Conditions associated with extreme hyperferritinaemia (>3000 µg/L) in adults.

BACKGROUND: The clinical significance of extreme hyperferritinaemia has come under scrutiny with the increasing recognition of haemophagocytic lymphohistiocytosis (HLH) in adults. Most studies of hyperferritinaemia have focused on serum ferritin greater than 1000 µg/L, often in ambulatory patients. The conditions associated with more extreme hyperferritinaemia are poorly understood. AIMS: To examine conditions associated with extreme hyperferritinaemia greater than 3000 µg/L in acutely ill adults at a quaternary care hospital. METHODS: Patients with serum ferritin greater than 3000 µg/L at Vancouver General Hospital between 1 August 2011 and 1 August 2012 were identified. Those over 18 years of age and with clinical data available were included in the study. RESULTS: Eighty-three subjects were identified. Twenty-one cases (25%) were due to transfusional iron overload, 16 (19%) due to liver disease and 15 (18%) due to mixed factors. Haemophagocytic lymphohistiocytosis (HLH) was diagnosed in six of 83 patients (7%) with ferritin greater than 3000 µg/L, but six of eight patients (75%) with ferritin greater than 20 000 µg/L. CONCLUSIONS: Extreme hyperferritinaemia greater than 3000 µg/L is uncommon in adult patients. The highest serum ferritin values are seen in HLH, but the differential diagnosis for serum ferritin greater than 3000 µg/L remains broad with iron overload and liver disease being the most common causes.

Hutchinson Smoking Prevention Project: long-term randomized trial in school-based tobacco use prevention--results on smoking.

BACKGROUND: No long-term impact has yet been observed with the use of the social-influences approach to school-based smoking prevention for youth. However, whether this lack of impact is due to methodologic problems with the studies or to the failure of the interventions is unclear. The Hutchinson Smoking Prevention Project (HSPP), conducted from September 1984 through August 1999, aimed to attain the most rigorous randomized trial possible to determine the long-term impact of a theory-based, social-influences, grade 3-12 intervention on smoking prevalence among youth. METHODS: Forty Washington school districts were randomly assigned to the intervention or to the control condition. Study participants were children enrolled in two consecutive 3rd grades in the 40 districts (n = 8388); they were followed to 2 years after high school. The trial achieved high implementation fidelity and 94% follow-up. Data were analyzed with the use of group-permutation methods, and all statistical tests were two-sided. RESULTS: No significant difference in prevalence of daily smoking was found between students in the control and experimental districts, either at grade 12 (difference [Delta] = 0.2%, 95% confidence interval [CI] = -4.6% to 4.4%, and P =.91 for girls; Delta = 0.3%, 95% CI = -5.0% to 5.5%, and P =.89 for boys) or at 2 years after high school (Delta = -1.4%, 95% CI = -5.0% to 1.6%, and P =.38 for girls; Delta = 2.6%, 95% CI = -2.5% to 7.7%, and P =.30 for boys). Moreover, no intervention impact was observed for other smoking outcomes, such as extent of current smoking or cumulative amount smoked, or in subgroups that differ in a priori specified variables, such as family risk for smoking. CONCLUSION: The rigor of the HSPP trial suggests high credence for the intervention impact results. Consistent with previous trials, there is no evidence from this trial that a school-based social-influences approach is effective in the long-term deterrence of smoking among youth.

Acute fructose administration improves oral glucose tolerance in adults with type 2 diabetes.

