Ari Harjula

Comparison of tissue reactions in the tracheal mucosa surrounding a bioabsorbable and silicone airway stents

BACKGROUNDnTreatment of tracheobronchial stenosis is problematic. Conservative methods include stenting the stenotic area, but an ideal stent has not yet been developed. Bioabsorbable airway stents offer benefits; the extraction of the device is unnecessary, and the airway preserves its normal function after stent resorption. The aim of this study was to examine the suitability of self-reinforced poly-L-lactide as a material for an airway stent.nnnMETHODSnA spiral airway stent made of 0.7-mm wire of self-reinforced poly-L-lactide was implanted operatively in 9 rabbits intratracheally; silicone stents served as controls.nnnRESULTSnSilicone stents had a tendency to become stenosed with encrustation material and to develop a hyperplastic polyp at both ends. Self-reinforced poly-L-lactide stents were well tolerated and caused no foreign body reaction, and they had a tendency to penetrate into the tracheal wall. They had disappeared at the end of the follow-up of 10 months.nnnCONCLUSIONSnThis experimental study showed that bioabsorbable self-reinforced poly-L-lactide is a promising material for an airway stent for treatment of airway stenosis.

Fibroblast nemosis arrests growth and induces differentiation of human leukemia cells

Interactive signaling between cancer cells and stroma plays an important role in determining tumor development. We recently found tumor cell‐derived factors to induce fibroblast clustering, and that the high amounts of hepatocyte growth factor/scatter factor (HGF/SF) produced by these cell–cell contact‐activated fibroblasts enhanced the invasiveness of c‐Met‐expressing cancer cells. We now observed that leukemia cells lacking c‐Met respond to this novel type of fibroblast activation, nemosis, with growth arrest and differentiation to a dendritic cell‐like phenotype. This effect was counteracted by introduction of c‐Met expression into these cells. Moreover, those leukemia cell lines harboring properly processed c‐Met showed no effect in response to nemosis. We propose this effect to be mediated by nemosis‐derived cytokine signals, and present the potential candidates induced in the nemotic fibroblasts: interleukins‐1, ‐6, ‐8, ‐11, leukemia inhibitory factor and granulocyte‐macrophage‐colony‐stimulating factor. Our results emphasize the role of activated stromal fibroblasts in controlling progression of certain hematologic malignancies in a c‐Met expression‐dependent manner.

Persistent susceptibility of cathepsin B to irreversible inhibition by nitroxyl (HNO) in the presence of endogenous nitric oxide

Nitrosation of enzyme regulatory cysteines is one of the key posttranslational modification mechanisms of enzyme function. Frequently such modifications are readily reversible; however, cysteine proteases, such as cathepsin B, have been shown to be covalently and permanently inactivated by nitroxyl (HNO), the one-electron reduction product of NO. Owing to the high reactivity of HNO with NO, endogenous NO production could provide direct protection for the less reactive protein cysteines by scavenging HNO. Additionally, endogenous cellular production of NO could rescue enzyme function by protective nitrosation of cysteines prior to exposure to HNO. Thus, we studied the effect of endogenous NO production, induced by LPS or IFN-gamma, on inhibition of cysteine protease cathepsin B in RAW macrophages. Both LPS and IFN-gamma induce iNOS with generation of nitrate up to 9 muM in the media after a 24-h stimulation, while native RAW 264.7 macrophages neither express iNOS nor generate nitrate. After the 24-h stimulation, the HNO-releasing Angelis salt (0-316 microM) caused dose-dependent and DTT-irreversible loss of cathepsin B activity, and induction of iNOS activity did not protect the enzyme. The lack of protection was also verified in an in vitro setup, where papain, a close structural analogue of cathepsin B, was inhibited by Angelis salt (2.7 microM) in the presence of the NO donor DEA/NO (0-316 microM). This clearly showed that a high molar excess of DEA/NO (EC(50) 406 microM) is needed to protect papain from the DTT-irreversible covalent modification by HNO. Our results provide first evidence on a cellular level for the remarkably high sensitivity of active-site cysteines in cysteine proteases for modification by HNO.

