Endocrine dysfunction after total body irradiation and bone marrow transplantation

The present report describes our data regarding changes of endocrine parameters after total body irradiation (TBI) and bone marrow transplantation (BMT). Endocrine glands are usually resistant to irradiation under morphological aspects. But new methods of determination and sensitive tests were developed in the last few years. Now it is possible to detect already small functional changes. Endocrine studies in the course of the disease were followed serially at 16 patients with TBI and BMT. Pretransplant conditioning consisted of single-dose irradiation combined with a high-dose, short-term chemotherapy. Reactions of the endocrine system showed a defined temporary order. Changes of ACTH and cortisol were in the beginning. The pituitary-adrenal cortex system responds in a different way. The pituitary-thyroid system develop a short-term "low-T3-syndrome" reflecting the extreme stress of the organism. At the same time we obtained an increase of thyroxine. Testosterone and luteotropic hormone, the sexual steroids showed levels representing a primary gonadal insufficiency. The studies in the posttransplant period yielded a return to the normal range at most of the hormonal levels with the exception of the sexual steroids. Sterility is one of the late effects of TBI. A tendency towards hypothyroidism could be noticed in some cases being only subclinical forms. Reasons and possible therapy are discussed.     

Acute zincteral oral poisoning

Zinc vapour poisoning by inhalation in the form of zinc fever is more frequent than oral zinc product poisoning, the product used in therapy. The main aim of the study was the evaluation of clinical manifestation present after Zincteral ingestion as well as attempt to find the relationship between the presence and aggravation of the clinical manifestation and zinc level in the blood. The course of acute clinical suicidal poisoning by ingestion of Zincteral 50 tablets (10.0 g) and 100 tablets (20.0 g) is presented. The clinical picture revealed the following symptoms and signs: tachycardia, changes of arterial BP, vascular shock; dyspeptic nausea, vomiting cramps in abdominal region, diarrhoea. Damage of the parenchymatous organs, mainly liver was evident. In pregnant woman (9-week-pregnancy) on the 12-th day of her stay in the Clinic complete miscarriage took place accompanied by haemorrhage from reproductive organs. The kind and exacerbation of the clinical manifestations in relation to the zinc level in body fluid were analysed.     

Assessment of DNA damage in canine peripheral blood and bone marrow after total body irradiation using the single-cell gel electrophoresis technique

DNA damage in single peripheral blood (pb) and bone marrow (bm) cells was studied in dogs which were exposed to total body X-ray irradiation (TBI) with a lethal dose of 3.9 Gy. The changes in pb and bm cell numbers were measured within 9 days after TBI. Using the alkaline single-cell gel electrophoresis technique (‘comet’ assay). DNA strand breaks and alkali labile sites were assessed in single cells derived from the blood before TBI, 1 h and 4 h after TBI and on days 1, 3 and 9 after TBI. Bone marrow cells subjected to the assay were collected before and on days 1 and 9 after TBI. Cells expressing the strongest DNA damage were most frequent in the blood 1 h after TBI and in the bone marrow 1 day after exposure. Thereafter, a continuous reduction of DNA damage in individual cells was observed in the course of progressive leukopenia and granulocytopenia.     

Experience with aprepitant in the prevention of nausea and vomiting caused by highly emetic chemotherapy of lung cancer

Approximately one half of cancer patients experience nausea or vomiting during chemotherapy containing high-dose cisplatin, despite the use of a corticosteroid and 5-hydroxytryptamine(3) (5-HT(3)) receptor antagonists. The addition of aprepitant, a neurokinin 1 receptor antagonist, improves control of emesis by a further 15-20%, and improves late phase symptoms (>24 h after chemotherapy). The cornerstone of standard first line lung cancer chemotherapy is high-dose cisplatin. Our experience with aprepitant in the chemotherapy of 10 lung cancer patients is described, who reported more than one episode of vomiting caused by chemotherapy despite the use of ondansetron previously. Aprepitant prevented acute and late phase oncoming vomiting in all 10 patients and acute and late phase nausea in 9 of the 10 patients. According to our experience on a limited number of patients, aprepitant may be of clinical benefit in the supportive treatment of lung cancer, in achieving better quality of life during chemotherapeutic cycles in these patients.     

