True risk of fetal/neonatal alloimmune thrombocytopenia in subsequent pregnancies: a prospective observational follow-up study.

OBJECTIVES: To assess neonatal platelet counts by comparing alloimmunised pregnancies from a Norwegian screening and intervention study with subsequent pregnancies from the same women. DESIGN: Prospective observational follow-up study. SETTING: A university hospital. POPULATION: HPA-1a immunised women from a large Norwegian screening study that gave birth to one or more children after the screening study ended (2004-2012). METHODS: Follow-up of maternal anti-HPA-1a antibody levels and neonatal platelet counts from the screening pregnancies were compared with subsequent pregnancies. None of the women received antenatal intravenous immunoglobulin (IVIG) treatment and neonatal platelet counts were therefore comparable. MAIN OUTCOME MEASURES: Change in neonatal platelet counts from one HPA-1a incompatible pregnancy to the next. Maternal anti-HPA-a1 antibody levels from one HPA-1a incompatible pregnancy to the next. RESULTS: Forty-five incompatible subsequent pregnancies were identified. Overall, the neonatal platelet count in the subsequent pregnancy was improved (18%), unchanged (52%), or worse (30%), compared with the corresponding screening pregnancy. There was one case of fetal intracranial haemorrhage (ICH) identified in the screening (intrauterine fetal death detected at 30 weeks of gestation) and no ICH cases recorded for the subsequent pregnancies. In cases where the platelet count was lower in the subsequent pregnancy, the maternal anti-HPA-1a antibody level was higher compared with the screening pregnancy. In comparison, the maternal antibody level was lower in subsequent pregnancies where the platelet count improved. CONCLUSIONS: In contrast to what is often stated, we found that the neonatal platelet count was increased or unchanged in the majority of subsequent pregnancies of HPA-1a-immunised women.

Bleeding complications after central line insertions: relevance of pre-procedure coagulation tests and institutional transfusion policy.

BACKGROUND: The aim of this study was to map pre-procedural variables for insertion of a central venous catheter, prophylactic blood component use and to investigate whether any independent variable could be identified as an independent risk factor for associated bleeding complications in patients outside the intensive care unit. METHODS: In this retrospective study, we investigated 1737 consecutive insertions of central venous catheters in 1444 patients in a large university hospital during 2009-2010. Pre-procedural coagulation status, blood component use, type of catheter, insertion site and complications during insertion were recorded and compared with bleeding complications documented on electronic charts. RESULTS: No serious bleeding complications were recorded in connection with the insertion of central venous catheters. Sixteen of 1769 (0.9%) insertions caused grade 2 bleeding, defined as bleeding requiring prolonged compression at the insertion site. Insertion of a large bore central dialysis catheter was found to be an independent risk factor for bleeding complications. Neither conventional coagulation tests nor accidental arterial puncture or the number of needle passes could predict bleeding complications in this study. CONCLUSION: This retrospective study, in non-ICU patients, shows that serious bleeding complications in association with central line insertions are uncommon and that insertion of a large bore catheter is likely to be an independent risk factor for mild-bleeding complications in this population.

Neonatal alloimmune thrombocytopenia is not what it was: a lesson learned from a large prospective screening and intervention program.

Controversies regarding the pathophysiology of neonatal alloimmune thrombocytopenia (NAIT) has hampered the development of consensus about how to identify, follow up and treat the women and children with this serious complication. One reason for this is that knowledge about the condition derived from previous retrospective studies do not necessarily conform with data derived from prospective investigations. The main obstacle to introduction of general screening programs to identify the pregnancies to treat, have been lack of reliable risk factors, and an effective treatment. Now, several recent prospective screening programs including up to 100,000 pregnant women has changed the understanding of the NAIT-pathology, and has shown that we are close to answering these critical questions.

Cost-effectiveness of antenatal screening for neonatal alloimmune thrombocytopenia.

