bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficiency of airway macrophage recovery by bronchoalveolar lavage in hamsters: a stereological approach
Authors: Geiser M , Serra AL , Cruz-Orive LM , Baumann M , Im Hof V , Gehr P
Published: July 2003

Macrophages play a central role in the defence of the respiratory tract against deposited particles. In addition to the well-studied alveolar macrophages, airway macrophages have been recognized as an important clearance factor. Bronchoalveolar lavage (BAL) has been used for functional and morphological investigations of macrophages in vitro, assuming that all macrophages are removed with equal probability from the lung surface. Airway macrophages have been found in close contact with the epithelial cells. These macrophages may not be easily removed by lavage, and they might constitute a functionally different macrophage population. We have tested the hypothesis that there exists a population of macrophages in the conducting airways that resists removal by lavage. We lavaged the lungs of four hamsters and fixed the lungs, thereafter, by intravascular perfusion. The number of macrophages in the intrapulmonary conducting airways was estimated with an unbiased stereological technique, the fractionator, and compared to the number of macrophages in the airways of four hamsters whose lungs had not been lavaged prior to fixation. This in situ study revealed that, in hamster lungs, 42% of the airway macrophages were not removed by BAL and that about 5% of all macrophages in the BAL fluid were airway macrophages. Additionally, ultrastructural alterations of the airway epithelium were found. It is concluded that there exists a population of airway macrophages that resists lavage. This is an aspect which has to be considered in studies performed with macrophages obtained by BAL, since they could represent a functionally different macrophage population.
Different functional and morphological characteristics in a nonadherent subpopulation of human macrophages recovered by bronchoalveolar lavage
Authors: Skold CM , Barck C , Lundahl J , Johansson A
Published: July 2003

The alveolar macrophages (AMs) constitute a morphologically and functionally heterogenous cell population. The adhesive properties of these cells are important for their role in host defence. To focus on the heterogeneity, a population of nonadherent macrophages were characterized functionally and morphologically. These cells were then compared with the total alveolar macrophage population. Alveolar cells (> 95% alveolar macrophages), were recovered by bronchoalveolar lavage (BAL) from healthy smokers. Nonadherent macrophages were separated by adhesion. The phagocytic capacity and the autofluorescent properties of the cell populations were determined in flow cytofluorometric assays. In addition, electron microscopic evaluation was performed. The alveolar macrophage adhesion to wells coated with albumin increased in a time-dependent manner. After 15 min, median 47%, interquartile range 42-52% (uncoated wells 68%, 67-72%) of the alveolar macrophages were attached; and after 60 min, 56%, 51-58% (uncoated wells 73%, 71-76%) of the alveolar macrophages were attached. The nonadherent alveolar macrophage population had less phagocytic capacity. The cell autofluorescence increased with increasing cell size and cell complexity/granularity in both populations. The nonadherent cells were more autofluorescent, indicating an increased granularity/complexity. These findings were confirmed with electron microscopy. Thus, the nonadherent alveolar macrophages had more cytoplasmic inclusions than the total alveolar macrophage population (volume density median 0.39, interquartile range 0.35-0.46 and 0.31, 0.26-0.34, respectively), but less surface protusions. We conclude that in lavage fluid from human smokers there is an ultrastructurally specific subpopulation of alveolar macrophages, showing less adhesive properties and impaired phagocytic capacity in vitro. These macrophages may be older alveolar cells or, alternatively, airway macrophages. Since only alveolar macrophages from smokers were investigated, we cannot draw any conclusions regarding alveolar cells from nonsmokers. Nevertheless, the heterogeneity of the lavaged cells should be taken into consideration when the functional ability of the alveolar macrophages are evaluated.
Role of bronchoalveolar lavage in children with lung disease
Authors: Riedler J , Grigg J , Robertson CF
Published: July 2003

The aim of the present study was to evaluate the clinical role of bronchoscopic and nonbronchoscopic bronchoalveolar lavage (BAL) in the diagnosis of infectious and interstitial lung disease in children. BAL was performed using three 1 mL.kg-1 aliquots of normal saline, with the flexible bronchoscope (Olympus 3.6 or 4.8 mm) wedged in a segmental or subsegmental bronchus of the lobe that showed most abnormality on chest radiograph. In seven children with severe diffuse lung disease who were intubated, a nonbronchoscopic suction catheter lavage was performed. Fluid cultures and cellularity were evaluated using identical methods for both techniques. Between January 1993 and April 1994, 41 BAL were performed in 32 children aged 2 months to 17 yrs (median 8 yrs). Of these lavages, 14 were in heart and heart-lung transplant recipients, 11 in children known to be immunocompromised, and 16 in children who had a lung biopsy for interstitial lung disease or who had presumed infective lung disease. Transbronchial biopsies (TBB) or open lung biopsies were performed coincident with 19 BAL procedures. In all transplant recipients without clinical symptoms, BAL and TBB cultures were negative and BAL cellularity was normal. TBB did not reveal infection or rejection in any of these patients. A diagnosis of infection was made by BAL in 1 out of 8 transplant recipients with clinical symptoms, and a diagnosis of rejection was made by TBB in 3 out of 8 patients. In 6 out of 11 BAL in immunocompromised children, an infectious agent was found in the BAL fluid. In three other patients who had an open lung biopsy, an interstitial lung disease was diagnosed. In these patients, BAL was abnormal but not diagnostic. In summary, BAL proved helpful in the diagnosis of infective lung disease, but had little value in the diagnosis of rejection or parenchymal noninfective lung disease in children.
Increased peak flow variability in children with asymptomatic hyperresponsiveness
Authors: Gibson PG , Mattoli S , Sears MR , Dolovich J , Hargreave FE
Published: July 2003

