[Prevention of young people's suicide: strengthen resilience and focus on mental health problems]. / Suïcidepreventie bij jongeren.

It is highly tragic when a young person commits suicide. Van Vuuren et al. show trends among self-reported suicidal thoughts and suicidal attempts among over 25.000 Amsterdam children, aged 13 and 14, of different educational levels and ethnic backgrounds, between 2010 and 2015. They advise policy makers to base their choice of suicide prevention measures on the information about trends. In this commentary, we state that policy makers should refrain from doing so, because of the unclear relation between highly prevalent self-reported suicidal thoughts and attempts and extremely rare actual suicide, because of negligence of cultural aspects of suicide in handling the evidence and because trends based on data from 2010-2015 are useless when devising policies in the midst of the covid-19 crisis. We advise policy makers to focus on strengthening young people's resilience and on the prevention of mental health problems instead.

Impact of overweight on effectiveness of treatment with human growth hormone in growth hormone deficient children: analysis of German KIGS data.

BACKGROUND: We hypothesized that overweight children with growth hormone deficiency (GHD) demonstrate a lower response to growth hormone (GH) as a result of a misclassification since obesity is associated with lower GH peaks in stimulation tests. METHODS: Anthropometric data, response, and responsiveness to GH in the first year of treatment were compared in 1.712 prepubertal children with GHD from the German KIGS database according to BMI (underweight=group A, normal weight=group B, overweight=group C) (median age: group A, B, C: 7.3, 7.28, and 8.4 years). RESULTS: Maximum GH levels to tests (median: group A, B, C: 5.8, 5.8, and 4.0 µg/ml) were significantly lower in group C. IGF-I SDS levels were not different between the groups. Growth velocity in the first year of GH treatment was significantly lower in the underweight cohort (median: group A, B, C: 8.2, 8.8, and 9.0 cm/yr), while the gain in height was not different between groups. The difference between observed and predicted growth velocity expressed as Studentized residuals was not significantly different between groups. Separating the 164 overweight children into obese children (BMI>97th centile; n=71) and moderate overweight children (BMI>90th to 97th centile, n=93) demonstrated no significant difference in any parameter. CONCLUSIONS: Overweight prepubertal children with idiopathic GHD demonstrated similar levels of responsiveness to GH treatment compared to normal weight children. Furthermore, the IGF-I levels were low in overweight children. Therefore, a misclassification of GHD in overweight prepubertal children within the KIGS database seems unlikely. The first year growth prediction models can be applied to overweight and obese GHD children.

Increased plasma aldosterone during atrial fibrillation declines following cardioversion.

OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) may be activated during atrial fibrillation (AF); our aim was to evaluate the level of aldosterone in patients with either permanent AF, persistent AF scheduled for cardioversion or patients in sinus rhythm (SR). We hypothesized that an increased level of aldosterone is found in patients with AF, decreasing in patients with restored SR. METHODS: The study included 60 patients with persistent AF scheduled for elective cardioversion, 19 patients with permanent AF, and a control group of 19 healthy individuals. All patients were examined and their aldosterone levels were measured. Measurement of aldosterone was repeated at follow-up 1, 30 and 180 days after successful cardioversion was achieved. Statistical analysis was conducted using the Kruskal-Wallis rank sum test and the paired t test. RESULTS: At follow-up, 1, 30, and 180 days after successful cardioversion of the patients with persistent AF, data showed that 49, 27, and 21 patients, respectively, were still in SR. At baseline, median values of plasma aldosterone in the healthy controls, the patients with persistent AF and those with permanent AF were 52, 68, and 80 pg/ml, respectively. The log aldosterone in patients with persistent AF was significantly increased when compared to the control group (p = 0.026). No effect of age and gender was observed. The level of aldosterone decreased over time in patients with AF undergoing cardioversion and maintaining SR, both at a follow-up of 30 days (p = 0.0032) and 180 days (p = 0.037). CONCLUSIONS: Patients with AF had a raised aldosterone level compared to the healthy control individuals. Restoration and maintenance of SR in patients with persistent AF significantly lowered the level of aldosterone up to 180 days after cardioversion, indicating activation of RAAS during AF.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

The utility of focus group interviews to capture dietary consumption data in the distant past: dairy consumption in Kazakhstan villages 50 years ago.