OBJECTIVES: To estimate the costs and health consequences of three different screening strategies for neonatal alloimmune thrombocytopenia (NAIT). DESIGN: Cost-utility analysis on the basis of a decision tree that incorporates the relevant strategies and outcomes. SETTING: Three health regions in Norway encompassing a 2.78 million population. POPULATION: Pregnant women (n = 100,448) screened for human platelet antigen (HPA) 1a and anti-HPA 1a antibodies, and their babies. METHOD: Decision tree analysis. In three branches of the decision tree, pregnant women entered a programme while in one no screening was performed. The three different screening strategies included all HPA 1a negative women, only HPA 1a negative, HLA DRB3*0101 positive women or only HPA 1a negative women with high level of anti-HPA 1a antibodies. Included women underwent ultrasound examination and elective caesarean section 2-4 weeks before term. Severely thrombocytopenic newborn were transfused immediately with compatible platelets. MAIN OUTCOME MEASUREMENTS: Quality-adjusted life years (QALYs) and costs. RESULTS: Compared with no screening, a programme of screening and subsequent treatment would generate between 210 and 230 additional QALYs among 100,000 pregnant women, and at the same time, reduce health care costs by approximately 1.7 million euros. The sensitivity analyses indicate that screening is cost effective or even cost saving within a wide range of probabilities and costs. CONCLUSION: Our calculations indicate that it is possible to establish an antenatal screening programme for NAIT that is cost effective.

Rheumatoid arthritis treated with vegetarian diets.

The notion that dietary factors may influence rheumatoid arthritis (RA) has been a part of the folklore of the disease, but scientific support for this has been sparse. In a controlled, single-blind trial we tested the effect of fasting for 7-10 d, then consuming an individually adjusted, gluten-free, vegan diet for 3.5 mo, and then consuming an individually adjusted lactovegetarian diet for 9 mo on patients with RA. For all clinical variables and most laboratory variables measured, the 27 patients in the fasting and vegetarian diet groups improved significantly compared with the 26 patients in the control group who followed their usual omnivorous diet throughout the study period. One year after the patients completed the trial, they were reexamined. Compared with baseline, the improvements measured were significantly greater in the vegetarians who previously benefited from the diet (diet responders) than in diet nonresponders and omnivores. The beneficial effect could not be explained by patients' psychologic characteristics, antibody activity against food antigens, or changes in concentrations of prostaglandin and leukotriene precursors. However, the fecal flora differed significantly between samples collected at time points at which there was substantial clinical improvement and time points at which there were no or only minor improvements. In summary, the results show that some patients with RA can benefit from a fasting period followed by a vegetarian diet. Thus, dietary treatment may be a valuable adjunct to the ordinary therapeutic armamentarium for RA.

Inhibition of growth of Proteus mirabilis and Escherichia coli in urine in response to fasting and vegetarian diet.

It has recently been shown that serum antibody levels against Proteus mirabilis decreased in patients with rheumatoid arthritis who improved clinically during treatment with 7-10 days of fasting followed by a one-year vegetarian diet. As P. mirabilis is commonly implicated in urinary tract infections, this study was carried out to examine whether fasting and vegetarian diet may influence the growth of P. mirabilis and Escherichia coli in urine. Urine samples were collected from 22 patients who were referred to a health farm for various reasons. The dietary regimen recommended by the health farm consisted of fasting for 7 to 10 days followed by a vegan diet. The growth of both bacteria in urine samples collected after 8 days was significantly slower than in samples collected at baseline. In urine samples collected after 18 days growth was also reduced, although not significantly for E. coli. Our results show that dietary manipulation may reduce the ability of urine to support the growth of P. mirabilis and E. coli.

Leukocyte counts and lymphocyte responsiveness associated with repeated bouts of strenuous endurance exercise.

