Modulation of Fas-mediated apoptosis of human thyroid epithelial cells by IgG from patients with Graves' disease (GD) and idiopathic myxoedema

The expression of two autoimmune thyroid diseases, GD and idiopathic myxoedema, is associated with antibodies to the thyroid-stimulating hormone (TSH) receptor. Thyroid stimulating antibodies (TSAb) in GD are TSH agonists and cause hyperthyroidism as well as goitre, whereas thyroid stimulation blocking antibodies (TSBAb) in idiopathic myxoedema are TSH antagonists and cause hypothyroidism and thyroid atrophy. We investigated the effect of antibodies to TSH receptor on Fas-mediated apoptosis of thyroid epithelial cells (thyrocytes). Human IgG was isolated from healthy donors, patients with GD and idiopathic myxoedema. Human thyrocytes were obtained from surgical specimens. Thyrocytes were cultured in the presence or absence of human IgG with or without interferon-gamma (IFN-γ) or IL-1β for a specified time. After incubation, we examined the level of cAMP in cultured supernatants and both Fas and Bcl-2 expression on thyrocytes. In addition, we examined anti-Fas-mediated apoptosis of thyrocytes. Fas expression on thyrocytes was significantly down-regulated by Graves' IgG and TSH, although idiopathic myxoedema IgG did not affect Fas expression on thyrocytes. Idiopathic myxoedema IgG abrogated the effect of TSH on both cAMP production and inhibition of Fas expression on thyrocytes. Treatment of thyrocytes with IL-1β or IFN-γ caused a marked augmentation of Fas expression on thyrocytes. The increase of Fas expression of thyrocytes induced by IL-1β or IFN-γ was significantly suppressed in the presence of TSH or Graves' IgG. Anti-Fas-induced apoptosis of thyrocytes was observed in thyrocytes treated with IL-1β or IFN-γ, but was markedly inhibited in the presence of TSH or Graves' IgG. Furthermore, idiopathic myxoedema IgG abrogated most of the inhibitory effect of TSH on Fas-mediated apoptosis of thyrocytes treated with IL-1β or IFN-γ. Bcl-2 expression of thyrocytes did not change after stimulation with TSH, Graves' IgG, idiopathic myxoedema IgG, IL-1β or IFN-γ. These results suggest that TSAb found in Graves' patients may be potentially involved in the development of goitre by inhibition of Fas-mediated apoptosis of thyrocytes. In addition, TSBAb inhibit the action of TSH and increase the sensitivity toward Fas-mediated apoptosis of thyrocytes, inducing thyroid atrophy seen in patients with idiopathic myxoedema.     

Two color flow cytometric analysis of lymphocytes in HTLV-I-carrier children

Phenotypic changes in lymphocytes from healthy children with antibody for human T lymphotrophic virus type I (HTLV-I) were studied using two color flow cytometry. The subjects were high school students within a small district of Kyushu, Japan. In the carrier group, a subset of lymphocytes which expressed CD8⁺CD57⁺ was significantly lower in percentage (P < 0.01) and in number (P < 0.05). There was no significant difference between carriers and non-carriers in the percentage and number of CD4⁺ Leu8⁺cells or CD4⁺ HLA-DR⁺ cells. The IgG levels were slightly higher in carriers than in non-carriers (P < 0.05). These findings suggest that HTLV-I-infected cells may affect the immune system in healthy carrier children.     

