Adult cystic fibrosis care in the 21st century.

Cystic fibrosis (CF) is the most common autosomal recessive inherited disease of Caucasian populations. As a result of a variety of diagnostic and therapeutic strategies there has been a dramatic increase in the life expectancy of patients with CF in the last decades and 50% of patients are now adults. This review will focus on the disease in adults and the provision of appropriate care. The complex care required to improve the survival and quality of life in the adult patients can best be provided in a dedicated adult cystic fibrosis unit. These units currently exist in many European countries, but more are needed in Italy.

Queratitis inflamatoria por acanthamoeba spp. análisis estructural por microscopía electrónica de transmisión / Infectious keratitis by acanthamoeba spp. amoeba structure. analysis using transmission electronics microscope

Se presenta el caso de una un paciente de 36 años, cuyo motivo de consulta fue visión borrosa y dolor ocular severo de 5 semanas de evolución, en ojo izquierdo. La paciente tenia como hábito el uso de lentes de contacto blandas con higiene inadecuada. Fue sometida a exámenes bacteriológicos y virológicos con resultados negativos. Para el presente estudio se extrajo material obtenido a través de una biopsia de córnea. Se realizó observación microscópica en fresco y con colorantes permanentes. Por medio de cultivos xénicos, se obtuvo trofozoitos y quistes de Acanthamoeba spp: Las colonias fueron observadas con microscopía óptica en fresco y con contraste de fases. Por MET (microscopía electrónica de transmisión) se analizó la ultraestructura de la ameba.

Exhaled nitric oxide after inhalation of isotonic and hypotonic solutions in healthy subjects.

Airway nitric oxide (NO) homoeostasis is influenced by chemical and mechanical stimuli in humans; airway epithelium, which is an important site of NO production, is sensitive to osmotic challenge. The effect of inhaled hypotonic solutions on exhaled NO (eNO) is not known. In this study we evaluated the effect of ultrasonically nebulized distilled water (UNDW), a hypotonic indirect stimulus, on eNO levels. A total of 10 non-smoking healthy subjects were enrolled in the study. eNO was detected by chemiluminescence, and specific airway conductance (sGaw) was measured by plethysmography. Bronchial challenges with UNDW and with an isotonic solution were performed according to a double-blind experimental design. Baseline levels of eNO were 28.1+/-14.7 p.p.b. UNDW did not cause any significant change in sGaw (from 0.190+/-0.029 to 0.181+/-0.036 cm H(2)O x s(-1)). With respect to baseline values, the eNO concentration decreased significantly after inhalation of 8 or 16 ml of UNDW (from 26.0+/-13.1 to 17.2+/-8.5 and 16.6+/-7.7 p.p.b. respectively; P<0.001, n=10). After bronchial challenge with UNDW, eNO was significantly reduced in comparison with after inhalation of the isotonic solution. In five subjects, pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor NO synthesis, decreased NO levels from 21.7+/-8.5 to 10.0+/-3.3 p.p.b. Subsequent inhalation of 16 ml of UNDW did not cause any further decrease in NO levels (10.1+/-3.7 p.p.b.; not significant compared with L-NAME). We conclude that inhalation of aqueous solutions decreases eNO levels in healthy subjects, and that this effect is not associated with any significant change in airway calibre. The UNDW-induced decrease in eNO is not enhanced by pretreatment with the NO synthase inhibitor L-NAME, suggesting that inhaled solutions may interfere with the airway NO pathway in humans.

Exhaled nitric oxide in patients with PiZZ phenotype-related alpha1-anti-trypsin deficiency.

