Multidrug–resistant organisms in cystic fibrosis: management and infection–control issues

Chronic infection and inflammation are the hallmarks of cystic fibrosis lung disease. As cystic fibrosis patients are living longer owing to more intense treatment, multidrug-resistant organisms are being isolated increasingly from patients’ respiratory tracts. While the adverse effects of Pseudomonas aeruginosa and Burkholderia cepacia complex are well described, less is known about the clinical significance of other emerging multidrug-resistant organisms, such as methicillin-resistant Staphylococcus aureus and Stenotrophomonas maltophilia. Owing to multiple mechanisms of antimicrobial resistance, these organisms are difficult to treat and often require combination antibiotic therapy. Until more is known about their pathogenicity and effect on clinical outcomes, physicians should be aware of the potential transmissibility of these organisms and implement adequate infection control strategies.     

ΔF508 CFTR protein expression in tissues from patients with cystic fibrosis

Heterologous expression of the cystic fibrosis transmembrane conductance regulator (CFTR) provided evidence that the major cystic fibrosis (CF) mutation DeltaF508 leads to defective protein folding in the endoplasmic reticulum, which prevents its processing and targeting to the cell surface. In this study, we investigated endogenous CFTR expression in skin biopsies and respiratory and intestinal tissue specimens from DeltaF508 homozygous and non-CF patients, using immunohistochemical and immunoblot analyses with a panel of CFTR antibodies. CFTR expression was detected at the luminal surface of reabsorptive sweat ducts and airway submucosal glands, at the apex of ciliated cells in pseudostratified respiratory epithelia and of isolated cells of the villi of duodenum and jejunum, and within intracellular compartments of intestinal goblet cells. In DeltaF508 homozygous patients, expression of the mutant protein proved to be tissue specific. Whereas DeltaF508 CFTR was undetectable in sweat glands, the expression in the respiratory and intestinal tracts could not be distinguished from the wild-type by signal intensity or localization. The tissue-specific variation of DeltaF508 CFTR expression from null to apparently normal amounts indicates that DeltaF508 CFTR maturation can be modulated and suggests that determinants other than CFTR mislocalization should play a role in DeltaF508 CF respiratory and intestinal disease.     

Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator–dependent bicarbonate secretion

The mechanisms underlying mucus-associated pathologies in cystic fibrosis (CF) remain obscure. However, recent studies indicate that CF transmembrane conductance regulator (CFTR) is required for bicarbonate (HCO₃^–) transport and that HCO₃^– is critical for normal mucus formation. We therefore investigated the role of HCO₃^– in mucus secretion using mouse small intestine segments ex vivo. Basal rates of mucus release in the presence or absence of HCO₃^– were similar. However, in the absence of HCO₃^–, mucus release stimulated by either PGE₂ or 5-hydroxytryptamine (5-HT) was approximately half that stimulated by these molecules in the presence of HCO₃^–. Inhibition of HCO₃^– and fluid transport markedly reduced stimulated mucus release. However, neither absence of HCO₃^– nor inhibition of HCO₃^– transport affected fluid secretion rates, indicating that the effect of HCO₃^– removal on mucus release was not due to decreased fluid secretion. In a mouse model of CF (mice homozygous for the most common human CFTR mutation), intestinal mucus release was minimal when stimulated with either PGE₂ or 5-HT in the presence or absence of HCO₃^–. These data suggest that normal mucus release requires concurrent HCO₃^– secretion and that the characteristically aggregated mucus observed in mucin-secreting organs in individuals with CF may be a consequence of defective HCO₃^– transport.     

Hyaluronic acid improves “pleasantness” and tolerability of nebulized hypertonic saline in a cohort of patients with cystic fibrosis

Introduction  

Inhaled hypertonic saline improves lung function and decreases pulmonary exacerbations in people with cystic fibrosis. However, side effects such as cough, narrowing of airways and saltiness cause intolerance of the therapy in 8% of patients. The aim of our study was to compare the effect of an inhaled solution of hyaluronic acid and hypertonic saline with hypertonic solution alone on safety and tolerability.     

Editorial on “Cardiac involvement in cystic fibrosis evaluated using cardiopulmonary magnetic resonance”. Cardiac involvement in cystic fibrosis: more than a lung-related disease?

The International Journal of Cardiovascular Imaging -     

Membranoproliferative glomerulonephritis in patients with cystic fibrosis: coincidence or comorbidity? A case series

Cystic fibrosis (CF) is perceived as a childhood illness. However, with advances in medical science, patients are enjoying lives extending well into adulthood. This article reviews two cases of membranoproliferative glomerulonephritis (MPGN) in adults with CF. One patient with severe CF pulmonary disease had concomitant renal failure during hospitalization for a pulmonary exacerbation. Subsequent evaluations, including complement levels, were consistent with MPGN. The second patient had been recently diagnosed with colon cancer and was found to be suffering from acute renal failure. Diagnostic evaluation likewise confirmed the MPGN diagnosis. Immunologic associations linking CF and MPGN, including derangements in the complement system and the effects of superantigen production, are reviewed.     

