Quantitative assessment of emphysema using hyperpolarized 3He magnetic resonance imaging.

In this experiment, Sprague-Dawley rats with elastase-induced emphysema were imaged using hyperpolarized (3)He MRI. Regional fractional ventilation r, the fraction of gas replaced with a single tidal breath, was calculated from a series of images in a wash-in study of hyperpolarized gas. We compared the regional fractional ventilation in these emphysematous rats to the regional fractional ventilations we calculated from a previous baseline study in healthy Sprague-Dawley rats. We found that there were differences in the maps of fractional ventilation and its associated frequency distribution between the healthy and emphysematous rat lungs. Fractional ventilation tended to be much lower in emphysematous rats than in normal rats. With this information, we can use data on fractional ventilation to regionally distinguish between healthy and emphysematous portions of the lung. The successful implementation of such a technique on a rat model could lead to work toward the future implementation of this technique in human patients.

A small animal model of regional alveolar ventilation using HP 3He MRI1.

RATIONALE AND OBJECTIVES: The aim of this study was to establish a standardized procedure for the measurement of regional fractional ventilation in a healthy rat model as a baseline for further studies of pulmonary disorder models. MATERIALS AND METHODS: The lungs of five healthy male Sprague-Dawley rats were imaged using hyperpolarized helium-3 magnetic resonance imaging. From these images, regional fractional ventilation was calculated and maps generated detailing the distribution of fractional ventilation in the lung. The 1.56 mm x 1.56 mm x 4 mm regions of interest were assigned on 5 cm x 5 cm field of view lung maps. Histograms were also generated showing the frequency distribution of fractional ventilation values. To compare fractional ventilation values between animals, the ventilation procedure was standardized to results from individual pulmonary function tests. Each animal's spontaneous tidal volume, respiratory rate, and inspiration percentage (percent of total respiratory cycle in inspiration) were used in their mechanical ventilation settings. RESULTS: Results were similar among all five healthy rats based on examination of ventilation distribution maps and frequency distribution histograms. Mean (0.13) and standard deviation (0.07) were calculated for fractional ventilation in each animal. However, these values were determined to be influenced by slice selection, and therefore the maps and histograms were favored in analysis of results. CONCLUSION: This study shows consistent results in healthy rat lungs and will serve as a baseline study for future measurements in emphysematous rat lungs.

Temporal aggregation bias and inference of causal regulatory networks.

Time course experiments with microarrays have begun to provide a glimpse into the dynamic behavior of gene expression. In a typical experiment, scientists use microarrays to measure the abundance of mRNA at discrete time points after the onset of a stimulus. Recently, there has been much work on using these data to infer causal regulatory networks that model how genes influence each other. However, microarray studies typically have slow sampling rates that can lead to temporal aggregation of the signal. That is, each successive sampling point represents the sum of all signal changes since the previous sample. In this paper, we show that temporal aggregation can bias algorithms for causal inference and lead them to discover spurious relations that would not be found if the signal were sampled at a much faster rate. We discuss the implications of temporal aggregation on inference, the problems it creates, and potential directions for solutions.

Revising regulatory networks: from expression data to linear causal models.

Discovering the complex regulatory networks that govern mRNA expression is an important but difficult problem. Many current approaches use only expression data from microarrays to infer the likely network structure. However, this ignores much existing knowledge because for a given organism and system under study, a biologist may already have a partial model of gene regulation. We propose a method for revising and improving these initial models, which may be incomplete or partially incorrect, with expression data. We demonstrate our approach by revising a model of photosynthesis regulation proposed by a biologist for Cyanobacteria. Applied to wild type expression data, our system suggested several modifications consistent with biological knowledge. Applied to a mutant strain, our system correctly modified the disabled gene. Power experiments with synthetic data that indicate that reliable revision is feasible even with a small number of samples.

Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma.

