Escaping traps: Malthusian and intellectual.

A review of Alan Macfarlane's The savage wars of peace: England, Japan and the Malthusian trap (1997).

Perceptions of spouse dominance predict blood pressure reactivity during marital interactions.

Cardiovascular reactivity (CVR) has been identified as a potential mechanism linking a variety of psychosocial processes to the development of cardiovascular disease. Although the effects of hostile and supportive social stimuli on CVR have been studied extensively, less is known about the effects of a second major dimension of social relations--dominance versus submissiveness. In the present study, 45 married couples participated in an interaction task involving the assertion of differing opinions. Subjects also provided ratings of their typical level of dominance versus submissiveness in relation to their spouse. Consistent with predictions derived from related conceptual models of psychological determinants of CVR, blood pressure reactivity was positively associated with perceptions of the spouse as dominant. At the highest level of perceived spouse dominance, CVR was attenuated, again consistent with prediction. Results are discussed in terms of the usefulness of conceptual models of interpersonal relations and motivation as guides in studying the social determinants of CVR, as well as the value of marital interactions as a context for understanding CVR.

Multidrug resistance gene expression in rodents and rodent hepatocytes treated with mitoxantrone.

Overexpression of P-glycoprotein in tumor cells can represent a severe drawback for cancer chemotherapy. P-glycoprotein acts as an efflux transporter for a variety of chemotherapeutic agents. It is encoded by multidrug resistance (mdr) genes of the subfamily 1 in humans (MDR1) and rodents (mdr1a and 1b). Because mdr1 gene expression is inducible in cultured rat hepatocytes and in rat liver with chemical carcinogens such as 2-acetylaminofluorene or aflatoxin B1, which form DNA-binding electrophiles during their metabolism, we investigated whether the DNA-damaging chemotherapeutic drug mitoxantrone may induce multidrug resistance in rodents and in hepatocytes in primary culture. In H4IIE rat hepatoma cells stably transfected with a luciferase construct containing the rat mdr1b promoter, mitoxantrone caused a concentration-dependent increase in promoter activity. Mdr1 gene expression in cultured rat hepatocytes was enhanced at mitoxantrone concentrations greater than or equal to 0.1 microM and in mouse hepatocytes at 5 microM. In hepatocytes from both species, a correlation was found between mdr1 induction and the inhibition of protein synthesis. In vivo, mitoxantrone was a very powerful inducer of mdr1 gene expression in rat liver and small intestine. In rat kidney, induction of mRNA was lower, and a marginal effect was seen in lung. In contrast with rats, no significant induction of mdr1 gene expression was obtained in mouse liver. Probably as a consequence of inhibition of protein synthesis, mitoxantrone did not lead to a pronounced elevation of P-glycoprotein levels in rat liver and kidney.

Characterization of the rat mdr2 promoter and its regulation by the transcription factor Sp1.

The mdr2 gene encodes a P-glycoprotein that transports phospholipids across the canalicular membrane in hepatocytes. In this report we describe the isolation, sequencing and first functional characterization of the promoter of mdr2. Analysis of 1.6 kb of DNA upstream of the initiation of translation revealed that this sequence has a high GC content, lacks a TATA element and contains a number of putative transcription factor binding sites. We observed that transcription initiates at several sites between -290 and -463 and that this region was critical for promoter activity. Gel mobility shift assays indicated that Sp1 protein binds to a Sp1 consensus site located at -263. Co-expression of Sp1 protein with a reporter construct containing the -263 GC box demonstrated that Sp1 regulates transcription of this promoter. Expression of a non-functional Sp1 protein did not increase transcription from the mdr2 promoter. Mutation of the -263 GC box diminished the response of the promoter to Sp1 protein. Mutation of this site also decreased expression of this promoter in cells which normally express this gene. These data show that Spl has a role in the regulation of mdr2 expression.

Experimental Mallory body formation is accompanied by modulation of the expression of multidrug-resistance genes and their products.

