Genetic alteration in carcinoid tumors of the lung.

Surgically resected specimens of 13 carcinoid tumors of the lung including nine typical carcinoids and four atypical carcinoids, and eight salivary gland type carcinomas (six mucoepidermoid carcinomas and two adenoid cystic carcinomas) were analyzed regarding p53 expression, loss of heterozygosity (LOH) in chromosome 3p, 9p, and K-ras mutation. The overexpression of p53 was identified in four atypical carcinoid tumors, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma, however, none of typical carcinoids showed p53 immunoreactivity. LOH in 3p14 was demonstrated in three of seven informative cases in all tumors. LOH in 9p was demonstrated in two of five informative cases in all tumors. Two of three cases with LOH at 3p14 had a poor prognosis, one of which also had LOH at 9p. No mutation of the K-ras gene was observed in any of these tumors. These data thus indicate that p53 overexpression might distinguish atypical carcinoid tumors from typical tumors and might therefore be useful as an adjunct modality in the differential diagnosis of pulmonary carcinoid tumors. The presence of LOH at 3p14 or 9p may thus help to identify lung cancer patients with a poor prognosis.     

Postoperative local thermo-chemotherapy in control of residual pleural diseases after resection of primary lung carcinoma--regulation of dissemination

Pleural dissemination was proved by intraoperative histodiagnosis in 11 of 121 patients who underwent pulmonary resection for non-small cell carcinoma of the lung between April, 1985 and December, 1986. To control such intrathoracic residual diseases, we devised a means of local thermo-chemotherapy. Ten of 11 patients were treated with intrapleurally administrated cisplatin (50-100mg, bolus) combined with simultaneous radiofrequency hyperthermia (13.56 MHz) for 2 to 3 weeks after surgery. Courses were repeated at 5-to 7-day intervals. Eight patients had N2-disease, one N1 and the other NX. Eight were adenocarcinomas. Thermal burn of the chest wall with hyperkalemia was observed in only one patient who received thermotherapy at the over a magnetrode power of 450 watts for 50 minutes. In the other 9, side effects were minimal under the thermotherapy to obtain a peripleural temperature beyond 42 degrees C. Of the 10 patients, three lived more than 12 months after treatment. Although distant metastases were recognized in 6 cases, none had local recurrence for the median follow-up period of 6 months. One patient had metastasis to the contralateral supraclavicular lymph nodes. Because there was no evidence of intrathoracic recurrences in this patient, radical neck dissection were performed 15 months after the initial operation. This experience warrants further investigation of thermo-chemotherapy as a treatment for controlling pleural dissemination after resection of primary tumor.     

Modulation of infection-induced inflammation and locomotive deficit and longevity in senescence-accelerated mice-prone (SAMP8) model by the oligomerized polyphenol Oligonol.

Oligonol is produced from the oligomerization of polyphenols (typically proanthocyanidin from a variety of fruits such as lychees, grapes, apples, persimmons, etc.) and contains catechin-type monomers and oligomers of proanthocyanidins. The ability of Oligonol to affect infection-dependent eye inflammation, locomotion and longevity in senescence-accelerated prone mice (SAMP8) (a model of senescence acceleration and geriatric disorders with increased oxidative stress and neuronal deficit) was investigated. Oligonol (60mg/kg) significantly modulated the extent of inflammation scores in the eye of SAMP8 mice. Examination of the mice indicated infection with mouse hepatitis virus and pinworm (Syphacia obvelata) in both males and females and with the intestinal protozoa (trichomonad) in males. A comparison of the two groups (using log-rank test) and the difference in the mean life span between groups (using Student's t-test) indicated significant differences in survival (p=0.043) and the mean life span (p=0.033) in male SAMP8 mice. Oligonol increased the mean life span and this was statistically significant. In the open-field locomotive test, the 7-week-old SAMP8 mice crossed more than 40 partitioned lines in 1min. At 48-week-old control untreated male SAMP8 crossed 2 lines. The Oligonol-treated 48-week-old male SAMP8 mice crossed 17 lines however. The improved locomotive activity was statistically significant even after 36weeks in the Oligonol-treated male SAMP8 but this was not the case throughout the time course of the study in the Oligonol-treated female SAMP8. Thus Oligonol treatment to SAMP8 mice modulated the severity of infection-dependent inflammation, prolonged life-span and significantly improved locomotive activity indicating potential benefit to aging-associated diseases such as Alzheimer's or Parkinson's diseases. This presents potential for further research to define infection-dependent inflammation associated with degenerative conditions and the molecular mechanism of dietary antioxidant protection.     