The relevance of increased methacholine airway responsiveness detected in children with no current or past symptoms of asthma is not known. We wished to determine whether the presence of airway hyperresponsiveness in asymptomatic children is also associated with abnormal variability of peak expiratory flow (PEF). In 12 asymptomatic children with methacholine hyperresponsiveness, we examined the diurnal variation of peak expiratory flow (PEF) and response to inhaled bronchodilator. Twelve asthmatic children with a comparable range of methacholine hyperresponsiveness, and 12 normal children without methacholine responsiveness, were used as positive and negative controls. The children were aged 11 (range 9-14) yrs. The mean diurnal variation of PEF in those children with asymptomatic hyperresponsiveness was increased at 9.3%, to a degree comparable to the symptomatic asthmatic children (10.7%), and greater than the normal children (5.7%). Methacholine stimulated airway constriction was associated with symptoms in subjects from each group, indicating that the children were capable of perceiving airway constriction. We conclude that asymptomatic children with methacholine airway hyperresponsiveness have other evidence of mild variable airflow obstruction with increased diurnal PEF variability, and can perceive airflow limitation. The lack of symptoms in the children with airway hyperresponsiveness could be due to an insufficient stimulus to cause symptomatic obstruction, or the absence of eosinophilic airway inflammation, which may be a requirement for the development of symptomatic airway hyperresponsiveness.
Wheeze in preschool children: who is followed-up, who is treated and who is hospitalized?
Authors: Luyt DK , Bourke AM , Lambert P , Burton P , Simpson H
Published: July 2003

This study determined the proportions of children < or = 5 yrs of age with reported wheeze who were undergoing medical follow-up, receiving anti-asthma medication, or admitted to hospital; and investigated factors important in determining which children would receive these treatments. The symptomatic children represented a wheeze prevalence of 16% of the study sample of 1,422 children. The cumulative incidence of treatment and hospitalization and point prevalence of current medical follow-up were determined using a parent-answered postal questionnaire study of a population-based random sample of 222 children. Odds ratios (OR) were calculated for wheeze severity, environmental, social, familial and demographic factors found to affect the likelihood of these treatment end-points. Among 222 children with wheeze, 99 (35%) were under current medical review, 165 (75%) had received medication, and 48 (22%) reported being hospitalized. Current follow-up was more likely in girls (OR 2.22; 95% confidence interval (95% CI) 1.12-4.38), with more than three attacks of wheeze in the last year (OR 17.44; 95% CI 5.22-58.3), or with a household pet (cat or dog) where inhalants were wheeze precipitants (OR 13.65; 95% CI 3.16-58.94). Treatment became more likely in older children (OR 3.91; 95% CI 1.10-12.71), with inhalants as wheeze precipitants (OR 4.66; 95% CI 1.08-20.14) or with a household pet (OR 2.28; 95% CI 1.04-5.03). Hospitalization was less likely with frequent wheeze (OR 0.30; 95% CI 0.12-0.77), but more likely if shortness of breath occurred with wheeze. Medical follow-up and treatment are related to wheeze severity and exposure to inhaled precipitants, whereas hospital admission occurred in children with attacks causing shortness of breath, and with decreasing frequency of attacks per year.
Comparing methods for assessing bronchial responsiveness in children: single step cold air challenge, multiple step cold air challenge, and histamine provocation
Authors: Modl M , Eber E , Steinbrugger B , Weinhandl E , Zach MS
Published: July 2003

