Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma.

BACKGROUND: Pitrakinra is a recombinant protein derived from human interleukin-4 (IL-4) that binds to IL-4Ralpha and acts as a competitive antagonist of IL-4 and IL-13. The studies reported here compare the dose-ranging effects of pitrakinra on allergen-induced airway hyperresponsiveness (AHR) and airway eosinophilia when administered subcutaneously (s.c.) or by inhalation to the Ascaris suum-sensitive cynomolgus monkey for the purpose of elucidating the primary site of pitrakinra's anti-asthmatic action. METHODS: Airway responsiveness to inhaled methacholine and bronchoalveolar lavage cell composition was determined before and after three allergen exposures with a 1-week course of twice-daily (b.i.d.) s.c. or inhaled pitrakinra or placebo treatment. RESULTS: Treatment with s.c. pitrakinra significantly reduced allergen-induced AHR, with a maximum effect of a 2.8- to 3.8-fold increase in methacholine PC(100) relative to control (P < 0.05) observed at b.i.d. s.c. doses of 0.05-0.5 mg/kg. Inhaled pitrakinra also significantly reduced AHR with a similar maximum effect of a 2.8- to 3.2-fold increase in methacholine PC(100) relative to control (P < 0.05) at nominal b.i.d. doses of 3-100 mg. The maximal effect on AHR following inhalation was observed at a plasma concentration which exhibited no efficacy via the subcutaneous route. The effect of pitrakinra on lung eosinophilia was not statistically significant following either route of administration, although lung eosinophil count was reduced in all studies relative to control. CONCLUSION: Local administration of pitrakinra to the lung is sufficient to inhibit AHR, one of the cardinal features of asthma, indicating the therapeutic potential of inhaled pitrakinra in the treatment of atopic asthma.

Macrophage inflammatory protein 1alpha/CCL3 is required for clearance of an acute Klebsiella pneumoniae pulmonary infection.

The objective of these studies was to determine the role of macrophage inflammatory protein 1alpha/CCL3 in pulmonary host defense during Klebsiella pneumoniae infection. Following intratracheal inoculation, 7-day survival of CCL3(-/-) mice was less than 10%, compared to 60% for CCL3(+/+) mice. Survival of CCR5(-/-) mice was equivalent to that of controls, indicating that the enhanced susceptibility of CCL3(-/-) mice to K. pneumoniae is mediated via another CCL3 receptor, presumably CCR1. At day 3, CFU burden in the lungs of CCL3(-/-) mice was 800-fold higher than in CCL3(+/+) mice, demonstrating that CCL3 is critical for control of bacterial growth in the lung. Surprisingly, CCL3(-/-) mice had no differences in the recruitment of monocytes/macrophages and even showed enhanced neutrophil recruitment at days 1, 2, and 3 postinfection, compared to CCL3(+/+) mice. Therefore, the defect in clearance was not due to insufficient recruitment of leukocytes. No significant differences in cytokine levels of monocyte chemoattractant protein 1 (MCP-1), interleukin 12, gamma interferon, or tumor necrosis factor alpha in lung lavages were found between CCL3(+/+) and CCL3(-/-) mice. CCL3(-/-) alveolar macrophages were found to have significantly lower phagocytic activity toward K. pneumoniae than CCL3(+/+) alveolar macrophages. These findings demonstrate that CCL3 production is critical for activation of alveolar macrophages to control the pulmonary growth of the gram-negative bacterium K. pneumoniae.

Ecological aspects of ntcA gene expression and its use as an indicator of the nitrogen status of marine Synechococcus spp.

