Relevance of multidrug-resistant Pseudomonas aeruginosa infections in cystic fibrosis.

Multidrug-resistant (MDR) Pseudomonas aeruginosa is an important issue for physicians who take care of patients with cystic fibrosis (CF). Here, we review the latest research on how P. aeruginosa infection causes lung function to decline and how several factors contribute to the emergence of antibiotic resistance in P. aeruginosa strains and influence the course of the infection course. However, many aspects of the practical management of patients with CF infected with MDR P. aeruginosa are still to be established. Less is known about the exact role of susceptibility testing in clinical strategies for dealing with resistant infections, and there is an urgent need to find a tool to assist in choosing the best therapeutic strategy for MDR P. aeruginosa infection. One current perception is that the selection of antibiotic therapy according to antibiogram results is an important component of the decision-making process, but other patient factors, such as previous infection history and antibiotic courses, also need to be evaluated. On the basis of the known issues and the best current data on respiratory infections caused by MDR P. aeruginosa, this review provides practical suggestions to optimize the diagnostic and therapeutic management of patients with CF who are infected with these pathogens.

Length of gestation and gender are associated with HLA genotypes at risk for Type 1 diabetes (Italian DIABFIN 3).

AIM: The aim of this study, which is part of the ongoing DIABFIN project, was to correlate HLA class II genotypes, classified for their effect on susceptibility to Type 1 diabetes (T1D), with various risk factors during pregnancy and the neonatal period. METHODS: Cord blood was collected from 4349 neonates; 1.0% were at high HLA risk (HR), 9.0% at moderate HLA risk (MR), and 90.0% at low HLA risk (LR) for T1D. Information about the mother's pregnancy, type of delivery, the neonates' clinical features at birth, and family history for autoimmune diseases were collected. RESULTS: Significant correlations were found between the different HLA risk categories and length of gestation, even when adjusted for sex, weight and length at birth of the neonate, birth order and mother's age (adjusted P = 0.007). The male : female ratio tended to increase from the LR to the HR category, from 1.00 and 1.21, respectively, in the LR and MR groups, to 1.62 in the HR group (P = 0.05). CONCLUSIONS: Length of gestation is inversely correlated with HLA risk categories for T1D. The higher the HLA risk for T1D, the shorter the gestational age, especially in male neonates.

Liver disease as risk factor for cystic fibrosis-related diabetes development.

AIM: To evaluate clinical and genetic factors, besides pancreatic insufficiency, associated with increased risk of cystic fibrosis-related diabetes. METHODS: Case-control (1:1) study on 138 cystic fibrosis patients. Data were collected on gender, age at diagnosis, reason for cystic fibrosis diagnosis, family history of type 1 or 2 diabetes mellitus, pre-existing severe liver disease, and class of cystic fibrosis transmembrane regulation mutation. Moreover, information was obtained on lung involvement and degree of exocrine pancreatic insufficiency evaluated 1 year before the diagnosis of cystic fibrosis-related diabetes in patients and age-matched controls. RESULTS: Compared to controls, patients with cystic fibrosis-related diabetes had a higher probability of having already been diagnosed with liver disease (16.7% versus 1.7%, OR = 11.6, 95% CI 1.43-93.0). Moreover, in the year before diabetes onset, cases had slightly worse pulmonary function compared to controls (FEV1 = 58.4 +/- 27% predicted versus 67.4 +/- 21% predicted; p = 0.05). No significant effects related to the other factors considered were found. CONCLUSION: Severe liver disease was found to significantly increase the risk of developing cystic fibrosis-related diabetes. Patients with liver disease should be scheduled for earlier diabetes screening in order to identify and possibly treat glucose intolerance.

Impact of inhaled corticosteroids on the risk of early Pseudomonas aeruginosa acquisition in cystic fibrosis.