Breath ethane generation during clinical total body irradiation as a marker of oxygen-free-radical-mediated lipid peroxidation: A case study

Total body irradiation (TBI) is used therapeutically for treatment of leukemias and other malignancies of the hemopoietic system. Ionizing radiation produces oxygen free radicals that contribute to cytotoxicity. Breath collected from one patient undergoing therapeutic TBI showed measurable changes in levels of ethane during treatment. Breath ethane is a marker of lipid peroxidation of n-3 fatty acids. The TBI treatment involved 4 days of irradiation. The largest changes in breath ethane occured on Day 2. The increased levels of breath ethane on Day 2 were correlated to clinical manifestations of toxicity. The correlation of the onset of gastrointestinal side effects with higher levels of breath ethane suggests that breath ethane may be a clinically useful measure of the toxicity of various TBI fractionation treatment protocols currently in use at different medical centers. The levels of breath ehtane on the other days of treatment were lower, suggesting that the oxidative-antioxidative balance of the patient may be important in protection against free radical mediated injury. These results for a single patient suggest that breath ethane may be a promising approach to elucidate the role of antioxidants in clinical TBI and should be extended for verification to a larger volunteer patient population.     

全身放疗在造血干细胞移植中的研究进展

全身照射疗法(TBI)是一种姑息治疗,该方法已经成功地应用在慢性淋巴细胞白血病或滤泡性淋巴瘤等无干细胞支持的放射敏感的疾病中。目前,在血液系统恶性疾病中造血干细胞移植是较为有效的治疗手段之一,其中全身放射治疗与大剂量化疗是造血干细胞移植疗法的经典预处理方案。TBI方法主要应用在造血移植环境中,具有较强的周期非特异性抗肿瘤效应和免疫抑制效能。TBI给予干细胞移植病人超过正常骨髓的辐射耐受量,通过重建病人的造血和免疫来达到治疗目的。     

Treatment effect and safety of EPs® 7630-solution in acute bronchitis in childhood: Report of a multicentre observational study

An open post-marketing surveillance study was conducted to examine the treatment effect and safety of EPs^® 7630-solution in the treatment of acute bronchitis in children.This study included a total of 742 children (aged between 0 and 12 years) with acute bronchitis (83.4%) or acute exacerbations of chronic bronchitis (14.3%), who were treated with different doses of the herbal drug for up to 14 days. Five bronchitis specific symptoms (BSS) were summed up to give an overall measure of disease severity. Non-specific disease symptoms (loss of appetite, diarrhoea, headache, vomiting, and fever) were also recorded, together with adverse events and overall ratings of efficacy and tolerability.The overall BSS score decreased during treatment from 6.0±3.0 points at baseline to 2.7±2.5 points after 7 days and to 1.4±2.1 points after 14 days. Remission or improvement in at least 80% of patients was recorded for all the individual component symptoms. The proportion of patients suffering from non-specific symptoms also substantially improved during treatment. For example, loss of appetite was present in 65.8% of patients at study begin, but only in 27.6% at the time point of last observation visit. In 88.3% of cases, the responsible physician rated the treatment as successful. Adverse events were minor and transitory.In conclusion, EPs^® 7630-solution was shown to be a safe and an effective treatment option for acute bronchitis or acute exacerbations of chronic bronchitis in children.     

Late effects of cyclophosphamide and total body irradiation as a conditioning regimen for bone marrow transplantation in rats (a preliminary report)

The longterm survival and occurrence of neoplastic and nonneoplastic lesions following total body irradiation (TBI), 8.5 Gy, with or without additional cyclophosphamide (Cy; 100 mg kg-1 i.p.) treatment as a conditioning regimen for bone marrow transplantation (BMT) were studied in male BN/BiRij rats. The two groups of rats that were treated with Cy (Cy and Cy + TBI) that survived beyond 100 days after treatment, had a severely decreased median (post treatment) survival time (Cy + TBI: 14.5 months and Cy: 14.1 months). Survival time in the TBI group was moderately decreased (18.5 months) as compared with the untreated controls (27.2 months). All treatment modalities were carcinogenic according to the raw data. After Cy-treatment a high incidence of, frequently multiple, malignant nerve-sheath tumours (Cy: 66 per cent, Cy + TBI: 31 per cent, controls: 2 per cent) was observed. TBI induced an increased occurrence of a great variety of tumours, especially mesenchymal tumours. This effect was more pronounced in animals receiving TBI alone as compared to animals receiving the combined treatment of Cy + TBI; an effect that most likely resulted from the longer median survival after TBI. The multi-target effect of TBI was also reflected in the occurrence of nonneoplastic effects in a variety of tissues, including high incidences of biliary cysts in the liver and severe testicular atrophy. The most important Cy-induced nonneoplastic lesion was incisor dysplasia, which resulted in feeding problems that could only be partly overcome by administering powdered food. Early mortality in the Cy-treated groups was associated with emaciation and generalized organ atrophy. A more definitive estimate of the late effects of supralethal chemoradiotherapy as part of a treatment of malignant disease has to await the results of various conditioning regimens for BMT in rats employing the acute BN myelocytic leukaemia (BNML) as a rat model for human acute myelocytic leukaemia (AML).     

