A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice

Studies in gene-targeted mice have demonstrated that factor B of the alternative complement pathway plays an important role in several disease models, but an exogenous inhibitor of factor B has not previously been available. We have developed an inhibitory monoclonal antibody directed against a critical epitope on mouse factor B and have tested it in a model of antiphospholipid (aPL) antibody (Ab)-induced fetal loss. Gene-targeted factor B-deficient mice (fB-/-) were injected with a fusion protein comprised of the second and third short consensus repeat (SCR) domains of mouse factor B linked to a mouse IgG1 Fc domain. Hybridomas were made from splenocytes of the immunized mouse. One mAb, designated 1379, produced an IgG1 antibody that inhibited alternative pathway activation in vitro and in vivo by preventing formation of the C3bBb complex. Strikingly, this mAb inhibited alternative pathway activation in serum from mice, rats, humans, monkeys, pigs and horses. Fab fragments made from this mAb also inhibited alternative pathway activation. Epitope mapping demonstrated that this antibody binds to factor B within the third SCR domain. When mAb 1379 was administered to mice that also received human IgG containing antiphospholipid antibodies, it provided significant protection from antiphospholipid antibody-induced complement activation and fetal loss. Thus, this mAb to factor B has broad species reactivity and effectively inhibits alternative pathway activation. The mAb protects mice in an in vivo model of antiphospholipid antibody syndrome, demonstrating the therapeutic potential for the inhibition of factor B in this disease.     

Inhibition of arachidonic acid cyclo-oxygenase and lipoxygenase activities of leukocytes by indomethacin and compound BW755C

Arachidonic acid is metabolized via two pathways in leukocytes: cyclo-oxygenase, leading to the stable prostaglandins, and lipoxygenase, leading to hydroxyacids. Indomethacin inhibits the cyclo-oxygenase selectively, whereas compound BW755C (3-amino-1-(m-(trifluoromethyl)phenyl)-2-pyrazoline) inhibits both pathways equally. This offers a possible explanation for the differing activities of these two compounds in inflammatory models in vivo. The patterns of product inhibition by the two compounds support the suggestion that 11-HETE (hydroxy-eicosatetraenoic acid) and 15-HETE can arise by incomplete operation of the cyclo-oxygenase pathway.     

Pharmacological evidence for stimulation of growth hormone secretion by a central noradrenergic system in dogs

The role of brain catecholamines in the regulation of growth hormone secretion was investigated in pentobarbital-anesthetized dogs by using drugs which modify the function of adrenergic neurons and receptors. Intravenous administration of L-dopa produced a prompt, statistically significant increase in plasma growth hormone concentration. This response was not significantly reduced by blockade of peripheral dopa decarboxylase activity with carbidopa. Clonidine, an alpha-agonist which penetrates the brain, increased plasma growth hormone secretion. Norepinephrine, epinephrine, dopamine and isoproterenol, catecholamines which do not penetrate the blood-brain barrier, failed to affect plasma growth hormone concentration when administered intravenously. Apomorphine did not produce a statistically significant increase in plasma growth hormone concentration when administered directly into the the third ventricle, and pimozide failed to abolish the increase in plasma growth hormone produced by L-dopa. The increase in plasma growth hormone concentration produced by intravenous L-dopa and clonidine was prevented by administration of phentolamine or phenoxybenzamine directly into the third ventricle. The response to L-dopa was also abolished by intraventricular procaine. In dogs in which central beta-adrenergic blockade was produced by intraventricular L-propranolol, the growth hormone response to L-dopa was greater than it was in control dogs treated with intraventricular D-propranolol. The data indicate that in pentobarbital anesthetized dogs, the increase in growth hormone secretion produced by L-dopa is mediated by norepinephrine, rather than dopamine, that the site of action of the norepinephrine is central, above the median eminence and inside the 'blood-brain barrier', and that the norepinephrine acts via alpha-adrenergic receptors.     

Prognostic values of galectin-3 and the macrophage migration inhibitory factor (MIF) in human colorectal cancers.

