Abstract. Recent studies demonstrate that apoptosis is an important process in physiological and pathological cell death. We examined the apoptotic phenomena in thyroid tissues by two methods: immunohistological and in situ end-labeling of fragmented DNA (ISEL). In thyroid tissues from patients with Hashimoto's thyroiditis and thyroid cancer, fragmented nuclear DNA and LeY (apoptosis associated antigen) were observed. In tissues from patients with Graves' disease, LeY and bcl-2 oncoprotein were expressed, but no ISEL positive cells were observed. In contrast, thyrocytes in normal thyroid tissues were not stained with ISEL or anti-L&' antibodies (Abs). Fas antigen (Ag) was expressed in various thyroid tissues, including normal subjects. The clinical meaning of this was not determined. These results suggest that the apoptotic process takes place in Hashimoto's thyroiditis and thyroid cancer, and is overcome in Graves' disease by bcl-2 expression.

An enantioselective total synthesis of both enantiomers of caryophyllene-type sesquiterpenoid pestalotiopsin A has been achieved, thereby establishing the absolute stereochemistry of natural (+)-pestalotiopsin A. Highlights of the synthesis include a [2 + 2] cycloaddition of N-propioloyl Oppolzer's camphorsultam and ketene dialkyl acetal and subsequent highly stereoselective 1,4-hydride addition/protonation, an aldol reaction of functionalized bicyclic lactone with aldehyde, an efficient intramolecular Nozaki-Hiyama-Kishi (NHK) reaction for the construction of the highly strained (E)-cyclononene ring, and a palladium-catalyzed reduction of allylic mesylate with retention of the E configuration.

To clarify whether the changes of free radicals and its scavengers are induced by thyroid disorders, we measured levels of free radical scavengers and checked °2 radical generating systems in the human thyroid gland.Thyroid specimens from patients with Graves' disease, follicular adenoma, and papillary and follicular carcinomas contained significantly higher concentrations of xanthine oxidase (XOD) and gluthathione peroxidase (GSH-PX), compared to those in the normal thyroid tissue. Catalase concentration was significantly lower in thyroid specimens from patients with Graves' disease and significantly lower in thyroid specimens from patients with follicular adenoma, compared to those in the normal thyroid tissue. Cu/Zn superoxide dismutase (CuIZn SOD) concentration was significantly lower in the specimens from follicular adenoma and papillary carcinoma and Mn SOD concentration was significantly higher in the specimens from papillary carcinoma than those in the normal thyroid tissue. The lipid peroxide concentration, expressed as malondialdehyde (MDA) concentration, was significantly higher in the specimens from papillary carcinoma than those in the normal thyroid tissue.These findings suggest that the levels of free radicals are increased and are scavenged and catalyzed in the thyroid of Graves' disease, whereas free radicals and lipid peroxide are not completely scavenged in papillary carcinoma tissues, suggesting that these substances affect some role in cell function of thyroid tumors.

