Preferentially expanding Vγ1+ γδ T cells are associated with protective immunity against Plasmodium infection in mice

γδ T cells play a crucial role in controlling malaria parasites. Dendritic cell (DC) activation via CD40 ligand (CD40L)‐CD40 signaling by γδ T cells induces protective immunity against the blood‐stage Plasmodium berghei XAT (PbXAT) parasites in mice. However, it is unknown which γδ T‐cell subset has an effector role and is required to control the Plasmodium infection. Here, using antibodies to deplete TCR Vγ1⁺ cells, we saw that Vγ1⁺ γδ T cells were important for the control of PbXAT infection. Splenic Vγ1⁺ γδ T cells preferentially expand and express CD40L, and both Vγ1⁺ and Vγ4⁺ γδ T cells produce IFN‐γ during infection. Although expression of CD40L on Vγ1⁺ γδ T cells is maintained during infection, the IFN‐γ positivity of Vγ1⁺ γδ T cells is reduced in late‐phase infection due to γδ T‐cell dysfunction. In Plasmodium‐infected IFN‐γ signaling‐deficient mice, DC activation is reduced, resulting in the suppression of γδ T‐cell dysfunction and the dampening of γδ T‐cell expansion in the late phase of infection. Our data suggest that Vγ1⁺ γδ T cells represent a major subset responding to PbXAT infection and that the Vγ1⁺ γδ T‐cell response is dependent on IFN‐γ‐activated DCs.     

Intradiscal pressure after intradiscal injection of hypertonic saline: an experimental study

Although chemonucleolysis with chymopapain is a long-established treatment for lumbar intervertebral disc herniation, serious complications have been reported. Accordingly, alternative substances for chemonucleolysis have been sought. The main beneficial effect of chemonucleolysis derives from the decrease in intradiscal pressure. Several previous studies have investigated the relationship between physiological saline injection and disc mechanics in cadaveric specimens [2, 5, 16]. However, no previous study has assessed the intradiscal pressure after intradiscal injection of “hypertonic saline” in living animals. The present study compared the changes in intradiscal pressure after intradiscal injection of hypertonic saline with those after chymopapain injection. The lumbar intervertebral discs of 26 living rabbits were examined: 10% hypertonic saline was injected in ten rabbits, and chymopapain (10 pikokatal units) was injected intradiscally in another ten, with the remaining six being used as controls. The intradiscal pressure was measured at 1, 4, and 12 weeks after injection. The intradiscal pressure of the hypertonic saline-injected group at 4 weeks was significantly lower than that of the control group, but by 12 weeks it had recovered. On the other hand, that of the chymopapain-injected group remained significantly lower than that of the control group at 12 weeks. The results of this study found that hypertonic saline injected into the intervertebral discs temporarily decreased the intradiscal pressure. Received: 26 July 1999 Revised: 26 November 1999 Accepted: 22 December     

Complexation of fluoxetine hydrochloride with beta-cyclodextrin. A proton magnetic resonance study in aqueous solution

A proton magnetic resonance spectroscopic study in D2O of mixtures of fluoxetine hydrochloride (guest) with beta-cyclodextrin (host) revealed the existence of two different equilibria for 1:1 inclusion complexes in which -CF3 substituted ring of the guest is more tightly held by the host cavity. The structures of the two complexes have been proposed which are supported by 2DROESY spectral data. The dissociation constant was also determined.     

