Diabetes can increase the prevalence of EBV infection and worsen the prognosis of nasopharyngeal carcinoma.

Epstein‒Barr virus (EBV) infection is a primary oncogenic factor of nasopharyngeal carcinoma (NPC) that elicits epithelial-mesenchymal transition (EMT). Although diabetic patients are more susceptible to various infectious diseases, the pathological association with virus-related NPC has not yet been clarified. Herein, we evaluated the influence of diabetes on the clinicopathological changes of 70 patients with NPC. Disease-specific survival (DSS) modified by viral infection was also analysed. The proportion of NPC patients with diabetes was 32.9% (23/70 cases), and 91.3% (21/23 cases) were infected with EBV detected by EBER-I in situ hybridisation. NPC with diabetes showed an effect on EMT evaluated by immunostaining for E-cadherin and vimentin, which was correlated with HbA1c levels. Receiver operating characteristic (ROC) curve analysis determined a HbA1c level of 6.5% as the cut-off value for primary disease death at 2 years [area under the curve (AUC) 0.76; sensitivity 0.64; and specificity 0.81]. High HbA1c levels (≥6.5%) significantly increased the number of lymph node metastases in NPC compared to low HbA1c levels (<6.5%, p<0.01). Diabetic NPC patients had a significantly poorer prognosis than all non-diabetic patients (DSS, 72 months vs not reached, p<0.05). Diabetic EBV-positive NPC patients had a significantly poorer prognosis than non-diabetic EBV-positive patients (DSS, 35 months vs not reached, p<0.01). Multivariate analysis using the Cox proportional hazards model also suggested that HbA1c ≥6.5% was a significant factor in poor prognosis, with a hazard ratio of 6.84 (p<0.05). Collectively, our results revealed for the first time a high prevalence of EBV infection, poor prognosis and the importance of proper glycaemic control in diabetic NPC patients.

Clostridium paraputrificum Bacteremia in a Patient with Rectal Cancer after Receiving Antibiotic Therapy for Acute Pharyngolaryngitis.

Clostridium paraputrificum bacteremia is very rare, and its clinical importance is poorly understood. An 86-year-old man was receiving lascufloxacin therapy for acute pharyngolaryngitis before presenting to our emergency department with a recurrent fever. Two sets of blood cultures on admission revealed C. paraputrificum. A stool culture showed a reduced presence of intestinal commensal bacteria. After admission, the patient's fever resolved without antibiotics. Colonoscopy revealed a rectal tumor. Rectal tumor and microbial substitutions caused by antibiotics may have led to bacteremia. When treating C. paraputrificum bacteremia, physicians should be mindful of coexisting gastrointestinal disorders and a history of antibiotic administration.

Major basic protein deposited at intra mucosal epithelium with probable eosinophilic chronic rhinosinusitis.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is diagnosed by Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) scoring system and histopathological eosinophil counts of dissected nasal polyps. Patients with low JESREC score and small number of tissue eosinophils are diagnosed with non-ECRS (NECRS). Due to the 2 parameters of this diagnostic system, chronic rhinosinusitis is to be divided to 4 groups and some patients fall into the 2 groups other than ECRS and NECRS: probable ECRS (pECRS) and probable non-ECRS (pNECRS). We attempted to clarify clinical and histopathological similarities and differences, especially concerning major basic protein (MBP), among those groups. Methods: One hundred twenty-eight patients treated by endoscopic sinus surgery was included. Clinical characteristics were compared among each group, and immunohistological analysis for MBP was performed to 35 randomly selected patients. MBP deposition at intra mucosal epithelium was evaluated by semiquantificational approach. Results: ECRS patients showed significantly higher comorbidity rate with allergic rhinitis (36 patients, 78.3%), asthma (36 patients, 78.3%) compared with other groups. Also, percentage of the patients complaining olfactory dysfunction (42 patients, 91.3%) was significantly higher (p < 0.001). Lund-Mackay score (mean, 14.5; 6-24) and recurrence rate (27 patients, 61.4%) was the highest in ECRS patients. Regarding pECRS, the number of patients with olfactory dysfunction (5 patients, 55.6%) was higher than pNECRS and NECRS groups. Also, comorbidity of asthma and percentage of blood eosinophils tended to be higher than those 2 groups. MBP score of pECRS group was significantly higher than NECRS (p < 0.05), despite of smaller tissue eosinophil counts. Conclusion: pECRS might share some characteristics with ECRS although tissue eosinophil count was significantly smaller compared with ECRS. The results of this study have shown that MBP score in pECRS nasal polyps was significantly higher than NECRS patients and close to ECRS. That might suggest that eosinophils have existed in the nasal polyps of pPECRS patients at some point before surgery.