AIM: To investigate the role of inhaled corticosteroids (IC) on the risk of Pseudomonas aeruginosa acquisition before the age of 10 y in cystic fibrosis (CF) patients. METHODS: For each subject the cumulative dose kg(-1) of IC received for each year of age was calculated until the end of follow-up. The age at CF diagnosis, the nutritional status (NS) and the number of respiratory exacerbations (RE) were used as surrogate measures for the severity of CF. RESULTS: A total of 83 patients (40 M, 43 F) entered the study. Their median length of follow-up was 4.4 y, for a total of 386 person-years at risk. Twenty-three patients acquired P. aeruginosa at a median age of 4.6 y (range 0.4-9.9 y). The estimated survival without P. aeruginosa acquisition was 65% at 10 y of age. The effect of different risk factors (IC, NS, RE and age at CF diagnosis) on the probability of P. aeruginosa acquisition was evaluated: none of them was significantly associated with the risk of P. aeruginosa acquisition. In particular, patients receiving very high cumulative doses of IC (4th quartile) had a non-significantly increased risk of P. aeruginosa acquisition compared with those receiving low doses of IC (1st quartile) (hazard ratio = 1.73, 95% confidence limits 0.40-7.38). CONCLUSION: This retrospective study was not able to demonstrate any role of IC in increasing the risk of P. aeruginosa acquisition. This complication seems to occur at a constant pace that is independent of CF severity and age. Prospective multi-institutional randomized studies are needed to investigate the effects of high-dose IC in CF patients.

Phenotype/genotype correlation and cystic fibrosis related diabetes mellitus (Italian Multicenter Study).

BACKGROUND: A genotype/phenotype correlation between early onset cystic fibrosis related diabetes (CFRD) and the N1303K mutation of the CF gene was previously identified in a small series of 28 CFRD patients, out of 313 CF patients. PATIENTS AND METHODS: In order to confirm the observation, data of 141 CFRD patients out of 1,229 CF patients attending 14 Italian CF centers were collected. All patients were older than 10 years and had been genotyped. RESULTS: DeltaF508 was the most frequent mutation (147/282 alleles: 52%) and N1303K the second most frequent mutation (18/282 alleles: 6.3%) in CFRD patients, without significant difference as compared with CF patients without DM (52% vs 48.6% and 6.3% vs 5.1%, respectively). W1282X was the third most frequent mutation in CFRD patients, more frequent than in CF patients without DM (5.3% vs 2%; p<0.001). CONCLUSIONS: Unlike the previous study, we did not find a higher frequency of the N1303K mutation in CFRD patients; moreover, data from this large CF series showed a significant correlation between the W1282X mutation and CFRD.

Cortical/subcortical disease burden and cognitive impairment in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: We assessed whether the extent of macro- and microscopic disease in the cortical and subcortical brain tissue, as revealed by MR and magnetization transfer (MT) imaging, correlates with cognitive dysfunction in patients with multiple sclerosis (MS). METHODS: Dual-echo rapid acquisition with relaxation enhancement (RARE), fast fluid-attenuated inversion recovery (fast-FLAIR), T1-weighted, and MT MR images of the brain were obtained from 16 MS patients with cognitive impairment and from six without. Impaired and unimpaired patients were similar across demographic and other disease-related variables. Total and cortical/subcortical lesion loads were assessed using RARE, fast-FLAIR, and T1-weighted sequences. In each patient, cortical/subcortical disease was also assessed by means of MT ratio (MTR) histographic analysis. RESULTS: All the impaired patients had multiple hyperintense lesions in the cortical/subcortical regions on both RARE and fast-FLAIR images; two unimpaired patients had such lesions on the RARE images and four had them on the fast-FLAIR images. Total and cortical/subcortical RARE/fast-FLAIR hyperintense and T1 hypointense lesion loads were significantly greater in the group of cognitively impaired patients. Patients with cognitive deficits also had significantly lower MTR histographic values for all the variables. A multivariate regression model showed that average cortical/subcortical brain MTR was the only factor that was significantly associated with cognitive impairment. CONCLUSION: The extent and severity of MS disease in the cortical and subcortical regions significantly influence the cognitive functions of MS patients. MTR histographic findings suggest that subtle changes undetectable by conventional imaging are also important in determining MS cognitive decline.

Reproducibility of magnetization transfer ratio histogram-derived measures of the brain in healthy volunteers.

Using two MR scanners, we evaluated the intraobserver, interobserver, image-reimage, and interimager variabilities in the assessment of magnetization transfer ratio (MTR) histograms obtained monthly on four occasions from five healthy volunteers. With multiple observers, the mean coefficients of variations ranged from 2.2% to 8.2% for "pure" image-reimage variability, from 1.2% to 4.9% for interobserver variability, and from 2.1% to 4.9% for image-reimage variability. The mean intraobserver coefficients of variations were always lower than 1%. The mean coefficients of variations ranged from 10.2% to 14.6% for pure interimager variability and from 8.6% to 14.3% for interimager variability with multiple observers. Interimager variability accounted for 96.0% of the overall variability of average MTR, for 96.7% of peak location, and for 41.1% of the peak height. The use of different MR scanners is the main source of variability when obtaining MTR histograms.

