Clinical and laboratory correlates of platelet alloimmunization and refractoriness in the PLADO trial.

BACKGROUND AND OBJECTIVES: Platelet alloimmunization and refractoriness to platelet transfusion are complications of platelet transfusion therapy. The platelet dose (PLADO) trial, as the largest prospective randomized trial of prophylactic platelet therapy to date, afforded an opportunity to analyse these two issues. MATERIALS AND METHODS: PLADO patient records were examined for evidence of platelet alloimmunization, defined as an increase in HLA Class I panel-reactive antibodies (PRA) to ≥20%, and clinical refractoriness, defined as two consecutive ≤4 h posttransfusion corrected platelet count increments (CCI) of <5000. Multivariate logistic regression, restricted to platelet-transfused subjects who received exclusively either in-process leucoreduction apheresis or whole blood-derived (WBD) leucocyte-reduced platelets, compared the frequency of these outcomes by platelet unit and patient characteristics. RESULTS: Forty of 816 evaluable platelet-transfused patients (5%) became alloimmunized during the trial. Prior pregnancy, chemotherapy only compared to progenitor cell transplant, and low platelet dose - all were associated with significantly higher rates of alloimmunization. Among 35 alloimmunized patients evaluated for refractoriness, 8 (23%) had two consecutive CCI < 5000/µl. Regardless of alloimmunization status, CCIs < 5000/µl were observed following 17% of platelet transfusions. Among 734 patients receiving at least two platelet transfusions, two consecutive CCIs of ≤5000 occurred in 102 (14%). CONCLUSIONS: The incidence of new platelet alloimmunization was low in the PLADO study, but follow-up was at most 30 days. Alloimmunization was present in only 8 of 102 (8%) of observed cases of refractoriness, suggesting that other causes of poor posttransfusion increments are frequent.

Rituximab for treatment of inhibitors in haemophilia A. A Phase II study.

The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m² weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5-10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies.

Transmission of GB virus type C via transfusion in a cohort of HIV-infected patients.

BACKGROUND: GB virus C (GBV-C) infection is transmitted by blood exposure and associated with lower human immunodeficiency virus (HIV) load and slower HIV disease progression. Few studies describe predictors of acute GBV-C infection following transfusion in HIV-infected patients. METHODS: We used a limited-access database from the National Heart Lung and Blood Institute's Viral Activation Transfusion Study, a randomized controlled trial of leukoreduced versus nonleukoreduced transfusions received by HIV-infected, transfusion-naive patients. Blood samples from 489 subjects were tested for GBV-C markers in pretransfusion and posttransfusion samples. We estimated the risk of acquiring GBV-C RNA and predictors of GBV-C acquisition, using pooled logistic regression. RESULTS: GBV-C RNA was detected ≤120 days following the first transfusion in 22 (7.5%) of 294 subjects who were GBV-C negative before transfusion. The risk of GBV-C RNA acquisition increased with each unit transfused (odds ratio, 1.09; 95% confidence interval, 1.06-1.11). Lower baseline HIV load and use of antiretroviral therapy were associated with subsequent GBV-C RNA acquisition, after control for units of blood transfused. Leukoreduced status of transfused units was not associated with GBV-C transmission. CONCLUSIONS: Blood transfusion is associated with a significant risk of GBV-C acquisition among HIV-infected patients. Transmission of GBV-C by blood transfusion was inversely related to HIV load.

Addressing the question of the effect of RBC storage on clinical outcomes: the Red Cell Storage Duration Study (RECESS) (Section 7).