This study compared leukocyte counts and lymphocyte responsiveness during and after a second bout of high-intensity endurance exercise on the same day with the response to a similar but single bout of exercise. Nine athletes participated in three 24-h trials: 1) rest in bed (Rest); 2) one bout of exercise (One); and 3) two bouts of exercise (Two). All bouts consisted of 75 min at approximately 75% of maximal O(2) uptake on a cycle ergometer. Lymphocytes in whole blood were stimulated with monoclonal antibodies against CD2 and assessed by flow cytometry for expression of the early activation molecule CD69. The second bout of exercise in the Two trial was associated with significantly increased concentrations of total leukocytes, neutrophils, lymphocytes, CD4(+), CD8(+), and CD56(+) cells and a significantly decreased percentage of CD56(+) cells expressing CD69 compared with a single bout. Additionally, there was a significantly decreased CD69 fluorescence in CD56(+) cells postexercise. These differences suggest a "carry-over" effect in the immune system from a first to a second bout of exercise on the same day.

A pilot study of the effect of an elemental diet in the management of rheumatoid arthritis.

To evaluate the extent of food allergy/intolerance in rheumatoid arthritis, an elemental (hypoallergenic) diet was studied in a controlled, double-blind pilot study. Ten patients were allocated to an experimental group and 7 to a control group. The patients in the experimental group received an elemental diet for 3 weeks, whereas the patients in the control group received a control soup consisting of milk, meat, fish, shellfish, orange, pineapples, tomatoes, peas and flour of wheat and corn. During the 4th week of the study the patients in both groups resumed their regular diet. A significant improvement was found in the number of tender joints (p = 0.04) in the experimental group, whereas improvement was found in the erythrocyte sedimentation rate (ESR) (p = 0.03) and in the thrombocyte count (p = 0.02) in the control group. Three patients in the elemental diet group and 2 patients in the control group improved in all of the measured disease variables during the dietary treatment period. There was no significant difference in disease activity variables between the two groups. These results suggest that some RA patients may respond to the elimination of offending food items. However, the results do not encourage treatment with an elemental diet in unselected RA patients.

Antibodies against dietary antigens in rheumatoid arthritis patients treated with fasting and a one-year vegetarian diet.

OBJECTIVE: To compare serum antibody activity against dietary antigens in patients with rheumatoid arthritis (RA) and healthy controls, and to examine whether anti-food antibody activity fluctuated with disease activity during a trial of fasting followed by a one-year vegetarian diet. METHODS: Serum IgG, IgA and IgM antibody activity against several food antigens was measured by an enzyme immunoassay. Abnormally high antibody activity was defined as values above the 90th percentile of the measurements in 30 healthy controls. Serum IgE antibody activity was measured by a radioallergosorbent test. RESULTS: During the trial 10 of 27 patients suspected that certain food items aggravated their arthritis symptoms. Elevated antibody activity against one or more of the dietary antigens was found in all RA patients, but these measurements could not be used to predict which food would aggravate the symptoms. Elevated IgG and IgA antibody activity against alpha-lactalbumin was found in a significantly larger number of RA patients than in controls. With the exception of one patient, there was no concordance between the clinical course and antibody activity against the various dietary antigens. CONCLUSION: The results indicate that a systemic humoral immune response against food items is probably not involved in the pathogenesis of RA.

Serum levels of interleukin-6 and dehydroepiandrosterone sulphate in response to either fasting or a ketogenic diet in rheumatoid arthritis patients.

