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Background: The risk for hypertension after kidney donation remains uncertain.Purpose: To see whether normotensive adults who donate a kidney develop higher blood pressure and risk for hypertension compared with nondonor adults acting as control participants.Data Sources: MEDLINE, EMBASE, and Science Citation Index were searched from 1966 until November 2005 for articles published in any language. Reference lists of pertinent articles were also reviewed.Study Selection: The authors selected studies involving 10 or more healthy normotensive adults who donated a kidney and in whom blood pressure was assessed at least 1 year later.Data Extraction: Two reviewers independently abstracted data on study and donor characteristics, blood pressure measurements, outcomes, and prognostic features. Comparison data were abstracted from donor studies with control participants. Thirty primary authors provided additional data.Data Synthesis: Forty-eight studies from 28 countries followed a total of 5145 donors. Before surgery, the average age of donors was 41 years, the average systolic blood pressure was 121 mm Hg, and the average diastolic blood pressure was 77 mm Hg for all studies. In controlled studies in which the average follow-up was at least 5 years after donation (range, 6 to 13 years), blood pressure was 5 mm Hg higher in donors than in control participants (the weighted mean for systolic blood pressure using 4 studies involving 157 donors and 128 control participants was 6 mm Hg [95% CI, 2 to 11 mm Hg], and the weighted mean for diastolic blood pressure using 5 studies involving 196 donors and 161 control participants was 4 mm Hg [CI, 1 to 7 mm Hg]). There was statistical heterogeneity among the 6 controlled studies that assessed hypertension; an increase in risk was noted in 1 study (relative risk, 1.9 [CI, 1.1 to 3.5]).Limitations: Most studies were retrospective and did not include control groups that were assembled and followed along with donors. Approximately one third of the donors had incomplete follow-up information.Conclusions: On the basis of the limited studies conducted to date, kidney donors may have a 5-mm Hg increase in blood pressure within 5 to 10 years after donation over that anticipated with normal aging. Future controlled, prospective studies with long periods of follow-up will better delineate safety and identify donors at lowest risk for long-term morbidity. [ABSTRACT FROM AUTHOR]

Objective: To quantify the incidence of diabetes during the acute phase of diarrhea-associated hemolytic uremic syndrome (D + HUS) and to identify features associated with its development.Research Design and Methods: A systematic review and meta-analysis of articles assessing diabetes during D + HUS was conducted. Relevant citations were identified from Medline, Embase, and Institute for Scientific Information Citation Index databases. Bibliographies of relevant articles were hand searched. All articles were independently reviewed for inclusion and data abstraction by two authors.Results: Twenty-one studies from six countries were included. Only 2 studies reported a standard definition of diabetes; 14 defined diabetes as hyperglycemia requiring insulin. The incidence of diabetes during the acute phase of D + HUS could be quantified in a subset of 1,139 children from 13 studies (1966-1998, age 0.2-16 years) and ranged from 0 to 15%, with a pooled incidence of 3.2% (95% CI 1.3-5.1, random-effects model, significant heterogeneity among studies, P = 0.007). Children who developed diabetes were more likely to have severe disease (e.g., presence of coma or seizures, need for dialysis) and had higher mortality than those without diabetes. Twenty-three percent of those who developed diabetes acutely died, and 38% of survivors required long-term insulin (median follow-up 12 months). Recurrence of diabetes was possible up to 60 months after initial recovery.Conclusions: Children with D + HUS should be observed for diabetes during their acute illness. Consideration should be given to long-term screening of D + HUS survivors for diabetes. [ABSTRACT FROM AUTHOR]