Cold air challenge (CACh) can be applied by either a single step (SSCACh) or a multiple step (MSCACh) protocol. The interrelationship of the responses of the different protocols has not yet been studied. Furthermore, there is contradictory information on the correlation of cold air challenge responses to the outcome of pharmacological provocations. A single and a multiple step cold air challenge and a histamine provocation were performed in random order on three consecutive days on 28 children and adolescents with bronchial asthma, who were currently symptom- and medication-free. Single step cold air challenge consisted of a 4 min isocapnic hyperventilation of dry, -10 degrees C air; the subjects's response was quantified by the induced change in forced expiratory volume in one second (FEV1). Multiple step cold air challenge consisted of a series of 3 min, cold dry air hyperventilation steps from 20 to 80% of maximal voluntary ventilation (MVV); response was expressed as the provocative dose causing a 10% fall in FEV1 (PD10). Histamine provocation consisted of a series of 2 min inhalations of stepwise increasing histamine concentrations from 0.03 to 8.0 mg.mL-1; response was expressed as the provocative concentration of histamine causing a 20% fall in FEV1 (PC20). Change in FEV1 (delta FEV1) (SSCACh) correlated closely with PD10 (MSCACh); scatter around the regression line was minimal. With one exception, both types of CACh identified the same subjects as hyper- and normoresponsive. delta FEV1 (SSCACh) correlated significantly to PC20 (histamine), but scatter around the regression line was substantial. The correlation of PD10 (MSCACh) to PC20 (histamine) failed to reach statistical significance. These results indicate that the stimulus applied and the bronchoconstrictor mechanism activated, and not the challenge protocol, determine the outcome of a cold air challenge. In clinical practice, a brief single step cold air challenge can substitute for a more time-consuming multiple step cold air challenge. As nonpharmacological challenges seem to measure a different type of bronchial responsiveness, neither a single step nor a multiple step cold air challenge can substitute for a pharmacological provocation.
Benign postpartum pleural effusion
Authors: Gourgoulianis KI , Karantanas AH , Diminikou G , Molyvdas PA
Published: July 2003

The conditions of labour appear to favour the development of pleural effusion. The frequency of postpartum pleural effusion was investigated in this study using thoracic ultrasonography. Thirty one postpartum and 22 healthy nonpregnant women of the same age-group were examined, both supine and seated, via an intercostal approach. Seven of the 31 (23%) postpartum women had pleural effusion within 1-24 h of normal delivery. None of the nonpregnant women had pleural effusion. No correlation was found between postpartum pleural effusion and age, weight-gain during pregnancy, duration of labour, use of intravenous fluid, or oxytocin administration. Pleural effusion seems to be a common finding postpartum, but of no clinical significance.
Management of sleep apnoea syndrome
Authors: Liistro G , Aubert G , Rodenstein DO
Published: July 2003

Obstructive sleep apnoea is a chronic condition characterized by repetitive episodes of upper airway collapse during sleep, leading to sleep fragmentation. The management of sleep apnoea consists of general and specific measures. General measures should include weight loss in overweight patients; avoidance of alcohol during the evening hours; avoidance of any hypnotic drug. Specific measures may range from simple position training in patients with positional sleep apnoea (sleep apnoea appearing only when lying on the back) of slight severity; to oral appliances with the aim of creating a prognathism during sleep, to the introduction of a nasopharyngeal tube during sleep every night. When position training, oral appliances or a nasopharyngeal tube are used, their effect should be monitored by full night polysomnography. The best specific treatment for sleep apnoea is nasal continuous positive airway pressure. The main problem with nasal continuous positive airway pressure is the long-term compliance which should be assessed regularly over the years. In cases where nasal continuous positive airway pressure is not tolerated or compliance is bad, a surgical treatment can be proposed. Uvulopalatopharyngoplasty seems to give disappointing results. By contrast, maxillomandibular surgery is credited with the best results available as far as surgery is concerned, comparable to nasal continuous positive airway pressure.
Chest percussion
Authors: Yernault JC , Bohadana AB
Published: July 2003

The direct method of chest percussion, first described by Auenbrugger but disseminated by Corvisart, has rapidly been replaced by the indirect or digitodigital method. Chest percussion has not been evaluated by modern acoustic means, so that our present knowledge of the method does not consistently differ from the 19th century approach. Auscultatory percussion is not superior to conventional percussion.
Acoustic properties of the normal chest
Authors: Dalmay F , Antonini MT , Marquet P , Menier R
Published: July 2003

Laennec invented the stethoscope in 1816 and published a treatise on auscultation in 1819. We then had to wait until the 1950s to observe development of modern devices and methods of recording and signal-processing, which allowed objective studies of lung sounds in time and frequency fields. Tracheobronchial sounds generated by ventilation originate in the upper airways, the frequency content of these sounds has led to extensive research. Consolidated lungs act as more efficient sound conductors to the chest wall (bronchial breathing murmur). Tracheobronchial sounds contain higher frequency components compared to vesicular lung sounds. The origin of vesicular lung sounds has been becoming progressively clear for about 10 yrs. It is at least partly produced locally, deep, and probably intralobular. Clearly, further studies need to be performed in order to elucidate the true mechanisms involved in generating vesicular lung sounds, the redistribution of intrapulmonary gas or vibrations caused by the stretching of lung tissue. The devices developed are already useful for monitoring the state of patients in intensive care. Sooner or later, real time analysis and automated diagnosis will become available.
Models and mechanisms of exercise-induced asthma
Authors: Freed AN
Published: July 2003