Mallory bodies (MBs) are characteristic morphological features of alcoholic hepatitis and are also found in other chronic liver disorders and hepatocellular neoplasms. MBs can be produced in mouse liver by chronic administration of the porphyrinogenic drugs griseofulvin (GF) and 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). The mechanisms causing the formation of MBs are poorly understood, and the significance of MB formation during the course of liver disease remains unclear. We investigated the relationship between the mechanisms underlying the formation of MBs and the regulation of multidrug resistance (mdr) genes and their products, the P-glycoproteins (Pgp). Immunofluorescence microscopy using the monoclonal antibody C219 revealed an increase of Pgp expression in almost all hepatocytes after 3 to 8 days of feeding mice DDC- and GF-containing diets. However, after approximately 4 weeks of DDC and approximately 8 weeks of GF feeding, when the first small MBs appeared and loosening and diminution of keratin intermediate filament (KIF) cytoskeleton occurred in some hepatocytes, a decrease or loss of Pgp staining in affected hepatocytes was observed. After feeding mice DDC for 6 weeks and GF for 12 weeks, many hepatocytes contained MBs and displayed a disruption of the immunohistochemically demonstrable KIF meshwork. Double immunofluorescence microscopy with the keratin polyclonal antibody and the mab C219 at this time point revealed a complete loss of Pgp staining in affected cells, although remaining hepatocytes with unaltered KIF meshwork showed a strong reaction with the C219 antibody. Northern blot analyses revealed a significant increase of mdr2 mRNA and, to a lesser extent, of mdr1a mRNA in the livers of DDC- and GF-fed animals.

Induction of a permeability transition in rat kidney mitochondria by pentachlorobutadienyl cysteine: a beta-lyase-independent process.

A Ca2+-dependent inner mitochondrial membrane permeability transition is induced by a number of agents, an effect which is thought to cause cytotoxicity. This transition involves formation of a pore allowing the passage of solutes of up to 1500 Da; it is blocked by cyclosporine A and Ca2+ chelating agents. The mitochondrial nephrotoxicant S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine (PCBC) caused collapse of the mitochondrial membrane potential, Ca2+-independent oxidation of pyridine nucleotides and release of accumulated Ca2+ in isolated rat kidney mitochondria, three hallmarks of the permeability transition. These effects were blocked by cyclosporine A and by ethylene glycol bis(beta-aminoethyl ether) tetraacetic acid (EGTA). Furthermore, EGTA was capable of reversing the collapse of the membrane potential. These data indicate that PCBC induced an inner membrane permeability transition. Interestingly, addition of aminoxyacetic acid, a beta-lyase inhibitor, did not prevent the permeability transition, and a nonmetabolizable analog of PCBC, S-(1,2,3,4, 4-pentachlorobutadienyl)-L-alpha-methyl cysteine, induced the permeability transition. Thus PCBC may act to induce the permeability transition through a mechanism that does not require metabolism by a beta-lyase. Since metabolism by a beta-lyase is required for PCBC toxicity, it is not clear that the permeability transition is involved in cysteine conjugate-mediated renal cell injury.

Regulation of mdr1b gene expression in Fischer, Wistar and Sprague-Dawley rats in vivo and in vitro.

Administration of 2-acetylaminofluorene (2-AAF) to rats increased mdr1b expression in Fischer, Wistar and Sprague-Dawley rat livers; however, the response was much smaller in Sprague-Dawley livers. To investigate the basis of this difference we further examined the regulation of the mdr1b gene in hepatocytes isolated from Fischer, Sprague-Dawley and Wistar rats. A time-dependent increase in basal expression of mdr1b but not mdr2 was observed in hepatocytes isolated from all three strains of rats. After 4 days in culture, a larger increase in mdr1b mRNA levels was observed in Fischer and Wistar rat hepatocytes (3.5- and 4.6-fold respectively) than Sprague-Dawley hepatocytes (2-fold). Treatment of primary hepatocytes with 2-AAF caused an induction of mdr1b expression that varied among the three strains. Notably, Sprague-Dawley hepatocytes were not responsive to 2-AAF. In contrast to the parent compound, the electrophilic metabolites N-hydroxy-2-acetylaminofluorene and N-acetoxy-2-acetylaminofluorene caused a dose-dependent induction of mdr1b expression in both Fischer and Sprague-Dawley hepatocytes, indicating that differences in the metabolic activation of 2-AAF between the strains may account for the differences in mdr1b by 2-AAF. Hepatocytes isolated from all three strains of rats showed an equivalent induction of mdr1b after treatment with cycloheximide. Nuclear run-on assays demonstrated that the increases in mdr1b expression with time in culture and after xenobiotic treatment were due to increased transcription.

