Effect of non-invasive ventilation on the measurement of ventilatory and metabolic variables.

The effect of non-invasive ventilation (NIV) on the accuracy of measurements of ventilation, oxygen consumption (V˙O2) and carbon dioxide production (V˙CO2) was examined using a simulator. Known gas volumes of oxygen and carbon dioxide were delivered to a metabolic system that measured tidal volume, respiratory rate, V˙O2 and V˙CO2, both with and without NIV. Bland-Altman analyses were used to compare between conditions. NIV at pressure support (PS) 20cm H2O compared to without NIV showed: VT, mean difference (MD) 0mL (limits of agreement (LOA) -21 to 21) mL; V˙O2 MD -413 (LOA -810 to 16) mL/min; and V˙CO2 MD 32 (LOA -32 to 97) mL/min. For V˙O2 measurements during NIV, a correction was applied to account for increased air density due to PS. After correction, V˙O2 measurement accuracy improved; MD -46 (LOA -108 to 17) mL/min. Tidal volume and metabolic variables can be measured with acceptable accuracy during NIV, providing V˙O2 is corrected for altered gas density.

Blood oxygen equilibration time after cessation of supplemental oxygen in chronic respiratory disease.

BACKGROUND: Measurement of the arterial partial pressure of oxygen (PaO2 ) while breathing air is an informative investigation in patients with hypoxaemia due to chronic respiratory disease, but there are a lack of published data on the time needed for blood oxygen levels to equilibrate after cessation of supplemental oxygen (O2 ) in such patients. AIM: To determine the blood oxygen equilibration time after cessation of O2 and thereby provide guidance on best timing of baseline arterial blood gas analysis in this population. METHODS: Medically stable subjects with chronic respiratory disease were administered O2 at a constant concentration. Continuous pulse oximetry was recorded from before cessation of O2 to beyond the point of oxygen saturation (SpO2 ) equilibration. Data were fitted to an exponential decay model. Blood oxygen equilibration time was defined as the t90, the time taken for SpO2 to fall 90% of the difference between initial (on O2 ) and final (on air) values. RESULTS: Eighty-two (82) subjects with a mean age of 66 years were included. The largest diagnostic category was chronic obstructive pulmonary disease (37), followed by interstitial lung disease (15) and bronchiectasis (12). The median t90 was 6 min 18 s (interquartile range: 4 min 32 s-10 min 30 s). The 95th centile t90 value was 20 min. CONCLUSION: In the majority of patients with chronic respiratory disease, a time delay of 20 min between cessation of supplemental O2 and PaO2 measurement allows confidence that the result is a true baseline value.

Igf2 ligand dependency of Pten(+/-) developmental and tumour phenotypes in the mouse.

The tumour suppressor PTEN is a key negative regulator of the PI3K-Akt pathway, and is frequently either reduced or lost in human tumours. Murine genetic studies have confirmed that reduction of Pten promotes tumourigenesis in multiple organs, and demonstrated dependency of tumour development on the activation of downstream components such as Akt. Insulin-like growth factors (IGFs) act via IGF1R to activate the PI3K-Akt pathway, and are commonly upregulated in cancer. A context-dependent interplay between IGFs and PTEN exists in normal tissue and tumours; increased IGF2 ligand supply induces Pten expression creating an autoregulatory negative feedback loop, whereas complete loss of PTEN may either cooperate with IGF overexpression in tumour promotion, or result in desensitisation to IGF ligand. However, it remains unknown whether neoplasia associated with Pten loss is dependent on upstream IGF ligand supply in vivo. We evaluated this by generation of Pten(+/-) mice with differing allelic dosage of Igf2, an imprinted gene encoding the potent embryonic and tumour growth factor Igf2. We show that biallelic Igf2 supply potentiates a previously unreported Pten(+/-) placental phenotype and results in strain-dependent cardiac hyperplasia and neonatal lethality. Importantly, we also show that the effects of Pten loss in vivo are modified by Igf2 supply, as lack of Igf2 results in extended survival and delayed tumour development while biallelic supply is associated with reduced lifespan and accelerated neoplasia in females. Furthermore, we demonstrate that reduction of PTEN protein to heterozygote levels in human MCF7 cells is associated with increased proliferation in response to IGF2, and does not result in desensitisation to IGF2 signalling. These data indicate that the effects of Pten loss at heterozygote levels commonly observed in human tumours are modified by Igf2 ligand, and emphasise the importance of the evaluation of upstream pathways in tumours with Pten loss.

Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial.

BACKGROUND: Sleep hypoventilation has been proposed as a cause of progressive hypercapnic respiratory failure and death in patients with severe chronic obstructive pulmonary disease (COPD). A study was undertaken to determine the effects of nocturnal non-invasive bi-level pressure support ventilation (NIV) on survival, lung function and quality of life in patients with severe hypercapnic COPD. METHOD: A multicentre, open-label, randomised controlled trial of NIV plus long-term oxygen therapy (LTOT) versus LTOT alone was performed in four Australian University Hospital sleep/respiratory medicine departments in patients with severe stable smoking-related COPD (forced expiratory volume in 1 s (FEV1.0) <1.5 litres or <50% predicted and ratio of FEV1.0 to forced vital capacity (FVC) <60% with awake arterial carbon dioxide tension (PaCO2) >46 mm Hg and on LTOT for at least 3 months) and age <80 years. Patients with sleep apnoea (apnoea-hypopnoea index >20/h) or morbid obesity (body mass index >40) were excluded. Outcome measures were survival, spirometry, arterial blood gases, polysomnography, general and disease-specific quality of life and mood. RESULTS: 144 patients were randomised (72 to NIV + LTOT and 72 to LTOT alone). NIV improved sleep quality and sleep-related hypercapnia acutely, and patients complied well with therapy (mean (SD) nightly use 4.5 (3.2) h). Compared with LTOT alone, NIV (mean follow-up 2.21 years, range 0.01-5.59) showed an improvement in survival with the adjusted but not the unadjusted Cox model (adjusted hazard ratio (HR) 0.63, 95% CI 0.40 to 0.99, p = 0.045; unadjusted HR 0.82, 95% CI 0.53 to 1.25, p = NS). FEV1.0 and PaCO2 measured at 6 and 12 months were not different between groups. Patients assigned to NIV + LTOT had reduced general and mental health and vigour. CONCLUSIONS: Nocturnal NIV in stable oxygen-dependent patients with hypercapnic COPD may improve survival, but this appears to be at the cost of worsening quality of life. TRIAL REGISTRATION NUMBER: ACTRN12605000205639.

Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells.

We examined the involvement of sphingosine kinase-1 (SphK1), which governs the ceramide/sphingosine-1-phosphate balance, in susceptibility to imatinib of either sensitive or resistant chronic myeloid leukemia cells. Imatinib-sensitive LAMA84-s displayed marked SphK1 inhibition coupled with increased content of ceramide and decreased pro-survival sphingosine-1-phosphate. Conversely, no changes in the sphingolipid metabolism were observed in LAMA84-r treated with imatinib. Overcoming imatinib resistance in LAMA84-r with farnesyltransferase or MEK/ERK inhibitors as well as with cytosine arabinoside led to SphK1 inhibition. Overexpression of SphK1 in LAMA84-s cells impaired apoptosis and inhibited the effects of imatinib on caspase-3 activation, cytochrome c and Smac release from mitochondria through modulation of Bim, Bcl-xL and Mcl-1 expression. Pharmacological inhibition of SphK1 with F-12509a or its silencing by siRNA induced apoptosis of both imatinib-sensitive and -resistant cells, suggesting that SphK1 inhibition was critical for apoptosis signaling. We also show that imatinib-sensitive and -resistant primary cells from chronic myeloid leukemia patients can be successfully killed in vitro by the F-12509a inhibitor. These results uncover the involvement of SphK1 in regulating imatinib-induced apoptosis and establish that SphK1 is a downstream effector of the Bcr-Abl/Ras/ERK pathway inhibited by imatinib but upstream regulator of Bcl-2 family members.

