Retinoblastoma in dizygotic twins born as extremely low birth weight infants.

A case of bilateral retinoblastoma affecting both of a pair of dizygotic twins was reported. To our knowledge, there has been only one previous report of dizygotic twins, both affected, with this disease. The present twins had no family history of retinoblastoma. They were born prematurely as extremely low birth weight infants after 26 weeks and 4 days of gestation, and 3 of the 4 tumors were detected at 33 weeks after conception. Using LINAC external radiation therapy followed by xenon photocoagulation when necessary, the tumors were successfully treated. These cases show that retinoblastoma can develop in the pre-term period, indicating that the second mutation involved in tumorigenesis can occur in the fetus.


Optic nerve glioma in Japanese patients with neurofibromatosis 1. Case reports and literature review.

Case 1, a 6-year-old boy, had multiple café-au-lait spots, no light perception OS, Lisch nodules OU, pale optic disc OS, enlarged left optic nerve on computed tomographic scan and magnetic resonance imaging, and histopathologically verified pilocytic astrocytoma (glioma). The patient's mother had neurofibromatosis 1 (NF-1). Case 2, a 12-year-old boy, had multiple café-au-lait spots, decreased visual acuity OU, Lisch nodules OU, pale optic discs OU, enlarged optic nerves and chiasm on computed tomographic scan, and histopathologically verified pilocytic astrocytoma. We also examined 38 Japanese patients with NF-1 and found Lisch nodules in 95% and optic nerve glioma in 5%. After reviewing the recent literature, we found that the association of optic nerve glioma and NF-1 in the Japanese population was less than that reported in North America.


Antibodies against human retinal proteins in serum from patients with cone dystrophy.

Eleven patients with cone dystrophy were examined for serum antibodies against human retinal proteins. Sera were screened by immunoblotting methods using human retinal proteins as antigens. Three cases from different families showed a distinct band at the molecular weight of 14 kDa; the hereditary pattern of these seropositive cases was autosomal recessive or sporadic with parental consanguinity. The serum antibodies were negative in the other sporadic or autosomal dominant cases of cone dystrophy with similar clinical features, in cases of various ocular diseases including macular dystrophies, and in healthy adults. No sera tested showed any specific antibodies against proteins from the human optic nerve or spinal cord.


S-antigen localization in developing rds mouse retina.

The morphology of the photoreceptor cell and localization of the cytoplasmic soluble protein, S-antigen, in the retina of the developing retinal degeneration slow (rds) mutant mouse (2-505 postnatal days) were studied by improved immunocytochemical and freeze-substitution methods. Anti-S-antigen antibody labeling was observed first in the postnatal 10-day retina under light microscope. Labeling signals increased progressively to a maximum level in 20 days, and then decreased gradually to an undetectable level by 505 postnatal days. By electron microscopic immunocytochemical methods, S-antigen was detected first in the photoreceptor cells at 3 postnatal days, and increased with development. It was located in the entire cytoplasm of the photoreceptor cell including the rudimentary outer segment, but degenerated and disappeared by 505 postnatal days. S-antigen was also present in the membranous vesicles budding off from the photoreceptor membrane to the subretinal space. The rds photoreceptor cell seems to lose other soluble proteins together with these vesicles. From these results and other published data, we speculate that the degeneration of the photoreceptor cells may be the secondary effects of the loss of a large amount of soluble and membrane proteins following the malfunction of membrane. Recent reports show the rds mouse must have a gene defect in the membrane component such as peripherin or the 39 kDa protein.


Effect of topical epinephrine on permeability of blood-aqueous barrier in human eyes.

The time-course of changes in the effects of topical epinephrine on the aqueous flow and the coefficient of protein entry into the anterior chamber (k(in)) were determined in 12 normal human subjects. Before and after instillation of 1.25% epinephrine in one eye, protein concentration in the anterior chamber (Ca) was determined from aqueous flare intensity using the laser flare-cell meter, and aqueous flow rate was determined by fluorophotometry. The k(in) was calculated from the Ca, plasma protein concentration, and aqueous flow rate. A single instillation of epinephrine affected neither the Ca nor the aqueous flow rate significantly. The calculated value of the k(in) showed no significant changes at any time of determination, which implied that a single instillation of epinephrine is insufficient to affect the permeability of the blood-aqueous barrier to plasma protein in the normal human eye.


Effect of rapid glycemic control on progression of diabetic retinopathy.

The effect of the start of glycemic control on the progression of retinopathy was investigated by a case-control study. The changes in glycosylated hemoglobin (HbA1) were compared between a case group, diabetic cases showing progression of retinopathy (Group 1), and a control group, diabetic cases showing no progression of retinopathy (Groups 2-A and 2-B). Group 2-A was matched with Group 1 on the basis of the grade of retinopathy at the first examination and other clinical data. Group 2-B was matched with Group 1 in terms of HbA1 value and methods of control, but had no retinopathy or background retinopathy. The retrospective follow-up period for the three groups was 24 months. On the basis of the respective matching factors, Groups 1 and 2-A were divided into 9 blocks of homogeneous subjects, and Groups 1 and 2-B were similarly divided into 6 blocks. The resulting data was evaluated block by block, using the analysis of variance (ANOVA) and a conditional logistic regression analysis. In Group 1, the HbA1 value decreased rapidly 10-6 months before the progression of retinopathy, but the HbA1 value did not change in Groups 2-A and 2-B during the 24-month follow-up. The difference in the estimated mean HbA1 value between 10-9 months and 1-0 month before the progression of retinopathy was 2.46% greater in Group 1 than in Group 2-A, as determined by ANOVA. The relative risks of a 1, 2 and 3% increase in HbA1 value for 7-6 months were estimated as 1.6, 2.4 and 3.8, respectively, by conditional logistic regression analysis. These findings indicate that the decrease in HbA1 value during any 6-month period should be limited to less than 2% in order to prevent the progression of retinopathy. It is also evident that too rapid a decrease at the initiation of glycemic control could cause severe or transient exacerbation of the progression of retinopathy.


[Estimation of pulmonary vascular permeability by indocyanine green in permeability pulmonary edema].

In this study we attempted to estimate pulmonary vascular permeability by indocyanine green (ICG). Permeability pulmonary edema was produced in 9 adult dogs by injecting 0.08 ml/kg oleic acid. We injected 50 mg ICG intravenously in 18 dogs (9 dogs with pulmonary edema and 9 control dogs). We measured the time course of ICG concentrations in pulmonary arterial blood, ICG concentration of peripheral lung tissue, tissue/serum ICG concentration ratios, and wet/dry lung weight ratios. The following results were obtained. The time course of ICG concentration in pulmonary arterial blood showed peak values at 2 minutes and became constant at 5 or 10 minutes after injection. The ICG concentration in peripheral lung tissue, tissue/serum ICG concentration ratios, and wet/dry lung weight ratios in the pulmonary edema group were significantly higher than those in the normal group. There was a strong linear correlation between wet/dry lung weight ratio and ICG concentration in peripheral lung tissue, with correlation coefficients of r = 0.936 (p < 0.01) in the right lung and r = 0.901 (p < 0.01) in the left lung. From these results, we conclude that estimation of pulmonary vascular permeability by ICG is a useful method.


[Evaluation of the distribution of ferruginous bodies and the kind of asbestos fibers in the lungs in lung cancer cases with definite occupational history of asbestos exposure].

The distribution of ferruginous bodies in the lungs of ten lung cancer patients with definite occupational history of asbestos exposure and the kind of core fibers in the center of the ferruginous bodies were evaluated. Six cases had a history of asbestos exposure in shipyards or Japanese naval dockyard, and the other four also had a definite history of occupational asbestos exposure. The largest number of ferruginous bodies was detected in the upper or middle lobes, but in only one case the lung cancer was present in the lobe in which the largest number of ferruginous bodies was detected. Therefore, the primary site of lung cancer is not dependent on the number of ferruginous bodies. The core of the ferruginous bodies was chrysotile in 7 cases, and amosite fibers were frequently detected in the three cases from the Japanese naval dockyard.


[Clinical course of asthmatics with severe asthma attack].

This study was conducted on 39 patients whose severe attacks of bronchial asthma with disturbance of consciousness required admission to the ICU of our hospital between 1984 and 1989. Among the 39 patients, there were 16 deaths. Most patients collapsed suddenly at home and were taken to our hospital. Arterial blood gas analysis at the time of admission to the ICU revealed that the PaO2 levels were as high as 252.6 +/- 57.6 (mean +/- S.E.) Torr in non-survivors and 221.0 +/- 29.7 Torr in survivors, with no significant difference because of prior oxygen therapy in almost all cases. Systolic blood pressure was 14.8 +/- 10.8 (mean +/- S.E.) mmHg, with marked circulatory disturbance in the fatal cases. Most patients displayed marked disturbance of consciousness, but maintenance of blood pressure led to recovery without sequelae despite marked disturbance of consciousness in most patients.


[Supplementary nutrition therapy is effective in patients with chronic obstructive pulmonary disease].

We examined the effects of supplementary nutritional therapy (calorie:REEx1.5) for one year using branched-chain amino acid (BCAA) enriched-elemental diet in addition to usual diet in 12 malnourished patients with COPD. Improvement in nutritional status was assessed by BW, %IBW, %AMC, transferrin, and plasma amino acid BCAA. PImax was significantly increased after 3 months' therapy. Although no significant change was found in pulmonary function and arterial blood gases, subjective symptoms evaluated by D.O.E., oxygen cost score and QOL index were improved. Significant correlations were found between delta BW and delta AMC and delta TSF, delta PImax and delta AMC, delta oxygen cost score and delta PImax, which suggest that improvements in nutritional status contributed to the improvement in respiratory muscle function and subjective symptoms. These findings suggest the effectiveness of supplementary nutritional therapy using BCAA-enriched elemental diet in patients with COPD.


[Superoxide dismutase activity in the broncho-alveolar lavage fluid in late asthmatic response model in guinea pigs].

In order to investigate the mechanism of the late asthmatic responses (LAR), LAR model in guinea pigs was made by inhalation of a large quantity of egg albumin antigen. Serial changes of inflammatory cells and superoxide dismutase activities in broncho-alveolar lavage fluids obtained from these animals were observed. In this model, increase in inflammatory cells, such as neutrophils, was observed in the broncho-alveolar lavage fluid during the late asthmatic responses of the attack and superoxide dismutase activity increased in the broncho-alveolar lavage fluid in parallel with the increase in inflammatory cells. These results suggest that change in superoxide dismutase activity in the broncho-alveolar lavage fluid may be involved in the onset of the late asthmatic responses.


[Obstructive pneumonitis in lung cancer patients--a retrospective study].

