CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells.
T cell adoptive transfer strategies that have produced clinical remissions against specific tumors have so far produced disappointing results against ovarian cancer. Recent evidence suggests that adoptively transferred CD4(+) T cells can trigger endogenous immune responses in particular patients with ovarian cancer through unknown mechanisms. However, conflicting reports suggest that ovarian cancer-infiltrating CD4(+) T cells are associated with negative outcomes. In this study, we elucidate the phenotypic attributes that enable polyclonal CD4(+) T cells briefly primed against tumor Ags to induce therapeutically relevant endogenous antitumor immune responses. Our results unveil a therapeutic mechanism whereby tumor-primed CD4(+) T cells transferred into ovarian cancer-bearing mice secrete high levels of CCL5, which recruits endogenous CCR5(+) dendritic cells to tumor locations and activate them through CD40-CD40L interactions. These newly matured dendritic cells are then able to prime tumor-specific endogenous CD8(+) T cells, which mediate long-term protection. Correspondingly, administration of tumor-primed CD4(+) T cells significantly delayed progression of MHC class II(-) ovarian cancers, similarly to CD8(+) T cells only, and directly activated wild-type but not CD40-deficient dendritic cells recruited to the tumor microenvironment. Our results unveil a CCL5- and CD40L-dependent mechanism of transferring immunity from exogenously activated CD4(+) T cells to tumor-exposed host cells, resulting in sustained antitumor effects. Our data provide a mechanistic rationale for incorporating tumor-reactive CD4(+) T cells in adoptive cell transfer immunotherapies against ovarian cancer and underscore the importance of optimizing immunotherapeutic strategies for the specific microenvironment of individual tumors.


Widespread Volumetric Reductions in Schizophrenia and Schizoaffective Patients Displaying Compromised Cognitive Abilities.
Progress toward understanding brain mechanisms in psychosis is hampered by failures to account for within-group heterogeneity that exists across neuropsychological domains. We recently identified distinct cognitive subgroups that might assist in identifying more biologically meaningful subtypes of psychosis. In the present study, we examined whether underlying structural brain abnormalities differentiate these cognitively derived subgroups. 1.5T T1 weighted structural scans were acquired for 168 healthy controls and 220 patients with schizophrenia/schizoaffective disorder. Based on previous work, 47 patients were categorized as being cognitively compromised (impaired premorbid and current IQ), 100 as cognitively deteriorated (normal premorbid IQ, impaired current IQ), and 73 as putatively cognitively preserved (premorbid and current IQ within 1 SD of controls). Global, subcortical and cortical volume, thickness, and surface area measures were compared among groups. Whole cortex, subcortical, and regional volume and thickness reductions were evident in all subgroups compared to controls, with the largest effect sizes in the compromised group. This subgroup also showed abnormalities in regions not seen in the other patient groups, including smaller left superior and middle frontal areas, left anterior and inferior temporal areas and right lateral medial and inferior frontal, occipital lobe and superior temporal areas. This pattern of more prominent brain structural abnormalities in the group with the most marked cognitive impairments-both currently and putatively prior to illness onset, is consistent with the concept of schizophrenia as a progressive neurodevelopmental disorder. In this group, neurodevelopmental and neurodegenerative factors may be important for cognitive function.


Biophysical and structural properties of DNA.diC(14)-amidine complexes. Influence of the DNA/lipid ratio.
Cationic liposomes are used as vectors for gene delivery both in vitro and in vivo. Comprehension of both DNA/liposome interactions on a molecular level and a description of structural modifications involved, are prerequisites to an optimization of the transfection protocol and, thus, successful application in therapy. Formation and stability of a DNA/cationic liposome complex were investigated here at different DNA:lipid molar ratios (rho). Isothermal titration calorimetry (ITC) of cationic liposomes with plasmid DNA was used to characterize the DNA-lipid interaction. Two processes were shown to be involved in the complex formation. A fast exothermic process was attributed to the electrostatic binding of DNA to the liposome surface. A subsequent slower endothermic reaction is likely to be caused by the fusion of the two components and their rearrangement into a new structure. Fluorescence and differential scanning calorimetry confirmed this interpretation. A kinetic model analyzes the ITC profile in terms of DNA/cationic liposome interactions.


Mucoepidermoid carcinoma of the breast.
Five cases of mucoepidermoid carcinoma (MEC) of the breast are reported. All patients were women ranging in age from 29 years to 80 years. As histological grading is one of the most important prognostic factors in breast invasive carcinomas, MEC was graded using the Auclair et al. [1] grading system specific for MEC of salivary glands and the Elston and Ellis [4] grading method, a widely employed grading system in breast cancer. It was found that the two different grading systems appear to be interchangeable in assessing the grade of MEC of the breast. Accordingly, three cases were regarded low grade (G. 1), one intermediate (G. 2) and one high grade (G. 3). The cases were studied with immunohistochemistry and were found to have the same keratin pattern shown by their salivary gland counterpart. It was found that there are more similarities than differences between MEC of the breast and of salivary glands.


Nystatin prophylaxis and treatment in severely immunodepressed patients.
Nystatin is sometimes used prophylactically in patients with severe immunodeficiency or in the treatment of fungal infection in such patients, although the effect seems to be equivocal. To study whether nystatin decreases morbidity and mortality when given prophylactically or therapeutically to patients with severe immunodeficiency. MEDLINE and The Cochrane Library using a comprehensive search strategy, date of last search November 2001. Contacted industry and scanned reference lists. Randomised trials comparing nystatin with placebo, an untreated control group, fluconazole or amphotericin B. Data on mortality, invasive fungal infection and colonisation were extracted by both authors independently. The outcomes were weighted by the inverse variance. A random effects model was used unless p>0.10 for the test of heterogeneity. We included 12 trials (1,464 patients). The drugs were given prophylactically in ten trials and as treatment in two. Seven trials were in acute leukaemia, two in cancer, one in liver transplant patients, one in critically ill surgical and trauma patients, and one in AIDS patients. Nystatin had been compared with placebo in three trials and with fluconazole in nine; the dose varied from 1.5 MIE to 72 MIE daily. The effect of nystatin was similar to that of placebo on fungal colonisation (relative risk 0.85, 95% confidence interval 0.65 to 1.13). There was no statistically significant difference between fluconazole and nystatin on mortality (relative risk 0.76, 0.49 to 1.18) whereas fluconazole was more effective in preventing invasive fungal infection (relative risk 0.37, 0.15 to 0.91) and colonisation (relative risk 0.49, 0.34 to 0.70). The results were very similar if the three studies which were not performed in cancer patients were excluded. Nystatin cannot be recommended for prophylaxis or treatment of Candida infections in immunodepressed patients.


Normocalcemic hyperparathyroidism after successful parathyroidectomy for single parathyroid adenoma: Prevalence, etiological factors, predictive markers, treatment and evolution.
Postparathyroidectomy normocalcemic hyperparathyroidism (PPNCHPPT) is a frequent situation for which we have no information in our country. The objective is to know our prevalence of PPNCHPPT, the associated etiological factors, the predictive markers, the treatment administered and the evolution. Retrospective observational cross-sectional study on 42 patients. Twelve patients with PPNCHPPT and 30 without PPNCHPPT are compared. HPPTNCPP prevalence: 28.6%. Etiological factors: vitamin D deficiency: 75%; bone remineralization: 16.7%; renal failure: 16.7%; hypercalciruria: 8.3%. No change in the set point of calcium-mediated parathormone (PTH) secretion was observed, but an increase in the preoperative PTH/albumin-corrected calcium (ACC) ratio was observed. Predictive markers: PTH/ACC ratio (AUC 0.947; sensitivity 100%, specificity 78.9%) and PTH (AUC 0.914; sensitivity 100%, specificity 73.7%) one week postparathyroidectomy. follow-up 30 ± 16.3 months: 50% normalized PTH and 8.3% had recurrence of hyperparathyroidism. Patients with PPNCHPPT less frequently received preoperative treatment with bisphosphonates and postoperative treatment with calcium salts. This is the first study in our country that demonstrates a mean prevalence of PPNCHPPT, mainly related to a vitamin D deficiency and a probable resistance to the action of PTH, which can be predicted by the PTH/ACC ratio and PTH a week post-intervention and often evolves normalizing the PTH. We disagree with the etiological effect of hypercalciuria and the change in the PTH/calcemia regulation set point, and we acknowledge the scant treatment administered with calcium salts in the postoperative period.


FR146687, a novel steroid 5 alpha-reductase inhibitor: in vitro and in vivo effects on prostates.
Steroid 5 alpha-reductase is implicated in the pathogenesis of benign prostatic hyperplasia (BPH). We studied the in vitro and in vivo effects of FR146687, a new inhibitor of 5 alpha-reductase. Two isozymes of rat and human 5 alpha-reductases were expressed in 293 cells. In vivo effects of drugs were evaluated on rat and dog prostates. Castrated immature rats were injected with testosterone propionate (TP) or 5 alpha-dihydrotestosterone propionate (DHTP) to induce growth of the ventral prostates. Testosterone and 5 alpha-dihydrotestosterone (DHT) contents in rat and dog prostates were measured by gas chromatography-mass spectrophotometry (GC-MS). FR146687 showed noncompetitive inhibition in both isozymes and no inhibitory effects on other steroid oxidoreductases. In mature rats and castrated immature rats treated with TP, FR146687 dose-dependently reduced ventral prostate and seminal vesicle weight at doses above 0.1 mg/kg, while castrated immature rats treated with DHTP were not affected by FR146687. FR146687 showed more potent reduction of rat prostates than finasteride. DHT concentration in the prostates was significantly reduced when FR146687 was administered to rats and beagles. FR146687 is a dual inhibitor for 5 alpha-reductase isozymes and significantly reduced the growth and DHT content in the prostate.


Temperature optimum of insulin-stimulated 2-deoxy-D-glucose uptake in rat adipocytes. Correlation of cellular transport with membrane spin-label and fluorescence-label data.
The effects of temperature alterations between 22 degrees C and 48 degrees C on basal and insulin-stimulated 2-deoxy-D-[1-14C]glucose uptake were examined in isolated rat adipocytes. A distinct optimum was found near physiological temperature for uptake in the presence of maximally effective insulin concentrations where insulin stimulation and hexose uptake were both conducted at each given assay temperature. Basal uptake was only subtly affected. Control and maximally insulin-stimulated cells incubated at 35 degrees C subsequently exhibited minimal temperature-sensitivity of uptake measured between 30 and 43 degrees C. The data are mostly consistent with the concept that insulin-sensitive glucose transporters are, after stimulation by insulin, functionally similar to basal transporters. Adipocyte plasma membranes were labelled with various spin- and fluorescence-label probes in lipid structural studies. The temperature-dependence of the order parameter S calculated from membranes labelled with 5-nitroxide stearate indicated the presence of a lipid phase change at approx. 33 degrees C. Membranes labelled with the fluorescence label 1,6-diphenylhexa-1,3,5-triene, or the cholesterol-like spin label nitroxide cholestane, reveal sharp transitions at lower temperatures. We suggest that a thermotropic lipid phase separation occurs in the adipocyte membrane that may be correlated with the temperature-dependence of hexose transport and insulin action in the intact cells.