From 1949 to 1962, residents of several villages in Kazakhstan received substantial doses of radiation to the thyroid gland resulting from nuclear tests conducted at the Semipalatinsk Nuclear Test Site. The primary source of radiation was internal from an intake of radioactive iodine by consumption of contaminated dairy products. A previous research study of childhood exposure and thyroid disease in this region gathered limited data on study participants' dairy intake at the time of the fallout for the purpose of estimating past radiation doses. As many participants were too young at the time of the nuclear tests to recall dietary consumption and existing sources of archival data are limited, it was necessary to interview parents and other village residents who cared for children during this time - older adults ranging in age from 75 to 90 years. Results from 11 focus group interviews conducted in 2007 with 82 women from 4 villages in Kazakhstan yielded group-level estimates of age-, gender-, ethnicity- and village-specific dairy consumption patterns in rural Kazakhstan during the 1950s. Children typically consumed cow's milk with limited consumption of mare, goat and sheep milk; and consumed dairy products such as sour milk (airan), soft cottage cheese (tvorog) and fermented mare milk (koumiss) with the greatest amounts of koumiss reported at ages 15-21 years. The consumption patterns differed by age, and between Kazakh and Russian children, which should lead to different estimates of radiation exposure to the thyroid. This study showed the utility of focus groups to obtain quantitative estimates for dietary intake in the distant past.

Radiation dose to the brain and subsequent risk of developing brain tumors in pediatric patients undergoing interventional neuroradiology procedures.

Radiation dose to the brain and subsequent lifetime risk of diagnosis of radiation-related brain tumors were estimated for pediatric patients undergoing intracranial embolization. Average dose to the whole brain was calculated using dosimetric data from the Radiation Doses in Interventional Radiology Study for 49 pediatric patients who underwent neuroradiological procedures, and lifetime risk of developing radiation-related brain tumors was estimated using published algorithms based on A-bomb survivor data. The distribution of absorbed dose within the brain can vary significantly depending on field size and movement during procedures. Depending on the exposure conditions and age of the patient, organ-averaged brain dose was estimated to vary from 6 to 1600 mGy. The lifetime risk of brain tumor diagnosis was estimated to be increased over the normal background rates (57 cases per 10,000) by 3 to 40% depending on the dose received, age at exposure, and gender. While significant uncertainties are associated with these estimates, we have quantified the range of possible dose and propagated the uncertainty to derive a credible range of estimated lifetime risk for each subject. Collimation and limiting fluoroscopy time and dose rate are the most effective means to minimize dose and risk of future induction of radiation-related tumors.

Ultrasound-detected thyroid nodule prevalence and radiation dose from fallout.

Settlements near the Semipalatinsk Test Site (SNTS) in northeastern Kazakhstan were exposed to radioactive fallout during 1949-1962. Thyroid disease prevalence among 2994 residents of eight villages was ascertained by ultrasound screening. Malignancy was determined by cytopathology. Individual thyroid doses from external and internal radiation sources were reconstructed from fallout deposition patterns, residential histories and diet, including childhood milk consumption. Point estimates of individual external and internal dose averaged 0.04 Gy (range 0-0.65) and 0.31 Gy (0-9.6), respectively, with a Pearson correlation coefficient of 0.46. Ultrasound-detected thyroid nodule prevalence was 18% and 39% among males and females, respectively. It was significantly and independently associated with both external and internal dose, the main study finding. The estimated relative biological effectiveness of internal compared to external radiation dose was 0.33, with 95% confidence bounds of 0.09-3.11. Prevalence of papillary cancer was 0.9% and was not significantly associated with radiation dose. In terms of excess relative risk per unit dose, our dose-response findings for nodule prevalence are comparable to those from populations exposed to medical X rays and to acute radiation from the Hiroshima and Nagasaki atomic bombings.