Study Design: This was a retrospective study of 2 different fusion techniques for the treatment of lumbar degenerative spondylolisthesis., Objective: To determine whether posterior lumbar interbody fusion (IF) is associated with improved patient-rated satisfaction and functional outcome when compared with posterolateral fusion (PLF)., Summary of Background Data: IF and PLF are widely used surgical approaches in the treatment of spondylolisthesis. Numerous studies have compared IF and PLF techniques, but inconsistent results, heterogeneous cohorts, and conflicting scientific evidence have made it difficult to reach a consensus on the optimal fusion technique., Materials and Methods: A consecutive cohort of 87 patients who had single-level degenerative spondylolisthesis and either PLF or IF were identified from a prospectively maintained database. Short Form-36 physical and mental component score, Oswestry Disability Index, back and leg pain, and complication rate were assessed to 24 months postoperatively. Patient characteristics, clinical outcome, and complications were compared between groups., Results: Of the 87 patients identified, 29 patients (33%) had PLF and 58 patients (67%) had IF. Patient follow-up was ≥85%. Foraminal stenosis (PLF, 13.8% vs. IF, 34.5%; P=0.046) was more common among the participants in the IF group. Intraoperative and postoperative complications were not different between groups (P>0.05). The reoperation rate was 3.4% in the PLF group and 10.3% in the IF group (P=0.416). Patients in the PLF group experienced similar gains in improvement in all outcome measures as those in the IF group (P>0.05). Four patients in the IF group and 3 in the PLF group were lacking evidence of radiographic fusion. These patients did have increased moderate back pain compared with patients demonstrating radiographic fusion but did not differ in any other postoperative outcomes measures., Conclusions: Type of fusion, IF or PLF, does not affect patient outcome or postoperative complication rates., Level of Evidence: Level IV.

Objective: To determine the reliability and dependability of magnetic resonance imaging (MRI) and computerized tomography (CT) in the assessment of lumbar spinal stenosis and correlate the qualitative assessment to both a quantitative assessment and functional outcome measures. Multiple studies have addressed the issue of CT and MRI imaging in lumbar spinal stenosis. None showed superiority of one modality., Methods: We performed a standardized qualitative and quantitative review of CT and MRI scans of 54 patients. Intra-observer and inter-observer reliability was determined between three reviewer using Kappa coefficient. Agreement between the two modalities was analyzed. ODI and SF-36 outcomes were correlated with the imaging assessments., Results: Almost perfect intra-observer reliability for MRI was achieved by the two expert reviewers (κ = 0.91 for surgeon and κ = 0.92 for neuro-radiologist). For CT, substantial intra-observer agreement was found for the surgeon (κ = 0.77) while the neuro-radiologist was higher (κ = 0.96). For both CT and MRI the standardized qualitative assessment used by the two expert reviewers had a better inter-observer reliability than that between the expert reviewers and the general reporting radiologist, who did not utilize a standardized assessment system. When the qualitative assessment was compared directly, CT overestimated the degree of stenosis 20-35 % of the time (p < 0.05) while MRI overestimated the degree of stenosis 2-11 % of the time (p < 0.05). No correlation was found between qualitative and quantitative analysis with functional status., Conclusions: This study directly demonstrates that MRI is a more reliable tool than CT, but neither correlates with functional status. Both experience of the reader and the standardization of a qualitative assessment are influential to the reliability.

Background: Waits for elective spine surgery are common in Canada. We examined whether a prolonged wait for surgery for lumbar degenerative spinal stenosis was detrimental to outcome., Methods: In this prospective observational study, we enrolled 166 consecutive patients referred to our centre for treatment of lumbar degenerative spinal stenosis between 2006 and 2010. Outcome measures were assessed at referral, preoperatively and until 24 months postoperatively. Primary outcome measures were the physical and mental component summary scores of the 36-Item Short-Form Health Survey and the Oswestry Disability Index. Secondary outcome measures included the symptom severity scale of the Zurich Claudication Questionnaire, a numeric rating scale for back and leg pain, and patient satisfaction with treatment. Wait time was defined as the time from referral to surgery., Results: The follow-up rate at 2 years was 85%. The median wait time was 349 days. All health-related quality of life measures deteriorated during the waiting period, but there was no significant correlation between wait time and magnitude of the change in outcome measure. At 6 months postoperatively, the Pearson correlation was significantly positive between wait time and change in disability (r = 0.223), Zurich Claudication Questionnaire score (r = 0.2) and leg pain score (r = 0.221). At 12 months, the correlation remained significant for change in disability (r = 0.205) and was significant for change in mental well-being (r = -0.224). At 12 months, patients with a shorter wait (≤ 12 months) showed greater improvement in mental well-being (mean difference in change [and 95% confidence interval (CI)] 5.7 [1.4-9.9]) and decrease in disability (-9.3 [95% CI -15.1 to -3.6]) and leg pain (-1.6 [95% CI -3.0 to -0.3]). There were no statistically significant differences in outcome or patient satisfaction with treatment between those with shorter and longer waits at 24 months., Interpretation: Patients awaiting spinal surgery experienced deterioration in health-related quality of life irrespective of the length of wait time. However, longer waits were associated with a delay in recovery during the first year after surgery.

