Experimental febrile seizures induce age-dependent structural plasticity and improve memory in mice.

Population-based studies have demonstrated that children with a history of febrile seizure (FS) perform better than age-matched controls at hippocampus-dependent memory tasks. Here, we report that FSs induce two distinct structural reorganizations in the hippocampus and bidirectionally modify future learning abilities in an age-dependent manner. Compared with age-matched controls, adult mice that had experienced experimental FSs induced by hyperthermia (HT) on postnatal day 14 (P14-HT) performed better in a cognitive task that requires dentate granule cells (DGCs). The enhanced memory performance correlated with an FS-induced persistent increase in the density of large mossy fiber terminals (LMTs) of the DGCs. The memory enhancement was not observed in mice that had experienced HT-induced seizures at P11 which exhibited abnormally located DGCs in addition to the increased LMT density. The ectopic DGCs of the P11-HT mice were abolished by the diuretic bumetanide, and this pharmacological treatment unveiled the masked memory enhancement. Thus, this work provides a novel basis for age-dependent structural plasticity in which FSs influence future brain function.

Neurological manifestations in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis in the Amazon.

STUDY DESIGN: A cross-sectional observational study was conducted. OBJECTIVE: The aim was to analyze the clinical-functional profile of patients diagnosed with HTLV-1 (human T-lymphotropic virus type 1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in the Amazon region. SETTING: Reference center for HTLV in the city of Belém, state of Pará, Brazil. METHODS: Muscle strength, muscle tone, balance and the need for gait assistance among patients with HAM/TSP were evaluated. RESULTS: Among the 82 patients infected with HTLV-1, 27 (10 men and 17 women) were diagnosed with HAM/TSP. No statistically significant difference in muscle tone or strength was found between the lower limbs. Muscle weakness and spasticity were predominant in the proximal lower limbs. Patients with HAM/TSP are at a high risk of falls (P=0.03), and predominantly use either a cane or a crutch on one side as a gait-assistance device (P=0.02). CONCLUSION: Patients with HAM/TSP exhibit a similar clinical pattern of muscle weakness and spasticity, with a high risk of falls, requiring gait-assistance devices.

Pure red cell aplasia associated with systemic lupus erythematosus.

Pure red cell aplasia is a rare condition described in patients with autoimmune diseases such as systemic lupus erythematosus. Bone marrow examination of a 52-year-old female showed selective severe hypoplasia, scarce hematopoietic reserves, and no abnormality in other cell lineages, which are findings compatible with red cell aplasia. This condition has not responded to corticosteroids, cytotoxic drugs or intravenous immunoglobulin. After therapy with high doses of glucocorticoids, cyclophosphamide, and immunoglobulin failed, she was treated with human recombinant erythropoietin, monthly pulses of methylprednisolone, and cyclophosphamide, simultaneously. Data on treatment with erythropoietin for pure red cell aplasia associated with systemic lupus erythematosus is limited, but it appears to be reasonable to try in refractory cases.

Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness.

p53 is an established tumor suppressor that can activate the transcription of multiple target genes. Recent evidence suggests that p53 may contribute to the regulation of cell invasion and migration. In this study, we show that the forkhead box transcription factor FOXF1 is a novel target of the p53 family because FOXF1 is upregulated by p53, TAp73 and TAp63. We show that FOXF1 is induced upon DNA damage in a p53-dependent manner. Furthermore, we identified a response element located within the FOXF1 gene that is responsive to wild-type p53, TAp73ß and TAp63γ. The ectopic expression of FOXF1 inhibited cancer cell invasion and migration, whereas the inactivation of FOXF1 stimulated cell invasion and migration. We also show that FOXF1 regulates the transcriptional activity of E-cadherin (CDH1) by acting on its FOXF1 consensus binding site located upstream of the E-cadherin gene. Collectively, our results show that FOXF1 is a p53 family target gene, and our data suggest that FOXF1 and p53 form a portion of a regulatory transcriptional network that appears to have an important role in cancer cell invasion and migration.

A novel approach to cancer treatment using structural hybrids of the p53 gene family.