There is no report of exhaled NO (eNO) in subjects with different phenotypes of alpha1-anti-trypsin (AAT) deficiency. Exhaled nitric oxide was evaluated by means of single-breath chemiluminescence analysis (fractional exhaled concentration at the plateau level [plFE(NO)]) in 40 patients with AAT deficiency. Patients were divided according to the protease inhibitor (Pi) phenotype: PiMZ/MS, n = 25; PiSZ n = 6; PiZZ, n = 9. Nineteen healthy subjects served as controls. Levels of eNO in PiZZ patients were also compared with those of subjects, without AAT deficiency (PiMM), matched for diagnosis, sex, age, smoking habit and forced expiratory volume in 1 sec (FEV1). In AAT deficiency subjects airway hyper-responsiveness to methacholine (PD20 FEV1) was also assessed. plFE(NO) was significantly lower in the PiZZ group (4.5+/-1.4 ppb) than in matched PiMM subjects (8.2+/-3.8 ppb), in healthy controls (9.3+/-2.8 ppb) and in patients of other phenotypes. Dynamic lung volumes and DL(CO) were significantly lower in PiZZ than in other AAT-deficient patients. Bronchial hyper-responsiveness was not different among AAT phenotypes. These results suggest that eNO may be significantly reduced in PiZZ as compared to healthy control subjects and to AAT subjects with other phenotypes, independent of the level of airway obstruction. Whether, at least potentially, eNO may be considered as an early marker of lung involvement in AAT deficiency must be confirmed with studies on larger number of subjects.

Smoothness of ablation on acrylic by four different excimer lasers.

PURPOSE: There are many different excimer laser devices available for photoablative refractive surgery. Smoothness of ablation may vary with different excimer lasers systems. METHODS: Ablations were performed on polymethylmethacrylate (PMMA) plates of 8 x 4 x 0.5 cm, with four different excimer lasers: VISX-Star, Coherent Schwind Keratom I/II, Chiron Technolas Keracor 117C (Plano Scan), and the Nidek EC-5000, to determine and compare the homogeneity and smoothness of the surface. Ten -3.00 D samples, ten -6.00 D samples, and ten -9.00 D samples were ablated with each laser. The PMMA discs were examined with optical microscopy, documented by photographs, and each sample was measured quantitatively using a Hommel-Werkel rugosimeter. We used the same PMMA material throughout. RESULTS: Statistically significant differences in smoothness were found between the Chiron Technolas 117C and the VISX-Star, Nidek and VISX-Star, and Coherent Schwind and VISX-Star in the homogeneities achieved by ablating -3.00 D. Ablations of -6.00 D resulted in homogeneities that were statistically significantly different: Chiron Technolas 117C with the other three devices, the Nidek EC-5000 with the VISX-Star, and the Coherent-Schwind with the VISX-Star. In the ablations for -9.00 D, statistically significant differences in homogeneity were found between the Chiron Technolas 117C and Nidek, between the Chiron and VISX-Star, between the Coherent Schwind and VISX-Star, and between the Nidek and VISX-Star. The laser with the scanning spot system was smoother. CONCLUSION: Scanning spot technology produced smooth ablations even up to -9.00 D.

Revascularization of severe hibernating myocardium in the beating heart: early hemodynamic and metabolic features.

BACKGROUND: We investigated the effects of coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB) in selected patients with severe hibernating myocardium. METHODS: Twelve patients (EF = 25% +/- 0.7%) with reversible ventricular dysfunction (from 2.0 +/- 0.06 to 1.6 +/- 0.05 left ventricular score index by echodobutamine, p < 0.01) in the territory of the left anterior descending artery (LAD) have been studied. Revascularization was achieved by anastomosing the left internal mammary artery to the LAD. The ischemic time of LAD was 9.0 +/- 0.4 minutes. RESULTS: Left ventricular function increased 6 hours and 48 hours after revascularization (left ventricular stroke work index from 32 +/- 1.8 to 42 +/- 1.5 and 40 +/- 0.6 gxm/m2, respectively: p = 0.0001). During the surgical procedure, the heart did not release lactate or creatine phosphokinase. There were no perioperative deaths or severe complications. CONCLUSIONS: Early hemodynamic and metabolic features of CABG without CPB in patients with hibernating myocardium suggest that this procedure is safe and results in a significant improvement of cardiac function without affecting myocardial metabolism.

Production of endogenous nitric oxide in chronic obstructive pulmonary disease and patients with cor pulmonale. Correlates with echo-Doppler assessment.

