Equilibrium electroconvective instability.

Since its prediction 15 years ago, hydrodynamic instability in concentration polarization at a charge-selective interface has been attributed to nonequilibrium electro-osmosis related to the extended space charge which develops at the limiting current. This attribution had a double basis. On the one hand, it has been recognized that neither equilibrium electro-osmosis nor bulk electroconvection can yield instability for a perfectly charge-selective solid. On the other hand, it has been shown that nonequilibrium electro-osmosis can. The first theoretical studies in which electro-osmotic instability was predicted and analyzed employed the assumption of perfect charge selectivity for the sake of simplicity and so did the subsequent studies of various time-dependent and nonlinear features of electro-osmotic instability. In this Letter, we show that relaxing the assumption of perfect charge selectivity (tantamount to fixing the electrochemical potential of counterions in the solid) allows for the equilibrium electroconvective instability. In addition, we suggest a simple experimental test for determining the true, either equilibrium or nonequilibrium, origin of instability in concentration polarization.

Controlled surface charging as a depth-profiling probe for mesoscopic layers

Probing the structure of material layers just a few nanometres thick requires analytical techniques with high depth sensitivity. X-ray photoelectron spectroscopy (XPS) provides one such method, but obtaining vertically resolved structural information from the raw data is not straightforward. There are several XPS depth-profiling methods, including ion etching, angle-resolved XPS (ref. 2) and Tougaard's approach, but all suffer various limitations. Here we report a simple, non-destructive XPS depth-profiling method that yields accurate depth information with nanometre resolution. We demonstrate the technique using self-assembled multilayers on gold surfaces; the former contain 'marker' monolayers that have been inserted at predetermined depths. A controllable potential gradient is established vertically through the sample by charging the surface of the dielectric overlayer with an electron flood gun. The local potential is probed by measuring XPS line shifts, which correlate directly with the vertical position of atoms. We term the method 'controlled surface charging' and expect it to be generally applicable to a large variety of mesoscopic heterostructures.

Reexamination of electrodiffusion time scales.

The characteristic time scales in ac ionic conduction near equilibrium are reassessed via consideration of a selection of one-dimensional model problems. It is observed that, in addition to the two basic electrodiffusion time scales, those of diffusion relaxation in the macroscopic- and Debye-scale domains, T and t{D} (the latter identical with the bulk charge relaxation time), some intermediate time scales are present in each system. It is concluded that, due to insensitivity of the electric double layers to harmonic voltage disturbances, the short-time response on the t{D} scale is determined by the quasielectroneutral bulk.

Paradoxical glottic narrowing in patients with severe obstructive sleep apnea.

Most patients with obstructive sleep apnea have increased pharyngeal collapsibility (defined in the present study as an increased lung volume dependence of pharyngeal area), which predisposes them to upper airway occlusion during sleep. However, there are patients with severe obstructive sleep apnea who have low-normal pharyngeal collapsibility. The factors leading to nocturnal upper airway obstruction in such patients have not been ascertained. We studied 10 overweight male patients with severe obstructive sleep apnea and low-normal pharyngeal collapsibility to determine the site of upper airway pathology in these patients. We found that all 10 patients exhibited paradoxical inspiratory narrowing of the glottis during quiet tidal breathing. This phenomenon was not observed in a matched group of 10 snoring, nonapneic male controls. We conclude that paradoxical glottic narrowing may be a contributing factor in the pathogenesis of upper airway obstruction in patients with severe obstructive sleep apnea who have low-normal pharyngeal collapsibility.

Mast cell chymase potentiates histamine-induced wheal formation in the skin of ragweed-allergic dogs.

