respondent characteristics and circumstances, including changes in marital status since the initial interview. The analysis reveals nontrivial inconsistency between women's stated birth intentions and their reports about the wantedness of subsequent births. Details across subgroups are examined. Results also provide new information about effects of duration since birth on intention reports.


Metabolic Activity and Energy Charge of Excised Maize Root Tips under Anoxia: CONTROL BY SOLUBLE SUGARS.
Energy charge and fermentative metabolism under anoxia were monitored in excised maize root tips after various times of aging in air and were related to their soluble sugar content. The energy charge value, which was 0.9 in air irrespective of the time of aging, dropped to a lower value within minutes of transfer to a nitrogen atmosphere. This value was dependent upon sugar content of the tissues which was itself a function of aging. The energy charge value after transfer to nitrogen was 0.6 in freshly excised tissue but only 0.2 in tissue aged for 4 hours. When aged tissues supplied with 0.2 molar glucose were transferred to nitrogen, the energy charge was 0.6, irrespective of the time of aging. When 0.2 molar glucose was added under nitrogen, energy charge rose to 0.6. This rise was faster in root tips aged for 8 hours than those aged for 24 hours.The rate of ethanol plus lactate production (representing 60 and 10%, respectively, of the total sugar consumption in anoxia) was closely correlated to the level of energy charge. It is concluded that, in anoxia, there is a quantitative relationship between the energy charge value and the level of metabolic activity via fermentative pathways.


The clinical morphology of human atherosclerotic lesions. Lessons from the PDAY Study. Pathobiological Determinants of Atherosclerosis in Youth.
The PDAY study addresses the role traditional risk factors play in the development and progression of arterial lesions in youth (15 to 34 years of age). This autopsy based study indicates that in the aorta and in the right coronary artery, atherosclerosis is positively associated with cholesterol (LDL+VLDL), glucose intolerance, smoking, hypertension, and obesity and negatively associated with HDL-cholesterol. When a high cholesterol group (> 240 mg/dl) is compared to a low cholesterol group (< 200 mg/dl) early fatty sudanophilic lesions decrease in the aorta from 35% to 29% (p < 0.03) surface area, while raised atherosclerotic lesions are lowered (from 5%) in the high cholesterol group (to 3%) in the low cholesterol group; p < 0.02). Clearly, risk factors particularly cholesterol levels, directly affect the development of atherosclerosis in the coronary arteries and the aorta of young people. The data presented suggest that risk factor modification would be beneficial in young people as from 15 years of age.


Magnetic resonance imaging, computed tomography, and 68Ga-DOTATOC positron emission tomography for imaging skull base meningiomas with infracranial extension treated with stereotactic radiotherapy--a case series.
Magnetic resonance imaging (MRI) and computed tomography (CT) with (68)Ga-DOTATOC positron emission tomography ((68)Ga-DOTATOC-PET) were compared retrospectively for their ability to delineate infracranial extension of skull base (SB) meningiomas treated with fractionated stereotactic radiotherapy. Fifty patients with 56 meningiomas of the SB underwent MRI, CT, and (68)Ga-DOTATOC PET/CT prior to fractionated stereotactic radiotherapy. The study group consisted of 16 patients who had infracranial meningioma extension, visible on MRI ± CT (MRI/CT) or PET, and were evaluated further. The respective findings were reviewed independently, analyzed with respect to correlations, and compared with each other. Within the study group, SB transgression was associated with bony changes visible by CT in 14 patients (81%). Tumorous changes of the foramen ovale and rotundum were evident in 13 and 8 cases, respectively, which were accompanied by skeletal muscular invasion in 8 lesions. We analysed six designated anatomical sites of the SB in each of the 16 patients. Of the 96 sites, 42 had infiltration that was delineable by MRI/CT and PET in 35 cases and by PET only in 7 cases. The mean infracranial volume that was delineable in PET was 10.1 ± 10.6 cm(3), which was somewhat larger than the volume detectable in MRI/CT (8.4 ± 7.9 cm(3)). (68)Ga-DOTATOC-PET allows detection and assessment of the extent of infracranial meningioma invasion. This method seems to be useful for planning fractionated stereotactic radiation when used in addition to conventional imaging modalities that are often inconclusive in the SB region.


