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Improved survival has shifted research focus toward understanding alternate PICU outcomes, including neurocognitive and functional changes. Bronchiolitis is a common PICU diagnosis, but its neuro-functional outcomes have not been adequately described in contemporary literature. The objective of the study is to describe the epidemiology and associated clinical characteristics of acute neuro-functional morbidity (ANFM) in critical bronchiolitis.Patients <2 years old admitted with bronchiolitis between 2014 and 2016 were identified. Demographics, medical history, length of stay (LOS), and need for intubation were collected. Children with a history of neurologic illness or illness associated with neurologic sequelae were termed “high risk”; others were termed “low risk.” ANFM was defined both at PICU and hospital discharge as the presence of swallowing difficulty, nasogastric tube feeds, hypotonia, or lethargy. Variables were compared by using χ2 and Wilcoxon rank tests.Among 417 children, 16.7% had ANFM, predominantly swallow difficulties (95.7%). Children with ANFM had lower weight (5.9 [4.4–8.2] vs 7.7 [5.5–9.7] kg, P = .001), longer LOS (6.6 [2.5–13.3] vs 1.9 [0.9–3.5] days, P < .001), intubation (51.4% vs 6.1%, P < .001) and high-risk status (37.1% vs 8.4%, P < .001). Among 362 low risk subjects, ANFM was identified in 44 (12%). In a multivariate logistic regression model, high-risk status, intubation, and ICU LOS were associated with ANFM. ANFM persisted to hospital discharge in 46% of cases.One out of 6 patients with critical bronchiolitis had documentation consistent with ANFM at PICU discharge. Risk factors included previous neurologic conditions, longer LOS, and intubation. Many were low-risk and/or did not require intubation, indicating a risk for neuro-functional morbidities despite moderate acuity.

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Headquartered in Oslo, Norway and listed on the Oslo Stock Exchange, Yara is a global fertiliser giant, with operations and offices in more than 50 countries, eight in Africa, and [...]

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Abstract Aim: To examine psychological distress in women at risk of familial breast–ovarian cancer (FBOC) or hereditary non-polyposis colorectal cancer (HNPCC) with absence of demonstrated mutations in the family (unknown mutation).Materials and methods: Two-hundred and fifty three consecutive women at risk of FBOC and 77 at risk of HNPCC and with no present or past history of cancer. They were aware of their risk and had received genetic counseling. Comparisons were made between these two groups, normal controls, and women who were identified to be BRCA1 mutation carriers. The questionnaires Beck Hopelessness Scale (BHS), General Health Questionnaire (GHQ-28), Hospital Anxiety and Depression Scale (HADS) and Impact of Event Scale (IES) were employed to assess psychological distress.Results: No significant differences concerning psychological distress were observed between women with FBOC and women with HNPCC. Compared to mutation carriers for BRCA1, the level of anxiety and depression was significantly higher in the FBOC group with absence of demonstrated mutation. Compared to normal controls, the level of anxiety was higher, while the level of depression was lower in the groups with unknown mutation.Conclusions: Women in the absence of demonstrated mutations have higher anxiety and depression levels than women with known mutation-carrier status. Access to genetic testing may be of psychologically benefit to women at risk for FBOC or HNPCC.

Background & Aims: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is caused by a mutated mismatch repair (MMR) gene. The aim of our study was to determine the cumulative risk of developing cancer in a large series of MSH6 mutation carriers. Methods: Mutation analysis was performed in 20 families with a germline mutation in MSH6. We compared the cancer risks between MSH6 and MLH1/MSH2 mutation carriers. Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) were performed in the available tumors. Results: A total of 146 MSH6 mutation carriers were identified. In these carriers, the cumulative risk for colorectal carcinoma was 69% for men, 30% for women, and 71% for endometrial carcinoma at 70 years of age. The risk for all HNPCC-related tumors was significantly lower in MSH6 than in MLH1 or MSH2 mutation carriers (P = 0.002). In female MSH6 mutation carriers, the risk for colorectal cancer was significantly lower (P = 0.0049) and the risk for endometrial cancer significantly higher (P = 0.02) than in MLH1 and MSH2 mutation carriers. In male carriers, the risk for colorectal cancer was lower in MSH6 mutation carriers, but the difference was not significant (P = 0.0854). MSI analysis in colorectal tumors had a sensitivity of 86% in predicting a MMR defect. IHC in all tumors had a sensitivity of 90% in predicting a mutation in MSH6. Conclusions: We recommend starting colonoscopic surveillance in female MSH6 mutation carriers from age 30 years. Prophylactic hysterectomy might be considered in carriers older than 50 years. MSI and IHC analysis are sensitive tools to identify families eligible for MSH6 mutation analysis.