Remission of diarrhoea due to cryptosporidiosis in an immunodeficient child treated with hyperimmune bovine colostrum.

A boy aged 6 months who presented with poor weight gain, diarrhoea, and infection with Pneumocystis carinii was found to have congenital hypogammaglobulinaemia, which did not improve despite monthly treatment with intravenous gammaglobulin. At the age of 3 years and 2 months he developed severe vomiting and diarrhoea due to cryptosporidiosis, which failed to respond to conventional treatment. Infusion of hyperimmune bovine colostrum produced against parasite antigen, given by nasogastric tube, was started after symptoms had persisted for three weeks. His vomiting and diarrhoea resolved within five days of treatment, and oocysts were no longer seen in the stools after eight days. Later, however, he developed a rare complication, and oocysts were found in the common bile duct. Hyperimmune bovine colostrum may be useful in the treatment of many patients with immunodeficiency disorders.     

Pathology and treatment of Eimeria zuernii coccidiosis in calves: investigations in an infection model

Two studies were conducted in the Eimeria zuernii infection model in order to investigate the pathology of E. zuernii coccidiosis and the efficacy of toltrazuril (Baycox 5% suspension) in this infection. For this purpose, a total of 30 calves were infected experimentally with E. zuernii oocysts and faecal samples taken regularly from the rectum and examined for faecal consistency and oocyst excretion. Six of the calves underwent pathological examination at various points in time after infection. Significant macroscopic and microscopic changes were demonstrated and parasitic stages were identified in the intestinal mucosa of infected calves during the late prepatent and patent period. Inflammatory reactions revealed by light microscopy were confirmed by electron microscopical investigations. Treatment of calves with toltrazuril during the late prepatent period resulted in significantly lower frequencies of diarrhoea and levels of oocyst excretion, and weight gain was significantly higher than in shamtreated animals.     

Prevention of experimental autoimmune encephalomyelitis and induction of tolerance with acute immunosuppression followed by syngeneic bone marrow transplantation.

Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disease widely used as a model of the acute/relapsing stage of multiple sclerosis. In the present study we examined the effect of acute immunosuppression induced by total body irradiation (TBI) (900 to 1100 centigray (cGy)) or by a single high dose of cyclophosphamide (CY) (300 mg/kg), followed by syngeneic bone marrow transplantation (SBMT), on the development of EAE in SJL/J mice. EAE was induced in SJL/J mice by immunization with spinal cord homogenate in adjuvant. Treatment with TBI (900 cGy) and SBMT on day 6 postimmunization caused a delayed onset and a marked reduction in the incidence and severity of EAE. A higher dose of irradiation (1100 cGy) or the administration of CY followed by SBMT completely abrogated the development of paralysis. None of the 21 mice treated with CY and SBMT, and only 1 of 7 mice treated with TBI (1100 cGy) and SBMT developed clinical signs of EAE during a period of 3 months. Furthermore, mice treated with CY and SBMT became resistant to rechallenge with the same encephalitogenic inoculum. In addition, the lymphocytes obtained from these mice did not proliferate in vitro in response to myelin basic protein or tuberculin-purified protein derivative, unlike lymphocytes from immunized but untreated animals. This absence of reactivity was not associated with alterations in the proportion of the L3T4 and Lyt-2 T-cell subsets nor with a loss in T cell competence as evidenced by the full response of lymphocytes to the T cell mitogen Con A and to a nonrelevant Ag (OVA). Our results indicate that the elimination of effector lymphocytes either by myeloablative doses of CY or ionizing irradiation followed by rescue with SBMT inhibits the development of the autoimmune process in EAE and leads to induction of tolerance to the immunizing Ag by newly developing lymphocytes. This approach of combining immunoablation and reconstitution with autologous bone marrow transplantation may be applicable in the treatment of life-threatening neurologic autoimmune diseases.     

Different onsets of oxidative damage to DNA and lipids in bone marrow and liver in rats given total body irradiation.

