Wearables for gait and balance assessment in the neurological ward - study design and first results of a prospective cross-sectional feasibility study with 384 inpatients.
Deficits in gait and balance are common among neurological inpatients. Currently, assessment of these patients is mainly subjective. New assessment options using wearables may provide complementary and more objective information. In this prospective cross-sectional feasibility study performed over a four-month period, all patients referred to a normal neurology ward of a university hospital and aged between 40 and 89 years were asked to participate. Gait and balance deficits were assessed with wearables at the ankles and the lower back. Frailty, sarcopenia, Parkinsonism, depression, quality of life, fall history, fear of falling, physical activity, and cognition were evaluated with questionnaires and surveys. Eighty-two percent (n = 384) of all eligible patients participated. Of those, 39% (n = 151) had no gait and balance deficit, 21% (n = 79) had gait deficits, 11% (n = 44) had balance deficits and 29% (n = 110) had gait and balance deficits. Parkinson's disease, stroke, epilepsy, pain syndromes, and multiple sclerosis were the most common diseases. The assessment was well accepted. Our study suggests that the use of wearables for the assessment of gait and balance features in a clinical setting is feasible. Moreover, preliminary results confirm previous epidemiological data about gait and balance deficits among neurological inpatients. Evaluation of neurological inpatients with novel wearable technology opens new opportunities for the assessment of predictive, progression and treatment response markers.


Phylogenic aspects of the amphibian dual olfactory system.
The phylogenic significance of the subdivision of dual olfactory system is reviewed mainly on the basis of our findings by electron microscopy and lectin histochemistry in the three amphibian species. The dual olfactory system is present in common in these species and consists of the projection from the olfactory epithelium (OE) to the main olfactory bulb (MOB) and that from the vomeronasal epithelium (VNE) to the accessory olfactory bulb (AOB). The phylogenic significance of subdivisions in the dual olfactory system in the amphibian must differently be interpreted. The subdivision of the MOB into its dorsal region (D-MOB) and ventral region (V-MOB) in Xenopus laevis must be attributed to the primitive features in their olfactory receptors. The middle cavity epithelium lining the middle cavity of this frog possesses both ciliated sensory cells and microvillous sensory cells, reminding the OE in fish. The subdivision of the AOB into the rostral (R-AOB) and caudal part (C-AOB) in Bufo japonicus formosus must be regarded as an advanced characteristic. The lack of subdivisions in both MOB and AOB in Cynops pyrrhogaster may reflect their phylogenic primitiveness. Since our lectin histochemistry to detect glycoconjugates expressed in the olfactory pathway reveals the subdivisions in the dual olfactory system in the amphibian, the glycoconjugates may deeply participate in the organization and function of olfactory pathways in phylogeny.


Further studies on the effects of ketotifen on guinea pig ileum.
Ketotifen (Ke) at the concentration of 10(-5) M or greater significantly inhibits guinea pig ileum contractions induced by cumulative dose response curves to Pg alpha F2 or BaCl2. This inhibitory effect of Ke is also observable against ileal contractions induced by isotonic and hypertonic solutions with high K+ and by electrical stimulation. In contrast to the long term antihistaminic effect of DSCG and Ke, the latter drug exhibits a shorter inhibitory effect when Ach and electrical stimulation are used to induce ileal contractions shortly after Ke is removed by washing from the organ bath. This nonspecific protective effect of Ke on smooth muscle against various spasmogens resembles the one reported recently by us for DSCG and might be relevant to the antiallergic and antiasthmatic properties of both drugs.


Correlation of self-reported pain severity and healthcare expenditures in older United States adults.
Healthcare expenditures of older United States (US) adults with different pain severity levels are important to investigate given the increasing prevalence of pain in this population. This study assessed the correlation of healthcare expenditures among older US adults with different pain severities, hypothesizing that expenditures would increase as pain severity increased. This retrospective cross-sectional database study used 2018 Medical Expenditure Panel Survey (MEPS) data and included US adults aged ≥50 with self-reported pain in the past four weeks and positive healthcare costs. Adjusted linear regression models with logarithmically transformed expenditure data compared differences in: total; office-based; outpatient; emergency room; inpatient; other; and prescription medication expenditures, between those with little, moderate, quite a bit, and extreme pain. Analyses were weighted to account for the complex MEPS design and to obtain nationally representative estimates. The a priori alpha level was 0.05. The eligible sample of 5,123 individuals produced a weighted study population of 57,134,711 US adults aged ≥50 with pain (little = 53.1%, moderate = 21.6%, quite-a-bit = 18.5%, extreme = 6.8%). In adjusted linear regression models, compared to little pain, extreme pain had the greatest level of costs, followed by quite a bit pain and moderate pain, for total, office-based, and prescription medication costs. For instance, compared to little pain, total healthcare costs were 78% greater for those with extreme pain, 51% greater for quite a bit pain, and 37% greater for moderate pain. However, this pattern was not observed for outpatient, emergency room, inpatient, and other costs, where ≥1 comparison for each cost category was not statistically significant. This study found total healthcare costs increased as pain severity increased, yet this was not always the case when analyzing subcategories of healthcare costs. Further research is needed to investigate why some types of healthcare costs are greater with increasing pain severity, yet others are not.


The intrinsic protein flexibility of endogenous protease inhibitor TIMP-1 controls its binding interface and affects its function.
Protein flexibility is thought to play key roles in numerous biological processes, including antibody affinity maturation, signal transduction, and enzyme catalysis, yet only limited information is available regarding the molecular details linking protein dynamics with function. A single point mutation at the distal site of the endogenous tissue inhibitor of metalloproteinase 1 (TIMP-1) enables this clinical target protein to tightly bind and inhibit membrane type 1 matrix metalloproteinase (MT1-MMP) by increasing only the association constant. The high-resolution X-ray structure of this complex determined at 2 A could not explain the mechanism of enhanced binding and pointed to a role for protein conformational dynamics. Molecular dynamics (MD) simulations reveal that the high-affinity TIMP-1 mutants exhibit significantly reduced binding interface flexibility and more stable hydrogen bond networks. This was accompanied by a redistribution of the ensemble of substrates to favorable binding conformations that fit the enzyme catalytic site. Apparently, the decrease in backbone flexibility led to a lower entropy cost upon formation of the complex. This work quantifies the effect of a single point mutation on the protein conformational dynamics and function of TIMP-1. Here we argue that controlling the intrinsic protein dynamics of MMP endogenous inhibitors may be utilized for rationalizing the design of selective novel protein inhibitors for this class of enzymes.


Complexity of ruminant masticatory evolution.
The evolution of robust jaws, hypsodont teeth, and large chewing muscles among grazing ruminants is a quintessential example of putative morphological adaptation. However, the degree of correlated evolution (i.e., to what extent the grazer feeding apparatus represents an evolutionary module), especially of soft and hard tissues, remains poorly understood. Recent generation of large datasets and phylogenetic information has made testing hypotheses of correlated evolution possible. We, therefore, test for correlated evolution among various traits of the ruminant masticatory apparatus including tooth crown height, jaw robustness, chewing muscle size, and characters of the molar occlusal surfaces, using phylogenetic and nonphylogenetic comparative methods as well as phylogenetic evolutionary model selection. We find that the large masseter muscles of grazing ruminants evolved with the inclusion of grass in the diet, an increase in the proportion of occlusal enamel bands oriented parallel to the chewing stroke, and possibly hypsodonty. We suggest that the masseter evolved under two evolutionary regimes: i) selection for higher masticatory forces during chewing and ii) flattening of the tooth profile, which resulted in reduced tooth guidance and, thus, a requirement for more chewing muscle activity during each chewing stroke, in agreement with previous research. The linear jaw metrics (depth of the mandibular angle, mandibular angle width, and length of the superficial masseteric scar) all show correlated evolution with hypsodonty and the proportion of enamel bands oriented parallel to the chewing stroke. We suggest that changes in the shape of the mandible represent the combined effects of selection for a reorientation of the chewing stroke, so as to emphasize horizontal translation of the teeth, and accommodation of high-crowned teeth. Our analyses show that the ruminant feeding apparatus is an evolutionary mosaic with its various components showing both correlated and independent evolution.


Revisiting Ross and Sims (1971): toward a molecular phylogeny of the Biddulphiaceae and Eupodiscaceae (Bacillariophyceae).
The ocellate and pseudocellate diatoms in the Eupodiscaceae and Biddulphiaceae (respectively) are common inhabitants of the marine littoral (and plankton zone) with a rich fossil history making them important components of marine stratigraphic studies and good candidates for molecular dating work. These diatoms are important for un-derstanding the phylogeny of the diatoms as a whole, as molecular phylogenies have blurred the traditional distinction between the pennate and multipolar non-pennate diatoms. However, the convoluted taxonomic history of these groups has the potential to disrupt both stratigraphic and molecular dating studies. Although efforts have been made to examine frustule morphology of several ocellate and pseudocellate diatoms and develop a morphological scheme to define genera, very little work has been done to determine how these groups are interrelated. In this study, we use nuclear and chloroplast molecular markers to construct a phylogeny of a diverse sampling of Eupodiscaceae and Biddulphiaceae taxa. The ocellus-bearing taxa (Eupodiscaceae) are monophyletic, and thus the ocellus may be a useful character in delimiting the Eupodiscaceae, the Biddulphiaceae are polyphyletic and scattered across a number of lineages of multipolar non-pennate diatoms. Hypothesis testing aimed at assessing the likeliness of several morphology based hypotheses against the molecular data highlights uncertainty in both types of data. We present evidence that there are monophyletic genera within both the Biddulphiaceae and Eupodiscaceae, and recommend the taxa within the Odontella mobilensis/sinensis/regia clade be transferred to a new genus: Trieres Ashworth & Theriot.


Plasma atherogenic indices are independent predictors of slow coronary flow.
Although the pathophysiology of coronary slow flow (CSF) has not been fully elucidated, emerging data increasingly support potential role for subclinical diffuse atherosclerosis in the etiology of CSF. We aimed to investigate relationship between atherogenic indices and CSF. 130 patients with CSF diagnosed according to Thrombolysis in Myocardial Infarction (TIMI)-frame count (TFC) method and 130 controls who had normal coronary flow (NCF) were included in this retrospective study. Atherogenic indices (atherogenic index of plasma [AIP], Castelli risk indices I and II [CRI-I and II]) were calculated using conventional lipid parameters. The logistic regression analyses demonstrated that AIP (OR, 5.463; 95% confidence interval [CI], 1.357-21.991; p = 0.017) and CRI-II (OR, 1.624; 95% CI, 1.138-2.319; p = 0.008) were independent predictors of CSF. Receiver operating characteristic analysis showed that the optimal cutoff value to predict the occurrence of CSF was 0.66 for AIP (sensitivity, 59%; specificity, 73%; area under curve [AUC], 0.695; p < 0.001) and 3.27 for CRI-II (sensitivity, 60%; specificity, 79%; AUC, 0.726; p < 0.001). AIP and CRI-II levels were independent predictors of CSF. Prospective studies in larger cohorts of patients may elucidate the role of atherogenic dyslipidemia in the pathophysiology of CSF.