Background: Intermittent claudication can be neurogenic or vascular. Physicians use a profile based on symptom attributes to differentiate the 2 types of claudication, and this guides their investigations for diagnosis of the underlying pathology. We evaluated the validity of these symptom attributes in differentiating neurogenic from vascular claudication., Methods: Patients with a diagnosis of lumbar spinal stenosis (LSS) or peripheral vascular disease (PVD) who reported claudication answered 14 questions characterizing their symptoms. We determined the sensitivity, specificity and positive and negative likelihood ratios (PLR and NLR) for neurogenic and vascular claudication for each symptom attribute., Results: We studied 53 patients. The most sensitive symptom attribute to rule out LSS was the absence of "triggering of pain with standing alone" (sensitivity 0.97, NLR 0.050). Pain alleviators and symptom location data showed a weak clinical significance for LSS and PVD. Constellation of symptoms yielded the strongest associations: patients with a positive shopping cart sign whose symptoms were located above the knees, triggered with standing alone and relieved with sitting had a strong likelihood of neurogenic claudication (PLR 13). Patients with symptoms in the calf that were relieved with standing alone had a strong likelihood of vascular claudication (PLR 20.0)., Conclusion: The classic symptom attributes used to differentiate neurogenic from vascular claudication are at best weakly valid independently. However, certain constellation of symptoms are much more indicative of etiology. These results can guide general practitioners in their evaluation of and investigation for claudication.

Spinal cord injury (SCI) activates circulating leukocytes that migrate into the injured cord and bystander organs using adhesion molecule-mediated mechanisms. These cells cause oxidative damage, resulting in secondary injury to the spinal cord, as well as injury to bystander organs. This study was designed to examine, over a 6-h to 2-week period, changes in adhesion molecule surface expression on human peripheral leukocytes after SCI (9 subjects), using as controls 10 uninjured subjects and 6 general trauma patients (trauma controls, TC). Both the percentage of cells expressing a given adhesion molecule and the average level of its expression was quantified for both circulating neutrophils and monocytes. The percentage of neutrophils and monocytes expressing the selectin CD62L was unchanged in TC and SCI patients after injury compared to uninjured subjects. Concurrently, the amount of surface CD62L on neutrophils was decreased in SCI and TC subjects, and on monocytes after SCI. The percentage of neutrophils expressing α4 decreased in TC, but not in SCI, subjects. Likewise, the percentage of neutrophils and monocytes expressing CD11d decreased markedly in TC subjects, but not after SCI. In contrast, the mean surface expression of α4 and CD11d by neutrophils and monocytes increased after SCI compared with uninjured and TC subjects. The percentage of cells and surface expression of CD11b were similar in neutrophils of all three groups, whereas CD11b surface expression increased after SCI in monocytes. In summary, unlike changes found after general trauma, the proinflammatory stimulation induced by SCI increases the surface expression of adhesion molecules on circulating neutrophils and monocytes before they infiltrate the injured spinal cord and multiple organs of patients. Integrins may be excellent targets for anti-inflammatory treatment after human SCI.