Leadership in Integrated Care Networks: A Literature Review and Opportunities for Future Research.
In many countries, elderly patients with chronic conditions require a web of services delivered by several providers collaborating in inter-organisational networks. In view of their global importance, it is surprising how little we know how these networks are led. Like traditional organisations, networks require leadership to function effectively. This paper reviews central characteristics of leadership in integrated care networks and proposes opportunities for future research. Analysing 73 studies published in leading academic journals, this paper consolidates research on leadership media, practices, activities and outcomes, covering the network, policy and organisation levels of analysis. Findings indicate that the field has focused on leadership media and outcomes at the network level. They also suggest that leadership in integrated care networks faces multiple tensions. Future research could usefully provide a fuller picture by examining leadership practices, activities and outcomes at the policy and organisation level, integrating advances in the wider leadership literature. These findings contribute to the debate on leadership in integrated care networks. They also inform practice, drawing attention to persistent tensions as a core leadership challenge and offering latest scholarly evidence practitioners can use to reflect on and advance their own leadership practice.


Synthesis and structure-activity relationships of substituted 1,4-dihydroquinoxaline-2,3-diones: antagonists of N-methyl-D-aspartate (NMDA) receptor glycine sites and non-NMDA glutamate receptors.
A series of mono-, di-, tri-, and tetrasubstituted 1,4-dihydroquinoxaline-2,3-diones (QXs) were synthesized and evaluated as antagonists at N-methyl-D-aspartate (NMDA)/glycine sites and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-preferring non-NMDA receptors. Antagonist potencies were measured by electrical assays in Xenopus oocytes expressing rat whole brain poly(A)+ RNA. Trisubstituted QXs 17a (ACEA 1021), 17b (ACEA 1031), 24a, and 27, containing a nitro group in the 5 position and halogen in the 6 and 7 positions, displayed high potency (Kb approximately 6-8 nM) at the glycine site, moderate potency at non-NMDA receptors (Kb = 0.9-1.5 microM), and the highest (120-250-fold) selectivity in favor of glycine site antagonism over non-NMDA receptors. Tetrasubstituted QXs 17d,e were more than 100-fold weaker glycine site antagonists than the corresponding trisubstituted QXs with F being better tolerated than Cl as a substituent at the 8 position. Di- and monosubstituted QXs showed progressively weaker antagonism compared to trisubstituted analogues. For example, removal of the 5-nitro group of 17a results in a approximately 100-fold decrease in potency (10a,b,z), while removal of both halogens from 17a results in a approximately 3000-fold decrease in potency (10v). In terms of steady-state inhibition, most QX substitution patterns favor antagonism at NMDA/glycine sites over antagonism at non-NMDA receptors. Among the QXs tested, only 17i was slightly selective for non-NMDA receptors.


Parents' perspectives on occupational therapy and physical therapy goals for children with cerebral palsy.
Contemporary rehabilitation literature emphasises functional goals for children with disabilities and use of a collaborative goal-setting process grounded in principles of family centred service delivery. To explore parents' experiences with goals and goal setting. We conducted a qualitative study with 11 focus groups and two individual interviews with 39 parents of children with cerebral palsy living in western Canada. We used an inductive, thematic analysis to identify prominent themes. The analysis revealed five themes representing goals that were meaningful to parents and provided insight into parents' experiences with goal-setting processes in occupational and physical therapy: (1) movement as the means to functional success; (2) physical health and fitness are important therapy goals; (3) the importance of leading happy, fulfilling lives and being accepted by others; (4) 'We can't do it all': balancing therapy with the demands of everyday life; and (5) shifting roles and responsibilities in goal setting. The variability noted both in parents' desired role in goal setting and in goals important to parents highlights the importance of establishing trusting relationships with families so that family goals, values, individual circumstances, and desired level of participation in goal setting can be openly discussed.


