Contraceptive method use among HIV-positive women in a US urban outpatient clinic: an exploratory cross-sectional study.

OBJECTIVE(S): Effective contraceptive method use is important for HIV-positive women to meet fertility goals, prevent unintended pregnancy and reduce risk of vertical HIV transmission. Our objective was to evaluate factors associated with HIV-positive women's contraceptive method use at last coitus defined as more effective [Tier 1 and 2 methods (T1/2)] versus less effective [Tier 3 or no method (T3/none)] by the US Medical Eligibility Criteria for contraception use. STUDY DESIGN: HIV-positive women, recruited from an HIV clinic in Atlanta, Georgia, between 2013 and 2014, completed a survey of demographic, clinical and reproductive health characteristics surrounding contraception. We examined the relationship between survey responses and contraceptive method use at last coitus using χ2 tests and multivariate logistic regression. RESULTS: Thirty-one percent of this HIV-positive and predominantly African-American (90%) cohort reported usage of T1/2 methods. T1/2 methods use was higher among younger women [adjusted odds ratio (aOR)=.90, p=.008] and those in noncommitted relationships (aOR =.32, p=.027). Only 21% reported dual method use at last intercourse. Fifty-three percent and 31% reported having heard of the intrauterine device and implant, respectively. Misconceptions about contraception were common. CONCLUSIONS: The use of T1/2 methods was more common in this cohort than in the general African-American population, but overall use and dual method use can still be improved, particularly among older women and those in noncommitted relationships. IMPLICATIONS: As this population had low awareness and usage of T1/2 methods and expressed many misconceptions, reoccurring contraceptive counseling may be helpful. Providers should address patient-level barriers, pregnancy intentions, and the importance of dual method and T1/2 method use.

A Systematic Review of the Current Status of Safer Conception Strategies for HIV Affected Heterosexual Couples in Sub-Saharan Africa.

We conducted a systematic review of safer conception strategies (SCS) for HIV-affected couples in sub-Saharan Africa to inform evidence-based safer conception interventions. Following PRISMA guidelines, we searched fifteen electronic databases using the following inclusion criteria: SCS research in HIV-affected couples; published after 2007; in sub-Saharan Africa; primary research; peer-reviewed; and addressed a primary topic of interest (SCS availability, feasibility, and acceptability, and/or education and promotion). Researchers independently reviewed each study for eligibility using a standardized tool. We categorize studies by their topic area. We identified 41 studies (26 qualitative and 15 quantitative) that met inclusion criteria. Reviewed SCSs included: antiretroviral therapy (ART), pre-exposure prophylaxis, timed unprotected intercourse, manual/self-insemination, sperm washing, and voluntary male medical circumcision (VMMC). SCS were largely unavailable outside of research settings, except for general availability (i.e., not specifically for safer conception) of ART and VMMC. SCS acceptability was impacted by low client and provider knowledge about safer conception services, stigma around HIV-affected couples wanting children, and difficulty with HIV disclosure in HIV-affected couples. Couples expressed desire to learn more about SCS; however, provider training, patient education, SCS promotions, and integration of reproductive health and HIV services remain limited. Studies of provider training and couple-based education showed improvements in communication around fertility intentions and SCS knowledge. SCS are not yet widely available to HIV-affected African couples. Successful implementation of SCS requires that providers receive training on effective SCS and provide couple-based safer conception counseling to improve disclosure and communication around fertility intentions and reproductive health.

Factors associated with sterilization among HIV-positive US women in an urban outpatient clinic.

