Deficiency of IL-5 receptor alpha-chain selectively influences the development of the common mucosal immune system independent IgA-producing B-1 cell in mucosa-associated tissues

Deletion of IL-5R alpha-chain (IL-5R alpha-/-) selectively influenced the mucosal IgA responses in vivo. While levels of IgA in mucosal secretions were more reduced in IL-5R alpha-/- mice than in wild-type mice, the levels of IgA in serum were not changed. The frequency of IgA-producing cells was reduced in mucosal effector sites (e.g., intestinal lamina propria and nasal passage), but not in inductive sites such as Payer's patches and nasal-associated lymphoreticular tissues in IL-5R alpha-/- mice. IgA-committed (surface IgA+; sIgA+) B-1 cells mainly resided in mucosal effector tissues, while conventional sIgA+ B (B-2) cells formed in mucosal inductive sites of wild-type mice. In contrast, in the effector tissue of IL-5R alpha-/- mice, sIgA+ B-1 cells, but not sIgA+ B-2 cells in the inductive site, were significantly reduced. IL-5R alpha was more expressed on sIgA+ B-1 cells than was IL-6R, while both IL-5R alpha and IL-6R were expressed on sIgA+ B-2 cells in wild-type mice. sIgA+ B-1 cells produced high levels of IgA with rIL-5 rather than of rIL-6 in vitro. Taken together, the findings suggest that the IL-5/IL-5R signaling pathway is critically important for the development of common mucosal immune system independent sIgA+ B-1 cell in mucosal effector tissues in vivo.     

Mouse thyroglobulin: conservation of sequence homology in C-terminal immunogenic regions of thyroglobulin

Gastrin-releasing peptide (GRP) has a wide range of biological actions, including stimulation of the frequency of antral contractions and delaying gastric emptying. The present study was designed to evaluate the role of GRP in the control of gastric emptying of liquid test meals in the rat. The emptying of methyl cellulose given by gavage to fasted rats, or of saline given via the fistula to conscious gastric fistula rats was not influenced by the GRP antagonists, NC-8-89 (Leu13-psi-(CH2NH)-Leu14-bombesin) and 2258U89 ((de-NH2)Phe19, D-Ala24, D-Pro26 psi (CH2NH)Phe27(-GRP (19-27)), at 2 mg/kg, s.c. However, both antagonists (0.02, 0.2 and 2 mg/kg) reversed the inhibitory effect of HCI on gastric emptying in gastric fistula rats (P < 0.05-0.001). When peptone was administered after a preload, but not otherwise, the inhibition of emptying was also partly reversed by both antagonists at all doses used (P < 0.05-0.001). Interestingly, the delay in the emptying of hyperosmolal saline compared to saline, was enhanced at a dose of 0.2 mg/kg of both antagonists (P < 0.05 and P < 0.01). Food intake did not change significantly with the two lower doses of antagonists, but was decreased by the highest dose of NC 8-89. We conclude that GRP specifically inhibits gastric emptying of acid and peptone solutions in the conscious rat.     

Probing interactions of the homotrimeric PII signal transduction protein with its receptors by use of PII heterotrimers formed in vitro from wild-type and mutant subunits