Skin mast cells release the neutral protease chymase along with histamine during degranulation. To test the hypothesis that chymase modulates histamine-induced plasma extravasation, we measured wheal formation following intradermal injection of purified mast cell chymase and histamine into the skin of ragweed-allergic dogs. We found that chymase greatly augments histamine-induced wheal formation. The magnitude of the potentiating effect increases with increasing doses of chymase and becomes maximal approximately 30 min after administration. Injection of chymase without histamine does not evoke wheal formation. The chymase potentiation of histamine-induced skin responses is prevented completely by pretreatment with the H1-receptor antagonist pyrilamine, and is prevented by inactivation of chymase with soybean trypsin inhibitor, suggesting that both histamine and preserved catalytic activity are required for the effects of chymase. To examine the effects of histamine and chymase released in situ in further experiments, we measured wheal size following local degranulation of mast cells by intradermal injection of ragweed antigen or compound 48/80. We found that pretreatment with either soybean trypsin inhibitor or pyrilamine markedly reduces ragweed antigen- or 48/80-induced wheal formation, supporting the results obtained by injection of exogenous chymase and histamine. These findings suggest a novel and important proinflammatory role for chymase in modulating the effects of histamine on vascular permeability during mast cell activation.

Involvement of nitric oxide system in experimental muscle crush injury.

Muscle crush injury is often complicated by hemodynamic shock, electrolyte disorders, and myoglobinuric renal failure. In this study, we examined the involvement of the nitric oxide (NO) system in the development of muscle damage in an experimental model of crush injury induced by exertion of standardized mechanical pressure on tibialis muscle of rat. The intact limb served as a control. Four days after injury, the crushed muscle was characterized by extreme capillary vasodilatation as demonstrated by histological morphometric analysis. These changes were accompanied by muscle hyperperfusion as evaluated by measurements of femoral blood flow (ultrasonic flowmetry) and capillary blood flow (laser-doppler flowmetry). Treatment with Nomega-nitro-L-arginine methyl ester, a NO synthase (NOS) inhibitor, largely decreased the hyperperfusion. Furthermore, the expression of the different NOS isoforms, assessed by reverse transcription-PCR and immunoreactive levels, determined by Western blot, revealed a remarkable induction of the inducible NOS in the crushed limb. Similarly, endothelial NOS mRNA increased gradually after the induction of muscle damage. In contrast, the major muscular NOS, i.e., neuronal isoform remained unchanged. In line with the alterations in the mRNA levels, Western blot analysis revealed parallel changes in the immunoreactive levels of the various NOS. These findings indicate that muscle crush is associated with activation of the NO system mainly due to enhancement of iNOS. This may contribute to NO-dependent extreme vasodilatation in the injured muscle and aggravate the hypovolemic shock after crush injury.

In vivo immunomodulatory profile of telithromycin in a murine pneumococcal infection model.

In addition to bactericidal activity, macrolide antibacterials possess clinically relevant properties such as immunomodulatory activity. Whether such activity extends to novel antibacterials that are structurally related to macrolides, such as the ketolides, remains largely unknown. The objective of this study was to evaluate the in vivo immunomodulatory profile of the first ketolide antibacterial - telithromycin in a murine neutropenic thigh infection model. Specific pathogen-free, female ICR mice were rendered transiently neutropenic with intraperitoneal cyclophosphamide. Thighs were inoculated with 10(6) colony-forming units of a single clinical isolate of Streptococcus pneumoniae. Once inoculated, mice (n=500) received single oral doses of telithromycin (10, 25 or 50 mg/kg of body weight) or no treatment (control). Blood was obtained via cardiac puncture prior to and at 2, 4, 8, and 24 h after dose administration for determination of cytokine concentrations. Significant post-inoculation elevations of interleukin (IL)-1beta, IL-6, and IL-10 were noted in untreated controls over 24 h. Telithromycin attenuated these increases and the suppression of both IL-6 and IL-10 release was observed to be dose dependent. Systemic concentrations of IL-2 and tumor necrosis factor alpha showed an upward trend over the initial 8-h post-inoculation period in the telithromycin group. These data therefore reveal novel in vivo immunomodulatory effects of telithromycin. Further studies are warranted to determine whether such effects contribute to the therapeutic efficacy of the drug in patients with acute respiratory tract infections.

Annexin I degradation in bronchoalveolar lavage fluids from healthy smokers: a possible mechanism of inflammation.