Airflow-induced bronchoconstriction (AIB) in mammals can be broadly categorized as either vagal-dependent or vagal-independent. Among mammals, rabbits and cats belong to the former and guinea-pigs belong to the latter categories. Although insufficient data are available to classify monkeys, dogs and man appear to occupy the middle ground in which a small but significant parasympathetic component modulates airflow-induced bronchoconstriction. The fact that vagal activity can only partially account for airflow-induced bronchoconstriction in some asthmatic subjects suggests that vagal-dependent models may be of limited value in studying the human condition, but should prove valuable in elucidating the parasympathetic component of this mechanism. Although airflow-induced bronchoconstriction appears to be remarkably similar in guinea-pigs, dogs and humans, there are important differences concerning the potential role of specific mediators in producing airflow limitation. Concordant data from animal models and man suggest that: 1) airflow-induced bronchoconstriction is a basic mammalian response to airway desiccation; 2) airway drying stimulates and cooling inhibits this response; 3) hyperpnoea with dry air may damage the bronchial mucosa and contribute to this response; 4) biochemical mediators contribute to the development of this response; 5) vascular engorgement and airway oedema do not appear to be the primary effectors of this response, and in fact may antagonize it; 6) airway smooth muscle constriction is involved in the production of airflow-induced bronchoconstriction, and airway oedema may enhance its effect; and 7) airway and vascular responses to dehydration may protect against acute dry air-induced mucosal injury. Finally, although one must be cautious in extrapolating results from animals to humans, the similarities that do exist suggest that the investigation of airflow-induced bronchoconstriction in carefully selected animal models will continue to provide new insights concerning its development in humans.
DNase trials in cystic fibrosis
Authors: Hodson ME , Shah PL
Published: July 2003

Cystic fibrosis (CF) is a disease with a high morbidity and mortality from pulmonary disease. Sputum from CF patients contains high levels of deoxyribonucleic acid (DNA), which contribute to its viscoelasticity. Recombinant deoxyribonuclease (rhDNase) has been developed and in vitro studies have showed reduction in the viscoelasticity of CF sputum. This article reviews the in vivo clinical trials conducted to determine the safety and efficacy of this treatment. Phase 1 studies showed preliminary safety data and some evidence of clinical benefit. The two Phase 2 short-term studies showed improvement in pulmonary function and important safety data. The Phase 3 study, which included 968 patients, showed improvement in forced expiratory volume in one second (FEV1) of 5.8% and 5.6% in patients treated once and twice daily, respectively. The risk of developing an exacerbation of infection was reduced by 28% with once daily and 37% with twice daily treatment, compared to placebo. The drug was safe and there was some improvement in quality of life data. Longer-term open labelled studies, the results of intermittent administration, administration to severely ill patients, and the use of different delivery systems are reviewed. In conclusion, recombinant deoxyribonuclease is a new treatment which has been shown to benefit patients with cystic fibrosis when used in conjunction with conventional treatment.
Choosing a negative pressure ventilation pump: are there any important differences?
Authors: Smith IE , King MA , Shneerson JM
Published: July 2003

Five negative pressure ventilator pumps were assessed to determine whether there were any differences in performance which were likely to be of clinical importance. The pumps tested were the NEV-100 (Lifecare Inc.), the Negavent Respirator DA-1 (Dima Italia), the Thompson Maxivent (Puritan Bennett), the CCP-001 and Newmarket pumps (Si-Plan Electronics Research Ltd). A patient model was employed to investigate the relationship between the pressure waveform of each pump and the tidal volume generated, the stability of performance on a continuous 8 h test, and the response to a change in leak. On the continuous tests, the stability was better than +/- 1% for the inspiratory/expiratory (I:E) ratio and rate, and better than +/- 10% for the peak negative pressure for all of the pumps. The Negavent and NEV-100 pumps generated a square wave of pressure and for the same peak negative pressure produced a tidal volume up to 30% greater than the CCP-001 and the Newmarket pumps, which produced a half sine wave. The Maxivent produced an intermediate waveform, with a plateau at peak negative pressure but a curved decay back to atmospheric pressure. It is argued that if the pressure of the pumps producing a half sine wave is made more negative to compensate and produce an equivalent tidal volume, they are more likely to induce upper airway obstruction. The leak compensation of the NEV-100 and Negavent pumps was nearly complete but took several breaths to develop, the CCP-001 and Newmarket pumps had a very rapid compensation but this was less complete, whilst the Maxivent has no mechanism for leak compensation. From these results, it seems that in patients liable to upper airway obstruction the NEV-100 and Negavent pumps would be advantageous, whilst when rapidly changing leaks impair the efficiency of negative pressure ventilation the CCP-001 and Newmarket pumps would be preferable. The Maxivent pump seems to offer no advantages.
Aortobronchial fistula after correction of congenital cardiovascular abnormalities
Authors: Hiep-van Casteren SC , Westermann CJ , Hamerlijnck RP , Cornelissen PH , Overtoom TT
Published: July 2003