We evaluated the frequency and the backgrounds of lung cancer patients with obstructive pneumonitis. Among 84 cases of lung cancer, 35 presented with bronchial obstruction at bronchoscopy or on radiological studies. Of these 35 cases, 8 had infectious obstructive pneumonitis. This complication was observed more commonly in patients with squamous cell carcinoma. A comparative analysis of the immunological and nutritional states before the occurrence of bacterial complication was performed on patients with infectious obstructive pneumonitis and those with non-infectious obstructive pneumonitis. The serum concentration of total protein, albumin and total cholesterol was significantly lower in patients who subsequently developed bronchial obstruction and bacterial infection, compared to concentrations in patients with non-infectious obstructive pneumonitis. Similarly, there was significant decrease in the number of peripheral lymphocytes, and neutrophils as well as a significant reduction of the serum concentration of IgM in the group of patients with infectious complications. These results suggest that nutritional and immunological deficiencies, in association with local airway obstruction, may be determining factors in the occurrence of infectious obstructive pneumonitis in patients with lung cancer.


[A case of secondary myelodysplastic syndrome following chemotherapy for lung cancer].

A case of secondary myelodysplastic syndrome (MDS) following chemotherapy for lung cancer is reported. A 78-year-old man, with a smoking history of 20 cigarettes/day for 55 years, was incidentally, diagnosed as having stage IV squamous cell carcinoma of the lung in 1987 during admission for transurethral resection of bladder cancer. He received combination chemotherapy of mitomycin C, vincristin, and cisplatin for his lung cancer between July and September 1988. His clinical course remained almost stable until October 1989, when his blood count showed severe anemia and thrombocytopenia. He was diagnosed as having secondary MDS induced by cytotoxic agents used for the treatment of lung cancer, based on the dysplastic findings of precursor cells in the bone marrow and the chromosome abnormality of 51XY, +8, +9, +21, 3p-, 5q-, +2mar. He died of infection with the progression of MDS in March 1990.


[A case of systemic arterialization of lung without sequestration].

Intralobar pulmonary sequestration is a congenital disease characterized by nonfunctioning lung tissue with an anomalous blood supply stemming from the systemic circulation. We report a rare case of anomalous systemic arterial supply to the lung without demonstrable pulmonary changes. It is controversial whether this abnormality, systemic arterialization of lung without sequestration, should be a subtype of sequestration complex or not. We discuss the spectrum of sequestration complex.


[Case report of Farmer's lung disease in siblings in Kagoshima Prefecture].

Two cases of farmer's lung disease in siblings are reported. A 54-year-old male farmer, who had been engaged in stock work for 20 years, presented to our clinic for the second episode of fever, productive cough and shortness of breath. Chest roentgenogram revealed diffuse micronodular pattern, and mild hypoxemia was recognized on arterial blood gas analysis. Cytology obtained from BALF showed lymphocytosis, with especially increased OKT3, OKT4 positive cells and OKT4/8 ratio. The diagnosis was confirmed by highly positive reaction of precipitins to Thermoactinomyces vulgaris and granulomatous interstitial pneumonitis on histopathological examination. The second case was a 51-year-old female patient, the sister of the first case, who also worked as a stock farmer of another farm for 20 years. She presented with an episode of similar symptoms to the first case, one and a half years after the onset of her brother's symptoms. The findings of roentgenogram, BALF analysis, precipitins to T. Vulgaris and pathology were similar to those of the first case. The finding of high OKT4/8 ratio on BALF analysis in both cases is characteristic of formers lung disease, in contrast to the summer-type hypersensitivity pneumonitis which usually shows low OKT4/8 ratio in BALF. To our knowledge, this is the first report of farmer's lung disease in an area other than the northern part of Japan. Thus we conclude that farmer's lung disease may occur in Japan under any environmental conditions, and that some genetic factor may take part in the onset of this disease.


[Two cases of pericardial diverticulum].

Two cases of resection of pericardial diverticulum are reported. The lesion was located in the right upper mediastinum in case 1 (66-year-old woman) and at the right anterior cardio-phrenic angle in case 2 (20-year-old woman). In case 1, the shape of the lesion varied on fluoroscopic observation when the position of the patient was changed, and in case 2, ICG instilled into the lesion operation diffused into the pericardial cavity. These procedures seemed to be useful in the diagnosis of pericardial diverticulum, differentiating it from pericardial cyst.


[A fatal case of acute mediastinitis caused by periodontal infection].

A 57-year-old man had suffered from poorly controlled diabetes mellitus and liver cirrhosis due to alcohol and hepatitis C for about 10 years. He developed fever and swelling of the right cheek and neck due to periodontal infection. The symptoms worsened in spite of antibiotic therapy and were accompanied by dyspnea. He was therefore referred to our hospital. Chest radiographs and computed tomographs revealed widening of the superior mediastinum, pulmonary infiltrates and right pleural effusion. He was diagnosed as having mediastinitis, right pyothorax and pneumonia caused by periodontal infection. Tracheotomy and mechanical ventilation were performed. Antibiotic therapy resulted in improvement of the mediastinitis and pyothorax. However, renal and liver dysfunction developed and the patient died of multiorgan failure after 35 days of hospitalization. Death due to periodontal infection is rare. We give a review of the literature.


[A case of pulmonary alveolar proteinosis with invasion of macrophages in alveolar interstitial region].

A 24-year-old woman was admitted to our hospital on November 2, 1989 for investigation and treatment of abnormal shadows detected in her routine chest radiograph on July 19, 1989. The chest X-ray film on admission showed diffuse infiltrative shadows in the peripheral regions of the bilateral middle and lower lung fields. In addition centrilobular shadows in the subpleural regions with increases irregular densities were found on chest CT. We therefore suspected pulmonary alveolar proteinosis. Bronchoalveolar lavage from the right middle bronchus and transbronchial lung biopsy of the right upper and lower lobes were performed. Electron microscopic examination of a specimen of bronchoalveolar lavage fluid revealed many multilamellar bodies, characteristic of pulmonary alveolar proteinosis. In addition, proteinaceous material containing multilamellar bodies was observed within the alveolar lumina. We diagnosed this case as pulmonary alveolar proteinosis. Electron microscopy also revealed many macrophages in the alveolar walls, some of which contained a few or numerous multilamellar bodies within the secondary lysosomes. We treated this patient with oral and inhaled Ambroxol, with improvement of her clinical condition.


[A case of interstitial pneumonitis associated with polymyositis complicated by renal cell carcinoma].

A 55-year-old woman was referred to the department of urology in our hospital with left renal tumor, discovered during examinations at another hospital for fever and dyspnea on exertion. Because surgery was difficult due to severe hypoxemia, pulmonary function impairment (restrictive) and bilateral diffuse interstitial shadows on chest X-ray film, the patient was referred to our department. Interstitial pneumonitis was found on transbronchial lung biopsy, and serum GOT, LDH and CPK values were elevated. These symptoms and abnormalities of laboratory data were improved by administration of prednisolone 60 mg/day, and left nephrectomy was performed without any complications. Pathological examination of the surgical specimen showed clear cell carcinoma (Grawitz). Steroid therapy was tapered off and her clinical course was good. Six months after surgery, the patient developed a recurrence of fever, which was not responsive to antibiotics. Polymyositis was diagnosed on the basis of elevated serum GOT, LDH and CPK, electromyogram and muscle biopsy findings and positive anti-Jo-1 antibody. Polymyositis/dermatomyositis is sometimes associated with interstitial pneumonitis or malignant neoplasms, but rarely with both simultaneously. Moreover, renal cell carcinoma is very rare among the malignant neoplasms associated with polymyositis/dermatomyositis, and we therefore report this unusual case.


[A case of hypersensitivity pneumonitis caused by a humidifier].

A 58-year-old woman was admitted complaining of dry cough and exertional dyspnea. Physical findings, chest X-ray films, chest CT scan and respiratory function tests were suggestive of interstitial pneumonia. Transbronchial lung biopsy showed specific findings of hypersensitivity pneumonitis. As a result of positive provocation test using her home humidifier, a diagnosis of humidifier lung was made. Many microorganisms including Flavobacterium meningosepticum were cultured from the water left in the humidifier for one week. As both complement fixation test and precipitation test were positive to humidifier water and to extract of Flavobacterium meningosepticum, the humidifier and Flavobacterium meningosepticum were suggested to be causative in this case.


[Three cases of pulmonary actinomycosis].

Three cases of pulmonary actinomycosis are reported. Case 1 was a 33-year-old man complaining of hemosputum. A large mass lesion was noted in the right upper lobe and surgically resected. Actinomycosis was diagnosed pathologically. The second case was a 41-year-old man with lung abscess. An actinomyces species was cultured by percutaneous aspiration biopsy. He was effectively treated with clindamycin. The third case was a 46-year-old man with a chronic cough and cavitary lesion. Gram staining of sputum revealed sulfur granules. Piperacillin was administered with prompt response. All three cases had dental disease and two had diabetes mellitus. In patients with a mass lesion or those with lung abscess not effectively treated by cephem antibiotics, actinomycosis should be suspected especially when diabetes mellitus and/or dental disease coexists. Adequate treatment may not always require long-term antibiotics.


[A case of intractable status asthmaticus treated by isoflurane inhalational anesthesia and bronchial lavage].

A case of severe asthmatic attack treated by isoflurane inhalational anesthesia and bronchial lavage is reported. A 24-year-old woman was admitted to our hospital with severe asthmatic attack. Although she was treated by intravenous administration of aminophylline and corticosteroids, pulmonary function and consciousness deteriorated. Therefore, she was intubated nasally and mechanically ventilated by IPPV with administration of aminophylline, corticosteroids and epinephrine. Despite this treatment, she remained in status asthmaticus with high airway pressure and barotrauma causing pneumomediastinum and subcutaneous emphysema. On the 3rd hospital day, a system was arranged so that isoflurane could be given in an air and oxygen mixture, and administration was started with a concentration of isoflurane of 1.5%. In addition, bronchial lavage via bronchoscopy was performed in order to clear any mucous plugs. After 24 hours, there was marked improvement of wheezing, airway pressure and arterial blood gas level. Eventually, she was weaned from the ventilator on the 6th hospital day without significant side effects. The use of halothane inhalational anesthetic treatment for status asthmaticus is widely known, but it has serious side effects such as arrhythmia and liver injury. Isoflurane may be the inhalational anesthetic agent of choice in the treatment of status asthmaticus.


[A case of asymptomatic endobronchial lipoma followed for 4 years].