Hereditary nonpolyposis colorectal cancer (HNPCC) may be caused by germline truncating mutations in DNA mismatch repair (MMR) genes. Whether or not missense or inframe mutations are disease-associated has become a practical clinical problem, because predictive genetic testing is employed to select high-risk persons for clinical examinations. Clinical examinations may reveal polyps to be removed and prevent cancer. One large kindred applying for health care had a N596del mutation in the MSH2 gene. The aim of this study was to determine whether or not the inframe mutation in this family was associated with disease, and to examine the tumours for presence of the MSH2 protein by immunohistochemistry. We demonstrated that the mutation was linked to disease with lod score 5.7 in the family, and all examined, but one manifest cancer, lacked the MSH2 protein.

The paper tells the story of how FV was discovered in 1943 and installed into the Morawitz theory, a dogma that had reigned the clotting field since 1905 without serious challenges. It is a witness to the fact, many times experienced throughout scientific history, that seminal achievements may arise from serendipity under awkward conditions. Under the worst of circumstances, only a brilliant mind, scientific curiosity and devotion, could the challenge Owren met in Mary's bleeding problem, lead to such a pivotal result. On top of establishing a new clotting factor, his work spurred an unprecedented activity in the field.

Background and aims:Hereditary non-polyposis colorectal cancer (HNPCC) may be caused by mutations in the mismatch repair (MMR) genes MLH1, MSH2 or MSH6. Family history (Amsterdam criteria) has traditionally been used to select patients for mutation testing. It has been demonstrated that germline mutations in the MMR genes are associated with lack of the corresponding gene product as assessed with immunohistochemistry (IHC) in tumour specimens. The aim of the study was to assess the value of the Amsterdam criteria II and IHC in predicting germline mutations. Methods:Fifty-six families that were previously tested for MLH1, MSH2 and MSH6 mutations were selected for this study. All pedigrees were extended and verified and the families were scored according to the original (I) and the revised Amsterdam criteria (II). The probabilities for MLH1 and MSH2 mutations were calculated by logistic regression. In addition, all available tumour material from indexed family members was examined by IHC for the presence of the three gene products. Results:Three out of seven (39%) families where the mutation could be identified complied with the Amsterdam criteria I, while all seven (100%) met the Amsterdam criteria II. All families carrying a MLH1 or MSH2 mutation had > 15% calculated probability of finding a mutation. Tumours from all seven mutation carriers lacked the immunohistochemical expression of the corresponding MMR gene. Conclusion:The results indicate that the Amsterdam criteria II in combination with immunohistochemistry of the mismatch repair proteins in tumours may be a cost-effective approach to select families for mutation analysis.

Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes. Copyright © 2000 John Wiley & Sons, Ltd.

Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non‐polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)‐driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1and MSH2germline mutations demonstrate an MSI‐high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6mutation carriers, only 36% (4 out of 11) demonstrate an MSI‐high phenotype. Interestingly, an MSI‐high phenotype was found in endometrial hyperplasias from MSH2mutation carriers, in contrast to hyperplasias from MLH1mutation carriers, which exhibited an MSI‐stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes. Copyright © 2000 John Wiley & Sons, Ltd.

