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PubMed1989

Patch clamp analysis of recovery of sodium channels from inactivation in mammalian myocardium in terms of a Markovian state model.

The kinetics of the recovery of Na channels from inactivation were investigated in ventricular cardiocytes of adult mice by a patch clamp technique. Single channel analysis showed an unaltered slope conductance of unitary currents during the recovery process to be 18.5 pS. The mean open time tau 0 and its monoexponential distribution remained also unchanged. The recovery time course of the apparent probability for a channel not to open coincided perfectly with the recovery time course determined from peak values of macroscopic currents which were recorded from cell-attached patches with up to 80 channels by averaging between 19 and 38 sweeps. Conclusively, the recovery was quantified by the time course of re-accumulation of the channels in a resting state. The initial recovery time course was sigmoidal. A serial Markov state model with three inactivated states in addition to the resting state was most appropriate for its description. The rate constants were assumed to be equal direction. A highly voltage-sensitive reaction towards the last inactivated state and a nearly voltage-independent reaction towards the resting state were obtained. Slow inactivation components were analyzed both during the recovery process (-100 mV ... -130 mV) after long preceding inactivation and at maintained depolarization (-50 mV ... -20 mV). For description, the model was extended by two further, serially coupled inactivated states. All four rate constants describing slow inactivation in the range of hundreds of milliseconds to seconds proved to be voltage-independent. Taken together, the results suggested the absorbing inactivated state I to be composed of five serially coupled inactivated states with only two transitions being steeply voltage-dependent.

Animals↗

PubMed1988

Inhibition of ionizing radiation recovery processes in polyamine-depleted Chinese hamster cells.

Polyamines are involved in many cellular processes, including DNA structure and function. Since DNA, or some DNA-containing structure, is known to be the target for cell killing induced by ionizing radiation and a number of chemotherapeutic agents, we investigated the effects of polyamine depletion on cytotoxic responses of Chinese hamster cells to X-irradiation. Colony forming ability after single, acute radiation exposures of cells growing under oxic conditions was minimally affected by endogenous putrescine and spermidine depletion, achieved after treatment with alpha-difluoromethylornithine. Survival of cells rendered hypoxic and then irradiated was unaffected by alpha-difluoromethylornithine treatment. However, cellular recovery processes were nearly completely suppressed in polyamine-depleted cells, including sublethal damage recovery, as evidenced by split-dose irradiations in log phase cultures, and potentially lethal damage recovery, observed when growth-inhibited cultures were allowed time to repair radiation damage prior to being plated for colony formation. Both these recovery processes were restored by exogenous putrescine treatment. Reaccumulation of intracellular spermidine content closely correlated with restoration of potentially lethal damage recovery. Depletion of putrescine and spermidine pools had little effect on either single or double strand DNA break production or rejoining. These data demonstrate that both sublethal and potentially lethal damage recovery are polyamine-dependent processes in Chinese hamster cells, and imply that the mechanisms by which hamster cells recovery from these types of radiation damage are unrelated to their ability to rejoin DNA strand breaks, at least during the first hour after irradiation. Finally, these results suggest that the depletion of tumor polyamine content may be an effective method of enhancing the sensitivity of human tumors to fractionated radiotherapy.

Animals↗

PubMed1988

Clinical observations on recovery from stroke.

Recovery from stroke occurs in a similar pattern in most patients, but the final functional status is difficult to predict. This recovery is most rapid in the first few months, but it may continue for years. The factors facilitating prolonged and more complete recovery are unclear and multiple. The neurophysiologic mechanisms of synaptic sprouting, unmasking, and redevelopment of inhibition may underlie recovery and provide the basis for developing therapeutic interventions in an attempt to promote return of function. Although the impact of current rehabilitation strategies on stroke recovery is uncertain, review suggests that it is beneficial in selected groups of patients. Further research is needed to answer the many questions surrounding recovery from stroke (a) to address the mechanisms of stroke recovery in human subjects with imaging or pathologic correlation, (b) to design therapeutic techniques based on neurophysiology and assess their effectiveness in groups of patients, (c) to determine if intensive rehabilitation reduces functional dependency resulting in decreased long-term social and economic costs, (d) to determine when rehabilitation should begin, where rehabilitation should take place, and how rehabilitation programs should be organized, and (e) to enable selection of patients most likely to succeed in rehabilitation programs. Although difficult to design, studies addressing these areas will provide much useful information that will further the development and delivery of rehabilitation services, resulting in improved patient care and reduced costs.