We examined time-dependent changes in antioxidant vitamins and oxidative damage to DNA and lipids in the bone marrow, liver, and plasma of rats given total body irradiation (TBI) with X-rays at 3 Gy. The oxidative damage to DNA and lipids was evaluated by measuring increases of 8-hydroxydeoxyguanosine (8OHdG) in DNA and 4-hydroxy-2-nonenal (HNE), respectively. After the TBI, marked increases in 8OHdG and HNE were detected at 3 to 5 h in the bone marrow, while gradual increases in these parameters were detected after a few days in the liver. These changes in 8OHdG and HNE were well correlated within each tissue. In the bone marrow, levels of both vitamin C and vitamin E were decreased by the TBI; however, the changes in vitamin C were earlier and greater than those in vitamin E. In the liver, the level of vitamin C did not decrease, but that of vitamin E decreased due to the TBI. Changes in HNE, vitamin C, and vitamin E in the plasma were similar to those in the liver. Within each tissue, the time of decrease in antioxidants was almost the same as that of the increase in oxidative damage. An increase in total iron due to the TBI was also detected in these tissues. In particular, the total iron in the bone marrow was markedly increased at a few hours after the TBI, with a slight increase in transferrin and no increase in ferritin. Exposure studies performed on cells or isolated DNA showed that an increase in 8OHdG was detected immediately after irradiation at more than 100 Gy in bone marrow cells and at less than 10 Gy in isolated DNA, suggesting that an increase in 8OHdG is undetectable even in bone marrow immediately after the TBI at 3 Gy. These results indicate that the onset of oxidative damage to DNA and lipids was delayed after TBI at 3 Gy, that it was quite different in the bone marrow and the liver, and that an increase in iron and decrease in antioxidant vitamins were involved in the mechanism of oxidative damage.     

Clinical aspects of cow milk protein and gluten intolerance in children

In two comparative groups of 50 children with cow milk proteins and 45 children with gluten intolerance retrospective analysis of initial symptoms was carried out. The initial symptoms of intolerance included: vomiting, loss of appetite, recurrent diarrhoea, and weight gain disorders. These symptoms closely correlated with the type of nutrition (mixed, artificial) and the duration of exposition to harmful component of the food. The symptoms appeared within first days after birth with peak intensity in 6-8 weeks of life in the group with cow milk proteins intolerance. The symptoms of intolerance were most frequent in children of group II in 7-12 months of life. To prevent food intolerance in Polish children, it is recommended to feed them naturally as long as possible and to introduce flour and 4 basic grains late (after the 6th months of life).     

重组人血小板生成素早期干预救治重症急性放射病猴的实验研究

重组人血小板生成素（rhTPO）是一种能促进巨核系祖细胞增殖、分化生成血小板的造血因子,研究表明它能促进射线照射小鼠造血功能恢复,前期工作证明rhTPO早期干预可显著提高致死剂量照射小鼠的活存率.本文以7.0Gy照射恒河猴为重度骨髓型急性放射病（ARS）模型,研究了rhTPO早期干预对重症ARS的治疗作用,并与WR2721和＂500＂的辐射防护作用进行了比较,结果发现rhTPO早期干预可明显促进ARS猴造血功能恢复,改善ARS猴症状,简化对症治疗措施,提高重度骨髓型ARS猴活存率,其对重度骨髓型ARS的防治作用优于现有的辐射防护药WR2721和＂500＂,有望开发成安全有效的新型辐射防治药物.     

Radiation-induced micronucleus frequency in peripheral blood lymphocytes is correlated with normal tissue damage in patients with cervical carcinoma undergoing radiotherapy

In an effort to find a test to predict the response of normal tissue to radiotherapy, the lymphocyte micronucleus assay was used on blood samples from patients with cervical carcinoma. Peripheral blood samples from 55 patients with advanced-stage (II B-IV B) cervical carcinoma were obtained before radiotherapy. The patients were treated with external-beam radiotherapy followed by high-dose-rate brachytherapy. Acute and late normal tissue reactions were scored and correlated with the micronucleus frequency in lymphocytes after irradiation with 4 Gy in vitro. Great interindividual variability was observed in the radiation-induced lymphocyte micronucleus frequency, especially at 4 Gy. The mean number of micronuclei per 100 binucleated cells in cells irradiated with 4 Gy in vitro was significantly higher in samples from patients who suffered from acute and/or late normal tissue reactions than in those from patients with no reactions (51.0 +/- 17.7 and 29.6 +/- 10.1, respectively). A significant correlation was also found between the micronucleus frequency at 4 Gy and the severity of acute reactions and late reactions. However, the overlap between the micronucleus frequencies of patients with high-grade late normal tissue reactions and low-grade reactions is too great to recommend the micronucleus assay in its present form for routine clinical application.     