The homotrimeric PII signal transduction protein of Escherichia coli interacts with two small-molecule effectors, 2-ketoglutarate and ATP, regulates two protein receptors, the kinase/phosphatase nitrogen regulator II (NRII) and the glutamine synthetase (GS) adenylyltransferase (ATase), and is subject to reversible uridylylation, catalyzed by the uridylyltransferase/uridylyl-removing enzyme (UTase/UR). The site of PII uridylylation, Y51, is located at the apex of the solvent-exposed T-loop (E. Cheah, P. D. Carr, P. M. Suffolk, S. G. Vasudevan, N. E. Dixon, and D. L. Ollis, Structure 2:981-990, 1994), and an internally truncated PII lacking residues 47 to 53 formed trimers that bound the small-molecule effectors but were unable to be uridylylated or activate NRII and ATase (P. Jiang, P. Zucker, M. R. Atkinson, E. S. Kamberov, W. Tirasophon, P. Chandran, B. R. Schefke, and A. J. Ninfa, J. Bacteriol. 179:4342-4353, 1997). We investigated the ability of heterotrimers containing delta47-53 and wild-type subunits to become uridylylated and activate NRII and ATase. Heterotrimers were formed by denaturation and renaturation of protein mixtures; when such mixtures contained a fivefold excess of A47-53 subunits, the wild-type subunits were mostly redistributed into trimers containing one wild-type subunit and two mutant subunits. The resulting population of trimers was uridylylated and deuridylylated by UTase/UR, stimulated the phosphatase activity of NRII, and stimulated adenylylation of GS by ATase. In all except the ATase interaction, the activity of the hybrid trimers was greater than expected based on the number of wild-type subunits present. These results indicate that a single T-loop region within a trimer is sufficient for the productive interaction of PII with its protein receptors. We also formed heterotrimers containing wild-type subunits and subunits containing the G89A alteration (P. Jiang, P. Zucker, M. R. Atkinson, E. S. Kamberov, W. Tirasophon, P. Chandran, B. R. Schefke, and A. J. Ninfa, J. Bacteriol. 179: 4342-4353, 1997). The G89A mutant form of PII does not bind the small-molecule effectors, does not interact with UTase or with NRII, and interacts poorly with ATase. Heterotrimers formed with a 10/1 starting ratio of G89A to wild-type subunits interacted with UTase/UR and ATase to a lesser extent than expected based on the number of wild-type subunits present but activated NRII slightly better than expected based on the number of wild-type subunits present. Thus, intersubunit interactions within the PII trimer can adversely affect the activity of wild-type subunits and may affect the interactions with the different receptors in a variable way. Finally, we formed heterotrimers containing delta47-53 and G89A mutant subunits. These heterotrimers were not uridylylated, did not interact with NRII, and interacted with the ATase only to the extent expected based on the number of G89A subunits present. Thus, the G89A subunits, which contain an intact T-loop region, were not "repaired" by inclusion in heterotrimers along with delta47-53 subunits.     

电感耦合等离子体原子发射光谱法测定钢丝黄铜镀层中铝磷锰铁镍砷锡锑铅

提出了一种用电感耦合等离子体原子发射光谱法(ICP-AES)快速测定钢丝黄铜镀层中铝、磷、锰、铁、镍、砷、锡、锑和铅元素含量的分析方法。利用稀氨水和过氧化氢将黄铜层从钢丝上剥离下来,取出钢丝后在镀层液中加入盐酸酸化,选择309.271, 178.284, 257.610, 238.204, 231.604, 189.042, 189.989,206.833和182.205 nm波长的光谱线分别作为铝、磷、锰、铁、镍、砷、锡、锑和铅的分析谱线,在优化的试验条件下用ICP-AES测定试液中铝、磷、锰、铁、镍、砷、锡、锑和铅含量。其信号强度与铝、磷、锰、铁、镍、砷、锡、锑和铅的质量浓度分别在0.05~15.0、 0.05~1.0、 0.05~15.0、 0.05~15.0、 0.05~20.0、 0.05~1.0、 0.05~1.0、 0.05~1.0和0.05~15.0 mg/L范围内呈线性关系,方法的检出限(3S/N)分别为0.009, 0.015, 0.001, 0.010, 0.002, 0.003, 0.009, 0.007和0.010 mg/L。方法可用于钢丝黄铜镀层中铝、磷、锰、铁、镍、砷、锡、锑和铅含量的测定,回收率在96%~107%之间,相对标准偏差(n=6)在0.46%~4.1%之间,不同方法间测定值一致。     

Glutathone and glutathione ethyl ester supplementation of mice alter glutathione homeostasis during exercise

