Weighing up the evidence -- a systematic review of measures used for the sensation of breathlessness in obesity.

Breathlessness on exertion is common in people with obesity. Assessments of breathlessness may include sensation (intensity, sensory quality or unpleasantness) and/ or the behavioral/emotional consequences of the sensation (respiratory-related functional impairment, disability or quality of life). This systematic review of primary studies published since 2005 evaluated how has the sensation of breathlessness been assessed in adults with increased adiposity. A total of 41 articles were retained from the systematic search strategy resulting in 20 instruments. The Modified Borg Scale (perceived exertion-intensity), the Medical Research Council (MRC) Scale and Baseline Dyspnea Index (BDI; both assess respiratory-related functional impairment) were, respectively, the most frequently reported instruments. Few instruments had been tested for reliability and validity in people with increased adiposity. Visual Analog Scale, Modified Borg Scale, descriptors of sensory quality, MRC and BDI can be recommended as instruments based on their psychometric properties (reliability (correlations >0.8) and concurrent validity (correlation with severity of airways obstruction and walking distance)). A greater number of instruments were identified that assessed the consequences of the breathlessness rather than breathlessness as a sensation. If sensation drives behavior, comprehensive data on the sensation of breathlessness might assist in understanding the behavioral consequences of interventions.

Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology.

Cultured primary epithelial cells are used to examine inflammation in cystic fibrosis (CF). We describe a new human model system using cultured nasal brushings. Nasal brushings were obtained from 16 F508del homozygous patients and 11 healthy controls. Cells were resuspended in airway epithelial growth medium and seeded onto collagen-coated flasks and membranes for use in patch-clamp, ion transport, and mediator release assays. Viable cultures were obtained with a 75% success rate from subjects with CF and 100% from control subjects. Amiloride-sensitive epithelial Na channel current of similar size was present in both cell types while forskolin-activated CF transmembrane conductance regulator current was lacking in CF cells. In Ussing chambers, cells from CF patients responded to UTP but not to forskolin. Spontaneous and cytomix-stimulated IL-8 release was similar (stimulated 29,448 ± 9,025 pg/ml; control 16,336 ± 3,308 pg/ml CF; means ± SE). Thus nasal epithelial cells from patients with CF can be grown from nasal brushings and used in electrophysiological and mediator release studies in CF research.

Middle ear osteoma: a rare cause of conductive hearing loss with normal tympanic membrane.

Osteomas of the temporal bone are benign osseous tumors usually located to the external auditory canal. Osteomas involving the middle ear are very rare. We report the case of a patient presenting with a progressive hearing loss caused by a middle ear osteoma involving the incus and contiguous to the tympanic segment of the facial nerve. This report highlights the value of CT scan in the work-up of conductive or mixed hearing loss with normal tympanic membrane. The management of middle ear osteoma is discussed.

Review of Conventional and High Dose Rate Brain Radiation (FLASH): Neurobehavioural, Neurocognitive and Assessment Issues in Rodent Models.

Ionising radiation causes secondary tumours and/or enduring cognitive deficits, especially in children. Proton radiotherapy reduces exposure of the developing brain in children but may still cause some lasting effects. Recent observations show that ultra-high dose rate radiation treatment (≥40 Gy/s), called the FLASH effect, is equally effective at tumour control but less damaging to surrounding tissue compared with conventional dose rate protons (0.03-3 Gy/s). Most studies on the FLASH effect in brain and other tissues with different radiation modalities (electron and photon radiation), show FLASH benefits in these preclinical rodent models, but the data are limited, especially for proton FLASH, including for dose, dose rate and neurochemical and neurobehavioural outcomes. Tests of neurocognitive outcomes have been limited despite clinical evidence that this is the area of greatest concern. The FLASH effect in the context of proton exposure is promising, but a more systematic and comprehensive approach to outcomes is needed.

MR Imaging Characteristics of Intraocular Perfluoro-n-Octane.

We describe the unique MR imaging characteristics of intraocular perfluoro-n-octane, a liquid used for intraoperative and postoperative tamponade in the context of complex retinal detachment repair, and contrast it with other intraocular pathologies. Because trace amounts of perfluoro-n-octane may be left in the globe postoperatively, it may be confused for other abnormalities, such as foreign bodies or tumors.