The question of whether storage of red blood cells (RBCs) alters their capacity to deliver oxygen and affects patient outcomes remains in a state of clinical equipoise. Studies of the changes which occur while RBCs are stored have led to several physiologically plausible hypotheses that these changes impair RBC function when the units are transfused. Although there is some evidence of this effect in vivo from animal model experiments, the results of several largely retrospective patient studies have not been consistent. Some studies have shown an association between worse clinical outcomes and transfusion of RBC which have been stored for longer periods of time, while others have found no effect. Three multicenter, randomized, controlled trials have been developed to address this important, but currently unanswered, question. Two clinical trials, one in low birth weight neonates and the other in intensive care unit patients, are enrolling subjects in Canada (the Age of Red Blood Cells in Premature Infants; the Age of Blood Study). The third trial, which is being developed in the United States, is the Red Cell Storage Duration Study (RECESS). This is a multicenter, randomized, controlled trial in which patients undergoing complex cardiac surgical procedures who are likely to require RBC transfusion will be randomized to receive RBC units stored for either 10 or fewer days or 21 or more days. Randomization will only occur if the blood bank has enough units of RBC of both storage times to meet the crossmatch request; hence, subjects randomized to the 21 day arm will receive RBC of the same storage time as they would have following standard inventory practice of "oldest units out first". The primary outcome is the change in the Multiple Organ Dysfunction Score (MODS), a composite measure of multiorgan dysfunction, by day 7. Secondary outcomes include the change in the MODS by day 28, all-cause mortality, and several composite and single measures of specific organ system function. The estimated total sample size required will be 1434 evaluable subjects (717 per arm).

[Dialysis and the risk of poverty]. / Dialyse und Armutsrisiko.

INTRODUCTION: For patients with severe kidney failure, the only alternative to transplantation today is an enduring dialysis treatment. But dialysis is associated with manifold physical and social restrictions. The study analyses the psychosocial consequences of the chronic disease of renal insufficiency: Does chronic kidney failure increase the patients' risk to sink into poverty? SAMPLE/METHODS: In the year 2006 625 dialysis patients participated in an enquiry in 77 dialysis centres in Germany. The newly developed questionnaire included 19 items about social situation, treatment conditions, and quality of life. The response rate was 54.3%. The analyses were calculated using descriptive statistics and discriminatory analyses. RESULTS: 51.8% of the patients lived in the new German federal states (the former GDR), 44.9% are female. The mean age of the sample was 62.2 years. 57.5% of the participants were married or cohabited. There was at least one person aged younger than 18 years in 12% of the households. 54.8% of the respondents had a German CSE, 25.3% had a German Remedial School Certificate of Completion, and 12.4% had a German Abitur (German university entrance qualification). At the time of the enquiry, 60.2% of the patients were below the poverty level (60% of the mean income in Germany). Important impact factors for an existence above the poverty level were the number of persons per household and the age of the participants. The more persons per household, the greater was the risk to be below the poverty level. Households with more than two persons had a significantly higher risk to be below the poverty level (OR=63.3). Persons aged younger than 50 years had a significantly higher risk to be below the poverty level than those aged 50 years or older (OR=2.0). CONCLUSIONS: Chronic renal insufficiency is associated with a higher poverty risk if the patients feature specific attributes. Although living alone is often regarded as a poverty risk because larger households usually have more opportunities to save costs, due to our findings patients living together with several persons in a household are at higher risk to sink into poverty. They are younger or middle-aged and have responsibility to support children or partners. A higher poverty risk results from the fact that they are at a younger age when their dialysis starts and usually receive a lower employment disability pension. The results correspond with data of the German Federal Statistical Office, which show that the number of paupers is greater within younger age groups. Relevant for prevention seems to be the impact of the physician on a possible further occupation of dialysis patients.

Brassinosteroids and plant function: some clues, more puzzles.

The role of brassinosteroids (BRs) in plant function has been intensively studied in the last few years. Mutant analysis has demonstrated that the ability to synthesize, perceive and respond to BRs is essential to normal plant growth and development. Several key elements of BR response have been identified using both genetic and biochemical approaches, and molecular models that parallel Wingless (Wnt), transforming growth factor beta (TGF beta) and receptor tyrosine kinase (RTK) signalling in animals have been proposed. Many studies have demonstrated the role of BRs, alone and in interaction with other plant hormones, in processes such as cell elongation and seed germination. In contrast, little is known about how the sensing of BRs is connected to specific physiological responses such as stress resistance. There remain many open questions about how these connections are made.