The present study examined the effect of glutathione (GSH) and glutathione ethyl ester (GSH-E) supplementation on GSH homeostasis and exercise-induced oxidative stress. Male Swiss-Webster mice were randomly divided into 4 groups: starved for 24 h and injected with GSH or GSH-E (6 mmol/kg body wt, i.p.) 1 h before exercise, starved for 24 h and injected with saline (S); and having free access to food and injected with saline (C). Half of each group of mice was killed either after an acute bout of exhaustive swimming (E) or after rest (R). Plasma GSH concentration was 100-160% (P < 0.05) higher in GSH mice vs. C or S mice at rest, whereas GSH-E injection had no effect. Plasma GSH was not affected by exercise in C or S mice, but was 44 and 34% lower (P < 0.05) in E vs. R mice with GSH or GSH-E injection, respectively. S, GSH- and GSH-E-treated mice had significantly lower liver GSH concentration and the GSH:glutathione disulfide (GSSG) ratio than C mice. Hepatic and renal GSH and the GSH:GSSG ratio were significantly lower in E vs. R mice in all groups. GSH-E-treated mice had a significantly smaller exercise-induced decrease in GSH vs. C, S, and GSH-treated mice and no difference in the GSH:GSSG ratio in the kidney. Activities of gamma-glutamylcysteine synthetase and gamma-glutamyltranspeptidase in the liver and kidney were not affected by either GSH treatment or exercise. GSH concentration and the GSH:GSSG ratio in quadriceps muscle were not different among C, S and GSH-treated mice, but significantly lower in GSH-E-treated mice (P < 0.05). Hepatic malondialdehyde (MDA) content was greater in exercised mice in all but GSH-E-treated groups. GSH and GSH-E increased MDA levels in the kidney of E vs. R mice, but attenuated exercise-induced lipid peroxidation in muscle. Swim endurance time was approximately 2 h longer in GSH (351 +/- 22 min) and GSH-E (348 +/- 27) than S mice (237 +/- 17). We conclude that 1) acute GSH and GSH-E supplementation at the given doses does not increase tissue GSH content or redox status; 2) both GSH and GSH-E improve endurance performance and prevent muscle lipid peroxidation during prolonged exercise; and 3) while both compounds may impose a metabolic and oxidative stress to the kidney, this side effect is smaller with GSH-E supplementation.     

Association between mother-infant salivary contacts and caries resistance in children: a cohort study

We selected 327 7-month-old infants and divided them into two groups based on the frequency of salivary close contacts between mother and infant. Five to seven years later, all first-born children (N = 55) whose dental development had been followed regularly, were examined for dental caries and prevalence of salivary mutans streptococci (MS) and lactobacilli. The children with frequent maternal close contacts (F group, N = 21) had significantly less MS in saliva than the children with rare close contacts (R group, N = 34, P = 0.02). Only 19% of the children in F group compared with 56% in R group had experienced caries in their primary molars and/or canines (P < 0.01). A significantly greater proportion of the children in F group (57%) than in R group (27%, P < 0.05) had a high intake of sugar-containing foods and drinks in a 2-day dietary history. The F and R groups did not differ significantly with respect to other children's caries risk factors, or in age, sex, stage of dental development, dental treatment, or the social aspects studied. There were no significant differences between F and R groups in maternal caries experience, salivary MS or lactobacillus counts, or in maternal background factors (age, breast feeding, or education). Frequent transfer of maternal saliva to the mouth of the baby before tooth eruption was negatively associated with oral infection by MS and to caries in the primary dentition, possibly due to protective immune mechanisms.     

Beneficial effects of N,N,N-trimethylsphingosine following ischemia and reperfusion in the isolated perfused rat heart

In a single-centre study the feasibility and efficacy of repeated antilymphocyte globulin (ALG) for patients with severe aplastic anaemia (SAA) not responding to an initial ALG treatment or relapsing after initial response to ALG was evaluated. 139 consecutive patients with newly diagnosed SAA were treated with ALG between 1976 and 1995. 89 patients responded to a first course; 50 patients did not become transfusion independent. Of the 89 responders, 66 remained in remission, 23 relapsed. 43 patients received a second or subsequent course of ALG for failure to respond (n = 25) or relapse (n = 18) and were given a total of 53 courses. Acute reactions in the multiply exposed patients occurred during the first ALG treatment in 11 (26%) and during subsequent exposures in 16/53 courses (30%; P > 0.2). Incidence of serum sickness was 63% (27/43) after the initial course compared to 57% (30/53) after subsequent courses (P > 0.2), but clinical signs of serum sickness occurred earlier after repeated (median 6 d) as compared to initial exposure (13d; P = 0.008). Transfusion-independent haemopoiesis was achieved in 27/43 (63%) and survival probabilities for the 43 patients receiving multiple courses of ALG was 52 +/- 8% at 10 years. The probability of developing a late clonal disorder was 53 +/- 10% after multiple, as compared to 34 +/- 7% after single exposure (P = 0.15). No difference in results was observed between patients retreated for failure to first ALG or for relapse. ALG of the same species can be repeated without increased risks of side-effects in patients with SAA. A second or subsequent course of ALG from the same source can be effective when the first course has failed.     