Aortobronchial fistula (ABF) is a rare but highly lethal condition. Four patients with ABF, 10-25 years after surgical repair of a congenital cardiovascular abnormality are reported. All patients presented with haemoptysis. Computed tomographic (CT) scan and aortography were inconclusive in two, diagnostic in one and not performed in another. Three patients underwent operation: all survived and are free of symptoms with a follow-up of 2-8 yrs. The fourth patient died before operation due to massive haemorrhage into the lung. In all patients, the fistula was secondary to aortic interposition of patch grafts.
An adult case of lymphangiomatosis of the mediastinum, pulmonary interstitium and retroperitoneum complicated by chronic disseminated intravascular coagulation
Authors: Takahashi K , Takahashi H , Maeda K , Homma S , Uekusa T , Dambara T , Kira S
Published: July 2003

Pulmonary lymphangiomatosis is a rare clinical and pathological entity which is distinct from lymphangiomyomatosis and from pulmonary lymphangiectasis. We report a case of a 20 year old man with diffuse lymphangiomatosis involving the mediastinum, lungs and retroperitoneum. The patient's intrathoracic lymphangiomatosis produced restrictive and obstructive impairment of his pulmonary function, but did not result in chylothorax or chylopericardium, which are two common manifestations of the disease. The patient's clinical course was remarkable for the concomitant development of chronic disseminated intravascular coagulation (DIC). Lymphangiomatosis involving both the mediastinum and pulmonary parenchyma is rare, and DIC is a very unusual complication of lymphangiomatosis.
Spontaneous pneumopericardium related to active cytomegaloviral infection in a lung transplant recipient. The Groningen Lung Transplantation Group
Authors: Mannes GP , van der Bij W , de Boer WJ
Published: July 2003

Spontaneous pneumopericardium occurred in a patient almost 4 weeks after bilateral lung transplantation for cystic fibrosis. The patient had no specific complaints and was in stable haemodynamic condition. We suggest that this pneumopericardium was related to a concomitant active cytomegalovirus (CMV) infection. After treatment of the CMV infection, the pneumopericardium resolved spontaneously.
Epidurual pneumatosis: a benign complication of benign pneumomediastinum
Authors: Defouilloy C , Galy C , Lobjoie E , Strunski V , Ossart M
Published: July 2003

Subcutaneous emphysema and pneumomediastinum are well-known complications of barotrauma. There are no fascial barriers between the posterior mediastinum and the retropharyngeal and epidural spaces; thus, air can diffuse freely to the epidural space and produce an epidural pneumatosis. We report a case of epidural pneumatosis caused by a pneumomediastinum following nasotracheal intubation for an attempted suicide. This benign complication of air leakage was easily recognized on computed tomography (CT) scan.
The perceptual acquisition of Thai phonology by English speakers: task and stimulus effects
Authors: Pater Joe
Published: July 2003

This article presents a follow-up to Curtin et al.’s study of the perceptual acquisition of Thai laryngeal contrasts by native speakers of English, which found that subjects performed better on contrasts in voice than aspiration. This finding - surprising in light of earlier cross-linguistic voice onset time (VOT) research - was attributed to the fact that the task tapped lexical representations, which are unspecified for aspiration according to standard assumptions in generative phonology. The present study further investigated possible task effects by examining the discrimination and categorization of the same stimuli in various experimental conditions. Stimulus effects were also investigated by performing token-based analyses of the results, and by comparing them to acoustic properties of the tokens. The outcome of the discrimination experiment was the opposite of the earlier study, with significantly better performance on contrasts in aspiration than voice, even on a lexical task. A second finding of this experiment is that place of articulation interacts with the perception of the laryngeal distinctions; the aspiration distinction is discriminated better on the labials, and voice on alveolars. A parallel effect of place of articulation was also found in a categorization experiment.
Perception of syllable-initial and syllable-final nasals in English by Korean and Japanese speakers
Authors: Aoyama Katsura
Published: July 2003

In both Korean and English, /m/ and /n/ contrast syllable-initially and /m/, /n/ and /&rhookn;/ contrast syllable-finally. In Japanese, /m/ and /n/ contrast syllable-initially while nasals do not contrast syllable-finally. Experiment 1 of this study investigated Korean and Japanese speakers’ perception of English nasals to examine how learners’ L1 influences the perception of L2 segments. The Japanese speakers had considerable difficulty distinguishing /&rhookn;/ from /n/ syllable-finally. Final /m/-/&rhookn;/ and /m/-/n/ were not particularly problematic for the Japanese speakers, although these contrasts do not exist in their L1. Experiment 2 examined the perceived relation between English /m/, /n/ and /&rhookn;/ and Japanese categories to investigate why final /n/-/&rhookn;/ was especially difficult for the Japanese speakers. In order to examine which Japanese categories are used to represent final nasals in English, Japanese speakers were asked to write English words used in Experiment 1 with the Katakana orthography. It was found that syllable-final /m/ was assimilated to one Japanese category, (see PDF for character), whereas two or more categories were used to classify /n/ and /&rhookn;/. There was a relatively high degree of overlap in classification between /n/ and /&rhookn;/ since both /n/ and /&rhookn;/ were classified with (see PDF for character) /N/ and yH (see PDF for character). The three final contrasts, /n/-/&rhookn;/, /m/-/&rhookn;/ and /m/-/n/ were classified as one of the assimilation types of the Perceptual Assimilation Model (PAM), based on the results from Experiment 2. The syllable-final /m/-/&rhookn;/ and /m/-/n/ contrasts were classified as Uncategorized-Categorized (UC), and the syllable-final /n/-/&rhookn;/ contrast was classified as Both Uncategorizable (UU). PAM expects discrimination to be very good for UC, but poor for UU if the two non-native categories are relatively similar to each other. The results from Experiment 1 for the Japanese speakers were consistent with the PAM prediction.
Phase III Trial of Carboplatin and Paclitaxel Compared With Cisplatin and Paclitaxel in Patients With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study
Authors: Ozols Robert F. , Bundy Brian N. , Greer Benjamin E. , Fowler Jeffrey M. , Clarke-Pearson Daniel , Burger Robert A. , Mannel Robert S. , DeGeest Koen , Hartenbach Ellen M. , Baergen Rebecca
Published: July 2003

