Evidence that stunning can be cumulative in man

Myocardial stunning and hibernation are two entities that have become increasingly recognised as clinically important causes of reversible left ventricular (LV) dysfunction. Their occurrence is important as resting myocardial dysfunction, which was once thought to be irreversible, may recover if ischaemia is lessened or abolished. Recent evidence has suggested that cumulative stunning can occur in man and may in fact be responsible for the phenomenon of hibernation. In this chapter we will review the evidence supporting the occurrence of cumulative stunning in man.     

Serum IgE and IgG antibody activity against Aspergillus fumigatus as a diagnostic aid in allergic bronchopulmonary aspergillosis.

Serum IgE and IgG antibody activity against Aspergillus fumigatus was measured in 3 groups of subjects by 2 different immunologic methods. Group A consisted of 23 patients with allergic bronchopulmonary aspergillosis (ABPA). Group B was composed of 19 patients with extrinsic asthma who had marked immediate type skin reactivity to A. fumigatus (prick skin test, 3 or 4+) but no other manifestation of ABPA. Group C, the control group, was composed of 12 healthy subjects. Two immunological methods, including a solid-phase polystyrene tube radioimmunoassay and an iodine-125-labeled, A. fumigatus antigen radioimmunoassay, were used to study each patient's serum sample, so as to demonstrate IgE antibody activity against A. fumigatus (IgE-Af) and IgG antibody activity against A. fumigatus (IgG-Af). Both IgE-Af and IgG-Af were significantly greater among patients in Group A than among those in Group B and Group C, as measured by both methods (P is less than 0.001). The results of this study suggest that either method can be used as a diagnostic aid for ABPA. These methods may provide a laboratory test permitting diagnosis of ABPA in its early stages before bronchial or pulmonary destruction occurs.     

Evidence that triiodothyronine and reverse triiodothyronine are sequentially deiodinated in man.

We have demonstrated that in patients given a single iv injection of T3, rT3, or, to a lesser extent, T4, all labeled with 125I in the outer or phenolic ring, chromatography of serum on columns of Sephadex G-25 superfine revealed the presence of a labeled material, separate from the administered hormone and from both iodide and iodoprotein. This peak has been termed pre-T3 because it elutes just before the T3 peak. Identification of the various compounds in pre-T3 was carried out by cation exchange chromatography. Pre-T3 generated from [125I]T3 consistently contained labeled compounds with the chromatographic behavior of 3,3'-diiodothyronine and 3'-monoiodothyronine, while pre-T3 generated from [125I]rT3 contained labeled products with the chromatographic mobility of 3',5'-diiodothyronine, 3,3'-diiodothyronine, and 3'-monoiodothyronine. In addition, pre-T3 also contained the glucuro- and sulfoconjugates of these several labeled products. These studies demonstrate that T3 and rT3 undergo progressive and probably sequential deiodination in the peripheral tissues, resulting in the formation of a variety of diiodothyronines and monoiodothyronine, as well as their glucuro- and sulfoconjugates.     

Serum and plasma inhibit neutrophil stimulation by hydroxyapatite crystals. Evidence that serum alpha 2-HS glycoprotein is a potent and specific crystal-bound inhibitor

Tissue deposits of basic calcium phosphate (BCP) crystals are associated with various clinical manifestations of inflammation. We addressed the possibility that native proteins modify the ability of hydroxyapatite (HA) crystals to stimulate human inflammatory cells. Neutrophil superoxide release and chemiluminescence in response to HA crystals (0.3-4.0 mg/ml) were blunted by serum and plasma. Inhibitory activity was progressively removed from serum by sequential adsorption with HA crystals, suggesting that the inhibitors were crystal-bound proteins. Thus, we characterized HA crystal-bound plasma proteins by O'Farrell gels: Fibronectin, transferrin, albumin, alpha 2-HS glycoprotein (AHSG), alpha 1-proteinase inhibitor, alpha 1-acid glycoprotein, Gc globulin, haptoglobin, and high density lipoprotein apolipoproteins were major bound species. Of these, AHSG was the most active inhibitor of HA-induced neutrophil superoxide release, and this glycoprotein partially (60%) restored inhibitory activity to HA-adsorbed serum. AHSG also bound in vitro to the related BCP crystal, octacalcium phosphate, but only minimally to calcium pyrophosphate dihydrate crystals and monosodium urate crystals. Suppressive effects on neutrophil stimulation exhibited by AHSG were also specific for BCP crystals. AHSG was present in noninflammatory synovial fluids bound to synthetic HA crystals in vitro, and AHSG could be detected on native synovial fluid HA crystals. We conclude that the binding of AHSG may modulate the inflammatory potential of BCP crystals.     

Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.

The mechanisms associated with the development of severe, corticosteroid (CS)-dependent asthma are poorly understood, but likely heterogenous. It was hypothesized that severe asthma could be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils, and that the inflammatory subtype would be associated with distinct structural, physiologic, and clinical characteristics. Thirty-four severe, refractory CS-dependent asthmatics were evaluated with endobronchial biopsy, pulmonary function, allergy testing, and clinical history. Milder asthmatic and normal control subjects were also evaluated. Tissue cell types and subbasement membrane (SBM) thickness were evaluated immunohistochemically. Fourteen severe asthmatics [eosinophil (-)] had nearly absent eosinophils (< 2 SD from the normal mean). The remaining 20 severe asthmatics were categorized as eosinophil (+). Eosinophil (+) severe asthmatics had associated increases (p < 0.05) in lymphocytes (CD3+, CD4+, CD8+), mast cells, and macrophages. Neutrophils were increased in severe asthmatics and not different between the groups. The SBM was significantly thicker in eosinophil (+) severe asthmatics than eosinophil (-) severe asthmatics and correlated with eosinophil numbers (r = 0.50). Despite the absence of eosinophils and the thinner SBM, the FEV(1) was marginally lower in eosinophil (-) asthmatics (p = 0.05) with no difference in bronchodilator response. The eosinophil (+) group (with a thicker SBM) had more intubations than the eosinophil (-) group (p = 0.0004). Interestingly, this group also had a decreased FVC/slow vital capacity (SVC). These results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment.     

Airway cooling: stimulus specific modulation of airway responsiveness in the canine lung periphery

We used a wedged bronchoscope technique in conjunction with an in situ isolated perfused left lower lobe preparation in anesthetized dogs to examine cold-associated airway modulation of peripheral lung responses to dry airflow, hypocapnia, and aerosols of histamine and hypertonic NaCl. In this preparation, airway wall temperature was rapidly lowered by decreasing the temperature of blood perfusing the wedged sublobar segment. Cooling significantly attenuated responses to dry air, hypertonic NaCl aerosol, and hypocapnic challenge. In contrast, cooling did not affect peripheral lung responses to aerosolized histamine. Thus, cooling per se does not inhibit the responsiveness of smooth muscle. We conclude that, depending on the stimulus, cooling can modulate airway reactivity. We speculate that cooling attenuates hypocapnia, hypertonic aerosol, and dry air-induced bronchospasm via a cold induced reduction in neuronal activity or mediator production and release.     

Chronic intranasal administration of Aspergillus fumigatus spores leads to aggravation of airway inflammation and remodelling in asthmatic rats

Background and objective:   Epidemiological evidence indicates a close link between exposure to fungi and deterioration of asthma. However, the role of fungi as an exogenous precipitant for initiation and progression of asthma has been incompletely explored. In this study, the effects of Aspergillus fumigatus exposure on airway inflammation and remodelling in a rat model of chronic asthma were investigated.
Methods:   The rat model of chronic asthma was established by systemic sensitization and repeated challenge with ovalbumin (OVA). The asthmatic rats were exposed to chronic intranasal inhalation of A. fumigatus spores. Changes in airway inflammation, remodelling and BHR were measured after exposure to the fungus.
Results:   Chronic inhalation of A. fumigatus spores elevated the production of T helper 2 (Th2) cytokines, increased the concentration of total serum IgE, and resulted in the recruitment of eosinophils and lymphocyte infiltration into the airways of asthmatic rats. Goblet cell hyperplasia, mucus hyperproduction and subepithelial collagen deposition were also induced by inhalation of the fungus. The remodelling changes induced by inhalation of the fungus paralleled the changes in BHR in this rat model of asthma.
Conclusions:   Chronic exposure to A. fumigatus aggravated Th2 airway inflammation, promoted airway remodelling and increased BHR in OVA-sensitized and -challenged rats.     