A Conserved Motif in Intracellular Loop 1 Stabilizes the Outward-Facing Conformation of TmrAB.
The ATP binding cassette (ABC) family of transporters moves small molecules (lipids, sugars, peptides, drugs, nutrients) across membranes in nearly all organisms. Transport activity requires conformational switching between inward-facing and outward-facing states driven by ATP-dependent dimerization of two nucleotide binding domains (NBDs). The mechanism that connects ATP binding and hydrolysis in the NBDs to conformational changes in a substrate binding site in the transmembrane domains (TMDs) is currently an outstanding question. Here we use sequence coevolution analyses together with biochemical characterization to investigate the role of a highly conserved region in intracellular loop 1 we define as the GRD motif in coordinating domain rearrangements in the heterodimeric peptide exporter from Thermus thermophilus, TmrAB. Mutations in the GRD motif alter ATPase activity as well as transport. Disulfide crosslinking, evolutionary trace, and evolutionary coupling analysis reveal that these effects are likely due to the destabilization of a network in which the GRD motif in TmrA bridges residues of the Q-loop, X-loop, and ABC motif in the NBDs to residues in the TmrAB peptide substrate binding site, thus providing an avenue for conformational coupling. We further find that disruption of this network in TmrA versus TmrB has different functional consequences, hinting at an intrinsic asymmetry in heterodimeric ABC transporters extending beyond that of the NBDs. These results support a mechanism in which the GRD motifs help coordinate a transition to an outward open conformation, and each half of the transporter likely plays a different role in the conformational cycle of TmrAB.


Gynecomastia due to hormone therapy for advanced prostate cancer: a report of ten surgically treated cases and a review of treatment options.
Gynecomastia is an abnormal increase in the volume of the male breast that is generally considered to be due to an increased estrogen/androgen ratio. Pathological causes of gynecomastia include organic diseases and therapy, such as the administration of estrogens and antiandrogens, which alter the ratio of circulating hormones. Hormone therapy for prostate cancer is generally well tolerated but often accompanied by the occurrence of gynecomastia and breast pain or tenderness. The increased use of antiandrogens as monotherapy is leading to an increase in the number of patients affected by gynecomastia. Treatments are available to alleviate or prevent the development of gynecomastia, including medical treatment with antiestrogens and aromatase inhibitors. Alternatively, mastectomy with excision of the gland, liposuction or an association of the two techniques have proved to be effective. Radiation therapy may provide effective relief from the breast pain associated with gynecomastia. In this paper we show the good results of mastectomy performed with a lower semicircular periareolar incision in men suffering from gynecomastia due to antiandrogen therapy for inoperable prostate cancer. In addition, we present a review of the various techniques used for the treatment of gynecomastia. During the period from September 1998 to May 2001, 10 patients receiving hormone treatment for metastatic or inoperable prostatic cancer were selected for the study if they had breast pain and bilateral gynecomastia. Five of these patients had been offered prophylactic radiotherapy before treatment but refused, while the remaining five patients had refused radiotherapy after hormone treatment. These patients were therefore given the option of surgical treatment. Before surgery all patients underwent clinical and ultrasound examination of the breast. All surgical samples were examined histopathologically. During follow-up clinical examinations were carried out one week, one month, six months, one year and two years after surgery. The results were satisfactory in all patients especially from an aesthetic point of view. Moreover, breast pain disappeared about one week after surgery. After a follow-up of 6-36 months (average, 22.8 months) no recurrences were observed. Only a few immediate postoperative complications were recorded (hematoma in one case and seroma in another). Histological examination of the excised glands showed fibrosclerotic tissue and a small amount of fat. Surgical liposuction can be considered an effective treatment for gynecomastia, in particular in the very early stages because the breast becomes irreversibly fibrous as the disease progresses. This surgical technique is simple and effective and is therefore to be considered favorable, especially because of the very short hospitalization and the absence of complications.