[Bisphosphonate therapy for children and adolescents with primary and secondary osteoporotic diseases]. / Bisphosphonat-Therapie bei Kindern und Jugendlichen mit primären und sekundären osteoporotischen Erkrankungen.

Bisphosphonates have a set place in the treatment of osteoporosis in adults. For the last 10 years they have also been used in pediatrics. Due to inhibition in differentiation and reduction in osteoclasts, both pamidronate and alendronate, the most commonly used preparations, cause an increase in bone density. Most experience comes from the i.v. treatment of forms with severe courses of osteogenesis imperfecta (OI). There is an increase in bone substance, a decrease in rate of fractures and a reduction in pain with higher mobility of those effected. In addition to the use of drugs, intramedullary nailing and physiotherapy are important therapeutic standards. Bisphosphonates are also used for other diseases involving bone remodeling, such as juvenile idiopathic osteoporosis or familial hyperphosphatemia. Acute side effects usually occur with the first infusion, involve "flu-like" symptoms and are self limiting. The question of long-term side effects cannot be answered with the currently available data.

The muscle-bone unit in adulthood: influence of sex, height, age and gynecological history on the bone mineral content and muscle cross-sectional area.

Bone and muscle development are both strongly influenced by sex hormones. The purpose of this study was to examine the changes in bone and muscle parameters (bone mineral content - BMC, muscle cross-sectional area - MA) in 130 men aged 31 -60 years, and in 180 pre-menopausal women aged 30-53 years with respect to age, body height and, with the women, their gynecological history (age-at-menarche, number of pregnancies, duration of lactation and use of oral contraception). The study was performed using peripheral quantitative computed tomography (pQCT) at a 65% site of the forearm length. Both BMC and MA were dependent on body height (p<0.0001), but not on age. The BMC/MA ratio was dependent neither on age nor on body height in both genders. MA as well as BMC were found significantly higher in males than in females (p<0.0001 for both variables). We observed a significantly higher BMC/MA ratio in females than in males (p<0.0001). We found no effect either of the analyzed variables of gynecological history on bone/muscle characteristics. The findings highlight the necessity of involving height-adjusted parameters and BMC/MA ratio into bone analysis in adults.

Seasonality of growth response to GH therapy in prepubertal children with idiopathic growth hormone deficiency.

OBJECTIVE: Longitudinal growth of children exhibits seasonal variation. In both healthy children and in children with growth hormone (GH) deficiency (GHD) receiving GH therapy, growth rate is maximal during spring and summer. In the present study, we analyzed the growth response to GH therapy in children with GHD as a function of the season when therapy was started. SUBJECTS AND METHODS: Anthropometric measurements and biochemical analyses of GH secretion status and bone formation were longitudinally assessed in a cohort of 52 prepubertal children with GHD (14 girls, mean age 7.6 years) who were treated with a fixed dose of GH (0.025 mg/kg/day). RESULTS: Auxological assessments over the 2-year observation period revealed a significantly better growth response to GH therapy in children who started therapy between the spring and summer (group 1) compared with children who started in the autumn or winter (group 2). The difference was largest in the initial 3-month treatment period (35%; P<0.01). The initial better gain in height of group 1 was sustained during the study period. Baseline peak GH levels during stimulation tests and insuin-like growth factor-I levels did not differ between the two groups. However, group 1 had significantly higher bone resorption and formation markers, either at the start or shortly after initiation of GH treatment. This suggests that children with GHD have higher bone turnover during spring and early summer, irrespective of GH therapy. CONCLUSIONS: In summary, this study suggests that the season of GH initiation is a determinant of the initial growth response to GH replacement in prepubertal children with GHD.

The bone mass concept: problems in short stature.

Bone densitometry is currently one of the mainstays in the evaluation of systemic bone diseases in adults and is also increasingly used to assess primary or secondary bone disorders in children and adolescents. The purpose of carrying out densitometric studies in such circumstances is to measure the densitometric indicators of bone stability. Following procedures which were established for diagnosing adult osteoporosis, a decrease in densitometric surrogates of bone stability is usually interpreted as indicating increased fracture risk. The most basic densitometric parameter is bone mineral content (BMC), which can be measured with most densitometric techniques. BMC is either defined as the mass of mineral contained in an entire bone or as the mass of mineral per unit bone length. While mineral mass can be expected to be a good surrogate for bone stability, BMC is obviously a size-dependent parameter, since small bones weigh less than big bones. This is a drawback in paediatric use, since many children and adolescents who are examined by densitometry suffer from chronic disorders and are small-for-age. Short children will have a lower BMC than their healthy age-matched peers, even if their (smaller) bones are otherwise completely normal.

