Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers.
A low molecular weight heparin (LMW-heparin) with a mean molecular weight of 4900 dalton was prepared by controlled enzymatic depolymerization of conventional porcine mucosal heparin. The effects of 2,500, 5,000 and 10,000 U (XaI; 29, 58 and 116 mg) on factor Xa inhibition (XaI), factor IIa inhibition (IIaI), APTT, AT III and platelet count were compared to those of 5,000 U (XaI; 26 mg) of conventional heparin given s.c. to 6 healthy volunteers. 5,000 U (XaI; 58 mg) of LMW-heparin was given i.v. A dose related response with regard to the XaI and the IIa-inhibitory activities with peak values at 4 hours after the s.c. injections was obtained. An increase of the XaI/IIaI ratio over the time after injection was seen only after i.v. administration of the LMW-heparin. The APTT was only slightly prolonged and remained within normal range after s.c. injection. AT III and platelet counts were unaffected. The biological half life of the LMW-heparin was 111 minutes if assayed by Xa inhibition, 76 minutes if assayed by IIa inhibition and 40 minutes if assayed by APTT. A strong correlation between the XaI activities obtained and body weight was seen, indicating that LMW-heparin should be administered individually according to body weight.


Burnout, compassion fatigue and psychological capital: Findings from a survey of nurses delivering palliative care.
Ageing populations worldwide and a concomitant increase in chronic conditions translates into an increased demand for the delivery of palliative and end of life care by nurses. This increasing demand for palliative care provision may produce stressors resulting in negative outcomes such as burnout and compassion fatigue. The purpose of this study was to explore burnout and compassion fatigue, as well as potential protective factors, among nurses in New Zealand. An online survey was conducted with 256 registered nurses (between January 2016 and February 2017) recruited through nursing organisations and a large tertiary level hospital. Data analysis consisted of descriptive statistics, multivariate analysis of variance, Pearson correlations, and hierarchical multiple regression. Psychological empowerment and the commitment and challenge components of psychological hardiness significantly predicted lower scores for the burnout while previous palliative care education and challenge predicted lower scores for the secondary traumatic stress component of compassion fatigue. Significant predictors of compassion satisfaction included previous palliative care education, psychological empowerment and both the commitment and challenge components of psychological hardiness. Nurses draw upon unique combinations of "psychological capital" to deal with caring for patients with life-limiting illnesses. Any interventions to increase nurse palliative care education uptake must be tailored to develop and support these internal resources.


The effect of hypertonic saline dextran on whole blood coagulation.
Hypertonic saline dextran (RescueFlow) is being promoted for resuscitation from hypovolaemia following injury. We studied the in vitro effect on coagulation of serial dilutions of blood with this fluid. There was a mild procoagulant effect up to a dilution of 11% and an anticoagulant effect above this level, which rapidly increased so that coagulation was grossly deranged at a 15% dilution. Although the clinical significance of these findings is not yet known, it may suggest that for hypertonic saline dextran there is little to separate the top of the therapeutic window from the threshold of potentially serious adverse effects.


Five years' experience with long saphenous catheterisation for chronic venous access.
The five-year experience by one surgical team of the implantation of 419 chronic venous access catheters in 368 adults and children is reported. The majority of the catheters were required for the management of malignant disease but some were used for long-term home parenteral nutrition. The inferior vena cava was cannulated through the long saphenous vein in 181 cases and the superior vena cava by the jugular or cephalic veins in 238. Mean catheter lives of over one year, with individual lives of more than three years were achieved by both routes. The overall infection rate was 18%. No excess of thrombotic or infective complications was observed in patients with long saphenous vein catheters. It is suggested that the long saphenous vein is an appropriate route for chronic venous access for chemotherapy in most patients.


Utilizing a substance use attitudes, practices and knowledge survey for multidisciplinary curriculum development.
Development and administration of a substance use attitudes questionnaire to social work students and clinicians, physician assistant students and practitioners, and medical interns is described.


Determinants of the uptake of very low density lipoprotein remnants by the perfused rat liver.
The receptor-mediated uptake of very low density lipoprotein (VLDL) remnants by the rat liver was studied. Livers were perfused with native 125I-VLDL remnants, radiolabeled apo E-deficient remnants, and radiolabeled remnants that contained reductively methylated apo B and unmodified apo E. The specific uptake of the apo E-deficient remnants was 20% of that for the native remnants, whereas the specific uptake of the remnants containing unreactive apo B was 78% of the control value. This suggests that the apo E of VLDL remnants is the principal ligand for binding to the receptor, and in the absence of apo E, apo B may participate in binding. This conclusion is supported by the finding that dimyristoyl phosphatidylcholine (DMPC)- apo E complexes were effective in competing for the hepatic uptake of 125I-VLDL remnants. The intracellular distribution of radioactivity was analyzed by Percoll density gradient centrifugation. At five minutes after perfusion, radioactivity was associated with the plasma membrane and lysosomal fractions, and at 30 minutes most of the radioactivity was associated with the lysosomal fraction. Binding and internalization of VLDL remnants was also directly visualized by electron microscopy. Internalization proceeded by coated pit-coated vesicle formation with subsequent delivery to lysosomes. Our findings demonstrate that the apo E of VLDL remnants mediates binding to the hepatic receptor and that the internalization and degradation of VLDL remnants is by a similar pathway to that previously described for LDL.


Synergetic degradation of konjac glucomannan by γ-ray irradiation and hydrogen peroxide.
Konjac glucomannan (KGM) samples were irradiated with (60)Co γ-rays with a radiation dose of 50kGy in the presence and absence of hydrogen peroxide. The average molecular weight (Mw) and polydispersity index (PDI) of untreated and degraded samples were measured by gel permeation chromatography (GPC), revealing that γ-rays and hydrogen peroxide had a synergetic effect on degradation. Structures of untreated and degraded products were characterized with ultraviolet-visible (UV) and Fourier-transform infrared (FT-IR) spectroscopies, and X-ray diffraction (XRD). Results showed that there was no significant change in the main chain of KGM following degradation, although the crystallinity of KGM decreased. A synergetic effect of γ-rays and hydrogen peroxide was also found in the structural characterization of KGM. The physical properties of KGM changed markedly following degradation, which may increase its application potential. The mechanism of degradation of KGM in the presence and absence of hydrogen peroxide was also investigated.


Study on improving the stability of adsorption-encapsulation immobilized Laccase@ZIF-67.
Laccase (Trametes versicolor) was immobilized onto/into zeolite imidazolate framework-67 (ZIF-67) for the first time, materials were performed by assisting one-pot synthesis strategy in aqueous solution at room temperature. The resulting laccase@ZIF-67 composite was characterized by powder X-ray diffraction (PXRD), fourier transform infrared (FT-IR) spectroscopies, field emission scanning electron microscopy (FE-SEM) and energy dispersive X-ray (EDX), thermal gravimetric analyses (TGA). The results showed that laccase could be well immobilized on ZIF-67 materials. Laccase@ZIF-67 was stable on storage stability and reuseablility, retaining 88 % (15 days at 4 °C) and 59 % (five reaction cycles) of residual enzyme activity. Laccase@ZIF-67 exhibited relatively stable activity at pH 3-5. In addition, the thermal deactivation kinetic studies of laccase@ZIF-67 showed a lower k value, higher t1/2 and ΔG values along with the enhancement of thermodynamic parameters than that of free laccase, and laccase@ZIF-67 had excellent level of thermostability.


The emerging role of the TIM molecules in transplantation.
Since their discovery in 2001, the T-cell immunoglobulin mucin (TIM) family members have been shown to play important roles in the regulation of immune responses. The TIM family comprises of eight genes in the mouse, three of which are conserved in humans (TIM-1, TIM-3 and TIM-4). Initially, TIM-1 and TIM-3 were thought to be expressed solely on T cells. However, emerging data suggest a much broader expression pattern where their presence on APCs confers differing functions, including the ability to mediate phagocytosis. In contrast, TIM-4 is exclusively expressed on APCs. Together, the TIM molecules provide a functional repertoire for determining the fate of T-cell activation and differentiation. To date, much of the knowledge about the TIM family members has been garnered from the models of asthma, allergy and autoimmunity. More recently, data from experimental models of transplantation demonstrate that TIM family members also have a key role in alloimmunity. This review will serve to highlight the emerging data regarding this unique family of molecules and to identify their potential in transplantation tolerance.


PTSD symptoms and cortisol stress reactivity in adolescence: Findings from a high adversity cohort in South Africa.
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in the pathophysiology of post-traumatic stress disorder (PTSD). However, there has been little study of HPA stress reactivity in association with PTSD symptoms (PTSS) in children; and there is limited research on PTSD in low and middle-income countries, where trauma exposure is more common and co-occurring stressors more likely. We assessed the relationship between PTSS and cortisol stress reactivity in children aged 13 years (N = 291) from an impoverished South African community. HPA axis stress reactivity was indexed by salivary cortisol during the Trier Social Stress Test (TSST). In regression analyses both trauma exposure and PTSS showed small inverse associations with total cortisol output (area under the curve with respect to ground) during the TSST, but PTSS effects did not withstand correction for covariates. In addition, hierarchical linear modelling (HLM) found that PTSS were associated with alterations in the shape of the profile of cortisol reactivity that were moderated by sex. In girls, PTSS were associated with reduced linear slope but larger quadratic slopes, whereas the opposite pattern was found in boys. Thus, elevated PTSS were associated with overall blunted profiles of cortisol stress reactivity in girls, but a larger quadratic slope in boys reflects a steeper cortisol increase and decline in boys. There was no relationship between trauma exposure (with or without PTSS) and cortisol reactivity profiles in HLM analyses. In children from a high adversity, low and middle income country context, sex specific associations were found between PTSS and cortisol responses to psychosocial stress. Further research should probe HPA axis functioning more comprehensively in such populations to understand the biological associations of PTSS.


Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study.
This 36-month, randomized, parallel-group study compared safety and efficacy of two doses of everolimus with mycophenolate mofetil (MMF) in de novo renal-transplant recipients. Renal-allograft recipients received 1.5 mg/day or 3 mg/day of everolimus or 2 g/day of MMF, plus full-dose cyclosporine (CsA) and corticosteroids after randomization. For at least their first year, patients received study medication according to a double-blinded, double-dummy design. Concerns over nephrotoxicity led to a protocol amendment to an open-label design with reduced CsA troughs. Incidences of primary efficacy failure at 36 months (biopsy-proven acute rejection, graft loss, death, or loss to follow-up) were everolimus 1.5 mg/day, 33.7% (65/193); everolimus 3 mg/day, 34.0% (66/194); and MMF, 31.1% (61/196) (P=0.810). Antibody-treated acute rejection at 36 months was significantly lower with everolimus 1.5 mg (9.8%) than MMF (18.4%, P=0.014). Discontinuation for adverse events was more frequent with everolimus and hemolytic uremic syndrome, lymphoproliferative disease, and proteinuria, and higher serum creatinine occurred at increased frequency relative to the MMF arm. Creatinine levels in the everolimus arms were stable in follow-up: the mean rise in creatinine over the first 6 months of the open-label phase was 3 micromol/L or greater with everolimus and 7 micromol/L with MMF. However, serum creatinine levels were lower in the MMF group throughout. Death and graft loss were higher in the everolimus arms (not significant). As part of triple-drug immunosuppression, everolimus (1.5 or 3 mg/day) was as efficacious as MMF, although the side-effect profile featured increased adverse events. Nephrotoxicity/calcineurin-inhibitor-related adverse events will require judicious lowering of CsA exposure with monitoring of everolimus troughs.


Triterpenoid saponins from the fruits and galls of Sapindus mukorossi.
Six saponins, sapinmusaponin K (1) [hederagenin-3-O-(3-O-acetyl-alpha-L-arabinopyranosyl)-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside], sapinmusaponin L (2) [hederagenin-3-O-(4-O-acetyl-alpha-L-arabinopyranosyl)-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabino-pyranoside], sapinmusaponin M (3) [hederagenin-3-O-(2,3-O-diacetyl-beta-D-xylopyranosyl)-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside], sapinmusaponin N (4) [hederagenin-3-O-(2,4-O-diacetyl-beta-D-xylopyranosyl)-(1-->3)-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside], sapinmusaponin O (5) [3,7,20(S)-trihydroxydammar-24-ene-3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranoside], and sapinmusaponin P (6) [3,7,20(R)-trihydroxydammar-24-ene-3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-d-glucopyranoside], along with seven known saponins (7-13), were isolated from fruits and the galls of Sapindus mukorossi. Their structures were elucidated by 1D and 2D NMR spectroscopic techniques and acid hydrolysis. Biological evaluation indicated that saponins 1-4 and 7-13 showed moderate cytotoxicity against several human tumor cell lines.


Characterization of cross-reacting antigens on the Epstein-Barr virus envelope and plasma membranes of producer cells.
A rabbit antiserum has been prepared against the B95-8 transforming strain of EBV. The antiserum has a high virus neutralizing titer (approximately 1:1000) against both the marmoset B95-8 EBV and the human P3HR-1 EBV. The neutralizing antibodies may be absorbed completely with EBV producer cell lines, but not with nonproducer cell lines or producer cell lines treated with phosphonoacetic acid (PAA) so as to be nonproducer. After repeated absorption with PAA-treated B95-8, the serum remains reactive with the membranes of producer cell lines as judged by immunofluorescence or the 125I--Staphylococcal protein A radioimmunoassay. Thus the neutralizing antigens are expressed on the membranes of producer cell lines and may be purified from this source using the serum and 125I--Staph A binding as an assay. The ability of the serum to differentiate between producer and nonproducer cells by means of cell surface determinants has been exploited to achieve a separation of these two populations from the same culture. Immunoprecipitation by the protein A technique shows that the serum recognizes two polypeptides from producer cells of approximate molecular weights 150,000 and 75,000.


Cytogenetic and immunologic phenotype findings in Hodgkin's disease.
There are very few chromosome studies using banding techniques of lymph nodes in Hodgkin's disease (HD), and determinations of immunologic phenotypes are scarce. We have performed both cytogenetic and immunologic studies in 12 of 22 lymph node biopsies of different histologic types obtained from 20 HD patients (no mitotic cells were found in the remaining ten lymph nodes). A near-diploid modal number was obtained in 80% of the cases, and 20% showed a bimodal distribution. Clones were observed in 50% of HD lymph nodes, with chromosome markers in 60% of them. Markers 15q+, 5p-, and der(X) and a trisomy of chromosome #21 were observed in our cases. Seventy-one percent of the lymph nodes studied showed a predominance of T lymphocytes. Within the lymph nodes, where the karyotype was determined, 4/12 lymph nodes presented a predominance of B lymphocytes, and they were all included in the group with structural chromosome abnormalities.


Chemerin-induced macrophages pyroptosis in fetal brain tissue leads to cognitive disorder in offspring of diabetic dams.
Chemerin is highly expressed in the serum, placenta tissue, and umbilical cord blood of diabetic mother; however, the impact of chemerin on cognitive disorders of offspring from mothers with diabetes in pregnancy remains unclear. A diabetic phenotype in pregnant mice dams was induced by streptozocin (STZ) injection or intraperitoneal injection of chemerin. Behavioral changes in offspring of diabetic dams and nondiabetic controls were assessed, and changes in chemerin, two receptors of chemerin [chemerin receptor 23 (ChemR23) and chemokine (C-C motif) receptor-like 2 (CCRL2)], macrophages, and neurons in the brain tissue were studied to reveal the underlying mechanism of the behavioral changes. Chemerin treatment mimicked the STZ-induced symptom of maternal diabetes in mice along with the altered behavior of offspring in the open field test (OFT) assay. In the exploring process for potential mechanism, the brain tissues of offspring from chemerin-treated dams were observed with an increase level of macrophage infiltration and a decrease number of neuron cells. Moreover, an increased level of NOD-like receptor family pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like (Asc) protein as well as pyroptosis [characterized by increased active caspase-1 content and secretion of cytokines such as interleukin (IL) 1 beta (IL-1β) and IL-18] more activated in macrophages is also observed in the brain of these diabetic dam's offspring, in the presence of ChemR23. In vitro, it was found that pyroptosis activation was increased in macrophages separated from the abdominal cavity of normal mice, after chemerin treatment. However, depletion of CCRL2 decreased the level of chemerin in the brain tissues of diabetic dams' offspring; depletion of ChemR23 decreased macrophage pyroptosis, and depletion of either receptor reversed chemerin-mediated neurodevelopmental deficits and cognitive impairment of offspring of diabetic pregnant dams. Chemerin induced diabetic pregnant disease and CCRL2 were required to enrich chemerin in the brain of offspring. Aggregation of chemerin could lead to macrophage recruitment, activation of pyroptosis, the release of inflammatory cytokines, a decrease in the number of neurons, and cognitive impairment in offspring in a ChemR23-dependent manner. Targeting CCRL2 and/or ChemR23 could be useful for treating neuropsychological deficits in offspring of dams with diabetes in pregnancy.


The effects of tocolysis on neonatal septic death in women with PPROM: a retrospective cohort study.
In women with preterm premature rupture of membranes (PPROM), particularly those with suspected chorioamnionitis, the benefit of tocolysis on neonatal outcome remains unclear. Our purpose was to evaluate the effect of tocolysis on neonatal septic death in women with PPROM with and without chorioamnionitis. A retrospective cohort study was used to address our study objective. We created a cohort consisting of all live births between 24 and 32 weeks' gestation that were registered in the Linked Birth and Infant Death data files (2009-2013) from the United States. Multivariate logistic regression was used to evaluate the effect of tocolysis on neonatal septic death at 7 and 28 days in births with and without chorioamnionitis. Of the 46,968 births that met our inclusion criteria, tocolysis was administered to 6264 (13.3%). Tocolysis was more commonly prescribed to Caucasians, smokers, in multiple birth pregnancies, and to women with a history of preterm births. Tocolysis was not significantly associated with neonatal septic death at 7 days (OR 0.66, 95% CI 0.39-1.13) or at 28 days (OR 0.85, 95% CI 0.60-1.19). This was consistent in pregnancies with and without chorioamnionitis. Furthermore, tocolysis was associated with a reduced risk of neonatal septic death at 7 days when administered between 24 and 27 weeks' gestation (OR 0.44, 95% CI 0.22-0.88). In the setting of PPROM, tocolysis does not appear to increase the risk of neonatal septic death at 7 and 28 days. Therefore, consideration should be given to its administration if clinically indicated.


Application of FISH to complex chromosomal rearrangements associated with chronic myelogenous leukemia.
Identification of complex chromosomal rearrangements can be difficult, due either to the limited number and sometimes poor quality of metaphases in bone marrow preparations or to the nature of the rearrangements. Fluorescence in situ hybridization (FISH) using chromosome-specific DNA libraries in conjunction with a cosmid probe for the c-ABL oncogene was performed to substantiate the preliminary G-banded karyotypes of six patients with chronic myelogenous leukemia (CML). Our results indicate that FISH is sufficiently sensitive to detect complex and subtle rearrangements, even in bone marrow preparations with suboptimal metaphases, and can provide valuable corroborative information.


Analysis of 665 thyroid nodules using both EU-TIRADS and ACR TI-RADS classification systems.
Ultrasound-based classification systems allow stratification of thyroid nodules to recommend fine-needle aspiration (FNA) based on their malignancy risk. However, these have discrepancies that may have an impact in thyroid cancer detection. We aimed to compare European Thyroid Association (EU-TIRADS) and American College of Radiology (ACR TI-RADS), in terms of FNA indication and diagnostic performance. Retrospective study of 665 thyroid nodules from 598 patients who underwent ultrasound and fine-needle aspiration at a tertiary-care institution between January 1st of 2016 and July 31st of 2019. Based on their sonographic features they were classified according to the EU-TIRADS and ACR TI-RADS classification and then their cytological results were obtained. Differences in FNA indications according to these two classifications were analysed. In patients who underwent surgical removal of the nodules, the final pathological diagnosis was obtained. A statistically significant association was found between EU-TIRADS and ACR TI-RADS classification systems (p < 0.001). ACR TI-RADS allowed greatest reduction in FNA performed (32% vs 24.5%). A different risk category was obtained in 174 (26.1%) nodules, mostly higher with EU-TIRADS. The indication to FNA changed in 54 (8.1%) nodules (49 only indicated following EU-TIRADS recommendations), of which 4 had Bethesda IV and 5 had Bethesda III cytology. The FNA indication in a higher number of nodules using EU-TIRADS was due to difference in the dimensional threshold for FNA on low-risk nodules; to the fact that hypoechogenicity in a mixed nodule ascribes it moderate risk, while using ACR TI-RADS it would only be considered of low risk, and to the use of isolated sonographic features, namely marked hypoechogenicity, microcalcifications and irregular margins, to automatically categorize a nodules as high risk in EU-TIRADS, while ACR TI-RADS requires a group of potentially suspicious features to consider a nodule of high risk. The analysis of pathology proven nodules revealed equally good sensitivity of both systems in the detection of malignancy, but weak specificity, slightly greater with ACR TI-RADS (27.1% vs 18.6%). The EU-TIRADS and ACR TI-RADS are both suitable to assess thyroid nodules and through risk stratification avoid unnecessary FNA. FNA was less performed using ACR TI-RADS, which was slightly more efficiency in excluding malignancy.


