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In this 'clinical conundrum', we propose a hypothetical anatomical model to explain the abnormal gag reflex that is consistently observed in a clinical population of children experiencing feeding delays. This model is based on the presence of 'transient' connections formed during the normal development of autonomic brainstem circuitry involving the nucleus tractus solitarius (NTS). We propose that, as a result of normal feeding and swallowing, the activity of these transient fibers typically diminishes shortly after birth. In children who are orally deprived during infancy, these transient connections persist and the aberrant gag reflex is maintained into childhood. The most critical feature of the proposed model is the idea that swallowing during feeding initiates the retraction of the tactile 'transient' input to NTS. In the NICU feeding clinics, it has been suggested that triggering the gag reflex in neonates by tactile stimulation of non-oral body areas and anterior portions of the mouth directly or indirectly may contribute to oral feeding delays. To the contrary, we propose an anatomical model to suggest that oral feeding delays and lack of swallowing food, when experienced by neonates, actually contribute to the development of the aberrant gag reflex observed in later developmental stages.

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Levels of nerve growth factor (NGF) and neurotrophin-3 (NT-3) protein and neurotrophin receptor mRNA in adult sympathetic neurons were investigated following surgical removal of preganglionic input and/or in vivo administration of NGF. Expression of trkC and p75, but not trkA, was significantly decreased following a 3-week deafferentation of the superior cervical ganglion (SCG). Protein levels of NGF and NT-3 in the SCG were unchanged by deafferentation. A 2-week intracerebroventricular infusion of NGF without deafferentation resulted in enhanced mRNA levels of trkA, trkC, and p75 as well as significantly increased NGF and NT-3 protein in the SCG. When NGF infusion followed deafferentation, both trkA and p75 showed significant increases while trkC levels were similar to control values. NGF protein was not increased in the SCG when deafferentation preceded exogenous NGF, yet NT-3 was elevated and levels were similar to cases receiving NGF infusion only. These results support a role for preganglionic input in trkC and p75 expression in adult sympathetic neurons. The increased levels of NT-3 protein and trkC gene expression observed following NGF infusion suggest that NGF influences NT-3 regulation in adult sympathetic neurons. In addition, the present findings provide evidence that, when preganglionic input is removed prior to the NGF infusion, NT-3 effectively competes with NGF for trkA binding. Taken together, we propose that NT-3 may play a role in the robust sprouting of sympathetic cerebrovascular axons previously observed following NGF administration, particularly when deafferentation precedes the NGF infusion period.

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The objective of the present study was to examine the remodeling of uninjured sympathetic axons in the adult rat trigeminal ganglion following a 2-week in vivo intracerebroventricular infusion of NGF. The accumulation of infused NGF in the trigeminal was assessed using ELISA and sympathetic fibers were localized immunohistochemically with an antibody to tyrosine hydroxylase (TH). In addition, high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD) allowed for biochemical measurements of the catecholamines norepinephrine (NE) and dopamine (DA). Increased NGF protein in the trigeminal ganglion was paralleled by a significant increase in sympathetic fibers and pericellular plexuses (i.e. baskets) in the cell body regions. Some ganglia showed elevated NE following NGF infusion, yet the 88% increase in mean NE did not reach significance. Following bilateral removal of the sympathetic superior cervical ganglia (SCG), a significant reduction was observed in overall NE levels and in TH-immunoreactive (-ir) fibers in the cell body regions and peripheral branches, suggesting the SCG as the origin of the sympathetic ingrowth. However, mean DA levels as well as TH-ir fibers within the trigeminal central branch were unaffected by NGF infusion or removal of the SCG and likely resulted from intrinsic dopaminergic cell bodies. In conclusion, our data provide evidence that the increased availability of NGF in the young adult rat trigeminal ganglion observed following in vivo NGF infusion enhanced sympathetic associations with the sensory neurons in the trigeminal, supporting a role for NGF in the regulation of sympathosensory interactions.

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A role for nerve growth factor (NGF) in the remodeling of sensory neurons in the trigeminal ganglion was examined. Intracerebroventricular NGF infusion and/or bilateral removal of the sympathetic superior cervical ganglia, both of which are believed to increase the availability of NGF to primary sensory neurons, resulted in a significant increase in the frequency of calcitonin gene-related peptide immunoreactive pericellular baskets. The results of this study suggest that increased NGF is sufficient to enhance the formation of sensory baskets in this ganglion, and provide evidence that NGF may mediate the formation of sensory baskets in the sensory ganglia following injury.