Outcomes of long-term nivolumab and subsequent chemotherapy in Japanese patients with head and neck cancer: 2-year follow-up from a multicenter real-world study.

BACKGROUND: We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy. METHODS: In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs). RESULTS: Overall, 256 patients received a median of 6.0 doses (range: 1-52) of nivolumab over a median duration of 72.5 days (range: 1-736). Median OS was 9.5 months [95% confidence interval (CI) 8.2-12.0] and median PFS was 2.1 months (95% CI 1.8-2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9-11.9) and 3.5 months (95% CI 2.3-5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis. CONCLUSIONS: Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.

Clofibric acid increases molecular species of phosphatidylethanolamine containing arachidonic acid for biogenesis of peroxisomal membranes in peroxisome proliferation in the liver.

The biogenesis of peroxisomes in relation to the trafficking of proteins to peroxisomes has been extensively examined. However, the supply of phospholipids, which is needed to generate peroxisomal membranes in mammals, remains unclear. Therefore, we herein investigated metabolic alterations induced by clofibric acid, a peroxisome proliferator, in the synthesis of phospholipids, particularly phosphatidylethanolamine (PE) molecular species, and their relationship with the biogenesis of peroxisomal membranes. The subcutaneous administration of clofibric acid to rats at a relatively low dose (130 mg/kg) once a day time-dependently and gradually increased the integrated perimeter of peroxisomes per 100 µm2 hepatocyte cytoplasm (PA). A strong correlation was observed between the content (µmol/mg DNA) of PE containing arachidonic acid (20:4) and PA (r2 = 0.9168). Moreover, the content of PE containing octadecenoic acid (18:1) positively correlated with PA (r2 = 0.8094). The treatment with clofibric acid markedly accelerated the formation of 16:0-20:4 PE by increasing the production of 20:4 and the activity of acyl chain remodeling of pre-existing PE molecular species. Increases in the acyl chain remodeling of PE by clofibric acid were mainly linked to the up-regulated expression of the Lpcat3 gene. On the other hand, clofibric acid markedly increased the formation of palmitic acid (16:0)-18:1 PE through de novo synthesis. These results suggest that the enhanced formation of particular PE molecular species is related to increases in the mass of peroxisomal membranes in peroxisome proliferation in the liver.

Effectiveness of nivolumab affected by prior cetuximab use and neck dissection in Japanese patients with recurrent or metastatic head and neck cancer: results from a retrospective observational study in a real-world setting.

BACKGROUND: To examine the effect of prior use of cetuximab and neck dissection on the effectiveness of nivolumab, we conducted a large-scale subgroup analysis in Japanese patients with recurrent/metastatic head and neck cancer. METHODS: Data on the effectiveness of nivolumab were extracted from patient medical records. All patients were analyzed for effectiveness by prior cetuximab use. In the analyses for prior neck dissection, only patients with locally advanced disease were included. RESULTS: Of 256 patients analyzed, 155 had received prior cetuximab. Nineteen of 50 patients with local recurrence underwent neck dissection. The objective response rate was 14.7 vs 17.2% (p = 0.6116), median progression-free survival was 2.0 vs 3.1 months (p = 0.0261), and median overall survival was 8.4 vs 12 months (p = 0.0548) with vs without prior cetuximab use, respectively. The objective response rate was 23.1 vs 25.9% (p = 0.8455), median progression-free survival was 1.8 vs 3.0 months (p = 0.6650), and median overall survival was 9.1 vs 9.9 months (p = 0.5289) with vs without neck dissection, respectively. CONCLUSIONS: These findings support the use of nivolumab for patients with recurrent/metastatic head and neck cancer regardless of prior cetuximab use or neck dissection history. TRIAL REGISTRATION NUMBER: UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436).

Effectiveness and safety of nivolumab in patients with head and neck cancer in Japanese real-world clinical practice: a multicenter retrospective clinical study.

