Autoimmune arthritis deteriorates bone quantity and quality of periarticular bone in a mouse model of rheumatoid arthritis.

This study showed that autoimmune arthritis induces especially severe osteoporosis in the periarticular region adjacent to inflamed joints, suggesting that arthritis increases the fragility fracture risk near inflamed joints, which is frequently observed in patients with RA. INTRODUCTION: Periarticular osteoporosis near inflamed joints is a hallmark of early rheumatoid arthritis (RA). Here we show that rheumatic inflammation deteriorates the bone quality and bone quantity of periarticular bone, thereby decreasing bone strength and toughness in a mouse model of RA. METHODS: Female BALB/c mice and SKG mice, a mutant mouse model of autoimmune arthritis on the BALB/c background, were used. At 12 weeks of age, BALB/c mice underwent either Sham surgery or bilateral ovariectomy (OVX), and SKG mice underwent intraperitoneal injection of mannan to induce arthritis. Eight weeks later, the mice were killed and the femurs and tibias were subjected to micro-computed tomography, Fourier transform infrared (FTIR) spectroscopic imaging, X-ray diffraction, histology, and mechanical testing. RESULTS: SKG mice developed significant trabecular bone loss in both the distal metaphysis of the femur and the lumbar vertebral body, but the extent of the bone loss was more severe in the distal metaphysis. Neither SKG nor OVX mice exhibited changes in the geometry and matrix properties of the diaphysis of the femur, whereas SKG mice, but not OVX mice, did exhibit changes in these properties in the distal metaphysis of the femur. Bone strength and fracture toughness of the distal metaphysis of the tibia adjacent to the inflamed ankle joint were significantly decreased in SKG mice. CONCLUSIONS: Autoimmune arthritis induces periarticular osteoporosis, characterized by deterioration of cortical bone geometry and quality as well as by trabecular bone loss, leading to severe bone fragility in periarticular bone adjacent to inflamed joints.

A case of severe low back pain associated with Richard disease (lumbosacral transitional vertebra).

The imaging findings in some cases of low back pain are difficult to describe and the pathophysiology is not clear because subjective findings are usually difficult to document. This report concerns a rare case about the lumbosacral joint causing persistent severe back pain which in itself does not usually have any pathological meaning. We describe the diagnosis, treatment, and outcome of a patient suffering from low back pain with lumbosacral transitional vertebra. The radiological examination showed the congenitally malformed transverse processes of the 5th lumbar vertebra to create a facet joint-like shape at the sacral ala region on both sides. Surgery resulted in immediate disappearance of the low back pain. When the lumbosacral junction shows some instability without fusion, the joint-like region could be the cause of low back pain. The lumbosacral transitional vertebra may be associated with low back pain. Electric denervation of the space between the transverse process of 5th lumbar vertebra and sacral ala is minimally invasive and effective for pain eradication.

A new active vitamin D analog, ED-71, causes increase in bone mass with preferential effects on bone in osteoporotic patients.

As a candidate for active vitamin D analogs that have selective effects on bone, 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71) has been synthesized and is currently under clinical trials. In ovariectomized rat model for osteoporosis, ED-71 caused an increase bone mass at the lumbar vertebra to a greater extent than 1alpha-hydroxyvitamin D3 (alfacalcidol), while enhancing calcium absorption and decreasing serum parathyroid hormone levels to the same degree as alfacalcidol. ED-71 lowered the biochemical and histological parameters of bone resorption more potently than alfacalcidol, while maintaining bone formation markers. An early phase II clinical trial was conducted with 109 primary osteoporotic patients. The results indicate that oral daily administration of ED-71 (0.25, 0.5, 0.75, and 1.0 microgram) for 6 months increased lumbar bone mineral density in a dose-dependent manner without causing hypercalcemia and hypercalciuria. ED-71 also exhibited a dose-dependent suppression of urinary deoxypyridinoline with no significant reduction in serum osteocalcin. These results demonstrate that ED-71 has preferential effects on bone with diminished effects on intestinal calcium absorption. ED-71 offers potentially a new modality of therapy for osteoporosis with selective effects on bone.

Contents and uptake rates of Mn, Fe, Co, Zn, and Se in Se-deficient rat liver cell fractions.

The contents of manganese (Mn), iron (Fe), cobalt (Co), zinc (Zn), and selenium (Se) in nuclear (NU), mitochondrial (MT), microsomal (MC), and cytosolic (CS) fractions of liver homogenates of normal and selenium-deficient (SeD) rats were determined by instrumental neutron activation analysis (INAA). The uptake rates of these elements in the liver cell fractions of both groups of rats were determined by multitracer analysis (MTA). The results indicated that Se-deficiency caused a significant increase in the content of Fe in the MC fractions. The MTA showed that the uptake rate of Fe was highest in the MC fraction, and that the uptake rate in the fraction was similar between the SeD and normal rats.