OBJECTIVE: To investigate the effects of either a 7-day fast or a 7-day ketogenic diet upon serum interleukin-6 (IL-6) and dehydroepiandrosterone sulphate (DHEAS) in RA patients. METHODS: We measured serum concentrations of DHEAS and IL-6 in 23 RA patients with active disease, 10 of whom followed a 7-day sub-total fast and 13 of whom consumed a ketogenic diet (isoenergetic, carbohydrate < 40 g/day) for 7 days. Clinical and laboratory variables were measured at baseline, on day 7 and after re-feeding on day 21. Correlation analyses were used to assess the associations between serum IL-6, DHEAS and disease activity variables at each timepoint. RESULTS: Fasting, but not the ketogenic diet, decreased serum IL-6 concentrations by 37% (p < 0.03) and improved disease activity at day 7. Both fasting and the ketogenic diet increased serum DHEAS levels by 34% as compared with baseline (both p < 0.006). Levels of IL-6, but not DHEAS, correlated with several disease activity variables. CONCLUSION: Both fasting and a ketogenic diet significantly increased serum DHEAS concentrations in RA patients. Only fasting significantly decreased serum IL-6 levels and improved disease activity. As the increases in serum DHEAS were similar in response to both fasting and a ketogenic diet, it is unlikely that the fall in serum IL-6 or clinical improvements after fasting were directly related to increases in serum DHEAS. The fasting-induced fall in serum IL-6 may underlie the fall in CRP and ESR observed in RA patients in response to a 7-day fast.

Reduction in serum leptin and IGF-1 but preserved T-lymphocyte numbers and activation after a ketogenic diet in rheumatoid arthritis patients.

OBJECTIVE: To assess the clinical, immunological and hormonal effects of carbohydrate restriction in rheumatoid arthritis (RA) patients via the provision of a ketogenic diet. METHODS: Thirteen RA patients with active disease consumed a ketogenic diet for 7 days, providing the estimated requirements for energy and protein whilst restricting their carbohydrate intake to < 40 g/day. This was followed by a 2-week re-feeding period. Clinical and laboratory evaluations were carried out on days 0, 7 and 21. Changes in serum glucose, beta-hydroxybutyrate (beta-HB), leptin, insulin-like growth factor-1 (IGF-1) and cortisol were also measured at these time points. To study CD4+ and CD8+ lymphocyte responses, mitogen stimulated T-cell activation was assessed in heparinised whole blood via flow-cytometric analysis of CD69 expression. RESULTS: After the 7-day ketogenic diet, there were significant increases in serum beta-HB and cortisol, and significant decreases in body weight, the total lymphocyte count, serum leptin, IGF-1 and glucose. However, with the exception of morning stiffness, there were no significant changes in any of the clinical or laboratory measures of disease activity, or in early T-lymphocyte activation and the absolute numbers of CD4+ and CD8+ cells. CONCLUSION: In RA patients several of the metabolic and hormonal responses to a ketogenic diet, such as a fall in serum IGF-1 and leptin, resemble those which occur in response to acute starvation. However, the clinical and immunological changes which occur in response to acute starvation do not take place with a ketogenic diet and thus may be dependent upon energy and/or protein restriction.

Vegetarian diet for patients with rheumatoid arthritis--status: two years after introduction of the diet.

We have previously reported that a significant improvement can be obtained in rheumatoid arthritis patients by fasting followed by an individually adjusted vegetarian diet for one year. The patients who changed their diet could be divided into diet responders and diet nonresponders. After the clinical trial the patients were free to change diet or medication and after approximately one year they were asked to attend a new clinical examination. We compared the change from baseline (i.e. at the time of study entry) to the time of the follow-up examination for diet responders, diet nonresponders and controls who ate an omnivorous diet. The following variables favoured diet responders: pain score, duration of morning stiffness, Stanford Health Assessment Questionnaire index, number of tender joints, Ritchie's articular index, number of swollen joints, ESR and platelet count [corrected]. The difference between the three groups were significant for all the clinical variables, except for grip strength. There was no significant difference between the groups with regard to laboratory or anthropometric variables. At the time of the follow-up examination all diet responders but only half of the diet nonresponders still followed a diet. Our findings indicate that a group of patients with rheumatoid arthritis benefit from dietary manipulations and that the improvement can be sustained through a two-year period.

Diet and disease symptoms in rheumatic diseases--results of a questionnaire based survey.