Controlled study of the frequency of anti-HSP 70 with the ELISA and the Western Blot methods in patients with Ménière Disease.
To establish the frequency of auto-antibodies anti-HSP 70 using ELISA and Western Blot (WB) methods and to compare the results of each method among patients with the Ménière's Disease (MD) and internal ear diseases (IED) who do not fulfill criteria for MD. Sensibility, specificity and predictive values of anti-HSP70 test in diagnosis of MD were calculated. Prospective, case-control. Blood samples were collected from 31 patients with MD and 78 patients with non Ménière IED. Data regarding cochlear and vestibular symptoms were obtained and blood sample was tested. ELISA tests results were positive in 4(13%) patients and results of WB were positive in 8(26%) patients. Among patients with positive ELISA results, 1 patient presented active disease and in the remaining 3 patients the disease was inactive. Among the 8 WB positive patients, only 2 patients presented active disease. Statistical analyses did not establish any association between serologic findings and clinical factors of MD. The presence of anti-HSP70 using the ELISA and the WB methods did not demonstrate clinical value for the diagnosis of MD. We did not find association between idiopathic MD nor unspecific etiology MD and the presence of anti-HSP70 auto-antibodies.


Dosimetry in magnetic fields with dedicated MR-compatible ionization chambers.
MR-integrated radiotherapy requires suitable dosimetry detectors to be used in magnetic fields. This study investigates the feasibility of using dedicated MR-compatible ionization chambers at MR-integrated radiotherapy devices. MR-compatible ionization chambers (Exradin A19MR, A1SLMR, A26MR, A28MR) were precisely modeled and their relative response in a 6MV treatment beam in the presence of a magnetic field was simulated using EGSnrc. Monte Carlo simulations were carried out with the magnetic field in three orientations: the magnetic field aligned perpendicular to the chamber and beam axis (transverse orientation), the magnetic field parallel to the chamber as well as parallel to the beam axis. Monte Carlo simulation results were validated with measurements using an electromagnet with magnetic field strength upto 1.1 T with the chambers in transverse orientation. The measurements and simulation results were in good agreement, except for the A26MR ionization chamber in transverse orientation. The maximum increase in response of the ionization chambers observed was 8.6% for the transverse orientation. No appreciable change in chamber response due to the magnetic field was observed for the magnetic field parallel to the ionization chamber and parallel to the photon beam. Polarity and recombination correction factor were experimentally investigated in the transverse orientation. The polarity effect and recombination effect were not altered by a magnetic field. This study further investigates the response of the ionization chambers as a function of the chambers' rotation around their longitudinal axis. A variation in response was observed when the chamber was not rotationally symmetric, which was independent of the magnetic field.


[Interest of image-guided radiotherapy for brain tumors and positioning control].
A narrow therapeutic index and more and more patients with long survival characterize primary and second brain tumors. Image-guided radiotherapy can increase accuracy of the patient's position during a course of intracranial irradiation thanks to a direct or indirect visualization of targets volumes. Treatment reproducibility and organ at risk-sparing are the primary issues, particularly with the development of stereotactic radiotherapy and protontherapy. Regarding intracranial treatments, image-guided radiotherapy seems to be a repetitive task based on skeletal structures registration. And yet, this innovation makes possible to assess the dosimetric impact of daily positioning variations avoiding invasive immobilizations. Image-guided radiotherapy offers automated tools to limit time consumption and furthers adaptive radiotherapy opportunities. Nevertheless, medical evaluation is still necessary and image processing should be strictly defined (frequency, use, performance). The purpose of this article is to describe image-guidance in brain irradiation, as repositioning tool and to focus on its recent prospects.


Uptake and degradation of low density lipoproteins (LDL) by confluent, contact-inhibited bovine and human endothelial cells exposed to physiological concentrations of LDL.
Metabolism of low density lipoproteins (LDL) was studied in cultures of endothelial cells derived from bovine aorta or heart and from human umbilical veins. At low LDL concentrations nonconfluent cultures of bovine endothelial cells catabolized more LDL protein than contact-inhibited confluent cultures but this difference was reduced at high LDL concentrations. Nonconfluent human endothelial cells displayed also a higher rate of LDL degradation than their contact-inhibited counterparts, but this difference was less pronounced than in the bovine cells. Bovine endothelial cells grown in the presence of fibroblast growth factor metabolized less LDL than those cultured without fibroblast growth factor (FGF), but this difference was not consistent in the human endothelial cells. The data presented provide evidence that contact-inhibited confluent human endothelial cells are capable of catabolizing LDL when exposed to physiological concentrations of this lipoprotein.


[An oral health program for preschool children in Araraquara, SP-results during 1988].
This paper reports the composition change of the dmf-teeth index, outcome from dental health program for the 3 to 6 year old pre-school children population, enrolled in kindergartens in Araraquara-SP, in 1988. The program performance promotes a major contribution of the "f" component to the dmf-teeth index.


Efficient entry inhibition of human and nonhuman primate immunodeficiency virus by cell surface-expressed gp41-derived peptides.
Membrane-anchored C-peptides (for example, maC46) derived from human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41 effectively inhibit HIV-1 entry in cell lines and primary human CD4+ cells in vitro. Here we evaluated this gene therapy approach in animal models of AIDS. We adapted the HIV gp41-derived maC46 vector construct for use in rhesus monkeys. Simian immunodeficiency virus (SIV and SHIV) sequence-adapted maC46 peptides, and the original HIV-1-derived maC46 expressed on the surface of established cell lines blocked entry of HIV-1, SIVmac251 and SHIV89.6P. Furthermore, primary rhesus monkey CD4+ T cells expressing HIV sequence-based maC46 peptides were also protected from SIV entry. Depletion of CD8+ T cells from PBMCs enhanced the yield of maC46-transduced CD4+ T cells. Supplementation with interleukin-2 (IL-2) increased transduction efficiency, whereas IL-7 and/or IL-15 provided no additional benefit. Phenotypic analysis showed that maC46-transduced and expanded cells were predominantly central memory CD4+ T cells that expressed low levels of CCR5 and slightly elevated levels of CD62L, beta7-integrin and CXCR4. These findings show that maC46-based cell surface-expressed peptides can efficiently inhibit primate immunodeficiency virus infection, and therefore serve as the basis for evaluation of this gene therapy approach in an animal model for AIDS.


Type IV congenital laryngeal web: Case report and 15 year follow up.
A five day old patient with mild VACTERL syndrome had repair of a type IV congenital laryngeal web with successful decannulation 76 days later. Voice and respiratory outcome is good with follow up 15 years later. This case presents a rare clinical finding of a type IV laryngeal web successfully repaired with a keel and subsequent long term follow up during an era when it was suggested that repair be delayed until 18 months of age at the earliest.


[Change of corneal thickness after laser in situ keratomileusis].
The corneal thickness was measured in and after in situ keratomileusis (LASIK) to investigate the accurate ablation depth on cornea during the operation and the possible mechanism of myopic after operation. From August 1999 to June 2000, 650 myopia patients were treated by LASIK. The changes in cornea thickness were measured before, during and 1 week, 1, 3, 6 and 12 month after the surgery. By the measurement of cornea thickness during the operation, the real cornea ablated thickness was (32.15 +/- 7.23) micro m different from the expected value. Central thickness of the cornea and the refraction could be stable in six months after the operation. The cornea thickness and the refraction would be stable in six months after the operation. Age of the patients is the key factor that influences the stability of ocular refraction.


Does therapeutic hypothermia reduce acute kidney injury among term neonates with perinatal asphyxia?--a randomized controlled trial.
The objective of this study is to evaluate whether therapeutic hypothermia reduces the incidence of acute kidney injury (AKI) among term neonates perinatal asphyxia. This randomized controlled trial conducted in a tertiary care teaching hospital, south India included 120 term neonates with perinatal asphyxia who were randomized to receive either therapeutic hypothermia or standard supportive care. Renal parameters of neonates in both the groups were monitored and AKI was ascertained as per Acute Kidney Injury Network criteria. The incidence of AKI was less in therapeutic hypothermia group compared to standard treatment group (32% versus 60%, p < 0.05). The incidence of Stages 1, 2, and 3 AKI was 22%, 5%, and 5% in therapeutic hypothermia group compared with 52%, 5%, and 3%, respectively, in the standard treatment group. The mortality was less in therapeutic hypothermia group compared with the standard treatment group (26% versus 50%, p < 0.05). Therapeutic hypothermia reduces the incidence and severity of AKI among term neonates with perinatal asphyxia.


Weekly mitoxantrone therapy of Hodgkin's disease, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. A Southeastern Cancer Study Group Trial.
A weekly schedule of mitoxantrone was evaluated in chronic lymphoproliferative disorders. One of 11 patients with Hodgkin's disease, 2 of 12 with favorable-histology non-Hodgkin's lymphoma, 4 of 27 with unfavorable-histology non-Hodgkin's lymphoma, and 1 of 11 with chronic lymphocytic leukemia showed a response. Since the use of a larger single dose every 3 weeks is well tolerated, simpler, and probably more effective, we do not recommend further evaluation of the weekly dose schedule.