Effects on plasma corticosterone levels and brain serotonin from interference with methamphetamine-induced corticosterone release in neonatal rats.

Methamphetamine (MA) induces multiple effects in rats including alterations to corticosterone (CORT) and adrenocorticotropic hormone (ACTH). This effect is age dependent showing a U-shaped function similar to that of other stressors during the stress hyporesponsive period. Neonatal MA treatment leads to adult learning and memory impairments, but whether these are related to MA-induced CORT release is unknown. Here in, four methods were tested in neonatal rats previously established in adult rats for inhibiting stress-induced CORT release: inhibiting synthesis (metyrapone (MET) or ketoconazole (KTZ)) or surgically by adrenalectomy or adrenal autotransplantation (ADXA). Pretreatment on postnatal day 11 with MET or KTZ prior to four doses of 10 mg/kg of MA initially suppressed MA-induced increases in plasma CORT, but 24 h later, even with additional inhibitor treatment, a large CORT increase was seen which exceeded that of MA alone. Adrenalectomy blocked MA-induced increases in CORT but caused a secondary effect on brain serotonin (5-HT) and dopamine (DA), causing greater reductions than those caused by MA alone. ADXA inhibited MA-induced CORT release without causing a 24-h CORT increase and did not produce additional effects on brain 5-HT or DA. Neonatal ADXA is a new model for developmental drug or stress experiments designed to test the role of CORT in mediating early effects on later outcomes.

Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8.

Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8 flox ) mice to create ubiquitous Slc6a8 knockout (Slc6a8-/y ) mice. Slc6a8-/y mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8-/y mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8flox mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8 -/y mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8 -/y mice. The results show that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8-/y mice.

[Superior semicircular canal dehiscence mimicking otosclerosis: usefulness of imaging]. / Déhiscence du canal semi-circulaire antérieur mimant une otospongiose: intérêt de l'imagerie.

OBJECTIVES: To emphasize the role of computerized tomography (CT) in the etiologic work-up of stapes surgery failure. MATERIAL AND METHODS: Helical high resolution CT scan of the temporal bone with axial and coronal views and multiplanar reconstructions was performed in a patient who had undergone unsuccessful stapedectomy. RESULTS: CT scan demonstrated a well located prosthesis, the absence of the radiological hallmarks of otosclerosis, and revealed a superior semicircular canal dehiscence (SSCD). The diagnosis of SSCD was retrospectively considered accountable for the preoperative clinical and audiometric presentation that had mimicked otosclerosis. CONCLUSION: CT is the diagnostic test of choice in elucidating stapes surgery failure (with persistent or recurrent conductive hearing loss), whereas SSCD should be systematically considered among its causes.

Phosphodiesterase-1b deletion confers depression-like behavioral resistance separate from stress-related effects in mice.

Phosphodiesterase-1b (Pde1b) is highly expressed in striatum, dentate gyrus, CA3 and substantia nigra. In a new Floxed Pde1b × CreCMV global knockout (KO) mouse model, we show an immobility-resistance phenotype that recapitulates that found in constitutive Pde1b KO mice. We use this new mouse model to show that the resistance to acute stress-induced depression-like phenotype is not the product of changes in locomotor activity or reactivity to other stressors (learned helplessness, novelty suppressed feeding or dexamethasone suppression), and is not associated with anhedonia using the sucrose preference test. Using tamoxifen inducible Cre, we show that the immobility-resistant phenotype depends on the age of induction. The effect is present when Pde1b is Reduced from conception, P0 or P32, but not if reduced as adults (P60). We also mapped regional brain expression of PDE1B protein and of the Cre driver. These data add to the suggestion that PDE1B may be a target for drug development with therapeutic potential in depression alone or in combination with existing antidepressants.

Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice.