Takayasu's arteritis and mitral stenosis

A 44-year-old housewife was found to have coarctation of the abdominal aorta secondary to Takayasu's arteritis. Since she also had mitral stenosis, possible etiological relation between Takayasu's arteritis and mitral stenosis is suspected.     

Dorsal skin responses to topical application with hydrogen peroxide in Mini and Wistar rats.

Mini rats (Jcl: WistarTGN(ARGHGEN) 1Nts) (MRs) are Wistar rat (WR)-derived transgenic rats in which the expression of growth hormone (GH) gene is suppressed under the presence of antisense RNA transgene. In order to evaluate the effects of GH-deficiency on the acute injury by external stimuli, the dorsal skin responses to a single topical application with 20% hydrogen peroxide (HPO), one of the environmental oxidative stressors, were histologically compared between male MRs and WRs of 8 weeks old, whose hair cycle was under the telogen phase. As a result, formation of granulation tissues, reepithelialization and regrowth of hair follicles were delayed in MRs compared with WRs. While hair follicles of MRs of this age are under a long-lasting telogen phase after their 2nd cycle, a new hair cycle started not only in the HPO-applied area but also in the solvent-applied area with a little time lag. These findings suggest that GH-deficiency may influence the skin responses to the external chemical stimuli.     

Accuracy of the Master's exercise test in detecting significant coronary artery disease

To assess the significance and accuracy of noninvasive tests in detecting significant coronary artery disease (CAD; greater than 50% stenosis), the Master's exercise test, treadmill exercise test and dipyridamole-loading myocardial perfusion scintigraphy were performed and their results were compared with coronary angiographic findings in 60 patients with angina but without myocardial infarction. Among these, 27 patients had significant CAD. The Master's test performed in outpatient clinics had an 85% sensitivity and a 76% specificity in detecting significant CAD, when the degree of ST depression was equal to or exceeded 1 mm. The sensitivity further improved to 96% by adding chest pain to the criteria; then all patients with multivessel disease or critical ischemia were identified by the Master's test. Treadmill tests performed after admission had a 78% sensitivity and a 67% specificity. When the severity of ischemia was judged either by exercise capacity or the degree of ST depression or the coronary T wave, the treadmill test was superior to the Master's test. Although patients without significant CAD had longer exercise capacity and the higher maximum heart rate in the treadmill test than did those in the Master's test, these trends were similar but less marked in patients with significant CAD. Dipyridamole-loading myocardial perfusion scintigraphy showed an excellent sensitivity and specificity; 96% and 94%, respectively, in detecting significant CAD. It was particularly useful in distinguishing false positive exercise results due to left ventricular hypertrophy and coronary spasm and that in women, from true positive results. In conclusion, the Master's test is a simple and useful method for screening CAD in community hospitals and in outpatient clinics.     

Detection of liver fibrosis with magnetic cross-relaxation

The utility of MRI using magnetization transfer (MT) enhanced pulse sequences to diagnose hepatic cirrhosis in a rat model was investigated. Hepatic T₁ was measured with and without MT off-resonance RF pulses in 17 treated and six control rats. The livers were evaluated histologically, and the hydroxyproline content quantitatively measured. We did not find a statistically significant linear correlation between the MR relaxation times and the degree of tissue injury. However, the MR measurements performed with MT were superior to those without differentiating the treated and control groups. Specifically, the T₁ times were 695 ±76 ms for the treated group, versus 748 ± 61 ms in the controls; P= 0.095. The T_1sat times were also lower in the treated group, with statistical significance: 367 ± 51 ms versus 421 ± 38 ms, P = 0.016. Finally, the change in the relaxation rates (the inverse of the relaxation times) with and without saturation were 1.31 ± 0.22 s^?1 (treated group) versus 1.05 ± 0.12 s^?1 (controls), which differed significantly, P= 0.001.     

CCR1 acts downstream of NFAT2 in osteoclastogenesis and enhances cell migration.

