Aerosolized Plus Intravenous Polymyxin B Versus Colistin in the Treatment of Pandrug-Resistant Klebsiella Pneumonia-mediated Ventilator-Associated Pneumonia: A Retrospective Cohort Study in Bangladesh.
Pandrug-resistant Klebsiella pneumoniae ventilator associated pneumonia (VAP) is associated with high rate of mortality in intensive care unit (ICU) and has been recognized as a difficult-to-treat infection worldwide. Polymyxin B or colistin-based combination therapies are frequently used worldwide though microbial eradication rate is not promising. The aim of this study is to compare the clinical outcome of intravenous with aerosolized polymyxin B versus colistin in the treatment of pandrug-resistant K. pneumoniae VAP. This retrospective cohort study was conducted on 222 mechanically ventilated patients admitted from May 11, 2019 to October 19, 2020. K. pneumoniae isolates were resistant to all available antibiotics, including polymyxins in culture sensitivity tests. As treatment, polymyxin B and colistin was administered in intravenous and aerosolized form concurrently twice daily in 106 patients and 116 patients in PMB and CLN group, respectively for 14 days. Survival rate, safety, and clinical outcomes were compared among the groups. The Cox proportional-hazard model was performed to calculate hazard ratio (HR) with 95% confidence intervals (CI). Patients in PMB group showed more microbial eradication than the patients CLN group [68.1% (n=116)/83% (n=106), respectively; P <0.05). The median day of intubation and ICU stay in PMB group was shorter than that in CLN group [10 (IQR: 9-12.25) vs. 14 (IQR: 11-19), P <0.05; 12 (IQR: 10-14) vs. 15 (IQR: 9-18.5), P=0.072, respectively] with reduced 60-day all-cause mortality rate [15% (n=106) vs. 21.55% (n=116)]. Polymyxin B improved survival compared to colistin (multivariate HR: 0.662; 95% CI=0.359-1.222, P=0.195). Concurrent administration of intravenous and aerosolized polymyxin B in patients with pandrug-resistant K. pneumoniae-associated VAP revealed better microbial eradication, reduced the length of intubation and ICU stay, and improved survival rate compared to colistin.


Whole body kinematics and knee moments that occur during an overhead catch and landing task in sport.
Athletes suffering an anterior cruciate ligament injury tend to exhibit similar body postures that in sidestep cutting are associated with increased knee moments. This relationship, however, has not been investigated in landing. Catching a ball in different overhead positions may affect landing postures and knee joint moments. This study investigated these possible relationships. It was anticipated that some joint postures would be associated increased knee loads during the landing task. Twenty-five healthy male team sports athletes performed four variations of a landing task. Full body kinematics were identified at initial contact. Peak flexion, valgus and internal rotation moments at the knee, measured during early landing, were normalized to mass and height and statistically compared. Intra-participant correlations were performed between all kinematics and each moment. Mean slopes for each correlation were used to identify the existence of relationships between full body kinematics and knee joint moments. Findings Landing after an overhead catch when the ball moved towards a player's support leg resulted in increased peak valgus moments. These increased valgus moments were correlated with increased knee flexion, hip flexion, and torso lean, as well as torso rotation towards the support leg, and foot and knee external rotation. Increased internal rotation moments were correlated with reduced hip abduction and external rotation, increased ankle inversion, knee external rotation and torso lean away from the support leg. Interpretation Learning to land with techniques that do not reflect postures associated with high knee moments may reduce an athlete's risk of non-contact anterior cruciate ligament injury.


Prevalence of mental illness in immigrant and non-immigrant U.S. Latino groups.
Although widely reported among Latino populations, contradictory evidence exists regarding the generalizability of the immigrant paradox, i.e., that foreign nativity protects against psychiatric disorders. The authors examined whether this paradox applies to all Latino groups by comparing estimates of lifetime psychiatric disorders among immigrant Latino subjects, U.S-born Latino subjects, and non-Latino white subjects. The authors combined and examined data from the National Latino and Asian American Study and the National Comorbidity Survey Replication, two of the largest nationally representative samples of psychiatric information. In the aggregate, risk of most psychiatric disorders was lower for Latino subjects than for non-Latino white subjects. Consistent with the immigrant paradox, U.S.-born Latino subjects reported higher rates for most psychiatric disorders than Latino immigrants. However, rates varied when data were stratified by nativity and disorder and adjusted for demographic and socioeconomic differences across groups. The immigrant paradox consistently held for Mexican subjects across mood, anxiety, and substance disorders, while it was only evident among Cuban and other Latino subjects for substance disorders. No differences were found in lifetime prevalence rates between migrant and U.S.-born Puerto Rican subjects. Caution should be exercised in generalizing the immigrant paradox to all Latino groups and for all psychiatric disorders. Aggregating Latino subjects into a single group masks significant variability in lifetime risk of psychiatric disorders, with some subgroups, such as Puerto Rican subjects, suffering from psychiatric disorders at rates comparable to non-Latino white subjects. Our findings thus suggest that immigrants benefit from a protective context in their country of origin, possibly inoculating them against risk for substance disorders, particularly if they emigrated to the United States as adults.


Differences on nitrogen availability in a soil amended with fresh, composted and thermally-dried sewage sludge.
Anaerobically-digested sludge called fresh sludge (F), composted sludge (C) and thermally-drying sludge (T), all from the same batch, were applied to the surface of a calcareous Udic Calciustept with loamy texture. Dosage equivalent was 10 t ha(-1) of dry matter. The concentration of mineral nitrogen (ammonium and nitrate) in the soil was measured in order to estimate the effects of the post-treatments to which the different kinds of sewage sludge are subjected in relation to the availability of N in the surface layer of the soil. The most significant differences in NH(4)-N and NO(3)-N concentrations due to the transformation of the organic matter were observed during the first three weeks following soil amendment. Thermally-dried and composted sludge initially displayed higher concentrations of ammonium and nitrate in soil. Five months after the amendment, soil applied with fresh sludge showed the highest concentrations of NH(4)-N and NO(3)-N (6.1 and 36.6 mg kg(-1), respectively). It is clear that the processes of composting and thermal-drying influence the bioavailability of nitrogen from the different types of sewage sludge.


The type 2 vascular endothelial growth factor receptor recruits insulin receptor substrate-1 in its signalling pathway.
Vascular endothelial growth factor (VEGF) isoforms exert their biological effects through receptors that possess intrinsic tyrosine kinase activity. Whether VEGF binding to its receptors recruits insulin receptor substrate (IRS) family of docking proteins to the receptor is not known. Following incubation of mouse kidney proximal tubular epithelial cells with VEGF, we observed an increase in tyrosine phosphorylation of several proteins, including one of approximately 200 kDa, suggesting possible regulation of phosphorylation of IRS proteins. VEGF augmented tyrosine phosphorylation of IRS-1 in kidney epithelial cells and rat heart endothelial cells in a time-dependent manner. In the epithelial cells, association of IRS-1 with type 2 VEGF receptor was promoted by VEGF. VEGF also increased association of IRS-1 with the p85 regulatory subunit of phosphoinositide 3-kinase (PI 3-kinase), and PI 3-kinase activity in IRS-1 immunoprecipitates was increased in VEGF-treated cells. Incubation of epithelial cells with antisense IRS-1 oligonucleotide, but not sense oligonucleotide, reduced expression of the protein and VEGF-induced PI 3-kinase activity in IRS-1 immunoprecipitates. Additionally, VEGF-induced protein synthesis was also impaired by antisense but not sense IRS-1 oligonucleotide. These data provide the first evidence that binding of VEGF to its type 2 receptor promotes association of IRS-1 with the receptor complex. This association may account for some of the increase in VEGF-induced PI 3-kinase activity, and the increase in de novo protein synthesis seen in renal epithelial cells.


On the selectivity, specificity and signalling potential of the long-distance movement of messenger RNA.
Messenger RNA (mRNA) can move through the vascular system in plants. Until recently the transport of mRNA had been demonstrated only for a few well-documented cases, leading to the suggestion that transport was selective and specific. The extent of this long-distance transport has now been shown to be on the genomic scale with thousands of transcripts covering broad regions of gene ontological space. In light of this recent data, I revisit proposed mechanisms of transport of mRNA and critically assess their potential role in signalling.


Persisting visual hallucinations and illusions in previously drug-addicted patients.
Tetrahydrocannabinol (cannabis) and lysergic acid diethylamide (LSD) are psychomimetic agents that induce impairment of sensory perception. Illusions and hallucinations are mostly visual. Most frequently the visual phenomena occur in conjunction with drug abuse. Three previously drug-addicted patients were examined for either persisting or spontaneously recurrent visual phenomena. Two patients complained of persisting visual illusions (vibrations, dyskinetopsia and impaired depth perception) during more than 12 months after an excessive use of cannabis. The third patient was a multiple drug abuser (LSD for 6 years) and complained of visual hallucinations and palinopsia following heavy ethanol intake, 20 years after stopping the use of any drug. Results from neuro-ophthalmic and neurological examinations were normal for the first two patients. The third patient presented abnormal visual fields with preserved visual acuity; electroencephalography was abnormal, suggesting an underlying toxic encephalopathy. Persistent visual illusions or hallucinations can occur during several months after an intake of cannabis. Flash-back phenomena are frequent amongst LSD abusers. They rarely occur at long times after the last intake (20 years in the present case); when they do so, precipitating factors are often present (ethanol, medication, anesthesia). Such phenomena reflect the cortical dysfunctions that can be induced by illegal substances.