Clinical predictors of abnormal magnetic resonance imaging findings in patients with asymmetric sensorineural hearing loss.
Asymmetric sensorineural hearing loss (ASNHL) is commonly encountered in an otolaryngologic clinical practice. Determining what factors are associated with abnormal magnetic resonance imaging (MRI) findings will help with diagnostic workup. To evaluate the association between clinical and audiometric factors and abnormal MRI findings in patients with ASNHL. Retrospective medical record review from an urban, tertiary referral center of 451 patients with ASNHL who underwent MRI testing between January 2005 and December 2011. Medical records were reviewed for audiometric parameters as well as clinical presentation and compared with MRI results, which were categorized as abnormal, normal, or incidental. Data analysis included χ2 tests, logistic regression analysis, and multivariate analysis. A total of 48 patients (10.6%) had abnormal MRI findings. Only 21 patients (4.7%) had a mass of the cerebellopontine angle/internal auditory canal on MRI, making up 40% of all abnormal MRI findings. The next most common MRI finding was labyrinthitis (n = 13; 25%). Vertigo/dizziness (n = 20; P = .01), tinnitus (n = 18; P = .02), sudden hearing loss (n = 15; P = .054), and 15-dB asymmetry at 3 kHz (n = 39; P = .01) were associated with abnormal MRI findings. Loud noise exposure was associated with normal MRI findings. Logistic regression analysis showed that vertigo/dizziness (odds ratio [OR], 2.14; 95% CI, 1.15-3.96; P = .02), unilateral tinnitus (OR, 2.15; 95% CI, 1.14-4.03; P = .02), and 15-dB asymmetry at 3 kHz (OR, 2.62; 95% CI, 1.24-5.57; P = .01) were significantly associated with abnormal MRI findings. Multivariate analysis showed that only 15-dB asymmetry at 3 kHz (OR, 2.42; 95% CI, 1.07-5.50; P = .03) was significantly associated with an abnormal MRI finding. This study found that asymmetry of 15 dB at 3 kHz on audiometry was associated with higher positive yield on use of MRI in evaluating patients with ASNHL. We recommend that patients who present with ASNHL with this audiometric characteristic undergo MRI as part of their diagnostic workup.


Multi-agent modeling of multiple FX-markets by neural networks.
We introduce an explanatory multi-agent approach of multiple FX-market modeling based on neural networks. We consider the explicit and implicit dynamics of the market price. This paper extends previous work of modeling a single FX-market to an integrated approach, which allows one to treat several FX-markets simultaneously. Our approach is based on feedforward neural networks. Neural networks allow the fitting of high-dimensional nonlinear models, which is often utilized in econometrics. Merging the economic theory of multi-agents with neural networks, our model concerns semantic specifications instead of being limited to ad hoc functional relationships. As an advantage, our multi-agent model allows one to fit the behavior of real-world financial data. We exemplify the USD/DEM and YEN/DEM FX-Market simultaneously. Fitting real-world data, our approach is superior to more conventional forecasting techniques.


Physical Fitness in Young Adults Born Preterm.
Young adults born preterm have higher levels of cardiometabolic risk factors than their term-born peers. Muscular and cardiorespiratory fitness have important cardiometabolic and other health benefits. We assessed muscular, cardiorespiratory, and self-rated fitness in preterm-born young adults. We studied unimpaired participants of the ESTER (Ennenaikainen syntymä ja aikuisiän terveys [Preterm Birth and Early-Life Programming of Adult Health and Disease]) birth cohort study at age 23.3 (SD: 1.2) years: 139 born early preterm (EPT; <34 weeks), 247 late preterm (LPT; 34-36 weeks), and 352 at term (control group). We measured muscular fitness with the number of modified push-ups performed in 40 seconds and maximal handgrip strength of the dominant hand, cardiovascular fitness with heart rate at the end of a 4-minute step test, and self-rated fitness. Data were analyzed with linear regression. Young adults born EPT (-0.8; 95% confidence interval: -1.5 to -0.1; adjusted for gender, age, and source cohort) and LPT (-0.8; -1.4 to -0.3) performed fewer modified push-ups than controls. Handgrip strength was 23.8 (0.9-46.8) N lower in EPT participants. Cardiorespiratory fitness, measured by submaximal step test, was similar. On a self-rated fitness scale (1-5), the EPT adults reported 0.2 (0.0-0.4) lower scores than controls. After adjustment for early-life confounders, the results remained. They attenuated after further adjustment for mediating factors. Young adults born EPT and LPT had lower muscular fitness than controls, which may predispose them to cardiometabolic and other chronic diseases. Adults born EPT also perceived themselves as less fit than controls.


Identification of the human papillomavirus type 6b L1 open reading frame protein in condylomas and corresponding antibodies in human sera.
Genital warts (condylomata acuminata) are among the most frequent sexually transmitted infections. Human papillomavirus type 6 (HPV-6), which is etiologically related to a majority of these lesions, has not been propagated in tissue culture. We generated two forms of HPV-6 viral antigens: a chemically synthesized oligopeptide (referred to as the C-terminal synthetic peptide) corresponding to residues 482 to 495 of the 500-amino-acid-long L1 open reading frame (ORF), and a bacterially expressed 54-kilodalton (kDa) fusion protein containing the N-terminal 13 amino acids encoded by the lambda bacteriophage cII gene followed by one vector-insert junctional residue and 462 amino acids of the L1 ORF sequence (residues 39 to 500). The cII-L1 fusion protein was specifically recognized by an antipeptide serum directed against the N-terminal 13 amino acids derived from the cII gene, an antiserum raised against the C-terminal synthetic peptide, and a genus-specific serum prepared by immunization with disrupted viral capsids. The 54-kDa fusion protein was purified, and the sequence of its first 36 amino acids was determined and found to be as predicted by the DNA sequence. Both the genus-specific anticapsid serum and the antiserum raised against the fusion protein identified authentic L1 ORF proteins in HPV-1-induced (58 kDa) and HPV-6/11-induced (56 kDa) papillomas. The synthetic peptide antiserum recognized the 56- to 58-kDa protein in HPV-6-induced warts, but not in HPV-1- or HPV-11-infected specimens. Using the fusion protein as antigen in immunoassays, we were able to detect the corresponding antibodies in human sera.


Zero-Shot Learning Using Synthesised Unseen Visual Data with Diffusion Regularisation.
Sufficient training examples are the fundamental requirement for most of the learning tasks. However, collecting well-labelled training examples is costly. Inspired by Zero-shot Learning (ZSL) that can make use of visual attributes or natural language semantics as an intermediate level clue to associate low-level features with high-level classes, in a novel extension of this idea, we aim to synthesise training data for novel classes using only semantic attributes. Despite the simplicity of this idea, there are several challenges. First, how to prevent the synthesised data from over-fitting to training classes? Second, how to guarantee the synthesised data is discriminative for ZSL tasks? Third, we observe that only a few dimensions of the learnt features gain high variances whereas most of the remaining dimensions are not informative. Thus, the question is how to make the concentrated information diffuse to most of the dimensions of synthesised data. To address the above issues, we propose a novel embedding algorithm named Unseen Visual Data Synthesis (UVDS) that projects semantic features to the high-dimensional visual feature space. Two main techniques are introduced in our proposed algorithm. (1) We introduce a latent embedding space which aims to reconcile the structural difference between the visual and semantic spaces, meanwhile preserve the local structure. (2) We propose a novel Diffusion Regularisation (DR) that explicitly forces the variances to diffuse over most dimensions of the synthesised data. By an orthogonal rotation (more precisely, an orthogonal transformation), DR can remove the redundant correlated attributes and further alleviate the over-fitting problem. On four benchmark datasets, we demonstrate the benefit of using synthesised unseen data for zero-shot learning. Extensive experimental results suggest that our proposed approach significantly outperforms the state-of-the-art methods.


[Effect of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis].
To determine the effect of raloxifene hydrochloride (RLX) on the lumbar spine and total hip bone mineral density (BMD), bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis. 204 Chinese postmenopausal women with osteoporosis from 3 hospitals in Beijing and Shanghai were randomly divided into 2 groups of 102 women: RLX group (RLX of the dosage of 60 mg/day was given for 12 months) and placebo group. In addition, 500 mg of elemental calcium and 200 units of vitamin D were given daily to all women. BMD, serum bone markers and lipids were measured before and after drug administration. The BMD of lumber spine and hip was measured by dual-energy X-ray absorptiometry (DEXA). Serum bone gamma-carboxyglutamic acid-containing protein (BGP) and C-teloppeptide were analyzed by one-step ELISA. Serum lipids were measured by enzymatic method. By the end of the 12-month study period, the lumbar spine BMD was increased by 3.3% +/- 4.8% in the RLX group and 1.0% +/- 4.9% in the placebo group (P < 0.001); the hip BMD was increased by 1.4% +/- 4.8%in the RLX group and decreased by 0.9% +/- 5.0% in the placebo group (P < 0.01). New vertebral fracture occurred in none of the subjects in the RLX group and in 5 subjects of the placebo group (P = 0.059). The serum BGP and CTX decreased by 41.7% and 61.5% respectively in the RLX group, both significantly more than those in the placebo group (10.6% and 35.6% respectively, both P < 0.001). Both the total cholesterol and low-density lipoprotein cholesterol were significantly lower in the RLX group than in the placebo group (both P < 0.001), however, there were no significant differences in high-density lipoprotein cholesterol and triglycerides between these two groups. One subject in the RLX group and 5 subjects in the placebo group discontinued the study due to adverse events. There were no differences in the number of subjects with hot flushes (3 in the RLX group and 1 in the placebo group) and the number of subjects with leg cramps (9 in the RLX group and 4 in the placebo group). No venous thromboembolic event was reported. RLX of the dosage of 60 mg/day for 12 months significantly increases the lumbar spine and total hip bone BMD, significantly decreases bone turnover and has favorable effects on serum lipids in Chinese postmenopausal women with osteoporosis.