BACKGROUND: To fill the data gap between clinical trials and real-world settings, this study assessed the overall effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) during Japanese real-world clinical practice. METHODS: This was a multicenter, retrospective study in Japanese patients with recurrent or metastatic HNC who received nivolumab for the first time between July and December 2017. Data on the clinical use, effectiveness, and safety of nivolumab were extracted from patient medical records. RESULTS: Overall, 256 patients were enrolled in this study. The median duration of nivolumab treatment was 72.5 days, with patients receiving a median of 6.0 (range 1-27) doses. Median overall survival (OS) was 9.5 (95% confidence interval [CI] 8.2-12.0) months and the estimated 12-month OS rate was 43.2%. The objective response rate (ORR) was 15.7% overall and 21.1%, 7.1%, and 13.6% in patients with primary nasopharynx, maxillary sinus, and salivary gland tumors, respectively, who had been excluded from CheckMate 141. Grade ≥ 3 immune-related adverse events occurred in 5.9% of patients. No new safety signals were identified compared with adverse events noted in CheckMate 141. CONCLUSIONS: The effectiveness and safety of nivolumab in real-world clinical practice are consistent with data from the CheckMate 141 clinical trial. Therapeutic response was also observed in the groups of patients excluded from CheckMate 141. TRIAL REGISTRATION NUMBER: UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436).

CD11c(+) dendritic cells coexpressing thymic stromal lymphopoietin receptor in animal model of eosinophilic otitis media.

BACKGROUND: Eosinophilic otitis media (EOM) is an intractable middle ear disease often associated with eosinophilic inflammatory airway conditions. Recently, dendritic cells (DCs) have been indicated as an essential component of Th2 allergic inflammation, such as bronchial asthma. DCs are activated by thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine. However, the relationship between TSLP and DCs in EOM remains unknown. OBJECTIVE: This study aimed to investigate the relationship between DCs and TSLP and to determine the involvement of DCs in EOM in an animal model. METHODS: Hartley guinea pigs were used as the animal model. Daily ovalbumin (OVA) stimulation of the middle ear was performed for 7 or 14 days. The temporal bone was dissected on the last day of stimulation, and paraffin-embedded sections were prepared. Immunostaining and immunofluorostaining for TSLP receptor (TSLPR) and CD11c, a surface marker of DCs, were performed. RESULTS: We found CD11c-immunopositive cells in the submucosal area of the middle ear epithelium, particularly around the eustachian tube. TSLPR-immunopositive cells exhibited a similar distribution as CD11c-positive cells. CONCLUSION: CD11c positive DCs coexpressing TSLPR were recruited after OVA challenge which might activate Th2 allergic reaction.

A single pretreatment with clofibric acid attenuates carbon tetrachloride-induced necrosis, but not steatosis, in rat liver.

The present study investigated whether a single pretreatment with clofibric acid suppresses liver injury in rats after CCl4 intoxication. Rats received a single pretreatment with clofibric acid (100 mg/kg, i.p.) 1 h prior to a CCl4 (1 mL/kg, p.o.) challenge, and were euthanized 24 h after the CCl4 administration. A single pretreatment with clofibric acid effectively suppressed increases in the serum aminotransferase activities and the severity of necrosis following the CCl4 challenge, whereas the pretreatment did not protect against CCl4-induced fatty liver. The clofibric acid pretreatment did not affect blood concentrations of CCl4 in the early stage after CCl4 dosing, or the level of the CCl4 reaching the liver 1 h after the CCl4 challenge. Moreover, the clofibric acid pretreatment did not affect the intensity of the covalent binding of the [14C]CCl4 metabolite to microsomal proteins and lipids. The clofibric acid pretreatment did not alter microsomal cytochrome P450 2E1 activity. Based on these results, we conclude that protection against CCl4-induced hepatocellular necrosis by a clofibric acid pretreatment does not require its repeated administration, and that a single and brief pre-exposure to clofibric acid prior to CCl4 dosing markedly suppresses necrosis without affecting the development and progression of steatosis.

Antidepressants with different mechanisms of action show different chronopharmacological profiles in the tail suspension test in mice.