[No convincing evidence for a causal relationship between childhood nasopharyngeal radium irradiation and head-neck tumors or hormone-related disorders later in life; a retrospective cohort study]. / Geen overtuigend bewijs voor een causaal verband tussen nasofaryngeale radiumbestraling op de kinderleeftijd en latere hoofd-halstumoren en hormonale aandoeningen; een historisch cohortonderzoek.

OBJECTIVE: To study the risk of malignant and benign tumours and hormone-related disorders among patients treated with nasopharyngeal radium irradiation for hypertrophic adenoid or hearing loss caused by otitis media serosa. DESIGN: Retrospective cohort study. METHOD: The medical record registries of 9 hospitals were used to identify a radium-exposed group (n = 5358) and a control group of unexposed patients (n = 5265), who were treated by an otolaryngologist in the period 1945-1981. The vital status of the subjects was determined using municipal resident registries, and the cause of death of decedents was retrieved from Statistics Netherlands (1950-1997). The data was also coupled with the Netherlands Cancer Registry (1989-1996). For the subjects still alive in 1997, the prevalence of relevant disorders was determined using a self-administered questionnaire and disorders reported by the participants were medically verified. The risk of disease in the radium group was then compared with that of the control group. RESULTS: The average radiation doses were 2.75, 0.109 and 0.015 Gy for nasopharynx, pituitary, and thyroid, respectively. There was no statistically significantly elevated risk for malignancies of the head and neck area (radium-exposed group; n = 14; control group: n = 11 (relative risk (RR): 1.2; 95% CI: 0.6-2.8)). Four of the five thyroid carcinomas were found in the radium-exposed group (RR: 3.8; 0.5-76). Elevated risks were observed for breast cancer (RR: 1.6; 0.9-2.7) and non-Hodgkin's lymphoma (RR: 2.7; 1.0-8.7). There was an increased risk for skin basal cell carcinoma (BCC) of the head and neck (odds ratio (OR): 2.6; 1.0-6.7), but the risk of BCC of other body parts was lower (OR: 0.3; 0.1-1.3). There were no major differences between radium and control subjects with respect to benign head and neck tumours (OR: 1.0; 0.5-1.7) or hormonal disorders. Exposed men reported slightly more fertility disorders than men in the control group (OR: 1.4; 1.0-2.1), but there was no clear dose-response relationship. CONCLUSION: After a mean follow-up of 31 years, there was no strong evidence for an elevated risk of head and neck tumours or hormone-related disorders in adulthood among subjects who had been treated with nasopharyngeal radium irradiation during childhood.

Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Ionization energy reductions in small 2,5-dihydroxybenzoic acid-proline clusters.

The photoionization of (pro)(n)DHB (pro = proline, DHB = 2,5-dihydroxybenzoic acid, n = 0, 1, 2 or 4) clusters was studied both experimentally and computationally. Experimentally the (pro)(n)DHB clusters are generated in the gas phase by laser desorption and supersonic jet entrainment. The photoionization thresholds are then determined by the mass-selective measurement of both one- and two-color photoionization efficiency curves. These experiments demonstrate that the ionization energies (IEs) of the (pro)(n)DHB clusters are substantially reduced in comparison with the IE of free DHB. Computational studies of the (pro)(n)DHB clusters provide insights into the mechanism of IE reduction. For the (pro)DHB system the IE reduction results from spin delocalization in the ion state of the cluster. In contrast, for the (pro)(2)DHB and (pro)(4)DHB clusters the IE reduction results from an inductive delocalization of electron density from pro to DHB in the ground state of the cluster. This latter effect, which is a result of the specific hydrogen-bonding interactions occurring in the mixed clusters, leads to IE reductions of >1 eV. Finally, determination of the energetics of the (pro)(2)DHB radical cation demonstrate that the DHB-to-proline proton transfer reaction is a barrierless, exoergic process in the ion state and that energetic demands for cluster dissociation to protonated (pro)(2) plus a deprotonated DHB radical are substantially lower than those for cluster dissociation to (pro)(2) plus DHB(+*). Cumulatively, these studies provide new energetic and mechanistic insights into both primary and secondary MALDI ionization processes.

