Blood flow acceleration in the carotid and brachial arteries of healthy volunteers: respective contributions of cardiac performance and local resistance

Summary— The influence of local resistance and cardiac performance on peripheral blood acceleration was investigated in 14 healthy male volunteers. Steady and pulsatile flow was studied in the brachial and in the common carotid arteries, ie, two territories that exhibit marked differences in resistive characteristics. Instantaneous blood velocity (V), mean blood velocity (V_m) and artery diameter (D) were evaluated at rest by an ultrasonic range-gated pulsed Doppler flowmeter using a double transducer probe, thus allowing the calculation of mean blood flow (Q). Mean local resistance (R) was obtained by dividing the mean arterial pressure by Q. The peak value of the local acceleration of the blood was obtained by computer-assisted calculation of the first derivative of instantaneous blood velocity (G_max = +dV/dt_max). Peak aortic blood acceleration (GAo) was simultaneously measured from the suprasternal notch using a pulsed Doppler velocity meter. In the brachial and the common carotid arteries, G_max was of a similar magnitude (551 ±30 and 555 ± 44 cm/s², respectively) despite major differences in the respective D, V_m, Q and R values. In neither artery was there a relationship between G_max and either resting Q or R. At the brachial artery level, G_max was positively related to GAo ( r = 0.79, P = 0.0008). At the common carotid artery level, there was a weak, although non significant relationship between G_max and GAo ( P = 0.08). Our results indicate that the local acceleration of peripheral blood flow in the brachial artery is related rather to upstream central impulse than to downstream hemodynamics, and suggest some regional differences in the hemodynamic determinants of the local acceleration of peripheral blood flow.     

Metabolism of the leukotriene receptor antagonist 5-(2-(8-phenyloctyl)phenyl)-4,6-dithianonanedioic acid (SK&F 102922) in the guinea pig. Rearrangement of the acyl glucuronide.

A primary route of inactivation of leukotrienes and their receptor antagonists (LTRA) is metabolism by omega oxidation. SK&F 102922 [5-(2-(8-phenyloctyl)phenyl)-4,6-dithianonanedioic acid] is a LTRA that was designed to be resistant to omega oxidation. Therefore, these experiments were designed to characterize the metabolic fate of [14C]SK&F 102922. Following iv administration of SK&F 102922 (5 mg/kg), 80% of injected radioactivity was excreted in bile in 1 hr. At least five metabolites and parent (18% of administered dose) were present in bile. One metabolite (M1), which accounted for less than 10% of the excreted radioactivity, was monohydroxylated. Three metabolites (M2, M3A, and M3B), which together accounted for greater than 50% of excreted radioactivity, had mass spectra consistent with acyl glucuronides. All three metabolites were alkali labile, whereas only one metabolite (M2) was susceptible to beta-glucuronidase hydrolysis. These data indicate that M3a and M3b are nonglycosidic isomers of M2 that were formed by a nonenzymic reaction involving migration of the aglycone (SK&F 102922) from C-1 to C-2, C-3, or C-4 of glucuronic acid. The 1-O-acyl-beta-glucuronide of SK&F 102922 (M2) exhibits pH dependent rearrangement, with half-lives ranging from 1 to greater than 1000 hr. Therefore, acyl glucuronidation can account for much of the metabolic fate of SK&F 102922 and, potentially, other structurally related LTRAs or endogenous leukotrienes themselves.     

Identifying types of female incontinence with retrograde urethrocystography

The most specific radiographic findings characterizing stress incontinence (SI) on upright retrograde urethrocystography include replacement of a flat or rounded bladder base with a concave funnelled base; patency of the bladder neck with contrast material pooling in the proximal urethra; the descent of the intravesical Foley balloon beyond the internal meatus and into the proximal urethra. We found that neither a cystocele nor the dependent position of the urethra at the bottom of the bladder were diagnostic of SI if the above stigmata were absent. On the other hand the defect of urgency incontinence (UI) is functional. The bladder can usually be filled by retrograde urethral infusion (though in severe UI this may not be the case). An alert technician can frequently obtain a film when the patient is experiencing uninhibited voiding. The finding of contrast material throughout the urethra, in the distal urethra alone, or in the parameatal area is strongly suspicious for UI, especially when trabeculation is also seen. These findings in association with the stigmata of SI give warning of combined SI and UI.     