PURPOSE: Some studies report a high risk of death from intercurrent disease (DID) after postoperative radiotherapy (XRT) for non-small-cell lung cancer (NSCLC). This study determines the risk of DID after modern-technique postoperative XRT. PATIENTS AND METHODS: A total of 202 patients were treated with surgery and postoperative XRT for NSCLC. Most patients (97%) had pathologic stage II or III disease. Many patients (41%) had positive/close/uncertain resection margins. The median XRT dose was 55 Gy with fraction size of 1.8 to 2 Gy. The risk of DID was calculated actuarially and included patients who died of unknown/uncertain causes. Median follow-up was 24 months for all patients and 62 months for survivors. RESULTS: A total of 25 patients (12.5%) died from intercurrent disease, 16 from confirmed noncancer causes and nine from unknown causes. The 4-year actuarial rate of DID was 13.5%. This is minimally increased compared with the expected rate for a matched population (approximately 10% at 4 years). On multivariate analysis, age and radiotherapy dose were borderline significant factors associated with a higher risk of DID (P =.06). The crude risk of DID for patients receiving less than 54 Gy was 2% (4-year actuarial risk 0%) versus 17% for XRT dose > or = 54 Gy. The 4-year actuarial overall survival was 34%; local control was 84%; and freedom from distant metastases was 37%. CONCLUSION: Modern postoperative XRT for NSCLC does not excessively increase the risk of intercurrent deaths. Further study of postoperative XRT, particularly when using more sophisticated treatment planning and reasonable total doses, for carefully selected high-risk resected NSCLC is warranted.

Expanded indications for transcervical thymectomy in the management of anterior mediastinal masses.

BACKGROUND: Transcervical thymectomy (TCT) is an accepted though controversial approach for thymectomy in myasthenia gravis (MG). The suggestion of thymoma on computed tomography (CT) has been considered a contraindication to TCT. We sought to determine whether the indications for TCT could be safely expanded to include selected patients with thymomas as well as other types of anterior mediastinal masses. METHODS: Between January 1992 and September 1999, we performed 121 TCTs: 98 in patients with MG and 23 in patients without MG. The patients' records were retrospectively reviewed. RESULTS: Among the 98 MG patients, 28 had CT scans suspicious for thymoma. Of these, 14 had a thymoma pathologically. These were classified as stage I (5), stage II (8), and stage III (1). Five patients required extension of the incision for completion of the procedure. There have been no thymoma recurrences to date with a mean follow-up of 48 months (range 3 to 96 months). In the 23 patients without MG, 12 had new anterior mediastinal masses, 4 had a history of treated lymphoma, 1 had a history of treated germ cell tumor, and 6 had suspected mediastinal parathyroid adenoma. Diagnostic tissue was obtained in all patients undergoing the procedure for diagnosis, and in 4 of 6 patients, a parathyroid adenoma was successfully resected. CONCLUSIONS: Transcervical exploration and thymectomy offers a less invasive approach to the diagnosis and/or definitive treatment of selected anterior mediastinal masses. We suggest that it is appropriate to expand its use to several clinical scenarios beyond the typical indication of thymectomy in MG patients without thymoma.

Bronchial anastomotic stricutre caused by ossification of an intercostal muscle flap.

We report a case of heterotopic ossification of a pedicled intercostal muscle flap that had been wrapped circumferentially around a bronchial sleeve anastomosis. This ossification caused severe bronchial stenosis and recurrent pneumonias. Stent insertion failed, and the patient ultimately required completion pneumonectomy. We recommended that caution be used when wrapping intercostal muscle around any important lumen.

Diaphragm adaptations elicited by severe chronic obstructive pulmonary disease: lessons for sports science.

In humans, the diaphragm adapts to severe chronic obstructive pulmonary disease with (a) fast-to-slow transformations of the fiber types and myofibrillar proteins and (b) increases in the activity of mitochondrial oxidative enzymes. We suggest that progressive endurance training over several decades accounts for these adaptations.

Lung volume reduction surgery restores the normal diaphragmatic length-tension relationship in emphysematous rats.