Serological evidence of pandemic (H1N1) 2009 virus in pigs, West and Central Africa.
Besides birds, pigs are another important reservoir of influenza A viruses that can be transmitted to human, as highlighted by the emergence and spread of the pandemic (H1N1) virus (pdm/09) in 2009. Surveillance in pigs is therefore necessary for public health and influenza pandemic preparedness. Nevertheless, there is a serious lack of data on influenza in Africa, especially in swine. We therefore collected serum samples from pigs in Nigeria (2009, 2012) and Cameroon (2011) in which the presence of anti-influenza A neutralizing antibodies was investigated. Our serological survey suggests that, before the 2009 pandemic, only rare swine and human H3N2 or human H1N1 infections occurred in Nigeria in swine. However, in 2011-2012, 27.4% of pigs in Nigeria and 5.6% in Cameroon had antibodies against H1N1 viruses. Higher antibody titres against pdm/09 suggested that pigs were exposed to this or a similar virus, either by multiple introductions or sustained circulation, and that reactivity against American and European swine H1N1 viruses resulted from cross-reaction.


Complete nucleotide sequence of tobacco necrosis virus strain DH and genes required for RNA replication and virus movement.
The complete genome sequence of tobacco necrosis virus strain D (Hungarian isolate, TNV-DH) was determined. The genome (3762 nt) has an organization identical to that reported for TNV-D. Highly infectious synthetic transcripts from a full-length TNV-DH cDNA clone were prepared, the first infectious necrovirus transcript reported. This clone was used for reverse genetic studies to map the viral genes required for replication and movement. Protoplast inoculation with delta 22 and delta 82 mutants revealed that both the 22 kDa and 82 kDa gene products are required for RNA replication. Although the products of three small central genes (p7(1), p7a and p7b) were not essential for RNA replication in protoplasts, mutations in these ORFs prevented infection of plants. In contrast, viral RNA accumulation and cell-to-cell movement were observed in the inoculated, but not the systemically infected, leaves of Nicotiana benthamiana challenged with RNA lacking the intact coat protein (CP) gene. These results strongly suggest that p7(1), p7a, p7b and CP are involved in TNV-DH cell-to-cell and long-distance movement, respectively.


A cognitive-existential intervention to improve existential and global quality of life in cancer patients: A pilot study.
We developed a specific cognitive-existential intervention to improve existential distress in nonmetastatic cancer patients. The present study reports the feasibility of implementing and evaluating this intervention, which involved 12 weekly sessions in both individual and group formats, and explores the efficacy of the intervention on existential and global quality of life (QoL) measures. Some 33 nonmetastatic cancer patients were randomized between the group intervention, the individual intervention, and the usual condition of care. Evaluation of the intervention on the existential and global QoL of patients was performed using the existential well-being subscale and the global scale of the McGill Quality of Life (MQoL) Questionnaire. All participants agreed that their participation in the program helped them deal with their illness and their personal life. Some 88.9% of participants agreed that this program should be proposed for all cancer patients, and 94.5% agreed that this intervention helped them to reflect on the meaning of their life. At post-intervention, both existential and psychological QoL improved in the group intervention versus usual care (p = 0.086 and 0.077, respectively). At the three-month follow-up, global and psychological QoL improved in the individual intervention versus usual care (p = 0.056 and 0.047, respectively). This pilot study confirms the relevance of the intervention and the feasibility of the recruitment and randomization processes. The data strongly suggest a potential efficacy of the intervention for existential and global quality of life, which will have to be confirmed in a larger study.


Does sleep restore the topology of functional brain networks?
Previous studies have shown that healthy anatomical as well as functional brain networks have small-world properties and become less optimal with brain disease. During sleep, the functional brain network becomes more small-world-like. Here we test the hypothesis that the functional brain network during wakefulness becomes less optimal after sleep deprivation (SD). Electroencephalography (EEG) was recorded five times a day after a night of SD and after a night of normal sleep in eight young healthy subjects, both during eyes-closed and eyes-open resting state. Overall synchronization was determined with the synchronization likelihood (SL) and the phase lag index (PLI). From these coupling strength matrices the normalized clustering coefficient C (a measurement of local clustering) and path length L (a measurement of global integration) were computed. Both measures were normalized by dividing them by their corresponding C-s and L-s values of random control networks. SD reduced alpha band C/C-s and L/L-s and theta band C/C-s during eyes-closed resting state. In contrast, SD increased gamma-band C/C-s and L/L-s during eyes-open resting state. Functional relevance of these changes in network properties was suggested by their association with sleep deprivation-induced performance deficits on a sustained attention simple reaction time task. The findings indicate that SD results in a more random network of alpha-coupling and a more ordered network of gamma-coupling. The present study shows that SD induces frequency-specific changes in the functional network topology of the brain, supporting the idea that sleep plays a role in the maintenance of an optimal functional network.


Routine serial computed tomographic scans in mild traumatic brain injury: when are they cost-effective?
Most case series involving routine serial computed tomography (CT) scans of the head in patients with mild traumatic brain injury (TBI) have suggested that they only occasionally provide useful information and imply that the practice is unnecessary and wasteful. No study has looked at the special case in which the initial scan revealed an intracranial abnormality which did not require surgery. We performed a structured review of the literature for the probabilities and costs of various outcomes in patients with mild TBI who demonstrate at least one intracranial abnormality on their admission CT scans. We supplemented this data with additional information from a large database of mild TBI patients. We then constructed a decision-analytic model to calculate costs and outcomes, comparing the strategy of routine serial scanning with that of awaiting clinical deterioration before repeating the study (expectant strategy). For the 20-year-old patient, the routine CT strategy is slightly more effective than the expectant strategy and is also only slightly more expensive. With advancing age, the relative cost-effectiveness of routine CT declines. Awaiting clinical deterioration in patients with mild TBI whose first CT scan reveals intracranial injury is not cost-effective compared with routine follow-up CT scans. Although the difference is not statistically significant, routine follow-up scanning is slightly more cost-effective, especially in younger patients.


Neighbourhood risk factors of recurrent tuberculosis in Cape Town: a cohort study using geocoded notification data.
Individuals with a history of tuberculosis (TB) disease are at higher risk of developing a subsequent episode than those without. Considering the role of social and environmental factors in tuberculosis, we assessed neighbourhood-level risk factors associated with recurrent tuberculosis in Cape Town, South Africa. This cohort consisted of patients who completed treatment for their first drug-sensitive TB episode between 2003 and 2015. Addresses were geocoded at neighbourhood level. Data on neighbourhood-level factors were obtained from the Census 2011 (household size, population density) and the City of Cape Town (Socio-Economic Index). Neighbourhood-level TB burden was calculated annually by dividing the number of notified TB episodes by the population in that neighbourhood. Multilevel survival analysis was performed with the outcome recurrent TB, defined as a second episode of TB, and controlling for individual-level risk factors (age, gender and time since first episode in years). Follow-up ended at the second episode, or on 31 December 2015, whichever came first. The study included 173 421 patients from 700 neighbourhoods. Higher Socio-Economic Index was associated with a lower risk of recurrence compared with average Socio-Economic Index. An increased risk was found for higher household size and TB burden, with an increase of 20% for every additional person in mean household size and 10% for every additional TB episode/100 inhabitants. No association was found with population density. Recurrent TB was associated with increased household size and TB burden at neighbourhood level. These findings could be used to target TB screening activities.


Initial dynamics of the Norrish Type I reaction in acetone: probing wave packet motion.
The Norrish Type I reaction in the S(1) (nπ*) state of acetone is a prototype case of ketone photochemistry. On the basis of results from time-resolved mass spectrometry (TRMS) and photoelectron spectroscopy (TRPES) experiments, it was recently suggested that after excitation the wave packet travels toward the S(1) minimum in less than 30 fs and stays there for more than 100 picoseconds [Chem. Phys. Lett.2008, 461, 193]. In this work we present simulated TRMS and TRPES signals based on ab initio multiple spawning simulations of the dynamics during the first 200 fs after excitation, getting quite good agreement with the experimental signals. We can explain the ultrafast decay of the experimental signals in the following manner: the wave packet simply travels, mainly along the deplanarization coordinate, out of the detection window of the ionizing probe. This window is so narrow that subsequent revival of the signal due to the coherent deplanarization vibration is not observed, meaning that from the point of view of the experiment the wave packets travels directly to the S(1) minimum. This result stresses the importance of pursuing a closer link to the experimental signal when using molecular dynamics simulations in interpreting experimental results.


Effect of castor oil emulsion eyedrops on tear film composition and stability.
An emulsion eyedrop containing castor oil has been shown to modify the tear film lipid layer and increase tear film stability. The primary objectives of this investigation were to measure the prevalence of castor oil in the tear fluid over time and quantify the effects on the lipid layer. A secondary objective was to quantify the initial effects on ocular symptomatology. The investigation was an open label pilot study on 5 normal and 10 dry eye subjects. A single eyedrop (Castor oil emulsion, Allergan) was instilled in each eye; the tear film appearance and composition were monitored for 4h via in vivo visualisation using the Tearscope and post in vivo tear samples analysis by HPLC. Combined results for both normal and dry eye subjects showed that castor oil was detected up to 4h after a single eyedrop instillation and associated with an increase in the level of tear film lipid. The relative amount of various lipid families was also changed. An increase in tear lipid layer thickness was significant up to one hour post-instillation for the symptomatic sub-population. The changes in tear film characteristics were associated with significantly lower symptoms up to four hours post-instillation for the symptomatic sub-population. This pilot investigation showed that castor oil eyedrops achieved a residence time of at least four hours post-instillation, producing a more stable tear film and an associated significant decrease in ocular symptoms over the entire follow-up period for the symptomatic subjects.