Current and emerging concepts in biological and analytical variation applied in clinical practice.
A single laboratory result actually represents a range of possible values, and a given laboratory result is impacted not just by the presence or absence of disease, but also by biological variation of the measurand in question and analytical variation of the equipment used to make the measurement. Biological variation refers to variability in measurand concentration or activity around a homeostatic set point. Knowledge of biological and analytical variation can be used to facilitate interpretation of patient clinicopathologic data and is particularly useful for interpreting serial patient data and data at or near reference limits or clinical decision thresholds. Understanding how biological and analytical variation impact laboratory results is of increasing importance, because veterinarians evaluate serial data from individual patients, interpret data from multiple testing sites, and use expert consensus guidelines that include decision thresholds for clinicopathologic data interpretation. The purpose of our report is to review current and emerging concepts in biological and analytical variation and discuss how biological and analytical variation data can be used to facilitate clinicopathologic data interpretation. Inclusion of veterinary clinical pathologists having expertise in laboratory quality management and biological variation on research teams and veterinary practice guideline development teams is recommended, to ensure that various considerations for clinicopathologic data interpretation are addressed.


Expression of the interleukin 6 gene in rheumatoid synovial fibroblasts.
A number of fibroblastoid synovial cell lines have been established from rheumatoid joints. These cell lines were shown to express the interleukin 6 (IL-6) gene constitutively, and exposure of these cells to 5 ng/ml of recombinant human interleukin 1 beta (IL-1 beta) increased IL-6 gene expression. Other recombinant human lymphokines, namely interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony stimulating factor had no enhancing effect on IL-6 gene expression. Dexamethasone added to the cultures at 10(-7) M concentration suppressed the constitutive expression of the IL-6 gene. At a concentration of 10(-5) M, dexamethasone partially suppressed the IL-1 enhanced expression of IL-6. The IL-6 gene probe also hybridized to RNA from unfractionated synovial fluid cells, peripheral blood T cells and non-T cells but not Epstein-Barr virus transformed peripheral blood B cells of patients with rheumatoid arthritis. Our results suggest that in rheumatoid arthritis, synovial fibroblasts actively participate in joint inflammation by lymphokine production. The coexpression of both IL-1 and IL-6 by one synovial fibroblast line suggests a mechanism for the perpetuation of synovitis.


[Satellite DNA restriction site variability as a molecular basis of taxonoprint method: evidence from the study of Caucasian rock lizards].
The restriction site distribution in satellite DNA of 17 Caucasian rock lizard species of the genus Lacerta (Darevskia gen. nov.), (Squamata, Lacertidae) was analyzed. The distribution patterns were shown to reflect the degree of satellite DNA evolutionary divergence, which could be revealed by taxonprint method, i.e., through the analysis of genomic DNA with a set of restriction endonucleases and subsequent computer-aided treatment. Thus, the taxonprint method offers an opportunity to examine the satellite DNA divergence in closely related species and infer their phylogeny of the species studied without reserting to costly and labor-consuming procedures. This is the advantage of using this technique at the early stages of genomic DNA phylogenetic analysis for rapid and effective estimation of relationships between closely related species as well as in the cases when DNA cloning and sequencing are too expensive or not feasible.


Identification of monoclonal anti-HMW-MAA antibody linear peptide epitope by proteomic database mining.
An efficient strategy is presented for the identification of antigenic sequences in the context of given MHC molecules of interest. The proteomic analysis of the antigenic peptide repertoire is described and demonstrated by using high-molecular weight melanoma-associated antigen. The identification of the epitopic sequence of a monoclonal antibody raised against the 250 kDa tumor associated antigen was reached by using only seven short synthetic peptide fragments, instead of the 155 non-overlapping 15-mer peptides theoretically necessary as minimum screening library. The present result has been obtained by applying as driving criteria the analysis of the peptide affinity to MHC class II molecules and the non-self discrimination concept.


An antibody to BP 180 kDa antigen is able to induce an increase of intracellular Ca2+ concentration in DJM-1 (human squamous cell carcinoma) cells.
To elucidate the induction of transmembrane signal transduction of keratinocytes by bullous pemphigoid (BP) antibodies, we assessed the intracellular Ca2+ concentration ([Ca2+]i) in DJM-1 cells (a squamous cell carcinoma cell line). The time course of fluo-3-fluorescence intensity was investigated, and transient increase of fluorescence intensity in DJM-1 cells was observed when the DJM-1 cells were incubated with rabbit IgG anti-human BP 180kDa antigen (BP 180). No increase of fluorescence intensity was observed when the cells were incubated with rabbit IgG anti-human BP 230 kDa antigen (BP 230). This transient increase of fluorescence intensity was inhibited by U-73122, a specific inhibitor of phospholipase C. These results indicate the possibility that an antibody to BP 180 induces transmembrane signal transduction in keratinocytes.


