Minimal important differences for the WOMAC osteoarthritis index and the Forgotten Joint Score-12 in total knee arthroplasty patients.
Total knee arthroplasty (TKA) is an effective treatment for end-stage osteoarthritis. Patient reported-outcome measures (PROMs) capture the patients' perception of the success of an intervention. The minimal important difference (MID) is an important characteristic of the PROM, which helps to interpret results. The aim of this study was to identify the MID for the Forgotten Joint Score-12 (FJS-12) and Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. Data were collected in a prospective cohort study. Patients were asked to complete the FJS-12, WOMAC osteoarthritis index and transition items evaluating change over time to determine the MID. We employed an anchor-based methodology relating score change to the response categories of the transition items using both binary logistic regression and receiver operating characteristic (ROC) analysis. Data from 199 patients were analysed. Mean age was 72.3 years, 58% were women. Employing binary logistic regression the MID for the FJS-12 was 10.8 points, for the WOMAC pain score 7.5 points and for the WOMAC function score 7.2 points. ROC analyses found a MID of 13.0 points for the FJS-12, 12.5 points for WOMAC pain and 14.7 points for WOMAC function. We report MIDs for the FJS-12 and the WOMAC Pain and Function scales in a TKA patient cohort, which can be used to interpret meaningful differences in score. In line with previous research, we found more advanced statistical methods to result in smaller MID estimates for both scores. Written consent for this study was obtained from all participants and ethical approval was granted by the local ethics committee (Ethikkommission St. Gallen; EKSG 14/973; Registered 03 July 2014; http://www.sg.ch/home/gesundheit/ethikkommission.html).


Effects of angiotensin II and angiotensin II antagonist saralasin on cell growth and renin in 3T3 and SV3T3 cells.
Components of the renin-angiotensin system were studied in established cell culture lines of 3T3 and SV3T3 mouse fibroblasts. The renin content in 3T3 cells was significantly higher than in virus-transformed SV3T3 cells. With time after infection, renin decreased in Simian virus 40 transformed cells, while it increased steadily in mock-infected 3T3 cells. In contrast to renin, angiotensinase activity was higher in SV3T3 cells. Angiotensin II stimulated cell proliferation in 3T3 mouse fibroblasts and decreased their renin content in a dose-related manner. In contrast, saralasin, an angiotensin receptor antagonist, inhibited cell growth in 3T3 and SV3T3 cells and caused an increase of cellular renin concentration. The angiotensin fragments angiotensin (2-8) heptapeptide and angiotensin (4-8) pentapeptide had no effect on cell growth. A significant negative correlation was found between cell proliferation and renin levels in 3T3 and SV3T3 cells irrespective of the treatment. Our results indicate (1) that angiotensin II may be involved in cell growth regulation, (2) that a negative feedback exist between angiotensin II added and intracellular renin content, and (3) that virus infection causes a decrease in intracellular renin synthesis, while non-specific angiotensinase activity is increased under this condition.


A note on Insider information and its relation with the arbitrage condition and the utility maximization problem.
We prove that Theorem 4.16 in [1] is false by constructing a strategy that generates $ (FLVR)_{ \mathcal{H}(\mathbb{G})} $. However, we success to prove that the no arbitrage property still holds when the agent only plays with strategies belonging to the admissible set called buy-and-hold.


[Evaluation of Fusarium spp. pathogenicity in plant and murine models].
The genus Fusarium is widely recognized for its phytopathogenic capacity. However, it has been reported as an opportunistic pathogen in immunocompetent and immunocompromised patients. Thus, it can be considered a microorganism of interest in pathogenicity studies on different hosts. Therefore, this work evaluated the pathogenicity of Fusarium spp. isolates from different origins in plants and animals (murine hosts). Twelve isolates of Fusarium spp. from plants, animal superficial mycoses, and human superficial and systemic mycoses were inoculated in tomato, passion fruit and carnation plants, and in immunocompetent and immunosuppressed BALB/c mice. Pathogenicity tests in plants did not show all the symptoms associated with vascular wilt in the three plant models; however, colonization and necrosis of the vascular bundles, regardless of the species and origin of the isolates, showed the infective potential of Fusarium spp. in different plant species. Moreover, the pathogenicity tests in the murine model revealed behavioral changes. It was noteworthy that only five isolates (different origin and species) caused mortality. Additionally, it was observed that all isolates infected and colonized different organs, regardless of the species and origin of the isolates or host immune status. In contrast, the superficial inoculation test showed no evidence of epidermal injury or colonization. The observed results in plant and murine models suggest the pathogenic potential of Fusarium spp. isolates in different types of hosts. However, further studies on pathogenicity are needed to confirm the multihost capacity of this genus.


Identification of antigenically distinct hemocyte subpopulations in Biomphalaria glabrata (Gastropoda) using monoclonal antibodies to surface membrane markers.
Five monoclonal antibodies (mABs) against surface antigens on circulating, glass-adherent hemocytes of the snail, Biomphalaria glabrata, were produced by somatic cell hybridization methods. Two mABs (IID2.6-Bg and IID4.8-Bg) are pan-hemocytic, reacting uniformly with epitopes shared by all adherent hemocytes. Determinants recognized by these mABs also are present in soluble form and appear to be associated with a hemoglobin-depleted ultracentrifuged fraction of snail hemolymph. Hybridoma-derived mABs IIC6.8-Bg and VB10.3-Bg recognize hemocyte surface epitopes expressed by only 50-60% of the adherent cell population. These mABs also are reactive with soluble hemolymph antigens but apparently recognize determinants which are different from the IID2.6-Bg and IID4.8-Bg reactive sites. Another antigenically distinct hemocyte subpopulation is recognized by mAB IID7.1-Bg. Epitopes that are reactive with this mAB differ from the previously described determinants by their asymmetrical distribution on the surface of positive cells and the absence of soluble antigenic components in hemolymph. Furthermore, unlike the other mABs, the prevalence of hemocytes staining with IID7.1-Bg antibodies differed between two strains of B. glabrata. Results of this study clearly demonstrate that circulating B. glabrata hemocytes, consisting of a single, predominant population of adherent cells, is composed of several distinct antigenic subpopulations based on the specific binding of anti-hemocyte mAB probes. Our successful application of hybridoma techniques to the study of molluscan hemocyte surface antigens underscores further the great potential usefulness of this method in analysing the molecular basis of hemocyte reactivity.


Transient abnormal myelopoiesis with extramedullary involvement in a down syndrome preemie leading to an unresponsive course despite chemotherapy.
Transient abnormal myelopoiesis (TAM) is a transient, clonal myeloproliferative disorder unique to Down Syndrome (DS) babies. It is characterized by increased peripheral blasts and presence of GATA1 mutation. The clinical spectrum ranges from jaundice and hepatosplenomegaly to multi-organ failure and death. Here we present a case of a premature baby with DS diagnosed to have TAM with extramedullary involvement at birth who had a fatal outcome. A 30.3-week-old female fetus with DS had leukocytosis (WBC: 187.82 K/uL) with neutrophilia (ANC 27.65 K/uL), macrocytic anemia (RBC: 2.41 m/uL, Hb 8.8 g/dL, MCV 108.3, MCH 36.5, MCHC 33.7) and thrombocytosis (platelet count 361 K/uL) at birth. Liver panels demonstrated normal bilirubin levels with elevated liver enzymes (AST = 239 U/L, ALT = 216 U/L). Peripheral smear showed marked leukocytosis with increased blasts (70%), nucleated RBCs, giant platelets, and megakaryocytic elements. Flow cytometry demonstrated two populations of cells: 20% myeloblasts and 26% dim CD45 CD34- cells. GATA1 mutation was present. Based on these findings a diagnosis of TAM with extramedullary hematopoiesis was made. She received two cycles of cytarabine chemotherapy. Though her WBC levels reached a low of 18.93 K/uL, she developed multi-organ failure, eventually leading to death on day 45. TAM is a transient condition resulting in disease resolution in around 80% of cases. Death is reported in 10% of cases. Risk factors associated with early death include prematurity, hyperleukocytosis, elevated bilirubin levels. Management of high-risk babies with chemotherapy is recommended to improve survival.


Immunohistochemical characterization of an amphicrine mucinous islet-cell carcinoma of the pancreas. Case report.
Immunohistochemical characteristics of a mucinous islet-cell carcinoma of the pancreas are described. The tumour presented with jaundice in a 59-year-old male. It consisted of polygonal atypical cells forming a reticular pattern, and invaded the common bile duct. In DNA flow cytometry, the tumour cells showed a clear-cut aneuploid peak. Intercellular mucin was abundant. A panel of antisera and monoclonal markers was applied in the immunohistochemical analysis. In addition to general epithelial and endocrine markers, the tumour cells showed a focal positive immunoreaction with anti-glucagon, anti-insulin, anti-vasoactive intestinal polypeptide, anti-pancreatic secretory trypsin inhibitor and anti-phospholipase A2 antigen. At the ultrastructural level, mucous and neuroendocrine granules were demonstrated in the same tumour cells.


Responses to paracrine chemotactic and autocrine chemokinetic factors and lung metastatic capability of mouse RAW117 large-cell lymphoma cells.
We studied the cell migration properties of poorly metastatic murine RAW117-P large-cell lymphoma cells, a highly lung metastatic subline (RAW117-L17) and a highly liver metastatic subline (RAW117-H10). L17 cells responded to the serum-free conditioned medium (CM) of mouse lung microvessel endothelial cells (MLEs) and mouse lung fibroblasts (MLFs). The migration of L17 cells was also stimulated by its own CM and, to a lesser extent, by the CM of parental (P) and H10 cells. RAW117-P and -H10 cells responded poorly to all of the CM tested. Chequerboard analyses revealed that the migration-stimulating activities of MLE CM and MLF CM were mainly chemotactic, whereas those of L17, P and H10 CM were chemokinetic. We also analysed the effect of MLE CM and MLF CM in combination with L17, P or H10 CM on cell migration of the RAW117 sublines. The migration of lung metastatic subline L17 cells to MLE or MLF CM was enhanced when L17 CM was also present. This enhancement effect was not seen when P or H10 cells were exposed to MLE or MLF CM plus the CM from P or H10 cells respectively. Thus we found that the chemotactic response of lung metastatic large-cell lymphoma cells to paracrine migration stimulation factors from lung endothelial cells and fibroblasts in concert with an autocrine chemokinetic factor may be involved in RAW117 lung-specific invasion and metastasis.