Quality of life in diverse groups of midlife women: assessing the influence of menopause, health status and psychosocial and demographic factors.

This paper examines whether menopausal status is associated with global quality of life (QOL) among women aged 40-55 and whether this association varies by race/ethnicity. We further examine the contributions of other health-related and psychosocial factors to QOL and whether these associations vary by racial/ethnic group. Analyses are based on 13,874 women who participated in the multi-ethnic, multi-race study of mid-aged women called the Study of Women's Health Across the Nation (SWAN). Study participants completed a 15-min telephone or in-person interview that contained questions on a variety of health-related topics. Items of interest for these analyses include global QOL, menstrual history (to assess menopausal status), sociodemographics, health status, lifestyle, and psychosocial variables. Results showed that in unadjusted analyses, early perimenopausal women reported lower QOL compared with premenopausal women, but menopausal status was no longer associated with QOL when analyses were adjusted for other variables. In multivariable models, being married and having low levels of perceived stress were associated with better QOL across all racial/ethnic groups. While there were many consistencies across racial/ethnic groups, we also found that the nature of the associations between QOL and education, marital status, perceived stress and social support varied across racial/ethnic groups.

Synthesis and characterization of colloidal fluorescent mesoporous silica particles.

Mesoporous silica particles with narrow size distribution were obtained by a seeded growth process. Depending on the size of seeds and on the time of addition of reactants, the size of particles can be varied between 300 and 1000 nm. In a second step the dye fluorescein isothiocyanate can be embedded. The structure of these new silica particles with low density was investigated by SEM, XRD, BET, and confocal microscopy.

A prospective, randomized clinical trial of universal WBC reduction.

BACKGROUND: Recipient exposure to allogeneic donor WBCs results in transfusion complications for selected populations of recipients. Whether or not WBC reduction should be universally applied is highly controversial. STUDY DESIGN AND METHODS: In a general hospital, a randomized, controlled clinical trial of conversion to universal WBC reduction was conducted. Patients (11%) with established medical indications for WBC-reduced blood were not eligible. All other patients who required transfusion were assigned at random to receive either unmodified blood components or stored WBC-reduced RBCs and platelets. Analysis for each patient was restricted to the first hospitalization. RESULTS: All eligible patients (n = 2780) were enrolled. Three specified primary outcome measures were not different between the two groups: 1) in-hospital mortality (8.5% control; 9.0% WBC-reduced; OR, 0.94 [95% CI, 0.72-1.22]; p = 0.64); 2) hospital length of stay (LOS) after transfusion (median number of days, 6.4 for control and 6.3 for WBC-reduced; p = 0.21); and 3) total hospital costs (median, $19,500 for control and $19,200 for WBC-reduced, p = 0.24). Secondary outcomes (intensive care LOS, postoperative LOS, antibiotic usage, and readmission rate) were not different between the two groups. Subgroup analysis based on patient age, sex, amount of blood transfused, or category of surgical procedure showed no effect of WBC reduction. Patients who received WBC-reduced blood had a lower incidence of febrile reactions (p = 0.06). CONCLUSION: A beneficial effect of conversion from selective to universal WBC reduction was not demonstrated.

The influence of amino acids on the biomineralization of hydroxyapatite in gelatin.

The effects of pH on the calcium phosphate phase, of Tris and of amino acids, such as aspartic acid, glutamic acid, and serine on hydroxyapatite formation and morphology, were studied in double diffusion experiments. In this system, hydroxyapatite was only formed when the pH was around 7.4 or higher for the duration of the reaction. A decrease in pH resulted in the transformation of hydroxyapatite to octacalcium phosphate. Amino acids and Tris or the buffering capacity of Tris have an effect on the morphology of the synthetic hydroxyapatite. The presence of the additive results in spheres consisting of needles, blades or plates depending on the reaction system.

