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Maternal anxiety and pain prolong labor and contribute to fetal distress. Hydrotherapy during labor may promote relaxation and decrease pain without the risks caused by other treatments. In this pilot study the psychophysiological effects of hydrotherapy on maternal anxiety and pain during labor were examined. Using a randomized, pretest-posttest control group design with repeated measures, 18 term parturients were assigned to a control or an experimental group. Experimental subjects were placed in a tub of 37 degrees C water for 1 hr during early labor. The Wilcoxon two-sample test revealed statistically significant effects. At 15 min bathers' anxiety and pain scores were decreased compared to nonbathers. At 60 min bathers' pain scores were decreased compared to nonbathers. After 15 min of immersion, bathers had a significantly greater increase in plasma volume than nonbathers. No significant differences were found in urine catecholamines or maternal-fetal complications. The small sample limits conclusions, but the findings offer preliminary support for the therapeutic effects of bathing in labor for acute, short-term anxiety and pain reduction.

The purpose of this study was to determine the effects of a single period of swim exercise to exhaustion on the cellular distribution of hexokinase in rat skeletal muscle. The gastrocnemius muscle from male rats exercised (n = 16) to exhaustion or allowed to remain inactive (n = 14) was analyzed for hexokinase activity (HK) in the whole muscle homogenate and the mitochondrial-rich fraction. Although exercise produced a slight, non-significant, increase in HK activity in the whole muscle homogenate (p less than 0.09), HK activity in the mitochondrial-rich fraction was significantly increased in the exercised muscle (p less than 0.02). This shift in the cellular distribution of HK is towards the more active mitochondrial bound form and indicates an enhanced regulation of HK activity during physical exercise.

Background Reelin (RELN) is a glycoprotein secreted preferentially by cortical γ-aminobutyric acid-ergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD) 67 , but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects. Methods Reelin, GAD 65 , GAD 67 , DAB1, and neuron-specific–enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody. Results Prefrontal cortex and cerebellar expression of RELN mRNA, GAD 67 protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD 65 and neuron-specific–enolase expression implying that RELN and GAD 67 down-regulations were unrelated to neuronal damage. Reelin and GAD 67 were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication. Conclusions The selective down-regulation of RELN and GAD 67 in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis.

Objective: Treatment of pregnant mothers with a single course of antenatal corticosteroids significantly reduces neonatal mortality and morbidity. Multiple weekly courses are often given. However, the safety and efficacy of repeated courses of antenatal corticosteroids have not been adequately studied. Study Design: A retrospective study was performed for 609 mothers and their 713 infants who were treated with 1 to 12 courses of antenatal corticosteroids. Data for 369 singleton preterm infants born at ≤34 weeks' gestation, 210 multiple gestations, and 134 infants delivered at ≥35 weeks' gestation were analyzed separately. Results: The incidence of respiratory distress syndrome was 45% for single-course and 35% for multiple-course groups ( P = .005; odds ratio, 0.44; 95% confidence interval, 0.25-0.79). The multiple-course group also had significantly less patent ductus arteriosus (20% vs 13%; P = .016). Incidence of death before discharge and other neonatal morbidities were similar. The multiple-course group had a reduction of 0.46 ± 0.19 cm in head circumference at birth ( P = .013) when adjusted for gestational age and preeclampsia. The 2 groups had similar birth weights. Infants born at ≥35 weeks' gestation, multiple-gestation infants, and infants who were born >7 days after the last corticosteroid dose had similar outcomes, regardless of the number of courses they received. Mothers treated with multiple courses compared with a single course had a significantly higher incidence of postpartum endometritis ( P = .013), even though they had a lower incidence of prolonged rupture of membranes (24% vs 33%, P = .06) and similar cesarean delivery rates. Conclusion: Exposure to multiple courses of antenatal corticosteroids compared with a single course resulted in a significant reduction in the incidence of respiratory distress syndrome in singleton preterm infants delivered within a week of the last corticosteroid dose. This was associated with a reduction in birth head circumference and an increased incidence of maternal endometritis. Whether the potential benefits of repeated therapy clearly outweigh the risks will ultimately be determined in randomized prospective controlled trials. (Am J Obstet Gynecol 2000;182:1243-9.)

The inflammatory effects of respirable cellulose fibres were studied in two short-term animal models: intraperitoneal injection in mice, and inhalation in rats. The mouse peritoneal cavity is particularly sensitive to fibrous compared to non-fibrous particles. Both cellulose fibres and the positive control fibre, crocidolite asbestos, were administered in doses ranging from 10(4) to 10(8) fibres and caused marked, dose-dependent recruitment of inflammatory cells to the mouse peritoneal cavity, which was highest 1 day following injection. Crocidolite was much more active than cellulose, despite the mass dose of cellulose being 66 times greater for an equivalent number of fibres. Crocidolite at the higher doses caused inflammation to persist through 7 days. For the inhalation study, rats were exposed daily, 5 days per week, to aerosols of cellulose dust for ca. 3 weeks at a concentration of 1000 fibres ml(-1). Inhalation exposure induced an early inflammatory response in rat lungs, as determined by bronchoalveolar lavage, which peaked at 1 day following the start of inhalation and thereafter declined, despite a further 13 days of exposure over a period of 18 calendar days. In vitro production of the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha) by lavaged alveolar macrophages was markedly depressed by the end of the exposure period in cellulose-exposed animals, compared to sham-exposed controls, and this effect was still present in rats that had been allowed to recover for 28 days beyond the end of exposure. We conclude that the cellulose material studied is less inflammogenic than crocidolite and that the extent of the inflammatory response within the lung appears to reduce with continued exposure over a 14-day period.

The purpose of the present study was to investigate the impact of the use of peripheral blood progenitor cells (PBPCs) on the induction of autologous graft-versus-host disease (GVHD) in patients with advanced breast cancer. 14 women with stage IIIB and 36 women with stage IV breast cancer received cyclosporine (CsA) 2.5 mg kg–1 i.v. daily, d 0–28, and interferon-gamma (IFNg) 0.025 mg/m2 s.c. qod, d7–28, following PBPC-T ± bone marrow transplantation (BMT). Preceding high-dose chemotherapy consisted of cyclophosphamide 6 g/m2 and thiotepa 800 mg/m2. Histologically proven ≥grade II cutaneous GVHD was induced in18/50 (36%) of patients and was independent of the source of haematopoietic support. In vitro studies showed that post-transplant, 76% of patients had developed auto-cytotoxicity against their own pre-transplant PHA-lymphoblasts. A significant correlation between the occurrence of GVHD ≥grade II and cytolysis was observed in the NK cell-line K562 and the T47D breast cancer cell-line. With a median follow-up of 2½ years, the overall survival (OS) is 58%, the disease-free survival (DFS) 26%, both independent of the development of GVHD and similar to what has been observed in other studies on high-dose chemotherapy in advanced breast cancer. It therefore remains unclear whether the induction of autologous GVHD with the occurrence of auto-cytotoxic lymphocytes can result in an anti-tumour effect in this group of patients. © 2000 Cancer Research Campaign http://www.bjcancer.com

Expertise in neonatal resuscitation is essential for all hospital personnel involved in the care of newborn infants. The guidelines to resuscitation reviewed here have been established by the American Academy of Pediatrics and the American Heart Association and have resulted in significantly improved training and expertise of delivery room personnel. Although widely accepted, many of these guidelines are only now being rigorously studied in controlled trials. This lack of rigorous testing has raised some questions regarding routine resuscitative practices and indicates that present-day standard therapies must always be under constant review.