Mice lacking phosphodiesterase 1B (PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 receptor agonist, SKF81297. These results indicated a possible regulatory role for PDE1B in pathways involving DARPP32. Here, we generated PDE1B x DARPP32 double-knockout (double-KO) mice to test the role of PDE1B in DARPP32-dependent pathways in vivo. Analysis of the response to d-methamphetamine on locomotor activity showed that the hyperactivity experienced by PDE1B mutant mice was blocked in PDE1B-/- x DARPP32-/- double-KO mice, consistent with participation of PDE1B and DARPP32 in the same pathway. Further behavioral testing in the elevated zero-maze revealed that DARPP32-/- mice showed a less anxious phenotype that was nullified in double-mutant mice. In contrast, in the Morris water maze, double-KO mice showed deficits in spatial reversal learning not observed in either single mutant compared with wild-type mice. The data suggest a role for PDE1B in locomotor responses to psychostimulants through modulation of DARPP32-dependent pathways; however, this modulation does not necessarily impact other behaviors, such as anxiety or learning. Instead, the phenotype of double-KOs observed in these latter tasks may be mediated through independent pathways.

[Imaging in adult chronic otitis]. / Imagerie des otites chroniques de l'adulte.

Chronic otitis media (COM) can be divided into two subtypes: COM with cholesteatoma (including precholesteatomatous states) is an aggressive form of otitis. Surgical treatment is mandatory because of the risk for labyrinthine or cerebromeningeal complications. CT is very important in the preoperative work-up (extension of cholesteatoma, anatomic variants). In patients who have undergone middle ear surgery, CT and presently MRI play an increasing role in the detection of recurrent or relapsing cholesteatoma. COM without cholesteatoma does not have an osteolytic potential, but may leave auditive sequelae that in selected cases may warrant surgical treatment to improve hearing. CT is useful in the etiological work-up of patients with severe hypoacusis. CT also plays an important role in cases of surgical failure, to detect a dislocation of the ossiculoplasty or impairment of the middle ear caused by fluid effusion. The objective of this paper is to specify the indications, the results and the limits of pre- and postoperative imaging in COM.

Characterization of microsomal methyl sterol demethylase in two Morris hepatomas.

Previously, we reported that the rate of metabolism of methyl sterol intermediates of cholesterol biosynthesis by broken-cell preparations of Morriss hepatoma 7777 is very slow, whereas the intact tumors are known to synthesize cholesterol quite efficiently. Active preparations have now been obtained by substitution of pyrophosphate for phosphate buffer. Although substitution of pyrophosphate buffer markedly enhances microsomal methyl sterol demethylation rates 3- to 4-fold in hepatoma 7777, other microsomal enzymes and electron carriers in either liver or a more slowly growing hepatoma appear to be unaffected by pyrophosphate. Several properties of the active microsomal methyl sterol demethylase have now been compared for control rat liver, host liver, tumor 7777, and tumor 5123C. Conditions necessary for the assay of initial velocities of enzymic reactions in the tumor microsomes have been established with respect to the amount of protein, time-course, concentrations of cofactors and substrate, pH, and other variables. The K'm and the responses to the variables studied above are very similar for methyl sterol demethylase of microsomes isolated from control liver, host liver, tumor 5123C, and tumor 7777. The multienzymic demethylase in the various preparations has been found to be inhibited similarly by in vitro additions of cyanide, cytochrome c, and bile salts. Thus, the enzymes of the microsomal-bound 4-methyl sterol demethylase of cholesterol biosynthesis appear to be very similar in liver and these 2 Morris hepatomas. When xenobiotic inducers of microsomal oxidases, such as phenobarbital and methylcholanthrene, are administered to normal and tumor-bearing rats, elevated rates of methyl sterol demethylation are observed with isolated liver microsomes obtained from both normal and tumor-bearing rats. Similar increases are not observed in the tumors. Furthermore, daily administration of an intestinal bile acid sequestrant elevates hepatic methyl sterol demethylase, but statistically significant changes were not observed in tumors 7777 and 5123C. Since the enzymes of methyl sterol demethylase appear to be grossly similar in liver and these hepatomas, regulation of the activity of the multienzymic system contained in the tumors may be altered. On the other hand, these agents in vivo simply may not affect liver and the hepatomas similarly, due to a lack of uptake of the foreign substances by the tumor that has been transplanted to the thighs.

Investigation of the rate-determining microsomal reaction of cholesterol biosynthesis from lanosterol in Morris hepatomas and liver.