OBJECTIVE: In normal adults, a small (catalytic) dose of fructose administered with glucose decreases the glycemic response to a glucose load, especially in those with the poorest glucose tolerance. We hypothesized that an acute catalytic dose of fructose would also improve glucose tolerance in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Five adults with type 2 diabetes underwent an oral glucose tolerance test (OGTT) on two separate occasions, at least 1 week apart. Each OGTT consisted of 75 g glucose with or without the addition of 7.5 g fructose (OGTT + F or OGTT - F), in random order. Arterialized blood samples were collected from a heated dorsal hand vein twice before ingestion of the carbohydrate and every 15 min for 3 h afterward. RESULTS: The area under the curve (AUC) of the plasma glucose response was reduced by fructose administration in all subjects; the mean AUC during the OGTT + F was 14% less than that during the OGTT - F (P < 0.05). The insulin AUC was decreased 21% with fructose administration (P = 0.2). Plasma glucagon concentrations declined similarly during OGTT - F and OGTT + F. The incremental AUC of the blood lactate response during the OGTT - F was approximately 50% of that observed during the OGTT + F (P < 0.05). Neither nonesterified fatty acid nor triglyceride concentrations differed between the two OGTTs. CONCLUSIONS: Low-dose fructose improves the glycemic response to an oral glucose load in adults with type 2 diabetes, and this effect is not a result of stimulation of insulin secretion.

Altered in vivo and in vitro behavior of butanol-modified bone marrow cells.

Cell-surface molecules, particularly glycoconjugates, appear to be involved in the in vivo homing of hematopoietic stem and progenitor cells and in their interactions with hematopoietic stromal cells. To study the role of cell-surface molecules of hematopoietic stem cells, the expression of some surface molecules was altered using n-butanol treatment. We examined the in vivo and in vitro colony-forming abilities, in vivo homing patterns, and cell-surface lectin receptor expression of butanol-treated bone marrow cells (BMC) from BDF1 mice. The butanol-treated/-modified BMC formed an increased number of significantly larger spleen colonies (CFU-S) in lethally irradiated (1050 rad) mice. The butanol-treated BM formed significantly larger in vitro granulocyte-macrophage progenitor cell colonies (CFU-C) and in vitro fibroblastic colonies (CFU-F), although the number of such colonies was not significantly altered. The homing pattern of butanol-treated BMC was studied by comparing the distribution in lethally irradiated mice of intravenously injected 51Cr-labeled butanol-treated BMC with that of untreated cells. The butanol treatment altered the in vivo homing pattern of these cells, with increased homing to liver, spleen, and bone marrow and decreased homing to thymus, lung, and mesenteric lymph nodes. Flow-cytometric analyses of butanol-treated BMC showed an increased expression of receptors for the lectins concanavalin A (conA) and wheat germ agglutinin (WGA), indicating an increased expression of mannosyl and galactosyl residues, which are known sugar moieties in hematopoietic stem/progenitor cell homing. These results indicate that cell surface modifications can influence homing and growth of transplanted BMC and that butanol treatment is a useful tool for studying the mechanisms of hematopoietic stem/progenitor cell homing in vivo and for further characterizing the molecules involved in this process.

Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults.

In animal models, a small (catalytic) dose of fructose administered with glucose decreases the glycemic response to the glucose load. Therefore, we examined the effect of fructose on glucose tolerance in 11 healthy human volunteers (5 men and 6 women). Each subject underwent an oral glucose tolerance test (OGTT) on 2 separate occasions, at least 1 week apart. Each OGTT consisted of 75 g glucose with or without 7.5 g fructose (OGTT+F or OGTT-F), in random order. Arterialized blood samples were obtained from a heated dorsal hand vein twice before ingestion of the carbohydrate and every 15 min for 2 h afterward. The area under the curve (AUC) of the change in plasma glucose was 19% less in OGTT+F vs. OGTT-F (P: < 0.05). Glucose tolerance was improved by fructose in 9 subjects and worsened in 2. All 6 subjects with the largest glucose AUC during OGTT-F had a decreased response during OGTT+F (31 +/- 5% decrease). The insulin AUC did not differ between the 2 studies. Of the 9 subjects with improved glucose tolerance during the OGTT+F, 5 had smaller insulin AUC during the OGTT+F than the OGTT-F. Plasma glucagon concentrations declined similarly during OGTT-F and OGTT+F. The blood lactate response was about 50% greater during the OGTT+F (P: < 0.05). Neither nonesterified fatty acid nor triglyceride concentrations differed between the two OGTT. In conclusion, low dose fructose improves the glycemic response to an oral glucose load in normal adults without significantly enhancing the insulin or triglyceride response. Fructose appears most effective in those normal individuals who have the poorest glucose tolerance.

