Detection of antibodies to HTLV-I and -III in sera from Japanese hemophiliacs.

Sera from 50 Japanese hemophiliacs were screened for antibodies to human T-lymphotropic retrovirus types I and III (HTLV-I and -III). As a whole, antibody to HTLV-I, antibody to HTLV-III, and antibodies to HTLV-I and -III were detected in sera from 2, 17, and 6 hemophiliacs, respectively. Among them, two hemophiliacs developed acquired immunodeficiency syndrome who were positive for both antibodies to HTLV-I and -III in sera. All of the others were asymptomatic. Most of the blood products transfused into these hemophiliacs were imported from abroad, whence the source of HTLV-III infection presumably originated. However, since quite a high percentage of these antibody-positive hemophiliacs was positive for antibody to HTLV-I, even though they are native residents in HTLV-I nonendemic areas of Japan, some special factors may have participated in HTLV-I infection. These special factors should be investigated in the future.

Immunological effects of 1alpha-hydroxycholecalciferol (1alpha-OH-D3) and its metabolites.

An immunosuppressive substance was detected in the serum and plasma of hemodialysis patients. There was a marked increase in its activity immediately after hemodialysis. This substance was not detected in the plasma of hemodialysis patients treated with 1alpha-hydroxycholecalciferol (1alpha-OH-D3), although its disappearance was unrelated to either the total dose or the duration of treatment with 1alpha-OH-D3. During in vitro studies, 1alpha-OH-D3 did not change the phytohemagglutinin-, staphage lysate- and concanavalin A-induced and spontaneous lymphoproliferation of peripheral blood lymphocytes (PBL) from a healthy person. Furthermore, addition of 1alpha-OH-D3 to the plasma of hemodialysis patients who had not received 1alpha-OH-D3 did not interfere with the suppressive activity. On the other hand, 1alpha,24(R)-dihydroxycholecalciferol, 1alpha,24(S)-dihydroxycholecalciferol, and 1alpha,25-dihydroxycholecalciferol, which are all metabolites of 1alpha-OH-D3, suppressed mitogen-induced lymphoproliferation of PBL from a healthy person.

Effects of serum and plasma from hemodialysis patients on the lymphoproliferative response.

The effect of serum and plasma from hemodialysis patients on the immune response was investigated in vitro using phytohemagglutinin(PHA)-, concanavalin A(Con A)-, and staphage lysate(SPL)-induced and spontaneous blastogenesis of peripheral lymphocytes from a healthy person. An immunosuppressive substance(s) was found to exist in these samples and markedly increased in activity after hemodialysis. This substances(s) was heat-labile (56 degrees C, 30 min) and had a molecular weight of 50,000 daltons or more. It was not related to heparin. The appearance of this substance(s) was not influenced by the patients' sex or age or by the duration of hemodialysis.

Exacerbation of hypothyroidism following tumor necrosis factor-alpha infusion.

A 46-year-old woman with chronic thyroiditis who had been receiving thyroid hormone treatment for 10 yr developed severe hypothyroidism (FT4 0.37 ng/dl, FT3 1.38 pg/ml, TSH 151.00 microU/ml) following tumor necrosis factor-alpha (TNF) infusion for the treatment of a complicated cutaneous T-cell lymphoma. Indirect immunofluorescence staining of thyroid follicular cells showed aberrant expression of HLA class II antigens. The mechanisms underlying the exacerbation of the hypothyroidism may be an augmentation of immunological processes in the thyroid and a direct action of TNF on the synthesis and secretion of thyroid hormone.

Cavernous sinus syndrome associated with nonsecretory myeloma.

The case of a 53-year-old man who developed cavernous sinus syndrome (CSS) four years after being diagnosed as having nonsecretory myeloma is described. He was admitted with diplopia and dull pain over the right infraorbital and zygomatic region in June 1997. The cause of CSS was the intracranial involvement of myeloma, which was diagnosed by fiberscopic biopsy. The results of endocrinologic evaluation were almost normal. The response to radiotherapy and chemotherapy was mild. CSS caused by nonsecretory myeloma is rare and its prognosis is poor. More aggressive chemotherapy with stem cell support may be indicated.

Effect of glucose levels during the in vitro culture in synthetic oviduct fluid medium on in vitro development of bovine oocytes matured and fertilized in vitro.