Hepatic spiral CT: reduction of dose of intravenous contrast material.

PURPOSE: To assess the potential for reduction of contrast material dose in hepatic spiral computed tomography (CT). MATERIALS AND METHODS: Four hundred eighty-seven outpatients were randomized prospectively into nine biphasic and eight uniphasic injection protocols: 75, 100, or 125 mL of 240, 300, or 350 mg of iodine per milliliter of iohexol (18-44 grams of iodine). Protocols were compared according to the maximum hepatic enhancement (MAX) and the contrast enhancement index (CEI). RESULTS: Uniphasic injection was superior to biphasic injection for all protocols. No statistically significant difference in contrast enhancement was present for 38-44 grams of iodine with the uniphasic technique. Adequate enhancement thresholds (MAX > 50 HU, CEI at 30 HU > 300 HU x sec) were exceeded in more than 70% of heavy patients ( > 183 lb [83 kg]) with uniphasic injection of 38 g. For thin patients ( < 183 lb [83 kg]), uniphasic injection of 26 g produced adequate enhancement. CONCLUSION: Contrast material dose may be reduced by up to 40% in thin patients undergoing hepatic spiral CT after uniphasic injection of contrast material; this may result in substantial cost savings.

Cost-effective use of low-osmolality contrast media for CT of the liver: evaluation of liver enhancement provided by various doses of iohexol.

OBJECTIVE: Because of pending efforts to reform health care in the United States, judicious use of low-osmolality contrast media is important. We studied the effects of using various concentrations and volumes of iohexol, compared with the conventional dose and concentration of diatrizoate meglumine used for CT, to determine if a more cost-effective dose results in diagnostically efficacious liver enhancement. SUBJECTS AND METHODS: A total of 902 patients received one of nine different doses of IV contrast media. Eight doses of iohexol were used: 125 ml of iohexol 350 (350 mg l/ml, 44 g l/dose), 100 ml of iohexol 350 (35 g l/dose), 150 ml of iohexol 300 (300 mg l/ml, 45 g l/dose), 120 ml of iohexol 300 (36 g l/dose), 100 ml of iohexol 300 (30 g l/dose), 175 ml of iohexol 240 (240 mg l/ml, 42 g l/dose), 150 ml of iohexol 240 (36 g l/dose), and 125 ml of iohexol 240 (30 g l/dose). A single dose (150 ml) of diatrizoate meglumine 60% (w/v) was used (42 g l/dose). Contrast material was injected at a rate of 2 ml/sec. Scanning began 35-45 sec after injection. Quantitative analysis of enhancement was performed by obtaining region-of-interest measurements through the liver on scans obtained before and after injection of contrast material. Mean and maximum changes in hepatic density and mean time to maximum enhancement were measured. Mean time-density curves were subsequently derived for each dose of contrast material. Qualitative analysis of enhancement was performed by using subjective, previously defined criteria. All studies were interpreted in a double-blind fashion. RESULTS: Mean hepatic enhancement was greater with 125 ml of iohexol 350 and 150 ml of iohexol 300 than with other doses of contrast material (p < .05). Both 125 ml of iohexol 350 and 150 ml of iohexol 300 produced actual hepatic enhancement of more than 50 H for over 60 sec. The greatest maximum increase in hepatic density occurred with 125 ml of iohexol 350. When analyzed qualitatively, 150 ml of iohexol 300 resulted in the highest percentage of optimum enhancement. CONCLUSION: According to quantitative analysis, 125 ml of iohexol 350 administered at a rate of 2 ml/sec produces the best enhancement, whereas according to qualitative analysis, 150 ml of iohexol 300 produces the best enhancement. All doses of iohexol 240 provide poor enhancement compared with a conventional dose of contrast material of 150 ml of diatrizoate meglumine 60% or 150 ml of iohexol 300. A moderate cost savings can be achieved by using 125 ml of iohexol 350 for dynamic sequential CT.

Cloning and regulation of the rat mdr2 gene.

