Gastrointestinal inflammation by gut microbiota disturbance induces memory impairment in mice.

In this study, we tested our hypothesis regarding mechanistic cross-talk between gastrointestinal inflammation and memory loss in a mouse model. Intrarectal injection of the colitis inducer 2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice caused colitis via activation of nuclear factor (NF)-κB and increase in membrane permeability. TNBS treatment increased fecal and blood levels of lipopolysaccharide (LPS) and the number of Enterobacteriaceae, particularly Escherichia coli (EC), in the gut microbiota composition, but significantly reduced the number of Lactobacillus johnsonii (LJ). Indeed, we observed that the mice treated with TNBS displayed impaired memory, as assessed using the Y-maze and passive avoidance tasks. Furthermore, treatment with EC, which was isolated from the feces of mice with TNBS-induced colitis, caused memory impairment and colitis, and increased the absorption of orally administered LPS into the blood. Treatment with TNBS or EC induced NF-κB activation and tumor necrosis factor-α expression in the hippocampus of mice, as well as suppressed brain-derived neurotrophic factor expression. However, treatment with LJ restored the disturbed gut microbiota composition, lowered gut microbiota, and blood LPS levels, and attenuated both TNBS- and EC-induced memory impairment and colitis. These results suggest that the gut microbiota disturbance by extrinsic stresses can cause gastrointestinal inflammation, resulting in memory impairment.

Anti-inflammaging effects of Lactobacillus brevis OW38 in aged mice.

In the present study, lactic acid bacteria (LAB) strains were collected from kimchi and were screened to isolate strains that inhibit lipopolysaccharide (LPS) production by Escherichia coli and p16 expression and nuclear factor-kappa B (NF-κB) activation in LPS-stimulated macrophages. Oral administration of Lactobacillus brevis OW38 (1×109 cfu/mouse) to aged mice (male, 18 months old) for 8 weeks reduced the LPS level in colon fluid and blood. In addition, OW38 treatment also reduced the ratio of Firmicutes or Proteobacteria to Bacteroidetes, which was significantly higher in aged mice than in young mice. Treatment with OW38 in aged mice inhibited the expression of inflammatory markers, such as myeloperoxidase, tumour necrosis factor (TNF), and interleukin (IL)-1ß, and inhibited NF-κB activation. Furthermore, it induced the expression of colonic tight junction proteins zonula occludens-1, occludin, and claudin-1. OW38 treatment also suppressed the expression of senescence markers p16, p53, and SAMHD1 in the colon and the hippocampus of aged mice. In addition, it significantly restored spontaneous alternation as well as the expression of brain-derived neurotrophic factor and doublecortin in aged mice compared to that in young mice (P<0.05). Based on these findings, we conclude that OW38 treatment may ameliorate aging-associated colitis and memory impairment by inhibiting gut microbiota LPS production, NF-κB activation, and p16 expression.

Lactobacillus pentosus var. plantarum C29 ameliorates age-dependent memory impairment in Fischer 344 rats.

UNLABELLED: To understand the anti-inflammaging effect of lactic acid bacteria, we selected NF-κB activation-inhibitory Lactobacillus pentosus var. plantarum C29 and investigated its memory-enhancing and anti-inflammatory effects in aged Fischer 344 rats. C29 (2 × 10(9) CFU rat(-1) ), which was orally administered once a day (6 days per week) for 8 weeks, significantly restored age-reduced spontaneous alternation to 95.2% of that seen in young rats (P < 0.05). C29 treatment also shortened the escape latency on the 4th day to 53.8% of that seen in young rats (P < 0.05). Twenty hours after the last training session, C29 significantly increased the swimming time within the platform quadrant, which was shortened in the aged control rats. Oral administration of C29 restored age-reduced doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) expression and cAMP response element binding protein (CREB) activation in aged rats. Treatment of aged rats with C29 suppressed the expression of p16, cyclooxygenase-2, and inducible nitric oxide synthase, as well as the activation of Akt, mTOR, and NF-κB in the hippocampus. These findings suggest that C29 ameliorates ageing-dependent memory impairment by inhibiting NF-κB signalling pathway, inducing DCX and BDNF expression and activating CREB. SIGNIFICANCE AND IMPACT OF THE STUDY: The anti-inflammatory Lactobacillus pentosus var. plantarum C29 had the memory-enhancing effect in aged Fischer 344 rats by restoring doublecortin and brain-derived neurotrophic factor expression and suppressing p16 expression and NF-κB activation in the brain. Therefore, C29 may be useful in ameliorating age-related degenerative dementia.

p47phox and reactive oxygen species production modulate expression of microRNA-451 in macrophages.