A decision tool for predicting sentinel node accuracy from breast tumor size and grade.
The ability to predict axillary lymph node involvement in breast cancer patients in the preoperative setting is invaluable. This study provides a simple set of formulae to enable clinicians to make informed decisions in the management of screen-detected breast cancer. The tumor pathology reports were obtained of all 4,585 women identified between 1996 and 1999 in New South Wales (NSW) with T1 or T2 breast cancer by the statewide co-ordinated breast screening service (BreastScreen NSW). Equations predicting node positivity were calculated by linear regression analysis and, from published sentinel node false-negative rates, the probability of retrieval of a false-negative axillary lymph node by sentinel node biopsy was calculated for tumors of different size and grade. Node involvement was identified in 1,089 (23.8%) of women. A linear relationship for tumor size, grade, and nodal involvement was predicted by: frequency (%) = 1.5 x tumor size (mm) + 2 (or 6 or 10) for grade I (or II or III) tumors. Assuming a 7.5% false-negative rate, the probability of retrieving a false-negative sentinel node ranged from 0.8% for a patient with a 5 mm, grade I carcinoma to 6.0% for a 50 mm, grade III tumor. These simple formulae are easy to use in a clinical setting. The reference table enables breast surgeons to inform a patient about the absolute probability of false-negative sentinel biopsy rates for patients with screen-detected carcinomas when size can be estimated from preoperative imaging and when tumor grade is often available from preoperative core biopsy. Patients with large, T2 breast tumors may be best treated with axillary dissection rather than sentinel node biopsy alone due to the risk of under-staging the woman's disease and also the high probability of finding a positive sentinel node.


Risk of mortality: the relationship with associated injuries and fracture treatment methods in patients with unilateral or bilateral femoral shaft fractures.
The aim of the study was to determine the relative contributions to mortality of a unilateral or a bilateral femoral fracture in patients with or without injuries to other body regions. An observational cohort study of the prospectively recorded England and Wales Trauma Registry data (Trauma Audit Research Network) from 1989 to 2003. Patients were divided into the following groups: UFi (isolated unilateral femur injury), BFi (isolated bilateral femur injury), and UFa and BFa, if an associated injury was present. Injury and treatment data were collected for each patient. Logistic regression data analysis was performed to determine variables that were associated with increased mortality. Patients in group BFa had an increased mortality rate (31.6% vs. 9.8%) than patients in isolated bilateral femur injury group. Group BFa patients had an increased number of associated injuries (80%) than group UFa patients. Bilateral fracture, even in isolation, significantly increased the odds of mortality by 3.07. Intramedullary nailing was the method of fracture fixation associated with the lowest patient mortality overall. When assessing patient mortality in the BFa group with an New Injury Severity Score of >40, seven other fracture fixation regimens were associated with a lower mortality. The increase in mortality with BFs is more closely associated with the presence of associated injuries and poor physiologic parameters than with the presence of the BF alone. The presence of BFs should alert the clinician to the very high likelihood (80%) of significant associated injuries in other body systems and their life-threatening potential. Damage control fixation options should be considered in the subgroup with a very high New Injury Severity Score.


[Farewell to the intra-aortic balloon pump?].
The intra-aortic balloon pump (IABP) has been a reliable friend in the catheterization laboratory and operating room. This good old friend of the cardiologist and cardiothoracic surgeon is about to disappear from the clinical scene. For more than 5 decades, it has largely been deployed for acute myocardial infarction and cardiogenic shock. Its more recent failure to demonstrate efficacy for cardiogenic shock will herald its demise. It may not disappear completely but its usage will become extremely limited. The lesson we have learned from the IABP history and other therapies is that we should never trust surrogate endpoints such as cardiac (power) output when it comes to cardiogenic shock. Newer devices should be tested in properly randomized controlled clinical trials before worldwide adoption.


The influence of prostate volume on pathological outcomes after radical prostatectomy: A single-center retrospective study.
Currently, the association between prostate volume (PV) or prostate weight with pathological outcomes in patients with prostate cancer (PCa) is not well understood. This study aimed to explore whether PV can predict the adverse pathological outcomes of PCa patients after radical prostatectomy (RP). A total of 1063 men with confirmed localized PCa who underwent RP at the First Affiliated Hospital of Zhejiang University from January 2014 to April 2019 were retrospectively analyzed. Patients were assigned into small, medium and large groups based on the PV. The analysis of variance, χ2 test or Student t test was performed to compare differences among groups. Univariate and multivariate analyses were performed to identify significant predictors of pathological outcomes upgrading. Among the 1063 cases, approximately 35.0% had an upgrade of postoperative pathology. Compared with the small prostate group, more patients in the large prostate group achieved a Gleason score (GS) 6 and International Society of Urological Pathology (ISUP) grade 1 of postoperative pathological findings, clinical cT1c and cT2a stages and pathological pT2a and pT2b stages; the incidence of positive surgical margins and extraprostatic extension was relatively low (all P < .001). In multiple logistic regression, PV served as a significant predictor of any Gleason score upgrading (GSU) (odds ratio [OR] 0.988, 95% confidence interval [CI] 0.978-0.998), major GSU (OR 0.980, 95% CI 0.965-0.995) and any ISUP grade group upgrading (GGU) (OR 0.989, 95% CI 0.979-0.999). This study shows that PV can predict adverse pathological outcomes in PCa patients after radical prostatectomy. Pca patients with smaller prostate volume tend to have the high-grade disease at postoperative pathology as well as pathological outcome upgrading.


MLV-10A1 retrovirus pseudotype efficiently transduces primary human CD4+ T lymphocytes.
Previously, we showed that retroviral vectors pseudotyped with the envelope of the amphotropic murine leukemia virus 10A1 (MLV-10A1) more efficiently transduce primary human CD8+ T lymphocytes when compared with other A-MLV, gibbon ape leukemia virus (GaLV) and feline endogenous retrovirus (RD114) vector pseudotypes. For the success of several gene therapeutic approaches (ADA, HIV) it is important to effectively transduce primary human CD4+ T lymphocytes. We have used retroviral vectors encoding the enhanced green fluorescent protein (EGFP) as a marker gene and carrying envelopes of MLV-10A1, A-MLV and GaLV and have analyzed the transduction efficiency of both human CD4+ T cell lines (CEM, H9, HUT78, J16) and primary human CD4+ T lymphocytes using a RetroNectin-assisted transduction protocol and virus-containing supernatant. In CD4+ T cell lines the MLV-10A1 vector pseudotype was most effective and infected up to 85% of cells which then stably expressed GFP over time. MLV-10A1 was also superior and infected approximately 32% of primary human CD4+ T lymphocytes in comparison to GaLV (18%) and A-MLV (12%). The superior efficiency of MLV-10A1 for the transduction of CD4+ T cells correlates with the longer half-life of this pseudotype in comparison to A-MLV and, as previously shown by interference analysis, with the usage of both the A-MLV (Pit2) and the GaLV receptor (Pitl) for cell entry. MLV-10A1 is a suitable vector for transferring genes with high efficacy into primary human CD4+ T lymphocytes. The use of MLV-10A1 pseudotyped vectors should make it easier to obtain a sufficient number of gene-modified T lymphocytes for an adoptive transfer.


Corn or sorghum wet distillers grains with solubles in combination with steam-flaked corn: in vitro fermentation and hydrogen sulfide production.
The effects of wet distillers grains with solubles (WDG) on in vitro rate of gas production, IVDMD, H(2)S production, and VFA were evaluated. Five substrate treatments that were balanced for ether extract content were arranged in a 2 x 2 + 1 factorial. Factors were concentration (15 or 30%; DM basis) and source of WDG (corn or sorghum WDG; CDG and SDG, respectively) plus a 0% WDG control in substrates with steam-flaked corn as the basal grain. Control substrates had greater (P < 0.01) IVDMD and total gas production per gram of substrate DM than WDG-based substrates, and IVDMD was greater (P = 0.03) for CDG than for SDG substrates. Increasing WDG inclusion from 15 to 30% decreased IVDMD and total gas production (P < 0.05), but H(2)S production (micromol/g of fermentable DM) increased (P = 0.01) as inclusion of WDG increased. There were no differences (P > or = 0.10) among treatments in proportions of major VFA, acetate:propionate ratio, and total VFA concentration. These results suggest that including WDG in the substrate decreased IVDMD and gas production, which was particularly evident as WDG increased from 15 to 30% of substrate DM. In addition, CDG seemed to be more digestible than SDG. Hydrogen sulfide production increased with increasing WDG in the substrate, reflecting greater S concentrations in WDG, but in vitro VFA profiles were not affected by WDG concentration or source.


Insect juvenile hormone binding protein shows ancestral fold present in human lipid-binding proteins.
Low molecular weight juvenile hormone binding proteins (JHBPs) are specific carriers of juvenile hormone (JH) in the hemolymph of butterflies and moths. As hormonal signal transmitters, these proteins exert a profound effect on insect development. The crystal structure of JHBP from Galleria mellonella shows an unusual fold consisting of a long alpha-helix wrapped in a highly curved antiparallel beta-sheet. JHBP structurally resembles the folding pattern found in tandem repeats in some mammalian lipid-binding proteins, with similar organization of one cavity and a disulfide bond between the long helix and the beta-sheet. JHBP reveals, therefore, an archetypal fold used by nature for hydrophobic ligand binding. The JHBP molecule possesses two hydrophobic cavities. Several lines of experimental evidence conclusively indicate that JHBP binds JH in only one cavity, close to the N- and C-termini, and that this binding induces a structural change. The second cavity, located at the opposite end of the molecule, could bind another ligand.


EGF and PDGF receptor tyrosine kinases as therapeutic targets for chronic lung diseases.
Cell-surface receptor tyrosine kinases play pivotal roles in development, tissue repair, and normal cellular homeostasis. Aberrant expression or signaling patterns of these kinases has also been linked to the progression of a diversity of diseases, including cancer, atherosclerosis, asthma, and fibrosis. Two major families of receptor tyrosine kinases, the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) families, have received a great deal of attention as potential therapeutic targets for pulmonary diseases, as these receptors have been shown to play key roles in chronic tissue remodeling in asthma, bronchitis, and pulmonary fibrosis. The EGFR system on epithelial cells and underlying mesenchymal cells (fibroblasts, myofibroblasts, and smooth muscle cells) drives numerous phenotypic changes during the progression of these pulmonary diseases, including epithelial cell mucous cell metaplasia and mesenchymal cell hyperplasia, differentiation, and extracellular matrix production. The PDGFR system, located primarily on mesenchymal cells, transduces signals for cell survival, growth and chemotaxis. The variety of EGFR and PDGFR ligands produced by the airway epithelium or adjacent mesenchymal cells allows for intimate epithelial-mesenchymal cell communication. A full understanding of the complex mechanisms involving these receptors and ligands should lead to therapeutic strategies for the treatment of a wide range of fibroproliferative lung diseases.