Experimental support for the hypothesized benefits of BCAA supplements on endurance performance is limited. However, it is theorized that the benefits may be enhanced if 1) BCAA are taken along with a pre-event carbohydrate meal as well as during exercise, and 2) the exercise is intermittent in nature. This study tested the effects of ingesting carbohydrate beverages with and without BCAA before and during intermittent high-intensity running to fatigue. Eight subjects performed 3 exercise trials consisting of intermittent shuttle running (walking, sprinting, and running) to fatigue. Subjects drank either carbohydrate drinks given 1 h before (5 mL/kg, 18% carbohydrate) and during exercise (2 mL/kg, 6% carbohydrate) (CHO), carbohydrate drinks with BCAA (7 g) added to the portions consumed 1 h before and immediately before exercise (CHO+BCAA), or flavored water placebos (P). Subjects ran longer when fed either CHO or CHO+BCAA as compared to P, with no differences between CHO and CHO+BCAA. CHO and CHO+BCAA also had higher plasma glucose and insulin, and lower FFA (p < 0.05). These findings confirm a beneficial effect of carbohydrate feedings on fatigue during exercise designed to mimic the activity pattern that occurs in sports like soccer, basketball, and hockey. They do not, however, support the hypothesis of an added benefit of BCAA supplements.

In 1994, the U.S. Environmental Protection Agency (EPA) denied a petition by Ethyl Corporation to allow the use of methylcyclopentadienyl manganese tricarbonyl (MMT) in unleaded gasoline, because of health concerns related to the inhalation of manganese (Mn) particulate emissions from combusted MMT. Although Ethyl successfully challenged EPA's denial of the petition on legal grounds, issues raised in EPA's health risk assessment have not been resolved to date. This paper summarizes features of the EPA health risk characterization, which included the use of various statistical techniques to derive several estimates of inhalation reference concentration (RfC) values for Mn as alternatives to the established value of 0.05 microgram Mn/m3. An exposure assessment projected distributions of personal exposure levels to particulate Mn if MMT were used in all unleaded gasoline. It was estimated that exposure levels of 5-10% of the modeled population might exceed a possible alternative RfC value of 0.1 microgram Mn/m3. However, due to data limitations, the risk characterization for Mn/MMT could raise only qualitative concerns about potential public health impacts and was unable to provide a quantitative estimate of risk. To improve the risk characterization, better information on Mn/MMT population exposures and health effects is needed. Much of this information is expected to be obtained under provisions of Section 211 of the Clean Air Act. Among the specific issues that remain to be resolved are the form or forms of Mn emitted from the combustion of MMT in gasoline and the potentially different toxic properties of Mn in different forms.

The objective was to examine and quantify the influence of fibre dimensions, persistence in the lung, and dissolution and cell toxicity in vitro, on the risks of developing lung tumours in rats. Data were brought together from the studies carried out at the IOM under the Colt Fibre Research Programme, and from studies carried out in Switzerland and the USA under the programme of the Thermal Insulation Manufacturers Association. In both studies, groups of rats were exposed by inhalation to a range of airborne fibres. At the end of their lives they were examined for the presence of benign and malignant lung tumours and mesothelioma. The studies differed in a number of details, but were combined on the basis of approximate equivalence of cumulative exposure to airborne fibres. Logistic regression models were used to relate differences in carcinogenicity to fibre characteristics; dimensions, persistence in the lung after intratracheal injection, dissolution rates from bench-top flow-through experiments, measures of inflammation, and other cell responses to fibres in vitro. Despite the small number of data points, the results suggested a primary influence of the airborne concentrations of the numbers of fibres thinner than 1 micron diameter and longer than 20 microns, and of the measured dissolution rate of the fibres. While these results are based on only a small number of fibre types, the statistical model fits the data reasonably well, and enables some cautious insights into the quantitative influences of dimensions and biopersistence. Results were broadly consistent with those from intraperitoneal injection studies of the same fibres, in that the responses were dependent on both the durability of the fibres and the numbers of long thin fibres. In vitro and in vivo cell responses did not predict significantly the risk of cancer following inhalation.

A range of respirable man-made mineral fibres were tested for evidence of carcinogenicity by injection into the peritoneal cavity of male SPF Wistar rats; and differences in carcinogenicity were related to the dimensions and biopersistence of the injected fibres. The fibres tested included an amosite asbestos, a silicon carbide whisker, a special purpose glass microfibre, and a range of other man-made vitreous fibres (MMVFs) and refractory ceramic fibres (RCFs) from the TIMA fibre repository. The injected dose of each was designed as the estimated mass required to contain 10(9) fibres5 microns in length, as determined by optical microscopy. The numbers of long fibres (15 microns) contained in these doses ranged across fibres from 0.1 x 10(9) to 0.8 x 10(9) fibres; the number of long fibres thinner than 0.95 micron ranged from 0.015 x 10(9) to 0.4 x 10(9). The treatment groups contained between 18 and 24 animals. Animals were killed when they showed signs of debilitation. At autopsy, the diagnosis of mesothelioma was usually obvious macroscopically. Otherwise, histological examination of peritoneal organs was used to search for early tumour development. Judged by median survival time, four of the fibre types, in the doses administered, presented higher mesothelioma activity than amosite asbestos. The other fibres tested were less carcinogenic than the amosite. Only a ceramic material derived by extreme heating to simulate the effect of furnace or oven conditions, produced no mesotheliomas. Attempts were made, using regression models, to relate these differences to fibre dimensions and to measures of durability from separate experiments. The results pointed principally to a link with the injected numbers of fibres20 microns in length and with biopersistence in the rat lung of fibres longer than 5 microns. Improved quantification of the relative importance of fibre dimensions and biopersistence indices requires experimentation with a range of doses.

