Effects of phototherapy in neonates on circadian sleep-wake and saliva cortisol level rhythms

The influence of phototherapy treatment during the neonatal period on sleep-wake rhythm, and its long-term effects on biological rhythms, was evaluated in preterm and full-term infants. Forty-three infants treated with phototherapy during the neonatal period and 47 untreated infants were examined for entrainment of sleep-wake rhythms between 16 and 52 weeks and for sleep-wake and saliva cortisol rhythms at 2.5 years of age. The age of sleep-wake rhythm entrainment was not significantly different between the 2 groups. No correlations between duration of exposure to phototherapy and corrected age of entrainment of sleep-wake rhythm were observed. At follow-up, no significant differences in sleep-wake and saliva cortisol rhythms were observed between the 2 groups, indicating that circadian variations were similar to those in adults.     

Acetic acid ulcers: a new method for producing solitary chronic ulcers in rat stomachs by intraluminal application of acetic acid solution

Acetic acid ulcer models remain popular because of the simplicity of the procedures, the reliability of development, and a strong resemblance to human ulcers in terms of both pathology and healing processes. Such ulcer models, however, possess the drawback of invariable adherence of the ulcer base to the liver. The present study demonstrates the production of new acetic acid ulcer, i.e., a single ulcer per stomach with bases that do not adhere to the liver. This new model will prove useful for both screening antiulcer medications and elucidating the mechanisms underlying ulcer healing.     

Effect of (S)-4-(1-(5-chloro-2-(4-fluorophenyoxy)benzamido)ethyl) benzoic acid (CJ-42794), a selective antagonist of prostaglandin E receptor subtype 4, on ulcerogenic and healing responses in rat gastrointestinal mucosa

Recent research showed the involvement of prostaglandin E receptor subtype 4 (EP4) in hypersensitivity to inflammatory pain and suggested that the EP4 receptor is a potential target for the pharmacological treatment of inflammatory pain. We examined the effects of (S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid (CJ-42794), a selective EP4 antagonist, on gastrointestinal ulcerogenic and healing responses in rats, in comparison with those of various cyclooxygenase (COX) inhibitors. CJ-42794 alone, given p.o., did not produce any damage in the gastrointestinal mucosa, similar to 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560) (COX-1 inhibitor) or rofecoxib (COX-2 inhibitor), whereas indomethacin (nonselective COX inhibitor) caused gross lesions. Rofecoxib but not CJ-42794, however, damaged these tissues when coadministered with SC-560 and aggravated gastric lesions produced by aspirin. Indomethacin and SC-560 worsened the gastric ulcerogenic response to cold-restraint stress, yet neither CJ-42794 nor rofecoxib had any effect. Furthermore, indomethacin and SC-560 at lower doses damaged the stomach and small intestine of adjuvant arthritic rats. In arthritic rats, rofecoxib but not CJ-42794 provoked gastric ulceration, whereas CJ-42794 produced little damage in the small intestine. The repeated administration of CJ-42794 and rofecoxib as well as indomethacin impaired the healing of chronic gastric ulcers with a down-regulation of vascular endothelial growth factor expression in the ulcerated mucosa. These results suggest that CJ-42794 does not cause any damage in the normal rat gastrointestinal mucosa and in the arthritic rat stomach and does not worsen the gastric ulcerogenic response to stress or aspirin in normal rats, although this agent slightly damages the small intestine of arthritic rats and impairs the healing of gastric ulcers.     

Gastro-intestinal patch system for the delivery of erythropoietin.

The absorption of erythropoietin (EPO) from rat small intestine was studied using gastro-intestinal patches (GI-PS) in the presence of absorption enhancers. Surfactants such as a saturated polyglycolysed C8-C18 glyceride (Gelucire 44/14), PEG-8 capryl/caprylic acid glycerides (Labrasol), and polyoxyethylene hydrogenated castor oil derivative (HCO-60) were used as absorption enhancers at 143, 94 and 20 mg/kg, respectively. The absorption of EPO was studied by measuring serum EPO levels by an ELISA method after small intestinal administration of EPO-GI-PS preparation in rats at the EPO dose level of 100 IU/kg. Labrasol showed the highest absorption enhancing effect after intrajejunum administration with maximum serum EPO level of 84.1+/-11.4 mIU/ml while Gelucire 44/14 and HCO-60 showed 43.5+/-9.8 and 26.5+/-2.3 mIU/ml, respectively. The appropriate site for EPO absorption was also investigated. Jejunum was found to be the most efficient absorption site for the absorption of EPO from GI-PS. Using Labrasol as the absorption enhancer and jejunum as the absorption site, the effect of EPO dose on EPO absorption was studied by increasing the EPO dose from 50, to 100, 300 and 600 IU/kg. It was found that 100 IU/kg was the optimum dose with a serum EPO level of 84.1+/-11.4 mIU/ml while escalating doses showed decreases in serum EPO levels 48.3+/-5.6 for 300 IU/kg and 50.6+/-10.3 mIU/ml for 600 IU/kg. The percent bioavailability (BA) of EPO-GI-PS with Labrasol as absorption enhancer was 7.9 at 50 IU/kg, 12.1 at 100 IU/kg, 3.2 at 300 IU/kg and 1.2 at 600 IU/kg. Histological studies showed no adverse effect at the site of administration.     

