Photosensitisation and green egg yolks in laying hens caused by the feeding of ensiled alfalfa leaves.

1. The present study was carried out to determine the effects of feeding ensiled alfalfa leaves (ALS) as an alternative protein source to laying hens under the terms of an organic diet. Due to the occurrence of unexpected negative health effects and undesirable egg yolk pigmentation in the test groups the trial was prematurely stopped and further analysis was conducted to evaluate the responsible substances.2. Body weights of the test groups decreased significantly already in week 2 of the trial. Performance variables dropped. Olive green pigmented egg yolks were found in groups fed diets containing ALS. Severe comb necrosis occurred in the experimental group receiving the highest level of ALS (20%) combined with the option of free-range access and therefore natural light exposure.3. The noxious agent found in ALS, blood serum and egg yolk was the photosensitising chlorophyll derivate pheophorbid a (PPBa), deriving from a strong depletion of chlorophyll contained in the alfalfa leaves. PPBa caused the olive-green pigmentation found in yolks and led to photosensitivity in groups with the highest level of ALS in the diet in combination with light exposure.4. By aiming for high protein and amino acid levels, harvesting and processing have, unintentionally and initially unnoticed, led to a strong accumulation of phototoxic PPBa. From these results it is strongly advised not to include ensiled alfalfa leaves as a protein source in organic laying hen diets.

Computational approaches to understanding interaction and development.

Audio-visual recording and location tracking produce enormous quantities of digital data with which researchers can document children's everyday interactions in naturalistic settings and assessment contexts. Machine learning and other computational approaches can produce replicable, automated measurements of these big behavioral data. The economies of scale afforded by repeated automated measurements offer a potent approach to investigating linkages between real-time behavior and developmental change. In our work, automated measurement of audio from child-worn recorders-which quantify the frequency of child and adult speech and index its phonemic complexity-are paired with ultrawide radio tracking of children's location and interpersonal orientation. Applications of objective measurement indicate the influence of adult behavior in both expert ratings of attachment behavior and ratings of autism severity, suggesting the role of dyadic factors in these "child" assessments. In the preschool classroom, location/orientation measures provide data-driven measures of children's social contact, fertile ground for vocal interactions. Both the velocity of children's movement toward one another and their social contact with one another evidence homophily: children with autism spectrum disorder, other developmental disabilities, and typically developing children were more likely to interact with children in the same group even in inclusive preschool classrooms designed to promote interchange between all children. In the vocal domain, the frequency of peer speech and the phonemic complexity of teacher speech predict the frequency and phonemic complexity of children's own speech over multiple timescales. Moreover, children's own speech predicts their assessed language abilities across disability groups, suggesting how everyday interactions facilitate development.

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

A baseline tool for predicting response to peginterferon alfa-2a in HBeAg-positive patients with chronic hepatitis B.

BACKGROUND: Peginterferon induces off-treatment responses in approximately one-third of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. AIM: To develop an easy-to-use baseline prediction score to identify hepatitis B virus (HBV) genotype B-/C-infected HBeAg-positive Asian patients likely to respond to peginterferon alfa-2a. METHODS: Generalised additive models, multiple logistic regression (MLR) analysis and internal validation methods were applied to data from 647 HBeAg-positive patients from China, Hong Kong and Taiwan to develop a scoring system to predict response 24 weeks after completing a 48-week course of peginterferon alfa-2a. RESULTS: Five baseline factors (age, sex, alanine aminotransferase ratio, hepatitis B surface antigen (HBsAg) level and HBV DNA level) were retained in the final MLR for HBeAg seroconversion and used to develop a scoring system from 0 to 7. Among patients with scores of 0-1, 2-3, 4 or ≥5, HBeAg seroconversion was achieved in 6.4% (6/94), 23.0% (61/265), 36.4% (67/184) and 54.8% (57/104), respectively, and a combined response (HBeAg seroconversion plus HBV DNA <2000 IU/mL) in 5.3% (5/94), 12.8% (34/265), 25.0% (46/184) and 36.5% (38/104), respectively. Among patients with scores of 0-1, 2-3, 4 or ≥5, 57.0% (53/93), 12.3% (31/253), 3.4% (6/178) and 1.0% (1/100) had HBsAg ≥20 000 IU/mL at treatment Week 12; only 3/91 (3.3%) with HBsAg ≥20 000 IU/mL experienced a combined response at 24 weeks post-treatment (negative predictive value = 97% [88/91]). CONCLUSION: A pre-treatment scoring system using readily available baseline characteristics identifies HBeAg-positive Asian patients likely to experience sustained HBeAg seroconversion after treatment with peginterferon alfa-2a.