Nitrogen nutrition in cyanobacteria is regulated by NtcA, a transcriptional activator that is subject to negative control by ammonium. Using Synechococcus sp. strain WH7803 as a model organism, we show that ntcA expression was induced when cells were exposed to nitrogen stress but not when they were subjected to phosphorus or iron deprivation. Transcript levels accumulated in cells grown on a variety of inorganic and organic nitrogen sources, with the sole exception of ammonium. ntcA transcription was induced when ammonium levels dropped below 1 microM and reached maximal levels within 2 h. Furthermore, the addition of more than 1 microM ammonium led to a rapid decline in ntcA mRNA. The negative effect of ammonium was prevented by the addition of L-methionine-D,L-sulfoximine (MSX) and azaserine, inhibitors of ammonium assimilation. Thus, basal ntcA transcript levels are indicative of ammonium utilization. Conversely, the highest ntcA transcript levels were found in cells lacking a nitrogen source capable of supporting growth. Therefore, maximal ntcA expression would indicate nitrogen deprivation. This state of nitrogen deprivation was induced by a 1-h incubation with MSX. The rapid response of ntcA gene expression to the addition of ammonium and MSX was used to design a protocol for assessing relative ntcA transcript levels in field populations of cyanobacteria, from which their nitrogen status can be inferred. ntcA was basally expressed in Synechococcus at a nutrient-enriched site at the northern tip of the Gulf of Aqaba, Red Sea. Therefore, these cyanobacteria were not nitrogen stressed, and their nitrogen requirements were met by regenerated nitrogen in the form of ammonium.

The role of macrophage inflammatory protein-1 alpha/CCL3 in regulation of T cell-mediated immunity to Cryptococcus neoformans infection.

Macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3) is a CC chemokine required for optimal recruitment of leukocytes in response to cryptococcal Ags. MIP-1alpha is expressed in the lungs by day 6 post Cryptococcus neoformans infection and could play a role in the development of cell-mediated immunity. To address this possibility, wild-type (MIP-1alpha(+/+)) mice and MIP-1alpha knockout (MIP-1alpha(-/-)) mice were infected intratracheally with a highly virulent strain of C. neoformans (145A). MIP-1alpha message was detected in the lungs on days 3, 7, and 14 in MIP-1alpha(+/+) mice, but it was undetectable in MIP-1alpha(-/-) mice. On day 16, MIP-1alpha(-/-) mice had a 7-fold increase in C. neoformans burden in the lungs, but no decrease in pulmonary leukocyte recruitment. MIP-1alpha(+/+) and MIP-1alpha(-/-) mice had similar numbers of recruited lymphocytes and monocytes/macrophages. Notably, MIP-1alpha(-/-) mice had a significantly greater number of eosinophils. MIP-1alpha(-/-) mice had extremely high levels of serum IgE. This switch of immune response to a T(2) phenotype was associated with enhanced IL-4 and IL-13 expression in the lungs of MIP-1alpha(-/-) mice compared with MIP-1alpha (+/+) mice. Progression of pulmonary cryptococcosis in the presence of nonprotective T(2) immunity resulted in profound lung damage in MIP-1alpha(-/-) mice (eosinophilic crystal deposition, destruction of lung parenchyma, and pulmonary hemorrhage). Twelve-week survival was dramatically decreased in MIP-1alpha(-/-) mice. These studies, together with our previous studies, demonstrate that MIP-1alpha plays a role in both the afferent (T(1)/T(2) development) and efferent (T(1)-mediated leukocyte recruitment) phases of cell-mediated immunity to C. neoformans.

Leukocyte recruitment during pulmonary Cryptococcus neoformans infection.

Leukocyte recruitment to the site of infection by the encapsulated yeast Cryptococcus neoformans is critical for clearance of the infection. We review data from our lab that chemokines, such as the CC chemokines MCP-1 and MIP-1alpha, are important mediators of leukocyte recruitment during C. neoformans infection. In addition, studies in CC chemokine receptor knockout mice have demonstrated that CCR2 and CCR5 are required not only for leukocyte recruitment but also for other aspects of immune response development and innate imunity to C. neoformans.

[Early discharge after delivery, a safe and cost-effective form of care]. / Tidig hemgång efter förlossning, en säker och effektiv vårdform.

