Clinical evaluation of Lugol's iodine staining in the treatment of stage I-II squamous cell carcinoma of the tongue.

Oral squamous cell carcinoma (OSCC) is often surrounded by epithelial dysplasia; leaving it unresected can result in local recurrence. Staining with Lugol's iodine solution detects epithelial dysplasia in oral mucosa, but whether it decreases local recurrence after OSCC surgery is unknown. This study investigated local recurrence rates in patients with early tongue cancer who underwent surgery using Lugol's staining. 93 patients with T1-2N0 tongue SCC underwent partial glossectomy using Lugol's staining during surgery. Resection was performed at least 5mm from the margin of the unstained area. Patients were investigated retrospectively for local recurrence status. Postoperative histology revealed negative surgical margins for SCC or epithelial dysplasia in 81 patients, close margins for SCC in 5, positive margins for mild epithelial dysplasia in 6, and a positive margin for SCC in one. Those with a positive or a close margin for SCC underwent additional resection 2-4 weeks after surgery; one was proved histologically to have residual SCC. No patients developed local recurrence, but 2 died of neck metastasis and 2 of distant metastasis. The 5-year disease specific survival rate was 93.8%. Lugol's staining during surgery can reduce local recurrence and improve survival in patients with early tongue SCC.

The influence of surgical procedure and the effect of chemotherapy on nodal and distant metastases of human malignant melanomas that have been grafted into nude mice.

Malignant melanoma of the oral mucosa is common in Japan. The effects on metastasis of puncturing the tumor before surgery or using chemotherapy after extirpation of the tumor were studied using animal models. G-361 cells were transplanted subcutaneously into mice. In half the animals, the subcutaneous tumor was punctured with an 18G needle twice a week from 2 weeks after transplantation until death. In the other mice, the subcutaneous tumor was extirpated 6 weeks after transplantation; the animals were killed 2 weeks later. Dimethyl triazeno imidazole carboxamide (DTIC) or cisplatin (CDDP) were injected into the peritoneal cavity 3 days before extirpation or during extirpation. Metastases to the axilla lymph node and the lung were examined in both groups. The animals that received puncturing developed lymph node and pulmonary metastasis earlier and more frequently than those without puncturing. 50% of mice that received no anticancer agent, had lymph node and pulmonary metastases after tumor extirpation. Preoperative DTIC or CDDP reduced the frequency of metastasis to 25-35%. DTIC or CDDP administration during extirpation, significantly reduced the metastasis rate to 7-10%. Prognosis for oral melanoma patients may be better when surgery and postoperative chemotherapy are performed simultaneously without preoperative surgical procedures.

Metastasis to the lateral retropharyngeal lymph node from squamous cell carcinoma of the oral cavity: report of three cases.

Carcinoma of the oral cavity sometimes metastasizes to the lateral retropharyngeal lymph node (LRPLN), especially when posteriorly invading the soft palate or oropharynx. CT or MRI imaging has enabled detection of LRPLN metastasis in the early stage, but the prognosis of patients with metastasis to this node is extremely poor. The authors report three patients with squamous cell carcinoma of the oral cavity with no posterior invasion who developed metastasis to LRPLN during observation. The primary sites of these three cases were gingiva of the upper incisor region, gingiva of the lower premolar region, and maxillary bone of the upper incisor region. Each patient underwent surgery as their initial therapy, but a recurrent tumor in the LRPLN was detected by CT or MRI despite good loco-regional control. A salvage operation with postoperative radiation therapy was performed for two patients, but only one is still alive with no evidence of tumor 14 months after the last surgery. Management of LRPLN metastasis in oral cancer patients is a challenge for oral surgeons, but early detection by CT or MRI and surgery with postoperative radiation therapy is likely to yield the best local control.

Reduction of white coat effect by cilnidipine in essential hypertension.

