c-MIR,a human E3 ubiquitin ligase,is a functional homolog of herpesvirus proteins MIR1 and MIR2 and has similar activity

Kaposi's sarcoma associated-herpes virus encodes two proteins, MIR (modulator of immune recognition) 1 and 2, which are involved in the evasion of host immunity. MIR1 and 2 have been shown to function as an E3 ubiquitin ligase for immune recognition-related molecules (e.g. major histocompatibility complex class I, B7-2, and ICAM-1) through the BKS (bovine herpesvirus 4, Kaposi's sarcoma associated-herpes virus, and Swinepox virus) subclass of plant homeodomain (PHD) domain, termed the BKS-PHD domain. Here we show that the human genome also encodes a novel BKS-PHD domain-containing protein that functions as an E3 ubiquitin ligase and whose putative substrate is the B7-2 co-stimulatory molecule. This novel E3 ubiquitin ligase was designated as c-MIR (cellular MIR) based on its functional and structural similarity to MIR1 and 2. Forced expression of c-MIR induced specific down-regulation of B7-2 surface expression through ubiquitination, rapid endocytosis, and lysosomal degradation of the target molecule. This specific targeting was dependent upon the binding of c-MIR to B7-2. Replacing the BKS-PHD domain of MIR1 with the corresponding domain of c-MIR did not alter MIR1 function. The discovery of c-MIR, a novel E3 ubiquitin ligase, highlights the possibility that viral immune regulatory proteins originated in the host genome and presents unique functions of BKS-PHD domain-containing proteins in mammals.     

The effects of alphaGalCer-induced TCRValpha24 Vbeta11(+) natural killer T cells on NK cell cytotoxicity in umbilical cord blood

Purpose The first objective of this study was to investigate in vitro effects of -galactosylceramide (GalCer) on the proliferation of umbilical cord blood (UCB) natural killer T (NKT) cells and enhancement of their cytotoxicity. The second one is to examine whether purified NKT cells could affect the cytotoxicity of UCB-NK cells either in the presence or absence of dendritic cells (DCs).Methods Mononuclear cells (MNCs) from UCB were cultured for 2 weeks in the presence of IL-2 (100 U/ml), with or without GalCer. The effect of neutralizing monoclonal antibodies (MoAb) against TCRV24 and CD1d was also examined. TCRV24 V11 double positive NKT cells were purified by FACS sorter and then cocultured with syngeneic isolated UCB^–CD56⁺NK cells in either the presence or absence of DCs. The cytotoxicity against various malignant cell targets and cytokine production was determined.Results The addition of GalCer induced human NKT cells to proliferate in UCB-MNCs to a greater extent than in adult PB-MNCs. However, it suppressed the cytotoxic activity against malignant cell targets. Anti-TCRV24 and CD1d MoAb recovered the cytotoxicity by inhibiting the proliferation of UCB-NKT cells. NKT cells cocultured with auto-DCs significantly increased NK cell cytotoxicity against K562, and Raji cells and produced IFN- at much higher levels than UCB-NKT cells alone.Conclusion In UCB samples, GalCer–pulsed DCs and NKT cells acted together to enhance NK cytotoxicity in vitro.     

Effects of selective cyclooxygenase-2 inhibitor and non-selective NSAIDs on Helicobacter pylori-induced gastritis in Mongolian gerbils