This cross-sectional study sought to determine factors associated with sterilization among HIV-positive US women. HIV-positive women aged 18-45 completed an Audio Computer Assisted Self Interview (ACASI) questionnaire. Chi-square tests and multivariable logistic regression evaluated factors associated with sterilization. The median age of the 187 participants was 37, the majority had at least a high school education, and 88% were African American. Nearly a quarter (22%) of women had undergone sterilization at an average age of 25; of these women, 71% cited their HIV-positive status as an important factor in deciding to have a tubal ligation, 22% expressed desire for future children, 32% reported sterilization regret, and 20% reported feeling pressure to undergo sterilization. In multivariable analysis, factors significantly associated with sterilization included non-African American race, no desire for future pregnancy, having heard of any birth control methods making it harder to get pregnant in the future, belief that women should take a break from hormonal methods every few years, and having had a child born with HIV. While almost a quarter of this HIV-positive group was sterilized, many during the height of the early HIV epidemic, a large proportion of sterilized women expressed sterilization regret. Counseling messages for sterilized HIV-positive women should be sensitive to the fact that women may have regret regarding a decision that, in some cases, may historically have been part of provider recommendations to prevent vertical transmission of HIV. Improved knowledge about contraceptive options such as the IUD and implant is needed among HIV-positive women.

Formal selection of measures for a composite index of NICU quality of care: Baby-MONITOR.

OBJECTIVE: To systematically rate measures of care quality for very low birth weight infants for inclusion into Baby-MONITOR, a composite indicator of quality. STUDY DESIGN: Modified Delphi expert panelist process including electronic surveys and telephone conferences. Panelists considered 28 standard neonatal intensive care unit (NICU) quality measures and rated each on a 9-point scale taking into account pre-defined measure characteristics. In addition, panelists grouped measures into six domains of quality. We selected measures by testing for rater agreement using an accepted method. RESULT: Of 28 measures considered, 13 had median ratings in the high range (7 to 9). Of these, 9 met the criteria for inclusion in the composite: antenatal steroids (median (interquartile range)) 9(0), timely retinopathy of prematurity exam 9(0), late onset sepsis 9(1), hypothermia on admission 8(1), pneumothorax 8(2), growth velocity 8(2), oxygen at 36 weeks postmenstrual age 7(2), any human milk feeding at discharge 7(2) and in-hospital mortality 7(2). Among the measures selected for the composite, the domains of quality most frequently represented included effectiveness (40%) and safety (30%). CONCLUSION: A panel of experts selected 9 of 28 routinely reported quality measures for inclusion in a composite indicator. Panelists also set an agenda for future research to close knowledge gaps for quality measures not selected for the Baby-MONITOR.

Plasma and tissue lipids of piglets fed formula containing saturated fatty acids from medium-chain triglycerides with or without fish oil.

Addition of fish oil (FO) with carbon chain 20 and 22 (long-chain polyunsaturated fatty acids; LCPs) n-3 fatty acids to formula has been considered as a method to provide 22:6n-3 to preterm infants. These studies determined the effects of including 0.73% n-3 LCPs from FO in formula containing saturated fatty acids as medium-chain triglyceride (MCT) oil on plasma and organ triglyceride (TG), phospholipid (PL), and cholesterol ester (CE) contents and compositions in piglets. Reference piglets were fed their own mother's milk. Piglets fed the formula with FO had significantly lower liver and kidney, but not plasma, TG concentrations; lower liver PL 20:4n-6; and higher plasma, liver, and kidney TG, PL, and CEn-3 LCPs than piglets fed the formula without FO. The increase in liver and kidney lipid n-3 LCPs and the decrease in kidney lipid content shows that inclusion of FO in formula with a high content of MCTs and 18:2n-6 does not promote tissue lipid metabolism similar to natural milk feeding. Piglets fed formula with FO had similar brain 20:4n-6 and 20:5n-3 but higher 22:6n-3 than did piglets fed sow milk. Diet-related differences in plasma and red blood cell PL were not reliable predictors of differences in brain LCP.

Nonessential fatty acids in formula fat blends influence essential fatty acid metabolism and composition in plasma and organ lipid classes in piglets.