Ultrasonic classification of carotid plaques causing less than 60% stenosis according to ultrasound morphology and events

Carotid plaque morphology studied by ultrasound has been used to classify 3 types of bifurcation plaques, producing less than 60% stenosis on duplex scanning: Type A, the homogeneous, highly echogenic plaque; Type B, the heterogeneous (mainly echogenic, B-1 or mainly echolucent, B-2) plaque; Type C, the complex plaque with irregular surface, echogenic and/or echolucent with calcifications. One hundred asymptomatic subjects in each plaque group were included in a prospective 4-year follow-up study to evaluate clinical events and brain damage by yearly cerebral CT and MR scans. After four years 96 subjects with type A plaque, 89 with type B-1 and 67 with type C plaques completed the study. While there were no clinical events or positive cerebral scans in subjects with type A plaques there was a significantly increasing number of cerebral and vascular events in subjects with plaque B and C type with a zero mortality in the plaque A group, a 2.24% mortality in type B plaques and a significantly higher (p > 0.05) mortality (13.4%) in type C plaques. CT and MR scans revealed brain damage which had been totally asymptomatic with MR detecting a larger number of lesions. Also the number of cerebral lesions observed by CT/MR were significantly greater than the number of recorded clinical episodes. ECG stress test revealed a larger number of asymptomatic coronary disease in the C type plaques. In conclusion ultrasound plaque morphology is linked to different incidences of cerebral and cardiac events, brain damage and asymptomatic coronary disease. Also CT and MR may reveal lesions which do not cause signs or symptoms.     

Concentrations of vitamins A, C and E in elderly patients with Parkinson''s disease

Concentrations of the naturally occurring antioxidant vitamins A, C and E were measured in 27 patients with Parkinson's disease and 16 age-matched control subjects, from a similarly disabled patient group. There was no significant difference in the serum concentrations of vitamins A and E in the two groups. Vitamin C was significantly higher (P < 0.05) in the Parkinson's disease group, however, the mean leucocyte vitamin C concentration in the control group was low (101 nmol/10(8) WBCS) compared to established data in healthy young individuals (119-301 nmol/10(8) WBCS). There was no correlation between the severity or duration of Parkinson's disease and concentrations of vitamins A, C and E. There is therefore no evidence from this study that a deficiency of these antioxidants contributes to the onset or progress of Parkinson's disease.     

Growth performance, intestinal microbial populations, and serum cholesterol of broilers fed diets containing Lactobacillus cultures

A study was conducted to determine the effects of adherent Lactobacillus culture on growth performance, intestinal microbial population, and serum cholesterol level of broilers. Four dietary treatments, consisting of the basal diet (control), basal diet + 0.05, 0.10, or 0.15% Lactobacillus culture (LC), were fed to 2,000 Arbor Acres broiler chicks from 1 to 42 d of age (DOA). The chicks were randomly assigned to 40 cages (50 chicks per cage, 10 cages per diet). The experimental period was 42 d. Body weights and feed to gain ratio were measured at 21 and 42 DOA. The intestinal microbial populations and serum cholesterol levels were determined at 10, 20, 30, and 40 DOA. The results showed that body weights and feed to gain ratios were improved significantly (P < 0.05) when compared to control broilers for broilers fed diets containing 0.05 or 0.10% LC, but not 0.15% LC, at 21 and 42 DOA. Coliform counts in the cecum of birds receiving 0.05% LC at 10, 20, and 30 DOA, and 0.10% at 10 and 20 DOA were significantly lower (P < 0.05) than those of the control birds. The total aerobes, total anaerobes, lactobacilli, and streptococci in the small intestines and ceca of the control birds were not significantly different from those of the treated groups. Serum cholesterol levels were significantly lower (P < 0.05) in broilers fed the three diets containing LC at 30 DOA, and in the birds fed 0.05 or 0.10% LC at 20 DOA.     