Experiences with food intake, diet manipulations and fast were registered in rheumatic patients. The study was a questionnaire-based survey in which 742 patients participated. It comprised 290 patients with rheumatoid arthritis, 51 patients with juvenile rheumatoid arthritis, 87 patients with ankylosing spondylitis, 51 patients with psoriatic arthropathy, 65 patients with primary fibromyalgia and 34 patients with osteoarthritis. One third of the patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthropathy reported aggravation of disease symptoms after intake of certain foods while 43% of the patients with juvenile rheumatoid arthritis and 42% of the patients with primary fibromyalgia stated the same. Twenty-six percent of the patients with juvenile rheumatoid arthritis and 23% of the patients with rheumatoid arthritis, ankylosing spondylitis and primary fibromyalgia had previously tried certain diets in the attempt to alleviate disease symptoms, whereas 13% of the patients with psoriatic arthropathy and 10% with osteoarthritis had tried diet therapy. Less pain and stiffness were reported by 46% of the patients and 36% reported reduced joint swelling. Similar beneficial effects of diet were also reported in other rheumatic disease groups. Fifteen percent of the patients with rheumatoid arthritis and ankylosing spondylitis had been through a fasting period. Less pain and stiffness were reported by 2/3 of the patients in both groups and half of the patients in both groups reported a reduced number of swollen joints.

The influence of fast and vegetarian diet on parameters of nutritional status in patients with rheumatoid arthritis.

Nutritional status was studied over a period of 13 months in 34 patients with rheumatoid arthritis (RA). Seventeen patients fasted for 7-10 days, were then transferred to a gluten-free vegan diet for 3.5 months and finally to a lactovegetarian diet for 9 months. The remaining 17 patients followed a "normal" diet. After one month, the values for body mass index (BMI) and triceps skinfold thickness (TSF) were significantly reduced in the diet group compared with the values at inclusion (p < 0.001), whereas upper arm muscle area (UAMA) was not significantly reduced. Evaluation of the whole study course revealed a significantly lower BMI (p = 0.04) and TSF (p < 0.01) in the diet group compared with the control group. The concentration of insulin-like growth factor 1 (IGF1) was significantly reduced in the diet group after one month compared with the value at inclusion (p = 0.01), but the overall difference between the two groups was not significant. There were no overall significant differences with regard to VAMA, concentration of serum albumin, haemoglobin, ferritin, zinc and copper between the two groups. Thus fast, followed by diet manipulations for one year, had a minor impact on nutritional status in patients with RA.

Decreased CD4+ lymphocyte activation and increased interleukin-4 production in peripheral blood of rheumatoid arthritis patients after acute starvation.

We investigated the effects of acute starvation on mitogen-induced T-cell activation and Th1/Th2 cytokine responses in rheumatoid arthritis (RA) patients. Ten RA patients with active disease underwent a 7-day fast followed by a 2-week refeeding period. Immunological, hormonal, laboratory and clinical evaluations were carried out on days 0, 7 and 21. Using flow cytometry, mitogen-stimulated T-cell activation was assessed in fresh heparinised blood via analysis of CD69 expression. Production of Th1 (interferon-gamma) and Th2 (interleukin-4, IL-4) cytokines was also assessed by ELISA. The 7-day fast significantly decreased the erythrocyte sedimentation rate, C-reactive protein level, joint count, morning stiffness, body weight, CD4+ and CD8+ counts and CD69+ expression on mitogen stimulated CD4+ lymphocytes. A significant increase in mitogen-induced IL-4 production after fasting was found. The fast markedly reduced serum leptin and insulin-like growth factor-1 concentrations. No significant differences occurred in serum cortisol or prolactin before and after fasting. Decreases in CD4+ lymphocyte activation during fasting correlated with decreases in body weight. Our results suggest that the clinical and laboratory improvements in fasting RA patients may be attributed to decreased CD4+ T-cell activation and an increase in the number and/or function of IL-4-producing Th2 cells. Factors associated with loss of body weight during acute starvation appear to have an inhibitory effect on CD4+ lymphocyte activation.

Proteus IgG antibodies and C-reactive protein in English, Norwegian and Spanish patients with rheumatoid arthritis.

