Biomedical subjects
Publications and source records attributed to D Humphreys.
The discovery of a potent intracellular inhibitor of human neutrophil elastase which is orally active and has a long duration of action is described. The pharmacodynamic and pharmacokinetic properties of a trans-lactam development candidate, GW311616A, are described.
Clusterin is a highly conserved glycoprotein which has been proposed to protect host cells against complement-mediated cytolysis. We tested the hypothesis that clusterin is a complement regulator using erythrocytes and cells which had been stably transfected with a membrane-anchored form of clusterin as targets for complement-mediated cytolysis. Clusterin gave dose-dependent protection of antibody-coated sheep erythrocytes against complement-mediated lysis by diluted normal human serum. There was a linear relationship between the concentration of clusterin giving 50% protection and the concentration of serum; extrapolation of this to the case of undiluted human serum showed that a clusterin concentration at least two orders of magnitude greater than its physiological plasma concentration would be needed to confer protection against complement-mediated cytolysis under physiological conditions. Physiological concentrations of clusterin did not protect rabbit erythrocytes against alternative complement pathway-mediated lysis using dilute human serum. Exogenous clusterin had no effect on lysis of human erythrocytes triggered by the addition of inulin to autologous human serum. Induction of cell-surface clusterin expression by L929 (murine fibroblast) cells which had been stably transfected with cDNA for human clusterin linked to DNA coding for the 44 C-terminal amino acid residues of CD55 did not protect the cells against complement-mediated lysis by either normal or clusterin-depleted human serum. These data suggest that clusterin may not be a physiologically relevant regulator of complement activation.
OBJECTIVE: To review the estimated suicide rates for the Region Metropolitan, the main socio-political center in Chile, for the period 1979-1994, and to determine whether they follow a seasonal pattern. METHOD: Data available for the period 1979-94 at the Forensic Services in Chile was analyzed using Analyses of variance. RESULTS: It was register 5,386 suicides. While the "warm" months (October, November, December & January) concentrated 39.0% of cases, the so called "cold" months reported 28.7%. This contrast is made even clearer by the month-to-month analysis, showing the highest suicide rate in December (10.6%) against the lowest rate in June (7.0%). Further statistical analysis revealed these differences to be significant. CONCLUSION: The study shows that in Chile, representing as it does the Southern Hemisphere, the suicide rates tend to present a seasonal variation as has elsewhere been determined for in the North Hemisphere.
Clusterin is a widely distributed and highly conserved protein for which many functions have been proposed. We used transfected L929 cells to study the effect of clusterin expression on the regulation of cell death signals. We showed that high levels of clusterin expression, about 0.2 pg clusterin secreted per cell per 48 h period, specifically protected L929 cells from TNFalpha-mediated cytotoxicity, while low expression (about 4 fg/cell/48 h) had no effect. However, clusterin expression did not provide transfected L929 cells with protection against death mediated by colchicine, staurosporine or azide. High level expression of clusterin in transfected L929 cells also potentiated the cytotoxicity of TGFbeta. It had previously been shown that exposure of L929 cells to TGFbeta provides protection against TNFalpha. We showed that this protective effect is not additive to that of clusterin expression. One interpretation of this data is that it suggests that clusterin and TGFbeta may act via a common mechanism to provide protection against the cytotoxicity of TNFalpha. Our results indicate that an intracellular action of clusterin protein is responsible for protection against TNFalpha cytotoxicity. Exposure to TNFalpha induces an increase in the level of cell-associated clusterin and specifically in the level of a novel clusterin molecule, which when analyzed under reducing conditions by SDS/PAGE and immunoblotting appears as two closely spaced bands at about 36 and 38.5 kDa. When analyzed under the same conditions, the normal form of intracellular clusterin, which is present with or without exposure to TNFalpha, appears as two poorly resolved bands at about 43-45 kDa. Since the novel form of clusterin is also expressed in cells exposed to TGFbeta, colchicine, staurosporine, and azide, it may result from toxin-induced disruption of processes of normal cellular protein production.
Cerebral blood velocity (CBV) (measured with transcranial Doppler, TCD) and other physiological and rating scale indices were measured before, during, and after inhaling a mixture of 40% nitrous oxide/oxygen and 40% nitrogen/oxygen, given during two separate visits in 7 normal male volunteers. During nitrous oxide/oxygen but not nitrogen/oxygen inhalation, CBV and euphoria increased significantly with minimal changes in other physiological indices except an increase in pulse rate after nitrous oxide/oxygen. In another 7 male volunteers, similar measurements were obtained while lying down and standing up during nitrous oxide/oxygen mixture and nitrogen/oxygen mixture inhalations, given during two separate visits. Nitrous oxide/oxygen inhalation produced significant CBV increase, which showed nonsignificant decrease of no clinical significance during standing up. There were no significant postural changes in blood pressure. Standing up during nitrous oxide/oxygen inhalation was associated with significant though mild dizziness.
