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Background: The effect of biphasic positive airway pressure (BPAP) at individualized pressures on the postoperative pulmonary recovery of morbidly obese patients (MOP) undergoing open bariatric surgery (OBS) and possible placebo device-related effects (sham BPAP) were investigated. Methods: Forty-eight MOP scheduled for OBS were initially enrolled. Subjects were randomly assigned to: A) the BPAP group in which BPAP, at individualized inspiratory positive airway pressure/expiratory positive airway pressure (IPAP/EPAP), was applied for 3 days postoperatively and B) the sham BPAP group in which sham BPAP was applied for the same time. Pulmonary function was assessed by spirometry 24 h prior to surgery and at 24, 48 and 72 h postoperatively and respiratory complications were recorded. Results: Thirty-five subjects, 21 in the BPAP group and 14 in the sham BPAP group, completed the study. Baseline characteristics and pulmonary function were similar between groups preoperatively. Subjects in the BPAP group showed in general better spirometric performance and SpO2 values postoperatively and expedited pulmonary recovery. Atelectasis combined with respiratory distress syndrome (RDS) symptoms was observed in 21% of subjects in the sham BPAP group and one of these subjects developed lower respiratory tract infection. No respiratory complications were recorded in the BPAP group. Use of higher BPAP pressures was not associated with anastomosis leakage or disruption in any patient. Conclusion: Use of BPAP, at individualized pressures, expedites postoperative pulmonary recovery and eliminates respiratory complications in MOP who have undergone OBS. © 2019 Via Medica. All rights reserved.

BACKGROUND: The 2009 pandemic influenza A (H1N1) virus was accompanied by high morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with documented 2009 influenza A (H1N1) virus admitted to a reference chest hospital, the disease outcome, and risk factors associated with ICU admission. METHODS: We assessed 109 subjects admitted to the respiratory infection unit of a hospital for chest disease with signs and symptoms of the 2009 influenza A (H1N1) virus between April 2009 and December 2010. Demographic data, comorbidities, clinical signs and symptoms, laboratory tests, radiographic findings, treatment, and final outcomes were all recorded. Factors associated with severe disease requiring ICU admission were determined. RESULTS: Ninety subjects (82.5%) had laboratory-confirmed 2009 influenza A (H1N1). Sixty-four percent of these subjects had pneumonia on admission, 26% had respiratory failure, and 11% required care in the ICU. Dyspnea and the presence of infiltrates on chest x-rays were the most common signs among the subjects with H1N1. All subjects were treated with antiviral therapy, and 75% received antibiotic treatment based on their clinical and laboratory findings. The predictive factors of ICU admission were severe hypoxemia and lymphocytosis. CONCLUSIONS: The outcome of subjects with influenza A (H1N1) virus infection was influenced by the severity of the disease on admission, the subjects’ underlying conditions, and complications during hospitalization. © 2014 Daedalus Enterprises.

Background: A variety of studies have demonstrated improvement in quality of life and depressive symptoms in obstructive sleep apnea (OSA) patients after continuous positive airway pressure (CPAP) treatment. However, very little is known about the effect of OSA treatment on physical activity and energy consumption. Objectives: The aim of this study was to evaluate the changes in depression, physical activity, energy expenditure, and quality of life (QoL) in OSA patients before and after CPAP therapy. Methods: Forty-one patients with OSA as revealed by polysomnography, were included to the study. They responded to the generic World Health Organization Quality of Life (WHOQoL) questionnaire, to the specific-disease Quebec Sleep Questionnaire, and to Center for Epidemiologic Studies Depression Scale (CES-D) in order to evaluate QoL and the incidence of depression. In addition, all patients wore an accelerometer which measured physical activity and energy expenditure during a week. At least 6 months after initiation of CPAP treatment (mean time, 9 months) we re-examined 24 patients who met the compliance with the treatment criteria. Results: Patients after CPAP therapy had significantly higher scores in all domains of the Quebec Sleep Questionnaire and in the domains of physical health/level of independence and psychological health/spirituality of the WHOQoL. Depression scores were also better in CES-D after treatment. However, despite the improvement in QoL and psychological status, CPAP therapy had no impact on physical activity and energy expenditure. Conclusions: CPAP therapy improves QoL and lessens depressive symptoms in our group of well-treated OSA patients. However, physical activity and energy expenditure did not present statistically significant improvement in the same group of OSA patients. © 2013 Springer-Verlag Berlin Heidelberg.