This study aims to investigate whether the immunohistochemical levels of expression of galectin-3 and the macrophage migration inhibitory factor (MIF) are associated with prognostic values in human colorectal tumors. This was performed on 99 specimens including 69 colorectal tumors (17 Dukes A, 19 Dukes B, 15 Dukes C and 18 metastatic tumors that we labeled as D), 10 hepatic metastases from colorectal cancers and 20 normal specimens (biopsies). The immunohistochemical levels of expression of MIF and galectin-3 were quantified on routine histological slides by means of computer-assisted microscopy. Separate analyses were performed on epithelial and connective tissue. The levels of expression of both MIF and galectin-3 were very significantly higher in epithelial tumor tissue when compared with normal epithelial specimens. A positive and significant correlation between MIF and galectin-3 expression was evidenced in connective tumor tissue, and in particular in the cases associated with short survival periods (less than 5 years). In the case of the Dukes A or B tumors, we established two new prognostic groups (labeled I and II) on the basis of the levels of galectin-3 expression measured in the tumor epithelium. In the case of the Dukes C or D tumors, we established two other prognostic groups (labeled III and IV) on the basis of the levels of MIF expression measured in the connective tissue. Kaplan-Meyer analyses confirmed the additional prognostic values (as compared with conventional clinical staging) given by this new classification (groups I to IV). They show that the Dukes A or B tumors characterized by low levels of galectin-3 expression in the tumor epithelium are associated with significantly better prognoses than those characterized by high levels. In addition, the Dukes C or D tumors characterized by high levels of MIF expression in the connective tumor tissue are associated with significantly better prognoses than those characterized by low levels. In conclusions, MIF and galectin-3 expression levels in colorectal tumors are related to their levels of biological aggressiveness. These markers could be used to identify patients at risk, for whom more aggressive adjuvant therapy seems to be indicated.     

Gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine: role of gastrectomy and duodenal reflux

The effect of gastrectomy and duodenal reflux on gastric carcinogenesis was studied because gastrectomized patients may be considered at "high risk" for the development of gastric stump cancer. Wistar rats received N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) (83 mg/liter) ad libitum in the drinking water for either four, eight, or twelve weeks. A control group received tap water. After MNNG administration animals were antrectomized. Antrectomy was not performed in a control group. Bowel continuity was restored either with a Billroth II (BIL) or with a ROUX en Y (ROUX) procedure. Duodenogastric reflux is possible after the BIL but not after the ROUX procedure. Eight months after the beginning of the experiment the stomachs of the animals were studied. In both operated and unoperated animals, the number of cancers observed was significantly related to the duration of MNNG administration. Animals receiving MNNG plus the BIL procedure had a significantly higher number of anastomotic cancers than the ROUX animals, indicating that duodenogastric reflux played a promotional role in gastric carcinogenesis. Three BIL gastrectomized rats not receiving the carcinogen had an adenocarcinoma on the anastomotic line further emphasizing the risk attached to the duodeno-gastric reflux.     

Human chorionic gonadotrophin and immature fish ovary: characterization and mechanism of the in vitro stimulation of cyclic adenosine monophosphate accumulation

Human chorionic gonadotrophin (hCG) increased cyclic adenosine monophosphate (cAMP) in pieces of eel ovary in vitro. Although the ED50 (about 0.1 micrograms/ml) was the same as for carp gonadotrophin (cGTH), the maximal stimulation (close to 3 times basal level) was about 10 times lower than that for the fish hormone. The mechanism of this atypical action of hCG was studied using different approaches. Human CG did not inhibit the action of cGTH. Desensitization experiments (cGTH or hCG being injected in vivo 18 hr before the sampling of the ovary) were carried out; the in vitro action of hCG was suppressed by both pretreatments; the in vitro action of cGTH was largely reduced by in vivo cGTH and to a much lesser extent by in vivo hCG. Together with other data the results indicated that hCG acts via binding to adenylate cyclase-coupled receptors which also recognize cGTH; moreover, they suggested that among those systems only a fraction can be activated by hCG. We propose that in teleosts the pool of GTH receptors is not homogeneous but contains classes of "isoreceptors" differing by their recognition specificity at least. Parallel studies with ovine lutrophin (oLH) indicated that this hormone binds to the same adenylate cyclase-coupled receptors which are sensitive to hCG but that it does it with a much lower affinity. Other characteristics of oLH/hCG-stimulated receptor-adenylate cyclase systems include an important release of cAMP into the incubation medium. The precise physiological significance of GTH "isoreceptors" still requires clarification. The ability of hCG to induce desensitization must be considered in fish culture experiments using this hormone.     

Takayasu's arteritis: a pathogenetic role for cytotoxic T lymphocytes?

Takayasu's arteritis is an inflammatory panarteritis of unknown aetiology affecting large elastic arteries. We examined a segment of abnormal common carotid artery removed at by-pass surgery from a 23-year-old man with typical angiographic features of Takayasu's arteritis. Using monoclonal antibodies we were able to demonstrate marked infiltration of the arterial wall with OKT8 positive lymphocytes (suppressor/cytotoxic cells) but not with OKT4 positive lymphocytes (helper cells). Studies of circulating lymphocytes showed increased numbers of "activated" cells and increased in vitro cytotoxicity against cultured human umbilical cord endothelial cells, compared to normal lymphocytes. Cellular immunological mechanisms may play an important role in the pathogenesis of Takayasu's arteritis, possibly through the direct action of cytotoxic T cells on large elastic arteries.     