The production of microRNAs (miRNA) is influenced by various stimuli, including environmental stresses. We hypothesized that reactive oxygen species (ROS)-associated stress could regulate macrophage miRNA synthesis. miRNAs undergo unique steps of maturation processing through either one of two pathways of cytoplasmic processing. Unlike the canonical pathway, the regulation of alternative cytoplasmic processing of miRNA has not been fully elucidated yet. We cultured bone marrow derived macrophages (BMDM) from wild type (WT) and p47(phox-/-) mice and profiled miRNA expression using microarrays. We analyzed 375 miRNAs including four endogenous controls to normalize the data. At resting state, p47(phox-/-) BMDM has the markedly reduced expression of miR-451 compared to WT BMDM, without other significant differences. Unlike majority of miRNAs, miR-451 goes through the unique alternative processing pathway, in which Ago2 plays a key role. In spite of significant reduction of mature miR-451, however, its precursor form, pre-mir-451, was similar in both BMDMs, suggesting that the processing of pre-mir-451 is impaired in p47(phox-/-) BMDM. Moreover, p47(phox-/-) BMDM expressed significantly reduced level of Ago2. In contrast, Ago2 mRNA levels were similar in WT and p47(phox-/-) BMDM, suggesting a post-transcriptional defect of Ago2 production in p47(phox-/-) macrophages, which resulted in impaired processing of pre-miR-451. In order to examine the functional significance of miR-451 in macrophages, we cultured BMDMs from miR-451 knock-out mice. Of interest, miR-451-deficient BMDM exhibited reduced ROS generation upon zymosan stimulation, compared to WT BMDM. Our studies suggest functional crosstalk between ROS and miR-451 in the regulation of macrophage oxidant stress.

Dose-dependent attenuation by fentanyl on cough during emergence from general anesthesia.

BACKGROUND: Although fentanyl suppresses tracheal tube-induced cough during anesthetic recovery, it has not been proven if its antitussive effect is dose dependent and complication free. The purpose of this study is to evaluate the relationship between fentanyl doses and cough suppression during emergence from sevoflurane anesthesia. METHODS: Sixty patients undergoing thyroidectomy were randomly allocated to one of four groups (F0, F1, F1.5, and F2) according to the fentanyl dose (0 mcg/kg, 1 mcg/kg, 1.5 mcg/kg, or 2 mcg/kg). Fentanyl was administered immediately after sevoflurane discontinuation. Coughing was assessed throughout the periextubation period. The relationship between fentanyl dose and incidence of cough was analyzed using Cochran-Armitage trend test. Incidence of more than 30% elevation of mean arterial pressure (MAP) and heart rate (HR), awakening time, extubation time, and respiratory rate after extubation were recorded and compared using Mantel-Haenszel chi-square test and one-way analysis of variance. RESULTS: Fentanyl suppressed emergence cough in a dose-related manner (P = 0.002), and the ED(50) and ED(90) were 1.1 mcg/kg and 2.1 mcg/kg, respectively. The higher dose of fentanyl further reduced the number of patient with MAP and HR elevation (P = 0.003 and 0.005, respectively). Awakening time (8.4 ± 1.9 min) in F2 was comparable with that in F1 and F1.5. Respiratory rate (9 ± 2 bpm) and extubation time (11.9 ± 1.8 min) in F2 were only different from those in F0 (13 ± 3 bpm and 10.4 ± 1.1 min, respectively). CONCLUSIONS: Fentanyl suppressed cough in a dose-related manner during recovery from general sevoflurane anesthesia, and 2 mcg/kg may be considered as a proper dose.