OBJECTIVE: Improved respiratory muscle function is a major effect of a lung volume reduction surgery. We studied length adaptation in rat diaphragmatic muscle in an attempt to elucidate the mechanism by which diaphragmatic function improves after this controversial operation. METHODS: We developed a model of elastase-induced emphysema and bilateral volume reduction through median sternotomy in rats. Five months after emphysema induction, maximum exchangeable lung volume was determined in intubated and anesthetized control animals and animals with emphysema. Costal diaphragmatic length was measured in vivo, and the length at which maximal twitch force is generated was determined on muscle strips in vitro. Also 5 months after elastase administration, another cohort underwent volume reduction or sham sternotomy. Five months after the operation, these animals were similarly studied. RESULTS: Lung volume was increased in emphysematous rats versus control rats (50.9 +/- 1.7 vs 45.4 +/- 1.3 mL, P =.001). Lung volume was decreased in emphysematous animals that had undergone volume reduction versus sham sternotomy (44.7 +/- 0.60 vs 49.4 +/- 1.0 mL, P =.001). In situ diaphragm length (1.99 +/- 0.04 vs 2.24 +/- 0.07 cm, P =.001) and the length at which maximal twitch force is generated (2.25 +/- 0.06 vs 2.48 +/- 0.09 cm, P =.038) were shorter in emphysematous than control animals. After volume reduction, in situ diaphragm length (2.13 +/- 0.06 vs 1.83 +/- 0.02 cm, P <.001) and the length at which maximal twitch force is generated (2.50 +/- 0.08 vs 2.27 +/- 0.06 cm, P =.013) were longer than in animals undergoing sham sternotomy. CONCLUSIONS: In this experimental model of emphysema and lung volume reduction surgery, emphysema shortens the length at which maximal twitch force is generated and shifts the diaphragmatic length-tension curve to lower lengths; volume reduction returns the length at which maximal twitch force is generated toward normal and shifts the diaphragmatic length-tension curve back to longer lengths. This restoration toward normal physiology may enable the improvement in diaphragmatic function seen after lung volume reduction surgery. The mechanism by which these length adaptations occur merits further investigation.

Human skeletal myosin heavy chain genes are tightly linked in the order embryonic-IIa-IId/x-ILb-perinatal-extraocular.

Myosin heavy chain (MyHC) is the major contractile protein of muscle. We report the first complete cosmid cloning and definitive physical map of the tandemly linked human skeletal MyHC genes at 17p13.1. The map provides new information on the order, size, and relative spacing of the genes. and it resolves uncertainties about the two fastest twitch isoforms. The physical order of the genes is demonstrated to contrast with the temporal order of their developmental expression. Furthermore, nucleotide sequence comparisons allow an approximation of the relative timing of five ancestral duplications that created distinct genes for the six isoforms. A firm foundation is provided for molecular analysis in patients with suspected primary skeletal myosinopathies and for detailed modelling of the hypervariable surface loops which dictate myosin's kinetic properties.

Lobectomy with tangential pulmonary artery resection without regard to pulmonary function.

BACKGROUND: Non-small cell carcinoma of the lung invading the pulmonary artery (PA) has traditionally been treated by pneumonectomy. Although PA resection and reconstruction (PAR) has begun to gain acceptance, previous series of PAR by the simplest technique of tangential excision and primary repair have been unfavorable. We have maintained a policy of performing PAR preferentially whenever anatomically feasible, and usually this has been possible by tangential excision and primary repair. This study sought to determine if this approach is sound. METHODS: Retrospective clinical and pathologic review. RESULTS: Thirty-three PARs were performed from 1992 to 1999. The patients, followed 6 to 65 months (mean 25), were aged 36 to 80 years (mean 61), and their tumors were pathologic stage IB (n = 7), IIB (n = 13), IIIA (n = 9), and IIIB (n = 4). The mean preoperative forced expiratory volume in 1 second was 70% predicted. The procedures included 14 bronchial sleeve lobectomies with PAR and 19 simple lobectomies with PAR. The PARs were performed without heparinization and included 19 tangential excisions with primary closure, 11 larger tangential excisions with pericardial patch closure, and 3 sleeve resections. There were no operative deaths and 2 (6.1%) early major complications, all unrelated to the PAR. Thirteen patients (39%) had early minor complications. Four-year Kaplan-Meier survival was 48.3% for stages I/II and 45% for stage III. Ipsilateral, central, intrathoracic recurrence occurred in 3 patients (9.1%). CONCLUSIONS: These data are not dramatically different from those reported for standard resections. Although the numbers are small, the results suggest that lobectomy with PAR by tangential excision is an acceptable alternative to pneumonectomy whenever anatomically possible.

Developmental myosin heavy chains in the adult human diaphragm: coexpression patterns and effect of COPD.