Purification and characterization of the larvicidal toxin of Bacillus sphaericus 1593M.
We present here a procedure for purifying the larvicidal toxin from sporulating cells of Bacillus sphaericus 1593M and describe some of the biochemical and biophysical properties of this toxin. The procedure involves solubilization of the cell-wall/membrane bound toxin by sonication of cells followed by repeated rounds of freezing and thawing at 50 degrees C. Further purification involved Sephadex G-100 and DEAE Sephacel chromatography. We show by Sephadex G-100 chromatography that at pH 7.5 the smallest active form of the toxin has an Mr of 38,000 and that this toxin can reversibly aggregate to molecular forms of a size higher than 2 X 10(5) Mr. By shifting the pH from 7.5 to 8.5 only the aggregated forms can be observed.


Effect of yoga therapy on facial emotion recognition deficits, symptoms and functioning in patients with schizophrenia.
Facial emotion recognition deficits have been consistently demonstrated in schizophrenia and can impair socio-occupational functioning in these patients. Treatments to improve these deficits in antipsychotic-stabilized patients have not been well studied. Yoga therapy has been described to improve functioning in various domains in schizophrenia; however, its effect on FERD is not known. Antipsychotic-stabilized patients randomized to receive Yoga (n=27), Exercise (n=17) or Waitlist group (n=22) were assessed at baseline, 2nd month, and 4th month of follow-up by raters blind to group status. Assessments included Positive and Negative Syndrome Scale (PANSS), Socio-Occupational Functioning Scale (SOFS), and Tool for Recognition of Emotions in Neuropsychiatric DisorderS (TRENDS). There was a significant positive correlation between baseline FERD and socio-occupational functioning (r=0.3, P=0.01). Paired samples t test showed significant improvement in positive and negative symptoms, socio-occupational functioning and performance on TRENDS (P<0.05) in the Yoga group, but not in the other two groups. Maximum improvement occurred at the end of 2 months, and improvement in positive and negative symptoms persisted at the end of 4 months. Yoga therapy can be a useful add-on treatment to improve psychopathology, FERD, and socio-occupational functioning in antipsychotic-stabilized patients with schizophrenia.


Complete mesocolic excision for right hemicolectomy: an updated systematic review and meta-analysis.
Complete mesocolic excision improves lymphadenectomy for right hemicolectomy and respects the embryological planes. However, its effect on cancer-free and overall survival is questioned. Therefore, we aimed to determine the potential benefits of the technique by performing a systematic review of the literature and meta-analysis of the available evidence. Web of Science, PubMed/Medline, and Embase were searched on February 22, 2023. Original studies on short- and long-term oncological outcomes of adult patients undergoing right hemicolectomy with complete mesocolic excision as a treatment for primary colon cancer were considered for inclusion. Outcomes were extracted and pooled using a model with random effects. A total of 586 publications were identified through database searching, and 18 from citation searching. Exclusion of 552 articles left 24 articles for inclusion. Meta-analysis showed that complete mesocolic excision increased the lymph node harvest (5 studies, 1479 patients, MD 9.62, 95% CI 5.83-13.41, p > 0.0001, I2 84%), 5-year overall survival (5 studies, 2381 patients, OR 1.88, 95% CI 1.14-3.09, p = 0.01, I2 66%), 5-year disease-free survival (4 studies, 1376 patients, OR 2.21, 95% CI 1.51-3.23, p < 0.0001, I2 0%) and decreased the incidence of local recurrence (4 studies, 818 patients, OR 0.27, 95% CI 0.09-0.79, p = 0.02, I2 0%) when compared to standard right hemicolectomy. Perioperative morbidity was similar between the techniques (8 studies, 3899 patients, OR 1.04, 95% CI 0.89-1.22, p = 0.97, I2 0%). Meta-analysis of observational and randomised studies showed that right hemicolectomy with complete mesocolic excision for primary right colon cancer improves oncologic results without increasing morbidity/mortality. These results need to be confirmed by high-quality evidence and randomised trials in selected patients to assess who may benefit from the procedure.


Study on gender difference based on metabolites in urine by ultra high performance liquid chromatography/time of flight mass spectrometry.
Metabolites in urine can illustrate the physical condition of an individual as a whole. Ultra high performance liquid chromatography/time of flight mass spectrometry (UPLC/TOF-MS) is a relative new technique for the separation of complex samples. The aim of this study is to assess the feasibility of metabonomics in gender difference in unrestricted conditions, i.e. for healthy volunteers there are no strict controls such as food, life style and the collection of urine samples. In this work, 31 spontaneous urine samples were collected and analyzed by using UPLC/TOF-MS. Principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models were tested and compared in samples classification. The gender discrimination was highly improved and some gender related biomarkers were found by PLS-DA. These preliminary results suggested that UPLC/MS-based approaches coupled with pattern recognition show promise for metabonomics.


Treating Raynaud phenomenon: Beyond staying warm.
Raynaud phenomenon is an overactive vascular response to cold and emotional stress that results in cutaneous color changes and sensory symptoms in the digits. It can be idiopathic (primary) or secondary to another condition; the latter can be more severe and more apt to lead to ischemic complications such as digital ulceration and even loss of digits. If nonpharmacologic interventions prove inadequate, then vasodilator agents are used.


Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls.
Occurrence of amyloid beta (Abeta) dense-core plaques in the brain is one of the chief hallmarks of Alzheimer's disease (AD). It is not yet clear what factors are responsible for the aggregation of Abeta in the formation of these plaques. Using Tg2576 and PSAPP mouse models that exhibit age-related development of amyloid plaques similar to that observed in AD, we showed that approximately 95% of dense plaques in Tg2576 and approximately 85% in PSAPP mice are centered on vessel walls or in the immediate perivascular regions. Stereoscopy and simulation studies focusing on smaller plaques suggested that vascular associations for both Tg2576 and PSAPP mice were dramatically higher than those encountered by chance alone. We further identified ultrastructural microvascular abnormalities occurring in association with dense plaques. Although occurrence of gross cerebral hemorrhage was infrequent, we identified considerable infiltration of the serum proteins immunoglobulin and albumin in association with dense plaques. Together with earlier evidence of vascular clearance of Abeta, our data suggest that perturbed vascular transport and/or perivascular enrichment of Abeta leads to the formation of vasocentric dense plaques in Tg2576 and PSAPP mouse models of AD.


Effect of endoscopic variceal obliteration by band ligation on portal hypertensive gastro-duodenopathy: endoscopic and pathological study.
A few studies have shown that the degree of portal hypertensive gastropathy (PHG) and duodenopathy (PHD) has been worsening after the introduction of therapeutic endoscopic interventions. This study aimed to determine the impact of esophageal variceal eradication by endoscopic variceal ligation (EVL) on PHG and PHD using endoscopic and histopathologic assessment. Fifty patients with esophageal varices for which EVL was indicated were included. EVL was carried out until complete variceal eradication was achieved. The degree of severity of PHG and PHD were recorded before and 4 weeks after variceal eradication. Biopsies were taken from various parts of the stomach and duodenum before and 4 weeks after variceal eradication. The whole Baveno score (4 vs. 2.5) increased significantly after variceal eradication when compared to those before eradication (p < 0.05). After obliteration, only 19 (38 %) patients had mild PHG versus 37 (74 %) before EVL, while severe PHG was found in 31 (62 %) patients versus 11 (22 %) before EVL and the difference was highly statistically significant. No significant changes were found regarding endoscopic PHD lesions before and after variceal eradication. Pathological changes as average blood vessel count, angiogenesis, ectasia and blood extravasation in stomach and duodenum significantly increased after EVL. Large esophageal varices (III-IV) and Baveno score (>1) at baseline endoscopy were independent risk factors for development of severe PHG after variceal obliteration (p < 0.05). PHG increased significantly, endoscopically and pathologically, after variceal obliteration by EVL. Although PHD did not significantly change as documented by endoscopy, pathological examination documented statistically significant changes in the duodenum after EVL.


The motley drivers of heat and cold exposure in 21st century US cities.
We use a suite of decadal-length regional climate simulations to quantify potential changes in population-weighted heat and cold exposure in 47 US metropolitan regions during the 21st century. Our results show that population-weighted exposure to locally defined extreme heat (i.e., "population heat exposure") would increase by a factor of 12.7-29.5 under a high-intensity greenhouse gas (GHG) emissions and urban development pathway. Additionally, end-of-century population cold exposure is projected to rise by a factor of 1.3-2.2, relative to start-of-century population cold exposure. We identify specific metropolitan regions in which population heat exposure would increase most markedly and characterize the relative significance of various drivers responsible for this increase. The largest absolute changes in population heat exposure during the 21st century are projected to occur in major US metropolitan regions like New York City (NY), Los Angeles (CA), Atlanta (GA), and Washington DC. The largest relative changes in population heat exposure (i.e., changes relative to start-of-century) are projected to occur in rapidly growing cities across the US Sunbelt, for example Orlando (FL), Austin (TX), Miami (FL), and Atlanta. The surge in population heat exposure across the Sunbelt is driven by concurrent GHG-induced warming and population growth which, in tandem, could strongly compound population heat exposure. Our simulations provide initial guidance to inform the prioritization of urban climate adaptation measures and policy.


3-(Phenethylamino)demethyl(oxy)aaptamine as an anti-dormant mycobacterial substance: Isolation, evaluation and total synthesis.
3-(Phenethylamino)demethyl(oxy)aaptamine (1) was re-discovered from the marine sponge of Aaptos sp. as an anti-dormant mycobacterial substance through the bioassay-guided separation. Compound 1 showed potent anti-microbial activity against Mycobacterium bovis BCG with a minimum inhibitory concentration of 0.75 µg/mL under both aerobic conditions and hypoxic conditions inducing dormant state. Compound 1 was also effective against pathogenic M. tuberculosis strains including clinical multidrug-resistant strains. Furthermore, the successful total syntheses of 1 and its analog 3-aminodemethyl(oxy)aaptamine (2) afford sufficient quantities for further biological studies.


Surgery of a splenic artery aneurysm during pregnancy.
We report a case of ligation of the splenic artery with splenectomy during pregnancy due to a splenic artery aneurysm. The risk of aneurysmal rupture is increased in multipara and during pregnancy. As a result of high maternal and fetal morbidity and mortality elective surgery should be performed.