Malignant pheochromocytoma with hepatic metastasis diagnosed 10 years after a resection of the primary incidentaloma adrenal lesion: report of a case.

A 40-year-old woman developed hepatic tumors 10 years after a resection of pheochromocytoma of the left adrenal gland. Computed tomography showed a round tumor measuring about 35mm in diameter at segment V of the liver (Couinaud's classification), and magnetic resonance imaging showed another tumor measuring about 5mm at segment V-VIII of the liver. The results of the endoscopic examination of her upper gastrointestinal tract and barium enema were normal. Owing to a suspected hepatic metastasis of malignant pheochromocytoma, a right lobectomy of the liver was performed. Postoperatively, [131I]metaiodobenzylguanidine scintigram and computed tomography showed no other residual tumors nor metastasis. The present case suggests that a long-term follow-up only by endocrinological examinations is insufficient to find newly developed metastatic foci, while routine diagnostic imaging at frequent intervals is necessary in cases of pheochromocytoma.

The complete primary structure of molluscan shell protein 1 (MSP-1), an acidic glycoprotein in the shell matrix of the scallop Patinopecten yessoensis.

The complete primary structure of MSP-1, a major water-soluble glycoprotein in the foliated calcite shell layer of the scallop Patinopecten yessoensis, is reported. The full-length complementary DNA for MSP-1 isolated by polymerase chain reaction contained a sequence for a signal peptide of 20 amino acids followed by a polypeptide of 820 amino acids with calculated molecular mass of 74.5 kDa. The deduced amino acid sequence of MSP-1 includes a high proportion of Ser (32%), Gly (25%), and Asp (20%), and the predicted isoelectric point is 3.2; in these respects, MSP-1 is a typical acidic glycoprotein of mineralized tissues. A repeated modular structure characterizes MSP-1, with a sequence unit between 158 and 177 amino acids in length being repeated 4 times in tandem in the middle part of the protein. The repeated unit comprises 3 modules (SG, D, and K domains), each having a distinct amino acid composition and sequence. The SG domain is almost exclusively composed of Ser and Gly residues. The D domain is rich in Asp residues, potential N-glycosylation and phosphorylation sites. The K domain is rich in Gly residues and has a core of basic residues. The Asp residues are arranged more or less regularly in the D domains, exhibiting some repeated motifs such as Asp-Gly-Ser-Asp and Asp-Ser-Asp. Further, the 4 D domains indicate remarkable overall sequence similarities to each other. These observations suggest that the regular arrangements of COO(-) groups in the D domain side chains may be important for specific control of crystal growth.

[State of the treatment for gastrointestinal cancer].

We reviewed the results of chemotherapy for gastrointestinal cancer. In Western countries, FAMTX or ECF is recognized as the standard therapy for gastric cancer. In Japan, no standard chemotherapeutic regimen has been established yet, but FP or MTX/5-FU are often used as a first line chemotherapy. There have been only a few clinical trials of adjuvant chemotherapy for gastric cancer in which this regimen was identified as having a statistically significant effect. For colon cancer, 5-FU plus LV are now used as the standard therapy. Recently, however, it has been shown that 5-FU + LV combined with CPT-11 is more active than 5-FU + LV alone. The efficacy of oral anticancer agents such as UFT + LV, S-1, and capecitabin have also been shown to be equally or more active than i.v. administration of 5-FU and LV, so that the standard therapy for colon cancer will be changed in near future.

Evidence of hepatic endogenous hydrogen peroxide in bile of selenium-deficient rats.

Hepatic endogenous hydrogen peroxide (H(2)O(2)) in bile of selenium-deficient rats (SeD) was for the first time found using the electron spin resonance (ESR) spin-trap technique, and the relationship between glutathione peroxidase (GPX) activity and H(2)O(2) amount is discussed. Normal rats and four groups of rats fed a selenium-deficient diet with different feeding periods were examined. The results showed that the GPX activity decreased depending on the feeding period with the selenium-deficient diet and that the hepatic endogenous H(2)O(2) amount in the bile of the rats fed the selenium-deficient diet for the longest period (a week before birth to 8 weeks old) was drastically higher than those in other groups of rats (P < 0.005). We found that generation of H(2)O(2) due to the decrease in the GPX activity has a threshold value. The results suggest that an exposure to selenium deficiency for long term will cause oxidative stress.

