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Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

With decreasing mortality in PICUs, a growing number of survivors experience long-lasting physical impairments. Early physical rehabilitation and mobilization during critical illness are safe and feasible, but little is known about the prevalence in PICUs. We aimed to evaluate the prevalence of rehabilitation for critically ill children and associated barriers.National 2-day point prevalence study.Eighty-two PICUs in 65 hospitals across the United States.All patients admitted to a participating PICU for greater than or equal to 72 hours on each point prevalence day.None.The primary outcome was prevalence of physical therapy- or occupational therapy-provided mobility on the study days. PICUs also prospectively collected timing of initial rehabilitation team consultation, clinical and patient mobility data, potential mobility-associated safety events, and barriers to mobility. The point prevalence of physical therapy- or occupational therapy-provided mobility during 1,769 patient-days was 35% and associated with older age (adjusted odds ratio for 13-17 vs3 yr, 2.1; 95% CI, 1.5-3.1) and male gender (adjusted odds ratio for females, 0.76; 95% CI, 0.61-0.95). Patients with higher baseline function (Pediatric Cerebral Performance Category, ≤ 2 vs2) less often had rehabilitation consultation within the first 72 hours (27% vs 38%; p0.001). Patients were completely immobile on 19% of patient-days. A potential safety event occurred in only 4% of 4,700 mobility sessions, most commonly a transient change in vital signs. Out-of-bed mobility was negatively associated with the presence of an endotracheal tube (adjusted odds ratio, 0.13; 95% CI, 0.1-0.2) and urinary catheter (adjusted odds ratio, 0.28; 95% CI, 0.1-0.6). Positive associations included family presence in children less than 3 years old (adjusted odds ratio, 4.55; 95% CI, 3.1-6.6).Younger children, females, and patients with higher baseline function less commonly receive rehabilitation in U.S. PICUs, and early rehabilitation consultation is infrequent. These findings highlight the need for systematic design of rehabilitation interventions for all critically ill children at risk of functional impairments.

There are established associations between adverse health outcomes and poverty, but little is known regarding these associations in critically ill children. We hypothesized that living in poorer communities would be associated with unfavorable outcomes in children with critical bronchiolitis. This retrospective study included children with bronchiolitis admitted to a pediatric intensive care unit (PICU) over a 2-year period. Median household income was estimated from patient ZIP codes and 2014 US Census Bureau data. The 2014 Federal Poverty Threshold (FPT) for a family of 4 was $24 008. Patients were classified as living in ZIP codes below or above the 150% FPT (150FPT). Living

OBJECTIVES Outcomes associated with a sedative regimen comprised ketamine + propofol for pediatric procedural sedation outside of both the pediatric emergency department and operating room are underreported. We used the Pediatric Sedation Research Consortium database to describe a multicenter experience with ketamine + propofol by pediatric sedation providers. DESIGN Prospective observational study of children receiving IV ketamine + propofol for procedural sedation outside of the operating room and emergency department using data abstracted from the Pediatric Sedation Research Consortium during 2007-2015. SETTING Procedural sedation services from academic, community, free-standing children's hospitals, and pediatric wards within general hospitals. PATIENTS Children from birth to less than or equal to 21 years old. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A total of 7,313 pediatric procedural sedations were performed using IV ketamine + propofol as the primary sedative regimen. Median age was 84 months (range, < 1 mo to ≤ 21 yr; interquartile range, 36-144); 80.6% were American Society of Anesthesiologists-Physical Status less than III. The majority of sedation was performed in dedicated sedation or radiology units (76.1%). Procedures were successfully completed in 99.8% of patients. Anticholinergics (glycopyrrolate and atropine) or benzodiazepines (midazolam and lorazepam) were used in 14.2% and 41.3%, respectively. The overall adverse event and serious adverse event rates were 9.79% (95% CI, 9.12-10.49%) and 3.47% (95% CI, 3.07-3.92%), respectively. No deaths occurred. Risk factors associated with an increase in odds of adverse event included ASA status greater than or equal to III, dental suite, cardiac catheterization laboratory or radiology/sedation suite location, a primary diagnosis of having a gastrointestinal illness, and the coadministration of an anticholinergic. CONCLUSIONS Using Pediatric Sedation Research Consortium data, we describe the diverse use of IV ketamine + propofol for procedural sedation in the largest reported cohort of children to date. Data from this study may be used to design sufficiently powered prospective randomized, double-blind studies comparing outcomes of sedation between commonly administered sedative and analgesic medication regimens.