The health implications of atmospheric particulate matter have become a topic of much interest on both sides of the Atlantic, but especially in the USA, where they were at the centre of the debate over the Environmental Protection Agency's (EPA) revision of the National Ambient Air Quality Standard in 1997. Much of this debate revolves around claims that particulate matter (usually represented by PM10) in the atmosphere directly influences mortality, hospital admissions with respiratory diseases, and so on. In this paper, we take a critical look at one of these issues, the influence of PM10 on deaths in the elderly population. Two data sets are considered, one from Birmingham (Alabama) and the other from Chicago. In both cases we find a significant PM10-mortality relationship in some of the models fitted, but not in others. Other issues considered include the existence of a threshold below which PM10 has no discernible influence, the interaction with other pollutants and the mortality displacement or harvesting effect (the theory that the direct effect of PM10 is limited to a very small subset of the population who are already critically ill and whose death is only advanced by a few hours or days as a result of air pollution). Overall, our conclusion is that there are too many uncertain issues to allow us to make definitive statements about a causal relationship between PM10 and mortality.

Prophylactic, intratracheal instillation of recombinant human Cu/Zn superoxide dismutase (rhSOD) has been shown to lessen lung injury produced by 48 h of hyperoxia and mechanical ventilation in neonatal piglets. However, instillation of small volumes of rhSOD intratracheally would not be expected to result in uniform pulmonary distribution. Aerosolization is a technique that may improve pulmonary distribution of drugs, but is limited by the poor efficiency of most nebulizers. A newly modified ultrasonic nebulizer was tested to assess pulmonary distribution of rhSOD compared to that achieved by intratracheal instillation. rhSOD was dual-labeled with technetium-99m (99mTc) and a fluorescent analog (permitting quantitative and qualitative assessments of pulmonary distribution), and administered to neonatal piglets by intratracheal instillation or by aerosolization. Intratracheal instillation of rhSOD to piglets when supine resulted in nonuniform distribution, with most of the drug being found in the right caudal lobe, and localized in airways. Placing animals in 30 degrees of Trendelenburg and administering half the dose in the left and half in the right lateral decubitus positions improved distribution, but alveolar deposition remained patchy. Aerosolization using a modified ultrasonic nebulizer uniformly delivered 45.8 +/- 3.8% of the rhSOD to the lungs that had been placed in the nebulizer. The rhSOD was still active and present in airways and alveoli in a homogeneous fashion. We conclude that intratracheal instillation of rhSOD in small volumes results in nonuniform pulmonary distribution, while aerosolization enhances rhSOD distribution and alveolar deposition. This has important implications for ongoing clinical trials of rhSOD for the prevention of acute and chronic lung injury in premature neonates.

Epidemiological evidence suggests a link between the intensity of exercise and infectious and neoplastic disease. One likely way by which exercise exerts its effect on cancer and infection is by altering the function of the immune system. Cells of the innate immune system (i.e., macrophage [Mphi], natural killer [NK] cell, and polymorphonuclear neutrophils [PMN]) are first-line defenders against cancer and infectious disease by nature of their phagocytic, cytolytic, and antimicrobial properties. The purpose of this review is to define the role of cells of the innate immune system (i.e., Mphi, PMN, and NK cells) in infection and cancer, present current information regarding the effects of acute and chronic exercise on the quantification and functional activities of these cells, and briefly to discuss potential mechanisms as to how exercise affects these cells and describe how these changes may potentially affect susceptibility to infection and cancer. The effects of exercise on the number, functions, and characteristics of cells of the innate immune system are complex and are dependent several factors, including 1) the cell function or characteristic being analyzed; 2) the intensity, duration and chronicity of exercise; 3) the timing of measurement in relation to the exercise bout; 4) the dose and type of immunomodulator used to stimulate the cell in vitro or in vivo; and 5) the site of cellular origin. Further studies are needed to determine whether the exercise-induced changes in immune function alter incidence or progression of disease. Likewise, the mechanisms as to how exercise alters innate immune function are as yet unresolved.

Determine the effect of PEGylation on in-vitro degradation for recombinant human Megakaryocyte Growth and Development Factor (rHuMGDF) in the neutral pH range.Degradation products were characterized by cation-exchange HPLC, N-terminal sequencing and mass spectrometry.The main route of degradation was through non-enzymatic cyclization of the first two amino acids and subsequent cleavage to form a diketopiperazine and des(Ser, Pro)rHuMGDE This reaction was prevented by alkylation of the N-terminus by polyethylene glycol (PEG).PEGylation of proteins is commonly performed to achieve increased in-vivo circulation half-lives. For rHuMGDF, an additional advantage of PEGylation was enhanced in-vitro shelf-life stability.

This randomized, double-blind, placebo-controlled study examined the influence of 6% carbohydrate ingestion on hormonal and lymphocyte proliferative responses (5 total samples over 9 hours) to 2.5 h of high-intensity running by 30 experienced marathon runners. The T-cell response differed between groups, with the placebo group exhibiting a greater increase immediately post-run and greater decrease at 3 h of recovery. No group differences were observed for Con A-, PHA-, or PWM-induced lymphocyte proliferation. However, when PHA was adjusted per T-cell, group differences were observed, highlighted by a decrease in the placebo group immediately post-run. Glucose and cortisol responses differed between groups, with glucose lower and cortisol higher in the placebo group immediately post-run. Post-run glucose correlated negatively with postrun cortisol (r=-0.670, P< 0.001) and epinephrine (r=-0.540, P=0.002). Post-run cortisol also correlated negatively with total lymphocytes and T-cells at 1.5 hours (r=-0.429, P=0.018 and r=-0.424, P=0.019, respectively) and 3 hours (r=-0.566, P=0.001 and r=-0.523, P=0.003, respectively) of recovery. The pre- to post-run change in glucose correlated to the same changes in PHA/T-cell (r=0.456, P=0.011). The data support an interactive effect of carbohydrate ingestion on plasma glucose and cortisol. The data support an interactive effect of carbohydrate ingestion on plasma glucose and cortisol, T-cell trafficking, and cell-adjusted PHA-induced lymphocyte proliferation following long endurance running.