In vivo electron spin resonance assessment of decay constant of nitroxyl radical in selenium-deficient rat.

In vivo reducing capacity and cytosolic glutathione peroxidase (GSH-Px) activity in liver homogenate were evaluated in 6 weeks old Se-deficient and normal rats. GSH-Px was significantly lower in Se-deficient rats than in normal rats. In vivo reducing capacity in head and liver parts, estimated from in vivo signal decay of a nitroxyl spin probe using a low frequency (300 MHz) ESR spectrometer, was significantly decreased in Se-deficient rats, suggesting a decrease of antioxidant capacity in Se-deficient rats.

CaNa2EDTA for improvement of radioimmunodetection and radioimmunotherapy with 111In and 90Y-DTPA-anti-CEA MAbs in nude mice bearing human colorectal cancer.

UNLABELLED: 111In and 90Y, dissociated from 111In-labeled-monoclonal antibody (MAb) and 90Y-labeled MAb, may cause deterioration of the image quality in radioimmunodetection (RID) and undesirable irradiation of nontargeted tissue in radioimmunotherapy (RIT), respectively. The aim of this study was to investigate any improvement in RID and RIT with 111In-MAb and 90Y-MAb by pre- and postadministration of calcium disodium ethylenetriaminetetraacetic acid (CaNa2EDTA). METHODS: Murine MAb F33-104 against carcinoembryonic antigen (CEA) was labeled with 111In or 90Y by the diethylenetriamine pentaacetic (DTPA)-anhydride method. The influence of CaNa2EDTA on loss of radioactivity from 111In-MAb or 90Y-MAb in serum was investigated in vitro. The effects of CaNa2EDTA, administered before and after 111In-MAb or 90Y-MAb, on the biodistribution of radioactive isotopes in nude mice bearing human colon adenocarcinoma LS 180 tumor expressing CEA, or human pulmonary carcinoma PC 9 tumor expressing no CEA, were then examined. As a control, 0.9% NaCl was used in both the in vitro and in vivo studies. RESULTS: CaNa2EDTA did not cause any decrease in levels of radioactivity of radiolabeled MAbs. Pre- and post-treatment with CaNa2EDTA reduced radioctivity in both specific and nonspecific tumors at 72 h after 111In-MAb injection resulting in an increase of the specific tumor-to-nonspecific tumor radioactivity ratio. The levels of hepatic and renal radioactivity were also subsequently decreased by CaNa2EDTA. On the other hand, CaNa2EDTA pre- and post-treatment reduced levels of bony, hepatic, and renal radioactivity at 24, 72, and 72 h, respectively, after 90Y-MAb injection, although it had no effect on tumor radioactivity. CONCLUSION: Pre- and post-treatment with CaNa2EDTA would be of great use in humans who undergo RID or RIT with 111In-MAb and 90Y-MAb accompanied by disassociation of the labeled radionuclides.

Labeling of phosphorothioate antisense oligonucleotides with yttrium-90.

Novel yttrium-90 (90Y)-labeled phosphorothioate antisense oligonucleotides were designed as a potential targeted radionuclide therapeutic agent for malignant tumors. A 15-mer phosphorothioate antisense oligonucleotide, which was complementary to the translation start region of the N-myc oncogene mRNA, was conjugated with isothiocyanobenzyl ethylenediamine tetraacetic acid (SCN-Bn-EDTA), via a C-5-substituted deoxyuridine that had replaced a thymine in the oligonucleotide, and was then labeled with 90Y-acetate. Following purification, the radiochemical purity of the 90-Y-Bn-EDTA-phosphorothioate antisense oligonucleotides was estimated by 2.0% agarose gel electrophoresis, and the specific hybridization of 90Y-Bn-EDTA-phosphorothioate antisense oligonucleotide to a phosphorodiester sense oligonucleotide was investigated by 20% polyacrylamide gel electrophoresis in a cell-free system. Radiochemical purity was 98.7 +/- 0.4% at 72 h after labeling and 90.3 +/- 0.9% after 72-h incubation with human normal serum. The 90Y-Bn-EDTA-phosphorothioate antisense oligonucleotide hybridized specifically to a complementary phosphorodiester sense oligonucleotide. In conclusion, phosphorothioate antisense oligonucleotides can be labeled stably with 90Y using SCN-Bn-EDTA without loss of hybridization properties.

[A case of multiple sclerosis with galactorrhea-amenorrhea syndrome].