A Biodegradable Poly-l-lactic Acid Coronary Stent in the Porcine Coronary Artery

Although biocompatibility of biodegradable stents is controversial, stents made of high molecular weight poly- l -lactic acid (PLLA) are thought to be the most promising. We investigated the biocompatibility of PLLA stents histologically and angiographically in porcine coronary arteries. The Igaki-Tamai stent is made of PLLA monofilaments (molecular mass 183 kD) with a zigzag helical coil design. Fourteen PLLA stents in 6 pigs and 9 Palmaz-Schatz half stents in 9 pigs were implanted in 15 normocholesterolemic pigs. Stents were mounted on a delivery catheter, and were implanted percutaneously into coronary arteries. Coronary angiography was performed before and immediately after stenting, at 2 and 6 weeks in five PLLA pigs and nine Palmaz-Schatz pigs. Histological studies were performed in PLLA pigs: 2 pigs at 2 weeks, 3 pigs at 6 weeks, and 1 pig at 16 weeks with hematoxylin-eosin and elastica van Giesons stains. All PLLA stents were successfully delivered. No stent thrombosis was detected in either group. There were no significant differences in minimal lumen diameter (MLD) or percent diameter stenosis between the PLLA and Palmaz-Schatz stent groups immediately after implantation, or at 2 or 6 weeks after implantation. Histological studies at 2, 6, and 16 weeks revealed no inflammation and minimal neointimal coverage on the PLLA stent struts. The PLLA stent maintained its structure for up to 16 weeks. These results suggest sufficient biocompatibility and strength of PLLA biodegradable stents in porcine coronary arteries. Clinical trial is now underway to validate the safety and usefulness of PLLA stents in humans.     

Synthesis of human angiotensinogen (1-17) containing one of the putative glycosylation binding sites and its hydrolysis by human renin and porcine pepsin

The N-terminal heptadecapeptide of human angiotensinogen (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-Glu-Ser-Thr-NH₂), with the C-terminal carboxyl group amidated, was synthesized in order to study the role of Asn-Glu-Ser, a putative carbohydrate binding site, on the hydrolysis by human renin. The synthesis was performed by fragment condensation using the Honzl and Rudinger azide procedure. In our conditions for azide segment condensation, histidine racemization was demonstrated to be negligible for most of the condensation reactions. Human renin liberates angiotensin I from h-angiotensinogen (1-17)-NH₂ with a K_m value of 3.4 × 10^?5m , at pH 7.3 and 37° being similar to h-angiotensinogen (1-13), an analog without the carbohydrate binding site. However, the V_max value of 4.1 × 10^?9mol/G.U. min is one order of magnitude higher. Porcine pepsin was demonstrated to cleave preferentially Leu¹⁰-Val¹¹ bond and, surprisingly, His⁹-Leu¹⁰ as well.     

Retroperitoneal extragonadal germ cell tumor in a patient with Klinefelter''s syndrome

A 22-year-old man was diagnosed with retroperitoneal seminoma associated with Klinefelter's syndrome. The tumor was 14 x 12 cm in size and surrounded the superior mesenteric artery. He received induction chemotherapy with bleomycin, etoposide and cisplatin (BEP) followed by salvage chemotherapy with paclitaxel, ifosfamide and cisplatin (TIP). The tumor considerably decreased in size and remains as a poorly defined plaque. At the time of writing, he is being followed closely and is free from progression.     

Case of cutaneous Scedosporium apiospermum infection successfully treated with voriconazole

We report a case of cutaneous infection due to Scedosporium apiospermum in a 75-year-old immunocompromised male patient who had received long-term corticosteroid and immunosuppressant therapy for the treatment of nephrotic syndrome. The patient came to our department complaining of erythema with a number of pustules on the dorsal surface of the right hand. S. apiospermum was identified from a culture taken from the pus. After unsuccessful treatment with topical ketoconazole, oral itraconazole and oral terbinafine, the lesion quickly resolved with the daily administration of 400 mg voriconazole. No recurrence was observed despite discontinuation of voriconazole due to drug-induced hepatitis. Voriconazole holds out the promise of an effective treatment for invasive Scedosporium infection.     

Experimental and Clinical Studies of Biodegradable Polymeric Stents

The metallic stent has become the most common device to reduce acute occlusion and late restenosis after balloon angioplasty, but the long-term effects of metallic stents in human coronary arteries are still unknown. To overcome several problems of conventional stenting, there have been many attempts to manufacture stents made of biodegradable materials. Although some studies have noted various degrees of inflammatory responses after biodegradable stent implantation, stents made of poly-1-lactic acid (PLLA) showed high biocompatibility with minimal inflammatory response and neointimal formation in porcine coronary arteries. A clinical study of PLLA self-expanding stent implantation is underway in Japan. The initial and 6-month results are favorable and suggest the feasibility, safety, and efficacy of the PLLA biodegradable stent in humans. However, long-term follow-up with larger numbers of patients will be required to validate the long-term efficacy of PLLA stents.