Nutritional intakes in community-dwelling older Japanese adults: high intakes of energy and protein based on high consumption of fish, vegetables and fruits provide sufficient micronutrients

The purpose of this study was to obtain detailed data on the dietary intake of energy, macronutrients, and micronutrients, especially minerals and vitamins, of healthy free-living people over the age of 70 in Japan and to clarify the correlations among nutrient intakes. The survey was conducted in November 2001 for 57 persons (men: 31, women: 26) aged 74 y (born in 1927) living in Niigata City, Japan. A precise weighing method was used to record food intake for three consecutive days. Nutrient intake was calculated based on the Standard Tables of Food Composition in Japan (5th ed.). The intakes of energy and total protein were 44.8+/-7.7 kcal/kg/d and 1.80+/-0.35 g/kg/d for men and 38.1+/-7.6 kcal/ kg/d and 1.51+/-0.26 g/kg/d for women. These values are significantly higher than those proposed by the current Recommended Dietary Allowances (RDAs) and the data by the 2001 National Nutrition Survey in Japan. The energy intake ratios from protein, carbohydrate and fat for men were 16 : 58 : 22, respectively, and the residual part was alcohol. For women, the ratios were 16 : 62 : 22. The proportion of total protein intake that consisted of animal protein was 57.8% for men and 52.8% for women. For both sexes, all of the mean daily intakes of nine minerals and 12 vitamins were higher than those prescribed for elderly Japanese people (> or =70 y) in the RDAs. Significant strong correlations were found between total protein intake and intakes of vitamins D, B2 and B6, as well as niacin and pantothenic acid (p<0.0001). Among the nine minerals, the correlations were very strong between potassium and magnesium, calcium and phosphorus, magnesium and iron, magnesium and copper, iron and copper, and zinc and copper (r's>0.700). For vitamins, strong correlations were found between vitamin A and folic acid, vitamin B2 and pantothenic acid, and folic acid and pantothenic acid. Furthermore, strong relationships were observed between potassium and folic acid, potassium and pantothenic acid, potassium and dietary fiber, phosphorus and vitamin B2, phosphorus and pantothenic acid, iron and folic acid, zinc and vitamin B12, and copper and vitamin B12. From these results, it is evident that age is not an important determinant of dietary intake among apparently healthy elderly Japanese people aged 74 y. In addition, the high intake of energy and protein in the Japanese dietary pattern, based upon high consumption of fish and/or shellfish, vegetables, and fruits, provide sufficient minerals and vitamins.     

FDA's decisions in oncology drug product approvals from 2006 to 2016

Objective

Under the circumstances that several oncology drugs have been approved under expedited programs in the US, this study aimed to analyze the relationship between the expedited programs and characteristics of approvals in the recent decade, and the attitude of the Food and Drug Administration (FDA) toward the development and review of oncology drugs.

Kefiran suppresses antigen-induced mast cell activation

Kefir is a traditional fermented milk beverage produced by kefir grains in the Caucasian countries. Kefiran produced by Lactobacillus kefiranofaciens in kefir grains is an exopolysaccharide having a repeating structure with glucose and galactose residues in the chain sequence and has been suggested to exert many health-promoting effects such as immunomodulatory, hypotensive, hypocholesterolemic activities. Here we investigated the effects of kefiran on mast cell activation induced by antigen. Pretreatment with kefiran significantly inhibited antigen-induced Ca(2+) mobilization, degranulation, and tumor necrosis factor-α production in bone marrow-derived mast cells (BMMCs) in a dose-dependent manner. The phosphorylation of Akt, glycogen synthase kinase 3β, and extracellular signal-regulated kinases (ERKs) after antigen stimulation was also suppressed by pretreatment of BMMCs with kefiran. These findings indicate that kefiran suppresses mast cell degranulation and cytokine production by inhibiting the Akt and ERKs pathways, suggesting an anti-inflammatory effect for kefiran.     

Mitochondria Take Up Ca²⁺ in Two Steps Dependently on Store-Operated Ca²⁺ Entry in Mast Cells

