Serial immunoreactive erythropoietin levels in autologous blood donors

The variations in plasma erythropoietin (EPO) concentration during preoperative deposit of autologous blood were studied in 12 patients (8 men, 4 women). Four donations were scheduled at weekly intervals. A predonation hemoglobin concentration of 11 g per dL (110 g/L) was required. Hemoglobin concentration decreased from 14.3 +/- 1.1 g per dL (143 +/- 11 g/L) (mean +/- SD) before the first donation to 11.7 +/- 0.7 g per dL (117 +/- 7 g/L) on Day 22 (p less than or equal to 0.0001). Reticulocyte counts increased from a median of 31,800 (range, 4900-95,000) per microL (median, 32 x 10(9)/L [range, 5-95 x 10(9)/L]) to 93,800 (16,800-194,900) per microL (median, 94 x 10(9)/L [range, 17-195 x 10(9)/L]) on Day 28 (p less than or equal to 0.01). Plasma EPO concentration was 17.8 +/- 5.1 mU per mL prior to the first donation and displayed a small and transient peak after each donation. A sustained elevation followed each peak. Although plasma EPO concentration differed significantly from the baseline value after the first donation, only the peak concentrations after the second (35.5 +/- 15.5 mU/mL), third (38.0 +/- 14.5 mU/mL), and fourth (36.1 +/- 11.0 mU/mL) donations exceeded the normal range. The moderate, biphasic increase in plasma EPO concentration and the moderate increase in erythropoiesis suggest two strategies in autologous blood donation that should be investigated with respect to efficiency and safety: 1) more aggressive donation schemes, which reduce donation intervals and/or the minimum hemoglobin concentration and 2) the administration of recombinant human EPO.     

Transmission of hepatitis G virus in patients with angioedema treated with steam-heated plasma concentrates of C1 inhibitor

BACKGROUND: Hepatitis G virus (HGV) is a blood-borne flavivirus that may cause acute and chronic transfusion-transmitted infections. Patients with complement component 1 (C1) inhibitor (C1-INH) deficiency may acquire blood-borne infections through infusion of plasma concentrates. STUDY DESIGN AND METHODS: Serum samples from 84 patients with C1-INH deficiency (19 who received unmodified C1-INH concentrates, 23 who received steam-heated concentrates, and 42 untreated patients) were tested for HGV RNA and hepatitis C virus (HCV) RNA by a nested polymerase chain reaction (PCR). The samples were also tested for antibodies to the E2 envelope protein of HGV (anti-HGV) and to HCV with enzyme-linked immunosorbent assays. RESULTS: Nine (11%) patients had serum HGV RNA; that is, 7 (17%) of 42 patients previously treated with C1-INH concentrates and 2 of 42 previously untreated patients. HGV RNA was as common in the 19 patients treated with unmodified concentrates as in the 23 given steam-heated concentrates (16 vs. 17%, p = 0.60). Anti-HGV was more common among the recipients of unmodified concentrates than among those given steam-heated concentrates (26 vs. 0%, p = 0.014). HCV RNA was more frequently detected in treated patients than in untreated patients (33 vs. 7%, p = 0.005) and in the 19 recipients of unmodified concentrates than in the 23 treated with steam-heated concentrates (58 vs. 16%, p = 0.003). Only one HGV RNA- seropositive patient had elevated serum aminotransferase activity, compared to 11 with HCV RNA. CONCLUSION: HGV was transmitted by both unmodified and steam-heated concentrates, but it caused persistent viremia in a minority of the cases and was rarely associated with liver disease.     

Adverse reactions in blood donors with a history of seizures or epilepsy

BACKGROUND: Individuals with epilepsy or seizure disorders are restricted from donating blood because of concern that they are prone to adverse donor reactions such as syncope and convulsions. A study evaluating whether that concern is warranted is reported. STUDY DESIGN AND METHODS: During a 2-year period beginning in 1987, blood donors in Maryland with a history of seizures were actively recruited by the American Red Cross. Adverse donor reactions were classified as "slight", indicating dizziness and nausea without loss of consciousness; "moderate," denoting syncope; and "severe," indicating convulsive syncope. RESULTS: There were 329,143 satisfactory blood donations; 613 individuals reporting a history of seizures donated blood a total of 723 times. Among donors with seizures, 186 (35.7%) were taking antiepileptic medication, and 61 (8.4%) had had one or more seizures in the preceding year. Individuals with seizures had a low incidence of adverse reactions (3.34%). Although this incidence was slightly higher than that in the entire population (2.24%), the difference was not significant. In particular, the risk of syncope with or without convulsive activity was low for people with seizures (0.21%) and not significantly greater than that in other donors (0.28%). CONCLUSION: Individuals with seizures or epilepsy are not at greater risk for adverse reactions after blood donation, and major restrictions on their participation as blood donors are not warranted.     