The p53 tumor suppressor belongs to a gene family that includes two other structurally and functionally related members: p73 and p63. The regulation of p53 activity differs significantly from that of p73 and p63. To enhance the tumor suppressive activity of p53, we constructed six recombinant adenoviruses that encode hybrid proteins with three functional domains derived from either p53 or TAp63γ. The potency of these hybrid molecules in suppressing tumorigenesis was evaluated using in vitro and in vivo models. Of the hybrid molecules tested, one hybrid named p63-53O was the most potent activator of apoptosis in human cancer cells. The p63-53O hybrid is composed of the transcriptional activation domain and DNA-binding domain of TAp63γ and the oligomerization domain of p53. The p63-53O hybrid efficiently transactivated p53AIP1. Moreover, silencing of p53AIP1 partially abolished the apoptotic response to p63-53O in human cancer cells. The p53-p63 hybrid molecule is a novel potent anti-proliferative agent for the treatment of cancer.

Carboplatin plus weekly paclitaxel treatment in non-small cell lung cancer patients with interstitial lung disease.

BACKGROUND: Since advanced non-small cell lung cancer (NSCLC) patients with the interstitial lung disease (ILD) have been excluded from clinical trials, it is uncertain whether chemotherapy really provides a benefit to these patients. PATIENTS AND METHODS: Fifteen advanced NSCLC patients with ILD that was detected on the chest X-rays were enrolled in this study. Carboplatin plus paclitaxel was administered by two methods (method A or method B). Method A: Carboplatin (AUC 6, day 1) and paclitaxel (70 mg/m(2), days 1, 8, 15) were administered every four weeks. Method B: Carboplatin (AUC 2, day 1, 8, 15) and paclitaxel (60 mg/m(2), days 1, 8, 15) were administered every four weeks. RESULTS: The response rate and the disease control rate were 33% and 53%. The median progression-free survival and the median overall survival time were 2.5 months and 7.0 months, respectively. The hematological toxicities were tolerable, but a grade 3 or higher pneumonitis was observed in 4 patients (27%). CONCLUSION: Carboplatin plus weekly paclitaxel must be administered carefully to advanced NSCLC patients with ILD that is detected on chest X-rays after a sufficient evaluation of the risks and the benefits.

Relation of dietary preference to bite force and occlusal contact area in Japanese children.

The purpose of this study was to examine the relationship of dietary preference to bite force and occlusal contact area in Japanese elementary school children. A total of 348 children, aged 7-12 years, from two public elementary schools located in Okayama Prefecture, Japan, participated in the study. Clinical examination included decayed, missing and filled teeth (dmft and DMFT), and total numbers of deciduous and permanent teeth. Bite force and occlusal contact area were measured using a pressure-detecting sheet. Dietary preference was assessed using a questionnaire in which the answers were given in like/dislike form. Mann-Whitney U-test and multiple logistic regression analysis were applied to analyse the data. In multiple logistic regression analysis after adjustment for age, gender and total number of teeth present, children who liked cabbage and celery showed significantly higher bite force (P = 0.05 and P < 0.01, respectively) than those who disliked these. Children who liked cabbage and celery also showed higher occlusal contact area (P < 0.05 and P < 0.01, respectively) than those who disliked these. The Japanese elementary school children who liked hard foods such as cabbage and celery showed higher bite force and higher occlusal contact area than those who disliked these foods. A positive attitude towards harder food items might contribute to healthy development of the masticatory apparatus.

Relationship between body mass index and periodontitis in young Japanese adults.

BACKGROUND AND OBJECTIVE: Obesity has been implicated as a risk factor for several chronic health conditions. Recent studies have reported a relationship between obesity and periodontitis, but few studies have investigated this relationship in adolescents. The purpose of the present study was to investigate the relationship between body composition (i.e. body mass index and body fat) and periodontitis in university students in Japan. MATERIAL AND METHODS: Medical and oral health data were collected in a cross-sectional examination conducted by the Health and Environment Center of Okayama University. Students aged 18-24 years (n = 618), who were interested in receiving an oral health examination, were included in the analysis. The community periodontal index was used to assess periodontal status. Subjects with a community periodontal index score of 0-2 were considered as controls and those with a community periodontal index score of > 2 were considered to have periodontitis. Logistic regression analysis was used to estimate the association between body mass index and periodontitis. RESULTS: The body mass index of all subjects was < 30 kg/m2. Age and body mass index were significantly associated with the community periodontal index. Logistic regression analysis revealed a 16% increased risk for periodontitis per 1-kg/m2 increase in body mass index (adjusted odds ratio, 1.16; 95% confidence interval, 1.03-1.31; p < 0.05). CONCLUSION: Body mass index could be a potential risk factor for periodontitis among healthy young individuals (i.e. those with a body mass index of < 30 kg/m2). It may be useful to include an evaluation of body mass index on a regular basis in university general and oral health examinations.

Neonatally born granule cells numerically dominate adult mice dentate gyrus.