Subtle developmental abnormalities in the inferior olive: an indicator of prenatal brainstem injury in the sudden infant death syndrome.

Subtle quantitative abnormalities in neuronal populations derived from the rhombic lip (i.e. arcuate nucleus at the ventral medullary surface, external granular layer of the cerebellum) have been reported in victims of the sudden infant death syndrome (SIDS). In this study, we examined the inferior olive, a major rhombic lip derivative, to determine if subtle rhombic lip abnormalities also involve this nucleus in SIDS. We analyzed the number and density of neurons and reactive astrocytes in the inferior olive in 29 SIDS cases and 29 controls. Computer-assisted cell counting procedures were used in sections stained with hematoxylin and eosin/Luxol fast blue. There was a significant difference in the postconceptionally age-adjusted mean for neuronal density between SIDS cases (7,687 +/- 255 neurons/mm(3)) and controls (8,889 +/- 255 neurons/mm(3)) (p = 0.002). The difference in age-adjusted mean neuronal number between SIDS cases (1,932 +/- 89 neurons/2 sections) and controls (2,172 +/- 89 neurons/2 sections) was marginally significant (p = 0.063). Reactive astrocytes were present in the inferior olive in SIDS cases, but their number, density, and developmental profile were not significantly different from that of control infants dying of diverse known causes. SIDS victims found dead in cribs, beds, and sofas, prone or supine had subtle olivary abnormalities, suggesting that affected infants are at risk in various sleeping situations. We propose that at least some SIDS victims experience intrauterine brainstem injury including the olivo-arcuato-cerebellar circuitry derived from the rhombic lip. These observations provide future directions for SIDS research concerning the role of early insults in pregnancy, the rhombic lip, and the interactions of the ventral medulla and cerebellum in cardioventilatory control.

Differences in difficulty adjudicating clinical events in patients with advanced HIV disease.

Adjudication of clinical events is often used as a quality assurance method in clinical research. During the design of the Viral Activation Transfusion Study (a clinical trial in patients with advanced HIV disease), a set of study endpoints was defined (primarily AIDS-defining conditions), criteria for confirmation of each event type were developed, and an adjudication procedure was established. The adjudication process included 1) an initial review of documentation of each event by two independent reviewers, 2) the opportunity to request additional information, 3) a second review either of additional documentation or of cases in which there was disagreement on first review, and 4) the consultation of a third reviewer if there was still disagreement. Overall, of 288 reported endpoints, 30% required additional documentation or more than one review, and 16% were not confirmed at the end of the adjudication process. However, these percentages varied widely over different types of events. For example, of 30 reported nonophthalmalogic cytomegalovirus events, 37% required additional documentation and 40% were not confirmed. In contrast, every one of 17 reported Pneumocystis cariini pneumonias were confirmed with no requirement for additional documentation. The results can be used to help design endpoint documentation and adjudication procedures for other studies, thereby improving data quality and reducing costs.

From milliseconds to millions of years: guard cells and environmental responses.

During the past year, significant advances have been made in our understanding of stomatal development and its response to climate change, and in our knowledge of how guard cell Ca(2+) oscillations encode environmental signals. Recent studies on (de)phosphorylation mechanisms have provided new information on how guard cells respond to abscisic acid and blue light.

WBC reduction in RBC concentrates by prestorage filtration: multicenter experience.