Responses are durable for up to 5 years after completion of peginterferon alfa-2a treatment in hepatitis B e antigen-positive patients.

BACKGROUND: In the large randomised NEPTUNE study, peginterferon alfa-2a 180 µg/wk for 48 weeks produced higher hepatitis B e antigen (HBeAg) seroconversion rates 24 weeks post-treatment (36%) than a lower dose (90 µg/wk) and/or shorter duration (24 weeks) (range 14%-26%). AIM: To determine seroconversion rates 5 years after completion of treatment in NEPTUNE. METHODS: HBeAg-positive patients who completed 24 weeks' follow-up in NEPTUNE (with peginterferon alfa-2a 90 µg/wk × 24 weeks [group 1]; 180 µg/wk × 24 weeks [2]; 90 µg/wk × 48 weeks [3] or 180 µg/wk × 48 weeks [4]) were followed up. RESULTS: Three hundred and eighty three of the 544 patients in the original study were enrolled in the long-term follow-up study. Many patients (196 overall; more in groups 1-3 than 4) received nucleos(t)ide analogues or immunomodulators during follow-up, and more patients had missing data at year 5 in groups 2 and 4 (48 weeks, 50/112) than in groups 1 and 3 (24 weeks, 23/103), which confounds the planned per-protocol analysis. HBeAg seroconversion rates in groups 1, 2, 3 and 4 at year 5 were 47.5%, 50.7%, 52.2% and 67.1%, respectively, (odds ratio for group 4 versus 1-3: 2.02; 95% CI 1.21, 3.38), using multiple imputation methods for missing measurements. CONCLUSION: Seroconversion rates are durable for up to 5 years after completion of peginterferon alfa-2a therapy and, consistent with NEPTUNE, the results suggest that the licensed regimen (180 µg × 48 weeks) is more efficacious for HBeAg-positive patients than a lower dose and/or shorter treatment duration.

Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses.

BACKGROUND: The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen. METHODS: Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg(-1) days 1 and 15 plus paclitaxel 90 mg m(-2) days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg(-1) day 1 plus capecitabine 1000 mg m(-2) bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs. RESULTS: The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP. CONCLUSIONS: A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340).

FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study.

BACKGROUND: This randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer. PATIENTS AND METHODS: Patients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m(2)) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences. RESULTS: Of 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74-2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63-1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56-1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%). CONCLUSIONS: Activity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.

Safety results from a phase III study (TURANDOT trial by CECOG) of first-line bevacizumab in combination with capecitabine or paclitaxel for HER-2-negative locally recurrent or metastatic breast cancer.

BACKGROUND: We report safety data from a randomised, phase III study (CECOG/BC.1.3.005) evaluating first-line bevacizumab plus paclitaxel or capecitabine for locally recurrent or metastatic breast cancer. PATIENTS AND METHODS: Patients aged ≥18 years with human epidermal growth factor receptor-2-negative breast adenocarcinoma were randomised to Arm A: bevacizumab 10 mg/kg days 1 and 15; paclitaxel 90 mg/m(2) days 1, 8, and 15, every 4 weeks; or Arm B: bevacizumab 15 mg/kg day 1; capecitabine 1000 mg/m(2) b.i.d., days 1-14, every 3 weeks, until disease progression, unacceptable toxicity or consent withdrawal. RESULTS: A post hoc interim safety analysis included 561 patients (Arm A: 284, Arm B: 277). The regimens demonstrated similar frequencies of all-grade and serious adverse events (SAEs), but different safety profiles. Treatment-related events occurred in 85.2% (Arm A) and 78.0% (Arm B) of patients. Fatigue was most common in Arm A (30.6% versus 23.5% Arm B), and hand-foot syndrome (HFS) most common in Arm B (49.5% versus 2.5% Arm A). Diarrhoea (Arm A: 0.4%, Arm B: 1.4%) and pulmonary embolism (Arm A: 0.7%, Arm B: 1.1%) were the most frequently reported SAEs. CONCLUSION: These findings are in-line with safety data for bevacizumab plus paclitaxel or capecitabine, reported in previous phase III trials.