We have cloned the complete cDNA encoding the rat mdr2 gene by a combination of library screening and the polymerase chain reaction. The sequence of rat mdr2 cDNA is highly similar to other members of the mdr gene family but the initiation of transcription, tissue distribution and regulation of expression of rat mdr2 diverge from the other isoforms. Primer extension analysis showed rat mdr2 mRNA to have a major transcription start point at -277 and a minor one at approximately -518. We constructed gene specific probes for rat mdr2 and mdr1b and compared the expression patterns of these two genes. The highest expression of mdr2 mRNA was in the muscle, heart, liver and spleen. Both mdr2 and 1b mRNA levels were elevated in the livers of rats treated with CCl4 or following partial hepatectomies although the time course of induction of each gene differed. Mdr1b increased by 12 to 24 hours while mdr2 did not increase until 48 hours. Treatment of isolated hepatocytes or RC3 cells with cycloheximide did not effect mdr2 mRNA. In contrast, mdr1b expression was increased. These data suggest that rat mdr2, unlike mdr1b, is not regulated by a negative trans-acting protein factor.

Ultrastructural changes in acquired perforating dermatosis.

We performed ultrastructural studies of skin lesions in seven adults with acquired perforating dermatosis. Three of the patients had diabetes mellitus and two were undergoing hemodialysis. Lesions in an early stage showed exocytosis of inflammatory cells and alteration of elastic fibers. Lesions in an intermediate stage featured discontinuities of the basement membrane and aggregates of electron-dense material lateral to the perforated focus, together with dermal edema, scattered macrophages, and densely aggregated collagen fibers that focally filled the papillary dermis. Later-stage lesions showed fibroblasts in the dermis and degenerated elastic fibers within transepidermal channels. In most cases there was a single large epidermal channel lined by flattened epithelial cells, and containing a variety of cellular and extracellular materials. Small "secondary" channels without abnormal keratinization were also observed within the epidermis. The findings suggest that altered keratinization is limited to the immediate vicinity of well-formed transepidermal channels, and that exocytosis of inflammatory cells and alterations of elastica are early and possibly key changes in lesion development. The unexpected discovery of hair fragments in one case suggests that curled hairs may play a role in the pathogenesis of some cases of acquired perforating dermatosis.

Comparison of iohexol 300 and diatrizoate meglumine 60 for body CT: image quality, adverse reactions, and aborted/repeated examinations.

Six hundred patients were prospectively randomized and given either diatrizoate meglumine 60 or iohexol 300 during dynamic contrast-enhanced body CT in order to compare image quality, contrast reactions, and the number of aborted studies or studies in which images had to be repeated. Three hundred two patients received iohexol 300, and 298 patients received diatrizoate meglumine 60. Thirty-nine percent (119/302) of the patients given iohexol 300 and 63% (188/298) of the patients given diatrizoate meglumine 60 had at least one adverse reaction thought to be related to contrast material during, or within 24 hr of, the body CT scan. When reactions of discomfort (heat or warmth, flushing, bad taste) were excluded, 16% (48/302) of the patients who received iohexol and 33% (99/298) of the patients who were given diatrizoate meglumine 60 had at least one adverse reaction. The differences in both types of reactions between the two agents were significant (p less than .001). Among scans evaluated for study quality, 71% (214/302) of the iohexol 300 group and 62% (184/298) of the diatrizoate meglumine 60 group had optimal enhancement (p = .02). However, when the optimal and adequate categories were combined, 301 of 302 patients given iohexol 300 and 292 of 298 patients given diatrizoate meglumine 60 had diagnostic-quality studies (no statistical difference). Studies were not terminated nor were images repeated in 97% (292/302) of the patients given iohexol 300 and in 94% (280/298) of those given diatrizoate meglumine 60. The CT study was repeated because of movement during the contrast injection or aborted because of contrast-related reactions in 0.7% of the patients given iohexol 300 and in 3.0% of the patients given diatrizoate meglumine 60. This difference was statistically significant (p = .04). Our results suggest that the difference in image quality, number of adverse reactions, and number of aborted/repeated CT scans performed with iohexol 300 or diatrizoate meglumine 60 are not sufficiently different to warrant conversion to nonionic agents for body CT scans.

Social influence, marriage, and the heart: cardiovascular consequences of interpersonal control in husbands and wives.

Human and experimental animal research suggests that social stress in general--and chronic, effortful attempts to exert social control in particular--may contribute to cardiovascular disease. We examined the effects of exerting social influence or control on cardiovascular responses in married couples. Compared to husbands discussing a problem with their wives, husbands attempting to influence or persuade their wives displayed larger increases in systolic blood pressure (SBP) before and during the discussion. Furthermore, these physiological effects were accompanied by increases in anger and a more hostile and coldly assertive interpersonal style. Although wives who engaged in social influence attempts displayed generally similar behavior, they did not show the elevated SBP response or anger. We discuss the results in terms of the social context of cardiovascular reactivity and potential marital factors in cardiovascular health.

