[New developments in molecular genetics and treatment of retinoblastoma]. / Neue Entwicklungen zur Genetik und Therapie des Retinoblastoms.

Retinoblastomas are the most frequent primary malignant intraocular tumours worldwide. Conventional and new treatment modalities have significantly improved the chance for survival and preservation of vision. The armamentarium of treatment modalities has been broadened recently by new techniques like intraarterial chemotherapy, which still has to be considered as experimental since long-term follow-up results are not yet available. The excellent prognosis for retinoblastomas in countries with a well developed health system is contrasted by the miserable prognosis for retinoblastomas in developing countries, which must be changed by a joint effort of all centres.

[Severe aplastic anaemia in six children after non-A-E hepatitis without hepatic failure]. / Schwere aplastische Anämie bei 6 Kindern nach Non-A-E-Hepatitis ohne Leberversagen.

Aplastic anaemia can coincide with non-A-E hepatitis. Treatment follows a standardised study protocol of the German Society of Paediatric Oncology and Haematology (GPOH). Patients receive immunosuppression and/or bone marrow transplantation. We present six cases of aplastic anaemia after non-A-E hepatitis with different courses. In four of these children illness first presented with acute gastroenteritis. Five out of six children fully recovered, two of these with immunosuppression alone, three after bone marrow transplantation. One patient died due to complications of the bone marrow transplantation. In two patients steroid therapy was carried out to treat the hepatitis. This did not have any effect on the course of their aplastic anemia. We emphasise this common combination of aplastic anemia following non-A-E hepatitis. This overview underlines the necessity of regular blood testing after non-A-E hepatitis. Often gastroenteritis seems to precede illness thus perhaps indicating an infectious trigger.

The measurement of analyte diffusion from hydrogel microcapsules in model aqueous environments.

Model flavor analytes with varying partition coefficients were successfully encapsulated in approximately 150 microm diameter hydrogel microcapsules containing medium chain triglycerides (MCT). Analyte diffusion from the microcapsules into water and dextrose solutions was measured using a UV-VIS spectrophotometer fitted with a fiber optic probe. The diffusion of acetophenone, considered a hydrophilic analyte, was reduced as the dextrose concentration was increased in the water environment. Diffusion comparison was noted as t(1/2) which is the measure of time when 50% of the analyte concentration is released from the microcapsules. The measured t(1/2) for acetophenone in distilled water was 0.40 min. The addition of 20% dextrose to distilled water increased the t(1/2) to 0.60 min while the 40% dextrose addition extended the t(1/2) to 1.4 min. The same t(1/2) trends were also noted with methyl salicylate which is considered a hydrophobic analyte. The measured t(1/2) for methyl salicylate in distilled water was 2.0 min. The addition of 20% dextrose to distilled water increased the t(1/2) to 4.0 min while the 40% dextrose addition extended the t(1/2) to 9.0 min. The addition of dextrose to the water media effectively changes the partitioning media, increasing the resulting partition coefficient (Log P) values. Large changes in the Log P values were confirmed by the GC/FID analysis. In essence, water becomes a poor solvent for the analytes and diffusion is slowed from the hydrophobic MCT contained within the microcapsules as higher concentrations of dextrose is added to the water phase. Since methyl salicylate has a larger Log P(MCT: Water) value compared to acetophenone, the addition of dextrose extends the t(1/2) to a larger extent.

[Retinoblastoma]. / Retinoblastom.

Retinoblastomas are the most frequent intraocular tumors in childhood. Untreated, the tumor is almost always fatal. Using a multidisciplinary approach combining the efforts of ophthalmologists, radiation oncologists, pediatric oncologists and geneticists a survival rate of more than 95% can be achieved. Molecular genetic research on the origin of retinoblastomas has substantially helped in our understanding of the origin of malignant tumors in general, as well as to the key role of the Rb-1 gene as a tumor suppressor.

Proliferation-associated SNF2-like gene (PASG): a SNF2 family member altered in leukemia.