Renal acid excretion and intracellular pH in salt-sensitive genetic hypertension

Acid-base status and renal acid excretion were studied in the Dahl/Rapp salt-sensitive (S) rat and its genetically salt-resistant counterpart (R). S rats developed hypertension while on a very high salt diet (8%) and while on a more physiological salt diet (1%) and remained normotensive while on a very low salt diet (0.08%). Under the high salt diet, intracellular pH measured in freshly isolated thymic lymphocytes using 2',7'-bis (carboxyethyl)-5 (6)-carboxyfluorescein acetomethyl ester, a pH-sensitive dye, was lower in S than in R rats both when measured in the presence of HCO3/CO2 (7.32 +/- 0.02 vs. 7.38 +/- 0.02, respectively, P < 0.05) and in its absence (7.18 +/- 0.04 vs. 7.27 +/- 0.02, respectively, P < 0.05). Under the high salt diet, net acid excretion was higher in S than R rats (1,777 +/- 111 vs. 1,017 +/- 73 muEq/24 h per 100 g body wt, respectively, P < 0.001), and this difference was due to higher rates of both titratable acid and ammonium excretion. Directionally similar differences in intracellular pH and net acid excretion between S and R rats were also observed in salt-restricted animals. In S and R rats placed on a normal salt intake (1%) and strictly pair-fed to control food intake as a determinant of dietary acid, net acid excretion was also higher in S than in R rats (562 +/- 27 vs. 329 +/- 21 muEq/24 h per 100 g, respectively, P < 0.01). No significant difference in either blood pH or bicarbonate levels were found between S and R rats on either the 0.08%, 1%, or 8% salt diets. We conclude that renal acid excretion is augmented in the salt-sensitive Dahl/Rapp rat. Enhanced renal acid excretion may be a marker of increased acid production by cells from subjects with salt-sensitive hypertension.     

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome

The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.     

Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma homocysteine concentrations in healthy, young women

BACKGROUND: Elevated plasma homocysteine concentrations are considered to be a risk factor for vascular disease and fetal malformations such as neural tube defects. Recent studies have shown that plasma homocysteine can be lowered by folic acid in amounts corresponding to 1-2 times the recommended dietary allowance. Preliminary evidence indicates that vitamin B-12 may be beneficial when included in supplements or in a food-fortification regimen together with folic acid. OBJECTIVE: We aimed to compare the homocysteine-lowering potential of a folic acid supplement with that of 2 supplements containing different doses of vitamin B-12 in addition to folic acid. DESIGN: Female volunteers of childbearing age (n = 150) received a placebo for 4 wk followed by a 4-wk treatment with either 400 microg folic acid, 400 microg folic acid + 6 microg vitamin B-12, or 400 microg folic acid + 400 microg vitamin B-12. RESULTS: Significant reductions (P < 0.001) in plasma homocysteine were observed in all groups receiving vitamin treatment. The effect observed with the combination of folic acid + 400 microg vitamin B-12 (total homocysteine, -18%) was significantly larger than that with a supplement containing folic acid alone (total homocysteine, -11%) (P < 0.05). Folic acid in combination with a low vitamin B-12 dose (6 microg) affected homocysteine as well (-15%). CONCLUSIONS: These results suggest that the addition of vitamin B-12 to folic acid supplements or enriched foods maximizes the reduction of homocysteine and may thus increase the benefits of the proposed measures in the prevention of vascular disease and neural tube defects.     