Nicotine induces resistance to epidermal growth factor receptor tyrosine kinase inhibitor by α1 nicotinic acetylcholine receptor-mediated activation in PC9 cells.
Nicotine, the major component among the 4000 identified chemicals in cigarette smoke, binds to nicotinic acetylcholine receptors (nAChRs) on non-small-cell lung cancer (NSCLC) cells and regulates cellular proliferation by activating mitogen-activated protein kinases [AQ: MAPK has been expanded to mitogen-activated protein kinases. Please approve.]and PI3K/Akt pathways. In patients with smoking-related lung cancer who continue smoking, the anticancer effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is weaker than that in nonsmokers; however, the precise reason for this difference remains unclear. We investigated the role of α1 nAChR subunit in this phenomenon. We screened for α1 nAChR mRNA in three NSCLC cell lines and analyzed the protein in resected primary NSCLC tissues. We used Western blot and RNA interference (siRNA) methodology to confirm the results. We determined that α1 nAChR plays an essential role in nicotine-induced cell signaling and nicotine-induced resistance to EGFR-TKI. In addition, we showed that silencing of α1 nAChR subunit in NSCLC may suppress the nicotine-induced resistance to EGFR-TKI. These results further implicate nicotine in lung carcinogenesis, and suggest that α1 nAChR may be a biomarker for EGFR-TKI treatment and also a personalizing target molecule for patients with smoking-related lung cancer.


Design, synthesis and evaluation of caffeic acid phenethyl ester-based inhibitors targeting a selectivity pocket in the active site of human aldo-keto reductase 1B10.
Inhibitors of a human aldo-keto reductase, AKR1B10, are regarded as promising therapeutics for the treatment of cancer, but those with both high potency and selectivity compared to the structurally similar aldose reductase (AKR1B1) have not been reported. In this study, we have found that, among honeybee propolis products, caffeic acid phenethyl ester (CAPE) inhibited AKR1B10 (IC(50) = 80 nM) with 7-fold selectivity over AKR1B1. Based on a model of docked CAPE in AKR1B10, its derivatives were designed, synthesized and evaluated for inhibitory potency. Among them, 3-(4-hydroxy-2-methoxyphenyl)acrylic acid 3-(3-hydroxyphenyl)propyl ester (10c) was the most potent competitive inhibitor (K(i) = 2.6 nM) with 790-fold selectivity for AKR1B10 over AKR1B1. Molecular docking of 10c and site-directed mutagenesis of AKR1B10 residues suggested that the interactions between the 2-methoxy and 3-hydroxy groups of 10c and the enzyme's Val301 and Gln114, respectively, are important for the inhibitor's selectivity. Additionally, the sub-μM concentration of 10c significantly suppressed the farnesal metabolism and cellular proliferation in AKR1B10-overexpressing cells.


Inflammatory particles stimulate thromboplastin production by human monocytes.
Several inflammatory particles (zymosan, two forms of asbestos, carrageenan) and the soluble inflammatory agent dextran sulphate induced a dose- and time-dependent increase in thromboplastin activity of cultured human monocytes. Two weakly inflammatory particles (latex and anatase) had little effect. The increase largely depended on protein synthesis; was slow, reaching a peak at about 18 h; and was not due to endotoxin. This procoagulant may contribute to the fibrin deposition frequently seen in inflammatory lesions.


Subdivisions of the inferior colliculus in the barn owl (Tyto alba).
The inferior colliculus in the barn owl contains three subdivisions: the central (ICC), external (ICX), and superficial (ICS) nuclei. The nuclei are distinguished on the basis of their cyto- and myeloarchitecture, connectivity, and physiological properties. The ICC may be further divided into dorsal (ICCd) and ventral (ICCv) parts. Auditory fibers ascending in the lateral lemniscus enter the ICCd and ICCv, but not the ICX or ICS. The ICX receives its auditory input from the ICC. The ICC and ICX in owls are similar in position, anatomy, connectivity, and physiology to the ICC and ICX in mammals, suggesting that these structures are homologous. Units in the ICC are organized tonotopically, whereas units in the ICX are organized according to the locations of their spatial receptive fields. This implies that a transformation from a tonotopic to a spatiotopic organization takes place in the ICX of the owl.


Value of pulmonary vein wedge angiography in visualization of obstructed ipsilateral pulmonary artery.
Left ventricular cineangiogram in a 2-year-old child with a large ventricular septal defect, pulmonary atresia and a previous Waterston anastomosis opacified clearly the right pulmonary artery but the left pulmonary artery could not be visualized. The later was thought to be due to obstruction or kinking of the right pulmonary artery proximal to the Waterston anastomotic site. A left pulmonary vein wedge angiogram performed via a No. 5 end-hole catheter with 4.0 cc of meglumine diatrizoate (75% Hypaque) injected under pressure (less than 100 PSI) visualized the left pulmonary artery in a retrograde fashion. The size of the left pulmonary artery at this study was comparable to its size measured at the time of a subsequent left Blalock-Taussig anastomosis. Pulmonary vein wedge angiography with 0.3 cc/kg body weight of contrast material injected over a two second period (less than 100 PSI) appears to be a useful technique in demonstrating the pulmonary arteries when these cannot be visualized by conventional antegrade techniques.


An epigallocatechin gallate-amorphous calcium phosphate nanocomposite for caries prevention and demineralized enamel restoration.
Biomineralization with amorphous calcium phosphate (ACP) is a highly effective strategy for caries prevention and defect restoration. The identification and interruption of cariogenic biofilm formation during remineralization remains a challenge in current practice. In this study, an epigallocatechin gallate (EGCG)-ACP functional nanocomposite was developed to prevent and restore demineralization by integrating the antibacterial property of EGCG and the remineralization effect of ACP. The synthesized EGCG-ACP showed good biocompatibility with L-929 cells and human gingival fibroblasts. Under neutral conditions, the sustained release of ACP from EGCG-ACP restored the microstructure and mechanical properties of demineralized enamel. Under acidic conditions, protonated EGCG released from EGCG-ACP exerted a strong antibacterial effect, and the ACP release rate doubled within 4 h, resulting in the prevention of demineralization in the presence of cariogenic bacteria. The pH-responsive features of EGCG-ACP to promote the protonation of EGCG and ACP release facilitated its performance in remineralization effect to overcome the difficulty of restoring demineralized enamel in a cariogenic acidic environment, which was evidenced by the in vivo experiment carried out in a rat oral cariogenic environment. The results of this study indicate the potential of EGCG-ACP for the prevention of enamel demineralization and provide a theoretical basis its application in populations with high caries risk.


Value of low-dose whole-body CT in the management of patients with multiple myeloma and precursor states.
To determine the value of low-dose whole-body CT (WBCT) in the management of patients with multiple myeloma (MM) and precursor states. The study group comprised 116 patients (mean age: 68 ± 11 years, 48% women) who underwent WBCT for the work-up or surveillance of MM or MM precursor disease. WBCTs were reviewed for the presence of MM-related bone disease and incidental findings requiring therapy. The medical records, results from bone marrow aspirations and biopsies and follow-up imaging studies were reviewed to assess the influence of WBCT on patient management. Whole-body CT led to a change in management in 32 patients (28%). Of those, 17 patients with MM precursor disease were found to have MM-related bone disease, 13 patients had progression of MM, requiring a change in treatment, in one patient hepatocellular carcinoma was diagnosed, requiring a change in therapy, and one patient had a rib lesion requiring intervention. In 65 patients (56%), WBCT was performed for surveillance of MM precursor disease or stable treated MM, and did not detect new lesions, thereby providing reassurance to the hematologist on disease status and management. In 15 patients (13%) WBCT was performed as a new baseline before a change or new therapy. In 4 patients (3%), WBCT was performed for a change in symptoms, but did not detect lesions that would lead to a change in management. Whole-body CT provides important information for disease monitoring and detection of incidental findings, thereby improving the management of patients with MM.


Gene Therapy-Based Modeling of Neurodegenerative Disorders: Huntington's Disease.
Huntington's disease is a fatal neurodegenerative disease characterized by impairments in motor control, and cognitive and psychiatric disturbances. In this chapter, viral vector-mediated approaches used in modeling the key neuropathological features of the disease including the production of abnormal intracellular protein aggregates, neuronal dysfunction and degeneration and motor impairments in rodents are described.


Nanomaterials: small particles show huge possibilities for cancer immunotherapy.
With the economy's globalization and the population's aging, cancer has become the leading cause of death in most countries. While imposing a considerable burden on society, the high morbidity and mortality rates have continuously prompted researchers to develop new oncology treatment options. Anti-tumor regimens have evolved from early single surgical treatment to combined (or not) chemoradiotherapy and then to the current stage of tumor immunotherapy. Tumor immunotherapy has undoubtedly pulled some patients back from the death. However, this strategy of activating or boosting the body's immune system hardly benefits most patients. It is limited by low bioavailability, low response rate and severe side effects. Thankfully, the rapid development of nanotechnology has broken through the bottleneck problem of anti-tumor immunotherapy. Multifunctional nanomaterials can not only kill tumors by combining anti-tumor drugs but also can be designed to enhance the body's immunity and thus achieve a multi-treatment effect. It is worth noting that the variety of nanomaterials, their modifiability, and the diversity of combinations allow them to shine in antitumor immunotherapy. In this paper, several nanobiotics commonly used in tumor immunotherapy at this stage are discussed, and they activate or enhance the body's immunity with their unique advantages. In conclusion, we reviewed recent advances in tumor immunotherapy based on nanomaterials, such as biological cell membrane modification, self-assembly, mesoporous, metal and hydrogels, to explore new directions and strategies for tumor immunotherapy.


Relationships between bird community and habitat structure in shelterbelts of Hokkaido, Japan.
The relationship between the bird community and habitat structure in wind shelterbelts of Ishikari district was examined.Breeding birds were classified into nesting guilds (hole, canopy, and bush) and also into foraging guilds (outside, canopy, and bush) Both density and species richness in the outside-foraging guild were positively related to forest age variables. On the other hand, bird density in all three nesting guilds and the other two foraging guilds (canopy and bush) was correlated with the vegetation cover of their nesting or foraging sites, and species richness was positively correlated with tree species complexity variables.Bird species diversity (BSD) was closely related to tree species complexity, but not to foliage height diversity (FHD) within woods. However, if woods were re-classified into two groups such as natural and artificial and these were separately analysed, the correlation between BSD and FHD was significant.From these results, it is concluded that both FHD and tree species complexity should be considered together in order to predict BSD within forests. A new index is proposed for this purpose, and its usefulness discussed.


Glucagon response to arginine in growth hormone deficient children before and after treatment with growth hormone and in children with non-endocrine short stature.
In order to assess the role of growth hormone in the modulation of alpha cell function, the plasma pancreatic glucagon response to intravenous arginine (0.5 g/kg) was determined in thirty-two children with non-endocrine short stature and in eighteen growth hormone deficient children. 60 min after arginine infusion, the growth hormone deficient children had significantly higher (P less than 0.05) plasma glucagon values than the children with non-endocrine short stature. Following short-term growth hormone therapy (2 iu qd or bid for 5 days) in eleven of these growth hormone deficient children, plasma pancreatic glucagon response to arginine was diminished, and there was a significantly (P less than 0.02) more rapid return to basal values than in the untreated group. The same trends persisted after long-term growth hormone therapy (2 iu three times per week for 12-30 months) in ten children but were not statistically significant. We conclude that growth hormone may play a role in modulating plasma pancreatic glucagon response. The persistent glucagon response to arginine noted in growth hormone deficient children might reflect a greater gluconeogenic stress imposed upon these children during fasting or decreased catabolism of glucagon in the growth hormone deficient state.


