Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1

Recombinant human tumor necrosis factor (rTNF alpha) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 microgram/kg) rTNF alpha and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 micrograms/kg) rTNF alpha produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNF alpha induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNF alpha. In addition, rTNF alpha and rIFN-gamma have a synergistic effect on IL-1 production. The biological activity of rTNF alpha could be distinguished from IL-1 in three ways: the monophasic pyrogenic activity of rIL-1 was destroyed at 70 degrees C, whereas rTNF alpha remained active; anti-IL-1 neutralized IL-1 but did recognize rTNF alpha or natural cachectin nor neutralize its cytotoxic effect; and unlike IL-1, rTNF alpha was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNF alpha fever and/or the induction of IL-1 was ruled-out in several studies: rTNF alpha produced fever in the endotoxin-resistant C3H/HeJ mice; the IL-1-inducing property of rTNF alpha was destroyed either by heat (70 degrees C) or trypsinization, and was unaffected by polymyxin B; pyrogenic tolerance to daily injections of rTNF alpha did not occur; levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of beta-hydroxymyristic acid. Although rTNF alpha is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNF alpha induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-alpha, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNF alpha is an endogenous inducer of IL-1.(ABSTRACT TRUNCATED AT 400 WORDS)     

Intra-bone marrow injection of bone marrow and cord blood cells: an alternative way of transplantation associated with a higher seeding efficiency

OBJECTIVE: Intravenous (IV) injection is currently the normal method for transplanting hematopoietic cells. However, the problem of seeding efficiency and homing is relevant especially when a limited number of stem cells is available. Intra-bone marrow (IBM) injection of bone marrow cells (BMCs) may overcome this problem. MATERIALS AND METHODS: Irradiated (750 cGy) C57BL/6J mice were transplanted with 1 x 10(5) BMCs harvested from transgenic mice expressing an enhanced version of the green fluorescent protein (EGFP+) via IBM or with 1 x 10(6) EGFP+ BMCs via IV. Irradiated (320 cGy) NOD/SCID mice were transplanted with 1 x 10(6) human cord blood (CB) cells via IBM or with 1 x 10(7) human CB cells via IV. RESULTS: In C57BL/6J mice after 90 days, the fraction of EGFP+ cells harvested was 37% and 53% in IV-treated and IBM-treated (contralateral tibia and femur in the IBM) mice, respectively: the expansion folds were 114 and 1760, respectively. In NOD/SCID mice, the percentages of CD45+ cells and CD45+/CD34+ cells were, at 30 days, 3.3% and 0.3% in IV-treated mice, and 4.4% and 1.1% in IBM-treated mice. At 60 days, the percentages of CD45+ cells and CD45+/CD34+ cells were 2.1% and 0.3% in IV-treated mice and 1.4% and 0.4% in IBM-treated mice. At day 90 the percentages of CD45+ cells and CD45+/CD34+ cells were 3% and 0.3% in IV-treated mice and 2.3% and 0.4% in IBM-treated mice. CONCLUSION: Our data demonstrate that IBM transplantation is associated with a seeding efficiency 15 times greater than IV transplantation. IBM transplantation may improve the results of transplant and may be useful in several settings: 1) when a limited number of hematopoietic progenitors are available; and 2) in experiments aiming to place in the bone marrow stem cells of other lineages (CNS, muscle, etc.).     

Evaluation of trauma care applying TRISS methodology in a Caribbean developing country

There have been conflicting reports regarding the applicability of Trauma Injury Severity Score (TRISS) methodology to evaluate trauma care in a developing country setting. The objective of this study was to apply TRISS methodology to evaluate trauma care in the public hospitals of a Caribbean developing country. A prospective, observational study was conducted in the three major general hospitals in Trinidad. Major trauma patients were included. Demographic data, waiting time in the Emergency Department, and nature of injury (blunt or penetrating) were noted. Revised Trauma Score, Injury Severity Score, and Glasgow Coma Scale were applied to all patients on admission. Hospital outcomes were noted. Predicted outcomes were calculated for adult patients using TRISS methodology. M, Z statistics and receiver operating characteristic (ROC) curve analysis were done. There were 326 trauma patients studied, of whom 279 adults were evaluated by the TRISS methodology. Men were more frequently involved in trauma than women; there was more blunt trauma than penetrating trauma. The M statistic was 0.98 and the overall Z statistic was 5.81. The ROC curve analysis showed TRISS to be a fair discriminator in the study case-mix with an area under the curve of 0.82 (95% confidence interval 0.69-0.96). There is a considerable disparity between predicted and observed outcomes when trauma patients are evaluated by the TRISS methodology in a developing country setting.     

A Model of a Quantum Particle in a Quantum Environment: A Numerical Study

We define and investigate, via numerical analysis, a one dimensional toy-model of a cloud chamber. An energetic quantum particle, whose initial state is a superposition of two identical wave packets with opposite average momentum, interacts during its evolution and exchanges (small amounts of) energy with an array of localized spins. Triggered by the interaction with the environment, the initial superposition state turns into an incoherent sum of two states describing the following situation: or the particle is going to the left and a large number of spins on the left side changed their states, or the same is happening on the right side. This evolution is reminiscent of what happens in a cloud chamber where a quantum particle, emitted as a spherical wave by a radioactive source, marks its passage inside a supersaturated vapour-chamber in the form of a sequence of small liquid bubbles arranging themselves around a possible classical trajectory of the particle.     