Traumatic injury can cause a systemic inflammatory response, increasing oxidative activity of circulating leukocytes and potentially exacerbating the original injury, as well as causing damage to initially unaffected organs. Although the importance of intraspinal inflammation after human spinal cord injury is appreciated, the role of the systemic inflammatory response to this injury is not widely recognised. We investigated oxidative activity of blood leukocytes from nine cord-injured subjects and six trauma controls (bone fractures without CNS injury) at 6 h-2 weeks after injury, comparing values to those of ten uninjured subjects. Neutrophil and monocyte free radical production, evaluated by flow cytometry, increased significantly more in cord injury subjects than in trauma controls (6-fold vs 50% increases). In leukocyte homogenates, the concentration of free radicals increased significantly more in cord injury subjects (2-fold) than in the trauma controls (1.6-fold) as did activity of myeloperoxidase (2.3-fold vs. 1.7-fold). Moreover, in homogenates and blood smears, expression of the NADPH oxidase subunit gp91(phox) and of the oxidative enzyme, inducible nitric oxide synthetase was 20-25% greater in cord injury subjects than in trauma controls. Expression of the pro-inflammatory transcription factor NF-kappaB and of cyclooxygenase-2 increased similarly after both injuries. Finally, aldehyde products of tissue-damaging lipid peroxidation also increased significantly more in the plasma of spinal cord injury subjects than in trauma controls (2.6 fold vs. 1.9-fold). Spinal cord injury causes a particularly intense systemic inflammatory response. Limiting this response briefly after cord injury should protect the spinal cord and tissues/organs outside the CNS from secondary damage.

The parasubthalamic nucleus (PSTN) projects extensively to the nucleus of the solitary tract (NTS); however, the function of PSTN in cardiovascular regulation is unknown. Experiments were done in alpha-chloralose anesthetized, paralyzed, and artificially ventilated rats to investigate the effect of glutamate (10 nl, 0.25 M) activation of PSTN neurons on mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA). Glutamate stimulation of PSTN elicited depressor (-20.4 +/- 0.7 mmHg) and bradycardia (-26.0 +/- 1.0 beats/min) responses and decreases in RSNA (67 +/- 17%). Administration (intravenous) of atropine methyl bromide attenuated the bradycardia response (46%), but had no effect on the MAP response. Subsequent intravenous administration of hexamethonium bromide blocked both the remaining bradycardia and depressor responses. Bilateral microinjection of the synaptic blocker CoCl(2) into the caudal NTS region attenuated the PSTN depressor and bradycardia responses by 92% and 94%, respectively. Additionally, prior glutamate activation of neurons in the ipsilateral NTS did not alter the magnitude of the MAP response to stimulation of PSTN, but potentiated HR response by 35%. Finally, PSTN stimulation increased the magnitude of the reflex bradycardia to activation of arterial baroreceptors. These data indicate that activation of neurons in the PSTN elicits a decrease in MAP due to sympathoinhibition and a cardiac slowing that involves both vagal excitation and sympathoinhibition. In addition, these data suggest that the PSTN depressor effects on circulation are mediated in part through activation of NTS neurons involved in baroreflex function.

We reviewed any study where 10 or more healthy adults donated a kidney, and proteinuria, or glomerular filtration rate (GFR) was assessed at least 1 year later. Bibliographic databases were searched until November 2005. 31 primary authors provided additional information. Forty-eight studies from 27 countries followed a total of 5048 donors. An average of 7 years after donation (range 1-25 years), the average 24 h urine protein was 154 mg/day and the average GFR was 86 ml/min. In eight studies which reported GFR in categories, 12% of donors developed a GFR between 30 and 59 ml/min (range 0-28%), and 0.2% a GFR less than 30 ml/min (range 0-2.2%). In controlled studies urinary protein was higher in donors and became more pronounced with time (three studies totaling 59 controls and 129 donors; controls 83 mg/day, donors 147 mg/day, weighted mean difference 66 mg/day, 95% confidence interval (CI) 24-108). An initial decrement in GFR after donation was not accompanied by accelerated losses over that anticipated with normal aging (six studies totaling 189 controls and 239 donors; controls 96 ml/min, donors 84 ml/min, weighted mean difference 10 ml/min, 95% CI 6-15; difference not associated with time after donation (P=0.2)). Kidney donation results in small increases in urinary protein. An initial decrement in GFR is not followed by accelerated losses over a subsequent 15 years. Future studies will provide better estimates, and identify those donors at least risk of long-term morbidity.