Respiratory control disorders in infancy and childhood.
Current contributions to the literature on disorders of respiratory control in infancy and childhood are reviewed. These encompass studies of cardiorespiratory control in preterm and term infants, apparent life-threatening events in infants, and obstructive sleep apnea including etiology, diagnosis, and alternatives to surgical management. In addition, alveolar hypoventilation is discussed in children with congenital central hypoventilation syndrome, myelomeningocele, and Prader-Willi syndrome.


Impact of a two-generation early education program on parenting processes at age 18.
The Infant Health and Development Program is a two-generation early education model designed to improve parenting competence and child well-being. As part of an 8-site randomized clinical trial involving low birthweight premature children, assessments of children and parents were gathered at the time of program completion (age 3), with follow-up at ages 5, 8, and 18. Two key parenting processes were assessed at age 18 based on theory stipulating the centrality of parenting to long-term development in children. Analyses based on 283 control group and 178 Infant Health and Development Program treatment group participants revealed that treatment group mothers scored higher on one, the provision of enriching experiences. Evidence of sustained impacts on parenting suggests that carefully structured two-generation early education programs may prove good investments for promoting competence and adaptive functioning in high-risk children.


Attitudes toward intentional weight loss and dietary behavior among U.S. Army reserve soldiers during annual training.
The command of a U.S. Army Reserve Combat Support Hospital designed this study to evaluate soldiers' behavior related to and attitudes toward skipping meals while on annual training (AT). The command administered an anonymous survey on attitudes about weight loss and weightloss behavior while on AT. Of 180 soldiers given the opportunity to respond, 100 responses were received (55%). Before AT, 50% of reservists responding thought about losing weight while on AT, 62% of soldiers were trying to lose weight while on AT, and 25% of soldiers skipped meals. Soldiers who felt that they were overweight had a 2.9-fold increased risk for skipping meals, and those who thought about losing weight before AT had a 3.0-fold risk. Neither age, gender, rank, nor history of previously being on weight control was a predictor of skipping meals. Most soldiers considered and tried to lose weight while at AT, and soldiers who considered themselves overweight or thought about losing weight were at increased risk for skipping meals.


Audit of antipsychotic prescribing in dementia: Cambridgeshire results and lessons learnt.
Behavioural and psychological symptoms in dementia (BPSD) are common and distressing. Anti psychotic medication has been shown to have modest efficacy but is associated with well documented risks including excess cardiovascular events and increased mortality. The current NICE recommendations are that antipsychotics should only be prescribed to those with severe BPSD after exploring other possible interventions. There should be adequate counselling of the patient/family, an explicit risk-benefit analysis and regular review. As part of the POMH-UK National Audit on antipsychotic prescribing in dementia we reviewed the notes of 67 patients in the Cambridgeshire area who had a diagnosis of dementia. Of the 67 patients reviewed, only 9 (13.4%) were currently being prescribed antipsychotics for BPSD. Of these patients, all were living in their own homes and were experiencing multiple distressing target symptoms. 5 had been prescribed an antipsychotic for less than 3 months and only 1 had a total duration of treatment of more than 1 year. There was good evidence in all cases that alternative diagnoses and management strategies had been explored before prescribing an antipsychotic. However, in none was the full range of potential causes or interventions explored. In 6 cases a risk/benefit analysis for use of antipsychotic medicine was recorded and in 5 cases there was documented discussion of this with family or carers. Of the four patients who had been prescribed an antipsychotic for more than 3 months, three had had two or more medication reviews. The fourth patient had had a trial of stopping the medication. Prescribing of other psychotropic medication was also reviewed. Benzodiazepines were used sparingly (7.5%). Of note a significant minority of patients (10.4%) were prescribed 3 or more different psychotropic medications. These results suggest that within this service antipsychotics are being used appropriately to enable patients with distressing and difficult behaviour to continue to remain at home. They were generally prescribed for a short time and reviewed. Areas for improvement include a documented discussion of risk in all cases and ensuring that all possible causes of BPSD have been ruled out. Regular review of efficacy and tolerability is essential for all pharmacological treatments for BPSD particularly for those prescribed multiple psychotropic medications.