Introduction: Increased levels of inflammatory mediators, such as hs-CRP, have been detected in patients with obstructive sleep apnea (OSA) and used as cardiovascular risk and disease outcome predictors. Calprotectin is an inflammatory marker regulating atherogenic processes not investigated in adult OSA patients. The aim of the present study as primary objective was to examine the role of calprotectin as an inflammatory molecule, acting through a distinct pathway to the atherogenic process in adult OSA patients and its associations with hs-CRP and the lipidemic profile of the patients. As a secondary objective was the evaluation of the atherogenic markers post-CPAP treatment. Materials and methods: Seventy-four participants underwent full overnight polysomnography. Blood samples were collected for calprotectin, hs-CRP, total cholesterol, triglycerides, LDL, HDL and glucose levels. Thirty-two OSA patients were reexamined 6. months post-CPAP treatment. Results: Out of 74 participants included in the study, 33 had moderate OSA, 27 had severe OSA and 14 were controls. Calprotectin and hs-CRP were significantly increased in patients with moderate and severe OSA compared to controls (p

Background: Recent studies suggest poor sleep quality in patients with idiopathic pulmonary fibrosis (IPF). However, so far, the impact of IPF-related sleep breathing disorders (SBDs) on survival has not been extensively studied. Methods: In a cohort of 31 (24 males) treatment-naïve, newly diagnosed consecutive IPF patients, we prospectively investigated the relationship of SBD parameters such as apnea-hypopnea index (AHI), maximal difference in oxygen saturation between wakefulness and sleep (maxdiff SpO2), and lowest sleep oxygen saturation (lowest SpO2) with clinical (survival, dyspnea, daytime sleepiness), pulmonary function, submaximal (6-min walk test [6MWT]) and maximal exercise variables (cardiopulmonary exercise test [CPET]), and right ventricular systolic pressure (RVSP). Results: Sleep oxygen desaturation exceeded significantly that of maximal exercise (p < 0.001). Maxdiff SpO2 was inversely related to survival, DLCO%, and SpO 2 after 6MWT, and directly with dyspnea, AHI, and RVSP. The lowest SpO2 was directly related to survival and to functional (TLC%, DLCO%) as well as submaximal and maximal exercise variables (6MWT distance, SpO 2 after 6MWT, peak oxygen consumption/kg, SpO2 at peak exercise), while an inverse association with dyspnea score, AHI, and RVSP was observed. Conclusions: Our findings provide evidence that intermittent sleep oxygen desaturation significantly exceeds that of maximal exercise and is associated with survival in IPF patients. Furthermore, they imply the existence of a link between lung damage and apnea events resulting to the induction and severity of intermittent sleep oxygen desaturation that aggravate pulmonary arterial hypertension and influence IPF survival.

Background. In IPF, defects in lung mechanics and gas exchange manifest with exercise limitation due to dyspnea, the most prominent and disabling symptom. Aim. To evaluate the role of exercise testing through the 6MWT (6-minute walk test) and CPET (cardiopulmonary exercise testing) in the survival of patients with IPF. Methods. This is a prospective, observational study evaluating in 25 patients the relationship between exercise variables through both the 6MWT and CPET and survival. Results. By the end of the observational period 17 patients were alive (33% mortality). Observation ranged from 9 to 64 months. VE/VCO2 slope (slope of relation between minute ventilation and CO2 production), VO2 peak/kg (peak oxygen consumption/kg), VE/VCO2 ratio at anaerobic threshold, 6MWT distance, desaturation, and DLCO% were significant predictors of survival while VE/VCO2 slope and VO2 peak/kg had the strongest correlation with outcome. The optimal model for mortality risk estimation was VO2 peak/kg + DLCO% combined. Furthermore, VE/VCO2 slope and VO2 peak/kg were correlated with distance and desaturation during the 6MWT. Conclusion. The integration of oxygen consumption and diffusing capacity proved to be a reliable predictor of survival because both variables reflect major underlying physiologic determinants of exercise limitation. © 2013 Christina Triantafillidou et al.