Use of recombinant factor VII in cardiac surgery.
The off-label use of recombinant human coagulation factor VIIa has been increasing to a number of different treatment areas since its original approval in 1999. Several US patents describe claims for FVIIa utilization in nonhemophilia patients, treatment of bleeding due to trauma, as a means to reverse major bleeding, including intracranial bleeding, induced from fibrinolytic therapy as well as a patent for using FVIIa in the treatment of bleeding for patients with bleeding disorders not caused by hemophilia, but rather bleeding disorders due to thrombocytopenia, platelet disorders, and von Willebrand's disease. Bleeding after cardiac surgery remains a serious complication that can increase both morbidity and mortality. We review the off-label usage of recombinant factor VIIa as a hemostatic agent that may help control bleeding following cardiac surgery.


Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet.
Human eNOS (NOS3) polymorphisms that lower its expression are associated with advanced diabetic nephropathy (DN), and the lack of eNOS accelerates DN in diabetic mice. Diabetes is associated with fibrin deposition. Lack of nitric oxide and fatty acids stimulates the NF-kB pathway, which increases tissue factor (TF). To test the hypothesis that TF contributes to the severity of DN in the diabetic eNOS(-/-) mice fed a high-fat diet (HF). We made eNOS(-/-) and wild-type mice diabetic with streptozotocin. Half of them were placed on HF. Blood glucose levels were not affected by either the diet or eNOS genotype. Lack of eNOS in the diabetic mice increased urinary albumin excretion, glomerulosclerosis, interstitial fibrosis, and glomerular basement membrane thickness. HF by itself did not affect DN in the wild-type mice, but significantly enhanced DN in eNOS(-/-) mice. More than half of diabetic eNOS(-/-) mice on HF died prematurely with signs of thrombotic complications. Diabetic kidneys contained fibrin and TF, and their levels were increased by the lack of eNOS and by HF in an additive fashion. The HF diet increased the kidney expression of inflammatory genes. The increase in TF preceded DN, and administration of an anti-mouse TF antibody to diabetic mice reduced the expression of inflammatory genes. Together, these data indicate a causal link between TF and the exacerbation of DN in eNOS(-/-) mice. The condition is significantly worsened by enhanced inflammatory responses to an HF diet via TF.


High-speed (2.5 Gbps) reconfigurable inter-chip optical interconnects using opto-VLSI processors.
Reconfigurablele optical interconnects enable flexible and high-performance communication in multi-chip architectures to be arbitrarily adapted, leading to efficient parallel signal processing. The use of Opto-VLSI processors as beam steerers and multicasters for reconfigurable inter-chip optical interconnection is discussed. We demonstrate, as proof-of-concept, 2.5 Gbps reconfigurable optical interconnects between an 850nm vertical cavity surface emitting lasers (VCSEL) array and a photodiode (PD) array integrated onto a PCB by driving two Opto-VLSI processors with steering and multicasting digital phase holograms. The architecture is experimentally demonstrated through three scenarios showing its flexibility to perform single, multicasting, and parallel reconfigurable optical interconnects. To our knowledge, this is the first reported high-speed reconfigurable N-to-N optical interconnects architecture, which will have a significant impact on the flexibility and efficiency of large shared-memory multiprocessor machines.


Factors influencing release of type III antigens by group B streptococci.
The release of serotype III group B streptococcal polysaccharides into the supernatant fluid was examined under a variety of physiological conditions. Release of both high- and low-molecular-weight type III antigens was fairly constant throughout exponential growth, but increased markedly upon entering the stationary phase of growth. Increased glucose and decreased phosphate concentrations both caused a large increase in release of antigens. Inhibition of protein synthesis in exponentially growing cells by chloramphenicol (10 micrograms/ml) caused a condition of unbalanced growth in which antigen release was increased greatly over control values. Strain variability in antigen release was also observed. Strains which are known to be high neuraminidase producers released elevated levels of both low- and high-molecular-weight type III antigens. Non-neuraminidase-producing strains released considerably less high-molecular-weight antigen, but similar levels of the low-molecular-weight antigen compared with the high neuraminidase producers. Strain D136C, a type III non-neuraminidase producer, released negligible quantities of the high-molecular-weight antigen in the supernatant fluid. These results indicate that both the physiological environment and the type III strain are important in determining the quantity of type-specific antigen released into the culture fluid.


Atrial natriuretic peptide stimulates salt secretion by shark rectal gland by releasing VIP.
Salt secretion by the isolated perfused rectal gland of the spiny dogfish shark, Squalus acanthias, is stimulated by synthetic rat atrial natriuretic peptide (ANP II) as well as extracts of shark heart, but not by 8-bromo-cyclic guanosine 5'-monophosphate. Cardiac peptides have no effect on isolated rectal gland cells or perfused tubules, suggesting that stimulation requires an intact gland. The stimulation of secretion by ANP II is eliminated by maneuvers that block neurotransmitter release. These include: perfusion with procaine (10(-2) M), perfusion with high Mg2+ (9.5 mM) and low Ca2+ (0.5 mM) concentrations, and addition to the perfusate of the calcium channel blockers nifedipine (10(-6)M), diltiazem (5 X 10(-5)M), or verapamil (10(-4)M). Cardiac peptides stimulate the release of vasoactive intestinal peptide (VIP), known to be present in rectal gland nerves, into the venous effluent or perfused glands in parallel with their stimulation of salt secretion, but the release of VIP induced by ANP II is prevented by perfusion with procaine. Cardiac peptides thus appear to regulate rectal gland secretion by releasing VIP from neural stores within the gland. It is possible that other physiological effects of these hormones might be explained by an action to enhance local release of neurotransmitters.


C-reactive protein and vasospasm after aneurysmal subarachnoid hemorrhage.
To evaluate the relationship between C reactive protein levels and clinical and radiological parameters with delayed ischemic neurological deficits and outcome after aneurysmal subarachnoid hemorrhage. One hundred adult patients with aneurismal SAH were prospectively evaluated. Besides the baseline characteristics, daily C-reactive protein levels were prospectively measured until day 10 after subarachnoid hemorrhage. The primary end point was outcome assessed by Glasgow Outcome Scale, the secondary was the occurrence of delayed ischemic neurological deficits (DINDs). A progressive increase in the CRP levels from the admission to 3rd postictal day was observed, followed by a slow decrease until the 9th day. Hemodynamic changes in TCD were associated with higher serum CRP levels. Patients with lower GCS scores presented with increased CRP levels. Patients with higher Hunt and Hess grades on admission developed significantly higher CRP serum levels. Patients with higher admission Fisher grades showed increased levels of CRP. A statistically significant inverse correlation was established in our series between CRP serum levels and GOS on discharge and CRP levels. Higher C-reactive protein serum levels are associated with worse clinical outcome and the occurrence of delayed ischemic neurological deficits. Because C-reactive protein levels were significantly elevated in the early phase, they might be a useful parameter to monitor.


Adopting nested case-control quota sampling designs for the evaluation of risk markers.
Two-phase study methods, in which more detailed or more expensive exposure information is only collected on a sample of individuals with events and a small proportion of other individuals, are expected to play a critical role in biomarker validation research. One major limitation of standard two-phase designs is that they are most conveniently employed with study cohorts in which information on longitudinal follow-up and other potential matching variables is electronically recorded. However for many practical situations, at the sampling stage such information may not be readily available for every potential candidates. Study eligibility needs to be verified by reviewing information from medical charts one by one. In this manuscript, we study in depth a novel study design commonly undertaken in practice that involves sampling until quotas of eligible cases and controls are identified. We propose semiparametric methods to calculate risk distributions and a wide variety of prediction indices when outcomes are censored failure times and data are collected under the quota sampling design. Consistency and asymptotic normality of our estimators are established using empirical process theory. Simulation results indicate that the proposed procedures perform well in finite samples. Application is made to the evaluation of a new risk model for predicting the onset of cardiovascular disease.


Psychological assessment of women on an early breast screening program after radiotherapy to the chest wall for childhood cancer.
This study investigates the psychological status in a population of female patients who received chest irradiation for a childhood cancer and were screened for second primary breast cancer. Sixty-eight consecutive such young women were included. Compilation of the Crown-Crisp Index questionnaire was requested and 49/68 patients accepted to fill it in; 14 women in the sample had children (28%). Twenty-seven of 49 patients achieved a normal score, whereas in 22 the score was slightly above the normal range in at least one scale. Pathological scores were more frequent among the women without children. Quality of life in this series of long-term survivors does not seem to be severely affected by previous treatment for cancer nor by the concern for the onset of a second primary malignancy.


Intrapulmonary vascular dilatations are common in portopulmonary hypertension and may be associated with decreased survival.
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are pulmonary vascular complications of portal hypertension with divergent clinicopathologic features and management. The presence of intrapulmonary vascular dilatations (IPVDs), detected by agitated saline contrast-enhanced transthoracic echocardiography (cTTE), is an essential feature of HPS but is not typically characteristic of POPH. Although IPVDs have been reported rarely in POPH, the prevalence and significance of this finding have not been systematically studied. We conducted a retrospective chart review of 80 consecutive patients diagnosed with POPH from January 1, 2002 to June 30, 2014 with documentation of cTTE findings, pulmonary hemodynamics, oxygenation, and survival. A total of 34 of the 80 patients (42%) underwent cTTE during initial diagnosis of POPH. IPVDs were detected in 20/34 patients (59%); intracardiac shunting was detected in 9/34 patients (26%; 4 also had IPVDs); and 9 patients (26%) had negative cTTE with no evidence of IPVD or intracardiac shunting. Patients with IPVD had decreased survival as compared to those without IPVD (P = 0.003), a trend that persisted after exclusion of liver transplant recipients (P = 0.07). The IPVD group had a trend toward higher Model for End-Stage Liver Disease score with and without incorporating sodium (MELD or MELD-Na; P = 0.05 for both). The right ventricular index of myocardial performance (RIMP) was lower in the IPVD group (median, 0.4 versus 0.6; P = 0.006). Patients with moderate or large IPVDs (n = 6) had worse oxygenation parameters (partial pressure of arterial oxygen, diffusing capacity of the lung for carbon monoxide, and alveolar-arterial oxygen gradient) as compared to the rest of the cohort. Unexpectedly, IPVDs were frequently documented in POPH and associated with decreased survival. To further understand this observation, we recommend screening for IVPD in all patients with POPH.