Early discharge after delivery, followed by home care, has been offered to maternity patients at Motala General Hospital since 1983. The results have been analysed retrospectively with regard to home care quality, morbidity, mortality, and cost-effectiveness. During the period, 1983-95, about 10,000 children were born at Motala General Hospital. Morbidity and mortality data have been elicited from the patients' records and from Statistics Sweden, the national bureau of statistics. The frequency of early discharge increased from about 20 per cent in 1984 to 66 per cent (79% of normal deliveries) in 1995. Hyperbilirubinaemia and nutritional problems were the predominant forms of morbidity among newborns in the early discharge subgroup, and mortality was zero. The numbers of nurses, assistant nurses and midwives were reduced by 50 per cent during the period, partly due to the early discharge programme, but also due to economies in Swedish health care expenditure. Provided a stable and well organised system is established, with home visits by a midwife and examination by a paediatrician 5-7 days after delivery, and alertness to the possibility of jaundice and nutritional problems is maintained, early discharge is a safe procedure.

Regulation of ntcA expression and nitrite uptake in the marine Synechococcus sp. strain WH 7803.

NtcA is a transcriptional activator involved in global nitrogen control in cyanobacteria. In the absence of ammonium it regulates the transcription of a series of genes encoding proteins required for the uptake and assimilation of alternative nitrogen sources (I. Luque, E. Flores, and A. Herrero, EMBO J. 13:2862-2869, 1994). ntcA, present in a single copy in the marine Synechococcus sp. strain WH 7803, was cloned and sequenced. The putative amino acid sequence shows a high degree of identity to NtcA from freshwater cyanobacteria in two functional domains. The expression of ntcA was negatively regulated by ammonium from a putative transcription start point located downstream of an NtcA consensus recognition sequence. Addition of either rifampin or ammonium led to a rapid decline in ntcA transcript levels with half-lives of less than 2 min in both cases. Nitrate-grown cells showed high ntcA transcript levels, as well as the capacity for active nitrite uptake. However, ammonium-grown cells showed low levels of the ntcA transcript and did not utilize nitrite. The addition of ammonium to nitrite uptake-active cells resulted in a gradual decline in the rate of uptake over a 24-h period. Active nitrite uptake was not induced in cells transferred to medium lacking a nitrogen source despite evidence of elevated expression of ntcA, indicating that ntcA expression is not sufficient for uptake capacity to develop. Nitrate and nitrite addition led to the development of nitrite uptake, whereas the addition of leucine did not. Furthermore, nitrite addition triggered the de novo protein synthesis required for uptake capacity to develop. These data suggest that nitrite and nitrate act as specific inducers for the synthesis of proteins required for nitrite uptake.

Community assessment for the home healthcare nurse.

Home health clients and their families live within the context of a community. To deliver effective care, home health nurses must understand how the community influences the health of their clients and families. This article describes a community assessment, how to incorporate it into daily practice, and suggests strategies for using the data to enhance the quality and efficiency of home healthcare.

IL-4 induced leucocyte trafficking in cynomolgus monkeys: correlation with expression of adhesion molecules and chemokine generation.