A randomized, between-groups, repeated measures design was used to evaluate changes in cerebral blood flow (CBF), rating scales, and physiologic indices under resting conditions, during 5% CO2 inhalation in combination with epinephrine or saline infusions, in generalized anxiety disorder patients and controls. Subjects were divided into those with decreased anxiety and mild and more severe anxiety increase. The first group was found to have most pronounced CBF increase during CO2 inhalation, with the second group showing less marked increase, and the last group the least increase. In animals, sympathetic activation limits hypercapnic cerebral vasodilation. Thus, the restricted hypercapnic cerebral vasodilation during severe anxiety may be mediated through cervical sympathetic fibers, which innervate cerebral vessels.
Collection of peripheral blood progenitor cells from small pediatric patients provides many social and technical challenges not faced when collecting from adult patients. This paper provides a single institutions experience with 85 collections from 14 patients less than 25 kg of weight over a 2 year period. Specific challenges include obtaining venous access, anticoagulation, volume shifts, and obtaining patient cooperation. A systematic analysis of options for access, alternative modes of anticoagulation, and the effect of large ratios of extra-corporeal volume to patient's blood volume are discussed. Access uniformly required central venous catheters (CVC) ranging from 7-10 Fr. Anticoagulation included systemic heparinization titrating dose by activated clotting time in all cases and combined with citrate at a ratio of 1:25-1:30 in most cases. Collections were performed on a COBE Spectra, after priming with leukoreduced irradiated red cells and omitting both the initial 120cc diversion and rinse back of red cells at the end. Social challenges include issues of assent and ability to distract patients for the duration of a prolonged collection. Progenitor yields from collections from 14 patients were quantitated by CD34+ assay in all cases and CFU-GM in ten of 14 patients. A median of 4.5 x 10(6)/kg CD34+ cells were obtained for each collection. Complications, including those related to catheter access, are enumerated. In summary, large volume peripheral blood progenitor collection can be safely and efficaciously performed in small pediatric patients.
BACKGROUND: Recruitment of progenitors during a large-volume collection, as defined by increasing relative and absolute numbers of progenitors (colony-forming units-granulocyte-macrophage [CFU-GM] of CD34+ cells), has been reported previously. STUDY DESIGN AND METHODS: To ascertain whether intra-apheresis recruitment occurs in pediatric patients who have undergone mobilization with chemotherapy and granulocyte-colony-stimulating factor (G-CSF), each hour's portion of a 4-hour leukapheresis was collected into separate bags, and assessed by complete blood count, CFU-GM, and CD34+ cell assays. Seven pediatric patients (median age, 7; range, 2-19) were studied in connection with 2 to 4 collections each, for a total of 21 collections (with hourly samples). The collections lasted for 4 hours, at an inlet rate of 1 to 3 mL per kg per minute, for daily processing totals of 5 to 12 blood volumes. (One blood volume [mL] is estimated by the patient's weight in kg x 70 mL/kg.) Smaller (younger) patients had inlet rates exceeding 2 mL per kg per minute, and larger (older) patients had rates of 1 to 1.5 mL per kg per minute. CFU-GM and CD34+ cell counts obtained each hour of the collection and divided by the first hour's value were compared by nonparametric repeated-measures ANOVA. RESULTS: Second-, third- and fourth-hour CD34+ progenitor cell counts were arithmetically higher than first-hour counts, but the trend did not reach significance (p = 0.1561). Second-hour counts were higher than first-hour counts in the overall analysis (mean +/- standard error [SE], 1.00 and 1.39 +/- 0.1, respectively; p = 0.0525) and in children older than 5 years (1.00 vs. 1.70 +/- 0.30, respectively; p = 0.0259), but not in children younger than 5 years (p = 0.8125). CFU-GM counts did not differ among the 4 hours of collection (p = 0.1717) or between the first and second hour (p = 0.9587). CONCLUSION: In larger (older) patients, from whom fewer blood volumes were collected, there is a trend toward intra-apheresis recruitment, although less than reported previously. In the smaller (younger) patients, from whom more blood volumes were collected, no trend was observed. Lack of (or submaximal) prior mobilization in previously reported studies may have facilitated intracollection recruitment. Alternatively, the larger number of blood volumes collected from the smaller (younger) patients may have masked intra-apheresis recruitment. The study documents the feasibility of large-volume, 4-hour leukapheresis in pediatric patients.