Effects of phenothiazine derivatives on the microclimate-pH in the rat jejunum.
The effects of several phenothiazine derivatives (PTDs) and quinidine (QD) on the jejunal microclimate-pH in rats were studied using a microelectrode. Chlorpromazine, thioridazine, chlorpromazine sulfoxide (CPZSO), trifluoperazine, prochlorperazine, and QD at concentrations of 1 mM increased this microclimate-pH by 0.15-0.3 pH units, while 1 mM diethazine and 1 mM promethazine had little effect on it. The increases in the microclimate-pH caused by PTDs and QD were concentration dependent and reversible. We studied the effects of PTDs on the fluidity of intestinal brush border membranes and on the release of proteins from the intestinal tissue to the lumen. The PTD-induced changes in microclimate-pH could not be explained by either of these nonspecific effects on the membranes. Then, the effects of PTDs on Na+,K+-ATPase activity and Mg2+-ATPase activity were studied using the jejunal homogenate. Each PTD inhibited Na+,K+-ATPase and Mg2+-ATPase activity to some extent. The inhibitory effects on Na+,K+-ATPase and Mg2+-ATPase activity were compared with the PTD-induced increases in the microclimate-pH. No good correlation was obtained between the IC50 values of PTDs for Na+,K+-ATPase activity and the concentrations required to increase the microclimate-pH by 0.1 pH unit, while IC50 values of PTDs for Mg2+-ATPase activity showed a relatively good correlation, except for that of CPZSO. These findings suggest that the effects of PTDs on the microclimate-pH were not nonspecific, although the increases in the microclimate-pH caused by PTDs cannot be fully explained by the inhibitory effects of these compounds on either Na+,K+-ATPase activity or Mg2+-ATPase activity alone.


Closed-loop supply chain models with considering the environmental impact.
Global warming and climate changes created by large scale emissions of greenhouse gases are a worldwide concern. Due to this, the issue of green supply chain management has received more attention in the last decade. In this study, a closed-loop logistic concept which serves the purposes of recycling, reuse, and recovery required in a green supply chain is applied to integrate the environmental issues into a traditional logistic system. Here, we formulate a comprehensive closed-loop model for the logistics planning considering profitability and ecological goals. In this way, we can achieve the ecological goal reducing the overall amount of CO2 emitted from journeys. Moreover, the profitability criterion can be supported in the cyclic network with the minimum costs and maximum service level. We apply three scenarios and develop problem formulations for each scenario corresponding to the specified regulations and investigate the effect of the regulation on the preferred transport mode and the emissions. To validate the models, some numerical experiments are worked out and a comparative analysis is investigated.


Modelling of an activated primary settling tank including the fermentation process and VFA elutriation.
A complete model of a primary settler including both sedimentation and biological processes is presented. It is a one-dimensional model based on the solids flux concept and the conservation of mass that uses the Takács model for the settling velocity, which is corrected by a compression function in the lower layers. The biological model is based on the ASM2 and enlarged with the fermentation model proposed by this research group. The settler was split in ten layers and the flux terms in the mass balance for each layer is obtained by means of the settling model. A pilot plant has been operated to study the primary sludge fermentation and volatile fatty acids (VFA) elutriation in a primary settler tank. The model has been tested with pilot plant experimental data with very good results. It has been able to simulate the VFA production in the settler and their elutriation with the influent wastewater for all the studied experiments. The developed model is easily applicable to secondary settlers and thickeners, also taking into account biological activity inside them.