Osteomyelitis due to Aspergillus spp. in patients with chronic granulomatous disease: comparison of Aspergillus nidulans and Aspergillus fumigatus.

OBJECTIVE: Chronic granulomatous disease (CGD) is a rare inherited disorder of NADPH oxidase in which phagocytes fail to generate reactive antimicrobial oxidants. Invasive fungal infections are an important cause of morbidity and mortality in CGD patients, with Aspergillus spp. being the most frequent fungal pathogens. We reviewed the reported cases of osteomyelitis in CGD patients due to Aspergillus nidulans and compared them with those due to Aspergillus fumigatus. METHODS: Twenty-four cases of osteomyelitis due to Aspergillus spp. in 22 male CGD patients were found in MEDLINE. RESULTS: Fourteen cases (58%) were due to Aspergillus nidulans and ten cases to Aspergillus fumigatus. No other aspergilli were reported as causes of osteomyelitis. Osteomyelitis due to Aspergillus nidulans was associated with pulmonary infection and involved 'small bones' more frequently than Aspergillus fumigatus osteomyelitis (p=0.032). Half of the CGD patients with Aspergillus nidulans osteomyelitis died compared with none of those with Aspergillus fumigatus osteomyelitis (p=0.019). In both Aspergillus nidulans and Aspergillus fumigatus cases, cure was achieved by prompt antifungal treatment combined with surgery and immunotherapy. CONCLUSION: Aspergillus nidulans causes osteomyelitis in CGD patients relatively frequently compared with Aspergillus fumigatus and may be accompanied by higher mortality. This contrasts with the low frequency with which Aspergillus nidulans causes osteomyelitis in patients with other types of immunodeficiency.     

Evidence against the hypothesis that hyperinsulinemia increases sympathetic nervous system activity in man.

To test the hypothesis that physiologic hyperinsulinemia activates the sympathetic nervous system in humans, we measured changes in plasma norepinephrine as well as epinephrine concentrations during euglycemic hyperinsulinemic clamp experiments in which normal volunteers were infused with insulin for up to 12 hours, at rates chosen to simulate the basal and postprandial hyperinsulinemia seen in insulin-resistant states. Infusions of insulin increased plasma insulin threefold (to approximately 200 pmol/L) and 15-fold (to approximately 1,000 pmol/L) in simulations of fasting and postprandial hyperinsulinemia. In neither experiment did plasma norepinephrine or epinephrine change significantly. In control experiments in which saline was infused for 12 hours, plasma epinephrine increased twofold (P less than .05), but plasma norepinephrine did not change. Therefore, we conclude that hyperinsulinemia of the magnitude seen in the insulin-resistant humans does not increase sympathetic nervous system activity.     

Pressure-volume properties of the upper airway in man.

We report a method of measuring the static pressure-volume properties of the upper airway in unanesthetised humans. In 10 normal subjects the pressure in the upper airway was measured during aspiration of air in 10 ml decrements from 30-40 ml above resting volume to 30-40 ml below resting volume, with the glottis closed voluntarily and the oro-pharyngeal muscles relaxed. The pressure-volume properties of the upper airway were well described by the pressure-volume rate upper airway elastance (UAE, cmH2O/ml). The mean (+/- 95% CI) UAE measured at near total lung capacity and with the neck in neutral position for all runs in all subjects was 0.22 +/- 0.06 cmH2O/ml. When UAE was measured repeatedly on different days the greatest change observed was from a mean value of 0.17 cmH2O/ml on one day to 0.25 cmH2O/ml on another, and the standard deviation of the means from different days ranged from 0.01 to 0.04. Neither hypoxia (SaO2 80-85%) nor hyperoxic hypercapnia (PETCO2 65-75 mmHg) had any influence on UAE. Maximal extension of the neck did not affect UAE, but flexion of the neck was associated with a rise in UAE from a mean of 0.23 +/- 0.05 cmH2O/ml to a mean of 0.53 +/- 0.14 cmH2O/ml. UAE was not affected by the lung volume at which measurements were made. We conclude that upper airway pressure-volume properties can be measured non-invasively in man, and that in their linearity, reproducibility and lack of sensitivity to hypoxia and hypercapnia they resemble those of experimental animals.     