To test the hypothesis that the increased health risk of children selected by a previously calculated and validated predictive model is associated with some maternal psychological characteristics, the universe of 107 mothers of children selected by this model was evaluated by means of Goldberg's General Health Questionnaire (GHQ-30), Raven (Ra) and Rorschach (Ro) tests; 37.4% were cases according to GHQ-30, 80.9% were < 50th percentile in Ra and 85% exhibited deviant responses in Ro tests. Children whose mother's IQ was < 50th percentile suffered more episodes of total morbidity (Tm) and of diarrhoea (p = 0.0364). Children whose mothers were normal in Ro had less Tm (p = 0.0364) and fewer respiratory symptoms (p = 0.0300) and tended to have less diarrhoea (p = 0.0690). In poor urban families in Santiago psychological maternal characteristics are associated with an increased health risk for the infants. Supportive programmes should consider both biological characteristics of the infants and maternal psychological needs.
A previously calculated predictive model for health risk selects infants who suffer 4-5 times more morbidity than their unselected peers. Preliminary results suggested that this risk is related to maternal neurotic symptomatology. To evaluate this hypothesis, 52 consecutive mothers whose infants had a positive predictive score (Group 1) and 52 in whom this was negative (Group 2) were evaluated by means of Goldberg's General Health Questionnaire (GHQ-30). A total of 41.9% and 20.5% of the mothers in Groups 1 and 2, respectively, scored above 11 points in GHQ-30, established as the cut off point. It is concluded that among poor urban families in Santiago mothers of infants with high risk of persistent diarrhoea have increased frequency of detectable neurotic symptoms. New programs aimed at this type of infant should include psychological support for their mothers.
Eight pediatric patients with fulminant meningococcemia, purpura, and disseminated intravascular cogulation who by multiple prognostic scoring systems were anticipated to have a poor outcome underwent intensive plasma exchange (IPE) or whole blood exchange (WBE) in addition to standard medical therapy. IPE/WBE was initiated shortly after admission with a mixture of both fresh frozen plasma and cryoprecipitate as the replacement solution. All IPE procedures were performed using a continuous flow system and a red cell prime. The mean fibrinogen level increased from 62 to 192 mg/dl, the prothrombin time (PT) decreased from a mean of 32.4 seconds to 15.1 seconds, and the mean activated partial thromboplastin time (APTT) decreased from 89.5 seconds to 40.1 seconds following completion of the initial IPE/WBE. There was a corresponding improvement in all coagulation factor levels but only slight improvement in antithrombin III (ATIII) and protein C levels. Seven of eight patients survived (87.5%) their initial presentation with the sole early death attributed to meningitis with cerebral edema. Mean fluid balance after the procedure was +10.8 +/- 5.87 cc/kg. There were no significant bleeding or cardiovascular complications during the procedure. There was no clinical or radiographic evidence of fluid overload after the procedure. This experience demonstrates that IPE/WBE may be conducted safely in critically ill, unstable pediatric patients and is effective in rapidly improving coagulopathy without fluid overload.
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Depersonalization and other behavioral and physiological indices were monitored before and after the administration of high- and low-potency marijuana cigarettes and a placebo cigarette in 35 physically and mentally healthy normal volunteers. The cigarettes were administered under double-blind conditions during three visits to the laboratory separated by a minimum of 1 week. Marijuana smoking, but not placebo smoking, was associated with significant depersonalization that was maximal 30 min after smoking the high-potency cigarettes. Other behavioral changes induced by marijuana included disintegration of time sense, sensation of "high," increased state anxiety, tension, anger, and confusion. Respiration, pulse rate, and systolic blood pressure also increased after marijuana smoking. Multiple regression identified temporal disintegration as the most significant predictor of depersonalization.
Marijuana is known to cause symptoms suggestive of orthostatic hypotension such as dizziness and fainting during upright posture. We examined changes in cerebral blood velocity (CBV) and peripheral circulation during upright posture after smoking marijuana in 10 right-handed male subjects with a previous history of exposure to marijuana. The participants were physically and mentally healthy and drug-free for a minimum of 3 months before the experiment. Middle cerebral artery CBV, blood pressure and pulse rate were recorded during reclining position and standing, before and after smoking a high-potency marijuana cigarette or a placebo cigarette administered during 2 separate visits to the laboratory. The participants were questioned about dizziness during the upright position. Six of 10 subjects reported moderate to severe dizziness during standing after marijuana but not placebo. Subjects who experienced severe dizziness during standing showed marked decreases in blood pressure and CBV. Those who reported moderate dizziness showed reduction in CBV but not blood pressure. Subjects who reported mild dizziness after marijuana and after placebo smoking showed minimal changes in blood pressure and CBV. Cerebral ischemia during upright position after marijuana smoking may be caused by hypotension and impaired cerebral autoregulation.
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The Rhesus variant Du is regarded as a weak form of the Rhesus D antigen, but haemolytic disease of the newborn may occur if the maternal serum contains Anti-D [5]. We describe the case of an infant with Rhesus Du incompatibility and high levels of Anti-D in the maternal serum, but without clinical evidence of haemolytic disease of the newborn.
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