Central Nervous System↗

PubMedDate not supplied

Mental distress and recovery in a high-risk bereavement sample three years after untimely death.

Recovery from postdisaster bereavement was the primary concern of this longitudinal study: would levels of mental distress and recovery reported 1 year following a natural disaster be better predictors of mental distress and recovery reported 3 years postdisaster than demographic variables, concurrent life stress, and mediating factors? The 119 bereaved and control participants studied in 1981, one year following the 1980 volcanic eruption of Mount Saint Helens, were recontacted in 1983; of these, 85 consented to follow-up. The 1983 data collection consisted of identical measurement tools and procedures used in 1981. Three regression analyses addressed prediction of mental distress and recovery. The first two analyses compared disaster-bereaved and nondisaster-loss controls; the third pertained only to the bereaved. For the bereaved/control comparisons, 1981 levels of mental distress, age, sex, education, and 1983 levels of negative life stress, self-efficacy, and social support were predictors of the dependent variable, mental distress. For the bereaved group, 1981 mental distress and 1983 self-efficacy scores were the only significant predictors of 1983 mental distress. In the control group, two additional variables, sex and concurrent negative life stress, were also significant predictors of 1983 mental distress. In the final regression analysis, predictors of self-rated recovery, importance of the deceased person rated by the bereaved 1 year postdisaster, and beliefs of preventability of death reported 3 years postdisaster were predictors of 1983 recovery. Only importance of the deceased person was a significant predictor in the latter analysis. Results suggest that recovery is a lengthy process and that much remains to be learned about influencing factors.

Adaptation, Psychological↗

PubMed1988

Neurologic injury and recovery patterns in burst fractures at the T12 or L1 motion segment.

Fourteen consecutive patients with burst fractures at T12 or L1, partial paralysis, and more than 30% canal compromise were prospectively evaluated pretreatment and posttreatment with roentgenograms to determine the initial fracture pattern, CT scans to determine the percent canal compromise and subsequent improvement, and a quantitative motor trauma index scale and bladder sphincter evaluation to determine neurologic recovery. The follow-up period averaged 32 months (range, 12-50 months). Treatment was as follows: nonoperative (three patients), Harrington rods and fusion (seven patients), and Harrington rods and fusion followed by anterior decompression and fusion (four patients). The initial severity of paralysis did not correlate with the initial fracture roentgenographic pattern or the amount of initial CT canal compromise. Neurologic recovery did not correlate with the treatment method or amount of canal decompression. Subsequent recovery did correlate with the initial fracture pattern. If the patient had a Type I or Type II fracture (both greater than 15 degrees kyphosis), greater than 90% neurologic recovery occurred, regardless of treatment. If the patient had a Type III fracture (less than 15 degrees kyphosis and the maximal canal compromise where bone encircles the canal) less than 50% neurologic recovery occurred. If the patient had a Type IV fracture (less than or equal to 15 degrees kyphosis and the maximal canal compromise at the level of the ligamentum flavum), the neurologic recovery was variable. Prognosis for neurologic recovery can be made based on initial roentgenograms. If greater than 15 degrees kyphosis is present, there is a good prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

Recovery of CFU-GM from cryopreserved marrow and in vivo evaluation after autologous bone marrow transplantation are predictive of engraftment.