Annexin I is a glucocorticoid-inducible, phospholipase A2-inhibitory protein and is proposed to have an anti-inflammatory role. Although annexin I is a cytosolic protein, it is found extracellularly in secreted fluids such as semen. We have examined the expression of annexin I in bronchoalveolar lavage fluids (BALF) from smokers and nonsmokers to investigate the role of annexin I in the airway. We find that annexin I is secreted in BALF. This secretion is not due to cell death or damage, because a cytosolic protein, 3-phosphoglycerate kinase, is not seen in BALF. We observed that BALF from smokers (n = 10) had high protein concentrations as compared with BALF from nonsmokers (n = 11). Annexin I levels were higher in BALF from smokers compared with nonsmokers. However, in smokers, annexin I was exclusively found in the Mr 34,000 form that lacks the Mr 3,000 N-terminal anti-inflammatory peptide. In nonsmokers, both the Mr 37,000 native annexin I and the Mr 34,000 proteolytically cleaved form are present, with the Mr 37,000 form being most abundant. The NH2-terminal Mr 3,000 peptide of annexin I exhibits anti-inflammatory actions (G. Cirino et al, Br. J. Pharmacol., 108: 573-574, 1993). Previous studies have implicated neutrophil elastase as the protease cleaving annexin I to the Mr 34,000 protein. We observed increased elastase levels in BALF from smokers. However, we find no correlation between bronchial sample percent of neutrophils in BALF and the relative amount of the Mr 34,000 band generated. Our data clearly demonstrate that annexin I is degraded in BALF from smokers, and we propose that proteolytic cleavage of annexin I in BALF from smokers may be a mechanism by which polymorphonuclear neutrophils infiltrate sites of inflammation; thus, inactivation of annexin I in smokers' lungs may lead to chronic and uncontrolled inflammation.

Nitric oxide synthase inhibitors attenuate human monocyte chemotaxis in vitro.

Nitric oxide synthase (NOS) inhibitors have been shown to modulate neutrophil migration. We hypothesized that the NOS inhibitors NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine methyl ester (L-NAME), and L-canavanine (L-CAN) also modulate human peripheral blood monocyte chemotaxis. To test this hypothesis, monocyte chemotaxis toward formylmethionylleucyl-phenylalanine (fMLP) was assessed using a modified blindwell chemotaxis chamber technique. L-NMMA and L-NAME, but not D-NMMA or L-CAN, significantly attenuated fMLP-induced monocyte chemotaxis (P < .05). L-Arginine and sodium nitroprusside, but not D-arginine, reversed NOS inhibitor-induced responses. Dibutryl cyclic guanyl monophosphate (cGMP) attenuated the inhibitory effects of L-NMMA on monocyte chemotaxis (P < .05). Finally, fMLP increased cGMP generation by monocytes, which was significantly attenuated by L-NMMA (P < .05). These data indicate that the L-arginine/NO biosynthetic pathway regulates human monocyte chemotaxis in vitro.

Fatal pulmonary emboli in hospitalized patients. An autopsy study.

To determine the accuracy of the antemortem diagnosis of major pulmonary embolism, we reviewed 1276 autopsy reports at St Michael's Hospital, Toronto, from 1980 to 1984. Of 44 patients identified with major pulmonary embolism as the cause of death or a major factor contributing to it, 14 (31.8%) had the diagnosis suspected before death. We could not find any distinctive features separating these patients from those in whom the diagnosis of pulmonary embolism was not suspected before death. We conclude that major pulmonary embolism is still underdiagnosed in hospitalized patients, despite the availability of lung scanning and pulmonary angiography.

Morphologic diagnosis of idiopathic pulmonary alveolar lipoproteinosis-revisited.

The usefulness of transbronchial biopsy in diagnosing idiopathic pulmonary alveolar lipoproteinosis (PAL) is not emphasized in the literature. Therefore, we decided to reassess our approach to the morphologic diagnosis of this disorder in 14 patients diagnosed over the past 13 years in two major teaching hospitals in Toronto. The morphologic diagnosis of idiopathic PAL was established by means of open lung biopsy in 11 patients; the use of transbronchial biopsy was not considered in eight of them. Transbronchial biopsy was performed in six patients, and the diagnosis of idiopathic PAL was reliably established in five cases. We conclude that transbronchial biopsy may be a worthwhile preliminary procedure to open lung biopsy in patients with suspected idiopathic PAL, and it can reliably establish the diagnosis in such cases.

