An advanced and detailed in vitro validation procedure for the radiolabeling of carrier-free terbutaline sulphate dry powder.

The aerodynamic properties of 99mTc radiolabeled carrier-free terbutaline sulphate (TBS) have been thoroughly investigated following delivery by Turbuhaler (AstraZeneca Lund, Sweden). A full and detailed radiolabeling procedure is also reported. The in vitro radiolabel validation was performed to determine whether TBS radiolabeled in this way would be representative of the commercially available product Bricanyl Turbuhaler during clinical trials. The results indicated that variations in aerodynamic properties had been introduced and that the radiolabel would slightly underestimate the fine particle fraction of Bricanyl, but would nonetheless act as a suitable marker in vivo. Assumptions regarding the aerodynamic properties of doses likely to be received by clinical trial subjects were also examined. This has been achieved by extending the validation procedures beyond those usually reported to include dose number, time, and homogeneity dependent studies. It was found that doses extracted for testing purposes and simulated patient doses extracted shortly afterward had similar properties. Doses extracted 2 h after initial testing also had similar properties to the test doses. These results suggested that data from the test doses could be used for quality control purposes, would be representative of the doses to be received by clinical trial subjects, and that a short delay between initial testing and trial subject inhalation would be acceptable.

Macrophage and lymphocyte chimerism in bronchoalveolar lavage cells from human lung allograft recipients.

BACKGROUND: Chimerism is suggested to predict a more favourable prognosis in solid organ transplantation. MATERIAL AND METHOD: Forty-eight bronchoalveolar lavages from 10 patients (5 females and 5 males) who had received sex-mismatched donor lungs were monitored for varying periods of time, of up to 2 years, at regular intervals (median 3.0 (0.5-24) months). To investigate the chimerism in macrophages and lymphocytes in bronchoalveolar lavage cells a cloned 2.12 kilobase large biotinylated Y-chromosome-specific DNA-probe was used for in situ hybridization. RESULTS: Donor macrophages disappeared in seven patients within the first 6 months after surgery (median 3.0 (1-6) months). But 15% donor macrophages could be detected in one patient 1 year and 10% in 2 patients two years after surgery. Donor lymphocytes disappeared in all patients within 3 months (median 1 (0.5-3) months). There was no correlation between periods or severity of acute rejection and percentage of donor macrophages and donor lymphocytes in bronchoalveolar lavage. None of the patients developed obliterative bronchiolitis. CONCLUSION: Macrophage chimerism in lung may exist for several years. Whilst our results do not elucidate the role of local macrophage chimerism, they do not currently support the view that chimerism prevents rejection.

The effect of modified ultrafiltration on the amount of circulating endotoxins in children undergoing cardiopulmonary bypass.

OBJECTIVE: To determine whether the use of modified ultrafiltration during pediatric cardiopulmonary bypass (CPB) diminishes the load of circulating endotoxins. DESIGN: Single-arm prospective observational study. SETTING: A university hospital operating room and intensive care unit. PARTICIPANTS: Twenty children undergoing CPB for correction of various congenital heart diseases. INTERVENTIONS: The amount of endotoxins in plasma was measured during CPB and before and after modified ultrafiltration. The ultrafiltrate was assayed for the presence of endotoxins. Postoperatively, the children were followed with relevant infectious parameters and cultures. MEASUREMENTS AND MAIN RESULTS: The amount of endotoxins increased significantly during the CPB procedure (from a median of 1.3 ng [range, 0 to 13.7 ng] to 24.2 ng [range, 2.1 to 75.9 ng]). After termination of CPB, modified ultrafiltration was shown to lower the amount of circulating endotoxins in blood (from a median of 24.2 ng [range, 2.1 to 75.4 ng] to 9.0 [range, 0.1 to 40.6 ng]). The major bulk of this reduction in endotoxin load was retrieved in the ultrafiltrate (median of 11.9 ng [range, 0 to 12.1 ng]). CONCLUSION: This study strongly suggests that modified ultrafiltration decreases the amount of circulating endotoxins in children undergoing cardiac surgery.

[The connection between delayed diagnosis of lung cancer and the intraoperative stage]. / Sammenhaengen mellem forsinket diagnose af lungecancer og stadium på operationstidspunktet.

