Nuclear translocation of IGF-1R via p150(Glued) and an importin-ß/RanBP2-dependent pathway in cancer cells.

Mounting evidence has shown that the insulin-like growth factor-1 receptor (IGF-1R) has critical roles in cancer cell growth. This has prompted pharmacological companies to develop agents targeting the receptor. Surprisingly, clinical trials using specific IGF-1R antibodies have, however, revealed disappointing results. Further understanding of the role of IGF-1R in cancer cells is therefore necessary for development of efficient therapeutic strategies. Recently, we showed that IGF-1R is sumoylated and translocated into the cell nucleus where it activates gene transcription. Several other studies have confirmed our findings and it has been reported that nuclear IGF-1R (nIGF-1R) has prognostic and predictive impact in cancer. To increase the understanding of IGF-1R in cancer cells, we here present the first study that proposes a pathway by which IGF-1R translocates into the cell nucleus. We could demonstrate that IGF-1R first associates with the dynactin subunit p150(Glued), which transports the receptor to the nuclear pore complex, where it co-localizes with importin-ß followed by association with RanBP2. Sumoylation of IGF-1R seems to be required for interaction with RanBP2, which in turn may serve as the SUMO E3 ligase. In the context of sumoylation, we provided evidence that it may favor nIGF-1R accumulation by increasing the stability of the receptor. Taken together, topographic and functional interactions between dynactin, importin-ß and RanBP2 are involved in nuclear translocation of IGF-1R. Our results provide new understanding of IGF-1R in cancer, which in turn may contribute to development of new therapeutic strategies.

Effectiveness of outpatient pulmonary rehabilitation in elderly patients with chronic obstructive pulmonary disease.

PURPOSE: Pulmonary rehabilitation (PR) has been shown to be an effective intervention in the management of patients with chronic obstructive pulmonary disease (COPD), but its role in elderly patients is not clearly defined. We investigated the effectiveness of rehabilitation in elderly patients with COPD. METHODS: Patients underwent multidisciplinary PR in a hospital outpatient gym twice weekly for 6 weeks. Lung function, shuttle walk distance, breathlessness (using a 10-point Borg scale), and responses to the Chronic Respiratory Questionnaire (CRQ) were assessed before and after rehabilitation. RESULTS: Patients (N = 200; 131 male) were divided into 2 groups: group A, those 70 years or older (n = 102, mean age 76 years); and group B, those younger than 70 years (n = 98, mean age 61.4 years). Shuttle walk distance increased significantly (P < .05) by a mean 33.6 m in group A and 50.1 m in group B. Borg score significantly improved (P < .05) by a mean -0.35 in both groups. There were significant improvements in CRQ components within the older and younger groups: dyspnea 0.9 and 1.1; fatigue 1.0 and 1.1; emotion 0.7 and 0.8; and mastery 1.0 and 1.2; respectively. Differences in improvement in CRQ components between groups A and B were not significantly different. CONCLUSION: Elderly patients with COPD gain similar improvements from PR as younger patients and should not be excluded from rehabilitation based on age alone.

Spontaneous pneumothorax: use of aspiration and outcomes of management by respiratory and general physicians.

BACKGROUND: Spontaneous pneumothorax is a common problem in hospital practice. Despite the publication of guidelines controversy over its initial management still exists, particularly over the use of simple aspiration. METHODS: The management of spontaneous pneumothorax by respiratory and general physicians at our hospital was analysed by retrospective case note review. Eighty five patients were identified over the study period (36 managed by respiratory and 49 by general physicians). RESULTS: There was a significantly greater use of simple aspiration by respiratory (81%) than general physicians (47%, p<0.001) and a higher rate of success in this group. As a result those patients managed by respiratory physicians had fewer intercostal drains inserted and significantly shorter length of stays (mean 5.6 (3.8) days respiratory group and 9.5 (6.8) days in general physicians group, p<0.05). CONCLUSIONS: The greater and more successful use of simple aspiration by respiratory physicians as an initial treatment for spontaneous pneumothorax resulted in improved outcomes and reduced length of hospital stays.

Asthma admissions and thunderstorms: a study of pollen, fungal spores, rainfall, and ozone.

Asthma admissions have been reported to increase during thunderstorms. In some cases, this has been attributed to rises in pollen or fungal spore counts occurring alone or in combination with rainfall. We tested the hypothesis that thunderstorms in general are associated with asthma admissions, and investigated the possible roles of pollen, fungal spores, ozone, and other meteorological factors. We obtained data on multiple pollen and fungal spore counts, rainfall, temperature, ambient ozone concentrations, and asthma admissions for 32 dates when lightning strikes were recorded in the Cardiff/Newport area, and 64 matched dates in previous and subsequent years. Poisson regression models were used to investigate associations between admissions and proposed causative environmental factors. The number of asthma admissions was greater on days with thunderstorms than on control days (p<0.001). There were no associations or interactions between admissions and any pollen or fungal spore counts or rainfall. After adjusting for thunderstorms, there was an independent association between increasing ozone concentration, when temperature was included in the model, and increasing admissions (p=0.02). Asthma admissions are increased during thunderstorms. The effect is more marked in warmer weather, and is not explained by increases in grass pollen, total pollen or fungal spore counts, nor by an interaction between these and rainfall. There was an independent, positive association between ozone concentrations and asthma admissions.

