Periodicity Pitch Perception Part III: Sensibility and Pachinko Volatility.
Neuromorphic computer models are used to explain sensory perceptions. Auditory models generate cochleagrams, which resemble the spike distributions in the auditory nerve. Neuron ensembles along the auditory pathway transform sensory inputs step by step and at the end pitch is represented in auditory categorical spaces. In two previous articles in the series on periodicity pitch perception an extended auditory model had been successfully used for explaining periodicity pitch proved for various musical instrument generated tones and sung vowels. In this third part in the series the focus is on octopus cells as they are central sensitivity elements in auditory cognition processes. A powerful numerical model had been devised, in which auditory nerve fibers (ANFs) spike events are the inputs, triggering the impulse responses of the octopus cells. Efficient algorithms are developed and demonstrated to explain the behavior of octopus cells with a focus on a simple event-based hardware implementation of a layer of octopus neurons. The main finding is, that an octopus' cell model in a local receptive field fine-tunes to a specific trajectory by a spike-timing-dependent plasticity (STDP) learning rule with synaptic pre-activation and the dendritic back-propagating signal as post condition. Successful learning explains away the teacher and there is thus no need for a temporally precise control of plasticity that distinguishes between learning and retrieval phases. Pitch learning is cascaded: At first octopus cells respond individually by self-adjustment to specific trajectories in their local receptive fields, then unions of octopus cells are collectively learned for pitch discrimination. Pitch estimation by inter-spike intervals is shown exemplary using two input scenarios: a simple sinus tone and a sung vowel. The model evaluation indicates an improvement in pitch estimation on a fixed time-scale.


Analysis of vascular access in hemodialysis patients: a report from a dialysis unit in Casablanca.
Vascular access (VA) for patients needing maintenance hemodialysis (HD) remains a major obstacle in the management of patients with end-stage renal disease (ESRD). We retrospectively analyzed 190 patients, (92 males and 98 females) who had been on HD for a period ranging from 12 to 240 months. Their mean age was 42.8 years (range: 13 to 83 years). The study was carried out to analyze the VA, including the management of its complications. The cause of renal failure was chronic glomerulonephritis in 34.2% and unknown in 30.5% of the study cases. In 164 patients (86.3%), HD was initiated through a temporary catheter inserted in the internal jugular vein. Each patient had, on an average, two catheters inserted that lasted for a mean duration of 29 days. All patients had a native arteriovenous fistula (AVF) as the permanent VA. A primary radial-cephalic AVF was created in 96.3% of the patients. The median period before cannulation was 15 days. Failure of AVF function occurred in 18.4% of cases while the median survival of the primary AVF was 54.8 months. Thrombosis, seen in 26.4% of the patients, was the predominant complication, and this event seemed to be causally related to prior insertion of temporary catheters. Ten patients had arterio-venous grafts (AVG) placed due to recurrent thrombosis of the AVF. The AVG was brachial-cephalic in five patients. A tunneled cuffed catheter was placed in four patients who had no other possible access sites available. These catheters were placed in the right internal jugular vein in all of these patients. The success of VA in patients on HD requires a multi-disciplinary approach and early referral to a vascular surgeon


Antibiotic consumption in laboratory confirmed vs. non-confirmed bloodstream infections among very low birth weight neonates in Poland.
Newborns are a population in which antibiotic consumption is extremely high. Targeted antibiotic therapy should help to reduce antibiotics consumption. The aim of this study was an assessment of antibiotic usage in bloodstream infections treatment in the Polish Neonatology Surveillance Network (PNSN) and determining the possibility of applying this kind of data in infection control, especially for the evaluation of standard methods of microbiological diagnostics. Data were collected between 01.01.2009 and 31.12.2013 in five teaching NICUs from the PNSN. The duration of treatment in days (DOT) and the defined daily doses (DDD) were used for the assessment of antibiotics consumption. The median DOT for a single case of BSI amounted to 8.0 days; whereas the median consumption expressed in DDD was 0.130. In the case of laboratory confirmed BSI, median DOT was 8 days, and consumption-0.120 DDD. Median length of therapy was shorter for unconfirmed cases: 7 days, while the consumption of antibiotics was higher-0.140 DDD (p < 0.0001). High consumption of glycopeptides expressed in DOTs was observed in studied population, taking into account etiology of infection. Even application of classical methods of microbiological diagnostics significantly reduces the consumption of antibiotics expressed by DDD. However, the high consumption of glycopeptides indicates the necessity of applying rapid diagnostic assays. Nevertheless, the assessment of antibiotic consumption in neonatal units represents a methodological challenge and requires the use of different measurement tools.


[Obesity as a risk factor for diseases of the digestive system].
Currently, the global prevalence of obesity among the worlds adult population is about 650 million people, which makes it possible to consider this chronic metabolic disease as a non-infectious pandemic of the 21st century. It has been proven that obesity is associated with several gastroenterological diseases, while the mechanisms of these associations are extremely heterogeneous and multifactorial. Hypertrophy and hyperplasia of adipocytes in obesity lead to a change in the profile of adipokine production (a decrease in adiponectin, an increase in leptin), an increase in the production of pro-inflammatory cytokines (interleukin-1, 6, 8, tumor necrosis factor ), C-reactive protein, free fatty acids, as well as active forms of oxygen (superoxide radicals, H2O2). All the above induces the development of chronic slowly progressive inflammation, oxidative stress, and insulin resistance. In addition, peptides secreted by adipocytes (adiponectin, leptin, nesfatin-1 and apelin) can modulate gastrointestinal motility, acting both centrally and peripherally. The qualitative and quantitative changes in the intestinal microbiota observed in obese patients (increased Firmicutes and decreased Bacteroidetes) lead to a decrease in the production of short-chain fatty acids and an increase in the intestinal permeability due to disruption of intercellular tight junctions, which leads to increased translocation of bacteria and endotoxins into the systemic circulation. Numerous studies have demonstrated the association of obesity with diseases of the esophagus (gastroesophageal reflux disease, Barretts esophagus, esophageal adenocarcinoma, esophageal motility disorders), stomach (functional dyspepsia, stomach cancer), gallbladder (cholelithiasis, gallbladder cancer), pancreas (acute pancreatitis, pancreatic cancer), liver (non-alcoholic fatty liver disease, hepatocellular carcinoma), intestine (diverticular disease, irritable bowel syndrome, colorectal cancer).


Genetic interactions and functional analyses of the fission yeast gsk3 and amk2 single and double mutants defective in TORC1-dependent processes.
The Target of Rapamycin (TOR) signalling network plays important roles in aging and disease. The AMP-activated protein kinase (AMPK) and the Gsk3 kinase inhibit TOR during stress. We performed genetic interaction screens using synthetic genetic arrays (SGA) with gsk3 and amk2 as query mutants, the latter encoding the regulatory subunit of AMPK. We identified 69 negative and 82 positive common genetic interactors, with functions related to cellular growth and stress. The 120 gsk3-specific negative interactors included genes functioning in translation and ribosomes. The 215 amk2-specific negative interactors included genes functioning in chromatin silencing and DNA damage repair. Both amk2- and gsk3-specific interactors were enriched in phenotype categories related to abnormal cell size and shape. We also performed SGA screen with the amk2 gsk3 double mutant as a query. Mutants sensitive to 5-fluorouracil, an anticancer drug are under-represented within the 305 positive interactors specific for the amk2 gsk3 query. The triple-mutant SGA screen showed higher number of negative interactions than the double mutant SGA screens and uncovered additional genetic network information. These results reveal common and specialized roles of AMPK and Gsk3 in mediating TOR-dependent processes, indicating that AMPK and Gsk3 act in parallel to inhibit TOR function in fission yeast.


Dynamics of growth hormone responsiveness to growth hormone releasing factor in aging rats: peripheral and central influences.
The in vivo and in vitro dynamics of somatotroph responsiveness to rGRF (1-29) NH2 (rat growth hormone releasing factor) were evaluated in 2-, 4-, 8-, 12-, and 20-month-old male rats. In vivo, using pentobarbital-anesthetized animals, we observed that the rGH (rat growth hormone) responsiveness to 0.4 and 1.6 micrograms/kg rGRF started to decline at the higher dose in 12-month-old rats and was completely blunted at both rGRF doses in 20-month-old animals. In vitro, using freshly dispersed perifused pituitary cells, we also documented a decrease of rGRF-induced rGH secretion in 12- and 20-month-old rats. Moreover, as the animals aged, the rGRF-induced rGH secretion was differentially affected by the inhibiting action of somatostatin (p less than 0.001), suggesting a loss of pituitary sensitivity to somatostatin in the presence of a high concentration of rGRF. The pituitary rGH content increased until rats reached 12 months of age, but was diminished in 20-month-old rats. In contrast, the pituitary somatostatin content increased twofold in 20-month-old rats as compared with younger rats. The hypothalamic somatostatin content was highest in 8-month-old rats and only slightly diminished in 20-month-old animals. Finally, plasma insulin-like growth factor I concentrations were highest in 8-month-old rats and lowest in 20-month-old animals. Altogether, these results indicate that the physiological loss of somatotroph responsiveness associated with the process of aging starts around 12 months of age.(ABSTRACT TRUNCATED AT 250 WORDS)


Randomised prior feedback modulates neural signals of outcome monitoring.
Substantial evidence indicates that decision outcomes are typically evaluated relative to expectations learned from relatively long sequences of previous outcomes. This mechanism is thought to play a key role in general learning and adaptation processes but relatively little is known about the determinants of outcome evaluation when the capacity to learn from series of prior events is difficult or impossible. To investigate this issue, we examined how the feedback-related negativity (FRN) is modulated by information briefly presented before outcome evaluation. The FRN is a brain potential time-locked to the delivery of decision feedback and it is widely thought to be sensitive to prior expectations. We conducted a multi-trial gambling task in which outcomes at each trial were fully randomised to minimise the capacity to learn from long sequences of prior outcomes. Event-related potentials for outcomes (Win/Loss) in the current trial (Outcomet) were separated according to the type of outcomes that occurred in the preceding two trials (Outcomet-1 and Outcomet-2). We found that FRN voltage was more positive during the processing of win feedback when it was preceded by wins at Outcomet-1 compared to win feedback preceded by losses at Outcomet-1. However, no influence of preceding outcomes was found on FRN activity relative to the processing of loss feedback. We also found no effects of Outcomet-2 on FRN amplitude relative to current feedback. Additional analyses indicated that this effect was largest for trials in which participants selected a decision different to the gamble chosen in the previous trial. These findings are inconsistent with models that solely relate the FRN to prediction error computation. Instead, our results suggest that if stable predictions about future events are weak or non-existent, then outcome processing can be determined by affective systems. More specifically, our results indicate that the FRN is likely to reflect the activity of positive affective systems in these contexts. Importantly, our findings indicate that a multifactorial explanation of the nature of the FRN is necessary and such an account must incorporate affective and motivational factors in outcome processing.