Quantitative volumetric MRI study of the cerebellum and vermis in schizophrenia: clinical and cognitive correlates.
Recent evidence suggests that the cerebellum may play a role in higher cognitive functions and, therefore, may play an important role in schizophrenia. The authors used magnetic resonance imaging to measure cerebellum and vermis volume in 15 patients with schizophrenia and 15 normal comparison subjects. They found that 1) vermis volume was greater in patients with schizophrenia than in normal subjects, 2) greater vermis white matter volume in the patients with schizophrenia significantly correlated with severity of positive symptoms and thought disorder and with impairment in verbal logical memory, and 3) patients with schizophrenia showed a trend for more cerebellar hemispheric volume asymmetry (left greater than right). These data suggest that an abnormality in the vermis may contribute to the pathophysiology of schizophrenia.


A Network Medicine Approach to Investigation and Population-based Validation of Disease Manifestations and Drug Repurposing for COVID-19.
The global Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of co-existing medical conditions while the underlying mechanisms remain unclear. Furthermore, there are no proven effective therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, diseases manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measure revealed underlying pathogenesis for broad COVID-19-associated manifestations. Multi-modal analyses of single-cell RNA-sequencing data showed that co-expression of ACE2 and TMPRSS2 was elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn's disease patients compared to uninflamed tissues, revealing shared pathobiology by COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicated that COVID-19 shared intermediate inflammatory endophenotypes with asthma (including IRAK3 and ADRB2). To prioritize potential treatment, we combined network-based prediction and propensity score (PS) matching observational study of 18,118 patients from a COVID-19 registry. We identified that melatonin (odds ratio (OR) = 0.36, 95% confidence interval (CI) 0.22-0.59) was associated with 64% reduced likelihood of a positive laboratory test result for SARS-CoV-2. Using PS-matching user active comparator design, melatonin was associated with 54% reduced likelihood of SARS-CoV-2 positive test result compared to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (OR = 0.46, 95% CI 0.24-0.86).


Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma.
Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) receptor induce a response in only a subgroup of patients with metastatic melanoma. Previous research suggests that transforming growth factor beta signaling and a collagen-rich peritumoral stroma (tumor fibrosis), may negatively interfere with the interaction between T cells and tumor cells and thereby contribute to resistance mechanisms by immune-exclusion, while increased tumor infiltration of M1-like macrophages enhances T cell activity. Hence, the current study aimed to assess the relationship between blood-based markers of collagen or vimentin turnover (reflecting M1 macrophage activity) and clinical outcome in patients with metastatic melanoma after PD-1 inhibition. Patients with metastatic melanoma who were treated with anti-PD-1 monotherapy between May 2016 and March 2019 were included in a prospective observational study. N-terminal pro-peptide of type III collagen (PRO-C3) cross-linked N-terminal pro-peptides of type III collagen (PC3X), matrix metalloprotease (MMP)-degraded type III (C3M) and type IV collagen (C4M), granzyme B-degraded type IV collagen and citrullinated and MMP-degraded vimentin (VICM) were measured with immunoassays in serum before (n=107), and 6 weeks after the first administration of immunotherapy (n=94). The association between biomarker levels and overall survival (OS) or progression-free survival (PFS) was assessed. Multivariate Cox regression analysis identified high baseline PRO-C3 (Q4) and PC3X (Q4) as independent variables of worse PFS (PRO-C3: HR=1.81, 95% CI=1.06 to 3.10, p=0.030 and PC3X: HR=1.86, 95% CI=1.09 to 3.18, p=0.023). High baseline PRO-C3 was also independently related to worse OS (HR=2.08, 95% CI=1.06 to 4.09, p=0.035), whereas a high C3M/PRO-C3 ratio was related to improved OS (HR=0.42, 95% CI=0.20 to 0.90, p=0.025). An increase in VICM (p<0.0001; in 56% of the patients) was observed after 6 weeks of treatment, and an increase in VICM was independently associated with improved OS (HR=0.28, 95% CI=0.10 to 0.77, p=0.014). Blood-based biomarkers reflecting excessive type III collagen turnover were associated with worse OS and PFS after PD-1 inhibition in metastatic melanoma. Moreover, an increase in VICM levels after 6 weeks of treatment was associated with improved OS. These findings suggest that type III collagen and vimentin turnover contribute to resistance/response mechanisms of PD-1 inhibitors and hold promise of assessing extracellular matrix-derived and stroma-derived components to predict immunotherapy response.


Developing a Comprehensive Cardio-Oncology Program at a Cancer Institute: The Moffitt Cancer Center Experience.
Cardio-oncology is a multidisciplinary field focusing on the management and prevention of cardiovascular complications in cancer patients and survivors. While the initial focus of this specialty was on heart failure associated with anthracycline use, novel anticancer agents are increasingly utilized and are associated with many other cardiotoxicities including hypertension, arrhythmias and vascular disease. Since its inception, the field has developed at a rapid pace with the establishment of programs at many major academic institutions and community practices. Given the complexities of this patient population, it is important for providers to possess knowledge of not only cardiovascular disease but also cancer subtypes and their specific therapeutics. Developing a cardio-oncology program at a stand-alone cancer center can present unique opportunities and challenges when compared to those affiliated with other institutions including resource allocation, cardiovascular testing availability and provider education. In this review, we present our experiences establishing the cardio-oncology program at Moffitt Cancer Center and provide guidance to those individuals interested in developing a program at a similar independent cancer institution.


Supramaximal intermittent running performance in relation to age and locomotor profile in highly-trained young soccer players.
The aim of the study was to examine supramaximal intermittent running performance in highly-trained young soccer players, with regard to age and locomotor profile. Twenty-seven Under 14, 19 U16 and 16 U18 highly-trained soccer players performed an incremental intermittent running test (30-15 Intermittent Fitness Test) to assess supramaximal intermittent running performance (VIFT), an incremental running test to estimate maximal aerobic speed (VVam-Eval) and a 40-m sprint to estimate maximal sprinting speed (MSS). U16 and U18 presented very likely greater VIFT (19.2 ± 0.9, 19.7 ± 1.0 vs. 17.4 ± 0.9 km · h(-1)) and VVam-Eval (16.2 ± 0.9, 16.7 ± 1.0 vs. 14.6 ± 0.9 km · h(-1)) than U14, while there was no clear difference between U16 and U18. MSS (25.1 ± 1.6, 29.3 ± 1.6 and 31.0 ± 1.1 km · h(-1) for U14, U16 and U18) was very likely different between all groups. When data were pooled together, VIFT was very largely correlated with VVam-Eval and MSS (overall r =0.89, partial r = 0.74 and 0.29, respectively). Within-age group correlations showed that the older the players, the greater the magnitude of the correlations between VIFT and VVam-Eval (r = 0.67, 0.73 and 0.87). In conclusion, the major predictors of VIFT were, in order of importance, VVam-Eval and MSS; however, the older the players, the greater the correlations with VVam-Eval.


In vitro membrane damage induced by half-fin anchovy hydrolysates/glucose Maillard reaction products and the effects on oxidative status in vivo.
Membrane damage via the Maillard reaction products of half-fin anchovy hydrolysates and glucose (designated as HAHp(9.0)-G MRPs) was evaluated using an in vitro Escherichia coli (E. coli) model. The incubation of HAHp(9.0)-G MRPs led to a significant increase in outer and inner membrane permeability. Furthermore, membrane integrity was seriously destroyed, as observed by scanning electron microscopy and indicated by the decreased fluorescence signal of 4',6-diamidino-2-phenylindole stain. Interestingly, HAHp(9.0)-G MRPs induced significant hydrogen peroxide (H2O2) production in E. coli after 3 h of incubation, which contributed to the antibacterial activity of HAHp(9.0)-G MRPs. As one of the reactive oxygen species, excess H2O2in vivo might impair the antioxidant balance. Therefore, the oxidative status of healthy mice after short-term intake of HAHp(9.0)-G MRPs was investigated. After the administration of HAHp(9.0)-G MRPs at low dose (0.1 g per kg per day body weight) and high dose (1.0 g per kg per day body weight) for 14 days, the body weight of female mice decreased, and the body weight of male mice increased. However, the administration of HAHp(9.0)-G MRPs did not affect the hepatic antioxidant defense in either female or male mice. Some positive responses, like increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as decreased lipid peroxidation (LPO) content, were detected, especially in liver. Though the decrease in catalase activity indicated that the glycation compounds from HAHp(9.0)-G MRPs might be absorbed in vivo, the lower SOD/GPx ratios of HAHp(9.0)-G MRPs-fed groups than those of the normal groups also suggested that the administration of HAHp(9.0)-G MRPs could reduce LPO stress in mice. Our results suggest that a higher antioxidant status could be generated in the healthy animals after fed with HAHp(9.0)-G MRPs for 14 days.


Transglutaminase inhibition protects against oxidative stress-induced neuronal death downstream of pathological ERK activation.
Molecular deletion of transglutaminase 2 (TG2) has been shown to improve function and survival in a host of neurological conditions including stroke, Huntington's disease, and Parkinson's disease. However, unifying schemes by which these cross-linking or polyaminating enzymes participate broadly in neuronal death have yet to be presented. Unexpectedly, we found that in addition to TG2, TG1 gene expression level is significantly induced following stroke in vivo or due to oxidative stress in vitro. Forced expression of TG1 or TG2 proteins is sufficient to induce neuronal death in Rattus norvegicus cortical neurons in vitro. Accordingly, molecular deletion of TG2 alone is insufficient to protect Mus musculus neurons from oxidative death. By contrast, structurally diverse inhibitors used at concentrations that inhibit TG1 and TG2 simultaneously are neuroprotective. These small molecules inhibit increases in neuronal transamidating activity induced by oxidative stress; they also protect neurons downstream of pathological ERK activation when added well after the onset of the death stimulus. Together, these studies suggest that multiple TG isoforms, not only TG2, participate in oxidative stress-induced cell death signaling; and that isoform nonselective inhibitors of TG will be most efficacious in combating oxidative death in neurological disorders.