Coagulation testing in pediatric blunt trauma patients.

OBJECTIVES: To determine the prevalence of abnormal coagulation studies and to identify variables associated with markedly elevated coagulation studies in children with blunt trauma. METHODS: We reviewed the medical records of all patients < 15 years old hospitalized at a Level 1 trauma center for either blunt head or torso trauma over a 4-year period. Data from each patient's emergency department (ED) presentation were abstracted. ED coagulation studies were defined prior to data analysis as elevated if the international normalized ratio (INR) was > or =1.2 or partial thromboplastin time (PTT) was > or =33.0 seconds and markedly elevated if the INR was > or =1.5 or PTT was > or =40 seconds. Variables associated with markedly elevated coagulation studies in a univariate analysis (P < 0.05) were entered into a backward elimination logistic regression analysis to identify variables independently associated with markedly elevated coagulation studies. RESULTS: A total of 1082 patients' records were reviewed, and the 830 (77%) patients with coagulation studies obtained composed the study population. Elevated coagulation studies were detected in 232 (28%) patients, and 49 (6%) of these were found to be markedly elevated. In the multivariate analysis, a GCS < or =13 (odds ratio [OR] 8.7, 95% confidence interval [CI] 4.3, 17.7), low systolic blood pressure (OR 4.0, 95% CI 1.6, 9.9), open/multiple bony fractures (OR 2.9, 95% CI 1.4, 6.2), and major tissue wounds (OR 2.8, 95% CI 1.4, 5.6) were independently associated with markedly elevated coagulation studies. CONCLUSION: Hospitalized pediatric blunt trauma patients frequently have minor elevations in ED coagulation studies. Marked elevations occur infrequently and are independently associated with a GCS < or =13, low systolic blood pressure, open/multiple bony fractures, and major tissue wounds.

A pooled analysis of case-control studies of thyroid cancer. VI. Fish and shellfish consumption.

OBJECTIVE: To better understand the role of fish and shellfish on thyroid cancer risk, we systematically re-analyzed the original data from 13 case-control studies conducted in the US, Japan, China, and Europe. METHODS: A total of 2497 cases (2023 women, 474 men) and 4337 controls (3268 women, 1069 men) were considered. Odds ratio (OR) and corresponding 95% confidence interval (CI) were estimated for each study by logistic regression models, conditioned on age and sex, and adjusted for history of goiter, thyroid nodules or adenomas, and radiation. Combined ORs were computed as the weighted average of the estimates from each study. RESULTS: The ORs for the highest level of total fish consumption (three or more times per week) as compared to the lowest one (less than once per week) was above unity in Hawaii, Connecticut, Japan, Norway, Tromsø, and Vaud. Conversely, the ORs for the studies in Los Angeles. Shanghai, southeastern Sweden, Uppsala, northern Sweden, northern Italy, and Athens were below one. The pattern of risk for salt water fish and shellfish was not substantially different from that of total fish. Fish was not associated with thyroid cancer risk in all studies combined (OR = 0.99, 95% CI 0.85-1.2 for moderate, and OR=0.88, 95% CI 0.71-1.1 for high total fish consumption), but there was a suggestion of a protective effect in endemic goiter areas (OR = 0.65, 95% CI 0.48-0.88). CONCLUSION: This combined analysis indicates that relatively elevated fish consumption does not appreciably increase thyroid cancer risk, and may have a favorable influence in areas where iodine deficiency is, or was, common.

Cancer mortality after nasopharyngeal radium irradiation in the Netherlands: a cohort study.

