A case of endocrine carcinoma of the sigmoid colon]

We report a case of endocrine carcinoma of the sigmoid colon. A 71-year-old man was admitted to our hospital because of constipation and bloody stool. Colonoscopy showed a mass lesion with irregular ulceration in the sigmoid colon. He was given a diagnosis of the poorly differentiated adenocarcinoma of the colon, and underwent sigmoidectomy with dissection of the lymph nodes. Histological and immunohistochemical examinations of the resected specimen revealed endocrine carcinoma. Endocrine carcinoma of the colon is rare, and the prognosis is very poor. We discuss this case with references.     

Recent changes in the trends of seasonal influenza outbreaks in the Nagano Prefectural area of Japan: an oseltamivir effect?

We carried out a study to assess the pharmacological role of oseltamivir in the regulation of influenza epidemics in Japan, examining data for the years 1998 to 2006 from Nagano Prefecture. Oseltamivir is effective for the treatment of influenza, and its use in Japan has increased in the 3 years from 2003 to 2006. We found that, in the Nagano Prefectural area, the peak in the number of influenza infections showed a deviation to later periods after the 2003 season. and after 2003, it also took a longer time to reach the end of the seasonal epidemics of influenza infections compared with data from 1998 to 2002. To prevent influenza outbreaks having a long duration, we believe that the period of isolation in patients receiving anti-influenza drugs has to be reconsidered.     

Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging

Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways.Experimental dietary restriction (DR) is based on a 10–30% reduction in food intake without leading to malnutrition (Omodei and Fontana, 2011). DR has been intensively studied and was shown to elongate the lifespan of Caenorhabditis elegans, Drosophila melanogaster, and rats (Fontana et al., 2010). Studies on inbred laboratory mice revealed that DR elongates lifespan in some mouse strains, whereas in others, the effects of DR were neutral or even resulted in lifespan shortening compared with ad libitum (AL)–fed controls (Harper et al., 2006). In long-lived nonhuman primates, two studies reported on the consequences of long-term DR on overall lifespan (Colman et al., 2009; Mattison et al., 2012). In both studies, DR did not result in a significant elongation of the lifespan compared with AL controls when all primates were included in the analysis (Colman et al., 2009; Mattison et al., 2012). These results stand in contrast to multiple studies having unambiguously documented beneficial effects of DR on health parameters and disease prevention in both murine models and primates, including suppression of cancer development, memory loss, hearing impairments, type 2 diabetes, hypertension, and heart disease (Shimokawa et al., 1993; Mattson, 2005; Cohen et al., 2009; Colman et al., 2009; Omodei and Fontana, 2011; Mattison et al., 2012).To better understand the effects of DR on health and lifespan, it is important to characterize the cellular consequences of DR at the level of adult tissue stem cells. Adult stem cells exist in many mammalian organs and tissues. Given that stem cells play essential roles in the maintenance of tissue homeostasis and tissue regeneration after damage, it is believed that age-related changes in stem cell function impact tissue aging (Dorshkind et al., 2009; Jones and Rando, 2011; Goldberg et al., 2015). Indeed, age-related declines in stem cell functionality occur in various tissues (Liu and Rando, 2011). However, the effects of DR on stem cell functionality and aging remain to be characterized in greater detail. It was reported that DR enhances muscle stem cell maintenance and activity to regenerate damaged muscle (Cerletti et al., 2012). In addition, it was shown that DR augments stem cell activity in the intestinal epithelium by stimulating mammalian target of rapamycin complex 1 (mTORC1) signaling in the Paneth cells that form a niche for intestinal stem cells (Yilmaz et al., 2012).In the hematopoietic system, DR ameliorated aging-associated increases in the self-renewal of phenotypic hematopoietic stem cells (HSCs) with reduced functionality as well as defects in the clearance of nonproliferative (senescent) and damaged T lymphocytes (Spaulding et al., 1997a; Chen et al., 1998, 2003; Ertl et al., 2008). However, DR-fed mice exhibited an enhanced susceptibility to infections indicative of impaired immune functions (Peck et al., 1992; Gardner, 2005; Kristan, 2007; Goldberg et al., 2015). Mechanistically, the effects of DR on HSC functionality remain incompletely understood but are influenced by genetic factors (Ertl et al., 2008).In this study, we analyzed the short- and long-term effects of adult-onset 30% DR on the capacity of HSCs and progenitor cells in maintaining hematopoietic repopulation and B lymphopoiesis in C57BL/6J mice. The study provides the first experimental evidence that long-term DR alters the lymphoid cell differentiation potential of HSCs and progenitor cells, resulting in immune defects in the context of prolonged bacterial infection. However, long-term DR from young adulthood to midlife improves the maintenance of the repopulation capacity of HSCs by enhancing stem cell quiescence. The study identifies distinct stress signaling factors (IL-6 and IL-7) and growth factors (insulin-like growth factor 1 [IGF1]) that contribute to both the positive and adverse effects of DR on HSC functionality.     