Establishment of epithelial cell lines from human and mouse thymus immortalized by the 12S adenoviral E1a gene product.
To understand the role of thymic epithelial cells in the development of immature thymocytes, the establishment and cloning of thymic epithelial cell lines must be required. In the present study, we established human and mouse thymic epithelial cell lines through the immortalization by the transfection of cDNA sequences of adenoviral E1a 12S mRNA. This procedure resulted in the isolation of five stable cell lines (one human cell line and four mouse cell lines). These cell lines were positive in cytokeratin demonstrated by immunohistochemistry. Electron microscopic study revealed that they had bundles of tonofilaments and desmosome-like tight junctions. These findings indicate that the cell lines immortalized by E1a gene have retained the properties of epithelial cells. MHC class II antigens were not expressed on these cell lines. When interferon-gamma was added to the cultured epithelial cell lines, MHC class II antigens were induced in their cytoplasm and on their surface membrane, demonstrated by immunohistochemical and immunofluorescent studies. It is suggested that these stable cell lines from human and mouse thymus might serve a good tool for the further study of thymocytes differentiation and of unknown cytokines derived from thymus epithelium.


Response Surface Methodology for Salmonella Inactivation during Extrusion Processing of Oat Flour.
An increase in the number of foodborne outbreaks and recalls due to Salmonella in low-moisture foods has resulted in the need for the development and validation of process controls to ensure their microbiological safety. Furthermore, the Food Safety Modernization Act Preventive Controls for Human Food final rule requires food processors to validate their process controls to ensure food safety. The objective of this study was to develop a response surface model to predict Salmonella inactivation in oat flour, as affected by moisture, fat content, screw speed, and temperature. Oat flour was adjusted to different moisture (14 to 26% wet basis) and fat (5 to 15% [w/w]) contents and was then inoculated with a five-strain cocktail of Salmonella. Inoculated material was extruded through a single-screw extruder running at different screw speeds (75 to 225 rpm) and temperatures (65 to 85°C), without a die. Once steady-state conditions were attained, extruded samples were collected, cooled, and stored under refrigeration, and Salmonella survivors were enumerated. A split-plot central composite second-order response surface design was used, with the central point replicated six times. Temperature showed a significant ( P < 0.0005) positive effect on microbial reduction. Moisture content showed significant linear ( P = 0.0014) and quadratic ( P = 0.0005) effects, whereas higher fat content showed a significant ( P < 0.0001) protective effect on Salmonella destruction. The screw speed did not play a major role in inactivating Salmonella, but it had a significant ( P = 0.0004) interactive effect with temperature. Results indicated that a >5.5-log reduction was achieved in oat flour extruded at a temperature above 85°C at all moisture and fat contents evaluated at a screw speed of 150 rpm. The developed response surface model can be used to identify the extrusion process conditions to achieve a desired reduction of Salmonella based on the moisture and fat contents of the product.


Retinoic acid signaling in the functioning brain.
Retinoic acid, an active form of vitamin A, regulates gene expression throughout the body, and many components of the signaling system through which it acts are present in the brain. Very little is known, however, about how retinoic acid functions in neurobiological systems. Several studies have provided evidence that retinoic acid plays a role in sleep, learning, and memory, but the precise mechanisms through which it influences these processes remain unclear. All of these processes involve local or long-range inhibition and synchronized neuronal activity between separate locations in the brain. A critical component in the generation of the synchronized firing of cortical neurons (cortical synchrony) is a network of inhibitory interneurons containing parvalbumin, a cell population affected by retinoid perturbations, such as exposure to a vitamin A overdose. An understanding of the role of retinoids in normal brain function would provide clues to the long-standing question of whether abnormalities in retinoic acid signaling contribute to the pathogenesis of some brain diseases with uncertain etiologies that involve both genetic and environmental factors.


Cloning and expression of a rat brain interleukin-1beta-converting enzyme (ICE)-related protease (IRP) and its possible role in apoptosis of cultured cerebellar granule neurons.
Several members of the IL-1beta-converting enzyme (ICE) family of proteases recently have been implicated in the intracellular cascade mediating the apoptotic death of various cell types. It is unclear, however, whether ICE-related proteases are involved in apoptosis of mammalian neurons and, if so, how they are activated. Here we report the cloning of an ICE-related protease (IRP) from rat brain, which displays strong sequence identity to human CPP32. In situ hybridization histochemistry reveals that this IRP mRNA is expressed in neuron-enriched regions of the developing and adult rat brain but is profoundly downregulated in the adult (compared with developing) brain. To investigate whether this IRP is involved in the death of neurons in the developing brain, we studied IRP expression in cultured cerebellar granule neurons. In cultured cerebellar granule neurons, reduction of extracellular K+ reliably induces apoptosis and stimulates overexpression of IRP mRNA. The latter is especially prominent 4 hr after switching from high K+ to low K+ medium. The expression of IRP mRNA was maintained at this level for at least 8 hr and was followed by apoptotic death of these neurons. Induction of IRP mRNA and cell death are blocked completely by adding depolarizing concentrations of K+ </=90 min after switching to low K+ medium (i.e., before the commitment point for apoptosis) and partially blocked by brain-derived neurotrophic factor (BDNF), which also partially rescues granule neurons from low K+-induced apoptosis. In addition, overexpression of IRP cDNA in HeLa cells results in cell death accompanied by strong internucleosomal cleavage of DNA, a typical feature of apoptosis. Finally, we detected cleavage of the putative death substrate poly (ADP-ribose) polymerase (PARP), beginning 8 hr after changing from high K+ to low K+ medium, coinciding with the time course of induced expression of the IRP gene. Our data suggest that transcriptional activation of IRP could be one of the mechanisms involved in the apoptotic death of cerebellar granule neurons.


Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production.
CD4+CD25+ regulatory T (Treg) cells control immunologic tolerance and antitumor immune responses. Therefore, in vivo modification of Treg function by immunosuppressant drugs has broad implications for transplantation biology, autoimmunity, and vaccination strategies. In vivo bioluminescence imaging demonstrated reduced early proliferation of donor-derived luciferase-labeled conventional T cells in animals treated with Treg cells after major histocompatibility complex mismatch bone marrow transplantation. Combining Treg cells with cyclosporine A (CSA), but not rapamycin (RAPA) or mycophenolate mofetil (MMF), suppressed Treg function assessed by increased T-cell proliferation, graft-versus-host disease (GVHD) severity, and reduced survival. Expansion of Treg and FoxP3 expression within this population was lowest in conjunction with CSA, suggesting that calcineurin-dependent interleukin 2 (IL-2) production is critically required for Treg cells in vivo. The functional defect of Treg cells after CSA exposure could be reversed by exogenous IL-2. Further, the Treg plus RAPA combination preserved graft-versus-tumor (GVT) effector function against leukemia cells. Our data indicate that RAPA and MMF rather than CSA preserve function of Treg cells in pathologic immune responses such as GVHD without weakening the GVT effect.


Measuring costs of child abuse and neglect: a mathematic model of specific cost estimations.
Few empirical facts exist regarding the actual costs of child abuse in the United States. Consistent data is not available for national or even statewide analysis. Clearly there is a need for such accounting in order to fully understand the damage created by child abuse and neglect. Policy makers and social welfare planners should take child abuse costs into consideration when determining expenditures for prevention and intervention programs. The real savings may far outweigh the costs of such programs when both direct and indirect costs of child abuse and neglect enter into the analysis. This paper offers a model in which the actual costs of child abuse and neglect, based on direct, indirect, and opportunity costs associated with each case. Direct costs are those associated with the treatment of abused and neglected children as well as the costs of family intervention programs or foster care. Indirect costs are costs to society created by the negative effects of child abuse and neglect evinced by individuals who suffer such abuse and then as teens or adults engage in criminal behavior. Indirect costs also derive from the long term and ongoing health care needs required by victims of abuse, for both physical and mental health disorders. With the existence of this model, the author hopes to stimulate the discussion and desire for better data collection and analysis. In order to demonstrate the utility of the model, the author has included some cost estimates from the Connecticut State Department of Children and Families and the works of other scholars looking into the question of costs for child abuse and neglect. This data represents the best available at this time. As a result, the model appearing here is specific to Connecticut. Even so, once more valid data becomes available, the model's structure and theoretical framework should adapt to the needs of other states to facilitate better measurement of relevant costs and provide a clearer picture of the utility of investment in the prevention and treatment of child abuse and neglect.


Treatment Outcomes of Angiolytic Laser-Assisted Glottoplasty in Patients With Sulcus Vocalis.
We have been performing glottoplasty using angiolytic laser, including pulsed dye laser (PDL) or potassium titanyl phosphate (KTP) laser, for the treatment of sulcus vocalis. In this study, we retrospectively reviewed the treatment results of sulcus vocalis patients who had undergone glottoplasty using angiolytic laser and evaluated the efficacy and safety of this surgical technique. From January 2008 to April 2016, 79 patients with sulcus vocalis who underwent angiolytic LASER-assisted glottoplasty were enrolled in the study. Of the 79 patients who participated in this study, 55 were male, and 24 were female. PDL was used for glottoplasty in 68 patients, and KTP was used in the remaining 11 patients. Seventy-seven patients underwent surgery for bilateral vocal cord lesions, and only 2 patients underwent surgery for unilateral vocal cord lesion. After glottoplasty using angiolytic laser, most patients showed continuous improvement of the GRBAS (grade, roughness, breathiness, asthenia, strain) score and Voice Handicap Index score until 6 months after the operation. In addition, we observed improvement of objective voice indices such as noise to harmonic ratio, jitter, shimmer, and maximal phonation time postoperatively. Based on these results, we confirmed the efficacy and safety of glottoplasty using angiolytic laser in sulcus vocalis patients. Further studies are needed to confirm appropriate laser settings such as frequency of treatments and total energy delivered to the lesion. Also, multi-institutional studies are needed to confirm the efficacy and safety of the operation.