Bronchoscopy was performed on a 68-year-old male patient with pulmonary tuberculosis, and revealed a yellow smooth polypoid tumor in the lumen of the left upper division bronchus. The histopathological diagnosis of the biopsy specimen was endobronchial lipoma. Since the patient did not have any symptoms due to the lipoma, we performed treatment for tuberculosis and continued careful observation of the tumor. During the subsequent 4 years, the patient developed no complications such as obstructive pneumonia, and the size of the tumor under bronchoscopic observation did not change. Endobronchial lipoma is a very rare benign tumor. Almost all reported cases have undergone operation or endoscopic surgery. This case is the first that was followed over 4 years without surgical procedure. The findings of follow-up bronchoscopic examination suggest that the growth rate of endobronchial lipoma is very slow. Furthermore, we reviewed 36 cases of endobronchial lipoma in the Japanese literature, including our case. Smoking seems to have a strong relation to the occurrence of the tumor. It is noteworthy that 6 cases had separate malignancies, but the direct relationship between endobronchial lipoma and such malignancies is unclear.


[A case of pulmonary adenocarcinoma in a young man with multiple metastasis to the nasopharynx and paranasal sinuses].

A 36-year-old man who complained of bloody sputum showed a mass-like shadow in the right upper lung field on chest X-ray, which was diagnosed as adenocarcinoma by sputum cytology in August, 1990. Since his clinical stage was too advanced for curative operation, chemotherapy was started on October 1, 1990. On October 26, he brought up a polyp-like mass, and was found to have polypoid tumors on the bilateral tonsils and nasopharynx, which were biopsied and diagnosed as poorly-differentiated adenocarcinoma. On November 21, CT of the face showed soft tissue density tumors in the bilateral paranasal sinuses. According to the clinical course, all tumors were thought to be metastatic lesions. Since he had suffered from epistaxis and nasal obstruction due to the enlargement of metastatic tumors, nebulization chemotherapy and palliative resection were performed. In February 1991, he developed severe headache due to brain metastasis. Despite irradiation therapy, he died from cerebral intra-tumorous hemorrhage on February 22. We reported a rare incurable case of lung cancer with metastasis to the nasopharynx and paranasal sinuses.


[A case of right pulmonary hypoplasia with congenital diaphragmatic hernia and dextrocardia].

Chest X-ray of a 28-year-old woman revealed an abnormal shadow in the right lower lung field and dextrocardia, for which detailed investigation was performed. Since the CT number of the tumor shadow corresponded to that of the liver on chest CT, diaphragmatic hernia of the liver was suspected, and was confirmed by MRI and angiography of the abdomen. In addition, the pulmonary artery and vein were hypoplastic, and angiography of the pulmonary artery demonstrated pulmonary hypoplasia. This case was considered to have primary pulmonary hypoplasia, because the dextrocardia was considered to have occurred secondary to pulmonary hypoplasia and the diaphragmatic hernia of the liver was not sufficiently large to cause pulmonary hypoplasia. Pulmonary hypoplasia first diagnosed in adulthood is rare, with a clinical course and roentgenographic appearance differing from those of pulmonary hypoplasia in children.


[Percutaneous transluminal coronary angioplasty in patients with high risk bypass surgery].

The purpose of this study was to assess the immediate and long-term results of incomplete percutaneous transluminal coronary angioplasty (PTCA) in high-risk coronary artery bypass surgery (CABG) patients. 24 pts (male-22, female-2, age - 39-60 years) were divided into 2 groups: I-8 pts with unstable angina pectoris who were definitely not CABG candidates because of very low ejection fraction (LVEF < 24%) and/or diffuse coronary atherosclerosis; II-16 pts selected for CABG only after failed PTCA. From this group 12 pts with unstable angina pectoris and history of myocardial infarction were at higher CABG risk because of LVEF < 40% and diffuse coronary atherosclerosis. 4 pts were poor surgical candidates because of coexistent medical disorders. The strategy of PTCA was to dilate first the most critical (culprit) lesion, responsible for the patient symptoms, usually situated in the artery supplying large area of viable myocardium. We did not achieve: complete revascularization in all our pts (incomplete revascularization by intent). Initial success rate of the PTCA in both groups was 100%. There were no serious complications. During follow-up (6 months--4 yrs) long-term clinical improvement was observed in 7 pts from group I (87.5%) and 14 pts from group II (87.5%). We conclude, that in most pts with unstable angina pectoris and with high-risk of CABG good immediate and long-term results of incomplete PTCA can be achieved.


[Modification of atrio-ventricular conduction in treatment of supraventricular reentry tachycardia. (preliminary results)].

Intracardiac defibrillation to produce complete heart block is a modern and effective method for treatment of refractory supraventricular arrhythmias. The main drawback of this technique is the necessity of implantation of permanent pacemaker. There is however a growing interest in modification of atrio-ventricular (A-V) conduction to prevent arrhythmias without producing complete heart block. A new energy source used for this purpose is the radiofrequency (RF) current. Preliminary clinical results of modification of antegrade conduction in 5 patients with recurrent supraventricular arrhythmias are presented. HAT 100 (Dr Osypka GmbH, Germany) a high frequency generator was used for modification. Electrophysiological studies showed slow/fast type of junctional reentry tachycardia in 4 patients and paroxysmal atrial flutter with rapid ventricular response in 1. Since RF current produces much smaller and more discrete lesion, the precise localization of the active electrode was of primary importance. We manipulated the catheter, used for modification, in AV region until a relatively large atrial potential with only barely visible His bundle deflection was obtained. During reentry tachycardia the place of the earliest retrograde atrial depolarization was searched for. Current and voltage were monitored during the modification procedure. It was possible to titrate the HF energy to achieve the desired effect changing the power and the time of current application. The modification was repeated several times since PQ and AH interval increased > 50%. No prolongation of HV was noted. The modification was effective in all patients and allowed to avoid the induction of reentry despite the persistence of 1:1 AV conduction.(ABSTRACT TRUNCATED AT 250 WORDS)


[Electrocardiography of high resolution in the diagnosis of arrhythmogenic dysplasia of the right ventricle].

To assess the diagnostic value of high resolution ECG in ARVD which is a rare and diagnostically difficult disease, cardiac micropotentials were evaluated in 32 pts with ventricular arrhythmias with LBBB pattern and right axis deviation. Typical ECG-, ECHO-, angiographic features of ARVD were found in 9 pts (mean age 36 y, VT 8 pts, MAS-5). Normal right ventricle (NRV) (Echo, Tc99) was seen in 23 pts (mean age 36 y, VT-14 pts, MAS-6). 25 healthy man (mean age 28 y) served as control (C). [table: see text] Morphology of total QRS complex in pts with ARVD, comparing to NRV pts and C, was exceptionally characteristic: it was composed of high frequency notches seen not only as prolonged LP but also within fundamental QRS complex. In pts with ARVD beside presence of LP, significantly prolonged TVAT and characteristic notches within QRS complex are observed, therefore the high resolution ECG is a promising method in noninvasive diagnosis of ARVD.


[Effect of physical exercise on the function of prosthetic heart valves--evaluation by doppler echocardiography].

Although considerable data exist regarding the function of prosthetic heart valves (PHV) at rest, few data exist regarding the response to exercise. Thus, we studied by Doppler echocardiography 81 asymptomatic patients with PHV (46 mitral, 45 aortic) of varying type and 20 normal persons before and after symptom limited upright bicycle exercise. Rest and exercise hemodynamics (blood velocity, gradients, heart rate, stroke volume and cardiac output) was examined. In patients with mitral PHV maximal (Gmax) and mean (Gmean) gradients increased from 9.9 to 17.8 mmHg and from 4.4 to 7.8 mmHg (both p < 0.001), respectively. In patients with aortic PHV Gmax and Gmean increased from 27 to 42 mmHg and from 16 to 24 mmHg (both p < 0.001), respectively. Linear regression analysis demonstrated a relationship between the % change in gradient with exercise nd % change in stroke volume and cardiac output. Importantly, the largest gradient produced by exercise is related and predicted by the rest gradient. In comparison with normal valves, maximal and mean blood velocity were significantly (p < 0.001) greater across PHV, but % change in velocity with exercise did no differ significantly between prosthetic and normal valves. In conclusion, exercise Doppler echocardiography provides a good method to assess PHV function.


[Increased tension on the sympathetic nervous system in arrhythmogenic right ventricular dysplasia. Participation in etiopathogenesis?].

To evaluate the suspected role of sympathetic nerve tone in pathogenesis of arrhythmogenic right ventricle dysplasia (ARVD), noradrenaline (NOR) and adrenaline (AD) plasma levels were determined by radioenzymatic method in 10 pts with ARVD (mean age 36 y, VT-8 pts, syncope-5) at rest and during peak exercise. 9 healthy men (mean age 28 y) served as control. [table: see text] Significant increase of norepinephrine serum level during peak exercise suggests essential role of sympathetic nerve tone in pathogenesis of ARVD.


[Opinions and fears of patients waiting for heart transplantation. (results of questionnaire)].

The purpose of the study was to assess the quality of life and opinions of heart transplant candidates about transplantation and to evaluate some psychological aspects of anticipation of the procedure. The study comprised 49 patients from the Department of Cardiac and Vascular Surgery according to a list of potential candidates from January 1991. The special questionnaire prepared by the authors was applied in the study. The main topics were: severity and treatment of heart disease, method of informing about necessity of operation and basics of transplantation, factors contributing to the ultimate decision, opinions about problems of donors and psychological aspects of disease and transplantation, especially anxiety and fear. 39 answers (34 men, 5 woman, mean age--49.6 years) were received, including 10 reports of patient's death. Respondents evaluated their compensation of illness as bad or average nearly in equal proportions, 48.3% and 51.7% respectively. They were treated in the intensive care units on average 2.6 times a year. 96.6% assessed highly the method of informing about heart transplantation, consisting of a private conversation with a physician. A similar proportion of respondents (93.1%) began to show concern about problems associated with this procedure. Up to 77.8% declared the desire of increasing their knowledge on that score emphasizing the significance of information coming from physicians. The majority of respondents were interested in postoperative management--but 40.4% stated that they did not know anything about it. 58.6% consent immediately after transplantation had been proposed by the physician.(ABSTRACT TRUNCATED AT 250 WORDS)


[Programmed noninvasive stimulation of the heart ventricle transcutaneously].

Possibility of performing of a programmed transcutaneous heart stimulation by combining two, easily purchasable noninvasive cardiac stimulators was examined in 4 healthy volunteers. Combining of a SP-5 transesophageal stimulator with a transcutaneous NP-4D stimulator made conduction of the programmed cardiac stimulation possible as well as two undisturbed ECG recordings. The quality of the obtained recordings (surface and transesophageal) made estimation of the retrograde AV conductivity possible. The performed examinations point out to a practical utility of the applied combination of transesophageal and transcutaneous stimulation-for conducting of noninvasive diagnostic heart examination.


Prey-catching and predator-avoidance in frog and toad: defining the schemas.