Hippocampal granule cells (GCs) are continuously generated in the subgranular zone of the dentate gyrus (DG) and functionally incorporated to dentate neural circuits even in adulthood. This raises a question about the fate of neonatally born GCs in adult DG. Do they exist until adulthood or are they largely superseded by adult-born GCs? To investigate this question, we examined the contributions of postnatally born GCs to the adult mouse DG. C57BL/6 mice were grouped in three different postnatal (P) ages (group 1: P0, group 2: P7, and group 3: P35) and received a daily bromodeoxyuridine (BrdU) injection for three consecutive days (P0/1/2, P7/8/9, and P35/36/37, respectively) to label dividing cells. At 6 months old, hippocampal sections were prepared from the animals and immunostained with anti-BrdU antibody and an antibody against the homeobox prospero-like protein Prox1, a marker of GCs. We defined BrdU- and Prox1-double positive cells as newborn GCs and analyzed their density and distribution in the granule cell layer (gcl), revealing that newborn GCs of each group still existed 6 months after BrdU injections and that the density of GCs born during P0-2 (group 1) was significantly higher compared with the other groups. Although the density of newborn GCs in the each group did not differ between male and female, the radial distribution of them in gcl showed some differences, that is, male newborn GCs localized toward the molecular layer compared with female ones in group 1, while to the hilus in group 2. These results suggest that GCs born in early postnatal days numerically dominate adult DG and that there exist sex differences in GC localizations which depend on the time when they were born.

Meningeal carcinomatosis from an ovarian primary with complete response to adjuvant chemotherapy after cranial irradiation.

Meningeal metastasis is rare in the clinical course of ovarian carcinoma, and its prognosis is poor. Meningeal dissemination of carcinoma is usually treated by intrathecal administration of methotrexate and total brain irradiation, although these treatments are usually ineffective. We experienced a case of meningeal relapse from ovarian carcinoma resistant to multiple antineoplastic agents in a 64-year-old woman who was treated with eight different chemotherapy regimens after her initial operation 7 years previously. Intrathecal administrations of methotrexate or cisplatin with dexamethasone were not effective. Fifty-Gy whole cranial irradiation inhibited increases in serum carbohydrate antigen (CA) 125 levels and further tumor growth. Adjuvant chemotherapy was required to alleviate frequent headaches and to decrease serum CA125 level and tumor size. Intravenous administration of 45 mg paclitaxel and 35 mg cisplatin, and oral administration of 50 mg etoposide were carried out for 5 days. This treatment was repeated every 3 weeks. After four courses of treatment, meningeal carcinomatosis was not detectable on computed tomography (CT) and magnetic resonance imaging (MRI) scans. The patient's serum levels of CA125 rapidly fell to beneath normal limits and remained normal. She is still alive and clinically free of recurrence 4 months after the last cycle of chemotherapy. As well as reporting our experience with this case, we also present a review of the literature on meningeal carcinomatosis from ovarian cancer.

Successful treatment of a case of relapsed acute promyelocytic leukemia with arsenic trioxide.

We report a patient with an initial relapse of acute promyelocytic leukemia (APL) who achieved a second complete remission (CR) after treatment with arsenic trioxide. The patient, a 66-year-old woman diagnosed as having relapsed APL, received arsenic trioxide intravenously at a dose of 10 mg/day. At day 36, the patient achieved a second CR. The side effects were slight neuralgia and mild skin erythematous changes, which improved following cessation of the drug. Although arsenic trioxide may be effective for relapsed APL, it should be used with caution because of various complications.

[Sézary syndrome showing a stable clinical course for more than four years after oral administration of etoposide and methotrexate].

A 62-year-old woman was admitted because of leukocytosis, systemic lymph node swelling and erythroderma. Laboratory data disclosed a WBC count of 15,600/microliter (CD4-positive cells: 91%). CD25 and HTLV-1 were negative. A skin biopsy revealed the involvement of T cells. These data and findings were consistent with a diagnosis of Sézary syndrome. Although the patient was treated with 2 courses of CHOP, the leukocyte count did not decrease. We then treated the patient orally with etoposide (25 mg/day) and methotrexate (10 mg/week), and this resulted in reduction of the leukocyte count and lymph node swelling, and amelioration of the erythroderma. As Sézary syndrome is an extremely rare disease, it is worthwhile reporting cases like the present one, where therapy was successful.

Interaction between NSAIDs and steroid in rat stomach: safety of nimesulide as a preferential COX-2 inhibitor in the stomach.