To identify genes involved in cell growth and/or apoptosis in leukemia, differential display was used to identify mRNAs that showed altered expression levels after cytokine withdrawal from the cytokine-dependent MO7e cell line. Sequence analysis of one transcript that showed a profound decrease in expression after cytokine withdrawal revealed it to be a member of the SNF2 family of chromatin remodeling ATPases. This cDNA had a 2514-nucleotide (838-amino acid) open reading frame and encoded an additional 230 amino acids at the NH2 terminus compared with the murine homologue, lsh, and the human counterpart, Hells. This gene locus has been designated SMARCA6 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 6). The highest levels of mRNA expression in humans are observed in proliferative tissues such as the thymus, testis, and bone marrow. Whereas cytokine withdrawal in MO7e cells leads to apoptosis and decreased mRNA expression, growth arrest without the induction of apoptosis of MO7e cells also leads to down-regulation of mRNA expression, suggesting an association with cell proliferation and not suppression of apoptosis. Nuclear localization of this SNF2-like putative helicase is dependent on a nuclear localization sequence located in the NH2-terminal region. Based on sequence homology to other SNF2-like helicases, the pattern of tissue expression, and the association of expression with cell proliferation, we refer to the protein product as proliferation-associated SNF2-like gene product [PASG (D. W. Lee et al., Blood, 94: 594a, 1999)]. Examination of acute myelogenous leukemia and acute lymphoblastic leukemia samples revealed a high frequency of a PASG transcript containing an in-frame 75-nucleotide deletion, which codes for a conserved motif known to be critical for the transactivation activity of a related yeast SWI/SNF polypeptide. These results extend our knowledge of this SNF2-like family member and suggest a role for PASG in leukemogenesis.

Community screening for diabetes by blood glucose measurement. Results of a five-year experience.

The Diabetes Association of greater Cleveland screened 307,000 individuals in the metropolitan area for diabetes with a 75-gm. oral load of carbohydrate. Of these subjects 12,600 (4.1 per cent) had a two-capillary blood glucose level of greater than 139 mg. per cent and were defined as positive. Seventy per cent of the positives were retested, and 65 per cent of these again had two-hour levels greater than 139 mg. per cent. Seventy-one per cent of the original screening values were between 104 and 199 mg. per cent. The rate of positivity on retesting increased with the original screening bracket reaching 90 per cent at an original screening level of 240 mg. per cent or higher. The frequency of positive retests also increased with age irrespective of whether the original screening level was less than or greater than 200 mg. per cent. The implications of this large detection experience for conducting future mass surveys for diabetes are discussed.

Incidence of dysarthria in children with cerebellar tumors: a prospective study.

The present study investigated dysarthric symptoms in children with cerebellar tumors. Ten children with cerebellar tumors and 10 orthopedic control children were tested prior and one week after surgery. Clinical dysarthric symptoms were quantified in spontaneous speech. Syllable durations were analyzed in syllable repetition and sentence production tasks. Localization of the cerebellar lesions were defined after manual transfer from individual 2D-MR images onto 3D images of a spatially normalized healthy brain. Cerebellar children showed few and mild clinical signs of dysarthria. No difference was present in the sentence production task compared to controls. In five cerebellar children, syllables were prolonged in the syllable repetition task after surgery. Syllable duration normalized in an additional four-week session in all but one case. The MR-analysis showed that superior paravermal cerebellar areas likely involved in dysarthria in adults (paravermal lobules HVI, Crus I) were not significantly affected. In children, speech impairments appear to be rare after cerebellar surgery because tumors most commonly affect posterior-inferior and medial parts of the cerebellum while critical cerebellar regions are likely spared. The results suggest a similar localization of speech functions in the cerebellum in children and adults.

Unusual events preceding hyperthyroidism with diffuse goiter.

Two unique patients with hyperthyroidism are presented here. A 48-year-old woman with a family history of Graves' disease was first evaluated and treated for a toxic adenoma with radioactive iodine. Three months later, she was again hyperthyroid, was found to have a diffuse thyromegaly, and was treated with radioactive iodine for the second time. This patient represents, to our knowledge, the first reported case of two sequential forms of endogenous hyperthyroidism. The second patient, a 64-year-old woman, had well-documented hypothyroidism that was presumably primary. She was admitted in thyroid storm and subsequently died. The autopsy disclosed characteristic changes in the thyroid of hyperthyroidism and a normal pituitary gland. The timing of the onset of Graves' disease with hyperthyroidism cannot be accurately determined.

Experience with low-dose insulin infusion in diabetic ketoacidosis and diabetic hyperosmolarity.

Forty patients with diabetic ketoacidosis and eight patients with the diabetic hyperosmolar state were treated with low-dose insulin infusion in four teaching hospitals in the Cleveland area. The clinical and biochemical responses observed support previous favorable reports on this treatment modality. Two elderly patients with the hyperosmolar syndrome died. The advantages of this form of treatment over intermittent insulin schedules are emphasized. Early potassium administration, unless otherwise contraindicated, is recommended. Rarely, increasing doses of insulin may be required if insulin resistance is encountered.

Relationship between sex hormones, myocardial infarction, and occlusive coronary disease.