Brief analysis of the retention process in RP-HPLC systems with a C(30) bonded stationary phase.
The influence of the mobile-phase composition on the retention of eight model substances in different RP-HPLC systems with a C(30) alkyl bonded stationary phase has been studied. The aim of this study was to compare the performance of four valuable retention models assuming the partition and adsorption mechanism of retention. All the models were verified for different experimental data by four criteria: the sum of squared differences between the experimental and theoretical data; the approximation of the standard deviation; the Fisher test; and the F-test ratio.


Biopsy-verified bronchiolitis obliterans and other noninfectious lung pathologies after allogeneic hematopoietic stem cell transplantation.
Bronchiolitis obliterans (BO) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Lung biopsy is the gold standard for diagnosis. This study describes the course of BO and assesses the congruity between biopsy-verified BO and a modified version of the National Institutes of Health's consensus criteria for BO syndrome (BOS) based exclusively on noninvasive measures. We included 44 patients transplanted between 2000 and 2010 who underwent lung biopsy for suspected BO. Of those, 23 were diagnosed with BO and 21 presented other noninfectious pulmonary pathologies, such as cryptogenic organizing pneumonia, diffuse alveolar damage, interstitial pneumonia, and nonspecific interstitial fibrosis. Compared with patients with other noninfectious pulmonary pathologies, BO patients had significantly lower values of forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity, and maximal mid-expiratory flow throughout follow-up, but there was no difference in the change in pulmonary function from the time of lung biopsy. The BO diagnosis was not associated with poorer overall survival. Fifty-two percent of patients with biopsy-verified BO and 24% of patients with other noninfectious pulmonary pathology fulfilled the BOS criteria. Pathological BO diagnosis was not superior to BOS criteria in predicting decrease in pulmonary function beyond the time of biopsy. A lung biopsy may provide a characterization of pathological patterns that can extend our knowledge on the pathophysiology of HSCT-related lung diseases.


Depression among female registered nurses.
Depression, the most frequently diagnosed psychiatric illness, is characterized by feelings of sadness, pessimism, self-dislike and loss of energy, motivation and concentration. The relationship of self-esteem, assertiveness and anxiety to depression is studied in a group of female nurses. Recognizing predisposing factors in this high-risk group can begin a process to treat this illness.


Cytokine targets in the treatment of myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are characterized by refractory cytopenias due to ineffective hematopoiesis in the marrow. Cytokines play an important role in the regulation of hematopoiesis; dysregulation of their levels can lead to hematopoietic failure. Considerable evidence implicates tumor necrosis factor alpha, transforming growth factor beta, interferons, interleukin 1beta, vascular endothelial growth factor (VEGF), and other inhibitory cytokines in the pathogenesis of MDS. These cytokines are produced by the interactions between the MDS clone and the bone marrow microenvironment. Therapeutic strategies therefore may augment the action of stimulatory growth factors or disrupt the effects of myelosuppressive cytokines. Erythropoietin alone and in combination with low-dose granulocyte colony-stimulating factor can lead to erythroid responses in selected patients. Agents targeting inhibitory cytokines include thalidomide, lenalidomide, etanercept, infliximab, VEGF receptor inhibitor PTK-787, antithymocyte globulin, and SCIO-469, a p38 mitogen-activated protein kinase inhibitor. Given the biologic heterogeneity of MDS, no single treatment is effective for all patients with the disease. With more detailed knowledge of cytokine signaling cascades, coupled with technological improvements in genomics and proteomics, the future treatment of this challenging disease may lie in combination therapies customized for relevant biologic effectors.


Prognostic and predictive role of elevated lactate dehydrogenase in patients with melanoma treated with immunotherapy and BRAF inhibitors: a systematic review and meta-analysis.
Levels of serum lactate dehydrogenase (LDH) are a recognized prognostic factor in malignant melanoma (MM). It is relevant to confirm its prognostic role in patients treated with targeted therapies [BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi)] and immunotherapy (IT). Furthermore, its role as a predictive marker in patients treated with these drugs had still not been investigated. We performed an electronic search for studies reporting information on overall survival (OS) or progression-free survival (PFS) according to LDH levels and on their predictive effect in patients treated with targeted therapies (BRAFi and MEKi) and IT. Data were pooled using hazard ratios (HRs) for OS and HRs for PFS according to a fixed-effect or a random-effect model. For predictive analysys, effect of new agents versus standard therapy was evaluated in LDH high population. A total of 71 publications were retrieved for a total of 16 159 patients. Overall, elevated LDH levels were associated with an HR for OS of 1.72 [95% confidence interval (CI): 1.6-1.85; P<0.0001]. Similarly, HR for PFS was 1.83 (95% CI: 1.53-2.2; P<0.0001). In the LDH elevated subgroup, new agents improved OS significantly (HR: 0.71; 95% CI: 0.62-0.82; P<0.0001) and PFS (HR: 0.63; 95% CI: 0.55-0.72; P<0.0001). In advanced MM treated with IT or BRAFi±MEKi, elevated LDH level at baseline represents a poor prognostic factor. However, patients with increased LDH levels and treated with these drugs gain significant benefits in terms of PFS and OS.


Mechanism of regulating macrophages/osteoclasts in attenuating wear particle-induced aseptic osteolysis.
Joint replacement surgery is the most effective treatment for end-stage arthritis. Aseptic loosening caused by periprosthetic osteolysis is a common complication after joint replacement. Inflammation induced by wear particles derived from prosthetic biomaterials is a major cause of osteolysis. We emphasize that bone marrow-derived macrophages and their fusion-derived osteoclasts play a key role in this pathological process. Researchers have developed multiple intervention approaches to regulate macrophage/osteoclast activation. Aiming at wear particle-induced periprosthetic aseptic osteolysis, this review separately discusses the molecular mechanism of regulation of ROS formation and inflammatory response through intervention of macrophage/osteoclast RANKL-MAPKs-NF-κB pathway. These molecular mechanisms regulate osteoclast activation in different ways, but they are not isolated from each other. There is also a lot of crosstalk among the different mechanisms. In addition, other bone and joint diseases related to osteoclast activation are also briefly introduced. Therefore, we discuss these new findings in the context of existing work with a view to developing new strategies for wear particle-associated osteolysis based on the regulation of macrophages/osteoclasts.


Energy Efficiency of D2D Multi-User Cooperation.
The Device-to-Device (D2D) communication system is an important part of heterogeneous networks. It has great potential to improve spectrum efficiency, throughput and energy efficiency cooperation of multiple D2D users with the advantage of direct communication. When cooperating, D2D users expend extraordinary energy to relay data to other D2D users. Hence, the remaining energy of D2D users determines the life of the system. This paper proposes a cooperation scheme for multiple D2D users who reuse the orthogonal spectrum and are interested in the same data by aiming to solve the energy problem of D2D users. Considering both energy availability and the Signal to Noise Ratio (SNR) of each D2D user, the Kuhn-Munkres algorithm is introduced in the cooperation scheme to solve relay selection problems. Thus, the cooperation issue is transformed into a maximum weighted matching (MWM) problem. In order to enhance energy efficiency without the deterioration of Quality of Service (QoS), the link outage probability is derived according to the Shannon Equation by considering the data rate and delay. The simulation studies the relationships among the number of cooperative users, the length of shared data, the number of data packets and energy efficiency.


Photophysical properties of the triangular [Au(HN[double bond, length as m-dash]COH)]3 complex and its dimer.
Rate constants for radiative and non-radiative transitions of the [Au(HN[double bond, length as m-dash]COH)]3 complex and its dimer were calculated within the Herzberg-Teller approximation based on quantum mechanical principles. A high triplet quantum yield was estimated for the monomer. Internal conversion (IC) was found to be the major competing process to the intersystem crossing (ISC) from the lowest excited singlet state (S1) to the lowest triplet state (T1). ISC and IC from the spin-mixed T[combining tilde]1 state also dominate the triplet relaxation process resulting in a negligible phosphorescence quantum yield for the monomer. The IC and ISC rate constants of the dimer are considerably smaller due to much lower Franck-Condon factors. For the dimer a triplet quantum yield of 0.71 was estimated using the extended multi-configuration quasi-degenerate second-order perturbation theory (XMCQDPT2) method to calculate the transition energies. Fluorescence is the major competing process to the ISC relaxation of the S1 state of the dimer. The ISC and IC processes are insignificant for the relaxation of the T1 state, resulting in unity phosphorescence quantum yield. The high triplet and phosphorescence quantum yields of the [Au(HN[double bond, length as m-dash]COH)]3 dimer make it and its higher oligomers potential candidates as dopants for phosphorescent organic light emitting diodes and as down-converters in solid-state lighting systems.


Acquired resistance to 5-fluorouracil via HSP90/Src-mediated increase in thymidylate synthase expression in colon cancer.
5-fluorouracil (5-FU), one of the first-line chemotherapeutic agents for the treatment of gastrointestinal malignancies, has shown limited efficacy. The expression of thymidylate synthase (TYMS) has been reported to be associated with the resistance to 5-FU. Here, we demonstrate that the enhanced HSP90 function and subsequent activation of Src induce expression of TYMS and acquired resistance to 5-FU in colon cancer. We show that the persistent 5-FU treatment granted 5-FU-sensitive HCT116 colon cancer cells morphologic, molecular, and behavioral characteristic of the epithelial-mesenchymal transition (EMT), contributing to emergence of acquired resistance to 5-FU. HCT116/R, a HCT116 colon cancer cell subline carrying acquired resistance to 5-FU, showed increased expression and activation of HSP90's client proteins and transcriptional up-regulation of TYMS. Forced overexpression of HSP90 or constitutive active Src in HCT116 cells increased TYMS expression. Conversely, pharmacological blockade of HSP90 or Src in HCT116/R cells effectively suppressed the changes involved in 5-FU resistance in vitro and xenograft tumor growth, hematogenous spread, and metastatic tumor development in vivo. This study suggests a novel function of HSP90-Src pathway in regulation of TYMS expression and acquisition of 5-FU resistance. Thus, therapeutics targeting this pathway may be an effective clinical strategy to overcome 5-FU resistance in colon cancer.