The circadian system regulates sleep/wake cycles, metabolism, mood, and other functions. It also influences medication efficacy. In this study, we studied the chronopharmacological profiles of antidepressants with various modes of action. We also investigated the effects of dosing time on the pharmacological activity of several antidepressants acting on serotonergic, noradrenergic, and/or dopaminergic neurons. C57BL/6 mice were intraperitoneally administered fluoxetine, imipramine, venlafaxine, or bupropion at 08:00 h (morning), 14:00 h (mid-day), 20:00 h (evening), or 02:00 h (mid-night). Antidepressant activity was evaluated by the tail suspension test. All antidepressants reduced immobility, and their activities varied according to the dosing time. Fluoxetine and imipramine induced relatively strong rhythms with high amplitudes. Their maximal effects were observed in the morning and evening, respectively. Venlafaxine and bupropion induced weak rhythms with maximal effects in the evening and dawn, respectively. These results suggest that the antidepressant activity is associated with circadian fluctuation, and antidepressants with different modes of action have different chronopharmacological profiles. They affect locomotor activity in animals placed in novel (unfamiliar) environments. Fluoxetine, imipramine, and venlafaxine reduced locomotor activity, whereas bupropion increased it. The effects on locomotor activity also vary with circadian rhythm, and the tested drugs showed a maximal effect during the light phase. The peak time was different from that in TST. Plasma and brain levels of all drugs were slightly higher in the morning than in the evening. The dosing time dependency of the antidepressant activity did not correlate with the sedative/stimulatory activity or tissue drug level. Therefore, these latter two factors may have only a small impact on circadian antidepressant activity fluctuations. The relative activity of the serotonergic, noradrenergic, and dopaminergic systems may determine the chronopharmacological profiles of each drug. These results suggest the possibility that drug therapy be optimized by considering the dosing time when the antidepressant activity is high and other pharmacological activities leading to adverse effects are low. Further studies using animal models of depression and in clinical settings are necessary to confirm the effects of dosing time on depressed subjects.

Time of Administration of Acute or Chronic Doses of Imipramine Affects its Antidepressant Action in Rats.

The pathogenesis and therapeutics of depression are linked to the operation of the circadian system. Here, we studied the chronopharmacological action of a tricyclic antidepressant, imipramine. Male adult Wistar-Hannover rats were administered imipramine acutely or chronically in the morning or in the evening. The antidepressant action of imipramine was analyzed using the forced swim test (FST). A single dose of imipramine (30 mg/kg) in the morning, but not in the evening, reduced immobility and increased climbing in the FST. The plasma concentrations of imipramine and its metabolite, desipramine, were slightly higher in the morning than in the evening, which might explain the dosing time-dependent action of imipramine. Next, we analyzed the effect of chronic imipramine treatment. Rats received imipramine in the morning or in the evening for 2 weeks. The morning treatment resulted in larger effects in the FST than the evening treatment, and was effective at a dose that was ineffective when administered acutely. The levels of brain α-adrenergic receptors tended to decrease after chronic imipramine treatment. Imipramine might interact with noradrenergic neurons, and this interaction might chronically alter receptor expression. This alteration seemed greater in the morning than in the evening, which might explain the dosing time-dependent action of imipramine.

Reduction in Secretion of Very Low Density Lipoprotein-Triacylglycerol by a Matrix Metalloproteinase Inhibitor in a Rat Model of Diet-Induced Hypertriglyceridemia.

Matrix metalloproteinase inhibitors (MMPIs) reduced serum triacylglycerol (TAG) levels in streptozotocin-induced diabetic rats and Zucker fa/fa rats in our previous study. However, the mechanisms underlying TAG reduction by MMPIs remain unclear. The present study aimed to elucidate the mechanism by which F81-1144b, an MMPI, lowers serum TAG levels in an animal model of high-sucrose diet (HSD)-induced hypertriglyceridemia. F81-1144b was repeatedly administered to rats fed HSD, and its effects were evaluated on TAG levels in serum and the liver, very low density lipoprotein (VLDL) secretion, de novo fatty acid (FA) synthesis in the liver, and the expression of genes regulating the metabolism of FA, TAG, and VLDL in the liver and serum. F81-1144b lowered TAG levels in serum and the liver, VLDL-TAG secretion, de novo FA synthesis in the liver, and serum levels of insulin and glucose. F81-1144b suppressed the expression of genes related to the de novo synthesis of FA and TAG, key proteins (lipin 1 and apolipoprotein CIII) responsible for VLDL metabolism, and sterol regulatory element-binding protein-1c and carbohydrate response element-binding protein. F81-1144b little affected the expression of genes related directly to the degradation of TAG or FA, but it upregulated that of gene for uncoupling protein 2 in the liver. These results suggest that MMPIs are a novel type of therapeutic agent for the treatment of hypertriglyceridemia, because the metabolic effects of F81-1144b expected from changes in the expression of genes regulating lipid metabolism would alter metabolism differently from those induced by fibrates, niacin, or n-3 FAs.