MiR-200b attenuates IL-6 production through IKKβ and ZEB1 in human gingival fibroblasts

Objective

MicroRNAs (miRNAs) play important roles in biological processes such as cell differentiation, development, infection, immune response, inflammation and tumorigenesis. We previously reported that the expression of miR-200b was significantly increased in inflamed gingiva compared with non-inflamed gingiva. To elucidate the roles of miR-200b in the inflamed gingiva, we have analyzed the effects of miR-200b on the expression of IL-6 in human gingival fibroblasts (HGF).

Materials and methods

Total RNA and protein were extracted from HGF after stimulation by interleukin-1β (IL-1β; 1 ng/ml) or tumor necrosis factor-α (TNF-α; 10 ng/ml) and transfected with miR-200b expression plasmid or miR-200b inhibitor. IL-6, IL-1β, inhibitor of nuclear factor kappa-B kinaseβ (IKKβ), Zinc-finger E-box-binding homeobox 1 (ZEB1) and E-cadherin mRNA and protein levels were analyzed by real-time PCR and Western blot.

Results

IL-1β and TNF-α increased IL-6 mRNA and protein levels, and they were significantly suppressed by miR-200b overexpression, whereas they were further increased by miR-200b inhibitor in HGF. IKKβ and ZEB1 which are target genes of miR-200b negatively regulate E-cadherin. MiR-200b suppressed the expression of IKKβ and ZEB1 and increased E-cadherin mRNA and protein levels in HGF.

Conclusions

These results suggest that miR-200b attenuates inflammatory response via IKKβ and ZEB1 in periodontal tissue.

     

Molecular characterization of a cephamycin-hydrolyzing and inhibitor-resistant class A beta-lactamase, GES-4, possessing a single G170S substitution in the omega-loop

The nosocomial spread of six genetically related Klebsiella pneumoniae strains producing GES-type beta-lactamases was found in a neonatal intensive care unit, and we previously reported that one of the six strains, strain KG525, produced a new beta-lactamase, GES-3. In the present study, the molecular mechanism of cephamycin resistance observed in strain KG502, one of the six strains described above, was investigated. This strain was found to produce a variant of GES-3, namely, GES-4, which was responsible for resistance to both cephamycins (cefoxitin MIC, >128 microg/ml) and beta-lactamase inhibitors (50% inhibitory concentration of clavulanic acid, 15.2 +/- 1.7 microM). The GES-4 enzyme had a single G170S substitution in the Omega-loop region compared with the GES-3 sequence. This single amino acid substitution was closely involved with the augmented hydrolysis of cephamycins and carbapenems and the decreased affinities of beta-lactamase inhibitors to GES-4. A cloning experiment and sequencing analysis revealed that strain KG502 possesses duplicate bla(GES-4) genes mediated by two distinct class 1 integrons with similar gene cassette configurations. Moreover, the genetic environments of the bla(GES-4) genes found in strain KG502 were almost identical to that of bla(GES-3) in strain KG525. From these findings, these two phenotypically different strains were suggested to belong to a clonal lineage. The bla(GES-4) gene found in strain KG502 might well emerge from a point mutation in the bla(GES-3) gene harbored by its ancestor strains, such as strain KG525, under heavy antibiotic stress in order to acquire extended properties of resistance to cephamycins and carbapenems.     