Anaphase onset before complete DNA replication with intact checkpoint responses.
Cellular checkpoints prevent mitosis in the presence of stalled replication forks. Whether checkpoints also ensure the completion of DNA replication before mitosis is unknown. Here, we show that in yeast smc5-smc6 mutants, which are related to cohesin and condensin, replication is delayed, most significantly at natural replication-impeding loci like the ribosomal DNA gene cluster. In the absence of Smc5-Smc6, chromosome nondisjunction occurs as a consequence of mitotic entry with unfinished replication despite intact checkpoint responses. Eliminating processes that obstruct replication fork progression restores the temporal uncoupling between replication and segregation in smc5-smc6 mutants. We propose that the completion of replication is not under the surveillance of known checkpoints.


Muscular strategy shift in human running: dependence of running speed on hip and ankle muscle performance.
Humans run faster by increasing a combination of stride length and stride frequency. In slow and medium-paced running, stride length is increased by exerting larger support forces during ground contact, whereas in fast running and sprinting, stride frequency is increased by swinging the legs more rapidly through the air. Many studies have investigated the mechanics of human running, yet little is known about how the individual leg muscles accelerate the joints and centre of mass during this task. The aim of this study was to describe and explain the synergistic actions of the individual leg muscles over a wide range of running speeds, from slow running to maximal sprinting. Experimental gait data from nine subjects were combined with a detailed computer model of the musculoskeletal system to determine the forces developed by the leg muscles at different running speeds. For speeds up to 7 m s(-1), the ankle plantarflexors, soleus and gastrocnemius, contributed most significantly to vertical support forces and hence increases in stride length. At speeds greater than 7 m s(-1), these muscles shortened at relatively high velocities and had less time to generate the forces needed for support. Thus, above 7 m s(-1), the strategy used to increase running speed shifted to the goal of increasing stride frequency. The hip muscles, primarily the iliopsoas, gluteus maximus and hamstrings, achieved this goal by accelerating the hip and knee joints more vigorously during swing. These findings provide insight into the strategies used by the leg muscles to maximise running performance and have implications for the design of athletic training programs.


Standardization of H-reflex analyses.
Variability in the H-reflex can make it difficult to identify significant changes using traditional pooled analysis techniques. This study was undertaken to introduce a normalisation approach to calculate both the relative size and the relative stimulus intensity required to elicit the H-reflex response so that comparisons can be made not only with results obtained during different experimental session but also between different subjects. This normalisation process fits the size of the measured M-responses and H-reflexes over the entire stimulus range with model curves to better facilitate the calculation of important parameters. This approach allows normalisation of not only the size of the response but also the relative stimulus intensity required to elicit the response. This eases the comparison of the reflex responses under various situations, and is capable of bringing out any genuine differences in the reflex in a reliable manner not previously possible. This study illustrates that comparison of the reflex between days is problematic, even in the same subject, as both the reflex size and the relative stimulus intensity required to obtain this reflex changed in all subjects. We suggest that H-reflex studies need to use normalisation not only for size of the reflex but also for the stimulus intensity, and also that all experiments for a single subject should be performed in the same session or during the same day using some level of background muscle activity in the muscle concerned as the variability of the muscle at rest was found to be larger.


Spin-valley lifetimes in a silicon quantum dot with tunable valley splitting.
Although silicon is a promising material for quantum computation, the degeneracy of the conduction band minima (valleys) must be lifted with a splitting sufficient to ensure the formation of well-defined and long-lived spin qubits. Here we demonstrate that valley separation can be accurately tuned via electrostatic gate control in a metal-oxide-semiconductor quantum dot, providing splittings spanning 0.3-0.8 meV. The splitting varies linearly with applied electric field, with a ratio in agreement with atomistic tight-binding predictions. We demonstrate single-shot spin read-out and measure the spin relaxation for different valley configurations and dot occupancies, finding one-electron lifetimes exceeding 2 s. Spin relaxation occurs via phonon emission due to spin-orbit coupling between the valley states, a process not previously anticipated for silicon quantum dots. An analytical theory describes the magnetic field dependence of the relaxation rate, including the presence of a dramatic rate enhancement (or hot-spot) when Zeeman and valley splittings coincide.


Presenting signs of retinoblastoma at a tertiary level teaching hospital in Ethiopia.
Retinoblastoma is a primary malignant intraocular neoplasm that arise from immature retinoblasts with in developing retina. The commonest presenting sign in developing country is proptosis which is the late presenting sign. We report presenting signs of retinoblastoma in Ethiopian children seen at a tertiary level teaching hospitals in Ethiopia. Prospective case series study was done on children who presented with retinoblastoma between May 1, 2005 and September 1, 2006. This study was done as part of requirement for partial fulfilment of certificate of specialty study in ophthalmology during the year 2005 to 2006. SPSS 11 statistical package was used to analyse the data. Among 41 patients seen during the study period, 24 (58.5%) were males and 17(41%) were females. Unilateral retinoblastoma was found in 32 (78%) patients and bilateral cases were found in 9(22%). Mean age of onset for right eye was 27.5 months and left eye 33.7 months. The mean ages of presentation at time of diagnosis for right and left eye were 34.4 and 40.2 months, respectively .In bilateral retinoblastoma mean age of presentation was 33.3 months. The commonest presenting sign was proptosis 22(53.7%) followed by leucocorea nine (22%),ocular inflammation four (9.0 %), strabismus three (7.3%), glaucoma one (2.4%), loss of vision one (2.4%)and hyphemaone (2.4%). The commonest presenting signs of retinoblastoma in our set up were Proptosis followed by leucocorea. This is due to late presentation of patient and late referral by medical professionals. Health education to the public and health professionals will help early detection of retinoblastoma.


Health districts as quality improvement collaboratives and multijurisdictional entities.
Local health departments are increasingly challenged to meet emerging health problems at the same time that they are being challenged with dwindling resources and the demands of accreditation. To assess the capacity of Multicounty health districts to serve as "Quality Improvement Collaboratives" and support local health departments to meet accreditation standards. The study used an online survey tool and follow-up phone calls with key informants in health districts and county health departments in Georgia. Data collection was primarily based on an instrument to measure Quality Improvement Collaboratives that was adapted and tested for use with public health agencies in Georgia. The Georgia PBRN conducted this study of health districts and county health departments. The Georgia Department of Public Health supports 18 health districts and 159 county health departments (GA DPH, 2011). The health districts range in county composition from 1 to 16 counties in each district. Key informants comprised district and county health department staff and county health department board members were identified by 13 participating health district offices. Key opinion leaders from both the rural and nonrural counties agreed that the Districts were important for providing essential services and supporting quality improvement collaboration. Psychometric testing of the Quality Improvement Collaborative assessment public health instrument yielded high scores for validity and reliability. Regionalization of local public health capacity is a critical emerging issue for public health accreditation and quality improvement. This study demonstrated the utility of regionalization across traditional local geopolitical boundaries.


Cleft palate with autosomal recessive transmission in Brittany spaniels.
In the course of maintaining a large colony of Brittany spaniels for studying a dominantly inherited motor neuron trait, cases of sporadic complete cleft palate were observed. Without intervention, the pups with cleft palate that attempt to nurse, aspirate and die. In this study, we report on the incidence of cleft palate in this dog kindred, describe the gross morphologic characteristics of the cleft, and present a morphometric analysis of the skull of two of the cleft palate pups and one unaffected pup that died at birth. Our data thus far indicate 26.9% incidence of cleft palate in the colony. Pedigree analysis indicates that this cleft palate trait is inherited as an autosomal recessive. High resolution computed tomography scans of the pup heads were used in morphometric comparison of normal and cleft palate pups. We found specific morphologic differences between the cranial base and palate of normal and cleft palate pups. Plans for future studies of the genetics and growth and development of this animal model are discussed. This canine cleft palate trait provides an ideal model for studying a malformation common in humans.


What Makes a Champion? Early Multidisciplinary Practice, Not Early Specialization, Predicts World-Class Performance.
What explains the acquisition of exceptional human performance? Does a focus on intensive specialized practice facilitate excellence, or is a multidisciplinary practice background better? We investigated this question in sports. Our meta-analysis involved 51 international study reports with 477 effect sizes from 6,096 athletes, including 772 of the world's top performers. Predictor variables included starting age, age of reaching defined performance milestones, and amounts of coach-led practice and youth-led play (e.g., pickup games) in the athlete's respective main sport and in other sports. Analyses revealed that (a) adult world-class athletes engaged in more childhood/adolescent multisport practice, started their main sport later, accumulated less main-sport practice, and initially progressed more slowly than did national-class athletes; (b) higher performing youth athletes started playing their main sport earlier, engaged in more main-sport practice but less other-sports practice, and had faster initial progress than did lower performing youth athletes; and (c) youth-led play in any sport had negligible effects on both youth and adult performance. We illustrate parallels from science: Nobel laureates had multidisciplinary study/working experience and slower early progress than did national-level award winners. The findings suggest that variable, multidisciplinary practice experiences are associated with gradual initial discipline-specific progress but greater sustainability of long-term development of excellence.