Chronopharmacological Analysis of Antidepressant Activity of a Dual-Action Serotonin Noradrenaline Reuptake Inhibitor (SNRI), Milnacipran, in Rats.

Biological rhythms are thought to be related to the pathogenesis and therapy of various diseases including depression. Here we investigated the influence of circadian rhythms on the antidepressant activity of the dual-action serotonin-noradrenaline reuptake inhibitor (SNRI) milnacipran. Rats administered milnacipran in the morning (8:00 a.m.; zeitgeber time [ZT]1) or in the evening (8:00 p.m.; ZT13) were analyzed in a forced swim test (FST). At ZT1, the rats' immobility was reduced and the swimming was increased, whereas at ZT13, their climbing was increased. These results suggest that the serotonergic and noradrenergic systems are preferentially affected at ZT1 and ZT13, respectively by milnacipran. We analyzed the plasma and brain levels of milnacipran after administration, and there were no differences between ZT1 and ZT13. The circadian rhythm of monoamine neurotransmitters was analyzed in several brain regions. The serotonin turnover showed rhythms with a peak during ZT18-ZT22 in hippocampus. The noradrenaline turnover showed rhythms with a peak during ZT22-ZT2. There was a difference of approx. 4 h between the serotonergic and noradrenergic systems. This time difference might be one of the factors that affect the action of milnacipran and contribute to the dosing time-dependent behavioral pattern in the FST.

Short and long photoperiods differentially exacerbate corticosterone-induced physical and psychological symptoms in mice.

Circadian disruption affects the pathogenesis and development of various diseases. Depression is one of the most common diseases that relate to circadian rhythm. In this study, we analyzed the effects of daily light/dark (LD) conditions on depression and other symptoms, and also analyzed the mixed effects of LD conditions and corticosterone treatment. Male adult C57BL/6 mice were treated with corticosterone in a normal LD cycle of 12 hours light and 12 hours dark (LD12 : 12), short day conditions of 6 hours light and 18 hours dark (LD6 : 18), or long day conditions of 21 hours light and 3 hours dark (LD21 : 3). The activity rhythms of mice in aberrant LD conditions were entrained within 2 weeks. After 6 weeks of exposure, several behavioral tests were conducted. Corticosterone induced body weight gain and depression-like symptoms. The short or long LD conditions had little effect on vehicle-treated mice behavior. However, the aberrant LD conditions exacerbated the corticosterone-induced symptoms. Mice treated with corticosterone in LD6 : 18 showed exacerbated depression-like symptoms in a novelty suppressed feeding test. On the other hand, LD21 : 3 did not show any effects on mood, but enhanced corticosterone-induced body weight gain. These results indicated that aberrant LD conditions could act as an exacerbating factor for corticosterone-induced symptoms, and that short and long photoperiods induce different psychological and physiological changes. This corticosterone + aberrant LD model could be a useful animal model for investigating the effect of LD conditions on depression, obesity, and other symptoms in stressful circumstances.

The expression of thymic stromal lymphopoietin in patients and animal models with eosinophilic otitis media.

OBJECTIVE: In the present study, we aimed to clarify the expression of thymic stromal lymphopoietin (TSLP), a key trigger of Th2-type allergic disease, in the middle ear mucosa of eosinophilic otitis media (EOM). METHODS: An immunohistological study of TSLP was conducted in patients with EOM and in animal models of EOM constructed by intraperitoneal and intratympanic injection of ovalbumin for 7 and 14 days. In addition, the messenger RNA (mRNA) expression of TSLP in the middle ear mucosa of the animal models was analyzed using real-time PCR, and was compared with that of the control animals. RESULTS: Immunoreactivities for TSLP were observed in the middle ear mucosa around the tympanic ostium of the eustachian tube of patients with EOM. In the animal model, strong immunoreactivity for TSLP was also observed in the eustachian tube epithelium, and mRNA expression of TSLP in the seven-day stimulated animals was significantly higher than that in the controls. CONCLUSION: The present study indicates that the presence of epithelium-derived TSLP in the eustachian tubes plays an important role in the onset of EOM.

Perfluorododecanoic Acid Induces Cognitive Deficit in Adult Rats.