We found that a chemokine receptor gene, CCR1, acts downstream of NFAT2 in RANKL-stimulated RAW264 and bone marrow cells. The upstream regulatory region of CCR1 showed RANKL-dependent and CsA-suppressible promoter activity. Downregulation of the expression and function of CCR1 suppressed cell migration. INTRODUCTION: We previously reported that the expression of NFAT2 induced by RANKL is a key process for progression to multinucleated cells in an in vitro osteoclastogenesis system. Identifying the target genes of NFAT2 would thus be informative about the differentiation process. We focused here on chemokine and chemokine receptor genes that act downstream of NFAT2 in RAW264 cells as well as osteoclast precursors prepared from bone marrow cells. MATERIALS AND METHODS: RAW264 mouse monocyte/macrophage line cells were cultured with or without cyclosporin A (CsA) in the presence of RANKL or glutathione S-transferase (GST). Osteoclast precursors were prepared from bone marrow cells. RANKL-inducible and CsA-suppressible genes were searched for by microarray analysis, and expression was confirmed by quantitative RT-PCR. Promoter activity was measured by luciferase gene reporter assay. Short interfering (si)RNA for CCR1 was introduced in RAW264 cells. Cell migration activity was examined using a Boyden chamber assay. RESULTS AND CONCLUSIONS: We identified the chemokine receptor gene CCR1 as a gene showing significant differential expression profiles in osteoclastogenesis in the presence versus the absence of CsA, an inhibitor of NFAT. This property was unique to CCR1 among the chemokine and chemokine receptor genes examined in both RAW264 and bone marrow cells. The upstream regulatory region was isolated from CCR1, and its RANKL-dependent and CsA-suppressible promoter activity was confirmed. The functional significance of CCR1 was assessed by monitoring the migration of cells in a transwell migration assay, and this activity was abolished when either CsA- or CCR1 siRNA-treated cells were used. Moreover, treatment with a Galpha inhibitor pertussis toxin (PTX) or methiolynated-regulated on activation, normal T cells expressed and secreted (Met-RANTES), an antagonist of CCR1, suppressed multinucleated cell formation in the bone marrow cell system. Together, these results suggest that the CCR1 signaling cascade is under the control of NFAT2 and seems to enhance the migration of differentiating osteoclasts.     

Eosinophilic fasciitis associated with Borrelia afzelii infection]

A 58-year-old woman suffered from stiffness, swelling, rubor and muscle pain in the extremities one month after she climbed a mountain in Kyushu, an island in southern Japan. On admission, mild proximal weakness was present in the extremities. Her range of motion in the extremities was limited due to firm skin and subcutaneous stiffness which was similar to scleroderma. She showed peripheral blood eosinophilia and hypergammaglobulinemia as well as a high erythrocyte sedimentation rate. An IgM antibody against Borrelia afzelii was positive. MRI of the skeletal muscles demonstrated enhancing fascia around the biceps brachii muscle, and a biopsy specimen revealed perivascular infiltration of mononuclear cells within the hypertrophic fascia. Eosinophilic infiltration was absent. We treated the patient with prednisolone, doxycycline and amoxicillin, which alleviated the symptoms. This is the first report to show that Borrelia afzelii was involved in eosinophilic fasciitis.     

Crossed cerebellar hypoperfusion in unilateral major cerebral artery occlusive disorders.

We evaluated regional blood flow and oxygen metabolism in the cerebral and cerebellar cortices of 15 patients with unilateral major cerebral artery occlusive disorders with PET. These patients showed a cortical blood flow asymmetry in middle cerebral artery distribution. Only subcortical abnormalities were detected on computed tomography. Nine patients showed crossed cerebellar hypoperfusion, a reduction in contralateral cerebellar blood flow, while six did not. No difference in the degree of cerebral blood flow asymmetry existed between the two patient groups. However, oxygen metabolism asymmetry was more pronounced and was more closely matched to blood flow asymmetry in patients with crossed cerebellar hypoperfusion. These findings suggest that a major cause of cerebral cortical blood flow reduction is reduced metabolic demand in patients with crossed cerebellar hypoperfusion. Crossed cerebellar hypoperfusion may have clinical significance as a reflection of the cerebral metabolic state on blood flow images.