A comparison between zinc polycarboxylate and glass ionomer cement in the orthodontic band cementation.
Fixed orthodontic appliances have been held responsible for demineralization and caries since the time they were first introduced. Zinc polycarboxylate and glass ionomer cements are the primary materials used in band cementing. In this study, we evaluated the re-cementing frequencies, enamel demineralization and the degree of cement remains of the bands cemented with glass ionomer and zinc polycarboxylate cements. We have concluded that given the retentive properties and enamel decalcification degree, the glass ionomer cements are to be preferred by the orthodontist.


Effect of steroids on DNA synthesis in an in vitro replication system: initial quantitative structure-activity relationship studies and construction of a non-estrogen receptor pharmacophore.
The molecular mechanism(s) by which steroids affect carcinogenesis is an active area of investigation. Recent studies with a series of related steroids in an in vitro DNA replication system produced a wide range of effects including enhancement and inhibition of DNA synthesis. The HeLa cell-free system used in these studies did not contain estrogen receptors. Since the majority of hormone effects on cellular replication have been attributed to interactions with estrogen receptors, an alternative description of the results was required. Quantitative structure-activity relationships (QSARs) were used to relate the observed bioactivity of these steroids with their structure. The results indicate that the percentage of DNA replication could be related to three parameters according to the following equation: %DNA = 23.9(+/-3.8)Xdipact + 57.8(+/-22.4)Hyd - 19.4(+/-10.4)Biophpi + 128.9, where Xdipact is the dipole moment on the X-axis, Hyd is the atomic hydrophobicity index, and Biophpi is the atomic pi population on the heteroatom found in the pharmacophore. For each molecule, the orientation of the functional groups changed the dipole moment value, and this descriptor was used as a selector of active conformations. A 3D-QSAR model was then constructed combining pharmacophoric features and global properties, and the active space and inactive space were defined using a Boolean volumetric operation.


Computational Approach to Identify Different Injuries by Firearms.
Complications arise in the analysis of gunshot wounds to the maxillofacial region, when neither the projectile nor the gun is found at the crime scene. We simulated 5- and 15-cm firing distances at a human mandible to investigate the external morphology of entrance wounds based on fire range. The ammunition models, .40-caliber S&W, .380-caliber, and 9 × 19-mm Luger, were constructed with free-form NURBS surfaces. In a dynamic simulation, projectiles were fired against mandibular body 3D model at 5 and 15 cm. All entrance wounds presented oval aspect. Maximum diameter and von Mises stress values were 16.5 mm and 50.8 MPa, both for .40-caliber S&W fired at 5 cm. The maximum energy loss was 138.4 J for .40 S&W fired at 15 cm. In conclusion, the mandible was most affected by .40-caliber S&W and morphological differences were observable in holes caused by different incoming projectile calibers fired at different distances.


Peripheral quantitative computed tomography (pQCT) reveals alterations in the three-dimensional bone structure in children with haemophilia.
Children with haemophilia are at risk of suboptimal bone mass accrual and low bone mineral density (BMD). We recently demonstrated that although BMD in Finnish children with haemophilia was within the normal range, their whole body BMD was significantly lower and hypercalciuria more prevalent than in controls. This study sought to determine the bone structure and strength in physically active children with haemophilia. To investigate the underlying mechanisms in this group, we conducted a case-control study to assess bone structure and strength by peripheral quantitative computed tomography (pQCT) at the radius. The study group comprised 29 patients (mean age 12.2 years) and 46 age-matched controls. Children with haemophilia had decreased total BMD Z-score at the distal radius (P ≤ 0.001), but increased cortical bone density at the proximal radius (P ≤ 0.001). Total bone area at the proximal radius was significantly lower in children with haemophilia (P = 0.002), whereas there were no differences in cortical bone area or in polar Strength-Strain Index, a parameter of bone strength, between the patients and controls. Patients with mild to moderate haemophilia and on-demand treatment had inferior bone strength compared to those with moderate to severe haemophilia and prophylaxis. Our findings suggest altered skeletal development in patients with haemophilia in the radius, resulting in smaller bone size and higher cortical bone density. Importantly, bone strength at the radius appears equal to healthy children. Prophylactic treatment seems to have a beneficial effect on bone health.


Continuum of Care: Positioning of the Virtual Hospital.
Patients with multiple chronic diseases suffer from reduced life expectancy. Care for these patients is often divided over multiple healthcare professionals. eHealth might help to integrate care for these patients and create a continuum. It is the primary purpose of this paper to describe an intervention that integrates first, second, and third line care in patients with multiple chronic conditions using remote monitoring, remote therapy and data automatization, all integrated in a virtual care center (VCC). Patients diagnosed with three or more chronic conditions are included and given smartphone compatible devices for remote monitoring and a tablet for video consultations. Patients will be followed-up by the VCC, consisting of nurses who will coordinate care, supervised by general practitioners and medical specialists. Data is reviewed on a daily basis and patients are contacted on a weekly basis. Review of data is automated by computer algorithms. Patients are contacted in case of outcome abnormalities in the data. Patients can contact the VCC at any time. Follow-up of the study is 1 year. The primary outcome of this study is the median number of nights admitted to the hospital per patient compared to the hospitalization data 12 months before enrolment. Secondary outcomes include all-cause mortality, event free survival, quality of life and satisfaction with technology and care. This study presents the concept of a VCC that integrates first, second, and third line care into a virtual ward using remote monitoring and video consultation.


Access to 1'-Amino Carbocyclic Phosphoramidite to Enable Postsynthetic Functionalization of Oligonucleotides.
We report a synthesis of a carbocyclic, abasic RNA phosphoramidite decorated with an amino functionality. The building block was efficiently incorporated into an RNA oligonucleotide in a site-specific manner, followed by deprotection to a free amino group. The amino moiety could be further derivatized as exemplified with fluorescein N-hydroxysuccinimide ester. Hence, this convertible building block may provide access to a variety of RNA oligonucleotides via postsynthetic amino group functionalization. In particular, providing a vector toward nucleobase replacements.


[The current perspectives of hepatitis A prevention].
In the paper the current views on HAV infection patterns of endemicity (high, intermediate and low) are presented, based on WHO informal consultation on the public health control of hepatitis A, C and E in Geneva (5-6.10.92). The epidemiological situation of HAV in Poland (1983-1992) is described, but based on symptomatic cases of non-B cases reporting. The highest morbidity in children aged 8-14 years, seasonal and cyclical variation in numbers of reported cases in Poland are specific for intermediate endemicity geographical areas. A special attention was paid to WHO recommendations for application of passive and active immunization against HAV in specific areas of endemicity.


Ceftriaxone-mediated upregulation of the glutamate transporter GLT-1 contrasts neurotoxicity evoked by kainate in rat organotypic spinal cord cultures.
Excitotoxicity is a major pathological trigger of neurodegenerative diseases like amyotrophic lateral sclerosis. This process is caused by excessive release of the transmitter glutamate that overwhelms the capacity of astroglia transporters to maintain a low extracellular level of this aminoacid and strongly stimulates neurons. Using an in vitro model of rat organotypic spinal slice culture, we explored if the excitotoxicity caused by the potent glutamate analogue kainate, widely employed as a paradigm to evoke neurotoxicity in the central nervous system, was prevented by the antibiotic ceftriaxone known to enhance glutamate transporter expression. We also tested if excitotoxicity was made worse by inhibiting glutamate uptake with dl-threo-β-benzyloxyaspartate (TBOA). These experiments were aimed at clarifying the relative contribution to neurotoxicity by kainate-activation of glutamate receptors or kainate-mediated release of glutamate. Neither ceftriaxone nor TBOA alone had adverse effects. Ceftriaxone (10μM; 3days) significantly decreased delayed cell death induced by kainate (100μM; 1h) and limited neuronal damage especially to motoneurons. This effect was associated to stronger astrocytic immunostaining of the glutamate transporter GLT-1. Conversely, pharmacological inhibition of glutamate uptake with TBOA was per se unable to induce neurotoxicity, yet it intensified cell death evoked by kainate. These data indicate that kainate-mediated glutamate release was critical to damage neurons, an effect prevented by up regulating glutamate uptake. These data suggest that modulating glutamate uptake is an important strategy to preserve neuronal networks.


Assessment of current serum levels of PCDD/Fs, dl-PCBs and PBDEs in a Dutch cohort with known perinatal PCDD/F exposure.
As part of a longitudinal cohort study, now in its second decade, we determined PCDDs/Fs dl-PCBs and PBDEs in serum of adolescents with known perinatal PCDD/F exposure. Of the original cohort, 33 adolescents aged 14-19 years, who had been studied previously during their neonatal (n=60), toddler and pre-pubertal period (n=41) agreed to participate in the current follow-up. PCDD/F-, dl-PCB- and PBDE congeners were measured using GC/MS. Current serum levels of PCDD/Fs determined in our cohort were relatively low (mean of 2.2 pg/g) compared to the perinatal exposure. No correlation between perinatal exposure and current serum PCDD/F was found. Planar PCB TEQ levels were 2.2 pg/g. Current summation operatorPBDE levels were 8.7 ng/g lipid. There was one outlier with a summation operatorPBDE of 74 ng/g lipid. The presence of this high value indicates that the exposure pathway is different from PCDD/F and PCB, most likely by dust and food contaminated with dust. Concluding we can say that current PCDD/F levels are quite low compared to the perinatal PCDD/F exposure of the cohort. PBDE levels however are relatively high compared to other European countries, more research on possible health effects of these levels, especially for subjects with outlier concentrations, should be performed.