Tzanakis score vs. Alvarado score in acute appendicitis.
Acute appendicitis is a common surgical emergency. Accurate diagnosis and timely intervention reduces mortality and morbidity. This study compared the efficacy of Tzanakis and Alvarado score in diagnosis of acute appendicitis. A prospective, non randomized study was conducted in 100 consecutive patients who had undergone emergency appendectomy from May 2008 to October 2008. Tzanakis and Alvarado scores were obtained at the time of admission. Final diagnosis of acute appendicitis was based on histological findings. The sensitivity, specificity and overall diagnostic accuracy of Tzanakis score was 91.48% and 66.66% and 90% respectively. The sensitivity, specificity and overall diagnostic accuracy of Alvarado score was 81.91% and 66.66% and 81% respectively. Negative appendectomy rate was 6%. Tzanakis score is an effective modality to establish the accurate diagnosis of acute appendicitis.


Attitudes of women who are currently using or recently stopped estrogen replacement therapy with or without progestins: results of the AWARE survey.
To examine the level of awareness of the findings of the Women's Health Initiative (WHI) study among recent users of hormone therapy (HT). A survey was conducted on Canadian women older than 45 years of age who had used either an oral, topical, or vaginal HT within the preceding 3 years. Questionnaires were mailed to a random sample of 210 eligible women within an academic subspecialty rheumatology/osteoporosis practice between April and June 2003. Questionnaires were also provided upon request to women attending tertiary care multidisciplinary clinics and 6 community pharmacies in Hamilton, Ontario. The 98 questions in the survey were either categorical in nature (yes or no response) or followed by a Likert scale. Using chi-square and Student t tests, the responses of women who used combination estrogen/progestin were compared to those who used estrogen alone. Of the 161 women who responded to the survey (128 from the osteoporosis practice, 33 from other clinics and pharmacies), 102 (63%) had used HT for more than 5 years. Ninety-one of 159 respondents (57%) discontinued HT, and 63% (57/91) of those stopped using HT after publication of the WHI principal findings. Sixty-four percent (33/52) of women on combination estrogen/progestin discontinued HT, compared to 50% (46/93) who were on estrogen only, and 5 other women who also discontinued HT but did not know what type of preparation they had been taking (P = .04 for the difference in rates between the 3 groups). Knowledge of the findings of the estrogen/progestin arm of the WHI study did not significantly differ among users of different types of hormone preparations. Of the women who indicated that they did not know if HT affected the risk of WHI-studied medical conditions, 44% (69/156) indicated being unaware of HT risks for stroke, 28% (44/157) for hip fracture, 39% (60/155) for myocardial infarction, 25% (39/155) for breast cancer, and 48% (73/152) for blood clots. Women who had recently taken HT generally did not regret their use of HT. Although many women discontinued HT following the publication of the principal findings of the estrogen/progestin arm of the WHI study, the majority of these women lacked a clear understanding of those findings.


Providers issue brief: nursing home staffing standards: year end report-2002.
For more than a decade, lawmakers have focused on improving care in the nation's nursing homes by mandating tighter regulations for the industry. With a growing population of elderly and recent findings that suggest a majority of nursing facilities are understaffed to the point of endangering the health of patients, states and the federal government are strengthening their resolve to crack down on delinquent facilities and introduce minimum requirements for staffing levels to improve quality of care. A common way states have chosen to impose these requirements is through minimum staff-to-patient ratios, but states also must reckon with how to fund mandated staff increases.


Crystal structure of glycoside hydrolase family 55 {beta}-1,3-glucanase from the basidiomycete Phanerochaete chrysosporium.
Glycoside hydrolase family 55 consists of beta-1,3-glucanases mainly from filamentous fungi. A beta-1,3-glucanase (Lam55A) from the Basidiomycete Phanerochaete chrysosporium hydrolyzes beta-1,3-glucans in the exo-mode with inversion of anomeric configuration and produces gentiobiose in addition to glucose from beta-1,3/1,6-glucans. Here we report the crystal structure of Lam55A, establishing the three-dimensional structure of a member of glycoside hydrolase 55 for the first time. Lam55A has two beta-helical domains in a single polypeptide chain. These two domains are separated by a long linker region but are positioned side by side, and the overall structure resembles a rib cage. In the complex, a gluconolactone molecule is bound at the bottom of a pocket between the two beta-helical domains. Based on the position of the gluconolactone molecule, Glu-633 appears to be the catalytic acid, whereas the catalytic base residue could not be identified. The substrate binding pocket appears to be able to accept a gentiobiose unit near the cleavage site, and a long cleft runs from the pocket, in accordance with the activity of this enzyme toward various beta-1,3-glucan oligosaccharides. In conclusion, we provide important features of the substrate-binding site at the interface of the two beta-helical domains, demonstrating an unexpected variety of carbohydrate binding modes.


[Factors associated with insulin self-administration by diabetes mellitus patients in the Family Health Strategy].
This cross-sectional study aimed to compare two groups of patients with diabetes mellitus treated under the Family Health Strategy, with insulin self-administration versus non-self-administration, in relation to socio-demographic variables, perceived difficulties, and the person responsible for the self-application. A total of 269 patients participated, included through simple random sampling, from 37 Family Health Strategy units in the urban area of a municipality in the State of Minas Gerais, Brazil. The self-administration group consisted of 169 individuals (62.8%), as compared to 100 (37.2%) in the non-self-administration group. Comparing the two groups, schooling was statistically significant; 45% of those who did not self-administer reported absence of physical or cognitive difficulties that might prevent them from conducting the procedure, demonstrating the potential for adherence; 90% reported needing assistance in the insulin administration process at home, and of these, 75% reported receiving assistance from family members. The Family Health Strategy favors the development of interventions centered on users' needs, encouraging them to adopt and develop self-care skills, and the results of the present study can contribute to the planning of such interventions.


Acute hemolytic transfusion reaction caused by anti-Yta.
Many patients with anti-Yta receive multiple transfusions of Yt(a+) red blood cells (RBCs) with no ill effects. However, anti-Yta has been implicated in hemolytic transfusion reactions. Antibody identification typically determines specificity of antibodies and their clinical significance to justify blood requirements for antigen-negative blood when clinically significant antibodies are involved. Occasionally, specificity of antibody is of variable significance. Variability in clinical significance is a characteristic of anti-Yta that may affect the clinical management of such patients. This case reports the outcome of an incompatible transfusion in an 83-year-old female patient with anti-Yta, -D, -C, -Leab, and -HI who was admitted to the hospital for a severe urinary tract hemorrhage and fever. The patient was transfused with 1 crossmatch-incompatible group A, Yt(a+), D-, C-, E-, S- RBC unit in an emergency medical event. During that time, the patient exhibited chills, shivering, and tachycardia. Decreases in hemoglobin and hematocrit were noted. Laboratory parameters for hemolysis, such as total bilirubin, direct bilirubin, and lactate dehydrogenase, were increased. Based on clinical and laboratory evaluation, it was concluded that the patient had an acute hemolytic transfusion reaction caused by anti-Yta. The patient was successfully treated with antipyretics, antihistamines, and corticosteroids. Urinary tract hemorrhaging was stopped. Anemia was additionally improved with parenteral iron supplementation, and further transfusion was not required. Immunohematology 2021;37:13-17. Many patients with anti-Yta receive multiple transfusions of Yt(a+) red blood cells (RBCs) with no ill effects. However, anti-Yta has been implicated in hemolytic transfusion reactions. Antibody identification typically determines specificity of antibodies and their clinical significance to justify blood requirements for antigen-negative blood when clinically significant antibodies are involved. Occasionally, specificity of antibody is of variable significance. Variability in clinical significance is a characteristic of anti-Yta that may affect the clinical management of such patients. This case reports the outcome of an incompatible transfusion in an 83-year-old female patient with anti-Yta, -D, -C, -Leab, and -HI who was admitted to the hospital for a severe urinary tract hemorrhage and fever. The patient was transfused with 1 crossmatch-incompatible group A, Yt(a+), D–, C–, E–, S– RBC unit in an emergency medical event. During that time, the patient exhibited chills, shivering, and tachycardia. Decreases in hemoglobin and hematocrit were noted. Laboratory parameters for hemolysis, such as total bilirubin, direct bilirubin, and lactate dehydrogenase, were increased. Based on clinical and laboratory evaluation, it was concluded that the patient had an acute hemolytic transfusion reaction caused by anti-Yta. The patient was successfully treated with antipyretics, antihistamines, and corticosteroids. Urinary tract hemorrhaging was stopped. Anemia was additionally improved with parenteral iron supplementation, and further transfusion was not required. Immunohematology 2021;37:13–17.


The German Version of the Dutch Eating Behavior Questionnaire: Psychometric Properties, Measurement Invariance, and Population-Based Norms.
The Dutch Eating Behavior Questionnaire is an internationally widely used instrument assessing different eating styles that may contribute to weight gain and overweight: emotional eating, external eating, and restraint. This study aimed to evaluate the psychometric properties of the 30-item German version of the DEBQ including its measurement invariance across gender, age, and BMI-status in a representative German population sample. Furthermore, we examined the distribution of eating styles in the general population and provide population-based norms for DEBQ scales. A representative sample of the German general population (N = 2513, age ≥ 14 years) was assessed with the German version of the DEBQ along with information on sociodemographic characteristics and body weight and height. The German version of the DEQB demonstrates good item characteristics and reliability (restraint: α = .92, emotional eating: α = .94, external eating: α = .89). The 3-factor structure of the DEBQ could be replicated in exploratory and confirmatory factor analyses and results of multi-group confirmatory factor analyses supported its metric and scalar measurement invariance across gender, age, and BMI-status. External eating was the most prevalent eating style in the German general population. Women scored higher on emotional and restrained eating scales than men, and overweight individuals scored higher in all three eating styles compared to normal weight individuals. Small differences across age were found for external eating. Norms were provided according to gender, age, and BMI-status. Our findings suggest that the German version of the DEBQ has good reliability and construct validity, and is suitable to reliably measure eating styles across age, gender, and BMI-status. Furthermore, the results demonstrate a considerable variation of eating styles across gender and BMI-status.