The present model postulates the construction of motor actions through the interaction of different motor schemas via a process of competition and co-operation wherein there is no need for a unique schema to win the competition (although that might well be the result) since two or more schemas may simultaneously be active and co-operate to yield a more complicated motor pattern. Based on lesion data, our model is structured on the principles of segregation of co-ordinate systems and participation of maps intermediate between sensory and motor schemas. The motor schemas are driven by specific internal maps which between them constitute a distributed internal representation of the world. These maps collectively provide the transition from topographically-coded sensory information to frequency-coded inputs to the diverse motor schemas that drive muscle activity. We stimulate data on approach and avoidance behavior of the frog or toad under normal conditions and under lesion of different brain centers. For example, the model generates different motor zones for prey-catching behavior which match those observed experimentally in normal conditions and in the medullary hemifield deficit, and offers predictions for new experiments on both approach and avoidance behaviors.


The population genetics of alleles affecting enzyme activity.

It is possible to predict the population genetics of allozymes by assuming that fitness is proportional to flux through a biochemical pathway. The model presented here extends previous work by incorporating two additional features of biological realism. Firstly, that more than one biochemical route may exist between any two metabolites. The major routes have been identified as the classical biochemical pathways but in the event of a mutation blocking a major route, minor routes become significant. These minor routes are named "bypass fluxes" and have profound effects on the population genetics of allozymes. Secondly, recent work has suggested that a metabolic cost is associated with enzyme synthesis; this will constitute an additional selective pressure on alleles which affect the amount of enzyme synthesized. The model generates a fitness curve which predicts the fitness associated with any level of enzyme activity. It can utilize data on null or near-null, structural or regulatory, mutations in the presence or absence of bypass fluxes. When data from natural populations of Drosophila are investigated, it is concluded that selection pressures acting on enzyme variants may be much higher than previously thought.


A coupled-oscillator model of ovarian-cycle synchrony among female rats.

The ovarian cycles of female rats become synchronized when they live together, as do the cycles of many other mammals. Ovarian cycles also become synchronized when rats live apart if they share a common air supply, indicating that ovarian-cycle synchrony is mediated by pheromones. We developed a coupled-oscillator model of ovarian-cycle synchrony to test several hypotheses about its pheromonal and neuroendocrine mechanisms and to guide our experimental research. The model spans three levels of organization: the group, the rat, and the neuroendocrine components of the ovarian system. The ovarian system (not the ovaries themselves) are modeled as an oscillating system. Coupling among ovarian systems is mediated by the exchange of two pheromones, one that delays the phase of the ovarian system and one that advances it. Computer simulation experiments showed that this coupled-oscillator model can explain the levels of ovarian-cycle synchrony observed in groups of female rats while, at the same time, matching an empirical distribution of ovarian-cycle lengths. By successfully matching computer simulation data with empirical data, we were able to infer theoretical predictions in a number of areas: (1) effect of initial conditions on the probability that a group will change to different synchrony level and phase relationships, i.e. the transition probability between all synchrony levels and phase relationships; (2) effects of individual differences in pheromone sensitivity on ovarian-cycle synchrony; (3) the timing of pheromone sensitivity during the ovarian cycle; and (4) the existence of partial luteinizing hormone surges, which may cause the "spontaneous" prolonged ovarian cycles associated with ovarian-cycle synchrony. The paper concludes by discussing the integrative role of this model for experimental research. In particular, we focus on the role of this model in interpreting theoretical aspects of ovarian-cycle synchrony as well as for guiding future experimental research into its mechanisms and functions.


A general approach to genetic equilibria with an uneven sex ratio.

It is shown that in a diploid population at a genetic equilibrium with an uneven sex ratio the distribution of all (inertial) autosomal genes is symmetric between the two sexes. If several allelic genes occur in the population then the sex ratios of the various genotypes uniquely determine the uneven population sex ratio. The equilibrium is unstable to invasion by new genes which are relatively more frequent among the less numerous sex. A new proof is given to the fact that if genotype sex ratios do not change then, following an invasion by a new allele, a new stable polymorphic equilibrium can only correspond to a sex ratio which is more even than the old one. Application of these general results to a model of offspring sex determination by parents' autosomal genes shows the equilibrium to be unstable to invasion by new genes which tend to increase the production of offspring of the minority sex, as proposed by Fisher. The relevance of the Shaw-Mohler formula in this context is shown to derive from its role in describing the dynamics of autosomal genes in general. In connection with a model for offspring sex determination by one parent, a new proof is given to the fact that, following an invasion by a new allele, a new stable polymorphic equilibrium can only correspond to a sex ratio which is more even than the old one.


Natural selection and dynamical coexistence of defective and complementing virus segments.

Defective interfering (DI) particles are known to coexist with wildtype viruses under high multiplicity of infection. The complementing segments of coviruses (multiparticle, segmented viruses) coexist under similar conditions. In all cases, within-cell reproductive advantage to one of the segments is rather common. This fact, and the observation that DI particles are parasites, whereas covirus segments are mutualists, call for a non-trivial model of stable dynamical coexistence. The methodical novelty is the application of the structured deme model to virus dynamics. It assumes that biochemical ("ecological") interactions occur among segments within a coinfection group, established through random infection of the cells, and there is complete mixing of the various types emerging from all the coinfection groups (cells) in the virus pool between two infections. Through the application of the model, analytic results on the coexistence of virus segments are obtained for the following cases: virus-DI particle, virus-DI particle-resistant virus, covirus pair, virus-covirus.


Strategies in the treatment of acute myelogenous leukemia.

The current treatment of acute myelogenous leukemia is far from satisfactory despite some recent advances. This review focuses on current strategies designed to improve treatment outcome. With advances in molecular biology, the definition of a complete remission should be redefined as a molecular remission where any abnormal gene rearrangement has disappeared or a clonal remission with morphologic characteristics of a complete remission, but with detectable genetics or molecular abnormalities. Abnormal gene rearrangements permit the detection of minimal residual disease, the significance of which remains to be determined. New drug development remains an important area of research and several new drugs are active in acute myelogenous leukemia. These include etoposide, idarubicin, mitoxantrone and carboplatin. Various combinations are undergoing clinical trials. Prognostic factors which predict for outcome include phenotyping, cytogenetics, cytokinetics, drug resistance and age. Proto-oncogene expression as a predictor of response is under investigation. Post-induction therapy remains controversial and approaches have included allogeneic bone marrow transplantation, autologous bone marrow transplantation with or without purging, intensive consolidation and maintenance programs. The superiority of one approach over the other has not been firmly established. Differentiating agents such as all-trans retinoic acid, and growth factors, the latter for supportive care, or recruitment of leukemic cells into the cycle are being investigated. Understanding the mechanisms of drug resistance should lead to the development of new approaches. Thus, with knowledge generated in many areas, the future should bring increasing success in treating AML.


Phenotypic and genotypic characterization of 14 leukemia and lymphoma cell lines with 11q23 translocations.

11q23 translocation is the most popular chromosomal abnormality in infant leukemia. In adults, it is often encountered in non-Hodgkin's lymphoma (NHL). In this study, we analyzed the phenotypic and genotypic characteristics of 9 acute leukemic cell lines with 11q23 translocations and one with deletion of the 11q23 locus, nine of which were established by researchers in this group, together with 4 NHL cell lines with 11q23 translocations. All lines were considered to belong to the B-cell lineage at different stages. All 10 leukemic lines showed clonal rearrangement of the immunoglobulin heavy chain (IgH) gene: two corresponded to the B-precursor stage (CD19+, cytoplasmic mu-), while the other 8 corresponded to the pre-B stage (cytoplasmic mu+). All 4 NHL lines showed rearrangements of both the IgH and Ig kappa genes with three expressing surface Ig; specifically, mature B-cell phenotype. As for myelocytic-monocytic markers, at least one out of 4 antigens examined were positive in 8 of the 10 leukemic cell lines, while only one of the 4 NHL lines was reactive. There were essentially no clear phenotypic or genotypic differences between t(4;11) and t(11;19) cell lines, supporting the view that both diseases have similar clinicopathological characteristics. These cell lines are also valuable for cloning genes at the chromosomal breakpoints.


Differential macrophage-mediated cytotoxicity to P388 leukemia cells and its drug-resistant cells examined by a new MTT assay.

After activation by interferon-gamma (INF-gamma) and lipopolysaccharide(LPS), mouse peritoneal macrophages were cocultured with P388 parental cell line (P388/PRT) and its adriamycin (ADM)-, cisplatin(CDDP)-, cyclophosphamide(CPM)-, and mitomycin-C(MMC)-resistant cell lines for one day at effector:target ratios (E:T) of 10:1, 5:1, and 2:1. The direct 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) cleavage assay and a new indirect MTT assay as well as clonogenic assay were used to quantitate activated macrophage-mediated cytotoxicity to these non-adherent leukemia targets. The results revealed that all the P388 cell lines can be suppressed efficiently by activated macrophages, but P388 CPM- and MMC-resistant cell lines (P388/CPM, P388/MMC) were more susceptible than P388/PRT while P388 ADM- and CDDP-resistant cell lines (P388/ADM, P388/CDDP) shared equal level of survival rates with P388/PRT. This study also showed that both non-activated and activated macrophages can produce formazan in a high level, which can interfere with the final results of direct MTT assay. The new indirect MTT assay can avoid such interference by separating the effectors from the targets before performing the MTT assay and reflects the real viability of the targets so the indirect MTT assay developed in this study could be a better way to examine cytostatic and cytotoxic effect of activated macrophages on non-adherent tumor cells in vitro.


Endogenous serum levels and surface receptor expression of GM-CSF and IL-3 in patients with myelodysplastic syndromes.

The majority of patients suffering from myelodysplastic syndromes (MDS) die of complications due to cytopenia. Clinical trials have demonstrated that in an essential number of MDS patients cytopenia can be ameliorated by exogenously supplied growth factors. We investigated endogenous serum levels of GM-CSF and IL-3 in 15 healthy individuals and 34 patients suffering from MDS. No circulating growth factors were detected in the serum of healthy controls, nor was IL-3 measurable in MDS patients. GM-CSF serum levels, however, were elevated in a significant number of patients (26.5%). Levels did not correlate with FAB classification, leukocyte count or chromosomal abnormalities. No significant differences in GM-CSF or IL-3 receptor expression were detected between healthy individuals and MDS patients. One patient with increased endogenous GM-CSF serum level and normal surface receptor expression responded to exogenously applied GM-CSF. In the light of these results, a functional alteration of growth factor receptors or disturbances of signal transduction pathways must be discussed for MDS.


Acute myelocytic leukemia associated with thrombocytosis and inv 3(q21.3; q26.2) in a case of Grönbland-Strandberg syndrome.

