Effects of ibuprofen on airway vascular response to cotton smoke injury

We studied the effects of ibuprofen on bronchial blood flow and myocardial function after inhalation injury. Sheep (n = 12) were chronically instrumented with cardiovascular and pulmonary catheters. After 5 days of recovery period, baseline data were collected and the sheep were divided into two groups. Group S (n = 6) were insufflated with 48 breaths of cotton smoke; while group I (n = 6) were pretreated with ibuprofen (12mg/kg bolus followed by 3 mg/kg/h continuous infusion for 24 h) and challenged with the same dose of smoke. All the animals were studied for 24h. Bronchial blood flow increased significantly in both groups throughout the experimental period; while stroke volume as well as right and left ventricular stroke work indices of both groups were significantly decreased (group I worse than group S) in the second half of the experimental period. These data suggest that vasodilatory prostaglandins do not play a major role in the bronchial vascular response to smoke inhalation injury and myocardial depression seen post injury is worse in animals treated with ibuprofen.     

Haloperidol and apomorphine differentially affect neuropeptidase activity

The effects of lipid peroxidation and the antioxidant vitamin E contained in LDL isolated from control plasma (LDL--) and from plasma preincubated with 0.5 mmol/ml alpha-tocopherol (LDL+) on the proliferation of estrogen-receptor positive (ER+ : ZR-75, T-47-D, MCF-7) and negative (ER--: HBL-100, MDA-MB-231) human breast cancer cells were studied. Human skin fibroblasts served as controls. Incubation of plasma with 0.5 mmol/ml alpha-tocopherol resulted in a 3-fold increase of its content and a significant reduction in lipid hydroperoxides and conjugated dienes in LDL. Incubation of fibroblasts or ER+ tumor cells with LDL- or LDL+ had an effect on neither cell proliferation nor on the cellular levels of peroxidation products as compared to control incubations in the absence of LDL. In ER- cells, however, LDL+ stimulated the proliferation, whereas LDL- yielded a cytotoxic effect. Moreover, LDL- supplementation resulted in an increase in the content of hydroperoxides and conjugated dienes. LDL+ supplemented cells exhibited hydroperoxide levels in these tumor cells comparable to the basal levels measured in the absence of LDL. Our data suggested that peroxidation products in LDL are cytotoxic to estrogen-receptor negative breast tumor cells and vitamin E counteracts this effect.     

The effect of sequential administration of octreotide alone and octreotide/growth hormone simultaneously on buserelin stimulated ovarian steroid secretion in women with polycystic ovary syndrome

The site of S1-S2 root activation following percutaneous high-voltage electrical (ES) and magnetic stimulation were located by analyzing the variations of the time interval from M to H soleus responses elicited by moving the stimulus point from lumbar to low thoracic levels. ES was effective in activating S1-S2 roots at their origin. However supramaximal motor root stimulation required a dorsoventral montage, the anode being a large, circular surface electrode placed ventrally, midline between the apex of the xiphoid process and the umbilicus. Responses to magnetic stimuli always resulted from the activation of a fraction of the fiber pool, sometimes limited to the low-thresholds afferent component, near its exit from the intervertebral foramina, or even more distally. Normal values for conduction velocity in motor and 1a afferent fibers in the proximal nerve tract are provided.     

Alpha-2 adrenoceptor subtype causing nitric oxide-mediated vascular relaxation in rats

The alpha-2 adrenoceptor subtype and its signal transduction pathway mediating vascular relaxation in rats were studied in vitro using rings of superior mesenteric arteries. Removal of endothelium or incubation with NG-nitro-L-arginine completely blocked relaxant responses to UK14,304, suggesting endothelium-derived nitric oxide mediates relaxation. The order of potency for full (F) or partial (P) agonists causing relaxation was guanabenz (P) > UK14,304 (F) > clonidine (P) > epinephrine (F) > norepinephrine (F). Affinities (Ka) of alpha-2 adrenoceptor subtype-selective drugs for blocking relaxation were obtained in side-by-side experiments comparing rat mesenteric arteries with pig coronary arteries. Relaxation of pig coronary arteries is known to be mediated by the alpha-2A adrenoceptor subtype. Ka values in nM for rauwolscine (19), WB-4101 (265), SKF-104078 (197), spiroxatrine (128), and prazosin (1531) for blocking relaxation in rat arteries were consistent with their affinities for binding at the alpha-2D adrenoceptor subtype. Ka values for rauwolscine and WB-4101, drugs distinguishing the alpha-2D from the alpha-2A adrenoceptor subtype, were significantly higher in blocking relaxation of rat arteries compared with pig arteries, suggesting the alpha-2D adrenoceptor subtype mediates NO-induced relaxation in rat arteries. We used forskolin to oppose alpha-2 adrenoceptor-mediated inhibition of cAMP formation by directly stimulating cAMP formation in endothelium. Forskolin did not affect the relaxant response to UK14,304, suggesting that cAMP is not involved in the coupling of alpha-2 adrenoceptors to nitric oxide-induced vascular relaxation.     