[Lessons from the Women's Health Initiative (WHI) using hormone replacement therapy with regard to heart disease--the dream that has been broken?].
The Women's Health Initiative (WHI) a double-blind, placebo-controlled trial studying the effects of continuous combined estrogen-progestin regimen (CEE 0.625 mg plus 2.5 mg MPA daily), was stopped prematurely on the basis of a slight increase in the risk of invasive breast cancer, myocardial infarction and stroke. The study was not planned to examine other important aspects of HRT treatment, such as menopausal symptoms and quality of life, since the CEE only arm of the study was not terminated, it is possible that the specific drug tested in the study had different effects on outcome than other preparations available in the market. One should remember that many previous observational studies actually demonstrated cardiovascular benefits in women using other types or regimens of hormones. There seems to be a consensus on the interpretation of the WHI trial: 1) hormones are the best treatment for symptomatic women since there are no real alternatives; 2) women who use HRT for more than 5 years should discuss the latest data with their physician, in order to consider their individual risk-benefit equation; 3) it is logical to prefer hormones, which are different from CEE plus MPA daily.


Pterostilbene on metabolic parameters: a randomized, double-blind, and placebo-controlled trial.
Introduction. The purpose of this trial was to evaluate the effect of pterostilbene on metabolic parameters. Methods. A prospective, randomized, double-blind, and placebo-controlled study that enrolled 80 patients with a total cholesterol ≥200 mg/dL and/or LDL ≥ 100 mg/dL. Subjects were divided into four groups: (1) pterostilbene 125 mg twice daily; (2) pterostilbene 50 mg twice daily; (3) pterostilbene 50 mg + grape extract (GE) 100 mg twice daily; (4) matching placebo twice daily for 6-8 weeks. Endpoints included lipids, blood pressure, and weight. Linear mixed models were used to examine and compare changes in parameters over time. Models were adjusted for age, gender, and race. Results. LDL increased with pterostilbene monotherapy (17.1 mg/dL; P = 0.001) which was not seen with GE combination (P = 0.47). Presence of a baseline cholesterol medication appeared to attenuate LDL effects. Both systolic (-7.8 mmHg; P < 0.01) and diastolic blood pressure (-7.3 mmHg; P < 0.001) were reduced with high dose pterostilbene. Patients not on cholesterol medication (n = 51) exhibited minor weight loss with pterostilbene (-0.62 kg/m(2); P = 0.012). Conclusion. Pterostilbene increases LDL and reduces blood pressure in adults. This trial is registered with Clinicaltrials.gov NCT01267227.


Splanchnic nerve stimulation inhibits duodenal HCO3- secretion in the rat.
Sympathoadrenergic inhibition of HCO3- secretion by the duodenal mucosa was studied in chloralose anesthetized rats. Duodenal HCO3- secretion was measured in situ by pH-stat titration. Direct efferent electrical stimulation of the cut splanchnic nerves (10 Hz, supramaximal intensity) inhibited the duodenal alkaline output by approximately 50%. This inhibitory response was blocked by the administration of either the adrenolytic agent guanethidine or the alpha 2-adrenoceptor antagonist yohimbine. However, neither the alpha 1-adrenoceptor antagonist prazosin nor the beta-adrenoceptor antagonist propranolol blocked the response to splanchnic nerve stimulation. The present data suggest that electrical splanchnic nerve stimulation inhibits duodenal HCO3- secretion via activation of adrenergic nerve fibers and alpha 2-adrenoceptors within the peripheral nervous system.


The dorsal raphe nucleus and serotonin: implications for neuroplasticity linked to major depression and Alzheimer's disease.
The dorsal raphe nucleus (DRN) is a heterogeneous brainstem nucleus located in the midbrain and pons. Via widespread projections, which target a multitude of brain areas, its neurons utilize many transmitters to control various physiological functions, including learning, memory and affect. Accordingly, the DRN has been strongly associated with brain dysfunction, especially mood disorders such as depression, but also Alzheimer's disease. The DRN's most abundant transmitter, serotonin, has received the most attention in studies on both normal brain function and disease, and lately its involvement in the regulation of neuroplasticity has been under particular scrutiny. This chapter begins with a systematic overview of what we currently know about the anatomy of the DRN and its neurons, including their ascending projections. It continues with a review of the transmitters of the DRN, followed by a discussion on the connection between the DRN and neuroplasticity. Special emphasis is put on serotonin and its central role in neuroplasticity, which is proving to be of high priority in unraveling the full picture of the cellular mechanisms and their interconnections in the etiology of major depression and Alzheimer's disease.


Clinical experiences in using cognitive-behavior therapy to treat panic disorder.
Although there is a growing body of research to support the use of psychological treatments for specific disorders, there has been no way for practitioners to provide feedback to researchers on the barriers they encounter in implementing these treatments in their day-to-day clinical work. In order to provide practitioners a means to give researchers information about their clinical experience, the Society of Clinical Psychology and the Division of Psychotherapy of the American Psychological Association collaborated on an initiative to build a two-way bridge between practice and research. A questionnaire was developed on the therapist, patient, and contextual variables that undermine the effective use of CBT in reducing the symptoms of panic disorder, a clinical problem that occurs frequently in clinical practice and has an extensive research base. An Internet-based survey was advertised internationally in listservs and professional newsletters, asking clinicians to indicate all aspects of CBT that they used in treating panic disorder, and to respond to a series of questions with variables that presumably limited successful symptom reduction in clinical work using CBT to treat panic disorder. The final database included responses from 338 participants who varied in experience in applying CBT to the treatment of panic disorders. Participants identified a wide range of patient factors that were barriers to symptom reduction, including symptoms related to panic, motivation, social system, and the psychotherapy relationship, in addition to specific problems with implementing CBT for the treatment of panic disorder.


Simultaneous determination of interfacial molarities of amide bonds, carboxylate groups, and water by chemical trapping in micelles of amphiphiles containing peptide bond models.
Chemical trapping is a powerful approach for obtaining experimental estimates of interfacial molarities of weakly basic nucleophiles in the interfacial regions of amphiphile aggregates. Here, we demonstrate that the chemical probe 4-hexadecyl-2,6-dimethylbenzenediazonium ion (16-ArN(2)(+)) reacts competitively with interfacial water, with the amide carbonyl followed by cleavage of the headgroups from the tail at the amide oxygen, and with the terminal carboxylate groups in micelles of two N-acyl amino-acid amphiphiles, sodium N-lauroylsarcosinate (SLS) and sodium N-lauroylglycinate (SLG), simple peptide bond model amphiphiles. Interfacial molarities (in moles per liter of interfacial volume) of these three groups were obtained from product yields, assuming that selectivity toward a particular nucleophile compared to water is the same in an aqueous reference solution and in the interfacial region. Interfacial carboxylate group molarities are ~1.5 M in both SLS and SLG micelles, but the concentration of the amide carbonyl for SLS micelles is ~4.6-5 times less (ca. 0.7 M) than that of SLG micelles (~3 M). The proton on the secondary N of SLG helps solubilize the amide bond in the aqueous region, but the methyl on the tertiary N of SLS helps solubilize the amide bond in the micellar core, reducing its reaction with 16-ArN(2)(+). Application of chemical trapping to proteins in membrane mimetic interfaces should provide insight into the topology of the protein within the interface because trapping of the amide carbonyl and cleavage at the C-N bond occurs only within the interface, and fragment characterization marks those peptide bonds located within the interface.


Simulating cellular dynamics through a coupled transcription, translation, metabolic model.
In order to predict cell behavior in response to changes in its surroundings or to modifications of its genetic code, the dynamics of a cell are modeled using equations of metabolism, transport, transcription and translation implemented in the Karyote software. Our methodology accounts for the organelles of eukaryotes and the specialized zones in prokaryotes by dividing the volume of the cell into discrete compartments. Each compartment exchanges mass with others either through membrane transport or with a time delay effect associated with molecular migration. Metabolic and macromolecular reactions take place in user-specified compartments. Coupling among processes are accounted for and multiple scale techniques allow for the computation of processes that occur on a wide range of time scales. Our model is implemented to simulate the evolution of concentrations for a user-specifiable set of molecules and reactions that participate in cellular activity. The underlying equations integrate metabolic, transcription and translation reaction networks and provide a framework for simulating whole cells given a user-specified set of reactions. A rate equation formulation is used to simulate transcription from an input DNA sequence while the resulting mRNA is used via ribosome-mediated polymerization kinetics to accomplish translation. Feedback associated with the creation of species necessary for metabolism by the mRNA and protein synthesis modifies the rates of production of factors (e.g. nucleotides and amino acids) that affect the dynamics of transcription and translation. The concentrations of predicted proteins are compared with time series or steady state experiments. The expression and sequence of the predicted proteins are compared with experimental data via the construction of synthetic tryptic digests and associated mass spectra. We present the mathematical model showing the coupling of transcription, translation and metabolism in Karyote and illustrate some of its unique characteristics.


Dissociable functional cortical topographies for working memory maintenance of voice identity and location.
In order to ascertain whether the neural system for auditory working memory exhibits a functional dissociation for spatial and nonspatial information, we used functional magnetic resonance imaging and a single set of auditory stimuli to study working memory for the location and identity of human voices. The subjects performed a delayed recognition task for human voices and voice locations and an auditory sensorimotor control task. Several temporal, parietal, and frontal areas were activated by both memory tasks in comparison with the control task. However, during the delay periods, activation was greater for the location than for the voice identity task in dorsal prefrontal (SFS/PreCG) and parietal regions and, conversely, greater for voices than locations in ventral prefrontal cortex and the anterior portion of the insula. This preferential response to the voice identity task in ventral prefrontal cortex continued during the recognition test period, but the double dissociation was observed only during maintenance, not during encoding or recognition. Together, the present findings suggest that, during auditory working memory, maintenance of spatial and nonspatial information modulates activity preferentially in a dorsal and a ventral auditory pathway, respectively. Furthermore, the magnitude of this dissociation seems to be dependent on the cognitive operations required at different times during task performance.


Systematic review with meta-analysis: pharmacological interventions for eosinophilic oesophagitis.
Eosinophilic oesophagitis (EoE) is a growing cause of dysphagia. Current therapies include dietary manipulation, steroids and biological drugs. To perform a systematic review and summarise the effect of different medical interventions on EoE. Two reviewers searched Pubmed and Embase for studies on treatment for EoE. We included randomised controlled trials (RCT) limited to pharmacological interventions. Two reviewers selected studies. Meta-analysis was done using random effects model to estimate odds ratio (OR). Heterogeneity was determined by Cochran's Q statistic and I(2) . Seventeen references met our inclusion criteria. Eleven RCTs involving 455 participants were included in the meta-analysis. 325 participants were evaluated for symptomatic improvement and 330 were evaluated for histological remission. Symptomatic improvement with topical steroids (7 studies, 250 participants) compared to the control group (placebo or PPI) was noted (OR: 3.03, 95% confidence interval, CI: 1.57-5.87). Histological remission was also noted in nine studies involving 330 participants (OR: 13.66, 95% CI: 2.65-70.34) comparing topical steroids to a control (placebo or PPI). There was no difference between anti-IL-5 drugs and placebo in terms of symptomatic improvement (OR: 0.69, 95% CI: 0.34-1.42). Topical steroids induce significant symptomatic and histological remission, and should be considered as a first line treatment. Anti-IL-5 therapy has a minor effect on eosinophilic oesophagitis. Future research in eosinophilic oesophagitis should standardise methodology according to published guidelines to improve quality and allow direct comparison between therapies.