Heart transplantation in repaired transposition of the great arteries.

Cardiac transplantation was carried out in a 40-year-old man with the diagnosis of repaired transposition of the great arteries and right-sided aortic arch who had end-stage cardiac failure due to myopathy of the ventricles. Because of several previous surgical repairs and the orientation of the great vessels, the operation presented some technical problems. Therefore, modifications of operative procedures were used, including recipient hypothermia, circulatory arrest, and changes in the donor heart implantation. The removal of the donor heart was modified in such a way that the graft included the aortic arch and both pulmonary arteries. With the extra length of ascending aorta and transverse arch, the innominate, left carotid, and left subclavian vessels were excised as a button, thereby leaving the distal orifice of the aorta in the superior portion of the transverse arch. For the recipient, the operation was performed using hypothermic total circulatory arrest to dissect free the huge pulmonary artery and the short right-sided aortic arch to place the clamp. Implantation of the donor heart was modified accordingly. The technical results were confirmed one and a half months later on a control digital angiogram. Thirty-five days postoperatively the patient was discharged. Six months after operation, the patient is doing better than ever before in his life. Our findings suggest that a complicated conotruncal development does not preclude cardiac transplantation.

Emergency procedure skills of graduating medical doctors

In the present study final-year medical students degree of theoretical knowledge and rate of successful performance of emergency procedures was assessed. A questionnaire was sent to all final-year medical students in Finland in 1997 (n=504) in all five medical faculties. The response rate was 80.2% (n=404). The questionnaire included questions on theoretical knowledge and successful performance of 10 emergency procedures. Over 90% of the final-year medical students knew the theory of emergency procedures, with the exceptions of chest tube insertion (84%), pericardiocentesis (47%), and planning and starting fluid infusion for an infant (83%), and over 90% had successfully performed insertion of an intravenous line (100%) and intubation of an adult (90%). However, fewer than 7% of the students had successfully performed chest tube insertion, planned fluid infusion for an infant, or pericardiocentesis. Males had significantly higher odds ratio than females for performing insertion of the intravenous line and intubation of an infant. Students with working experience had higher odds ratios for performing cardiopulmonary resuscitation. The highest overall frequency of the procedure performance was at the university in which a student logbook was systematically used. Conclusions are that final-year medical students have good theoretical knowledge of emergency procedures, but practical teaching should be encouraged, since even in emergency procedures students experience of practical measures was low.

Paracrine factors from fibroblast aggregates in a fibrin-matrix carrier enhance keratinocyte viability and migration.

Efficient re-epithelialization of skin lesions is dependent on paracrine support from connective tissue fibroblasts. In deep skin defects, the supporting growth factor incentive is lacking. Current methods of keratinocyte transplantation with compromised attachment, spread, and cell proliferation warrant improvement and refinement. We describe here how human keratinocytes can be stimulated by matrix-embedded factors from a novel process of fibroblast activation: nemosis. Interestingly, the unique set of mediators released in this process also plays a key role in normal wound healing. To develop a system for targeted delivery of nemosis-derived paracrine effectors, herein designated as Finectra, we combined them with fibrin to establish a controlled-release gel. Keratinocytes seeded to cover this active matrix showed better adherence, outgrowth, and viability than did cells on control matrix. The matrix incorporating Finectra supported viability of both primary keratinocytes and green fluorescent protein (GFP)-labeled HaCaT cells, as evaluated by MTT assay and persistence of GFP-fluorescence. The fibrin-Finectra matrix promoted migration of keratinocytes to cover a larger area on the matrix, suggesting better wound coverage on transplantation. An inhibitor of EGFR/c-Met receptor tyrosine kinases abolished keratinocyte responses to fibrin-Finectra matrix. This matrix can thus deliver biologically relevant synergistic stimuli to keratinocytes and hasten re-epithelialization.