Physiological capacity of the reticuloendothelial system for the degradation of hemoglobin vesicles (artificial oxygen carriers) after massive intravenous doses by daily repeated infusions for 14 days

A hemoglobin vesicle (HbV; diameter 252 +/- 53 nm) or liposome-encapsulated Hb is an artificial oxygen carrier developed for use as a transfusion alternative, and its oxygen-transporting capacity has been well characterized, although critical physiological compartments for the Hb degradation after a massive infusion of HbV and the safety outcome remain unknown. In this study, we aimed to examine the compartments for its degradation by daily repeated infusions (DRI) of HbV, focusing on its influence on the reticuloendothelial system (RES). Male Wistar rats intravenously received the HbV suspension at 10 ml/kg/day for 14 consecutive days. The cumulative infusion volume (140 ml/kg) was equal to 2.5 times the whole blood volume (56 ml/kg). The animals tolerated the DRI well and survived, and body weights continuously increased. One day after DRI, hepatosplenomegaly occurred significantly through the accumulation of large amounts of HbV. Plasma clinical chemistry was overall normal, except for a transient elevation of lipid components derived from HbV. These symptoms subsided 14 days after DRI. Hemosiderin deposition and up-regulation of heme oxygenase-1 coincided in the liver and spleen but were not evident in the parenchyma of these organs. Furthermore, the plasma iron and bilirubin levels remained unchanged, suggesting that the heme-degrading capacity of the RES did not surpass the ability to eliminate bilirubin. In conclusion, phospholipid vesicles for the encapsulation of Hb would be beneficial for heme detoxification through their preferential delivery to the RES, a physiological compartment for degradation of senescent RBCs, even at doses greater than putative clinical doses.     

Assessment of regional wall motion by strain Doppler during biventricular pacing in patients with conventional indications for a pacemaker

Biventricular pacing therapy is effective in patients with severe congestive heart failure. Strain Doppler imaging (SDI) is a new tool for measuring regional myocardial deformation. We evaluated regional wall motion by strain Doppler imaging in 13 patients who had conventional indications for a pacemaker (74 +/- 6 years old) and in six with NYHA Class III or IV heart failure with a biventricular pacemaker (HF-RV: during right ventricular pacing, HF-BV: during biventricular pacing). The other seven patients had normal LV function (N-RV). Wall motion was assessed by strain of the myocardium, and the interval between the Q wave of the surface ECG and the peak strain (QPSI) was measured in three septal and three lateral segments. Interventricular contraction delay was determined as the interval between the onset of the left and right ventricular outflow waves. Intraventricular contraction delay was determined as the time difference between minimum and maximum QPSI. Strain of HF-RV was significantly greater than that of N-RV (-9.6%+/- 2.5% vs -14.4%+/- 2.3%, P < 0.0001). Intraventricular contraction delay of HF-RV was significantly greater than that of N-RV (273 +/- 12 vs 151 +/- 69 ms, P = 0.0004). Strain of HF-RV was not significantly greater than that of HF-BV (-9.6% +/- 2.5% vs -10.6% +/- 2.9%). Interventricular contraction delay of HF-RV was greater than that of HF-BV (37.2 +/- 44.7 vs 16.2 +/- 47.4 ms, P < 0.0001). Intraventricular contraction delay of HF-RV was significantly greater than that of HF-BV (322 +/- 101 vs 209 +/- 88 ms, P = 0.0006). In conclusion, biventricular pacing improves both interventricular contraction delay and intraventricular contraction delay in patients with conventional indications for a pacemaker with severe congestive heart failure, and SDI is useful to predict the efficacy of biventricular pacing.