Correlations between clinical and MRI involvement in multiple sclerosis: assessment using T(1), T(2) and MT histograms.

The degree of disability and cerebellar and brainstem impairments in multiple sclerosis (MS) patients were correlated with several magnetic resonance imaging (MRI) measures of tissue damage in the whole brain, cerebellum and brainstem to determine the relative contributions of the factors underlying the development of disability in MS. Dual-echo conventional spin-echo, T(1)-weighted and magnetization transfer (MT) scans were obtained from 72 patients with MS and 20 age- and sex-matched controls. The following MRI-derived quantities were considered for the brain as a whole, for the cerebellum and for the brainstem: (a) the number and volume of lesions seen on T(2)-weighted images; (b) the number and volume of lesions seen on T(1)-weighted images; (c) the size of these structures measured on T(1)-weighted scans; (d) the average MT ratio (MTR), peak height and peak position for the MT histogram. With univariate analysis, many MRI measures were significantly different in patients with different levels of disability or cerebellar and brainstem functional system impairments. However, with multivariate analysis, only whole-brain average MTR was significantly related to physical disability, while cerebellar and brainstem T(1) lesion volume and average MTR were related to cerebellar and brainstem impairment. This study shows that increased pathological damage in clinically eloquent sites is the major cause of disability in patients with MS. It also suggests that measures derived from MT histogram analysis and T(1) hypointense lesion load should be considered when evaluating long-term MS evolution.

Spatial mapping of T2 and gadolinium-enhancing T1 lesion volumes in multiple sclerosis: evidence for distinct mechanisms of lesion genesis?

It is generally believed that most T2-weighted (T2) lesions in the central white matter of patients with multiple sclerosis begin with a variable period of T1-weighted (T1) gadolinium (Gd) enhancement and that T1 Gd-enhancing and T2 lesions represent stages of a single pathological process. Lesion probability maps can be used to test this hypothesis by providing a quantitative description of the spatial distribution of these two types of lesions across a patient population. The simplest prediction of this hypothesis would be that the spatial distributions of T1 Gd-enhancing and T2 lesions are identical. We generated T1 Gd-enhancing and T2 lesion probability maps from 19 patients with relapsing-remitting multiple sclerosis. There was a significantly higher probability (P = 0.001) for T2 lesions to be found in the central relative to the peripheral white matter (risk ratio 4.5), although the relative distribution of T1 Gd-enhancing lesions was not significantly different (P = 0.7) between central and peripheral white matter regions (risk ratio 0.6). Longitudinal data on the same population were used to demonstrate a similar distribution asymmetry between new T1 Gd-enhancing and new T2 lesions that developed over the course of 1 year. Alternative hypotheses to explain this observation were tested. We found no spatial difference in the likelihood of development of persistent T2 lesions following T1 Gd enhancement. The relative distribution of T1 Gd-enhancing lesions was shown to be independent of the dose of Gd contrast agent and the frequency of scanning. Our findings suggest that a proportion of the periventricular T2 lesion volume may arise from mechanisms other than those associated with early breakdown of the blood-brain barrier leading to T1 Gd enhancement.

Quantitative MRI in CADASIL: correlation with disability and cognitive performance.

OBJECTIVE: To study correlations between total lesion load on brain MRI and clinical features, and to evaluate the influence of demographic variables on quantitative MRI variables in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). BACKGROUND: CADASIL is a hereditary form of small-vessel disease caused by mutations within the Notch3 gene. MRI abnormalities have been found both in asymptomatic and symptomatic CADASIL individuals. METHODS: Quantitative measurements on cerebral MRI were performed in 64 CADASIL individuals. MRI lesions were quantified using a semi-automated segmentation technique based on local thresholds. RESULTS: MRI total lesion volume correlated significantly with disability (Rankin Scale) on both T1- and proton density (PD)-weighted images. There was a significant inverse correlation between total lesion volume and overall cognitive performance as determined by the Mini-Mental State Examination. Age but not sex was correlated with lesion load both on T1- and PD-weighted images. There was no detectable influence of the Notch3 genotype on quantitative MRI variables. CONCLUSIONS: This study demonstrates correlations between MRI lesion volume and clinical characteristics in CADASIL. Longitudinal studies are now warranted to investigate whether quantitative MRI could be used as an adjunct outcome measure in future therapeutic trials in CADASIL.

Magnetization transfer imaging of patients with definite MS and negative conventional MRI.

