Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis.

Niemann-Pick diseases are hereditary neurovisceral lysosomal lipid storage disorders, of which the rare type C2 almost uniformly presents with respiratory distress in early infancy. In the patient presented here, the NPC2 exon 4 frameshift mutation c.408_409delAA caused reduced NPC2 protein levels in serum and lung lavage fluid and the synthesis of an aberrant, larger sized protein of around 28 kDa. Protein expression was strongly reduced also in alveolar macrophages. The infant developed failure to thrive and tachypnea. Lung lavage, computer tomography, and histology showed typical signs of pulmonary alveolar proteinosis with an abnormal intraalveolar accumulation of surfactant as well as macrophages. An NPC2-hypomorph animal model also showed pulmonary alveolar proteinosis and accumulation of macrophages in the lung, liver, and spleen long before the mice died. Due to the elevation of cholesterol, the surfactant had an abnormal composition and function. Despite the removal of large amounts of surfactant from the lungs by therapeutic lung lavages, this treatment was only temporarily successful and the infant died of respiratory failure. Our data indicate that respiratory distress in NPC2 disease is associated with a loss of normal NPC2 protein expression in alveolar macrophages and the accumulation of functionally inactive surfactant rich in cholesterol.

Cathepsin H and napsin A are active in the alveoli and increased in alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a group of rare diseases with disturbed homeostasis of alveolar surfactant. While 90% of the primary adult forms are caused by granulocyte-macrophage colony-stimulating factor autoantibodies, the underlying cause of the juvenile form remains unknown. In order to distinguish primary from secondary effects in the pathogenesis of these two forms, the present authors studied the surfactant protein processing proteases napsin A and cathepsin H. In total, 16 controls, 20 patients with juvenile PAP and 13 adults with idiopathic PAP were enrolled. Amounts and activities of the proteases in the bronchoalveolar lavage fluid (BALF) were determined by immunoblotting and specific substrate cleavage. Both proteases were present and active in BALF from controls and increased in juvenile and adult PAP patients. The amount of active cathepsin H in relation to total cathepsin H was increased in PAP patients compared with controls. Cystatin C, the physiological inhibitor of cathepsin H in the alveolar space, was not increased to the same degree as cathepsin H, resulting in an imbalance of inhibitor to protease in the alveolar space. A general defect in napsin A or cathepsin H expression or activity was not the specific cause for abnormal surfactant accumulation in juvenile pulmonary alveolar proteinosis.

Orbito-ocular granulocytic sarcoma (OOGS) and acute myeloblastic leukemia (AML) with duplication of Philadelphia chromosome.

A 6-year-old Turkish boy with bilateral orbito-ocular granulocytic sarcoma and AML is described. Cytogenetic studies on peripheral blood disclosed an abnormal hyperdiploid population with a double Ph chromosome. Despite intensive chemotherapy, he achieved only partial remission. Repeated cytogenetic studies on bone marrow during relapse revealed the persistence of double Ph chromosome. The aggressive course and the short survival time of this patient, despite adequate chemo-radiotherapy, may be explained by the presence of the double Ph chromosome.

Burkitt's lymphoma in Turkish children: clinical, viral [EBV] and molecular studies.

Eighty-one Turkish children with Burkitt's lymphoma (BL) were observed during a period of 24 years (1968-1992). The diagnosis was established histologically according to WHO criteria. BL represented 48.5% of NHL in this series. The median age of patients was 5 years with a sex (M/F) ratio of 2.3/1. The most common primary site of tumor involvement at initial presentation was the abdomen (70.4%), which was followed by facial tumors, in particular the jaw and orbit (45.7%). The majority of the patients (84.0%) were in advanced stages (C and D) at initial diagnosis. Facial tumors observed in Turkish children with BL were more similar to African Burkitt's lymphoma than American or European cases. High titers of antibodies against VCA and EA of EBV were also observed in 32 recent cases of BL. Preliminary molecular and immunologic studies revealed EBV-DNA (type I) and T cell deficiency. The clinical presentation, median age, and association with EBV revealed that BL appears to be inbetween African and non-African types in Turkish children. This will be further elucidated in the future by direct examination of tumor cells for EBV and investigation of the molecular characteristics in these cases.

Late effects of chemoradiotherapy in pediatric Hodgkin's disease.