Increased salivary calcium levels as an indicator of digoxin intoxication.

One hundred ten individuals were divided into patients with digoxin intoxication; patients treated with digoxin; patients treated with digoxin and diuretics; patients treated with diuretics; and control subjects. Measurement of salivary potassium and calcium levels showed that 81% of the patients with digoxin intoxication had noticeable elevation of the salivary calcium level. In 22%, elevation of the salivary calcium level preceded clinical manifestations of intoxication. The high calcium level in the saliva was not accompanied by changes in serum or urinary calcium levels. The elevation of salivary calcium levels can be used not only as an additional indicator of digoxin intoxication but also for detecting impending intoxication in patients treated with this drug.

Initial characterization of hamsters with spontaneous hypertension.

The purpose of this study was to begin to characterize a new inbred strain of adult male hamsters with established spontaneous hypertension along with their genetically/age-matched normotensive controls. We found that mean arterial pressure was 162+/-3 mm Hg in hypertensive hamsters and 94+/-4 mm Hg in controls (mean+/-SEM; P<.05). Body weight was significantly lower in hypertensive hamsters relative to normotensive hamsters (P<.05). Hypertension was associated with a significant increase in heart weight, thickness of the left ventricular wall, and amplitude of the QRS complex in standard electrocardiographic leads I and aVR (P<.05). No gross or microscopic abnormalities were observed in other organs. Plasma renin activity and the number of circulating neutrophils were significantly increased in hypertensive hamsters relative to controls (P<.05). Serum concentrations of creatinine, blood urea nitrogen, sodium, potassium, and calcium as well as urinalysis were similar in both groups. Overall, these data suggest that the spontaneously hypertensive hamster could be a suitable model for the study of spontaneous hypertension.

Tissue angiotensin I-converting enzyme activity in aging hamsters with and without cardiomyopathy.

The purpose of this study was to determine tissue angiotensin I-converting enzyme (ACE) activity in aging hamsters with and without cardiomyopathy, and the factors that regulate its activity in vitro. We found that ACE activity was significantly increased in the heart and significantly decreased in the lung of aging hamsters with hereditary cardiomyopathy in comparison to age/genetically-matched controls (P < 0.05). Kidney and cheek pouch ACE activity was similar in both groups. Lisinopril inhibition curves of tissue ACE activity were similar in aging hamsters with and without cardiomyopathy. In both groups, tissue ACE activity was dependent on chloride anion concentration in the assay buffer. Substituting citrate for chloride abrogated, in part, this response. We conclude that cardiomyopathy is associated with significant changes in cardiac and lung ACE activity in aging hamsters in comparison to age/genetically-matched controls. However, regulation of tissue ACE activity in vitro is similar in both groups.

Interactions of VIP, secretin and PACAP(1-38) with phospholipids: a biological paradox revisited.

Vasoactive intestinal peptide (VIP), secretin and pituitary adenylate cyclase-activating peptide(1-38)(PACAP(1-38)) are widely distributed amphipathic mammalian neuropeptides that exert diverse biological effects in target tissues located distant from their site of release. However, the half-life of exogenously-administered VIP, secretin and PACAP(1-38) in the bloodstream is relatively short (minutes) due to rapid degradation and inactivation. This seemingly paradoxical behavior suggests the presence of an innate system(s) that protects the peptides from degradation in vivo. To this end, VIP, secretin and PACAP(1-38) express distinct biophysical properties that once released may protect them from degradation in biological fluids. They self-aggregate at low (nanomolar) concentrations and interact avidly with biomimetic phospholipid monolayers and bilayers at physiological concentrations. The latter evokes conformational transition of the VIP, secretin and PACAP(1-38) molecules from predominantly random coil in aqueous solution to alpha-helix, the preferred peptide conformation for receptor interaction, in phospholipids. These features increase peptide stability and amplify bioactivity in vivo. Collectively, these data suggest the presence of an endogenous targeted delivery platform for VIP, secretin and PACAP(1-38). This innate system may constitute a novel molecular recognition paradigm that could also apply to other amphipathic neuropeptides. Importantly, the distinct behavior of VIP, secretin and PACAP(1-38) in the presence of phospholipids could be exploited to develop novel, long-acting therapeutic formulations of these peptides.