Management of spinal trauma

The objective of the study was to evaluate the relationship between curing light intensity and (1) linear post-gel polymerization contraction strain, and (2) degree of conversion of a dental composite. Cylindrical specimens of a dental resin composite were cured from a distance of 7 mm for 40 s at four attenuated light intensities (71%, 49%, and 34% of control intensity and for 20 s at 71% plus 20 s at 100% intensity). A group cured at full intensity served as a control. Degree of conversion (DC) was measured at the top and bottom and linear contraction strain was measured at the bottom of the composite samples. DC at the sample top was significantly different (P < 0.05) between all groups except the 71% and 49% intensity groups. At the sample bottom, DC resulting from the two highest intensities (71% and 100%) were not significantly different from each other (P > 0.05). All other groups were significantly different from each other (P < 0.05). DC for the sample cured at two light intensities was not significantly different from those cured at the lower intensity or higher intensity for 40 s (P > 0.05). The sample cured with two intensities showed a 21.8% reduction from the contraction strain predicted by a light energy density calculation. Application of light at less than the maximum intensity of the curing light resulted in significant reduction of polymerization contraction strain without significantly affecting the degree of conversion.     

Effect of single oral dose of azithromycin, clarithromycin, and roxithromycin on polymorphonuclear leukocyte function assessed ex vivo by flow cytometry

Azithromycin was given as a single oral dose (20 mg/kg of body weight) to 12 volunteers in a crossover study with roxithromycin (8 to 12 mg/kg) and clarithromycin (8 to 12 mg/kg). Flow cytometry was used to study the phagocytic functions and the release of reactive oxygen products following phagocytosis by neutrophil granulocytes prior to administration of the three drugs, 16 h after azithromycin administration, and 3 h after clarithromycin and roxithromycin administration. Phagocytic capacity was assessed by measuring the uptake of fluorescein isothiocyanate-labeled bacteria. Reactive oxygen generation after phagocytosis of unlabeled bacteria was estimated by the amount of dihydrorhodamine 123 converted to rhodamine 123 intracellularly. Azithromycin resulted in decreased capacities of the cells to phagocytize Escherichia coli (median [range], 62% [27 to 91%] of the control values; P < 0.01) and generate reactive oxygen products (75% [34 to 26%] of the control values; P < 0.01). Clarithromycin resulted in reduced phagocytosis (82% [75 to 98%] of control values; P < 0.01) but did not alter reactive oxygen production (84% [63 to 113%] of the control values; P > 0.05). Roxithromycin treatment did not affect granulocyte phagocytosis (92% [62 to 118%] of the control values; P > 0.05) or reactive oxygen production (94% [66 to 128%] of the control value; P > 0.05). No relation between intra- and/or extracellular concentrations of azithromycin and/or roxithromycin and the polymorphonuclear phagocyte function and/or reactive oxygen production existed (P > 0.05 for all comparisons). These results demonstrate that the accumulation of macrolides in neutrophils can suppress the response of phagocytic cells to bacterial pathogens after a therapeutic dose.     

Clinical, endocrine, and metabolic effects of two doses of gestrinone in treatment of pelvic endometriosis

AIM: To study the effect of prokinetic treatment with cisapride in patients with constipation-predominant irritable bowel syndrome. PATIENTS AND METHODS: Ninety-six patients were randomly assigned to treatment with either cisapride 5 mg three times daily or placebo three times daily for a period of 12 weeks. The dosage could be doubled after 4 weeks. Presence of the target symptoms abdominal pain, constipation and abdominal bloating was an obligatory criterion for inclusion in the study. RESULTS: After 12 weeks of treatment, 31%, 56% and 27% of the cisapride treated patients were found to be without the three target symptoms (P < 0.05). The corresponding percentages for the placebo-treated patients were 31%, 58% and 19%, respectively, (P < 0.05). The visual analogue scale (VAS) symptom scores assessed by the patients for global rating of bowel disease, general well-being and frequency of stool passage improved significantly within each treatment group (P < 0.05). Evaluation of efficacy parameters using intention-to-treat analysis showed no statistically significant differences between the groups. Using efficacy analysis, the difficulty of stool passage showed a significantly higher improvement with cisapride (P < or = 0.05). CONCLUSIONS: These results indicate that cisapride is not superior to placebo in the treatment of constipation and abdominal discomfort as components of irritable bowel syndrome. It may, however, be of use in improving the difficulty of stool passage.     