This article discusses the results of work in progress on two sites -one in Cyprus (Shillourokambos ), the other in centred Anatolia (Asikh Höyük). Both sites are situated to the west of the east Anatolian cradle of animal domestication. Both provide evidence for animal husbandry in the Pre-Pottery Neolithic, between the end of the 9 and the middle of the 8th millennium cal. ВС. In Cyprus, this early husbandry clearly results from a diffusion process since that animals such as Pig, Fallow Deer, Sheep, Goat and Cattle were deliberately imported onto the island from the mainland before the end of the 9th millennium cal. ВС. On the opposite, the process of domestication in central Anatolia appears to have followed a period during which Caprines (sheep and. goats) were more intensively and selectively managed. We still do not know if early domestication in this area had developed contemporaneously or later than in Eastern Anatolia. In both Central Anatolia and Cyprus, it is clear that several species maintained a "wild-type" morphology for several centuries following their initial domestication. A closer look at the archaeology of this period in the Near East reveals the importance of this intermediate phase in animal domestication and of the intensive management of such wild-type domestic animals (also called herein "pre-domestic" animals). Trends are proposed for future research., Les auteurs exposent les résultats des analyses encore en cours sur deux sites, l'un à Chypre (Shillourokambos), l'autre en Anatolie centrale (Asikh Höyük). Ces sites illustrent tous deux, pour des régions pareillement situées à l'Ouest du foyer de domestication de l'Anatolie orientale, les premiers pas de l'élevage au Néolithique précéramique, entre la fin du 9e et le milieu du 8e millénaire av. J.-C. (dates calibrées). À Chypre, il s'agit clairement d'un processus de diffusion puisque différentes espèces- appropriées par l'homme {Porc, Daim, Mouton, Chèvre, Bœuf...) ont été délibérément importées du continent dès la fin du 9e millénaire. Le processus de domestication en Anatolie centrale semble, en revanche, résulter principalement de l'émergence d'une gestion intensive et très spécialisée des Caprines, dont on ne peut préciser pour l'instant si elle est contemporaine ou postérieure à celles qui sont attestées dans la région Euphrate-Tigre. Dans les deux cas on observe cependant que certaines espèces, bien que probablement élevées par les groupes humains, ont conservé une forme sauvage durant plusieurs siècles (populations «pré-domestiques »). Ces constats font par ailleurs ressortir l'importance anthropologique et historique de cette phase «intermédiaire» de gestion intensive de populations «pré-domestiques », qui précède l'apparition d'espèces pleinement domestiques. Des pistes de recherche archéologique sont dégagées pour Chypre, l'Anatolie centrale et occidentale, et l'ensemble du Proche-Orient., Vigne Jean-Denis, Buitenhuis Hijkle, Davis Simon. Les premiers pas de la domestication animale à l'Ouest de l'Euphrate : Chypre et l'Anatolie centrale.. In: Paléorient, 1999, vol. 25, n°2. pp. 49-62.

Mice exercised to fatigue and exposed to herpes simplex virus type 1 (HSV-1) exhibit greater mortality than control mice. In this study, we examined lung macrophage resistance to HSV-1 after exercise in terms of both viral replication and interferon (IFN)-β production. We utilized the reverse transcriptase-rapid polymerase chain reaction to measure the IFN-β mRNA content in alveolar macrophages. IFN release was measured with a bioassay, and viral replication within the macrophage was assessed by plaque titration. Exercised (Ex) mice ran on a treadmill until fatigue while control (Con) mice remained in lanes above the treadmill. After exercise, alveolar macrophages were removed and incubated with HSV-1. Alveolar macrophage IFN-β mRNA was greater in Ex than in Con mice. Culture supernatant from infected macrophages showed a higher degree of IFN release and a higher number of infectious viral particles in Ex vs. Con mice. It is likely that the increase in IFN-β mRNA occurs in response to a higher degree of viral replication. These results suggest that macrophages from Ex mice are less resistant to infection with HSV-1.

Imidazenil, a benzodiazepine recognition site ligand that acts as partial positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors, inhibits in a dose-dependent manner (0.56-2.5 micromol/kg i.p. to rats) the cocaine-induced increase in dopamine (DA) content in the dialysates of the nucleus accumbens shell and striatum and also inhibits cocaine-induced locomotor activity. Diazepam, a full allosteric modulator of GABA action at GABAA receptors, in a dose of 4.4 micromol/kg i.p. also attenuates the cocaine-induced increase in DA content in the dialysates of nucleus accumbens shell, and striatum and the cocaine-induced locomotor activity. However, imidazenil (2.5 micromol/kg i.p.) fails to reduce spontaneous locomotor activity, whereas diazepam (4.4 micromol/kg i.p.) elicits sedation and ataxia and clearly impairs spontaneous locomotor activity. When added in vitro, both imidazenil and diazepam potentiate the GABA-mediated reduction of the ventral tegmental area DA neuron firing rate. After protracted treatment (14 days/three times a day with an increasing-dose schedule), the inhibitory actions of imidazenil fail to develop tolerance, whereas the actions of diazepam exhibit high tolerance liability. We conclude that imidazenil is devoid of tolerance liability and that, via a GABAA-mediated reduction in the extracellular DA in nucleus accumbens shell, it might reduce the psychomotor activity and reinforcing properties of cocaine.

This study examined the effects of moderate and prolonged exercise on 1) lung tumor metastases and 2) alveolar macrophage antitumor response in vitro. C57Bl/6 mice were assigned to either Ex-30 (30-min run), Ex-F (run to fatigue), Ex-F-24 h (run to fatigue 24 h before tumor injection), or Con (rested in lanes above the treadmill). Mice received intravenous injections of syngeneic B16 melanoma cells 30 min postexercise. Lungs were removed 7 or 10 days later, and tumor foci were counted. Ex-F had fewer tumors than either Ex-30 or Con, whereas Ex-F-24 h also showed a strong trend toward fewer tumors. The initial localization of tumor cells in the lungs after injection was not different among groups. For the in vitro experiment, mice were killed immediately after exercise or 8 h later. Alveolar macrophages were removed and cultured in vitro with B16 melanoma cells. The growth of the tumors cultured with macrophages from Ex-F was lower than Con after exercise and, to a lesser extent, 8 h later. In Ex-30, this effect was only found immediately after exercise. The data suggest that prolonged exercise has a protective effect on lung tumor metastases and enhances alveolar macrophage antitumor cytotoxicity.

T cell depletion (TCD) performed by elutriation has decreased the incidence of acute and chronic graft-versus-host disease (GvHD) following bone marrow transplantation (BMT). However, as with all forms of TCD, patients may experience graft failure (10%), delayed engraftment, and mixed chimerism. Because 66%-75% of the CD34+ cells coseparate with the small lymphocytes, which are removed by elutriation, we designed a phase I trial in HLA-identical siblings to determine if the readdition of these previously lost small CD34+ cells would improve elutriation's engraftment kinetics. CD34+ cells were isolated from the small cell fraction of 10 consecutive donor grafts and infused into the recipients along with the TCD graft. The positively selected product had a mean T cell content of 1.2 x 10(5)/kg and was 80% CD34+, doubling the CD34+ content of the graft. All patients engrafted promptly with a median time to 500 neutrophils/mm3, untransfused 50,000 platelets/mm3, and discharge from the hospital of 19 (range 10-25), 24 (14-52), and 24 (18-29) days, respectively. Acute GvHD occurred in 2 patients, and no patient had chronic GvHD. Augmenting stem cell dose may be an efficient and safe alternative for overcoming TCD-associated delayed engraftment and graft failure, rather than increasing immunosuppression.