Background: There is a dispute about the potential effects of radiographic contrast media (CM) on thrombogenesis. The nonionic CM iohexol triggers platelet β-thromboglobulin (β-TG) secretion, and thus may activate the platelets and promote thrombosis. We addressed this topic in a study employing a human model of arterial thrombus formation in the presence of aspirin and heparin. This was a follow-up to our initial study (on thrombus formation in native blood) which did not include antithrombotic drugs. The nonionic CM iohexol (monomer) and iodixanol (dimer) and the ionic CM ioxaglate (dimer) were compared.Methods and Results: Thrombus formation was triggered by a surface rich in either collagen or tissue factor, positioned in a parallel-plate perfusion chamber device at an arterial wall shear rate of 2600 s−1. Blood from healthy volunteers, following ingestion of 1 g aspirin, was mixed with 40 vol CM and 2.0 IUml heparin and passed over the surfaces. Thrombus formation in the presence of either CM showed no difference, despite the fact that iohexol triggered a pronounced platelet β-TG secretion; iodixanol or ioxaglate were virtually inert.Conclusion: There was no association between iohexol-induced β-TG secretion and thrombus formation on collagen (platelet-driven) or on tissue factor (thrombin-driven) in the presence of a standard antithrombotic regimen of aspirin and heparin as used in the clinic. The notion of a thrombotic risk due to platelet activation by iohexol was thus not substantiated by this study.

Inhibition of thrombin formation in flowing native blood reduces thrombus formation on subendothelium, dacron, or collagen fibrils at arterial wall shear rates of 450 to 650 s-1. In the present study, we have investigated the role of low levels of factor VII (FVII) in thrombus formation on collagen fibrils at arterial wall shear rates of 650 s-1 (coronary arteries), 2,600 s-1 (mildly stenosed arteries), and 10,510 s-1 (severely stenosed arteries) in parallel-plate perfusion chambers. In the perfusion chamber with the highest wall shear rate, thrombus formation took place at the apex of an eccentric stenosis, which reduced the cross-sectional area of the blood flow channel by 80%, thus simulating thrombus formation at an atherosclerotic plaque rupture. Native blood from 21 healthy volunteers and 12 homozygous FVII- deficient patients was drawn by a pump directly from an antecubital vein over a surface of fibrillar collagen positioned in the respective perfusion chambers. The patients had FVII coagulant activities ranging from 1.3% to 4.5% and FVII antigen levels of 16% to 23% of normal. Immunoaffinity purification of the patients' FVII followed by electrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis [SDS-PAGE]) and immunoblotting showed a protein with similar molecular mass as normal FVII. In the perfusion studies, a reduction in thrombus volume of 54% of normal (P < .007) at 10,510 s-1 was observed. The deposition of fibrin on the thrombogenic surface and the plasma level of fibrinopeptide A (FPA) in blood samples collected distal to the perfusion chamber were concomitantly reduced (P < .002 and P < .04, respectively). The plasma FPA level was also reduced at 2,600 s-1 (P < .04), but not at 650 s-1. However, at the lower shear conditions, the thrombus volume and the fibrin deposition were within the ranges observed in normal blood. The platelet-collagen adhesion was not affected at any of the three shear conditions. Thus, low plasma levels of FVII result in significantly less formation of thrombin and fibrin in and around growing platelet masses at high shear condition. This may weaken the thrombus stability and reduce platelet recruitment, thereby lowering thrombus volume. In support of this theory, one patient with afibrinogenemia had an 83% reduction in thrombus volume at this high shear condition.

A simple method for the detection of Fletcher factor-prekallikrein deficiency is described. The method is based on the necessity of this factor for the cold induced EACA acceleration of the thromboplastin time. It reveals both homozygotes and heterozygotes. To make the diagnosis specific, factor XII deficient plasma is needed.

The most recent information about platelets and their role in hemostasis is presented. The intimate cooperation between platelets, coagulation, and the vessel wall (the thrombohemorrhagic balance) is outlined. Clinical correlates (congenital and acquired bleeding states) to the various physiological stages and the possible effects on hemostasis of the unique acidic environment of the stomach are briefly discussed.

This paper reviews the basic mechanisms of the thrombohemorrhagic balance, and ways in which contrast media (CM) influence these processes. Coagulation and platelet functions are strongly inhibited by ionic CM, but weakly so by nonionic CM, whereas the former are more detrimental to endothelium, and thus thrombogenic in this sense. Some observations indicate a lower rate of thromboembolic events with the ionic CM in percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG), but this purported difference does not affect mortality or frequency of re-PTCA and emergency CABG. Thus, to challenge these events, strong acting antithrombotics, which also, unlike heparin, inactivate fibrin-bound thrombin, are necessary. Aggressive anti-atherogenic prophylaxis may hamper both thrombosis and reocclusion. The ideal antithrombotic in this setting is yet to be found.