BACKGROUND: As universal leukocyte (WBC) reduction (ULR) is being considered as a new standard, few data are available on the performance of WBC-reduction filtration in routine practice. The performance of WBC-reduction in RBCs, using varied filtration practices, in meeting the current FDA requirement (<5 x 10(6)), Council of Europe (EC) recommendation, the proposed FDA requirement (<1 x 10(6)), and a more stringent proposal (<5 x 10(5)) for residual WBCs per RBC unit was assessed and compared. STUDY DESIGN AND METHODS: Participating facilities were the 11 sites of the Viral Activation Transfusion Study (VATS), a prospective study of the impact of transfusion with and without WBC-reduction on survival and HIV viral load in HIV-1-infected patients. Patients randomly assigned to undergo WBC reduction were required to receive RBCs < or =14 days old that had undergone prestorage (within 72 hours of collection) WBC-reduction filtration by a method devised to achieve a postfiltration WBC count of <5 x 10(6). Residual WBC quantitation was performed by PCR in the central VATS laboratory by using frozen WBC-reduced RBC samples obtained at issue for transfusion. RESULTS: A total of 1869 WBC-reduced RBC units were studied. Filtration practices varied within and between sites. There were significant differences in mean residual WBC counts at the 11 sites (p<0.001). Among the WBC-reduced RBC units, 0.8 percent exceeded 5 x 10(6) WBCs per unit, 8.3 percent exceeded 1 x 10(6) WBCs per unit, and 14.3 percent exceeded 5 x 10(5) WBCs per unit. CONCLUSION: Residual WBCs in WBC-reduced RBC units vary within and between sites. WBC reduction was successful, in that over 99 percent and 91 percent of VATS WBC-reduced RBC units met US and EC thresholds, respectively. However, the small but measurable failure rate indicates that not every unit will meet these guidelines.

Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease.

BACKGROUND: Mortality and morbidity related to AIDS have decreased among HIV-infected patients taking highly active anti-retroviral therapy (HAART), but previous studies may have been confounded by other changes in treatment. OBJECTIVE: To assess the benefit of HAART in patients with advanced AIDS and anemia. DESIGN: Prospective, multicenter cohort study. SETTING: The Viral Activation Transfusion Study (VATS), with enrollment from August 1995 through July 1998 and follow-up through June 1999. PATIENTS: 528 HIV-infected patients with cytomegalovirus (CMV) seropositivity or disease who were receiving a first red blood cell transfusion for anemia. MEASUREMENTS: In a person-year analysis of follow-up before and after initiation of HAART, Poisson regression was used to calculate crude rate ratios and rate ratios adjusted for CD4 count, HIV RNA level, calendar period, time on study, sex, ethnicity, and injection drug use. RESULTS: At baseline, patients had a median CD4(+) lymphocyte count of 0.015 x 10(9) cell/L, median plasma HIV RNA level of 4.8 log(10) copies/mL, and median hemoglobin concentration of 73 g/L. Use of HAART increased from 1% of active patients in January 1996 to 79% of active patients in January 1999. The crude death rate was 0.24 event/person-year among patients taking HAART and 0.88 event/person-year among those not taking HAART (rate ratio, 0.26; adjusted rate ratio, 0.38; P < 0.001 for both comparisons). Rates of non-CMV disease were 0.15 event/ person-year after HAART and 0.45 event/person-year before HAART (crude rate ratio, 0.34 [ P < 0.001]; adjusted rate ratio, 0.66 [ P < 0.05]). Rates of CMV disease were 0.10 event/person-year after HAART and 0.25 before HAART (crude rate ratio, 0.42 [ P < 0.01]; adjusted rate ratio, 1.01 [ P > 0.2]). Results were similar in patients with baseline CD4(+) lymphocyte counts less than 0.010 x 10(9) cells/L. CONCLUSIONS: The data support an independent reduction in mortality and opportunistic events attributable to HAART, even in patients with very advanced HIV disease. However, patients with CMV infection or disease may not have a reduction in new CMV events due to HAART.

Survival of transfused donor white blood cells in HIV-infected recipients.