Stress elevates blood pressure (BP) by increased sympathetic nerve activity. Cilnidipine, a novel dihydropyridine calcium antagonist that has inhibitory actions on N-type as well as L-type voltage-dependent calcium channels, has been reported to attenuate the cold stress-induced increase in plasma norepinephrine and BP in rats. Because white coat effect is associated with an enhanced pressor response to mental stress, we postulated that cilnidipine would attenuate white coat effect in patients with essential hypertension. Sixty-one consecutive outpatients (50 men, 11 women) with essential hypertension were studied prospectively. Twenty-nine patients were treated with either cilnidipine (n = 15) or nifedipine, a representative L-type voltage-dependent calcium antagonist (n = 14). Gender, age, body mass index, duration of hypertension, target organ damage of hypertension, and BP and heart rate (HR) were not significantly different between cilnidipine and nifedipine groups, and both systolic (SBP) and diastolic BP (DBP) were significantly decreased after treatment in both groups. White coat effects on systolic and DBP and HR were not significantly different between groups before antihypertensive treatment. Cilnidipine, but not nifedipine, significantly reduced white coat effects on SBP and HR. Furthermore, white coat effects on systolic BP and HR were significantly lower after treatment in the cilnidipine group compared with the nifedipine group. These data suggest that cilnidipine may reduce white coat effect in hypertensive patients by N-type calcium channel antagonism.

Role of the central nervous system in the development of hypertension produced by chronic nitric oxide blockade in rats.

We examined the role of the central nervous system, and particularly the renin-angiotensin (RA) system, in the development of hypertension produced by chronic inhibition of NO synthesis. In experiment 1, Wistar rats drank either nitro-L-arginine-methyl ester (L-NAME) or tap water. Before L-NAME treatment rats were divided into 6 groups. Four of them were administered either losartan or artificial cerebroventricular fluid (a-CSF) intracerebroventricularly (i.c.v.) for 1 week using an osmotic mini pump. The other two groups were administered the same amount of losartan intravenously (i.v.). In experiment 2, cardiovascular responses to acute i.c.v. losartan and muscimol, a GABA(A) agonist, were examined in conscious L-NAME-treated rats. Finally, in experiment 3, effects of ablation of the AV3V (anteroventral third ventricle) area, known to be one of the centers of cardiovascular control, were tested in the development of L-NAME hypertension. The development of hypertension by L-NAME treatment was attenuated with chronic i.c.v. losartan in a dose-dependent manner, while i.v. losartan had no effect. One week after cessation of i.c.v. losartan, blood pressure was elevated to the same level as in a-CSF-infused, L-NAME-treated rats. Acute i.c.v. losartan produced no cardiovascular changes in either L-NAME-treated or control rats. On the other hand, although i.c.v. muscimol elicited depressor effects in both groups, these responses were significantly larger in L-NAME-treated rats. Cardiovascular responses to i.v. hexamethonium were similar in both groups. The existence of prior lesions in the AV3V area significantly attenuated the development of L-NAME-induced hypertension. These results indicate that the central RA system plays an important role in the development of hypertension produced by chronic inhibition of NO synthase. Moreover, disorder of the central GABA system, rather than that of the RA system, might be important in the maintenance of hypertension in this model.

Densin-180 forms a ternary complex with the (alpha)-subunit of Ca2+/calmodulin-dependent protein kinase II and (alpha)-actinin.

Densin-180 is a transmembrane protein that is tightly associated with the postsynaptic density in CNS neurons and is postulated to function as a synaptic adhesion molecule. Here we report the identification of the alpha-subunit of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and alpha-actinin-4 as potential binding partners for the densin-180 intracellular segment. We demonstrate by yeast two-hybrid and biochemical assays that the intracellular portion of densin-180, the alpha-subunit of CaMKII (CaMKIIalpha), and alpha-actinin interact with each other at distinct binding sites and can form a ternary complex stabilized by multiple interactions. Densin-180 binds specifically to the association domain of CaMKIIalpha and does not bind with high affinity to holoenzymes of CaMKII that contain beta-subunit. The PDZ (PSD-95, DIg, Z0-1) domain of densin contributes to its binding to alpha-actinin. A distinct domain of alpha-actinin interacts with the kinase domains of both alpha- and beta-subunits of CaMKII. Autophosphorylation of CaMKII increases its affinity for densin-180 from an EC(50) of >1 micrometer to an EC(50) of <75-150 nM. In contrast, phosphorylation of densin-180 by CaMKII at serine-1397 only slightly decreases its affinity for CaMKII. The specific interaction of densin-180 with holoenzymes of CaMKII containing only alpha-subunit and the increased affinity of CaMKII for densin-180 after autophosphorylation suggest that densin-180 may be involved in localization of activated CaMKII synthesized in dendrites.