Effect of water on overbased sulfonate engine oil additives.

The presence and effect of water on calcium carbonate nanoparticles used in engine additives, stabilized with a sulfonate surfactant, is investigated using small-angle neutron scattering, dynamic light scattering, Fourier transform infrared spectroscopy, and rheometry. These techniques provide complementary data that suggests the formation of a layer of water around the core of the particles ensuring continued colloidal stability yet increasing the dispersion viscosity. Through the use of small-angle neutron scattering, the dimensions of this layer have been quantified to effectively one or two water molecules in thickness. The lack of a significant electrostatic repulsion is evidence that the water layer is insufficient to cause major dissociation of surface ions.

Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation.

BACKGROUND: Untreated, obesity hypoventilation is associated with significant use of health care resources and high mortality. It remains unclear whether continuous positive airway pressure (CPAP) or bilevel ventilatory support (BVS) should be used as initial management. The aim of this study was to determine if one form of positive pressure is superior to the other in improving daytime respiratory failure. METHODS: A prospective randomised study was performed in patients with obesity hypoventilation referred with respiratory failure. After exclusion of patients with persisting severe nocturnal hypoxaemia (Spo(2) < 80% for > 10 min) or carbon dioxide retention (> 10 mm Hg) despite optimal CPAP, the remaining patients were randomly assigned to receive either CPAP or BVS over a 3-month period. The primary outcome was change in daytime carbon dioxide level. Secondary outcome measures included daytime sleepiness, quality of life, compliance with treatment and psychomotor vigilance testing. RESULTS: Thirty-six patients were randomised to either home CPAP (n = 18) or BVS (n = 18). The two groups did not differ significantly at baseline with regard to physiological or clinical characteristics. Following 3 months of treatment, daytime carbon dioxide levels decreased in both groups (CPAP 6 (8) mm Hg; BVS 7 (7) mm Hg) with no between-group differences. There was no difference in compliance between the two treatment groups (5.8 (2.4) h/night CPAP vs 6.1 (2.1) h/night BVS). Although both groups reported an improvement in daytime sleepiness, subjective sleep quality and psychomotor vigilance performance were better with BVS. CONCLUSIONS: Both CPAP and BVS appear to be equally effective in improving daytime hypercapnia in a subgroup of patients with obesity hypoventilation syndrome without severe nocturnal hypoxaemia. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Registry ACTRN01205000096651.

One drug or two? Step-down therapy after i.v. antibiotics for community-acquired pneumonia.

BACKGROUND: The aim of the study was to describe the oral antibiotics prescribed as step-down therapy for patients hospitalized for community-acquired pneumonia (CAP). METHODS: A comparative audit of patient records in a Sydney teaching hospital, a district referral hospital and a regional hospital was carried out. Patients older than 15 years admitted between 1 July 2004 and 31 December 2004 with a diagnosis of CAP were identified by diagnostic code. The medical records were reviewed for patient demographics, the specialty of the attending physician, comorbidities, adverse drug events, relevant microbiological results and the antibiotic therapy prescribed for the treatment of pneumonia. Cases were randomly selected from all pneumonia admissions, with approximately equal numbers from urban and regional hospitals. One hundred and ninety-six admissions for CAP (in 193 patients) were included in this review. Patients were predominantly cared for by respiratory physicians (62%) and geriatricians (14%). Eighty-nine per cent of patients received dual antibiotic therapy on admission. RESULTS: For patients commenced on two antibiotics, 62% were prescribed two oral antibiotics after completing i.v. therapy, 27% were prescribed one oral agent and 11% were prescribed no step-down therapy. Geographic location and the presence of a documented antibiotic allergy affected prescribing practice. Neither the specialty of the attending medical officer nor the identification of a likely pathogen affected prescribing practice. CONCLUSION: Although most of the patients with CAP were initially prescribed two antibiotics, there was considerable variability in whether one, two or no oral agents were prescribed as step-down therapy.

Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines.