An in vitro and in vivo study of the effect of ionic and nonionic contrast media (CM) on coagulation and platelet function is reported. The methods employed were tests for extrinsic and intrinsic coagulation together with a fibrinolytic parameter and aggregation using ADP and collagen as inducers. The in vivo study utilized patients undergoing routine cerebral angiography. The in vitro results showed a modest influence of the nonionic CM in contrast to the ionic. The marked inhibitory effect of the latter was mainly caused by inherent toxicity, osmolalityionic strength being of minor importance. The in vivo results showed a negligible influence of CM on systemic hemostatic parameters, but catheterderived samples indicated desirability of premedication with ASA or heparin. The nonionic CM caused less discomfort than the ionic CM.

Background: the aims of the present study were to investigate whether ionic and nonionic contrast media (CM) affect: 1) the procoagulant and fibrinolytic activities of cultured human vessel endothelium; and 2) early events of tissue-factor-induced arterial thrombus formation under conditions which may follow a percutaneous transluminal coronary angioplasty (PTCA) procedure. the following 3 CM were studied: iohexol (nonionic monomer, Omnipaque); iodixanol (nonionic dimer, Visipaque); and ioxaglate (ionic dimer, Hexabrix). Saline (0.9) and glucose (40 vol) were used as control.Methods and Results: Exposing endothelium to 40 vol CM for 10 min did not affect the selected parameters of cellular procoagulant (tissue factor), anticoagulant (thrombomodulin), fibrinolytic (tissue plasminogen activator) or antifibrinolytic (plasminogen activator inhibitor-1) activity or antigen. However, ioxaglate had a profound impact on the cell morphology, which was noted already after one minute of exposure. the cells contracted and rounded, exposing large areas of extracellular matrix. Iohexol showed this phenomenon to a considerably lesser extent, whereas iodixanol induced a slight swelling of the cells without detectable exposure of extracellular matrix. the effect of the respective CM on tissue-factor-driven thrombus formation at an arterial shear rate of 2600 s-1was studied in an ex vivoparallel-plate perfusion chamber device. In this model, human native blood was passed over a tissue factorphospholipid-rich surface following 30 s exposure to 100 CM. the CM was washed out by nonanticoagulated blood drawn directly from an antecubital vein by a pump positioned distal to the perfusion chamber. Such a pre-exposure of the procoagulant surface to iodixanol reduced the fibrin deposition around the platelet thrombi by 50 (p<0.01). However, iohexol and ioxaglate did not affect fibrin deposition. None of the 3 CM affected the recruitment of platelets in the thrombi, since similar values were obtained with pre-exposure to 40 vol of saline.Conclusion: Iodixanol appears to be most biocompatible with endothelium, and has a moderate inhibitory effect on fibrin deposition in flowing blood. This differs from iohexol, and in particular from ioxaglate, which induce endothelial changes in morphology with no effect on fibrin deposition. Since none of the CM affected the platelet aggregate formation, and since ioxaglate has been reported to have stronger anticoagulant and antithrombotic properties than iodixanol or iohexol in in vitroassays, it is apparent that these properties were not reflected in thrombus formation under the experimental conditions of high arterial shear.

The anticoagulant effect of heparin was studied in 20 patients undergoing aortocoronary bypass surgery. The protamine dose necessary to reverse heparin after extracorporeal circulation (ECC) was assessed in ten patients from individual heparin dose-response curves (HDR group). The other ten patients received protamine according to a routine protocol (control group). The protamine administration was followed in both groups by injection of 3-5 g tranexamic acid (Cyklokapron®). A wide range of sensitivity to heparin was shown by the patients. Although almost twice as much protamine was given to the control group as to the HDR group, the effect on heparin reversal was similar. The variability of protamine dose did not influence the post-bypass levels of fibrinogen, AT-III, activated coagulation time (ACT) or Cepho-test, and fibrinolysis was not observed in either of the groups. During ECC there was poor correlation between ACT and plasma heparin levels, and the use of heparin dose-response curves was grossly misleading in regard to true heparin concentration. The postoperative bleeding was not related to the levels of heparin or coagulation parameters after heparin reversal. The concentrations of fibrinogen and AT-III showed variations dependent on the changes in haematocrit. A number of factors other than heparin that influence ACT are discussed.