In 18 patients with non-Hodgkin's lymphomas or solid tumors treated with intensive chemotherapy and/or total-body irradiation followed by autologous bone marrow transplantation (ABMT), we assessed the value of granulocyte-macrophage progenitor cells (CFU-GM) monitoring to predict engraftment. We studied CFU-GM in cryopreserved marrow and attempted to settle whether detection of CFU-GM in vivo after ABMT has a predictive value on engraftment. Our data showed: The absence of linear correlation linking recovery of hematopoiesis to the dose of CFU-GM/kg infused. The existence of a CFU-GM threshold in respect to engraftment. Patients receiving doses of CFU-GM greater than 10(3)/kg had significantly faster recovery kinetics for hematopoiesis than did patients receiving doses below this threshold, with median recoveries to 0.5 and 1.0 X 10(9) neutrophils/liter, respectively, on days 14 and 15 versus days 29 and 31.5 (p less than 0.05 and p less than 0.02) and median recoveries to 1.0 and 2.5 X 10(9) leukocytes/liter respectively, on days 12.5 and 16 versus days 28 and 30.5 (p less than 0.05 and p less than 0.02). Considering the entire course of events during the first four weeks, we were able to show that white blood cell recovery was significantly faster in the group of patients receiving doses of CFU-GM greater than 10(3)/kg (p less than 0.001). Sequential studies of the reappearance of CFU-GM in marrow and peripheral blood indicated that the kinetics of CFU-GM recovery in vivo after ABMT predict engraftment. By day 7 after the graft, CFU-GM were already detectable in the marrow at a level of 10% of the dose infused for patients with optimal engraftment--median time to recovery to 1.0 and 2.5 X 10(9) leukocytes/liter and 1.0 X 10(9) neutrophils/liter on days 11, 15, and 14.5 versus days 18, 23, and 23 (p less than 0.02, less than 0.05, and less than 0.05), respectively after. On day 10 after ABMT, a 15% CFU-GM level in bone marrow confirmed engraftment, with a significant correlation of all parameters studied--1.0 and 2.5 X 10(9) leukocytes/liter (p less than 0.02 and less than 0.01), 0.5 and 1.0 X 10(9) neutrophils/liter (p less than 0.05), 50.0 and 100.0 X 10(9) platelets/liter (p less than 0.05). On day 14, a 50% CFU-GM level was reached in all patients with optimal engraftment; p less than 0.01 on 1.0, and 2.5 X 10(9) leukocytes on 0.5 and 1.0 X 10(9) neutrophils/liter. The detection of circulating CFU-GM in the blood by day 10 or 14 indicated engraftment.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1984

Hypocarbia and spontaneous recovery from vecuronium neuromuscular blockade in anesthetized patients.

The effect of hypocarbia on the recovery from the neuromuscular blockade produced by vecuronium was studied in 20 anesthetized patients. Vecuronium was administered until twitch tension was reduced to between 0-15% of control. Neuromuscular function was then allowed to spontaneously recover during continued normocarbia (end-tidal PCO2 5.5 kPa [41 mm Hg]) in half the patients, and in the other half of the patients hyperventilation producing hypocarbia (mean end-tidal PCO2 of 3.1 +/- 0.4 kPa SD [23 +/- 3 mm Hg] at the completion of twitch force recovery) was initiated at the beginning of spontaneous recovery from neuromuscular blockade. The mean vecuronium recovery index (time for spontaneous recovery from 25-75% of control twitch tension) was slightly but not significantly shorter in the hyperventilated patients (8.4 +/- 1.8 min SD) than in the normally ventilated patients (10.4 +/- 3.4 min SD). We conclude the vecuronium recovery index in anesthetized patients is not significantly changed by hyperventilation with hypocarbia when induced at the beginning of recovery from neuromuscular blockade.

Adult↗

PubMed1984

[Determination of the sinus node recovery time].

The interrelationship between the sinus node recovery time and the rate of atrial stimulation was investigated in clinical experiments. The sinus node recovery time measured with the aid of atrial stimulation according to the recovery of atrial activity after stimulation was completed did not mirror the genuine sinus node recovery time. An empiric formula is suggested, permitting the determination of the genuine sinus node recovery time on the basis of the initial rhythm rate and maximal value of the sinus node recovery time measured according to the atrial activity recovery.

Animals↗

PubMed1983

Hematologic recovery following autologous and allogeneic bone marrow transplantation.

Posttransplant hematologic recovery was compared between 9 autologous and 11 allogeneic marrow transplant patients who received similar marrow-lethal chemoradiotherapies before transplantation. Although the autotransplant patients were infused with much lower marrow doses compared with the allotransplant patients, they showed adequate hematologic recovery with acceptable risk. Regardless of marrow doses, delayed platelet recovery and failure of platelet recovery were observed in 7 patients. All of these patients experienced early transplantation-related complications before engraftment. Despite the limited number of patients, a number of myeloid progenitor cells (CFUC) infused correlated significantly with the period for recovery of polymorphonuclear cells in autologous marrow recipients while there was no significant correlation found between marrow dose and hematologic recovery in both groups of patients. Furthermore, autotransplant patients showed a characteristic recovery pattern of peripheral blood lymphocytes in an early posttransplant period, whic was not observed in allotransplant patients.