Non-Expert Ratings of Infant and Parent Emotion: Concordance with Expert Coding and Relevance to Early Autism Risk.

This study investigated a novel approach to obtaining data on parent and infant emotion during the Face-to-Face/Still-Face paradigm, and examined these data in light of previous findings regarding early autism risk. One-hundred and eighty eight non-expert students rated 38 parents and infant siblings of children who did (20) or did not (18) have autism spectrum disorders. Ratings averaged across 10 non-experts exhibited high concordance with expert facial-action codes for infant emotion, and 20 non-experts were required for reliable parent ratings. Findings replicated the well-established still-face effect and identified subtle risk associations consonant with results from previous investigations. The unique information offered by intuitive non-expert ratings is discussed as an alternative to complex and costly behavioral coding systems.

Peginterferon alpha-2a (40 kDa) and ribavirin: comparable rates of sustained virological response in sub-sets of older and younger HCV genotype 1 patients.

The average age of patients initiating therapy for HCV is increasing, with older patients exhibiting lower responses to therapy than younger patients. Identification of those older patients likely to respond needs to be addressed. Using data from 569 genotype-1 patients enrolled in two phase III studies (NV15801/NV15942) randomized to peginterferon alpha-2a (40 KDa) 180 microg/week plus ribavirin 1000/1200 mg/day for 48-weeks, we investigated factors associated with sustained virological response (SVR; undetectable HCV-RNA 24-weeks post-treatment) in patients >50 years. SVR rates among patients 50 years (52%vs 39%; P = 0.0073). Older patients with a rapid virological response (RVR; undetectable HCV-RNA at treatment week 4) or complete early virological response (cEVR; detectable HCV-RNA at week 4 but HCV-RNA <50 IU/mL at week-12) demonstrated high SVR rates (83% and 61% respectively). Older patients had lower cumulative peginterferon alpha-2a exposure and significantly lower cumulative ribavirin exposure (252 g vs 304 g in younger patients; P < 0.0001). Higher relapse rates were observed in older patients (41%vs 25%; P = 0.0042). Cumulative drug exposure and achievement of RVR or cEVR were significantly predictive of SVR by multiple logistic regression analysis in patients >50 years. Other baseline characteristics predictive of SVR in those >50 years of age were lower baseline HCV-RNA level (P = 0.0067), higher ALT-ratio (P = 0.0113) and absence of cirrhosis (P = 0.0482). Response rates were high among patients >50 years without cirrhosis who maintained adequate drug exposure and those achieving an RVR or cEVR. More frequent dose modifications of ribavirin in those >50 years likely contributed to the observed higher relapse rates.

Hepatic steatosis in chronic hepatitis C: baseline host and viral characteristics and influence on response to therapy with peginterferon alpha-2a plus ribavirin.

Hepatic steatosis is common in hepatitis C virus (HCV)-infected patients and may be associated with the metabolic syndrome. We studied steatosis in patients treated with peginterferonalpha-2a plus ribavirin. Forty-five of 207 patients (22%) had >5% hepatic steatosis at baseline. Significantly more patients with steatosis than without were HCV genotype 3 (51%vs 14%; P < 0.0001) had higher HCV-RNA (P = 0.0045), body weight (P = 0.0176), body mass index (BMI, P = 0.0352) and serum triglycerides (TG) (P = 0.0364), hypertriglyceridaemia (P = 0.0009), elevated blood pressure/history of hypertension (P = 0.0229) and lower cholesterol (P = 0.0009). Significant steatosis predictors were genotype 3 (OR 9.04, 95% CI 3.85-21.21, P < 0.0001), HCV-RNA (OR 2.96, 1.49-5.88, P = 0.0019) and triglycerides (OR 1.06, 1.02-1.11, P = 0.0071). In genotype 3 patients, HCV-RNA was the only significant predictor (OR 11.15, 2.60-47.81, P = 0.0012). In non-genotype 3 patients, hypertriglyceridaemia was the only significant predictor (OR 1.07, 1.02-1.12, P = 0.0041). 134 of 207 patients (65%) achieved an sustained virological response (SVR) with peginterferon alpha-2a plus ribavirin, similar to the overall response rate. In genotype 3 patients with an SVR, steatosis decreased from 48% to 13% (baseline to end-point). No change was seen in the steatosis rate in non-genotype 3 patients with an SVR. This large and comprehensive analysis of a large data base from a multinational trial further adds to the observations that chronic HCV is associated with hepatic steatosis in approximately a fifth of patients. Further, features of the metabolic syndrome are associated with hepatic steatosis in most of these patients. Steatosis is significantly more common in genotype 3 compared with other genotypes, and in these patients, an SVR is associated with steatosis clearance.