Epidemiology and Economic Burden of Atopic Dermatitis: Real-World Retrospective Data from a Large Nationwide Israeli Healthcare Provider Database.
Real-world data on the epidemiology and economic burden of atopic dermatitis (AD) are limited. Here we describe the epidemiology and economic burden of AD using electronic healthcare data from Israel. A retrospective study was performed using the Maccabi Healthcare Services database. AD incidence in 2008-2017 and point prevalence (ADprev) on 31 December 2017 were described using diagnosis codes for overall patients, and sex and age subgroups. For ADprev, severity was defined using recently dispensed treatments for AD. Annual healthcare resource utilization in AD prevalent patients was compared with non-AD matched controls using generalized linear modelling. Direct annual costs were estimated also. AD incidence was 7.0/1000 person-years; overall prevalence was 4.4% (female patients 4.5%, male patients 4.3%; age 0 to less than 6 months, 0.9%; 6 months to less than 12 years, 11.0%; 12 to less than 18 years, 5.8%; 18 years or older, 2.2%). Among ADprev (n = 94,483), mild, moderate, and severe AD comprised 57.7%, 36.2%, and 6.1% (adults 43.8%, 46.3%, 9.9%), respectively. Dermatologist and allergist visits and hospitalization rates (at least one) were 40.7%, 6.6%, and 3.8% in 2017. Compared with controls, overall and moderate-to-severe AD were associated with 36% and 52% increases in annual per-person costs (incremental costs $126 and $190). AD epidemiology in Israel is comparable with other real-world database studies. AD imposes an economic burden that increases with disease severity.


Size-selected infrared predissociation spectroscopy of neutral and cationic formamide-water clusters: stepwise growth of hydrated structures and intracluster hydrogen transfer induced by vacuum-ultraviolet photoionization.
Vibrational spectroscopy of size-selected formamide-water clusters, FA-(H2O)n , n = 1-4, prepared in a supersonic jet is performed with vacuum-ultraviolet-ionization detected-infrared predissociation spectroscopy (VUV-ID-IRPDS). The cluster structures are determined through comparisons of the observed IR spectra with theoretical calculations at the MP2/6-31++G** level. The FA-(H2O)n , n = 1-3, clusters have ring-type structures, where water molecules act as both single donor and single acceptor in the hydrogen-bond network between the amino and carbonyl groups of FA. For FA-(H2O)4, on the other hand, the absence of the free NH stretching vibration indicates formation of a double ring type structure, where two NH bonds of the amino group and the carbonyl oxygen of FA form hydrogen bonds with water molecules. An infrared spectrum of the formamide-water cluster cation, [FA-H2O](+), is also observed with infrared predissociation spectroscopy of vacuum-ultraviolet-pumped ion (IRPDS-VUV-PI). No band is observed for the free OH stretches of neutral water. This shows [FA-H2O](+) has such a structure that one of the hydrogen atoms of the water moiety is transferred to the carbonyl oxygen of FA(+).


The Role of Clinical Proteomics, Lipidomics, and Genomics in the Diagnosis of Alzheimer's Disease.
The early diagnosis of Alzheimer's disease (AD) has become important to the reversal and treatment of neurodegeneration, which may be relevant to premature brain aging that is associated with chronic disease progression. Clinical proteomics allows the detection of various proteins in fluids such as the urine, plasma, and cerebrospinal fluid for the diagnosis of AD. Interest in lipidomics has accelerated with plasma testing for various lipid biomarkers that may with clinical proteomics provide a more reproducible diagnosis for early brain aging that is connected to other chronic diseases. The combination of proteomics with lipidomics may decrease the biological variability between studies and provide reproducible results that detect a community's susceptibility to AD. The diagnosis of chronic disease associated with AD that now involves genomics may provide increased sensitivity to avoid inadvertent errors related to plasma versus cerebrospinal fluid testing by proteomics and lipidomics that identify new disease biomarkers in body fluids, cells, and tissues. The diagnosis of AD by various plasma biomarkers with clinical proteomics may now require the involvement of lipidomics and genomics to provide interpretation of proteomic results from various laboratories around the world.


Epinephrine auto-injector needle length: what is the ideal length?
The purpose of this manuscript is to review the literature on the clinical effects of the needle length of epinephrine (adrenaline) auto-injectors. Epinephrine has maximal pharmacodynamic effect within 10 min of intramuscular administration into the thigh. Prefilled epinephrine auto-injectors are designed for simplicity of use and safety. Auto-injectors are primarily used by patients in an unsupervised setting in cases of anaphylaxis. There are weight-appropriate doses of epinephrine available with auto-injectors that are prefilled, to prevent dosing errors, with 0.15, 0.30, and 0.50 mg amounts. In addition, needle lengths vary from 1.17 to 2.50 cm. The recommended needle lengths differ between adults and pediatric patients. In addition, the needle lengths differ between devices as well. There are concerns that the needle length may be too short in select obese patients. Yet, there are also concerns that the needle length may be too long in some patients. Factors that affect the depth of the injection, and therefore the pharmacokinetics of the drug, include not only the needle length but also the BMI, obesity, compression of soft tissue, and propulsion. Epinephrine auto-injectors have different needle lengths. Using the right device with appropriate needle length based on BMI, obesity, and employing the proper technique can improve the outcome in an anaphylactic event.


Clinical significance of cervical MRI in brachial plexus birth injury.
Background and purpose - Patient selection for nerve surgery in brachial plexus birth injury (BPBI) is difficult. Decision to operate is mostly based on clinical findings. We assessed whether MRI improves patient selection. Patients and methods - 157 BPBI patients were enrolled for a prospective study during 2007-2015. BPBI was classified at birth as global plexus injury (GP) or upper plexus injury (UP). The global plexus injury was subdivided into flail upper extremity (FUE) and complete plexus involvement (CP). Patients were seen at set intervals. MRI was scheduled for patients that had either GP at 1 month of age or UP with no antigravity biceps function by 3 months of age. Type (total or partial avulsion, thinned root), number and location of root injuries and pseudomeningoceles (PMC) were registered. Position of humeral head (normal, subluxated, dislocated) and glenoid shape (normal, posteriorly rounded, pseudoglenoid) were recorded. Outcome was assessed at median 4.5 years (1.6-8.6) of age. Results - Cervical MRI was performed on 34/157 patients at median 3.9 months (0.3-14). Total root avulsions (n = 1-3) were detected on MRI in 12 patients (8 FUE, 4 CP). Reconstructive surgery was performed on 10/12 with total avulsions on MRI, and on all 10 with FUE at birth. Sensitivity and specificity of MRI in detecting total root avulsions was 0.88 and 1 respectively. Posterior shoulder subluxation/dislocation was seen in 15/34 patients (3.2-7.7 months of age). Interpretation - Root avulsion(s) on MRI and flail upper extremity at birth are both good indicators for nerve surgery in brachial plexus birth injury. Shoulder pathology develops very early in permanent BPBI.


Identification of nitrogen, phosphorus, and potassium deficiencies in rice based on static scanning technology and hierarchical identification method.
Establishing an accurate, fast, and operable method for diagnosing crop nutrition is very important for crop nutrient management. In this study, static scanning technology was used to collect images of a rice sample's fully expanded top three leaves and corresponding sheathes. From these images, 32 spectral and shape characteristic parameters were extracted using an RGB mean value function and using the Regionprops function in MATLAB. Hierarchical identification was used to identify NPK deficiencies. First, the normal samples and non-normal (NPK deficiencies) samples were identified. Then, N deficiency and PK deficiencies were identified. Finally, P deficiency and K deficiency were identified. In the identification of every hierarchy, SVFS was used to select the optimal characteristic set for different deficiencies in a targeted manner, and Fisher discriminant analysis was used to build the diagnosis model. In the first hierarchy, the selected characteristics were the leaf sheath R, leaf sheath G, leaf sheath B, leaf sheath length, leaf tip R, leaf tip G, leaf area and leaf G. In the second hierarchy, the selected characteristics were the leaf sheath G, leaf sheath B, white region of the leaf sheath, leaf B, and leaf G. In the third hierarchy the selected characteristics were the leaf G, leaf sheath length, leaf area/leaf length, leaf tip G, difference between the 2nd and 3rd leaf lengths, leaf sheath G, and leaf lightness. The results showed that the overall identification accuracies of NPK deficiencies were 86.15, 87.69, 90.00 and 89.23% for the four growth stages. Data from multiple years were used for validation, and the identification accuracies were 83.08, 83.08, 89.23 and 90.77%.


From broken windows to busy streets: a community empowerment perspective.
In the present article, we introduce a community empowerment perspective to understanding neighborhoods. A preponderance of literature exists on neighborhood risk factors for crime. Yet less is known about positive factors that make neighborhoods safe and desirable. We propose community empowerment as a conceptual foundation for understanding neighborhood factors that promote social processes, and ultimately, lead to an improvement in structural factors. We suggest that neighborhoods are empowered because they include processes and structures for positive social interactions to emerge and develop. We present busy streets as a mechanism that creates a positive social context, in which social cohesion and social capital thrive. Thus, empowered communities are characterized by climates that promote busy streets. Our article underscores the need to examine both the broader, structural context and social processes operating within this context. Such an integrative perspective is necessary to fully understand how to empower neighborhoods, particularly in the face of structural challenges.


The distribution of nuchal translucency at 10-13 weeks of pregnancy.
There is a need for a simple method of expressing nuchal translucency measurement in early pregnancy that will allow for gestational age and be useful in screening for Down's syndrome. To achieve this objective, we conducted a prospective study of 561 women with singleton pregnancies that were not affected by Down's syndrome at 10-13 weeks of gestation. Nuchal translucency measurements and crown rump length measurements were determined. Nuchal translucency measurement increased by about 17 per cent per week. Expressing the result as a multiple of the median (MOM) nuchal translucency for a given crown rump length allowed for this increase with gestational age and yielded a distribution of values that was approximately Gaussian. About 96 per cent of values lay between 0.5 and 2.0 MOM. The variance and therefore the false-positive rate of nuchal translucency were significantly reduced by recording several measurements and using the average: for example, the false-positive rate reduced from 8.3 per cent to 5.0 per cent if the average of six measurements were used instead of one--a potential 40 per cent reduction in the false-positive rate if the test were used in screening. Estimating the distribution of nuchal translucency in MOM values will assist in specifying the statistical parameters to be used in prenatal screening for Down's syndrome and the use of repeated nuchal translucency measurements is expected to have a useful effect on reducing the screening false-positive rate at a given MOM cut-off level.


Enrolling in Clinical Research While Incarcerated: What Influences Participants' Decisions?
As a 2006 Institute of Medicine report highlights, surprisingly little empirical attention has been paid to how prisoners arrive at decisions to participate in modern research. With our study, we aimed to fill this gap by identifying a more comprehensive range of factors as reported by prisoners themselves during semistructured interviews. Our participants described a diverse range of motives, both favoring and opposing their eventual decision to join. Many are well-recognized considerations among nonincarcerated clinical research participants, including a desire for various forms of personal benefit, altruism, and concern about study risks and inconveniences. However, a number of influences seem unique to prisoners. Participants did not report that they were not coerced into enrolling, and they have even been under pressure not to enroll. However, many sought to enroll in order to obtain access to better health care, raising a concern about whether they were unfairly exploited.