The five-year survival after surgery for non-small cell lung cancer is good with respect to Stage I and Stage II and poor with respect to higher stages. The aim of this retrospective study of 172 patients was to detect a connection between the intraoperative stage and the pre-operative delay. Concerning the intervals from first symptom to operation and from first contact with the healthcare system to operation, the delay was significantly shorter for the patients in Stage I and II compared to Stage III and IV. The fraction of lung cancers detected by coincidence was significantly higher in Stage I and II compared with Stage III and IV. In conclusion, a few months' delay before final treatment of a non small-cell lung cancer has an impact on the perioperative stage, and thereby on the patient's prognosis. Screening asymptomatic risk-group patients will result in recognition of early lung cancer.

The impact of delayed diagnosis of lung cancer on the stage at the time of operation.

OBJECTIVE: The purpose of this investigation was to study the correlation between diagnostic delay and the stage of the lung cancer at the time of operation. A second objective was to study differences in symptoms between the patients grouped according to stage. METHODS: A total of 172 patients consecutively admitted for surgery between 1 January 1994 and 1 June 1995 at the Department of Thoracic and Cardiovascular Surgery of Rigshospitalet National Hospital of Denmark were included in the retrospective study. Two groups of patients were compared, one group with good prognosis (patients in Stages I and II) and one group with poor prognosis (patients in Stages III and IV). The time-spans studied were: (1) interval from the patient's perception of the first symptom to operation; and (2) the time from first contact with the healthcare-system to operation. The median delay between the patient-groups was compared using the Mann-Whitney U-test. To compare the symptoms which brought the patients in contact with the healthcare-system, the chi2-test was used. RESULTS: In the time interval between appearance of the first symptom and operation, a significantly shorter median delay was found for patients with Stages I and II compared to Stages III and IV (P = 0.037). Concerning the interval from first contact with the healthcare system to operation a significantly shorter median delay was found for the group of patients in Stage I and II compared to the patients-group in Stage III and IV (P = 0.017). It was found that the cancer was an accidental finding, significantly more often in patients in Stages I or II compared to patients in Stages III or IV (P = 0.0002). CONCLUSIONS: A few months delay before final treatment of a non-small-cell lung cancer seems to have an impact on the perioperative stage of the cancer, and thereby on the patients prognosis. A screening of asymptomatic risk-group patients will result in recognition of early lung cancer.

Transplantation of a lobe of lung from mother to child following previous transplantation with maternal bone marrow.

A left lower lobe of the lung was transplanted from a mother to her child, who had previously received a maternal bone marrow transplant for an immune defect. Following the bone marrow transplantation, the child had developed severe pulmonary fibrosis. Surgery and the early postoperative course have been uncomplicated. Immunosuppression with corticosteroids was administered for a short period, after which all immunosuppressive treatment was discontinued. The operation and the outcome are described both in the donor and recipient. Rehabilitation was slow, but one year later the patient is doing well.

[Lung transplantation. Indications, preoperative evaluation and postoperative treatment]. / Lungetransplantation. Indikationer, proeoperativ bedømmelse og postoperativ behandling.

Thirty-six heart-lung and lung transplantations have been performed in Denmark from January 1992 to January 1994. Heart-lung transplantations was initially carried out in patients with pulmonary vascular diseases. Single lung, double lung and heart-lung transplantation have become therapeutical alternatives and the indications have been expanded to terminal patients with pulmonary diseases. Careful selection of patients and donors, careful surgical techniques and a stringent immunosuppressive treatment have minimized the perioperative mortality. Daily lung function measurements, transbronchial biopsies and bronchoalveolar lavage have created possibilities for an early and safe diagnosis of infections and rejections. A high frequency of obliterative bronchiolitis with loss of pulmonary function is still a serious and unsolved problem. Intensive investigations with the aim of understanding, preventing and treating obliterative bronchiolitis are going on.

[Switching of the great vessels (arterial switch surgery) in transpositio vasorum]. / Omskifning af de store kar (arteriel switch operation) ved transpositio vasorum.