The appearance and expansion of donor white blood cells in a recipient after transfusion has many potential biologic ramifications. Although patients with HIV infection are ostensibly at high risk for microchimerism, transfusion-associated graft-versus-host disease (TA-GVHD) is rare. The purpose of this study was to search for sustained microchimerism in such patients. Blood samples were collected from 93 HIV-infected women (a subset from the Viral Activation Transfusion Study, an NHLBI multicenter randomized trial comparing leukoreduced versus unmodified red blood cell [RBC] transfusions) before and after transfusions from male donors. Donor lymphocytes were detected in posttransfusion specimens using a quantitative Y-chromosome-specific polymerase chain reaction (PCR) assay, and donor-specific human leukocyte antigen (HLA) alleles were identified with allele-specific PCR primers and probes. Five of 47 subjects randomized to receive nonleukoreduced RBCs had detectable male lymphocytes 1 to 2 weeks after transfusion, but no subject had detectable male cells more than 4 weeks after a transfusion. In 4 subjects studied, donor-specific HLA haplotypes were detected in posttransfusion specimens, consistent with one or more donors' cells. None of 46 subjects randomized to receive leukoreduced RBCs had detectable male lymphocytes in the month after transfusion. Development of sustained microchimerism after transfusion in HIV-infected patients is rare; HIV-infected patients do not appear to be at risk for TA-GVHD.

Number of RBC units and rate of transfusionto anemic HIV-positive patients assigned to receiveWBC-reduced or non-WBC-reduced RBCs: the viral activation transfusion study experience.

BACKGROUND: It is known that the use of filtration to reduce WBCs in RBC units is associated with a 6- to 15-percent loss of RBCs. It is not known if the use of such WBC-reduced RBCs results in an increased need for RBC units or in the transfusion of more units per year to patients with anemia. STUDY DESIGN AND METHODS: In the multicenter Viral Activation Transfusion Study (VATS), anemic HIV-positive patients were randomly assigned to receive either WBC-reduced or non-WBC-reduced RBCs. The number of RBC units transfused per patient and the rate of RBC use were studied. All RBC units given after the enrollment transfusion were counted, until the end of follow-up or the occurrence of bleeding (receiving >5 RBCs within 2 consecutive days). RESULTS: As expected, the WBC-reduced RBC units in VATS were lighter in weight than the non-WBC-reduced units (median weight: WBC-reduced, 300 g; non-WBC-reduced, 330 g; p<0.0001). After the enrollment transfusion, 258 WBC-reduced arm patients received 1279 units of RBCs (average, 5.0 units/patient, median, 2 units) while 262 patients in the non-WBC-reduced arm received 1111 RBCs (4.2 units/patient; median, 2 units). The number of units transfused for anemia was slightly greater in the WBC-reduced arm, but the difference was not significant (p = 0.41). Similarly, the rate of RBC use was somewhat higher in the WBC-reduced arm, but the difference was not significant (p = 0.14). The median was 2.3 units per patient per year of follow-up in the WBC-reduced arm; the median in the non-WBC-reduced arm was 1.2 units. CONCLUSION: This study confirms that WBC-reduced RBC units are significantly lighter in weight than non-WBC-reduced RBCs. However, in the setting of a large, randomized, blinded study of transfusion for anemia, the smaller size of the WBC-reduced RBC units had no significant effect on the number of RBC units transfused or on the rate at which RBC units were used. In this study, the frequency of blood transfusion may have had a greater relationship to the frequency of routine, scheduled appointments or transfusion orders for a specified Hb trigger than to the actual Hb content of the unit.

G protein regulation of ion channels and abscisic acid signaling in Arabidopsis guard cells.

The phytohormone abscisic acid (ABA) promotes plant water conservation by decreasing the apertures of stomatal pores in the epidermis through which water loss occurs. We found that Arabidopsis thaliana plants harboring transferred DNA insertional mutations in the sole prototypical heterotrimeric GTP-binding (G) protein alpha subunit gene, GPA1, lack both ABA inhibition of guard cell inward K(+) channels and pH-independent ABA activation of anion channels. Stomatal opening in gpa1 plants is insensitive to inhibition by ABA, and the rate of water loss from gpa1 mutants is greater than that from wild-type plants. Manipulation of G protein status in guard cells may provide a mechanism for controlling plant water balance.

Distribution of alpha 2-adrenergic receptor binding in the developing human brain stem.