Patients with multiple sclerosis sometimes show subthalamic lesions presenting syndrome of inappropriate secretion of ADH (SIADH), hypothermia, hyperprolactinemia, weight loss, and cachexia. Hyperprolactinemia also has been found in the patients with active systemic lupus erythematosus, because prolactin can be produced from human activated lymphocytes. We described a case of multiple sclerosis showing galactorrhea-amenorrhea syndrome with hyperprolactinemia. A 31-year-old woman showed a high level of prolactin in the serum (79.6 ng/ml) during remission stage 5 months after the onset of multiple sclerosis. She showed galactorrhea-amenorrhea syndrome 3 years later. She showed dysesthesia in her limbs, relapsing monoparesis, visual disturbance and Gd-enhanced plaques in Brain MRI for 6 years. She was admitted to our hospital on November 24, 1995. A neurological examination showed hyporeflexia of the upper extremities, hyperreflexia of the lower extremities, bilateral ankle clonus, truncal ataxia, and neurogenic bladder. Laboratory tests revealed increased level of serum prolactin, exaggerated secretion of serum prolactin after intravenous injection of 500 micrograms TRH, and marked suppression after oral administration of 2.5 mg bromocriptine. Brain MRI showed demyelinating lesions near the lateral ventricle, and cervical MRI (T2 image) showed high signal intensity lesions in the spinal cord from C2 to C5. In the previous case, galactorrhea-amenorrhea syndrome was found during the exacerbation stage of multiple sclerosis. Hyperprolactinemia may be caused from subthalamic lesions or by activated lymphocytes in multiple sclerosis. We considered that hyperprolactinemia and galactorrhea-amenorrhea syndrome in our patient might be caused from subthalamic lesions because lymphocytes were not activated during the remission stage of multiple sclerosis.

[Jargon agraphia in a case with Broca aphasia: dissociation between language and writing dominancy].

A 69-year-old left-handed man developed Broca aphasia and jargon agraphia following a right cerebral infarction. He learned to write with his right hand. There is no family history of left-handedness. Neurological examination revealed hemiparesis, sensory impairment, and hyperreflexia with pathological reflexes on the left side. An MRI demonstrated lesions in the area including the pre- and post-central gyri, the posterior part of the middle and inferior frontal gyri, and inferior parietal lobule on the right side. Neuropsychologically he was alert and cooperative. He demonstrated severe Broca aphasia and his verbal output was limited to a few residual words. On the other hand, he could communicate through writing Kanji words. Writing words was relatively preserved with Kanji but not with Kana characters. Asked to write a Japanese folk tale, he showed jargon agraphia mixed with some correct Kanji words. His comprehension of spoken and written sentences was well preserved. He showed mild ideomotor and buccofacial apraxia, left unilateral spatial neglect, and constructional impairment. Dissociation between spoken and written language is a prominent feature of this patient's language output. In this patient, right hemisphere seems to be dominant for language and praxis, and left hemisphere for motor engram of writing. Learning to write with the right hand may have enhanced the establishment and maintenance of motor engram for writing in the left hemisphere. The intact motor engram of characters in the left hemisphere could be retrieved by the right hand without control from the language area in the diseased right hemisphere, resulting in jargon agraphia especially with Kana characters. In left handed people, the hand with which they learn to write may effect interhemisphere lateralization of language functions.

Vasoacting agents flavone acetic acid and hydralazine given in combination enhance antitumor effects under condition of hyperthermia.

The combined effects of flavone acetic acid (FAA), hydralazine (HYD) and hyperthermia on B16 melanoma cells and solid tumor were examined in vitro and in vivo. In vitro, hyperthermia did not enhance the cytotoxicity of the combined use of FAA and HYD. In vivo, growth inhibition of B16 melanoma solid tumor by FAA (150 mg/kg) combined with HYD (5.0 mg/kg) could not be differentiated from that by FAA or HYD alone. Increased antitumor effect was recognized when FAA combined with HYD was used under conditions of hyperthermia. FAA combined with HYD significantly reduced tumor blood flow compared to FAA alone or HYD alone. We thus conclude that the significant reduction in tumor blood flow may play an important role in the enhanced antitumor effects of the combined treatment with FAA, HYD, and hyperthermia.

Grade II astrocytoma visualized by technetium-99m-ECD SPECT.

We present a case of primary brain tumor demonstrating increased uptake of 99mTc-ECD. Astrocytoma (Grade II) showed significantly increased cerebral blood perfusion on dynamic images and homogeneously increased uptake on static images with 99mTc-ECD brain SPECT. There seems to be some difference in perfusion and mechanism of tumor uptake among the cerebral blood flow imaging agents (99mTc-ECD, 99mTc-HMPAO and [123I]-IMP) and 201TI-chloride.

Effect of hyperthermia on tumor uptake of radiolabeled anti-neural cell adhesion molecule antibody in small-cell lung cancer xenografts.