The relative risk of development of peptic ulcer with the use of nonsteroidal antiinflammatory drugs (NSAIDs) has been reported to increase when these drugs are administered in combination with steroids. We investigated the ulcerogenic potential of a combination of NSAIDs and steroids in rats and the underlying pathogenic mechanisms. Indomethacin alone produced gastric lesions, and the severity of the lesions markedly increased with concomitant administration of prednisolone. However, nimesulide, even in excessive doses, did not produce any gastric lesions, regardless of concomitant administration with prednisolone. Furthermore, we showed that the ulcerogenic potential of indomethacin administered in combination with prednisolone may be related to the induction of physiological changes, such as endogenous prostaglandin deficiency, an increase in neutrophil activation, and gastric hypermotility, by indomethacin and alteration of normal epithelial renewal by the steroid. These results suggest that the ulcerogenic potential of preferential a COX-1 inhibitor increases following concomitant administration with a steroid, whereas, nimesulide, a preferential COX-2 inhibitor, is nonulcerogenic, even when administered concomitantly with a steroid, and is therefore a clinically useful antiinflammatory agent.

GST-pi gene-transduced hematopoietic progenitor cell transplantation overcomes the bone marrow toxicity of cyclophosphamide in mice.

Autologous transplantation of bone marrow cells (BMCs) transduced with the multidrug resistance 1 (MDR1) gene or dihydrofolate reductase (DHFR) gene has already been applied in clinical chemoprotection trials. However, anticancer drugs frequently used in high-dose chemotherapy (HDC), such as alkylating agents, are not relevant to MDR1 or DHFR gene products. In this context, we have previously reported that glutathione S-transferase-pi (GST-pi) gene-transduced human CD34(+) cells showed resistance in vitro against 4-hydroperoxicyclophosphamide, an active form of cyclophosphamide (CY). In the present study, a subsequent attempt was made in a murine model to evaluate the effectiveness of transplantation of GST-pi-transduced BMCs to protect bone marrow against high-dose CY. The gene transfection was carried out retrovirally, employing a recombinant fibronectin fragment. Transfection efficiency into CFU-GM was 30%. After the transplantation, recipient mice (GST-pi mice) received three sequential courses of high-dose CY. As the chemotherapy courses advanced, both shortening of recovery period from WBC nadir and shallowing of WBC nadir were observed. In contrast to the fact that three of seven control mice died, possibly due to chemotoxicity, all seven GST-pi mice were alive after the third course, at which point the vector GST-pi gene was detected in 50% of CFU-GM derived from their BMCs and peripheral blood mononuclear cells. When BMCs obtained from these seven mice were retransplanted into secondary recipient mice, 20% of CFU-GM from BMCs showed positive signals for vector GST-pi DNA after 6 months. These data indicate that the GST-pi gene can confer resistance to bone marrow against CY by being transduced into long-term repopulating cells.

Asef, a link between the tumor suppressor APC and G-protein signaling.

The adenomatous polyposis coli gene (APC) is mutated in familial adenomatous polyposis and in sporadic colorectal tumors. Here the APC gene product is shown to bind through its armadillo repeat domain to a Rac-specific guanine nucleotide exchange factor (GEF), termed Asef. Endogenous APC colocalized with Asef in mouse colon epithelial cells and neuronal cells. Furthermore, APC enhanced the GEF activity of Asef and stimulated Asef-mediated cell flattening, membrane ruffling, and lamellipodia formation in MDCK cells. These results suggest that the APC-Asef complex may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function.

A case of diffuse large B-cell lymphoma transformed from immunoglobulin A-producing marginal zone B-cell lymphoma.

We present a rare case of diffuse large B-cell lymphoma transformed from immunoglobulin (Ig) A-secreting marginal zone B-cell lymphoma. A 62-year-old woman was admitted to our hospital for examination of a disseminated pulmonary shadow. Gradual swelling of bilateral axilla and right inguinal lymph nodes were noted after admission. Histological examination of the lymph node biopsy specimen revealed the appearance of marginal zone B-cell lymphoma. The surface Ig of lymphoma cells was IgA-kappa, which coincided with the class of monoclonal Ig found in the patient's serum. The lymph node swelling and pulmonary shadow subsided, and the serum IgA level was normalized by 3 courses of systemic chemotherapy. However, after 4 courses of treatment, new tumor lesions at the right chest wall and left arm progressively became apparent. The biopsy specimen of the tumor showed a feature of diffuse large B-cell lymphoma. Despite intensive chemotherapy, the patient died of spreading tumor burden into the central nervous system.