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The present study investigated the potential for neurotrophin uptake by cerebrovascular axons and subsequent accumulation in the aged superior cervical ganglion (SCG) following a two week intracerebroventricular infusion of nerve growth factor (NGF). In the SCG from aged rats, NGF protein levels declined significantly compared with the SCG from young adult rats. Following NGF infusion, perivascular axons from both young adult and aged rats showed intense NGF immunostaining. In addition, significant increases in NGF protein were shown using enzyme-linked immunosorbent assay (ELISA) and in counts of NGF immunopositive cell bodies in the SCG when compared with age-matched controls. NGF accumulation in ganglia from aged rats, however, was significantly less when compared with ganglia from young adult rats. The results of the present study suggest that NGF protein is significantly reduced in aged ganglia with the neurons retaining some capacity to take up and transport exogenous neurotrophin. Even so, the potential for NGF accumulation is dramatically reduced in aged rats when compared with that of young adult rats. While previous results have shown robust NGF-induced neurotransmitter responses by sympathetic neurons from the aged animal, the present finding of reduced accumulation of NGF in aged sympathetic neurons suggests an age-related difference in the utilization or transport of NGF.

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The present study investigated the atrophy of aged perivascular sympathetic axons and the response of these cerebrovascular neurons to the neurotrophin nerve growth factor (NGF). Using high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD) to quantify catecholamines and immunohistochemical methods to quantify the density of TH immunoreactive fibers, we found a significant decrease in norepinephrine (NE) and TH in aged sympathetic axons. However, following in vivo administration of exogenous neurotrophin, aged neurons exhibited a robust response to NGF that was similar to the young adult, suggesting little decline in the capability of aged neurons to utilize exogenous neurotrophin. These results suggest that the age-related atrophy of aged sympathetic axons may result primarily from reduced availability of target-derived neurotrophin rather than from intrinsic alterations of neuronal function.

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Treatments designed to increase neurochemical levels may also result in increases in the numbers of axons that produce the neurochemicals of interest. A natural research question is how does one compare the average neurochemical production per axon between two (or more) experimental groups. Two statistical methods are proposed for this problem. The first method utilizes a delta-method approximation to the variance of a function of random variables while the second method is based on the bootstrap. These methods are illustrated with data obtained from perivascular norepinephrine following intracerebroventricular infusion of neurotrophin nerve growth factor in adult rats and are studied in a small simulation experiment. The delta-method confidence intervals exhibited better coverage properties than the bootstrap alternative.

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In previous studies, we found that a 2-week in vivo intracerebroventricular infusion of nerve growth factor (NGF) elicited a sprouting response by sympathetic perivascular axons associated with the intradural segment of the internal carotid artery. We hypothesized that NGF infused into the ventricular system would be internalized by responsive sympathetic cerebrovascular axons, retrogradely transported to parent cell bodies in the superior cervical ganglion (SCG), and subsequently released into the local ganglionic environment. Because fibers exhibiting immunoreactivity for calcitonin gene related peptide (CGRP) have been localized in the SCG, we used immunohistochemical methods to investigate whether a response by CGRP-immunoreactive axons in the SCG occurred following the proposed transport to and release of exogenous NGF in the ganglion. In consecutive tissue sections of the SCG stained for either CGRP or NGF, we found CGRP pericellular 'baskets' surrounding identified NGF-immunoreactive cell bodies. Nerve growth factor infusion resulted in a significant increase both in the number of CGRP pericellular baskets and in NGF-immunoreactive cell bodies. A significant positive correlation (r=0.95, P<0.05) between the pericellular baskets and NGF-immunoreactive cell bodies was observed, suggesting that intracranial projection neurons in the SCG released infused NGF (or possibly a converted signal) into the local ganglionic environment to elicit remodeling of CGRP fibers to form pericellular baskets. These findings were confirmed in sections double labeled for NGF and CGRP immunoreactivity. This remodeling suggests that exogenous NGF may mediate retrograde transneuronal plasticity, allowing for future in vivo examinations of the mechanisms involved in neurotrophin transport and release.

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Language impairments are commonly observed among children referred for psychiatric services. The most frequent psychiatric diagnosis of children with language impairment (LI) is Attention Deficit Hyperactivity Disorder (ADHD). It is not clear whether there are differences between children with ADHD and comorbid LI and children with other psychiatric disorders who are also comorbid for LI. In the present study the language, achievement, and cognitive processing characteristics of 166 psychiatrically referred 7-14-year-old children were examined using a 2 x 2 (ADHD, LI) design to examine four groups: children with ADHD + LI, children with ADHD who have normally developing language, children with psychiatric diagnoses other than ADHD with a language impairment (OPD + LI) or without a LI (OPD). Results indicated that children with LI were at the most disadvantage regardless of the nature of the psychiatric diagnosis. Contrary to prediction, working memory measures, used to tap the core cognitive deficit of ADHD in executive functions, were more closely associated with LI than with ADHD. It was concluded that caution must be exercised in attributing to children with ADHD what might be a reflection of problems for children with language impairment generally. As most therapies are verbally based it is notable that language competence is rarely evaluated systematically before such therapies are undertaken.