In preliminary experiments we noted developmental (i.e., embryonic and neonatal) myosin heavy chains (MHCs) in the diaphragms of patients with severe chronic obstructive pulmonary disease (COPD). We hypothesized that this finding represented new fiber formation secondary to injury associated with the mechanical stress of COPD or previously undescribed MHCs in the human diaphragm. To distinguish between these possibilities, we analyzed diaphragmatic biopsies obtained from 9 patients with severe COPD (forced expiratory volume in 1 s = 21 +/- 2% predicted, residual volume = 283 +/- 22% predicted) and 10 age-matched controls. First, using immunocytochemistry with specific monoclonal antibodies, we noted that control diaphragms had greater proportions of fibers expressing embryonic (50 +/- 2 vs. 28 +/- 3%, P < 0.0001) and neonatal (52 +/- 2 vs. 32 +/- 3%, P < 0.001) MHCs than COPD diaphragms. Second, SDS-PAGE demonstrated that these developmental MHCs represented only a very small fraction of the diaphragmatic MHC content. Third, the RT-PCR demonstrated mRNA coding for embryonic and neonatal MHCs in COPD and control diaphragms. Last, COPD and control diaphragms exhibited normal histology on light microscopy. We conclude that the presence of developmental MHC isoforms does not indicate new fiber formation in diaphragms of patients with severe COPD. Although these results represent the first systematic description of embryonic and neonatal MHCs in normal adult human diaphragms, their function remains to be elucidated.

Thoracoscopic lung biopsy. Five commonly asked questions about video-assisted thoracic surgery.

VATS has proved to be an extremely useful diagnostic tool. Perhaps its most frequent application has been in lung biopsy to diagnose indeterminate solitary pulmonary nodules and interstitial infiltrates. In many institutions, VATS procedures have largely replaced previous methods of attempting to establish the nature of a solitary pulmonary nodule. In ambulatory patients with indeterminate infiltrates, VATS techniques have prompted earlier referral to establish a tissue diagnosis, with apparently decreased morbidity. VATS has clearly found a place in the modern practice of thoracic surgery and is likely to play an ever-increasing role in the management of diseases of the chest.

Bronchopulmonary carcinoid tumors associated with Cushing's syndrome: a more aggressive variant of typical carcinoid.

OBJECTIVES: Our objectives were to delineate the clinicopathologic characteristics of adrenocorticotropin-secreting bronchopulmonary carcinoid tumors causing Cushing's syndrome and to derive from these findings a rational approach to diagnosis and surgical management of this unusual condition. METHODS: We conducted a retrospective, chart-review analysis of seven consecutive patients treated at the Massachusetts General Hospital over a 16-year period. RESULTS: The patients uniformly had symptoms of marked hypercortisolism, and the underlying lung lesions remained clinically occult for a mean of 24 months. Standard endocrine testing was misleading in 83% of patients, reinforcing the need for an alternative diagnostic strategy based on petrosal sinus catheterization and computed tomography of the chest. Although 72% of the tumors were typical carcinoids by standard criteria, 57% demonstrated microscopic evidence of local invasiveness, and 43% were associated with mediastinal lymph node metastases. Eighty-six percent of patients have been cured by pulmonary resection a mean of 59 months after the operation, but 50% of these required a second operation for resection of involved lymph nodes after an initial relapse. CONCLUSIONS: These data suggest that adrenocorticotropin-secreting bronchopulmonary carcinoid tumors represent a distinct, more aggressive subtype of the usual, typical carcinoid. The high rate of lymphatic and local spread demands a surgical approach consisting of anatomic resection and routine mediastinal lymph node dissection.

Oral pigmentation representing Laugier-Hunziker syndrome.

Oral pigmentation is seen fairly commonly in dermatologic practice. Several conditions must be considered in the differential diagnosis. We present a patient whose condition highlights the clinical syndrome known as Laugier-Hunziker and provides the opportunity to review the clinical course, pathologic features, and literature of this uncommon syndrome.

Treatment of refractory, nonmalignant hydrothorax with a pleurovenous shunt.

We present a case of long-term successful application of pleurovenous shunting for the management of pleural effusion. Intractable symptomatic hydrothorax developed as a result of transdiaphragmatic migration of hepatic ascites. After failure of traditional treatment by mechanical pleurodesis, a pleurovenous shunt was inserted. After 1 year of follow-up, the effusion is well controlled, and the shunt remains patent.

Perforated villous adenoma of the cecum: report of a case.

Villous adenomas are common neoplasms of the colon, often causing anemia or hemoccult positive stools. Less typically, these lesions may result in abdominal pain, melena, obstruction, or change in bowel habits. Intussusception may occur, but this complication is unusual in adults. Spontaneous bowel perforation attributable to colonic polyps has not been previously reported. We present here the first reported case of an adenomatous polyp with bowel perforation and bladder involvement.