In situ monitoring of internal water storage reveals nitrogen first flush phenomena, intermittent denitrification, and seasonal ammonium flushing.
Internal water storage (IWS) can be included in bioretention practices to increase storage capacity or promote denitrification-the microbial reduction of nitrate to nitrogen gas. IWS and nitrate dynamics are well studied in laboratory systems. However, the investigation of field environments, consideration of multiple nitrogen species, and determination between mixing versus denitrification is lacking. This study employs in situ monitoring (∼24 h duration) of water level, dissolved oxygen (DO), conductivity, nitrogen species, and dual isotopes of a field bioretention IWS system for nine storms events over a year period. Rapid peaks in IWS conductivity, DO, and total nitrogen (TN) concentrations occurred along the rising limb of the IWS water level and indicated a first flush effect. TN concentrations generally peaked during the first ∼0.33 h of sampling and the average peak IWS TN concentration (Cmax = 4.82 ± 2.46 mg-N/L) was 38% and 64% greater than the average TN along the IWS rising and falling limb, respectively. Dissolved organic nitrogen (DON) and nitrate plus nitrite (NOx) were the dominant nitrogen species of IWS samples. However, average IWS peak ammonium (NH4+) concentrations August through November (0.28 ± 0.47 mg-N/L) demonstrated statistically significant shifts compared to February through May (2.72 ± 0.95 mg-N/L). Average lysimeter conductivity measurements were more than ten times higher February through May. The sustained presence of sodium observed in lysimeters, from road salt application, contributed to NH4+ flushing from the unsaturated media layer. Dual isotope analysis showed denitrification occurred for discrete time intervals along the tail of the NOx concentration profile and the hydrologic falling limb. Longer antecedent dry periods (17 days) did not correlate to enhanced denitrification but did correspond to more leaching of soil organic nitrogen. Results from field monitoring highlight the complexities of nitrogen management in bioretention systems. First flush behavior into the IWS suggests management to prevent TN export is most critical during the onset of a storm.


Socioeconomic status dependent medical complexities in children with sickle cell disease in Saudi Arabia.
A look into the associations of socioeconomic status (SES) with prevalence of various complications in sickle cell disease (SCD) is necessary, for an improvement of societal norms, governmental health policies and strategies. We therefore studied the influence of SES indices on certain hematological and clinical parameters in children with SCD in Saudi Arabia. We included 32 female and 33 male patients aged 5-16 years, who were classified based upon their family income. Family monthly income was divided into 4 categories from lowest to highest, with socioeconomic class1 having low earnings of <5000 SAR; the middle income class divided further into class 2 with earnings >5000-10,000 SAR, and class 3 with earnings >10,000-15,000 SAR; and the higher income class 4 with earnings of >15,000 SAR. The assessment indices used were, the frequency of vaso-occlusive crisis (VOC), adverse events, and hematological parameters. A higher percentage of children affected with the disease were from class1, which is the low socio-economic class. It was found that the percentage of frequency of VOC pain crisis, and adverse events was higher in social class 1 patients than in the classes 2, 3, and 4. Also, the age group 5-10 years appeared more susceptible to adverse events and VOC. Our findings suggest the need to conduct future larger studies, to deduce the modifying influence of disparity in SES on certain clinical and hematological indices in children with SCD.


Dynamics and Physics of Integrin Activation in Tumor Cells by Nano-Sized Extracellular Ligands and Electromagnetic Fields.
Integrins are stress-sensing proteins expressed on the surface of cells. They regulate bidirectional signal transduction during cell-cell or cell-extracellular matrix (ECM) contacts. Integrins link the ECM with the cytoplasm through interaction with their ligands. Biophysically, such interactions can be understood as changes in stress fields at specific integrin stress-sensing domains, such as the MIDAS and ADMIDAS domains. Stress changes between ligands and cytoskeletal structures are involved in cancer cell growth by altering signal transduction pathways dependent on integrin activation. In this chapter, previous results regarding integrin activation and tumor cell growth using nanoparticles (NPs) of different materials, sizes and shapes are placed within a framework of polarized NPs in the ECM by external electromagnetic fields, in which the synergic action between polarized NPs and electromagnetic fields activates the integrins. Small size NPs activate integrins via the polar component of the dipole force between NPs and integrin sensing stress sites, while large size NPs exercise a similar action via the radial component. A quantum electrodynamic model also accounts for ECM overstressing by electromagnetic mode trapping between coherent symmetric and antisymmetric quantum states.


Crystal structure of a new type of NADPH-dependent quinone oxidoreductase (QOR2) from Escherichia coli.
Escherichia coli QOR2 [NAD(P)H-dependent quinone oxidoreductase; a ytfG gene product], which catalyzes two-electron reduction of methyl-1,4-benzoquinone, is a new type of quinone-reducing enzyme with distinct primary sequence and oligomeric conformation from previously known quinone oxidoreductases. The crystal structures of native QOR2 and the QOR2-NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) complex reveal that QOR2 consists of two domains (N-domain and C-domain) resembling those of NmrA, a negative transcriptional regulator that belongs to the short-chain dehydrogenase/reductase family. The N-domain, which adopts the Rossmann fold, provides a platform for NADPH binding, whereas the C-domain, which contains a hydrophobic pocket connected to the NADPH-binding site, appears to play important roles in substrate binding. Asn143 near the NADPH-binding site has been identified to be involved in substrate binding and catalysis from structural and mutational analyses. Moreover, compared with wild-type strain, the qor2-overexpressing strain shows growth retardation and remarkable decrease in several enzymes involved in carbon metabolism, suggesting that QOR2 could play some physiological roles in addition to quinone reduction.


[Research Progress in the Treatment of Brain Metastases from Non-small Cell Lung Cancer].
Lung cancer is the leading cause of cancer-related deaths worldwide. The most common pathological type of lung cancer is non-small cell lung cancer (NSCLC). The incidence of brain metastases caused by NSCLC has been on the rise. Brain metastasis seriously affects the patient's cognitive function, survival time and quality of life, and the prognosis is extremely poor. The natural course of the disease is about 1 mon-3 mon. After treatment, the median survival time is only 3 mon-6 mon, the one year survival rate is 14%, and the two years survival rate is only 7.6%. The location, number, and size of brain metastases are related to their symptoms and survival. Patients with central nervous system symptoms have a worse prognosis. The goal of brain metastasis treatment is to optimize overall survival and quality of life, and to prioritize the preservation of neurocognitive functions. At present, the main treatments for brain metastases in NSCLC include radiotherapy, surgery, chemotherapy, molecular targeting, and immunotherapy. Clinically, it is necessary to conduct a multidisciplinary assessment of the best treatment methods for patients according to the heterogeneity of patients (clinical characteristics, pathological types, tissue types, etc). This article aims to review the research progress of current treatment methods. .


Allosteric binding of anionic guests to a bicyclic host which imitates the action of a 'turnstile'.
A bicyclic host 1, which has a diethynyl tetrafluorophenyl axis and is expected to behave as an anion-binding 'turnstile', has been designed.


Effect of diphenylhydantoin on patterns of insulin secretion in obese subjects.
The effect of short-term treatment with diphenylhydantoin (DPH) on the insulin secretion patterns during OGTT and on the daily insulin profile was studied in obese patients. DPH treatment for 3 days with a dose of 300 mg/die (100 mg, 3 times daily) significantly decreased the insulin release after glucose ingestion, but did not alter the basal insulin level. No effect on the fasting glucose concentration as well as on the glucose profiles during OGTT was observed after short-term DPH treatment. A smaller decrease of plasma free fatty acid concentration during OGTT performed after DPH administration confirmed the inhibitory effect of the drug on insulin release. Short-term DPH treatment was also shown to decrease markedly the postpradial insulin release in obese patients. No difference was noted between plasma 11-OHCS and serum HGH concentrations during OGTT before and after DPH treatment. The possible therapeutic role of DPH in obesity is discussed.


Adsorption behaviors of recombinant E-cadherin-IgG Fc fusion protein on polystyrene surface.
Adsorption behaviors of recombinant E-cadherin-IgG Fc (E-cad-Fc) fusion protein and mutated E-cad-Fcs on the polystyrene (PS) surface were investigated using a 27 MHz quartz-crystal microbalance (QCM) and ELISA. The amount of adsorbed E-cad-Fc on PS surface was increased with an increase of E-cad-Fc concentration as a Langmuir-type in a monolayer. Adsorbed E-cad-Fc on PS surface was stable even after washing if calcium ions are absent in the washing solution due to the calcium ion dependence in the adsorption. E-cadherin homophilic adhesion among E-cadherins during adsorption of E-cad-Fc was involved. Deglycosylation of the E-cad in the E-cad-Fc did not affect adsorption of E-cad-Fc on the PS surface although deglycosylation of the E-cad in the E-cad-Fc enhanced cell adhesion compared with E-cad-Fc.


The rat liver mitochondrial proteins.
Subcellular fractionation increases the probability of detection of low-abundance proteins. We prepared a fraction highly enriched in mitochondrial proteins from rat liver. The proteins were analyzed by two-dimensional (2-D) electrophoresis using broad-and narrow-range immobilized pH gradient strips, and identified by matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS). 192 different gene products were detected, of which approximately 70% were enzymes with a broad spectrum of catalytic activities. Most of the identified proteins were detected in other rat protein samples as well, which were analyzed in our laboratory. Eight gene products were detected for the first time. These were represented by one spot each, whereas most of the frequently detected proteins were represented by multiple spots. In average, approximately 10-15 spots corresponded to one gene product.


Nitrogen relations of ruderal communities (Rumicion alpini) in the Northern Calcareous Alps.
The total nitrogen and nitrate turnovers of three plots of plant communities typical of cattle resting sites in the Bavarian Alps were investigated. Annual net N mineralisation of the soil and N content of the above-ground phytomass at maximum development are low in the Senecio cordatus dominated community "W" at 1,450 m altitude (80 and 57 kg N/ha respectively) and highest in the nearly pure Rumex alpinus stand "K" (1,240 m) (156 and 148 kg N/ha). The subalpine mixed Rumex alpinus community "S" (1,790 m) is intermediate with low mineralisation but high N content in the aboveground parts (69 and 128 kg N/ha). In general the mineralisation values are below those from other comparable plant communities. The main component of N mineralisation is nitrification in all three plots.The nitrate content in the phytomass at full development increases from 0.1 g/m2 in W to 0.3 g/m2 in S and to 1.0 g/m2 in K. With one exception (Adenostyles alliariae) no species showed a real nitrate accumulation in the leaf laminae towards the end of the growing season.