High-dose therapy with peripheral blood stem cell transplantation results in a significant reduction of the haemopoietic progenitor cell compartment

In order to study the effect of high-dose therapy with peripheral blood stem cell transplantation (PBSCT) on the haemopoietic reserve in man, the number and composition of bone marrow (BM) and peripheral blood (PB)-derived progenitor cells were examined in 137 cancer patients. In 45 patients, paired samples from BM and PB were obtained before PBSC mobilization and 6-27 months after transplantation. Following PBSCT. the proportion of CD34+ cells was significantly smaller than before mobilization (BM 1.99 +/- 0.24 versus 0.8 +/- 0.09, P < 0.001), and no change was observed at several follow-up visits thereafter. The reduction was most pronounced for the primitive BM progenitor subsets such as the CD34+/DR- and CD34+/ Thy-1+ cells. The impairment of hematopoiesis was also reflected by a significant reduction in the plating efficiency of BM and PB samples. No relationship was found between the decrease in the proportion of CD34+ cells and any particular patient characteristics, kind of high-dose therapy or the CD34+ cell content in the autograft. In conclusion, high-dose therapy with PBSC transplantation is associated with a long-term impairment of the haemopoietic system. The reduction in the number of haemopoietic progenitor cells is not associated with a functional deficit, as peripheral blood counts post-transplantation were normal in the majority of patients.     

Changes in DNA distributions and ploidy of CHO cells as a function of time in culture

Chinese hamster ovary (CHO) cells maintained in continuous culture for 3 to 5 months may undergo subtle changes in drug sensitivity response, growth kinetics, plating efficiencies, et cetera. Our studies done independently in two different laboratories, using flow cytometry, indicate that the DNA histogram patterns change at about 11 wk, from populations with an approximate diploid DNA content to populations also composed of triploid and tetraploid cells. Chromosome counts also change from distributions of 21 to 22 to populations of cells having 21 to 22, 34 to 35 and 44 to 46 chromosomes. These alterations occur earlier (at 8 to 9 wk) in cell populations previously treated with anticancer drugs.     

Serum 27-hydroxycholesterol in patients with primary biliary cirrhosis suggests alteration of cholesterol catabolism to bile acids via the acidic pathway

Reduced cholesterol synthesis has been reported in patients with primary biliary cirrhosis but no data are available on changes in cholesterol catabolism induced by the disease. Serum levels of 7alpha-hydroxycholesterol and 27-hydroxycholesterol have been measured in 25 patients (either normocholesterolemic or hypercholesterolemic) with primary biliary cirrhosis and in control subjects. To evaluate cholesterol synthesis, serum levels of lathosterol were measured, and campesterol and sitosterol were considered to reflect intestinal absorption and biliary elimination of sterols. In normocholesterolemic patients with primary biliary cirrhosis, lathosterol was significantly lower than in normocholesterolemic controls (P < 0.05) whereas no difference was found between hypercholesterolemic patients and hypercholesterolemic controls. Serum concentrations of sitosterol were significantly higher in both normocholesterolemic and hypercholesterolemic patients with primary biliary cirrhosis as compared with the respective controls (P < 0.01). In patients with primary biliary cirrhosis, serum 7alpha-hydroxycholesterol was slightly higher than in controls. 27-Hydroxycholesterol was significantly higher in hypercholesterolemic compared to normocholesterolemic controls (P < 0.05) and a significant linear correlation (r = 0.771; P < 0.001) was found between 27-hydroxycholesterol and cholesterol. In contrast, in patients with primary biliary cirrhosis, high cholesterol concentrations were not associated with increased serum levels of 27-hydroxycholesterol. Our data confirm that in patients with primary biliary cirrhosis, cholesterol synthesis and biliary elimination of sterols are impaired and also suggest that both the feedback regulation of retained bile acids on cholesterol 7alpha-hydroxylase and the scavenger effect on elevated serum cholesterol by cholesterol 27-hydroxylase are deficient in these patients. acids via the acidic pathway.