Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation.

BACKGROUND: Aberrant epithelial repair is a key event in the airway remodelling which characterises obliterative bronchiolitis (OB) in the transplanted lung. The potential for airway epithelium from lung transplant recipients to undergo epithelial to mesenchymal cell transition (EMT) was assessed in culture and in vivo in lung allograft tissue. METHODS: Change in epithelial and mesenchymal marker expression was assessed after stimulation with transforming growth factor beta(1) (TGF-beta(1)) alone or in combination with tumour necrosis factor alpha (TNFalpha) and compared with untreated controls. The ability of cells to deposit extracellular matrix, secrete matrix metalloproteinases (MMPs) and invade collagen was investigated. Immunolocalisation of epithelial and mesenchymal markers was compared in airway tissue from stable recipients and those with OB. RESULTS: Untreated cells maintained epithelial morphology and phenotype. TGF-beta(1) reduced expression of epithelial markers, increased expression of vimentin and fibronectin, promoted collagen I and fibronectin deposition and increased MMP-9 production. Co-treatment with TNFalpha dramatically accentuated phenotypic and some functional features of EMT. Airway epithelial biopsies from recipients with OB demonstrated significantly increased staining for mesenchymal markers and significantly reduced E-cadherin staining compared with stable recipients. CONCLUSIONS: These observations demonstrate the ability of human airway epithelium to undergo EMT and suggest this phenomenon may be a potential link between inflammatory injury and TGF-beta(1)-driven airway remodelling in the development of OB.

Airway epithelial cell senescence in the lung allograft.

Chronic lung allograft dysfunction, manifesting as bronchiolitis obliterans syndrome (BOS), is characterized by airway epithelial injury, impaired epithelial regeneration and subsequent airway remodeling. Increased cellular senescence has been reported in renal and liver allografts affected by chronic allograft dysfunction but the significance of cellular senescence in the airway epithelium of the transplanted lung is unknown. Thirty-four lung transplant recipients, 20 with stable graft function and 14 with BOS, underwent transbronchial lung biopsy and histochemical studies for senescence markers in small airways. Compared to nontransplant control lung tissue (n = 9), lung allografts demonstrate significantly increased airway epithelial staining for senescence-associated beta galactosidase (SA beta-gal) (p = 0.0215), p16(ink4a) (p = 0.0002) and p21(waf1/cip) (p = 0.0138) but there was no difference in expression of these markers between stable and BOS affected recipients (p > 0.05). This preliminary cross-sectional study demonstrates that cellular senescence occurs with increased frequency in the airway epithelium of the lung allograft but does not establish any association between airway epithelial senescence and BOS. A prospective longitudinal study is required to better address any potential causal association between airway epithelial senescence in stable allograft recipients and the subsequent development of BOS.

Evaluation of a transcutaneous carbon dioxide monitor ("TOSCA") in adult patients in routine respiratory practice.

BACKGROUND: Non-invasive measurement of oxygenation is routine in adult clinical practice but transcutaneous monitoring of PCO(2) (PtcCO(2)) is used much less due to technical difficulties with earlier transcutaneous electrodes. OBJECTIVE: Our aim was to determine the reliability of estimating arterial PCO(2) (PaCO(2)) using a recently introduced combined SaO(2)/PtcCO(2) monitor ("TOSCA", Linde Medical Systems) in adult patients in routine clinical respiratory practice. METHODS: PtcCO(2) was measured in patients requiring arterial blood gases for clinical reasons. Ten minutes after the probe had been attached to an earlobe PtcCO(2) was recorded, immediately before arterial blood sampling. The PCO(2) values obtained were compared by Bland-Altman analysis. RESULTS: Samples were taken from 48 unselected patients with varied pathology. There were no technical problems. Median age was 56 years (range 20-86 years). The mean difference between PaCO(2) and PtcCO(2) was -0.04kPa, sd of the difference 0.67kPa. Bland-Altman analysis showed generally good agreement between the two measurements across the range of PaCO(2) values (4-10.9kPa). Four of 48 measurements showed a PCO(2) difference >1kPa with no technical or clinical explanations apparent. CONCLUSIONS: The accuracy of estimation of PaCO(2) by the TOSCA transcutaneous electrode was generally good and the device appears promising for use in routine clinical respiratory practice.

Palmitate potentiation of glucose-induced insulin release: a study using 2-bromopalmitate.

The mechanisms whereby fatty acids (FA) potentiate glucose-induced insulin secretion from the pancreatic beta cell are incompletely understood. In this study, the effects of palmitate on insulin secretion were investigated in isolated rat islets. Palmitate did not initiate insulin secretion at nonstimulatory glucose concentrations, but markedly stimulated insulin release at concentrations of glucose > or = 5.6 mmol/L. At concentrations of palmitate > or =0.5 mmol/L, the important determinant of the potency of the FA was its unbound concentration. At total concentrations < or = 0.5 mmol/L, both the total and unbound concentrations appeared important. Surprisingly, 2-bromopalmitate did not affect palmitate oxidation, but significantly diminished palmitate esterification into cellular lipids. Neither methyl palmitate, which is not activated into a long-chain acyl-CoA ester, nor 2-bromopalmitate affected glucose-stimulated insulin release. Further, 2-bromopalmitate partly inhibited the potentiating effect of palmitate. These results support the concept that FA potentiation of insulin release is mediated by FA-derived signals generated in the esterification pathway.