Acute Disease↗

PubMedDate not supplied

Recovery from potentially lethal damage induced by spirohydantoin mustard on 9L cells in vitro.

Spirohydantoin mustard (SHM) has been shown to cross the blood-brain barrier in dogs and has shown activity against mouse brian tumors in vivo and against 9L rat brain tumor cells in vitro. Factors influencing the recovery of monolayer 9L cells from SHM-induced potentially lethal damage were studied. The pattern of recovery was similar in exponentially growing and plateau-phase cultures. Recovery occurred in either Earle's balanced salt solution (EBSS) or depleted medium (DM), and was inhibited in fresh medium (FM). The recovery process had a half-life of approximately 4 hours and was completed within 18 hours. The enhancement of survival was dependent on drug concentration and temperature. The magnitude of recovery decreased as the temperature was lowered and was inhibited at ambient temperature, which suggested that an enzymatic repair process was responsible for recovery. The distribution of cells through the cell cycle after SHM treatment was determined using a flow cytometer. Incubation of exponentially growing and plateau-phase cells in either EBSS or DM impeded the progression of cells from G1 into S phase, but cells incubated in FM progressed into S phase by 24 hours. We conclude that the recovery occurred primarily when cells were in G1 phase and potentially lethal damage would be fixed when cells initiate DNA synthesis within 18 hours after administration of SHM. Therefore, optimal therapeutic benefit may depend on drug scheduling.

Animals↗

PubMed1994

Mast cell growth factor enhances multilineage hematopoietic recovery in vivo following radiation-induced aplasia.

Based on in vitro studies, mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has been implicated as an important hematopoietic regulator, especially in the presence of additional hematopoietic cytokines. Since hematopoietic regeneration follows sublethal radiation-induced hematopoietic injury and is thought to be mediated by endogenously produced cytokines, the ability to accelerate recovery from radiation-induced hematopoietic hypoplasia was used to evaluate in vivo effects of MGF administration. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of 60Co radiation followed by subcutaneous administration of either saline or 100, 200, or 400 micrograms/kg/d recombinant murine MGF on days 1 to 17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-S), granulocyte-macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC), and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF accelerated hematopoietic recovery at the 100 and 200 micrograms/kg/d doses. The 100 micrograms/kg/d dose accelerated recovery of only GM-CFC, while the 200 micrograms/kg/d dose accelerated CFU-S, GM-CFC, WBC, and PLT recoveries. In contrast, hematopoietic recovery was delayed in mice receiving the 400 micrograms/kg/d dose. These studies demonstrate the in vivo dose-dependent ability of MGF to accelerate multilineage hematopoietic regeneration following radiation-induced hematopoietic hypoplasia. They also document detrimental effects of providing "supraoptimal" doses of this growth factor and suggest caution in dose-escalation trials in humans.

Animals↗

PubMed1995

Expression of adhesion molecules on CD34+ cells: CD34+ L-selectin+ cells predict a rapid platelet recovery after peripheral blood stem cell transplantation.

