An integrated model of provision of palliative care to patients with cystic fibrosis.

Palliative care of patients with cystic fibrosis (CF) is often undertaken by CF teams rather than palliative care teams because of the specialist nature of the disease and the potential role of lung transplantation. We developed an integrated model of provision of palliative care whereby most care is delivered by the CF team using palliative guidelines and pathways, with additional support available from the specialist palliative care team when needed. We report our experience of the terminal care of 40 patients with CF with regard to the circumstances of death, lung transplantation status, specific symptoms and provision of palliative treatments. The transition from disease modifying treatments to palliative care was particularly complex. Patients had a high level of symptoms requiring palliation and most died in hospital. Palliative care is a crucial component of a CF service and requires the specialist skills of both the CF and palliative care teams.

Aquagenic palmar wrinkling as a presenting feature of cystic fibrosis gene dysfunction.

Aquagenic palmar wrinkling (APW) is characterized by the rapid and transient oedematous wrinkling of the palms after brief immersion in water. APW has been associated with cystic fibrosis (CF). Since the discovery of the CF gene, the clinical spectrum of CF has broadened from classic severe CF to include milder 'atypical CF' and 'CF-related disorders'. We report an unusual case in which APW occurred in a patient with no lung disease, and in whom investigations showed evidence of CF gene dysfunction. APW may be a presenting feature of a CF-related disorder and should prompt investigation of CF gene dysfunction.

Nontuberculous mycobacteria in gastrostomy fed patients with cystic fibrosis.

Multi-drug resistant Mycobacterium abscessus complex (MABSC) is a form of Nontuberculous mycobacteria (NTM) of special, international concern in Cystic Fibrosis (CF). We hypothesised that gastric juice and percutaneous endoscopic gastrostomy (PEG) feeding devices might yield MABSC isolates. Gastric juice and sputa from sixteen adult PEG fed CF patients and five replaced PEG tubes were studied. Bacterial and fungal isolates were cultured. Mycobacterium were identified by rpoB, sodA and hsp65 gene sequencing and strain typed using variable number tandem repeat. Bacteria and/or fungi grew from all gastric juice, sputa and PEG samples. MABSC were detected in 7 patients. Five had MABSC in their sputum. Two had an identical MABSC strain in their sputum and gastric juice and one had the same strain isolated from their PEG tube and sputum. Two patients who were sputum sample negative had MABSC isolated in their gastric juice or PEG tube. MABSC were therefore identified for the first time from a gastric sample in a minority of patients. We conclude that gastric juice and PEG-tubes may be a potential source of MABSC isolates in CF patients, and these findings warrant further study.

Microbiological profiles of sputum and gastric juice aspirates in Cystic Fibrosis patients.

Gastro-Oesophageal Reflux (GOR) is a key problem in Cystic Fibrosis (CF), but the relationship between lung and gastric microbiomes is not well understood. We hypothesised that CF gastric and lung microbiomes are related. Gastric and sputum cultures were obtained from fifteen CF patients receiving percutaneous endoscopic gastrostomy feeding. Non-CF gastric juice data was obtained through endoscopy from 14 patients without lung disease. Bacterial and fungal isolates were identified by culture. Molecular bacterial profiling used next generation sequencing (NGS) of the 16S rRNA gene. Cultures grew bacteria and/or fungi in all CF gastric juice and sputa and in 9/14 non-CF gastric juices. Pseudomonas aeruginosa(Pa) was present in CF sputum in 11 patients, 4 had identical Pa strains in the stomach. NGS data from non-CF gastric juice samples were significantly more diverse compared to CF samples. NGS showed CF gastric juice had markedly lower abundance of normal gut bacteria; Bacteroides and Faecalibacterium, but increased Pseudomonas compared with non-CF. Multivariate partial least squares discriminant analysis demonstrated similar bacterial profiles of CF sputum and gastric juice samples, which were distinct from non-CF gastric juice. We provide novel evidence suggesting the existence of an aerodigestive microbiome in CF, which may have clinical relevance.

Alpha-adrenoreceptor influences on liquid movements by in vitro lungs from fetal guinea pigs.