The reduction of alpha-tocopherolquinone by human NAD(P)H: quinone oxidoreductase: the role of alpha-tocopherolhydroquinone as a cellular antioxidant.
alpha-Tocopherolquinone (TQ), a product of alpha-tocopherol oxidation, can function as an antioxidant after reduction to alpha-tocopherolhydroquinone (TQH2). We examined the ability of human NAD(P)H:quinone oxidoreductase (NQO1) to catalyze the reduction of TQ to TQH2 in cell-free and cellular systems. In reactions with purified human NQO1, TQ was reduced to TQH2. Kinetic parameters for the reduction of TQ by NQO1 (Km = 370 microM; k(cat) = 5.6 x 10(3) min(-1); k(cat)/Km = 15 min(-1) x microM(-1)) indicate that NQO1 can efficiently reduce TQ to TQH2. A comparison of the rate of reduction of TQ and coenzyme Q10 by NQO1 showed that TQ is reduced more efficiently than coenzyme Q10. Experiments with either Chinese hamster ovary (CHO) cells stably transfected with human NQO1 or CHO cell sonicates demonstrated a correlation between NQO1 activity and TQ reduction to TQH2. CHO cells with elevated NQO1 generated and maintained higher levels of TQH2 after treatment with TQ relative to NQO1-deficient CHO cells. TQH2 generated from NQO1-mediated reduction of TQ prevented cumene hydroperoxide-induced lipid peroxidation in rat liver microsomes. In addition, cumene hydroperoxide-induced lipid peroxidation was inhibited more efficiently by TQ in CHO cell lines with elevated NQO1 activity. These data demonstrate that NQO1 can reduce TQ to TQH2 and that TQH2 can function as an efficient antioxidant. This work suggests that one of the physiological functions of NQO1 may be to regenerate antioxidant forms of alpha-tocopherol.


[Results of urolithiasis treatment in pilots with the use of a new domestic lithotripter "Kompakt" during remote lithotripsy].
Results of treating urolithiasis in pilots on new Russian lithotriptor Kompakt were analyzed. Length of the shock-wave pulse is 0.3-0.4 microsecond w/o the negative phase prevents damaging of the kidney tissue. Urolithiasis was treated in 45 pilots in 69 ESWL sessions: 6.2 concrements, mostly in calyces renales (95.6% of the patients), were crushed. In more than 30% of the patients concrements were no larger than 5 mm and in 66.7% of the patients they were X-ray negative (urate). Concrements were crushed in all 45 patients into fine-dyspersated fragments (< 3 mm). At no time after ESWL complications or secretory-excretory dysfunctions of kidneys were observed. In-hospital examination following 1.5-2 mos. since ESWL did not detect residual fragments in urinary tracts of the pilots. No renal or any other pathologies were found. All the patients were admitted to flight.


The interaction of RNA helicase DDX3 with HIV-1 Rev-CRM1-RanGTP complex during the HIV replication cycle.
Molecular traffic between the nucleus and the cytoplasm is regulated by the nuclear pore complex (NPC), which acts as a highly selective channel perforating the nuclear envelope in eukaryotic cells. The human immunodeficiency virus (HIV) exploits the nucleocytoplasmic pathway to export its RNA transcripts across the NPC to the cytoplasm. Despite extensive study on the HIV life cycle and the many drugs developed to target this cycle, no current drugs have been successful in targeting the critical process of viral nuclear export, even though HIV's reliance on a single host protein, CRM1, to export its unspliced and partially spliced RNA transcripts makes it a tempting target. Due to recent findings implicating a DEAD-box helicase, DDX3, in HIV replication and a member of the export complex, it has become an appealing target for anti-HIV drug inhibition. In the present research, we have applied a hybrid computational protocol to analyze protein-protein interactions in the HIV mRNA export cycle. This method is based on molecular docking followed by molecular dynamics simulation and accompanied by approximate free energy calculation (MM/GBSA), computational alanine scanning, clustering, and evolutionary analysis. We highlight here some of the most likely binding modes and interfacial residues between DDX3 and CRM1 both in the absence and presence of RanGTP. This work shows that although DDX3 can bind to free CRM1, addition of RanGTP leads to more concentrated distribution of binding modes and stronger binding between CRM1 and RanGTP.


Expanded inverted repeat region with large scale inversion in the first complete plastid genome sequence of Plantago ovata.
Plantago ovata (Plantaginaceae) is an economically and medicinally important species, however, least is known about its genomics and evolution. Here, we report the first complete plastome genome of P. ovata and comparison with previously published genomes of related species from Plantaginaceae. The results revealed that P. ovata plastome size was 162,116 bp and that it had typical quadripartite structure containing a large single copy region of 82,084 bp and small single copy region of 5,272 bp. The genome has a markedly higher inverted repeat (IR) size of 37.4 kb, suggesting large-scale inversion of 13.8 kb within the expanded IR regions. In addition, the P. ovata plastome contains 149 different genes, including 43 tRNA, 8 rRNA, and 98 protein-coding genes. The analysis revealed 139 microsatellites, of which 71 were in the non-coding regions. Approximately 32 forward, 34 tandem, and 17 palindromic repeats were detected. The complete genome sequences, 72 shared genes, matK gene, and rbcL gene from related species generated the same phylogenetic signals, and phylogenetic analysis revealed that P. ovata formed a single clade with P. maritima and P. media. The divergence time estimation as employed in BEAST revealed that P. ovata diverged from P. maritima and P. media about 11.0 million years ago (Mya; 95% highest posterior density, 10.06-12.25 Mya). In conclusion, P. ovata had significant variation in the IR region, suggesting a more stable P. ovata plastome genome than that of other Plantaginaceae species.


Impact of solar ultraviolet-B on the proteome in soybean lines differing in flavonoid contents.
Two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) was used to systematically investigate the impact of solar ultraviolet-B (UV-B) radiation on the soybean leaf proteome. In order to investigate the protective role of flavonoids against UV-B, two isolines of the Clark cultivar (the standard line with moderate levels of flavonoids and the magenta line with reduced flavonoids) were grown in the field with or without natural levels of UV-B. The 12-day-old first trifoliates were harvested for proteomic analysis. More than 300 protein spots were reproducibly resolved and detected on each gel. Statistical analysis showed that 67 protein spots were significantly (P<0.05) affected by solar UV-B. Many more spots were altered by UV-B in the magenta line than in the standard line. Another 12 protein spots were not altered by UV-B but showed significantly (P<0.05) different accumulations between the two lines, and for most spots the line-specific differences were also observed under UV-B exclusion. Most of the differentially accumulated spots were identified by mass spectrometry. The proteins were quite diverse, and were involved in metabolism, energy, protein destination/storage, protein synthesis, disease/defense, transcription, and secondary metabolism. The results suggest that high levels of flavonoids lead to a reduction in UV-B sensitivity at the proteomic level.


Non-extraction treatment of a thirteen-year-old boy with a Class III skeletal discrepancy and severe crowding in both the upper and lower dentitions.
A thirteen-year-old boy presented with a Class III skeletal tendency in association with severe crowding in both the upper and lower arches. Whilst there was not a frank posterior crossbite, it was felt that the upper arch was narrow and that the lower arch was similarly constricted. Taking this into account along with the fact that his upper lip was flat and the nasolabial angle obtuse, it was decided to pursue a non-extraction treatment, with the aim of providing by expansion an extra 16 mm of space in the upper arch and 8 mm in the lower arch to accommodate the full dentition, and with a view to extracting third molar teeth later. This proved to be successful, albeit over an extended period of time, with active treatment taking nearly three and a half years. A realistic alternative would have been to remove four bicuspid teeth and pursue an orthodontic/surgical approach to treatment. In retrospect, and with the benefit of reviewing his records without surgical intervention, the treatment plan decided upon has been well justified.


Deriving Convergent and Divergent Metabolomic Correlates of Pulmonary Arterial Hypertension.
High-dimensional metabolomics analyses may identify convergent and divergent markers, potentially representing aligned or orthogonal disease pathways that underly conditions such as pulmonary arterial hypertension (PAH). Using a comprehensive PAH metabolomics dataset, we applied six different conventional and statistical learning techniques to identify analytes associated with key outcomes and compared the results. We found that certain conventional techniques, such as Bonferroni/FDR correction, prioritized metabolites that tended to be highly intercorrelated. Statistical learning techniques generally agreed with conventional techniques on the top-ranked metabolites, but were also more inclusive of different metabolite groups. In particular, conventional methods prioritized sterol and oxylipin metabolites in relation to idiopathic versus non-idiopathic PAH, whereas statistical learning methods tended to prioritize eicosanoid, bile acid, fatty acid, and fatty acyl ester metabolites. Our findings demonstrate how conventional and statistical learning techniques can offer both concordant or discordant results. In the case of a rare yet morbid condition, such as PAH, convergent metabolites may reflect common pathways to shared disease outcomes whereas divergent metabolites could signal either distinct etiologic mechanisms, different sub-phenotypes, or varying stages of disease progression. Notwithstanding the need to investigate the mechanisms underlying the observed results, our main findings suggest that a multi-method approach to statistical analyses of high-dimensional human metabolomics datasets could effectively broaden the scientific yield from a given study design.