Primary anterior cruciate ligament repair: Current concepts.
The renewed interest in ACL repair over the last two decades stems from advances in modern arthroscopic techniques and clinical studies that have provided evidence that the ACL can reliably heal, and patients can return to sport at a comparable rate to ACL reconstruction patients. The ability to maintain and utilize native ACL tissue, with proprioceptive capabilities, and the smaller drill tunnels needed to repair an ACL leads to an overall less invasive procedure and improved early rehabilitation. Additionally, repair avoids a variety of comorbidities associated with autograft harvest. This current concept review details modern techniques of ACL repair and their current studies, a review on the use of biologic enhancement in ACL repair, and other considerations to appropriately integrate ACL repair into the sports medicine orthopaedic surgeon's practice.


Influence of oxidized low-density lipoproteins (LDL) on the viability of osteoblastic cells.
Cardiovascular diseases have recently been noted as potential risk factors for osteoporosis development. Although it is poorly understood how these two pathologies are related, it is a known fact that oxidized low-density lipoproteins (OxLDL) constitute potential determinants for both of them. The current study investigated the metabolism of OxLDL by osteoblasts and its effect on osteoblastic viability. The results obtained show that OxLDL are internalized but not degraded by osteoblasts while they can selectively transfer their CE to these cells. It is also demonstrated that OxLDL induce proliferation at low concentrations but cell death at high concentrations. This reduction of osteoblast viability was associated with lysosomal membrane damage caused by OxLDL as demonstrated by acridine orange relocalization. Accordingly, chloroquine, an inhibitor of lysosomal activity, accentuated cell death induced by OxLDL. Finally, we demonstrate that osteoblasts have the capacity to oxidize LDL and thereby potentially increase the local concentration of OxLDL. Overall, the current study confirms the potential role of OxLDL in the development of osteoporosis given its influence on osteoblastic viability.


Susceptibility of rainbow trout to three different genogroups of infectious pancreatic necrosis virus.
Infectious pancreatic necrosis (IPN) is a globally distributed viral disease that is highly prevalent in rainbow trout Oncorhynchus mykiss farms in Finland. Seven genogroups (1-7) of infectious pancreatic necrosis virus (IPNV) exist, of which genogroup 5 (serotype Sp) is generally considered to be the most virulent in European salmonid farming. In Finland, 3 genogroups (2, 5 and 6) have been detected. Genogroup 2 is the most widespread and to date is the only genogroup associated with clinical disease in field observations. A bath challenge model infection trial was conducted to investigate the potential pathogenicity of the existing Finnish IPNV genogroups on IPNV-negative rainbow trout fry. Three Finnish IPNV isolates, a positive control (a Norwegian genogroup 5 isolate previously associated with high virulence in Atlantic salmon Salmo salar) and a negative control were used, and mortality was recorded daily for 8 wk. The Finnish IPNV genogroup 5 isolate caused the highest cumulative mortality, and the genogroup 2 isolate also caused elevated mortalities. The genogroup 6 isolate caused only low mortality, and the positive control treatment showed negligible mortality. Fish exposed to the Finnish genogroup 2 and 5 isolates had IPN-associated lesions, while no lesions were noted in the other treatment groups. These results indicate that Finnish IPNV genogroup 5 is potentially the most virulent IPNV genogroup for Finnish rainbow trout. Interestingly, the Norwegian IPNV genogroup 5 isolate caused only a subclinical IPN infection, providing further evidence for a host species-dependent, virus isolate-related difference in virulence in IPNV genogroup 5. The results also support the continuation of legislative disease control of IPNV genogroup 5 in Finnish inland waters.


The efficacy and safety of nalbuphine (NUBAIN) in balanced anesthesia. A double blind comparison with fentanyl in gynecological and urological surgery.
In a prospective double blind study the efficacy and safety of nalbuphine as an analgesic in balanced anesthesia has been compared to fentanyl. In 63 patients, ASA class I-III, major gynecological or urological surgical procedures were performed under balanced anesthesia. Analgesia could be satisfactory maintained in all cases, but in cases of nalbuphine more hypnotics were necessary to keep the patients unconscious. The ratio of fentanyl and nalbuphine consumption was 1:200 (by weight). The nalbuphine cases can be distinguished by: more stable but higher arterial pressures and absence of arrythmia; lower incidence of nausea and vomiting in the postoperative period; less respiratory depression at the end of anesthesia, not needing antagonists, as compared to 11 patients needing antagonization in the fentanyl group; and a larger incidence of minor local allergic reactions at the injection site. Awareness was not observed in any patient of either group. Although nalbuphine has a weaker analgesic and hypnotic effect, it is perfectly possible to provide balanced anesthesia in combination with a hypnotic and a muscle relaxant. Advantages are the absence of respiratory depression as well as nausea and vomiting in the postoperative period.


[Algodystrophy and metabolic abnormalities].
The French Society of Rheumatology national study of reflex dystrophy revealed a serum glucose greater than 1.20 g/l in 9.09 p. cent of cases, a serum uric acid greater than 70 mg/l in 25 p. cent of men and greater than 60 mg/l in 14 p. cent of women. Serum cholesterol was normal in males, but higher than the mean + 2 sigma in 23 p. cent of females. Serum triglycerides were higher than m + 2 sigma in 55 p. cent of men and 56 p. cent of women. From a group of 80 patients, 54 (67.5 p. cent) had at least one of the three metabolic abnormalities and 49 (61.25 p. cent) were hypertriglyceridaemic. This hypertriglyceridaemia is the most frequent abnormality found. When hyperglycaemia or hyperuricaemia are present it is almost always in association with hypertriglyceridaemia. Hypertriglyceridaemia is more common in algoneurodystrophy of the lower limbs (54/78, 69 p. cent) than in algoneurodystrophy of the upper limbs (5/22, 22.7 p. cent). Algoneurodystrophy is more often primary, when it occurs in the lower limbs and post-traumatic when it occurs in the upper limbs. A prospective study comparing several parameters of lipid metabolism in 24 patients with algoneurodystrophy and 15 matched controls showed a significant drop in the HDL Chol/HDL P1 ratio and in the DHL - HDL Chol/TG ratio in patients with algoneurodystrophy. Serum insulin was comparable in the 2 groups. Lecithin cholesterol acyl transferase (LCAT), SGOT, SGPT and GGT were normal. The essential role of hypertriglyceridaemia in the genesis of the characteristic bony lesions of algoneurodystrophy is discussed.


Automated detection of hospital outbreaks: A systematic review of methods.
Several automated algorithms for epidemiological surveillance in hospitals have been proposed. However, the usefulness of these methods to detect nosocomial outbreaks remains unclear. The goal of this review was to describe outbreak detection algorithms that have been tested within hospitals, consider how they were evaluated, and synthesize their results. We developed a search query using keywords associated with hospital outbreak detection and searched the MEDLINE database. To ensure the highest sensitivity, no limitations were initially imposed on publication languages and dates, although we subsequently excluded studies published before 2000. Every study that described a method to detect outbreaks within hospitals was included, without any exclusion based on study design. Additional studies were identified through citations in retrieved studies. Twenty-nine studies were included. The detection algorithms were grouped into 5 categories: simple thresholds (n = 6), statistical process control (n = 12), scan statistics (n = 6), traditional statistical models (n = 6), and data mining methods (n = 4). The evaluation of the algorithms was often solely descriptive (n = 15), but more complex epidemiological criteria were also investigated (n = 10). The performance measures varied widely between studies: e.g., the sensitivity of an algorithm in a real world setting could vary between 17 and 100%. Even if outbreak detection algorithms are useful complementary tools for traditional surveillance, the heterogeneity in results among published studies does not support quantitative synthesis of their performance. A standardized framework should be followed when evaluating outbreak detection methods to allow comparison of algorithms across studies and synthesis of results.


Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a once-daily modified release tacrolimus-based regimen.
Modified release (MR) tacrolimus is an extended release formulation administered once daily. The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure in stable liver transplant recipients converted from Prograf twice a day to MR tacrolimus once daily. This was an open-label, multicenter study with a single sequence, four-period crossover design. Eligible patients were 18 to 65 years of age, >6 months posttransplant with stable renal and hepatic function and receiving stable doses of Prograf twice a day for >2 weeks prior to enrollment. Patients received Prograf twice a day on days 1 to 14 and 29 to 42. Patients were converted to the same milligram-for-milligram daily dose of MR once daily on days 15 to 28 and 43 to 56. Twenty-four-hour PK profiles were obtained on days 14, 28, 42, and 56. Laboratory and safety parameters were also evaluated. Of 70 patients, 62 completed all four PK profiles. The AUC0-24 of tacrolimus was comparable for Prograf twice a day (days 14 and 42) and MR tacrolimus once daily (days 28 and 56). The 90% confidence intervals for MR tacrolimus versus Prograf at steady state (days 28 and 56 vs days 14 and 42) was 0.85 to 0.92 for AUC0-24. MR tacrolimus was well tolerated with a safety profile comparable to that of Prograf. AUC0-24 was highly correlated to Cmin for Prograf (day 14, r = .93; Day 42, r = .89) and for MR tacrolimus (day 28, r = .93; day 56, r = .92). Renal and liver function remained stable. One patient experienced acute rejection. The steady-state tacrolimus exposure of MR tacrolimus once daily is equivalent to Prograf twice a day after a milligram-for-milligram conversion in stable liver transplant recipients.


Comparative functional genomics identifies unique molecular features of EPSCs.
Extended pluripotent or expanded potential stem cells (EPSCs) possess superior developmental potential to embryonic stem cells (ESCs). However, the molecular underpinning of EPSC maintenance in vitro is not well defined. We comparatively studied transcriptome, chromatin accessibility, active histone modification marks, and relative proteomes of ESCs and the two well-established EPSC lines to probe the molecular foundation underlying EPSC developmental potential. Despite some overlapping transcriptomic and chromatin accessibility features, we defined sets of molecular signatures that distinguish EPSCs from ESCs in transcriptional and translational regulation as well as metabolic control. Interestingly, EPSCs show similar reliance on pluripotency factors Oct4, Sox2, and Nanog for self-renewal as ESCs. Our study provides a rich resource for dissecting the regulatory network that governs the developmental potency of EPSCs and exploring alternative strategies to capture totipotent stem cells in culture.