Background: In nephrogenic diabetes insipidus (NDI), the kidney is unable to produce concentrated urine because of the insensitivity of the distal nephron to antidiuretic hormone (arginine vasopressin). In settings in which fluid intake cannot be maintained, this may result in severe dehydration and electrolyte imbalances. The risk for conversion of reversible to irreversible NDI seems to be a potential complication. This review summarizes the reversible causes of acquired NDI to facilitate earlier recognition and more effective treatment by clinicians., Methods: Two reviewers independently searched MEDLINE, Experta Medica (EMBASE), and ISI bibliographic databases. Human studies that described NDI caused by drugs, substances, or metabolic disturbances were included. To evaluate the causal role of the risk factor, data were abstracted according to Koch's postulates., Results: One hundred fifty-five studies published between 1957 and March 2004 described 30 risk factors. Of 155 studies, 58 studies provided a "definite" diagnosis of NDI; 83 studies, a "probable" diagnosis; and 14 studies, a "possible" diagnosis. Nine factors were considered "definite" causes of NDI; 15 factors, "probable" causes; and 6 factors, "possible" causes. The most reported risk factors were lithium (84 studies), antibiotics (16 studies), antifungals (11 studies), antineoplastic agents (9 studies), antivirals (8 studies), and metabolic disturbances (8 studies). Duration of NDI reversal, as well as conversion to irreversible symptoms, seemed to depend on the duration of exposure., Conclusion: Most risk factors for reversible NDI were medications, and their identification and removal resulted in resolution of the condition. Long-term treatment with lithium seemed to result in irreversible NDI.

Context: Developers of health care software have attributed improvements in patient care to these applications. As with any health care intervention, such claims require confirmation in clinical trials., Objectives: To review controlled trials assessing the effects of computerized clinical decision support systems (CDSSs) and to identify study characteristics predicting benefit., Data Sources: We updated our earlier reviews by searching the MEDLINE, EMBASE, Cochrane Library, Inspec, and ISI databases and consulting reference lists through September 2004. Authors of 64 primary studies confirmed data or provided additional information., Study Selection: We included randomized and nonrandomized controlled trials that evaluated the effect of a CDSS compared with care provided without a CDSS on practitioner performance or patient outcomes., Data Extraction: Teams of 2 reviewers independently abstracted data on methods, setting, CDSS and patient characteristics, and outcomes., Data Synthesis: One hundred studies met our inclusion criteria. The number and methodologic quality of studies improved over time. The CDSS improved practitioner performance in 62 (64%) of the 97 studies assessing this outcome, including 4 (40%) of 10 diagnostic systems, 16 (76%) of 21 reminder systems, 23 (62%) of 37 disease management systems, and 19 (66%) of 29 drug-dosing or prescribing systems. Fifty-two trials assessed 1 or more patient outcomes, of which 7 trials (13%) reported improvements. Improved practitioner performance was associated with CDSSs that automatically prompted users compared with requiring users to activate the system (success in 73% of trials vs 47%; P = .02) and studies in which the authors also developed the CDSS software compared with studies in which the authors were not the developers (74% success vs 28%; respectively, P = .001)., Conclusions: Many CDSSs improve practitioner performance. To date, the effects on patient outcomes remain understudied and, when studied, inconsistent.