BACKGROUND: Interleukin-4 (IL-4) is an immunoregulatory cytokine which has a wide variety of effects on immune cell function. In addition, recent studies suggest that IL-4 may have effects on other cells including endothelial cells in terms of the regulation of adhesion molecule expression and leucocyte extravasation from the vascular space to sites of tissue inflammation. Consequently, IL-4 may have an important role in the pathogenesis of allergic inflammation and disease. OBJECTIVE: The purpose of this study was to learn more about the potential role of IL-4 in inflammatory disease, specifically in regard to the potential of IL-4 to induce the expression of adhesion molecules on vascular endothelial cells and promote the adherence and transmigration of circulating leucocytes to sites of tissue inflammation. METHODS: Single subcutaneous injections of human IL-4 were administered to cynomolgus monkeys and tissue biopsy samples were obtained and analysed for adhesion molecule expression on vascular endothelium and inflammatory cell infiltrates. In another series of experiments, multiple subcutaneous injections of human IL-4 were administered (bid on four consecutive days) and the effects on peripheral blood leucocytes and plasma levels of various cytokines and chemokines were examined. RESULTS: Intradermal injection of IL-4 induced the expression of vascular cell adhesion molecule-1 (VCAM-1) on cutaneous vascular endothelium that was present at 8 hr and persisted out to 24 h post injection. The expression of VCAM-1 was associated with an inflammatory cell infiltrate comprised of granulocytes and mononuclear cells. Multiple injections of IL-4 resulted in a dose-related decrease in the relative percentage and total number of circulating lymphocytes and an increase in circulating neutrophils (4.6 +/- 1-2.1 +/- 0.2 x 10(6)/mL and 1.7 +/- 0.3-7.0 +/- 1 x 10(6)/mL, respectively). Analysis of cell surface markers by flow cytometry revealed a transient decrease in the number of CD4+T lymphocytes and a sustained decrease in CD16+ cells. In addition, IL-4 administration resulted in a large increase in plasma MCP-1 concentration. CONCLUSION: This is the first study to demonstrate an acute effect of IL-4 consistent with lymphocyte trafficking out of the vascular space, the induction of VCAM-1 expression on vascular endothelium and increases in plasma levels of MCP-1 in vivo. We suggest that IL-4 may be involved in the early recruitment of mononuclear cells to sites of tissue inflammation by the upregulation of VCAM-1 expression on vascular endothelium and the generation and release of potent chemoattractants.

Tolerance and efficacy of Omniscan (gadodiamide injection) in MR imaging of the central nervous system.

PURPOSE: This Swedish multicenter trial was performed on patients with known or suspected lesions of the CNS for which an MR examination using a contrast medium was indicated. A total of 8 MR centers participated in the study to establish the safety and efficacy of Omniscan (gadodiamide injection) in clinical routine using a standard dose of 0.1 mmol Gd/kg b.w. MATERIAL AND METHODS: Seven hundred adult patients who had been referred for MR investigation of suspected CNS lesions were included in the study. Since most patients were examined on an outpatient basis, it was decided to use an explicit questionnaire regarding adverse events that developed within 24 h after examination. The efficacy evaluation involved comparisons of detectability, delineation, and number of lesions before and after injection of Omniscan. RESULTS: No serious or unexpected adverse event was found. There were a total of 70 (10.2%) patients with adverse events, excluding those judged not to be contrast media-related. However, only 15 patients (2.2%) had adverse events that possibly or probably were related to the contrast medium. Usually, the symptoms were headache, dizziness, abnormal taste, and nausea. Two patients complained of itching, but only one developed urticaria. The efficacy was similar to that of other currently used Gd-based MR agents. Lesions were more often seen on T2-weighted images, but the contrast medium improved lesion delineation, contributing to higher certainty in diagnosis, and provided more confidence in excluding suspected abnormality. CONCLUSION: Omniscan was found to be a safe and clinically valuable contrast medium for MR imaging of the CNS.

Scoliosis as the first sign of a cystic spinal cord lesion.

We reviewed the cases of ten patients with scoliosis as the first sign of a cystic spinal cord lesion with the aim of identifying and studying early patient and curve characteristics. All patients were examined with magnetic resonance (MR) imaging of the brain and spinal cord and quantitative thermal testing (QTT). The mean Cobb angle was 22 degrees and the curves were right thoracic in seven patients, left thoracic in two, and left lumbar in one, when first seen for scoliosis. In six patients the cystic lesion was found in routine screening for syringomyelia, which is performed in all cases of congenital and juvenile scoliosis and in adolescent scoliosis before bracing. In four patients, it took up to 17 years following the initial diagnosis of scoliosis before neurologic deterioration warranted MR imaging, disclosing two Chiari I associated syrinxes and two cystic spinal cord tumors. QTT revealed a subclinically decreased sensation in two of the patients with no findings other than scoliosis. It also verified the decreased sensation in all patients in whom neurologic deterioration had complicated the clinical course of their scoliosis. More frequent spinal MR screening of patients with supposed juvenile or adolescent idiopathic scoliosis is indicated, regardless of curve type, to exclude a neurogenic cause. QTT documents subclinical as well as overt decreased sensation, and is valuable in the serial follow-up of these patients to monitor the progress or the response to treatment of the cystic lesion.