Previously, we reported that the properties or microsomal 4-methyl sterol demethylase isolated from liver and Morris hepatomas 5123C and 7777 are grossly similar. The individual enzymic steps of this multicomponent system have now been studied, and the rate-determining step has been determined and shown to be identical for liver and these hepatomas. The rates of microsomal oxidative attacks of the 4alpha-methyl, 4alpha-hydroxymethyl, and 4-aldehydic groups are similar for microsomes prepared from rat liver and hepatoma 7777. The rates of mixed-function oxidative attack appear to increase in the order;--CH3 less than --CH2OH less than --CHO. Furthermore, the hepatic and hepatoma NAD-dependent decarboxylase, which catalyzes the reaction following the three oxidative attacks is similar in properties and velocity. The fifth step, an NADPH-dependent reduction of the 3 ketosteroid that is produced by decarboxylation, is also similar. For both tissues, the latter two reactions, under in vitro conditions, proceed at rates that exceed the initial oxidative process. Thus, for elimination of both of the 4-methyl groups of lanosterol, the 10 individual reactions catalyzed in this multicomponent system are identical in liver and hepatoma 7777 microsomes, and the rate-determining stop for both liver and hepatoma is the inital oxidative attack on the 4alpha-methyl group of cholesterol procursors. When the rate-determining reaction of both liver and hepatoma 7777 microsomes is assayed at different temperatures, the same activation energies and the same characteristic breaks in the arrhenius plots are observed. Thus, for both liver and hepatoma, both the nature and the site of rate determination in this multienzymic system must be similar. Since the microsomal enzymes of liver nad hepatoma appear to be catalytically similar and rate determination appears to be similar, too, the characteristic lact of response of tumor microsomes to treatments in vivo that alter host liver microsomal demethylation activity suggests that the insensitivity of these tumors to dietary cholesterol should not be ascribed to alterations in the catalytic proteins. Evidence in this report suggests that the postmicrosomal supernatant fraction of both liver and hepatoma contains a cytosolic protein that may participate in the regulation of the rate-determining attack of 4alpha-methyl sterol substrates. Thus, either qualitative or quantitative differences between the postmicrosomal supernatant fractions obtained from liver and heptomas may account for the observed differences in rates of cholesterol biosynthesis.

Liver microsomal inactivation of 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone as an inhibitor of ribonucleotide reductase.

Studies were carried out to determine the effects of preincubation of 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIQ) with hepatic microsomes on the ability of MAIQ to inhibit CDP reductase activity in vitro. An aliquot from the 100,000 x g supernatant fraction from this incubation was used in the CDP reductase assay. MAIQ incubated in the absence of microsomes inhibited CDP reductase activity in a dose-dependent manner. At high MAIQ concentration (5 microM) CDP reductase activity was inhibited 95%. When MAIQ (5 microM) was first incubated in the presence of hepatic microsomes and NADPH, CDP reductase activity was inhibited only 30%. This attenuation of MAIQ inhibition was dependent on time of incubation and microsomal protein concentration and showed an obligatory requirement for NADPH or NADH. Significant attenuation was observed at pyridine nucleotide concentrations as low as 0.1 mM. Heat denaturation of microsomal proteins inactivated their ability to attenuate the MAIQ inhibition. Microsomes prepared from Ehrlich tumor cells were ineffective as inactivators of MAIQ. Results of our studies show that hepatic microsomes contain an enzyme(s) which can inactive MAIQ as an inhibitor of CDP reductase.

Usefulness of delayed postcontrast magnetic resonance imaging in the detection of residual cholesteatoma after canal wall-up tympanoplasty.

