Regulation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor expression in human neutrophils

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily, which is capable of inducing apoptosis in many cell types, including tumour and virus-infected cells, but rarely in normal cells. Expression of TRAIL mRNA and TRAIL receptors has previously been detected in neutrophils; however, the expression of TRAIL protein and the regulation of TRAIL and TRAIL receptor expression in these cells remain unknown. Here we report, for the first time, that neutrophils constitutively express TRAIL protein on their cell surface and that the TRAIL protein is shed during culture. TNF-alpha is a down-regulator of TRAIL expression, whereas IFN-gamma up-regulates the expression of TRAIL. Neutrophils did not express a detectable level of TRAIL-R1 or -R4, but constitutively expressed a low, but substantial, level of TRAIL-R2 and a high level of TRAIL-R3. Although the level of TRAIL-R2 was not significantly altered during culture under different experimental conditions, approximately 30% of TNF-alpha-treated cells rapidly lost their high-level TRAIL-R3 expression, whereas the majority of IFN-gamma-treated cells retained a high level of TRAIL-R3 expression. Anti-TRAIL neutralizing antibody significantly inhibited neutrophil apoptosis during cultures in medium alone, or in the presence of TNF-alpha or IFN-gamma. Thus, our study identified human neutrophils as a cellular source of TRAIL and suggests that neutrophil-derived TRAIL may play a role in immune surveillance. Our results also suggest a role for the TRAIL/TRAIL receptor system in neutrophil apoptosis.     

A LIGHT- AND ELECTRON-MICROSCOPIC STUDY OF THE SO-CALLED UNI-VISCERAL SHWARTZMAN REACTION

A morphological study was made on a particular model of Shwartzman reaction which was so designed as to occur mainly in the liver with minimal influence to the other parts of the body. The study was mainly focused on its mechanism; the role of the granulocytes, Kupffer cells, platelets and precipitated fibrin. It was revealed that Kupffer cells were severely damaged by the first, preparative injection and the most conspicuous finding after the second, provocative injection was marked granulocytic infiltration followed by massive hepatic cell necrosis. The infiltrating granulocytes sticked to the endothelium, degenerated Kupffer cells, or other granulocytes and, often aggregated around precipitated fibrin. The erythrocytes in the sinusoid also showed aggregation after the provocative injection of the endotoxin, which was, however, rather loose and easily washed out from the sinusoid by perfusion. It is suggested from the above observations that aggregation of granulocytes as well as precipitated fibrin plays an important role to disturb blood stream mechanically and leads to massive necrosis in the liver.     

Maternal Quercetin Consumption during Pregnancy May Help Regulate Total Cholesterol/HDL-Cholesterol Ratio without Effect on Cholesterol Levels in Male Progeny Consuming High-Fat Diet

Quercetin has been shown to have anti-obesity effects, but it is unknown whether these effects can be transmitted from mothers to their progeny. In this study, we investigated whether maternal quercetin consumption during pregnancy has a protective effect on high-fat diet–induced hyper lipid levels and overweight in progeny. Female mice consumed a control diet or a diet containing 1.0% quercetin during breeding. The male progeny were then divided into four groups that were (1) sacrificed at postnatal day 3; (2) born to dams fed the control diet and also fed the control diet (C-C), (3) born to dams fed the control diet and then fed a 30% high-fat diet (C-HF), or (4) born to dams fed the Q-diet and then fed the HF diet (Q-HF). Maternal consumption of quercetin did not affect body weight or blood lipid parameters in either dams or neonates at postnatal day 3. After 13 weeks, the Q-HF group exhibited greater body and liver weights, and higher blood cholesterol levels than the C-HF group. However, the total cholesterol/ high density lipoprotein (HDL)-cholesterol ratios in the Q-HF and C-C groups remained similar. In conclusion, maternal quercetin consumption does not appear to protect the next generation from high-fat diet–induced hyper cholesterol level in the blood and liver, and consequently overweight, but may help regulate the total cholesterol/HDL-cholesterol ratio.     

Angiosarcoma of the breast: Report of a case and autopsy findings

We report a case of angiosarcoma of the breast and the autopsy findings. The patient was a 35-year-old premenopausal woman who complained of a tumor in her left breast. We found a tumor measuring 55 mm in diameter in the lower external quadrant. The tumor was elastic and soft, smooth surfaced, well-defined and mobile. Dimpling sign or change of skin color were not observed. Clinically it was diagnosed as phyllodes tumor, but tumorectomy revealed primary angiosarcoma of the breast. Further extended surgery was recommended, but the patient refused additional therapy. Histological findings revealed a free surgical margin and neither lymph node metastasis nor distant metastasis were clinically observed. Seven months later, local recurrence in the same breast was recognized and finally radical mastectomy was carried out. Histological findings showed recurrence of angiosarcoma in the left breast but lymph node metastasis was not detected. Two months after mastectomy, metastases to the cervical and thoracic vertebrae were observed and radiation therapy was performed. Sixteen months from onset, she died due to multi-organ failure as general metastases of angiosarcoma. At autopsy, metastases to many organs including the digestive system were observed. The incidence of primary angiosarcoma of the breast is low but its prognosis is poor. This case emphasized the difficulties in clinical diagnosis and treatment for the angiosarcoma of the breast.     