Impact of Managed Entry Agreements on availability of and timely access to medicines: an ex-post evaluation of agreements implemented for oncology therapies in four countries.
Despite the increased utilisation of Managed Entry Agreements (MEAs), empirical studies assessing their impact on achieving better access to medicines remains scarce. In this study we evaluated the role of MEAs on enhancing availability of and timely access to a sample of oncology medicines that had received at least one prior rejection from reimbursement. Funding decisions and their respective timelines for all oncology medicines approved between 2009 and 2018 in Australia, England, Scotland and Sweden were studied. A number of binary logit models captured the probability (Odds ratio (OR)) of a previous coverage rejection being reversed to positive after resubmission with vs. without a MEA. Gamma generalised linear models were used to understand if there is any association between time to final funding decision and the presence of MEA, among other decision-making variables, and if so, the strength and direction of this association (Beta coefficient (B)). Of the 59 previously rejected medicine-indication pairs studied, 88.2% (n = 45) received a favourable decision after resubmission with MEA vs. 11.8% (n = 6) without. Average time from original submission to final funding decision was 404 (± 254) and 452 (± 364) days for submissions without vs. with MEA respectively. Resubmissions with a MEA had a higher likelihood of receiving a favourable funding decision compared to those without MEA (43.36 < OR < 202, p < 0.05), although approval specifically with an outcomes-based agreement was associated with an increase in the time to final funding decision (B = 0.89, p < 0.01). A statistically significant decrease in time to final funding decision was observed for resubmissions in Australia and Scotland compared to England and Sweden, and for resubmissions with a clinically relevant instead of a surrogate endpoint. MEAs can improve availability of medicines by increasing the likelihood of reimbursement for medicines that would have otherwise remained rejected from reimbursement due to their evidentiary uncertainties. Nevertheless, approval with a MEA can increase the time to final funding decision, while the true, added value for patients and healthcare systems of the interventions approved with MEAs in comparison to other available interventions remains unknown.


Raman spectroscopic sensing of carbonate intercalation in breast microcalcifications at stereotactic biopsy.
Microcalcifications are an early mammographic sign of breast cancer and frequent target for stereotactic biopsy. Despite their indisputable value, microcalcifications, particularly of the type II variety that are comprised of calcium hydroxyapatite deposits, remain one of the least understood disease markers. Here we employed Raman spectroscopy to elucidate the relationship between pathogenicity of breast lesions in fresh biopsy cores and composition of type II microcalcifications. Using a chemometric model of chemical-morphological constituents, acquired Raman spectra were translated to characterize chemical makeup of the lesions. We find that increase in carbonate intercalation in the hydroxyapatite lattice can be reliably employed to differentiate benign from malignant lesions, with algorithms based only on carbonate and cytoplasmic protein content exhibiting excellent negative predictive value (93-98%). Our findings highlight the importance of calcium carbonate, an underrated constituent of microcalcifications, as a spectroscopic marker in breast pathology evaluation and pave the way for improved biopsy guidance.


The metabolism of 3-methoxyamphetamine in dog, monkey and man.
1. The metabolism of 3-methoxyamphetamine in vivo was examined in dog, monkey and man. 2. The metabolites identified in all three species were 3-O-methyl-alpha-methyldopamine, 1-(3-methoxy-4-hydroxyphenyl)propan-2-ol, 3-hydroxyamphetamine, 1-(3-hydroxyphenyl)propan-2-one, 1-(3-hydroxyphenyl)propan-2-ol, 1-(3-methoxyphenyl)propan-2-ol and 1-(3-methoxyphenyl)propane-1,2-diol. 3. 1-Hydroxyl-1(3-hydroxyphenyl)propan-2-one was tentatively identified in the urine of all three species. 4. 4-O-Methyl-alpha-methyldopamine was also found in the urine of dog and monkey but not in human urine.


[Morphological characteristics of acute viral hepatitis].
From the literature and their own observations the authors present morphological criteria of acute viral hepatitis which may be used for differential diagnosis from hepatites of other etiology (toxic, drug). Examinations of liver biopsies from patients with viral hepatitis permit to establish the stage of the disease and to predict its possible outcomes.


Polysaccharides from fermented coix seed modulates circulating nitrogen and immune function by altering gut microbiota.
Coix lachryma-jobi L. seed is an important food item in Asia with culinary and medicinal values. The effects of non-fermented coix seed (NFC), fermented coix seed with Lactobacillus plantarum NCU137 (FC) and polysaccharides from NFC, FC (FCP) on mice circulating nitrogen and immune disorder induced by high relative humidity (RH, 90 ± 2%) exposure were compared. All the treatments reduced circulating nitrogen (BUN and ammonia) might via increasing excretion of fecal nitrogen induced by altering gut microbiota. In comparison, FC and FCP restored erythrocyte morphology by promoting erythrocyte Na+/K+ ATPase activity more effectively, and immune function was modulated by reducing plasma IgM and IFN-γ levels, up-regulating IL-4 and IL-6 levels. Herein, these results indicated that FCP, as the main active ingredient in FC, modulated circulating nitrogen through altering gut microbiota, and restored immune homeostasis by regulating Th1/Th2 cytokines in mice receiving high RH exposure.


Healthcare improvement as planned system change or complex responsive processes? a longitudinal case study in general practice.
Interest in how to implement evidence-based practices into routine health care has never been greater. Primary care faces challenges in managing the increasing burden of chronic disease in an ageing population. Reliable prescriptions for translating knowledge into practice, however, remain elusive, despite intense research and publication activity. This study seeks to explore this dilemma in general practice by challenging the current way of thinking about healthcare improvement and asking what can be learned by looking at change through a complexity lens. This paper reports the local level of an embedded case study of organisational change for better chronic illness care over more than a decade. We used interviews, document review and direct observation to explore how improved chronic illness care developed in one practice. This formed a critical case to compare, using pattern matching logic, to the common prescription for local implementation of best evidence and a rival explanation drawn from complexity sciences interpreted through modern sociology and psychology. The practice changed continuously over more than a decade to deliver better chronic illness care in line with research findings and policy initiatives--re-designing care processes, developing community linkages, supporting patient self-management, using guidelines and clinical information systems, and integrating nurses into the practice team. None of these improvements was designed and implemented according to an explicit plan in response to a documented gap in chronic disease care. The process that led to high quality chronic illness care exhibited clear complexity elements of co-evolution, non-linearity, self-organisation, emergence and edge of chaos dynamics in a network of agents and relationships where a stable yet evolving way of organizing emerged from local level communicative interaction, power relating and values based choices. The current discourse of implementation science as planned system change did not match organisational reality in this critical case of improvement in general practice. Complexity concepts translated in human terms as complex responsive processes of relating fit the pattern of change more accurately. They do not provide just another fashionable blueprint for change but inform how researchers, policymakers and providers participate in improving healthcare.


Cardiopulmonary function in pectus excavatum.
The results of recent studies clearly support a cardiopulmonary impairment resulting from pectus excavatum, but resolving the apparent discrepancies between studies is necessary. Several factors must be taken into consideration. The severity of the deformity of the chest wall must be defined, whether by the sternovertebral distance or by various means proposed by others. Without some index of the degree of sternal depression, it is impossible to compare patients or results among studies. No study has enrolled a sufficient number of patients to provide an accurate correlation between the severity of the deformity and the extent of the cardiopulmonary deficit, nor has any defined how severe the deformity must be to result in cardiopulmonary dysfunction. The second factor that is important in evaluating results is what controls were used. Studies in which each patient functioned as his own control after surgical repair are preferable. In the pediatric age group where growth and increased pulmonary parameters would be expected, the follow-up studies should be performed at a defined time after surgical treatment. Studies completed years later cannot assess the effect of surgical repair upon cardiopulmonary function. Studies wherein persons matched for age and height to serve as controls are available from the same laboratory are also needed. The degree of co-operation and effort of patients will vary, particularly in the pediatric age group. Constancy of the experimental protocol and personnel is important. Least reliable are reports of experimental findings compared with standardized normal values. In early studies, measurements of vital capacity and total lung capacity produced variable results when compared with normal persons matched for age. The wide range of "normal values" makes statistical comparison difficult, if not impossible. A wide spectrum of cardiopulmonary function exists among individuals, depending upon prior physical training and body habitus. Sufficient physiologic reserve is generally present, such that extensive impairment must exist before patients become symptomatic at rest. Physiologic reserve during exercise is rapidly consumed and differences can be more readily determined. Exercise studies must go beyond the measurement of intracardiac pressures and pulmonary volumes at rest.(ABSTRACT TRUNCATED AT 250 WORDS)


Investigations on the quantitative determination of nickel and chromium in human lung tissue. Industrial medical, toxicological, and occupational medical expertise aspects.
Nickel (Ni) and some of its relatively insoluble compounds as well as chromates may be able to induce cancer in the region of the lungs, as well as in the nose and paranasal sinuses after occupational exposure. Latency periods may amount to 20 years and more. The results of recent investigations have shown that these metals cumulate in the lung tissue after inhalation of relatively insoluble chromium and nickel compounds. The quantitative detection of these heavy metals in samples of pulmonary tissue hence permits the amount of past exposure to be estimated. To establish the normal values, samples of pulmonary tissue from 30 normal subjects were investigated for chromium and nickel content. The samples were taken from different segments and lobes of the lungs, taking topographical anatomical criteria into consideration. In addition, 15 persons who had formerly been exposed to nickel and/or chromium (11 nickel refinery workers, of whom 10 had died of lung cancer, 2 stainless steel welders, 1 foundry worker, 1 electrical technician) were also investigated. From the results of 495 tissue samples from the normal group, median chromium concentrations between 130 and 280 ng/g were calculated, with median nickel concentrations of 20-40 ng/g (wet weight). If these values are related to the nickel concentrations measured in refinery workers, values 112-5,860 times higher were found. The concentrations were about 500 times higher than normal for nickel, and about 60 times higher than normal for chromium in the stainless steel welders. For the foundry workers who died of lung cancer, chromium and nickel concentrations in the normal range were calculated, with the exception of the nickel concentrations in the upper and lower lobes of the right lung. The very high nickel concentrations found in the samples of lung tissue from former nickel refinery workers should be regarded as a guideline with regard to the appraisal of the causal relationship between lung cancer and occupational exposure to relatively insoluble nickel compounds. This result is also supported by epidemiological investigations on this subgroup and must thus be considered etiologically conclusive. For the welders, chromium and nickel concentrations were found that were markedly above normal, but as yet there is no epidemiologically reliable verification for the increased occurrence of malignancies in this occupational group.(ABSTRACT TRUNCATED AT 400 WORDS)


Simultaneous superior oblique tenotomy and inferior oblique recession in Brown's syndrome.
The technique and results of simultaneous superior oblique tenotomy and 14-mm inferior oblique recession for true Brown's syndrome are presented for 16 eyes of 13 patients. A good or excellent result was achieved in 15 of 16 eyes (94%). Reoperation for overcorrection was not necessary; however, repeat tenotomy was required in two cases. Inferior oblique underaction was present in 12 of 16 eyes (75%) in the early postoperative period; however, elevation in adduction improved over time. At most recent examination, 92% of eyes demonstrated greater than 25 degrees elevation in adduction. Underaction of the superior oblique occurred in 3 of 16 eyes (19%). A simultaneous superior oblique tenotomy and inferior oblique recession is recommended in all patients selected to undergo surgery for true Brown's syndrome to prevent reoperation for iatrogenic superior oblique palsy.