Background. It is still a point of controversy whether Helicobacter pylori‐infected patients are more likely to develop mucosal damage while taking NSADIs. Selective cyclooxygenase (COX‐2) inhibitors may be associated with less severe gastric mucosal damage than conventional NSAIDs, but this association is undefined in H. pylori‐induced gastritis. The aim of this study was to evaluate the effects of selective COX‐2 and nonselective NSAIDs on H. pylori‐induced gastritis. Methods. After intragastric administration of indomethacin, NS‐398 or vehicle alone, once daily for 5 days in H. pylori‐infected and uninfected Mongolian gerbils, we evaluated gastric mucosal damage, inflammatory cell infiltration and prostaglandin E₂ (PGE₂) concentration. We investigated whether H. pylori infection induced the COX‐2 expression. Results. In H. pylori‐uninfected groups, the indomethacin‐treated group showed the highest mucosal damage score and the lowest PGE₂ concentration. There was no difference in mucosal damage scores and PGE₂ concentration between NS‐398 and vehicle‐alone treated group. In H. pylori‐infected groups, there was no difference in mucosal damage scores, irrespective of the type of drugs administered. The indomethacin‐treated group showed the lowest PGE₂ concentration, similar to that of the NS‐398 and vehicle‐alone treated groups, both without H. pylori infection. Gastric neutrophil and monocyte infiltration scores were higher in H. pylori‐infected groups than in uninfected groups. However, there was no difference in these scores according to the type of drugs administered, within H. pylori‐infected or uninfected groups. COX‐2 protein expression was observed in H. pylori‐infected Mongolian gerbils but not in uninfected ones. Conclusions. Our animal study showed that H. pylori infection induced COX‐2 expression and increased prostaglandin concentration. Administration of NSAIDs decreased the prostaglandin concentration, but did not increase mucosal damage in H. pylori‐induced gastritis. Selective COX‐2 inhibitors, instead of conventional NSIADs, had no beneficial effect on preventing mucosal damage in H. pylori‐induced gastritis.     

Platelets, after exposure to a high shear stress, induce IL-10-producing, mature dendritic cells in vitro

There is evidence for immune system involvement in atherogenesis. In the present study the effect of platelets on dendritic cells (DC), an important immunologic regulator, was examined in vitro. Platelet-rich plasma, after exposure to shear stress, was added to human monocyte-derived immature DC, which were then examined for surface Ag expression, allogeneic T lymphocyte stimulatory activity, and cytokine production. After exposure, the number of anti-CD40 ligand (anti-CD40L) and anti-P-selectin IgG molecules bound per platelet was increased. These activated platelets induced DC maturation, as revealed by significant up-regulation of CD83, CD80, and CD86 Ags. The addition of platelets in the presence of IFN-gamma plus LPS significantly enhanced IL-10 production from immature DC. After platelet addition, mature DC provoked a significant proliferation of allogeneic naive T lymphocytes. These activated T cells showed lower IFN-gamma production than those stimulated by LPS- and IFN-gamma-treated DC. CD40L on the platelet surface was not involved in maturation of DC, as mAb to CD40L failed to block maturation. The effect of platelets was observed even if platelets and DC were separated using large pore-sized membranes or when platelets were depleted from plasma by centrifugation. Furthermore, it was abrogated after the depletion of protein fraction. Thus, soluble protein factors excreted from activated platelets contribute to IL-10-producing DC maturation.     

Ultrasound-assisted lipoplasty treatment for axillary bromidrosis: clinical experience of 375 cases

Bromidrosis is a condition of abnormal offensive body odor caused mostly by apocrine gland secretion from the axilla. Although no morbid sequelae are known, the odor can be disturbing enough to cause social impairment and psychological distress. Medical care is available but is temporary and yields limited clinical benefit. Surgical treatment may provide a more definite remedy through reduction of the apocrine gland. However, there are risks for complication following surgical treatment such as subdermal excision, subcutaneous shaving, en bloc excision, and liposuction. The search for a less invasive but still effective procedure has led the authors to use ultrasound-assisted liposuction, which has reduced the risk of complication and recurrence. The purpose of this article was to evaluate the long-term outcome of ultrasound-assisted liposuction for the treatment of bromidrosis. From August 1998 to September 2002, 375 consecutive patients underwent ultrasound-assisted liposuction for bromidrosis of the axilla. The average age of the patients was 25.7 years (range, 15 to 55 years) and the average follow-up period was 18.8 months (range, 7 to 56 months). Subjective complaints of recurrences were noted in 22 patients (5.9 percent) and secondary ultrasound-assisted liposuction was performed, resulting in no further complaints. Complications other than recurrences were mild skin sloughing (3.2 percent), hematoma (1.3 percent), subcutaneous band (0.3 percent), and hypesthesia of the hand (0.3 percent), all of which healed spontaneously. Through a questionnaire that was answered by 264 patients, a subjective satisfaction rate was measured. Among the completed questionnaires, 91.7 percent reported satisfactory reduction of odor. Ultrasound-assisted liposuction to treat bromidrosis of the axilla provides advantages such as rapid recovery, less restriction of movement, unnoticeable scars, and a low rate of recurrence. The long-term outcome supports the benefits of this procedure. The authors recommend the use of ultrasound-assisted liposuction as first-line treatment for bromidrosis of the axilla.     