An alteration in sex hormones has been considered a risk factor for myocardial infarction. In this study, estradiol (E2) and testosterone (T) levels were evaluated in healthy firefighters, patients with myocardial infarction acutely and during their convalescence, patients with no evidence of occlusive coronary artery disease on arteriography, and patients with chronic angina pectoris in whom there was at least one vessel that indicated 50% occlusive coronary artery disease. Although T levels were similar in all groups, E2 levels were substantially higher in patients with myocardial infarction and in patients with chronic angina pectoris. These results support the hypothesis that elevated estrogen levels may be a risk factor for myocardial infarction and coronary artery disease, possibly by promoting clotting or coronary spasm.

Elevated testosterone-binding globulin in Klinefelter's syndrome.

Seven consecutive patients with Klinefelter's syndrome were studied and found to have elevated levels of testosterone-binding globulin. The mechanism could not be accounted for by increased levels of circulating estradiol.

Effect of synthetic gonadotropin-releasing hormone (GnRH) in a patient with the "fertile eunuch" syndrome.

A patient with isolated LH deficiency ("fertile eunuch" syndrome) was given synthetic gonadotropin releasing hormone (GnRH) by a single intravenous injection and serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and dihydrotestosterone were measured. A significant rise in both gonadotropins was found after GnRH and the increase was similar to that reported for normal men. No significant change was noted in the serum androgen levels. The patient was re-tested with another single intravenous injection after a 6-h infusion of GnRH two days later. The rise in serum Fsh and LH levels during the infusion was greater than with the initial bolus. A further increase in LH but not FSH concentration was noted when a 150 mug bolus was given at the end of the infusion. Acute (4 day) treatment with human chorionic gonadotropin (hCG) resulted in an increase in the serum testosterone and dihydrotestosterone levels to those observed in normal adult males. The "fertile eunuch" syndrome thus appears to be a hypothalamic disorder. It is consistent with the concept of more than one hypothalamic factor controlling gonadotropin secretion. Other possibilities would be deficient or defective production of a releasing factor affecting one or both gonadotropins. The lack of a definite response of serum androgens to GnRH would appear to be secondary to a decreased number of differentiated Leyding cells.

The effect of rapid weight loss due to jejunoileal bypass on total cholesterol and high-density lipoprotein.

Twelve patients undergoing a 10 to 4 inch end-to-side jejunoileal bypass for morbid obesity were measured pre- and postsurgically for total cholesterol and high-density lipoprotein (HDL) cholesterol levels. After a mean weight loss period of 7 months, results showed a significant decrease in total cholesterol (p less than 0.001) and in the total cholesterol: HDL cholesterol level (p less than 0.01). The change in HDL cholesterol levels was not significant (p less than 0.05). The decrease in total cholesterol accompanied by no change in HDL cholesterol indicates an increased transport of cholesterol as HDL in these patients. This results suggests that these subjects are placed at a decreased risk of coronary heart disease postsurgically.

Certain metabolic consequences of jejunoileal bypass.

Jejunoileal bypass for obesity has been shown to be associated with increased hepatic triglycerides during the period of brisk weight loss. The current report describes certain metabolic changes observed in 29 patients 21 months after bypass. Significant decreases in serum cholesterol, serum triglycerides, blood sugar after a glucose load, and fasting plasma insulin levels were noted. Increased oxalate excretion and occasional episodes of hypomagnesemia occurred. Repeated clinical and laboratory observations by a medical-surgical team offer the best opportunity to evaluate this procedure.

Rat antigen-induced arthritis: cartilage alterations assessed with iodine-123-antileukoproteinase.

UNLABELLED: Imaging of cartilage alterations was attempted in joints of rats with chronic antigen-induced arthritis (AIA) using the cationic 123I-labeled serine proteinase inhibitor antileukoproteinase (123I-ALP; pI > 10), which selectively accumulates in normal cartilage, presumably through interaction with negatively charged proteoglycans. METHODS: Iodine-123-ALP or 123I-myoglobin, a control protein of comparable size but with different isoelectric point (pI=7.3) was injected intravenously into normal or AIA rats. Joint accumulation was followed by scintigraphy for 14 hr. Tissue radioactivity was assessed by well-counter measurements after dissection. The content of charged molecules in articular cartilage was determined by toluidine blue staining; the degree of joint destruction was assessed in parallel by x-ray, ex vivo MRI and histopathology. RESULTS: In intact articular cartilage, ALP accumulated to a significantly higher degree than myoglobin. This preferential accumulation was lost in rats with chronic AIA. The target-to-background ratio for 123I-ALP negatively correlated with the loss of toluidine blue staining in cartilage, which documents depletion of charged matrix molecules (r=-0.92, p < 0.01 at 4 hr; r=-0.97, p < 0.01 at 13 hr). ALP scintigraphy was sensitive in detecting cartilage alterations, even though the degree of joint destruction and inflammatory infiltration was mild, as demonstrated by x-ray, MRI and histopathology. CONCLUSION: In rat AIA, loss of ALP accumulation appears to document proteoglycan depletion in mildly altered arthritic cartilage. ALP scintigraphy may represent a functional assay for early, premorphological cartilage alterations in human arthritis as well.