Purpose: In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population.

Patients and Methods: Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were randomly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II).

Results: Seven hundred ninety-two eligible patients were enrolled onto the study. Prognostic factors were similar in the two treatment groups. Gastrointestinal, renal, and metabolic toxicity, as well as grade 4 leukopenia, were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II. Neurologic toxicity was similar in both regimens. Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval [CI], 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02).

Conclusion: In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel.
Expression and Localization of Secreted Frizzled-Related Protein-4 in the Rodent Ovary: Evidence for Selective Up-Regulation in Luteinized Granulosa Cells
Authors: Hsieh Minnie , Mulders Sabine M. , Friis Robert R. , Dharmarajan Arun , Richards JoAnne S.
Published: July 2003

Secreted frizzled-related protein-4 (sFRP-4) belongs to a family of soluble proteins that have a Frizzled-like cysteine-rich domain and function as modulators of Wnt-Frizzled (Fz) signals. As several Wnts and Fz are expressed at defined stages of follicular development in rodent ovaries, these studies were undertaken to evaluate the hormone-regulated expression and localization of sFRP-4. In the mouse ovary, the expression of sFRP-4 mRNA was up-regulated in granulosa cells of large antral follicles after human chorionic gonadotropin administration and was also elevated in corpora lutea, as determined by RT-PCR and in situ hybridization analyses. In hypophysectomized rat ovaries, sFRP-4 expression was similarly induced by human chorionic gonadotropin and further up-regulated by PRL. PRL also stimulated the secretion of sFRP-4 protein from luteinized rat granulosa cells in culture. Therefore, regulation of sFRP-4 by LH and PRL may be important for modulating Fz-1, which is known to be expressed in periovulatory follicles, and Wnt-4/Fz-4, which are expressed in corpora lutea.
Programming of Hypertonicity in Neonatal Lambs: Resetting of the Threshold for Vasopressin Secretion
Authors: Desai Mina , Guerra Catalina , Wang Shengbiao , Ross Michael G.
Published: July 2003

Lambs exposed in utero to maternal hypertonicity demonstrate plasma hypertonicity and arterial hypertension. To determine whether hypertonicity is due to an altered osmoregulatory set point, we examined arginine-vasopressin and cardiovascular responses to hypertonic saline infusion in these offspring. Study lambs [dehydrated (Dehy)] were exposed to maternal hypernatremia (8–10 mEq/liter increase; 110–150 d gestation) induced by water restriction. Control singleton and Control twins were born to ewes provided ad libitum water. We anticipated reduced birth weight due to maternal dehydration-induced anorexia and therefore included a Control group of twin gestations to approach a similar birth weight near term. After delivery, ewes from all three groups were provided ad libitum water, and their newborns were allowed ad libitum nursing. At 15 ± 2 d of age, lambs were prepared with bladder and vascular catheters. At 23 ± 2 d, after a 2-h basal period, neonatal lambs were iv infused with hypertonic 0.83 m NaCl (0.075 ml/kg·h) for 2 h, followed by a 2-h recovery. Neonatal mean arterial pressure and urine flow were continuously monitored, and blood samples were obtained before, during, and after infusion. During the basal period, Dehy neonates and Control twins demonstrated significantly increased plasma sodium levels and mean arterial pressure than Control singletons. In addition, the Dehy neonates had significantly increased plasma osmolality compared with Control singletons and twins. In response to hypertonic infusion, the Dehy offspring continued to exhibit hypertonicity and hypertension. Importantly, plasma tonicity and blood pressure were greatest in Dehy singletons, lowest in singleton controls, and intermediate in twin controls. Furthermore, the plasma osmolality threshold for AVP secretion was significantly higher in Dehy singletons (290 ± 2 mOsm/kg) than Control twins (285 ± 1 mOsm/kg) and Control singletons (280 ± 2 mOsm/kg), indicating in utero programming of an altered set point for systemic osmolality and blood pressure regulation. Because both twin gestation and dehydration-anorexia incur potential fetal nutritional stress, the results suggest that both in utero hypertonicity and nutrition reduction contribute to offspring programming. We postulate that the nutritional stress associated with twins (as well as dehydration-induced anorexia) contributes to increased plasma sodium levels, whereas the increased plasma osmolality is due to in utero hypertonicity.
High Glucose Stimulates Angiotensinogen Gene Expression and Cell Hypertrophy via Activation of the Hexosamine Biosynthesis Pathway in Rat Kidney Proximal Tubular Cells
Authors: Hsieh Tusty-Jiuan , Fustier Pierre , Zhang Shao-Ling , Filep Janos G. , Tang Shiow-Shih , Ingelfinger Julie R. , Fantus I. George , Hamet Pavel , Chan John S. D.
Published: July 2003