Imatinib mesylate is a selective inhibitor of the oncogenic tyrosine kinase, Bcr-Abl, and is widely used as a first-line treatment for chronic myeloid leukaemia (CML). Prolonged monotherapy is frequently associated with patients becoming refractory to imatinib. Therefore, there is considerable interest in small molecule inhibitors which may be used either as replacements or as adjuncts to existing imatinib therapy. For this purpose, it is most likely that drugs which do not share imatinib's mechanism of action will be most valuable. We compared two such compounds with different modes of action, adaphostin and 17-allylamino-17-demethoxygeldanamycin (17-AAG), for their cytotoxic effect and ability to induce the downregulation of cellular proteins in a murine haemopoietic cell line transformed with human p210(Bcr-Abl), and two subclones resistant to imatinib owing to an Abl-kinase domain mutation (E255K) or amplification of the BCR-ABL gene, respectively. We found that, whereas 17-AAG selectively killed Bcr-Abl-positive cells and inhibited proteins dependent on heat-shock protein 90 for their stability (p210(Bcr-Abl) and Akt), adaphostin induced the downregulation of multiple cell-signalling proteins (p210(Bcr-Abl), Akt, Bcr, Abl and STAT5a) and was cytotoxic to both Bcr-Abl-positive and -negative cells. We suggest that both compounds may prove useful in the treatment of CML but caution that undesirable side-effects may result from the inhibition of multiple cell signalling proteins.

Pharmacological strategies for self-management of asthma exacerbations.

Written action plans are effective within asthma self-management, but there are few guidelines about the specific medication adjustments which can be recommended for self-treatment of exacerbations. This review examines pharmacological strategies for self-management of asthma exacerbations in adults, including those for inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) users. Oral corticosteroids are well-established in clinical practice and clinical trials for the treatment of severe exacerbations, including during combination therapy. Evidence supports 7-10 days treatment, with no need to taper except to reduce side-effects. Doubling the dose of ICS is not effective. Several studies have shown benefit from high-dose ICS (2,400-4,000 microg beclomethasone equivalent) for 1-2 weeks. This may be achieved by adding a high-dose ICS inhaler to maintenance ICS or ICS/LABA therapy. There is inconclusive evidence about acutely increasing the dose of maintenance budesonide/formoterol for exacerbations, and no studies of this approach with fluticasone/salmeterol. For patients taking maintenance budesonide/formoterol, use of the same medication as-needed reduces exacerbations. Short-acting beta2-agonists are still effective in producing bronchodilation during combination therapy; however, a higher dose may be required. There is a need for further studies to clarify remaining issues about self-management of asthma exacerbations, particularly with regard to side-effects of treatment and patient acceptability.

Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells.

Although imatinib mesylate has revolutionized the treatment of chronic myeloid leukaemia (CML), resistance to the drug, manifesting as relapse after an initial response or persistence of disease, remains a therapeutic challenge. In order to overcome this, alternative or additional targeting of signaling pathways downstream of Bcr-Abl may provide the best option for improving clinical response. Bisphosphonates, such as zoledronate, have been shown to inhibit the oncogenicity of Ras, an important downstream effector of Bcr-Abl. In this study, we show that zoledronate is equally effective in inhibiting the proliferation and clonogenicity of both imatinib-sensitive and -resistant CML cells, regardless of their mechanism of resistance. This is achieved by the induction of S-phase cell cycle arrest and apoptosis, through the inhibition of prenylation of Ras and Ras-related proteins by zoledronate. The combination of imatinib and zoledronate also augmented the activity of either drug alone and this occurred in imatinib-resistant CML cells as well. Since zoledronate is already available for clinical use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of CML.

Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate.

Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been cast into shadow by the evolution of clinical resistance during therapy. Resistance to imatinib can arise by multiple mechanisms including amplification or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor option for either of these patient groups. Recently, however, a structurally distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described, and these compounds are predicted to make different molecular contacts in the Abl kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase activities, both of which are thought to be relevant to survival of the leukemic cell. We asked whether these drugs could selectively induce cell death in murine cell line models of CML cells sensitive and resistant to imatinib by different mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant cells, they are almost completely ineffective against cells expressing the T315I mutant. This implies that despite structural differences from imatinib, these drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl protein, but may be effective in cases where selection of cells overexpressing the oncoprotein leads to refractoriness to imatinib.