Grönbland-Strandberg syndrome is an inherited connective tissue disorder with cutaneous, ophthalmologic, and systemic manifestations. Here we report a case of AML with thrombocytosis arising in a patient with this syndrome. Karyotypic analysis of bone marrow cells revealed the inversion 3 (q21.3;q26.2). To our knowledge, this is the first report of the association of AML with thrombocytosis and Grönbland-Strandberg syndrome. This might be a coincidental association, but it suggests some interesting speculations regarding the pathogenesis of these diseases.


Interleukin 4 potentiates the antiproliferative effect of 1 alpha, 25-dihydroxyvitamin D3 on mouse monocytic leukemia cells but antagonizes the antiproliferative effects of interferon alpha, beta and interleukin 6.

Mouse monocytic leukemia Mm cells are a line of spontaneously differentiated cells obtained from mouse myeloblastic leukemia M1 cells. The effect of interleukin 4(IL-4) on the proliferation of Mm cells in the presence or absence of growth inhibitory substances was investigated. In semi-solid agar culture, IL-4 markedly inhibited colony formation by Mm cells, reducing the number of colonies to 50% of that in control cultures at concentration of 3 U/ml. In contrast, IL-4 did not inhibit colony formation by the parent M1 cells. In liquid culture, IL-4 alone inhibited the proliferation of Mm cells only slightly. However, a combination of IL-4 and 1 alpha,25-dihydroxyvitamin D3 (VD3), which alone did not inhibit growth significantly, markedly inhibited the growth of Mm cells. This combination also increased the lysozyme activity of Mm cells significantly. On the other hand, IL-4 suppressed the antiproliferative effects of interferon alpha, beta and IL-6, which are growth inhibitory cytokines for these Mm cells. These results indicate that IL-4 can modulate the growth of monocytic leukemia Mm cells and that its modulatory effects depend on growth inhibitory substances.


CD10 antigen density in childhood common acute lymphoblastic leukaemia: comparisons of race and sex.

During the 25 month period from July 1989 until August 1991, 58 children with FAB defined acute lymphoblastic leukaemia (ALL) were referred for immunophenotypic analysis. Of these, 42 children with a common/pre-B phenotype (CD19/CD10-positive) were studied specifically to assess CD10 antigen density. A pattern of segregation was found between males and females and between black and white children. Black males, who are the worst prognostic group, had the lowest CD10 density, while white females, known to constitute the best prognostic group, had significantly higher CD10 antigen density than the other groups. Black females and white males occupied intermediate positions with respect to CD10 antigen density. A two way analysis of variance showed that although sex had contributed significantly to this variation (p = 0.0038), the contribution of race was marginal (p = 0.0530). It is hypothesized that low CD10 antigen density patterns in males and in Blacks could be causally related to poor prognosis.


FcRIII (CD16) expression on neutrophils from chronic myeloid leukemia. A flow cytometric study.

FcRIII (CD16) expression on neutrophils from 17 patients with chronic myeloid leukemia (CML) was studied by flow cytometry using monoclonal antibodies. A variable proportion of CD16-negative neutrophils were found both in CML patients in chronic phase (3 out of 8 patients) and in CML patients in hematological remission (3 out of 9 patients). Neutrophils with reduced FcRIII expression showed more defective chemiluminescence and phagocytosis than neutrophils with normal FcRIII expression. Circulating myeloid cells from three patients in chronic phase, showing a normal percentage of CD16-positive neutrophils, were isolated and fractionated by discontinuous Percoll gradients. This study showed that CD16 appears at the stage of metamyelocyte, that band cells and segmented neutrophils display an identical pattern of membrane FcRIII, and that the fluorescence intensity shown by metamyelocytes is different from that displayed by more mature cells. The association between low FcRIII expression and function abnormality could be suggestive of a defect in CML neutrophil maturation.


Has the climacteric been medicalized? A study on the use of medication for climacteric complaints in four countries.

In order to compare the use of hormone replacement therapy (HRT), non-hormonal treatment for the menopause, and tranquillizers, samples of about 300 women aged over 40 were interviewed in France, the United Kingdom, the former West Germany and Italy. The proportion of women in the samples using HRT varied from 3% in Italy to 25% in Germany. The figures for non-hormonal treatment ranged from 2-13%, and for tranquillizers from 5-28%. The use of both HRT and non-hormonal treatment was found to be related to the perimenopause and the corresponding age groups and that of HRT to higher educational level. Tranquillizer use was related to the postmenopause and lower educational level. After controlling for potential confounding effects of menopausal status, educational level, gainful employment and civil status, it emerged that HRT use rates varied significantly between the countries surveyed. It is concluded that cultural differences exist between these countries as to the prescription and acceptance of HRT.


Attitudes towards and level of information on perimenopausal and postmenopausal hormone replacement therapy among Norwegian women.

In order to investigate women's attitudes towards and level of information on perimenopausal and postmenopausal hormone replacement therapy (HRT) 1019 women over 17 years of age constituting a representative sample of the Norwegian female population were interviewed in 1990 as part of a monthly national opinion poll (response rate 96.5%). Women's magazines proved to be the most important source of information on hormone therapy. Only in the over-45 age group were doctors mentioned frequently as information sources. A high self-assessed information level was associated with a positive attitude towards hormone therapy. Those who had obtained information from a doctor were more positive than those who had not. More than half of those who expressed an opinion believed that hormone therapy increased the risk of heart infarction, stroke, breast cancer and cancer in general. There was a strong association between a negative attitude, towards using hormones and belief in an increased risk of serious disease. The women were more positive towards the use of HRT for the prevention of osteoporosis and for postmenopausal urogenital complaints than for the alleviation of climacteric symptoms.


A transdermal regimen for continuous combined hormone replacement therapy in the menopause.

Transdermal systems for oestrogen therapy in the menopause have become very popular. The compliance, however, is impeded by the cyclic addition of oral progestins which leads to monthly withdrawal bleeds. In this pilot study a skin patch releasing 0.05 mg oestradiol and 0.25 mg norethisterone acetate per day, which was originally designed for sequential therapy, was used in a continuous manner. Results were quite favourable. Menopausal complaints were efficiently relieved and the Kupperman score dropped from 27.6 to 5.0. Out of 10 women, 1 had mild breakthrough bleeding, and 7 patients recorded one or several spotting episodes, mainly within the first 3 treatment months. No endometrial hyperplasia was observed and there was no significant change in plasma lipids, i.e. cholesterol, triglycerides, HDL-, HDL2-, HDL3-cholesterol, LDL-cholesterol and apolipoproteins A1 and B. The regimen might be a useful alternative to oral continuous combined replacement therapy.


Effects on lipids and lipoproteins in women treated with oestradiol and progesterone.

Thirty women with climacteric symptoms were treated for 4 months with 2 mg 17 beta-oestradiol and different doses of progesterone (50, 100 or 200 mg). The concentrations of total and free cholesterol, phospholipids, triglycerides (TG), apoprotein A1 and apoprotein B were determined in high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) fractions and in serum. HDL levels increased and LDL levels decreased, while TG levels in VLDL remained unchanged, which indicates that the lipoprotein pattern is oestrogen-induced and that progesterone exerts little or no influence.


Effect of 17 beta-oestradiol and norethisterone acetate on vertebral bone mass and lipid metabolism in early postmenopausal women.

We studied the effects on vertebral bone density and lipid metabolism of long-term administration of 17 beta-oestradiol combined with norethisterone acetate in a 2-year prospective study carried out in 40 women, divided into 2 groups of 20 subjects. One group received treatment, while the other constituted the control group. In the untreated group, vertebral bone density was found to be decreased significantly by 1.1% at 12 months and by 4.4% at 24 months in relation to initial values (P < 0.001). Total cholesterol was significantly higher (P < 0.05) at the end of the 2-year period. By contrast, in the treated group, bone density showed significant increases of 5.6% at 12 months and 7% at 24 months (P < 0.001). Significant reductions in the biochemical markers of bone remodelling (osteocalcin and the urinary calcium/urinary creatinine ratio) were also observed. Total cholesterol, high-density-lipoprotein cholesterol, low-density-lipoprotein cholesterol and triglycerides did not change significantly during treatment. These results, as well as the good compliance with treatment (78%), suggest that this treatment regimen could be useful in the prevention of postmenopausal bone loss.


Effects of continuous and cyclic nasal calcitonin administration in ovariectomized women.

The aim of the present study was to assess the effects of continuous and cyclic salmon calcitonin (sCT) administration in the prevention of the rapid bone loss that follows ovariectomy in humans. Patients who had undergone bilateral ovariectomy 10-30 days previously received either calcium supplementation alone (500 mg/day, n = 12) or such supplementation together with nasal sCT (200 IU/day) according to a continuous (n = 20) or a cyclic (3 months on, 1 month off) regimen (n = 16) for 2 years. In the calcium-only-treated subjects urinary hydroxyproline excretion, serum alkaline phosphatase and plasma bone Gla protein levels showed a substantial increase (P < 0.01) 6 months after surgery, while radial bone density was found to have decreased significantly (P < 0.01). The patterns of biochemical markers in the sCT-treated groups indicated that nasal sCT can positively uncouple the two bone remodelling processes without inducing any significant change in radial bone density over a 2-year period. No differences were observed between the two sCT-treated groups. These results demonstrate that the rapid bone loss that follows ovariectomy can be prevented by either cyclic or continuous nasal sCT administration. Thus, cyclic nasal sCT represents an attractive alternative for the prevention of osteoporosis in postmenopausal women with contraindications to oestrogen replacement therapy.


Total and regional bone mineral content in relation to menopause.

Total body bone mineral content (TBBM) and anatomical region bone mineral content (head, trunk and extremities) were measured using dual-energy X-ray absorptiometry in 188 women aged 60 +/- 6 years, of whom 154 were normal and 34 were osteoporotic. Of the 154 normal subjects, 90 were premenopausal (40 aged 44 +/- 3 years and 50 aged 34 +/- 8 years), the remaining 64 being postmenopausal and aged 58 +/- 7 years. There were no TBBM or regional changes in the premenopausal women, whereas there was a significant reduction in bone mineral content in the postmenopausal as compared with the premenopausal women in all regions. The osteoporotic subjects showed a general decrease (P < 0.001) in all measurements which was more marked in the trunk. The rate of TBBM reduction was 16% in the normal postmenopausal women and 29% in the osteoporotic subjects. All the postmenopausal women (both normal and osteoporotic) showed lower TBBM values than those in the Wisconsin trial, similar results being obtained in the case of the premenopausal group. Such differences can only be explained by hardship experienced by these now postmenopausal women during their childhood and adolescence.