Whole body vibration: a new therapeutic approach to improve muscle function in cystic fibrosis?

Disease progression in cystic fibrosis (CF) leads to muscle wasting and loss of muscle function. The aim of this prospective pilot study was to evaluate the effects of whole body vibration (WBV) on muscle function in adult patients with CF. Ten patients (three males; seven females) of the CF Center Cologne, Germany, have completed the 3-month study (age: 24-47 years; forced expiratory volume in 1 s (FEV1) 17-109% predicted (49+/-29) and body mass index (BMI) 16.6-24.4 kg/m2 (19.3+/-2.5). WBV was provided by a vibration platform (Galileo 2000). The patients were standing in an upright position receiving vertical vibration of frequencies between 20 and 25 Hz. The vibration exercise evokes muscle contractions via stretch reflexes improving muscular activity. The training schedule consisted of three 3-min sessions twice a day, 5 days per week for 3 months. Every 4 weeks the following tests were carried out: FEV1, forced vital capacity (FVC), BMI, chair-rising test (CRT), one-leg and two-leg jump test as well as maximal isometric grip force. The study has been approved by the local ethics committee. After 3 months of WBV all parameters in the CRT significantly improved: chair-rising time (P=0.03), maximal force (P=0.02), maximal power (P=0.01) as well as velocity (P=0.02). The peak jump force (P=0.02) and velocity (P=0.01) of the two-leg jump significantly improved. Parameters in the one-leg jump as well as maximal isometric grip force showed no significant improvement. Weight and BMI showed a slightly positive trend whereas FEV1 and FVC did not significantly change. Any change in mechanographic parameters did not correlate with FEV1 or FVC in this study. These results demonstrate that WBV can improve muscle function in CF patients.     

Idiopathic retroperitoneal fibrosis with particular perirenal and intrarenal extension associated with left renal artery stenosis. The atheromatous periaortitis with retroperitoneal fibrosis suggests a pathogenic relationship between atherosclerosis and fibrosis?

We present a case of idiopathic retroperitoneal fibrosis (RPF) in a female patient of 45 years, obese (BMI = 39 kg/sqm), hypertensive since 2005, with diabetes mellitus treated with diet and diabetes insipidus in whom, during a routine control, the following has been found: serum creatinine 1.74 mg/dl, and an inflammatory syndrome associated with fever. Spiral-CT (Multi-slice-Sensation 64) scan shows retroperitoneal fibrosis in relation with periaortitis that affects the thoracic and abdominal aorta. RPF is extending perirenally and at the level of the renal hilum with subsequent calyceal dilations (hydrocalycosis) associated with left renal artery stenosis. The particularity of the case is represented by the perirenal and intrarenal evolution of fibrosis with left renal artery stenosis with moderate impairment of renal function reversible under treatment with Tamoxifen. This case, with chronic periaortitis subsequent to an extended aortic atherosclerosis with retroperitoneal fibrosis can be representative for the pathogenic relationship between atherosclerosis and fibrosis.     

What have we learned from mouse models for cystic fibrosis?

Genetically modified mouse strains are important research tools for the study of numerous human diseases. These models provide us with differentiated tissues, which are not often available from human sources. Furthermore, they allow for testing the effects of genetic manipulation and experimental therapeutics on physiology and pathology. Their importance relies on the assumption that biological processes in the mouse very closely resemble those in humans. Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian population. CF is a monogenic disease whose phenotype variability is also attributed to genetic variation in other genes, the so-called modifier genes. Modulation of such modifier genes could be a therapeutic strategy to treat CF. CF mice models have been essential not only for understanding the disease better, but also for the discovery of modifier genes and testing of chemical compounds developed to repair the main protein dysfunction in CF, the CF transmembrane conductance regulator. Mice were also indispensable in gene therapy trials and for the study of CF and non-CF lung response to bacterial infections and inflammation challenges, although no spontaneous lung disease is developed in these mice. In this review, mouse models and their most important contribution to the understanding and management of CF will be presented and discussed.     

A case of a GH–producing pituitary adenoma associated with a unilateral headache with autonomic signs

A 66–year–old man suffered from a drug–resistant, leftsided headache with autonomic signs, triggered by the supine position. The acromegalic facies initially suggested a possible increase in basal plasma levels of GH, but routine haematological controls excluded abnormal values of GH. Cerebral and facial CT scan and MRI did not detect any alterations in the nasal sinuses, except for a mucous cyst. Surgical ablation of the cyst did not alleviate the pain. Further endocrinological tests demonstrated an increase of IGF–1 (somatomedin C), and another MRI scan of the sellar region confirmed the presence of a pituitary macroadenoma on the left paramedian side. After an initial improvement of the symptomatology due to trans–sphenoidal ablation of a benign GH–producing macroadenoma, the headache worsened again. Pain was well correlated with the increased plasma levels of IGF–1. The patient died suddenly for myocardial infarct.     

Liver fibrosis: a balance of ACEs?