Comparison of cimetidine 800 mg once daily and 400 mg twice daily in acute duodenal ulceration.
A double blind trial was conducted in seven centres to evaluate the safety and efficacy of cimetidine 800 mg given at night compared with 400 mg given at breakfast and at bedtime. Altogether 197 patients with active duodenal ulcer confirmed by endoscopy entered the study, of whom 187 were eligible for analysis. After four weeks' treatment the ulcer was healed in 76 of 91 patients (84%) receiving the once daily regimen and in 65 of the 96 patients (68%) receiving the twice daily regimen (p less than 0.05). Both dosage regimens were equally effective in reducing ulcer pain and consumption of antacids. Pain relief was considerable within the first two weeks, and most of the patients were free of symptoms by the end of treatment. No patients were withdrawn because of adverse events as these were few and mild, consistent with the proved safety profile of cimetidine. Cimetidine 800 mg given at night is as effective as 400 mg twice daily; the single dose regimen may improve patient compliance, thus facilitating treatment.


Dynamic modulation of frontal theta power predicts cognitive ability in infancy.
Cognitive ability is a key factor that contributes to individual differences in life trajectories. Identifying early neural indicators of later cognitive ability may enable us to better elucidate the mechanisms that shape individual differences, eventually aiding identification of infants with an elevated likelihood of less optimal outcomes. A previous study associated a measure of neural activity (theta EEG) recorded at 12-months with non-verbal cognitive ability at ages two, three and seven in individuals with older siblings with autism (Jones et al., 2020). In a pre-registered study (https://osf.io/v5xrw/), we replicate and extend this finding in a younger, low-risk infant sample. EEG was recorded during presentation of a non-social video to a cohort of 6-month-old infants and behavioural data was collected at 6- and 9-months-old. Initial analyses replicated the finding that frontal theta power increases over the course of video viewing, extending this to 6-month-olds. Further, individual differences in the magnitude of this change significantly predicted non-verbal cognitive ability measured at 9-months, but not early executive function. Theta change at 6-months-old may therefore be an early indicator of later cognitive ability. This could have important implications for identification of, and interventions for, children at risk of poor cognitive outcomes.


The Vienna Frailty Questionnaire For Persons with Intellectual Disabilities--Revised.
Frailty is a theoretical concept used to track individual age-related declines. Persons with intellectual disabilities (ID) often present with pre-existing deficits that would be considered frailty markers in the general population. The previously developed Vienna Frailty Questionnaire for Persons with ID (VFQ-ID) was aimed at assessing frailty in this specific population. However, findings of the initial frailty study in 2007 revealed some weaknesses. This paper reports on the development of the Vienna Frailty Questionnaire for Persons with ID - Revised (VFQ-ID-R) as well as its first application and psychometric evaluation. The authors re-administered the VFQ-ID-R to participants with ID who had been assessed with the VFQ-ID in 2007. The goal was to study the factor structure and reliability of the revised test. Internal consistency of the VFQ-ID-R was found to be very good for the entire scale and was moderate for the four domains of the scale. Inter-rater reliability and retest reliability were found to be good. The revisions made to the VFQ-ID will be useful in assessing and supporting ageing individuals with ID.


The mechanism and regioselectivities of (NHC)nickel(ii)hydride-catalyzed cycloisomerization of dienes: a computational study.
Transition metal-catalyzed hydroalkenylation is widely applied in organic synthesis to construct carbon-carbon bonds and synthesize substituted alkenes. In this work, the mechanism and regioselectivities of [(NHC)NiH]+-catalyzed intramolecular cycloisomerization of dienes are studied by density functional theory (DFT) calculations. Through an initial hydride insertion, [(NHC)NiH]+ reacts with the diene substrate to generate the alkyl nickel species. This alkyl nickel species is the resting state of the catalytic cycle, and the hydroalkenylation reaction involves sequential olefin insertion and β-hydride transfer. The selectivity between the possible cycloisomerization products is determined by both the olefin insertion and β-hydride transfer steps. The olefin insertion favors the exo-cyclization due to the high ring strain of the insertion transition states for the endo-cyclization. In the β-hydride transfer step, the hydride transfers to the internal olefin position selectively to avoid the steric repulsions between the bulky NHC ligand and the alkyl substituent of the olefin substrate. This selectivity of β-hydride transfer leads to the n-exo cyclization instead of the (n - 1)-exo cyclization. These mechanistic insights will shed light on the future development of transition metal-catalyzed hydroalkenylation reactions.


Play, Learn, and Teach Outdoors-Network (PLaTO-Net): terminology, taxonomy, and ontology.
A recent dialogue in the field of play, learn, and teach outdoors (referred to as "PLaTO" hereafter) demonstrated the need for developing harmonized and consensus-based terminology, taxonomy, and ontology for PLaTO. This is important as the field evolves and diversifies in its approaches, contents, and contexts over time and in different countries, cultures, and settings. Within this paper, we report the systematic and iterative processes undertaken to achieve this objective, which has built on the creation of the global PLaTO-Network (PLaTO-Net). This project comprised of four major methodological phases. First, a systematic scoping review was conducted to identify common terms and definitions used pertaining to PLaTO. Second, based on the results of the scoping review, a draft set of key terms, taxonomy, and ontology were developed, and shared with PLaTO members, who provided feedback via four rounds of consultation. Third, PLaTO terminology, taxonomy, and ontology were then finalized based on the feedback received from 50 international PLaTO member participants who responded to ≥ 3 rounds of the consultation survey and dialogue. Finally, efforts to share and disseminate project outcomes were made through different online platforms. This paper presents the final definitions and taxonomy of 31 PLaTO terms along with the PLaTO-Net ontology model. The model incorporates other relevant concepts in recognition that all the aspects of the model are interrelated and interconnected. The final terminology, taxonomy, and ontology are intended to be applicable to, and relevant for, all people encompassing various identities (e.g., age, gender, culture, ethnicity, ability). This project contributes to advancing PLaTO-based research and facilitating intersectoral and interdisciplinary collaboration, with the long-term goal of fostering and strengthening PLaTO's synergistic linkages with healthy living, environmental stewardship, climate action, and planetary health agendas. Notably, PLaTO terminology, taxonomy and ontology will continue to evolve, and PLaTO-Net is committed to advancing and periodically updating harmonized knowledge and understanding in the vast and interrelated areas of PLaTO.


Selective EGF-Receptor Inhibition in CD4+ T Cells Induces Anergy and Limits Atherosclerosis.
Several epidermal growth factor receptor (EGFR) inhibitors have been successfully developed for the treatment of cancer, limiting tumor growth and metastasis. EGFR is also expressed by leukocytes, but little is known about its role in the modulation of the immune response. The aim of this study was to determine whether EGFR expressed on CD4+ T cells is functional and to address the consequences of EGFR inhibition in atherosclerosis, a T cell-mediated vascular chronic inflammatory disease. The authors used EGFR tyrosine kinase inhibitors (AG-1478, erlotinib) and chimeric Ldlr-/-Cd4-Cre/Egfrlox/lox mouse with a specific deletion of EGFR in CD4+ T cells. Mouse CD4+ T cells expressed EGFR, and the EGFR tyrosine kinase inhibitor AG-1478 blocked in vitro T cell proliferation and Th1/Th2 cytokine production. In vivo, treatment of Ldlr-/- mice with the EGFR inhibitor erlotinib induced T cell anergy, reduced T cell infiltration within atherosclerotic lesions, and protected against atherosclerosis development and progression. Selective deletion of EGFR in CD4+ T cells resulted in decreased T cell proliferation and activation both in vitro and in vivo, as well as reduced interferon-γ, interleukin-4, and interleukin-2 production. Atherosclerotic lesion size was reduced by 2-fold in irradiated Ldlr-/- mice reconstituted with bone marrow from Cd4-Cre/Egfrlox/lox mice, compared to Cd4-Cre/Egfr+/+ chimeric mice, after 4, 6, and 12 weeks of high-fat diet, associated with marked reduction in T cell infiltration in atherosclerotic plaques. Human blood T cells expressed EGFR and EGFR inhibition reduced T cell proliferation both in vitro and in vivo. EGFR blockade induced T cell anergy in vitro and in vivo and reduced atherosclerosis development. Targeting EGFR may be a novel strategy to combat atherosclerosis.


In vitro ischemia triggers a transcriptional response to down-regulate synaptic proteins in hippocampal neurons.
Transient global cerebral ischemia induces profound changes in the transcriptome of brain cells, which is partially associated with the induction or repression of genes that influence the ischemic response. However, the mechanisms responsible for the selective vulnerability of hippocampal neurons to global ischemia remain to be clarified. To identify molecular changes elicited by ischemic insults, we subjected hippocampal primary cultures to oxygen-glucose deprivation (OGD), an in vitro model for global ischemia that resulted in delayed neuronal death with an excitotoxic component. To investigate changes in the transcriptome of hippocampal neurons submitted to OGD, total RNA was extracted at early (7 h) and delayed (24 h) time points after OGD and used in a whole-genome RNA microarray. We observed that at 7 h after OGD there was a general repression of genes, whereas at 24 h there was a general induction of gene expression. Genes related with functions such as transcription and RNA biosynthesis were highly regulated at both periods of incubation after OGD, confirming that the response to ischemia is a dynamic and coordinated process. Our analysis showed that genes for synaptic proteins, such as those encoding for PICK1, GRIP1, TARPγ3, calsyntenin-2/3, SAPAP2 and SNAP-25, were down-regulated after OGD. Additionally, OGD decreased the mRNA and protein expression levels of the GluA1 AMPA receptor subunit as well as the GluN2A and GluN2B subunits of NMDA receptors, but increased the mRNA expression of the GluN3A subunit, thus altering the composition of ionotropic glutamate receptors in hippocampal neurons. Together, our results present the expression profile elicited by in vitro ischemia in hippocampal neurons, and indicate that OGD activates a transcriptional program leading to down-regulation in the expression of genes coding for synaptic proteins, suggesting that the synaptic proteome may change after ischemia.