Experiments were done in the anaesthetized rat to determine the effect of activation of renal receptors following renal arterial occlusion (RAO) on the induction of c-fos in neurons of the lamina terminalis in the forebrain. Following RAO, fos labeled neurons were found in both the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT). Transection of the renal nerves ipsilateral to RAO reduced ( approximately 61%) the number of fos labeled neurons in the SFO and prevented the fos labeling in the OVLT. Similarly, administration of the angiotensin II converting enzyme inhibitor enalapril maleate prior to RAO also reduced ( approximately 27%) the number of fos labeled neurons in the SFO to RAO. However, the number of fos labeled neurons was not altered in the OVLT. The number of fos labeled neurons in the SFO of the intact animals after RAO was found to be greater than the algebraic sum of the number of fos labeled neurons in the renal nerve transected and enalapril treated animals. These results suggest that neurons in the SFO are activated by at least two different mechanisms following renal artery occlusion; those involving the activation of afferent renal nerves and those due to changes in circulating levels of angiotensin II. In addition, afferent renal nerve inputs combined with the effect of increased circulating levels of angiotensin II produce a greater activation of the SFO than either input alone. On the other hand, the OVLT appears to be selectively activated by afferent renal nerve inputs following RAO. Taken together, these data suggest that neural inputs from the kidney may play an important role in controlling body fluid balance and arterial pressure (AP) by influencing the activity of forebrain circumventricular organs neurons that function in the detection of blood borne signals associated with changes in extracellular fluid volume.

Context: The long-term renal prognosis of patients with diarrhea-associated hemolytic uremic syndrome (HUS) remains controversial., Objectives: To quantify the long-term renal prognosis of patients with diarrhea-associated HUS and to identify reasons for different estimates provided in the literature., Data Sources: We searched MEDLINE and Experta Medica (EMBASE) bibliographic databases and conference proceedings, and we contacted experts until February 2003. We also searched the Institute for Scientific Information index and reference lists of all studies that fulfilled our eligibility criteria. The search strategy included the terms hemolytic-uremic syndrome, purpura, thrombotic thrombocytopenic, Escherichia coli O157, longitudinal studies, kidney diseases, hypertension, and proteinuria, Study Selection: Any study that followed up 10 or more patients with primary diarrhea-associated HUS for at least 1 year for renal sequelae., Data Extraction: Two authors independently abstracted data on study and patient characteristics, renal measures, outcomes, and prognostic features. Disagreements were resolved by a third author or by consensus., Data Synthesis: Forty-nine studies of 3476 patients with a mean follow-up of 4.4 years (range, 1-22 years at last follow-up) from 18 countries, 1950 to 2001, were summarized. At the time of recruitment, patients were aged 1 month to 18 years. In the different studies, death or permanent end-stage renal disease (ESRD) ranged from 0% to 30%, with a pooled incidence of 12% (95% confidence interval [CI], 10%-15%). A glomerular filtration rate lower than 80 mL/min per 1.73 m2, hypertension, or proteinuria was extremely variable and ranged from 0% to 64%, with a pooled incidence of 25% (95% CI, 20%-30%). A higher severity of acute illness was strongly associated with worse long-term prognosis. Studies with a higher proportion of patients with central nervous system symptoms (coma, seizures, or stroke) had a higher proportion of patients who died or developed permanent ESRD at follow-up (explaining 44% of the between-study variability, P =.01). Studies with a greater proportion of patients lost to follow-up also described a worse prognosis (P =.001) because these patients were typically healthier than those followed up. One or more years after diarrhea-associated HUS, patients with a predicted creatinine clearance higher than 80 mL/min per 1.73 m2, no overt proteinuria, and no hypertension appeared to have an excellent prognosis., Conclusions: Death or ESRD occurs in about 12% of patients with diarrhea-associated HUS, and 25% of survivors demonstrate long-term renal sequelae. Patients lost to follow-up contribute to worse estimates in some studies. The severity of acute illness, particularly central nervous system symptoms and the need for initial dialysis, is strongly associated with a worse long-term prognosis.