Lungs from near-term fetal guinea pigs (60 +/- 2 days of gestation) were supported in vitro for 3 h; lung liquid production was monitored by a dye-dilution method. Studies of 30 fetuses showed that untreated preparations produced fluid at 1.34 +/- 0.21 ml.h-1.kg body wt-1, but epinephrine at concentrations known at delivery (10(-8) and 10(-7) M) produced significant reductions or fluid reabsorption (analysis of variance, regression analysis); at high levels (10(-6) and 10(-5) M, epinephrine had no effect. Maximal responses from 10(-7) M epinephrine involved alpha-adrenoreceptors, since they were abolished by 10(-6) M phentolamine (alpha-antagonist) but were unaffected by 10(-6) M propranolol (beta-antagonist; n = 36). Activation was through alpha2-adrenoreceptors, since responses were abolished by 10(-4) M yohimbine (alpha-antagonist; n = 24) but were resistant to 10(-5) M prazosin (alpha 1-antagonist; n = 24). At high levels of epinephrine (10(-5) M), where responses did not normally occur, reductions in lung liquid production were large if prazosin was also present (n = 24), and increases were significant if yohimbine was included (n = 24). In guinea pigs, epinephrine appears to activate lung fluid reabsorption through alpha 2-adrenoreceptors; at high concentrations only, it can also increase production through alpha 1-adrenoreceptors. Therefore, species differences appear to exist.

Are clinical parameters and biomarkers predictive of severity of acute pulmonary emboli on CTPA?

BACKGROUND: Previous studies have shown that findings of computed tomography pulmonary angiography (CTPA) relate to outcome in pulmonary embolus (PE). These include clot burden as quantified using an obstruction index and markers of pressure overload such as right ventricle to left ventricle size ratio (RV/LV ratio). Little data exists correlating these findings with clinical presentation and biomarkers. AIM: To explore the link between clinical presentation and biomarkers with CTPA findings. METHODS: Retrospective case note analysis of consecutive cases presenting to a large teaching hospital. An independent radiologist reviewed CTPAs and clot burden quantified using an obstruction index. RESULTS: One hundred and seventy cases were identified and notes retrieved in 137 cases. (i) CLINICAL PRESENTATION: correlation was seen between clot burden and systolic blood pressure (BP) (r = -0.299, P = 0.0006) and heart rate (r = 0.240, P = 0.0056). Median obstruction index was significantly higher in those with a presenting BP <90 mmHg [41.25% (95% CI 30-50) vs. 15% (95% CI 12.5-25), (P = 0.0004)]. Clot burden was significantly higher in patients with temperature of >37.5 degrees C [30% (95% CI 25.0-42.5) vs. 15% (95% CI 12.5-28.3), P = 0.02)] and (ii)Biomarkers: significant correlation between clot burden and D-dimer was seen (r = 0.36, P = 0.0001). Location of thrombus was associated with significant differences in D-dimer level. A subgroup of patients had cardiac biomarkers measured (n = 24). There was a statistically significant correlation between troponin I and clot burden (r = 0.412, P = 0.048) and RV/LV ratio (r = 0.699, P = 0.0013). DISCUSSION: These findings suggest that clinical parameters and biomarkers have a role in predicting the radiological severity of PE. These data support the need for further studies of risk stratification in patients presenting with acute PE.

Patient segregation and aggressive antibiotic eradication therapy can control methicillin-resistant Staphylococcus aureus at large cystic fibrosis centres.

BACKGROUND: The prevalence of MRSA in patients with CF has risen in recent years. We adhere to a policy of segregation and barrier nursing to manage patients with MRSA, and we actively pursue eradication of MRSA. We have evaluated our experiences of MRSA infection in our large adult CF centre. METHOD: A retrospective review of all MRSA-positive patients from 1998 to 2008 was undertaken. Isolates were subjected to molecular identification to elucidate possible patient-to-patient transmission events. Eradication attempts were scrutinised. RESULTS: We have maintained a low incidence and prevalence (below 3%) of MRSA within this large cohort. A total of 15 pulsotypes of MRSA were identified among the 24 isolates examined, epidemiological data suggested no patient-patient transmission. Based on 6 month follow-up data, successful eradication was achieved in 81% patients. This includes those who had harboured infection for some time. Twenty-one (80.8%) required only one course of treatment, 3 (11.6%) patients required two different regimes and 2 (7.5%) required three courses to fully eradicate the organism. CONCLUSION: Strict infection control procedures can control MRSA infection and keep the prevalence low in CF clinics. Eradication is achievable in the majority of patients even when significant time has lapsed from initial isolation. In some instances, up to 3 courses of antibiotics were required to achieve eradication.