Cynical hostility, attempts to exert social control, and cardiovascular reactivity in married couples.

Chronically hostile persons may be at greater risk of cardiovascular illness, perhaps because of their more pronounced physiologic responses to interpersonal stressors. The present study of married couples examined the association between Cook and Medley Hostility (Ho) Scale scores and cardiovascular reactivity while couples were engaged in a discussion task with or without an incentive to exert control over their partner. Cynical hostility was associated with greater heart rate (HR) reactivity among husbands in both conditions and with greater systolic blood pressure (SBP) reactivity among husbands attempting to influence their wives. Further, husbands' cynical hostility was associated with greater SBP reactivity in their wives. Wives' cynical hostility was unrelated to their own or their husbands' reactivity. These results underscore the importance of social contexts in the association between hostility and psychophysiologic processes and suggest that the motive to exert social control may be important for hostile persons.

Effect of allyl alcohol on xanthine dehydrogenase activity in the perfused rat liver.

Xanthine oxidase has been implicated in the production of reactive oxygen species and cell injury produced by various toxic compounds. Since allyl alcohol injuries the liver by an oxygen-dependent mechanism, we examined the actions of this hepatotoxicant on the conversion of xanthine dehydrogenase into xanthine oxidase in perfused livers. A microassay for NAD(+)-dependent xanthine dehydrogenase, based on measuring the production of NADH fluorometrically under anaerobic conditions, was developed and used to examine the actions of allyl alcohol on this activity in periportal and pericentral regions of the liver lobule. The oxygen-dependent activity, xanthine oxidase, was monitored in whole liver homogenates by uric acid formation at 302 nm under aerobic conditions. Perfusion of the liver with allyl alcohol (350 microM) increased xanthine oxidase and decreased xanthine dehydrogenase in whole liver consistent with the hypothesis that allyl alcohol enhanced calcium-dependent proteolytic conversion of the NAD(+)-dependent to the O2-dependent form. Xanthine dehydrogenase was higher in pericentral than in periportal regions of the liver lobule and tended to decrease selectively in periportal zones of livers exposed to allyl alcohol. O2 uptake was stimulated transiently by allyl alcohol followed by subsequent inhibition of respiration. These results are consistent with the idea that conversion of NAD(+)-dependent xanthine dehydrogenase to xanthine oxidase is involved in the zone-specific hepatotoxicity of allyl alcohol.

The toxicity of menadione (2-methyl-1,4-naphthoquinone) and two thioether conjugates studied with isolated renal epithelial cells.

Menadione (2-methyl-1,4-naphthoquinone) was used as a model compound to test the hypothesis that thioether conjugates of quinones can be toxic to tissues associated with their elimination through a mechanism involving oxidative stress. Unlike menadione, the glutathione (2-methyl-3-(glutathion-S-yl)-1,4-naphthoquinone; MGNQ) and N-acetyl-L-cysteine (2-methyl-3-(N-acetylcysteine-S-yl)-1,4-naphthoquinone; M(NAC)NQ) thioether conjugates were not able to arylate protein thiols but were still able to redox cycle with cytochrome c reductase/NADH and rat kidney microsomes and mitochondria. Interestingly, menadione and M(NAC)NQ were equally toxic to isolated rat renal epithelial cells (IREC) while MGNQ was nontoxic. The toxicity of both menadione and M(NAC)NQ was preceded by a rapid depletion of soluble thiols and was associated with a depletion of soluble thiols and was associated with a depletion of protein thiols. Treatment of IREC with the glutathione reductase inhibitor, 1,3-bis(2-chloroethyl)-1-nitrosourea, potentiated the thiol depletion and toxicity observed with menadione and M(NAC)NQ indicating the involvement of oxidative stress in this model of renal cell toxicity. The lack of MGNQ toxicity can be attributed to an intramolecular cyclization reaction which destroys the quinone nucleus and therefore eliminates its ability to redox cycle. These findings have important implications with regard to our understanding of the toxic potential of quinone thioether conjugates and of quinone toxicity in general.