OBJECTIVES: No guidelines are available regarding initiation of enteral nutrition in children with bronchiolitis on high-flow nasal cannula (HFNC) support. We hypothesized that the incidence of feeding-related adverse events (AEs) would not be associated with HFNC support. METHODS: This retrospective study included children ≤24 months old with bronchiolitis receiving HFNC in a PICU from September 2013 through April 2014. Data included demographics, respiratory support during feeding, and feeding-related AEs. Feeding-related AEs were extracted from nursing documentation and defined as respiratory distress or emesis. Feed route and maximum HFNC delivery were recorded in 8-hour shifts (6 am–2 pm, 2 pm–10 pm, and 10 pm–6 am). RESULTS: 70 children were included, with a median age of 5 (interquartile range [IQR] 2–10) months. HFNC delivery at feed initiation varied widely, and AEs related to feeding occurred rarely. Children were fed in 501 of 794 (63%) of nursing shifts, with AEs documented in only 29 of 501 (5.8%) of those shifts. The incidence of AEs at varying levels of respiratory support did not differ (P = .092). Children in the “early feeding” (fed within first 2 shifts) group (n = 22) had a shorter PICU length of stay (2.2 days [IQR 1.4–3.9] vs 3.2 [IQR 2.5–5.3], P = .006) and shorter duration of HFNC use (26.0 hours [IQR 15.8–57.0] vs 53.5 [IQR 37.0–84.8], P = .002), compared with children in the “late feeding” group (n = 48). CONCLUSIONS: In this small, single-institution patient cohort, feeding-related AEs were rare and not related to the delivered level of respiratory support.

Most studies of ketamine administered to children for procedural sedation are limited to emergency department use. The objective of this study was to describe the practice of ketamine procedural sedation outside of the operating room and identify risk factors for adverse events.Observational cohort review of data prospectively collected from 2007 to 2015 from the multicenter Pediatric Sedation Research Consortium.Sedation services from academic, community, free-standing children's hospitals and pediatric wards within general hospitals.Children from birth to 21 years old or younger.None.Describe patient characteristics, procedure type, and location of administration of ketamine procedural sedation. Analyze sedation-related adverse events and severe adverse events. Identify risk factors for adverse events using multivariable logistic regression. A total of 22,645 sedations performed using ketamine were analyzed. Median age was 60 months (range,1 mo to22 yr); 72.0% were American Society of Anesthesiologists-Physical Status less than III. The majority of sedations were performed in dedicated sedation or radiology units (64.6%). Anticholinergics, benzodiazepines, or propofol were coadministered in 19.8%, 57.9%, and 35.4%, respectively. The overall adverse event occurrence rate was 7.26% (95% CI, 6.92-7.60%), and the frequency of severe adverse events was 1.77% (95% CI, 1.60-1.94%). Procedures were not completed in 39 of 19,747 patients (0.2%). Three patients experienced cardiac arrest without death, all associated with laryngospasm.This is a description of a large prospectively collected dataset of pediatric ketamine administration predominantly outside of the operating room. The overall incidence of severe adverse events was low. Risk factors associated with increased odds of adverse events were as follows: cardiac and gastrointestinal disease, lower respiratory tract infection, and the coadministration of propofol and anticholinergics.

OBJECTIVES New definitions of pediatric acute respiratory distress syndrome include criteria to identify a subset of children "at risk for pediatric acute respiratory distress syndrome." We hypothesized that, among PICU patients with bronchiolitis not immediately requiring invasive mechanical ventilation, those meeting at risk for pediatric acute respiratory distress syndrome criteria would have worse clinical outcomes, including higher rates of pediatric acute respiratory distress syndrome development. DESIGN Single-center, retrospective chart review. SETTING Mixed medical-surgical PICU within a tertiary academic children's hospital. PATIENTS Children 24 months old or younger admitted to the PICU with a primary diagnosis of bronchiolitis from September 2013 to April 2014. Children intubated before PICU arrival were excluded. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Collected data included demographics, respiratory support, oxygen saturation, and chest radiograph interpretation by staff radiologist. Oxygen flow (calculated as FIO2 × flow rate [L/min]) was calculated when oxygen saturation was 88-97%. The median age of 115 subjects was 5 months (2-11 mo). Median PICU length of stay was 2.8 days (1.5-4.8 d), and median hospital length of stay was 5 days (3-10 d). The criteria for at risk for pediatric acute respiratory distress syndrome was met in 47 of 115 subjects (40.9%). Children who were at risk for pediatric acute respiratory distress syndrome were more likely to develop pediatric acute respiratory distress syndrome (15/47 [31.9%] vs 1/68 [1.5%]; p < 0.001), had longer PICU length of stay (4.6 d [2.8-10.2 d] vs 1.9 d [1.0-3.1 d]; p < 0.001) and hospital length of stay (8 d [5-16 d] vs 4 d [2-6 d]; p < 0.001), and increased need for invasive mechanical ventilation (16/47 [34.0%] vs 2/68 [2.9%]; p < 0.001), compared with those children who did not meet at risk for pediatric acute respiratory distress syndrome criteria. CONCLUSIONS Our data suggest that the recent definition of at risk for pediatric acute respiratory distress syndrome can successfully identify children with critical bronchiolitis who have relatively unfavorable clinical courses.