Exhaled nitric oxide (NO) production in stable chronic obstructive pulmonary disease (COPD) has been loosely related to the severity of illness, being significantly reduced in the most severe cases. Pulmonary hypertension is associated with lower NO output from the lung. In this study expired NO was measured in patients with severe stable COPD with or without cor pulmonale (CP). Echocardiographic estimates of right heart function, lung function, diffusion capacity, respiratory muscle strength, and arterial blood gases were obtained in 34 consecutive patients with stable COPD (mean age, 68 +/- 7 yr). Expired NO was measured by chemiluminiscence to obtain fractional exhaled concentrations at peak (FENOp) and at plateau (FENOpl) points of the single-breath curve and resting NO output (V NO). All measurements of expired NO output, FENOp, FENOpl and V NO showed a negative correlation with both systolic pulmonary artery pressure (Pspa) (r = -0.51, -0.63, and -0.63, respectively, p < 0.01 for all) and right ventricle wall dimension (r = -0.41, -0.59, and -0.43, respectively, p < 0.05 for all), but not with any measurement of lung function. When the patients were divided according to the Pspa using a cutoff limit of 35 mm Hg, those subjects with CP showed lower FENOp (13.2 +/- 4.0 versus 36.7 +/- 30.8 ppb, p < 0.05), FENOpl (5.7 +/- 1.9 versus 8.9 +/- 4.7 ppb, p < 0.05), and V NO (69. 2 +/- 5.6 versus 107.6 +/- 14.6 nl/ min, p = 0.02) than did those with a normal resting Pspa. NO production from the airways was significantly lower and inversely related to development of CP in patients with severe COPD. Impaired endothelial release may account for the reduced levels of expired NO.

Hydrodissection after nucleus fracture.

We introduce a technique of hydrodissection that reduces capsular bag distension and thus lowers the risk of capsular block syndrome. In 100 consecutive cases in which this method was used for cataract surgery, no complications occurred. Postoperative best corrected visual acuity was better than 20/40 in 96% of patients.

The acute effects of dexfenfluramine on human and porcine pulmonary vascular tone and resistance.

STUDY OBJECTIVES: Treatment with anorectics has become an important aspect of care for the severely obese. One such anorectic, the phenylethylamine dexfenfluramine (dFen), has been associated with the development of pulmonary hypertension. It works by reducing the neuronal uptake of 5-hydroxytryptamine (5-HT; serotonin) through inhibition of the 5-HT transporter. In this study we investigated whether dFen has a direct vasoconstrictor action on human and porcine pulmonary vasculature. DESIGN: For the human study, tissue was obtained from patients who had undergone lung and heart-lung transplantation. The effect of dFen was studied in seven isolated colloid perfused human lungs and in rings of human pulmonary artery (PA) dissected from the lungs of a further 19 patients. For the porcine study, regional pulmonary vascular resistances (PVRs) were measured in isolated perfused porcine lungs. Vasoconstriction was assessed following dFen alone and in combination with hypoxia, cyclo-oxygenase blockade (indomethacin, 10(-5) mol/L), or nitric oxide synthase (NOS) blockade (N(G)-nitro-L-arginine, 10(-5) mol/L). RESULTS: In the human study, 5-HT and dFen caused only limited increases in tension of isolated rings of PA. The concentration of dFen, 10(-4) mol/L, that was needed to increase tension was higher than that found normally in treated patients where peak levels are 3. 3 x 10(-7) mol/L. Other vasoconstrictors such as prostaglandin F(2)alpha, 10(-5) mol/L, and the thromboxane analog U46619, 10(-6) mol/L, produced far greater increases in tension. Ketanserin, 10(-4) mol/L, attenuated the constrictor response to 5-HT but had no effect on the constrictor response to dFen. Removal of the endothelium did not influence the response to dFen. In the isolated ventilated and perfused lungs, dFen caused an increase in PVR again only at a comparatively high concentration, 10(-4) mol/L. In the porcine study, dFen, 10(-4) mol/L, did not increase any PVR during normoxia or following NOS blockade. Small insignificant increases in PVR occurred during hypoxia and after cyclo-oxygenase blockade. CONCLUSION: These results do not support the view that dFen would act as a direct vasoconstrictor when given in the usual doses. However, delayed elimination of dFen could raise tissue concentrations to high levels and give rise to vasoconstriction and pulmonary hypertension.

Hemodynamic effects of basal and stimulated release of endogenous nitric oxide in isolated human lungs.

