Activation of CD44 facilitates DNA repair in T-cell lymphoma but has differential effects on apoptosis induced by chemotherapeutic agents and ionizing radiation.

Expression of CD44s (standard form) in malignant lymphoma is a poor indicator of survival. To investigate whether activation of CD44s can protect from cell death, this study compared the extent of apoptosis induced by chemotherapeutic agents and ionizing radiation (IR) on T-lymphoma cell lines in the presence or absence of adherent hyaluronan and monoclonal antibodies (MoAbs). Growth in the presence of adherent ligands enhanced apoptosis induced by dexamethasone (Dex), but protected cells from epirubicin-induced apoptosis. In IR-induced apoptosis, mouse lymphoma cells had resistance against apoptosis when treated with hyaluronan (HA), although acute cell death reached the same plateau regardless of treatment with adherent MoAbs in human lymphoma cell line. However, the post-irradiated repopulation of lymphoma cells was strikingly accelerated in those treated with CD44 adherent ligands. This repopulation process correlated with the remarkable upregulation of proliferating cell nuclear antigen (PCNA), which is a protein involved in DNA repair. Unscheduled DNA synthesis (UDS), a measure of DNA repair, was consistently enhanced in CD44s-stimulated cells after exposure to radiation. The results suggest that the poor prognostic indication of CD44 expression is more a consequence of enhanced DNA repair following genotoxic damage than of direct resistance to apoptosis.

Polymorphism in the transmembrane region of the MICA gene and type 1 diabetes.

Although MHC class II genes have a stronger association with type 1 diabetes than MHC class I genes, studies have shown that MHC class I molecules play an independent role in the etiology of type 1 diabetes, and the existence of susceptibility genes within a segment of MHC between the HLA-B and TNF genes has been predicted, where MHC class I chain-related gene A (MICA) resides. MICA has a triplet repeat polymorphism in the transmembrane region consisting of five alleles. We analyzed this polymorphism in 162 unrelated children (82 boys) with type 1 diabetes (age at diagnosis 7.01 +/- 3.76 yr) and 154 randomly selected unrelated children (87 boys), age 2.81 +/- 2.12 yr. Phenotype frequency of allele A9 in children with type 1 diabetes was significantly higher than in controls (RR = 2.42, 95% CI = 1.52-3.85, p = 0.000162, pc = 0.00081). Gene frequency of allele A9 was also significantly higher in children with type 1 diabetes when compared with control children (RR = 2.73, 95% CI = 1.85-4.03, p = 2.62 x 10(-7), pc = 1.31 x 10(-6)). This study demonstrates that MICA allele A9 confers risk of type 1 diabetes.

Response of Epstein-Barr virus-associated Ki-1+ anaplastic large cell lymphoma to 13-cis retinoic acid and interferon alpha.

The response of peripheral T-cell lymphoma to 13-cis retinoic acid (13-cis-RA) has been well established, especially in Ki-1+ anaplastic large cell lymphoma (ALCL) confined to the skin. Here, we report the use of 13-cis-RA in combination with interferon alpha in a patient with refractory ALCL. The patient, an 18-year-old man, suffered from retroperitoneal, hepatic, and splenic ALCL. Reactive hemophagocytic syndrome also developed. Active Epstein-Barr virus infection was demonstrated by serologic tests and in situ hybridization of Epstein-Barr virus early RNA-1. Although high-dose intravenous immunoglobulin (IgG), etoposide, and steroids were administered, only chemotherapy (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) successfully controlled the progress of hemophagocytosis. However, the retroperitoneal mass and splenic tumor did not show a satisfactory response to three cycles of chemotherapy. Hence, interferon 4.5 MU/m2 every other day with 13-cis-RA 1 mg/kg/day was instituted. Abdominal computed tomogram after 58 days of treatment revealed that the tumor had significantly reduced in size. Bone marrow biopsy demonstrated alleviation of hemophagocytosis as well. However, lymphoma cells had begun to infiltrate the bone marrow. Our findings suggest that 13-cis-RA and interferon alpha may be partially effective in treating ALCL.

DQA1*Arg52,DQB1*nonAsp57, and DRB1*04 genotypes in Chinese children with insulin-dependent diabetes mellitus.