This randomized, double-blind, placebo-controlled study was designed to determine the influence of exercise mode and 6% carbohydrate (C) versus placebo (P) beverage ingestion, on blood cell counts, plasma glucose, hormone, and inflammatory cytokine responses (five total samples over 9 h) to 2.5 h of high-intensity running and cycling (approximately 75% VO2max) by 10 triathletes who acted as their own controls. Statistical significance was set at Por = 0.05.C relative to P ingestion (but not exercise mode) was associated with higher plasma levels of glucose and insulin, lower plasma cortisol and growth hormone, and diminished perturbation in blood immune cell counts. The pattern of change over time for interleukin (IL)-6 was significantly different between C and P conditions (P = 0.021) and between running and cycling modes (P0.001), with the lowest postexercise values seen in the C-cycling sessions (10.7 +/- 1.8 pg x mL(-1)) and the highest in the P-running sessions (51.6 +/- 14.2 pg x mL(-1)). The pattern of change over time between C and P conditions (but not modes) was significantly different for IL-1 receptor antagonist (P = 0.003), with values once again lowest for the C-cycling sessions (1.5 h postexercise, 301 +/- 114 pg x mL(-1)) and highest for the P-running sessions (1171 +/- 439 pg x mL(-1)).These data indicate that carbohydrate versus placebo ingestion (4 mL x kg(-1) carbohydrate or placebo every 15 min of the 2.5-h exercise bout) is associated with higher plasma glucose levels, an attenuated cortisol response, and a diminished pro- and anti-inflammatory cytokine response.

We hypothesized that a previously observed exercise-induced suppression of alveolar macrophage antiviral resistance results from increases in corticosterone and/or epinephrine. Mice (CD-1) were run to fatigue on a treadmill (exercise), or placed in Plexiglas lanes above the treadmill (control). The role of corticosterone was assessed by further dividing mice into groups receiving one of the following treatments; sham surgery, adrenalectomy, or adrenalectomy plus corticosterone replacement. Macrophage antiviral function was suppressed in the exercised mice compared to the control mice. However, macrophage antiviral function was not suppressed in the exercised mice that underwent adrenalectomy or adrenalectomy plus corticosterone replacement. We tested whether another adrenal factor (epinephrine) may be involved by dividing mice into exercise and control groups treated with either saline or propranolol. Macrophage antiviral function was again suppressed in the saline-treated exercised mice compared to saline-treated control mice, but no differences were found between the exercised mice receiving propranolol, control mice receiving propranolol, or saline-treated control mice. Isoproterenol, when added to alveolar macrophages in culture, also suppressed antiviral resistance. These findings suggest that decreased macrophage antiviral function following exercise may be due to increased release of adrenal catecholamines.

The effects of ingesting carbohydrate drinks on fatigue during intermittent. high-intensity cycling in men and women were determined. Physically active but untrained women (n = 7) and men (n = 9) completed one practice trial and two experimental sessions separated by 1 week. Sessions consisted of repeated 1-min cycling bouts on a bicycle ergometer at 120-130% V˙O2max separated by 3 min rest until fatigue. Carbohydrate (CHO) or placebo (P) beverages (4 ml · kg body weight−1) were ingested immediately before exercise (18% CHO) and every 20 min during exercise (6% CHO). Plasma glucose and insulin were higher. RPE for the legs was lower, and time to fatigue was longer in CHO than P. Men's and women's responses were not different for any variable measured. These data suggest a beneficial role of CHO drinks on performance of intermittent. high-intensity exercise in men and women.

The objectives of this study were to (1) assess the role of the 26S proteasome complex in regulating the expression of the inducible isoform of nitric oxide synthase (iNOS) and vascular cell adhesion molecule-1 (VCAM-1) in a model of chronic granulomatous colitis in vivo and (2) determine the role of the proteasome in regulating the inflammatory response observed in this model of chronic gut inflammation. The selective proteasome inhibitor MG-341 (0.3 mg/kg) was administered by gavage beginning immediately before the induction of colitis and continuing daily thereafter for the entire 14-day experimental period. We found that chronic proteasome inhibition using MG-341 significantly attenuated the peptidoglycan/polysaccharide (PG/PS)-induced up-regulation of iNOS in the colon and spleen and the consequent increase in plasma levels of nitrate and nitrite. Furthermore, we found that the proteasome inhibitor suppressed the up-regulation of the adhesion molecule VCAM-1 in the colon. We also found that MG-341 attenuated PG/PS-induced increases in macroscopic colonic inflammation, bowel wall thickness, colonic dry weight and colonic MPO activity. Treatment with MG-341 also significantly reduced PG/PS-induced increases in macroscopic spleen inflammation, spleen weight and spleen MPO activity. We conclude that the 26S proteasome complex plays an important role in regulating the PG/PS-induced up-regulation of iNOS and VCAM-1 in vivo and appears to be important in regulating colonic and splenic inflammation.

This randomized, double-blind, placebo-controlled study was designed to determine the influence of vitamin C supplementation on the immune response to 2.5 hr of high-intensity running. Twelve experienced marathon runners (VO2 max 51.6 +/- 1.5 ml.kg-1.min-1, age 40.5 +/- 2.0 years) were randomized into vitamin C (1,000 mg/day for 8 days) or placebo groups. On the test day, subjects ran at 75-80% VO2 max for 2.5 hr, with five blood samples taken before and for 6 hr after. Blood samples were analyzed for cortisol and catecholamines; leukocyte subsets; interleukin-6; natural killer cell activity; lymphocyte proliferation as induced by concanavalin A, phytohemagglutinin, and pokeweed mitogen; and granulocyte phagocytosis and activated oxidative burst. Compared with placebo, vitamin C supplementation had no significant effect on the pattern of change in any of these hormonal or immune measures following 2.5 hr of intensive running.

The aim of this study was to compare the effect of ferric sulfate (FS) to that of dilute formocresol (DFC) as pulp dressing agents in pulpotomized primary molars. Ninety-six primary molars in 72 children were treated by a conventional pulpotomy technique. Fifty-eight teeth were treated by a FS solution for 15 sec, rinsed, and covered by zinc oxide-eugenol paste (ZOE). In another 38 teeth, a cotton pellet moistened with 20% DFC was placed for 5 min, removed, and the pulp stumps were covered by ZOE paste. The teeth of both groups were sealed by a second layer of intermediate restorative material (IRM) and restored with a stainless steel crown. This is a report of the clinical and radiographic examination of 55 teeth dressed with FS and 37 teeth fixed with DFC, that have been treated 6 to 34 months previously (mean 20.5 months). Four teeth were excluded from the study due to failure of the patient to present for recall. Success rates of 92.7% for the FS, and of 83.8% for the DFC were not significantly different. Four teeth (7.2%) of the FS group and two (5.4%) of the DFC group presented internal resorption. Inter-radicular radiolucencies were observed in two teeth of the FS group and three teeth of the DFC group. The latter also presented periapical lesions. Success rates of both groups were similar to those of previous studies utilizing the traditional Buckley's formocresol.