OBJECTIVES/HYPOTHESIS: Imaging takes an increasing place in the follow-up of patients who have undergone surgery for cholesteatoma, with computed tomography (CT) as the first line imaging technique. However, in case of complete opacity of the tympanomastoid cavities, CT is not able to differentiate residual cholesteatoma from postoperative scar tissue. The aim of this study was to assess the usefulness of magnetic resonance imaging (MRI) using delayed postcontrast T1-weighted images for the detection of residual cholesteatoma after canal wall-up tympanoplasty (CWU) in cases where CT was not conclusive. STUDY DESIGN: Prospective study. METHODS: MRI, with delayed postcontrast T1-weighted images (30-45 minutes after contrast injection), was performed before revision surgery in 41 consecutive patients who had undergone CWU for cholesteatoma and presenting with a nonspecific complete opacity of the mastoid bowl on CT. In all the cases, imaging results were compared with operative findings at surgical revision. RESULTS: A residual cholesteatoma was found in 19 of 41 patients at revision surgery and was correctly detected on MRI in 17 patients. In the two remaining cases, cholesteatoma pearls smaller than 3 mm were not seen. There was no false-positive case. Statistics were as follows: sensitivity 90%; specificity 100%; positive predictive value 100%; negative predictive value 92%. CONCLUSION: When postoperative CT is not conclusive because of complete opacity of the tympanomastoid cavities, MRI with delayed postcontrast T1-weighted images is a reliable additional technique for the detection of a residual cholesteatoma when its diameter is at least 3 mm.

Estradiol inhibition of luteinizing hormone-stimulated progesterone synthesis in isolated bovine luteal cells.

The effects of several steroid hormones on progesterone synthesis and cAMP accumulation in isolated bovine corpora luteal cells were investigated in an attempt to determine if any of the steroids would affect the basal level of these processes or their response to gonadotropin. Isolated bovine corpora luteal cells responded to LH with a significant (P less than 0.05) increase in progesterone synthesis and cAMP accumulation when incubated at 37 C for up to 1 h. Exogenous cAMP and analogs of cAMP also significantly stimulated steroidogenesis in these incubated cells. Stimulation of progesterone synthesis by 1 microgram/ml LH was significantly suppressed (P less than 0.05) in the presence of 5--10 microgram/ml estradiol. This inhibition appeared to be largely specific for 17beta-estradiol, in that other steroids such as estrone, estriol, 17alpha-estradiol, cortisol, and dihydrotestosterone were not inhibitory. Testosterone was found to be inhibitory, but it is uncertain if this effect was due to the androgen itself or to its conversion to estradiol. Estradiol did not affect the increase in endogenous cAMP caused by LH in these cells, but did inhibit the effect of exogenous dibutyryl cAMP on progesterone synthesis. The magnitude of this inhibition of the effect of dibutyryl cAMP was not, however, equal to the estradiol inhibition of the stimulation of progesterone synthesis by LH. These data indicate that estradiol, a possible physiological luteolytic agent, has a direct inhibitory action on the corpus luteum and produces its suppression by blocking the stimulatory effect of LH at a step after cAMP.

Inhibition of human chorionic gonadotropin-induced progesterone synthesis by estradiol in isolated human luteal cells.

The purpose of this study was to determine whether estrogens exerted a direct inhibitory effect on progesterone synthesis in isolated human luteal cells in vitro. It was found that hCG stimulated progesterone synthesis by luteal cells, obtained from corpora lutea of the menstrual cycle, whereas cells isolated from corpora lutea of pregnancy were unresponsive to exogenous hCG. Estradiol markedly inhibited (P less than 0.001) this hCG effect in luteal cells of the menstrual cycle, and this inhibition was dose dependent. Estradiol did not block the stimulation of cAMP accumulated by hCG in the luteal cells of the cycle but did inhibit the stimulatory effect of dibutyryl cAMP on progesterone synthesis. These data suggest that estrogens may directly cause functional luteolysis in the human and that its site of action may be after the accumulation of cAMP.

Effects of pregnant mare serum gonadotrophin and oestradiol benzoate on enzymes associated with xenobiotic metabolism in immature and hypophysectomized female rats.