Sensory symptoms and signs and results of quantitative sensory thermal testing in patients with lacunar infarct syndromes.

BACKGROUND AND PURPOSE: Quantitative data on sensory impairment in stroke patients are limited. We measured the perception thresholds for temperature and thermal pain in patients with different lacunar syndromes, correlated the results with clinical and magnetic resonance imaging (MRI) findings, and studied the long-term prognosis of sensory dysfunction. METHODS: Quantitative thermal testing was performed by means of the Marstock method in 39 patients with lacunar syndromes (pure motor, sensorimotor, or pure sensory stroke) and MRI findings compatible with occlusion of a single perforating artery. Thresholds for cold, warmth, and heat pain were obtained bilaterally from the cheek, hand, and leg. The unaffected side was used as control. Follow-up included clinical assessments and repeated quantitative thermal testing (in 17 patients) up to 1 year after stroke onset. RESULTS: Patients with pure sensory stroke and sensorimotor stroke (n = 22) had a significant thermal hypoesthesia on the affected side for all modalities and test locations. Patients with pure motor stroke (n = 17) exhibited thermal hypoesthesia for cold and heat pain in the hand and for cold perception in the leg. On MRI, infarcts causing pure motor and sensorimotor stroke were predominantly lenticulocapsular, while a thalamic site of infarction was found in pure sensory stroke. The prognosis of sensory impairment was favorable, except for poststroke pain syndromes in three patients. CONCLUSIONS: Quantitative thermal testing confirmed an involvement of spinothalamic pathways in lacunar infarcts causing pure sensory and sensorimotor stroke and revealed a subclinical sensory impairment in patients with pure motor stroke. Infarction sites were similar in patients with pure motor and sensorimotor stroke.

Detection and identification of a pathogenic marine Mycobacterium from the European seabass Dicentrarchus labrax using polymerase chain reaction and direct sequencing of 16S rDNA sequences.

Mycobacteriosis has become a major concern for the commercial mariculture of the European sea bass Dicentrachus labrax in Israel. The disease remains asymptomatic for a long time, is virtually impossible to eradicate with antibiotics, stunts the growth of the fish and renders the fish unmarketable. The pathogen was identified as Mycobacterium marinum by direct sequencing and analysis of approximately 600 bp of the pathogen ribosomal encoding DNA (rDNA). The polymerase chain reaction technique was evaluated as a diagnostic tool for detecting the infection in D. labrax and found to be highly specific and sensitive.

Spinal cord and brain stem anomalies in scoliosis. MR screening of 26 cases.

The spinal cord and brain were examined with magnetic resonance (MR) in 26 patients with idiopathic scoliosis to study the prevalence of spinal cord and brainstem anomalies. Two patients had small centrally located spinal cord syrinxes, one at C6-C8 and the other at T6-T8, without association with any brainstem or cerebellar deformity. The lowest position of the cerebellar tonsils was 0.5 cm below the foramen magnum, which was also seen in 2 other patients. Scoliosis associated with syringomyelia may be more common than previously thought, and may be wrongly classified as idiopathic. A neurogenic cause of scoliosis should always be considered, and at least in atypical cases be excluded by MR imaging of the spinal cord. MR should be mandatory before bracing or operative correction of scoliosis.

Bacterial vaginosis and the effect of intermittent prophylactic treatment with an acid lactate gel.