Preoperative treatment with oestradiol in women scheduled for vaginal operation for genital prolapse. A randomised, double-blind trial.

To disclose a clinical and histopathological effect of local low-dose oestradiol treatment on the vagina. A randomised, double-blind trial. Two gynaecological departments at University Hospitals. Forty-eight postmenopausal women scheduled for surgery because of genital prolapse. 25 micrograms oestradiol or placebo, administered as vaginal pessaries daily, 3 weeks prior to surgery. Cytological, histological and clinical changes of the vaginal mucosa. The thickness of the vaginal wall increased as did the oestrogenic index. No clinical effect was seen apart from decreased incidence of recurrent cystitis postoperatively. Preoperative oestrogen treatment has been shown to reduce the incidence of recurrent cystitis and may be needed for stimulation of vaginal mucosa; the short-term clinical effect is not convincing, however.


Arginine synthesis by the proximal convoluted tubule in rats with chronic renal failure.

The high plasma level of citrulline (Cit) is one of a number of abnormalities in the plasma amino acid pattern in chronic renal failure (CRF). Synthesis of arginine (Arg) from citrulline in the kidney is the major source of Arg for the body. In order to evaluate the renal activity of Arg synthesis in CRF, we studied arginine production in proximal convoluted tubules (PCT) isolated from male Sprague-Dawley rats 1 month after 5/6 nephrectomy and from sham-operated rats (n = 6 of each). PCT segments were incubated in a sealed chamber with 50 or 200 microM of [L-ureido 14C]-Cit (simulating in vivo plasma concentrations in healthy rats or rats with CRF, respectively). Arginase and urease were added to the medium to hydrolyze Arg into 14CO2 + NH3. 14CO2 was trapped in KOH and counted. Results showed that: (1) in CRF, Arg production per unit tubular length is increased in proportion to hypertrophy of PCT (x 1.5); (2) in CRF, as in the healthy kidney, Arg production increases with Cit concentration (x 2.5 from Cit 50 to 200 microM). Taking into account the hypertrophy and the elevation in Cit concentration, the increase in Arg production per unit length (x 3.6) is not sufficient to compensate for the reduction in nephron number. Most likely, a greater length of maximal tubule is recruited for renal Arg synthesis in CRF.


Ammonium chloride increases kidney cell protein content.

Augmented renal ammoniagenesis and renal hypertrophy often occur together. Ammonia may increase cell protein content by modulating protein synthesis, protein degradation, or both. We conducted experiments to examine the effect of ammonium chloride on the synthesis and degradation of protein in cultured kidney cells. Quiescent opossum kidney cells were exposed to 20 mM NH4Cl for two days. Monolayers were then analyzed for cell number, protein content, protein synthesis ([14C]valine incorporation), protein degradation ([14C]valine release) and DNA synthesis ([3H]thymidine incorporation). Cell protein content was increased by 18% in NH4Cl-treated cells (190 +/- 6 pg/cell control vs. 225 +/- 7 pg/cell NH4Cl, p < 0.001). NH4Cl suppressed protein degradation (1.36 +/- 0.02%/h control vs. 1.12 +/- 0.04%/h NH4Cl, p < 0.001) but did not change protein synthesis, DNA synthesis, or cell number. Thus, reduced protein degradation accounts entirely for enhanced protein accumulation at 2 days in this in vitro model of kidney cell hypertrophy.


Effect of protein intake and unilateral nephrectomy on renal function and eicosanoid excretion in rats.

Vasoactive eicosanoids may be involved in glomerular hyperfiltration following a high protein intake or removal of renal mass. We sequentially measured glomerular filtration rate (GFR), proteinuria (UpV), and urinary eicosanoid excretion in sham-operated (2K) and uninephrectomized (NX) rats on two diets. Compared with 12% protein (LP), 36% protein (HP) initially resulted in a higher GFR and UpV in both 2K and NX rats. Urinary excretion of 6kPGF1 alpha and TxB2 was higher on the HP diet. Ten weeks after NX, PGE2 excretion was slightly reduced, while that of TxB2 and 6kPgF1 alpha was the same as in 2K rats, indicating that the excretion per kidney had increased. From week 40, the GFR of NX rats on the HP decreased, preceded by a progressive increase in UpV. Excretion of PgE2, TxB2, and 6kPgF1 alpha was highest in the phase of proteinuric chronic renal failure. Thus, vasoactive eicosanoids are involved to maintain hyperfiltration induced by high protein intake or NX.


Involvement of renal autacoids in the direct effects of mixed amino acids on the kidney.

A pharmacological approach has been employed to investigate the involvement of renal autacoids in the direct effect of amino acids on the isolated rat kidney. The increase in renal perfusate flow induced by 6 mM mixed amino acids was inhibited by sulpiride, a dopamine antagonist. The change in GFR induced by 6 mM mixed amino acids was abolished by L-nitro-arginine methyl ester, an inhibitor of nitric oxide biosynthesis and partially inhibited by either sulpiride or indomethacin. It is concluded that several autacoids may mediate the direct effect of amino acids on the kidney with dopamine being primarily involved in hyperperfusion and nitric oxide involved primarily in hyperfiltration.


Effect of diet composition on renal morphology in diabetic rats.

Streptozotocin-induced diabetic rats were fed rodent diets with standard (4.5%) or high (10%) polyunsaturated fatty acid content for up to 12 months. Diabetic rats fed a standard diet developed thickening of glomerular basement membrane (GBM) when compared to similarly fed controls (285 +/- 21 vs. 243 +/- 18 nm, respectively; p = 0.0003). No differences in GBM thickening were observed between control and diabetic rats fed high-fat diets (188 +/- 23 vs. 195 +/- 21 nm, respectively; p = n.s.). Regardless of diabetes, all rats fed high polyunsaturated fat diets had decreased GBM thickness compared to standard-fed rats (p = 0.0001). Glomerular and mesangial volumes were similar in control and diabetic rats fed standard or high fat diets. Diets high in polyunsaturated fatty acids prevent GBM thickening in diabetes and reduce GBM thickness in control rats.


Relationships between oxidant and non-oxidant mechanisms in the pathogenesis of acute renal failure.

During the past several years studies using freshly isolated proximal tubules in suspension have contributed to understanding several of the major cellular processes underlying ischemic and related forms of acute renal failure. Tubules have a large capacity to augment their intracellular ATP content when supplemented with exogenous purines. This process has been shown to be mostly explained by adenosine uptake. Reductions of cell pH such as occur prominently during ischemia strongly protect tubules against a variety of insults. Increases of cytosolic free calcium to micromolar levels are highly damaging to tubules and do occur prior to lethal cell injury induced by ATP-depleting metabolic inhibitors, but do not critically determine the outcome in the latter setting. Given their ubiquitous occurrence and well-documented importance in a variety of systems, reactive oxygen metabolites play a surprisingly small role in oxygen deprivation-induced injury to isolated tubules. Several small neutral amino acids, glycine being the prototype and most potent, have a critical, constitutive effect to maintain tubule cell structural integrity during a variety of acute insults.


Mechanism of organ dysfunction in phosphate depletion: a critical role for a rise in cytosolic calcium.

Phosphate depletion (PD) is associated with multiorgan dysfunction. It has been proposed that this phenomenon is due to two metabolic derangements: (a) there is a reduction in ATP content of cells and hence reduced availability of energy-rich phosphate compounds, and (b) there is a decrease in 2,3-diphosphoglycerate in red blood cells, a change that would increase the affinity of hemoglobin to oxygen resulting in tissue hypoxia. Recent studies have demonstrated that PD is associated with a significant elevation in basal levels of cytosolic calcium [Ca2+]i in many cells. This is due to an increased entry into and decreased extrusion of calcium out of cells. This rise in [Ca2+]i plays a major role in organ dysfunction in PD and in the genesis of decreased ATP content of cells.


Hypoxia-induced von Willebrand factor release is blocked by verapamil.

Hypoxia-induced stimulation of the rate of von Willebrand factor (vWF) release from human umbilical vein endothelial cells in culture, and the influence of the calcium antagonist verapamil, was studied using a system in which a pO2 of 20 mm Hg was achieved over 60 min. The mean +/- SEM rate of vWF release over 60 min in normoxia was 0.42 +/- 0.07% pooled plasma standard. The addition of verapamil did not alter the basal rate of vWF release, but after 60 min of hypoxia, the rate was increased to 0.71 +/- 0.03% plasma standard (p < 0.01). Verapamil at a concentration of 0.1 microgram/ml of media had no influence on the stimulated rate of release (0.78 +/- 0.07%), but increasing concentrations of verapamil up to a maximum of 1 microgram/ml attenuated the hypoxia induced stimulation (0.48 +/- 0.07%; p = 0.04 vs. hypoxic control). Thus, verapamil at this concentration completely blocked the hypoxia-induced stimulation.


Effect of hemodialysis on intracellular calcium in human polymorphonuclear neutrophils.

Hemodialysis (HD) leads to neutrophil activation depending on the membrane material used. Calcium plays a major role in PMN function and metabolism. A rise of cytosolic free calcium [Ca2+]i is an important intracellular messenger for neutrophils. In this study we measured intracellular resting Ca2+ and the chemotactic peptide FMLP-stimulated intracellular Ca2+ during HD using membranes made of polysulfone and polymethylmethacrylate (PMMA). Also, we investigated the effect of continuous infusion of nifedipine in a dose of 18 micrograms/kg/h during HD with PMMA. Only HD with PMMA causes an increase of both resting and FMLP-stimulated [Ca2+]i after 30 min of starting HD. Polysulfone did not affect [Ca2+]i. Continuous infusion of nifedipine during HD with PMMA completely inhibited these changes of [Ca2+]i. Although the existence of voltage-sensitive calcium channels has not been proved, the present data provide further indirect evidence either for the existence of calcium channels or for a mechanism of action that is independent of antagonism.


The vitamin D/parathyroid hormone axis in the pathogenesis of hypertension and insulin resistance in uremia.

Recent evidence suggests a pathogenetic link between hypertension and insulin resistance. In addition, disturbances of vitamin D/parathyroid hormone axis have been reported in various hypertensive and insulin-resistant states. Chronic renal failure is characterized by high incidence of hypertension, insulin resistance and disturbances in the vitamin D/parathyroid hormone axis. Preliminary studies in both patients and rats with end-stage renal disease who were hypertensive, insulin resistant and 1,25-dihydroxycholecalciferol deficient with hyperparathyroidism; parenteral administration of pharmacological doses of 1,25-dihydroxycholecalciferol led to reversal of hypertension and insulin resistance without significant changes in serum calcium or parathyroid hormone concentrations. Thus, vitamin D deficiency may be an important factor in the pathogenesis of hypertension and insulin resistance in end-stage renal disease.


