IL-1β and TNF-α produced by peripheral blood mononuclear cells before and during interferon therapy in patients with chronic hepatitis C

We investigated the spontaneous and phytohemagglutinin-stimulated production of interleukin-1 (IL-1) and tumor necrosis factor- (TNF-) by peripheral blood mononuclear cells in patients with chronic hepatitis C during treatment with interferon- (IFN-). Spontaneous productions of these were significantly higher in patients with chronic hepatitis C than in healthy subjects. For patients prescribed interferon, stimulated production of TNF- was significantly higher in complete responders than in partial responders, but the differences were small between the other cytokine levels and outcome of IFN treatment. Spontaneous production of these cytokines was higher in patients with genotype III with complete response than in genotype III patients with a partial response, but this was not the case in patients with genotype II. There was a negative correlation between these cytokines and histological activity index. Spontaneous production of cytokines was decreased only in complete responders after the administration of interferon. These data suggest that the elevated production of cytokines in patients with chronic hepatitis C may be due to host response to the virus, and monitoring cytokines along with alanine aminotransferase and hepatitis C virus RNA during treatment may provide more precise information of the effectiveness of therapy.     

Chronic hypertension induced by streptozotocin in rats

Summary An intravenous injection of 40 or 65 mg/kg streptozotocin induced not only diabetes but also severe hypertension in rats. Whereas the hyperglycemia developed fully within a few days after the injection of streptozotocin, the hypertension progressively advanced and reached maximum level several weeks after the treatment and lasted more than 20 weeks. Twenty mg/kg streptozotocin did not induce hyperglycemia but significantly increased blood pressure several weeks after the treatment. Arrest of growth, polyuria, glycosuria, hyperlipemia and lenticular cataracts developed in the animals treated with 40 or 65 mg/kg streptozotocin, but in none of the animals treated with 20 mg/kg. In histological examinations in the 24th week after the treatment, degranulation and necrosis in the pancreatic -cells, and vacuolization and deposition of PAS-positive materials in the renal proximal tubules were found in the animals treated with 40 or 65 mg/kg streptozotocin.     

Regional differences in skin blood flow and temperature during total spinal anaesthesia

Three patients were studied to determine the changes in regional skin temperature and blood flow during extensive sympathetic blockade following total spinal anaesthesia (TSA). Skin temperature was measured at the right upper arm, the right anterior chest at the nipple level, the right hand and the foot, using infrared thermography. Skin blood flow of the right upper arm (C6 area) was measured with a laser Doppler flowmeter. The temperature of the truncal area, arm and leg decreased by 1 degree C following TSA, whereas the temperature of the hand and foot increased by 3 degrees C. The mean blood flow in three patients decreased to 26.1, 61.4, 51.7% of the control values 15 min after TSA. Our results indicate that extensive sympathetic nervous blockade during total spinal anaesthesia induces regional different changes in skin temperature and decrease in truncal skin blood flow.     

Haemodynamic responses to the intubating laryngeal mask and timing of removal

We determined (a) the haemodynamic responses to intubating laryngeal mask (ILM) airway insertion/intubation and removal in anaesthetized patients, and (b) whether the timing of ILM removal influences these responses. One-hundred and twenty patients without cardiovascular disease were studied. ILM airway insertion/intubation was 5 min after induction with propofol 2 mg kg(-1) and maintenance of anaesthesia with sevoflurane 2% in oxygen 33% and nitrous oxide. Patients were randomly assigned for removal of the intubating laryngeal mask airway at 1, 3 and 5 min after successful intubation. Systolic and diastolic arterial pressures and heart rate were recorded preinduction (baseline), before ILM airway insertion/intubation, at 1-min intervals after insertion/intubation, and at 1-min intervals for 5 min after ILM removal. ILM insertion was successful at the first attempt in all patients, but 46 patients required more than one intubation attempt. Compared with baseline values, there were no increases in systolic or diastolic arterial pressure, but there was an increase in heart rate 1 min after ILM insertion/intubation (9%, P<0.001) and 1 min after ILM removal (8%, P<0.01). There was a significant increase in systolic and diastolic pressures and heart rate 1 min after ILM insertion/intubation (30%, 31% and 15%; all: P<0.002) compared with before ILM insertion/intubation values and 1 min after ILM removal (9%, 8% and 7%; all P<0.05) compared with 1 min after ILM insertion/intubation values. Removal of the ILM 1 min after successful intubation resulted in higher arterial pressure compared with removal at 3 min (systolic arterial pressure 10% higher for 1 min, P = 0.01) and 5 min (systolic arterial pressure 10-23% higher for 3 min, P<0.01; diastolic arterial pressure 10-20% higher for 4 min, P>0.02), but there were no differences in heart rate between groups. Systolic and diastolic arterial pressures were greater if more than one intubation attempt was required. Early removal or multiple intubation attempts did not exceed baseline haemodynamic values. We conclude that ILM insertion/intubation and removal in anaesthetized patients produces little or no haemodynamic response, even if multiple intubation attempts are required. The timing of removal exerts a small, but clinically unimportant influence on these responses.     