Background: Airway and vascular remodeling may play a prominent role in the clinical severity of severe refractory asthma (SRA). Angiopoietin-1 (Ang-1) is an essential mediator of angiogenesis by establishing vascular integrity, whereas angiopoietin-2 (Ang-2) acts as its natural inhibitor. Objective: We aimed to determine the levels of angiopoietins in sputum supernatants of patients with SRA and to investigate the possible associations with mediators and cells involved in both the inflammatory and the vascular remodeling processes. Methods: Thirty-eight patients with SRA, 35 patients with moderate asthma, and 20 healthy subjects were studied. All participants underwent lung function tests, bronchial hyperresponsiveness assessment and sputum induction for cell count identification and Ang-1, Ang-2, VEGF, TGF-β1, Cys-LTs, MMP-2, IL-13, ECP, and IL-8 measurement in supernatants. Airway vascular permeability (AVP) index was also assessed. Results: Ang-1 (ng/ml) and Ang-2 (pg/ml) levels were significantly elevated in patients with SRA compared with patients with moderate asthma and control subjects [median, interquartile ranges: 30 (17-39) vs 7.5 (5-11) vs 4.7 (3.8-5.9) respectively, P < 0.001; and 506 (400-700) vs 190 (146-236) vs 96 (89-120) respectively, P < 0.001]. Regression analysis showed a significant positive association between Ang-2 and AVP index, MMP-2, Ang-1, and VEGF in SRA. A weak association was also observed between Ang-1 and sputum eosinophils% in SRA. Conclusion: Our results indicate that both angiopoietins levels are higher in SRA compared with moderate asthma and healthy subjects. In SRA, Ang-2 is associated with mediators involved in both the inflammatory and the vascular remodeling processes. © 2012 John Wiley & Sons A/S.

Exercise-induced dynamic hyperinflation and large intrathoracic pressure swings may compromise the normal increase in cardiac output (Q) in Chronic Obstructive Pulmonary Disease (COPD). Therefore, it is anticipated that the greater the disease severity, the greater would be the impairment in cardiac output during exercise. Eighty COPD patients (20 at each GOLD Stage) and 10 healthy age-matched individuals undertook a constant-load test on a cycle-ergometer (75% WRpeak) and a 6min walking test (6MWT). Cardiac output was measured by bioimpedance (PhysioFlow, Enduro) to determine the mean response time at the onset of exercise (MRTon) and during recovery (MRToff). Whilst cardiac output mean response time was not different between the two exercise protocols, MRT responses during cycling were slower in GOLD Stages III and IV compared to Stages I and II (MRTon: Stage I: 45±2, Stage II: 65±3, Stage III: 90±3, Stage IV: 106±3s; MRToff: Stage I: 42±2, Stage II: 68±3, Stage III: 87±3, Stage IV: 104±3s, respectively). In conclusion, the more advanced the disease severity the more impaired is the hemodynamic response to constant-load exercise and the 6MWT, possibly reflecting greater cardiovascular impairment and/or greater physical deconditioning. © 2012 Elsevier B.V.

During recent years there has been a growing interest in using non-invasive biomarkers to understand and monitor the airway inflammation in subjects with respiratory tract disorders and mainly asthma and chronic obstructive pulmonary disease (COPD). Sputum induction is generally a well-tolerated and safe procedure and a European Respiratory Society Task Force has published a comprehensive review on sputum methodology. Induced sputum cell count and, to a lesser extent, mediator measurements have been particularly well validated. In asthma, the sputum and the cell culture supernatant can be used for the measurement of a variety of soluble mediators, including eosinophil-derived proteins, nitric oxide (NO) derivatives, cytokines and remodelling-associated proteins. Sputum eosinophilia (> 3%) is a classic feature of asthma although half of the patients seems to be non eosinophilic. Measuring the percentage of sputum eosinophils has proved to be useful in the clinical arena in helping to predict short term response to inhaled corticosteroids (ICS) and tailor the dose of ICS in the severe patients but there is scope for the application of other induced sputum markers potentially useful in clinical practice. The widespread application of induced sputum in asthma across the spectrum of disease severity has given insight into the relationship between airway function and airway inflammation, proposed new disease phenotypes and defined which of these phenotypes respond to current therapy, and perhaps most importantly provided an additional tool to guide the clinical management of asthmatic patients. To date sputum induction is the only non-invasive measure of airway inflammation that has a clearly proven role in asthma management. © 2011 Bentham Science Publishers Ltd.