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In the past decade, young people in the United States have been two to three times more likely than in the two previous decades to commit homicides, while those 25 years and older have been less likely to commit homicides than were members of their age groups in the earlier time period. These changes in youth homicide rates are associated with two cohort characteristics that are theoretically linked to criminality: relative size of cohorts and the percentage of cohort member born to unwed mothers. These effects persist throughout the life span, are independent of age and historical period, and can explain fluctuations in homicide arrest rates before the recent upturn.

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The extent to which the loss of plasticity by aged neurons is due to changes in the neuronal environment or to a loss of growth potential of the neurons has not been determined. In previous studies we observed that young adult cerebrovascular axons undergo a sprouting response following a 2-week intracerebroventricular infusion of nerve growth factor (15 microg; NGF). The present study used electron microscopy to examine the innervation of the intradural segment of the internal carotid artery of the aged rat and to determine whether aged sympathetic perivascular axons would respond to in vivo infusion of NGF. Young adult and aged Fischer 344 female rats received a 2-week intracranial infusion of NGF (15 microg) or vehicle (VEH) and were perfused for electron microscopy. Although there was no change in the total number of perivascular axons associated in aged VEH when compared with young adult VEH, a significant reduction was observed in aged VEH when total axons and sympathetic axons were expressed per microm2 vascular wall, reflecting an age-related increase in blood vessel size. Following NGF infusion, aged sympathetic axons were significantly increased by 192% compared with aged VEH cases. These results suggest that there is a proportional reduction in sympathetic cerebrovascular neurons with aging but that they exhibit robust sprouting in response to an exogenous neurotrophin.

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PURPOSE: Managed care whether through risk or through capitated contracts results in reduction in resources, reduced length of hospital stay, and reduced utilization of hospital resources (collectively referred to as resource reductions). These resource reductions will become even more noticeable as a greater proportion of Medicare patients who need vascular operations select a managed-care senior product. We examined the results of a 4-year experience with resource management in an academic vascular surgery practice during which best practice plans were developed and implemented. METHODS: We analyzed hospital cost data, which included both total hospital and intensive care unit length of stay, average units per operation for laboratory, pharmacy, and radiology services and operating room and direct hospital costs for 257 carotid endarterectomies performed over fiscal years (FY) 1994, 1995, 1996, and 1997 (6 month data) and 175 infrainguinal bypass procedures performed during the same period. RESULTS: For carotid endarterectomy, length of stay decreased 66% over the 4-year period to an average of 2.07 days in FY97. Both radiology and pharmacy utilization were reduced after the first year of institution of best practice plans (56% and 32% respectively) with 4-year total reductions of 86% and 55% by FY97. The most notable changes included elimination of routine postoperative laboratory testing, use of aspirin rather than low-molecular-weight dextran, emphasis on oral rather than intravenous vasoactive drugs, and routine use of duplex scanning alone rather than angiography for diagnosis after FY94-95. The length of operating room time for carotid endarterectomy remained relatively constant from FY94 to FY97. As a result of these multiple factors, our study showed a 30% decrease in total average direct hospital costs for carotid endarterectomy from $9974 to $7002 in this 4-year period. Infrainguinal bypass graft procedures showed a progressive decrease in total cost of 28% for patients without complications to $15,186 but remained unchanged for those with complications. Laboratory use, pharmacy use, and radiology use were not significantly different. CONCLUSIONS: Case management for patients undergoing carotid endarterectomy and infrainguinal bypass grafting involving an integrated team of vascular surgeons, surgical house staff, a dedicated vascular nurse, and a social work case manager resulted in dramatic reductions both in length of stay and hospital resource utilization. As these costs decreased, operating room expenses assumed increasing importance. Operating room costs account for 60% of the direct costs of carotid endarterectomy and a comparable percentage for uncomplicated infrainguinal bypass grafting. Further substantial reductions in direct hospital costs will depend primarily on reductions in operating room costs, particularly those related to length of time in the operating room.