The n-6 and n-3 fatty acid status of developing organs is the cumulative result of the diet lipid composition and many complex events of lipid metabolism. Little information is available, however, on the potential effects of the saturated fatty acid chain length (8:0-16:0) or oleic acid (18:1) content of the diet on the subsequent metabolism of the essential fatty acids 18:2n-6 and 18:3n-3 and their elongated/desaturated products. The effects of feeding piglets formulas with fat blends containing either coconut oil (12:0 + 14:0) or medium chain triglycerides (MCT, 8:0 + 10:0) but similar levels of 18:1, 18:2n-6 and 18:3n-3, or MCT with high or low 18:1 but constant 18:2n-6 and 18:3n-3 on the fatty acid composition of plasma, liver and kidney triglycerides, phospholipids and cholesteryl esters, and of brain total lipid, were studied. Diet-induced changes in the fatty acid composition of lipid classes were generally similar for plasma, liver and kidney. Dietary 18:1 content was reflected in tissue lipids and was inversely associated with levels of 18:2n-6. Lower percentage of 18:2n-6, however, was not associated with lower levels of its elongated/desaturated product 20:4n-6 but was associated with higher levels of 22:6n-3. Feeding coconut oil vs. MCT resulted in lower 18:1 levels in all lipids, and higher percentages of 20:4n-6 in tissue phospholipid. Increasing the dietary n-6/n-3 ratio from 5 to 8 significantly increased tissue percentage of 18:2n-6 and decreased phospholipid 22:6n-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelin acts at the subfornical organ to influence the activity of putative vasopressin and oxytocin-secreting neurons.

Systemic endothelin-1 (ET-1) enhances the activity of subfornical organ (SFO) neurons with identified projections to the paraventricular nucleus of the hypothalamus (PVN). The present electrophysiological experiments were undertaken to examine the mechanisms through which systemic ET influences vasopressin secretion. Systemic ET-1 (50-100 pmol) was found to influence the excitability of antidromically identified vasopressin and oxytocin-secreting neurons in the PVN or supraoptic nucleus (SON) of urethane-anaesthetized rats. Long-term stable recordings from 95 antidromically identified neurons showed 56% of putative vasopressin- (n = 41), and 37% of putative oxytocin- (n = 54) secreting neurons were activated by ET-1. Such effects normally demonstrated a short latency (less than 10 s), with a duration ranging between 10 and 300 s. In contrast, unidentified neurons in the vicinity of PVN and SON (n = 27) were unaffected by ET-1. The inability of peptides to cross the normal blood-brain barrier suggested that such effects of ET-1 result from actions of this peptide at the SFO which lacks this barrier and sends efferent neural projections to both SON and PVN. This hypothesis was tested by obtaining similar recordings from animals in which this structure was destroyed prior to experimentation. In these studies recordings from 15 putative vasopressin- and 29 putative oxytocin-secreting neurons showed that only 7% and 14%, respectively, were excited by systemic ET-1 in lesioned animals. These data show that increases in circulating levels of ET have predominantly excitatory effects on vasopressin- and oxytocin-secreting neurons in SON and PVN. The modified responsiveness of these neurons to ET-1 in SFO-lesioned animals suggests this as a likely CNS site at which this peptide acts within the central nervous system to elicit such effects.

Central actions of angiotensin in cardiovascular control: multiple roles for a single peptide.

Angiotensin II (ANG II) acts peripherally as a hormone, with actions on the vasculature, adrenals, and kidney. In addition, certain actions of ANG II in the central nervous system are directed toward cardiovascular control and fluid volume homeostasis. Dense binding sites for ANG II are found at circumventricular organs, which apparently have the ability to relay information to cardiovascular centers via neural circuitry. Microinjection of ANG II into the subfornical organ (SFO) or area postrema (AP) produces site-specific increases in blood pressure. In addition, electrophysiological studies demonstrate profound effects of ANG II, acting at the SFO, on activity of neurohypophysial neurons and release of oxytocin and vasopressin, which can be antagonized by ANG II blockers or attenuated by SFO lesions. Evidence from microinjection, electrophysiological, and lesion studies indicate a complex interaction between central sites involved in mechanisms of cardiovascular control: the SFO, AP, organum vasculosum of the lamina terminalis, and paraventricular and supraoptic nuclei of the hypothalamus. Not only is ANG II a humoral messenger in this central scenario, but evidence suggests it acts as a neurotransmitter or neuroendocrine substance within specific CNS pathways, suggesting multiple roles for this peptide in central cardiovascular control.