The distribution of Proteus antibody levels was compared in English, Norwegian and Spanish patients with rheumatoid arthritis (RA). Using an indirect immunofluorescence method, the IgG antibody titre against Proteus mirabilis was measured in the sera of 27 English, 53 Norwegian and 34 Spanish patients with RA and divided into active and inactive disease groups according to the serum C-reactive protein (CRP) level (> or = 10 mg/l). Serum samples were also collected from 25 English, 30 Norwegian and 14 Spanish healthy individuals who served as controls. The levels of Proteus IgG antibodies were significantly higher in the sera of active RA patients (p<0.001) when compared with the corresponding healthy controls, whether these groups belonged to the English, Norwegian or Spanish populations. Furthermore, active RA patients from each country showed significantly higher levels of Proteus antibodies when compared with inactive English (p<0.01), Norwegian (p<0.001) or Spanish (p<0.001) RA patients. Finally, a significant correlation was observed between Proteus IgG antibody levels and the CRP concentrations in RA patients whether each population was tested individually or all together (p<0.001). The increased levels of Proteus antibodies in RA patients from three different European countries support the concept of a possible aetiopathogenetic role for Proteus microorganisms in the development of RA.

A preliminary study of circadian serum cortisol concentrations in response to a 72-hour fast in rheumatoid arthritis patients not previously treated with corticosteroids.

The aim of the study was to investigate the effects a 72-h fast upon serum total and free cortisol concentrations in RA patients not previously treated with glucocorticoids. Total serum cortisol and transcortin concentrations were measured in four RA patients with active disease at 4-h intervals during two 24-h periods (1200 h-1200 h), the first while eating a normal diet (fed state) and the second during the last 24 h of a 72-h water fast. Free cortisol concentrations were calculated from the total cortisol and transcortin values. The 3-day fast increased overall 24-h free and total cortisol concentrations by 50% and 35%, respectively. This was due largely to a marked increase in nocturnal serum cortisol concentrations during fasting, particularly at 0400 h, when mean total and free cortisol levels were increased by 170% and 260% compared to the fed state. Between 2000 and 0800 h overall total- and free cortisol concentrations were increased by 72% and 99%, respectively. These results suggest that an increase in nocturnal concentrations of cortisol occurs in response to fasting in RA patients not previously treated with glucocorticoids. These increases may mediate the beneficial clinical response previously found in studies of longer fasting periods in RA patients.

Clinical effect of buffy-coat vs. apheresis platelet concentrates in patients with severe thrombocytopenia after intensive chemotherapy.

BACKGROUND AND OBJECTIVES: Therapeutic or prophylactic use of platelet concentrates (PC) is essential for patients with thrombocytopenia due to intensive chemotherapy for various malignancies. PC quality has been improved after introduction of storage containers that are more oxygen permeable than the second-generation PC containers. Consequently, shelf life of PCs at our blood bank has been extended to 6.5 days after monitoring each PC for bacterial contamination. In this prospective observational study, we compared apheresis PCs harvested by Amicus cell separator with buffy-coat (BC) PCs during storage for up to 6.5 days. MATERIALS AND METHODS: All PCs were collected from healthy volunteer donors and were prepared for routine clinical use. A total of 446 transfusion episodes with 688 PCs for 77 adult patients with oncological and haematological diseases were registered during a 13-month period. Outcome measures were corrected count increment after 1 h (CCI-1), after 18-24 h (CCI-2), and transfusion intervals. Transfusions were carried out after storage from 1.5 to 6.5 days. RESULTS: Both CCI and the transfusion intervals decreased statistically significantly by increasing storage time after transfusions with apheresis PCs or BC PCs. However, less than 4% of the variation in CCI and transfusion interval could be explained by platelet storage time. There were no significant differences between BC PCs and apheresis PCs, regarding CCI and transfusion intervals. CONCLUSION: We can conclude that BC PCs are not inferior to apheresis PCs, and may serve the clinical purposes as well as apheresis PCs harvested by Amicus.