Safety and immunogenicity of three seasonal inactivated influenza vaccines among pregnant women and antibody persistence in their infants.
Inactivated influenza virus vaccines (IIVs) are recommended for all pregnant women in the United States. We conducted a prospective, randomized, double blind study of three licensed seasonal trivalent IIVs (IIV3s) to assess their safety and immunogenicity in pregnant women and determine the level and persistence of passively transferred maternal antibody in infants. 139 pregnant women ages 18-39 years and 14-33 weeks' gestation, and 44 non-pregnant women, were randomized 1:1:1 to receive a single intramuscular dose of one of three licensed IIV3s (Agriflu®, Fluzone®, or Fluarix®) prior to the 2010-2011 influenza season. Reactogenicity, adverse events (AEs) and pregnancy outcomes were documented. Serum samples for hemagglutination inhibition (HAI) and neutralization antibody assays were collected prior to and 28 and 180 days after immunization. Maternal sera and cord blood were collected at the time of delivery and sera were obtained from 44 infants at 6 weeks of age. Pregnant and non-pregnant women experienced similar frequency of injection site (92% and 86%, respectively) and systemic (95% and 87%, respectively) reactions, the majority of which were mild. There were no vaccine-associated maternal or infant serious AEs. Antibody responses to the three vaccine antigens were not different between pregnant and non-pregnant women. The ratios of cord blood (infant) to maternal HAI antibody titers at delivery ranged between 1.1 and 1.7 for each of the vaccine antigens. Influenza antibody concentrations in infants were 70-40% of the birth titer by 6 weeks of age. The three IIV3s were well tolerated in pregnant women. Antibody responses were comparable in pregnant and non-pregnant women, and after second or third trimester vaccination. Transplacental transfer of maternal antibodies to the infant was efficient. However, antibody titers decline rapidly in the first 6 weeks of life.


Dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.


An implementation of sensor-based force feedback in a compact laparoscopic surgery robot.
Despite the rapid progress in the clinical application of laparoscopic surgery robots, many shortcomings have not yet been fully overcome, one of which is the lack of reliable haptic feedback. This study implemented a force-feedback structure in our compact laparoscopic surgery robot. The surgery robot is a master-slave configuration robot with 5 DOF (degree of freedom corresponding laparoscopic surgical motion. The force-feedback implementation was made in the robot with torque sensors and controllers installed in the pitch joint of the master and slave robots. A simple dynamic model of action-reaction force in the slave robot was used, through which the reflective force was estimated and fed back to the master robot. The results showed the system model could be identified with significant fidelity and the force feedback at the master robot was feasible. However, the qualitative human assessment of the fed-back force showed only limited level of object discrimination ability. Further developments are underway with this result as a framework.


Death by chocolate: a fatal problem for an inquisitive wild parrot.
An adult male kea (Nestor notabilis) in good body condition was found dead at Aoraki/Mt Cook Village, in the Southern Alps of New Zealand. The bird had previously been involved in behavioural tests of problem-solving ability. The bird had substantial subcutaneous and abdominal reserves of fat. The crop contained 20 g of what appeared to be dark chocolate; a conservative estimate of the dose of methylxanthines ingested by the bird was 250 mg/kg theobromine, 20 mg/kg caffeine and 3 mg/kg theophylline. Histopathological examination revealed acute degenerative changes to hepatocytes, renal tubules, and cerebrocortical neurons. Acute combination methylxanthine toxicity after opportunistic ingestion of chocolate. This is the first report of the pathological findings of methylxanthine toxicity in a wild parrot, and illustrates the need to ensure that kea are protected from the toxic by-products of human habitation, and the difficulties in ensuring this against a neophilic, inquisitive and innovative parrot.


Oral health of individuals aged 3-80 years in Jönköping, Sweden during 30 years (1973-2003). I. Review of findings on dental care habits and knowledge of oral health.
The aim of the present study was to compare data on dental care habits and knowledge of oral health in four cross-sectional epidemiological studies carried out in 1973,1983,1993, and 2003. The 1973 study constituted a random sample of 1,000 individuals evenly distributed in the age groups 3, 5, 10, 15, 20, 30, 40, 50, 60, and 70 years. The same age groups with addition of a group of 80-year-olds were included in the 1983, 1993 and 2003 studies, which comprised 1,104, 1,078, and 987 individuals, respectively. A questionnaire about dental care habits and knowledge of oral health was used in connection with a clinical and radiographic examination. The same questions were used in all the four studies. An addition to the 1993 and 2003 investigations were questions concerning ethnic background. In 2003 approximately 90-95 per cent of all individuals were visiting the dentist on a regular basis every or every second year. The 30- and 40-yea r-olds, however, did not visit a dentist as regularly in 2003 as in 1993. In these age groups 21-24 per cent of the individuals, respectively, reported that they had not visited a dentist in the last 2 years. Almost all children 3-15 years old received their dental care within the Public Dental Service (PDS). During the period 1973-2003 an increase in percentage of individuals aged 20-50 years treated by the PDS was seen compared to private practice, while among 60-80 year-olds there were only minor changes. Most so-year-olds and older received their dental care by private practitioners. About 70-80 per cent of all adults in 2003 were enrolled in a recall system on the dentist's initiative while in 1973 most appointments were based on the patient's own initiative. The number of individuals who were frightened, 5-17 per cent, or felt discomfort at the prospect of an appointment with the dentist was more or less the same during the whole period. The knowledge of the etiology of dental diseases did not changed much between 1973 and 2003. The frequency of toothbrushing increased since 1973 and in 2003 more than 90 per cent of all individuals brushed their teeth twice or once a day. The use of dental floss and toothpicks decreased in 2003 compared to 1983 and 1993. Almost all individuals in 2003 used fluoride toothpaste. It was obvious that the dental team constituted the main source of dental health information. For the age groups 20 and 30 years information from friends and relatives was also important. In the age groups 3-20 years up to 45 per cent of the individuals were consuming soft drinks every day or several times a week.


Isolation from the horse genome of a new DNA transposon belonging to the Tigger family.
Tigger elements are human DNA transposons homologous to the pogo element of Drosophila melanogaster. They contain an open reading frame for a transposase very similar to the major mammalian centromere protein CENP-B. We found in the horse genome a DNA element ( Ecatig3) sharing 88% homology with human Tigger3. The presence of Tigger elements in the horse genome confirms previous data that date these elements before the divergence between Perissodactyla and Primates (80-90 Myr ago). Copy number evaluation indicates that the horse element is much more abundant than its human counterpart. Southern blot analysis demonstrates that Ecatig3 elements are extremely homogeneous; this may indicate that the evolution of this DNA transposon has been driven by some kind of selection and has not been neutral.


Information primary care physicians want to receive about their hospitalized patients.
Communication between physicians caring for hospitalized patients and those patients' primary care providers (PCPs) is often suboptimal, which can lead to diminished health care quality and safety. It is unclear what hospital information PCPs would find most valuable in their patients' continuing care, as is how and when they would prefer to receive such information. Using the modified Delphi survey methodology, we developed a consensus list of information items PCPs want to receive about their hospitalized patients, using general internists and family physicians considered experts in primary care. Panelists rated items on a 5-point Likert scale signifying their level of agreement with the information's importance and with the information communication mode. Consensus agreement or disagreement was determined using 95% confidence intervals. Twelve physicians (five family physicians, seven general internists), averaging 19.6 years of primary care experience, participated in Delphi round 1; 41.6% (37 of 89) of the items were accepted by consensus, one item was rejected (receiving daily progress notes), and the remaining 51 items were equivocal. In round 2, nine physician panelists participated (four family physicians, five general internists), and six additional items were accepted. They generally preferred notification at the patient's first hospital interaction and at discharge. No consensus was found regarding communication mode; e-mail was most favored. We found broad areas of consensus regarding information PCPs wish to receive about their hospitalized patients that are generally consistent with previous surveys. Our findings also suggest that physicians are becoming more comfortable with patient-related electronic communications.


Finance, providers issue brief: HMO medical directors.
Medical directors of managed care organizations have the ultimate responsibility of deciding the treatments for which a health plan will pay. Cognizant of consumer concerns over the power inherent in the position, states are seeking to inject more accountability into the decision-making process. Among the issues with which they have begun to grapple: whether medical directors should be required to hold a medical license from the state in which they work and, by extension, whether they should be under the jurisdiction of the state medical board.