Efferent microvascular responses to electrical stimulation of the area postrema in rats.

As part of its role to transduce blood-borne and afferent neural stimuli to the brain, the area postrema conducts efferent projections monosynaptically to individual nuclei of the medulla oblongata and pons. We hypothesized that electrical activation of the area postrema would mimic this transduction process and couple microvascular responses in efferent sites to local increases in tissue metabolism reported previously. We used quantitative autoradiographic techniques and image analysis to measure capillary transfer constants for [14C]alpha-aminoisobutyric acid (AIB, a small, neutral amino acid) and blood flow (iodo[14C]antipyrine) in individual brainstem structures of anesthetized rats. The area postrema was stimulated electrically by means of a monopolar microelectrode positioned stereotaxically 100 microns deep in the dorsocentral aspect of the organ. There were no significant effects of stimulation on [14C]AIB influx or blood flow in control hindbrain structures where postremal projections are sparse or absent--the spinal trigeminal nucleus, reticular formation, or cerebellar vermis. Stimulation of the area postrema produced equivalent increases in transcapillary influx of [14C]AIB and capillary blood flow in the nucleus of the solitary tract, dorsal motor nuclei of the vagus nerves, ventrolateral medullary C1 region, locus coeruleus, dorsal tegmental nuclei, and lateral parabrachial nuclei. Formation of ratios interrelating rates of [14C]AIB influx and blood flow with previously assessed values of tissue glucose metabolism indicated that these measures increased proportionately during postremal stimulation. Such proportional increases in capillary [14C]AIB transfer and blood flow during tissue activation by area postrema stimulation are consistent with interpretation that the increase in blood flow resulted from recruitment of unused surface area in the capillary networks of individual efferent nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional quantitative permeability of blood-brain barrier lesions in rats with chronic renal hypertension.

Blood-brain transfer constants for a small, neutral amino acid tracer, [14C]alpha-aminoisobutyric acid (AIB), were measured by quantitative autoradiography and image analysis in 15 individual brain structures of 2-kidney, 1-clip renal hypertensive rats (RHR) and age-matched normotensive controls (NR). Mean arterial pressures (MAP) for 4 month-old RHR and NR were 182 +/- 19 and 121 +/- 3 mmHg, respectively. Most brain structures in RHR had very low [14C]AIB transfer constants similar to those in NR (1-3 microliters.g-1.min-1), indicative of normal blood-brain barrier (BBB) function. Focal lesions, however, having transfer constants 2-7x normal and measuring less than 1.7 mm2 in area, appeared in RHR primarily in the cerebellar vermian and cerebral cortices. Chronic unilateral cervical sympathectomy did not influence the incidence or magnitude of BBB lesions in the denervated hemisphere of RHR. Acute arterial hypertension produced by systemic infusion of phenylephrine (elevation of MAP in RHR by 43%) increased the incidence and magnitude of lesions by 48% and 2-12x, respectively, although many brain regions in acutely hypertensive RHR retained normal permeability to [14C]AIB. The results demonstrate normal BBB permeability for much of the brain in chronic renal hypertension, with focal lesions having 7x or less the normal rate of blood-brain transfer for a small physiological probe.

Morphology and function of capillary networks in subregions of the rat tuber cinereum.