Intestinal glucose uptake is increased in aged mice.

Carbohydrate metabolism is impaired in the aged. Whether this is related to impaired glucose uptake or to other factors remains unclear. We measured changes in proliferative activity, glucose uptake, and disaccharidase activity in the intestinal mucosa of mice aged 2, 12, 24, and 30+ months to evaluate glucose absorption and its relationship to intestinal structure and proliferative activity. In vitro glucose uptake was increased significantly in the 30+ month-old mice compared to the younger animals. Similarly, crypt cell production rate and thymidine uptake were also increased. However, there were no significant changes in intestinal weight and length and villus height and crypt depth. These findings suggest that altered carbohydrate absorption in the aged is related to factors other than diminished mucosal glucose uptake. Whether this increased function is related to structural changes in the gut remains unclear.

Detection of malignant cells in histologically normal bone marrow using culture techniques.

Cellular material retained on screens used to filter aspirated bone marrow for future autologous marrow transplantation was studied using long-term culture techniques in 20 consecutive patients. All patients had marrow aspirate and biopsy specimens that were normal histologically. Cultures from five patients grew malignant cells similar to those of the known underlying malignancy. Two types of culture methods were used in these studies. Method I consisted of a long-term bone marrow culture system which predominantly favors adherent cells, and Method II consisted of a suspension type culture system favoring expansion of mononuclear cell types. These findings suggest that tumor cells are reinfused more often at the time of autologous bone marrow transplantation than has been previously suspected. Although the clinical significance of these findings is not known, it is clear that culture techniques combined with special stains and molecular probing will allow the improved detection of occult tumor cells in bone marrow from patients undergoing autologous marrow transplantation. These observations emphasize the need for a comprehensive study of histologically normal autologous marrow using culture techniques to determine the frequency of occult involvement by viable malignant cells and the clinical implications of these findings.

Comparison of glucose polymer and glucose for screening and tolerance tests in pregnancy.

Forty-eight of 100 pregnant women received a 100-g (nonfasting) glucose screening test at about 28 weeks' gestation, followed by a 100-g glucose tolerance test. Another 52 received a 100-g (nonfasting) glucose polymer screening test followed by a 100-g glucose polymer tolerance test. Mean plasma glucose one hour after the glucose screening test was significantly lower than after the glucose polymer screening test. A further 178 women received a glucose polymer screening test and a glucose polymer tolerance test (230 in total). These women and the infants they delivered were studied to derive diagnostic criteria for the 100-g glucose polymer tolerance test by correlating maternal carbohydrate tolerance with indexes of neonatal metabolic performance, and to determine an adequate method of screening for carbohydrate intolerance of pregnancy (gestational diabetes). Diagnostic criteria similar to those of O'Sullivan and Mahan were also developed for the glucose polymer tolerance test. These values are up to 5% lower than those recommended by the National Diabetes Data Group (1979) for the 100-g glucose tolerance test.

Oligonucleotide enhanced cytotoxicity of Idarubicin for lymphoma cells.