Coordination Flexibility Aided CO2 -specific Gating in an Iron Isonicotinate MOF.
Coordination flexibility assisted porosity has been introduced into an Iron-isonicotinate metal-organic framework (MOF), (Fe(4-PyC)2 ⋅ (OH). The framework showed CO2 -specific gate opening behavior, which gets tuned as a function of temperature and pressure. The MOF's physisorptive porosity towards CO2 , CH4 , and N2 was investigated; it adsorbed only CO2 via a gate opening phenomenon. The isonicotinate, representing a borderline soft base, is bound to the hard Fe3+ centre through monodentate carboxylate and pyridyl nitrogen. This moderately weak binding enables isonicotinate to spin like a spindle under the CO2 pressure opening the gate for a sharp increase in CO2 uptake at 333 mmHg (At 298 K, the CO2 uptake increases from 0.70 to 1.57 mmol/g). We investigated the MOF's potential for CO2 /N2 and CO2 /CH4 gas separation aided by this gating. IAST model reveals that the CO2 /N2 selectivity jumps from 325 to 3131 when the gate opens, while the CO2 /CH4 selectivity increases three times. Interestingly, this Fe-isonicotinate MOF did not follow the trend set by our earlier reported Hard-Soft Gate Control (established for isostructural M2+ -isonicotinate MOFs (M=Mg, Mn)). However, we account for this discrepancy using the different oxidation state of metals confirmed by X-ray photoelectron spectroscopy and magnetism.


Biosynthesis and turnover of a Mr = 110,000 glycoprotein localized to the hepatocyte bile canaliculus.
Antiserum was raised in rabbits against a bile canalicular glycoprotein of Mr = 110,000 purified to homogeneity from of rat liver. The antisera specifically immunoprecipitated a Mr = 110,000 polypeptide from hepatocytes metabolically labeled with [35S]methionine. When hepatocytes in primary culture were incubated with tunicamycin before labeling with [35S]methionine in the presence of tunicamycin, the major polypeptide immunoprecipitated by the specific antiserum from Triton X-100 extracts of cells had a molecular weight of 59,000. Enzymatic removal of N-linked carbohydrates from the Mr = 110,000 glycoprotein by N-glycanase digestion also yielded a polypeptide with minimum Mr = 59,000. In pulse-chase experiments using [35S]methionine, the Mr = 110,000 protein detected by the specific antisera first appears as Mr = 85,000 and 75,000 intermediate species which are endoglycosidase H sensitive. The Mr = 85,000 intermediate form is lost first with time followed by the Mr = 75,000 form giving rise to the Mr = 110,000 form that is endoglycosidase H resistant. Neuraminidase digestion of the Mr = 110,000 form generated an Mr 85,000 form but with a different carbohydrate structure than the intermediate Mr 85,000 form detected in the pulse-chase experiments. The time required to accomplish the processing of the Mr = 85,000 and 75,000 forms is relatively slow. Finally, the terminal sugars are added and the mature Mr = 110,000 glycoprotein is rapidly transported to the cell surface. A minimum time of 90 min is required for the Mr = 110,000 bile canalicular glycoprotein to be synthesized, processed, and reach the cell surface which is long relative to the time required (10 min) for another domain-specific protein, the receptor for asialoglycoproteins, to reach the sinusoidal surface. The Mr = 110,000 bile canalicular glycoprotein turns over in the bile canalicular domain with a half-life of 43 h while the asialoglycoprotein receptor turns over in the sinusoidal domain with a half-life of 23 h.


Promoting scientific integrity in nursing research. Part I: Current approaches in doctoral programs.
Schools of nursing with doctoral programs were surveyed to determine current approaches and elicit suggestions for institutional- and professional-level strategies to promote scientific integrity. Results from 38 schools are reported in a two-part series. Part 1 reports findings concerning formal and informal instruction about responsible science and the standards, norms, and guidelines being used to direct scientific inquiry. Information on misconduct and scientific integrity was typically included in required research methods, courses, and optional workshops, but the extent and scope of the instruction was variable, and a majority of respondents judged it to be marginal or inadequate. A high value was placed on informal student-mentor interaction. Where they existed, institutional guidelines were more specific than federal guidelines, but dealt primarily with procedures for handling alleged misconduct rather than for promoting responsible science. Findings suggest the need for a more proactive and consistent approach to promoting scientific integrity in doctoral programs.


[Effect of phospholipomannan of Candida albicans on the production of interleukin 6 and interleukin 8 in monocytes].
To investigate whether Candida albicans-native phospholipomannan (PLM) induce an inflammation response through Toll-like receptor(TLRé2 in human acute monocytic leukemia cell line (THP-1) cells. Human THP-1 monocytes were challenged with PLM in vitro. The mRNA expressions of TLR2, TLR4, proinflammatory cytokine [interleukin(IL)-6], and chemokine (IL-8) were assayed by real time reverse transcription polymerase chain reaction. The secretions of IL-6 and IL-8 were measured by enzyme-linked immunosorbent assay. The expression of TLR2 was analyzed with Western blot. PLM increased the mRNA expressions and secretions of proinflammatory cytokines (IL-6) and chemokines (IL-8) in THP-1 cells (all P=0.0000). PLM up-regulated the mRNA and protein levels of TLR2 (P=0.0000), whereas the mRNA level of TLR4 was not altered. PLM hydrolyzed with β-D-mannoside manno hydrolase failed to induce gene and protein expressions of TLR2, IL-6, and IL-8. Anti-TLRS-neutralizing antibody blocked the PLM-induced secretions of IL-6 and IL-8 in THP-1 cells (P = 0.0003, P = 0.0010). Canidada albicans-native PLM may contribute to the inflammatory responses during Candida infection in a TLR2-dependent manner.


Impact of serum biomarkers and clinical factors on intensive care unit mortality and 6-month outcome in relatively healthy patients with severe pneumonia and acute respiratory distress syndrome.
This study aimed to identify the independent biomarkers and clinical factors that could predict ICU mortality and 6-month outcomes in relatively healthy patients with severe pneumonia and acute respiratory distress syndrome (ARDS). We prospectively enrolled patients with severe pneumonia-related ARDS that required mechanical ventilation. Patients were excluded if they were unable to take care of themselves. Several biomarkers and clinical factors were evaluated prospectively on day 1 and day 3 after ICU admission. All biomarkers and clinical factors were collected for analysis. 56 patients were enrolled in this study. We determined that the initial appropriate antibiotics use was an independent clinical factor and day 1 high-mobility group protein B1 (HMGB1) concentration was an independent biomarker for ICU mortality. Interestingly, we also found that a low day 1 albumin level was an independent biomarker for predicting patient life dependence 6 months after a pneumonia event. Patients with severe pneumonia and ARDS requiring mechanical ventilation experience high rates of ICU mortality or disability, even if they were quite healthy before. Initial appropriate antibiotics use and day 1 level of HMGB1 were independent factors for predicting ICU mortality. Day 1 albumin level was predictive of 6-month patient life dependence.


Stage-specific protein synthesis by asexual blood stage parasites of Plasmodium knowlesi.
P. knowlesi parasites with a maximum age distribution of 3 h were metabolically labelled with [35S]methionine during 9 sequential non-overlapping intervals, from young rings to mature segmented schizonts. The proteins synthesised at the different stages were compared using sodium dodecyl sulphate-polyacrylamide gel electrophoresis; more than 40 polypeptides (Mr 20 000 to over 200 000) were identified in the different parasite preparations. The major polypeptides synthesised by rings and trophozoites of different ages were similar, but differences in minor polypeptides could always be recognised. At the onset of schizogony ring and trophozoite specific proteins ceased to be synthesised and proteins specific to schizogony emerged. In general, schizont-specific proteins were of higher molecular weight than ring stage proteins. Details of the morphological changes which occurred during the metabolic labelling episode permits correlation between parasite structure and synthesis of particular polypeptides. Comparison of parasite components metabolically labelled with [3H]glucosamine during defined periods of development also revealed stage-specific synthesis of glycoproteins. The extent to which proteins are altered after synthesis has been investigated by pulse-chase experiments.


Outcome of self-inflicted gunshot wounds of the brain.
A consecutive series of 67 patients who had sustained self-inflicted gunshot wounds of the brain was reviewed retrospectively to evaluate factors determining outcome. Weapon caliber, site of bullet entry, degree of brain wounding on computerized tomographic scan, and presenting Glasgow Coma Scale (GCS) score were examined. Overall mortality, degree of disability in survivors, and survival time after injury in fatally wounded patients were assessed. Ninety-eight percent of all patients with an initial GCS score of 8 or less died. When the GCS score was more than 8, 91% of patients survived (P less than .0001). Survival rate was significantly increased in patients with injury limited to one lobe of the brain, compared with patients with brain wounds of greater severity demonstrated on computerized tomographic scan (P less than .05), while a missile crossing both vertical anatomic planes of the brain or coming to rest in the posterior fossa was lethal in 100% of cases. Survivors scored relatively well on the Glasgow Outcome Scale. Almost all (98%) fatally injured patients maintained vital functions for a time ample for transportation and evaluation at a major referral center. These findings hold important implications for trauma center and critical care resource allocation as well as organ transplantation programs.