We treated 137 Turkish children with biopsy-proven Hodgkin's disease, followed up between the years 1964 and 1989. Most patients were treated and were in advanced stage with histological subtype of mixed cellularity (67.5%). Radiotherapy (Mantle form) and/or MOPP, ABVD and OPPA combination chemotherapy regimens were used in 75.84% of patients. The follow-up period in these patients ranged from 5 to 24 years. The late effects in 28 patients who were evaluated for the late sequelae of chemoradiotherapy are presented. Seven out of 28 patients showed retarded sexual maturation. Testicular and ovarian functions were assessed in 11 patients, all of whom showed elevated serum FSH levels and 2 azoospermia. Analysis of thyroid functions was carried out in patients receiving radiotherapy to the neck. The thyroid gland was palpable in 6 patients. Further analysis showed diffuse hyperplasia in 5 and nodular in 1 patient. The nodule was excised and reported as "nodular colloidal goiter". Two patients had elevated TSH levels. "Swan-like neck" was observed in 3 patients who had received 40 to 42 Gy radiotherapy to the neck. Cirrhosis due to chronic hepatitis B infection was diagnosed in 2 patients as an unusual late complication. The secondary malignancy occurred in only 1 case in the form of "fibrosarcoma". The second neoplasm was probably radiation-induced as it occurred in the field of prior radiotherapy.

Granulocyte-macrophage colony stimulating factor (rh-GM-CSF) in the treatment of chemotherapy-induced neutropenia.

Neutropenic pediatric patients with solid tumors and malignant lymphomas were treated with recombinant granulocyte-macrophage colony stimulating factor (rh-GM-CSF). Eleven patients, including seven lympho-reticular malignancies, two Ewing's sarcoma and one patient in each group with the diagnosis of nasopharyngeal rhabdomyosarcoma, malignant mesenchymal tumor, entered the study. Six were females and five were males, the mean age was 10.4 yr, the range was 4 to 21 years. rh-GM-CSF was given at the dose of 5 micrograms/kg s.c. daily, starting either on the day following the last day of cytotoxic chemotherapy or when ANC < 1000/ml was determined. All patients received rh-GM-CSF for a total of seven days. Hematopoietic recovery occurred in all children except one. The response to rh-GM-CSF was achieved in a mean time of 7.4 days. Tolerance to rh-GM-CSF treatment was good. Adverse events were documented as fever, nausea, vomiting, fatigue, chills and itching. Sagittal sinus thrombosis developed in one patient 5 days following the completion of chemotherapy and rh-GM-CSF cycle. In conclusion, rh-GM-CSF can be applied during the intensive chemotherapy schedules of pediatric cancer patients.

Aggressive Kaposi's sarcoma in children: a case report.

A three-year-old-boy with generalized Kaposi's sarcoma (KS) is presented. The child died of progressive pulmonary insufficiency on the eighteenth day of the course of his illness, the tenth hospital day. On postmortem examination diffuse KS infiltration was observed in the respiratory and gastrointestinal tracts, lymph nodes, liver, spleen and thymus. The patient was considered to be a case of KS unrelated to AIDS because of his negative HTLV-III antibody and epidemiologic characteristics, and therefore was believed to have primary aggressive KS.

[Effect of different thermal properties and different pontic frame designs to breaking strength of metal-porcelain bridges]. / Metal destekli porselen koprulerde farkli isisal özelliklerin ve degisik govde tasarimlarinin porselenin kirilma direncine etkisi.

Bonding of two different materials, like porcelain and metal, is affected by many factors during the firing process. Thermal compatibility is one of the prerequisites in metal-porcelain bonding. Plus, the geometric differences are also accepted as an effect in thermal compatibility. In this study it is observed that the metal framework designs that we used had no effect on the strength of porcelain; however the thermal compatibility of metal and porcelain had an important effect. Besides, it is also witnessed that in metal-porcelain restorations, structures in similar strengths are achieved with hollow type pontic designs as with solid type, if they are prepared in proper conditions.

[Thermal expansion of dental alloys and porcelains]. / Dental alasim ve porselenlerin isisal genlesmeleri.

