Interleukin-3 treatment of rhesus monkeys leads to increased production of histamine-releasing cells that express interleukin-3 receptors at high levels

To understand the hematopoietic and nonhematopoietic responses to interleukin-3 (IL-3), expression of cell-surface IL-3 receptors (IL-3R) was examined on bone marrow (BM) cells and peripheral blood (PB) cells of rhesus monkeys during the course of in vivo IL-3 treatment. Whereas IL-3R expression is low in untreated monkeys, IL-3 administration led to a gradual increase in both low- and high-affinity binding sites for IL-3. This increase reflected the total number of cells expressing IL- 3Rs, as detected by flow cytometry using biotinylated IL-3. Most of these IL-3R+ cells in both BM and PB could be characterized as basophilic granulocytes that contained high levels of histamine. In contrast to the effect on these differentiated cells, IL-3 administration did not significantly alter the low level IL-3R expression on immature, CD34+ cells. Further flow cytometric analysis using biotinylated growth factors showed that the IL-3R+ basophils also expressed receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), but not for IL-6 or Kit ligand. These findings indicated that the IL-3R+ cells included neither monocytes, which express GM-CSFRs and IL-6Rs abundantly, nor mast cells, which express c- kit. By combining flow cytometric and Scatchard data, it was calculated that the basophils contain as many as 1 to 2 x 10(3) high-affinity IL- 3Rs and 15 to 30 x 10(3) low-affinity sites. The finding that in vivo IL-3 treatment leads to the production of large numbers of cells that express high levels of IL-3R and are capable of producing histamine provides an explanation for the often severe allergic reactions that occur during prolonged IL-3 administration. It also indicates that IL- 3, in addition to its direct effects on hematopoietic cells, may also stimulate hematopoiesis through the release of secondary mediators such as histamine by IL-3-responsive mature cells.     

Outcome prediction in chest injury by a mathematical search and display program

OBJECTIVE: This study applies a stochastic or probability search and display model to prospectively predict outcome and to evaluate therapeutic effects in a consecutively monitored series of 396 patients with severe thoracic and thoracoabdominal injuries. STUDY DESIGN: Prospective observational study of outcome prediction using noninvasive hemodynamic monitoring by previously designed protocols and tested against actual outcome at hospital discharge in a level 1 trauma service of a university-run, inner-city public hospital. METHODS: Cardiac index (CI), heart rate (HR), mean arterial pressure (MAP), arterial oxygen saturation measured by pulse oximetry (Sp(O2)), transcutaneous oxygen tension (PtC(O2)), and transcutaneous carbon dioxide tension (Ptc(CO2)) were monitored beginning shortly after admission to the emergency department. The stochastic search and display model with a decision support program based on noninvasive hemodynamic monitoring was applied to 396 severely ill patients with major thoracic and thoracoabdominal trauma. The survival probability (SP) was calculated during initial resuscitation continuously until patients were stabilized, and compared with the actual outcome when the patient was discharged from the hospital usually a week or more later. RESULTS: The CI, Sp(O2), Ptc(O2), and MAP were appreciably higher in survivors than in nonsurvivors. HR and Ptc(CO2) were higher in the nonsurvivors. The calculated SP in the first 24-h observation period of survivors of chest wounds averaged 83 +/- 18% (+/- SD) and 62 +/- 19% for nonsurvivors. Misclassifications were 9.6%. The relative effects of alternative therapies were evaluated before and after therapy, using hemodynamic monitoring and SP as criteria. CONCLUSIONS: Noninvasive hemodynamic monitoring with an information system provided a feasible approach to early outcome predictions and therapeutic decision support.     

In vivo release and turnover of secreted platelet antiheparin proteins in rhesus monkey (Macaca mulatta)

Human and rhesus monkey platelets secrete at least two antiheparin proteins: platelet factor 4 (PF4) and low affinity platelet factor 4 (LA-PF4). Neither of these proteins showed species-related antigenic differences. As determined by radioimmunoassay, the levels of PF4 and LA-PF4 antigen per 10(9) monkey platelets amounted to 10.7 and 20.3 microgram, respectively. One milliliter of monkey plasma prepared from blood collected into an anticoagulant composed of EDTA, prostaglandin E1, and theophylline solution contained 22.4 ng LA-PF4 and 8.0 ng PF4. Concentrations of these two platelet-specific proteins in monkeys closely resembled levels found in human platelets and plasma. Infusion of prostacyclin (PGI2) (100 or 300 ng/kg/min) into monkeys for 15 min resulted in a significant decrease of plasma levels of LA-PF4 antigen and of PF4 by 40%--60% (p < 0.0001). This decrease was related to the inhibitory effect of PGI2 on the secretion of platelets stimulated by a catheter or by venipuncture. Longer infusion of PGI2 did not produce further significant change. The supernate obtained after aggregation of human platelets stimulated by thrombin was injected into monkeys receiving PGI2 infusion. The disappearance of LA-PF4 antigen in monkey plasma followed a biphasic exponential curve with half-lives for the fast and slow components of 8.4 and 63 min. PF4 disappeared faster but followed the same pattern (half-lives for the fast and slow component of 2.1 and 70 min). Analysis of the experimental data suggests that the low levels of secreted platelet proteins in monkey plasma are related to their minimal in vivo release and to their rapid clearance.     