This randomized, double-blind, placebo-controlled study was designed to determine the influence of carbohydrate supplementation on the granulocyte and monocyte response to 2.5 h of high-intensity running [76.7 ± 0.4% of maximal oxygen consumption (VO 2 max)]. Thirty experienced marathon runners (VO 2 max 53.4 ± 1.0 mL. kg -1 . min -1 , age 41.5 ± 1.4 y) were randomly assigned to carbohydrate-supplement (n = 17) and placebo (n = 13) groups. Subjects rested for 10-15 min before a blood sample was taken at 0715, and then ingested 0.75 L carbohydrate beverage or placebo. At 0730 subjects began running at 75-80% of VO 2 max for 2.5 h, and drank 0.25 L carbohydrate or placebo fluid every 15 min. Immediately after the 2.5-h run (1000), another blood sample was taken, followed by 1.5-h, 3-h, and 6-h recovery samples. Carbohydrate supplementation had a significant effect compared with placebo on the pattern of change in plasma glucose and cortisol, and the blood concentration of neutrophils (F [4, 112] = 5.13, P = 0.001) and monocytes (F [4, 112] = 4.78, P = 0.001), but not on blood granulocyte and monocyte phagocytosis or oxidative burst activity after 2.5 h of intensive running.

We have studied gut mucosal perfusion in 24 infants, aged 0.7-45 weeks, requiring cardiopulmonary bypass (CPB). Group 2 patients (n = 12) had received the angiotensin converting enzyme inhibitor captopril 0.8-0.9 mg kg-1 orally, 45 min before induction of anaesthesia. Group 1 infants were of similar age and size and required a similar duration of CPB, but did not receive any preoperative medication. An orogastric tonometer allowed intermittent calculations of gastric intramucosal pH (pHi), and rectal mucosal perfusion ("flux") was monitored using laser Doppler flowmetry. Measurements of arterial base deficit and lactate and pyruvate concentrations were made intermittently. We found no significant difference in femoral arterial pressure between the groups at any time before, during or after surgery. Similarly, we found no significant differences in our measures of regional or global tissue perfusion between the groups at any time before, during or after surgery. We conclude that preoperative administration of captopril produced no beneficial effect on gut mucosal perfusion in infants undergoing hypothermic, non-pulsatile CPB.

PURPOSE A pilot study to validate the use of CD34+ selection (Ceprate SC) of blood stem-cell collection in patients with advanced follicular lymphoma receiving myeloablative chemoradiotherapy. PATIENTS AND METHODS Seventeen patients were entered onto the protocol. Thirteen of 17 patients have undergone transplantation; the median age is 42.5 years (range, 33 to 51), seven of 13 are stage IVB, two stage IVA, three stage IIIB, and one stage IIB. All except two patients were treated after first or subsequent relapses after receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to achieve a good partial (six of 13) or complete (seven of 13) response before stem-cell mobilization with cyclophosphamide 3 g/m2 and filgrastim 300 microg once daily. RESULTS Eleven of 13 patients had a detectable t(14;18) by nested polymerase chain reaction (PCR). Median CD34+ count before selection was 2.9 x 10(6)/kg (range, 1.17 to 11.3) and after CD34+ selection was 1.54 x 10(6)/kg (range, 0.88 to 7.6) with a median CD34+ yield of 62.4% (range, 17% to 95%) and purity of 60% (range, 39.3% to 73%). Of the 11 patients known to have t(14;18), 10 had PCR-detectable contamination of stem-cell harvests that became PCR negative in six of the 10 after CD34+ selection. Engraftment was rapid with a median day to absolute neutrophil count (ANC) greater than 0.5 x 10(9)/L of 13 days (range, 11 to 21) and platelet count greater than 20 x 10(9)/L of 14 days (range, 10 to 44). With a median follow-up duration of 15 months, three patients have remained persistently PCR-positive, two of whom received PCR-positive stem cells. Two have relapsed. Of the seven patients who received PCR-negative stem cells, five have had no PCR-detectable disease in posttransplant bone marrow samples. CONCLUSION Longer follow-up duration is required to determine the significance of these findings, but we have confirmed the feasibility of CD34+ selected cells to deplete peripheral-blood stem cells of tumor cells from patients undergoing high-dose therapy for follicular lymphoma.

Leukotriene B4 is a potent inflammatory mediator that is derived from the 5-lipoxygenase pathway of arachidonic acid metabolism and that has been implicated in the pathophysiology of polymorphonuclear leukocyte-dependent reperfusion injury in a variety of organ systems. The objectives of these investigations were to determine whether inhibition of leukotriene B4 attenuates postischemic polymorphonuclear leukocyte infiltration and subsequent injury in myocutaneous flaps. Anesthetized female Yorkshire pigs were randomized to receive normal saline (n = 8), the 5-lipoxygenase inhibitor diethylcarbamazine (n = 7), or the leukotriene B4 receptor antagonist SC-41930 (n = 7). All animals underwent 6 hours of rectus abdominis myocutaneous flap ischemia followed by 4 hours of reperfusion. In saline-treated controls, flap ischemia was associated with massive polymorphonuclear leukocyte infiltration at 1 and 4 hours of reperfusion (252 +/- 70 and 619 +/- 137 polymorphonuclear leukocytes per 25 high-power fields, respectively). Skeletal muscle neutrophil content was significantly attenuated by pretreatment with diethylcarbamazine (72 +/- 29 and 229 +/- 63 polymorphonuclear leukocytes per 25 high-power fields; p0.05) or SC-41930 (25 +/- 3 and 193 +/- 25 polymorphonuclear leukocytes per 25 high-power fields; p0.05). Wet-to-dry weight ratios of full-thickness flap biopsies were lower in the diethylcarbamazine and SC-41930 groups (2.98 +/- 0.15 and 2.90 +/- 0.26, respectively) than in the control group (4.13 +/- 0.23; p0.01), and mean muscle infarct size, as determined by nitroblue tetrazolium staining, diminished from 47.6 +/- 11.3 percent in controls to 25.1 +/- 6.5 percent in diethylcarbamazine-treated animals and 7.3 +/- 4.8 percent in SC41930-treated animals (p0.05). These data indicate that leukotriene B4 plays a critical role in mediating neutrophil-dependent injury in postischemic skeletal muscle flaps.

Nehlsen-Cannarella, S. L., O. R. Fagoaga, D. C. Nieman, D. A. Henson, D. E. Butterworth, R. L. Schmitt, E. M. Bailey, B. J. Warren, A. Utter, and J. M. Davis. Carbohydrate and the cytokine response to 2.5 h of running. J. Appl. Physiol. 82(5): 1662–1667, 1997.—This randomized, double-blind, placebo-controlled study was designed to determine the influence of 6% carbohydrate (C) vs. placebo (P) beverage ingestion on cytokine responses (5 total samples over 9 h) to 2.5 h of high-intensity running (76.7 ± 0.4% maximal O2uptake) by 30 experienced marathon runners. For interleukin-6 (IL-6), a difference in the pattern of change between groups was found, highlighted by a greater increase in P vs. C immediately postrun (753 vs. 421%) and 1.5 h postrun (193 vs. 86%) [ F(4,112) = 3.77, P = 0.006]. For interleukin-1-receptor antagonist (IL-1ra), a difference in the pattern of change between groups was found, highlighted by a greater increase in P vs. C 1.5 h postrun (231 vs. 72%) [ F(2,50) = 6.38, P = 0.003]. No significant interaction effects were seen for bioactive IL-6 or IL-1β. The immediate postrun plasma glucose concentrations correlated negatively with those of plasma cortisol ( r = −0.67, P < 0.001); postrun plasma cortisol ( r = 0.70, P < 0.001) and IL-6 levels ( r = 0.54, P = 0.003) correlated positively with levels of IL-1ra. Taken together, the data indicate that carbohydrate ingestion attenuates cytokine levels in the inflammatory cascade in response to heavy exertion.