Tuberculosis in the elderly.

Tuberculosis is still a major cause of morbidity and mortality worldwide. Recent studies have suggested that even in the developed world its incidence in the elderly is increasing. Symptoms of active tuberculosis are non-specific and less pronounced in the elderly. Radiological features are more likely to be 'atypical' in the older subject and skin tests more frequently negative. This results in delay in diagnosis and higher mortality from tuberculosis in the aged population. A high degree of clinical suspicion is therefore required to ensure the diagnosis is not missed and appropriate treatment instigated.

Recent advances in the sleep apnoea/hypopnoea syndrome.

This review highlights some of the advances in sleep apnoea/hypopnoea syndrome made over the last few years, particularly in diagnosis and treatment. Recent evidence of the controversial associations of sleep apnoea/hypopnoea syndrome with increased morbidity and mortality, particularly from cardiovascular disease, is presented.

Domiciliary nocturnal intermittent positive pressure ventilation in patients with respiratory failure due to severe COPD: long-term follow up and effect on survival.

BACKGROUND: There is increasing interest in the use of non-invasive nocturnal intermittent positive pressure ventilation (NIPPV) in the management of patients with chronic hypercapnoeic (type II) respiratory failure. Although this treatment enables patients requiring mechanical ventilatory support to the treated more readily at home, few studies have been done to demonstrate its long term benefits in chronic obstructive pulmonary disease (COPD) and the application of NIPPV in these circumstances remains controversial. METHODS: Eleven patients in severe stable chronic type II respiratory failure due to COPD who were unresponsive to conventional treatments experienced symptomatic hypercapnia when receiving sufficient supplementary oxygen to result in an arterial oxygen saturation (SaO2) of > 90%. They were assessed for treatment with NIPPV, and its effects were observed for over two years using arterial blood gas tensions, spirometric parameters and body mass index (BMI), survival, hospital admissions, use of general practitioner resources, and patient satisfaction. RESULTS: Hospital admissions and GP consultations were halved after one year compared with the year before NIPPV and there was a sustained improvement in arterial blood gas tensions at 12 and 24 months when breathing air, despite progressive deterioration in ventilatory function. BMI did not change during the period of observation. The median survival was 920 days, with no patient dying within the first 500 days. CONCLUSIONS: Domiciliary NIPPV results in improvements in arterial blood gas tensions which are sustained after two years of treatment and reduces both hospital admissions and general practitioner visits by patients with severe COPD in hypercapnoeic respiratory failure. It is well tolerated and, although there was no control group, survival appears to be prolonged when these results are compared with those of the NOTT and MRC (LTOT) trials.

Trial development of unit response changes during conditioning in cats.

Single-cell and evoked potential (EP) activity in the postcruciate cortex of acutely prepared cats was recorded during a classical conditioning procedure. The temporal pattern of response (PSH) of the neuron was separated into three components, and the trial development of learning changes for these components was examined individually. Changes over trials in the similarity of the EP waveform and the unit PSH were also examined. The unit response components showed changes in response at different trial periods; these changes could not be accounted for by changes at lower brain levels that projected to the cortex. This suggests that local learning changes were taking places in the cortex. The EP-PSH similarity decreased for neurons showing the largest changes in response during conditioning. Since the EP reflects the response of the whole population of neurons and a majority did not show learning changes, this could account for the observed decrease.

Sequelae of carbon monoxide-induced hypoxia in the rat.

Rats were exposed to carbon monoxide, and conduction velocity of ventral caudal nerve (VCN), visual cortical evoked potential (VEP), electroencephalogram, and vital functions were determined in relation to the degree of CO-induced hypoxia. The conduction velocity of VCN and VEP (latency of P2 [second positive deflection of the visual evoked response]) were unaffected until carboxyhemoglobin (COHb) levels reached between 60% and 70%. These levels were maintained for approximately one hour before decreased conduction velocity or increased latency of P2 occurred. Decrease in mean arterial blood pressure resulted in impaired neurological function. Recovery of conduction velocity was discontinuous. Conduction was lost and recovered again within a three-hour period after exposure. It decreased again 9 to 13 days later, recovering in approximately four days. Data on P2 latency after exposure were fragmentary, but suggest that later increases might occur. Similar effects of CO-induced hypoxia on peripheral and central nervous systems were found. Decrease of mean arterial blood pressure was consistently associated with impaired nervous system function.

Extreme toxicity from combustion products of a fire-retarded polyurethane foam.

The products from nonflaming combustion of wood and a trimethylol-propane-based rigid-urethane foam that was not fire-retarded produced elevated carboxyhemoglobin levels but no abnormal neurological effects. However, when this type of foam contained a reactive phosphate fire retardant, the combustion products caused grand mal seizures and death in rats. The toxic combustion product responsible for the seizures has been identified as 4-ethyl-1-phospha-2,6,7-trioxabicyclo(2.2.2.)octane-1-oxide.