Use of oral stable strontium to provide an index of intestinal calcium absorption in chronic ambulatory peritoneal dialysis patients.

Recent interest in the role of oral calcium carbonate and low calcium dialysate has emphasised the need for a simple, safe and inexpensive test of intestinal calcium absorption. The stable, non-radioactive, strontium absorption test fits these requirements. Stable strontium and calcium-45 were administered simultaneously to 19 fasting CAPD patients and their serum levels were subsequently measured. There was a close correlation between the absorption of calcium and strontium at both 60 and 120 min post-ingestion. The two markers resulted in the same classification of patients as normal or malabsorbers in 18 of 19 cases (95%), suggesting that strontium could be substituted for calcium-45 in a 60-min test of absorption enabling safe, simple and repeated measurements in renal failure patients.


Changes in total body bone mineral content and regional bone mineral density in renal patients following renal transplantation.

We performed serial measurements of total body bone mineral content (BMC) and bone mineral density (BMD), and of regional BMD at the lumbar spine and femoral neck using dual energy X-ray absorptiometry. Twenty-six patients (15 females and 11 males) were studied at the time of transplantation, and 3 and 6 months post-transplant. At baseline, the total body BMC and regional BMD values of the patients did not differ significantly from age- and sex-matched controls. Total body BMC had fallen progressively at 3 months, followed by partial recovery at 6 months. Significant decreases of BMD were seen in the lumbar spine and femoral neck at 3 months with no evidence of recovery at 6 months. The changes in these indices correlated well with the duration of hospital stay in the first 3 post-transplant months. This preliminary study demonstrated rapid deterioration of skeletal integrity following renal transplantation and that this might be progressive. Preventative strategies to avoid this early bone loss may need to be investigated.


New insights into endocrine disturbances of chronic renal failure.

Secondary hyperparathyroidism occurs in the very early stages of renal failure. In the past, there has been considerable controversy concerning the signal triggering secondary hyperparathyroidism. Recently, it has become clear that secondary hyperparathyroidism is, at least to a major extent, the consequence of the deranged endocrine feedback between calcitriol, the secretory product of renal 1-alpha-hydroxylase, and parathyroid hormone. Another recent insight concerns disturbances of the secretion of hypophyseal hormones. These hormones, e.g. GH, gonadotropins and TSH, are secreted in a pulsatile fashion. For all three hormones, reversible abnormalities of secretory rhythmicity have been demonstrated in renal failure. Disturbed oscillatory patterns of hormone secretion provide a new dimension to our understanding of the genesis of endocrine disturbances.


Effect of malnutrition and uremia on impaired cellular host defence.

There is a high incidence of infection in hospitalized patients with chronic renal failure. Nutritional and metabolic factors, as well as vitamins and trace elements are involved in impaired host defence and altered PMN function in dialysis patients. A circulating peptide (GIP) could be isolated from uremic serum that inhibits PMN glucose uptake, chemotaxis, oxidative metabolism and intracellular killing of Staphylococcus aureus. In addition to enhanced susceptibility to infection by impaired PMN function, uremic patients show profound defects of specific immune system represented by monocytes, B cells and T cells. T cells show decreased proliferation and Il-2 production on the one hand and enhanced Il-2 receptor expression on the other. Monocytes fail to elicit adequate help for T cell proliferation despite normal production of Il-1 and Il-6, but they produce elevated amounts of TNF alpha. B cells secrete decreased amounts of IgG and respond insufficiently to various vaccines. Malnutrition and uremia induce severe alterations of host defence and specific immune system if a combination of both these diseases occur.


Ketone body-induced dissociation between hepatocyte gluconeogenesis and ureagenesis in acutely uremic rats.

Ketone body production in isolated liver cells and the effect of ketone bodies on hepatocyte urea and glucose production were investigated in acutely uremic rats. Blood beta-hydroxybutyrate levels of starved acutely uremic rats were reduced compared to starved sham-operated controls, suggesting a failure to develop hyperketonemia. On the other hand, beta-hydroxybutyrate concentration is elevated in the liver. Hepatocyte beta-hydroxybutyrate production of acutely uremic animals is enhanced using serine as a substrate. Addition of ketone bodies abolishes this effect. Blood acetoacetate levels of starved acutely uremic rats are elevated compared to sham-operated controls. Liver acetoacetate concentration is unchanged in acute uremia. Hepatocyte acetoacetate production of acutely uremic rats is stimulated using serine and alanine as substrates. Again, this effect is reversed by addition of ketone bodies. Addition of ketone bodies does not affect enhanced glucose production from serine or alanine in hepatocytes of acutely uremic rats but decreases markedly enhanced urea production from serine (156 +/- 35.2 versus 27.4 +/- 7.1) and alanine (80.0 +/- 22.3 versus 42.0 +/- 4.4 nmol mg-1. 30 min-1), especially after bilateral nephrectomy. The data show that the two processes of gluconeogenesis and ureagenesis can be dissociated in hepatocytes of bilaterally nephrectomized rats by the addition of ketone bodies. The finding that ketone bodies decrease the rate of urea production may be worth further study.


Creatine and creatinine metabolism in uraemia.

Measurements of serum creatinine to monitor the progression of chronic renal failure may be misleading and influenced by factors other than GFR. Creatinine is produced by the degradation of creatine which is stored in muscle. The effect of biochemical changes observed in uraemia on the transport of [1-14C]creatine were examined in a cultured muscle model. In a Na-free medium flux of [1-14C]creatine was reduced (p < 0.001), however the addition of various uraemic toxins, insulin, parathyroid hormone and the alteration of pH had no effect on creatine influx. The variance of red cell creatine levels in uraemic patients was significantly different from controls (p < 0.02) and the plasma to red cell creatine gradient was low in some patients.


Increased plasma homocysteine concentration in patients with chronic renal failure.

Since moderate hyperhomocysteinemia is associated with premature occlusive arterial disease, a frequent complication in uremic patients, we prospectively determined fasting plasma concentration of total homocysteine (Hcy) in 79 nondialyzed patients (47 males) with chronic renal failure. None received folate supplementation. Mean (+/- SD) Hcy concentrations were 16.2 +/- 8.1, 23.3 +/- 14.7 and 29.5 +/- 14.4 mumol/l in patient groups with creatinine clearance (Ccr) of, respectively, 30-75, 10-30 and < 10 ml/min, and significantly higher (p < 0.01) than in 45 healthy controls (8.2 +/- 2.2 mumol/l). Linear regression analysis showed a significant negative correlation between Ccr and Hcy (r = 0.40, p < 0.01). Among 37 male patients aged > or = 50 years, Hcy was significantly higher in 15 who had clinical evidence of occlusive arterial disease than in 22 who did not (28.9 +/- 13.3 vs. 17.8 +/- 8.9 mumol/l, p < 0.01). We conclude that hyperhomocysteinemia is present from the early stage of chronic renal failure and may constitute a risk factor for premature arteriosclerosis in uremic patients.


Increased concentrations of Apo B-containing triglyceride-rich lipoprotein particles in patients with chronic renal failure.

The dyslipoproteinemia of chronic renal failure (CRF) was characterized by discrete Apo B-containing lipoprotein particles separated by sequential immunoprecipitation of VLDL, IDL and LDL with antisera to Apo E and Apo C-III. CRF patients before and during dialysis had increased concentrations of Apo B-containing lipoproteins (LP) due to increased levels of triglyceride-rich LP-B:C and LP-B:C:E particles with no significant change in the levels of cholesterol-rich LP-B. Patients on hemodialysis had lower concentrations of LP-B:C and higher concentrations of LP-B:C:E than predialytic patients. The increase of Apo B-containing lipoprotein particles in CRF may contribute to atherosclerotic vascular disease and to glomerulosclerosis and progression of renal insufficiency.


Effect of dietary manipulation on the lipid abnormalities and urinary protein loss in nephrotic patients.

We performed two trials. The former was a multicentric trial on 24 untreated patients with nephrotic syndrome due to membranous nephropathy to ascertain whether or not a long-term reduction of protein intake reduces urinary protein loss. In a randomized cross-over design the patients ate sequentially each for 3 months a normal protein diet (1.1 +/- 0.3 g/kg/day of proteins) and a low-protein diet (0.7 +/- 0.1 g/kg/day). Both diets were low in fat (< 30% of total calories). Neither urinary protein excretion nor serum albumin concentration were significantly different at the end of the low protein diet period or the normal protein diet period. We found that after 6 months of dietary manipulation serum total and LDL-cholesterol were reduced by 24 and 27% from the values at the beginning of the run-in period, also the mean 24 h proteinuria was significantly lower. In the later trial, after a baseline control period of 2 months on free diet, 20 untreated nephrotic patients were fed for two months a vegetarian soy diet, low in fat (28% of total calories) and in proteins (0.71 +/- 0.36 g/kg ideal body weight/day). At the end of the diet period all patients ate the same free diet as in the baseline period for 2 more months. The soy diet induced highly significant decreases in total serum cholesterol (28%). LDL-cholesterol (33%), apolipoprotein B (19%), urinary protein excretion (32%), that reversed on discontinuation of the diet.(ABSTRACT TRUNCATED AT 250 WORDS)


Protein restriction affects fat intake and serum lipids in children with chronic renal failure.

Cardiovascular complications in patients with chronic renal failure have been associated with the hyperlipidemia present in many of these patients. Since a protein-restricted diet is often prescribed in an attempt to preserve renal function, we performed a randomized controlled study in children with chronic renal failure on the effect of a protein-restricted diet on fat intake and serum lipid profiles. Although total fat intake did not change, we found a lower cholesterol intake and a higher polyunsaturated/saturated fat ratio in the patients with the protein-restricted diet. This is probably caused by the restriction of animal protein which results in the replacement of animal fat by vegetable fat in the protein-restricted group. Moreover, we observed an increase of plasma cholesterol and low-density lipoprotein cholesterol in patients with a normal protein intake which was absent in the protein-restricted group. This suggests a favourable effect of the institution of a protein-restricted diet on lipid intake and plasma profile.


Nephrotic hyperlipidemia: primary abnormalities in both lipoprotein catabolism and synthesis.

