Cardiorenal destiny: the role of genes and environmental factors

For many years, it has been known that genes and environmental factors interact to determine an individual's blood pressure. The purpose of this article is twofold. First, the authors review current molecular genetic approaches to delineating genes that lead to the development of hypertension, focussing on the renin-angiotensin system. We then consider perinatal environmental factors that impact adult blood pressure. Epidemiologic data suggest that good maternal nutritional status is essential to avoid programming individuals for future health problems as adults. One factor that appears to play an important role in programming for hypertension in adulthood is maternal dietary protein restriction during pregnancy, possibly by suppression of the fetal renin-angiotensin system and consequent impairment of renal development. The association between lower birthweight and increased adult blood pressure, established in epidemiologic studies, may be caused by suboptimal maternal diet or placental insufficiency, resulting in transient changes in fetal hormone systems or gene expression that permanently alter the structure and function of the kidney and vasculature.     

Genetic defects of human brain development

This review focuses on malformations of the central nervous system that have a genetic etiology. One can view each malformation as giving us unique details on a map entitled "how to make a human brain." The gene(s) that cause each malformation are being identified, allowing discovery of their specific role in neurodevelopment, and defining a "road" on the map. The malformation is then the developmental consequence of "taking a wrong turn." Assimilation of complementary data from other species with human malformation phenotype and genotype is revealing just how wonderful and complex the neurodevelopment map is. Here we highlight recent research on brain malformations and how this is illuminating the map of normal human brain formation.     

Potential toxicity of retrograde uterine passage of particulate matter

Dusting powders are commonly used on surgical gloves, examination gloves, and condoms. In addition, they are used in diaphragms, sanitary napkins, and toiletries. These dusting powders can gain access to the abdominal cavity through the vagina or through surgical intervention. The toxicity of these dusting powders in the abdominal cavity can be divided into acute and chronic complications that may be life-threatening. The use of medical and surgical products without dusting powders is strongly recommended.     

An obligation to provide abortion services: what happens when physicians refuse?

Access to abortion services in the United States continues to decline. It does so not because of significant changes in legislation or court rulings but because fewer and fewer physicians wish to perform abortions and because most states now have "conscientious objection" legislation that makes it easy for physicians to refuse to do so. We argue in this paper that physicians have an obligation to perform all socially sanctioned medical services, including abortions, and thus that the burden of justification lies upon those who wish to be excused from that obligation. That is, such persons should have to show how requiring them to perform abortions would represent a serious threat to their fundamental moral or religious beliefs. We use current California law as an example of legislation that does not take physicians' obligations into account and thus allows them too easily to declare conscientious objection.     

The discriminative stimulus effects of MK-801 in pigeons

The discriminative stimulus effects of MK-801 [(+)-5-methyl-10, 11-dihydroxy-5H-dibenzo (a,d) cyclohepten-5, 10-imine], a proposed noncompetitive N-methyl-D-aspartate (NMDA) antagonist, were studied in pigeons discriminating MK-801 from saline, responding being maintained by food. Compounds with noncompetitive NMDA antagonist effects in other preparations (PCP [0.18-5.6mg/kg], dextrorphan [1-32mg/kg], ketamine [1-32mg/kg] and dexoxadrol [1-10mg/kg]) produced MK-801-appropriate responding dose-dependently. The potency order for this effect, and for response rate decreasing effects, closely mirrored the potency order for these compounds in causing catalepsy, an effect believed to be mediated by antagonism at the NMDA receptor complex. NMDA (0.32-5.6mg/kg), morphine (1-10mg/kg) and pentobarbital (1-17.8mg/kg) produced almost no MK-801-appropriate responding. There were no consistent potency differences among the (+)-isomer (1-32mg/kg), the (-)-isomer (1-17.8mg/kg) and the racemate (1-17.8mg/kg) of SKF 10,047 in producing MK-801-appropriate responding. The competitive NMDA antagonist CGS 19755 (1-10mg/kg) produced partial MK-801-appropriate responding (maximum value = 77.8%) up to 8h after administration. The homogeneity of the discriminative stimulus effects among compounds with noncompetitive NMDA antagonist effects in vitro, as well as the partial substitution for MK-801 by CGS 19755, suggest that the MK-801 discriminative stimulus in pigeons is due to noncompetitive NMDA antagonism.     

Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine

The effects of oral administration of the ₂ adrenergic receptor antagonists idazoxan (20 mg, 40 mg, 80 mg) and yohimbine (20 mg) were compared using a placebo-controlled within-subjects design. Healthy subjects completed 5 test days during which medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were assessed. Idazoxan dose-dependently increased plasma MHPG, plasma cortisol, systolic and diastolic blood pressure, and Panic Attack Symptom Scale scores in healthy subjects. Overall, yohimbine and idazoxan produced a similar pattern of behavioral and neuroendocrine responses. Since idazoxan possesses relatively greater receptor specificity compared to yohimbine, it may be a more useful ₂ antagonist in humans.     

Dynamic SPECT imaging of dopamine D2 receptors in human subjects with iodine-123-IBZM.

We studied the uptake, distribution, metabolism and washout of the dopamine D2 receptor ligand [123I]IBZM in healthy subjects (n = 12) with dynamic brain SPECT. The highest radioactivity level was detected in the striatum. Operationally-defined striatal "specific" uptake peaked at 69 min postinjection of radioligand and showed a gradual decline of 15% per hour thereafter. "Specific" uptake at maximal counts represented 53% of the total striatal radioactivity. Two subjects received haloperidol (20 micrograms/kg i.v.) 80 min postinjection of radioligand. Haloperidol caused a 2.6-fold increase in the rate of washout of specific striatal activity in comparison to that in the 10 control subjects and was consistent with drug-induced displacement of radioligand from the dopamine D2 receptor. Two classes of metabolites were detected in plasma and urine: a polar fraction, not extracted by ethyl acetate, and a nonpolar, extractable fraction consisting of parent compound and two compounds having shorter retention times on reversed-phase HPLC. Greater than half the plasma parent was metabolized within 10-15 min after administration. The volume of distribution, estimated from the peak arterial plasma concentration at 50-75 sec, was 7.7-10.2 l; the free (nonprotein bound) fraction of [123I]IBZM after in vitro incubation with blood or plasma was 4.4% +/- 0.4%. These results suggest that [123I]IBZM exhibits uptake in brain regions with high D2 receptor density and shows a relatively stable washout during which drugs affecting dopaminergic transmission may be administered.