Mediastinal neurogenic tumours: early and late results of surgical treatment

Early and late results of surgery for neurogenic mediastinal tumour were evaluated in 66 cases with a mean follow-up of 12 years. The series comprised 48 neurilemmomas, 8 neurofibromas, 7 ganglioneuromas, and neurinoma, neurofibrosarcoma and ganglioneuroblastoma each in one case. There were two early deaths (3%), one due to peroperative bleeding from the left subclavian artery and the other to acute myocardial infarction. Operative complications arose in 12 cases (18%), the most common being wound infection (3 cases). There were 17 late deaths (26.6%). In the neurilemmoma group, 3 of the 13 late deaths were related to the tumour or its treatment, and both deaths in the neurofibroma group were related to malignant transformation. Recurrence of tumour appeared in 3 of the 48 patients with neurilemmoma and also in the single patient with neurinoma as tumour classification. One neurilemmoma was a dumb-bell tumour, and operation in this case resulted in paraplegia. Malignant transformation appeared in 2 of the 8 neurofibromas 5 and 13 years postoperatively. Because of the risks of malignant degeneration and of recurrence, patients operated on for neurogenic mediastinal tumour should be carefully followed up for many years.

Plasma cell granuloma of lung and pleura

A report is presented of seven patients with plasma cell granuloma of the lung or pleura. Two were operated on in 1970, three in 1971, one in 1973 and one in 1984. None of the patients had smoked cigarettes. Five had a history of infection. Most of the patients were young, healthy and working. The surgical treatment was lobectomy in four cases, bilobectomy in one case and resection of tumour in two cases. The histology of the tumours was re-evaluated, and was similar in all cases. They were composed mainly of plasma cells, lymphocytes and granulocytes, and small foci of calcification were also seen. No recurrence of tumour was found in observation up to 13 years postoperatively. One patient died of pancreatic carcinoma after 6 years. The others are doing well.

Atria1 pressure and hormonal and renal responses to acute cardiac tamponade

The effect of acute cardiac tamponade on atrial pressures, plasma atrial natriuretic factor concentration and renin activity, and renal water and electrolyte excretion was studied in pigs loaded intravenously with hydroxyethyl starch and maintained on a continuous intravenous infusion of isotonic saline solution. Saline solution was infused into the pericardial space in 6 anesthetized pigs until a predetermined decrease of 20% in mean arterial pressure was achieved. Another 6 sham-treated pigs served as controls. Tamponade increased atrial intracavitary pressures but decreased atrial transmural (distending) pressures. These changes in atrial pressures were reversed after release of tamponade. Changes in plasma atrial natriuretic factor concentration correlated positively with changes in atrial transmural pressures. Tamponade increased plasma renin activity and decreased urine flow and renal sodium and potassium excretion, and release of tamponade reversed these changes. Thus, the tamponade-induced reduction in atrial distention is associated with hormonal changes, which may contribute to the reductions in diuresis and natriuresis observed in this connection.

Combined Valve Replacement and Myocardial Revascularization: Factors Influencing Early and Late Results

The risk factors involved in simultaneous valve replacement and coronary artery bypass grafting were evaluated in 54 consecutive patients, 42 men and 12 women, aged 22 to 73 years. The predominant valve anomalies were aortic stenosis (30 patients), aortic regurgitation (9), mitral regurgitation (10) and mitral stenosis (5). All the patients had angina. Myocardial infarction had occurred in 22 cases and was impending at the time of operation in 10. The diseased valves were replaced with mechanical prostheses, and on average 2.5 coronary arteries per patient were bypassed with vein or with internal mammary artery grafts. Four of the 54 patients died in association with surgery, and four more during follow-up (0.5-6 years). The operative mortality was 2/39 in the aortic valve group and 2/14 in the mitral valve group. The late mortality was equal in both groups. A relatively small ejection fraction and long aortic cross-clamping were the only factors which attained statistical significance as surgical risks, but mitral regurgitation due to ischaemic papillary muscle dysfunction, advanced rheumatic mitral regurgitation and tight aortic stenosis combined with coronary artery disease also seemed to be indicators of poor prognosis.