The mechanism of action of the immunosuppressive drug FK-506.

The novel immunosuppressive drug FK-506 inhibits the induction of lymphocyte proliferation in vitro by mitogenic combinations of phorbol esters and calcium ionophores. Early events inducible by phorbol esters alone are unaffected, while changes induced by calcium ionophores alone are completely suppressed by as little as 0.1 nM FK-506. The event in lymphocyte activation inhibited by FK-506 is completed early in the response. Its completion requires the provision of a Ca2+ signal and concurrent activation of protein kinase C and is accelerated as a function of the strength of protein kinase C activation.

Effects of epinephrine on lung liquid production by in vitro lungs from fetal guinea pigs.

Lungs from near-term fetal guinea pigs (62 +/- 2 days of gestation) were supported in vitro for 3 h; lung liquid production was monitored by a dye dilution method. Studies based on 42 preparations investigated effects of epinephrine at different concentrations. Untreated preparations produced lung liquid with no significant change (ANOVA; regression analysis; rates in successive hours 1.37 +/- 0.30; 1.36 +/- 0.30, and 1.28 +/- 0.27 mL.kg-1 body weight.h-1); those given epinephrine at 10(-9), 10(-8), 5 x 10(-8), and 10(-7) M showed significant reductions in production or fluid reabsorption, and there was a linear relationship (r = 0.99) between log concentration and the percent reductions. Above these levels, responses decreased, and at 10(-5) M epinephrine there was no response. There was no evidence for activation of beta-adrenoreceptors; responses to 10(-8) M epinephrine were resistant to propranolol (based on 24 studies), and the specific beta-agonist isoproterenol was without effect (based on 18 studies). However, the alpha-antagonist phentolamine completely eliminated responses to epinephrine at physiological levels (10(-8) M epinephrine; based on 24 studies) and also at levels that gave maximal responses (10(-7) M epinephrine; based on 24 studies). It is concluded that epinephrine is able to promote lung fluid reabsorption at concentrations reported at birth, but that, in contrast with beta-activation in sheep, responses in the guinea pig are mediated through alpha-adrenoreceptors. Clearly, species differences exist.

Effects of norepinephrine on lung liquid production by in vitro lungs from fetal guinea pigs.

Lungs from near-term fetal guinea pigs (61 +/- 2 days of gestation) were supported in vitro for 3 h; lung liquid production was monitored by a dye dilution method. Untreated control preparations produced fluid at 1.38 +/- 0.30 mL x kg(-1) body weight x h(-1), with no significant change (ANOVA; regression analysis); those given 1.24 x 10(-9) or 1.24 x 10(-8) M norepinephrine during the middle hour showed no significant change, but those given concentrations between 5.24 x 10(-8) and 1.24 x 10(-5) M all showed significant reductions or fluid reabsorption (based on 42 fetuses). The responses showed a linear relationship with the log concentration (r = 0.97). They appeared to involve alpha-adrenoreceptors, since responses to 10(-7) M norepinephrine were unaffected by 10(-6) M propranolol, but those to 10(-7) and 1.24 x 10(-6) M norepinephrine were abolished by 10(-6) and 1.78 x 10(-5) M phentolamine, respectively (based on 48 fetuses). Activation was through alpha2-adrenoreceptors, since responses to 10(-7) and 10(-5) M norepinephrine were abolished by 10(-4) M yohimbine, but not by 10(-5) M prazosin (based on 60 fetuses). The results show that norepinephrine is able to reduce lung liquid production when at plasma levels present at birth, and that it can produce reabsorption; unlike epinephrine, there was no reduction in responses at high concentrations. This work reintroduces a neglected factor, norepinephrine, into possible controls of lung liquid reabsorption, and opens up the potential for neural controls.

Inhibition of T and B lymphocyte proliferation by rapamycin.