Transforming growth factor-beta1 (TGF-beta1) induces thrombopoietin from bone marrow stromal cells, which stimulates the expression of TGF-beta receptor on megakaryocytes and, in turn, renders them susceptible to suppression by TGF-beta itself with high specificity.

The present study was designed to test the concept that platelets release a humoral factor that plays a regulatory role in megakaryopoiesis. The results showed that, among various hematoregulatory cytokines examined, transforming growth factor-beta1 (TGF-beta1) was by far the most potent enhancer of mRNA expression of bone marrow stromal thrombopoietin (TPO), a commitment of lineage specificity. The TPO, in turn, induced TGF-beta receptors I and II on megakaryoblasts at the midmegakaryopoietic stage; at this stage, TGF-beta1 was able to arrest the maturation of megakaryocyte colony-forming units (CFU-Meg). This effect was relatively specific when compared with its effect on burst-forming unit-erythroid (BFU-E) or colony-forming unit-granulocyte-macrophage (CFU-GM). In patients with idiopathic thrombocytopenic purpura (ITP), the levels of both TGF-beta1 and stromal TPO mRNA were correlatively increased and an arrest of megakaryocyte maturation was observed. These in vivo findings are in accord with the aforementioned in vitro results. Thus, the results of the present investigation suggest that TGF-beta1 is one of the pathophysiological feedback regulators of megakaryopoiesis.

Effect of caffeine on ibuprofen-induced gastric mucosal damage in rats.

During investigations on the effect of caffeine on ibuprofen-induced gastric mucosal lesions in rats, we have found that caffeine (p.o.) inhibits the development of ibuprofen-induced gastric lesions in a dose-dependent manner (ED50 18.4 mg kg(-1)). To investigate this protective effect of caffeine, we have studied the effect of caffeine on HCl-ethanol-induced gastric mucosal lesions with or without indomethacin pretreatment. Caffeine inhibited the development of HCl-ethanol-induced gastric lesions with and without indomethacin pretreatment. These results indicate that caffeine did not act as a mild irritant but, on the contrary, had protective effects. We measured the gastric mucosal prostaglandin E2 (PGE2) concentrations and gastric mucosal blood flow, as representative protective factors for gastric mucosa. Caffeine did not affect the gastric mucosal PGE2 concentrations 4h after administration of ibuprofen. However, topical administration of caffeine resulted in an increase in gastric mucosal blood flow, as measured by laser Doppler flowmetry. We investigated the gastric acid secretion and gastric mucosal myeloperoxidase activity as representative aggressive factors for gastric mucosa. When caffeine was administered intraduodenally in pylorus-ligated rats, gastric acid secretion decreased in a dose-dependent manner, with an ED50 of 44.9 mg kg(-1). Caffeine decreased ibuprofen-induced gastric myeloperoxidase activity in a dose-dependent manner, with an ED50 of 9.1 mg kg(-1). These findings indicate that caffeine, at least in rats, may inhibit the development of acute gastric mucosal injury. The mechanisms underlying the protective actions of caffeine are unclear, but may be related in part to an increase in gastric mucosal blood flow and suppression of neutrophil activation.

Rheologic analysis of gastric mucosal hemodynamics in patients with cirrhosis.

BACKGROUND: Portal hypertensive gastropathy causes some gastric mucosal microcirculatory disorders in cirrhotic patients, but the nature of the rheologic dysfunction in the gastric microcirculation remains to be clarified. METHODS: To examine the rheologic properties of the gastric microcirculation, we subjected 112 cirrhotic patients and 51 control subjects to endoscopic laser Doppler flowmetry and measured multiple variables of flow, red blood cell volume, and velocity. Furthermore, based on these results, we analyzed the shear rate which reflects the status of the microcirculatory system. To validate the laser Doppler flowmetry, we derived the relationship between red blood cell volume and cross-sectional areas of submucosal collecting venules; near-infrared endoscopy was used to evaluate this relationship. RESULTS: Analysis of shear rate according to the severity of portal hypertensive gastropathy showed that the mucosa was exposed to strong hemokinetic stress in severe cases, characterized by a higher shear rate than in control subjects or in mild cases. Nitroglycerin, administered by intravenous infusion (1.0 microg/kg/min), reduced blood flow and restored shear rate to control levels in patients with severe portal hypertensive gastropathy. CONCLUSION: This rheologic study of the gastric mucosa suggests that a disorder of the shear rate control mechanism in the microcirculation is associated with severe portal hypertensive gastropathy.