The differentiated cytology, cytochemistry, and functions within subdivisions of the tuber cinereum prompted this morphometric and physiological investigation of capillaries in the medium eminence and arcuate nucleus of albino rats. Morphometric studies established that the external zone of the median eminence had 3-5 times the number and surface area of true and sinusoidal capillaries than the internal or subependymal median eminence zones, or either of two subdivisions examined in the arcuate nucleus. Type-I true capillaries, around which Virchow-Robin spaces comprise 1% of arcuate tissue area, were situated proximally to the median eminence border. This finding is consistent with a premise that confluent pericapillary spaces enable infiltration of arcuate neurons by factors from capillary blood from the median eminence or Virchow-Robin spaces. Physiologically, the rate of penetration across the median eminence capillaries by blood-borne [14C]alpha-amino-isobutyric acid (a neutral amino acid used as a capillary permeability tracer) was 142 times greater than for capillaries in the distal arcuate nucleus within 12 s of tracer administration. A new finding was that the proximal arcuate nucleus had a permeability x surface area product of 69 microliters g-1 min-1, 34 times greater than that in more distal aspects of the tuber where blood-brain barrier properties exist. We also found that the microcirculatory transit time of a plasma space marker, [14C]sucrose, was considerably longer (1.2 s) in the median eminence and proximal arcuate nucleus than in the distal arcuate or ventromedial nucleus (0.4 s). By virtue of its high capillary permeability and extensive blood-tissue surface area, including the wide Virchow-Robin spaces, the median eminence external zone could be a gateway for flooding other tuberal compartments with blood-borne factors. This effect may be compounded by capillary bed specializations in the proximal arcuate nucleus where Type-I true capillaries, Type-III sinusoids, and pericapillary spaces are confluent with those in the median eminence. The results indicate that the proximal arcuate parenchyma could be exposed to circulating neuroactive substances on a moment-to-moment basis.

Actions of endothelin at the subfornical organ.

Endothelin (ET), a potent vasoconstrictor peptide, is believed to have central sites of action and potential neurohormonal effects relating to body fluid homeostasis and blood-pressure regulation. Systemic endothelin binds to receptors at circumventricular organs and has been shown to increase plasma concentrations of vasopressin and increase the firing frequency of neurohypophysial vasopressin and oxytocin neurons. In the present study we have examined the effects of ET on blood-pressure following micro-injection into the subfornical organ (SFO). Micro-injection of 0.5 and 5.0 pmol of endothelin into SFO caused significant increases (10.1 +/- 1.1 and 10.2 +/- 2.1, respectively) in blood pressure, while lower doses were without effect. In addition, we have used single unit recording techniques to evaluate the effects of systemic ET on the activity of SFO neurons. Extracellular recordings from SFO neurons, antidromically identified as projecting to PVN, showed predominantly excitatory responses to systemic ET (21/35 cells). The data demonstrate that ET has excitatory actions on SFO neurons, and further raise the possibility that one of the functional consequences of such effects is an increase in arterial blood pressure.

Efferent metabolic effects of area postrema stimulation in renal hypertensive rats.

Electrical microstimulation of area postrema in anesthetized normotensive (NR) and renal hypertensive (RHR) rats produced increases of about 53% in rates of glucose metabolism in nucleus tractus solitarii and dorsal motor nucleus of the vagus nerves. However, in nucleus ambiguus, ventrolateral medullary C1 region, locus coeruleus, and lateral parabrachial nucleus, all of which are monosynaptically innervated by area postrema neurons, metabolic responsiveness to postremal stimulation was considerably attenuated in RHR (average increase of 16%) compared to the same structures in NR (average increase of 36%). Disturbances of brainstem neurotransmission or tissue reactivity to postremal pathway activation thus appear to be part of the central pathophysiology of chronic renal hypertension.

Hypoperfusion of cerebral cortex in renal hypertensive rats.

Morphometric and physiological measurements in the parietal cortex of rats with 2-kidney-1-clip renal hypertension and their normotensive controls indicated a 23% increase in capillary bed volume accompanied by a 32% reduction in the rate of cortical blood flow in the renal hypertensive animals. From these measures, we estimated an 83% increase in the duration of blood transit through the cortical capillary network of renal hypertensive rats, a new expression of altered microvascular function in the brain of this hypertensive model. The rate of glucose utilization in the cerebral cortex of renal hypertensive animals was not different from that observed for normotensive animals. Thus, for capillary networks in cerebral cortex of renal hypertensive rats, we demonstrated markedly reduced rates of perfusion independent of tissue metabolic factors, despite expansion of capillary bed volume.