Oligonucleotides offer the potential to manipulate gene expression in targeted cells which might be exploitable for therapeutic benefit. The effects of combining a phosphorothioate oligonucleotide OL(1) p53, which transiently down-regulates p53 levels, with an anthracycline, Idarubicin, on the growth of wild-type p53 WMN gene-expressing lymphoma cells was evaluated. Fluorescent OL(1) p53, was used to demonstrate oligonucleotide uptake and retention by the WMN cells. Uptake was maximal at 24 hours and compared to baseline (0 hours) increasing apoptotic cells were evident in WMN cells treated with OL(1) (1 microM) alone and in combination with Idarubicin (0.2 nM) for 24 to 48 hours. In cells treated with OL(1) p53 and Idarubicin, truncated p53 message of a predicted 201 base pair length based on RNAase H cleavage of the OL(1) p53-p53 mRNA heteroduplex was detected after 7 hours of incubation. The message for p53 was transiently downregulated as detected by RT-PCR analysis at 24 hours, and protein levels transiently reduced at 36 hours, as shown by a quantitative Western blot. Corresponding to these events, the growth of WMN cells ceased after 48 hours in the concurrent presence of OL(1) p53 and Idarubicin and, the lymphoma cells were dead after 72 hours. No reduction in hematopoietic colony forming cell capacity of similarly treated hematopoietic progenitor cells harvested from cytokine-mobilized blood by apheresis was observed. Therefore, synergistic cytotoxicity of Idarubicin for lymphoma cells treated with an oligonucleotide targeting p53 message was demonstrated at oligonucleotide and Idarubicin concentrations which were minimally toxic to hematopoietic progenitor cells. This approach offers new opportunities for purging of lymphoma cells from hematopoietic harvests and systemic lymphoma therapy.

Generation differences in hospital inpatient care of children aged 1 to 5 years.

STUDY OBJECTIVE: To describe differences in childhood hospital admissions at ages 1 to 5 years in two generations, and to compare the intergenerational differences in risks of admission. DESIGN: Information was taken from a longitudinal birth cohort study of a national sample and their firstborn offspring. SETTING: England, Wales, and Scotland. SUBJECTS: the 5022 birth cohort members for whom information is available from ages 1 to 5 years and their 2205 firstborn offspring. MEASUREMENTS AND MAIN RESULTS: Data comprised reports of hospital admissions, which were checked with hospitals. Mean numbers of days spent in hospital were fewer in the offspring generation than in their parents, but the proportion ever admitted fell by only 1%. Low birth weight babies (< 2500 g), who comprised 6% of cohort births and 7% of the following generation, used a high proportion of all inpatient time in the offspring population, rising from 3% to 14% of all days of admission. CONCLUSIONS: Compared with the early years of the NHS, published statistics show that the effectiveness of paediatric care has improved greatly, and that childhood mortality and the risk of serious illness have decreased significantly. This study reports intergenerational changes in the reasons for hospital admission and shows, with the benefit of good denominator data, that although there was only a small intergenerational decrease in the proportion of children treated in hospital, there was a large reduction in the time spent in hospital and an increase in admissions of children of low birth weight.

Accumulation of factors influencing respiratory illness in members of a national birth cohort and their offspring.

STUDY OBJECTIVE: The aim was to investigate predictors of childhood lower respiratory tract illness in two generations, and predictors of adult lower respiratory disorders in the first generation. DESIGN: Data on respiratory health and environmental factors from a national birth cohort study were examined from birth to 36 years. Data were also collected on the parents of the subjects and on the subjects' first born offspring from birth to eight years. Main outcome measures were: reports of lower respiratory tract illness before 2 years; lower respiratory tract illness of a week or more between age 20 and 36 years; regular phlegm production at 25 and 36 years; reports of wheeze or asthma at age 36 years; peak expiratory flow rate (PEFR) at age 36 years measured by nurses during home visits; and mothers' reports of lower respiratory illness in first born offspring before 2 years. SUBJECTS: Subjects were a sample of 5362 single, legitimate births taken from all those occurring in England, Wales, and Scotland in one week in 1946, and studied regularly from birth to age 43 years. Data on the subjects' parents and on their 1676 first offspring born while they were aged 19-25 years were also collected. MAIN RESULTS: Lower respiratory tract illness before 2 years fell from 25% in the population born in 1946 to 13% in their first born offspring. In those born in 1946, poor home environment, parental bronchitis, and atmospheric pollution were the best predictors of lower respiratory illness before 2 years, and these three factors and childhood lower respiratory illness and later smoking were the best predictors of adult lower respiratory tract problems. Risk factors for lower respiratory illness in the offspring were manual social class, parental and grandparental lower respiratory disease, and parental smoking. CONCLUSIONS: Risks for adult lower respiratory problems accumulated in childhood through illness, poor social circumstances, and atmospheric pollution. Smoking exacerbated early life risks and was an independent risk factor. In the offspring generation, parental smoking was a risk factor for early life chest illness, together with parental illness and low social class. Reduction of prevalence in the offspring generation was probably accounted for by improvement in home circumstances, reduced atmospheric pollution, and lower rates of parental lower respiratory illness, but current rates of smoking seem likely to prevent much further reduction in early life lower respiratory illness, and thus in this aspect of risk for subsequent adult lower respiratory problems. The accumulation of risk in childhood and adolescence for later adult problems implies a long time scale for the reduction of adult lower respiratory disorders.