Ethnic comparisons are extremely important and useful for studying the HLA component involved in insulin-dependent diabetes mellitus (IDDM) predisposition. To date there have been only a few reports on the association of HLA loci and IDDM in Chinese. We report here a study on DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 in IDDM children and control adults among Han Chinese living in Taiwan. One hundred and fourteen unrelated children (62 boys) with IDDM were studied. Their ages at diagnosis were between 0.3 and 15.0 years (6.8 +/- 3.6 years). The control population consisted of 120 randomly selected normal adults. DQA1*Arg52(+/+), DQB1*nonAsp57(+/+), and DRB1*04(+/-) were associated with IDDM (RR = 11.50, 2.21, and 2.82; p = 1.11 x 10(-15), 2.84 x 10(-3), and 1.98 x 10(-4), respectively). DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 conferred risks for IDDM (RR = 12.79, 7.11, and 2.83; pc = 8.22 x 10(-4), 5.35 x 10(-3), and 5.68 x 10(-4), respectively). Combinations of DQA1*Arg52 and DRB1*04 conferred the highest risk for IDDM (RR = 19.64, pc = 5.4 x 10(-5)). DQA1*Arg52 was associated with IDDM in subjects with DQB1*nonAsp57+ (RR = 14.87, pc = 2.41 x 10(-4)) and DQB1*nonAsp57 was also associated with IDDM in subjects with DQA1*Arg52+ (RR = 8.41, pc = 1.54 x 10(-3)), suggesting that DQA1*Arg52 and DQB1*nonAsp57 are interacting. This study demonstrates that DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 confer susceptibility for IDDM to Chinese children. A combination of DQA1*Arg52 and DRB1*04 confers the highest risk and it is suggested that a susceptibility gene might be situated between DQA1*Arg52 and DRB1*04 or both are synergistic. There is an interaction between DQA1*Arg52 and DQB1*nonAsp57 and homozygosity for DQA1*Arg52/DQB1*nonAsp57, which encodes four susceptibility DQ heterodimers, confers a high risk.

Graves' disease and diabetes mellitus associated with acute suppurative thyroiditis: a case report.

Acute suppurative thyroiditis (AST) is a rare disorder. The rarity of AST is a result of the resistance of the thyroid gland to local infection. Thyroid function tests are usually normal in AST. In a review of the literature from 1966 to 1995, only three cases of AST associated with thyrotoxicosis have been convincingly demonstrated. The thyrotoxicosis in these cases was caused by diffuse inflammation of the thyroid gland and to the disruption of follicles with the release of pre-formed thyroid hormone into the circulation. Thus, the thyrotoxicosis in these cases was transient. With successful therapy, nearly all patients showed complete recovery of thyroid function within two to three months. The patient in the case here was a diabetic woman with Graves' disease in whom thyrotoxicosis occurred after Klebsiella pneumoniae thyroiditis, with relapse nine months after discharge. Thus, the patient's thyrotoxicosis might not have been caused simply from thyroid tissue destruction by AST, but also as a result of enhancing autoimmune activity. No previous case has ever been reported in the English literature. In diabetics, the impairment of chemotaxis and phagocytosis has been noted. Therefore, diabetes mellitus (DM) might have been the precipitating factor for this patient's acquiring this unusual infection. Thyrotoxicosis and AST will increase insulin requirements and thus aggravate diabetes. In addition, poor control of blood sugar will enhance the severity of AST.

Clinical trial of low-dose rHuG-CSF in neutropenic cancer patients following anti-cancer chemotherapy.

Low-dose, subcutaneous recombinant human granulocyte colony-stimulating factor (rHuG-CSF, Lenograstim) was administered to 40 cancer patients (17 men, 23 women) enrolled from two medical centers to verify its clinical effectiveness and safety. The patients' mean age was 50.3 +/- 14.9 years. In this study, there were 20 patients with non-Hodgkin's lymphoma, 10 with breast cancer and 10 with various other solid tumors. The patients first received a course of chemotherapy without rHuG-CSF (control cycle). All patients had at least one episode of neutropenia or leukopenia during the control cycle. rHuG-CSF (2 micrograms/kg/day) was given subcutaneously for 10 days during the study cycle starting on the fourth day of chemotherapy. The nadirs of absolute neutrophil counts (ANC) were 1.8 +/- 0.25 x 10(9)/L and 0.27 +/- 0.05 x 10(9)/L for the rHuG-CSF cycle and pre-rHuG-CSF control cycle, respectively. The number of days of ANC < 1 x 10(9)/L were 1.03 +/- 0.29 and 7.38 +/- 0.58 for rHuG-CSF and control cycles, respectively. The duration from nadir to recovery of ANC (> or = 2 x 10(9)/L) was 9.68 +/- 1.15 days in the rHuG-CSF cycle, vs 22.53 +/- 1.03 days in the control cycle (p < 0.0001). No patient withdrew from the study. Adverse events were mild, with 12.5% to 40% of patients developing myalgia, general malaise, back pain, anorexia or fever. These side-effects were tolerable in all cases. The biochemical abnormalities were subtle and negligible. rHuG-CSF 2 micrograms/kg/day given subcutaneously for 10 days beginning on the fourth day of chemotherapy is very effective (90%), safe and convenient.