There is an increasing body of evidence to suggest that the RAS (renin-angiotensin system) contributes to tissue injury and fibrosis in chronic liver disease. A number of studies have shown that components of a local hepatic RAS are up-regulated in fibrotic livers of humans and in experimental animal models. Angiotensin II, the main physiological effector molecule of this system, mediates liver fibrosis by stimulating fibroblast proliferation (myofibroblast and hepatic stellate cells), infiltration of inflammatory cells, and the release of inflammatory cytokines and growth factors such as TGF (transforming growth factor)-beta1, IL (interleukin)-1beta, MCP (monocyte chemoattractant protein)-1 and connective tissue growth factor. Furthermore, blockade of the RAS by ACE (angiotensin-converting enzyme) inhibitors and angiotensin type 1 receptor antagonists significantly attenuate liver fibrosis in experimental models of chronic liver injury. In 2000 ACE2 (angiotensin-converting enzyme 2), a human homologue of ACE, was identified. ACE2 efficiently degrades angiotensin II to angiotensin-(1-7), a peptide which has recently been shown to have both vasodilatory and tissue protective effects. This suggests that ACE2 and its products may be part of an alternate enzymatic pathway in the RAS, which counterbalances the generation and actions of angiotensin II, the ACE2-angiotensin-(1-7)-Mas axis. This review focuses on the potential roles of the RAS, angiotensin II and ACE2 in chronic liver injury and fibrogenesis.     

The use of rpoB sequence analysis in the differentiation of Mycobacterium abscessus and Mycobacterium chelonae: a critical judgement in cystic fibrosis?

Individuals suffering from fibrocystic disease may acquire non-tuberculous mycobacteria as colonizing or infecting organisms. Mycobacterium abscessus is of particular concern because it may be very difficult to eradicate and may mitigate against lung transplantation. However, this species may be difficult to reliably differentiate from the closely related M. chelonae. We have developed a rapid, low-cost, short sequence-based technique to confirm species identity by analysis of a segment of the RNA Polymerase B (rpoB) gene.     

Macrolide-resistant Staphylococcus aureus colonization in cystic fibrosis patients: is there transmission to household contacts?

OBJECTIVES: Patients with cystic fibrosis (CF) are frequently colonized by macrolide-resistant Staphylococcus aureus, a result of maintenance macrolide therapy. As transmission of S. aureus between household contacts is common, we examined the prevalence of macrolide-resistant S. aureus colonization in CF patients on maintenance azithromycin therapy and their household contacts and compared this with the S. aureus macrolide resistance prevalence in the community. PATIENTS AND METHODS: Sixty-five CF patients on maintenance macrolide therapy and 194 household contacts were screened for S. aureus colonization by culturing sputa, cough swabs and nasal swabs. Resistance to macrolide, lincosamide and methicillin was determined by disc diffusion tests. The prevalence of macrolide-resistant S. aureus colonization in both groups was compared with figures from a nationwide study into S. aureus carriership and resistance. To assess possible transmission, genotyping of S. aureus was performed using the spa-typing method. RESULTS: Macrolide resistance among CF patients with S. aureus colonization was 69.6%; 75% of these isolates displayed lincosamide resistance too. Among household contacts, macrolide resistance prevalence did not differ significantly from resistance prevalence in the community (9.6% versus 6.3%; P = 0.358). No methicillin resistance was observed. No identical (macrolide-resistant and -susceptible) S. aureus genotypes were observed between CF patients and their household contacts except for one household, suggesting a probable transmission. CONCLUSIONS: No significant increase in macrolide-resistant S. aureus colonization was observed among household contacts of CF patients on long-term azithromycin therapy. Transmission of macrolide-resistant S. aureus could not be proved by genotyping in the majority of households.     

Design of a haptic device with grasp and push–pull force feedback for a master–slave surgical robot

Purpose

We propose a portable haptic device providing grasp (kinesthetic) and push–pull (cutaneous) sensations for optical-motion-capture master interfaces.

Methods

Although optical-motion-capture master interfaces for surgical robot systems can overcome the stiffness, friction, and coupling problems of mechanical master interfaces, it is difficult to add haptic feedback to an optical-motion-capture master interface without constraining the free motion of the operator’s hands. Therefore, we utilized a Bowden cable-driven mechanism to provide the grasp and push–pull sensation while retaining the free hand motion of the optical-motion capture master interface. To evaluate the haptic device, we construct a 2-DOF force sensing/force feedback system. We compare the sensed force and the reproduced force of the haptic device. Finally, a needle insertion test was done to evaluate the performance of the haptic interface in the master–slave system.

Results

The results demonstrate that both the grasp force feedback and the push–pull force feedback provided by the haptic interface closely matched with the sensed forces of the slave robot. We successfully apply our haptic interface in the optical-motion-capture master–slave system. The results of the needle insertion test showed that our haptic feedback can provide more safety than merely visual observation.

Conclusions

We develop a suitable haptic device to produce both kinesthetic grasp force feedback and cutaneous push–pull force feedback. Our future research will include further objective performance evaluations of the optical-motion-capture master–slave robot system with our haptic interface in surgical scenarios.