Early Hyperglycemia after Initiation of Glucocorticoid Therapy Predicts Adverse Outcome in Patients with Acute Graft-versus-Host Disease.
Because of first-line treatment with high-dose glucocorticoids (GC), steroid-induced hyperglycemia develops frequently in patients with acute graft-versus-host disease (aGVHD), potentially affecting their outcome. We performed a retrospective analysis on 104 patients who received systemic GC for aGVHD and investigated the consequences of aberrant glucose metabolism. In particular, we focused on glucose parameters early after initiation of GC. With a median of 50 (range, 4 to 513) blood glucose measurements during GC treatment, increasing mean, median, and maximum glucose levels and the need for insulin treatment were associated with decreased overall survival (OS) in simple and multiple survival analysis. Early hyperglycemia, as defined by mean blood glucose levels >125 mg/dL during the first 3 days of GC therapy, was also found to be highly associated with adverse outcome (hazard ratio [HR], 2.5 for death; 95% confidence interval [CI], 1.3 to 4.8, and HR of 3.5 for death due to nonrelapse mortality, 95% CI, 1.7 to 7.5, in a competing risk analysis). A score based on early hyperglycemia and nonresponse to GC within 7 days allowed the identification of 3 risk groups: patients with both risk factors had an inferior OS at 5 years of 4.1% compared with 75.4% in patients with none. Patients with 1 risk factor had a 5-year OS rate of 32.0% (P = .0002 for trend). Early hyperglycemia after GC initiation is a prominent risk factor for adverse outcome in patients with aGVHD. A score based solely on early hyperglycemia and lack of response to GC can predict survival in these patients.


Do authors check their references? A survey of accuracy of references in three public health journals.
We verified a random sample of 50 references in the May 1986 issue of each of three public health journals. Thirty-one per cent of the 150 references had citation errors, one out of 10 being a major error (reference not locatable). Thirty per cent of the references differed from authors' use of them with half being a major error (cited paper not related to author's contention).


Emergency Department Crowding Disparity: a Nationwide Cross-Sectional Study.
In this study, we evaluated national differences in emergency department (ED) crowding to identify factors significantly associated with crowding in institutes and communities across Korea. This was a cross-sectional nationwide observational study using data abstracted from the National Emergency Department Information System (NEDIS). We calculated mean occupancy rates to quantify ED crowding status and divided EDs into three groups according to their occupancy rates (cutoffs: 0.5 and 1.0). Factors potentially related to ED crowding were collected from the NEDIS. We performed a multivariate regression analysis to identify variables significantly associated with ED crowding. A total of 120 EDs were included in the final analysis. Of these, 73 were categorized as 'low crowded' (LC, occupancy rate < 0.50), 37 as 'middle crowded' (MC, 0.50 ≤ occupancy rate < 1.00), 10 EDs as 'high crowded' (HC, 1.00 ≤ occupancy rate). The mean ED occupancy rate varied widely, from 0.06 to 2.33. The median value was 0.39 with interquartile ranges (IQRs) from 0.20 to 0.71. Multivariate analysis revealed that after adjustment, ED crowding was significantly associated with the number of visits, percentage of patients referred, number of nurses, and ED disposition. This nationwide study observed significant variety in ED crowding. Several input, throughput, and output factors were associated with crowding.


From Pine Cones to Read Clouds: Rescaffolding the Megagenome of Sugar Pine (Pinus lambertiana).
We investigate the utility and scalability of new read cloud technologies to improve the draft genome assemblies of the colossal, and largely repetitive, genomes of conifers. Synthetic long read technologies have existed in various forms as a means of reducing complexity and resolving repeats since the outset of genome assembly. Recently, technologies that combine subhaploid pools of high molecular weight DNA with barcoding on a massive scale have brought new efficiencies to sample preparation and data generation. When combined with inexpensive light shotgun sequencing, the resulting data can be used to scaffold large genomes. The protocol is efficient enough to consider routinely for even the largest genomes. Conifers represent the largest reference genome projects executed to date. The largest of these is that of the conifer Pinus lambertiana (sugar pine), with a genome size of 31 billion bp. In this paper, we report on the molecular and computational protocols for scaffolding the P. lambertiana genome using the library technology from 10× Genomics. At 247,000 bp, the NG50 of the existing reference sequence is the highest scaffold contiguity among the currently published conifer assemblies; this new assembly's NG50 is 1.94 million bp, an eightfold increase.


Infliximab for the Treatment of Inflammatory Labyrinthitis: A Retrospective Cohort Study.
Inflammatory labyrinthitis is defined as a fluctuant vestibulo-cochlear syndrome associated with an impairment of the blood-labyrinthine barrier (BLB) on delayed FLAIR MRI sequences. Systemic and intratympanic corticosteroids are the gold standard treatment but their effect is frequently insufficient. The objective is here to determine whether infliximab could be of value in the treatment of bilateral inflammatory labyrinthitis. A retrospective monocentric study was conducted between January 2013 and December 2021. All patients included in the study were affected with a bilateral vestibulo-cochlear syndrome associated with bilateral blood-labyrinthine barrier impairment. Patients were administered infliximab at the dose of 5 mg/kg every 6 weeks for 6 months. Audiometry, MRI with delayed FLAIR sequences on the labyrinth, and corticosteroid doses still required were assessed both before and after treatment with infliximab was completed. Pure-tone average (PTA) was the primary outcome. The secondary outcomes were the speech recognition threshold (SRT), the Dizziness Handicap Inventory (DHI) score, and the corticosteroid (CS) dose. A total of nine patients including five men and four women were enrolled in the study. Thirteen ears were analyzed. After a 6-month period of treatment, the mean PTA (54 ± 24 db versus 66 ± 22 db; p = 0.027), SRT (54 ± 37 db versus 66 ± 32 db; p = 0.041) and DHI score (27 ± 15 versus 9 ± 2; p = 0.032) significantly improved. After the 6-month treatment period, the mean CS dose decreased from 38 ± 33 to 6 ± 5 mg/day (p = 0.003). We conclude that infliximab substantially improves the vestibulo-cochlear function in patients with bilateral inflammatory labyrinthitis and could be of value in corticosteroid-dependent cases.


Evaluation of mitotic activity index in breast cancer using whole slide digital images.
Mitotic Activity Index (MAI) is an important independent prognostic factor and an integral part of the breast cancer grading system. Thus, correct estimation of this prognostically relevant feature is essential for guiding treatment decision and assessing patient prognosis. The aim of this study was to validate the use of high resolution Whole Slide Images (WSI) in estimating MAI in breast cancer specimens. MAI was evaluated in 100 consecutive breast cancer specimens by three observers on two occasions, microscopically and on WSI with a wash out period of 4 months. MAI was also translated to mitotic scores as in grading. Inter- and intra-observer agreement between microscopic and digital MAI counts and scores was measured. Almost perfect inter-observer agreements were obtained from counting MAI using a conventional microscope (intra-class correlation coefficient (ICCC) 0.879) as well as on WSI (ICCC 0.924). K coefficients reflected good inter-observer agreements among observers' microscopic mitotic scores (average kappa 0.642). Comparable results were also observed among digital mitotic scores (average kappa 0.635). There was strong to perfect intra-observer agreements between MAI counts and mitotic scores for the two diagnostic modalities (ICCC 0.716-0.863, kappa 0.506-0.617). There were no significant differences in mitotic scores using both diagnostic modalities. Scoring mitoses using WSI in breast cancer seems to be just as reliable and reproducible as when using a microscope. Further development of software and image quality will definitely encourage the use of WSI in routine pathology practice.


Fixation of the medial malleolar fracture: a simplified technique.
A technique for fixation of the medial malleolar fracture is presented as an alternative to cannulated screws or conventional screw fixation. Two partially threaded screws are inserted in to the same corridors created by the temporary fixation after anatomic reduction. The procedure minimizes soft tissue stripping of the fracture fragments and facilitates expedient delivery of the hardware. In addition to the simplicity of the technique, there is substantial cost savings and better thread purchase compared to cannulated screws.


Leukocyte lactate dehydrogenase changes as an indicator of infection prior to overt symptoms.
Lactic acid dehydrogenase (LDH) concentration of rabbit serum and leukocytes was followed during the course of an acute infection with Diplococcus pneumoniae. Control values were obtained prior to infection, and again 4, 24, and 48 hr later. LDH isozymes were characterized by acrylamide gel electrophoresis and quantitated by densitometry. An increase in serum LDH was observed as early as 4 hr after infection. These levels returned to normal in 24 hr and rose again 48 hr after infection. The LDH level of leukocytes, from 10 of 12 infected rabbits, rose rapidly during the 24-hr period after exposure. The levels were two to three times the original preinoculation level for that animal. In six of these rabbits, this LDH elevation occurred 4 hr after inoculation and preceded the onset of fever. Change in the type of leukocyte did not account for the increase in cellular LDH. All infected rabbits showed approximately the same increase in polymorphonuclear leukocytes, but not all developed comparable increases in LDH. The isozyme patterns obtained, when defined amounts of enzyme were applied to the gel for electrophoresis, were characterized for the most part by a three-enzyme pattern. Increasing amounts of enzyme occasionally revealed a fourth, more cathodal, enzyme. The more cathodic enzymes appear to be the most responsive when sudden shifts in enzyme concentration occur within the cell.


Utility of methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses.
The value of CT-guided puncture with methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses was explored. A total of 113 patients with 146 nodules and masses were treated with methylene blue mixed with autologous blood for preoperative localization and thoracoscopic surgery in the Department of Thoracic Surgery, the First Affiliated Hospital of Fujian Medical University between October 2021 and October 2022. The localization effect, complications, and pathological conditions were observed. The localization success rate was 98.63% (144/146). The localization failed nodules and masses could still be located by looking for needle eyes and reading films. The whole group successfully completed thoracoscopic surgery. The average interval of operation after puncture was 22.16 ± 6.22 h. There was a small amount of suspicious hemothorax after puncture. There was no pneumothorax after puncture in the whole group. There were no hemoptysis, irritating dry cough, and other reactions. The overall complication rate was 2.65%, and no special treatment was given. It is safe and effective to use methylene blue mixed with autologous blood for CT-guided preoperative puncture and localization of small pulmonary nodules and masses.