Preferential induction of a Th1 immune response and inhibition of specific IgE antibody formation by plasmid DNA immunization.

We compared the antigen-specific antibody isotypes and lymphokine secretion by CD4+ T cells in BALB/c mice immunized intradermally with either Escherichia coli beta-galactosidase (beta-gal) or plasmid DNA (pDNA) encoding beta-gal in a cytomegalovirus-based expression vector (pCMV-LacZ). pCMV-LacZ induced mainly IgG2a, whereas beta-gal in saline or alum induced IgG1 and IgE beta-gal-specific antibodies. In addition, splenic CD4+ T helper (Th) cells isolated from pDNA-immunized mice secreted interferon-gamma but not interleukin (IL)-4 and IL-5, whereas Th cells from beta-gal-injected mice secreted IL-4 and IL-5 but not interferon-gamma after in vitro stimulation with antigen. Together these data demonstrate that pDNA immunization induced a T helper type 1 (Th1) response, whereas protein immunization induced a T helper type 2 (Th2) response to the same antigen. Interestingly, priming of mice with pCMV-LacZ prevented IgE antibody formation to a subsequent i.p. beta-gal in alum injection. This effect was antigen-specific, because priming with pCMV-LacZ did not inhibit IgE anti-ovalbumin antibody formation. Most importantly, intradermal immunization with pCMV-LacZ (but not pCMV-OVA) of beta-gal in alum-primed mice caused a 66-75% reduction of the IgE anti-beta-gal titer in 6 weeks. Also, pCMV-LacZ induced specific IgG2a antibody titers and interferon-gamma secretion by Th cells in the beta-gal in alum-primed mice. The data demonstrate that gene immunization induces a Th1 response that dominates over an ongoing protein-induced Th2 response in an antigen-specific manner. This suggests that immunization with pDNA encoding for allergens may provide a novel type of immunotherapy for allergic diseases.     

Transformation and replication in mouse cells of a bovine papillomavirus--pML2 plasmid vector that can be rescued in bacteria.

The unique ability of bovine papillomavirus (BPV-1) DNA to replicate as a stable, multicopy plasmid in transformed mouse cells has led to its utilization as a eukaryotic cloning vector. One limitation of the system has been the marked reduction in transformation efficiency when BPV-1 DNA or the subgenomic transforming segment of BPV-1 DNA (BPV69T) is covalently linked to pBR322 sequences. A dual host replicon consisting of BPV-1 DNA and pML2d, a deletion variant of pBR322, was constructed and shown to be highly efficient for transformation of mouse cells in vitro. The hybrid molecule replicates as a stable, unintegrated, multicopy plasmid in transformed mouse cells. The resident BPV-1-pML2d plasmid DNA was rescued in bacteria and the recovered plasmids were shown to be identical in structure and to have the same transformation efficiency as the original transforming DNA. In contrast, the transforming efficiency of BPV69T DNA is less than 1/100th that of BPV-1 DNA when the DNA is left covalently linked to pML2d. These observations indicate that, although the nontransforming region of BPV-1 (BPV31NT) DNA is not essential for transformation, it has a facilitative role in the transformation process.     

Aspergillus fumigatus pacemaker lead endocarditis: a case report and review of the literature

The diagnosis of fungal endocarditis requires a high index of clinical suspicion. Rarely, pacemaker implantation may be a risk factor for the development of fungal endocarditis. A 71-year-old man with a history of multiple transvenous pacemaker manipulations and fever of an uncertain source is described. A diagnosis of culture-negative pacemaker endocarditis was established only after repeat transthoracic echocardiography. Amphotericin B was instituted; however, the patient developed a cerebral infarct and died. Postmortem examination demonstrated Aspergillus fumigatus within a large pacemaker lead thrombus, tricuspid and aortic valve vegetations, and septic pulmonary and renal emboli. The present report describes the clinical and pathological features of a rare case of Aspergillus fumigatus pacemaker lead endocarditis and suggests that serial echocardiograms may be effective in the early detection of pacemaker lead vegetations. The diagnostic features and therapeutic management of pacemaker lead endocarditis are reviewed.