Thiopyrano[2,3,4-cd]indoles as 5-lipoxygenase inhibitors: synthesis, biological profile, and resolution of 2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5 -dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]butanoic acid

Leukotriene biosynthesis inhibitors have potential as new therapies for asthma and inflammatory diseases. The recently disclosed thiopyrano[2,3,4-cd]indole class of 5-lipoxygenase (5-LO) inhibitors has been investigated with particular emphasis on the side chain bearing the acidic functionality. The SAR studies have shown that the inclusion of a heteroatom (O or S) in conjunction with an alpha-ethyl substituted acid leads to inhibitors of improved potency. The most potent inhibitor prepared contains a 2-ethoxybutanoic acid side chain. This compound, 14d (2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methox y]- 4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]-butanoic acid, L-699,333), inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50s of 22 nM, 7 nM and 3.8 microM, respectively). The racemic acid 14d has been shown to be functionally active in a rat pleurisy model (inhibition of LTB4, ED50 = 0.65 mg/kg, 6 h pretreatment) and in the hyperreactive rat model of antigen-induced dyspnea (50% inhibition at 2 and 4 h pretreatment; 0.5 mg/kg po). In addition, 14d shows excellent functional activity against antigen-induced bronchoconstriction in the conscious squirrel monkey [89% inhibition of the increase in RL and 68% inhibition in the decrease in Cdyn (0.1 mg/kg, n = 3)] and in the conscious sheep models of asthma (iv infusion at 2.5 micrograms/kg/min). Acid 14d is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of human 15-LO, porcine 12-LO and ram seminal vesicle cyclooxygenase (IC50 > 5 microM) or competition in a FLAP binding assay (IC50 > 10 microM). Resolution of 14d affords 14g, the most potent diastereomer, which inhibits the 5-HPETE production of human 5-LO and LTB4 biosynthesis of human PMN leukocytes and human whole blood with IC50s of 8 nM, 4 nM, and 1 microM respectively. The in vitro and in vivo profile of 14d is comparable to that of MK-0591, which has showed biochemical efficacy in inhibiting ex vivo LTB4 biosynthesis and urinary LTE4 excretion in clinical trials.     

Delayed childbearing--are there any risks?

OBJECTIVE: To determine whether women delivering their first child at age 35 years or older are at increased risk of adverse (non-genetic) pregnancy outcomes. DESIGN AND SETTING: A cross-sectional analytic study of singleton deliveries in Northern Sydney Area Health Service (NSAHS) hospitals. PARTICIPANTS: All women aged > or = 20 years delivering their first child between 1 January 1990 and 31 December 1991. MAIN OUTCOME MEASURES: Obstetric complications and procedures, type of delivery and neonatal outcomes. RESULTS: Compared with women aged 20-29 years, women delivering their first child at > or = 35 years were at increased risk of pre-existing maternal hypertension (adjusted odds ratio [OR], 3.5; 95% confidence interval [CI], 1.7-7.0), antepartum haemorrhage (adjusted OR, 2.4; 95% CI, 1.6-3.7), preterm delivery (33-36 weeks) (adjusted OR, 2.0; 95% CI, 1.5-2.8) and breech presentation (adjusted OR, 1.8; 95% CI, 1.3-2.4). Women aged > or = 35 years were also substantially more likely to have an operative delivery, induced labour and/or epidural anaesthesia. Neither these women nor their infants were at increased risk of pregnancy-induced hypertension, gestational diabetes, threatened premature labour, postpartum haemorrhage, very preterm delivery (< or = 32 weeks), perinatal death, low Apgar scores or the need for neonatal resuscitation. CONCLUSIONS: Women who delay the birth of their first child face some increased risks, but these risks, for the most part, are manageable in the context of modern obstetric care.     

Variation in the survival of women with breast cancer in Scotland. The Scottish Breast Cancer Focus Group and The Scottish Cancer Therapy Network

We have investigated factors influencing the survival of women with early breast cancer in Scotland. In a retrospective study, clinical, treatment and 'service' factors, e.g. surgical case load, deprivation and geographical area (health board of first treatment) were recorded from hospital records. A total of 2148 women with invasive breast cancer diagnosed in 1987 were identified from the Scottish Cancer Registry, of whom 1619 without metastases at diagnosis underwent surgery as part of their primary treatment. In a multivariate analysis, clinical factors (age, clinical stage, pathological tumour size, node status and oestrogen receptor status) all influenced survival. After allowing for these clinical factors, surgical case load and deprivation did not have statistically significant effects on survival. By contrast, health board did affect survival. This was explained in part by the selection of patients for surgery. There appeared, however, to be a residual effect that may be related to differences in the use of adjuvant systemic treatment among the different health boards. We conclude that, in Scotland, geographical variation in both surgical and non-surgical treatment has a greater effect on variability in survival for women with breast cancer than surgical case load and deprivation.     