Rapid and dramatic changes occur in cardiorespiratory function during early human life. Catecholamines within select brain stem nuclei are implicated in the control of autonomic and respiratory function, including in the nucleus of the solitary tract and the dorsal motor nucleus of X. Animal and adult human studies have shown high binding to alpha 2-adrenergic receptors in these regions. To determine the developmental profile of brainstem alpha 2-adrenergic binding across early human life, we studied brain stems from five fetuses at midgestation, three newborns (37-38 postconceptional weeks), and six infants (44-61 postconceptional weeks). We used quantitative tissue receptor autoradiography with [3H]para-aminoclonidine as the radioligand and phentolamine as the displacer. In the fetal group, binding was high (63-93 fmol/mg tissue) in the nucleus of the solitary tract, dorsal motor nucleus of X, locus coeruleus, and reticular formation; it was low (< 32 fmol/mg tissue) in the principal inferior olive and basis pontis. Binding decreased in all regions with age: in infancy, the highest binding was in the intermediate range (32-62 fmol/mg tissue) and was localized to the nucleus of the solitary tract and dorsal motor nucleus of X. The most substantial decrease in binding (75%-85%) between the fetal and infant periods occurred in the pontine and medullary reticular formation and hypoglossal nucleus. Binding remained low in the principal inferior olive and basis pontis. The decreases in binding with age remained significant after quench correction. These data suggest that rapid and dramatic changes occur in early human life in the brain stem catecholaminergic system in regions related to cardiorespiratory control.

Leukocyte-reduced red blood cell transfusions in patients with anemia and human immunodeficiency virus infection: the Viral Activation Transfusion Study: a randomized controlled trial.

CONTEXT: Allogeneic blood transfusions have immunomodulatory effects and have been associated with activation of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) in vitro and of HIV in small pilot studies. Retrospective studies suggest that transfusions adversely affect the clinical course of HIV. Data in selected non-HIV-infected patients requiring blood transfusion have suggested clinical benefit with leukocyte-reduced red blood cells (RBCs). OBJECTIVE: To compare the effects of leukoreduced and unmodified RBC transfusions on survival, complications of acquired immunodeficiency syndrome, and relevant laboratory markers in HIV-infected patients. DESIGN AND SETTING: Double-blind randomized controlled trial conducted in 11 US academic medical centers from July 1995 through June 1999, with a median follow-up of 12 months (24 months in survivors). PATIENTS: A total of 531 persons infected with HIV and CMV, aged 14 years or older, who required transfusions for anemia; 259 received leukoreduced transfusions and 262 received unmodified transfusions (10 did not receive the planned transfusion). MAIN OUTCOME MEASURES: Survival and change in plasma HIV RNA level 7 days after transfusion, compared by type of transfusion. RESULTS: At entry, the groups were similar in demographic, clinical, and relevant laboratory characteristics. A total of 3864 RBC units were transfused. Two hundred eighty-nine deaths occurred (151 with leukoreduced transfusion; 138 with unmodified transfusion); median survival was 13.0 and 20.5 months, respectively (relative hazard [RH], 1.20; 95% confidence interval [CI], 0.95-1.51; log-rank P =.12). Analyses adjusted for prognostic factors suggested possible worse survival with leukoreduction (RH, 1.35; 95% CI, 1.06-1.72). There was no difference in time to new opportunistic event/death or frequency of transfusion reactions. No changes in plasma HIV RNA level were seen in either group at days 7, 14, 21, or 28, even in patients not taking antiretroviral drugs. There were no differences in trends between groups in CMV DNA, CD4 cell counts, activated (CD38% or human leukocyte antigen-DR) CD8 cell counts, or plasma cytokine levels. CONCLUSIONS: We found no evidence of HIV, CMV, or cytokine activation following blood transfusion in patients with advanced HIV infection. Leukoreduction provided no clinical benefit in these patients. These data demonstrate the importance of conducting controlled studies of effects of leukoreduction in different patient populations, since smaller studies in other patient populations have suggested leukoreduction may be beneficial.