Loss and representativeness in a 43 year follow up of a national birth cohort.

STUDY OBJECTIVE: The aim was to describe rates of loss and assessment of representativeness during 43 years of a national birth cohort study. DESIGN: The study population is a class stratified random sample of all single, legitimate births that occurred during one single week in 1946; it has been studied at regular intervals, so far to 1989. MAIN RESULTS: Losses through death and emigration were comparable to those in the national population of the same age. Response rates from the population resident in Britain have remained high, and the responding population is in most respects representative of the native population born in the early postwar years. Response rates within some serious physical illnesses did not differ from those of the healthy population. CONCLUSIONS: The continuing high response rate and representativeness of this national birth cohort is likely to be the result of home based data collections and of the regular contact to provide feedback of information and to check addresses of the study population.

Re-thinking the analysis of intergenerational social mobility: a comment on John W. Fox's "Social class, mental illness, and social mobility".

The method of analyzing social mobility described by Fox (1990) is flawed in its adjustment for between-group differences in destination status when estimating the extent of the mentally ill's mobility as compared with the general population. Use of the recommended model with hypothetical data sets resulted in a significant finding when no overall upward or downward mobility occurred, and a non-significant result when the downward mobility of a psychotic group was contrived to be massive. An alternative model for the test of group differences in mobility is suggested within the framework of log-linear analysis commended by Fox (1990). This method indicated significantly more downward and less upward mobility in mentally ill groups when data from four studies were re-analyzed. We conclude that the weight of evidence from published studies supports the notion of social selection-drift, although this does not imply the inconsequence of social factors in the aetiology of schizophrenia (and other psychoses) or in its prognosis and occupational consequences.

Descriptions of early triers.

The onset of smoking behavior in adolescents has been described as a process, beginning when children are young. Little empirical evidence is available, however, on the nature and specifics of the onset process in young children. More information is needed about the early stages of smoking onset in order to design interventions for young children and for early triers. The purpose of the present study was to describe several onset-related variables in young girls and boys and to discuss implications for designing prevention interventions that target young children. A total of 1,663 5th-grade students completed a questionnaire assessing smoking behavior, psychosocial characteristics, and perceptions of a "smoker" image. Saliva samples for cotinine analysis were also collected. Students were classified as either never-triers (never tried a cigarette) or early triers (tried one or more cigarettes) on the basis of self-reported smoking. Most students who had tried a cigarette were in the early stages of smoking onset, because approximately 30% had tried one cigarette and less than 10% had tried a second. Triers versus never-triers differed on their reported images of smokers, and several psychosocial characteristics predicted trying a cigarette and intentions to smoke for boys.

Predictive performance of Acute Physiological and Chronic Health Evaluation releases II to IV: a single New Zealand centre experience.