The brain level of perfluorododecanoic acid (PFDoA) was compared with those of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in rats 9 days after a single oral dose (50 mg/kg). The PFDoA level in the brain was 44.0 ± 2.0 µg/g, which was higher than that in the serum (24.4 ± 1.0 µg/ml). In contrast, the concentrations of PFOA and PFDA in the brain were low (<0.8 and 4.7 ± 0.4 µg/g, respectively), and less than one-tenth of those in the serum. Next, to investigate the effects on brain function, the cognitive function alterations of PFOA, PFDA, and PFDoA were estimated by the novel object recognition test 5-6 days after dosing. A significant decrease in the discrimination index was observed in PFDoA-treated rats while no significant alteration was observed in PFDA- and PFOA-treated rats. The effects of PFDoA were further assessed by other behavioral tests. PFDoA-associated alteration was observed in the elevated-plus maze test, but not in the Y-maze test, open-field test, and forced swim test. A decrease in the discrimination index of the novel object recognition test was dependent on the PFDoA dose and the PFDoA concentration in the brain. PFDoA concentration in the brain was 28.6 ± 2.6 µg/g 30 days after dosing, and a decrease in discrimination index was observed. Taken together, these results suggest that PFDoA distributes in the brain easier than PFOA and PFDA and causes cognitive deficit.

Immunohistological analysis of eotaxin and RANTES in the model animal of eosinophilic otitis media.

BACKGROUND: The most crucial clinical problem of Eosinophilic Otitis Media (EOM) is sensorineural hearing loss. A previous report revealed that repeated antigen stimulation of middle ear causes eosinophilic inflammation not only in the middle ear but also in the inner ear. OBJECTIVE: The purpose of the present study was to elucidate the mechanism of eosinophil infiltration to the inner ear in the animal model of EOM. METHODS: Continuous OVA stimulation to the middle ear of guinea pigs was performed for 7 days, 14 days, and 28 days. Histological observation was made for eosinophil infiltration and morphological change of the inner ear. Immunostaining for eotaxin and RANTES was performed to study immunoreactivity of those chemokines. RESULTS: In the 7-day stimulation side, a few eosinophils were found in the scala tympani, without obvious morphological damage of the inner ear. Moreover, immunoreactivity of both eotaxin and RANTES was significantly higher in the OVA stimulation sides than control sides. For both eotaxin and RANTES, the number of immunopositive cells was significantly increased in the 14-day stimulation side over the 7-day stimulation side. CONCLUSIONS: Eotaxin and RANTES seem to play some important roles for the eosinophil infiltration in the middle and inner ear of model animal of EOM.

Fatty Acid ß-Oxidation Plays a Key Role in Regulating cis-Palmitoleic Acid Levels in the Liver.

Different monounsaturated fatty acid (MUFA) species have distinct pathophysiological activities. cis-Palmitoleic acid (16:1n-7) was previously reported to improve insulin sensitivity in animal studies. The proportions of hepatic MUFAs are generally considered to reflect changes in the activities of fatty acid modifications (∆9 desaturation and fatty acid elongation). However, hepatic levels of 16:1n-7 are markedly lower than those of oleic acid (18:1n-9). Nevertheless, no convincing explanation has yet been provided for the low level of 16:1n-7. We hypothesized that fatty acid degradation plays a key role in maintaining a low 16:1n-7 proportion in the liver. In order to corroborate the link between ß-oxidation and the proportion of 16:1n-7, rats were fed a control diet, fed a fat-free diet to up-regulate fatty acid modifications, but not ß-oxidation, or treated with clofibric acid to up-regulate fatty acid modifications and ß-oxidation. The nutritional manipulation markedly increased the proportions of 16:1n-7, 18:1n-9, and cis-vaccenic acid (18:1n-7). Although the pharmacological manipulation enhanced fatty acid modifications to largely the same extent as the nutritional manipulation and markedly elevated the proportion of 18:1n-9, those of 16:1n-7 and 18:1n-7 remained largely unchanged. The oxidation rates of 16:1n-7, 18:1n-9, and 18:1n-7 in liver slices were in the following order: 16:1n-7>18:1n-7≑18:1n-9 in control livers, and were increased by the pharmacological manipulation and decreased by the nutritional manipulation. These results strongly suggest that ß-oxidation, in concert with fatty acid modifications, plays a key role in regulating the MUFA profile and is crucially involved in maintaining low 16:1n-7 levels in the liver.