[Improved detection of fill-in using sublingual nitroglycerin in technetium-99m tetrofosmin exercise/rest single photon emission computed tomography one day protocol for old myocardial infarction].

This study assessed the effect of sublingual nitroglycerin administered before rest imaging in the technetium-99m (99mTc) tetrofosmin exercise and rest same day protocols to determine whether the use of nitroglycerin improved the detection of fill-in the rest single photon emission computed tomography (SPECT) images 3 hours after peak exercise. Twenty-one patients with old myocardial infarction underwent repeated 99mTc-tetrofosmin exercise/rest same day protocols with and without the administration of sublingual nitroglycerin (0.3 mg) 5 min before the second injection of 99mTc-tetrofosmin for rest SPECT imaging. Twelve of these patients also underwent ordinary exercise/redistribution 201T1 SPECT imaging. The control study protocol images showed decreased uptake of 99mTc-tetrofosmin on exercise in 157 of 420 segments and the presence of fill-in at rest in 58 segments. Images obtained with administration of nitroglycerin showed decreased uptake of 99mTc-tetrofosmin on exercise in 163 of 420 segments and fill-in in 74 segments at rest. The frequency of fill-in was greater in the nitroglycerin protocol than in the control protocol (p < 0.05). The segments were scored as different grades according to 99mTc-tetrofosmin uptake between 2 protocols. Fill-in was only present or more remarkable in 31 segments in the nitroglycerin protocol than in the control protocol. Fill-in was only present or more remarkable in 10 segments in the control protocol than in the nitroglycerin protocol. In the nitroglycerin protocol, the mean defect score of the exercise images, calculated from the bull's eye image automatically, was higher than that of the rest images (121 +/- 40 vs 94 +/- 53, p < 0.01). The mean severity score of the exercise images, also calculated from the bull's eye image automatically, was likewise higher than that of the rest images (691 +/- 382 vs 524 +/- 431, p < 0.01), whereas the mean severity score of the stress images and rest images in the control protocol was not significantly different. Moreover, the mean defect score and severity score of the rest images from the nitroglycerin protocol were significantly lower than those obtained from the control protocol (p < 0.05). Sublingual nitroglycerin administration before the injection of 99mTc-tetrofosmin at the rest study in the one day exercise/rest studies enhanced fill-in, so may enhance the detection of viable myocardium, allowing more informed decisions regarding cardiac revascularization in patients with chronic coronary artery disease.

A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II.

Ca2+ influx through N-methyl-D-aspartate- (NMDA-) type glutamate receptors plays a critical role in synaptic plasticity in the brain. One of the proteins activated by the increase in Ca2+ is CaM kinase II (CaMKII). Here, we report a novel synaptic Ras-GTPase activating protein (p135 SynGAP) that is a major component of the postsynaptic density, a complex of proteins associated with synaptic NMDA receptors. p135 SynGAP is almost exclusively localized at synapses in hippocampal neurons where it binds to and closely colocalizes with the scaffold protein PSD-95 and colocalizes with NMDA receptors. The Ras-GTPase activating activity of p135 SynGAP is inhibited by phosphorylation by CaMKII located in the PSD protein complex. Inhibition of p135 SynGAP by CaMKII will stop inactivation of GTP-bound Ras and thus could result in activation of the mitogen-activated protein (MAP) kinase pathway in hippocampal neurons upon activation of NMDA receptors.

Acute necrotizing eosinophilic myocarditis with giant cell infiltration after remission of idiopathic thrombocytopenic purpura.

Acute necrotizing eosinophilic myocarditis is characterized by acute onset, fulminant congestive heart failure, and extensive necrosis of myocytes with striking eosinophilic infiltration. However, multinucleated giant cells sometimes appear in the fulminant phase of severe myocarditis. This is the first case of a patient with a 1 year previous history of idiopathic thrombocytopenic purpura, who presented with acute necrotizing eosinophilic myocarditis with giant cell infiltration.