Environmental noise spectroscopy with qubits subjected to dynamical decoupling.
A qubit subjected to pure dephasing due to classical Gaussian noise can be turned into a spectrometer of this noise by utilizing its readout under properly chosen dynamical decoupling (DD) sequences to reconstruct the power spectral density of the noise. We review the theory behind this DD-based noise spectroscopy technique, paying special attention to issues that arise when the environmental noise is non-Gaussian and/or it has truly quantum properties. While we focus on the theoretical basis of the method, we connect the discussed concepts with specific experiments, and provide an overview of environmental noise models relevant for solid-state based qubits, including quantum-dot based spin qubits, superconducting qubits, and NV centers in diamond.


An attribute control chart for a Weibull distribution under accelerated hybrid censoring.
In this article, an attribute control chart has been proposed using the accelerated hybrid censoring logic for the monitoring of defective items whose life follows a Weibull distribution. The product can be tested by introducing the acceleration factor based on different pressurized conditions such as stress, load, strain, temperature, etc. The control limits are derived based on the binomial distribution, but the fraction defective is expressed only through the shape parameter, the acceleration factor and the test duration constant. Tables of the average run lengths have been generated for different process parameters to assess the performance of the proposed control chart. Simulation studies have been performed for the practical use, where the proposed chart is compared with the Shewhart np chart for demonstration of the detection power of a process shift.


Ensemble optimal interpolation for adjoint-free biogeochemical data assimilation.
Advanced marine ecosystem models can contain more than 100 biogeochemical variables, making data assimilation for these models a challenging prospect. Traditional variational data assimilation techniques like 4dVar rely on tangent linear and adjoint code, which can be difficult to create for complex ecosystem models with more than a few dozen variables. More recent hybrid ensemble-variational data assimilation techniques use ensembles of model forecasts to produce model statistics and can thus avoid the need for tangent linear or adjoint code. We present a new implementation of a four-dimensional ensemble optimal interpolation (4dEnOI) technique for use with coupled physical-ecosystem models. Our 4dEnOI implementation uses a small ensemble, and spatial and variable covariance localization to create reliable flow-dependent statistics. The technique is easy to implement, requires no tangent linear or adjoint code, and is computationally suitable for advanced ecosystem models. We test the 4dEnOI implementation in comparison to a 4dVar technique for a simple marine ecosystem model with 4 biogeochemical variables, coupled to a physical circulation model for the California Current System. In these tests, our 4dEnOI reference implementation performs similarly well to the 4dVar benchmark in lowering the model observation misfit. We show that the 4dEnOI results depend heavily on covariance localization generally, and benefit from variable localization in particular, when it is applied to reduce the coupling strength between the physical and biogeochemical model and the biogeochemical variables. The 4dEnOI results can be further improved by small modifications to the algorithm, such as multiple 4dEnOI iterations, albeit at additional computational cost.


ERK1/2 signaling is required for the initiation but not progression of TGFβ-induced lens epithelial to mesenchymal transition (EMT).
Transforming Growth Factor Beta (TGFβ) potently induces lens epithelial to mesenchymal transition (EMT). The resultant mesenchymal cells resemble those found in plaques of human forms of subcapsular cataract. Smad signaling has long been implicated as the sole driving force of TGFβ-mediated activity. Rat lens epithelial explants were used to examine the role of the Smad-independent signaling, namely the MAPK/ERK1/2 signaling pathway, in the initiation and progression of TGFβ-induced EMT. Phase contrast microscopy was used to observe the morphological changes associated with TGFβ-induced EMT in this model, including cell elongation, cell membrane blebbing, cell loss as indicated by the area of bare capsule and capsular wrinkling. The levels of Smad2, Smad2/3 and ERK1/2 phosphorylation measured using western blotting confirmed that the addition of UO126 was sufficient in blocking all TGFβ-induced ERK1/2 activation, as well as reducing Smad signaling at 18 h. Immunofluorescent labeling and further western blotting confirmed that TGFβ-induced EMT was associated with an increase in α-smooth muscle actin (α-SMA) and a reduction of E-cadherin at cell borders. Pre-treatment with UO126 was effective at blocking the TGFβ-induced EMT, as evidenced by a reduction of α-SMA expression and protein labeling, E-cadherin labeling at cell borders, and a reduction of cell loss, cell elongation and capsular wrinkling. Post-treatment with UO126 at 2 and 6 h after TGFβ addition was also effective at blocking EMT while post-treatment with UO126 at 24 and 48 h was not sufficient in hampering TGFβ-induced EMT. Our data implicates ERK1/2 signaling in the initiation but not the progression of TGFβ-induced EMT in rat lens epithelial cells. The tight regulation of intracellular signaling pathways such as ERK1/2 are required for the maintenance of lens epithelial cell integrity and hence tissue transparency. A greater understanding of the molecular mechanisms that drive the induction and progression of EMT in the lens will provide the basis for potential therapeutics for human cataract.


[A Case of Sigmoid Colon Cancer It Was Found from Penetration of Sigmoid Diverticulum].
A 52-year-old woman presented with sudden left lower abdominal pain, fever, and vomiting. As the symptom got improved immediately she went home then. She consulted our hospital with chief complaint of the left lower abdominal mass. Abdominal computed tomography revealed sigmoid colon cancer with abscess. She was diagnosed with sigmoid colon cancer via colonoscopy. Sigmoidectomy including partial resection of the abdominal wall was performed(D3 lymphadenectomy). Surgical specimen showed penetration of diverticulum on mucous membrane of the lesion which had been thought of a abdominal wall permeation and a tumor of I sp type at anal side. Pathological examination showed diverticulitis with penetration and the tumor was tubular adenocarcinoma(tub1, pT1bpN0, pStage I ). We had doubted penetration of sigmoid colon cancer most, but the cause of penetration turned out to be diverticulitis. We experienced a case in which we could performed surgery of sigmoid colon cancer and penetration of diverticulum at the same time.


A Smartphone-Integrated Molecularly Imprinted Fluorescence Sensor for Visual Detection of Chlortetracycline Based on N,P-Codoped Carbon Dots Decorated Iron-Based Metal-Organic Frameworks.
The residue of chlortetracycline is potentially hazardous to human health; it is meaningful to exploit a portable, rapid, sensitive, and selective method for detection of chlortetracycline (CTC). In this study, a novel fluorescence bionic sensing probe (NH2-MIL-53&N,P-CDs@MIP) was successfully prepared based on the nitrogen and phosphorus codoped carbon dots decorated iron-based metal-organic frameworks combining with molecular imprinted polymer for the detection of CTC. A fluorescence intensity-responsive "on-off" detection of CTC on account of the inner-filter effect (IFE) was achieved by NH2-MIL-53&N,P-CDs@MIP. Under the optimal conditions, the fluorescence quenching degree of NH2-MIL-53&N,P-CDs@MIP presented a good linear relationship with the CTC concentration in the range 0.06-30 μg mL-1 and the limit of detection (LOD) was 0.019 μg mL-1. The fluorescent probe was applied to detect CTC in milk samples, and experimental results showed a good recovery rate (88.73%-96.28%). Additionally, a smartphone-integrated fluorescence sensing device based on NH2-MIL-53&N,P-CDs@MIP was exploited to replace the expensive and bulky fluorescence spectrophotometer for quantitative determination of CTC with the LOD of 0.033 μg mL-1. The sensing system showed high selectivity, strong stability, high specificity, and portability, which provide a great strategy for the quantitative detection of antibiotic residue.


Gabaergic control of anxiety-like behavior, but not food intake, induced by ghrelin in the intermediate medial mesopallium of the neonatal chick.
Ghrelin (Grh) is an endogenous ligand of the growth hormone secretagogue receptor. In neonatal chicks, central Ghr induces anxiogenic-like behavior but strongly inhibits food intake. The intermediate medial mesopallium (IMM) of the chick forebrain has been identified to be a site of the memory formation, and the modulation of the GABAA receptors that are present here modifies the expression of behavior. Thus, the GABAergic system may constitute a central pathway for Ghr action in regulating the processes of food intake and stress-related behaviors. Therefore, we investigated if the effect of systemic administration of bicuculline (GABAA receptor antagonist) and diazepam (benzodiazepine receptor agonist) on the anxiety in an Open Field test and inhibition in food intake induced by Grh (30pmol) when injected into IMM, were mediated by GABAergic transmission. In Open Field test, bicuculline was able to block the anxiogenic-like behavior induced by Ghr, whereas diazepam did not produce it. However, the co-administration of bicuculline or diazepam plus Ghr did not show any change in food intake at 30, 60 and 120min after injection compared to Ghr alone. Our results indicate for the first time that Ghr, injected into the forebrain IMM area, induces an anxiogenic-like behavior, which was blocked by bicuculline but not diazepam, thus suggesting that Ghr plays an important role in the response pattern to acute stressor, involving the possible participation of the GABAergic system. Nevertheless, as neither drug affected the hypophagia induced by intra-IMM Ghr, this suggests that it may be mediated by different mechanisms.


Residues within the Foot-and-Mouth Disease Virus 3Dpol Nuclear Localization Signal Affect Polymerase Fidelity.
Many RNA viruses encode a proof-reading deficient, low-fidelity RNA-dependent polymerase (RdRp), which generates genetically diverse populations that can adapt to changing environments and thwart antiviral therapies. 3Dpol, the RdRp of the foot-and-mouth disease virus (FMDV), is responsible for replication of viral genomes. The 3Dpol N terminus encodes a nuclear localization signal (NLS) sequence,MRKTKLAPT, important for import of the protein to host nucleus. Previous studies showed that substitutions at residues 18 and 20 of the NLS are defective in proper incorporation of nucleotides and RNA binding. Here, we use a systematic alanine scanning mutagenesis approach to understand the role of individual residues of the NLS in nuclear localization and nucleotide incorporation activities of 3Dpol We identify two residues of 3Dpol NLS, T19 and L21, that are important for the maintenance of enzyme fidelity. The 3Dpol NLS alanine substitutions of T19 and L21 results in aberrant incorporation of nucleoside analogs, conferring a low fidelity phenotype of the enzyme. A molecular dynamics simulation of RNA- and mutagen (RTP)-bound 3Dpol revealed that the T19 residue participates in a hydrogen bond network, including D165 in motif F and R416 at the C terminus of the FMDV 3Dpol and RNA template-primer. Based on these findings and previous studies, we conclude that at least the first six residues of theMRKTKLAPT sequence motif play a vital role in the maintenance of faithful RNA synthesis activity (fidelity) of FMDV 3Dpol, suggesting that the role of the NLS motif in similar viral polymerases needs to be revisited.IMPORTANCE In this study, we employed genetic and molecular dynamics approaches to analyze the role of individual amino acids of the FMDV 3Dpol nuclear localization signal (NLS). The NLS residues were mutated to alanine using a type A full-genome cDNA clone, and the virus progeny was analyzed for defects in growth and in competition with the parental virus. We identified two mutants in 3Dpol, T19A and L21A, that exhibited high rate of mutation, were sensitive to nucleotide analogs, and displayed reduced replicative fitness compared to the parental virus. Using molecular dynamics simulation, we demonstrated that residues T19 and L21 played a role in the structural configuration of the interaction network at the 3Dpol palm subdomain. Cumulatively, our data suggest that the T19 and L21 3Dpol amino acids are important for maintaining the fidelity of the FMDV polymerase and ensuring faithful replication of the FMDV genome.