Methimazole-induced agranulocytosis treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF): a case report.

Methimazole 5 mg three times daily was prescribed in 1994 spring to a woman, aged 53 years, with relapsed hyperthyroidism. The drug was discontinued six weeks after initiation because of leukopenia. Two weeks still later, the patient developed chills, high fever, and a sore throat. The leukocyte count was 1,100/mm3 with 23% granulocytes, 76% lymphocytes and 1% monocytes. The granulocyte count stopped decreasing only three weeks after the drug was discontinued when the recombinant human granulocyte colony-stimulating factor (rhG-CSF) was given; the patient recovered uneventfully. Thus we recommend that the peripheral leukocyte count of patients who receive methimazole therapy must be carefully monitored during the first three months. Furthermore, the use of rhG-CSF for methimazole-induced agranulocytosis abbreviates the period required for marrow recovery after cessation of this offensive drug.

Plasma levels of atrial natriuretic factor in moderate to severe obstructive sleep apnea syndrome.

To evaluate atrial natriuretic factor (ANF) secretion during sleep in obstructive sleep apnea syndrome (OSAS), plasma ANF was measured every 3 hours before and after effective nasal continuous positive airway pressure (CPAP) treatment in 10 patients with moderate to severe OSAS and 10 normal subjects. The results showed daily changes in ANF levels in normal controls and in OSAS patients after effective therapy, with a nadir at 0300 hours and a peak at 2100 hours. There was no significant daily variation of ANF levels in patients with OSAS before therapy, and ANF levels from midnight to 0900 hours were significantly higher before, as compared with after, therapy. These results indicate that OSAS patients have abnormal ANF secretion. Effective nasal CPAP therapy led to normalization of ANF secretion during sleep.

The relationship between sleep apnea syndrome and hypothyroidism.

To evaluate the prevalence of obstructive sleep apnea syndrome (OSAS) in patients with hypothyroidism, the prevalence of hypothyroidism in patients with OSAS, the possible factors predisposing to sleep-related breathing disorder in hypothyroid patients, and the effect of thyroid hormone in treating hypothyroidism associated with OSAS, we studied 65 patients with proven OSAS (apnea index [AI] > 5) and 20 hypothyroid patients. All patients were monitored for one overnight sleep study using polysomnography (Grass 78). We found only two (3.1 percent) of 65 OSAS patients had thyroid hypofunction. Of 20 patients with hypothyroidism, two showed moderate to severe OSAS and three had mild OSAS. Patients with both hypothyroidism and OSAS had impaired respiratory drive, but this was corrected by thyroid hormone therapy. Patients with hypothyroidism without OSAS were younger and had a lower percentage of ideal body weight than those with both hypothyroidism and OSAS. All hypothyroid patients were snorers. Thyroid hormone replacement was effective in correcting snoring only after one year of therapy. We conclude the following: (1) an overnight sleep study is not necessary in every case of hypothyroidism; (2) thyroid function studies need not be done routinely for every OSAS patient; (3) thyroid hormone therapy is effective for OSAS but it takes longer to correct the snore than respiratory drive; and (4) age and body weight are related to the development of OSAS.

Cyproheptadine in the control of Cushing's disease.

A patient with Cushing's disease was treated with cyproheptadine with concomitant remission of the disease for 60 months. Despite clinical improvement and achievement of normal levels of cortisol excretions, her menstruation-related cyclic surge of cortisol secretion was supranormal. The mode of action of cyproheptadine was studied by the administration of metyrapone. Long-term administration of cyproheptadine appeared to normalize excessive adrenocorticotropic hormone (ACTH) production by reducing the frequency and the peak levels of episodic secretion of ACTH.

An electron microscopic and radioautographic study on experimental kernicterus. II. Bilirubin movement within neurons and release of waste products via astroglia.

Response of the neurons to bilirubin in asphyxiated newborn rabbits was studied in vivo with the use of the electron microscope and radioautographic technics. A morphologic basis for the mode of intraneuronal bilirubin movement in kernicterus has been established. The absorbed bilirubin had ready access to the Golgi complex from the dendrite through the neurotubules by a mechanism of centripetal dendroplasmic flow. The endoplasmic reticulum provided a subcellular canalicular system for the directed passage from the Golgi complex to the nuclear membrane. Proximodistal flow of bilirubin in the axoplasm caused spotty destruction of axons. The release of waste products from the affected neurons toward the capillaries is very likely an effect of reverse transastroglial transport.