The present study was conducted to determine the optimal glucose levels during the in vitro culture of bovine oocytes matured and fertilized in vitro for blastocyst development. Oocytes matured in TCM-199 + 10% FCS + hormones and granulosa cells were fertilized in vitro in a TALP medium with frozen-thawed, swim-up separated, and heparin-treated spermatozoa. After insemination, 1199 oocytes were cultured for 3 days in synthetic oviduct fluid medium (SOFM) supplemented with 10% human serum (HS) and with 10 different glucose levels (0 to 5 mM), and further cultured for 5 days in SOFM + 10% HS containing 1.5 mM glucose (Experiment 1). In Experiment 2, 739 oocytes were cultured for 3 days following insemination in either SOFM + human serum albumin or SOFM + 10% HS containing 0.188 mM glucose. From Days 4 to 8, the oocytes were cultured in SOFM containing 4 different glucose levels. A high level of glucose (3.0 and 5.0 mM) at Days 0 to 3 significantly reduced the rate of blastocyst development (3.0 to 4.2%), and a yet higher (5.0 mM) glucose level at Days 4 to 8 also significantly lowered the rate of blastocyst development as compared with 1.5 mM glucose (19.5% vs 29.3%). The present results indicate that a lower level (0.188 mM: 28.8% in blastocyst development) of glucose is preferable in SOFM for the in vitro development to blastocysts at Days 0 to 3 after insemination. At Days 4 to 8, the original level (1.5 mM) of glucose contained in SOFM appears to be the most effective treatment.

A case of refractory hypothyroidism requiring daily intravenous thyroxine.

Most patients with hypothyroidism respond to administration of oral thyroxine at a maintenance dose of 50-175 micrograms/day. This is the first documented patient with post-operative hypothyroidism who required about 10 times the standard dose of thyroxine, and whose symptoms only resolved when intravenous thyroxine was administered daily. Our findings support the benefits of daily intravenous therapy with thyroxine in this case.

Acting mechanisms of Lentinan in human--I. Augmentation of DNA synthesis and immunoglobulin production of peripheral mononuclear cells.

The immunopotentiating activity and acting mechanisms of Lentinan were investigated in the human system, resulting in clarification of the following characteristics. (a) Augmentation of DNA synthesis of peripheral mononuclear cells (PMNC) occurred both in vitro and in vivo by adding or injecting Lentinan, for which the coexistence of T cells, B cells and adherent cells (mainly monocytes) was essential. (b) No additional mitogenic effect of Lentinan was observed when PMNC were incubated with both Lentinan and other mitogens. (c) In vitro production of immunoglobulin by PMNC induced with pokeweed mitogen was enhanced through the inhibition of suppressor T cell activity by Lentinan.

In vitro antibody-dependent cellular cytotoxicity against human T-cell leukemia/lymphoma virus (HTLV)-producing cells.

Human T-cell leukemia/lymphoma virus (HTLV)-producing cells were lysed by peripheral mononuclear cells (PMNC) from both anti-HTLV antibody-positive and -negative healthy persons in the presence of natural humoral antibodies against HTLV-related antigens (antibody-dependent cellular cytotoxicity, ADCC). PMNC from patients with T-cell leukemia, however, did not possess the positive reaction even in the presence of natural antibodies. In contrast, when the antibodies were absent, no cytotoxicity was caused by PMNC from any donors. Additionally, the complement present in the antibody-positive plasma did not contribute to humoral antibody-dependent cytotoxicity in the presence of plasma without PMNC. Therefore, ADCC against HTLV-producing cells may correlate with the prophylaxis of HTLV-induced malignancy in vivo.

Acting mechanisms of Lentinan in human--II. Enhancement of non-specific cell-mediated cytotoxicity as an interferon inducer.

The immunopotentiator "Lentinan" augmented the cell-mediated cytotoxicity in humans. (a) The activation of killer T cells by the mixed lymphocyte culture was accelerated only when responder cells were mixed with both a suboptimum number of stimulator cells and Lentinan. (b) The interferon level in the peripheral blood circulation of cancer patients was elevated in 12 h following Lentinan administration, and natural killer activity of peripheral mononuclear cells was enhanced in 48 h. These data indicate that Lentinan favorably affects the host mechanisms of man.

Low natural killer syndrome: clinical and immunologic features.

Twenty-three patients with low natural killer syndrome (LNKS), 7 males and 16 females, are reported here. These LNKS patients had an age range from 14 to 77 years, with a median of 36.5 years. LNKS is a newly proposed category of immune disorders, being characteristically diagnosed by lowered NK cell activity against K562 target cells as a definite laboratory abnormality, in association with general clinical symptoms of remittent fever and uncomfortable fatigue, persisting without explanation for more than 6 months. Other immune parameters, such as the DNA synthesis of peripheral blood mononuclear cells (PBMCs) in either the presence or absence of mitogens, the T4+/T8+ ratio and the number of Leu-11+ PBMCs, were usually within the normal range. Also, routine laboratory tests did not detect any abnormal findings. The LNKS patients responded well to the administration of an immunopotentiator called 'lentinan', a glucan extracted from the Japanese mushroom Lentinus edodes, despite no responses to conventional fever treatments such as the administration of antipyretics or antibiotics. All LNKS patients observed were universally free of antibodies in their sera to human T-lymphotropic retroviruses I and III, and lymphadenopathy was infrequent, indicating that the LNKS is a syndrome independent of acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. Antibodies to other known viruses tested such as Epstein-Barr or measles virus, or cytomegalovirus were also negative or not significantly elevated in the sera before the initiation of lentinan administration. If a virus is the cause of LNKS, it may be a new, unknown virus or an unknown substrain of known viruses. None of the LNKS patients has died of this syndrome.