There is debate in Australia and New Zealand around the appropriate use of illness severity scoring systems in Australasian intensive care units. The international benchmark is the Acute Physiological and Chronic Health Evaluation (APACHE) system. In order to compare the performance of recent APACHE releases, we audited 2080 sequential patients admitted between 1 January 2006 and 31 March 2008 to the Middlemore Hospital intensive care unit, Auckland, New Zealand. We compared the predictive performance of the proprietary APACHE II, IIIh, IIIj and IV releases, and the performance of a 'localised' version of APACHE II containing re-estimated coefficients derived from a legacy dataset (7703 sequential patients admitted between 1 January 1997 and 31 December 2005). Discrimination assessed by receiver operating characteristic curves was highest with the APACHE III and IV releases, and significantly better than the APACHE II releases. Calibration assessed by the Hosmer-Lemeshow statistic was poor with all releases, although it was best with APACHE IV and 'localised' version of the APACHE II release. Overall accuracy assessed by the Brier Mean Probability score and Shapiro's R statistic was best with APACHE IV. Our study suggests the possibility of improved prediction in moving to APACHE IV from older releases, although broader multicentre study within the Australian and New Zealand critical care community is warranted. Our study also suggests localisation of the APACHE system offers further opportunity to improve prediction, although these improvements may not be major without ground-up development of a new risk prediction model within our local critical care setting.

Segregation and characterization of lymphohematopoietic stromal elements.

In the mouse, long-term maintenance of multipotent hematopoietic stem cells in vitro currently requires the establishment of an appropriate adherent layer. When established employing culture medium supplemented with 20% horse serum and 10(-6) M hydrocortisone, the initial adherent layer contains primitive stem cells that are the major contributor of multipotent stem cells (CFUs) assayed subsequently in the supernatant regardless of the addition of fresh bone marrow cells. In contrast, when the adherent layer is established employing 25% fetal calf serum without hydrocortisone, few if any stem cells survive in the adherent layer. Such cultures are dependent upon a recharge with fresh bone marrow as a source of CFUs. A comparison of the latter stem cell-depleted system with the former intact system permits an evaluation of the relative contributions of the adherent layer and stem cells to the long-term maintenance of hematopoiesis in vitro. Studies of the effects of irradiation of the donor animal for the adherent layer and using the intact system demonstrated a reduction in the supernatant CFUs production that was dose- and time-related and evident at doses of 100 and 500 rads. If the adherent layer itself was irradiated immediately before refeeding, a reduction in supernatant CFUs was evident at a dose of 5 rads. These effects, both in vivo and in vitro, cannot be explained solely on the basis of cell killing. Rather, we propose that such doses inactivate, render impotent, or reduce the self-renewal capacity of stem cells that occupy a limited number of "niches" in the adherent layer. Although they are not killed, these impotent stem cells occupy stem cell niches but do not provide an effective contribution of CFUs to the supernatant cells. The adherent layer consists primarily of fibroblasts with significant numbers of macrophages and endothelial cells. The cellular composition of the adherent layer differs between the intact and stem cell-depleted systems in that the latter has a relatively larger proportion of endothelial cells. The composition of the adherent layer influences the type of differentiated cells in the supernatant. The stem cell-depleted adherent layer cultures had a greater proportion of granulocytes among the supernatant cells than macrophages that eventually predominate in the intact system. We have cloned stromal cells from the intact cultures and obtained several stromal cell lines by spontaneous transformation. One of these stromal cell lines (MC1) transfers at least a partial hematopoietic "microenvironment" (granulocytes, macrophages, erythroid cells) to ectopic sites on transplantation to syngeneic recipients.(ABSTRACT TRUNCATED AT 400 WORDS)

Ultrasonic and comparative angiographic appearances of a spontaneous aorto-caval fistula.

A 71-year-old man with an atherosclerotic abdominal aortic aneurysm developed a spontaneous aorto-caval fistula. The ultrasound appearances showing a direct fistulous communication between the inferior vena cava and the aorta are presented and these are correlated with the angiographic appearances.