OBJECTIVE: To assess, in a group of patients with clinically or laboratory-supported definite MS and negative conventional MRI scans of the brain, whether magnetization transfer imaging (MTI) is able to detect subtle white matter changes. BACKGROUND: MTI of the brain in patients with MS frequently demonstrates the presence of microscopic damage to white matter, which appears normal on conventional MRI. METHODS: Brain MRI and MTI scans were obtained from 11 patients with negative conventional MRIs of the brain, selected from 618 clinically or laboratory-supported definite MS cases scanned in the last 2 years in three Italian MS centers. RESULTS: Compared with control subjects, patients had significantly lower mean MT ratios (MTR) in the pons, cerebellum, and periventricular regions. The percentages of pixels with MTR values below 1, 2, and 3 SD of the mean MTR value of the control subjects were 7.6% (range, 3.2% to 11.8%), 5.2% (range, 2.0% to 8.5%), and 3.6% (range, 1.2% to 6.1%), respectively. They were mainly located in the white matter of the centra semiovalia, and usually were isolated. CONCLUSIONS: MTI can detect white matter abnormalities in patients with MS and negative conventional brain MRI scans. The detection of such abnormalities may increase diagnostic confidence in those cases where MS is clinically suspected, but conventional MRI does not suggest the diagnosis.

Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI.

OBJECTIVE: To identify differences in pathology between the principal clinical phenotypes of MS using conventional and magnetization transfer (MT) MRI. METHODS: T1-weighted and T2-weighted images as well as MT scans were obtained from 20 controls, 21 patients presenting with clinically isolated syndromes suggestive of MS, and 93 MS patients with relapsing-remitting, secondary progressive, benign, or primary progressive course. Metrics considered: hypointense T1 and T2 lesion volumes, average lesion MT ratio, average brain MT ratio, peak height and position from MT histograms. RESULTS: MS patients had lower MT metrics than controls. Patients with clinically isolated syndromes had MT measures similar to controls, whereas primary progressive MS patients had lower histogram peak height with normal peak position. Relapsing-remitting MS patients had lower MT measures, higher T2 lesion load and ratio of hypointense T1 to T2 lesion volumes than patients with clinically isolated syndromes, and lower MT ratio and peak height than benign MS patients. Benign MS patients were similar to controls and patients with clinically isolated syndromes. Secondary progressive MS patients had the lowest MT measures and highest lesion loads. CONCLUSIONS: Pathology in patients with clinically isolated syndromes is confined to modest tissue damage in the lesions seen on T2-weighted scans. Severe damage is important for the later development of disability. However, microscopic damage in normal-appearing white matter may be a major contributor to disability in primary progressive MS.

Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis.

OBJECTIVE: This study correlated the extent of abnormalities detected by different magnetic resonance imaging (MRI) techniques [proton density (PD)-weighted, T1-weighted, and magnetization transfer imaging (MTI)] with the overall cognitive, frontal lobe, and memory impairments in patients with MS. PATIENTS: There were 30 clinically definite MS patients, with different disease courses. EXCLUSION CRITERIA: psychoactive/steroid treatments, mood disorders, acute relapse phase. MAIN OUTCOME MEASURES: Neuropsychological test results. Total (TLL) and frontal (FLL) lesion loads assessed from PD-weighted, T1-weighted (22 patients), and MTI (22 patients) MRI scans. Average lesion MT ratios (MTR) and analysis of the MTR histograms from brain tissue axial slabs on MTI scans. RESULTS: Patients with frontal lobe deficits (n=15) or memory impairment (n-17) had a higher TLL on PD scans (p=0.04 and p=0.01, respectively). Patients with frontal lobe deficits had higher FLL on PD scans (p=0.01) and TLL on MTI (p=0.03) scans. No significant relationships between the extent of T1-weighted lesion loads and the presence of any neuropsychological impairment. Mean MTR of both MS lesions and whole brain tissue was lower in patients with frontal lobe impairment (p=0.04). MRI lesion loads correlated significantly with some neuropsychological test scores. CONCLUSIONS: Lesion loads on PD-weighted MRI and MTI-derived measures are associated with cognitive decline in MS patients. Overall macroscopic and microscopic brain damage is more important than the corresponding regional brain disease in determining deficits of selective cognitive domains.

Magnetization transfer ratios in multiple sclerosis lesions enhancing after different doses of gadolinium.