High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma.

Children with metastatic retinoblastoma are considered to have a poor prognosis after conventional chemotherapy. We used high-dose chemotherapy (HDC) with peripheral hematopoietic stem cell transplantation in such patients in an attempt to improve their survival. Four patients with bone marrow metastases and one child with extraorbital disease were treated with HDC after achieving complete remission by enucleation and conventional chemotherapy. The child with extraorbital tumor was the only one to receive local irradiation. The conditioning regimen included thiotepa (900 mg/m(2)), etoposide (40 mg/kg) and carboplatin (1.5 g/m(2)) in four patients, and BCNU (300 mg/m(2)), cyclophosphamide (6.8 g/m(2)) and etoposide (1.6 g/m(2)) in one child. Hematologic recovery occurred without delay in all patients. The main toxicities were diarrhea, mucositis and infectious complications. No toxic deaths or any major late toxicities were observed. The child treated with the BCNU regimen developed a meningeal relapse 10 months after HDC, which was partially resected and treated with conventional chemotherapy, but not with radiotherapy. He is in complete remission (CR) 105 months off treatment. The other patients are in CCR for 107, 57, 9 and 8 months after HDC. HDC with thiotepa, etoposide and carboplatin may represent a curative option for children with extrabulbar or disseminated retinoblastoma responsive to chemotherapy. It may control occult CNS disease. The necessity to irradiate these children and the curative potential of this strategy for patients with bulky CNS disease remain to be determined.

Isolated adrenocorticotropic hormone deficiency with antepartum pituitary infarction in a type I diabetic.

Isolated adrenocorticotropic hormone (ACTH) deficiency was documented after cesarean delivery in a patient with type I diabetes. A preceding severe headache, subsequent declining insulin requirements, and hypotension are consistent with pituitary infarction in a patient without computed tomography evidence of a pituitary tumor. Antepartum incomplete pituitary infarction with isolated ACTH deficiency is an unusual but potentially catastrophic complication of the pregnant diabetic.

Cushing's syndrome complicating pregnancy. A case report.

PIP: A case of a rare association between pregnancy and the development of Cushing's syndrome is discussed. A 29-year-old woman developed Cushing's syndrome, characterized by hypokalemia, a high level of urinary 17-hydroxycorticoids not suppressed by dexamethasone therapy, a high level of plasma 11-hydroxycorticoids which did not show diurnal variation and failed to show suppression after dexamethasone therapy, and a high level of urinary 17-ketosteroids, within 12 weeks of her first pregnancy. Clinical and biochemical abnormalities disappeared rapidly after dilatation and curettage. No evidence of an ectopic ACTH-producing tumor or an adrenal cortical tumor was found. Abnormalities did not reappear with administration of HCG or with sequential estrogen-progestogen treatment.^ieng

Colchicine in the treatment of Paget disease of bone: a new therapeutic approach.

Paget disease of the bone (PDB) has been treated effectively with various agents including calcitonins, diphosphonates, and mithramycin. Each agent has relatively serious toxic side effects or practical inconveniences associated with its use. An effective agent with fewer adverse reactions and a more convenient route of administration would be preferable. The purpose of this study was to evaluate the effect of colchicine for the treatment of PDB in five patients. All patients were symptomatic and had typical changes on roentgenograms and bone scans consistent with the disease. Serum alkaline phosphatase ranged from 408 to 1,311 mU/ml (normal, 30 to 115 mU/ml), and urinary excretion of total hydroxyproline ranged from 68 to 205 mg/24 hr (normal, 30 to 65 mg/24 hr). Colchicine, 0.6 mg, was given orally three times a day to each patient, who had subsequent follow-up with clinical and laboratory determinations evaluated at each visit. The duration of follow-up was eight to 28 weeks, with a mean of 20 weeks. Pain was relieved in all patients, and two became asymptomatic. Serum alkaline phosphatase decreased 18% to 38%, and urinary hydroxyproline decreased 26% to 53% from the pretreatment values. The biochemical values and and clinical symptoms changed markedly in two patients, correlating with withdrawal and reinstitution of colchicine. These results indicate that colchicine may be effective in the treatment of PDB. Although the mode of action and long-term efficacy of colchicine in this disorder remains to be evaluated, the antimitotic effect on osteoprogenitor cells, the adherence of colchicine to the microtubular structures in preexisting osteoblasts, and the nonspecific anti-inflammatory effect of this agent may explain the therapeutic response noted in this study.