Vendor differences in starvation-induced gastric ulceration.
The incidence of starvation-induced gastric lesions was observed in Sprague-Dawley rats obtained from four different vendors (ARS/Sprague-Dawley, Hilltop, Holtzman, and Charles River). Food was withheld for 5 days from rats weighing 150, 200, 260 or 330 g. Glandular lesions occurred in 150 g rats; rumenal lesions occurred in 200+ rats. ARS/Sprague-Dawley rats developed more glandular lesions, whereas Hilltop rats developed more rumenal lesions.


Park characteristics, use, and physical activity: A review of studies using SOPARC (System for Observing Play and Recreation in Communities).
The System for Observing Play and Recreation in Communities (SOPARC) can obtain information on park users and their physical activity using momentary time sampling. We conducted a literature review of studies using the SOPARC tool to describe the observational methods of each study, and to extract public park use overall and by demographics and physical activity levels. We searched PubMed, Embase, and SPORTDiscus for full-length observational studies published in English in peer-reviewed journals through 2014. Twenty-four studies from 34 articles were included. The number of parks observed per study ranged from 3 to 50. Most studies observed parks during one season. The number of days parks were observed ranged from 1 to 16, with 16 studies observing 5 or more days. All studies included at least one weekday and all but two included at least one weekend day. Parks were observed from 1 to 14times/day, with most studies observing at least 4 times/day. All studies included both morning and afternoon observations, with one exception. There was a wide range of park users (mean 1.0 to 152.6 people/park/observation period), with typically more males than females visiting parks and older adults less than other age groups. Park user physical activity levels varied greatly across studies, with youths generally more active than adults and younger children more active than adolescents. SOPARC was adapted to numerous settings and these review results can be used to improve future studies using the tool, demonstrate ways to compare park data, and inform park promotions and programming.


Synaptic inputs of neuropeptide Y-immunoreactive noradrenergic nerve terminals to neurons in the nucleus preopticus medianus which project to the paraventricular nucleus of the hypothalamus of the rat: a combined immunohistochemical and retrograde tracing method.
The nucleus preopticus medianus (POMe) is known to serve as a relay site in the neural pathway, from the subfornical organ to the paraventricular nucleus of the hypothalamus (PVN), and to play an important role in the regulation of fluid balance and cardiovascular control. A neural connection of noradrenergic nerve terminals in the POMe was examined using electron microscopic immunohistochemistry with the retrograde tract tracing method. Double immunofluorescent labeling revealed nerve terminals immunoreactive to both tyrosine hydroxylase (TH) and neuropeptide Y (NPY) and those immunoreactive to both TH and noradrenaline in the POMe. This indicates that there is an NPY-immunoreactive noradrenergic innervation in the POMe. At the electron microscopic level, nerve terminals immunoreactive to TH or NPY in the POMe formed synapses with dendrites or cell bodies of neurons which were retrogradely labeled after injection of the retrograde tracer, WGA-HRP-colloidal gold, in the PVN. These observations suggest that neurons in the POMe with projections to the PVN may be directly affected by NPY-immunoreactive noradrenergic afferent fibers which presumably originate in the brainstem.


Prevalence of Cannabis Use Disorder and Reasons for Use Among Adults in a US State Where Recreational Cannabis Use Is Legal.
Medical and nonmedical cannabis use and cannabis use disorders (CUD) have increased with increasing cannabis legalization. However, the prevalence of CUD among primary care patients who use cannabis for medical or nonmedical reasons is unknown for patients in states with legal recreational use. To estimate the prevalence and severity of CUD among patients who report medical use only, nonmedical use only, and both reasons for cannabis use in a state with legal recreational use. This cross-sectional survey study took place at an integrated health system in Washington State. Among 108 950 adult patients who completed routine cannabis screening from March 2019 to September 2019, 5000 were selected for a confidential cannabis survey using stratified random sampling for frequency of past-year cannabis use and race and ethnicity. Among 1688 respondents, 1463 reporting past 30-day cannabis use were included in the study. Patient survey-reported reason for cannabis use in the past 30 days: medical use only, nonmedical use only, and both reasons. Patient responses to the Composite International Diagnostic Interview-Substance Abuse Module for CUD, corresponding to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition CUD severity (0-11 symptoms) were categorized as any CUD (≥2 symptoms) and moderate to severe CUD (≥4 symptoms). Adjusted analyses were weighted for survey stratification and nonresponse for primary care population estimates and compared prevalence of CUD across reasons for cannabis use. Of 1463 included primary care patients (weighted mean [SD] age, 47.4 [16.8] years; 748 [weighted proportion, 61.9%] female) who used cannabis, 42.4% (95% CI, 31.2%-54.3%) reported medical use only, 25.1% (95% CI, 17.8%-34.2%) nonmedical use only, and 32.5% (95% CI, 25.3%-40.8%) both reasons for use. The prevalence of CUD was 21.3% (95% CI, 15.4%-28.6%) and did not vary across groups. The prevalence of moderate to severe CUD was 6.5% (95% CI, 5.0%-8.6%) and differed across groups: 1.3% (95% CI, 0.0%-2.8%) for medical use, 7.2% (95% CI, 3.9%-10.4%) for nonmedical use, and 7.5% (95% CI, 5.7%-9.4%) for both reasons for use (P = .01). In this cross-sectional study of primary care patients in a state with legal recreational cannabis use, CUD was common among patients who used cannabis. Moderate to severe CUD was more prevalent among patients who reported any nonmedical use. These results underscore the importance of assessing patient cannabis use and CUD symptoms in medical settings.


Comparison of gastric reactance with commonly used perfusion markers in a swine hypovolemic shock model.
The gut has been hypothesized to be a protagonist tissue in multiple organ dysfunction syndrome (MODS) for the past three decades. Gastric reactance (XL) is a potential perfusion marker derived from gastric impedance spectroscopy (GIS), which is an emerging tool through which living tissue can be continuously measured to determine its pathophysiological evolution. This study aimed to compare the performance of XL [positive predictive values (PPV), negative predictive values (NPV), and area under the curve (AUC)] against commonly used perfusion markers before and during hypovolemic shock in swine subjects. Prospective, controlled animal trial with two groups, control group (CG) N = 5 and shock (MAP ≤ 48 mmHg) group (SG) N = 16. Comparison time points were defined as T-2 (2 h before shock), T-1 (1 h before shock), T0 (shock), T1 (1 h after shock), and T2 (2 h after shock). Shock severity was assessed through blood gases, systemic and hemodynamic variables, and via histological examination for assessing inflammation-edema and detachment in the gastric mucosa. Macroscopic assessment of the gastric mucosa was defined in five levels (0-normal mucosa, 1-stippling or epithelial hemorrhage, 2-pale mucosa, 3-violet mucosa, and 4-marmoreal mucosa). Receiver Operating Characteristic (ROC) curves of perfusion markers and XL were calculated to identify optimal cutoff values and their individual ability to predict hypovolemic shock. Comparison among the CG and the SG showed statistically significant differences in XL measurements at T-1, T0, T1, and T2, while lactate showed statistically significant differences until T1 and T2. Statistically significant differences were detected in mucosa class (p < 0.001) and in inflammation-edema in the gastric body and the fundus (p = 0.021 and p = 0.043). The performance of the minimum XL value per subject per event (XL_Min) was better (0.81 ≤ AUC ≤ 0.96, 0.93 ≤ PPV ≤ 1.00, 0.45 ≤ NPV ≤ 0.83) than maximum lactate value (Lac_Max) per subject per event (0.29 ≤ AUC ≤ 0.82, 0.82 ≤ PPV ≤ 0.91, 0.24 ≤ NPV ≤ 0.82). Cutoff values for XL_Min show progressive increases at each time point, while cutoff values for Lac_Max increase only at T2. XL proved to be an indirect and consistent marker of inadequate gastric mucosal perfusion, which shows significant and detectable changes before commonly used markers of global perfusion under the hypovolemic shock conditions outlined in this work.


Twenty-four hour monitoring of deep body temperature with a novel flexible probe.
A portable thermomemory unit with a light, thin and flexible probe has been developed for the measurement of whole-day variations in deep body temperature. The probe consists of a thermistor, a heat-flow sensor and a heater. The probe detects heat flow from the skin; the heater then compensates for the heat lost and consequently the skin is effectively insulated from the ambient microenvironment. Skin temperature beneath the probe is therefore determined by the deep body temperature. The probe is 46 mm in diameter and 3 mm thick, its weight is 5 g. The probe is light and flexible and makes close contact with the skin. A 2 kbyte RAM in the unit enables up to 34 h of data to be collected with a sampling rate of once per minute. The device was applied to the chest and abdominal walls, and to the calf; the chest and abdominal deep body temperatures showed a significant dual phase diurnal variation, usually being low during sleep. In contrast, the calf showed a dynamic deep body temperature variation which depended on the amount of leg exercise. The device was found to be effective for analysing daily variations; measurements on the limbs suggested that it could be used for monitoring peripheral circulatory disorders.


Diaminosulfide based polymer microparticles as cancer vaccine delivery systems.
The aim of the research presented here was to determine the characteristics and immunostimulatory capacity, in vivo, of antigen and adjuvant co-loaded into microparticles made from a novel diaminosulfide polymer, poly(4,4'-trimethylenedipiperdyl sulfide) (PNSN), and to assess their potential as cancer vaccine vectors. PNSN microparticles co-loaded with the antigen, ovalbumin (OVA), and adjuvant, CpG 1826, (PNSN(OVA + CpG)) were fabricated and characterized for size (1.64 μm diameter; PDI=0.62), charge (-23.1 ± 0.3), and loading efficiencies of antigen (7.32 μg/mg particles) and adjuvant (0.95 μg/mg particles). The ability of PNSN(OVA + CpG) to stimulate cellular and humoral immune responses in vivo was compared with other PNSN microparticle formulations as well as with poly(lactic-co-glycolic acid)(PLGA)-based microparticles, co-loaded with OVA and CpG (PLGA(OVA + CpG)), an adenovirus encoding OVA (Ad5-OVA), and OVA delivered with incomplete Freund's adjuvant (IFA(OVA)). In vivo OVA-specific IgG1 responses, after subcutaneous prime/boosts in mice, were similar when PNSN(OVA + CpG) and PLGA(OVA + CpG) were compared and the presence of CpG 1826 within the PNSN microparticles demonstrated significantly improved responses when compared to PNSN microparticles loaded with OVA alone (PNSN(OVA)), plus or minus soluble CpG 1826. Cellular immune responses to all particle-based vaccine formulations ranged from being negligible to modest with PNSN(OVA + CpG) generating the greatest responses, displaying significantly increased levels of OVA-specific CD8+ T lymphocytes compared to controls and IFA(OVA) treated mice. Finally, it was shown that of all vaccination formulations tested PNSN(OVA + CpG) was the most protective against subsequent challenge with an OVA-expressing tumor cell line, E.G7. Thus, microparticles made from poly(diaminosulfide)-based macromolecules possess promising potential as vaccine vectors and, as demonstrated here, may have impact as cancer vaccines in particular.