CDK4 down-regulation induced by paclitaxel is associated with G1 arrest in gastric cancer cells

Paclitaxel induces a cell cycle block at G2-M phase by preventing the depolymerization of microtubules and induces p53-independent apoptosis in many cancer cells. We observed that gastric cancer cells treated with paclitaxel have shown a cyclin-dependent kinase (CDK)4 down-regulation. This paclitaxel-induced CDK4 down-regulation resulted in a cell cycle arrest at G1-S phase. To confirm this observation, we prepared stable transfectants that overexpressed CDK4 and analyzed the cell cycle progression. Ectopic expression of CDK4 in SNU cells resulted in a release of paclitaxel-induced G1 arrest. The release of G1 arrest by enforced expression of CDK4 seems to make the cells more sensitive to paclitaxel-induced apoptosis. From this finding, we could then suggest that paclitaxel treatment induces both G1-S and G2-M blocks in the cell cycle progression of gastric cancer cells.     

Resistance to polyoma virus-induced tumors correlates with CTL recognition of an immunodominant H-2Dk-restricted epitope in the middle T protein

The natural mouse pathogen polyoma virus is highly oncogenic in H-2k mice carrying the endogenous superantigen encoded by the mouse mammary tumor provirus Mtv-7. This superantigen results in deletion of Vbeta6 TCR-expressing polyoma-specific CD8+ CTL, which appear to be critical effectors against polyoma tumorigenesis. Here we have isolated cloned lines of CD8+ T cells from resistant (i.e., Mtv-7-) H-2k mice that specifically lyse syngeneic polyoma virus-infected cells and polyoma tumor cells. Nearly all these CTL clones express Vbeta6 and are restricted in their recognition of virus-infected cells by H-2Dk. Screening a panel of synthetic peptides predicted to bind to Dk, for which no consensus peptide binding motif is known, we identified a peptide corresponding to a nine-amino acid sequence in the carboxyl-terminus of the middle T (MT) protein (amino acids 389-397) that was recognized by all the Vbeta6+ CD8+ CTL clones. The inability of MT(389-397)-reactive CTL to recognize cells infected with a mutant polyoma virus encoding a MT truncated just proximal to this sequence indicates that MT(389-397) is a naturally processed peptide. The frequencies of precursor CTL specific for polyoma virus and MT(389-397) peptide were similar, indicating that MT(389-397) is the immunodominant epitope in H-2k mice. In addition, polyoma-infected resistant mice possess a 10- to 20-fold higher MT(389-397)-specific precursor CTL frequency than susceptible mice. This highly focused CTL response to polyoma virus provides a valuable animal model to investigate the in vivo activity of CTL against virus-induced neoplasia.     

Can adrenal incidentalomas be safely observed?

We currently recommend excision of adrenal incidentalomas > or = 4 cm in size and all hormonally active tumors. The optimal management and follow-up of smaller nonfunctioning tumors are controversial. The aim of this study was to determine the clinical outcome of a well defined population of patients with incidentalomas followed without operative intervention. The study group comprised 231 patients, identified from the records of abdominal or thoracic computed tomographic (CT) scans performed between 1985 and 1989. The primary outcome variable analyzed was survival. Follow-up was obtained by office records, telephone contact, or letter. There were 101 male and 130 female patients with a mean age at diagnosis of 64 years (range 5-86 years). Most adrenal tumors were unilateral (right 113; left 98); 20 were bilateral. Mean tumor size was 2 cm (range 1-6 cm). In nine (4%) patients the tumor was > or = 4 cm. Follow-up [mean 7 years; range 1 month (patient died) to 11.7 years] was complete in 224 (97%) patients. Ninety-one (39%) patients had one or more additional CT scans performed during the follow-up period, with only four patients demonstrating a > 1 cm increase in the size of the adrenal mass. Surgical excision of these four lesions identified benign pathology. Eighty-one (35%) patients died of conditions unrelated to adrenal pathology. No patient developed subsequent adrenal hyperfunction or adrenal malignancy. Within the context of our guidelines, conservative management of adrenal incidentalomas considered benign or nonfunctioning at diagnosis is appropriate. Additional information provided by repeat CT scanning appears to confer limited benefit. This study does not support laparoscopic removal of small, nonfunctional adrenal tumors, as has been suggested.