Cocaine exposure is associated with subtle compromises of infants' and mothers' social-emotional behavior and dyadic features of their interaction in the face-to-face still-face paradigm.

Prenatal cocaine and opiate exposure are thought to subtly compromise social and emotional development. The authors observed a large sample of 236 cocaine-exposed and 459 nonexposed infants (49 were opiate exposed and 646 nonexposed) with their mothers in the face-to-face still-face paradigm. Infant and maternal behaviors were microanalytically coded. No opiate-exposure effects were detected. However, mothers of cocaine-exposed infants showed more negative engagement than other mothers. The cocaine-exposed dyads also showed higher overall levels of mismatched engagement states than other dyads, including more negative engagement when the infants were in states of neutral engagement. Infants exposed to heavier levels of cocaine showed more passive-withdrawn negative engagement and engaged in more negative affective matching with their mothers than other infants. Although effect sizes were small, cocaine exposure, especially heavy cocaine exposure, was associated with subtly negative interchanges, which may have a cumulative impact on infants' later development and their relationships with their mothers.

Prenatal drug exposure and maternal and infant feeding behaviour.

OBJECTIVE: To evaluate feeding difficulties and maternal behaviour during a feeding session with 1 month old infants prenatally exposed to cocaine and/or opiates. METHODS: The study is part of the maternal lifestyle study, which recruited 11 811 subjects at four urban hospitals, then followed 1388 from 1 to 36 months of age. Exposure to cocaine and opiates was determined by maternal interview and meconium assay. At the 1 month clinic visit, biological mothers were videotaped while bottle feeding their infants. This sample included 364 exposed to cocaine, 45 exposed to opiates, 31 exposed to both drugs, and 588 matched comparison infants. Mothers were mostly black, high school educated, and on public assistance. Videotapes were coded without knowledge of exposure status for frequency, duration and quality of infant sucking, arousal, feeding problems, and maternal feeding activity and interaction. RESULTS: No cocaine effects were found on infant feeding measures, but cocaine-using mothers were less flexible (6.29 v 6.50), less engaged (5.77 v 6.22), and had shorter feeding sessions (638 v 683 seconds). Opiate exposed infants showed prolonged sucking bursts (29 v 20 seconds), fewer pauses (1.6 v 2.2 per minute), more feeding problems (0.55 v 0.38), and increased arousal (2.59 v 2.39). Their mothers showed increased activity (30 v 22), independent of their infants' feeding problems. CONCLUSIONS: Previous concerns about feeding behaviour in cocaine exposed infants may reflect the quality of the feeding interaction rather than infant feeding problems related to prenatal exposure. However, opiate exposed infants and their mothers both contributed to increased arousal and heightened feeding behaviour.

Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies.