Experiments were performed to investigate the effect of 17beta-estradiol (E; 30 pg/ml plasma) treatment (15-25 days) in the ovariectomized (OVX) female Wistar rat on the cardiovascular responses to hypocretin-1 (hcrt-1) in the nucleus tractus solitarius (NTS). In an initial series of experiments, the distribution of hcrt-1-like immunoreactivity within the region of the NTS was mapped in both OVX only and OVX+E animals. Hcrt-1 immunoreactivity was found throughout the NTS region in both groups of females, predominantly within the caudal interstitial, commissural, medial and lateral subnuclei of the NTS. The relative density of hcrt-1 immunoreactivity in all NTS subnuclei was similar in both female groups. Microinjections of hcrt-1 (0.5-10 pmol) into the caudal lateral and medial subnuclei of the NTS complex of the alpha-chloralose of the urethane-anaesthetized E-treated OVX rat elicited a dose-related decrease in heart rate (HR). On the other hand, although a dose-response effect on arterial pressure was evident, significant arterial pressure responses were observed only at the higher dose of hcrt-1 (>2.5 pmol). In the OVX only female rat, microinjection of hcrt-1 into similar NTS sites elicited a bradycardia and depressor response only at the highest dose of hcrt-1, and these responses were significantly smaller in magnitude than those elicited in the OVX+E animal. In addition, in the OVX only animals, a few sites within the caudal commissural subnucleus of the NTS complex were found at which hcrt-1 elicited tachycardia and pressor responses. Finally, it was found that the reflex bradycardia to the activation of arterial baroreceptors as a result of increasing systemic arterial pressure with phenylephrine (2-4 microg/kg) was significantly potentiated in the OVX+E animals only. These data suggest that hcrt-1 in the NTS of the female activates a neuronal circuit that controls the circulation and that the circulating level of E alters the sensitivity of these cardiovascular circuits to hcrt-1.

Experiments were done in male Wistar rats to investigate the effects of microinjection of hypocretin-1 (Hcrt-1) into the nucleus of the solitary tract (NTS) on mean arterial pressure (MAP), heart rate (HR), and the baroreflex. In the first series, the distribution of Hcrt-1-like immunoreactivity (Ir) was mapped within the region of NTS. Hcrt-1 Ir was found throughout the NTS region, predominantly within the caudal dorsolateral (Slt), medial (Sm), and interstitial subnuclei of the NTS. In the second series, in alpha-chloralose or urethane-anesthetized rats, microinjection of Hcrt-1 (0.5-5 pmol) into the caudal NTS elicited a dose-dependent decrease in MAP and HR. A mapping of the caudal NTS region showed that the largest depressor and bradycardia responses elicited by Hcrt-1 were from sites in the Slt and Sm. In addition, doses >2.5 pmol at a small number of sites localized to the caudal commissural nucleus of NTS elicited pressor and tachycardia responses. Intravenous administration of the muscarinic receptor blocker atropine methyl bromide abolished the bradycardia response and attenuated the depressor response, whereas subsequent administration of the nicotinic receptor blocker hexamethonium bromide abolished the remaining MAP response. Finally, microinjection of Hcrt-1 into the NTS significantly potentiated the reflex bradycardia to activation of arterial baroreceptors as a result of increasing MAP by systemic injections of phenylephrine (2-4 microg/kg). These results suggest that Hcrt-1 in the NTS activates neuronal circuits that increases vagal activity to the heart, inhibits sympathetic activity to the heart and vasculature, and alters the excitability of NTS neuronal circuits that reflexly control the circulation.