Background-We compared the hemodynamic responses to inhibition or stimulation of endothelial nitric oxide (NO) release of isolated explanted lungs from transplantation recipients with pulmonary hypertension and in normotensive unallocated donor lungs. Methods and Results-Lungs from 10 patients with severe pulmonary hypertension (SPH) and from 16 patients with severe chronic obstructive lung disease (COLD) were studied. Fourteen normotensive lungs were studied as controls. The lungs were perfused at a constant flow. In protocol 1 N(G)-nitro-L-arginine methyl ester caused a similar rise in baseline pulmonary artery pressure (PAP) that was similar in SPH (+17.1+/-4.2 mm Hg; n=5), COLD (+15.5+/-4.8 mm Hg; n=8), and control lungs (+14.5+/-1.5 mm Hg; n=7). Arterial occlusion demonstrated that most of the changes with N(G)-nitro-L-arginine methyl ester were precapillary. The response to sodium nitroprusside (10(-8) to 10(-4) mol/L) was similar in all groups. In protocol 2, the lungs were preconstricted, and acetylcholine (10(-9) to 10(-5) mol/L) caused a lesser fall in PAP in both COLD and SPH lungs compared with control (-41.9+/-8.6%, -55. 7+/-7.6%, and -73.2+/-2.5%, respectively; P<0.05), whereas sodium nitroprusside (10(-5) mol/L) decreased PAP to initial levels in all lungs. Conclusions-Stimulated release of NO is impaired in arteries of lungs with plexogenic or hypoxemic pulmonary hypertension. In contrast, basal release of NO appears to be maintained.

High-dose heparin impairs nitric oxide pathway and vasomotion in rats.

BACKGROUND: Platelet-activating effects have been reported with high-dose heparin in acute thrombotic disorders. Recent studies have shown that increased platelet aggregation is due to reduced nitric oxide (NO) production in endothelial cells cultured in the presence of high-dose heparin. The aim of this study was to determine whether heparin can affect the NO pathway and the regulation of the vascular tone in vivo. METHODS AND RESULTS: Anesthetized and mechanically ventilated Sprague-Dawley rats were treated with high-dose heparin. After 4 hours, the endothelial constitutive NO synthase (ecNOS) protein content in the aorta decreased (36% reduction, P<0.05), as detected by immunoblotting, and NO-dependent vascular reactivity was impaired. In fact, the increase in mean arterial blood pressure after inhibition of ecNOS with NG-nitro-L-arginine methyl ester (30 mg/kg) was smaller in heparin-treated animals than in controls (+26. 9+/-4.8 versus +48.3+/-9.1 mm Hg, P<0.05), and further infusion of the biological ecNOS substrate L-arginine (0.5 g/kg) was ineffective in reversing systemic vasoconstriction (-1% versus 28% vasodilatation, P<0.001). CONCLUSIONS: High-dose heparin can significantly affect vascular reactivity in vivo by downregulation of ecNOS protein expression.

Detection of nitric oxide in exhaled air of different animal species using a clinical chemiluminescence analyser.

The aim of the present study was to evaluate the nitric oxide (NO) concentrations present in end-expired gas (FENO) of different animal species under basal and stimulated conditions using a clinical chemiluminescence analyser, which has been developed for measurement of single exhalations in humans. Anaesthetised, tracheotomised and artificially ventilated guinea pigs, rats and rabbits were prepared for recording systemic blood pressure and FENO. Stable levels of FENO were detected in expired air over a 1-h observation period in the three animal species tested. Rabbits exhibited the highest concentrations and output (FENO 12.9+/-1.0 ppb, VNO 9.0+/-0.7 nl min-1), followed by guinea pigs (FENO 6.2+/-0.70 ppb, VNO 1.7+/-0.19 nl min-1) and rats (FENO 0.9+/-0.01 ppb, VNO 0.25+/-0.00 nl min-1). L-arginine (1 g kg-1 i.v.) evoked significant increments in VNO in guinea pigs and rabbits but was ineffective in rats. However, L-arginine showed a direct effect on blood pressure in all the animal species tested, causing a rapid fall in the mean arterial blood pressure (MABP; 38, 48 and 50% decrease in rabbits, guinea pigs and rats, respectively; P<0.05). An inhibitor of endogenous NO synthesis, NG-nitro-L-arginine methyl ester (L-NAME, 20 mg kg-1 i.v.), decreased both basal and L-arginine-induced VNO in guinea pigs and rabbits, but was ineffective in rats. L-NAME increased MABP in all the animal species tested (58% in guinea pigs, 43% in rats and 18% in rabbits; P<0.05). The results indicate that it is possible to detect NO in the exhaled air of different animal species using a clinical chemiluminescence analyser and that different species exhibit striking differences in the levels of basal and stimulated NO output.