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In 1996 two highly oxygenated caryophyllene sesquiterpenoids, pestalotiopsins A (1) and B (2) (Scheme 1), were isolated by Sugawara and co-workers from Pestalotiopsis sp., an endophytic fungus associated with the bark and leaves of Taxus brevifolia (the Pacific yew).[1] Later, several related natural products were found from the species of Pestalotiopsis.[2] Among them, pestalotiopsin A showed cytotoxicity and immunosuppressive activity in the mixed lymphocyte reaction. The structures of the pestalotiopsins were determined by extensive spectroscopic studies and finally confirmed by X-ray crystallographic analysis; however, the absolute stereochemistry remained unclear. Pestalotiopsin A (1) consists of an unprecedented oxatricyclic structure bearing seven stereogenic centers and it is comprised of a cyclobutane ring fused with both an (E)-cyclononene ring and a g-lactol unit. In contrast, bicyclic pestalotiopsin B (2) exists as a mixture of two atropisomers at the C4ÀC5 carbon-carbon double bond. The synthetically formidable structure of 1 has attracted considerable attention among chemists concerned with natural product synthesis. The research groups of Procter, [3] Paquette, [4] and Markó, [5] in addition to our group, [6] have reported a number of synthetic studies of 1. Herein, we describe the first total synthesis of (À)-pestalotiopsin A (1) and the assignment of its absolute configuration as the antipode of natural pestalotiopsin A.Since embarking on this research we have devoted our efforts to the efficient formation of the strained (E)-cyclononene moiety in 1. Although early attempts were unsuccessful, [7] we envisioned that a Nozaki-Hiyama-Kishi (NHK) reaction approach [8] would enable efficient (E)-cyclononene ring formation. As shown in Scheme 1, we considered 1 could be synthesized by using the intramolecular NHK reaction of aldehyde/alkenyl iodide 3 as a key step and subsequent deoxygenation of the newly formed hydroxy group at C3. The formation of 3 would, in turn, be achieved by the aldol reaction of functionalized bicyclic lactone 4 and g-iodo-b,gunsaturated aldehyde 5, both in high enantioenriched forms. We expected that stereogenic centers at C7 and C8 of 3 would be introduced stereoselectively as desired in the aldol process by taking advantage of the 2-oxabicyclo[3.2.0]heptan-3-one structure of 4. This bicyclic g-lactone 4, in turn, would be prepared from a highly enantioenriched cyclobutane derivative analogous to that described in our preliminary report. [6] Earlier we reported [6] the asymmetric synthesis of functionalized cyclobutanes which featured the [2+2] cycloaddition of the N-propioloyl derivative of Oppolzers camphorsultam (6) (Scheme 2) and ketene bis(trimethylsilyl) acetal. However, the bis(trimethylsilyl) acetal moiety was not stable under the conditions used for the removal of the camphorsultam, and it gave rise to some additional steps for the conversion of the cyclobutane derivativeinto the bicyclic lactone intermediate. To overcome this disadvantage, ketene dialkyl acetal...

A 34-year-old Japanese male was admitted to Okayama University Hospital with severe hypertension, rapidly progressive renal failure, blurred vision, dyspnea and hemoptysis. Clinical diagnosis of malignant hypertension was given and antihypertensive therapy and hemodialysis were immediately started. Renal biopsy was performed on the sixth day in hospital to examine the underlying disease, such as microscopic form of polyarteritis, since the complaint of hemoptysis and pulmonary alveolar hemorrhage was noted by computed tomography of the lungs. Typical pathological changes of malignant hypertension, i.e. fibrinoid necrosis of the afferent arterioles and proliferative endoarteritis at the interlobular arteries were observed. There was no evidence of active necrotizing glomerulonephritis and crescent formation. Renal function was gradually recovered and pulmonary hemorrhage completely disappeared by treatment with antihypertensive agents. The authors report a case of malignant hypertension with a rare complication of pulmonary alveolar hemorrhage and speculate that it may be related to vascular injuries at the alveolar capillary level caused by malignant hypertension.

A case of malignant thymomawith pure red cell aplasia (PRCA)complicated by syndrome of inappropriate secretion of antidiuretic hormone (SIADH) following intrathoracic cisdichlorodiammine platinum (CDDP) administration is reported. A 59-year-old Japanese woman who presented with severe general fatigue was diagnosed with PRCAassociated with a thymoma, based on the findings of a bone marrow biopsy, computed tomography of the chest, and the existence of anti-acetylcholine receptor antibodies. She underwenta thymectomyafter frequent blood transfusions.This was followed by intrathoracic CDDPadministration, because of pleural dissemination. Nine days following chemotherapy, her serum sodium concentration was found to be 104 mM,while her consciousness was drowsy with severe fatigue and vomiting. This hyponatremic state was diagnosed as SIADHinduced by CDDPinfusion into the thoracic space, based on the hypo-osmolality of her serum, the hyper-osmolality of her urine, and an inappropriate level of plasma vasopressin. (Internal Medicine 35: 290-294, 1996)