Background With the advent of novel drugs improved overall survival in patients with multiple myeloma, including patients who received up-front autologous stem cell transplantation (ASCT), has been reported from several centers. Here we report on overall survival in a population-based cohort of patients receiving ASCT as first line treatment and in whom novel agents were an option for second and later lines of treatment. Methods Patients with multiple myeloma ≤ 65 years of age who were considered for ASCT from 01.01.2001–31.06.2005 (period 1) and from 01.07.2005 until 31.12.2009 (period 2) at Oslo University Hospital (OUH) were identified. Relevant data were collected from the patients’ medical records. Results Altogether, 293/355 patients received ASCT. In all, median OS was 82.9 months in patients ≤ 60 years of age and 59.0 months in patients 61–65 years. For patients ≤ 60 years of age median OS increased from 70.6 months to 87.7 months (p = 0. 22) and median survival after start of second line therapy increased from 34.5 months to 46.5 months (p = 0.015) between the two periods. For patients 61–65 years of age median OS increased from 57.3 months to 61.2 months (p = 0. 87) and median survival after start of second line therapy was practically unchanged (32.6 months vs. 33.1 months (p = 0.97) between the periods. In patients ≤ 60 years of age salvage ASCT was used in 34% of the patients while in patients 61–65 years of age salvage ASCT was used in 7.3% of the patients. The use of salvage ASCT and novel drugs, as well as the number of treatment lines, were higher in patients ≤ 60 years of age and increased during the study period. Conclusion In patients ≤ 60 years of age an increased median OS of 17 months between the two periods were noted, but the difference failed to reach statistical significance. However, a statistically significant difference in median survival of 12 months after start of second line therapy was found in this age group, which may be explained by a more active second line treatment. In patients 61–65 years only a slight increase of survival, not statistically significant, was noted between the periods.

Background Post-infectious fatigue syndrome (PIFS), also known as post-viral fatigue syndrome, is a complex condition resulting in physical, cognitive, emotional, neurological, vocational and/or role performance disabilities in varying degrees that changes over time. The needs for health care resources are high, and costly, as is the economic burden on the affected individuals. Many factors may impact the trajectory, and frequently PIFS develops into a chronic condition. Health professionals lack understanding and knowledge, which results in delayed diagnosis, lack of recognition, appropriate treatment, support and practical help. The aim of our study was to explore, from the perspective of persons who had lived with PIFS for four years following an outbreak of Giardia l. induced enteritis, factors that may have impacted their illness trajectory and how these factors had played a role during different phases. Methods In this retrospective exploratory qualitative study a group of 26 affected adults between 26 and 59 years old were selected for in-depth interviews. A maximum variation sample was recruited from a physician-diagnosed cohort of persons with PIFS enrolled at a tertiary outpatient fatigue clinic. The interviews were audio-recorded, transcribed verbatim and subjected to qualitative content analysis. Results Unhelpful and helpful factors were associated with the healthcare system, health professionals and the affected persons were experienced as having an impact on the trajectory. External impacting factors which are related to the health care system, providers and the social security system are misdiagnosis, trivialization of symptoms, unhelpful advice, delayed diagnosis and lack of appropriate help. Internal impacting factors related to the affected individuals were lack of knowledge, overestimating functional capacity, assuming the condition will pass, ignoring body signals and denial. A model of impacting factors in each phase of the trajectory is presented. Conclusion Unmet needs may result in unnecessary disability and high societal and personal costs. Enhanced knowledge of impacting factors in each phase of the trajectory may contribute to more timely and tailored health care services and less use of health services. Increased functional capacity, improved health and ability to work or study may reduce the societal costs and the economic burden for the affected individuals.

Procedural sedation/anesthesia outside the operating room for a variety of procedures is well described with an overall low adverse event rate in certain settings. Adverse event associated with procedural sedation/anesthesia outside the operating room for gastrointestinal procedures have been described, albeit in small, single-center studies with wide variance in outcomes. Predictors of such outcomes are unclear. We aimed to estimate the prevalence of adverse event in children undergoing procedural sedation/anesthesia outside the operating room for esophagogastroduodenoscopy, colonoscopy, or both to identify predictors of adverse event.Retrospective analysis of Pediatric Sedation Research Consortium database, a large data repository of pediatric patients aged 21 years old or younger undergoing procedural sedation/anesthesia outside the operating room during September 2007 to November 2011. Twenty-two of the 40 centers provided data pertaining to the procedure of interest.None.Primary outcome variable is any adverse event. Independent variables include: age (five groups), sex, American Societyof Anaesthesiologists status, procedure (esophagogastroduodenoscopy, colonoscopy, or both), provider responsible, medication used, location, and presence of coexisting medical conditions. Descriptive statistics used to summarize the data. Using multivariablelogistic regression model, odds ratio, 95% CI) were computed. A total of 12,030 procedures were performed (esophagogastroduodenoscopy, 7,970; colonoscopy, 1,378; and both, 2,682). A total of 96.9% of patients received propofol. Eighty-three percent were performed in a sedation unit. Prevalence of adverse event was 4.8%. The most common adverse event were persistent desaturations (1.5%), airway obstruction (1%), cough (0.9%), and laryngospasm (0.6%). No deaths or CPR occurred. Infants and children aged 5 years old or younger had a higher adverse event rate than older children (15.8%, 7.8% vs 4%). Regression analysis revealed age 5 years old or younger, American Society of Anaesthesiologists greater than or equal to 2, esophagogastroduodenoscopy ± colonoscopy, and coexisting medical conditions of obesity and lower airway disease were independent predictors of higher adverse event.Overall prevalence of any adverse event was 4.8%. Independent predictors of adverse events in procedural sedation/anesthesia outside the operating room in pediatric esophagogastroduodenoscopy/colonoscopy onoscopy were identified. Recognition of such risk factors may enable optimization of procedural sedation.