The present study investigated whether activation of the hexosamine biosynthesis pathway might mediate at least in part the high glucose effect on angiotensinogen (ANG) gene expression and immortalized renal proximal tubular cell (IRPTC) hypertrophy. IRPTC were cultured in monolayer. ANG, renin, and β-actin mRNA expression were determined by specific RT-PCR assays. Phosphorylation of p38 MAPK, activating transcription factor-2 (ATF-2), and cAMP-responsive element-binding protein (CREB) was determined by Western blot analysis. Cell hypertrophy was assessed by flow cytometry, intracellular p27kip1 protein levels, and [3H]leucine incorporation into proteins. Glucosamine stimulated ANG and renin mRNA expression and enhanced p38 MAPK, ATF-2, and CREB phosphorylation in normal glucose (5 mm) medium. Azaserine and 6-diazo-5-oxo-l-norleucine (inhibitors of glutamine: fructose-6-phosphate amino transferase enzyme) blocked the stimulatory effect of high glucose, but not that of glucosamine, on ANG gene expression in IRPTCs. SB 203580 (a specific p38 MAPK inhibitor) attenuated glucosamine action on ANG gene expression as well as p38 MAPK and ATF-2 phosphorylation, but not that of CREB. GF 109203X and calphostin C (inhibitors of protein kinase C) blocked the effect of glucosamine on ANG gene expression and CREB phosphorylation, but had no impact on p38 MAPK and ATF-2 phosphorylation. Finally, both glucosamine and high glucose induced IRPTC hypertrophy. The hypertrophic effect of glucosamine was blocked in the presence of GF 109203X, but not azaserine and SB 203580. In contrast, the hypertrophic effect of high glucose was blocked in the presence of azaserine and GF 109203X, but not SB203580. Our studies demonstrate that the stimulatory effect of high glucose on ANG gene expression and IRPTC hypertrophy may be mediated at least in part via activation of hexosamine biosynthesis pathway signaling.
Intracellular Transport of Calcium from Plasma Membrane to Mitochondria in Adrenal H295R Cells: Implication for Steroidogenesis
Authors: Lalevée Nathalie , Resin Véronique , Arnaudeau Serge , Demaurex Nicolas , Rossier Michel F.
Published: July 2003

Angiotensin II and extracellular potassium stimulate aldosterone production in adrenal glomerulosa cells by mobilizing the calcium messenger system. This response requires calcium influx across the plasma membrane, followed by calcium uptake into the mitochondria. It has been proposed that calcium is transported to the mitochondria via the lumen of the endoplasmic reticulum, acting as a kind of intracellular calcium pipeline. This hypothesis has been tested in the present study by measuring intramitochondrial calcium variations in H295R cells with a new fluorescent calcium probe, ratiometric pericam. Calyculin A, a protein phosphatase inhibitor, induced the formation of a large cortical layer of actin filaments, removing the peripheral endoplasmic reticulum away from the plasma membrane and thereby physically uncoupling the calcium channels from the pipeline. The mitochondrial calcium response to potassium was markedly reduced after calyculin treatment, but that of AngII was unaffected. Under the same conditions, potassium-stimulated pregnenolone and aldosterone production was significantly reduced, whereas the steroidogenic response to AngII remained unchanged. The inhibitory action of calyculin A on the responses to potassium was not mediated by a modification of the calcium channel activity and was not accompanied by a reduction of the cytosolic calcium response. It therefore appears that, in H295R cells, the organization of the actin cytoskeleton at the cell periphery influences the steroidogenic action of potassium, but not the response to angiotensin II. The response to potassium is proposed to be dependent on the endoplasmic reticulum-mediated transfer of calcium entering through plasma membrane calcium channels to the mitochondria.
Determinants of Iodothyronine Deiodinase Activities in Rodent Uterus
Authors: Wasco Emily C. , Martinez Elena , Grant Katherine S. , St. Germain Emily A. , St. Germain Donald L. , Galton Valerie Anne
Published: July 2003