Minimizing the inhaled dose of NO with breath-by-breath delivery of spikes of concentrated gas.

BACKGROUND: Pulmonary vasodilatation with a 100 ppm concentration of NO given as a short burst of a few milliliters at the beginning of each breath (NOmin) was compared with conventionally inhaled NO, in which a full breath of 40 ppm of NO was inhaled (NOCD). METHODS AND RESULTS: NOmin was studied in 16 patients with severe pulmonary hypertension and in 16 isolated porcine lungs with experimentally induced pulmonary hypertension. We compared volumes of 8 to 38 mL of 100 ppm NO in N2 injected at the beginning of each breath with conventional inhalation of 40 ppm NO in air. NOCD and NOmin were studied in 4 pigs after inhibition of NO synthase with NG-nitro-L-arginine methyl ester (1 to 2 mg/kg IV) had raised the pulmonary vascular resistance index (PVRI) from 4.4+/-0.8 to 10. 0+/-1.6 mm Hg. L-1. min-1. kg-1. A similar comparison was made in 7 isolated porcine lungs after the thromboxane analogue U46619 (10 pmol. L-1. min-1) increased the mean PVRI from 4.6+/-0.8 to 12.2+/-1. 3 mm Hg. L-1. min-1. kg-1. Patients' mean PVRI was reduced from 29. 2+/-3.7 to 24.0+/-3.1 with NOmin and 24.5+/-3.3 mm Hg. L-1. min-1. m-2 (mean+/-SEM) with NOCD. In isolated porcine lungs, there was the same reduction of PVRI for NOmin and NOCD between 12.7% and 34.8%. CONCLUSIONS: A small volume of NO inhaled at the beginning of the breath was equally effective as NOCD but reduced the dose of NO per breath by 40-fold, which ranged from 1.2x10(-8) (0.4 microg) to 1. 6x10(-7) mol/L (4.8 microg) compared with 5.3x10(-7) (16 microg) to 1.2x10(-6) mol/L (36 microg) per breath with NOCD.

Treatment of pulmonary hypertension with the continuous infusion of a prostacyclin analogue, iloprost.

OBJECTIVE: To compare prostacyclin with an analogue, iloprost, in treatment of severe pulmonary hypertension. PATIENTS: Eight patients with severe pulmonary hypertension: primary in five, thromboembolic pulmonary hypertension in three. METHODS: All patients underwent right heart catheterisation. Mean (SEM) right atrial pressure was 9.9 (2.2) mm Hg, mean pulmonary artery pressure 67.4 (3.0) mm Hg, cardiac index 1.75 (0.13) l/min/m2 and mixed venous oxygen saturation 59.1(3.1)%. Continuous intravenous epoprostenol (prostacyclin, PGI2) or iloprost was given for phase I (three to six weeks); the patients were then crossed over to receive the alternate drug in an equivalent phase II. MAIN OUTCOME MEASURES: Exercise tolerance was measured at baseline and at the end of phase I and II with a 12 minute walk; distance covered, rest period, percentage drop in arterial oxygen saturation (delta Sao2%) and percentage rise in heart rate (delta HR%). RESULTS: Walking distance covered rose from (mean (SEM)) 407.5 (73) to 591 (46) m with PGI2 (p = 0.004) and to 602.5 (60) m while on iloprost (p = 0.008). Rest period decreased from 192 (73) seconds at baseline to 16 (16) seconds with PGI2 (p = 0.01) and to 58 (34) seconds with iloprost (p = 0.008). Delta HR% was 37.5(6)% at baseline, 35(3)% on PGI2, and 24(6)% on iloprost (p = 0.04). CONCLUSIONS: Both intravenous PGI2 and iloprost caused significant improvement in exercise tolerance. Iloprost offers an alternative to PGI2 treatment of severe pulmonary hypertension.