Stormorken syndrome is a rare autosomal-dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca(2+) depletion in the endoplasmic reticulum lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca(2+) release-activated Ca(2+) channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the coiled-coil 1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain-of-function mutation in STIM1, blood platelets from patients were in a preactivated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca(2+) levels were elevated in platelets from the patients compared with controls, and store-operated Ca(2+) entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near-maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome.

A recently described familiar syndrome consists of the following components: A bleeding tendency with thrombocytopathia, miosis, muscular weakness and spasms, ichthyosis, asplenia, dyslexia, and headache. Four definite and 2 probable patients have been identified in 4 generations. In the present study, the pupillary behaviour was scrutinized in two 'definite' cases with the infrared, binocular pupillometer. The forehead sweating pattern was also investigated with an Evaporimeter. The basal pupillary widths were: 1.25-1.75 mm. Only minor responses were noted upon topical stimulation with an indirectly acting pupillodilating agent (OH-amphetamine). A directly acting sympathicomimetic drug (phenylephrine) exerted a more marked influence on the pupil, indicating a relative supersensitivity. The evaporimetric pattern in the forehead seemed to be within reference limits, at variance with what is the case in Horner's syndrome. Further findings were: the orbit seemed to be smaller than normal; a bilateral VI. cranial nerve palsy was identified, and a marked upward gaze palsy coexisted with pupils with Argyll Robertson's traits. There is no readily acceptable explanation for the ocular abnormalities. The disorder underlying the pupillary abnormality may possibly be located in the upper mesencephalon.

A cytochemical method for studying fibrinolytic (proteolytic) activity in specified white cells in blood and bone marrow smears has been developed and the spontaneous fibrinolytic activity at pH 6.0 and 7.65 as well as the activity of a plasminogen-like proenzyme were studied. These fibrinolytic enzymes appeared in the granulocytic and monocytic series; their activity depending upon the maturation stage. The enzymes appear in promyelocytes, reach the highest activity in metamyelocytes and in band cells and then gradually decrease during maturation. No significant differences between mature neutrophils, eosinophils and basophils were observed. Megakaryocytes, erythroblasts, erythrocytes and lymphocytes were devoid of significant fibrinolytic activity. Some implications of these findings are discussed.

A study of platelet adhesiveness using platelet-rich plasma with ADP has been performed in different groups of men. Despite large day-to-day variations the method registered individual characteristics in platelet function. A seasonal variation and an increase in adhesiveness with age were found, but the method failed to show any difference between a prospective and a post-infarction group of the same age. Thus this variant for assessing platelet adhesiveness is not useful for detecting the coronary-prone patient.

Among 2014 apparently healthy men aged 40-59 years platelet function was studied with Hellem's retention method in 488 men. In 55 of these 488 men coronary heart disease (CHD) was strongly suspected and coronary angiography confirmed the diagnosis in 34 of 51 angiographied men. Platelet responsiveness was significantly lower among those who had angina pectoris than among their CHD-suspect counterparts without angina, regardless of coronary angiographic findings. Since angiopositive men without angina and 408 "normals" had similar retention values, it seems as if presenting symptoms, but not the development of CHD are linked to platelet function. During a near maximal bicycle exercise test significantly higher peak exercise blood pressure was found among men with very low retention values than among men with retention values in the middle and upper range. This could not be explained by differences in maximal heart rate or work performance. This indicates that blood pressure regulation during exercise may in part be linked to platelet function related mechanisms.

In recent years persons at risk for colorectal cancers (CRC) have been subjected to follow-up with colonoscopy in many centres. There is, however, limited knowledge about the effect of such interventions. The objective of this study was to report the results of our observations during the past 15 years.Healthy persons were included in the study according to their family history of CRCs, and prospectively followed with colonoscopies.Altogether, 1133 individuals were included and observed for a total of 3474 follow-up years from the first to the last colonoscopy initiated by our activity. Mismatch repair (MMR) mutations were detected in 6.5% of cases. A total of 1383 polyps were removed, 72% were less than 5 mm in diameter. Findings were scored as hyperplastic polyps (n=887), adenomas with mild to moderate dysplasia (n=460), adenomas with high-grade dysplasia (n=30) and cancers (n=6). Two cancers were observed after the first colonoscopy, compared with 2.6 expected by chance and more than 20 expected under the hypothesis of predominant inherited diseases in the families. Observed annual incidence rates for adenomas were similar in all groups, while in the mutation carriers there was a higher frequency of progression to severe dysplasia or infiltrating cancer.A simple explanation for the combined findings may be that all selected families had a similar tendency to produce adenomas, while mutation carriers more frequently demonstrated dysplasia/cancer in the adenomas. The low annual incidence rates for CRC indicated that the removal of adenomas may have prevented cancers.