The deiodinase types 2 and 3 (D2, D3), which convert T4 to active and inactive metabolites, respectively, are expressed in the rodent uterus and highly induced during pregnancy. To examine the factors regulating the expression of these enzymes in this tissue, we studied D2 and D3 activity in pregnant rats, in pseudopregnant rats before and after the induction of artificial decidualization, and in ovariectomized rats treated with 17β-estradiol (E2) and/or progesterone (P). Our results demonstrate that induction of D3 activity begins immediately after implantation and increases markedly over the next 72 h. A similar time course and magnitude of D3 induction is noted in the artificially decidualized uterus in pseudopregnant rats, whereas only minimal increases in activity are observed in the nondecidualized control uterine horns in the same animal. In contrast, D2 activity is not induced by a decidualization stimulus. In spontaneously cycling female rats, both D2 and D3 were observed to be 3- to 8-fold higher in proestrus, compared with diestrus. Furthermore, levels of D2 and D3 activity were greatly increased in ovariectomized rats given E2 and P in various combinations. D2 activity was stimulated primarily by E2, whereas E2 and P acted synergistically to increase D3 activity. These results demonstrate that E2 and P regulate thyroid hormone metabolism in the uterus, and that the implantation process is a potent stimulus for the induction of D3 activity in this organ. Such precise and profound changes in deiodinase expression are likely to play important physiological roles in fetal development and may influence uterine function.
Profiling of Estrogen Up- and Down-Regulated Gene Expression in Human Breast Cancer Cells: Insights into Gene Networks and Pathways Underlying Estrogenic Control of Proliferation and Cell Phenotype
Authors: Frasor Jonna , Danes Jeanne M. , Komm Barry , Chang Ken C. N. , Lyttle C. Richard , Katzenellenbogen Benita S.
Published: July 2003

Estrogens are known to regulate the proliferation of breast cancer cells and to alter their cytoarchitectural and phenotypic properties, but the gene networks and pathways by which estrogenic hormones regulate these events are only partially understood. We used global gene expression profiling by Affymetrix GeneChip microarray analysis, with quantitative PCR verification in many cases, to identify patterns and time courses of genes that are either stimulated or inhibited by estradiol (E2) in estrogen receptor (ER)-positive MCF-7 human breast cancer cells. Of the >12,000 genes queried, over 400 showed a robust pattern of regulation, and, notably, the majority (70%) were down-regulated. We observed a general up-regulation of positive proliferation regulators, including survivin, multiple growth factors, genes involved in cell cycle progression, and regulatory factor-receptor loops, and the down-regulation of transcriptional repressors, such as Mad4 and JunB, and of antiproliferative and proapoptotic genes, including B cell translocation gene-1 and -2, cyclin G2, BCL-2 antagonist/killer 1, BCL 2-interacting killer, caspase 9, and TGFβ family growth inhibitory factors. These together likely contribute to the stimulation of proliferation and the suppression of apoptosis by E2 in these cells. Of interest, E2 appeared to modulate its own activity through the enhanced expression of genes involved in prostaglandin E production and signaling, which could lead to an increase in aromatase expression and E2 production, as well as the decreased expression of several nuclear receptor coactivators that could impact ER activity. Our studies highlight the diverse gene networks and metabolic and cell regulatory pathways through which this hormone operates to achieve its widespread effects on breast cancer cells.
Various Phosphorylation Pathways, Depending on Agonist and Antagonist Binding to Endogenous Estrogen Receptor α (ERα), Differentially Affect ERα Extractability, Proteasome-Mediated Stability, and Transcriptional Activity in Human Breast Cancer Cells
Authors: Marsaud Véronique , Gougelet Angélique , Maillard Sébastien , Renoir Jack-Michel
Published: July 2003

Estrogen receptor-α (ER) is down-regulated in the presence of its cognate ligand, estradiol (E2), as well as in the presence of antiestrogens, through the ubiquitin proteasome pathway. Here, we show that, at pharmacological concentrations, the degradation rate of pure antagonist/endogenous ER complexes from human breast cancer MCF-7 cells is 10 times faster than that of ER-E2 complexes, while 4-hydroxy-tamoxifen (4-OH-T)-ER complexes are stable. Whereas pure antagonist-ER complexes are firmly bound to a nuclear compartment from which they are not extractable, the 4-OH-T-ER accumulates in a soluble cell compartment. No difference was observed in the fate of ER whether bound to pure antiestrogens ICI 182,780 or RU 58668. Cycloheximide experiments showed that, while the proteasome-mediated destruction of E2-ER (unlike that of RU 58668- and ICI 182,780-ER) complexes could implicate (or not) a protein synthesis-dependent process, both MAPKs (p38 and ERKs p44 and p42) are activated. By using a panel of kinase inhibitors/activators to study the impact of phosphorylation pathways on ER degradation, we found that protein kinase C is an enhancer of proteasome-mediated degradation of both ligand-free and ER bound to either E2, 4-OH-T, and pure antagonists. On the contrary, protein kinase A, MAPKs, and phosphatidyl-inositol-3 kinase all impede proteasome-mediated destruction of ligand free and E2-bound ER while only MAPKs inhibit the degradation of pure antiestrogens/ER species. In addition, no correlation was found between the capacity of kinase inhibitors to affect ER stability and the basal or E2-induced transcription. These results suggest that, in MCF-7 breast cancer cells, ER turnover, localization, and activity are maintained by an equilibrium between various phosphorylation pathways, which are differently modulated by ER ligands and protein kinases.