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The perivascular axons associated with the intradural segment of the internal carotid artery undergo a sprouting response following intracerebroventricular infusion of nerve growth factor (NGF). The objective of the present study was to determine whether a relationship exists between the number of sprouted axons and the amount of NGF infused into the ventricular system. Using regression analysis, we observed a significant log-log relationship between the dose of NGF and number of axons. No significant relationship was observed for the control (VEH) group. A significant increase in axonal number was observed following infusion of 3.0 micrograms NGF and higher when compared with VEH treatment of similar concentration. Results of this analysis suggest that a maximal response to NGF is approximated at doses of 15 micrograms or higher. These findings suggest a dose-dependent relationship between the response of mature sympathetic cerebrovascular axons in vivo and the dose of exogenous NGF.

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The anatomical relationships between postganglionic sympathetic neurons, their targets, and their afferent inputs provide an opportunity to experimentally distinguish between the anterograde and the retrograde influences on neuronal responsivity to growth factors. In the present study, the effect of decentralization of the superior cervical ganglion (SCG) on the NGF-induced sympathetic sprouting response by mature cerebrovascular axons was assessed in young adult rats. Growth by the perivascular axons associated with the intradural segment of the internal carotid artery was quantified using electron microscopy and changes in norepinephrine (NE) levels were monitored using high-performance liquid chromatography coupled with electrochemical detection. The mean number of perivascular axons observed in the treatment group receiving decentralization of the SCG prior to NGF infusion was not significantly different from that in NGF-infused cases, suggesting that central input was not required for axonal growth of intact sympathetic neurons. However, decentralization prevented the typical NGF-induced increase in perivascular NE associated with the ICA, indicating that afferent input was necessary for the neurotransmitter increase to occur. Thus, afferent input appears to play a role in the regulation of neurotransmitter expression of the sprouted axons but is not required for trophic factor-induced axonal growth.

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In the present study, we used high performance liquid chromatography coupled with electrochemical detection to examine perivascular catecholamines associated with the intradural segment of the internal carotid artery following a 2-week in vivo intracerebroventricular infusion of the neurotrophin nerve growth factor (NGF). Following administration of NGF, a significant increase (87.3%) in perivascular norepinephrine (NE; microgram/g) was observed when compared with vehicle-infused controls, suggesting that increased sympathetic neurotransmitter accompanies the NGF-induced sprouting response by sympathetic perivascular axons previously observed using electron microscopy (13, 15). The biochemical quantification of perivascular NE in the present study taken together with our previous morphological quantification of perivascular sprouts at the ultrastructural level reveal that the increase in NE is not proportional to the increase in the number of axons. Thus, when compared with controls, the relative amount of norepinephrine per axon apparently is reduced following NGF infusion. The apparent decrease in NE per axon following NGF infusion suggests that, during the 2-week infusion period, exogenous NGF did not stimulate the biosynthesis of perivascular NE beyond that necessary to accommodate the newly sprouted axons. These results extend our morphological findings and provide evidence for plasticity of neurotransmitter expression by adult sympathetic perivascular axons in vivo. In addition, we provide evidence that the increased perivascular catecholamine histofluorescence previously observed following NGF infusion results from an increase in the number of perivascular axons associated with the vessel rather than from an increase in the amount of NE within individual axons.

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1. Using cyclic AMP to stimulate perfused tsetse fly Malpighian tubules bathed in SO42- Ringer frequently causes an immediate but transient peak in transtubular potential (Vt), before stabilisation of Vt at an increased value. 2. These transients were investigated by monitoring the associated changes in cable properties and current­voltage (I/V) relationships. Tubules were perfused and bathed in either Cl- Ringer or SO42- Ringer (containing 8 mmol l-1 Cl-). 3. Tubules bathed in Cl- Ringer showed a transient swelling of the cells on exposure to cyclic AMP. Cable analysis confirmed the visually observed narrowing of the tubular lumen and revealed transient increases in core resistance (Rc) and transtubular resistance (Rt). As the cells returned to their initial volume, the lumen became distended, and Rc and Rt fell below their initial levels. These changes were accompanied by an increase, and a subsequent decrease, in the slope of the I/V plot. 4. None of the above changes was apparent in SO42- Ringer, other than a fall in Rt and in the slope of the I/V plot. 5. The results suggest that, in Cl- Ringer, cyclic AMP induces swelling of the tubular cells by promoting increased basolateral solute (and water) entry and that the subsequent rapid return to normal cell volume, with a concomitant progressive increase in the rate of tubular secretion, reflects the operation of a specific cell-volume regulatory mechanism of transepithelial transport. 6. The cyclic-AMP-induced peak that occurs in Vt in SO42- Ringer appears to be primarily due to a transient overshoot in the fall in series resistance (i.e. an increase in basolateral Na+ conductance), accompanied by a proportionately lesser increase in shunt resistance.