Neural decoding based on probabilistic neural network.
Brain-machine interface (BMI) has been developed due to its possibility to cure severe body paralysis. This technology has been used to realize the direct control of prosthetic devices, such as robot arms, computer cursors, and paralyzed muscles. A variety of neural decoding algorithms have been designed to explore relationships between neural activities and movements of the limbs. In this paper, two novel neural decoding methods based on probabilistic neural network (PNN) in rats were introduced, the PNN decoder and the modified PNN (MPNN) decoder. In the experiment, rats were trained to obtain water by pressing a lever over a pressure threshold. Microelectrode array was implanted in the motor cortex to record neural activity, and pressure was recorded by a pressure sensor synchronously. After training, the pressure values were estimated from the neural signals by PNN and MPNN decoders. Their performances were evaluated by a correlation coefficient (CC) and a mean square error (MSE). The results show that the MPNN decoder, with a CC of 0.8657 and an MSE of 0.2563, outperformed the traditionally-used Wiener filter (WF) and Kalman filter (KF) decoders. It was also observed that the discretization level did not affect the MPNN performance, indicating that the MPNN decoder can handle different tasks in BMI system, including the detection of movement states and estimation of continuous kinematic parameters.


Comparison of Reoperation after Fusion and after Decompression for Degenerative Lumbar Spinal Stenosis: A Single-Center Experience of 987 Cases.
Reoperation for lumbar spinal stenosis (LSS) is technically challenging. Studies comparing preoperative risk factors and reoperation outcomes between spinal fusion and spinal decompression are limited. Thus this study compared fusion and decompression with respect to reoperation rates, preoperative factors related to re-surgery, and clinical outcomes. This retrospective cohort study included prospectively collected data from patients who underwent revision surgeries for degenerative LSS between May 2001 and March 2015. The reoperation rate, risk factors (proportional hazards analysis of index surgery), surgery type, main reason for revision, and final clinical outcomes (pain, quality-of-life modification, patient satisfaction, and complication rate) were analyzed and compared between the fusion and decompression surgeries. Among 987 cases during 13 years, 25 cases of reoperation after fusion and 23 cases of reoperation after decompression were identified, accounting for reoperation rates of 5.88% and 4.00%, respectively. Combined comorbidities (hazard ratio [HR]: 1.98 for fusion; multilevel involvement [with fusion, HR: 2.92; decompression, HR: 1.95]) were strongly correlated with preoperative demographic risk factor for each procedure. The main reason for reoperation in fusion cases was proximal junctional kyphosis (40%) and implant failure (20%), and in decompression cases, recurrent lesions (48.8%) and incomplete surgery (17.4%) An additional fusion after initial fusion and re-decompression without fusion after initial decompression were the most common surgical procedure. Back pain and patient satisfaction after fusion were better compared with those after decompression. The reoperation rate, preoperative risk factors, reason for revision, reoperation type, clinical outcomes, patient satisfaction, and time interval between index and re-surgery were different between the primary fusion and primary decompression. A better understanding of disease pathophysiology and surgical procedure characteristics will facilitate improvement in disease management and the development of treatment strategies.


Synthesis and properties of compressed dihydride complexes of iridium: theoretical and spectroscopic investigations.
Reaction of [Cp*Ir(P-P)Cl][B(C6F5)4] (P-P = bisdimethydiphosphinomethane (dmpm), bisdiphenyldiphosphinomethane (dppm)) with [Et3Si][B(C6F5)4] in methylene chloride under 1 atm of hydrogen gas affords the dicationic compressed dihydride complexes [Cp*Ir(P-P)H2][B(C6F5)4]2. These dicationic complexes are highly acidic and are very readily deprotonated to the corresponding monohydride cations. When the preparative reaction is carried out under HD gas, the hydride resonance exhibits JHD = 7-9 Hz, depending upon the temperature of observation, with higher values of JHD observed at higher temperatures. A thermally labile rhodium analogue, [CpRh(dmpm)(H2)][B(C6F5)4]2, was prepared similarly. A sample prepared with HD gas gave JHD = 31 Hz and J(HRh) = 31 Hz, allowing the Rh complex to be identified as a dihydrogen complex. Quantum dynamics calculations on a density functional theory (DFT) potential energy surface have been used to explore the structure of the Ir complexes, with particular emphasis on the nature of the potential energy surface governing the interaction between the two hydride ligands and the Ir center.


Role for PKC-epsilon in neuronal death induced by oxidative stress.
We investigated which isoforms of PKCs can be modulated and what their roles are during l-buthionine-S,R-sulfoximine (BSO)-induced neuronal death. We observed the isoform specific translocation of PKC-epsilon from the soluble fraction to the particulate in cortical neurons treated with 10 mM BSO. The translocation of PKC-epsilon by BSO was blocked by antioxidant trolox, suggesting the PKC-epsilon as a downstream of reactive oxygen species (ROS) elevated by BSO. Trolox inhibited the ROS elevation and the neuronal death in BSO-treated cortical cells. The BSO-induced neuronal death was remarkably inhibited by both the pharmacological inhibition of PKC-epsilon with epsilonV1-2 and the functional blockade for PKC-epsilon through overexpression of PKC-epsilon V1 region, suggesting the detrimental role of PKC-epsilon. These results suggest that PKC-epsilon is the major PKC isoform involved in the pathways triggered by ROS, leading to neuronal death in BSO-treated cortical neurons.


[Patients' rights: a threat to caregivers?].
In recent years, advocacy groups promoting patients' rights have lead to significant changes including the implementation of policies reducing measures of seclusion and restraint of patients with mental disorders. These policies are unanimous in that constraint is to be used as a solution of last resort and must be applied only under unique and exceptional circumstances. The reaction of healthcare workers to these new policies and to increase attention of patients'rights is often ignored in the current literature. Indeed, it is not rare for healthcare workers to come to think that the patients' rights supersede their own. In this article, this issue is examined from two perspectives. First, the author examines experiences of healthcare workers followed by a presentation of ethical and legal issues arising from the policies which promote the reduction of seclusion and restraint measures.


Extinction of biotic interactions due to habitat loss could accelerate the current biodiversity crisis.
Habitat loss disrupts species interactions through local extinctions, potentially orphaning species that depend on interacting partners, via mutualisms or commensalisms, and increasing secondary extinction risk. Orphaned species may become functionally or secondarily extinct, increasing the severity of the current biodiversity crisis. While habitat destruction is a major cause of biodiversity loss, the number of secondary extinctions is largely unknown. We investigate the relationship between habitat loss, orphaned species, and bipartite network properties. Using a real seed dispersal network, we simulate habitat loss to estimate the rate at which species are orphaned. To be able to draw general conclusions, we also simulate habitat loss in synthetic networks to quantify how changes in network properties affect orphan rates across broader parameter space. Both real and synthetic network simulations show that even small amounts of habitat loss can cause up to 10% of species to be orphaned. More area loss, less connected networks, and a greater disparity in the species richness of the network's trophic levels generally result in more orphaned species. As habitat is lost to land-use conversion and climate change, more orphaned species increase the loss of community-level and ecosystem functions. However, the potential severity of repercussions ranges from minimal (no species orphaned) to catastrophic (up to 60% of species within a network orphaned). Severity of repercussions also depends on how much the interaction richness and intactness of the community affects the degree of redundancy within networks. Orphaned species could add substantially to the loss of ecosystem function and secondary extinction worldwide.


Discovery of new inhibitors of D-alanine:D-alanine ligase by structure-based virtual screening.
The terminal dipeptide, D-Ala-D-Ala, of the peptidoglycan precursor UDPMurNAc-pentapetide is a crucial building block involved in peptidoglycan cross-linking. It is synthesized in the bacterial cytoplasm by the enzyme d-alanine:d-alanine ligase (Ddl). Structure-based virtual screening of the NCI diversity set of almost 2000 compounds was performed with a DdlB isoform from Escherichia coli using the computational tool AutoDock 4.0. The 130 best-ranked compounds from this screen were tested in an in vitro assay for their inhibition of E. coli DdlB. Three compounds were identified that inhibit the enzyme with K(i) values in micromolar range. Two of these also have promising antibacterial activities against Gram-positive and Gram-negative bacteria.


Factors Associated With Psychotropic Medication Use in Individuals in Brazilian Primary Health Care Units: A Descriptive, Cross-Sectional Study.
The current descriptive, cross-sectional study aimed to investigate the rate of psychotropic medication use and its association with sociodemographic factors, pharmacotherapy, health history, and presence of common mental disorders in individuals in Brazilian primary health care (PHC) units. A sample of 442 individuals was interviewed in 10 PHC units. Tools used included a structured questionnaire and the Self Reporting Questionnaire-20. The rate of psychotropic medication use was 38.7%. Demographic characteristics associated with psychotropic medication use were age 60 or older with common mental disorders and physical illness, a primary-level education or less, no occupation, and family income greater than three times the minimum wage. The strongest predictor of psychotropic medication use was monthly family income. The results highlight the need for interventions to improve patient outcomes. [Journal of Psychosocial Nursing and Mental Health Services, 55(3), 38-45.].