A Randomized Crossover Pilot Study Evaluating Glucose Control During Exercise Initiated 1 or 2 h After a Meal in Adults with Type 1 Diabetes Treated with an Automated Insulin Delivery System.
Aims: To assess the safety and efficacy of two exercise sessions performed 60- and 120-min postmeal with a combination of meal bolus reduction and increased glucose target to the automated insulin delivery (AID) system. Methods: A randomized crossover trial in 13 adult participants (6 females) living with type 1 diabetes using AID (A1c = 7.9% ± 0.6%, age = 53.5 ± 15.5 years, T1D duration = 29.0 ± 16.0 years) was conducted. Just before breakfast, at the time of meal bolus, the AID glucose target was increased from 6 to 9 mmol/L, and a meal bolus reduction of 33% was applied. Two 60-min exercise sessions (60% of VO2 peak) were undertaken either 60 min (60EX) or 120 min (120EX) after a standardized breakfast, followed by a 90-min recovery period. Results: The mean reduction in plasma glucose (PG) levels from prebreakfast to postexercise (-0.8 ± 2.4 mmol/L vs. +0.3 ± 2.3 mmol/L, P = 0.082) were similar between 60EX and 120EX. From prebreakfast to postexercise, PG times in range (3.9-10.0 mmol/L; 63.4% ± 43.1% 60EX vs. 51.9% ± 29.7% 120EX, P = 0.219) and time above range (>10.0 mmol/L; 36.3% ± 43.3% 60EX vs. 48.1% ± 29.7% 120EX, P = 0.211) did not differ between interventions. The 60EX attenuated the glucose rise between premeal to pre-exercise (+1.8 ± 2.1 mmol/L 60EX vs. +3.9 ± 2.1 mmol/L 120EX, P = 0.001). No hypoglycemic events (<3.9 mmol/L) occurred during the study. Conclusion: Premeal announcement combining meal bolus reduction and increased glucose target was effective and safe during 60 min of moderate-intensity aerobic exercise, whether exercise onset was 60 or 120 min following a meal. Clinical Trial Registration No.: NCT04031599.


Neprilysin Confers Genetic Susceptibility to Alzheimer's Disease in Han Chinese.
Alzheimer's disease (AD) is a progressive neurodegenerative disease, with increasing incidence all over the world. Amyloid-β (Aβ) was considered to be the original cause to AD, and many reported pathogenic or risk genes for AD were located in the Aβ generation and degradation pathways. Neprilysin (NEP), insulin-degrading enzyme (IDE), and matrix metalloprotease-9 (MMP-9) are the most important Aβ-degrading proteases. Accumulating genetic evidence suggested that single nucleotide polymorphisms (SNPs) of these genes confer susceptibility to AD in Caucasian populations. In this study, we screened eight SNPs within these three Aβ-degrading protease genes in 1475 individuals of two independent Han Chinese case-control cohorts. SNP rs1816558 of NEP was found to be significantly associated with AD after adjustment for ε4 allele of the apolipoprotein E gene (APOEε4) and the Bonferroni correction. The remaining variants were not associated with risk of AD in Han Chinese sample set. Further data mining revealed that messenger RNA (mRNA) level of NEP substantially increased during the development of AD and was positively correlated with APP expression. The combined results indicated that NEP confers genetic susceptibility to AD in Han Chinese populations.


Intracellular pH during secretion in the perfused rabbit mandibular salivary gland measured by 31P NMR spectroscopy.
Intracellular pH (pHi) was measured in the isolated, perfused rabbit mandibular salivary gland by 31P NMR spectroscopy. In the unstimulated gland perfused with HCO3-/CO2-buffered Ringer's solution, pHi was 7.27 +/- 0.01. Continuous stimulation with acetylcholine elicited dose- and time-dependent changes in pHi. 10(-6) mol/l acetylcholine caused a brief intracellular acidosis (-0.19 +/- 0.06 pH units) followed by an increase in pHi to a more alkaline steady-state value (7.33 +/- 0.02). In the absence of perfusate HCO3- or in the presence of 10(-4) mol/l DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid), the transient acidosis was abolished and pHi increased rapidly to give a sustained alkalosis (7.49 +/- 0.03 and 7.44 +/- 0.03 respectively). In the presence of 10(-3) mol/l amiloride, the response to acetylcholine was a rapid decrease in pHi to 7.02 +/- 0.02. The data suggest that, during perfusion with HCO3-/CO2- buffered solutions, stimulation with acetylcholine results in a transient loss of HCO3- from the acinar cells (causing a transient acidosis), and, independently, the activation of Na+-H+ exchange (causing a sustained alkalosis). In the unstimulated gland, DIDS and the HCO3- -free perfusate caused decreases in pHi to 7.12 +/- 0.02 and 7.04 +/- 0.01 respectively. In contrast, amiloride had little effect. The relatively high value of pHi maintained by the unstimulated gland is therefore probably not due to Na+-H+ exchange.


Dronedarone: Basic Pharmacology and Clinical Use.
Dronedarone is the newest antiarrhythmic drug approved for the maintenance of sinus rhythm in patients with nonpermanent atrial fibrillation (AF). It is a multi-channel blocker with diverse electrophysiologic properties. Dronedarone decreases the incidence of AF recurrence and the ventricular rate during recurrence. Dronedarone decreases rates of cardiovascular hospitalizations in patients with paroxysmal and persistent AF. Dronedarone increases mortality in patients with permanent AF and those with moderate-severe heart failure, and should thus be avoided in these populations. Dronedarone is less effective than amiodarone but also has less toxicity. Direct comparison with other antiarrhythmic drugs is not available.


The preparation of a new 57cobalt-labelled thyroxine for use in single/dual radioimmunoassay techniques.
The preparation of L-thyroxine labelled with 57cobalt for use as a second tracer in dual radioimmunoassay techniques for different biological molecules is described. The labelling procedure was monitored by paper chromatography and polyacrylamide gel electrophoresis; a yield of 42 +/- 10% (mean +/- 1 SD) was achieved in a total of 39 conjugation reactions. The method was optimized in terms of pH, reaction completion time, reactant concentration, and solubility of the tracer. A radioimmunoassay for thyroxine in human serum was developed utilizing this tracer, and this compared favorably with an established technique in which 125iodine was used as the tracer (n = 71, r = 0.91, y = 0.988 x - 1.93).


Otological and Visual Implications of Diabetes Mellitus in North Indian Population.
The worldwide population of diabetic patients is increasing alarmingly with India claiming number one position. It causes irreversible damage to cochlear hair cells, vestibular apparatus, visual pathway, nephrons, nerves, if not checked in time. A total of 188 patients of diabetes mellitus were included in this prospective study. The patients underwent routine anamnesis, hearing handicap inventory and dizziness handicap inventory assessment along with clinical examination for audiological, vestibular, neurological and ophthalmological (fundoscopy) status. In our study a sensorineural hearing loss, retinopathy, neuropathy, vestibulopathy was seen in diabetic patients.


In vitro increases in plasmid DNA supercoiling by hydrostatic pressure.
By conducting topoisomerase I-mediating supercoiling assays, effects of elevated pressure on DNA supercoiling were investigated for the first time. It was found that pressure elevations induced a progressive increase in plasmid DNA linking numbers, winding the DNA duplex by a magnitude of 1.1-1.6x10(-3) angular degree/base/MPa. Implications for the findings were discussed in terms of disturbance of the tertiary structure of DNA by elevated pressure.


Structure-activity relationship in PAF-acether. 3. Hydrophobic contribution to agonistic activity.
The synthesis of some selected PAF-acether homologues with an alkoxy-chain length from C1 to C20 in position 1 is described. All agonist activities are closely correlated among themselves and with the calculated fatty-chain hydrophobicity. After a discussion on recent published results and comparison with our data, we conclude that the ether oxide function is absolutely essential at the glycerol 1-position for potent agonist activity and that potency correlates well with hydrophobicity parameters. We indicate the importance of steric and configurational constraints.


Preliminary Experience With the Human Acellular Vessel: A Descriptive Case Series Detailing Early Use of a Bioengineered Blood Vessel for Arterial Repair.
An infection-resistant, immediately available conduit for trauma and urgent vascular reconstruction remains a critical need for successful limb salvage. While autologous vein remains the gold standard, vein-limited patients and size mismatch are common issues. The Human Acellular Vessel (HAV) (Humacyte, Inc., Durham, NC) is a bioengineered conduit with off-the-shelf availability and resistance to infection, ideal characteristics for patients with challenging revascularization scenarios. This report describes HAV implantation in patients with complex limb-threatening ischemia and limited conduit options who may have otherwise faced limb loss. The Food and Drug Administration (FDA) expanded-access program was used to allow urgent implantation of the HAV for arterial reconstruction. Electronic medical records were reviewed with extraction of relevant data including patient demographics, surgical implantation, patency, infectious complications, and mortality. The HAV was implanted in 8 patients requiring vascular reconstruction. Graft or soft tissue infection was present in 2 patients. One patient with severe penetrating pelvic injury had 4 HAV placed to repair bilateral external iliac artery and vein injuries. There was 1 technical failure due to poor outflow, 2 patients died unrelated to HAV use, and 5 lower extremity bypasses maintained patency at an average of 11.4 months (range: 4-20 months). No HAV infectious complications were identified. This report is the first United States series describing early outcomes using the HAV under the FDA expanded-access program for urgent vascular reconstruction. The HAV demonstrates resistance to infection, reliable patency, and offers surgeons an immediate option when confronted with complex revascularization scenarios. Assessment of long-term outcomes will be important for future studies.


Insights into cortical oscillations arising from optogenetic studies.
Cortical oscillations in the theta (4-10 Hz) and gamma (30-100 Hz) frequency range have been hypothesized to play important roles in numerous cognitive processes and may be involved in psychiatric conditions including anxiety, schizophrenia, and autism. This review provides background information about these oscillations and their possible roles in psychiatric illness. Findings from recent studies that used optogenetic tools to demonstrate that 1) a particular class of inhibitory interneurons expressing the calcium binding protein parvalbumin plays a central role in gamma oscillations, 2) gamma oscillations can entrain rhythmic firing in pyramidal neurons, and 3) rhythmic firing at theta and gamma frequencies can enhance communication between neurons are described. Finally, how these findings may relate to the pathophysiology of psychiatric conditions, as well as questions for future studies, are discussed.