Adhesion molecules play a role in the migration of hematopoietic progenitor cells and regulation of hematopoiesis. To study whether the mobilization process is associated with changes in expression of adhesion molecules, the expression of CD31, CD44, L-selectin, sialyl Lewisx, beta 1 integrins very late antigen 4 (VLA-4) and VLA-5, and beta 2 integrins lymphocyte function-associated 1 and Mac-1 was measured on either bone marrow (BM) CD34+ cells or on peripheral blood CD34+ cells mobilized with a combination of granulocyte colony-stimulating factor (G-CSF) and chemotherapy. beta 1 integrin VLA-4 was expressed at a significantly lower concentration on peripheral blood progenitor cells than on BM CD34+ cells, procured either during steady-state hematopoiesis or at the time of leukocytapheresis. No differences in the level of expression were found for the other adhesion molecules. To obtain insight in which adhesion molecules may participate in the homing of peripheral blood stem cells (PBSCs), the number of CD34+ cells expressing these adhesion molecules present in leukocytapheresis material was quantified and correlated with hematopoietic recovery after intensive chemotherapy in 27 patients. The number of CD34+ cells in the subset defined by L-selectin expression correlated significantly better with time to platelet recovery after PBSC transplantation (r = -.86) than did the total number of CD34+ cells (r = -.55). Statistical analysis of the relationship between the number of CD34+L-selectin+ cells and platelet recovery resulted in a threshold value for rapid platelet recovery of 2.1 x 10(6) CD34+ L-selectin+ cells/kg. A rapid platelet recovery (< or = 14 days) was observed in 13 of 15 patients who received > or = 2.1 x 10(6) CD34+ L-selectin+ cells/kg (median, 11 days; range, 7 to 16 days), whereas 10 of 12 patients who received less double positive cells had a relative slow platelet recovery (median, 20 days; range, 13 to 37 days). The L-selectin+ subpopulation of CD34+ cells also correlated better with time to neutrophil recovery (r = -.70) than did the total number of reinfused CD34+ cells (r = -.51). However, this latter difference failed to reach statistical significance. This study suggests that L-selectin is involved in the homing of CD34+ cells after PBSC transplantation.

Adult↗

PubMedDate not supplied

Pharmacological activity of the Ginkgo biloba extract (EGb 761) on equilibrium function recovery in the unilateral vestibular neurectomized cat.

Locomotor balance recovery after unilateral vestibular neurectomy has been found strongly accelerated in the cat when the animals received a postoperative treatment with Ginkgo biloba Extract (EGb 761:50 mg/kg/d, i.p.), a result due to the improvement of plasticity mechanisms involved in vestibular compensation. The aim of this study was to determine which of the two main biochemical components (terpenes vs. flavonoids) contained in the extract was the most active in the recovery process, to test the influence of the route of administration, and to look for dose-dependent effects. Experiments were performed in six experimental groups of cats that were compared with each other and with three control groups. Comparisons were done on the recovery profile and time course of equilibrium function restoration, as quantified by the rotating beam test. Four experimental groups were treated with the standardized extract EGb 761 given orally (p.o.:2 groups; 40 mg and 80 mg/kg) or intraperitoneally (i.p.: 2 groups; 50 mg and 25 mg/kg), whereas the two others received only a special extract that did not contain the terpenes (i.p. administration: 25 mg and 10 mg/kg). Treatment was always given until complete recovery of locomotor balance function. The control groups received either no treatment (untreated cats), an oral vehicle (placebo cats), or a sham i.p. injection (sham cats). Results showed that locomotor balance recovery was significantly improved in all the experimental groups as compared to the control groups of cats, which recovered similarly and more slowly. Efficacy of the special extract without the terpenes was comparable to that of the total extract, indicating that the nonterpenic fraction was the most active biochemical constituent in this experimental model of central nervous system (CNS) plasticity. Pharmacological activity of the extract was also significantly better when given i.p. as compared to the p.o. route of administration, and dose-dependent effects were evidenced with the i.p. administration of the special extract without the terpenes, with a lower efficacy for the lowest dose (10 mg/kg). These data confirm that EGb 761 treatment serves as useful therapy in supporting brain functional recovery in this animal model of vestibular compensation and lead to a more precise understanding of the biochemical component that is active in this recovery process.

Administration, Oral↗

PubMed1994

[Effects of succinylcholine on neuromuscular transmission during recovery from vecuronium].

Effects of succinylcholine (SCC), 1 mg.kg-1, given following incomplete recovery from muscle paralysis induced by vecuronium were investigated in 27 female patients undergoing elective surgery, which was performed under epidural anesthesia. Anesthesia was induced with thiamylal 5 mg.kg-1 followed by SCC to facilitate orotracheal intubation. Vecuronium bromide 0.08 mg.kg-1 was given and the lungs were ventilated with 67% N2O in O2 and 0.6% sevoflurane. Neuromuscular function was monitored by means of the induced EMG. The ulnar nerve was stimulated at the wrist. Supramaximal trains of four stimuli (2 Hz for 2 s: pulse width 0.2 ms) were administered every 20 s. The effect of SCC varied depending upon the degree of recovery from vecuronium. At the 25% recovery point, the response to SCC was biphasic, showing an initial reversal followed by an increase of the partial vecuronium block which recovered showing a fade phenomenon on train-of-four stimulation. At the 50% recovery point, an initial reversal was slight. Administered at 75% recovery from vecuronium, SCC produced total neuromuscular blockade without initial recovery. The overall duration of the SCC effect (time from the administration to 90% recovery) was 7-18 min. No prolonged paralysis from SCC occurred.