Contains fulltext : 185698.pdf (Publisher’s version ) (Open Access) PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations. PATIENTS AND METHODS: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives. RESULTS: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant. CONCLUSION: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered.

Two-thirds of osteogenesis imperfecta (OI) patients claimed that they bruised easily. We have studied haemostasis in 58 subjects with OI, tarda type. The most frequent abnormalities were increased capillary fragility (35%), decreased platelet retention (33%) and reduced factor VIII R:Ag (23%). Reduced ristocetin cofactor, deficient platelet aggregation induced by collagen and prolonged bleeding time were less common findings. The combination of vascular, platelet related and plasmatic defects may reflect that OI is a heterogeneous group of disorders with common clinical expression. The tourniquet test is the most valuable screening test of the haemostatic defects observed in OI.

This is a case of a 3-week-old male who presented to the emergency department with intermittent apnea and cyanosis. While in the emergency department, he had respiratory compromise with stress and required intubation. Further evaluation confirmed the diagnosis of a thyroglossal duct cyst. Congenital lesions causing extrinsic airway compression should be considered in all neonates with apnea, cyanosis, and respiratory compromise. Knowledge of pediatric airway anatomy and physiology is important in all cases where obstructive apnea is suspected.

No standardized educational curriculum exists for pediatric sedation practitioners. We sought to describe the curriculum and implementation of a pediatric sedation provider course and assess learner satisfaction with the course curriculum.The course content was determined by formulating a needs assessment using published sedation guidelines, reports of sedation related adverse events, and a survey of sedation practitioners. Students provided feedback regarding satisfaction with the course immediately following the course and 6 months later.The course consisted of 5 didactic lectures, 1 small-group session, 6 simulation scenarios, a course syllabus, and a written examination. The course was conducted over 1 day at 3 different locations. Sixty-nine students completed the course and were uniformly satisfied with the course curriculum.A standardized pediatric sedation provider course was developed for sedation practitioners and consisted of a series of lectures and simulation scenarios. Overall satisfaction with the course was positive.

Lynch syndrome (LS) is characterised by the\ud development of colorectal cancer, endometrial cancer\ud and various other cancers, and is caused by a mutation\ud in one of the mismatch repair genes: MLH1, MSH2,\ud MSH6 or PMS2. In 2007, a group of European experts\ud (the Mallorca group) published guidelines for the clinical\ud management of LS. Since then substantial new\ud information has become available necessitating an\ud update of the guidelines. In 2011 and 2012 workshops\ud were organised in Palma de Mallorca. A total of 35\ud specialists from 13 countries participated in the\ud meetings. The first step was to formulate important\ud clinical questions. Then a systematic literature search\ud was performed using the Pubmed database and manual\ud searches of relevant articles. During the workshops the\ud outcome of the literature search was discussed in detail.\ud The guidelines described in this paper may be helpful for\ud the appropriate management of families with LS.\ud Prospective controlled studies should be undertaken to\ud improve further the care of these families.

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−1 was studied in an ex vivo parallel-plate perfusion chamber device. In this model, human native blood was passed over a tissue factor/phospholipid-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% (pConclusion: 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 vitro assays, it is apparent that these properties were not reflected in thrombus formation under the experimental conditions of high arterial shear.

SummaryTwelve different mutations in the WASP gene were found in twelve unrelated families with Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT). Four frameshift, one splice, one nonsense mutation, and one 18-base-pair deletion were detected in seven patients with WAS. Only missense mutations were found in five patients diagnosed as having XLT. One of the nucleotide substitutions in exon 2 (codon 86) results in an Arg to Cys replacement. Two other nucleotide substitutions in this codon, R86L and R86H, have been reported previously, both giving rise to typical WAS symptoms, indicating a mutational hot spot in this codon. The finding of mutations in the WASP gene in both WAS and XLT gives further evidence of these syndromes being allelic. The relatively small size of the WASP gene facilitates the detection of mutations and a reliable diagnosis of both carriers and affected fetuses in families with WAS or XLT.