Aerosols in coastal and inland areas in the equatorial African belt.
Aerosols affect the climate directly through absorption and reflection of sunlight back to space and indirectly by acting as cloud condensation nuclei. This paper is based on more than three decades of satellite data (1979-1994 and 1996-2012) from total ozone mapping spectrometer (TOMS) and ozone monitoring instrument (OMI), which have provided measurements of backscattered radiances in the wavelength range from 331 to 380 nm. These data have been used to determine the aerosol climatology and to investigate the influence of the aerosol index (AI) on the ultraviolet index (UVI) in coastal land areas in Serrekunda (13.28°N, 16.34°W), The Gambia, and Dar-es-Salaam (6.8°S, 39.26°E), Tanzania, as well as in inland areas in Kampala (0.19°N, 32.34°E), Uganda. Heavy aerosol loadings were found to occur in the dry seasons at all three locations. To reduce the influence of clouds, we disregarded TOMS and OMI data for days during which the UV reflectivity was larger than 9% and investigated the correlation of the AI with the UVI for the remaining days at the three locations. We found a high correlation coefficient of 0.82 for Serrekunda, but poor correlation for Kampala and Dar-es-Salaam. The average AI for Serrekunda was found to be about three times higher than that for Kampala or Dar-es-Salaam, and a positive trend was found for the AI in Kampala and Dar-es-Salaam, whereas a negative trend was found for the AI in Serrekunda.


Using psychological theory to understand the clinical management of type 2 diabetes in Primary Care: a comparison across two European countries.
Long term management of patients with Type 2 diabetes is well established within Primary Care. However, despite extensive efforts to implement high quality care both service provision and patient health outcomes remain sub-optimal. Several recent studies suggest that psychological theories about individuals' behaviour can provide a valuable framework for understanding generalisable factors underlying health professionals' clinical behaviour. In the context of the team management of chronic disease such as diabetes, however, the application of such models is less well established. The aim of this study was to identify motivational factors underlying health professional teams' clinical management of diabetes using a psychological model of human behaviour. A predictive questionnaire based on the Theory of Planned Behaviour (TPB) investigated health professionals' (HPs') cognitions (e.g., beliefs, attitudes and intentions) about the provision of two aspects of care for patients with diabetes: prescribing statins and inspecting feet.General practitioners and practice nurses in England and the Netherlands completed parallel questionnaires, cross-validated for equivalence in English and Dutch. Behavioural data were practice-level patient-reported rates of foot examination and use of statin medication. Relationships between the cognitive antecedents of behaviour proposed by the TPB and healthcare teams' clinical behaviour were explored using multiple regression. In both countries, attitude and subjective norm were important predictors of health professionals' intention to inspect feet (Attitude: beta = .40; Subjective Norm: beta = .28; Adjusted R2 = .34, p < 0.01), and their intention to prescribe statins (Attitude: beta = .44; Adjusted R2 = .40, p < 0.01). Individuals' self-reported intention did not predict practice-level performance of either clinical behaviour. Using the TPB, we identified modifiable factors underlying health professionals' intentions to perform two clinical behaviours, providing a rationale for the development of targeted interventions. However, we did not observe a relationship between health professionals' intentions and our proxy measure of team behaviour. Significant methodological issues were highlighted concerning the use of models of individual behaviour to explain behaviours performed by teams. In order to investigate clinical behaviours performed by teams it may be necessary to develop measures that reflect the collective cognitions of the members of the team to facilitate the application of these theoretical models to team behaviours.


Monocyte chemoattractant protein 1 is a prognostic marker in ANCA-associated small vessel vasculitis.
The (anti neutrophil cytoplasmatic autoantibody ANCA), associated small vessel vasculitides (ASVV) are relapsing-remitting inflammatory disorders, involving various organs, such as the kidneys. (Monocyte chemoattractant protein 1 MCP-1) has been shown to be locally up regulated in glomerulonephritis and recent studies have pointed out MCP-1 as a promising marker of renal inflammation. Here we measure urinary cytokine levels in different phases of disease, exploring the possible prognostic value of MCP-1, together with (interleukin 6 IL-6), (interleukin 8 IL-8) and (immunoglobulin M IgM). MCP-1, IL-6 and IL-8 were measured using commercially available ELISA kits, whereas IgM in the urine was measured by an in-house ELISA. The MCP-1 levels in urine were significantly higher in patients in stable phase of the disease, compared with healthy controls. Patients in stable phase, with subsequent adverse events; had significantly higher MCP-1 values than patients who did not. MCP-1 and IgM both tended to be higher in patients relapsing within three months, an observation, however, not reaching statistical significance. Urinary levels of IL-6 correlated with relapse tendency, and IL-8 was associated with disease outcome. Patients with ASVV have raised cytokine levels in the urine compared to healthy controls, even during remission. Raised MCP-1 levels are associated with poor prognosis and possibly also with relapse tendency. The association with poor prognosis was stronger for U-MCP-1 than for conventional markers of disease like CRP, BVAS, and ANCA, as well as compared to candidate markers like U-IgM and U-IL-8. We thus consider U-MCP-1 to have promising potential as a prognostic marker in ASVV.


Amphioxus functional genomics and the origins of vertebrate gene regulation.
Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus (Branchiostoma lanceolatum) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis-regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that-in vertebrates-over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations.


A novel instrument for separating large DNA molecules with pulsed homogeneous electric fields.
A new instrument has been developed for the electrophoretic separation of large DNA molecules that can independently regulate the voltage of each of 24 electrodes and allow the magnitude, orientation, homogeneity, and duration of the electric field to be precisely controlled. Each parameter can be varied at any time during the electrophoretic process. Thus distinct sets of conditions can be combined to optimize the separation of various fragment sizes in a single run. Independent control of electrode voltage allows all of the fields to be generated with electrodes arranged in a closed contour, independent of a particular geometry. This device increases both the resolution in any size range and the speed of separation, especially for DNA molecules larger than 3 megabases.


Swimming training and functional assessment of sciatic nociception in rats.
The protective effect of exercise on individuals with peripheral neuropathy is controversial. To assess the influence of physical training of moderate and progressive intensity on nociception of rats in an experimental sciatica model. The study assessed 18 rats divided into the following three groups: control group (CG); low-intensity swimming group (LISG); progressive-time swimming group (PTSG). To meet the physical training protocol, the animals were placed in a water tank for six weeks, three alternate days per week. In LISG group, the animals swam ten minutes per session, and, in PTSG group, the animals began swimming for ten minutes, and had a ten-minute increase per week. In CG group, the animals swam less than one minute per day, only to get used to the water environment. After finishing the swimming training, the experimental sciatica model protocol was started with constrictive ligature of the sciatic nerve with chromic catgut. Nociception was assessed using the functional disability test, which measures, in a one-minute interval, the time during which the animal holds its hind paw (THHP) in a guarded position. Assessments were performed preoperatively, and on the third, sixth, and tenth post-operative (PO) days. All groups showed a significant increase in THHP on third, sixth, and tenth PO days, as compared to preoperative values. In CG, no significant change was observed in PO assessments, unlike what happened in LISG and PTSG groups. Exercise produced greater hyperalgesia.


Action of thrombopoietin at the megakaryocyte progenitor level is critical for the subsequent proplatelet production.
Formation of proplatelets from megakaryocytes is believed to be the first step of platelet production in vitro. In this study, we evaluated the effects of recombinant human thrombopoietin (hTPO) on the development of proplatelets from a GpIIb/IIIa+ population of rat bone marrow cells highly enriched for late megakaryocyte progenitors (GpIIb/IIIa+ CFU-MK) that we recently found to be a primary target population of TPO. Quantitative measurement of hTPO-induced proplatelet formation was performed in liquid cultures. Proplatelet formation from megakaryocytes derived from GpIIb/IIIa+ CFU-MK in the presence of hTPO began on day 4 of culture and peaked the following day. On day 5 of culture, lower concentrations of hTPO expanded the number of megakaryocytes, increased the number of proplatelets and the percentage of proplatelet-developing megakaryocytes. Increasing hTPO concentrations resulted in a modest decrease in proplatelet development. We next used hTPO to derive immature or mature megakaryocytes from GpIIb/IIIa+ CFU-MK. These populations of cultured megakaryocytes spontaneously formed proplatelets when recultured in the absence of exogenous hTPO. The addition of hTPO at higher concentrations modestly augmented proplatelet production from immature megakaryocytes derived from 2-day liquid cultures. However, either murine interleukin-6 (IL-6) or human IL-11, but not rat IL-3, was more potent than hTPO in augmenting proplatelet formation from immature megakaryocytes. Each of these four cytokines had an inhibitory effect on proplatelet formation from more differentiated megakaryocytes derived from 3-day liquid cultures. These results indicate that TPO enhances proplatelet production primarily by stimulating CFU-MK to increase the number of proplatelet-forming megakaryocytes and that its action is clearly different from those of other cytokines that also stimulate megakaryocytopoiesis.


A global relationship between trabecular bone morphology and homogenized elastic properties.
An alternative concept of the relationship between morphological and elastic properties of trabecular bone is presented and applied to human tissue from several anatomical locations using a digital approach. The three-dimensional morphology of trabecular bone was assessed with a microcomputed tomography system and the method of directed secants as well as the star volume procedure were used to compute mean intercept length (MIL) and average bone length (ABL) of 4 mm cubic specimens. Assuming isotropic elastic properties for the trabecular tissue, the general elastic tensors of the bone specimens were determined using the homogenization method and the closest orthotropic tensors were calculated with an optimization algorithm. The assumption of orthotropy for trabecular bone was found to improve with specimen size and hold within 6.1 percent for a 4 mm cube size. A strong global relationship (r2 = 0.95) was obtained between fabric and the orthotropic elastic tensor with a minimal set of five constants. Mean intercept length and average bone length provided an equivalent power of prediction. These results support the hypothesis that the elastic properties of human trabecular bone from an arbitrary anatomical location can be estimated from an approximation of the anisotropic morphology and a prior knowledge of tissue properties.