Inhaled nitric oxide and arterial oxygen tension in patients with chronic obstructive pulmonary disease and severe pulmonary hypertension.

BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator which can improve gas exchange in acute lung injury. However, it is uncertain that this effect on arterial oxygenation can be generalised to all lung diseases. METHODS: The effects of inhaled NO on gas exchange were studied in nine patients with chronic obstructive pulmonary disease (COPD), 11 patients with severe pulmonary hypertension, and 14 healthy volunteers. A randomized sequence of 40 ppm of NO or air was inhaled for 20 minutes through an orofacial mask. RESULTS: Inhaled NO reduced mean (SE) transcutaneous arterial oxygen tension (TcPO2) from 9.6 (0.3) to 8.9 (0.4) kPa in healthy volunteers and from 7.4 (0.6) to 7.0 (0.5) kPa in patients with COPD. There was no change in TcPO2 in patients with severe pulmonary hypertension. During inhalation of NO and air no change occurred in transcutaneous arterial carbon dioxide tension (TcPCO2), arterial oxygen saturation (SaO2) measured by pulse oximeter, or cardiac output determined by the transthoracic impedance method. CONCLUSIONS: Inhaled NO does not improve TcPO2 nor increase cardiac output in normal subjects and patients with COPD, suggesting that inhaled NO worsens gas exchange. This could represent inhaled NO overriding hypoxic pulmonary vasoconstriction in COPD. The finding that TcPO2 also fell when normal subjects inhaled NO suggests that a similar mechanism normally contributes to optimal gas exchange. Whilst inhaled NO can improve oxygenation, this effect should not be considered to be a general response but is dependent on the type of lung disease.

Nature and site of action of endogenous nitric oxide in vasculature of isolated pig lungs.

The site of action of endogenous and exogenous nitric oxide (NO) in isolated pig lungs was investigated by using arterial, double, and venous occlusions, which allowed precapillary, postcapillary, and venous segments to be partitioned into arterial, precapillary, postcapillary, and venous segments. NG-nitro-L-arginine (L-NNA; 10(-5) M) increased resistance in the arterial (35 +/- 6.6%. P = 0.003), precapillary (39.3 +/- 5.1%, P = 0.001), and venous (18.3 +/- 4.8%, P = 0.01) segments, respectively. Sodium nitroprusside (10(-5) M) NO (80 parts/million) reversed the effects of L-NNA. Total pulmonary vascular resistance fell with increasing flow, due to a fall in precapillary resistance and dynamic resistance, and was significantly lower than mean total resistance. L-NNA increased the resistances but did not alter the pattern of the pressure-flow relationships. It is concluded that, in isolated pig lungs, the effect of endogenous NO seems to be dependent on flow in the arterial segment and independent of flow in the precapillary segment, but variation of its release does not appear to be fundamental to accommodation to changes in steady flow.

Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome.

The hypoxaemia of hepatopulmonary syndrome, seen in severe chronic liver dysfunction, occurs as a result of precapillary pulmonary arterial dilatation and arteriovenous communications. These abnormalities contribute to the mismatch between ventilation and perfusion, and the right to left blood flow shunting. Nitric oxide (NO) is a powerful vasodilator concerned with the regulation of pulmonary vascular tone in man. Using a chemiluminescence analyser, we have measured endogenously produced NO in the exhaled air of three patients with the hepatopulmonary syndrome, six normoxaemic cirrhotic patients and six healthy volunteers. The subjects breathed NO-free air throughout the measurements. The molar rate of production of exhaled NO was raised almost threefold in the patients with hepatopulmonary syndrome compared with normal volunteers and with normoxaemic cirrhotic patients. Hypoxia per se, achieved in the normal volunteers by breathing a hypoxic gas mixture, reduced rather than increased the exhaled NO. One hepatopulmonary syndrome patient received an orthotopic liver transplant and achieved normoxaemia after 3 months. The exhaled NO also returned to normal. Increased pulmonary production of NO could contribute to the development of the hepatopulmonary syndrome.