Comparison of large- and small-bore intercostal catheters in the management of spontaneous pneumothorax.

BACKGROUND: Spontaneous pneumothoraces (SP) are a common cause of presentation to emergency departments and subsequent hospitalization. In recent years there has been an increasing trend towards the use of small-bore pleural catheters (PC) rather than conventional large-bore intercostal catheters (ICC) in their initial management. AIMS: To compare the effectiveness and complication rate of ICC and PC in the treatment of SP. METHODS: A retrospective chart audit was conducted of 67 cases of SP admitted to the Royal Prince Alfred Hospital, Sydney, Australia, between 1 July 1997 and 30 June 2000. Demographic data were recorded, including: (i) patient age, (ii) smoking status, (iii) pneumothorax size, (iv) pneumothorax type and (v) aetiology. Outcome data relating to length of hospital stay (LOS) and treatment failure rates and complications of treatment devices were also recorded. RESULTS: Successful pneumothorax resolution was achieved (P = 0.72) in 20 of the 31 (65%) patients initially treated with a ICC, and in 26 of the 36 (72%) patients treated with a PC. The mean LOS in the ICC and PC group was 7 days and 5 days, respectively (P = 0.11). The complication rates in the PC and ICC group were 25% and 10%, respectively (P = 0.13), and the recurrence rates for each group were 17% and 6% (P = 0.20), respectively. However, the combined rate of complications and pneumothorax recurrence within 2 months was 42% in those initially treated with PC, compared with 16% in those treated with ICC (P = 0.04). CONCLUSIONS: PC were as effective as ICC in treating SP in terms of initial pneumothorax resolution and LOS. There were trends towards higher complication and recurrence rates in those treated with PC, but individually these results did not reach statistical significance. However, the combined rate of complications and pneumo-thorax recurrence was significantly higher in those patients treated with the PC than in those treated with ICC.

The efficacy of an antibiotic protocol for community-acquired pneumonia.

OBJECTIVE: To assess the efficacy of an antibiotic protocol to avoid empirical use of third-generation cephalosporins in community-acquired pneumonia (CAP). DESIGN AND SETTING: Retrospective case review of patients with CAP one year after implementing the protocol. Comparison was made with patients with CAP treated at a metropolitan tertiary referral hospital (where use of third-generation cephalosporins was common). PARTICIPANTS: 86 patients (district hospital with an antibiotic protocol) and 72 patients (metropolitan tertiary referral hospital), January - June 1999. OUTCOME MEASURES: Rate of staff adherence to the protocol; patient characteristics associated with poor protocol adherence; demographic and prognostic features of both groups at presentation; duration of intravenous therapy, time to defervescence, length of stay; inpatient mortality rates; and drug cost savings per patient treated according to the protocol. RESULTS: Overall protocol adherence rate was 60%. Patients with penicillin allergy were significantly less likely to receive treatment according to the protocol (P<0.001). At the district hospital, patients were generally older and taking more regular medications. Patients at each hospital had similar prognostic factors and demographic features at presentation. Inhospital mortality (P=0.92; 95% CI, -0.08 to 0.07), duration of fever (P=0.57) and length of stay (P=0.78) were not significantly different between patients treated empirically with penicillin and those treated empirically with third-generation cephalosporins. Treating a patient according to the protocol saved an average of $77.44 in drug costs. CONCLUSION: One year after implementation, our protocol for treating CAP is proving efficacious, although levels of adherence could improve.

Malignant fibrous histiocytoma of the trachea.

Primary tracheal sarcomas are rare. Only 23 cases have previously been reported in the English literature. The present case describes a 72-year-old woman with a malignant fibrous histiocytoma of the trachea. She underwent an endoscopic resection followed by radiotherapy and is well at 12 months follow up. Other cases are reviewed. Tracheal resection is the standard care. However, local resection with postoperative radiotherapy remains an option. Adjuvant chemotherapy may improve local control. Long-term survival has been documented.