Exposure to 1-bromopropane causes ovarian dysfunction in rats.

Although 1-bromopropane has been used in chemical and electronic industries as an alternative to ozone layer-depleting solvents, its toxicity on female reproductive organs has not been fully elucidated. The aim of this experiment was to determine the effect of 1-bromopropane on female reproductive function in rats. Forty female Wistar rats were divided into four equal groups. Each group was exposed daily to 0, 200, 400, or 800 ppm of 1-bromopropane for eight h a day. After exposure for 7 weeks, all rats in the 800-ppm group became seriously ill and were sacrificed during the 8th week. The other dose groups were exposed for 12 weeks. In the 800-ppm group, but not in the other two exposed groups, body weight was significantly less than the control at each time point from 2 to 7 weeks after the beginning of exposure. Tests of vaginal smears showed a significant increase in the number of irregular estrous cycles with extended diestrus in the 400- and 800-ppm groups. Histopathological examination of the ovary showed a significant dose-dependent reduction of the number of normal antral follicles and a decrease in the number of normal growing follicles in the 400-ppm group. No significant change was found in plasma concentrations of LH or FSH in any group when compared with the control. Our results indicate that 1-bromopropane can induce a dose-dependent ovarian dysfunction in nonpregnant female rats associated with disruption in follicular growth process.     

An angiogenesis inhibitor E7820 shows broad-spectrum tumor growth inhibition in a xenograft model: possible value of integrin alpha2 on platelets as a biological marker.

We reported previously that an angiogenesis inhibitor, E7820, inhibits in vitro tube formation of human umbilical vein endothelial cell through the suppression of integrin alpha2 expression. Here we describe the antiangiogenic and antitumor effects of E7820 in mice and discuss the feasibility of using platelet integrin alpha2 expression on platelets as a biological marker of the efficacy of E7820. Oral administration of E7820 significantly inhibited basic fibroblast growth factor-induced angiogenesis in Matrigel implants and human colon WiDr tumor-induced angiogenesis in a dorsal air sac model. Twice-daily treatment with E7820 clearly inhibited the s.c. tumor growth of seven tumor cell lines derived from human colon, breast, pancreas, and kidney, and completely suppressed the growth of human pancreatic KP-1 and human colon LoVo cell lines. Moreover, E7820 significantly inhibited the growth of KP-1 and human colon tumor Colo320DM cells orthotopically implanted in the pancreas and cecum, respectively. The efficacy of E7820 was comparable in the s.c. and orthotopic transplantation models. Immunohistochemical analyses using anti-CD31 antibody showed that E7820 significantly reduced microvessel density in orthotopically implanted KP-1 tumor. E7820 reduced integrin alpha2 expression on a megakaryocytic cell line, Dami cells, induced by phorbol 12-myristate 13-acetate treatment. It also decreased the expression level of integrin alpha2 on platelets withdrawn from mice bearing s.c. KP-1 tumor at a dosage close to that affording antitumor activity. These data demonstrate that E7820 showed a broad-spectrum antitumor effect in mice through inhibition of angiogenesis and indicate that the decrease of integrin alpha2 on platelets might serve as a biological marker for the antitumor efficacy of E7820.     

毛穗藜芦中茋类化合物的化学研究

目的：对毛穗藜芦根茎进行化学成分研究。方法：采用柱层析和薄层层析法进行分离，用ＵＶ，ＩＲ，ＭＳ，Ｈ-ＮＭＲ等光谱技术鉴定化合物的结构。结果：得到２个类化合物，为白藜芦醇和２，３′，４，５′-四羟基。结论：为首次从该植物中分离得到。     

Accumulation of class I mutant p53 and apoptosis induced by carboplatin in a human glioma cell line

Following DNA damage, wild-type p53 increases and mediates the multiple cellular responses for the repair of DNA damage or apoptosis. Inactivation of p53 by single-amino-acid substitutions contributes to the malignant phenotype and confers resistance to therapy. Among tumor-derived p53 mutants, class I mutants still retain a native-like three-dimensional structure, whereas class II mutants have unfolded DNA-binding domains. Sequencing analysis demonstrated that a human glioma cell line (U-373MG) had only a class I mutant form of p53 of His273, which targets an Arg273 that contacts DNA but retains the native structure. In this study, we investigated the metabolic alteration of the class I mutant p53 in apoptosis of U-373MG. The cell cycle progression of U-373MG cells was affected by the addition of carboplatin, while the amount of mutant p53 also increased in their nuclei. The treated cells underwent apoptosis 48h after exposure to 50 μg/ml carboplatin. Although the exact mechanism of the class I mutant p53 in the process of apoptosis has not yet been clarified, the fact that accumulation of the activated mutant p53 in the nucleus of U-373MG is concomitant with apoptosis, just as wild-type p53 does, implies that the class I mutant p53 might retain the ability to participate in apoptosis.