Essential biochemistry and physiology of (NT-pro)BNP.
Brain natriuretic peptide (BNP) is a 32 amino acid cardiac natriuretic peptide hormone originally isolated from porcine brain tissue. The human BNP gene is located on chromosome 1 and encodes the prohormone proBNP. The biologically active BNP and the remaining part of the prohormone, NT-proBNP (76 amino acids) can be measured by immunoassay in human blood. Cardiac myocytes constitute the major source of BNP related peptides. The main stimulus for peptide synthesis and secretion is myocyte stretch. Recently, cardiac fibroblasts have also been shown to produce BNP. Other neurohormones may stimulate cardiac BNP production in different cardiac cell types. In contrast to atrial natriuretic peptides (ANP/NT-proANP), which originate mainly from atrial tissue, BNP related peptides are produced mainly from ventricular myocytes. Ventricular (NT-pro)BNP production is strongly upregulated in cardiac failure and locally in the area surrounding a myocardial infarction. In peripheral organs BNP binds to the natriuretic peptide receptor type A causing increased intracellular cGMP production. The biological effects include diuresis, vasodilatation, inhibition of renin and aldosterone production and of cardiac and vascular myocyte growth. In mice BNP gene knockout leads to cardiac fibrosis, gene over-expression to hypotension and bone malformations. BNP is cleared from plasma through binding to the natriuretic peptide clearance receptor type C, but it seems relatively resistant to proteolysis by neutral endopeptidase NEP 24.11. Clearance mechanisms for NT-proBNP await further study. While the plasma concentration of NT-proBNP and BNP is approximately equal in normal controls, NT-proBNP plasma concentration is 2-10 times higher than BNP in patients with heart failure. This relative change in peptide levels may be explained by shifts in cardiac secretion and/or clearance mechanisms.


Acetylator phenotype and congenital malformations.
The hypothesis has been tested that an unusual maternal acetylator phenotype can predispose to congenital malformations in the fetus. The acetylator phenotype of normal caucasian control women and of mothers of malformed children was established by measuring urinary sulphadimidine and its acetylated metabolite. A further control group was the fathers of the malformed newborn. The malformations studied were facial-cleft, spina-bifida and congenital heart disease. The acetylator phenotype was shown not be modified by pregnancy. 49 of 100 (49%) control women were rapid acetylators. Amongst the 108 mothers of malformed babies, 56 (52.8%) were slow acetylators and 52 (47.2%) were fast acetylators, 42 out of 83 (50.5%) of the fathers of malformed were slow acetylators and 41 (49.5%) were fast acetylators. Thus, the acetylator phenotype of the mothers of malformed children is no different from the acetylator phenotype of controls.


Enantioselective characteristics, bioaccumulation and toxicological effects of chlordane-related compounds in laying hens.
Chlordane-related compounds are ubiquitously detected in the environment and can transfer and accumulate to animals through food chain to cause adverse effects. In this study, the dynamic distribution and the enantiomeric profile of chlordane-related compounds in laying hens over time were investigated. The effect of these compounds on immune-associated cells in the intestinal tract and histopathology in some tissues were also evaluated after long-term exposure. The chlordane-related compounds preferentially accumulated in fat, followed by the intestines, ovum, and egg yolk during long-term exposure. The metabolites heptachlor epoxide and oxychlordane were mainly formed in the liver of hens by epoxidation or hydroxylation. The high accumulation ratios of trans-nonachlor and MC5 were found in ovum and egg yolk after long-term exposure, implying a greater risk to the hens' offspring. Chlordane-related compounds may cause abnormal lipometabolism and glycometabolism in liver of hens. Additionally, (-)-Cis-chlordane was dominant in all tissues of laying hens and its dominance increased over time. Conversely, (+)-isomer of metabolite oxychlordane was overwhelmingly dominant during the experiment. These findings about enantioselectivity, metabolic processes and toxicological effects are crucial in understanding the exposure risk of chlordane-related compounds.


Enough is enough! Patients who do not conceive on 600 IU/d of gonadotropins show no improvement from an additional 150 IU of LH activity.
Studies have suggested that supplemental LH improves outcomes in assisted reproductive technology (ART) cycles. In this retrospective review, an additional 150 IU of LH activity did not improve ART outcomes in women undergoing a second round of IVF/ intracytoplasmic sperm injection (ICSI) after an initial failed cycle using 600 IU of gonadotropins.


Regional anesthesia for obstetrics.
The practice of administration of labor analgesia has undergone dramatic changes this decade. This is largely attributable to unparalleled interest in the field by many dedicated and capable investigators around the world. Through their efforts, this decade has witnessed the introduction of new techniques (pencil point needles, CSE, PCEA, ultradilute epidural regimens) that have permitted us to come closer than ever to realizing the goal of complete relief from the pain and suffering of labor while safeguarding the well-being of mother and child and minimizing effects on the labor process. Neuraxial anesthetic techniques and modern multimodal analgesic approaches to postoperative pain relief now minimize the effects of cesarean delivery on maternal satisfaction and participation in the birth process.


Implementing "from here to there": A case study of conceptual and practical challenges in implementation science.
There is a significant challenge in global health and development research that pivots on the difficulties of delivering (cost-)effective treatments or interventions that are scalable andtransferable across settings. That is, how does one deliver "true effects", proven treatments, into new settings? This is often addressed in pragmatic trials or implementation research in which one makes adjustments to the delivery of the treatment to ensure that it works here and there. In this critical analytical review, we argue that the approach mis-characterises the cause-effect relationship and fails to recognise the local, highly contextual nature of what it means to say an intervention "works". We use an ongoing randomised controlled trial (RCT)-an informal settlement redevelopment intervention in Indonesia and Fiji to reduce human exposure to pathogenic faecal contamination-as a vehicle for exploring the ideas and implications of identifying interventions that work in global health and development. We describe the highly contextualised features of the research and the challenges these would pose in attempts to generalise the results. In other words, we detail that which is frequently elided from most RCTs. As our critical lens, we us the work of American philosopher, Nancy Cartwright, who argued that research produces dappled regions of causal insights-lacunae against a backdrop of causal ignorance. Rather than learn about a relationship between a treatment and an outcome, we learn that in the right sort of context, a treatment reliably produces a particular outcome. Moving a treatment from here to there becomes, therefore, something of an engineering exercise to ensure the right factors (or "shields") are in place so the cause-effect is manifest. As a consequence, one cannot assume that comparative effectiveness or cost-effectiveness would be maintained.


Carcinoma in the defunctionalized bladder: report of a case and review of the literature.
There are few reports in the literature of carcinoma developing in the post-diversionary bladder. The sixth such case is reported and the pertinent literature is reviewed. All cases of carcinoma in defunctionalized bladders have been associated with chronic inflammation of the bladder and all tumors became apparent within 4 years of diversion. Simple cystectomy at the time of diversion should be considered for patients with a long history of bladder inflammation.


Underemployment and its impacts on mental health among those with disabilities: evidence from the HILDA cohort.
Underemployment (defined as when a person in paid employment works for fewer hours than their desired full working capacity) is increasingly recognised as a component of employment precarity. This paper sought to investigate the effects of underemployment on the mental health of people with disabilities. Using 14 waves of the Household, Income and Labour Dynamics in Australia survey, we used fixed-effects models to assess whether the presence of a disability modified the association between underemployment and mental health. Both disability and underemployment were assessed as time-varying factors. Measures of effect measure modification were presented on the additive scale. The experience of underemployment was associated with a significantly greater decline in mental health when a person reported a disability (mean difference -1.38, 95% CI -2.20 to -0.57) compared with when they did not report a disability (mean difference -0.49, 95% CI -0.84 to -0.14). The combined effect of being underemployed and having a disability was nearly one point greater than the summed independent risks of having a disability and being underemployed (-0.89, 95% CI -1.75 to -0.03). People with disabilities are more likely to experience underemployment and more likely to have their mental health adversely affected by it. There is a need for more research and policy attention on how to ameliorate the effects of underemployment on the mental health of persons with disabilities.


Effect of antioxidants on atherosclerotic plaque formation in balloon-denuded and irradiated hypercholesterolemic rabbits.
The oxidative modification of low-density lipoprotein (LDL) hypothesis implies that antioxidants should be effective in suppressing atherosclerosis. This study is designed to test the potential of antioxidants to inhibit atherosclerotic plaque progression in balloon-denuded and irradiated hypercholesterolemic rabbits. Rabbits were fed with a 1% cholesterol diet supplemented with or without a mixture of antioxidants (vitamin E, vitamin C, selenium, zinc, copper, manganese, N-acetylcysteine, glutamine). At 7 days both iliac arteries were balloon denuded, and 4 weeks later, 1 iliac artery underwent endovascular irradiation (n=12), while the contralateral was sham treated (n=12). Four weeks after irradiation, animals were euthanized, and arteries were fixed and processed for histo- or immunohistochemistry for determining the plaque area, macrophage count, and oxidized LDL-positive areas. Plasma antioxidant levels were significantly higher in the animals fed with antioxidant diet. Plasma (thiobarbituric acid-reactive substances) and arterial tissue oxidized LDL (immunoreactive to specific oxidized LDL antibody) levels were significantly higher in the irradiated as compared with nonirradiated animals (0.69+/-0.09 and 31.05+/-4.21 versus 0.24+/-0.04 and 18.42+/-4.62, P<0.001 and 0.05), and antioxidants partially lowered the oxidized LDL levels (0.35+/-0.14 and 25.41+/-4.82, P<0.001 and 0.01). Plaque area in the irradiated animals was 175% greater than in nonirradiated animals (P<0.05). Antioxidant supplementation resulted in a 50% decrease in plaque area of both control and irradiated animals. Antioxidants reduced both the cholesterol-induced and radiation-enhanced circulating and tissue oxidized LDL levels, resulting in reduced plaque.