Interrelation of ethylene glycol, urea and water transport in the red cell.
The reflection coefficient, sigma j, which measures the coupling between the jth solute and water transport across a semipermeable membrane, varies between 0 and 1.0. Values of sigma j significantly less than 1.0 provide irreversible thermodynamic proof that there is coupling between the transport of solute and solvent and thus that they share a common pathway. We have developed an improved method for measuring sigma and have used it to determine that sigma ethylene glycol = 0.71 +/- 0.03 and sigma urea = 0.65 +/- 0.03, in agreement with many, but not all, previous determinations. Since both of these values are significantly lower than 1.0, they show that there is a common ethylene glycol/water pathway and a common urea/water pathway. Addition of first one and then two methyl groups to urea increases sigma to 0.89 +/- 0.04 for methylurea and 0.98 +/- 0.4 for 1,3-dimethylurea, consistent with passage through an aqueous pore with a sharp cutoff in the 6-7 A region.


Magnetic resonance imaging is a complementary method to stereological measurement of testicular volume.
The objective of our research was to determine the accuracy and precision of the Cavalieri principle with images obtained from magnetic resonance imaging (MRI) in estimation of the actual testicular volume in humans. We performed volume measurements of 42 testes from 21 patients scheduled for bilateral orchiectomy for prostate cancer. We performed volume estimation measurements with ultrasonography (US), Prader's orchidometer (PrOM), and Cavalieri principle MRI (we used views in axial sagittal and planes) before orchiectomy. We measured actual testes volume with the fluid displacement technique after orchiectomy. Differences and correlations between estimated and actual volumes were evaluated. For all patients, we compared right and left testicular volumes independently with these measurements. Mean +/- SD actual testicular volume and estimated testicular volumes with US, PrOM, and Cavalieri principle using MRI axial and sagittal images were 15.3 +/- 3.3 and 17.7 +/- 3.0 cm(3), 20.0 +/- 3.5 cm(3), and 16.0 +/- 3.7 and 16.0 +/- 3.6 cm(3), respectively. Estimated and measured volumes were not different from each other. US and PrOM measured volumes were correlated with the actual volume. However, r-values with Pearson correlation test for estimated volumes measured with the Cavalieri principle with MRI were higher than US and PrOM (r-values were 0.934 and 0.961 vs 0.919 and 0.757, respectively). The results of this study demonstrate that testicular volume measurements with the Cavalieri principle using images obtained from MRI may be considered a complementary method to traditional techniques to estimate the actual testicular volume.


Acute renal failure due to profound haemolysis--an unusual complication of cusp rupture in cardiac bioprostheses.
Haemolysis due to prosthetic cardiac valves is well documented in the literature, with an increased incidence in mechanical prostheses as compared to bioprostheses. We report this unusual complication in two patients who developed profound haemolysis rapidly resulting in acute renal failure following cusp rupture in mitral Ionescu-Shiley valves. One of the patients developed irreversible renal failure in spite of successful reoperation, while renal function normalized in the second case.


A Phase II Trial of Rivoceranib, an Oral Vascular Endothelial Growth Factor Receptor 2 Inhibitor, for Recurrent or Metastatic Adenoid Cystic Carcinoma.
This open-label, single-arm, phase II study evaluated the vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) rivoceranib in patients with recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC). Eligible patients had confirmed disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) with ≥20% increase in radiologically or clinically measurable lesions or appearance of new lesions within the preceding 6 months. Patients received oral rivoceranib 700 mg once daily. Primary outcomes were objective response rate (ORR) by investigator review and by blinded independent review committee (BIRC). Eighty patients were enrolled and 72 were efficacy evaluable. Seventy-four patients had distant metastases and 49 received prior systemic treatment (14 received VEGFR TKIs). Per investigator and BIRC, respectively, ORR was 15.3% [95% confidence interval (95% CI), 7.9-25.7] and 9.7% (95% CI, 4.0-19.0); median duration of response was 14.9 months (95% CI, 4.9-17.3) and 7.2 months (95% CI, 3.5-8.4); and median progression-free survival was 9.0 months (95% CI, 7.3-11.5) and 9.0 months (95% CI, 7.7-11.5). Grade ≥3 treatment-related adverse events occurred in 56 patients (70.0%); the most common were hypertension (34, 42.5%) and stomatitis (6, 7.5%). Four grade 5 events occurred with one attributed to rivoceranib (epistaxis). Sixty-eight patients (85.0%) had ≥1 dose modifications and 16 patients (20.0%) discontinued rivoceranib for toxicity. In patients with progressing R/M ACC, rivoceranib demonstrated antitumor activity and a manageable safety profile consistent with other VEGFR TKIs.


Accuracy of aortic stenosis severity assessment by Doppler echocardiography: importance of image quality.
The aim of the present study was to investigate which factors could influence the accuracy of aortic stenosis severity assessment by Doppler echocardiography in an unselected population. Doppler echocardiographic determination of mean transvalvular pressure gradient and aortic valve area by continuity equation was performed in 101 patients before catheterization. According to the catheterization data, aortic stenosis was classified into 2 categories: mild to moderate (orifice area [Gorlin formula] > 0.75 cm2, mean transvalvular gradient < 50 mmHg) and severe (orifice area < or = 0.75 cm2, mean transvalvular gradient > or = 50 mmHg). The influence of eight factors on the absolute difference in aortic valve area and mean transvalvular pressure gradient and on the concordant classification in the same category by both methods was investigated. By multivariate analysis, the absolute difference in aortic valve area by both methods was significantly associated with poor image quality, absolute difference between mean catheterization and Doppler transvalvular gradient and inversely related to body mass index. Absolute difference in mean transvalvular gradients by both methods was significantly associated only with image quality. Poor image quality emerged as the only significant factor influencing the concordant classification between invasive and noninvasive studies according to orifice area (but not according to transvalvular pressure gradient). Echographic image quality significantly influences the accuracy of Doppler echocardiographic determination of aortic valve area and, to a lesser extent, of transvalvular pressure gradient. Therefore, the mere noninvasive approach is not suitable to every consecutive patient with aortic stenosis. Qualifications concerning overall image quality should identify patients most likely to benefit from catheterization.


Experiences of staff members participating in primary care research activities: a qualitative study.
The aim of this paper was to study primary care staff members' experiences and perceptions of participating in a randomized controlled trial concerning Internet therapy. Data were collected via five focus groups, each containing four to eight nurses or general practitioners. The systematic text condensation method described by Malterud was used for thematic analysis of meaning and content of data across cases. The informants believed it was important to conduct research within the primary care setting, but it was difficult to combine clinical work and research. They stressed also that there was a need for continuous information and communication between primary care centers and researchers as well as internally at each primary care center. Staff members' experiences of participating in a research study were positive, although associated with various difficulties. It is important to include staff members when designing clinical studies; information should be given continuously during the study and communication facilitated between different occupational groups working at the primary care center.


Expression of ECRG4 is associated with lower proliferative potential of esophageal cancer cells.
We have shown that ECRG4 suppressed Fas-induced apoptosis in Jurkat cells. ECRG4 mRNA expression was ubiquitously detected in normal adult human tissues, suggesting that ECRG4 plays a major role in human tissues. ECRG4 mRNA expression was down-regulated in tumor cells. Expression of ECRG4 suppressed cell growth. We established an anti-ECRG4 monoclonal antibody. Our immunohistochemical analysis demonstrated that ECRG4-positive cells tended to be distributed in the region that was negative for Ki-67 in esophageal squamous cell carcinoma tissues. There was a significant inverse correlation between ECRG4 expression and Ki-67 labeling index in esophageal squamous cell carcinoma. This study provides the first functional evidence for an association of endogenous expression of ECRG4 with cell proliferation. ECRG4 is a candidate tumor suppressor gene that might be involved in the proliferation of esophageal squamous cell carcinoma.


Afferents to brain stem nuclei (brain stem raphe, nucleus reticularis pontis caudalis and nucleus gigantocellularis) in the rat as demonstrated by microiontophoretically applied horseradish peroxidase.
Using a retrograde tracer technique with microiontophoretically applied horseradish peroxidase (HRP), afferent projections to the brain stem raphe nuclei (BR, raphe magnus, pallidus and obscurus) and to two adjacent reticular nuclei, nucleus reticularis pontis caudalis (nRPC) and nucleus gigantocellularis (nGC) were identified. The most striking difference between the afferent projections to the BR and the adjacent nuclei as determined by this method is that afferents to the BR originate primarily from structures rostral to the pons, especially the mesencephalic central gray and the dorsal and ventral tegmentum. In contrast, the two reticular nuclei studied (nGC and nRPC) received afferent projections within or caudal to the pons-medulla. For example, the nGC receives prominent afferent projections from the gray matter of the spinal cord. In addition, evidence for interconnections between all of the adjacent nuclei (BR, nGC and nRPC) was found. Such afferent projections are compatible with the notion that the brain stem raphe nuclei may serve as connections within the brain stem for a descending system, while the nGC may be a relay in a feedback loop between the spinal cord and the reticular formation.


A pilot study to assess the safety and radiological performance of a new low-profile locking plate for high tibial osteotomy.
We report the first results of a new low-profile titanium locking plate for fixation of opening wedge high tibial osteotomy (OWHTO). Short spacer plates have been associated with a high hardware complication rate, whilst fixed angle locking plates have been associated with a high incidence of soft tissue irritation. This plate aims to achieve stable fixation whilst maintaining a low profile, allowing space for combined procedures. All patients undergoing OWHTO with the Activmotion plate were retrospectively reviewed. Patients were allowed to progress to full weight bearing after two weeks. Radiographic assessment included the medial proximal tibial angle (MPTA) and posterior tibial slope at six weeks and then three monthly until union. All complications were recorded. Thirty-seven patients with 40 OWHTOs were included in the study. The mean MPTA increased from 85.2 preoperatively to 91.9 postop. Tibial slope changed from 5.2 to 4.2°. The correction was sustained until union with no loss of correction in the MPTA (median change 0.0, 95% CI for median (-0.25, 0.4)) or tibial slope (mean increase 0.32, 95% CI (-0.02, 0.67)). In this pilot study the Activmotion plate raised no safety concerns with regard to implant related adverse events or loss of initial correction. Early rehabilitation with immediate partial weight bearing was possible and all cases proceeded to osteotomy union with the exception of one case that needed to undergo bone grafting with implant retention. Premature removal of the implant was necessary in four cases due to symptomatic hardware irritation.