The immunosuppressive macrolide rapamycin shows marked structural similarity to FK-506, and like FK-506 inhibits the activation of cultured T and B lymphocytes at concentrations as low as 10(-10) M. However, rapamycin blocks T-lymphocyte proliferation at a much later stage than FK-506. It also inhibits human, porcine and murine T- and B-lymphocyte activation by all pathways tested, including pathways which are insensitive to FK-506, such as interleukin-2 (IL-2)-mediated proliferation of IL-2-dependent T-cell lines, activation of human peripheral blood T lymphocytes by phorbol ester and anti-CD28 and activation of murine B lymphocytes by bacterial lipopolysaccharide. Thus these two macrolides that bind competitively to the same major intracellular receptor protein inhibit T- and B-lymphocyte activation by quite distinct mechanisms.

Development of an ED teaching program aimed at reducing prehospital delays for patients with chest pain.

OBJECTIVE: Delays in providing thrombolytic agents to patients with chest pain occur mainly in the prehospital arena. To reduce prehospital delay in treating patients with chest pain, we created a discharge teaching video that emphasized calling 911 in the event of a possible heart attack and a written action plan to be posted near the telephone. We also gave patients their EKG readings to bring with them on their next visit to the emergency department. SETTING AND SAMPLE: All patients with chest pain admitted to the Chest Pain Observation Unit at Baystate Medical Center, Springfield, Mass, were eligible for this teaching effort. We tracked 127 nonconsecutive patients from January 1997 to May 1997. Of these patients, 108 were included in the study. RESULTS: We interviewed 102 patients (94%) 3 days after they were discharged from the Chest Pain Observation Unit. Within this group, 92% were able to describe what a heart attack might feel like, and 81.4% said they would call 911 or go to the hospital if they had symptoms of a heart attack. If they thought that their symptoms might be indigestion, 69% said they would take an antacid, then go to the hospital if they did not feel better. Fifty-one percent remembered what to do with their EKG readings, and 60.7% knew how to take their nitroglycerin correctly. CONCLUSION: We concluded that patients understood the message they were given and retained some of the material 3 days after discharge from the Chest Pain Observation Unit. The follow-up telephone calls revealed areas for improvement in the discharge teaching tools.

Inhibition of T-lymphocyte activation by the immunosuppressive drug FK-506.

Nanamolar concentrations of the immunosuppressive drug FK-506 inhibit the induction of T-lymphocyte proliferation by the lectins concanavalin A (Con A) and phytohaemagglutinin (PHA). Activation by Con A is more sensitive to inhibition than the response to PHA. FK-506 inhibits an early Ca2+-dependent step in the activation process, and its effects are not reversible by the addition of recombinant interleukin-2 (IL-2) or lymphokine-rich culture supernatant. While the effects of suboptimal concentrations of FK-506 and cyclosporin A (CsA) are additive, FK-506 does not enhance the effects of optimal concentrations of CsA. Both drugs also have similar effects on the expression of specific mRNA in Con A-activated lymphocytes. A brief preincubation of unstimulated cells with FK-506 irreversibly inhibits their subsequent responsiveness to Con A. The mechanism of action of FK-506 thus resembles that of CsA, except that it is effective at two to three orders of magnitude lower concentrations and its effects are much less readily reversible.

PKCdelta-dependent cleavage and nuclear translocation of annexin A1 by phorbol 12-myristate 13-acetate.

Annexin A1 (ANX-1), a calcium-dependent, phospholipid binding protein, is known to be involved in diverse cellular processes, including regulation of cell growth and differentiation, apoptosis, and inflammation. The mitogen phorbol 12-myristate 13-acetate (PMA) induces expression and phosphorylation of ANX-1. However, the roles of ANX-1 in PMA-induced signal transduction is unknown. Here, we study the cellular localization of ANX-1 in the PMA-induced signal transduction process. We have found that PMA induces the cleavage of ANX-1 in human embryonic kidney (HEK) 293 cells, and that the cleaved form of ANX-1 translocates to the nucleus. The PMA-induced nuclear translocation of ANX-1 was inhibited by the protein kinase C (PKC)delta-specific inhibitor rottlerin, indicating that PKCdelta plays a role in nuclear translocation of the cleaved ANX-1. We propose a novel mechanism of PMA-induced translocation of ANX-1 to the nucleus that may participate in the regulation of cell proliferation and differentiation.