Recent advances in technology and novel pharmaceutical research findings have added new grounds in the fields of medical treatment and quality of life of patients diagnosed with pulmonary arterial hypertension (PAH). Collective assessment of new data is mandatory and useful for specialist medical doctors. This review aims to present the latest therapeutic developments of the last two years (2009-2010) in PAH. Moreover, recent patents (of the year 2010) regarding therapeutic novelties in PAH that expand treatment modalities, are hereby presented. © 2011 Bentham Science Publishers Ltd.

Introduction: Heart failure (HF) is a major public health problem associated with high rates of morbidity and mortality. Patients with HF exhibit a high prevalence of sleep-disordered breathing (SDB). We have investigated the long-term impact of positive airway pressure (PAP) therapy on heart function and clinical outcomes in patients with advanced HF and concomitant SDB. Materials and methods: We assessed 18 patients with advanced HF (New York Heart Association (NYHA) functional classification III-IV) and concomitant SDB (diagnosed with polysomnography) either of obstructive or central type. Eleven patients who received PAP therapy (auto-titrating PAP or adaptive servo-ventilation) for 12 months were compared with seven patients who refused this therapy. All participants were assessed at both baseline and end of follow-up for NYHA functional status, left and right ventricular function, neurohormonal activation, and exercise tolerance. The rates of hospitalization, deaths, and the combination of both were also recorded. Results: Patients treated with PAP achieved better functional status, higher left ventricular ejection fraction, improved longitudinal right ventricular contractile function, lower levels of b-type natriuretic peptide, and greater exercise performance compared to those who remained untreated. PAP-treated group had a significantly lower incidence of the prespecified combined end-point (i.e., hospital admissions and death) than the control group (87.5 vs. 18.2%, p= 0.013). Interestingly, the mortality rate was 28% (two out of seven patients) in the control group, while no deaths were recorded in the PAP-treated group. Discussion: In this preliminary study, we found that treatment of SDB, irrespective of type, in stable patients with advanced HF receiving optimal medical therapy was associated with improvement in cardiac functional status, ventricular contraction, physical performance, and neurohormonal status, leading to better clinical outcomes. © Springer-Verlag 2010.

Background: Laparoscopic Roux-en-Y gastric bypass (RYGBP) for morbid obesity is a challenging operation. The application of robotic techniques has been shown to ease the technical difficulties and reduce perioperative morbidity, mainly because it facilitates the construction of the gastrojejunal anastomosis (GJ). Robotic laparoscopic RYGBP (LRYGBP) has been reported either as totally robotic with manual suturing of the GJ or as robotically assisted with the use of the robot only for the construction of the GJ. A totally robotic LRYGBP with a combined stapled and manual GJ has never been reported. Patients and Methods: Nine consecutive patients underwent totally robotic LRYGBP. The GJ was fashioned with a combination of the linear stapler and manual suturing. Results: Mean preoperative body mass index was 45.3 ± 4.7 kg/m 2. In 1 case, we had to undock the Da Vinci Surgical System at the time of the jejunojejunostomy due to unfavorable ergonomics. Mean time to dock the robot was 16.3 ± 3.3 minutes, whereas mean total operative time was 197.2 ± 12.3 minutes. Immediate postoperative morbidity and mortality equaled zero. One patient developed a stenosis of the GJ amenable to endoscopic dilatation. The mean excess weight loss rate 1-year postoperative was 79% ± 15%. Conclusion: Totally robotic LRYGBP can duplicate precisely any conventional technique without any compromise in operative time, short- or long-term results. © 2010, Mary Ann Liebert, Inc.