The ability of mitochondria to take up Ca²⁺ has important functional implications for modulation of cellular Ca²⁺ signaling. Mitochondrial Ca²⁺ uptake is stimulated by an increase in cytosolic Ca²⁺ concentration ([Ca²⁺]c). Here, we found that the increase in mitochondrial Ca²⁺ concentration ([Ca²⁺]m) occurs in two steps in a single antigen-activated mast cell in the presence of extracellular Ca²⁺ (1.0?mM). The two-step elevation of [Ca²⁺]m was also observed after adding thapsigargin, an inhibitor of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase. The proportion of mitochondria showing the two-step Ca²⁺ elevation dropped off in direct accord with decrease in extracellular Ca²⁺ concentration. The second step of the [Ca²⁺]m increase was suppressed significantly in the absence of extracellular Ca²⁺ and in knockdown cells of stromal interaction molecule 1 (STIM1), an essential molecule on endoplasmic reticulum (ER) membrane for store-operated Ca²⁺ entry, in the presence of extracellular Ca²⁺ (1.0?mM), while the first elevation was not affected in either case. The results indicate that mitochondria take up cytosolic Ca²⁺ in two steps; first and second uptakes are derived from the Ca²⁺ release from ER and the Ca²⁺ influx through store-operated Ca²⁺ channels, respectively. Additionally, rotenone and antimycin A, which are inhibitors of mitochondrial electron transport complex I and III, respectively, diminished mitochondrial Ca²⁺ uptake and significantly suppressed degranulation stimulated with antigen. The mitochondrial Ca²⁺ uptake may modulate mast cell function by regulating the [Ca²⁺]c.     

Sex Differences in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Heart: The Role of Estrogen Against Myocardial Ischemia-reperfusion Damage Via an NO-mediated Mechanism

ABSTRACT:: The purpose of this study is to elucidate the relationship between sex difference and norepinephrine (NE) release in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Isolated male and female rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. Compared with male hearts, I/R-induced cardiac dysfunction, such as decreased left ventricular developed pressure and dP/dtmax and increased left ventricular end diastolic pressure, was significantly attenuated in female hearts. An excessive NE overflow in the coronary effluent from the postischemic heart in females was much less than that in males. These sex differences were abolished by ovariectomy, but in vivo treatment with 17β-estradiol recovered it. This ameliorating effect of 17β-estradiol was not observed in the presence of nitric oxide (NO) synthase inhibitor N-nitro-L-arginine. When NOx (NO2/NO3) levels in the coronary effluent after onset of reperfusion were measured, reversed correlated relationships between NOx production and I/R-induced cardiac dysfunction, and NE overflow, were observed. These findings suggest that sex differences in the postischemic cardiac dysfunction are closely related to the NE overflow from the postischemic heart and that estrogen plays a key role in the cardioprotective effect against I/R injury in female rats, by suppressing NE release via the enhancement of NO production.     

Synergistic effects of (-)-epigallocatechin gallate with sulindac against colon carcinogenesis of rats treated with azoxymethane.

(-)-Epigallocatechin gallate (EGCG), a major constituent of green tea, has been shown to exhibit anti-cancer activity. Sulindac is also well known as a cancer-preventive agent against colon cancer, but its usage is restricted because of its adverse effects, as exemplified by gastrointestinal bleeding. In the present study, we examined whether a combination of EGCG and sulindac shows synergistic effects for cancer-preventive activity for rat colon carcinogenesis induced by azoxymethane (AOM); we examined the number of aberrant crypt foci (ACF) representing preneoplastic lesions, the argyrophilic nucleolar organizer region (AgNOR) as an indicator of cell proliferation, and the incidence of apoptosis. The AOM treatment induced an average of 46.2+/-4.9 ACF/colon, and sulindac and EGCG significantly reduced the incidence of ACF/colon to 21.4+/-3.4 and 19.5+/-5.8, respectively (P<0.01). The co-treatment with EGCG and sulindac resulted in significantly reduced ACF formation (10.0+/-3.2; P<0.01). The results of the AgNOR analysis indicated that the treatment with EGCG and/or sulindac suppressed AOM-induced cell proliferation. The present results also revealed that the combination of EGCG and sulindac synergistically enhanced apoptosis significantly (P<0.01). Thus, our findings suggest that EGCG with sulindac synergistically suppresses ACF formation by enhancing apoptosis and, therefore, that EGCG is a suitable candidate for use in combination with cancer-preventive agents, such as sulindac, to reduce their adverse effects.