Pathogenic Functions of Tumor Necrosis Factor Receptor-Associated Factor 6 Signaling Following Traumatic Brain Injury.
Neuroinflammation contributes to delayed (secondary) neurodegeneration following traumatic brain injury (TBI). Tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling may promote post-TBI neuroinflammation, thereby exacerbating secondary injury. This study investigated the pathogenic functions of TRAF6 signaling following TBI in vivo and in vitro. A rat TBI model was established by air pressure contusion while lipopolysaccharide (LPS) exposure was used to induce inflammatory-like responses in cultured astrocytes. Model rats were examined for cell-specific expression of TRAF6, NF-κB, phosphorylated (p)-NF-κB, MAPKs (ERK, JNK, and p38), p-MAPKs, chemokines (CCL2 and CXCL1), and chemokine receptors (CCR2 and CXCR2) by immunofluorescence, RT-qPCR, western blotting, and ELISA, for apoptosis by TUNEL staining, and spatial cognition by Morris water maze testing. These measurements were compared between TBI model rats receiving intracerebral injections of TRAF6-targeted RNAi vector (AAV9-TRAF6-RNAi), empty vector, MAPK/NF-κB inhibitors, or vehicle. Primary astrocytes were stimulated with LPS following TRAF6 siRNA or control transfection, and NF-κB, MAPKs, chemokine, and chemokine receptor expression levels evaluated by western blotting and ELISA. TRAF6 was expressed mainly in astrocytes and neurons of injured cortex, peaking 3 days post-TBI. Knockdown by AAV9-TRAF6-RNAi improved spatial learning and memory, decreased TUNEL-positive cell number in injured cortex, and downregulated expression levels of p-NF-κB, p-ERK, p-JNK, p-p38, CCL2, CCR2, CXCL1, and CXCR2 post-TBI. Inhibitors of NF-κB, ERK, JNK, and p38 significantly suppressed CCL2, CCR2, CXCL1, and CXCR2 expression following TBI. Furthermore, TRAF6-siRNA inhibited LPS-induced NF-κB, ERK, JNK, p38, CCL2, and CXCL1 upregulation in cultured astrocytes. Targeting TRAF6-MAPKs/NF-κB-chemokine signaling pathways may provide a novel therapeutic approach for reducing post-TBI neuroinflammation and concomitant secondary injury.


[Acute hepatitis associated with Colpachi intake. Apropros of 5 cases].
The use of herbal medicines believed to have therapeutic properties is becoming increasingly widespread. These medicines are usually taken by patients on their own initiative and physicians are often unaware of which patients are taking these substances. Herbal medicines can be taken in the form of teas, powders, and liquid extracts. In the last few years, it has come to light that these natural remedies are not free of risks, especially the risk of interaction with other drugs or hepatotoxicity, ranging from asymptomatic forms to massive hepatic necrosis. We describe a series of 5 patients notified to the Spanish Pharmacovigilance System of medicinal products for human use. All the patients developed acute hepatitis during Colpachi treatment lasting several months, which resolved after discontinuing intake of this substance. Systematic examination of the literature revealed the existence of 6 other reported cases of suspected Colpachi-induced hepatotoxicity.


Risk factors for cancer of the oesophagus in Kerala, India.
A case-control study of oesophageal cancer was carried out in Trivandrum, Kerala, involving 267 cases and 895 controls. Risk factors studied in males were pan (betel)-tobacco chewing, bidi and cigarette smoking, drinking alcohol and taking snuff. Only pan-tobacco chewing was investigated in females as very few indulged in the other habits. Among males significant associations with higher risk were observed for bidi smoking (p less than 0.001), bidi plus cigarette smoking (p greater than 0.05) and drinking alcohol (p less than 0.001). While a significant effect of duration of pan-tobacco chewing (p less than 0.005) was observed in males, there was no significant trend, the risk first falling then rising as duration of use increased. This was partly due to confounding with smoking. No effect of pan-tobacco use was observed in females. A step-wise model was fitted, retaining only those risk factors which were significant when adjusted for other factors; the risk factors included were duration of pan-tobacco chewing, duration of bidi smoking, daily frequency of bidi and cigarette smoking and alcohol use (yes or no). An adjusted relative risk of 2.03 was observed for a pan-tobacco habit of more than 40 years' duration, of 4.70 for more than 20 years of bidi smoking, of 4.80 for more than 20 bidis/cigarettes per day, and of 2.33 for regular alcohol use (in each category relative to a baseline of those never indulging in the relevant habit).


Large porous particles for pulmonary drug delivery.
A new type of inhalation aerosol, characterized by particles of small mass density and large size, permitted the highly efficient delivery of inhaled therapeutics into the systemic circulation. Particles with mass densities less than 0.4 gram per cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs' natural clearance mechanisms until the inhaled particles delivered their therapeutic payload. Inhalation of large porous insulin particles resulted in elevated systemic levels of insulin and suppressed systemic glucose levels for 96 hours, whereas small nonporous insulin particles had this effect for only 4 hours. High systemic bioavailability of testosterone was also achieved by inhalation delivery of porous particles with a mean diameter (20 micrometers) approximately 10 times that of conventional inhaled therapeutic particles.


Managed care, networks and trends in hospital care for mental health and substance abuse treatment in Massachusetts: 1994-1999.
Rates of inpatient care for mental health and substance abuse treatment have been reported to fall after the introduction of managed care, but the actual decline may be overstated. Almost all managed care impact studies are based on pre-post comparisons, which have two drawbacks: secular downward trends may be attributed to a managed care effect and self-selection may exaggerate the impact of managed care. Therefore it is useful to examine long-term population-based trends in use associated with the growth of managed care. This paper examines trends in inpatient care for mental health and substance abuse treatment in Massachusetts between 1994 and 1999 by service provider and payer. We analyze how managed care impacts the trends in mental health and substance abuse care. We provide an overview of the health market in Massachusetts and compare trends in mental health and substance abuse services with all inpatient services. To analyze the impact of managed care, we compare the per discharge cost of managed care and fee for service plans in Medicare and Medicaid. Finally, we examine the role played by hospital networks in managed care. The reduction in service costs for mental health and substance abuse, about 25% in six years, is mostly due to the decline in the average cost per inpatient episode. This is only slightly greater than the decline in costs for all inpatient care. Managed care has reduced both the quantity (average length of stay) and intensity of health care (expenditure per day). Simulations suggest that the creation of hospital networks by managed care accounts for around 50% of the differential between the average costs of the HMO and FFS sectors. We find that the cost reductions in mental health and substance abuse services are larger than for physical health, but not by much. The average length of stay and average day cost is lower for managed care plans than for FFS plans, and much of this difference is attributable to the hospitals managed care plans select to participate in their networks. The data are limited to inpatient discharges from Massachusetts and therefore our conclusions may not be readily extended to other places. Furthermore, our analysis is based on the estimated cost rather than the actual payments to hospitals. IMPLICATION FOR HEALTH CARE PROVISION AND USE: The analysis highlights the importance of hospital selection and networks in affecting the cost of care. Contrary to popular belief, the analysis shows that the experience of mental health and substance abuse and non-mental health and substance abuse services is similar. Creation of networks is an important strategy in managed care. This paper provides the groundwork for extending the analysis to areas with market characteristics different to those of Massachusetts. Further research should focus on the long-term trends in health outcomes between managed care and fee for service patients.


The use of complementary and alternative medicine among hypertensive and type 2 diabetic patients in Western Jamaica: A mixed methods study.
The simultaneous or intermittent use of alternative treatments and prescription medications for hypertension and type 2 diabetes mellitus can have adverse health effects. To identify beliefs and practices associated with the use of alternative treatments for hypertension and type 2 diabetes mellitus among patients. A mixed-methods study including an investigator-administered survey and focus group discussion sessions using convenience sampling was conducted among patients aged ≥18 years during May to August 2018. Descriptive statistics were used to describe and compare demographic characteristics among groups of survey participants using JMP Pro 14.0. Thematic analysis was conducted to analyze the qualitative data using NVivo. Most study participants (87-90%) were on prescription medication for their condition. Of survey participants, 69% reported taking their medication as prescribed and 70% felt that prescription medicine was controlling their condition. Almost all participants (98%) reported using alternative treatments, mainly herbal medications, and 73-80% felt that herbal medicines controlled their conditions. One-third believed that herbal medicines are the most effective form of treatment and should always be used instead of prescription medication. However, most participants (85%) did not believe that prescription and herbal treatments should be used simultaneously. Most (76-90%) did not discuss herbal treatments with their healthcare providers. Four themes emerged from the focus group sessions: 1) Simultaneous use of herbal and prescription medicine was perceived to be harmful, 2) Patients did not divulge their use of herbal medicine to healthcare providers, 3) Alternative medicines were perceived to be highly effective, and 4) Religiosity and family elders played key roles in herbal use. This study provides useful insights into perceptions and use of alternative treatments by patients that can be used by healthcare providers in developing appropriate interventions to encourage proper use of prescription medicines and alternative medicines resulting in improved management of these chronic diseases.


A Cadaveric Study of Splenic Fissures and Bilobed Spleen.
Anatomical knowledge regarding the external morphology of the spleen is essential for surgical intervention and radiological diagnosis. A characteristic feature of the spleen is the presence of splenic notches at the superior border; however, such notches rarely extend deep enough to be considered fissures or to separate the spleen into multiple lobes. To date, there are very few cadaveric reports of splenic fissures. This study aimed to examine the anatomy and morphological structure of spleens collected from cadavers in order to identify the prevalence and clinical significance of splenic notches, fissures and lobation. This study was conducted at the Department of Anatomy, Katuri Medical College and Hospital, Guntur, Andhra Pradesh, India. A total of 50 spleens were collected from cadavers over a period of seven years from 2012-2019 and examined to determine the presence of splenic notches or fissures. Of the 50 spleens, 40% had notches at the superior border, 10% had notches at the inferior border and 50% had no notches at either border. Fissures were present in five spleens (10%); of these, three showed incomplete fissures and the remaining two had complete fissures that divided the spleen into two lobes. The findings of this study provide valuable information regarding the anatomy and prevalence of splenic fissures and bilobed spleens. A bilobed spleen is a rare congenital malformation which should be considered distinct from other known splenic anomalies. The presence of splenic fissures in bilobed spleens can serve as a guide for surgeons during conservatory splenectomy procedures.