PURPOSE: To investigate the effect of recombinant human erythropoietin (epoetin beta) on anemia, transfusion need, and quality of life (QOL) in severely anemic patients with low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM). PATIENTS AND METHODS: Transfusion-dependent patients with NHL (n = 106), CLL (n = 126), or MM (n = 117) and a low serum erythropoietin concentration were randomized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks. Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival (hemoglobin [Hb] > 8.5 g/dL) between weeks 5 to 16. Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need. QOL was assessed by the Functional Assessment of Cancer Therapy scale. RESULTS: Transfusion-free (P =.0012) survival and transfusion- and severe anemia-free survival (P =.0001) were significantly greater in the epoetin beta group versus placebo (Wald chi(2) test), giving a relative risk reduction of 43% and 51%, respectively. The response rate was 67% and 27% in the epoetin beta versus the placebo group, respectively (P <.0001). After 12 and 16 weeks of treatment, QOL significantly improved in the epoetin beta group compared with placebo (P <.05); this improvement correlated with an increase in Hb concentration (> or = 2 g/dL). A target Hb that could be generally recommended could not be identified. CONCLUSION: Many severely anemic and transfusion-dependent patients with advanced MM, NHL, and CLL and a low performance status benefited from epoetin therapy, with elimination of severe anemia and transfusion need, and improvement in QOL.

All smiles are positive, but some smiles are more positive than others.

Disagreement as to whether all smiling or specific types of smiling index positive emotion early in life was addressed by examining when infants produced different types of smiling and other facial expressions. Thirteen infants were observed weekly from 1 to 6 months of age. Smiling alone--without cheek raising or mouth opening--was relatively more likely than periods without smiling both when mothers were smiling and when infants were gazing at their mothers' faces. Cheek-raise (Duchenne) smiling was relatively more likely than smiling alone only when mothers were smiling. Open-mouth (play) smiling was relatively more likely than smiling alone only when infants were gazing directly at mothers' faces. Smiling involving both cheek raising and mouth opening was relatively likely both when mothers were smiling and when infants were gazing at mothers' faces and became increasingly likely with age when both conditions co-occurred. The cheek-raise and open-mouth dimensions of smiling appear to be associated with, respectively, the amplification of processes of sharing positive affect and of visual engagement that are present to a lesser degree in smiling alone.

What's in a smile?

In positive social contexts, both adults and older infants show more Duchenne smiling (which involves high cheek raising) than non-Duchenne smiling (which does not). This study compared Duchenne and non-Duchenne smiles in early infancy for clues to their emotional significance. Infants (N = 13) from 1 to 6 months of age were videotaped weekly for 5 min in 208 face-to-face interactions with their mothers. Levels of Duchenne and non-Duchenne smiling were correlated within interactive sessions, and the 2 smiles had similar developmental trajectories. Duchenne smiles were typically preceded by non-Duchenne smiles. The results suggest these frequently contrasted types of smiles occur in similar situations and are often different temporal phases of a continuous emotional process. In contrast to adults, infant Duchenne smiles had longer durations than non-Duchenne smiles, suggesting infant smiling does not fit adult models of emotional functioning.

The Bayley Scales of Infant Development. II: Where to start?

This study examines whether the Bayley Scales of Infant Development-Second Edition (Bayley II) Mental Scale scores vary on the basis of which item set is considered the starting point of an infant's assessment. The Bayley II was administered to 78 12-month-old infants by certified examiners beginning with the 12-month age item set. A second certified examiner then administered 10 additional items that completed the 11-month and 13-month age item sets. Of the 78 infants tested, 73 (94%) met basal and ceiling criteria in all three item sets. Three separate Mental Developmental Index (MDI) scores were calculated using 12-month norms for each subject, which were based on the raw scores generated from the 11-, 12-, and 13-month age item sets. Scores calculated on the 11-month set were significantly lower than those on the 12-month set, which were in turn significantly lower than those on the 13-month set. When tested on the 11-month instead of on the 12-month item set, twice as many infants received lower than normal (< 85) MDI scores, indicating an impact on referability decisions. Minor adjustments in administration of the Bayley II, such as those based on assumptions regarding an infant's current level of functioning, significantly affect infant test scores and eligibility for follow-up services. Standardized use of this test should minimize variability in test scores.

An event-based analysis of the coordination of early infant vocalizations and facial actions.

This study used an event-based approach to provide empirical evidence regarding the nature of coordination in 3- and 6-month-old infants. Vocalizations and facial actions of 12 normally developing infants interacting with their caregivers were coded. Coded vocalizations and facial actions were considered coordinated when they temporally overlapped. Results indicate that infants coordinated their vocalizations and facial actions more than expected by chance. Coordinated events were governed by 2 sequence patterns. When 2 communicative events were temporally associated across modalities, 1 event tended to be completely embedded within the other, and vocalizations tended to end before facial actions. This study provides new information about how infant communication is structured, confirms results from other coordination studies, and describes a new method for analysis of event-based data.