Adult↗

PubMed1993

Effect on the speech reception threshold in noise of the recovery time of the compressor in the high-frequency channel of a two-channel aid.

This paper describes two experiments in a series evaluating and optimising a hearing aid incorporating two forms of automatic gain control (AGC). The first form is a front-end AGC which is normally slow acting and which compensates for variations in the overall level of speech from one situation to another. The second form of AGC follows the front-end AGC. The signal is split into two frequency bands, and fast-acting AGC is applied in the upper band only. The bands are then recombined. The two experiments described here were aimed at determining the optimum value of the recovery time of the AGC in the high-frequency channel. Speech reception thresholds (SRTs) were measured in the presence of speech-shaped noise as a function of the recovery time, for subjects with mild-to-moderate sensorineural loss. In the first experiment the recovery time was varied over the range 10-80 ms. SRTs tended to be lowest (best) at the shorter recovery times but the effects were small. In the second experiment, the recovery time was varied over the range 5-320 ms. In this case, there was a clear trend for SRTs to increase with increasing recovery time. A recovery time of about 20 ms appears to be optimal.

Aged↗

PubMed1993

Nitroglycerin improves functional recovery of neonatal lamb hearts after 2 hours of cold ischemia.

BACKGROUND: Vascular events during initial reperfusion after a period of hypothermic cardioplegic ischemia may play an important role in the recovery of mechanical function. Prior studies have shown (1) that dysfunction of the postischemic myocardium after normothermic ischemia can be ameliorated by vasodilation and (2) that endothelial dysfunction in the coronary bed and mechanical dysfunction were correlated after hypothermic ischemia. The present study was undertaken to further explore the relation between vascular events during reperfusion and the recovery of mechanical function after hypothermic ischemia by the infusion of the endothelium-independent vasodilator nitroglycerin during reperfusion. METHODS AND RESULTS: We assessed the effect of an infusion of nitroglycerin on the recovery of isolated blood-perfused neonatal lamb hearts arrested for 2 hours with 15 degrees C K+ cardioplegic solution, comparing 8 hearts receiving a nitroglycerin infusion with 9 control hearts. After 30 minutes of reperfusion, nitroglycerin-infused hearts compared with control hearts had better percent recovery of maximum left ventricular developed pressure (83.5 +/- 8.1% vs 73.6 +/- 8.9%, mean +/- SD), left ventricular dP/dt (77.2 +/- 7.7% vs 67.4 +/- 10.3%), coronary blood flow (141.2 +/- 30.6% vs 84.4 +/- 10.4%), and myocardial oxygen consumption (100.7 +/- 51.3% vs 71.2 +/- 18.6%), (all except myocardial oxygen consumption with P < .05). In each heart, we also tested the coronary vascular resistance response to 10(-6) mol/L acetylcholine infusion to assess endothelial function. The recovery of the coronary vascular resistance response to acetylcholine was reduced after reperfusion in both groups compared with the preischemic response to acetylcholine (nitroglycerin, 14.9 +/- 53.8%; control, 13.4 +/- 38.3%). CONCLUSIONS: These results suggest that the effects of hypothermia and reperfusion on recovery of mechanical function after hypothermic ischemia can be offset by an infusion of nitroglycerin. Vasospasm secondary to endothelial dysfunction may play an important role in cardiac recovery after hypothermic ischemia.

Animals↗

PubMed1996

Megakaryocyte growth and development factor stimulates enhanced platelet recovery in mice after bone marrow transplantation.