OBJECTIVE: Although obstructive sleep apnoea syndrome (OSAS) is accompanied by an increased atherosclerotic cardiovascular disease burden, its relationship with arterial stiffness is not yet well determined. We investigated whether essential hypertensive individuals with OSAS are characterized by increased arterial stiffness. METHODS: Our study population consisted of 46 consecutive patients with newly diagnosed untreated stage I-II essential hypertension suffering from OSAS (35 men, aged 49 ± 8 years) and 53 hypertensive individuals without OSAS, matched for age, sex, and smoking status. All subjects underwent polysomnography, echocardiography and aortic stiffness evaluation by means of carotid-femoral pulse wave velocity (c-fPWV) measurements. RESULTS: Hypertensive subjects with OSAS [apnoea/hypopnoea index (AHI) < 5] compared with hypertensive subjects without OSAS (AHI < 5) demonstrated increased levels of body mass index (31.4 ± 4 versus 29.3 ± 4 kg/m, P = 0.015), office systolic/diastolic blood pressure (151/99 versus 145/94 mmHg, respectively, P < 0.05, for both cases) and relative wall thickness (RWT; 0.46 ± 0.06 versus 0.42 ± 0.07, P = 0.010). Hypertensive subjects with OSAS compared with those without OSAS had significantly increased c-fPWV by 9% (8.56 ± 0.49 versus 7.85 ± 0.93 m/s, P = 0.001) and this difference remained significant even after adjustment for confounders (P = 0.04). In the total study population, c-fPWV was correlated with age (r = 0.35, P = 0.015), office systolic blood pressure (r = 0.30, P = 0.007), RWT (r = 0.30, P = 0.03), logAHI (r = 0.389, P = 0.0001) and minimum oxygen saturation (r = -0.418, P = 0.0001). CONCLUSIONS: OSAS has a significant incremental effect on aortic stiffening in the setting of middle-aged essential hypertensive subjects. This finding suggests that the presence of OSAS in a hypertensive patient accelerates vascular damage, increasing cardiovascular risk. © 2007 Lippincott Williams & Wilkins, Inc.

Cognitive deficits in patients with obstructive sleep apnea syndrome (OSAS) are well demonstrated, but the pathophysiology of these deficits is still controversial, as the relationship between OSA severity and cognitive deficits is usually weak. Our study considers the possible relationship between OSA-related cognitive deficits and the overall intellectual function of OSA patients. Forty-seven OSA patients and 36 normal individuals underwent a neuropsychological battery test assessing attention and alertness. According to the resulting IQ score, patients and controls were divided into a high-intelligence group (IQ greater than or equal to 90th percentile) and a normal-intelligence group (50 less than or equal to IQ < 90%ile). Between the two patient groups there were no significant differences noticed, regarding OSA severity or sleepiness. High-intelligence patients showed the same attention/alertness performance compared with the high-intelligence controls. On the contrary, patients with normal-intelligence showed attention/alertness decline compared with the normal-intelligence control group. The two patient groups were re-examined with the same battery test after at least 1 year of CPAP treatment. At re-examination neither patient group showed any differences regarding attention and alertness compared with the control groups. We assume that high-intelligence may have a protective effect against OSA-related cognitive decline, perhaps due to increased cognitive reserve.

Patients with obstructive sleep apnoea syndrome frequently have cognitive deficits, especially related to executive functions, which cannot be fully explained by daytime sleepiness and are partial irreversible after nasal continuous positive airway pressure treatment. The causal mechanism of these cognitive deficits is not yet known, but it has been proposed that they are associated with chemical and structural brain cell injury. The aim of this study was to investigate brain metabolism in patients with sleep apnoea syndrome. Twenty-two patients with severe sleep apnoea and 10 healthy volunteers of comparable age were studied using single voxel proton magnetic resonance spectroscopy. Magnetic resonance spectra were obtained from prefrontal cortex, parieto-occipital and frontal periventricular white matter. N-acetylaspartate-to-creatine and choline-to-creatine ratios were significantly lower in the frontal white matter of obstructive sleep apnoea patients when compared to controls. Absolute concentrations of N-acetylaspartate and choline were also significantly reduced in the frontal white matter of patients with sleep apnoea. Frontal lobe white matter lesions are known to be associated with cognitive executive dysfunction. The findings of this study may offer an explanation for the sometimes irreversible cognitive deficits associated with sleep apnoea.