Thermal behaviour of metal and porcelain against heat is an important factor in metal-porcelain bonding. For this reason thermal compatibility and the thermal expansion of metal and porcelain are some of the important subjects to be studied carefully. In this study, by means of dilatometric measurements, we determined the thermal expansion coefficients of metal alloy (Ivotect P) and porcelain (ITS-HTE, Ivoclar) which we use in routine practice. As a result we found that the porcelain has a nonlinear expansion as oppose to metal alloy and also the firing conditions affect the thermal expansion. In addition we observed that the thermal expansion coefficient of metal alloy had changed very little in repeated castings.

[Evaluation of stresses in different cingulum rest seats]. / Farkli singulum rest yuvalarinin kuvvet iletimi yönünden karsilastirilmalari.

Both lingual and incisal rest seats are used on anterior teeth. Lingual rest seats are preferred since they are more acceptable esthetically and located closer to the centre of rotation of the tooth. Lingual rest seats can be prepared directly on the abutment teeth as grooves, shoulders or may require restorations such as crowns, inlays and prefabricated rest seats to provide proper contour. In this study, the stress induced by two conventionally applied rest seats were compared with that of the U shaped rest seats which were recently induced. As a result it is found that more uniform stress distribution occurred in U and inverted "v" type rest seat designs.

T-lymphocyte sub-populations in orbito-ocular granulocytic sarcoma (OOGS) and acute myelocytic leukemia (AML): a preliminary study.

The aetiology of GS remains obscure and a little is known about the immune competence of these patients. Interestingly, all children with OOGS were from low 'socio-economic status' and showed diminished delayed hypersensitivity reactions and reduced T cell counts (E-R) in our previous observation. We present herewith a preliminary data on evaluation of T cell sub-populations determined by monoclonal antibodies (CD3, CD4, CD8 and CD16 cells) in 10 patients with OOGS and AML prior to treatment. Quantitative immunoglobulin determinations of IgA, IgM, IgG were also made. The percentage of Pan T (CD3), CD4, CD8 cells were significantly lower than those in the controls (p < 0.01). The immunoglobulin levels were slightly elevated suggesting normal B cell functions. In conclusion, these preliminary findings suggest that cellular immune deficiency may be an underlying cause.

Post-transfusion acute graft versus host disease in a 17-year-old girl with a malignant mesenchymal tumor--report of a case.

Post-transfusion graft-versus-host disease (PT-GVHD) is seldom, but it has a high mortality rate, exceeding 90 percent. There is no standard treatment for PT-GVHD and irradiation of blood and its components before transfusion is broadly accepted for the prevention of PT-GVHD. In this report we present a case (a 17-year-old female) of PT GVHD, who died in spite of the use of all available therapeutic options.

Burkitt's lymphoma in 63 Turkish children diagnosed over a 10 year period.

Sixty-three Turkish children with Burkitt's lymphoma (BL) diagnosed over a 10-year period in a single institution were retrospectively analyzed. Burkitt's lymphoma included 41.7% of non-Hodgkin's lymphomas and 17.2% of all childhood malignant solid tumors diagnosed in our department in this duration. The patients studied with BL were aged between 3 and 14 years (mean 5.9 years), with a male of female ratio of 2:1. While the age distribution in our patients was similar to that in African BL (endemic), the predominance of abdominal involvement and the frequency of bone marrow infiltration and pleural effusion were reminiscent of American BL (sporadic). The incidence of jaw involvement (15.9%) in our group was higher than in American BL, however, and was not a high as in African BL. Most of the patients were of a lower socioeconomic status. Significant growth retardation was found in the children with BL compared with 40 age-matched children without malignancy, nor chronic or endocrinologic disorders, who were of a similar socioeconomic status. A serological study for Epstein-Barr virus (EBV) was performed in 18 children, and the IgG-type antibody to the viral capsid antigen of EBV was found to be positive in all of them. As a result, BL seems to include a considerable proportion of all childhood malignant solid tumors in Turkey. The epidemiological and clinical presentation and course indicate that BL appears in Turkish children in a form that is between the African and American types of the disease. Further molecular and chromosomal studies in Turkish children with BL are needed.

Hodgkin's disease in 82 Turkish children diagnosed over a 10-year period: epidemiological, clinical, and histopathologic features and prognosis with prolonged chemotherapy.