Bioavailability of valine in spray-dried L-valine biomass is not different from that in crystalline L-valine when fed to weanling pigs1.
An experiment was conducted to test the hypothesis that Val from a spray dried L-Val fermentation biomass (Val-FB; 64.4% L-Val) has a bioavailability of 100% relative to Val from L-Val (98% L-Val) when fed to weanling pigs. A Val-deficient basal diet containing 0.63% standardized ileal digestible (SID) Val was formulated. Six additional diets were prepared by supplementing the basal diet with 0.08%, 0.17%, or 0.25% L-Val or 0.12%, 0.25%, or 0.37% Val-FB to create experimental diets from both Val sources that contained 0.71%, 0.79%, or 0.87% SID Val. Two hundred twenty-four weaned pigs (6.87 ± 0.64 kg initial BW) were allotted to a randomized complete block design with 7 diets, 4 pigs per pen, and 8 replicate pens per diet. Diets were fed for 20 d. At the conclusion of the experiment, a blood sample from 1 pig per pen was analyzed for blood urea nitrogen (BUN) and plasma free AA. A linear regression model was used to estimate the relative bioavailability (RBV) of Val in Val-FB relative to Val from L-Val. Results indicated that the final BW and ADG were greater (P < 0.01) for pigs fed diets supplemented with Val-FB than pigs fed diets supplemented with L-Val. The ADFI decreased (linear, P ≤ 0.01), whereas G:F increased (linear, P < 0.01) by increasing inclusion of both Val sources in the diets. Regardless of source of dietary Val, BUN values were reduced (linear and quadratic, P < 0.01) as the concentration of Val in the diet increased. Pigs fed diets supplemented with L-Val had increased (linear and quadratic, P ≤ 0.05) concentrations of Val and Arg in plasma, and plasma concentrations of Ile, Leu, Lys, Ala, Cys, and Pro linearly increased (P < 0.05). There was also an increase (linear, P < 0.05) in plasma concentrations of Ile, Leu, Met, Ala, Asp, Cys, and Pro as Val-FB was added to the diets, and the concentration of Val in plasma increased (linear and quadratic, P < 0.05). Using L-Val as the standard, the RBV of Val in Val-FB as determined by ADG, G:F, and final BW was 146%, 135%, and 143%, respectively, with 95% confidence intervals of 99% to 191%, 83% to 187%, and 70% to 217%, respectively. In conclusion, the linear regression estimated a RBV of at least 100% for Val in Val-FB relative to Val from L-Val, and pigs fed diet supplemented with Val-FB had greater final BW, ADG, and G:F than pigs fed diets supplemented with the same amount of Val from L-Val.


A survey of orthopaedic journal editors determining the criteria of manuscript selection for publication.
To investigate the characteristics of editors and criteria used by orthopaedic journal editors in assessing submitted manuscripts. Between 2008 to 2009 all 70 editors of Medline listed orthopaedic journals were approached prospectively with a questionnaire to determine the criteria used in assessing manuscripts for publication. There was a 42% response rate. There was 1 female editor and the rest were male with 57% greater than 60 years of age. 67% of the editors worked in university teaching hospitals and 90% of publications were in English. The review process differed between journals with 59% using a review proforma, 52% reviewing an anonymised manuscript, 76% using a routine statistical review and 59% of journals used 2 reviewers routinely. In 89% of the editors surveyed, the editor was able to overrule the final decision of the reviewers. Important design factors considered for manuscript acceptance were that the study conclusions were justified (80%), that the statistical analysis was appropriate (76%), that the findings could change practice (72%). The level of evidence (70%) and type of study (62%) were deemed less important. When asked what factors were important in the manuscript influencing acceptance, 73% cited an understandable manuscript, 53% cited a well written manuscript and 50% a thorough literature review as very important factors. The editorial and review process in orthopaedic journals uses different approaches. There may be a risk of language bias among editors of orthopaedic journals with under-representation of non-English publications in the orthopaedic literature.


Procurement of Category 2 Vaccines in China.
Internationally, vaccine pricing is relatively opaque, although many low- or lower-middle-income countries belong to international consortiums that jointly procure vaccines. China procures vaccines domestically, and vaccines that require payment from the public ("category 2 vaccines"), have undergone several regulatory changes over the past 15 years. This study aims to describe the vaccine procurement method changes in China since 2005 and to analyze how the procurement method impacted vaccine price. This review of vaccine procurement reforms found that a shift to provincial-level Group Purchasing Organizations after 2016 was accompanied by an increase in most prices. There was more variability in vaccine prices across provinces for vaccines with only one supplier, and these vaccines have a higher price than what is found in United Nations Children's Fund (UNICEF)-supported countries. China's current procurement system for non-mandatory vaccines leaves these vaccines costing several-fold more than in other countries, and in particular those supported by Gavi, the Vaccine Alliance. Exploring a variety of methods to reduce vaccine purchase prices will not only directly benefit the general population, but also the government, as they aim to implement more programs to benefit public health in a cost-effective manner.


Detection of sleep-disordered breating with Pressure Bed Sensor.
A Pressure Bed Sensor (PBS) can offer an unobtrusive method for sleep monitoring. This study focuses on the detection of the sleep related breathing disorders using a PBS in comparison to the methods used in a sleep laboratory. A newly developed PCA modeling approach for the eight sensor signals of the PBS is evaluated using the Reduced Respiratory Amplitude Index (RRAI) as a central measure. The method computes the respiration amplitude with the Hilbert transform, and then detects the events based on a 20% amplitude reduction from the baseline signal. A similar calculation was used for the sleep laboratory RIP measurements, and both PBS and RIP were compared against the reference based on the nasal flow signal. In the reference RRAI method, the respiratory-disordered events were obtained using RemLogic respiration analyzer to detect over 50% amplitude reduction in the nasal respiratory flow, but removing the RemLogic standard hypopnea event associations on the oxygen desaturation events and the sleep arousals. The movement artifacts were automatically detected based on the movement activity signal of the PBS. Twenty-five (25) out of 28 patients were finally analysed. On average 87% of a night measurement has been covered by the system. The correlation coefficient was 0.92 between the PBS and the reference RRAI, and the performance of the PBS was similar with the RIP belts. Classifying the severity of the sleep related breathing by dividing RRAI in groups according to the severity criteria, the sensitivity was 92% and the specificity was 70% for the PBS. The results suggest that PBS recording can provide an easy and un-obstructive alternative method for the detection of the sleep disordered breathing and thus has a great promise for the home monitoring.


Effects of tourniquet number and exsanguination on amikacin concentrations in the radiocarpal and distal interphalangeal joints after low volume intravenous regional limb perfusion in horses.
To determine the influence of a dual tourniquet technique and limb exsanguination on amikacin concentrations in the synovial fluid of the radiocarpal joint (RCJ) and distal interphalangeal joint (DIPJ) after low volume, cephalic intravenous regional limb perfusion (IVRLP). Randomized cross-over design. Six healthy adult horses. One gram of amikacin in 6 mL of 0.9% NaCl was infused via cephalic IVRLP in 6 standing, sedated horses using 4 techniques: proximal pneumatic tourniquet (P), proximal pneumatic tourniquet with exsanguination (PE), proximal pneumatic and distal Esmarch tourniquet (PD), and proximal pneumatic with distal Esmarch tourniquet and exsanguination (PDE). Amikacin concentrations were measured in RCJ and DIPJ synovial fluid samples, collected just before perfusion (time 0), and at 15 and 30 minutes (before tourniquet release) after perfusion. Synovial fluid amikacin concentrations achieved in the RCJ were higher with techniques PD and PDE than those achieved with techniques P and PE 15 and 30 minutes after perfusion (P < .0001). Synovial fluid amikacin concentrations in the DIPJ were higher with techniques P and PE than those achieved with techniques PD and PDE at 15 minutes (P = .0002) and were higher than technique PDE at 30 minutes after perfusion (P < .0001). Low volume (10 mL) cephalic IVRLP should be combined with the placement of 2 tourniquets (proximal and distal to the carpus) to achieve therapeutic amikacin concentrations in the RCJ. Exsanguination prior to low volume IVRLP does not alter synovial fluid amikacin concentrations.


Truncation of small matrix elements based on the Euclidean norm for blocked data structures.
Methods for the removal of small symmetric matrix elements based on the Euclidean norm of the error matrix are presented in this article. In large scale Hartree-Fock and Kohn-Sham calculations it is important to be able to enforce matrix sparsity while keeping errors under control. Truncation based on some unitary-invariant norm allows for control of errors in the occupied subspace as described in (Rubensson et al. J Math Phys 49, 032103). The Euclidean norm is unitary-invariant and does not grow intrinsically with system size and is thus suitable for error control in large scale calculations. The presented truncation schemes repetitively use the Lanczos method to compute the Euclidean norms of the error matrix candidates. Ritz value convergence patterns are utilized to reduce the total number of Lanczos iterations.


Toxoplasmosis in wild turkeys: a case report and serologic survey.
Toxoplasmosis was diagnosed in a free-ranging wild turkey (Meleagris gallopavo) from West Virginia (USA) in June 1993. Gross findings included emaciation, splenomegaly, multifocal necrotizing hepatitis and splenitis, and crusting dermatitis on the head and neck. Histologically, multifocal necrosis with mononuclear inflammation was present in kidney, liver, spleen, heart, lungs, and pancreas. Toxoplasma gondii was confirmed in sections of liver by avidin-biotin immunohistochemical analysis. Subsequently, a retrospective serosurvey of wild turkeys for T. gondii antibodies was conducted using turkey sera collected between 1984 and 1989. An antibody prevalence of 10% was detected in 130 birds from 21 locations in the southeastern United States. While wild turkeys in the Southeast have T. gondii antibodies, this is only the second natural case of fatal toxoplasmosis reported; it appears that wild turkeys infrequently develop clinical disease when infected with T. gondii.


Translational control of human cytomegalovirus gp48 expression.
Posttranscriptional controls modulate the expression of several human cytomegalovirus genes. Previous studies have shown that one cytomegalovirus gene transcript leader contains AUG codons which inhibit translation of a downstream reading frame. However, two other cytomegalovirus gene transcript leaders of similar structure do not inhibit translation. We have extended these studies to the analysis of the structural glycoprotein gp48, whose predominant transcript contains three upstream AUG codons. The 5' leader of this transcript strongly inhibits downstream translation in fibroblasts. Analyses of deletions and point mutations identify the second upstream AUG codon as an essential component of the inhibitory signal. Other leader sequences, but neither the first nor the third AUG codon, are also required. Intriguingly, the inhibitory signal appears also to depend on the amino acid coding information of the short reading frame associated with the second AUG codon. Insights derived from these studies are germane to understanding the translational regulation of other viral and cellular genes of similar structure.


Planning and implementing an implanted fiducial programme for prostate cancer radiation therapy.
Using implanted gold seeds as fiducial markers to verify the position of the prostate in radiation therapy is well accepted and is becoming the standard of practice and requirement for international multicentre trials. In 2006 the decision was made at the Peter MacCallum Caner Centre (Peter Mac) to plan for and implement this process as standard clinical practice for radical dose prostate treatments (74-78 Gy). Before this, programme verification of field placement for prostate cancer radiation treatment was routinely carried out using regular off-line electronic portal imaging with matching of bony anatomy. A small multidisciplinary team investigated and assisted in the implementation of this new practice across the Peter Mac sites at East Melbourne and our three satellite centres. Issues considered included seed size, number and position in the prostate, implant equipment, imaging equipment and procedure and consent and information forms. The use of a custom made fiducial pack, comprehensive patient information and a daily on-line imaging process was implemented. The experience of the first 28 patients at Peter Mac from January 2007 to May 2007 inclusive is reported on.