The Surgery Innovation and Entrepreneurship Development Program (SIEDP): An Experiential Learning Program for Surgery Faculty to Ideate and Implement Innovations in Health care.
Surgeons are continually engaged in the incorporation of new technologies in their practice. In the operating room and beyond, they combine technical skill with creative problem solving to improve tools and techniques for patient care, making them natural innovators. However, despite their innovative tendencies, education on entrepreneurship and commercialization is severely lacking. Moreover, with increasing pressure to meet productivity metrics, their availability to learn the complexities of commercialization is limited. To address these challenges, we designed the Surgery Innovation and Entrepreneurship Development Program (SIEDP) with the objective to advance faculty innovations, develop new departmental innovation initiatives, and improve faculty education in the area of innovation, entrepreneurship, and commercialization. The SIEDP is a first-of-its-kind experiential learning program specifically designed for busy clinical and research faculty in a major academic surgery department. Participants ideated and formed teams around health care innovations as they progressed through a 9-month curriculum of expert guest lectures and interactive workshops. A postprogram evaluation and outcome tracking method was used to evaluate attainment of educational objectives and project development milestones. The Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan. Eleven surgery faculty of varying academic rank and surgical subspecialties. The program generated 2 faculty startup companies, 1 departmental commercial product, 3 patent disclosures, and 3 innovations that received additional funding. All participants in the program reported a significant increase in their understanding of innovation and entrepreneurship and that participation was a worthwhile faculty development activity. Despite the various challenges and time constraints of surgical practices, programs like SIEDP can educate surgeons and other academicians on innovation, entrepreneurship, and commercialization and add value to the academic mission of providing excellent education, research, and clinical care.


Pulmonary cryptococcosis: Clinical, radiographical and serological markers of dissemination.
This study aimed to identify markers of disseminated infection in patients presenting with pulmonary cryptococcosis. Patients diagnosed with pulmonary cryptococcosis at a tertiary hospital between April 1998 and April 2005 were included and their clinical, radiological and pathological data analysed retrospectively. Thirty-one patients (14 male) were recruited into the study. Disseminated infection was seen in nine patients (29%), with the isolation of Cryptococcus neoformans from the blood of five patients and the cerebrospinal fluid of seven (three patients had both positive blood and cerebrospinal fluid findings). Patients with disseminated infection had a significantly higher incidence of impaired cellular immunity (immunosuppressant use, AIDS and haematological malignancy) (P = 0.015), fever (P < 0.001), interstitial abnormalities on CXR (P < 0.001), pleural effusion (P = 0.017) and death (P = 0.04) when compared with patients with localized infection. Serum cryptococcal antigen (sCRAG) was positive in 17 of the 19 patients tested at the time of diagnosis. Significantly higher sCRAG titres were noted in patients who had fever (P = 0.001), interstitial abnormalities on CXR (P = 0.004), pleural effusion (P = 0.018), disseminated disease (P = 0.003) and in those who died (P = 0.05). In pulmonary cryptococcosis patients, the presence of fever, interstitial abnormalities on CXR or pleural effusion should lead clinicians to suspect disseminated infection. High titres of sCRAG may indicate more extensive extra-pulmonary involvement and a worse prognosis.


pH-labile PEGylation of siRNA-loaded lipid nanoparticle improves active targeting and gene silencing activity in hepatocytes.
Lipid nanoparticles (LNPs) are one of the promising technologies for the in vivo delivery of short interfering RNA (siRNA). Modifying LNPs with polyethyleneglycol (PEG) is widely used to inhibit non-specific interactions with serum components in the blood stream, and is a useful strategy for maximizing the efficiency of active targeting. However, it is a widely accepted fact that PEGylation of the LNP surface strongly inhibits fusion between LNPs and endosomal membranes, resulting in poor cytosolic siRNA delivery, a process that is referred to as the 'PEG-dilemma'. In the present study, in an attempt to overcome this problem, siRNA-loaded LNPs were modified with PEG through maleic anhydride, a pH-labile linkage. The in vitro, suppression of cationic charge, stealth function at physiological pH up to 1h and the rapid desorption of PEG and restoration of fusogenic activity under slightly acidic conditions (within only 2min) were achieved by PEG modification of the LNPs through maleic anhydride. In vivo, PEG modification through maleic anhydride resulted in a dramatic improvement in the targeting capability of the active targeting of ligand (N-acetyl-d-galactosamine)-modified LNPs to hepatocytes, with an approximately 14-fold increase in gene silencing activity in factor 7 model mice. Taken together, the maleic anhydride-mediated pH-labile PEGylation of the active targeting LNPs is a useful strategy for achieving the specific and efficient delivery of siRNAs in vivo.


Occupational stress in consultants in accident and emergency medicine: a national survey of levels of stress at work.
To assess levels of occupational stress in UK accident and emergency (A&E) consultants. Postal survey of complete enumeration of UK consultants. GHQ-12 and SCL-D, and respondents' reported perceptions of stressors. Of 371 valid respondents (78%), 21 declined to participate. Of the remaining 350, 154 (44.4%) had GHQ-12 scores over the threshold for distress, which is much higher than found in other studies of doctors. Levels of depression as measured by the SCL-D at 18% (n=63) were slightly higher than other groups. Thirty four (10%) reported suicidal ideation. Women had significantly higher SCL-D scores than men (U=6604, p<0.01). Respondents were highly satisfied with A&E as a specialty. Protective factors found in other occupational groups did not apply. Only one demographic or work related factor; number of hours reportedly worked during previous week by respondents in full time posts (median=57, interquartile range=57), significantly correlated with either stress outcome measure (GHQ-12 scores) (rho=0.126, p<0.03). Logistic regression modelling revealed "being overstretched" (OR=1.18), "effect of hours (OR=0.82) and stress (OR=1.58) on family life", and "lack of recognition" (OR=1.32) were significant predictors of GHQ identified caseness, while "the effect of stress on family life" (OR=1.53), low prestige of specialty (OR=1.20), and "dealing with management" (OR=1.28) predicted SCL-D scores. There are high levels of psychological distress among doctors working in A&E compared with other groups of doctors. There is likely to be an effect on staff morale and career longevity. Interventions to improve the working lives of A&E consultants are required, in particular a reduction in hours worked.


Therapeutic and diagnostic applications of dendrimers for cancer treatment.
Dendrimers are prepared with a level of control not attainable with most linear polymers, leading to nearly monodisperse, globular macromolecules with a large number of peripheral groups. As a consequence, dendrimers are an ideal delivery vehicle candidate for explicit study of the effects of polymer size, charge, composition, and architecture on biologically relevant properties such as lipid bilayer interactions, cytotoxicity, internalization, blood plasma retention time, biodistribution, and tumor uptake. Over the last several years, substantial progress has been made towards the use of dendrimers for therapeutic and diagnostic purposes for the treatment of cancer, including advances in the delivery of anti-neoplastic and contrast agents, neutron capture therapy, photodynamic therapy, and photothermal therapy. The focus of this review is on dendrimer developments from the last four years for oncological applications, with emphasis on distinct architectures and the biological responses these structures elicit.


Recognition of autologous lymphoblastoid cells by cloned human T cells: inhibition of cytotoxicity by anti-HLA antibody but not by antibody to Epstein-Barr virus induced cell surface antigen.
Cytotoxic T cells (Tc) can be primed in vitro to specifically kill autologous Epstein-Barr virus (EBV) transformed lymphoblastoid cell line cells (LCL). The antigen recognized by Tc on the LCL cells is designated LYDMA (lymphocyte determined membrane antigen). Recognition of LYDMA may also require simultaneous recognition of HLA determinants. Despite its immunogenic potency, the genetic origin and molecular structure of LYDMA remains undetermined. Most LCL cells do not produce EBV virus, but all LCL cells appear to express an immunogenic, non-HLA class I, 47,000 Dalton determinant which is detected by several independently derived mouse monoclonal antibodies. This determinant is not readily detected on peripheral blood lymphocytes, nor on EBV-associated Burkitt's lymphoma cell lines. We examined the potential relationship between this 47,000 MW Epstein-Barr virus associated cell surface antigen (the EBVCS antigen) and LYDMA. Populations of Tc generated by in vitro activation with irradiated autologous LCL cells were potent at destroying EBVCS bearing autologous LCL cells. The addition of anti-EBVCS antibody to this cytotoxic interaction had no suppressive effect. Furthermore, single cell derived, LYDMA reactive, Tc clones able to specifically destroy autologous LCL were studied. Cytotoxicity could be inhibited by monoclonal antibody to HLA-Class I determinants, but not by monoclonal antibodies to EBVCS. Thus, these LYDMA reactive Tc clones do not recognize the same antigenic determinant as the monoclonal antibodies specific for EBVCS. It remains uncertain whether this 47,000 MW glycoprotein that carries the serologically detected EBVCS antigen may be directly recognized by human T cells.


Left ventricular pseudoaneurysm complicating mitral valve replacement: transesophageal echocardiographic diagnosis and impact on management.
Left ventricular pseudoaneurysm formation after mitral valve replacement, although infrequent, is a serious complication with potential catastrophic results. We describe a case of an anterobasal pseudoaneurysm compressing all branches of the left coronary artery, which was missed by initial transthoracic echocardiography and was well characterized with the transesophageal approach. Although the pseudoaneurysm was detected at contrast ventriculography, the transesophageal study provided new specific details regarding the exact site of origin of the pseudoaneurysm and its relationship to the coronary arteries that significantly influenced planning the surgical procedure and patient management.


Utilization management: a European perspective.
Utilization management (UM) in health care, based on the collection, assessment and monitoring of data pertaining to patient services and treatment, ultimately assures efficiency and effectiveness. The central role of laboratory services in modern medicine created the need to utilize UM programs in clinical laboratories in order to reduce costs, enhance efficiency and improve on quality for patients. Some UM programs have focused on improving efficiency by reducing the cost per test. Consolidation and networking have been proposed as opportunities to increase test volumes, thus achieving economy of scale, and a better ratio between test volumes and fulltime equivalent (FTE) staff. However, little evidence is available in the literature to demonstrate the efficiency of these models, and concern has been expressed regarding the possible increase in pre-analytical errors and the loss of efficient communication between clinicians and laboratory professionals. In Europe, we have seen an increasing emphasis on the importance of demand management strategies as the key to reducing costs and improving on quality in laboratory medicine. The cost of inappropriate requesting includes not only test consumables and reagents, but also additional consultations, treatment and investigations. A number of studies in literature describe strategies and initiatives designed to change and improve test requesting, but the following two items are mandatory for real improvement: a) the active involvement of requesting physicians and other stakeholders, including patients; and b) the use of combined interventions instead of a single strategy. Therefore, the use of approaches for demand management that considers pre-, within- and post-laboratory initiatives is on the increase in clinical laboratories throughout Europe.


Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis.
Telomere shortening and telomerase activation both occur in human tumors. Telomere shortening has been proposed to have two conflicting roles in tumorigenesis: tumor suppression and initiation of chromosomal instability. Similarly, while telomerase activation is suggested to be necessary for tumor growth, telomerase may help to stabilize genomic instability. Here we review what is known about these conflicting roles and propose a framework to understand the role of telomerase in cancer progression.