Treatment of immature (22-day-old) female Sprague-Dawley rats with pregnant mare serum gonadotrophin (PMSG) resulted in a significant increase in hepatic microsomal cytochrome P-450 concentrations when compared with animals treated with 0.9% (w/v) NaCl solution. Cytochrome P-450 concentrations in microsomes from control and PMSG-treated animals were 0.49 +/- 0.07 and 0.78 +/- 0.18 nmol/mg microsomal protein respectively (mean +/- S.D.). When hypophysectomized rats were treated with PMSG no significant difference was observed between saline-treated and PMSG-treated animals (0.84 +/- 0.06 vs 0.88 +/- 0.08 nmol/mg microsomal protein). Cytochrome b5 concentration and NADPH-cytochrome c reductase and ferricyanide reductase activities were not significantly affected by PMSG treatment. Similar results were obtained when immature and hypophysectomized rats were treated with oestradiol benzoate. Hepatic glutathione (GSH) S-transferase activity was significantly stimulated over control values when hypophysectomized or immature animals were treated with PMSG, oestradiol benzoate or 3-methylcholanthrene. Treatment of animals simultaneously with PMSG or oestradiol benzoate and 3-methylcholanthrene resulted in higher transferase activity than did either treatment alone. Oestradiol benzoate or PMSG treatment of immature female rats resulted in an approximate twofold increase in hepatic aryl hydrocarbon hydroxylase (AHH) activity. However, AHH activity in hypophysectomized animals was not significantly increased by PMSG or oestradiol benzoate treatment. It is concluded that PMSG or oestradiol benzoate treatment of immature female rats resulted in increased total cytochrome P-450 concentration and AHH activity in hepatic microsomes. Glutathione S-transferase activity was also stimulated. Neither PMSG nor oestradiol benzoate stimulated cytochrome P-450 levels or AHH activity in hypophysectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of cyclic AMP and cyclic GMP accumulation and steroidogenesis during stimulation of bovine luteal cells with luteinizing hormone.

The relationship between LH-induced steroidogenesis and the production of cyclic AMP and cyclic GMP was studied as a function of LH dose and time in isolated luteal cells from pregnant cows. Submaximal steroidogenic concentrations of LH caused a transient but significant rise in cyclic AMP that peaked after incubation for 5 min. A consequent rise in progesterone occurred at 30 min even though cyclic AMP had returned to the basal level at that time. Higher steroidogenic doses of LH elicited a maximum increase of cyclic AMP at 5 min and this was sustained for up to 1 h; the related progesterone production was significantly raised at 15 min and reached a maximum plateau at 30 min. The corresponding levels of cyclic GMP did not appear to be altered by any of the LH concentrations used. The present study has provided direct evidence that even at very low doses of LH, cyclic AMP plays an intermediary role in the stimulation of steroidogenesis in a mixed population of cells isolated from the bovine corpus luteum. Cyclic GMP, on the other hand, did not appear to play a role in the action of LH on the same population of luteal cells.

Effects of inhibitors of RNA and protein synthesis on hepatic microsomal cytochrome P-450 concentration in fasted and fed rats.

A number of sex-related differences in the metabolism of drugs, steroids and xenobiotics have been reported in studies on rats. Generally, male rats tend to metabolize these compounds more efficiently than females. In the studies presented here, male and female rats were fasted for 24-48 hr, and the effects of fasting on total hepatic microsomal cytochrome P-450 were examined. Hepatic cytochrome P-450, as determined by CO difference spectra, was increased significantly as a percentage of control in microsomes from fasted female rats when compared to fasted male rats. Cytochrome P-450 concentration increased from 0.57 +/- 0.07 nmole/mg protein to 0.99 +/- 0.08 nmole/mg protein following a 24-hr fast. In male rats, cytochrome P-450 levels were essentially unaffected by the 24-hr fast. Cytochrome b5 concentration was not altered by fasting. When female rats were fasted for 24 hr and refed, cytochrome P-450 levels were not significantly different from cytochrome P-450 levels in continuously fed animals. Treatment of fasted female rats with the protein synthesis inhibitor ethionine, or the RNA synthesis inhibitor actinomycin D, prevented the induction of cytochrome P-450 in the fasting animal. Cytochrome P-450 concentration in fed animals was not affected significantly by either inhibitor. Induction of cytochrome P-450 by phenobarbital (PB) and 3-methylcholanthrene (MC) under fed and fasted conditions was also investigated in male and female rats. Xenobiotic-induced cytochrome P-450 concentration was significantly higher in fasted female hepatic microsomes when compared to microsomes from fed female rats. Fasting did not significantly affect xenobiotic-induced cytochrome P-450 in male rats. Our results suggest that fasting in female rats results in an increase in cytochrome P-450 which is dependent upon synthesis of RNA and protein.