Effect of thermal pulsation treatment on tear film parameters in dry eye disease patients.
The goal of this study was to evaluate the effect of thermal pulsation treatment on tear film parameters, specifically osmolarity and matrix metalloproteinase-9 (MMP-9), in patients with meibomian gland dysfunction (MGD) and dry eye disease (DED). A single-center review of 189 eyes that underwent thermal pulsation treatment was performed. Data were collected on pre and posttreatment osmolarity, MMP-9, tear break-up time (TBUT), and ocular surface disease index (OSDI) score. Statistical analyses were performed to detect any significant differences after treatment. Thermal pulsation treatment led to significant improvements in TBUT (mean increase from 4.5 to 8.5 seconds [P<0.001]), OSDI score (mean decrease from 50.5 to 41.6 [P=0.024]), and MMP-9 (50% positive rate pretreatment compared to 26% positive rate post treatment [P<0.0001]). In the subset of patients who had a baseline osmolarity >307 mOsm/L (ie, diagnostic for DED), there was a significant improvement in the mean tear osmolarity from 317.1 to 306.6 mOsms/L after treatment (P=0.002). Treating MGD is an important component of caring for the DED patient. Thermal pulsation treatment can improve MMP-9 levels on the ocular surface of patients with MGD and DED, as well as improve osmolarity in those with abnormal initial values. The present study suggests that meibomian glands play an important role in tear film dynamics and, as such, effective therapy such as thermal pulsation treatment aimed at improving meibomian gland health, can aid the restoration of normal tear film parameters and decrease patient symptoms of DED and MGD.


Management of diastolic heart failure.
Diastolic heart failure (HF) is also referred to as HF with preserved left ventricular systolic function. The distinction between systolic and diastolic HFs is a pathophysiological one and isolated forms of left ventricular dysfunction are rarely observed. In diastolic HF left ventricular systolic function is normal or only slightly impaired, and the typical manifestations of HF result from increased filling pressure caused by impaired relaxation and compliance of the left ventricle. The predisposing factors for diastolic dysfunction include elderly age, female sex, obesity, coronary artery disease, hypertension and diabetes mellitus. Treatment of diastolic HF is aimed to stop the progression of the disease, relieve its symptoms, eliminate exacerbations and reduce the mortality. The management should include antihypertensive treatment, maintenance of the sinus rhythm, prevention of tachycardia, venous pressure reduction, prevention of myocardial ischemia and prevention of diabetes mellitus. The European Society of Cardiology specifies the type of therapy in diastolic HF based on: angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, non-dihydropyridine calcium channel blockers, diuretics. In order to improve the currently poor prognosis in this group of patients the treatment of diastolic HF must be optimised.


Test-performance after cognitive training in persons at risk mental state of schizophrenia and patients with schizophrenia.
This exploratory study aims to examine the differential effects of a computer-based cognitive training in 'prodromal' patients (mean age 27.20 years, S.D. 5.31 years) compared with patients with full-blown schizophrenia (mean age 30.13 years, S.D. 7.77 years). Ten patients at risk for schizophrenia and 16 patients suffering from schizophrenia underwent a computerized cognitive training program (Cogpack). Cognitive functioning before and after a total of 10 training sessions was assessed by different tests controlling for memory, attention, and logical thinking. Prodromal patients turned out to be able to significantly improve their long-term memory functions and their attention after cognitive training with the Cogpack software package whereas in the group of patients with schizophrenia no improvement occurred (e.g. continuous performance test, identical pairs-subtest 'shapes': improvement from 0.73 to 0.88 in persons at risk of schizophrenia vs. no improvement in patients with schizophrenia (0.55 to 0.53). Cognitive training using Cogpack is helpful for the improvement of cognitive functioning in persons at risk of schizophrenia. Thus, the application of cognitive training should be provided as early as possible in the prodromal phases of schizophrenia in order to use the full rehabilitative potential of the patients. These results should be confirmed by further investigations including larger sample sizes.


Quantitative global plaque characteristics from coronary computed tomography angiography for the prediction of future cardiac mortality during long-term follow-up.
Adverse plaque characteristics determined by coronary computed tomography angiography (CTA) have been associated with future cardiac events. Our aim was to investigate whether quantitative global per-patient plaque characteristics from coronary CTA can predict subsequent cardiac death during long-term follow-up. Out of 2748 patients without prior history of coronary artery disease undergoing CTA with dual-source CT, 32 patients suffered cardiac death (mean follow-up of 5 ± 2 years). These patients were matched to 32 controls by age, gender, risk factors, and symptoms (total 64 patients, 59% male, age 69 ± 10 years). Coronary CTA data sets were analysed by semi-automated software to quantify plaque characteristics over the entire coronary tree, including total plaque volume, volumes of non-calcified plaque (NCP), low-density non-calcified plaque (LD-NCP, attenuation <30 Hounsfield units), calcified plaque (CP), and corresponding burden (plaque volume × 100%/vessel volume), as well as stenosis and contrast density difference (CDD, maximum percent difference in luminal attenuation/cross-sectional area compared to proximal cross-section). In patients who died from cardiac cause, NCP, LD-NCP, CP and total plaque volumes, quantitative stenosis, and CDD were significantly increased compared to controls (P < 0.025 for all). NCP > 146 mm³ [hazards ratio (HR) 2.24; 1.09-4.58; P = 0.027], LD-NCP > 10.6 mm³ (HR 2.26; 1.11-4.63; P = 0.025), total plaque volume > 179 mm³ (HR 2.30; 1.12-4.71; P = 0.022), and CDD > 35% in any vessel (HR 2.85;1.4-5.9; P = 0.005) were associated with increased risk of future cardiac death, when adjusted for segment involvement score. Among quantitative global plaque characteristics, total, non-calcified, and low-density plaque volumes as well as CDD predict cardiac death in long-term follow-up.


Expression Profile of Six RNA-Binding Proteins in Pulmonary Sarcoidosis.
Sarcoidosis is characterised by up-regulation of cytokines and chemokine ligands/receptors and proteolytic enzymes. This pro-inflammatory profile is regulated post-transcriptionally by RNA-binding proteins (RBPs). We investigated in vivo expression of six RBPs (AUF1, HuR, NCL, TIA, TIAR, PCBP2) and two inhibitors of proteolytic enzymes (RECK, PTEN) in pulmonary sarcoidosis and compared it to the expression in four control groups of healthy individuals and patients with other respiratory diseases: chronic obstructive pulmonary disease (COPD), asthma and idiopathic interstitial pneumonias (IIPs). RT-PCR was used to quantify the mRNAs in bronchoalveolar (BA) cells obtained from 50 sarcoidosis patients, 23 healthy controls, 30 COPD, 19 asthmatic and 19 IIPs patients. Flow cytometry was used to assess intracellular protein expression of AUF1 and HuR in peripheral blood T lymphocytes (PBTLs) obtained from 9 sarcoidosis patients and 6 healthy controls. Taking the stringent conditions for multiple comparisons into consideration, we consistently observed in the primary analysis including all patients regardless of smoking status as well as in the subsequent sub-analysis limited for never smokers that the BA mRNA expression of AUF1 (p<0.001), TIA (p<0.001), NCL (p<0.01) and RECK (p<0.05) was decreased in sarcoidosis compared to healthy controls. TIA mRNA was also decreased in sarcoidosis compared to both obstructive pulmonary diseases (COPD and asthma; p<0.001) but not compared to IIPs. There were several positive correlations between RECK mRNA and RBP mRNAs in BA cells. Also sarcoidosis CD3+, CD4+ and CD8+ PBTLs displayed lower mean fluorescence intensity of AUF1 (p≤0.02) and HuR (p≤0.03) proteins than control healthy PBTLs. mRNA expressions of three RBPs (AUF1, TIA and NCL) and their potential target mRNA encoding RECK in BA cells and additionally protein expression of AUF1 and HuR in PBTLs were down-regulated in our sarcoidosis patients compared to healthy individuals. Its significance, e.g. for stability of mRNAs encoding pro-inflammatory factors, should be further explored in sarcoidosis.


Does intensive rehabilitation improve the functional outcome of patients with traumatic brain injury (TBI)? A randomized controlled trial.
To evaluate the effects of an increase in the intensity of rehabilitation on the functional outcome of patients with traumatic brain injury (TBI). Sixty-eight patients (age 12-65 years) with moderate-to-severe TBI were included. They were randomized into high (4-hour/day) or control (2-hour/day) intensity rehabilitation programmes at an average of 20 days after the injury. The programmes ended when the patients achieved independence in daily activities or when 6 months had passed. No significant differences were found in the Functional Independence Measure (FIM) (primary outcome) and Neurobehavioural Cognitive Status Examination (NCSE) total scores between the two groups. There were significantly more patients in the high intensity group than in the control group who achieved a maximum FIM total score at the third month (47% vs. 19%, p = 0.015) and a maximum Glasgow Outcome Scale (GOS) score at the second (28% vs. 8%, p = 0.034) and third months (34% vs. 14%, p = 0.044). Early intensive rehabilitation may improve the functional outcome of patients with TBI in the early months post-injury and hence increase the chance of their returning to work early. Intensive rehabilitation in this study speeded up recovery rather than changed the final outcome.


Stress Analysis of a Class II MO-Restored Tooth Using a 3D CT-Based Finite Element Model.
A computational method has been developed for stress analysis of a restored tooth so that experimental effort can be minimized. The objectives of this study include (i) developing a method to create a 3D FE assembly model for a restored tooth based on CT images and (ii) conducting stress analysis of the restored tooth using the 3D FE model established. To build up a solid computational model of a tooth, a method has been proposed to construct a 3D model from 2D CT-scanned images. Facilitated with CAD tools, the 3D tooth model has been virtually incorporated with a Class II MO restoration. The tooth model is triphasic, including the enamel, dentin, and pulp phases. To mimic the natural constraint on the movement of the tooth model, its corresponding mandible model has also been generated. The relative high maximum principal stress values were computed at the surface under loading and in the marginal region of the interface between the restoration and the tooth phases.