Iotrol versus metrizamide in lumbar myelography: a double-blind study

In a prospective, randomized, double-blind study, 49 patients underwent lumbar myelography using iotrol (24 patients) or metrizamide (25 patients). The diagnostic imaging adequacy of iotrol was comparable with that of metrizamide. After iotrol myelography, adverse reactions were fewer, less severe, and of shorter duration than were those following metrizamide myelography. Thirteen of 24 patients (54%) receiving iotrol reported some adverse reactions compared with 24 of 25 patients (96%) receiving metrizamide. Five moderate and one severe adverse reaction occurred in the group receiving iotrol. Fourteen moderate and eight severe adverse reactions occurred in the group receiving metrizamide. Thirty-eight patients underwent electroencephalography both before and after myelography (19 iotrol and 19 metrizamide). None of the EEGs obtained after iotrol myelography changed from baseline, while seven of the EEGs obtained after metrizamide myelography showed changes from baseline. Iotrol was judged superior to metrizamide as a contrast medium in this patient population.     

Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: inhibition of conversion of pre-IL-1 alpha to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity in mice by IL-1 alpha

Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre- IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.     

Anosognosia in mild cognitive impairment: Relationship to activation of cortical midline structures involved in self-appraisal.

Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer's disease (AD), is variable. Anosognosia, or unawareness of loss of function, is beginning to be recognized as an important clinical symptom of MCI. However, little is known about the brain substrates underlying this symptom. We hypothesized that MCI participants' activation of cortical midline structures (CMS) during self-appraisal would covary with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each MCI participant). To address this hypothesis, we first compared 16 MCI participants and 16 age-matched controls, examining brain regions showing conjoint or differential BOLD response during self-appraisal. Second, we used regression to investigate the relationship between awareness of deficit in MCI and BOLD activity during self-appraisal, controlling for extent of memory impairment. Between-group comparisons indicated that MCI participants show subtly attenuated CMS activity during self-appraisal. Regression analysis revealed a highly significant relationship between BOLD response during self-appraisal and self-awareness of deficit in MCI. This finding highlights the level of anosognosia in MCI as an important predictor of response to self-appraisal in cortical midline structures, brain regions vulnerable to changes in early AD.     

Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line.

We selected two drug resistant variants of the MCF7 human breast cancer cell line by chronic in vitro exposure to doxorubicin (MCF7/D40 cell line) and mitoxantrone (MCF7/Mitox cell line), respectively. The cell lines are similar in growth characteristics including doubling time, DNA synthetic phase and cell size. Resistance to mitoxantrone conferred only partial resistance to doxorubicin; whereas resistance selected for doxorubicin appeared to confer complete resistance to mitoxantrone. Both agents selected for cross resistance to the Vinca alkaloids. MCF7/D40 cells display a classic-multi-drug resistance phenotype with expression of P-glycoprotein, decreased drug accumulation relative to the parental line and reversal of drug accumulation and drug resistance by verapamil. MCF7/Mitox cells likewise display resistance to multiple drugs, but in contrast to MCF7/D40 cells do not express P-glycoprotein by immunoblot or RNA blot analysis. Net drug accumulation in MCF7/Mitox cells was decreased relative to the parental cells but there was no selective modulation of drug accumulation or in vitro drug resistance by the addition of verapamil. Efflux of mitoxantrone was enhanced in both the MCF7/D40 and MCF7/Mitox cell lines relative to the MCF7/S cell line. We conclude that the two drug resistant cell lines have different mechanisms of decreased drug accumulation.