Immunomodulatory activity of isoprinosine on experimental viral infections in avian models.
The immunomodulatory activity of Isoprinosine treatments have been experimentally verified on chicken infected by three different viruses: Newcastle disease, fowl plague and avian infectious bronchitis. In protection tests, positive variations in the mean day of death rather than in the mortality rate were found depending on the modality of treatment. A stimulatory influence on primary anti-Newcastle disease virus antibody response was observed. In the avian model the Isoprinosine antiviral effect appears as due mainly to the enhancement of interferon production and to a synergistic interferon-isoprinosine interaction.


A Computational Geometry Approach for Modeling Neuronal Fiber Pathways.
We propose a novel and efficient algorithm to model high-level topological structures of neuronal fibers. Tractography constructs complex neuronal fibers in three dimensions that exhibit the geometry of white matter pathways in the brain. However, most tractography analysis methods are time consuming and intractable. We develop a computational geometry-based tractography representation that aims to simplify the connectivity of white matter fibers. Given the trajectories of neuronal fiber pathways, we model the evolution of trajectories that encodes geometrically significant events and calculate their point correspondence in the 3D brain space. Trajectory inter-distance is used as a parameter to control the granularity of the model that allows local or global representation of the tractogram. Using diffusion MRI data from Alzheimer's patient study, we extract tractography features from our model for distinguishing the Alzheimer's subject from the normal control. Software implementation of our algorithm is available on GitHub (https://github.com/UCSB-VRL/ReebGraph.


Carbon Nanomembranes.
Carbon nanomembranes (CNMs) are synthetic 2D carbon sheets with tailored physical or chemical properties. These depend on the structure, molecular composition, and surroundings on either side. Due to their molecular thickness, they can be regarded as "interfaces without bulk" separating regions of different gaseous, liquid, or solid components and controlling the materials exchange between them. Here, a universal scheme for the fabrication of 1 nm-thick, mechanically stable, functional CNMs is presented. CNMs can be further modified, for example perforated by ion bombardment or chemically functionalized by the binding of other molecules onto the surfaces. The underlying physical and chemical mechanisms are described, and examples are presented for the engineering of complex surface architectures, e.g., nanopatterns of proteins, fluorescent dyes, or polymer brushes. A simple transfer procedure allows CNMs to be placed on various support structures, which makes them available for diverse applications: supports for electron and X-ray microscopy, nanolithography, nanosieves, Janus nanomembranes, polymer carpets, complex layered structures, functionalization of graphene, novel nanoelectronic and nanomechanical devices. To close, the potential of CNMs in filtration and sensorics is discussed. Based on tests for the separation of gas molecules, it is argued that ballistic membranes may play a prominent role in future efforts of materials separation.


Work and social adjustment in patients with anorexia nervosa.
The Work and Social Adjustment Scale (WSAS) assesses patients' perceptions of impairment in everyday functioning and has been reported as a simple and reliable self-report measure in different psychiatric disorders. This study compared WSAS data from an anorexia nervosa (AN) patient group with that from healthy controls (HCs) and published data from other patient groups. A total of 160 female participants (AN, 77; HC, 83) completed the WSAS as well as measures of eating disorder symptom severity and brief assessments of anxiety and depression. Work and Social Adjustment Scale scores for the AN group were found to be in the severely impaired range, whereas the scores for those within the HC group indicated very little, or no impairment. Total WSAS scores in the AN group were significantly correlated with severity of clinical symptoms, and eating disorder-specific symptoms were the best predictor of social and occupational functional impairment. The greatest impairment in the AN group was reported in the realm of social leisure. Consistent with reports in other clinical populations, it is suggested that the WSAS could be an extremely useful and meaningful measure to assess social and occupational functioning in people with eating disorders, in addition to eating disorder-specific assessments.


Blockade of voltage-sensitive K+ channels increases contractility more in transverse than in longitudinal rat detrusor strips.
To investigate the effects of voltage-sensitive K(+) channel blockade on phasic contractions in transverse (TR) and longitudinal (LO) rat detrusor strips. The contractility of LO detrusor strips has been studied more extensively than that of TR ones, with the latter hardly used in experiments. Phasic contractions, regulated by various types of K(+) channels, are present in normal bladders and are more commonly seen in diseased bladders. Contractility was measured in TR and LO detrusor strips from young adult rats. Concentration-response curves of tetraethylammonium and 4-aminopyridine (4-AP) were constructed. Both the mean developed tension and the cyclic height of the phasic contractions were determined. At > or = 10(-2) mol/L, tetraethylammonium increased the developed tension and amplitude of the phasic contractions without differences between the TR and LO strips. 4-AP also increased the developed tension and amplitude of the phasic contractions but with greater effects in the TR than in the LO strips. At a maximal 4-AP concentration (10(-2) mol/L), the mean developed tension was 52.96% +/- 6.39% in the TR strips and 28.88% +/- 5.91% in the LO strips. The amplitude of the phasic contractions was 11.07% +/- 2.78% for the TR strips and 3.15% +/- 1.31% for the LO strips. Both nonselective K(+) channel blockade by tetraethylammonium and selective voltage-sensitive K(+) channel blockade by 4-AP resulted in increased contractions in LO and TR strips; however, the latter displayed greater effects only with 4-AP treatment. Thus, measuring detrusor contractions in different orientations might reveal heterogeneous responses that are dependent on the pharmacologic stimulus.


Comparison of adenosine 5'-monophosphate and methacholine for the differentiation of asthma from chronic airway diseases with the use of the auscultative method in very young children.
Methacholine and adenosine 5'-monophosphate bronchial challenges were performed in 54 young children--39 with asthma and 15 with other chronic airway diseases (CADs), with the use of the auscultative method. Children with asthma were sensitive to both methacholine and adenosine; children with CAD responded only to methacholine. We conclude that bronchial challenge with adenosine can help differentiate asthma from CAD in young children.


Correction to: Anti-cyclic citrullinated peptide antibody in the cerebrospinal fluid in patients with rheumatoid arthritis who have central nervous system involvement.
The authors regret that the original published version of the above article contained errors. The authors requested that these be noted.


Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling.
Receptor interacting protein 3 (RIP3) is a protein kinase essential for TNF-induced necroptosis. Phosphorylation on Ser-227 in human RIP3 (hRIP3) is required for its interaction with human mixed lineage kinase domain-like (MLKL) in the necrosome, a signaling complex induced by TNF stimulation. RIP1 and RIP3 mediate necrosome aggregation leading to the formation of amyloid-like signaling complexes. We found that TNF induces Thr-231 and Ser-232 phosphorylation in mouse RIP3 (mRIP3) and this phosphorylation is required for mRIP3 to interact with mMLKL. Ser-232 in mRIP3 corresponds to Ser-227 in hRIP3, whereas Thr-231 is not conserved in hRIP3. Although the RIP3-MLKL interaction is required for necroptosis in both human and mouse cells, hRIP3 does not interact with mMLKL and mRIP3 cannot bind to hMLKL. The species specificity of the RIP3-MLKL interaction is primarily determined by the sequence differences in the phosphorylation sites and the flanking sequence around the phosphorylation sites in hRIP3 and mRIP3. It appears that the RIP3-MLKL interaction has been selected as an evolutionarily conserved mechanism in mediating necroptosis signaling despite that differing structural and mechanistic bases for this interaction emerged simultaneously in different organisms. In addition, we further revealed that the interaction of RIP3 with MLKL prevented massive abnormal RIP3 aggregation, and therefore should be crucial for formation of the amyloid signaling complex of necrosomes. We also found that the interaction between RIP3 and MLKL is required for the translocation of necrosomes to mitochondria-associated membranes. Our data demonstrate the importance of the RIP3-MLKL interaction in the formation of functional necrosomes and suggest that translocation of necrosomes to mitochondria-associated membranes is essential for necroptosis signaling.


Electrochemical engineering approach to the irrigation of tooth canals under the influence of a vibrating file.
Doubt exists concerning the irrigation of secondary tooth canals when the vibration of a file introduced into the main root canal is superimposed on flow-through irrigation of the main canal. Depending on the type of commercial equipment used, the vibrations of the file are sonic or ultrasonic. We use the methodology of an electrochemical engineering approach in a study of the intensity of the irrigation of the secondary canals under the influence of sonic and ultrasonic vibrations of a file located at various heights in the main canal. The tooth canals are simulated by small electrochemical cells containing electrodes located at the end of cavities simulating the secondary canals. An electrochemical method is used to measure the mass transfer coefficients at these electrodes, a classical method in electrochemical engineering laboratories. The values of the mass transfer coefficients are representative of the importance of the irrigation of the electrodes. Thus they give a quantitative idea of the vibrations on the irrigation of secondary tooth canals. The work demonstrates the usefulness of the electrochemical engineering approach in contributing to the solution of a biomedical problem.


Initial findings on RESTORE for healthcare workers: an internet-delivered intervention for COVID-19-related mental health symptoms.
Many healthcare workers on the frontlines of the COVID-19 pandemic are experiencing clinical levels of mental health symptoms. Evidence-based interventions to address these symptoms are urgently needed. RESTORE (Recovering from Extreme Stressors Through Online Resources and E-health) is an online guided transdiagnostic intervention including cognitive-behavioral interventions. It was specifically designed to improve symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD) associated with COVID-19-related traumatic and extreme stressors. The aims of the present study were to assess the feasibility, acceptability, and initial efficacy of RESTORE in healthcare workers on the frontline of the COVID-19 pandemic. We conducted an initial uncontrolled trial of RESTORE in 21 healthcare workers who were exposed to COVID-19-related traumatic or extremely stressful experiences in the context of their work and who screened positive for clinical levels of anxiety, depression, and/or PTSD symptoms. RESTORE was found to be feasible and safe, and led to statistically significant and large effect size improvements in anxiety, depression, and PTSD symptoms over the course of the intervention through follow-up. RESTORE has the potential to become a widely disseminable evidence-based intervention to address mental health symptoms associated with mass traumas.Clinical Trials Registration: This trial was registered with ClinicalTrials.gov ID: NCT04873622.