Evaluation of anticancer drug schedule dependency using an in vitro human tumor clonogenic assay

Summary A human tumor clonogenic assay (HTCA) has been used to evaluate standard and experimental anticancer drugs with respect to thrir inhibition of clonogenicity of both fresh human cancers and human tumor cell lines. By comparing the inhibitory effect on tumor colony-forming unit (TCFU) growth of 1-h and continuous drug exposures in the HTCA we were able to identify and separate schedule-dependent (e.g., bleomycin, vinblastine, and etoposide) and schedule-independent drugs (e.g., actinomycin D, adriamycin, basantrene, and cis-platinum). Vinblastine, bleomycin, and etoposide, which are known to have cell cycle-specific characteristics, caused exponential reduction in tumor colony formation when given by continuous exposure, whereas when given with a short exposure each of these drugs caused plateau-type dose-response curves. For comparison of the relative efficacy of the two dosing schedules, a ratio (1-h versus continuous exposures) was calculated of the drug concentrations which reduced growth of TCFU to 50% of the control values (ID₅₀) for fresh human tumors and human tumor cell lines. For fresh tumors, ID₅₀ ratios for adriamycin, actinomycin D, and bisantrene ranged between 2 and 60 (median 14), whereas the ID₅₀ ratios for bleomycin, vinblastine, and etoposide ranged between 100 and 3,000 (median 600). The fact that actinomycin D, adriamycin, and bisantrene (a new anthracene-type drug) had similarly shaped dose-response curves and very low ID₅₀ ratios suggests that the cytotoxicity of these compounds may not be schedule-dependent. On the other hand, the steep dose-survival curves we observed after continuous drug exposure and the high ID₅₀ ratios of bleomycin, vinblastine, and etoposide suggest that these drugs may possess schedule-dependent cytotoxicity characteristics. Before final conclusions are drawn concerning a drug's schedule dependency it is essential to evaluate its in vitro stability and protein-binding characteristics. Finally, it must be emphasized that unlike the results obtained with 1-h exposure studies, the in vitro continuous exposure schedules have yet to be shown to be predictive of clinical response for any agent or tumor type.     

Perceptions of Sexual Images: Factors Influencing Responses to the Ubiquitous External Ejaculation

The debate over pornography has drawn attention to sex differences not only in the frequency of pornography consumption but also in the different ways males and females may perceive sexually explicit images and respond to them. Some of these differences may be due to sex differences in a variety of factors including sexual strategies and disgust, in particular, disgust related to pathogen avoidance. There is a large literature that focuses on how pathogen avoidance has shaped human behavior from political ideology to in-group/outgroup behavior to sexual risk taking/avoidance. This study examined sex differences in perceptions and how they are influenced by the emotional context of the image as well as individual difference factors, including disgust sensitivity, mate value, sociosexuality, and sexual orientation. Participants viewed a series of sexually explicit images of external ejaculations and rated them in terms of being positive, neutral, or negative. The factors accounting for the greatest variance in perceptions were target affect and sex, sexual orientation, and respondent sex, followed by pathogen and sexual disgust, self-perceived mate value, and sociosexual attitudes and desire.

     

The prevalence of dementia and Alzheimer's disease in Shanghai, China: impact of age, gender, and education

We report the prevalence rates for dementia and Alzheimer's disease (AD) obtained from a probability sample survey of 5,055 noninstitutionalized older persons in Shanghai, China. A two-stage procedure was used for case finding and case identification. A Chinese version of the Mini-Mental State Examination was used to determine cases of possible dementia. Three different cutoff points on this mental status test were used depending on the respondent's level of education. Clinical evaluations, based on functional assessments and psychiatric interview, medical and neurological examinations, three standardized mental status tests, and a selected group of psychometric tests, were made in the second stage of the study to ascertain the clinical diagnosis of dementia and AD utilizing the Diagnostic and Statistical Manual for Mental Disorders, edition 3 and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, respectively. The prevalence rate of dementia in persons 65 years and older was 4.6%. Clinically diagnosed AD accounted for 65% of the subjects with dementia. These findings indicate that the prevalence of dementia in Shanghai is very much higher than figures published earlier for China and Japan, and at the lower part of the range of values reported for community residents in the United States and other Western countries, but less than half of that reported in the recently published survey of the elderly in East Boston. Increasing age, gender (female), and low education are each highly significant and independent risk factors for dementia. One hypothesis to explain the increased prevalence in elderly women who had received no formal education invokes the possibility of an effect of early deprivation, perhaps lowering brain "reserve," allowing the symptoms of dementia to appear at an earlier date during disease progression.