Induced hyperthermia exacerbates neurologic neuronal histologic damage after asphyxial cardiac arrest in rats

BACKGROUND: Temperature is an important modulator of the evolution of ischemic brain injury--with hypothermia lessening and hyperthermia exacerbating damage. We recently reported that children resuscitated from predominantly asphyxial arrest often develop an initial spontaneous hypothermia followed by delayed hyperthermia. The initial hypothermia observed in these children was frequently treated with warming lights which, despite careful monitoring, often resulted in overshoot hyperthermia. We have previously reported in a rat model of asphyxial cardiac arrest that active warming, to prevent spontaneous hypothermia, worsens brain injury. OBJECTIVE: We sought to determine whether delayed induction of hyperthermia would worsen brain injury after asphyxial arrest in rats. DESIGN: Male Sprague-Dawley rats were asphyxiated for 8 mins and resuscitated. An implantable temperature probe was placed into the peritoneum before asphyxia. The probe is a component of a computer-based, radiofrequency, telemetry system (Minimitter, Sunriver, OR) that allowed continuous acquisition and manipulation (via heating and cooling devices) of core (intraperitoneal) body temperature. Body temperature was monitored but not manipulated for the first 24 hrs of recovery. Rats were assigned to: no temperature manipulation (n = 21), induced hyperthermia (40 +/- 0.5 degrees C) for 3 hrs beginning at 24 hrs (n = 21), or induced hyperthermia at 48 hrs (n = 10). Control groups included sham rats (all surgical procedures except asphyxia) treated with induced hyperthermia at 24 hrs (n = 4) or 48 hrs (n = 4) and na?ve rats (n = 4). Rats were killed at 7 days and injured neurons in hematoxylin and eosin stained coronal brain sections through dorsal hippocampus were scored in a semiquantitative manner on a scale of 0 to 10 (0 = normal; 1 = up to 10% neurons with ischemic neuronal changes; 10 = 90-100% neurons with ischemic neuronal changes). Normal-appearing neurons were also counted in CA1. The number of normal-appearing neurons in a 20x field in CA1 were also counted. MAIN RESULTS: All na?ve and sham hyperthermia control rats survived the protocol. There was a trend toward a larger mortality rate in asphyxiated rats treated with induced hyperthermia at 24 hrs (9 of 21 died) vs. asphyxiated rats without induced hyperthermia (3 of 21) or with hyperthermia induced at 48 hrs (3 of 10) (Kaplan-Meier p=.0595). Asphyxiated rats with hyperthermia induced at 24 hrs had larger (worse) histopathology damage scores than rats subjected to asphyxia without induced hyperthermia (9.3 +/- 1.5 vs. 6.2 +/- 2.6; p=.001). Histopathology damage scores in asphyxiated rats with hyperthermia induced at 48 hrs did not differ from those in rats asphyxiated without induced hyperthermia (6.4 +/- 3.0 vs. 6.2 +/- 2.6; p=.907). There were fewer normal-appearing CA1 neurons in asphyxiated rats with hyperthermia induced at 24 hrs vs. rats subjected to asphyxia without induced hyperthermia (33 +/- 13 vs. 67 +/- 36; p=.002). The number of normal-appearing CA1 neurons in asphyxiated rats with hyperthermia induced at 48 hrs did not differ from that in rats asphyxiated without induced hyperthermia (59 +/- 21 vs. 67 +/- 36; p=.885). CONCLUSIONS: Induced hyperthermia when administered at 24 hrs, but not 48 hrs, worsens ischemic brain injury in rats resuscitated from asphyxial cardiac arrest. This may have implications for postresuscitative management of children and adults resuscitated from cardiac arrest. The common clinical practice of actively warming patients with spontaneous hypothermia might result in iatrogenic injury if warming results in hyperthermic overshoot. Avoidance of hyperthermia induced by active warming at critical time periods after cardiac arrest may be important.     