UNLABELLED: This study was performed to examine the effect of hyperthermia on the intratumor accumulation of a monoclonal antibody (Mab) in an animal model. Mab NE150 (IgG1) recognizes the neural cell adhesion molecule (NCAM) expressed by human small-cell lung cancer (SCLC) cells. METHODS: Athymic mice inoculated with NCI-H69, an SCLC cell line, received an intravenous injection of 125I- and 111In-NE150 and the serial changes of the biodistribution were determined. Furthermore, athymic mice bearing NCI-H69 were either sham-treated or treated by a single hyperthermia at 42 degrees C or 43 degrees C for 1 hr, with the tumor-bearing leg in a water bath using pentobarbital anesthesia. Immediately after heating, the mice were given an intravenous injection of radiolabeled NE150, and the biodistribution was examined at 24 and 48 hr. RESULTS: NE150 localized well in the transplanted tumor when compared with a control Mab. In mice treated at 43 degrees C, there was a 1.34- to 1.67-fold increase in the tumor uptake of 125I- and 111In-NE150 compared to sham-treated mice at both 24 and 48 hr. In addition, a 1.84- to 2.22-fold increase of the tumor-to-blood ratio was demonstrated, since radiolabeled NE150 cleared faster from the circulation in the mice given hyperthermia. A histological study demonstrated the infiltration of neutrophils in the perivascular spaces, indicating an increase of tumor vascular permeability, which might be one of the main reasons for the enhancement of Mab uptake. CONCLUSION: Hyperthermia seems to be a potential method of achieving an increased tumor accumulation of Mab in the radioimmunotargeting of SCLC.

Prediction of the ability to purge clonogenic B cell lymphoma from normal BM in vitro by heat: their survival curves correspond to a curve reflecting mortality in humans.

To develop new purging regimens for ABMT the ability to predict potential for purging of tumor cells from BM is important. Since the sensitivity of human B cell lymphoma to hyperthermia is not known, we examined its effect on the growth of B cell lymphoma cell lines (Raji and Daudi) in vitro to evaluate potential for purging clonogenic tumor cells from normal marrow by heat, using a limiting dilution assay to measure log depletion of tumor cells in a 20-fold excess of normal BM. When exposed to heat (42-43 degrees C) for 120 min, both clonogenic Raji and Daudi cells were dramatically reduced (a 4-to-6 log reduction) with time, whereas at 42 degrees C over half and at 43 degrees C 10% of normal granulocyte-macrophage progenitor cells survived for the same time period. This high level of lymphoma cell depletion by heat correlated with that of immunologic and pharmacologic studies. In addition, these survival curves during heating were found to correlate with the Gompertz-Makeham formula--a law of human mortality. This formula may be useful in predicting the purging effect of heat. These results suggest that in vitro hyperthermia could be applied effectively for the elimination of residual, clonogenic lymphoma cells in autologous marrow grafts before ABMT.

Effect of dietary fat and fiber on fecal flora, bacterial metabolites, and fecal properties in Japanese volunteers.

The effects of dietary fat and dietary fiber (DF) levels in diet on fecal flora, activities of three fecal enzymes, putrefactive metabolites, fecal mutagenicity and fecal properties were studied in eight healthy volunteers. They were given low fat and low DF diet (LF: fat energy ratio was 13.9%, and DF intake was 9.0 g/day) for 10 days, high fat and low DF diet (HF: fat energy ratio was 52.7%, and DF intake was 7.1 g/day) for 10 days, and high fat and high DF diet (HFF: fat energy ratio was 52.0%, and DF intake was 24.8 g/day) for 10 days. No change of fecal flora at the bacterial group level was observed throughout the experimental period, except that the population of lactobacilli showed a tendency to increase in HF period. Fecal activities of beta-glucuronidase, beta-glucosidase and nitroreductase and some putrefactive products were unchanged between LF and HF, while these values decreased in HFF period. No significant change of fecal properties was observed between LF and HF, while by HFF supplementation fecal weight increased and fecal pH value was lower than that in LF and HF. Excretions of iron, zinc and calcium in feces did not increase by high DF supplementation.

Ciwujianosides D1 and C1: powerful inhibitors of histamine release induced by anti-immunoglobulin E from rat peritoneal mast cells.

In rat peritoneal mast cells induced by anti-immunoglobulin E, ciwujianosides D1 (1) and C1 (2) from Acanthopanax senticosus (ciwujia) strongly inhibited histamine release in a concentration-dependent manner. The inhibitory effect of 1 was approximately 6800 times stronger than that of disodium cromoglycate.