In vitro low frequency electromagnetic field effect on fast axonal transport.
The objective of this study was to evaluate the effects of a low frequency electromagnetic field on fast axonal transport for future neuroprosthetic applications. Changes in speeds and densities of retrograde fast organelle transport in rat sciatic nerve preparations were measured in vitro upon exposure to 15 and 50 Hz pulsed magnetic fields with peak intensities of 4.4 and 8.8 mT. Maximum current density of the induced eddy current was calculated to be about 40 microA/cm2. Video enhanced differential interference contrast microscopy was used to record axons supporting active organelle transport. Strong effects were observed in myelinated axons (cessation of transport in up to 10 min). Such effects may eventually be used as part of a neuroprosthesis to noninvasively modify or couple to various parts of the nervous system.


Synthesis and biological activity of new dimers in the 7H-pyrido[4,3-c] carbazole antitumor series.
Ditercalinium (NSC 366241) is a 7H-pyrido[4,3-c]carbazole dimer with a diethylbipiperidine rigid chain linking the two heterocyclic rings. Ditercalinium is characterized by a high DNA affinity and bisintercalating ability, associated with potent antitumor properties, involving an original mechanism of action. Unfortunately as ditercalinium is hepatotoxic, its clinical evaluation has been interrupted. In order to eliminate or at least minimize the serious drawbacks related to its toxic effects, several chemical modifications have been made to the structure of ditercalinium, and their influence has been evaluated by measuring the DNA affinities, intercalation properties, and toxicity toward leukemia cells of the newly synthesized dimers. Reduction of the pyridinic moieties of ditercalinium, in order to suppress the permanent charges provided by the quaternizing chain, led to an almost complete loss of activity, although the DNA bisintercalating property of the dimer was preserved. Dimerization of the 7H-pyrido[4,3-c]carbazole rings by introduction of the rigid spacer on the N7- or C6-positions corresponding to the convex face of the pyridocarbazole, instead of the N2-position in ditercalinium, led to DNA bisintercalating dimers practically devoid of antitumor properties. However after quaternarization of the N2 atoms, the dimer linked by the N7 atoms exhibited a very high DNA affinity (greater than 10(9) M-1) and recovered antitumor activity, supporting the requirement of positive charges for the emergence of antitumor activity in these dimers. Introduction on the C6 of the 7H-pyridocarbazole ring of an aminomethyl or carboxyl group, a sugar residue, or C or N free amino acids such as Lys or Glu has also been carried out, in order to increase the hydrophilic properties of the molecules or to enable them to use amino acid transport systems. Although some of these compounds were active, none of them exhibited the pharmacological potency of ditercalinium.


Spo5/Mug12, a putative meiosis-specific RNA-binding protein, is essential for meiotic progression and forms Mei2 dot-like nuclear foci.
We report here a functional analysis of spo5(+)(mug12(+)) of Schizosaccharomyces pombe, which encodes a putative RNA-binding protein. The disruption of spo5(+) caused abnormal sporulation, generating inviable spores due to failed forespore membrane formation and the absence of a spore wall, as determined by electron microscopy. Spo5 regulates the progression of meiosis I because spo5 mutant cells display normal premeiotic DNA synthesis and the timely initiation of meiosis I but they show a delay in the peaking of cells with two nuclei, abnormal tyrosine 15 dephosphorylation of Cdc2, incomplete degradation of Cdc13, retarded formation and repair of double strand breaks, and a reduced frequency of intragenic recombination. Immunostaining showed that Spo5-green fluorescent protein (GFP) appeared in the cytoplasm at the horsetail phase, peaked around the metaphase I to anaphase I transition, and suddenly disappeared after anaphase II. Images of Spo5-GFP in living cells revealed that Spo5 forms a dot in the nucleus at prophase I that colocalized with the Mei2 dot. Unlike the Mei2 dot, however, the Spo5 dot was observed even in sme2Delta cells. Taken together, we conclude that Spo5 is a novel regulator of meiosis I and that it may function in the vicinity of the Mei2 dot.


Querying non-materialized ontology views.
One approach to simplifying ontologies, for inclusion in a more tractable semantic web, is through the use of non-materialized view queries. View queries define how a simplified "view" or "application" ontology is derived from larger more complex ontologies. In this work we look at a language for specifying view queries over OWL/RDFS sources, and we illustrate some initial ideas for how to execute user queries over our view ontology, without materializing it first.