There is limited information on the development of left ventricular (LV) dysfunction in patients with obstructive sleep apnoea (OSA) in the absence of lung and cardiac comorbidity. This study aimed to investigate whether OSA patients without heart morbidity develop LV dysfunction, and to assess the effect of continuous positive airway pressure (CPAP) on LV function. Twenty-nine OSA patients and 12 control subjects were studied using technetium-99m ventriculography to estimate LV ejection fraction (LVEF), LV peak emptying rate (LVPER), time to peak emptying rate (TPER), peak filling rate (LVPFR) and time to peak filling rate (TPFR) before and after 6 months of treatment with CPAP. A significantly lower LVEF was found in OSA patients, compared to control subjects, (53+/-7 versus 61+/-6%) along with a reduced LVPER (2.82+/-0.58 versus 3.82+/-0.77 end-diastolic volumes(.)s(-1)). Furthermore, OSA patients had significantly lower LVPFR (2.67+/-0.71 versus 3.93+/-0.58 end-diastolic volumes(.)s(-1)) and delayed TPFR (0.19+/-0.04 versus 0.15+/-0.03 s) in comparison with the control group. Six-months of CPAP treatment was effective in significantly improving LVEF, LVPER, LVPFR and TPFR. In conclusion, obstructive sleep apnoea patients without any cardiovascular disease seem to develop left ventricular systolic and diastolic dysfunction, which may be reversed, either partially or completely, after 6 months of continuous positive airway pressure treatment.

Background. Limited information exists regarding the development of pulmonary hypertension in patients with obstructive sleep apnea (OSA) in the absence of lung and heart comorbidity. Objectives: The aims of this study were to investigate whether OSA patients without any other cardiac or lung disease develop pulmonary hypertension, and to assess the effect of continuous positive airway pressure (CPAP) treatment on pulmonary artery pressure (P-PA). Methods: Twenty-nine patients aged 51 +/- 10 years with OSA and 12 control subjects were studied with pulsed-wave Doppler echocardiography for estimation Of P-PA before and after 6-month effective treatment with CPAP. Results: A significantly higher mean P-PA was found in OSA patients as compared to control subjects (17.2 +/- 5.2 vs. 12.1 +/- 1.9 mm Hg, p < 0.001). Six out of the 29 OSA patients had mild pulmonary hypertension (P-PA greater than or equal to 20 mm Hg). Significant differences were observed between pulmonary hypertensive and normotensive OSA patients with respect to age (62 +/- 4 vs. 48 +/- 15 years, respectively, p < 0.05), body mass index (41 +/- 7 vs. 32 +/- 4 kg/m(2), p < 0.02) and daytime PaO2 (81 +/- 9 vs. 92 +/- 9 mm Hg, p < 0.05). CPAP treatment was effective in reducing mean PPA in both groups of pulmonary hypertensive and normotensive OSA patients (decreases in P-PA from 25.6 +/- 4.0 to 19.5 +/- 1.5 mm Hg, p < 0.001; from 14.9 +/- 2.2 to 11.5 +/- 2.0 mm Hg, respectively, p < 0.001). Conclusions: A proportion (20.7%) of OSA patients without any other lung or heart disease and characterized by older age, greater obesity and lower daytime oxygenation develop mild pulmonary hypertension which has been partially or completely reversed after 6-month CPAP treatment. In conclusion, OSA alone constitutes an independent risk factor for the development of pulmonary hypertension. Copyright(C)2001 S. KargerAG, Basel.

Deletions in the 5q14 region have been described in a variety of neoplasms, such as testicular germ cell tumors, ovarian, gastric and lung cancer. The high frequency of allelic losses observed in this region implies the presence of putative tumor suppressor gene(s) (TSGs). In the present study, we investigated in a series of 56 non-small cell lung carcinomas (NSCLCs) the allelic imbalance (Alm) within the 5q14 region, employing the D5S644 marker, and its relationship with p53 abnormalities, the kinetic parameters [proliferation index (PI) and apoptotic index (AI)] and the ploidy status of the carcinomas. AI at D5S644 was found at a frequency of 51.2%. The rather high percentage of Alm in stage I tumors suggests an early involvement in NSCLC development. LOH at 5q14 was associated with decreased AR in lung tumors insinuating the presence of a putative TSG(s) (P = 0.008). Simultaneous alterations of both p53 and D5S644 locus were the most frequent pattern observed (37.5%). Cases demonstrating this profile also exhibited a marked decrease in AI (P = 0.001). These findings imply a synergistic mechanism of co-operation between different TSGs. However, proliferation activity was dependent only on p53 status, leading to the assumption that the putative TSG(s) present at 5q14 may probably be involved in normal apoptotic procedures. Further studies are needed to identify the candidate gene(s). (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.