Item does not contain fulltext Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis. 01 juli 2010

Genetic predisposition to prostate cancer includes multiple common variants with a low penetrance (single nucleotide polymorphisms) and rare variants with higher penetrance. The mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 are associated with Lynch syndrome where colon and endometrial cancers are the predominant phenotypes. The purpose of our study was to investigate whether germ-line mutations in these genes may be associated with prostate cancer. One hundred and six male carriers or obligate carriers of MMR mutations were identified. Nine had contracted prostate cancer. Immunohistochemical analysis was done on tumor tissue from eight of the nine tumors. Observed incidence, cumulative risk at 60 and 70 years of age, age of onset, and Gleason score were compared with expected as assessed from population-based series. Absence of gene product from the mutated MMR gene was found in seven of eight tumors. Expected number of prostate cancers was 1.52 compared with 9 observed (P < 0.01). Mean age of onset of prostate cancer was 60.4 years compared with 66.6 expected (P = 0.006); the number of men with a Gleason score between 8 and 10 was significantly higher than expected (P < 0.00001). Kaplan-Meier analysis suggested that cumulative risk by 70 years in MMR mutation carriers may be 30% (SE, 0.088) compared with 8.0% in the general population. This is similar to the high risk associated with BRCA2 mutations. To our knowledge, this study is the first to indicate that the MMR genes may be among the rare genetic variants that confer a high risk of prostate cancer when mutated. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2460–7)

BACKGROUND Experimental animal and clinical studies indicate that blood platelets have an important role in atherosclerosis and formation of thrombi. Prospective studies presenting evidence of an association between blood platelet count and cardiovascular mortality have not been performed. METHODS AND RESULTS From 1973 to 1975, blood platelets were counted, and their responsiveness to aggregating agents was studied in healthy middle-aged men. The aim was to assess the possible association between these variables and coronary heart disease. At 13.5 years of follow up, a significantly higher coronary heart disease mortality was observed among the 25% of subjects with the highest platelet counts. Platelet aggregation performed in a random subsample (150 of the 487 men), moreover, revealed that the 50% with the most rapid aggregation response after ADP stimulation had significantly increased coronary heart disease mortality compared with the others. These associations could not be explained by differences in age, lipids, blood pressure, or smoking habits. CONCLUSIONS The present study is the first to present conclusive, prospective evidence of an association between platelet concentration and aggregability and long-term incidence of fatal coronary heart disease in a population of apparently healthy middle-aged men.

SummaryDetailed studies on the rare disorder X-linked thrombocytopenia showed that it resembles the Wiskott-Aldrich syndrome (WAS) in inheritance, clinical bleeding tendency, platelet morphology, marked thrombocytopenia and microplatelets. The calculated platelet mass was 5% of normal. Functional and biochemical studies indicated qualitatively normal aggregation and release mechanisms, whereas a moderate storage pool defect was present. The classical platelet membrane glycoproteins and lymphocyte sialophorin (CD 43) were normal.The reason for the bleeding tendency was concluded to be deficient hemostatic plug formation resulting from the low platelet mass and a moderate storage pool defect.The only clear distinction from WAS was the normal immunofunctional tests, the moderate tendency to infections and the absence of eczema. We therefore consider the trait as an attenuated form of WAS. That women are affected may indicate a particular variant.

Item does not contain fulltext BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for

The aim of the study was to estimate the prevalence of hereditary cancers and the need for surveillance in Telemark county, Norway.All persons attending the Norwegian Colorectal Cancer Prevention (NORCCAP) trial in Telemark were interviewed about cases of cancer in the family. Diagnoses were verified, pedigrees constructed and families classified according to preset criteria aiming at identifying hereditary cancer. Mutation analyses were performed in kindreds at risk for breast cancers when possible. Immunohistochemistry of tumors in assumed inherited colorectal cancer families was undertaken.The screening examination was attended by 7,224 persons among whom 2,866 had cancer in the family. Of these, 2,479 had no suspicion of any known inherited cancer syndrome. Family information questionnaires were mailed to 387 persons and returned by 191. Sixty-four of these 191 met the clinical criteria for familial cancer by family history after verification of diagnoses. Observed prevalences for being at risk for hereditary breast and breast-ovarian cancer (HBOC) or hereditary non-polyposis colorectal cancer (HNPCC) were 2.8 per thousand and 0.77 per thousand, respectively.The number of colonoscopies and mammograms obtained per year serving those who needed them was limited and reduced by clinical genetic work-up from 2,866 with a family history of cancer to 64 proven cases. Continued surveillance of an unnecessarily high number leads to unjustified cancer worry, is costly and uses up health-care facilities. Genetic work-up is a one-time job that reduces input numbers to surveillance programs, provides a starting-point for mutation testing and is economically cost beneficial if inherited cancers are prevented or cured by the health-care programs offered.

Detailed studies of a family with a strong clustering of fibromyalgia revealed that the affected members had eight or more urinations per day and at least one per night. As this feature was not known to be an important symptom in this ailment, we carried out a questionnaire-based study.Questionnaires were mailed to a random group of 285 subjects drawn from the member list of the Norwegian Fibromyalgia Association, and to 160 healthy females, free of urinary tract pains. Response rates were 70% and 74%.The fibromyalgia group reported 8 or more daily and 1 permanent nocturnal urinations; the corresponding figures for healthy females were 6 and 0.2. This corresponds to a sensitivity and specificity for fibromyalgia of 78 and 91% for daytime urinations, and to 89% and 92% for one or more permanent nocturia.The study indicates that an abnormally high frequency of urinations is a characteristic feature in fibromyalgia and a useful diagnostic variable. It is also objectively verifiable by urodynamic investigation. The pattern is that of urge, sometimes with incontinence.