We performed serial monthly magnetization transfer (MT) imaging to evaluate whether MS lesions that enhance only after the injection of a triple dose (TD) of gadolinium-DTPA (Gd) have different pathologic characteristics and evolution than those that enhance after the injection of a standard dose (SD). Every 4 weeks for 3 months and in two separate sessions, we obtained T1-weighted scans from 10 patients with relapsing-remitting MS, 5 minutes after SD (0.1 mmol/kg) or TD (0.3 mmol/kg) Gd injection. During each of the first monthly sessions, we obtained MT images and dual-echo scans before Gd injection. We measured the MT ratio (MTR) of newly enhancing lesions on co-registered quantitative MTR images. During the 3-month follow-up, 81 newly enhancing lesions were seen on SD scans. An additional 46 lesions enhanced only on TD scans. The mean (+/- standard deviation) MTR values were 31.4% +/- 8.4% for lesions enhancing after SD and 38.2% +/- 6.0% for lesions enhancing only after TD injection (p < 0.0001). The mean MTR values of lesions seen with both SD (p < 0.00001) and TD (p = 0.002) increased significantly during the follow-up. At each time point during the follow-up, the MTR values of TD lesions were significantly higher than the SD lesions. These results indicate that the enhancing lesion population in MS is heterogeneous and that the tissue damage occurring within lesions enhancing only after TD injection is less severe than in lesions enhancing after the injection of an SD.

Effects of vitamin E and selenium on antioxidant defense in rat heart.

Heart mitochondria, isolated from rats fed diets deficient or supplemented with vitamin E (E) and/or selenium (Se), were subjected to time-course assays of lipid peroxidation stimulated by ascorbate/ADP/Fe3+. Mitochondria depleted of alpha-tocopherol (alpha-TH) peroxided rapidly as assessed by formation of thiobarbituric acid reactive substances (TBARS). Formation of TBARS was strongly inhibited in mitochondria from rats fed diets supplemented with E. Selenium deficiency, reduced glutathione (GSH), glutathione disulfide (GSSG) or GSH + GSSG did not affect the course of lipid peroxidation in mitochondria from rats supplemented or deficient in E. Combined E and Se deficiency resulted in significantly lower total (oxidized+reduced) mitochondrial coenzyme Q-9 (CoQ-9) concentration compared with control rats supplemented with dietary E and Se. Time-course changes in mitochondrial alpha-TH and total CoQ-9 during oxidizing conditions were minor in +E rats. Total CoQ-9 was reduced substantially, however, during the course of lipid peroxidation in mitochondria depleted of alpha-TH. Selenium-dependent glutathione peroxidase (Se-GSHPx) activity was reduced by approximately 96% in heart cytosol, and to a somewhat lesser extent in mitochondria, by dietary Se deficiency. Non-Se GSHPx activity was not detected in heart cytosol but was detected in very small amounts in heart mitochondria. Glutathione S-transferase activity of heart cytosol was decreased in E and/or Se deficiency. The results of these experiments indicate that membrane alpha-TH was most effective in inhibiting lipid peroxidation in heart mitochondria.

[The use of ofloxacin in cystic fibrosis patients]. / Uso dell'ofloxacin nei pazienti con fibrosi cistica.

The new quinolones represent the latest possibility of specific oral antibiotic treatment of infections caused by gram-negative bacteria. Among the new quinolones, ciprofloxacin and ofloxacin are characterized by strong in vitro activity against most Pseudomonas species strains, favourable kinetic in body fluids, good tolerability and the possibility of oral administration. For these reasons they appear to be ideal antibiotics for long-term home therapy of chronic obstructive pulmonary disease in cystic fibrosis (CF). The efficacy of ciprofloxacin has been recently assessed. In this study, actual effectiveness of ofloxacin in long-term home antibiotic treatment of patients affected by CF was evaluated. The study was a no-blind cross-over study, designed to compare ofloxacin treatment with conventional oral antibiotic therapy. Young adult patients, who needed long-term antibiotic therapy and whom sputum culture were positive for sensitive strains, were randomly assigned to 2 groups. One group received ofloxacin, the other group was given a non-quinolone oral antibiotic, selected according to sputum culture sensitivity. Oral antibiotics were administered for 20 days, then a break of 10 days was allowed during which patients received nebulized aminoglucosides, usually tobramycin. After 3 months, therapies were rotated: the first group received a non-quinolone oral antibiotic and the second group received ofloxacin for another 3 months. The clinical score (according to Huang et al., see table I) and the lung function (FVC, FEV1, pulsed SaO2) were assessed in all the patients at the beginning and at the end of each three months period of oral antibiotic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)