In this study, 82 Turkish children with Hodgkin's disease (HD) between 1 and 14 years of age and diagnosed over a 10-year period were evaluated retrospectively. More than half of the patients (54%) presented with advanced stages of HD. Mixed cellularity (MC) was the most frequent (56.1%) histopathologic type, which was followed by nodular sclerosing (NS, 18.3%) in frequency. None of the patients received radiotherapy as initial treatment. In 67 children the COPP regimen alone and in 15 the ABVD regimen alternating with COPP were started, to be given as a total of 12 courses. In the patients who presented with stage I-II HD the overall survival (OAS) rate and 5-year event free survival (EFS) rate were 92.3% and 77.8%, respectively. In the patients with advanced disease (stage III-IV) OAS and 5-year EFS were estimated to be 89.5% and 67.4%, respectively. No serious toxicity of chemotherapy was detected during the follow-up. In this group, clinical, epidemiological and histopathologic features of the disease showed a special pattern close to the type I pattern of HD. Regarding the survival rules and occurrence of low toxicity in our patients, results of prolonged chemotherapy alone seem to be encouraging in most of the children with HD. However, the follow-up duration is not yet sufficient to declare a clear conclusion related to the late complications.

The clinical value of flow cytometric DNA content analysis in patients with soft tissue sarcomas.

Purpose. The purpose of this study was to evaluate: (1) the correlation between grade and ploidy or S-phase fraction (SPF), (2) the prognostic value of DNA flow cytometric study in soft tissue sarcomas.Patients /Methods. In all, 47 tissue samples from soft tissue sarcoma patients, surgically treated in the same center, were included. Flow cytometric analyses were performed according to a modified version of the original method of Hedley et al.Results. DNA ploidy status could be determined in 44 samples out of 47 (success rate 94%). Of these 44, S-phase fraction could be calculated in 34 samples (77%). In the study group as a whole, aneuploidy was significantly correlated with high grade. Survival analyses were carried out in 21 patients with soft tissue sarcoma, all surgically treated in the same center, without chemotherapy or radiotherapy. In univariate analyses, DNA ploidy was found to be a significant factor for overall survival (OAS) and metastasis-free survival MFS. Mean OAS for aneuploid tumors and diploid tumors were 35 and 65 months (p=0.034), and mean MFS 23 and 61 months, respectively (p=0.005) .Discussion.There is a relation between histological grade and ploidy in soft tissue sarcomas. It appears that low-grade tumors are generally diploid, whereas high-grade tumors tend to be aneuploid. In a subgroup of patients treated only with surgery, DNA ploidy was found to be an important factor for predicting OAS and MFS.

Prospective randomized comparison of morning versus night daily single subcutaneous administration of granulocyte-macrophage-colony stimulating factor in patients with soft tissue or bone sarcoma.

BACKGROUND: Hematopoietic growth factors (HGFs) have been used to reduce the neutropenic complications of cytotoxic chemotherapy so that higher doses may be given. The authors have previously shown that endogenous serum granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) levels at night (p.m.) were significantly higher than those in the morning (a.m.). METHODS: Twenty-four patients with soft tissue or bone sarcoma who were treated with high dose ifosfamide-based chemotherapy were enrolled in this study. Patients were randomized to either a.m. or p.m. treatment. GM-CSF was administered at a dose of 5 microg/kg/day at 10 a.m. or 10 p.m., beginning 36-48 hours after the last chemotherapy dose. GM-CSF therapy was continued until the neutrophil count exceeded 1,000/mm3 for 2 consecutive days. Leukocyte, neutrophil, monocyte, and platelet counts were measured immediately before GM-CSF administration and exactly 12 hours after the first dose of GM-CSF, and every 24 hours until 3 days after the cessation of GM-CSF. RESULTS: The mean duration of Grade 3-4 neutropenia was 5.3 +/- 0.4 days for the a.m. treatment arm and 6.5 +/- 0.3 days for the p.m. treatment arm (P = 0.017). Although the duration of neutropenia in the a.m. arm was significantly shorter than in the p.m. arm, there were no differences related to the number of febrile neutropenic episodes or the duration of antibiotic administration. Also, there were no differences in the side effects observed in the a.m. and p.m. arms. CONCLUSIONS: The finding of 1.2 days' difference in the duration of Grade 3-4 neutropenia warrants further study of chronotherapy with HGFs.