Delayed, spontaneous hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats

OBJECTIVE: Core temperature is reduced spontaneously after asphyxial cardiac arrest in rats. To determine whether spontaneous hypothermia influences neurologic damage after asphyxial arrest, we compared neurologic outcome in rats permitted to develop spontaneous hypothermia vs. rats managed with controlled normothermia. INTERVENTIONS: Male Sprague-Dawley rats were asphyxiated for 8 mins and resuscitated. After extubation, a cohort of rats was managed with controlled normothermia (CN) by placement in a servo-controlled incubator set to maintain rectal temperature at 37.4 degrees C for 48 hrs. CN rats were compared with permissive hypothermia (PH) rats that were returned to an ambient temperature environment after extubation. Rats were killed at either 72 hrs (PH72hr, n = 14; CN72hr, n = 9) or 6 wks (PH6wk, n = 6, CN6wk, n = 6) after resuscitation. PH72 rats were historic controls for the CN72 rats, whereas PH6 and CN6 rats were randomized and studied contemporaneously. MEASUREMENTS: A clinical neurodeficit score (NDS) was determined daily. A pathologist blinded to group scored 40 hematoxylin and eosin -stained brain regions for damage by using a 5-point scale (0 = none, 5 = severe). Quantitative analysis of CA1 hippocampus injury was performed by counting normal-appearing neurons in a defined subsection of CA1. MAIN RESULTS: Mean rectal temperatures measured in the PH6wk rats (n = 6) were 36.9, 34.8, 35.5, 36.7, and 37.4 degrees C at 2, 8, 12, 24, and 36 hrs, respectively. Mortality rate (before termination) was lower in PH compared with CN (0/20 vs. 7/15; p < .005). PH demonstrated a more favorable progression of NDS (p = .04) and less weight loss (p < .005) compared with CN. Median histopathology scores were lower (less damage) in PH72hr vs. CN72hr for temporal cortex (0 vs. 2.5), parietal cortex (0 vs. 2), thalamus (0 vs. 3), CA1 hippocampus (1.5 vs. 4.5), CA2 hippocampus (0 vs. 3.5), subiculum (0 vs. 4), and cerebellar Purkinje cell layer (2 vs. 4) (all p < .05). There was almost complete loss of normal-appearing CA1 neurons in CN72hr rats (6 +/- 2 [mean +/- SD] normal neurons compared with 109 +/- 12 in na?ve controls). In contrast, PH72hr rats demonstrated marked protection (97 +/- 23 normal-appearing neurons) that was still evident, although attenuated, at 6 wks (42 +/- 24 normal-appearing neurons, PH6wk). CONCLUSION: Rats resuscitated from asphyxial cardiac arrest develop delayed, mild to moderate, prolonged hypothermia that is neuroprotective.     

Angiotensin‐converting enzyme inhibition increases glucose‐induced insulin secretion in response to acute restraint

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Selective early cardiolipin peroxidation after traumatic brain injury: an oxidative lipidomics analysis

OBJECTIVE: Enhanced lipid peroxidation is well established in traumatic brain injury. However, its molecular targets, identity of peroxidized phospholipid species, and their signaling role have not been deciphered. METHODS: Using controlled cortical impact as a model of traumatic brain injury, we employed a newly developed oxidative lipidomics approach to qualitatively and quantitatively characterize the lipid peroxidation response. RESULTS: Electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry analysis of rat cortical mitochondrial/synaptosomal fractions demonstrated the presence of highly oxidizable molecular species containing C(22:6) fatty acid residues in all major classes of phospholipids. However, the pattern of phospholipid oxidation at 3 hours after injury displayed a nonrandom character independent of abundance of oxidizable species and included only one mitochondria-specific phospholipid, cardiolipin (CL). This selective CL peroxidation was followed at 24 hours by peroxidation of other phospholipids, most prominently phosphatidylserine, but also phosphatidylcholine and phosphatidylethanolamine. CL oxidation preceded appearance of biomarkers of apoptosis (caspase-3 activation, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positivity) and oxidative stress (loss of glutathione and ascorbate). INTERPRETATION: The temporal sequence combined with the recently demonstrated role of CL hydroperoxides (CL-OOH) in in vitro models of apoptosis suggest that CL-OOH may be both a key in vivo trigger of apoptotic cell death and a therapeutic target in experimental traumatic brain injury.     

CD40‐activated B cells can be generated in high number and purity in cancer patients: analysis of immunogenicity and homing potential

Cellular adjuvants such as dendritic cells (DC) are in the focus of tumour immunotherapy. In DC‐vaccine trials, induction of tumour antigen‐specific immunity is observed frequently and well‐documented clinical responses have been reported. However, the overall response rate is less than 3%, therefore alternative strategies are being investigated. CD40‐activated B cells (CD40‐B) have been characterized previously as an interesting alternative because they present antigen efficiently and can be expanded by several logs from small amounts of peripheral blood. To determine the central technical challenges of cell‐based vaccines we performed a single‐patient analysis of 502 patients from DC‐based tumour vaccine trials and identified at least three factors contributing to their limited efficiency: (1) lack of cell numbers; (2) lack of documented purity thus high contamination of bystander cells; and (3) lack of quality control and thus heterogeneous or unknown expression of important surface molecules such as major histocompatibility complex (MHC) and chemokine receptors. Based on these findings we re‐evaluated the CD40‐B approach in cancer patients. Here, we show that proliferation of B cells from cancer patients is equivalent to that observed in healthy donors. Purity is always > 90% after 2 weeks and remains stable for several weeks. They have comparable antigen‐presenting capability determined phenotypically and by allogeneic mixed lymphocyte reaction. Expression of CCR7 and CD62L was detected in all samples and B cells migrated towards the relevant homing chemokines. Taken together, CD40‐B cells from cancer patients can be expanded in virtually unlimited numbers at high purity and full function concerning antigen‐presentation and migratory properties.