BACKGROUND: Nasopharyngeal radium irradiation (NRI) was used widely from 1940 through 1970 to treat otitis serosa in children and barotrauma in airmen and submariners. We assessed whether NRI-exposed individuals were at higher risk for cancer-related deaths than were nonexposed individuals. METHODS: We conducted a retrospective cohort study of all-cause and cancer-related mortality in 5358 NRI-exposed subjects and in 5265 frequency-matched nonexposed subjects, who as children were treated at nine ear, nose, and throat clinics in The Netherlands from 1945 through 1981. We recorded personal and medical data from original patient medical records and assessed vital status through follow-up at municipal population registries. Risk of mortality was evaluated by standardized mortality ratios (SMRs). All statistical tests were two-sided. RESULTS: The average radiation doses were 275, 10.9, 1.8, and 1.5 cGy for the nasopharynx, pituitary, brain, and thyroid, respectively. The median follow-up was 31.6 years. Three hundred two NRI-exposed subjects had died, with 269.2 deaths expected (SMR = 1.1; 95% confidence interval [CI] = 1.0 to 1.3); among nonexposed subjects, 315 died, with 283.5 deaths expected (SMR = 1.1; 95% CI = 0.99 to 1.2). Cancer-related deaths of 96 exposed subjects (SMR = 1.2; 95% CI = 0.95 to 1.4) and 87 nonexposed subjects (SMR = 1.0; 95% CI = 0.8 to 1.3) were documented. There were no excess deaths from cancers of the head and neck area among exposed subjects. However, there were excess deaths from cancers of lymphoproliferative and hematopoietic origin (SMR = 1.9; 95% CI = 1.1 to 3.0), mainly from non-Hodgkin's lymphoma (SMR = 2.6; 95% CI = 1.0 to 5.3). We found no evidence that breast cancer deaths were less than expected (SMR = 1.7; 95% CI = 0.9 to 2.8) in contrast to an earlier study. CONCLUSIONS: Our findings do not indicate an increased cancer mortality risk in a population exposed to NRI in childhood. More prolonged follow-up of this and other NRI cohorts is recommended.

Mortality after cerebral angiography with or without radioactive Thorotrast: an international cohort of 3,143 two-year survivors.

There are few studies on the long-term sequelae of radionuclides ingested or injected into the human body. Patients exposed to radioactive Thorotrast in the 1930s through the early 1950s provide a singular opportunity, since the administration of this radiographic contrast agent resulted in continuous exposure to alpha particles throughout life at a low dose rate. We evaluated cause-specific mortality among an international cohort of 3,143 patients injected during cerebral angiography with either Thorotrast (n = 1,736) or a similar but nonradioactive agent (n = 1,407) and who survived 2 or more years. Standardized mortality ratios (SMRs) for Thorotrast and comparison patients were calculated, and relative risks (RR), adjusted for population, age and sex, were obtained by multivariate statistical modeling. Most patients were followed until death, with only 94 (5.4%) of the Thorotrast patients known to be alive at the closure of the study. All-cause mortality (n = 1,599 deaths) was significantly elevated among Thorotrast subjects [RR 1.7; 95% confidence interval (CI) 1.5-1.8]. Significantly increased relative risks were found for several categories, including cancer (RR 2.8), benign and unspecified tumors (RR 1.5), benign blood diseases (RR 7.1), and benign liver disorders (RR 6.5). Nonsignificant increases were seen for respiratory disease (RR 1.4) and other types of digestive disease (RR 1.6). The relative risk due to all causes increased steadily after angiography to reach a threefold RR at 40 or more years (P < 0.001). Excess cancer deaths were observed for each decade after Thorotrast injection, even after 50 years (SMR 8.6; P < 0.05). Increasing cumulative dose of radiation was directly associated with death due to all causes combined, cancer, respiratory disease, benign liver disease, and other types of digestive disease. Our study confirms the relationship between Thorotrast and increased mortality due to cancer, benign liver disease, and benign hematological disease, and suggests a possible relationship with respiratory disorders and other types of digestive disease. The cumulative excess risk of cancer death remained high up to 50 years after injection with >20 ml Thorotrast and approached 50%.