Since April 1992 the arterial switch operation (ASO) has been the treatment of neonates with transposition of the great arteries (TGA) at Rigshospitalet, Copenhagen. Thirteen mature neonates with TGA underwent ASO. Ten patients had simple TGA, two had TGA associated with a ventricular septal defect (VSD), and one had TGA with VSD and in addition moderate right ventricular hypoplasia. All patients survived the operation and are still alive. Perioperative bleeding was a problem in three cases. Eleven patients had an uncomplicated postoperative course. One patient had peri- and postoperative left ventricular failure and was reoperated after three months for a residual VSD. One child developed renal failure and needed peritoneal dialysis. The patients have been followed for 5.5 (range 0-12) months, they are all in good condition and thriving well. The presented early results after ASO justify continued recommendation of ASO as the operation of choice for TGA in neonates at Rigshospitalet.

Cytomegalovirus infection rate among heart transplant patients in relation to anti-thymocyte immunoglobulin induction therapy. Copenhagen Heart Transplant Group.

During a 2-year period, 49 patients underwent heart transplantation at Rigshospitalet, Copenhagen. Nine (18%) were females and the mean age for all patients was 44 years (range 14-56 years). Immunosuppressive therapy included cyclosporin, azathioprine and steroids in all patients. 43 patients received in addition short-term (approx. 4 days) induction treatment with antithymocyte immunoglobulin (ATG). 17 patients received ATG Fresenius, 2.5 mg/kg/day or ATGAM, 12.5 mg/kg/day, whereas the remaining 26 patients received ATG Merieux, 2.5 mg/kg/day. Prophylactic antimicrobial chemotherapy included ceftriaxone, acyclovir (1 g daily), nystatin, and pyrimethamine in toxoplasmosis mismatch patients. Serological assays for cytomegalovirus (CMV), Epstein-Barr virus, varicella-zoster virus, herpes simplex virus, legionella and toxoplasmosis as well as CMV and bacterial culturing were carried out before transplantation, at regular intervals and when clinically indicated. Five patients developed septicaemia. Nine had pulmonary bacterial infections, including 2 cases of legionella pneumonia. Two had Clostridium difficile diarrhoea. Three patients had Pneumocystis carinii pneumonitis. 24 patients (49%) had evidence of CMV infection/reactivation. Seven out of 10 CMV mismatch (pos donor/neg recipient) patients and 3 out of 12 CMV match (pos donor/pos recipient) patients developed clinical CMV disease. The rate of CMV infection/reactivation was significantly higher among patients who had CMV-positive donors (p < 0.01) and among patients receiving ATG Merieux induction treatment (p < 0.0001). Logistic regression analysis showed that both positive CMV donor status and ATG Merieux induction treatment were significant independent predictors of CMV infection. Six patients (12%) died. Two out of 4 infection related deaths could be ascribed to CMV disease.

Efferent innervation of the small intestine by adrenergic neurons from the cervical sympathetic and stellate ganglia, studied by retrograde transport of peroxidase.

The nervous pathways between the small intestine of cat and guinea pig and various sympathetic ganglia were investigated by the retrograde horse-radish peroxidase (HRP) technique. HRP was injected at multiple sites in the wall of the duodenum and the first third of the jejunum. At 1--5 days after the injections, the HRP reaction product was searched for in various sympathetic ganglia. Not only the coeliac and nodose ganglia, but also the superior cervical, medial cervical, stellate and thoracic ganglia contained HRP-positive nerve cells. Crushing the cervical vagal nerve prevented the occurrence of HRP-reaction in the cervical ganglia, indicating that the HRP was transported from the gut to the cervical ganglia via axons in the vagal nerve. The results demonstrate that the sympathetic ganglia in the neck (sup, and med. cerv. ganglia and stellate ggl.) send efferent fibres to the small intestine.

Antischistosomal and some toxicological properties of a nitrodiphenylaminoisothiocyanate (C 9333-Go/CGP 4540).

A procedure to enhance the schistosomicidal effectiveness in vivo of an isothiocyanate derivative and some of its antischistosomal properties are reported. Determinations of the effects of this compound on tissue thiol levels and on highly sensitivity bacterial tester strains have indicated that its mutagenic potential is of a low order and that the latter is decreased further after reduction of the host's intestinal bacterial flora.