Megakaryocyte growth and development factor (MGDF) is a recently characterized ligand for the cell surface receptor mpl. We have evaluated the effects of polyethylene glycollated recombinant human MGDF (PEG-rHuMGDF) on recovery of hematopoietic cells in mice following bone marrow transplantation (BMT) to support lethal irradiation. Mice treated with PEG-rHuMGDF (50 micrograms/kg/d) had accelerated recovery of platelet numbers compared with BMT mice treated with carrier or recombinant human granulocyte colony-stimulating factor (rHuG-CSF, 72 or 200 micrograms/kg/d). In contrast, PEG-rHuMGDF had no effect on white blood cell (WBC) or red blood cell (RBC) recovery. As previously reported, animals treated with rHuG-CSF had an enhanced recovery of WBC but not platelet or RBC levels. Interestingly, BMT receipient mice treated with the combination of PEG-rHuMGDF and rHuG-CSF showed simultaneous enhanced recovery of both leukocytes and platelets. PEGylated rHuMGDF was found to be considerably more potent than non-PEGylated rHuMGDF in this setting. PEG-rHuMGDF is an effective growth factor for enhancing platelet recovery in mice following BMT either alone or in combination with rHuG-CSF. It will be of interest to evaluate in a clinical setting the ratios of PEG-rHuMGDF and rHuG-CSF for simultaneous administration of these factors and accelerated recovery of both leukocytes and platelets.

Animals↗

PubMedDate not supplied

[Immuno-nutritional recovery of children with severe malnutrition].

In developing countries, more than 12 million children die each year from the combined effects of malnutrition and infection. Malnourished children have impaired cellular immunity and are particularly sensitive to opportunistic infections. However, immune recovery has rarely been investigated during nutritional rehabilitation. Indeed, mortality remains high during renutrition, and relapses are frequent. We established a center in Cochabamba, Bolivia, specifically to save these children by treating both clinical and nutritional problems and restoring immune function. The CRIN (center for immuno-nutritional recovery) admits children with severe malnutrition from the Cochabamba suburban area. They are from low income families, in crowded living conditions with poor sanitation and are weaned early. Nutritional diagnosis was based on weight-for-height, arm to head circumference ratio and clinical examination for edema, loss of subcutaneous tissue and diminished muscle mass. The children were examined daily, and first treated for respiratory and intestinal infections. Sociological and psychological aspects were also included in our holistic approach to treating severe malnutrition. Children received a four-stage diet lasting 2 months. During the initial phase (1 week) they were given an oil-sugar-milk based diet, with half lactose concentration, seven times a day. This supplied 1.5 to 2.5 g of protein and 120 to 150 kcal/kg of body weight, according to the PEM pattern. Protein and energy intake was then slowly increased during the transition phase (1 week). During the next, 'calorific-protein bombing' phase (6 weeks) 5 g of protein and 200 kcal/kg of body weight were given daily, such that there was sufficient energy for protein accumulation. During the last, discharge phase (1 week), the protein and energy contents were slowly decreased. Weight, height, arm and head circumferences, and triceps skin-fold thickness were measured weekly by standardized methods. Thymus size was assessed weekly by mediastinal ultrasound scanning with a portable scanner (ALOKA SSD-210 DXII, Tokyo) using a 5 MHz linear pediatric probe. Lymphocyte subpopulations in peripheral blood were investigated monthly using monoclonal antibodies. Compared to controls, the malnourished group had severe involution of the thymus, a significantly higher proportion of circulating immature T lymphocytes and a lower proportion of mature T lymphocytes. The two month longitudinal study showed that normal anthropometric values (90% NCHS weight for height) were recovered after one month of rehabilitation. However, immune recovery (thymic area of 350 nm2) required two months. This may explain the frequent relapses among malnourished children discharged after one month on the basis of 'apparent nutritional health'. Such children may remain immunodepressed, and should therefore be considered as high risk children. To test an immunostimulatory treatment, we designed a historical cohort study of malnourished children who received 2 mg of zinc per day. The children were matched for age, sex, anthropometric criteria and nutritional status with malnourished control children (treated previously with zinc). Anthropometric recovery was obtained in both groups in one month. Children receiving zinc attained immunological recovery within one month, whereas children not receiving zinc took two months. Thus zinc hastened immunological recovery concomitant with nutritional recovery such that the duration of hospitalization could be halved: after one month of this immuno-nutritional treatment, malnourished children appear to be sufficiently healthy to face their pathogenic home environment.

Adjuvants, Immunologic↗