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Mature perivascular sympathetic axons associated with the intradural segment of the internal carotid artery (ICA) of the adult rat respond by sprouting following a two week infusion of nerve growth factor (NGF) into the lateral ventricle of the brain. Because nonsympathetic axons such as those comprising the sensory and parasympathetic population have been shown to respond to NGF, the present study was carried out to determine whether mature sensory axons respond to in vivo NGF infusion and whether competitive interactions between the innervating populations might affect the responsiveness of these axons to NGF. Standard electron microscopic techniques as well as calcitonin-gene-related peptide (CGRP) immunohistochemistry at the light microscopic level were used to examine the effects of intracerebroventricular NGF infusion on mature perivascular fibers with and without prior sympathetic denervation (i.e., bilateral superior cervical ganglionectomy). Following NGF infusion, CGRP-immunoreactive fibers appeared thicker and more numerous in the longitudinal plane when compared with vehicle controls. However, at the ultrastructural level, a significant increase in the total number of axons was not observed, although there was an increase in the number of large granular vesicles, suggesting that the CGRP fibers responded to exogenous NGF with an increase in neurotransmitter content, but not by sprouting. Sympathetic denervation, on the other hand, resulted in a significant increase in the number of fibers passing in the circumferential plane. The most dramatic change in CGRP immunoreactivity was observed following combined sympathetic denervation and subsequent NGF infusion, where, in addition to the presence of thicker immunoreactive fibers, a significant increase in the perivascular density of immunoreactive fibers associated with the intradural blood vessels was observed. These findings suggest that exogenous NGF has different effects on mature sympathetic and nonsympathetic fibers that innervate intradural blood vessels. The former exhibit robust sprouting, whereas the latter do not sprout in response to NGF but show evidence for increased neuropeptide content. In addition, the heightened response by sensory axons following denervation and subsequent NGF infusion provides support for the idea that sensory and sympathetic axons normally compete for target space and/or target-derived neurotrophic factors.

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We reported previously that a 2-week infusion of the trophic protein nerve growth factor (NGF) into the lateral ventricle of the adult rat brain elicits a sprouting response by perivascular axons associated with the intradural segment of the internal carotid artery. In the present study, we used electron microscopy to determine whether the sprouted axons persist following cessation of NGF delivery and, if not, to determine the time course of their disappearance. Our results demonstrate that NGF-induced sprouted axons do not persist following cessation of NGF delivery. The total number of axons at 1 week following the end of the NGF infusion was elevated compared to control values, but significantly reduced compared with NGF cases sacrificed immediately following the infusion period. Three weeks following the end of the NGF infusion, the total number of axons was similar to controls although there were no signs of axonal degeneration. These results suggest that continued elevation of NGF levels is necessary to maintain the sprouted axons and that endogenous levels of NGF, or other factors produced by the vascular target tissue, are not sufficient to maintain the newly formed axons. The demonstration that mature perivascular axons proliferate and disappear as a function of exogenous NGF exposure supports the accumulating evidence for continued plasticity in the mature nervous system.

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PURPOSE: To evaluate the results of axillary vein to popliteal vein valve transplantation (VVTX), we reviewed the clinical, phlebographic, and noninvasive hemodynamic results in 15 patients. METHODS: All patients had postthrombotic destruction of deep venous valves as determined by ascending phlebography, whereas descending phlebography demonstrated grade III or IV reflux in all patients. A segment of valve-bearing axillary vein was transplanted to the popliteal vein in the affected limb. Postoperative evaluation was by clinical, noninvasive, and phlebographic means. RESULTS: Over a mean follow-up period of 5.3 years (1.25 to 11 years), 13 of 14 patients (93%) had symptomatic improvement with relief of swelling, whereas all 14 patients who were admitted with pain had relief after operation. Thirteen of 15 patients (87%) returned to work or household duties. Physical findings of edema, skin pigmentation, and lipodermatosclerosis improved in most patients. Only three patients (21%) had development of recurrent ulcers, with an average postoperative ulcer-free interval of 4 years by life-table analysis. The cumulative ulcer-free survival rate for the group averaged 62% at late follow-up. All three patients with ulcer recurrence had a functioning valve by descending phlebography, but recurrent perforating veins were found in two patients, and deep venous thrombosis above a patent VVTX was observed in the third. Late assessment of reflux by venous filling index and valve closure times for the entire sample demonstrated mean values of 4.9 seconds in the latter and 6.8 ml/sec in the former. Residual volume fraction, which correlates with invasive ambulatory venous pressures, was reduced to a mean of 31%. No deterioration in late sequential noninvasive values could be detected. CONCLUSION: VVTX is a durable procedure for preventing recurrent venous ulcers.

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