Subregional topography of capillaries in the dorsal vagal complex of rats: I. Morphometric properties.

Cytoarchitectonic and neurochemical studies of the dorsal vagal complex in the caudal medulla oblongata of rats indicate the existence of distinct anatomical and functional compartments within its components. We applied morphometric methods to discern whether capillary networks differed quantitatively between subregions and zones of area postrema, nucleus tractus solitarii (NTS), and dorsal motor nucleus of the vagus nerve (DMN) of rats. Analysis of 11 subdivisions of area postrema identified both "true" (range in luminal diameter of 3-7.5 microns) and sinusoidal (luminal diameter greater than 7.5 microns) capillaries that, together, made the capillary density for most of area postrema 75% greater than that found in NTS and DMN (526/mm2 vs about 300/mm2). The rank order of true capillary density in area postrema along its rostracaudal axis was caudal greater than central greater than rostral, whereas the reverse order was true for sinusoidal capillaries. Dorsal (periventricular) and medial zones of area postrema throughout its rostrocaudal axis tended to have higher values for capillary density, volume, surface area, luminal diameter, and pericapillary space volume than lateral or ventral zones bordering NTS. Within 200 microns of obex, the ventral zone of rostral area postrema was distinct, having a relatively sparse capillary density that may indicate morphological specializations limiting blood-tissue communication in this subregion. There were no quantitative differences in capillary dimensions between DMN and three subnuclei of NTS. These studies add to extant evidence that the dorsal vagal complex is differentiated for specific functions. Area postrema, especially, has topographical diversity in its capillary organization that likely corresponds to complex roles in neuroendocrine, autonomic, and chemosensory mechanisms.

Subregional topography of capillaries in the dorsal vagal complex of rats: II. Physiological properties.

The differentiated cytoarchitecture, neurochemistry, and capillary organization of the rat dorsal vagal complex prompted this comprehensive investigation of microvascular physiology in 11 subdivisions of area postrema, 5 subnuclei of nucleus tractus solitarii (NTS), the dorsal motor nucleus of the vagus nerve, and 4 other gray matter structures in the dorsal medulla oblongata. Microvascular exchangeable volume (residual plasma volume), capillary blood and plasma flow, and unidirectional transfer constants for a tracer amino acid, [14C]alpha-aminoisobutyric acid (AIB), varied considerably among the structures analyzed. Exchangeable volume, largest in area postrema medial zones (about 29 microliters.g-1) and smallest in medullary gray matter (7-11 microliters.g-1), correlated directly with subregional densities of capillaries and rates of tissue glucose metabolism. Capillary blood flow (range of 1,430-2,147 microliters.g-1.min-1), plasma flow, and tissue glucose metabolism (range of 0.48-0.71 mumol.g-1.min-1) were linearly related in the dorsal vagal complex. The most striking quantitative difference among structures in this brain region were the rates of transcapillary influx and derived permeability X surface area (PS) products of [14C]AIB, which has physicochemical properties resembling those of hormones. PS products for AIB were negligible in most medullary gray matter regions (less than 1 microliter.g-1.min-1, indicative of blood-brain barrier properties), but were 20-59X and 99-402X higher in NTS subnuclei and area postrema, respectively. An extraordinary feature of the microcirculation in area postrema was the long-duration transit of tracer sucrose and blood, a characteristic that would amplify the sensing ability of area postrema as it monitors the composition of the circulation.

Microvascular specializations promoting rapid interstitial solute dispersion in nucleus tractus solitarius.