Snoring and upper airway properties.

Habitual snoring in adults may be related to upper airway dysfunction, although the precise relationship has never been studied. We quantitatively measured snoring and correlated it with upper airway properties in 50 apneic and 59 nonapneic adult male patients. Both groups were similar in terms of nasal airflow resistance and pulmonary function tests. We found a significant correlation between the severity of snoring and nasal airflow resistance in both groups, and between the severity of snoring and pharyngeal and glottic areas in the apneic group. We conclude that snoring may be associated with abnormalities in upper airway properties.

Neurosarcoidosis associated with hypersomnolence treated with corticosteroids and brain irradiation.

Narcoleptic features developed in a young man with CNS sarcoidosis. This was associated with a structural lesion in the hypothalamus as demonstrated on CT scans of the head. The diagnosis of narcolepsy was established by compatible clinical history and the Multiple Sleep Latency Test. Treatment with high-dose corticosteroids was ineffective, but when the low-dose, whole-brain irradiation was added, complete resolution of the narcoleptic features ensued.

Exhaled pentane levels in acute asthma.

BACKGROUND: Exhaled pentane, a product of lipid peroxidation, has been proposed as an objective, nonspecific, and noninvasive marker of active inflammation. Reactive oxygen species, which elicit lipid peroxidation, are increased in asthma and contribute to airway dysfunction. OBJECTIVE: To determine whether exhaled pentane levels are increased in acute asthma, and whether they decrease once acute asthma subsides. METHODS: Expired air was collected through a mouthpiece into a pentane-impermeable collection bag from 12 patients (40+/-5 years; mean+/-SEM) presenting to the emergency department of the University of Illinois Hospital in Chicago with acute asthma. Exhaled air was also collected after discharge from the hospital once acute asthma subsided. Eleven patients with stable asthma (40+/-5 years) and 17 healthy volunteers (31+/-5 years) served as control subjects. Exhaled air and ambient room air were analyzed for pentane content by gas chromatography. Peak expiratory flow rates were determined in each subject. RESULTS: Peak expiratory flow rates were 202+/-29 L/min during acute asthma and 327+/-26 L/min once acute asthma subsided (p<0.05). Exhaled pentane levels were 8.4+/-2.9 nmol/L during acute asthma and decreased significantly to 3.5+/-0.5 nmol/L once acute asthma subsided (p<0.05). Exhaled pentane levels were similar in patients with stable asthma and normal control subjects (3.6+/-0.4 nmol/L and 2.6+/-0.2 nmol/L, respectively; p>0.05). No pentane was detected in ambient air. CONCLUSION: Exhaled pentane levels are increased in patients with acute asthma and decrease significantly once acute asthma subsides.

Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma.

Prolonged use of prednisone is associated with serious side effects, such as osteoporosis, particularly among elderly individuals. Macrolide antibiotics exhibit anti-inflammatory effects that are distinct from their antimicrobial properties. Thus, the purpose of this case report is to describe the effects of prolonged treatment with clarithromycin, 500 mg bid, in reducing prednisone requirements in three elderly patients with prednisone-dependent asthma. Three patients (one woman and two men) aged 63 to 69 years, who had been treated with 5 to 10 mg prednisone daily for at least the last 12 months, were given clarithromycin, 500 mg bid. They were followed regularly for changes in daily prednisone dose, spirometry, quality of life, and adverse events. The prednisone dose was tapered in a stepwise fashion at each clinic visit. Within 3 to 6 months of initiation of treatment with clarithromycin, and throughout the 12-month follow-up, two of three patients discontinued prednisone therapy, while the third patient displayed increased spirometry readings and noted an increasingly better quality of life. Pulmonary function tests were stable or improved over this time period, with no reported adverse events, including increased rate of infections. One patient relapsed upon discontinuation of clarithromycin therapy but has since responded to re-initiation of treatment. Long-term oral clarithromycin may have a role in reducing prednisone requirements in elderly patients with prednisone-dependent asthma.