Pharmacokinetic model incorporating mechanism-based inactivation of CYP2D6 can explain both non-linear kinetics and drug interactions of paroxetine.
To develop a pharmacokinetic model able to describe the nonlinear pharmacokinetics of paroxetine (PRX) and to predict the drug-drug interaction between PRX and metoprolol under various dosage regimens. A pharmacokinetic model of PRX incorporating mechanism-based inhibition was developed. This model was fitted to the drug concentration profiles obtained after single and repeated administrations of PRX to estimate the pharmacokinetic parameters of PRX and degradation rate constant of cytochrome P450 (CYP) 2D6. It was also fitted to the time profile of S-metoprolol after coadministration of metoprolol and PRX, and the fractional contribution of CYP2D6 to overall clearance of S-metoprolol was estimated. Using the developed model and estimated parameters, an optimal dosage regimen for metoprolol during withdrawal of PRX was simulated. The developed model well described the time profiles of both PRX and metoprolol concentration during concomitant administration. The estimated parameters were consistent with reported values. The nonlinear and accumulation properties of PRX could be explained by mechanism-based inhibition of CYP2D6 by PRX. Upon tapering PRX from 20 mg/ day to 10 mg/day for 14 days then 5 mg/day for 14 days until cessation, the optimal dosage regimen to resume 120 mg/day of metoprolol based on the developed model was as follows: 30 mg/day during concomitant administration, 40 mg/day for the next 14 days, 60 mg/day for the next 14 days, and finally 120 mg/day. The developed model enabled us to quantitatively estimate drug-drug interactions of PRX and CYP2D6 substrate drugs, and to predict optimal dosage regimens.


Increased mortality after a first myocardial infarction in human immunodeficiency virus-infected patients; a nested cohort study.
HIV infection may be associated with an increased recurrence rate of myocardial infarction. Our aim was to determine whether HIV infection is a risk factor for worse outcomes in patients with coronaray artery disease. We compared data aggregated from two ongoing cohorts: (i) the Acute Myocardial Infarction in Switzerland (AMIS) registry, which includes patients with acute myocardial infarction (AMI), and (ii) the Swiss HIV Cohort Study (SHCS), a prospective registry of HIV-positive (HIV+) patients. We included all patients who survived an incident AMI occurring on or after 1st January 2005. Our primary outcome measure was all-cause mortality at one year; secondary outcomes included AMI recurrence and cardiovascular-related hospitalisations. Comparisons used Cox and logistic regression analyses, respectively. There were 133 HIV+, (SHCS) and 5,328 HIV-negative [HIV-] (AMIS) individuals with incident AMI. In the SHCS and AMIS registries, patients were predominantly male (72% and 85% male, respectively), with a median age of 51 years (interquartile range [IQR] 46-57) and 64 years (IQR 55-74), respectively. Nearly all (90%) of HIV+ individuals were on successful antiretroviral therapy. During the first year of follow-up, 5 (3.6%) HIV+ and 135 (2.5%) HIV- individuals died. At one year, HIV+ status after adjustment for age, sex, calendar year of AMI, smoking status, hypertension and diabetes was associated with a higher risk of death (HR 4.42, 95% CI 1.73-11.27). There were no significant differences in recurrent AMIs (4 [3.0%] HIV+ and 146 [3.0%] HIV- individuals, OR 1.16, 95% CI 0.41-3.27) or in hospitalization rates (OR 0.68 [95% CI 0.42-1.11]). HIV infection was associated with a significantly increased risk of all-cause mortality one year after incident AMI.


Isolation and Identification of a Leptospire of The Hebdomadis Serogroup (L. Hardjo) From Cattle in Canada.
During the summer of 1961 an outbreak of atypical mastitis in a small herd of dairy cattle was investigated. The clinical findings, which included a single abortion, were suggestive of leptospirosis and serological studies indicated that a serotype other than the usual L. pomona was the causative agent. A fastidious leptospire recovered from the urine of one cow has been identified as L. hardjo, a member of the hebdomadis group. The difficulties encountered in isolation, adaptation to standard media and serotyping are described.


Novel nuclear magnetic resonance spectroscopy methods demonstrate preferential carbon source utilization by Acinetobacter calcoaceticus.
Novel nuclear magnetic resonance spectroscopy techniques, designated metabolic observation, were used to study aromatic compound degradation by the soil bacterium Acinetobacter calcoaceticus. Bacteria which had been rendered spectroscopically invisible by growth with deuterated (2H) medium were used to inoculate cultures in which natural-abundance 1H hydrogen isotopes were provided solely by aromatic carbon sources in an otherwise 2H medium. Samples taken during the incubation of these cultures were analyzed by proton nuclear magnetic resonance spectroscopy, and proton signals were correlated with the corresponding aromatic compounds or their metabolic descendants. This approach allowed the identification and quantitation of metabolites which accumulated during growth. This in vivo metabolic monitoring facilitated studies of catabolism in the presence of multiple carbon sources, a topic about which relatively little is known. A. calcoaceticus initiates aromatic compound dissimilation by forming catechol or protocatechuate from a variety of substrates. Degradation proceeds via the beta-ketoadipate pathway, comprising two discrete branches that convert catechol or protocatechuate to tricarboxylic acid cycle intermediates. As shown below, when provided with several carbon sources simultaneously, all degraded via the beta-ketoadipate pathway, A. calcoaceticus preferentially degraded specific compounds. For example, benzoate, degraded via the catechol branch, was consumed in preference to p-hydroxybenzoate, degraded via the protocatechuate branch, when both compounds were present. To determine if this preference were governed by metabolites unique to catechol degradation, pathway mutants were constructed. Studies of these mutants indicated that the product of catechol ring cleavage, cis,cis-muconate, inhibited the utilization of p-hydroxybenzoate in the presence of benzoate. The accumulation of high levels of cis,cis-muconate also appeared to be toxic to the cells.


[Surgical treatment of vasorenal hypertension in children and adolescents].
Problems of the surgical treatment of vasorenal hypertension in children are elucidated as well as types of reconstruction of the renal arteries, indications and contra-indications for surgery. Results of 34 operations fulfilled for fibromuscular lesions of the renal arteries in 32 patients and causes of reoperations and resection of the organs are analyzed.


Dissociation of Proactive and Reactive Cognitive Control in Individuals with Schizotypy: An Event-Related Potential Study.
Patients with schizophrenia and individuals with schizotypy, a subclinical group at risk for schizophrenia, have been found to have impairments in cognitive control. The Dual Mechanisms of Cognitive Control (DMC) framework hypothesises that cognitive control can be divided into proactive and reactive control. However, it is unclear whether individuals with schizotypy have differential behavioural impairments and neural correlates underlying these two types of cognitive control. Twenty-five individuals with schizotypy and 26 matched healthy controls (HCs) completed both reactive and proactive control tasks with electroencephalographic data recorded. The proportion of congruent and incongruent trials was manipulated in a classic colour-word Stroop task to induce proactive or reactive control. Proactive control was induced in a context with mostly incongruent (MI) trials and reactive control in a context with mostly congruent (MC) trials. Two event-related potential (ERP) components, medial frontal negativity (MFN, associated with conflict detection) and conflict sustained potential (conflict SP, associated with conflict resolution) were examined. There was no significant difference between the two groups in terms of behavioural results. In terms of ERP results, in the MC context, HC exhibited significantly larger MFN (360-530 ms) and conflict SP (600-1000 ms) amplitudes than individuals with schizotypy. The two groups did not show any significant difference in MFN or conflict SP in the MI context. The present findings provide initial evidence for dissociation of neural activation between proactive and reactive cognitive control in individuals with schizotypy. These findings help us understand cognitive control deficits in the schizophrenia spectrum.


John Ruskin's relapsing encephalopathy.
John Ruskin (1819-1900) is chiefly remembered for his works on painting and architecture, and for his powerful and original prose style. In middle age, he suffered recurring episodes of delirium with visual hallucinations and delusions. At about the same time, his writing developed a disjointed polemical character, with cryptic and intemperate elements that disorientated some readers. The nature of Ruskin's 'madness' is a key to understanding his later writing career but the psychiatric explanations given by many of his literary biographers seem unsatisfactory. Ruskin left numerous clues about the illness in his diaries, correspondence and publications. It is likely that he had a relapsing-progressive neurological disorder with neuropsychiatric manifestations. It could have been a fluctuating metabolic or immunological encephalopathy, but the diagnosis that best fits the time course of his illness and the prior history of mood disorder and of migraine with aura is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Whatever the pathology, its first effects on frontal lobe function may have actually enhanced Ruskin's creative energy for a long time before stepwise cognitive impairment degraded his ability to write.


An update on the microbiology, immunology and genetics of seborrheic dermatitis.
The underlying mechanism of seborrheic dermatitis (SD) is poorly understood but major scientific progress has been made in recent years related to microbiology, immunology and genetics. In light of this, the major goal of this article was to summarize the most recent articles on SD, specifically related to underlying pathophysiology. SD results from Malassezia hydrolysation of free fatty acids with activation of the immune system by the way of pattern recognition receptors, inflammasome, IL-1β and NF-kB. M. restricta and M. globosa are likely the most virulent subspecies, producing large quantities of irritating oleic acids, leading to IL-8 and IL-17 activation. IL-17 and IL-4 might play a big role in pathogenesis, but this needs to be further studied using novel biologics. No clear genetic predisposition has been established; however, recent studies implicated certain increased-risk human leucocyte antigen (HLA) alleles, such as A*32, DQB1*05 and DRB1*01 as well as possible associations with psoriasis and atopic dermatitis (AD) through the LCE3 gene cluster while SD, and SD-like syndromes, shares genetic mutations that appear to impair the ability of the immune system to restrict Malassezia growth, partially due to complement system dysfunction. A paucity of studies exists looking at the relationship between SD and systemic disease. In HIV, SD is thought to be secondary to a combination of immune dysregulation and disruption in skin microbiota with unhindered Malassezia proliferation. In Parkinson's disease, SD is most likely secondary to parasympathetic hyperactivity with increased sebum production as well as facial immobility which leads to sebum accumulation.