Adenosine diphosphate (ADP) and prostaglandin derivatives play important roles in thrombogenesis. Their roles in platelet function have been extensively studied for more than three and two decades, respectively. Of further importance for thrombogenesis, and perhaps for atherogenesis as well, is that these compounds are involved in the regulation of vascular wall tone, both as constrictors and dilators. The aim of this brief essay is to highlight the relative importance of ADP and TxA various well-defined shear conditions. To achieve this goal, we employed a human ex vivo model of thrombus formation, because well-defined and reproducible blood shear conditions are best created in such a device. The blood flow conditions varied from those encountered atherosclerotic disease. These experiments were performed as parts of clinical phase I studies with novel antagonists of ADP- or TxA-induced platelet aggregation. Probes for ADP and TxA 2 receptor antagonist clopidogrel and the TxA receptor 2 rombotic activities were compared with results obtained with the cyclo-oxygenase inhibitor aspirin. These studies demonstrated a significant effect of both ADP and TxA formation. W hereas ADP promoted platelet thrombus formation independently of the local shear, TxA promoted platelet thrombus formation at high arterial shear only, and increasingly by increasing shear. However, at blood flow conditions triggering shear-induced formation did not affect collagen-induced platelet thrombus formation since aspirin administration was insensitive to the thrombotic response. This contrasts with the need for ADP in shear-induced platelet aggregation. Thus, the function of ADP in human ex vivo platelet thrombus formation appears more global than the role of TxA . These observations are in agreement with recent published clinical findings. 2 in collagen-induced thrombus formation at 2 in healthy veins to vessels with severe included the ADP 2 antagonist linotroban, respectively. Their antithon collagen-induced ex vivo thrombus 2 2 platelet activation and aggregation, TxA 2

The species specificity of thromboplastin (tissue factor) is an important fact to take into consideration when clotting assays or experiments are planned. We have (re)investigated all possible combinations of thromboplastin and plasma from several of the most commonly used species of experimental animals.

A method for assaying plasma prekallikrein has been developed applying the chromogenic substrate Chromozym PK. Different variables have been investigated, and the final assay system was found to give a reproducible and reliable assay procedure. A normal value of 99.0 ± 18% was found, the coefficient of variation being 7.9. Studies on material from patients with various liver diseases indicated that the main site of prekallikrein biosynthesis is the liver.

A technique for electronic platelet counting is described. The erythrocytes in whole blood were removed by sedimentation at 1 × g in a two-phase system, using dextran as the erythrocyte-aggregating agent. The platelets in the plasma layer were counted electronically. By means of the haematocrit value, the plasma platelet count was converted to whole blood platelet count, which corresponded well with the microscope count. At low platelet numbers, corrections must be made for contaminating erythrocytes and leucocytes. At low platelet numbers, both microscope counts and celloscope counts became inaccurate. For the use of electronic counting in clinical medicine, this difficulty can easily be avoided by reducing the degree of dilution.

The relation between milk ejection and antidiuretic response was studied on lactating cows using different stimuli.The stimuli, utilized to induce milk ejection, could be classified according to increasing effectiveness as follows: (1) showing the calf to the mother (visual stimulation); (2) washing the udder with water at 40° C in trained animals; (3) washing combined with visual stimulation; (4) suckling. Experimental conditions (hydration, bladder catheter) exerted a marked inhibiting effect in most animals on the milk-ejecting reflex induced by stimuli 1, 2 and 3. The reactions of domesticated cows under these circumstances are analogous to those of primitive breeds under normal conditions.Generally, the antidiuretic response seemed to be quantitatively correlated with the release of oxytocin. However, exceptions to this rule were observed.An antidiuretic response was obtained in cows after milk ejection unaccompanied by withdrawal of milk.The effect of known amounts of oxytocin on milk ejection was studied, and the dose-response curve was nearly a straight line when log dose was plotted against the volume of milk ejected. The slope of the curves, however, varied in different cows.