Distal metatarsal osteotomy for hallux varus following surgery for hallux valgus.

We reviewed the outcome of distal chevron metatarsal osteotomy without tendon transfer in 19 consecutive patients (19 feet) with a hallux varus deformity following surgery for hallux valgus. All patients underwent distal chevron metatarsal osteotomy with medial displacement and a medial closing wedge osteotomy along with a medial capsular release. The mean hallux valgus angle improved from -11.6° pre-operatively to 4.7° postoperatively, the mean first-second intermetatarsal angle improved from -0.3° to 3.3° and the distal metatarsal articular angle from 9.5° to 2.3° and the first metatarsophalangeal joints became congruent post-operatively in all 19 feet. The mean relative length ratio of the metatarsus decreased from 1.01 to 0.99 and the mean American Orthopaedic Foot and Ankle Society score improved from 77 to 95 points. In two patients the hallux varus recurred. One was symptom-free but the other remained symptomatic after a repeat distal chevron osteotomy. There were no other complications. We consider that distal chevron metatarsal osteotomy with a medial wedge osteotomy and medial capsular release is a useful procedure for the correction of hallux varus after surgery for hallux valgus.

Differential effects of lidocaine and remifentanil on response to the tracheal tube during emergence from general anaesthesia.

BACKGROUND: I.V. lidocaine administration and target-controlled infusion (TCI) of remifentanil may each be used to reduce cough and haemodynamic stimulation during emergence from general anaesthesia. We therefore compared the effects of these two treatments on patients' responses to the tracheal tube during recovery from general anaesthesia after thyroid surgery. METHODS: Seventy female patients undergoing thyroidectomy under general anaesthesia using sevoflurane and remifentanil were randomly assigned to i.v. lidocaine (Group L, n=35) or remifentanil by TCI (Group R, n=35). At the end of surgery, sevoflurane was turned off, and the remifentanil infusion was stopped in Group L and maintained in Group R at an effect-site concentration of 2.0 ng ml(-1) until extubation. At the same time, i.v. lidocaine 1.5 mg ml(-1) was administered in Group L. The incidence and severity of cough, haemodynamic parameters, and recovery profiles were evaluated during the emergence. RESULTS: The incidence of cough during the emergence was significantly higher in Group L than in Group R (72.7% vs 20.6%, P<0.001) and so was the grade of cough (P<0.001). The mean arterial pressure and heart rate were significantly lower in the R group than in the L group during the emergence period (P<0.05), although the two groups showed comparable recovery profiles. CONCLUSIONS: TCI of remifentanil reduces responsiveness to the tracheal tube during emergence from general anaesthesia more effectively than does i.v. lidocaine in female patients undergoing thyroid surgery.

Incidence and clinical behavior of papillary thyroid carcinoma in renal allograft recipients: a single center experience.

The chronic use of immunosuppressive therapy in transplant recipients increases the long-term risk for carcinoma. However, there is insufficient knowledge regarding the incidence and biological behavior of papillary thyroid carcinomas (PTC) in renal allograft recipients. In the present study we examined the incidence and biological behavior of PTCs among 1739 patients transplanted between January 1986 and December 1999 who had been followed for a mean period of 137 months (range, 84-238 months). During the follow-up, 129 (7.4%) recipients were identified to display posttransplantation malignancies, including 12 (0.7%) with PTCs. The 6 male and 6 female patients had a mean age of 41 years (range, 23-57 years). Nine cases (incidentalomas) were diagnosed based on ultrasonographic (US) screening. Eight of those 9 were TNM stage I, 2 of the 3 clinical carcinomas were TNM stage IVa. During a mean follow-up of 94 months (range, 18-159 months), 2 (16.7%) PTC patients developed locoregional recurrence, but no patients showed distant metastases. These data showed that recipients had a higher incidence of PTC compared with the general Korean population (0.7% vs 0.02%). Posttransplantation PTC tended to show no difference in gender distribution, and was often associated with aggressive lymphatic metastasis. However, most incidentalomas showed favorable treatment outcomes. In conclusion, routine surveillance of the thyroid gland using US screening is recommended to ensure early detection, treatment, and favorable prognosis of PTC.