A global analysis of the determinants of maternal health and transitions in maternal mortality.
The reduction of maternal mortality and the promotion of maternal health and wellbeing are complex tasks. This Series paper analyses the distal and proximal determinants of maternal health, as well as the exposures, risk factors, and micro-correlates related to maternal mortality. This paper also examines the relationship between these determinants and the gradual shift over time from a pattern of high maternal mortality to a pattern of low maternal mortality (a phenomenon described as the maternal mortality transition). We conducted two systematic reviews of the literature and we analysed publicly available data on indicators related to the Sustainable Development Goals, specifically, estimates prepared by international organisations, including the UN and the World Bank. We considered 23 frameworks depicting maternal health and wellbeing as a multifactorial process, with superdeterminants that broadly affect women's health and wellbeing before, during, and after pregnancy. We explore the role of social determinants of maternal health, individual characteristics, and health-system features in the production of maternal health and wellbeing. This paper argues that the preventable deaths of millions of women each decade are not solely due to biomedical complications of pregnancy, childbirth, and the postnatal period, but are also tangible manifestations of the prevailing determinants of maternal health and persistent inequities in global health and socioeconomic development. This paper underscores the need for broader, multipronged actions to improve maternal health and wellbeing and accelerate sustainable reductions in maternal mortality. For women who have pregnancy, childbirth, or postpartum complications, the health system provides a crucial opportunity to interrupt the chain of events that can potentially end in maternal death. Ultimately, expanding the health sector ecosystem to mitigate maternal health determinants and tailoring the configuration of health systems to counter the detrimental effects of eco-social forces, including though increased access to quality-assured commodities and services, are essential to improve maternal health and wellbeing and reduce maternal mortality.


Early-onset climacterium is not associated with impaired vitamin D status: a population-based study.
To investigate vitamin D status in women with the onset of the climacteric phase by age 46 as both early menopause and inadequate vitamin D status may increase the risk of adverse health outcomes. A cross-sectional study included 2,544, 46-year-old women from a birth cohort. Women were divided into the following two groups according to their menstrual history and follicle-stimulating hormone (FSH) concentration: 1) climacteric (FSH ≥25 IU/L and amenorrhea ≥4 mo, n = 351) and 2) preclimacteric women (FSH <25 IU/L and having regular/irregular menstrual cycles, n = 2,193). Serum 25-hydroxyvitamin D (25(OH)D) concentrations were compared between the groups. A linear regression model was performed to investigate which factors are associated with 25(OH)D status. Mean serum 25(OH)D concentrations were higher in climacteric compared with preclimacteric women (68.1 ± 19.8 nmol/L vs 65.2 ± 19.3 nmol/L, P = 0.01). However, in the linear regression model, climacteric status was not associated with 25(OH)D status (multivariable adjusted mean difference 4.5 nmol/L, 95% confidence interval -1.4 to 10.4, P = 0.137). A total of 76 of the climacteric women were using systemic estrogen hormone therapy (HT). In a subanalysis, including only climacteric women, the use of HT was associated with higher 25(OH)D status (multivariable adjusted mean difference 5.9 nmol/L, 95% confidence interval 1.3-10.5, P = 0.013). The onset of the climacteric phase by age 46 was not associated with inadequate 25(OH)D concentrations, whereas HT use was associated with higher 25(OH)D status in women with early-onset climacterium.


Self-healing on mismatched fractured composite surfaces of SiC with a diameter of 180 nm.
Self-healing on fractured surfaces of silicon carbide (SiC) is highly desirable, to avoid the catastrophic failure of high-performance devices working at extreme environments. Nevertheless, self-healing on a fractured surface of an amorphous and crystalline (AAC) composite structure of a brittle nanowire (NW) has not been demonstrated. In this study, self-healing is demonstrated on mismatched fractured surfaces of the AAC composite structure of a brittle solid for a SiC NW with a diameter of 187 nm. Fracture strength is 10.18 GPa for the AAC structure, recovering 11.7% after self-healing on its mismatched fractured surfaces. To the best of our knowledge, we firstly report the self-healing on mismatched fractured surfaces of the AAC structure for a brittle NW. This is a breakthrough of the previous prediction that self-healing could not be realized on a brittle NW with a diameter over 150 nm. A growth of 3 nm was found after self-healing on the gap induced by mismatched fractured surfaces, which is different from previous reports for pure amorphous and monocrystalline brittle NWs. To reduce the potential energy, coherent rebonding and debonding were performed to realize the atomic migration to fill the gap, resulting in the growth of gap of 3 nm to perform self-healing. Our findings shed light on the potential of self-healing for design and fabrication of next-generation high-performance SiC devices used in the vacuum and aerospace industries.


Interhead distance measurements in myosin VI via SHRImP support a simplified hand-over-hand model.
Myosin VI walks in a hand-over-hand fashion with an average step size of 30 nm, which is much larger than its 10 nm lever arm. Recent experiments suggest that the myosin VI structure has an unfolded and flexible region in the proximal tail which makes such a large step possible. In addition, cryoelectron microscopy images of actomyosin VI show the two heads bound to the actin monomers with a broad distribution of distances, including some as close as a few nanometers. This observation, when combined with the existence of a flexible region in the structure, which takes part in stepping, challenged the hand-over-hand model. In the hand-over-hand model, the lever arm is considered to be rigid and the interhead separation should not be very different from 30 nm. We considered an alternative model in which myosin VI heads sequentially take 60 nm steps whereas the interhead separation alternates between a large and small value (x and 60 - x, where x < 30). To clarify these issues, we used a new technique, SHRImP, to measure the interhead distance of nearly rigor myosin VI molecules. Our data show a single peak at 29.3 +/- 0.7 nm, in agreement with the straightforward hand-over-hand model.


Direct measurement of sarcomere length from isolated cardiac cells.
Isolated cardiac muscle cells enzymatically digested with collagenase and hyaluronidase from whole rat myocardium demonstrate the characteristics of an intact membrane in that they tolerate millimolar concentrations of free Ca2+ and exhibit phasic contractions with electrical excitation. These isolated cells maintain their characteristic A-I band striation patterns when at rest or during contraction. An apparatus has been developed to directly image these cells with phase-contrast micrography onto a 1,728-element charge-coupled device photodiode array for rapid data storage in a digital computer. The digitized striation pattern profile was analyzed for individual and average sarcomere spacing. In isotonic media the average resting sarcomere length ranged from 1.77 to 1.91 micrometers in 13 cells, with a mean length of 1.83 +/- 0.12 micrometers. Electrically stimulated phasic contractions in three cells demonstrated a synchronous 20% decrease in sarcomere spacing to a mean of 1.51 micrometers. Striation spacing decreased under hypertonic stress but elongated only up to 1.93 micrometers in hypotonic solutions, suggesting that some internal elastic constraint exists that limits elongation of the cell.


Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence.
There is increasing recognition of the involvement of the immune signaling molecule, tumor necrosis factor (TNF), in the pathophysiology of stroke and chronic brain dysfunction. TNF plays an important role both in modulating synaptic function and in the pathogenesis of neuropathic pain. Etanercept is a recombinant therapeutic that neutralizes pathologic levels of TNF. Brain imaging has demonstrated chronic intracerebral microglial activation and neuroinflammation following stroke and other forms of acute brain injury. Activated microglia release TNF, which mediates neurotoxicity in the stroke penumbra. Recent observational studies have reported rapid and sustained improvement in chronic post-stroke neurological and cognitive dysfunction following perispinal administration of etanercept. The biological plausibility of these results is supported by independent evidence demonstrating reduction in cognitive dysfunction, neuropathic pain, and microglial activation following the use of etanercept, as well as multiple studies reporting improvement in stroke outcome and cognitive impairment following therapeutic strategies designed to inhibit TNF. The causal association between etanercept treatment and reduction in post-stroke disability satisfy all of the Bradford Hill Criteria: strength of the association; consistency; specificity; temporality; biological gradient; biological plausibility; coherence; experimental evidence; and analogy. Recognition that chronic microglial activation and pathologic TNF concentration are targets that may be therapeutically addressed for years following stroke and other forms of acute brain injury provides an exciting new direction for research and treatment.


A heterogeneous lineage origin underlies the phenotypic and molecular differences of white and beige adipocytes.
A worldwide epidemic of obesity and its associated metabolic disorders raise the significance of adipocytes, their origins and characteristics. Our previous study has demonstrated that interscapular brown adipose tissue (BAT), but not intramuscular adipose, is derived from the Pax3-expressing cell lineage. Here, we show that various depots of subcutaneous (SAT) and visceral adipose tissue (VAT) are highly heterogeneous in the Pax3 lineage origin. Interestingly, the relative abundance of Pax3 lineage cells in SAT depots is inversely correlated to expression of BAT signature genes including Prdm16, Pgc1a (Ppargc1a) and Ucp1. FACS analysis further demonstrates that adipocytes differentiated from non-Pax3 lineage preadipocytes express higher levels of BAT and beige adipocyte signature genes compared with the Pax3 lineage adipocytes within the same depots. Although both Pax3 and non-Pax3 lineage preadipocytes can give rise to beige adipocytes, the latter contributes more significantly. Consistently, genetic ablation of Pax3 lineage cells in SAT leads to increased expression of beige cell markers. Finally, non-Pax3 lineage beige adipocytes are more responsive to cAMP-agonist-induced Ucp1 expression. Taken together, these results demonstrate widespread heterogeneity in Pax3 lineage origin, and its inverse association with BAT gene expression within and among subcutaneous adipose depots.


Risk factors predicting Candida infective endocarditis in patients with candidemia.
Candida infective endocarditis (CIE) is a rare but serious complication of candidemia. Incidence and risk factors associated with CIE among candidemic patients are poorly defined from small cohorts. Identification of clinical predictors associated with this entity may guide more judicious use of cardiac imaging. We conducted a retrospective analysis of all inpatients aged ≥18 years diagnosed with candidemia at our institution. CIE was diagnosed by fulfilling two of the major Duke criteria: specifically a vegetation(s) on echocardiogram and positive blood cultures for Candida spp. We used univariable and multivariable regression analyses to identify risk factors associated with CIE. Of 1,873 patients with candidemia, 47 (2.5%) were identified to have CIE. In our multivariable logistic model, existing valvular heart disease was associated with a higher risk for CIE (adjusted odds ratio [aOR], 7.66; 95% confidence interval [CI], 2.95-19.84). Predictors that demonstrated a decreased risk of CIE included infection with C. glabrata (aOR, 0.17; 95% CI, 0.04-0.69), hematologic malignancy (aOR, 0.09; 95% CI, 0.01-0.68), and receipt of total parenteral nutrition (aOR, 0.38; 95% CI, 0.16-0.91). The 90-day crude mortality for CIE was 48.9%, similar to the overall non-CIE mortality of 41.9% (P = .338). We identified a set of clinical factors that can predict the presence of CIE among patient with candidemia. These findings may reduce the need for unnecessary expensive and invasive imaging studies in a subset of patients with a lower risk profile for endocarditis and alternative infection source.