RPFdb: a database for genome wide information of translated mRNA generated from ribosome profiling.
Translational control is crucial in the regulation of gene expression and deregulation of translation is associated with a wide range of cancers and human diseases. Ribosome profiling is a technique that provides genome wide information of mRNA in translation based on deep sequencing of ribosome protected mRNA fragments (RPF). RPFdb is a comprehensive resource for hosting, analyzing and visualizing RPF data, available at www.rpfdb.org or http://sysbio.sysu.edu.cn/rpfdb/index.html. The current version of database contains 777 samples from 82 studies in 8 species, processed and reanalyzed by a unified pipeline. There are two ways to query the database: by keywords of studies or by genes. The outputs are presented in three levels. (i) Study level: including meta information of studies and reprocessed data for gene expression of translated mRNAs; (ii) Sample level: including global perspective of translated mRNA and a list of the most translated mRNA of each sample from a study; (iii) Gene level: including normalized sequence counts of translated mRNA on different genomic location of a gene from multiple samples and studies. To explore rich information provided by RPF, RPFdb also provides a genome browser to query and visualize context-specific translated mRNA. Overall our database provides a simple way to search, analyze, compare, visualize and download RPF data sets.


Induction of HLA-A*33-restricted cytotoxic lymphocytes against renal cell carcinoma targeting galectin 9 and PINCH.
Galectin 9, a ligand of T cell immunoglobulin and mucin domain 3 (TIM-3), and PINCH, an epithelial-to-mesenchymal transition (EMT)-promoting molecule, are expressed at much higher levels in cancerous lesions of clear cell type renal cell carcinoma (RCC) compared to normal renal tissues, and their expression levels are extremely low in normal tissues, except for galectin 9 in the spleen. Galectin 9- and PINCH-derived peptides have previously been shown to induce human leukocyte antigen (HLA)-A*2402-restricted and HLA-A*0201-restricted cytotoxic lymphocytes (CTLs) with specific and highly cytotoxic activities toward RCC cells. The present study aimed to identify the peptides that induced HLA-A*33-restricted CTLs that exhibited specific and highly cytotoxic activities toward RCC cells. Specific CTLs were induced significantly, as shown by cluster of differentiation 107a degranulation stimulated with VMRC-RCW renal carcinoma cells. Therefore, peptide vaccines targeting galectin 9 and PINCH appear to be promising for clinical application.


Inhibition of filovirus replication by the zinc finger antiviral protein.
The zinc finger antiviral protein (ZAP) was recently shown to inhibit Moloney murine leukemia virus and Sindbis virus replication. We tested whether ZAP also acts against Ebola virus (EBOV) and Marburg virus (MARV). Antiviral effects were observed after infection of cells expressing the N-terminal part of ZAP fused to the product of the zeocin resistance gene (NZAP-Zeo) as well as after infection of cells inducibly expressing full-length ZAP. EBOV was inhibited by up to 4 log units, whereas MARV was inhibited between 1 to 2 log units. The activity of ZAP was dependent on the integrity of the second and fourth zinc finger motif, as tested with cell lines expressing NZAP-Zeo mutants. Heterologous expression of EBOV- and MARV-specific sequences fused to a reporter gene suggest that ZAP specifically targets L gene sequences. The activity of NZAP-Zeo in this assay was also dependent on the integrity of the second and fourth zinc finger motif. Time-course experiments with infectious EBOV showed that ZAP reduces the level of L mRNA before the level of genomic or antigenomic RNA is affected. Transient expression of ZAP decreased the activity of an EBOV replicon system by up to 95%. This inhibitory effect could be partially compensated for by overexpression of L protein. In conclusion, the data demonstrate that ZAP exhibits antiviral activity against filoviruses, presumably by decreasing the level of viral mRNA.


Effects of dietary calcium on renal calcium, magnesium and phosphate excretion by the rabbit.
The renal handling of calcium, phosphate and magnesium was evaluated in rabbits fed diets varying in calcium content. Rabbits fed a low calcium diet (0.29%) exhibited a significant decrease in 24-hour excretion of calcium and in plasma calcium, and a significant increase in 24-hour excretion of phosphate, compared with rabbits fed a normal calcium diet (0.61%). Rabbits fed a high-calcium diet (1.89%) excreted significantly more calcium and less phosphate than the group fed normal dietary calcium. When measured under acute clearance conditions, the fractional excretion of calcium averaged 1-2% in rabbits fed either the low- or normal-calcium diets and increased to 6% in rabbits fed the high-calcium diet. In both acute and chronic studies, fractional phosphate excretion declined as the content of dietary calcium was raised. Magnesium excretion was not altered by the dietary calcium levels. Although calcium excretion by rabbits is set proportionately higher than that of other species, renal calcium handling in the rabbit is appropriate. Phosphate handling by the rabbit kidney similarly responds appropriately to dietary calcium manipulation.


Local mechanical properties of polymeric nanocomposites.
The inclusion of a nanoparticle into a polymer matrix is studied by efficient Monte Carlo simulations. The resulting structural changes in the melt and glass exhibit a strong dependence on the strength of the polymer attraction to the surface of the filler. The mechanical properties of the nanocomposite are analyzed in detail through a formalism that permits calculation of local elastic constants. The average shear and Young's modulus of the nanocomposite are higher than those of the pure polymer for neutral or attractive nanoparticles. For repulsive particles, these moduli are lower. Simulation of local properties reveals that a glassy layer is formed in the vicinity of the attractive filler, contributing to the increased strength of the composite material. In contrast, a region of negative moduli emerges around repulsive fillers, which provides a mechanism for frustration relief and a lowering of the glass transition temperature.


An electron microscopic study of the circulatory system in Nereis japonica.
Blood vessels in Nereis japonica were studied by electron microscopy. It was found that blood vessels regardless of location were similar in the basic organization of the basal lamina and the usual presence of collagen fibrils on the vessel wall. Differences arise, depending on whether the outside of the basal lamina is covered by peritoneal cells, by gut epithelium, or by epidermis. These relate to the location of the vessels in mesenteries, gut or epidermis, but do not reflect basic structural differences in the vessels themselves. Furthermore, it was concluded that true endothelial cells do not exist in the circulatory system of Nereis japonica and that, in this respect, the system is essentially different from that of vertebrates, in which endothelial cells line the vessels of a closed circulatory system. These considerations lead to the further conclusion that the vascular lumen in Nereis is essentially interstitial space and that the system, which has been known as a typical "closed" circulatory system in annelids, is actually an open circulatory system. Peritoneal cells covering the walls of internal vessels show various degrees of muscular differentiation and those possessing myofilaments may be called "myomesothelial cells."


[Difficult Airway Management in Thoracic Anaesthesia].
Difficult airway management in thoracic anesthesia has rarely been addressed in current guidelines. However, difficult airway management may be a challenge in thoracic anaesthesia: Achieving lung separation and collapse in combination of potentially distorted upper airway anatomy (difficult upper airway), the presence of subglottic pathologies (difficult lower airway) and the need for one-lung ventilation (difficult lung separation). This review will focus on identification of patients at risk, recommendations and algorithms for the airway management in the anticipated and unexpected difficult in-/extubation, and choice of devices for lung separation in this context.


L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor.
A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with Ki values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1IIIb-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.


The impact of age on the cost-effectiveness of hypertension treatment: an analysis of randomized drug trials.
The aim of this study was to investigate whether any consistent pattern exists with respect to the cost-effectiveness of hypertension treatment and age, based on the results of randomized drug trials. Data about age, entry diastolic blood pressure, and relative risks of coronary heart disease (CHD) and stroke from 19 randomized trials were used to derive point estimates of the cost-effectiveness of each trial. The relationship between age and cost per life-year gained was then estimated by regression analysis, controlling for entry diastolic blood pressure. The regression analysis shows a statistically significant average decrease in the cost per life-year gained of about SEK 15,000 per year of older age for both men and women ($1 = SEK 6). Sensitivity analysis showed that the improvement in cost-effectiveness with age was stable towards various assumptions, but that the magnitude of the improvement varied greatly with the discount rate. Based on the results of randomized drug trials, it is concluded that the cost-effectiveness of hypertension treatment improves with patient age for both men and women.


Peritonitis due to Moraxella Osloensis: An Emerging Pathogen.
Peritonitis is a very serious complication encountered in patients undergoing peritoneal dialysis and healthcare providers involved in the management should be very vigilant. Gram-positive organisms are the frequent cause of peritonitis compared to gram-negative organisms. There has been recognition of peritonitis caused by uncommon organisms because of improved microbiological detection techniques. We report a case of peritonitis caused by Moraxella osloensis (M. osloensis), which is an unusual cause of infections in humans. A 68-year-old male, who has been on peritoneal dialysis for 2 years, presented with abdominal pain and cloudy effluent. Peritoneal fluid analysis was consistent with peritonitis and peritoneal fluid culture grew gram-negative bacteria. M. osloensis was identified by 16 S PCR phenotypic and sequencing techniques. Patient responded well to the treatment, with intraperitoneal cephalosporin, and repeat peritoneal fluid culture yielded no growth. M. osloensis rarely causes infection in humans and responds well to treatment, as reported in literature.


Adding Intermittent Vibration to Varied-intensity Work Intervals: No Extra Benefit.
Varied-intensity work intervals have been shown to induce higher fractions of maximal oxygen uptake during high-intensity interval training compared with constant-intensity work intervals. We assessed whether varied-intensity work intervals combined with intermittent vibration could further increase cyclists' fraction of maximal oxygen uptake to potentially optimise adaptive stimulus. Thirteen cyclists (V̇O2max: 69.7±7.1 ml·kg-1·min-1) underwent a performance assessment and two high-intensity interval training sessions. Both comprised six 5-minute varied-intensity work intervals within which the work rate was alternated between 100% (3×30-second blocks, with or without vibration) and 77% of maximal aerobic power (always without vibration). Adding vibration to varied-intensity work intervals did not elicit a longer time above ninety percent of maximal oxygen uptake (415±221 versus 399±209 seconds, P=0.69). Heart rate- and perceptual-based training-load metrics were also not affected (all P≥0.59). When considering individual work intervals, no between-condition differences were found (fraction of maximal oxygen uptake, P=0.34; total oxygen uptake, P=0.053; mean minute ventilation, P=0.079; mean heart rate, P=0.88; blood lactate concentration, P=0.53; ratings of perceived exertion, P=0.29). Adding intermittent vibration to varied-intensity work intervals does not increase the fraction of maximal oxygen uptake elicited. Whether intermittent exposure to vibration can enhance cyclists' adaptive stimulus triggered by high-intensity interval training remains to be determined.