The development of a small bowel volvulus in the early postoperative period following a distal gastrectomy: Report of a case

A 51-year-old Japanese man who underwent a standard distal gastrectomy for cancer of the stomach developed abdominal pain when oral intake was commenced on the 6th postoperative day after an uneventful postoperative course. Complete obstruction of the jejunum led to a sudden deterioration in his general condition and a laparotomy was performed, revealing counterclockwise rotation of the mesenterium. The necrotic portion of the small intestine was removed, while 10 cm of the upper jejunum and 100 cm of the terminal ileum were preserved. His second postoperative course was uneventful apart from the development of intestinal hurry, which is now under medical control 9 months after his second laparotomy.     

Nocturnal eating/drinking syndrome and neuroleptic-induced restless legs syndrome

Nocturnal eating/drinking syndrome secondary to neuroleptic-induced restless legs syndrome (RLS) occurred under treatment with low-dose haloperidol in a 51-year-old female schizophrenic patient. Polysomnographic investigation showed a low level of sleep efficacy, periodic leg movements, and a strict relationship between nocturnal eating episodes and non-rapid eye movement sleep. Her nocturnal eating and RLS were completely inhibited by clonazepam treatment. To our knowledge, this is the first published case of nocturnal eating/drinking syndrome secondary to neuroleptic-induced RLS.     

Differential cardiorespiratory response to combined exercise with different combinations of forearm and calf exercise

The purpose of this study was to examine whether cardiorespiratory responses to combined rhythmic exercise (60 contractions · min^–1) was affected by different combinations of upper and lower limb exercise in seven healthy women. Six different rhythmic exercises were compared: 6-min rhythmic handgrip at 10% of isometric maximal voluntary contraction (MVC) (H10); 6-min rhythmic plantar flexion at 10% MVC (P10); exhausting rhythmic handgrip at 50% MVC (H50); exhausting rhythmic plantar flexion at 50% MVC (P50); H50 was added to P10 (P1OH50); and P50 was added to H10 (H10P50). Exercise duration, after handgrip was combined with plantar flexion (P10H50), was shorter than that of H50, although the exercise duration of HIOP50 was not significantly different from P50. No significant difference was found between the difference from rest in oxygen uptake ( O₂) during H10P50 and the sum of O₂ during H10 and P50. Also, the differences from rest in forearm blood flow ( FBF) and calf blood flow ( CBF) during H10P50 were not significantly different from FBF in H10 and from CBF in P50. In contrast, O₂ in P10H50 was lower than the sum of O₂ in P10 and H50 (P < 0.05), and J FBF in P10H50 was lower than that in H50 (P < 0.05) , while CBF was not significantly different between P1OH50 and P10. The changes in heart rate from rest (d HR) during the combined exercises were lower than the sums of HR in the corresponding single exercises (P < 0.05). These results demonstrated an inhibitory summation of several cardiorespiratory responses to combined exercise resulting in a reduction in exercise performance which would seem to occur easily when upperlimb exercise is added to lower limb exercise.     

Plasticity of central monoaminergic systems during aging]

The locus coeruleus (LC), located within the caudal pontine central gray, is composed of noradrenaline-containing neurons. The axons of these neurons form extensive collateral branches that project widely to many brain sites. The function of the LC is still unclear at present, however, LC neurons are known to exhibit marked axonal regeneration and sprouting in response to brain damage. We investigated the age-related changes in noradrenergic innervations of the frontal cortex, using in vivo electrophysiological techniques and immunohistochemistry. While noradrenergic innervations gradually decreased with age in the frontal cortex, a high degree of sprouting occurred in the LC axon terminals in middle age. Neither the electrophysiological properties of LC neurons nor NA levels in the frontal cortex changed with age. These findings suggested that the LC neurons preserve a strong capacity to remodel their axon terminals even in the aging brain. Exogenous brain-derived neurotrophic factor (BDNF) infusion caused a marked increase in the density of noradrenergic axon in the aged brain, but no trophic action of BDNF was observed in the young or middle-aged brain. The result suggests that BDNF is necessary for the maintenance of noradrenergic innervations in the aged brain.     

Influx and efflux transport of H1-antagonist epinastine across the blood-brain barrier.

We investigated influx and efflux transporters involved in blood-brain barrier transport of the nonsedative H1-antagonist epinastine. The basal-to-apical transport of [14C]epinastine was markedly higher than that in the opposite direction in LLC-GA5-COL150 cells stably transfected with human multidrug resistance (MDR)1 gene. The brain-to-plasma concentration ratio of [14C]epinastine in mdr1a/b(-/-) mice was 3.2 times higher than that in wild-type mice. The uptake of both [3H]mepyramine and [14C]epinastine into immortalized rat brain capillary endothelial cells (RBEC)1 showed temperature and concentration dependence. The kinetic parameters, K(m), V(max), and uptake clearance (V(max)/K(m)), of the initial uptake of [3H]mepyramine and [14C]epinastine by RBEC1 were 150 microM, 41.8 nmol/min/mg protein, and 279 microl/min/mg protein for mepyramine and 10.0 mM, 339 nmol/min/mg protein, and 33.9 microl/min/mg protein for epinastine, respectively. The uptake of [3H]mepyramine and [14C]epinastine by RBEC1 was inhibited by organic cations such as quinidine, amantadine, and verapamil, but not by other organic cations, tetraethyl ammonium, guanidine, and carnitine. Organic anions such as benzoic acid, estrone-3-sulfate, taurocholate, and neutral digoxin were not inhibitory. Furthermore, some cationic H1 antagonists (chlorpheniramine, cyproheptadine, ketotifen, and desloratadine) inhibited the [3H]mepyramine and [14C]epinastine uptake into RBEC1. In conclusion, the present study demonstrated that the combination of efficient efflux transport by P-glycoprotein and poor uptake by the influx transporter, which is identical with that responsible for the uptake of mepyramine, account for the low brain distribution of epinastine.