Treatment for postchemoradiotherapy hypopharyngeal stenosis: Pharyngoesophageal bypass using an anterolateral thigh flap—A case report

Radiation‐induced pharyngoesophageal stenosis is a frequent and unwanted consequence of nonsurgical treatment of hypopharyngeal carcinomas. Current treatment mainly includes endoscopic dilatations, but a poor response to this modality and/or a severe stenosis may lead to a radical resection (pharyngolaryngectomy) and reconstruction with tubed flaps, which allow oral feeding but fail to preserve speech. In this report, we present a case of radiation‐induced hypopharyngeal stenosis treated with a pharyngoesophageal bypass using an anterolateral thigh (ALT) flap with the intention of preserving the larynx. We describe the case of a 59‐year‐old male with severe pharyngoesophageal stenosis after chemoradiotherapy due to a squamous cell carcinoma, where conventional dilatation treatment failed to restore pharyngoesophageal passage of solids or liquids. Since the patient rejected a pharyngolaryngectomy due the loss of speech entailed, a pharyngoesophageal bypass was performed using an ALT flap. The flap measured 13 × 20 cm, which ensured a 4‐cm‐diameter tube and enough length to communicate the lateral pharyngeal wall with the cervical esophagus. Endoscopy did not reveal flap failure, and during the immediate postoperative period, the patient had a small cervical leak detected only by imaging that did not affect the skin and resolved with antibiotic treatment. The patient also required a tracheostomy on day 4 and initially had no passage of saliva through the bypass; we attributed this to edema that resolved spontaneously after 1 month with complete liquid and solid passage and laryngeal competence that led to tracheal decannulation. Good functional results were achieved both for speech and swallowing at 5‐year follow‐up. We believe that this procedure may be considered before performing a pharyngolaryngectomy for the treatment of a persistent benign stenosis in patients with a functional larynx.     

Subarachnoid and intramedullary cysts secondary to epidural anesthesia for gynecological surgery.

Three women who received epidural anesthesia for gynecological surgery developed spinal arachnoiditis leading to subarachnoid cysts and cord cavitation. MRI was useful to show the subarachnoid and intramedullary cysts, as well as to monitor lesion extent and progress. Associated MRI findings were a Chiari anomaly in 1 case and a tethered cord in another. Two cases underwent surgery: 1 improved, but the other suffered progressive neurological deterioration. Although the 3rd patient had no treatment, there was spontaneous reduction in cavity size and clinical improvement. Careful handling of this procedure is urged to avoid such severe complications in young mothers.     

Autografting with Ph-negative progenitors in patients at diagnosis of chronic myeloid leukemia induces a prolonged prevalence of Ph-negative hemopoiesis

OBJECTIVE: In many patients with chronic myeloid leukemia (CML), a residual population of primitive normal (Ph-negative) progenitors persists despite the marked expansion of the leukemic (Ph-positive) clone. These cells may be found in the blood of patients studied soon after diagnosis or during the period of endogenous hematopoietic recovery that follows myeloreductive therapy. Based on those observations, we have developed a clinical protocol that allows collection of Ph-negative peripheral blood progenitor cells (PBPC) with transplantable hematopoietic regenerative potential. The aim of this study is to examine changes that occur in the percentage of Ph-negative- and Ph-positive-committed progenitor cells and to determine the relationship between changes and clinical outcome. MATERIALS AND METHODS: We followed 15 patients with CML, mobilized and autografted soon after diagnosis with 85%-100% Ph-negative PBPC for a median time of 28 months (range 18-50) after transplant. At 6 months, 1 year, 2 years, and last follow-up, cytogenetic analyses were performed on fresh bone marrow cells and on colony-forming cells (CFC). RESULTS: Autologous transplantation induces a reduction in the proportion of Ph-positive CFC, from 70%-100% to 0%-25% in the majority of patients (78%). After autografting, 8 of 15 patients achieved a long-lasting cytogenetic remission (median, 24 months; range, 21-43) with a Ph-positivity ranging between 0% and 20% at the level of mature mononuclear cells and colony-forming cells (CFC). In some patients, the majority of CFC remained Ph-negative, whereas the majority of the mature cells were Ph-positive. Other patients (5/15) developed cytogenetic relapse (100% Ph-positive), although they were in hematological remission. We found that detection of Ph-positive long-term-culture initiating cells (LTC-IC) in the marrow at diagnosis was the only factor significantly associated with recurrence of the disease (p < 0.01); on the other hand, the number of Ph-negative LTC-IC infused showed a significant correlation with a better outcome (p < 0.03). CONCLUSION: We have shown that a prolonged period of complete or almost complete Ph-negative hemopoiesis can be achieved in patients with CML who undergo autografting with Ph-negative progenitors. Longer follow-up study will be needed to assess whether these changes are associated with improved survival.