Sexual arousal to erotic stimuli depicting various levels of force were examined among college men. Study 1 used phallometric indices to measure penile circumferential change during combined audio-tape and slide presentations varying in degree of force. The results indicated that the sexually coercive group exhibited more penile tumescence than controls to scenes involving verbal pressure and verbal threats. Analyses across time blocks suggested that control participants inhibited sexual arousal with the introduction of force cues but that the sexually coercive group did not. Study 2 was a replication of Study 1 without slides. Both groups showed increases in penile tumescence in response to the consent scenario. Only the sexually coercive men demonstrated significant tumescence in response to force scenarios. The results indicated that the sexually coercive males had a lower threshold for arousal to sexual cues and did not inhibit sexual arousal when force cues were introduced.

We have cloned, sequenced, and examined the expression of genes from pine trees that appear to encode extracellular class II chitinase. Nucleotide sequence analysis indicates a coding sequence composed of three exons interrupted by two introns at locations identical to those found in other chitinase genes that possess introns. One of the genes, Pschi4, potentially encodes a protein that shares 62% amino acid sequence identity through the catalytic domain with class II chitinase from tobacco. In contrast, Pschi1 contains a stop codon in the first exon and may be a pseudogene. Pschi4 genes are conserved in several species of pine, and appear to comprise a small multigene family. Treatment of pine cell suspension cultures with the general elicitor chitosan induced Pschi4 expression. The regulatory sequences associated with the Pschi4 gene were sufficient to direct chitosan-inducible expression of Pschi4 in transgenic tobacco plants, which indicates that Pschi4 is an actively expressed member of the multigene family. The observation that the Pschi4 gene from pine (a gymnosperm) was appropriately regulated by chitosan in tobacco (an angiosperm) suggests that the signaling pathways that mediate chitosan-induced transcription are highly conserved in the plant kingdom.

We have investigated the temporal relationship among proinflammatory cytokine expression, nitric oxide (NO) production and joint inflammation in the acute phase of bacterial cell wall-derived peptidoglycan polysaccharide (PG/PS)-induced arthritis. Acute joint inflammation was induced in female LEW/N rats by a single intraperitoneal injection of PG/PS. Arthritis index and paw volume were quantified and joint histopathology was evaluated during acute joint inflammation (0-10 days). Tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) were determined by bioassay whereas nitric oxide (NO) was quantified by measuring serum nitrate/nitrite levels via the Griess procedure. We found that serum levels of TNF and serum IL-1 preceded the increase in IL-6 and NO production. Furthermore, the production of these proinflammatory cytokines and NO preceded bone erosion and osteoclast activity. Erosion of subchondral bone preceded pannus formation and cellular synovitis in the acute phase of PG/PS-induced arthritis. The temporal expression of TNF, IL-1, IL-6 and NO suggest a cascade of inflammatory mediators in which monocytes and macrophages respond to PG/PS with enhanced synthesis of TNF and IL-1, which may in turn promote the synthesis of IL-6 and NO. We postulate that one or more of these inflammatory events are responsible for initiating the subchondral bone erosion observed in acute joint inflammation.

Exercise effects on natural killer cell (NK) activity in men appear to be intensity dependent, but there is very little data in women. We tested the effect of high versus moderate-intensity exercise relative to non-exercising controls on NK cytolytic activity (NK activity) in women using oral contraceptives. Subjects (n = 8) participated in 3 treatments consisting of 25 min of cycle ergometer exercise at 80% (HI-INT) and 40% (MOD-INT) VO2max, and a 25 min control (CON) session in which the subject remained seated on the cycle ergometer, but did not exercise. Blood was obtained prior to exercise, immediately after, and at 90 min and 3 h after exercise. During CON, NK activity gradually increased and cortisol gradually decreased during the approximately 3.5 h experimental period. Relative to CON, HI-INT increased NK activity, %CD56+ (NK) cells, and plasma norepinephrine immediately post exercise (p < or = 0.05). There was also a trend for decreased NK activity at 90 min (p = 0.075). No differences among treatment groups were found by 3 h post exercise. In MOD-INT, there were no differences from CON in any variable at any time. These data suggest that the typical NK response to intensive exercise in men, which consists of a brief increase followed by a more prolonged suppression, also occurs in women using oral contraceptives. However, it is important to use time-matched control measurements in determining this response.

Fatigue of voluntary muscular effort is a complex phenomenon. To date, relatively little attention has been placed on the role of the central nervous system (CNS) in fatigue during exercise despite the fact that the unwillingness to generate and maintain adequate CNS drive to the working muscle is the most likely explanation of fatigue for most people during normal activities. Several biological mechanisms have been proposed to explain CNS fatigue. Hypotheses have been developed for several neurotransmitters including serotonin (5-HT; 5-hydroxytryptamine), dopamine, and acetylcholine. The most prominent one involves an increase in 5-HT activity in various brain regions. Good evidence suggests that increases and decreases in brain 5-HT activity during prolonged exercise hasten and delay fatigue, respectively, and nutritional manipulations designed to attenuate brain 5-HT synthesis during prolonged exercise improve endurance performance. Other neuromodulators that may influence fatigue during exercise include cytokines and ammonia. Increases in several cytokines have been associated with reduced exercise tolerance associated with acute viral or bacterial infection. Accumulation of ammonia in the blood and brain during exercise could also negatively effect the CNS function and fatigue. Clearly fatigue during prolonged exercise is influenced by multiple CNS and peripheral factors. Further elucidation of how CNS influences affect fatigue is relevant for achieving optimal muscular performance in athletics as well as everyday life.