Contamination of river water by Cryptosporidium parvum oocysts in western Japan

In Japan, only a few rivers have been inspected for Cryptosporidium parvum contamination, and the methods used had low sensitivity. In 1998 and 1999, we used a method with higher sensitivity to examine all large rivers used as sources of water supply in one prefecture (which we divided into four areas) in western Japan for Cryptosporidium oocysts. One sample was collected at each of 156 sites along 18 rivers, and samples were tested for Cryptosporidium oocysts by immunomagnetic separation. Samples were classified as being obtained on an island with livestock and fishing industries, a densely populated urban area, a western region including farming villages, or a still more rural northern area with agriculture and fishing. Restriction fragment length polymorphism analysis was used for identification of the C. parvum found as the bovine or human type. C. parvum was detected in at least one sample from 13 of the 18 rivers and in 47% (74 of 156) of the samples. One-third to all of the samples from each area contained C. parvum oocysts. The number of C. parvum oocysts per 20 liters of river water varied in the same pattern as the number of cattle kept in the four kinds of areas (as determined by the Mantel extension test). Oocysts isolated were of the bovine type; the C. parvum detected in rivers probably came from cattle kept in that valley. As we had expected, when tested with a more sensitive method, river water in western Japan was found to be greatly contaminated with C. parvum oocysts, as reported in other countries.     

Thermoregulatory responses to low-intensity prolonged swimming in water at various temperatures and treadmill walking on land

The purpose of the present study was to examine the effect of water temperature on the human body during low-intensity prolonged swimming. Six male college swimmers participated in this study. The experiments consisted of breast stroke swimming for 120 minutes in 23 degrees C, 28 degrees C and 33 degrees C water at a constant speed of 0.4 m.sec-1 in a swimming flume. The same subjects walked on a treadmill at a rate of approximately 50% of maximal oxygen uptake (VO2max) at the same relative intensity as the three swimming trials. Rectal temperature (Tre) in 33 degrees C water was unchanged during swimming for 120 minutes. Tre during treadmill walking increased significantly compared to the three different swimming trials. Tre, mean skin temperature (Tsk) and mean body temperature (Tb) in 23 degrees C and 28 degrees C water decreased significantly more than in both the 33 degrees C water and walking on land. VO2 during swimming in 23 degrees C water increased more than during swimming in the 28 degrees C and 33 degrees C trials; however, there were no significant differences in VO2 between the 23 degrees C swimming trial and treadmill walking. Heart rate (HR) during treadmill walking on land increased significantly compared with HR during the three swimming trials. Plasma adrenaline concentration at the end of the treadmill walking was higher than that at the end of each of the three swimming trials. Noradrenaline concentrations at the end of swimming in the 23 degrees C water and treadmill walking were higher than those during the other two swimming trials. Blood lactate concentration during swimming in 23 degrees C water was higher than that during the other two swimming trials and walking on land. These results suggest that the balance of heat loss and heat production is maintained in the warm water temperature. Therefore, a relatively warm water temperature may be desirable when prolonged swimming or other water exercise is performed at low intensity.