The estimation of efficacy of oral iron supplementation during treatment with epoetin beta (recombinant human erythropoietin) in patients undergoing cardiac surgery.

We estimated the efficacy of oral iron therapy during treatment with rhEPO in patients undergoing cardiac surgery who were contraindicated for autologous blood donation. Seventy-six patients were enrolled in this double-blind, placebo-controlled trial and assigned to the 2 treatment groups (5x500 U/kg body weight rhEPO or placebo intravenously over 14 d before surgery). During the treatment period all patients received 300 mg Fe2+ (iron glycine sulfate) orally per day. rhEPO therapy produced significant increases in hemoglobin concentration (Hb), reticulocyte count, hematocrit (Hct) and the hypochromic red blood cells (HRBC), and a decrease in transferrin saturation (41%) compared to the placebo group before surgery. However, the preoperative increase in HRBC was independent of the baseline ferritin and even correlated positively with the preoperative increase in Hct (r=0.47, p<0.01). In rhEPO patients there were inverse correlations between baseline serum iron and the preoperative increases in Hb (r=-0.39, p<0.05), Hct (r=-0.50, p<0.01) and HRBC (r=-0.53, p<0.001). With this treatment regimen the HRBC appear to reflect the degree of erythropoietic stimulation rather than functional iron deficiency. The preoperative increases in reticulocytes, HRBC and Hb/Hct in patients with ferritin <100 mg/l or transferrin saturation <16% showed no significant difference compared to their complementary groups. The preoperative decrease in storage iron and the inverse correlation between the baseline ferritin and the preoperative change in ferritin (r=-0.94, p<0.0001) in the rhEPO group indicate that the iron requirement for hemoglobin synthesis is probably covered by the breakdown of stored iron and an increase in the rate of absorption of orally administered Fe2+. Intravenous rhEPO treatment with 5x500 U/kg body weight in combination with 300 mg oral Fe2+/d given over 14 d before surgery is a suitable regimen to increase Hb by about 1.61 g/dl and Hct by 0.06.

Randomized multicentre trial of the influence of recombinant human erythropoietin on intraoperative and postoperative transfusion need in anaemic patients undergoing right hemicolectomy for carcinoma.

BACKGROUND: The possible immunosuppressive effect of blood transfusion and its influence on survival after surgery for cancer makes it worthwhile to seek methods to avoid transfusion wherever possible. Patients with right-sided colonic cancer are frequently anaemic. Such patients were entered into a study that employed erythropoietin to avoid homologous transfusion. METHODS: In a prospectively randomized double-blind placebo-controlled multicentre trial, patients with moderate anaemia (haemoglobin concentration greater than 8.5 g/dl and less than or equal to 13.5 g/dl) presenting with right-sided colonic cancer and scheduled for hemicolectomy were treated with recombinant human erythropoietin (epoetin beta) 20,000 units/day subcutaneously or placebo for at least 10 days over the operative period. RESULTS: Perioperative treatment with epoetin beta was well tolerated and there were no significant differences in morbidity and mortality. Following hemicolectomy, median cumulative blood loss in the two groups was similar (epoetin beta 440 ml versus placebo 345 ml). Sixteen (33 per cent) of 48 patients treated with epoetin beta and 15 (28 per cent) of 54 in the placebo group received perioperative blood transfusions (P not significant). The increase in reticulocyte count between baseline and the last preoperative value was more pronounced in the epoetin beta group than in those receiving placebo (P = 0.036). CONCLUSION: Despite the perioperative administration of 20,000 units erythropoietin per day for at least 10 days, it was not possible to reduce the intraoperative and postoperative transfusion need. None the less, a positive change in the haematological variables of treated patients was clearly discernible. The negative result may be due to the short treatment interval and to iron deficiency, which was present in the majority of patients. The general change of attitude towards allogeneic blood transfusion is demonstrated by the overall low frequency of blood transfusion in this study.