PURPOSE The objective of this study was to characterize CD34+ cell grafts, obtained using a novel technique, from children undergoing autologous bone marrow transplantation (BMT) for cancer therapy. In particular, we wanted to determine if the CD34+ marrow cell grafts generated hematopoietic reconstitution, since a positive result would motivate further development and use of this methodology. PATIENTS AND METHODS This pilot feasibility clinical trial involved 13 patients < or = 25 years of age with advanced solid tumors, including seven children with neuroblastoma. Harvested bone marrow underwent immunomagnetic CD34+ selection. RESULTS In three of 13 enrolled patients, low purities of the CD34+ preparations disqualified the use of the CD34+ marrow grafts. Ten patients received myeloablative chemotherapy with etoposide, carboplatin, and cyclophosphamide, then were transplanted with CD34+ marrow grafts. In the 10 patients transplanted with CD34(+)-selected cells, the CD34+ cell purity (nucleated RBCs excluded) in the cell graft preparation was 91% total cell recovery from the starting light-density cells 2.2%, CD34+ cell recovery 38%, colony-forming unit-granulocyte-macrophage (CFU-GM) recovery 23%, and estimated tumor-cell depletion 2.6 logs (medians). The CD34+ marrow grafts administered to these patients contained a median of 2.3 x 10(6) nucleated cells, 1.4 x 10(6) CD34+ cells, and 1.3 x 10(4) CFU-GM per kilogram patient weight. Most patients experienced only the toxicities previously observed with this myeloblative chemotherapy regimen, although two unusual toxicities were observed. All 10 patients transplanted with CD34+ cell grafts engrafted. CONCLUSION The CD34+ purified grafts were enriched in stem/progenitor cells, with five of these 10 preparations containing > or = 94% CD34+ cells. Engraftment with CD34(+)-purified cell grafts as pure as 99% confirms that autologous CD34+ cells, alone, are sufficient to provide hematopoietic rescue for myeloablated patients. The best purification results were obtained on small marrow harvests from patients with neuroblastoma. The engraftment of highly purified CD34+ cells obtained by this technology and the antitumor effect of the transplant, by which two of 10 poor prognosis patients remain clinically free of tumor, have stimulated further clinical trials.

The administration of gram-negative bacterial lipopolysaccharide (LPS) to rats results in hepatic parenchymal cell injury within 6 hr. The coagulation system is critical to the pathogenesis, but previously reported results suggested that its critical role is independent of insoluble clot formation and that thrombin may be a key mediator of liver injury. To test the hypothesis that thrombin is involved in LPS-induced liver injury, animals were treated with the selective thrombin inhibitor, hirudin. The hirudin treatment regimen effectively inhibited thrombin, as evidenced by prolonged activated partial thromboplastin time and by maintenance of plasma fibrinogen concentrations in LPS-treated rats. Treatment with hirudin prevented LPS-induced liver injury, assessed by plasma alanine aminotransferase activity and histological evidence of hepatocellular necrosis. Previous studies have shown that LPS exposure results in the accumulation of neutrophils and platelets within the liver and that both of these cell types are critical for the development of LPS-induced liver injury. Hirudin attenuated in part the decrease in blood platelet concentration that accompanied LPS administration, but did not alter hepatic platelet or neutrophil accumulation. These results support the hypothesis that thrombin is required for hepatic injury from LPS exposure, but that it does not act by promoting the accumulation of platelets or neutrophils within the liver.

As a first step in the evaluation of recombinant human CuZn superoxide dismutase (rhSOD) in the prevention of neonatal lung injury, safety and pharmacokinetics of intratracheally (IT) administered rhSOD were studied.Twenty-six preterm infants weighing 750 to 1250 g with respiratory distress syndrome were studied in three sequential groups (placebo, 0.5, and 5 mg/kg). Placebo or rhSOD was administered IT 30 minutes after the first surfactant dose. Serial blood and urine studies, rhSOD levels, tracheal aspirate fluid (TAF) markers of acute inflammation, radiographs, and ultrasounds were performed over the 28-day study period.Serum SOD concentrations were similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.1 to 0.2 microgram/mL). In the 0.5-mg/kg group, levels were highest at 12 hours (geometric mean 0.7, upper-lower limit 0.5 to 0.8 microgram/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were highest at 6 hours (geometric mean 3.0, upper-lower limit 2.3 to 4.0 micrograms/mL) and returned to baseline by day 4. Concentrations of SOD in TAF were also similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.2 to 0.3 microgram/mL). There were no significant increases in the placebo group, but levels in the 0.5-mg/kg group were highest when first sampled at 24 hours (geometric mean 1.1, upper-lower limit 0.8 to 1.4 micrograms/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were also highest when sampled at 24 hours (geometric mean 1.4, upper-lower limit 0.9 to 2.1 micrograms/mL) and returned to baseline by day 4. Urine levels were highest at 12 hours in both the 0.5-mg/kg (geometric mean 1.3, upper-lower limit 1.0 to 1.7 micrograms/mL) and 5-mg/kg infants (geometric mean 6.4, upper-lower limit 3.9 to 10.4 micrograms/mL) and decreased significantly by day 2 to 3. rhSOD activity assays (serum, TAF, and urine) demonstrated that the enzyme still possessed significant activity. No adverse effects of rhSOD were found. TAF neutrophil chemotactic activity and albumin concentrations, important acute lung injury markers, were significantly lower in the high-dose rhSOD group compared with the other groups.Data suggest that a single IT dose of rhSOD results in significant increases in both concentration and activity of the antioxidant in serum, TAF, and urine for 2 to 3 days. The enzyme appears to be well tolerated, and TAF inflammatory markers are reduced after administration. This has important implications in rhSOD trials to prevent acute and chronic lung injury in preterm neonates.

The revolutionary "Zeitgeist" in the Europe of the 1840s left its mark no less in science than it did in the social and political life of the population. The essence of the scientific revolution was the change in paradigm from a vitalist-inductive to a mechanistic hypothetico-deductive approach, in which the experiment assumed the central role. The initiator of this new approach was a young physiologist in Marburg, Germany-Carl Friedrich Wilhelm Ludwig- and the first document his 1842 Habilitation thesis. Although this thesis was limited to a study on renal function, the impact of this epochal new approach, namely the analysis and explanation of living phenomena solely on the basis of physics and chemistry, went far beyond renal physiology: it revolutionised thinking in all the biological sciences. In this thesis, Carl Ludwig enunciated the principle of glomerular ultrafiltration driven by physical forces alone, i.e., the difference in the hydrostatic and oncotic pressures of the blood in the glomerular capillaries, a concept which remains valid today. Ludwig thus became the first scientist to describe correctly a principal component of renal function, the process of glomerular filtration.

Skin breakdown and high fluid requirements are common problems in extremely low birth weight infants that may be reduced by application of a semipermeable skin dressing (SPD). An SPD was applied to 39 study infants who weighed1000 gm (control subjects, n = 37) to determine whether it would protect the skin and decrease fluid requirements. Randomization occurred before 12 hours of life and SPD was applied to the chest, abdomen, and back. Sixty-one infants survived the first 14 days. Skin remained nonerythematous, intact, and undamaged under the dressing, whereas uncovered skin sustained significant breakdown in both groups. No significant differences were found in fluid or electrolyte status. Although the SPD did not affect fluid requirements, the significant improvement in skin integrity under the SPD may justify its use in premature infants with delicate skin.