Mechanism and stereochemistry of the 5-aminolaevulinate synthetase reaction.
1. Two mechanisms for the biosynthesis of 5-aminolaevulinate from glycine and succinyl-CoA (3-carboxypropionyl-CoA) are considered. One of the mechanisms involves the retention of both the C-2 H atoms of glycine during the synthesis of 5-aminolaevulinate, whereas the other predicts the retention of only one of the C-2 H atoms of glycine. 2. Highly purified 5-aminolaevulinate synthetase from Rhodopseudomonas spheroides was used to show that the C-2 H atom of glycine with R configuration is specifically removed during the biosynthesis of 5-aminolaevulinate. 3. The mechanism of the condensation therefore differs from the analogous reaction of the biosynthesis of sphinganine from palmitoyl-CoA and serine, in which the C-2 H of serine is retained (Wiess, 1963).


[Analysis of disease burden of lung cancer attributable to chromium in Chinese population from 1990 to 2019].
Objective: To analyze the disease burden and change trend of lung cancer attributable to chromium in Chinese population from 1990 to 2019, and to provide reference for the formulation of health policies and strategies of disease prevention and control. Methods: In October 2022, using the data and findings of the burden of disease, injury and risk factor published in the Global Burden of Disease Study 2019 (GBD 2019), the burden of lung cancer and its changes caused by occupational hexavalent chromium exposure in Chinese population from 1990 to 2019 were analyzed according to year and gender. The average age structure of the world population was used as the standard population to calculate standardized indicators, and then compared with the global population. Results: The incidence number, death number, disability adjusted life years (DALY) of lung cancer attributable to chromium in Chinese population of 2019 were 833 cases, 790 cases and 22118 person years, respectively. Compared with 1990 (257 cases, 277 cases, 8631 person years), the increase was 224.1%, 185.2%, 156.3%, higher than the global level (101.0%, 134.2%, 117.2%). The standardized morbidity, mortality and DALY rates of lung cancer attributable to chromium in Chinese population of 2019 were 0.059/100000, 0.056/100000 and 1.555/100000, which respectively increased by 169.7%, 137.4%, 113.3% in comparison with that of 1990 (0.022/100000, 0.023/100000 and 0.729/100000). The average annual percent changes were 18.8%, 15.1% and 13.5%, which were higher than the global level (5.7%, 8.4% and 7.0%). In 2019, the DALY caused by chromium-related lung cancer in the Chinese population accounted for 0.0058% (22118/382205568) of the all-cause disease burden in the Chinese population, and 51.8% (22118/42718) of the global population. In 2019, the disease burden of lung cancer attributable to chromium was higher in males than in females, the number of incidence, death and DALY were 576 cases (69.1%), 525 cases (66.5%) and 14717 person years (66.5%), respectively. Conclusion: In 2019, the proportion of disease burden caused by lung cancer attributable to chromium in the Chinese population is low, but it accounts for a high proportion of the global population burden of lung cancer attributable to chromium, and the standardized incidence, mortality and DALY rates show an increasing trend year by year from 1990 to 2019.


Combination of the Thermodilution-Derived Index of Microcirculatory Resistance and Coronary Flow Reserve Is Highly Predictive of Microvascular Obstruction on Cardiac Magnetic Resonance Imaging After ST-Segment Elevation Myocardial Infarction.
The aim of this study was to investigate the predictive accuracy of invasive coronary microvascular indexes for identifying microvascular obstruction (MVO) on cardiac magnetic resonance imaging (CMR) in patients treated with primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). We hypothesized that a combination of the index of microcirculatory resistance (IMR) and the thermodilution-derived coronary flow reserve (CFRthermo) will enhance the predictive accuracy of detecting MVO compared with either index alone. The IMR and CFRthermo were measured using a single pressure sensor/thermistor-tipped guidewire in 40 STEMI patients immediately after PCI and related to MVO assessed by CMR day 7. The primary endpoint was the predictive accuracy of the IMR for detecting MVO. Patients with an IMR >36 (upper tertile) had a higher rate of MVO compared with those with an IMR ≤36 (93% vs. 39%; p = 0.001). MVO occurred in all patients with an IMR >36 and a CFRthermo ≤1.7 and in no patients with an IMR ≤36 and a CFRthermo >1.7. The IMR remained an independent predictor of MVO (odds ratio: 1.212, 95% confidence interval [CI]: 1.004 to 1.464; p = 0.045) after adjustment for age, creatine kinase-myocardial band, myocardial blush grade, thrombus burden, and CFRthermo. Both the IMR (area under the curve, 0.868, 95% CI: 0.719 to 0.956; p = 0.001) and the CFRthermo (area under the curve, 0.706, 95% CI: 0.536 to 0.842; p = 0.03) were predictive of MVO. Combined IMR and CFRthermo increased the area under the curve for MVO to 0.941. In patients who underwent primary PCI for STEMI, an increased IMR has an independent predictive value for MVO detection, and combined high IMR and low CFRthermo are highly predictive of MVO. These indexes could be used to further risk-stratify patients and guide regional and systemic therapies.


Long-term cell survival and hemodynamic improvements after neonatal cardiomyocyte and satellite cell transplantation into healed myocardial cryoinfarcted lesions in rats.
Cell engraftment is a new strategy for the repair of ischemic myocardial lesions. The hemodynamic effectiveness of this strategy, however, is not completely elucidated yet. In a rat model of cryothermia-induced myocardial dysfunction, we investigated whether syngeneic transplantation of neonatal cardiomyocytes or satellite cells is able to improve left ventricular performance. Myocardial infarction was induced in female Lewis rats by a standardized cryolesion to the obtuse margin of the left ventricle. After 4 weeks, 5 x 10(6) genetically male neonatal cardiomyocytes (n = 16) or satellite cells (n = 16) were engrafted into the myocardial scar. Sham-transplanted animals (n = 15) received injections with cell-free medium. Sham-operated animals (n = 15) served as controls. Left ventricular performance was analyzed 4 months after cell engraftment. Chimerism after this sex-mismatched transplantation was evaluated by detection of PCR-amplified DNA of the Y chromosome. The average heart weight of the infarcted animals significantly exceeded that of controls (p < 0.05). In sham-transplanted animals, mean aortic pressure, left ventricular systolic pressure, aortic flow (indicator of cardiac output), and left ventricular systolic reserve were significantly lower (p < 0.05) compared with sham-operated controls. This was associated with deterioration of ventricular diastolic function (maximal negative dP/dt, time constants of isovolumic relaxation; p < 0.05). Transplantation of satellite cells was found more effective than transplantation of neonatal cardiomyocytes, resulting in i) normalization of mean aortic pressure compared with sham-operated controls, and ii) significantly improved left ventricular systolic pressure and aortic flow (p < 0.05) compared with sham-transplanted animals. Left ventricular systolic reserve and diastolic function, however, were improved by neither satellite cell nor neonatal cardiomyocyte transplantation. Analysis of male genomic DNA revealed 3.98 +/- 2.70 ng in hearts after neonatal cardiomyocyte engraftment and 6.16 +/- 4.05 ng in hearts after satellite cell engraftment, representing approximately 10(3) viable engrafted cells per heart. Our study demonstrates i) long-term survival of both neonatal cardiomyocytes and satellite cells after transplantation into cryoinfarcted rat hearts, ii) slight superiority of satellite cells over neonatal cardiomyocytes in improving global left ventricular pump performance, and iii) no effect of both transplant procedures on diastolic dysfunction.


Aequorin luminescence, myosin phosphorylation, and active stress in tracheal smooth muscle.
During muscarinic activation of canine tracheal smooth muscle with carbachol, myosin phosphorylation is significantly more sensitive than stress to the external Ca2+ concentration ([Ca2+]o) [W. T. Gerthoffer. Am. J. Physiol. 250 (Cell Physiol. 19): C597-C604, 1986]. To determine whether the intracellular Ca2+ concentration ([Ca2+]i) correlated more closely with changes in phosphorylation or force, we measured isometric force and light emitted by the luminescent intracellular Ca2+ indicator aequorin as [Ca2+]o was increased in the presence of 1 microM carbachol or 60 mM K+. Myosin phosphorylation was measured using an immunoblot assay in a second set of muscle strips treated identically. Stimulation with carbachol increased aequorin luminescence slightly in strips incubated in Ca2+-free solution. Active stress and aequorin luminescence subsequently increased in parallel as [Ca2+]o was increased. Myosin phosphorylation at 0.05 mM [Ca2+]o (0.30 +/- 0.04 mol Pi/mol light chain) was significantly higher than phosphorylation in Ca2+-free solution with no carbachol (0.12 +/- 0.048 mol Pi/mol light chain) and increased to a maximum of 0.56 +/- 0.03 mol Pi/mol light chain at 1.6 mM [Ca2+]o. In contrast, active stress and aequorin luminescence remained low at low [Ca2+]o and reached a maximum at 2.4 mM [Ca2+]o. Stimulation with carbachol produced greater increases in myosin phosphorylation and active stress for a given change in aequorin luminescence than did K+ depolarization. Stimulation with carbachol also produced a different phosphorylation-stress relationship than did K+ depolarization. These observations are consistent with the possibility that carbachol induces increases in the Ca2+ sensitivity of contractile proteins in tracheal smooth muscle.


Inflammatory response to oxygen and endotoxin in newborn rat lung ventilated with low tidal volume.
Herein, we determined the contribution of mechanical ventilation, hyperoxia and inflammation, individually or combined, to the cytokine/chemokine response of the neonatal lung. Eight-day-old rats were ventilated for 8 h with low ( approximately 3.5 mL/kg), moderate ( approximately 12.5 mL/kg), or high ( approximately 25 mL/kg) tidal volumes (VT) and the cytokine/chemokine response was measured. Next, we tested whether low-VT ventilation with 50% oxygen or a preexisting inflammation induced by lipopolysaccharide (LPS) would modify this response. High-, moderate-, and low-VT ventilation significantly elevated CXCL-2 and IL-6 mRNA levels. Low-VT ventilation with 50% oxygen significantly increased IL-6 and CXCL-2 expression versus low-VT ventilation alone. LPS pretreatment combined with low-VT ventilation with 50% oxygen amplified IL-6 mRNA expression when compared with low VT alone or low VT + 50% O2 treatment. In contrast, low VT up-regulated CXCL-2 levels were reduced to nonventilated levels when LPS-treated newborn rats were ventilated with 50% oxygen. Thus, low-VT ventilation triggers the expression of acute phase cytokines and CXC chemokines in newborn rat lung, which is amplified by oxygen but not by a preexisting inflammation. Depending on the individual cytokine or chemokine, the combination of both oxygen and inflammation intensifies or abrogates the low VT-induced inflammatory response.