Long‐term treatment of localized gastric marginal zone B‐cell mucosa associated lymphoid tissue lymphoma including incidence of metachronous gastric cancer

Background and Aim: According to a few recent reports on the long‐term clinical outcome of gastric marginal zone B‐cell mucosa associated lymphoid tissue lymphoma (MALT lymphoma); localized gastric MALT lymphoma generally has a favorable prognosis. However, the risk of metachronous gastric cancer has not been evaluated. In this study, we analyzed long‐term outcomes of localized gastric MALT lymphoma including the incidence of metachronous gastric cancer. Methods: Between April 1996 and May 2008, 60 patients (31 men and 29 women; mean age 58.1 years) with localized gastric MALT lymphoma (stage I and II¹ according to Lugano classification) were analyzed retrospectively. Results: Forty‐eight patients (82.6%) achieved complete remission by eradication therapy. Radiation therapy was conducted on eight patients as second‐line treatment, and all of them achieved remission. The median follow‐up period was 76 months (range, 12–157 months). One patient had local relapse after remission for 5 years and three patients developed early gastric cancer without recurrence of lymphoma (5%). All of the three gastric cancers appeared in the same areas where MALT lymphoma had been eradicated. Conclusion: Eradication therapy and radiation therapy for localized gastric MALT lymphoma have a favorable long‐term outcome, though regular follow‐up endoscopy should be performed for detecting metachronous early gastric cancer.     

Miller Fisher syndrome with transient coma: comparison with Bickerstaff brainstem encephalitis

We herein report a 4-year-old boy with Miller Fisher syndrome (MFS) who presented with transient coma in addition to the typical triad of internal and external ophthalmoplegia, cerebellar ataxia and areflexia after an influenza type B infection. The electroencephalogram findings revealed intermittently generalized slow wave bursts. The cerebrospinal fluid revealed high protein and a lack of any cellular response. The serum anti-GQ1b IgG antibody was elevated in the acute phase and disappeared in the convalescent phase. The transient coma with the triad of MFS in this patient indicated an extended brainstem lesion including a reticular formation, which is also the responsible lesion of Bickerstaff brainstem encephalitis (BBE), but the magnetic resonance imaging repeatedly showed no abnormal finding. Our patient suggested the involvement of central nervous system in addition to the peripheral nerve injury in MFS. He also suggested that MFS and BBE may belong to the same group of disorders as syndrome of ophthalmoplegia, ataxia and areflexia (SOAA).     

Epidermal growth factor prolongs survival time of tumor-bearing mice

We observed that human epidermal growth factor (hEGF) alone prolonged the survival time of mice bearing various murine syngeneic tumors as well as athymic nude mice bearing human xenografts. No changes in the subcutaneous solid tumor mass volume were observed. Prolongation of survival time by hEGF was observed in mice bearing murine epidermoid carcinoma (BSC) and human gastric carcinoma (KATO III), but not in murine epidermoid carcinoma (KLN205) or human epidermoid carcinoma (A431). Human tumor cells such as A431, KATO III, and murine tumor cells, KLN205, BSC had roughly 2 X 10(6), 3 X 10(4), 1.3 X 10(3) and 1 X 10(3) EGF receptors/cell, respectively. Although KLN205 and BSC tumor cells maintained nearly the same number of EGF receptors, the effects of hEGF were very different. Although A431 tumor cells had nearly 100 times more receptors than KATO III cells, the prolongation of survival time of mice bearing A431 by hEGF was no better than that of mice bearing KATO III. Accordingly, it appears that this prolongation of survival time by hEGF is independent of the number of EGF receptors on tumor cells. In addition, hEGF was shown to inhibit experimental pulmonary metastasis of murine BSC tumor, but was ineffective with murine KLN205 tumor. These results suggest that prolongation of survival time by hEGF may result from the inhibition of tumor cell metastasis and EGF may play a role in preventing the metastasis of certain malignant neoplasms unrelated to its effects through the EGF receptor on tumor cells.     