Nucleus tractus solitarius (NTS), an aggregate of several individual nuclear groups in the dorsal medulla oblongata, is involved in virtually all autonomic functions as the first synaptic site in the brain for many peripheral viscerosomatic inputs. We found morphological evidence that dorsocaudal subregions of rat NTS (approximately 800 microns caudal from obex) had fenestrated capillaries and enlarged Virchow-Robin (perivascular) spaces that were similar to those in area postrema but unlike capillaries elsewhere in the medulla oblongata. Complexes of microvessels, consisting of up to 10 small vessels with smooth muscle layers (luminal diameters of 10-45 microns) and several capillaries (average luminal diameter of 4.5 microns), were located in the dorsal midline of NTS within large Virchow-Robin spaces measuring some 2,000 microns 2 in area. In physiological studies, we determined that most of NTS had a definable blood-brain barrier [permeability-surface area (PS) products for a neutral amino acid near 0], but medial and lateral aspects of the commissural subnucleus of NTS had PS products of 16-63 microliters.g-1.min-1 for alpha-[14C]aminoisobutyric acid 12 s after intravenous injection. Microvascular differentiations permitting such brisk tracer influx from blood resemble those of area postrema and appear to afford the rich neuropil of commissural NTS with a constant stream of blood-borne information for expediting its regulation of viscerosensory and autonomic functions.

Uncoupling of cerebral blood flow and glucose metabolism in conscious rats with chronic renal hypertension.

In an analysis of 46 individual brain structures and regions, we found that 12-14 weeks of renal hypertension in rats were associated with a 42% increase in cerebrovascular resistance, an average 28% reduction in cerebral blood flow, and no general change in cerebral glucose metabolism. A specific increase in metabolic activity, however, was identified in locus coeruleus. Generalized cerebral vasoconstriction resulting from central noradrenergic innervation originating in locus coeruleus is a possible explanation for the uncoupling of cerebral blood flow and metabolism in rats with chronic renal hypertension.

Decreases in brain protein synthesis elicited by moderate increases in plasma phenylalanine.

Large increases in plasma phenylalanine concentration (greater than 1 mM) adversely affect brain function and inhibit cerebral protein synthesis. The threshold hypothesis predicts that moderate increases in plasma phenylalanine concentrations below a 1 mM threshold have no adverse effects on brain function or protein synthesis. Using a new in situ internal carotid artery perfusion technique and measurement of the amino acyl-tRNA specific activities by high performance liquid chromatography (HPLC) separation of phenylisothiocyanate (PITC) derivatized amino acids, the present studies demonstrate a linear decrease in cerebral protein synthesis in vivo in proportion to moderate increases in plasma phenylalanine. A 50% inhibition of brain protein synthesis in vivo is observed at a plasma phenylalanine concentration of approximately 0.40 mM. Since moderate increases in plasma phenylalanine concentrations may be achieved in humans with ingestion of phenylalanine, the present findings should be considered in evaluating the safety of liberal and selective increases in dietary phenylalanine.

Metabolic activation of efferent pathways from the rat area postrema.

We used the quantitative [14C]deoxyglucose method and autoradiography to evaluate metabolic activity in 47 individual cerebral structures or subregions that are part of neural pathways emanating from the brain stem circumventricular organ, area postrema. Electrical stimulation of the dorsocentral area postrema in halothane-ventilated rats produced hypotension and increased glucose metabolism by several structures within the ascending trajectories of efferent neural projections from the nucleus. Structures in the caudal medulla oblongata, including three subnuclei of the nucleus of the solitary tract, dorsal motor nucleus of the vagus nerve, and nucleus ambiguus-A1 noradrenergic region, had increases of metabolism during stimulation of 32-62%. Pontine activation occurred specifically in the locus coeruleus and lateral parabrachial nuclei (increases of 24-36%). Magnocellular and parvocellular subdivisions of the hypothalamic paraventricular nucleus, supraoptic and suprachiasmatic nuclei, and median eminence showed increases in metabolism of 22-34%. An 89% elevation of glucose metabolism by the pituitary neural lobe resulted. The findings are evidence for functional activation of specific structures within ascending neural pathways from area postrema to forebrain mechanisms regulating blood pressure and fluid balance.