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.

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.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.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 had15% calculated probability of finding a mutation. Tumours from all seven mutation carriers lacked the immunohistochemical expression of the corresponding MMR gene.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.

In 1985, a new syndrome with the following characteristics was described: thrombopathia, thrombopenia, asplenia, miosis, headache, ichthyosis, dyslexia, muscle defect, and subsequently also hypocalcaemia. Skin and deep bleedings, leg spasms, disturbed dark vision and dyslexia are main worries. This paper describes these patients with a review of the investigations performed. Causes of the bleeding tendency are complex disturbances of the platelet membrane causing insufficient stability of the haemostatic plug, the nature of which is unresolved, but involves membrane scrambling. The muscle defect consists in tubular aggregates and high blood values of creatine kinase. A connection with the hypocalcaemia is possible, because increasing the ionic Ca with calcitriol significantly improves muscle function. Miosis is resistant to mydriatics and causes decreased dark vision, possibly also influencing dyslexia. The asplenia has little influence on immunocompetence, and the patients have survived 300 patient years without critical infections. The gene defect has not yet been unravelled.

Background: The nonionic monomer iohexol triggers in vitro platelet secretion of β-thromboglobulin (β-TG). This iohexol platelet activation may promote intravascular thrombosis. We studied this relationship by employing a human model of collagen-induced platelet thrombus formation at arterial flow. The ionic dimer ioxaglate, the nonionic dimer iodixanol, and glucose were included. Methods and Results: In vitro platelet activation as measured by β-TG secretion following a 1-min incubation of native blood with 50 vol% of iohexol was significant. Glucose solutions of 300, 580 and 825 mosmol, corresponding to the osmolalities of respectively iodixanol, ioxaglate and iohexol, increased the β-TG secretion in parallel with the osmolalities. Ioxaglate and iodixanol were virtually inert. Continuous infusion of iohexol or 580 or 825 mosmol glucose (40 vol%) into flowing native blood at an arterial wall shear rate of 2600 s−1 in an ex vivo collagen-induced platelet thrombus formation device triggered pronounced secretion of β-TG. However, the platelet thrombus formation in blood mixed with iohexol was within the same range as that observed with ioxaglate or iodixanol. Increasing glucose osmolality induced increasing β-TG secretion, which paralleled gradually decreasing platelet thrombus formation. Conclusion: Iohexol and 580 or 825 mosmol glucose trigger platelet secretion of β-TG. This secretion is not associated with enhanced collagen-induced platelet thrombus formation at high arterial shear.

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 IU/ml 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.

SummaryA missense mutation at codon 100 in the second epidermal growth factor-like domain, resulting in Gln100→Arg, was detected in 19 out of 21 available severely factor VII (FVII) deficient patients in Norway. Seventeen patients were homozygous, and the two remaining were compound heterozygotes. In the homozygous patients, FVII antigen was measured to 10-28%, and activity to 0.6-6.5% of that in normal pooled plasma. Recombinant FVII containing the mutation was expressed transiently in CHO cells to a mean antigen level of 57% of the wild type FVII protein, and with a specific activity of 6% of wild type. The mutant protein had a 14-fold reduction in affinity for tissue factor (TF), whereas binding of FX seemed unaffected. In line with the experimental data, molecular modelling of the mutation based on the coordinates of the tissue factor/FVIIa complex showed that substituting arginine for glutamine disrupts the interface between the catalytic and second epidermal growth factor-like domains.

The Stormorken syndrome is a multifacetted syndrome including a bleeding tendency. No deviations were found in the coagulation- or fibrinolytic systems. Platelet number was low normal, and size abnormal, whereas EM findings were unremarkable. Survival time was half normal. Clot retraction was initially rapid, but clearly decreased, whereas prothrombin consumption was also initially rapid, but complete. Membrane GP's were normal, so was AA metabolism, PI-cycle, granule storage and secretion, and c-AMP function, whereas 5-HT uptake and storage was decreased. Optical platelet aggregation was low normal with all physiological agonists. The only clearly abnormal finding was that coagulant activity was present on non stimulated platelets at the same level as kaolin-stimulated normal platelets. This indicated a platelet abnormality which should lead to a thrombogenic, not to a haemorrhagic trait. This paradox may have its origin in rheology, because when challenged with in vivo shear rates in an ex vivo perfusion chamber, platelet cohesion was abnormally low. Further studies to better delineate the membrane abnormality are underway.

We have studied the possible influence of season of birth on prevalence of fibromyalgia. Data from the Norwegian Fibromyalgia Association, where diagnosis is compulsory, were compared with mean figures for 1936-65 from the National Register of Births. Figures for 8,125 patients were correlated with figures for two million persons from the register. Unlike other musculoskeletal diseases, which are more prevalent in summerborn persons, and certain mental diseases, which are more prevalent in winterborn persons, no such association was found for fibromyalgia.