Intermittent treatment with an acid lactate gel (Lactal, ACO, Sweden) reduced symptoms of bacterial vaginosis (BV) and promoted the reestablishment of the normal vaginal flora of lactobacilli. Forty-two women seriously affected by recurrent BV were initially given acid gel (lactate gel, pH 3.8, 5 ml) to be inserted into the vagina daily for 7 consecutive days. Thereafter they entered into a double blind clinical trial and were treated prophylactically 3 days monthly for 6 months with either lactate gel or a placebo gel. Women treated with the lactate gel were clinically improved, i.e. no signs of BV in 88% compared to 10% in the placebo group (p less than 0.001). The vaginal lactobacilli flora was reestablished in 83% of the lactate group and in 16% of the placebo group. Local intermittent application of lactate gel was found to be free of side effects and is a preferable alternative to repeated treatments with antibiotics in patients with recurrent BV.

Psychological aspects of early and late discharge after hospital delivery. An interview study of 44 families.

Early discharge after hospital delivery is common in other countries. In Sweden it was not introduced until recent years. Previous investigations have mainly focused on medical risk factors. However, few investigations have been done regarding psychological factors. This study, comprising 44 families (7 primaparae and 37 multiparae) in an early discharge group (discharge 0-2 days after hospital birth) and a late discharge group (discharge 5-6 days), indicates that parents in the early discharge group had more negative experiences of their earlier postpartum stay. The mothers in the early discharge group experienced less sibling revalry compared to the mothers in the control group. There were no other differences between the groups. The parents were equally satisfied with their choices in both groups. Early discharge, as a voluntary alternative, presents an increased service for parents, since the parents may choose the most suitable postpartum care.

Rupture of renal arterial aneurysm in pregnancy. Case report.

The case is described of a patient at term of her second pregnancy with spontaneous rupture of a renal arterial aneurysm, successfully delivered by caesarean section with primary repair of the renal artery. Sixteen cases have previously been reported, but only one was dealt with in a similar way. The literature is reviewed and the aetiology of pregnancy-related arterial aneurysm is discussed.

Glucose stimulation of somatostatin and insulin release from the isolated, perfused rat pancreas.

Insulin and somatostatin release from the isolated perfused rat pancreas was studied under conditions of 50 and 300 mg/dl glucose as well as a linear 50-300 mg/dl glucose gradient. The glucose-stimulated response profile of somatostatin was nearly parallel to that of insulin in both the acute and gradient dose experiments. Antisomatostatin serum was without significant effect on glucose-stimulated insulin release. In spite of the marked, fifteenfold stimulation of somatostatin release (1.5 x 10-10 M in the perfusate effluent) by glucose, the concentration of somatostatin was insufficient to significantly alter glucose-stimulated insulin release in the isolated perfused rat pancreas.

Serial bone scanning in the evaluation of stage and clinical course in carcinoma of the prostate.

Bone scanning with 99mTc-EHDP or 99mTc-MDP was compared with skeletal X-ray survey, determination of acid phosphatase levels and clinical symptoms in a consecutive series of 176 patients with prostatic carcinoma. Skeletal metastases were present in 24%. In these metastatic cases 27% had negative radiographics at the time of initial diagnosis, 29% had normal serum acid phosphatase values and 74% had symptoms other than skeletal, which dominated the clinical picture. When bone scanning was negative for metastases such lesions were never detected in the radiographs. Hence, bone scanning was sufficient for the initial diagnosis of skeletal metastases in 55% of cases. When scans were judged as equivocal or positive an X-ray survey should be done. The variations in count density in metastatic disease were followed by visual assessment of serial bone scans. A densitometric method for quantification of the variations was developed as an aid in the evaluation. Serial bone scanning using a quantitative method appears to offer a readily available objective index of early therapeutic response for use in general clinical practice as well as in controlled therapeutic trails.

Hiatal incompetence and gastro-oesophageal reflux.

Gastro-oesophageal reflux and hiatal incompetence were analysed in 191 patients using a new radiographic contrast medium, polyiodostyrene, with the same density (1.0 g/cm3) as ordinary gastric contents, and correlated with supplementary oesophagoscopy and intraluminal pressure measurements. A normal hiatus seems to be an important protection against gastro-oesophageal reflux. An incompetent hiatus involves a real risk for oesophagitis. A low-density, low-viscosity contrast medium improves the roentgenologic diagnosis of gastro-oesophageal reflux.