Developments in the treatment of visceral leishmaniasis.
Visceral leishmaniasis (VL) is one of the most neglected parasitic diseases causing large scale mortality and morbidity among the poorest of the poor in the Indian subcontinent and Africa. This review aims to describe the potential and the (lack of) current impact of newly developed treatments on the control of VL. It describes how the problem of an empty research pipeline is addressed, and discusses the emerging threat of incurable HIV/VL coinfection. The literature was searched for drugs used in VL. Research and development of VL drugs has received a financial boost but no new drugs are expected in the next 5 years. Only three new and highly effective treatments have been licensed in the past 10 years. These remain, however, largely inaccessible as VL control programs in the developing world are lacking. This is deserving of immediate and urgent attention, especially in the context of the rapidly expanding HIV/VL coinfection.


Autosomal dominant osteopetrosis revisited: lessons from recent studies.
Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.


Masticatory hypermuscularity is not related to reduced cranial volume in myostatin-knockout mice.
It has been suggested recently that masticatory muscle size reduction in humans resulted in greater encephalization through decreased compressive forces on the cranial vault. Following this logic, if masticatory muscle size were increased, then a reduction in brain growth should also occur. This study was designed to test this hypothesis using a myostatin (GDF-8) knockout mouse model. Myostatin is a negative regulator of skeletal muscle growth, and individuals lacking this gene show significant hypermuscularity. Sixty-two [32 wild-type (WT) and 30 GDF-8 -/- knockout], 1, 28, 56, and 180-day-old CD-1 mice were used. Body and masseter muscle weights were collected following dissection and standardized lateral and dorsoventral cephalographs were obtained. Cephalometric landmarks were identified on the radiographs and cranial volume was calculated. Mean differences were assessed using a two-way ANOVA. KO mice had significantly greater body and masseter weights beginning at 28 days compared with WT controls. No significant differences in cranial volumes were noted between KO and WT. Muscle weight was not significantly correlated with cranial volume in 1, 28, or 180-day-old mice. Muscle weights exhibited a positive correlation with cranial volume at 56 days. Results demonstrate that masticatory hypermuscularity is not associated with reduced cranial volume. In contrast, there is abundant data demonstrating the opposite, brain growth determines cranial vault growth and masticatory apparatus only affects ectocranial morphology. The results presented here do not support the hypothesis that a reduction in masticatory musculature relaxed compressive forces on the cranial vault allowing for greater encephalization.


Chromosome-length genome assembly and structural variations of the primal Basenji dog (Canis lupus familiaris) genome.
Basenjis are considered an ancient dog breed of central African origins that still live and hunt with tribesmen in the African Congo. Nicknamed the barkless dog, Basenjis possess unique phylogeny, geographical origins and traits, making their genome structure of great interest. The increasing number of available canid reference genomes allows us to examine the impact the choice of reference genome makes with regard to reference genome quality and breed relatedness. Here, we report two high quality de novo Basenji genome assemblies: a female, China (CanFam_Bas), and a male, Wags. We conduct pairwise comparisons and report structural variations between assembled genomes of three dog breeds: Basenji (CanFam_Bas), Boxer (CanFam3.1) and German Shepherd Dog (GSD) (CanFam_GSD). CanFam_Bas is superior to CanFam3.1 in terms of genome contiguity and comparable overall to the high quality CanFam_GSD assembly. By aligning short read data from 58 representative dog breeds to three reference genomes, we demonstrate how the choice of reference genome significantly impacts both read mapping and variant detection. The growing number of high-quality canid reference genomes means the choice of reference genome is an increasingly critical decision in subsequent canid variant analyses. The basal position of the Basenji makes it suitable for variant analysis for targeted applications of specific dog breeds. However, we believe more comprehensive analyses across the entire family of canids is more suited to a pangenome approach. Collectively this work highlights the importance the choice of reference genome makes in all variation studies.


Exophytic benign mixed epithelial stromal tumour of the kidney: case report of a rare tumour entity.
Mixed epithelial and stromal tumour (MEST) represents a recently described benign composite neoplasm of the kidney, which predominantly affects perimenopausal females. Most tumours are benign, although rare malignant cases have been observed. A 47-year-old postmenopausal female presented to the urologist with flank pain. A CT scan of the abdomen showed a 30-mm-in-diameter uniform mass adjacent to the pelvis of the left kidney. Surgical exploration showed a tumour arising from the lower anterior hilus of the left kidney. The tumour could be excised by preserving the kidney. By intraoperative frozen section the tumour showed characteristic features of MEST with epithelial-covered cysts embedded in an "ovarian-like" stroma. Additional immunohistochemistry investigations showed expression for hormone receptors by the stromal component of the tumour. MEST typically presents in perimenopausal women as a primarily cystic mass. Commonly, the tumour arises from the renal parenchyma or pelvis. The tumour is composed of an admixture of cystic and sometimes more solid areas. The stromal cells typically demonstrate an ovarian-type stroma showing expression for the estrogen and progesterone receptors. MEST represents a distinctive benign tumour entity of the kidney, which affects perimenopausal woman. The tumour should be distinguished from other cystic renal neoplasms. By imaging studies it is difficult to distinguish between a benign or malignant nature of the tumour. Thus, intraoperative frozen section is necessary for conservative surgery, since the overall prognosis is favourable and renal function can be preserved in most cases.


Atmospheric correction using near-infrared bands for satellite ocean color data processing in the turbid western Pacific region.
A regional near-infrared (NIR) ocean normalized water-leaving radiance (nL(w)(λ)) model is proposed for atmospheric correction for ocean color data processing in the western Pacific region, including the Bohai Sea, Yellow Sea, and East China Sea. Our motivation for this work is to derive ocean color products in the highly turbid western Pacific region using the Geostationary Ocean Color Imager (GOCI) onboard South Korean Communication, Ocean, and Meteorological Satellite (COMS). GOCI has eight spectral bands from 412 to 865 nm but does not have shortwave infrared (SWIR) bands that are needed for satellite ocean color remote sensing in the turbid ocean region. Based on a regional empirical relationship between the NIR nL(w)(λ) and diffuse attenuation coefficient at 490 nm (K(d)(490)), which is derived from the long-term measurements with the Moderate-resolution Imaging Spectroradiometer (MODIS) on the Aqua satellite, an iterative scheme with the NIR-based atmospheric correction algorithm has been developed. Results from MODIS-Aqua measurements show that ocean color products in the region derived from the new proposed NIR-corrected atmospheric correction algorithm match well with those from the SWIR atmospheric correction algorithm. Thus, the proposed new atmospheric correction method provides an alternative for ocean color data processing for GOCI (and other ocean color satellite sensors without SWIR bands) in the turbid ocean regions of the Bohai Sea, Yellow Sea, and East China Sea, although the SWIR-based atmospheric correction approach is still much preferred. The proposed atmospheric correction methodology can also be applied to other turbid coastal regions.


The shift in urea orientation at protein surfaces at low pH is compatible with a direct mechanism of protein denaturation.
Surface-specific spectroscopic data has shown that urea undergoes a shift in orientation at protein surfaces in acidic media. Since urea denatures proteins at a wide range of pHs, the variable chemical nature of protein-urea interactions has been used to support an indirect mechanism of urea-induced denaturation. Here, we use molecular dynamics simulations, minimum-distance distribution functions (MDDFs), and hydrogen-bond analysis, to characterize the interactions of urea with proteins at neutral and low pH, as defined by the protonation state of acidic residues. We obtain the expected preferential solvation by urea and dehydration, consistently with urea-induced denaturation, while the MDDFs allow for a solvent-shell perspective of protein-urea interactions. The distribution functions are decomposed into atomic contributions to show that there is indeed a shift in the orientation of urea molecules in the vicinity of acidic side-chains, as shown by the experimental spectroscopic data. However, this effect is local, and the interactions of urea with the other side chains and with the protein backbone are essentially unaffected at low pH. Therefore, hydrophobic solvation and urea-backbone hydrogen bonds can play a role in a direct mechanism of urea-induced protein denaturation without contradicting the observed variations in the chemical nature of protein-urea interactions as a function of the acidity of the solution.


Influence of limb alignment on mediolateral loading in total knee replacement: in vivo measurements in five patients.
Malalignment after total knee replacement could cause overloading of the implant bearing as well as of the bone itself, leading to osteolysis and early loosening. To quantify the stresses the implant has to withstand and to define a safe zone of limb alignment, the total contact forces as well as their mediolateral distribution have to be determined. Analytical gait data and mathematical models have been used for this purpose. We performed this study to determine in vivo loads of five patients after implantation of an instrumented tibial baseplate. Five patients with osteoarthritis of the knee received total knee replacement. The tibial component was instrumented with strain gauges for the measurement of three forces and three moments. The signals from the gauges were transferred telemetrically to an external receiver. At twelve months after surgery, postoperative measurements were obtained with the patients walking at a self-selected comfortable speed across a level walkway. Peak axial and medial forces of fifteen to twenty gait cycles were averaged and reported as a percent of individual body weight. During the stance phase of the gait cycle, two maxima of the axial force occurred. Typical values were 215% of body weight at the first peak and 266% of body weight at the second peak. The medial load share was typically 73% at the first axial force peak and 65% at the second axial force peak. Analysis of inter-individual variations revealed a linear correlation with limb alignment. A deviation of 1° varus from neutral alignment increased the medial load share by 5%. Consistent with the results of previous studies, we found that the force transferred by the medial compartment was usually greater than that transferred by the lateral compartment. Concerning the design of total knee replacements, an asymmetric tibial component with a larger medial contact area could possibly reduce peak contact stress on the bone and improve fixation of the implant. Mediolateral load distribution was quantified and correlated with limb alignment, thereby permitting the effects of malalignment after total knee replacement to be estimated.