Characterization of the insulin resistance in liver cirrhosis: a comparison with non-insulin dependent diabetes mellitus.

To characterize the mechanisms of insulin resistance in liver cirrhosis (LC), we estimated the peripheral tissue sensitivity and responsiveness to insulin using the euglycemic clamp technique and determined the insulin binding to erythrocytes in patients with compensated LC as well as in patients with non-insulin dependent diabetes mellitus (NIDDM). The insulin dose-response curves of the glucose metabolic clearance rates (MCR) were shifted to the right and downward both in patients with LC and NIDDM, indicating a reduced sensitivity and responsiveness to insulin. In the cirrhotics, MCR at the maximally effective insulin level, an index of insulin responsiveness, was correlated with fasting insulin levels (r = -0.57, P < 0.01) and sigma BG in 75 gOGTT (r = -0.43, P < 0.05), but no correlations were found between them and the diabetics. Although specific insulin bindings to erythrocytes were significantly lower in patients both with LC and NIDDM, Scatchard analysis revealed a significant decrease in the number of insulin receptors in the cirrhotics, and a decrease in the empty-site affinity in the diabetics. These findings suggest that insulin resistance in LC consists of a combination of binding and postbinding defects. The latter defect may be caused by basal hyperinsulinemia and contribute to the development of glucose intolerance. Although binding and postbinding abnormalities are also found in NIDDM, the mechanisms of insulin resistance in LC and NIDDM may be different.

[A case of pseudohypoparathyroidism (PHP) type II associated with Bartter's syndrome--restoration of phosphaturic response to parathyroid hormone (PTH) by treatment for hypopotassemia].

We report a case of PHP Type II whose phosphaturic response to PTH was restored by treatment for complicated Bartter's syndrome. A 34-year-old woman was admitted to our hospital in July 1990 because of tetanic convulsion. The physical examination showed normal blood pressure (118/62mmHg), round face without shortness of metacarpal bones and positive Trousseau's sign. Although renal function was normal, hypocalcemia (6.5mg/dl) and hyperphosphatemia (4.8mg/dl) in association with high levels of serum PTH (942pg/ml) and 1.25 (OH)2D3 (86pg/ml) were disclosed. Ellsworth-Howard test revealed that there was no increase in the urinary secretion of phosphate despite an increase in urinary cAMP excretion. On the other hand, hypopotassemia (2.5mEq/l) and metabolic alkalosis with high plasma renin activity (22.8ng/ml/hr) and aldosterone concentration (22.7ng/dl) were coexistent. Pressor response to angiotensin II infusion was blunted. Although no glomeruli were obtained by renal biopsy specimen, vacuolar degeneration on proximal tubules were noted. These findings indicated that she had PHP Type II associated with Bartter's syndrome. By administration of potassium (24mEq/day), spironolactone (50mg/day) and only small doses of 1 alpha-hydroxyvitamin D3 (0.5mg/day), serum levels of potassium as well as calcium were normalized and tetanic attacks disappeared. In March 1991, she was re-examined by Ellsworth-Howard test in order to clarify the effects of hypopotassemia on renal tubular response to PTH. Interestingly, phosphaturic response to PTH was restored, and the degree of increase in urinary cAMP excretion was 4 times as high as that on the first admission. These results suggest that hypopotassemia changes the response of renal proximal tubular cells to PTH, particularly such as reabsorption of phosphate and cAMP response, although it is possible that hypocalcemia may contribute to the blunted phosphaturic response to PTH. The mechanism of hypocalcemia seen in this case remains to be elucidated.

Cyclosporine A inhibits the secretion of certain anterior pituitary hormones in patients with nephrotic syndrome.

To clarify the effects of cyclosporine A (CsA) on the secretion of serum thyrotropin (TSH), prolactin (PRL), luteinizing hormone (LH) and follicular stimulating hormone (FSH), we performed TRH and LH-RH testing in 4 patients with the nephrotic syndrome before and after the administration of CsA, 6 mg/kg/day for 4 to 12 weeks. Prior to CsA all patients responded normally to TRH with respect to TSH and PRL secretion. Two patients showed normal response of LH and FSH to LH-RH stimulation while the response in 2 other patients, who were both menopausal, was exaggerated. By the third or fourth week of CsA administration the basal and peak TSH and PRL values declined significantly in all patients in response to TRH stimulation while those of LH and FSH showed only a modest decrease in response to LH-RH stimulation. Two to 4 weeks after the cessation of CsA the response of TSH, PRL and FSH returned to the pretreatment level. These observations suggest that: 1) CsA exerts an inhibitory effect on the secretion of at least TSH and PRL in humans, and 2) the effect of CsA on the pituitary may be partially reversible after the cessation of the therapy.