One of the most prominent manifestations of the nephrotic syndrome is hyperlipidemia. Lipoprotein synthesis is increased and catabolism is reduced in nephrotic patients and animals. The observation that infusion of either albumin or dextran reduces lipid levels suggests that oncotic pressure (pi) may regulate lipogenesis. It has been postulated that prolonged plasma half-life of lipoproteins in nephrosis is a consequence of saturation of catabolic sites and is secondary to the hyperlipidemia that results from increased lipogenesis. However, the absolute rate of triglyceride catabolism is reduced in nephrotic rats in comparison to normal suggesting that defective lipid catabolism may be a cause rather than a consequence of hyperlipidemia. Furthermore, chylomicrons (CM) and very-low-density lipoproteins (VLDL) are cleared normally in rats with hereditary analbuminemia despite increased lipid synthesis. When we cause proteinuria in analbuminemic rats, the clearance of CM and VLDL becomes greatly prolonged, suggesting that proteinuria, and not reduced serum albumin or pi, is responsible for defective lipoprotein catabolism. Maneuvers that reduce proteinuria, such as administration of an angiotensin-converting enzyme inhibitor, reduce lipid levels in nephrotic patients and animals even when plasma albumin concentration is unchanged supporting a hypothesis that proteinuria may lead to reduced catabolism of lipoproteins.


Muscle protein turnover and amino acid metabolism in patients with chronic renal failure.

Muscle protein turnover and amino acid (AA) exchange were studied in 4 patients with chronic renal failure (CRF) and in 5 controls in the postabsorptive state by using the forearm perfusion method together with the systemic infusion of 3H-Phe. In CRF patients muscle protein breakdown is increased and is associated with a parallel increase in protein synthesis. Protein breakdown is inversely related to arterial bicarbonate. Net proteolysis is unchanged. The release of total AA, glutamine and alanine is not different from controls, whereas the release of valine and leucine is reduced and serine uptake tends to be decreased. In conclusion, in postabsorptive patients with CRF, well before the uremic stage, an increased protein breakdown associated with metabolic acidosis takes place; net proteolysis is unaffected. Alterations in BCAA metabolism suggest the occurrence of increased BCAA degradation proceeding beyond the transamination step.


Protein synthesis in skeletal muscle of uremic patients: effect of low-protein diet and supplementation with ketoacids.

The purpose of this study was to investigate the modifications of muscle protein synthesis activity in uremic patients fed a low-protein diet and a low-protein diet supplemented with a keto acid-amino acid mixture. The protein synthesis activity was evaluated in vitro on isolated muscle ribosomes incubated in a cell-free medium with tritiated leucine. Simultaneously, nitrogen kinetics and amino acid patterns were examined. Protein synthesis activity is correlated with the protein content of the diet in uremic patients. The keto acid-amino acid supplementation enhances protein synthesis. Variations of protein synthesis can be correlated with the variations of nitrogen balance which implies a major role of protein synthesis activity in muscle protein metabolism. Variations in plasma levels of the essential amino acids, mainly leucine and valine, can be correlated with the variations of protein synthesis activity, and these amino acids seem therefore to be mediators of the dietary effects on protein synthesis in uremia.


Muscle protein synthesis is impaired in nephrotic rats.

Muscle protein synthesis is impaired in nephrotic rats: muscle and hepatic protein synthesis was measured as the incorporation of [3H]phenylalanine [3H]phe) into muscle and liver in male Sprague-Dawley rats with passive Heymann nephritis (HN) in comparison to both normal male (SDM) and female Sprague-Dawley rats (SDF). Incorporation of [3H]phe was significantly less muscle in HN (1.55 +/- 0.08 x 10(4) cpm/g muscle/h) than in SDM (2.55 +/- 0.14 x 10(4), p < 0.01) and no different than in SDF (1.64 +/- 0.23 x 10(4)). Growth rate was also significantly less in SDF and HN compared to SDM. Total [3H]phe incorporation and the % of [3H]phe incorporated into muscle correlated inversely with urinary albumin excretion in HN (p < 0.01) but not with serum albumin. In contrast, [3H]phe incorporation was increased in livers of HN (13.89 +/- 0.99 x 10(3) cpm/g rat/h) compared to either SDM (5.96 +/- 0.38 x 10(3), p < 0.01) or SDF (4.71 +/- 0.35 x 10(3), p < 0.01). Total liver mass, liver protein content, and the ratio of liver weight/body weight were all increased in HN. There were no differences in liver weight, liver protein content, or the ratio of liver weight/body weight between SDM and SDF. We have previously shown that decreased muscle protein accrual in HN cannot be overcome by increasing dietary protein intake. Hepatic protein synthesis and mass are increased in proteinuric rats while muscle protein synthesis is reduced. As a consequence growth rate and muscle protein accrual are diminished in nephrosis. The mechanism responsible for reduced muscle protein synthesis in the nephrotic syndrome is unknown.


Mechanisms for protein catabolism in uremia: metabolic acidosis and activation of proteolytic pathways.

Accelerated protein catabolism in uremia occurs in animals and patients with acute (ARF) and chronic renal failure (CRF). Possible causes include resistance to both insulin-induced inhibition of protein-degradation and insulin-induced stimulation of protein synthesis. The mechanisms for these effects are unknown. However, metabolic acidosis has been shown to increase proteolysis in rat skeletal muscle even in the presence of insulin and this effect is absent in adrenalectomized rats. Similarly, metabolic acidosis accounts for increased muscle proteolysis in rats with CRF. Metabolic acidosis also stimulates branched-chain amino acid (BCAA) breakdown by increasing the activity of branched-chain keto acid decarboxylase. Uremia causes high corticosterone levels in ARF and CRF and this hormone could contribute significantly to increased proteolysis, BCAA-breakdown and possibly, the inhibition of protein synthesis. Besides changing glucocorticoids, uremia could inhibit the activity of transporters which regulate intracellular pH and ultimately, the metabolism of protein and amino acids. For example, uremia inhibits ion transporters including Na/H exchange in a variety of tissues and therefore, could increase the susceptibility to metabolic acidosis. Research directed at identifying specific, proteolytic pathways stimulated by metabolic acidosis has excluded a major role for Ca2+ activated and lysosomal proteases and suggests activation of an ATP- and ubiquitin-dependent proteolytic pathway.


Hepatic glutamine metabolism and acid-base regulation.

Switching of hepatic nitrogen disposal from urea synthesis to glutamine production has been proposed as a mechanism for countering acidosis, with glutamine synthesis providing a route for the detoxification of ammonium not incorporated into urea. Isolated livers from starved rats were perfused with ammonium (0.8 mM); increasing perfusate lactate concentration 0-2 mM raised glutamine synthesis threefold whilst increasing perfusate glucose concentration 0-20 mM did not. This was true under normal and acidotic conditions. In the presence of both substrates plus either 14C-glucose or 14C-lactate, the mean specific activity of glutamine synthesised was greater for 14C-lactate. Thus, the preferred substrate for hepatic glutamine synthesis is lactate, a proton neutral reaction. Perfusion with lactate and glutamine over the pH range 6.9-7.5 with or without the glutamine synthase inhibitor L-methionine-s-sulphoxime showed that the switch in acidosis to net glutamine production is entirely due to inhibition of glutamine removal by periportal hepatocytes.


Severity of chronic metabolic acidosis and growth of rats with chronic uremia.

To determine what levels of chronic metabolic acidosis affect growth in uremia, we compared two groups of uremic rats receiving a 30% protein diet. This diet induced acidosis in A rats (n = 52; pH: 6.9-7.35) which was prevented by the addition of NaHCO3 in the diet of B rats (n = 52; pH: 7.38-7.46). A rats were separated into five groups by increasing severity of acidosis and were matched with B rats of similar renal function. Comparison between A and B rats showed: (1) no difference in food intake; (2) a reduction of weight gain only for severe acidosis with pH around 7.20 or less; (3) a reduction of length gain which was observed for less severe acidosis than reduction of weight gain, but which did not exist for marginal acidosis (pH > 7.25).


Metabolic acidosis accelerates whole body protein degradation and leucine oxidation by a glucocorticoid-dependent mechanism.

Previous work documented an acceleration of proteolysis and branched-chain amino acid oxidation when muscles from rats with chronic metabolic acidosis were incubated in vitro. The present study examines the impact of chronic metabolic acidosis on whole body amino acid turnover and oxidation in chronically catheterized, awake, male Sprague-Dawley rats using stochastic modeling and a primed continuous infusion of L[1-14C] leucine. Whole body protein turnover was accelerated by acidosis as reflected in a 70% increase in proteolysis and a 55% increase in protein synthesis. Amino acid oxidation was increased by 145% in rats with acidosis relative to control rats receiving diets identical in protein and calories based on a reciprocal pool model and plasma alpha-ketoisocaproate specific radioactivity. These changes were accompanied by a 104% increase in liver branched-chain ketoacid dehydrogenase (BCKAD) activity in rats with acidosis, similar to previously documented increases in skeletal muscle BCKAD activity caused by acidosis. In contrast, kidney BCKAD activity was decreased by 38%, illustrating the tissue specificity of the changes that were present. We conclude that chronic metabolic acidosis accelerates whole body protein turnover and reduces the efficiency of protein utilization by accelerating amino acid oxidation. These changes may require an intact glucocorticoid axis.


Protein synthesis and growth in uremic rats with and without chronic metabolic acidosis.

The effects of uremia-induced chronic acidosis on fractional protein synthesis rate (FSR), degradation (FDR) and protein tissue growth (FRG) in skeletal muscle were examined in young rats fed a 30% protein diet. This diet induced acidosis in UA rats, which was corrected by NaHCO3 supplementation in UB rats. Blood pH and plasma HCO3- were 7.22 +/- 0.01 and 15.2 +/- 0.8 mmol/l in UA rats vs. 7.41 +/- 0.01 and 25.8 +/- 0.9 in UB rats. Both UA and UB groups had similar renal function and food intake. Acidosis impaired weight gain (4.0 +/- 0.3 vs. 5.0 +/- 0.4 g/day, p < 0.05) and length gain (0.31 +/- 0.02 vs. 0.42 +/- 0.02 cm/day, p < 0.001). UA and UB rats showed similar muscle FSR (10.4 +/- 0.5 vs. 10.8 +/- 0.5%/day) and RNA content (6.3 +/- 0.2 vs. 6.2 +/- 0.2 micrograms/g protein). UA rats had lower FGR than UB rats (3.9 +/- 0.8 vs. 5.9 +/- 0.6%/day, p < 0.05). Therefore, muscle FDR was increased in UA rats (6.30 +/- 0.99 vs. 5.10 +/- 0.7%/day).


Expression of insulin-like growth factor in adult and embryonic kidney.

Insulin-like growth factors (IGFs) I and II are proinsulin-like peptides. IGF I is produced in adult and embryonic kidney. It is likely that IGF I produced locally in adult kidney regulates processes of renal transport, metabolism and growth. Renal IGF I production is stimulated by growth hormone (GH) and by epidermal growth factor (EGF). The identity of additional factors that regulate IGF I gene expression in settings such as compensatory hypertrophy and diabetes mellitus is unknown. IGF I and IGF II produced in embryonic kidney promote the metanephrogenic process. The identity of factors that regulate metanephric IGF gene expression is yet to be determined.