Evaluation of anti-emetic action of domperidone in patients treated with cytostatics]

Domperidone was administered to 40 patients with various neoplastic syndromes to prevent nausea and vomiting observed during previous courses of chemotherapy. It was found, that daily dose of 30 mg completely prevents nausea and vomiting in 30% of patients and significantly lowers such symptoms in further 58% of patients. An increase in a daily dose of 60 mg abolishes nausea and vomiting in 60%, and decrease their intensity in 35% of patients. Domperidone was administered orally during the whole period of chemotherapy without any adverse reactions related to its anti-dopamine actions.     

Monitoring the course of bacterial infections by hemolymph pressure pulses in insects

Changes in rhythmic pulsations of hemolymph pressure have been continuously monitored from several hours before injection of the pathogenic bacteria until death of the infected Tenebrio pupae. Lethality induced by five different species of entomopathogenic bacteria was associated with specific changes in the hemolymph pressure pattern. During the initial stages of infection (incubation period) the pupae continued to produce regular and synchronized series of normal pulsations. The pathophysiological symptoms of the acute disease became manifested by successive desynchronisation of the frequency and simultaneous depression of the amplitude of the pulsations. This irreversibly proceeded, with species specific modifications, until death of the pupae when all peaks in hemolymph pressure disappeared. Duration of the incubation period was inversely proportional to the injected dose, while the later period characterized by development of the pathophysiological symptoms had more or less constant course in infection with each bacterial species. Certain toxic enzymes, protease and phospholipase C, had similar action on hemolymph pressure pulses. Application of the tensometric method to pathophysiological studies in insects has been discussed.     

Changes in functional activity of the synthetic apparatus of rat thymocytes under acute and chronic gamma-irradiation

The changes in functional activity of rat thymocyte synthetic apparatus (synthetic activity) under acute (7.5 Gy) and continuous (dose rates 14.4 and 0.43 cGy/day) gamma-irradiation were studied by the fluorescent microspectral analysis. It has been shown that after the acute irradiation the changes in synthetic activity occurred in three main stages. The stages reflect the depression and activation of synthetic processes that is due to interphase and reproductive cell death and urgent recovery of thymus cellularity and secondary repopulating. Under continuous irradiation with a dose rate 14.4 cGy/day in long-term period both the decrease of thymocyte synthetic activity (in most animals) and activation (in the animals with pronounced symptoms of radiation damage) were observed. This reflects the depression processes in immune system and augmentation of immunoreactivity due to mass antigen influence of transformed cells and infectious agents on thymocytes. Under low dose ionizing irradiation (dose rate 0.43 cGy/day) the undulating changes in synthetic processes in thymus cells were observed. This depends on the recurrence of depression and recovery processes in the blood-forming tissue.     

Myeloablative irradiation in non-human primates

Purpose  We used total body irradiation (TBI) as conditioning for cord blood transplantation studies in pigtailed macaques. In these studies, different doses of TBI were explored to obtain optimal myelosuppression with acceptable radiation-related side effects.
Methods  Four macaques received TBI ranging from 800 to 1320 cGy, followed by standard post-transplant care. Hematopoietic recovery was monitored by CBC and donor contribution by variable number of tandem repeats analysis.
Results  Animals receiving 800 or 1020 cGy TBI tolerated the irradiation well with autologous recovery of neutrophils within 24 days. At a dose of 1200 cGy, neither autologous recovery nor extramedullary toxicity was observed. A fourth animal received 1320 cGy of TBI and suffered significant toxicity necessitating termination of the study.
Conclusions  We conclude that previously considered myeloablative doses of TBI allowed for autologous recovery in the pigtailed macaque, and that a dose of 1200 cGy may be most appropriate, providing both myeloablation and acceptable non-hematopoietic toxicities.     

The irradiation consequencees of animals with alloxan-induced diabetes

The effects of external acute irradiation at dose 1.0 Gy on biologic, haematologic and metabolic changes in blood of alloxan-induced diabetic rats were studied. It was found that the deterioration of diabetic animals occurs in different terms after irradiation exposure, resulting in considerable body weight decrease, well-marked hyperglycemia, abrupt falling of leukocytic system parameters, intensification energetic processes of extant lymphocytes, imbalance of lipid metabolism and thyroid state, as well as significant inhibition of 5'-deiodinase activity in liver tissue.