Regulation of prostaglandin biosynthesis by interleukin-1 in cultured bovine endometrial cells

Interleukin-1 (IL1) has been shown to be a potent stimulator of prostaglandin (PG) production in bovine endometrium. The aim of the present study was to determine the cell types in the endometrium (epithelial or stromal cells) responsible for the secretion of PGE2 and PGF2alpha in response to IL1A, and the intracellular mechanisms of IL1A action. Cultured bovine epithelial and stromal cells were exposed to IL1A or IL1B (0.006-3.0 nM) for 24 h. IL1A and IL1B dose-dependently stimulated PGE2 and PGF2alpha production in the stromal cells, but not in the epithelial cells. The stimulatory effect of IL1A (0.06-3.0 nM) on PG production was greater than that of IL1B. The stimulatory actions of IL1A on PG production was augmented by supplementing arachidonic acid (AA). When the stromal cells were incubated with IL1A and inhibitors of phospholipase (PL) C or PLA2 (1 microM; anthranilic acid), only PLA2 inhibitor completely stopped the stimulatory action of IL1A on PG production. Moreover, a specific cyclooxygenase-2 (COX2) inhibitor blocked the stimulatory effect of IL1A on PG production. IL1A (0.06 nM) promoted COX2 and microsomal PGE synthase-1 (PGES1) gene and its protein expression. The expression of COX1, PGES2, PGES3, and PGF synthase (PGFS) mRNA was not affected by IL1A in the stromal cells. The overall results indicate that 1) the target of IL1A and IL1B for stimulating both PGE2 and PGF2alpha production is the stromal cells, 2) IL1A is a far more potent stimulator than IL1B on PG production in stromal cells, 3) the stimulatory effect of IL1A on PG production is mediated via the activation of PLA2 and COX2, and (4) IL1A induced PG production by increasing expressions of COX2 and PGES1 mRNAs and their proteins in bovine stromal cells.     

Pioglitazone prevents reactive hypoglycemia in impaired glucose tolerance

A 42-year-old woman with hypoglycemic symptoms that occurred several hours after a meal visited our hospital. The hypoglycemic symptoms appeared when she was 37 years old, and her plasma glucose level had been assessed as less than 60 mg/dL when she experienced the symptoms. One year before, she had been diagnosed with reactive hypoglycemia by 75 g-oral glucose tolerance test (OGTT), which showed a normal glucose tolerance (NGT) pattern, and had begun taking an alpha-glucosidase inhibitor and nutritional treatment. A 75 g-OGTT on admission showed hypoglycemia at 240 min after glucose loading, excessive insulin secretion and an impaired glucose tolerance (IGT) pattern. A euglycemic-hyperinsulinemic clamp study demonstrated decreased insulin sensitivity. Therefore, we suspected that she had reactive hypoglycemia associated with insulin resistance and treated her with 15 mg/day pioglitazone. Her hypoglycemic symptoms completely disappeared after treatment with pioglitazone; insulin sensitivity in a euglycemic-hyperinsulinemic clamp study improved. Another 75 g-OGTT revealed that the excessive insulin secretion and hypoglycemia at 240 min after glucose loading had disappeared, and glucose tolerance was normalized from an IGT pattern to an NGT pattern. Thus, we believe that pioglitazone is effective for reactive hypoglycemia and aggravated glycemic metabolism associated with insulin resistance.     

Risk of Etoposide-Related Acute Myeloid Leukemia in the Treatment of Epstein-Barr Virus—Associated Hemophagocytic Lymphohistiocytosis

We studied the impact of etoposide on the prognosis of 81 patients (77 of whom were children <15 years old) with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The study group received a median cumulative dose of 1,500 mg/m2 etoposide (range, 0-14,550 mg/m2), with a median follow-up period of 44 months (range, 20-88 months) from the diagnosis. Only 1 patient, who received 3150 mg/m2 etoposide, developed therapy-related acute myeloid leukemia (t-AML), at 31 months after diagnosis. Excluding 9 patients who underwent hemopoietic stem cell transplantation during the course of treatment, the prognosis was poorer for those patients who received less than a 1,000 mg/m2 cumulative dose of etoposide. Our results indicate that the risk of etoposide-related t-AML is low. An appropriate dosage of etoposide for the treatment of EBV-HLH would be in the range of 1,000 to 3,000 mg/m2. However, even at these doses, care must be taken to prevent the rare risk of t-AML.