Radiographic Landmarks for the Femoral Attachment of the Medial Patellofemoral Complex: A Cadaveric Study.
To report the radiographic landmarks for the medial patellofemoral complex (MPFC) footprint on the medial femur and describe the difference between the radiographic positions corresponding to the medial quadriceps tendon femoral ligament (MQTFL) and medial patellofemoral ligament (MPFL) fibers. In 8 unpaired cadaveric knees, the MPFC footprint was exposed on the medial femur, and the proximal and distal boundaries of the footprint were marked. Lateral fluoroscopic images of the knee were obtained and analyzed using Image J. The proximal boundary corresponding to the MQTFL, the MPFC midpoint, and distal boundary corresponding to the MPFL were described radiographically and compared for differences in position. The proximal MQTFL footprint was 0.8 ± 0.6 mm anterior (P = .013) and 5.2 ± 1.8 mm proximal to the MPFC midpoint (P <.001), whereas the distal MPFL footprint was 0.8 ± 0.7 mm posterior (P = .012) and 5.9 ± 1.1 mm distal to the radiographic MPFC midpoint (P <.001). The radiographic point corresponding to the distal MPFL footprint was 0.8 ± 0.9 mm posterior (P = .011) and 11.1 ± 2.3 mm distal to the radiographic point of the proximal MQTFL footprint (P <.001). When using the point of intersection of the posterior cortical line and the proximal posterior condyle as a reference, 91.6% of all points correlating to the MQTFL, MPFC midpoint and MPFL, were within 10 mm in any direction from this radiographic landmark. On fluoroscopic imaging, the proximal MQTFL and distal MPFL fibers had significantly different radiographic positions from the MPFC midpoint on the femur. These findings should be considered when reconstructing specific components of the MPFC. As fluoroscopy is often used intraoperatively to guide graft placement, our findings may serve as a reference when differentiating the locations of the MPFL vs MQTFL on the femur for anatomic reconstruction.


Social Anxiety and Shame Among Young Adults with Autism Spectrum Disorder Compared to Typical Adults.
Social anxiety (SA) is common among young adults with autism spectrum disorder (ASD). While shame feelings predict SA among typical adults, the relationship between shame and SA in ASD remains unclear. The current study compared the relationship between SA and shame in ASD. SA, shame, and autistic self-assessment questionnaires were administered to 33 young adults with ASD (28 M/5F) and 38 typical young adults (32 M/6F, Mage = 24 years, range = 20-28 in both groups). Results showed higher SA levels in ASD than typical adults, but lower levels of shame characteristics in the former than in the latter group. Moreover, a significant moderation model showed that some aspects of shame were related to SA only in the typical group but not in ASD.


Effect of immediate enteral feeding on trauma patients with an open abdomen: protection from nosocomial infections.
Damage-control laparotomy has become increasingly common after operative resuscitation of severe hemorrhagic shock after injury. Despite increased use, uncertainty exists about the safety and timing of enteral nutrition. The purpose of this study was to determine the safety and effect of immediate enteral nutrition. Data were obtained from a multicenter prospective cohort study evaluating clinical outcomes in adults with hemorrhagic shock after injury and were limited to patients with an open abdomen and no hollow viscus injury. The immediate enteral nutrition cohort was defined as initiation of enteral feeds within 36 hours after acute resuscitation completion. Multivariate stepwise logistic regression was used to evaluate factors associated with immediate enteral nutrition. One hundred subjects met inclusion criteria; 32 immediate enteral nutrition and 68 nonimmediate enteral nutrition. Nearly all patients underwent fascial closure (93.8% immediate enteral nutrition versus 94.1% nonimmediate enteral nutrition), with an average closure day of 6.47 +/- 0.83 with immediate enteral nutrition and 8.55 +/- 0.85 with nonimmediate enteral nutrition (p = 0.129). No significant difference in multiorgan dyfunction syndrome, length of ventilator days, ICU days, hospital days, or mortality was seen between groups. The rate of pneumonia was significantly different: 14 (43.8%) in immediate enteral nutrition and 49 (72.1%) in nonimmediate enteral nutrition (p = 0.008). Immediate enteral nutrition remained independently associated with a reduction in pneumonia within our stepwise regression (odds ratio = 0.32; 95% CI, 0.13 to 0.79). Immediate enteral nutrition after damage control appears safe, with no effect on abdominal closure rate. In addition, the reduction in pneumonia associated with immediate enteral nutrition suggests a tangible benefit. Immediate enteral nutrition should be considered in patients with open abdomens after severe trauma.


Genetic variation in the activity of the histidine catabolic enzymes between inbred strains of mice: a structural locus for a cytosol histidine aminotransferase isozyme (Hat-1).
Variation in activity of the main histidine catabolic enzymes (histidase, urocanase, and aminotransferase) has been surveyed using inbred strains of mice (C57BL, DBA, Peru, SM, and SWR). Some variation was found in the activity of all enzymes, but only in the case of cytosolic histidine aminotransferase was it greater than twofold (SM 3.3-fold greater than C57BL). The divergent strains for the activity of this enzyme were crossed and the F1's were backcrossed; the segregation analysis indicated a single locus with additively acting alleles (designated Hat-1: a allele SM, b allele C57BL). Cytosolic histidine aminotransferase differed in heat stability between SM and C57BL, indicating that Hat-1 is a structural locus. The conflict in the biochemical literature (Morris et al., 1973; Noguchi et al., 1976a,b) over the number and subcellular distribution of the histidine aminotransferase isozymes is partly resolved by the acquisition of a variant at the Hat-1 locus. Hat-1 affects the cytosolic form but not the mitochondrial form of the enzyme. Purification and analysis of the isozymes of histidine aminotransferase from livers of C57BL and SM mice will further clarify the situation.


Placental Histopathology Differences and Neonatal Outcome in Dichorionic-Diamniotic as Compared to Monochorionic-Diamniotic Twin Pregnancies.
We aimed to compare the differences in placental histopathology lesions and pregnancy outcome in dichorionic-diamniotic (DCDA) versus uncomplicated monochorionic-diamniotic (MCDA) twin gestations. Maternal characteristics, neonatal outcome, and placental histopathology reports of all twin deliveries between 24 and 41 weeks were reviewed. Excluded were pregnancies complicated by twin-to-twin transfusion syndrome, twin anemia-polycythemia sequence, selective intrauterine growth restriction, placenta previa, intrauterine fetal death, and malformation. Placental lesions were classified to maternal/fetal vascular malperfusion lesions. Umbilical cord abnormalities included hypo-/hypercoiling and abnormal insertion. Composite adverse neonatal outcome was defined as 1 or more early complications. Small for gestational age (SGA) was defined as birth weight ≤10th percentile. The DCDA group (n = 362) was characterized by higher rates of assisted reproductive techniques ( P < .001) and nulliparity ( P = .03) as compared to the MCDA group (n = 65). Gestational age at delivery was similar between groups. Placental maternal vascular malperfusion lesions were more common in placentas from DCDA group (38.2% vs 23.1%; P = .016), while fetal vascular malperfusion lesions and abnormal cord insertion were more common in placentas from MCDA group ( P = .027; P< .001). The SGA and composite adverse neonatal outcome were more common in the MCDA group ( P = .031 and P = .038, respectively). By multivariate regression analysis, composite adverse neonatal outcome was found to be independently associated with the MCDA group, adjusted odds ratio (aOR) = 1.2, 95% confidence interval (CI) = 1.04 to 1.89, P = .041, and with placental fetal malperfusion lesions aOR = 1.3, 95% CI = 1.1 to 2.09, P = .038. Placental pathology differs between MCDA and DCDA twin pregnancies. Adverse neonatal outcome in uncomplicated MCDA twins, as compared to DCDA twins, could be related to increased placental fetal malperfusion lesions and abnormal cord insertion.


Glucocorticoid exposure and fracture risk in patients with new-onset rheumatoid arthritis.
Retrospective claims analysis indicated that high levels of daily and cumulative doses of systemic glucocorticoids were associated with elevated fracture risk in a large cohort of new RA patients under age 65. Heightened risk began to decline within months of discontinuation. Findings were similar among patients age <50 years. We evaluated the impact of systemic glucocorticoid exposure on fracture risk among relatively young patients with new-onset rheumatoid arthritis (RA). Using administrative data, we identified 42,127 RA patients diagnosed January 1, 2005-December 31, 2012, age 18-64 years, with benefits coverage for ≥12 months before RA diagnosis. Follow-up extended to clinical fracture, cancer diagnosis, or December 31, 2012. Glucocorticoid users were new to therapy. Fracture incidence rates (IR) were stratified by glucocorticoid exposure expressed as prednisone equivalent doses. Cox's proportional hazards models estimated fracture risk adjusted for demographics and baseline clinical characteristics to assess dose-response relationships with current (daily) and prior (cumulative) dose, and by time since discontinuation. Most patients (85 %) had glucocorticoid exposure. Exposed and unexposed patients were demographically similar (74 % female; mean age 49.7 and 48.8 years); 1 % had prior fracture. Fracture IRs (95 % confidence intervals) were 5 to 9 per 1000 person-years at doses <15 mg/day, 16.0 (11.0, 22.6) at doses ≥15 mg/day, and 13.4 (10.7, 16.7) at cumulative doses ≥5400 mg. Adjusted fracture risk was approximately 2-fold higher at highest dose levels compared with 0 mg/day current daily dose and <675 mg cumulative dose, respectively. Fracture risk was 29 % lower at 60-182 days post-discontinuation compared with ongoing use and was similar to unexposed patients by 12 months. Findings were similar among patients age <50 years. Among younger, new-onset RA patients, fracture risk was significantly elevated at high levels of daily and cumulative dose, and was similar to unexposed patients by 12 months post-discontinuation.


Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor.
Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.


Hyperhomocysteinia is a risk factor for retinal venous occlusion: a case control study.
We evaluated the role of hyperhomocysteinemia as a risk factor for retinal vein occlusion (RVO) in Indian patients. Matched case control type of longitudinal study was conducted in 2006-2007. Two medical retina specialists examined the eyes having an event of RVO in the last 15 days. A similar number of eyes without RVO were also examined. The serum and urine homocysteine levels of these persons were tested. Matched pair analysis was carried out to determine the risk of RVO among those with hyperhomocysteinemia. We included 20 cases of RVO and 20 age- and sex-matched persons without RVO. The risk of RVO was significantly higher in persons with hyperhomocysteinemia [difference of mean 31.62 μmol/L (95% Confidence Interval 16.60-47 . 86), P = 2.1 × 10-13 ]. The mean urine homocysteine level among cases and controls was not statistically significant. There were 12 persons with hypertension in both cases and control groups. Hyperhomocysteinemia is a risk factor for RVO. Any list of investigations for a case of RVO should include total plasma homocysteine (tHcy) levels.