Risk factors for avascular bone necrosis in systemic lupus erythematosus

OBJECTIVE: To study the predictive factors for avascular necrosis (AVN) of bone in patients with systemic lupus erythematosus (SLE). METHOD: The records of 38 SLE patients who developed clinically apparent AVN during the course of their disease were reviewed. Information on clinical presentation, corticosteroid usage and autoantibody profiles was obtained, and comparison was made between these patients and 143 consecutive control SLE patients who did not have AVN. RESULTS: The point prevalence of AVN in our SLE population was 12%. Patients with AVN, when compared with controls, had a significantly higher incidence of neurological disease (39% vs 14%; P < 0.001) and Cushingoid body habitus after steroid treatment (79% vs 53%; P = 0.004). The highest cumulative prednisolone dose in 1 and 4 months was significantly higher in the AVN group than the controls (1.8 vs 1.1 and 4.5 vs 2.8 g, respectively; P < 0.01 in both) and showed a linear trend with the incidence of AVN (chi2 test for trend, P < 0.01 in both). Lupus anticoagulant was associated with AVN (P = 0.02, odds ratio 2.88 [1.14- 7.28]). Logistic regression analysis revealed that the highest cumulative prednisolone dose administered in 4 months, the maximum and mean daily prednisolone dosage, and the lupus anticoagulant were independent risk factors for AVN. CONCLUSIONS: Corticosteroid remains the major predisposing factor for AVN in SLE. Patients who require an initial high-dose steroid for disease control are at risk of AVN, especially if they are positive for the lupus anticoagulant or develop Cushingoid habitus after steroid treatment. High-risk patients should be closely monitored so that early AVN can be diagnosed by sensitive techniques such as magnetic resonance imaging and radioisotope bone scanning.      

The cytoskeleton in Chediak-Higashi syndrome fibroblasts

The Chediak-Higashi syndrome (CHS) trait is expressed in cultured human skin fibroblasts as an abnormal perinuclear concentration of moderately enlarged lysosomes. The cytoskeleton of CHS fibroblasts appears intact. Microtubules are normal in number and morphology, as assessed by colchicine binding studies, antitubulin immunofluorescence, and electron microscopy. Deformability by shear force is unaltered and microfilaments are abundant. However, CHS lysosomes appear to interact abnormally with the cytoskeleton, since the perinculear aggregation partially disperses after depolymerization of cell microtubules with colchicine. These results suggest that CHS is associated with a defect of either the lysosomal membrane itself or of lysosomal membrane- microtubule interaction.     

Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.     

The provision of a time-critical elective surgical service during the COVID-19 Crisis: a UK experience

IntroductionWith the emergence of the COVID-19 pandemic, all elective surgery was temporarily suspended in the UK, allowing for diversion of resource to manage the anticipated surge of critically unwell patients. Continuing to deliver time-critical surgical care is important to avoid excess morbidity and mortality from pathologies unrelated to COVID-19. We describe the implementation and short-term surgical outcomes from a system to deliver time-critical elective surgical care to patients during the COVID-19 pandemic.Materials and methodsA protocol for the prioritisation and safe delivery of time-critical surgery at a COVID-19 ‘clean’ site was implemented at the Nuffield Health Exeter Hospital, an independent sector hospital in the southwest of England. Outcomes to 30 days postoperatively were recorded, including unplanned admissions after daycase surgery, readmissions and complications, as well as the incidence of perioperative COVID-19 infection in patients and staff.ResultsA total of 128 surgical procedures were performed during a 31-day period by a range of specialties including breast, plastics, urology, gynaecology, vascular and cardiology. There was one unplanned admission and and two readmissions. Six complications were identified, and all were Clavien-Dindo grade 1 or 2. All 128 patients had preoperative COVID-19 swabs, one of which was positive and the patient had their surgery delayed. Ten patients were tested for COVID-19 postoperatively, with none testing positive.ConclusionThis study has demonstrated the implementation of a safe system for delivery of time-critical elective surgical care at a COVID-19 clean site. Other healthcare providers may benefit from implementation of similar methodology as hospitals plan to restart elective surgery.     

Association of benign recurrent vertigo and migraine in 208 patients

The aim of this study was to determine the association of benign recurrent vertigo (BRV) and migraine, using standardized questionnaire-based interview of 208 patients with BRV recruited through a University Neurotology clinic. Of 208 patients with BRV, 180 (87%) met the International Classification of Headache Disorders 2004 criteria for migraine: 112 migraine with aura (62%) and 68 without aura (38%). Twenty-eight (13%) did not meet criteria for migraine. Among patients with migraine, 70% experienced headache, one or more auras, photophobia, or auditory symptoms with some or all of their vertigo attacks, meeting the criteria for definite migrainous vertigo. Thirty per cent never experienced migraine symptoms concurrent with vertigo attacks. These met criteria for probable migrainous vertigo. Among patients without migraine, 21% experienced either photophobia or auditory symptoms with some or all of their vertigo attacks; 79% experienced only isolated vertigo. The age of onset and duration of vertigo attacks did not differ significantly between patients with (34 ± 1.2 years) and patients without migraine (31 ± 3.0 years). In patients with migraine, the age of onset of migraine headache preceded the onset of vertigo attacks by an average of 14 years and aura preceded vertigo by 8 years. The most frequent duration of vertigo attacks was between 1 h and 1 day. Benign recurrent vertigo is highly associated with migraine, but a high proportion of patients with BRV and migraine never have migraine symptoms during their vertigo attacks. Other features such as age of onset and duration of vertigo are similar between patients with or without migraine.