Objectives. The main purpose of the study was to assess a possible association between haematocrit (Hct) and long-term cardiovascular disease (CVD) mortality. Design. An extensive examination programme was carried out in 2014 men, defined as apparently healthy, during the period 1972 to 1975, including Hct measurements in a 25% random subsample. Sequential, cause-specific mortality was followed prospectively over a period of 16 years. Setting. The survey was conducted at Medical Department B, Rikshospitalet, Oslo, Norway. Subjects. The participants represented 86% of all eligible apparently healthy men working in five preselected companies in Oslo. Interventions. No intervention was given by the study group during follow-up. Main outcome measures. Complete, cause-specific mortality figures after 8–16 years were obtained from the Norwegian Central Bureau of Statistics. Results. Hct measures were obtained in 488 men (24.2%). Mean Hct was 47.2% (sd 2.9%). After correcting for differences in age, plasma cholesterol, systolic blood pressure, erythrocyte sedimentation rate and smoking habits (Cox proportional hazards model), an increase in Hct by 2 SDS was associated with an increase in CVD mortality by a factor ranging between 2.9 at 10, and 1.9 at 16 years (P < 0.05). A similar increased risk was observed earlier during follow-up but the number of deaths was too small for meaningful statistical analysis. No association was found between Hct and non-CVD mortality. Conclusions. Our data show that increased Hct is associated with an increased risk of dying from CVD—independent of conventional CVD risk factors.

(1992). Fibromyalgia: Family Clustering and Sensory Urgency with Early Onset Indicate Genetic Predisposition and Thus a “True” Disease. Scandinavian Journal of Rheumatology: Vol. 21, No. 4, pp. 207-207.

SummaryIn a prospective study on latent coronary heart disease (CHD) in 2,014 presumably healthy men aged 40–59 years, 115 had strong clinical evidence of CHD never diagnosed nor suspected prior to the survey. Coronary angiography was performed in 105 of these. In 80 of them – whereof 57 were angiopositive and 23 angionegative – AT III and factor VIII Ag were assayed as well as in 35 normals from the same material. The results showed that:1. AT III was significantly lower in the angiopositive than in the normal controls.2. Subdivision of the angiopositive into those with and those without angina pectoris revealed significantly lower level of AT III in the former.3. Within blood group A only did the angiopositive subjects have significantly lower AT III than the remaining subjects in the group, and this was entirely due to the low values in those with angina pectoris.4. Blood group 0 individuals had significantly lower factor VIII Ag level than all other blood groups.The significance of these findings for the possible relation to development of atheromatosis is briefly discussed.

In 10 children with Politano and Leadbetter's antireflux operation, tranexamic acid reduced the blood loss, especially postoperatively. In three patients renewed bleeding occurred when the treatment stopped. Antifibrinolytic treatment probably reduced the need for blood transfusions in these operations. In six children, however, large clots were passed with the urine from the fourth to the ninth day postoperatively, probably due to inhibition of the advantageous clot lysis.

Sufficient increase in plasma of factor VIII activities with a view to carrying out surgery in mild and moderate Haemophilia A and von Willebrand's disease was achieved by intravenous infusion of 1-desamino-8-D-arginine vasopressin (DDAVP). 15 patients were treated with success and three patients had to be transfused with factor VIII concentrates to control postoperative hemorrhage. DDAVP therapy makes transfusion unnecessary in selected patients. This is an important therapeutic advance as long as the use of blood products does involve danger of infecting the recipient. Another advantage is that DDAVP therapy is much cheaper than factor VIII concentrate.

Adverse reactions to intravascular contrast media are well documented (Andrews, 1974; Ansell, 1976; Lalli, 1980; Shehadi & Toniolo, 1980). However, allergic and toxic reactions to drugs have to be differentiated from adverse reactions to the procedure. To illustrate this, we report the following. In a Phase I tolerance and pharmacokinetic study, iopentol (Nycomed AS), a new 3.0 non-ionic contrast medium, was to be injected into 24 healthy male volunteers (Aakhus et al, 1987). As part of the study, eight subjects received normal saline intravenously. One of the volunteers was a 30-year-old healthy male. On the trial day, approximately 30 s after the start of the injection of normal saline into his left cubital vein, an adverse reaction occurred (Table I). The subject became pale and dizzy. Three minutes after venepuncture, the blood pressure had fallen to 69/45 mm Hg and the electrocardiogram (ECG) showed absence of the P-wave. The heart rate dropped slightly and the pulse was weak. The condition gradually...

The effects of iohexol, a new non-ionic contrast medium, after intravenous injection into humans are reported. After injection of small doses into 2 subjects, iohexol was injected intravenously into 20 healthy male volunteers in doses of 125 to 500 mg I/kg body weight. A large number of physiologic, biochemical, hematologic and pharmacokinetic parameters were analysed. The results indicated that iohexol was well tolerated and that clinical trials in patients could be undertaken.