Extramammary Paget's disease with diffuse involvement of the lower female genito-urinary system.

Extramammary Paget's disease of the lower female genito-urinary system is an uncommon neoplasm with a high rate of recurrence. A 52-year-old white female with a history of extramammary Paget's disease, originally excised in 1985 by skinning vulvectomy and who had multiple recurrences, including two in a vaginal graft and with extension to the urethra and the uterine cervix, in 1992 underwent an anterior pelvic exenteration for control of the disease process. Standard surgical management for extramammary Paget's disease without invasion or without an underlying adenocarcinoma is simple or skinning vulvectomy. However, because the disease commonly recurs, diffuse involvement may require more extensive surgery including pelvic exenteration in extraordinary cases.

Successful transplantation of a kidney with early membranous nephropathy.

This report describes a patient with end-stage renal disease secondary to long-standing type II diabetes mellitus who received a cadaveric renal transplant from a 37-year-old woman who died of massive cerebral infarction. An autopsy performed on the donor following organ procurement revealed no obvious contraindications to transplantation. A renal biopsy of the donor kidney performed at the time of transplantation, however, subsequently showed early membranous nephropathy by electron microscopy. There was immediate graft function and the recipient continues to have good renal function 3 years post-transplantation.

CRAHCA (Center for Research in Ambulatory Health Care Administration): member involvement leads to practical applications.

The research undertaken by CRAHCA results in many new techniques and ideas being adopted by medical practice managers. However, it is not merely a one-way street. In this article, six group practice managers respond to questions about how they have used and been involved with research activities the Center has developed.

Making room in the marketplace: a special initiative for the poor.

Faced with increased concern over the role of the voluntary healthcare sector, specifically Catholic providers, in the care of the poor, Mercy Health Services (MHS), a healthcare system, established a two-year, three-phase planning and development effort known as the Special Initiative for the Poor (SIP). Established in March 1986, SIP was designed to find out: Who are the poor? What are their needs? What is MHS's responsibility in meeting these needs? Among its objectives, SIP was charged with: 1. Educating and raising awareness of governance and management staffs. 2. Developing a way to assess human needs. 3. Determining the financial implications of the organization's commitment to the poor. 4. Recommending ways to enhance the understanding, energy, and commitment to the poor throughout the system. During the first six months, SIP staffers traveled to hospitals and subsidiaries throughout the system, meeting with management and staff, explaining the project, laying the groundwork, and gaining support. In the development phase, SIP created the Community Assessment of Human Needs, a systematic approach to identify and understand the unmet human needs of the poor. It also developed a simple inventory formula to help hospitals determine which of their programs were specifically for the poor and determine what these programs cost. Finally, in the implementation stage, several of SIP's recommendations are challenging the organization to move beyond its current commitments.

Forward locomotion elicited by electrical stimulation in the diencephalon and mesencephalon of the awake rat.

Stimulation electrodes were implanted in 63 rats at a total of 208 sites in the diencephalon and midbrain. The sites were tested for elicited forward locomotion, i.e., alternate stepping of the forelimbs and/or hindlimbs, while the rats stood on a treadmill belt in a 27 X 9 X 24-cm chamber. Current levels of 50-300 microA and pulse frequencies of 50, 100 and 154 Hz were presented as single 5-sec trains and as 20 repetitive trains of 1-sec duration with a 3-sec intertrain interval. Locomotion was elicited with low current (50 or 100 microA) single trains at 28% of the sites. Of the regions sufficiently well sampled to warrent comparisons, two showed high densities of locomotion-positive sites with single low current trains. They were the medial hypothalamus (the dorsomedial and the posterior nuclei) and the ventral tegmental area. The medial forebrain bundle and the zona incerta were generally positive but many sites in these regions required repetitive trains. Among the regions with few locomotion-positive sites were the subthalamic nucleus, the fields of Forel and the habenular complex. In the dorsal midbrain, in and around the central gray, low current single trains elicited leaping. The results are discussed in terms of the existence of a delimited subthalamic locomotor region and a ventral midbrain locomotor system independent of a dorsal midbrain system.

Unilateral lesions of the anteromedial cortex in the rat impair approach to contralateral visual cues.

This experiment determined the effects of large unilateral lesions of the anteromedial cortex (AMC) on visually guided performance of rats in a cross maze. Deficits were found in the approach to only visual cues that were located in the arm contralateral to the lesion. The deficit appeared in three testing conditions: when the cue was continuously visible throughout the trial; when it was visible only at the choice point; and when it was seen only at the start of the trial but not at the choice point. The failure to approach a contralateral cue was not due to a simple ipsilateral turning bias; rats with lesions could approach cues in the anterior arm as efficiently as controls. The deficit was most apparent on the initial sessions and recovery occurred for all conditions. The findings indicate that the AMC participates in the visual guidance of approach behavior.

Protrusio acetabuli in rheumatoid arthritis.

Protrusio acetabuli is common is rheumatoid arthritis. Progression of this deformity can be measured by serial roentgenograms. The inward progression of the femoral head is the result of upward migration of the acetabular roof and collapse of the femoral head which appears to occur in a ratio of approximately two to one. Adrenal cortical steroids may play a significant role in the etiology of this condition in rheumatoid arthritis. This complication of intrapelvic protrusion of the prosthetic acetabulum following total hip replacement has been presented and suggestions made to overcome this problem. Early operation on those patients showing rapid development of protrusio may prevent complications.