Orexins (hypocretins) are neuropeptides which have recently been identified exclusively within lateral hypothalamic and perifornical neurons, and these orexin (ox) containing neurons appear to have extensive projections to all levels of the neuraxis. In this study, we report the identification of two distinct clusters of neurons containing ox-B-like immunoreactivity within the amygdaloid complex of the rat. A cluster of small to medium size ovoid shaped neurons containing ox-B-like immunoreactivity was found predominantly within the lateral division of the central nucleus of the amygdala (ACe). A second distinct, but smaller group of ox-B labelled neurons with similar shapes and sizes to those in ACe was also identified in the anterior lateral subnucleus of the bed nucleus of the stria terminalis (BST) immediately adjacent the internal capsule, and in an area just ventral to the lateral ventricle. Neurons containing ox-A-like immunoreactivity were not observed in either structure. However, both structures contained ox-A- and ox-B labelled varicose fibers. Unilateral electrolytic lesions of the lateral hypothalamic area that contained ox-A and ox-B neurons did not alter the labelling of either ACe or BST ox-B pericarya. As both the ACe and BST are known to be involved in integrating complex homeostatic mechanisms associated with behaviours, these data suggest that a specific subset of ox-B neurons within the amygdaloid complex may serve as a component of neuronal circuits coordinating these responses.

A double-staining immunocytochemical study was done in ovariectomized (OVX) female rats that were either treated with 17beta-estradiol (E(2)) (OVX+E(2)) to produce an approximate circulating level of 30 pg/ml plasma, or not-treated with E(2) (OVX), to investigate the distribution of subfornical organ (SFO) neurons that contained estrogen receptors (ER), and to determine whether these neurons also contained the angiotensin II AT(1)-receptor (AT(1)R). Neurons that contained either ER-like immunoreactivity only, AT(1)R-like immunoreactivity only, or both ER and AT(1)R immunoreactivity were found throughout the extent of the SFO in both the OVX+E(2) and OVX rats. However, some regional differences were apparent in both groups of female rats. Neurons containing the ER were predominantly found in the peripheral regions of the SFO, near large blood vessels and the ependymal layer of the third ventricle. A number of lightly stained ER containing neurons was also observed scattered throughout the central core region of the SFO. OVX only animals were found to have a larger number of ER containing neurons in the SFO compared to the E(2) treated animals. Neurons containing AT(1)R were also found throughout the SFO, but without a distinct distribution pattern in either group of rats, although there were more neurons that exhibited AT(1)R immunoreactivity in the OVX animals. Finally, a distinct group of SFO neurons was found that exhibited both ER and AT(1)R immunoreactivity in both groups of animals, although a larger number of these double labelled neurons was found in the OVX animal. Most of these neurons were also found along the peripheral border of the SFO in close proximity to blood vessels and the ventricular lining. These data have demonstrated the co-existence of ER and AT(1)R in SFO neurons of the female rat, and suggest that circulating level of E(2) alter the expression of both the ER and AT(1)R in these neurons. In addition, these data suggest that E(2) may alter the physiological responses of SFO neurons to angiotensin II by down regulating the number of AT(1)R., (Copyright 1999 Elsevier Science B.V.)

Experiments were done in chloralose anesthetized, paralyzed and artificially ventilated male Wistar rats to investigate the effects of microinjections of either norepinephrine (NE) or tyramine into the central nucleus of the amygdala (ACe) on the arterial pressure (AP) and heart rate (HR) responses elicited by glutamate (Glu) stimulation of the ACe. Microinjections of Glu into the ACe elicited decreases in mean AP (-23+/-3 mmHg) and HR (-11+/-3 bpm). Microinjections of NE or tyramine into these sites did not elicit cardiovascular responses. However, Glu into the ACe in the presence of NE or tyramine elicited depressor or bradycardic response that were significantly smaller (70-100%) in magnitude than to Glu alone. These data suggest that noradrenergic mechanisms in the ACe alter the excitability of ACe neurons involved in mediating changes in systemic AP and HR., (Copyright 1999 Elsevier Science B.V.)

Experiments were done in the anesthetized rat to identify the dorsal root ganglia (DRG) and the spinal cord segments that contain neurons activated by either renal venous occlusion (RVO) or by renal arterial occlusion (RAO). Fos induction, detected immunohistochemically in DRG and the spinal cord neurons, was used as a marker for neuronal activation. RVO induced Fos immunoreactivity in neurons in the DRG of spinal segments T8-L2 on the side ipsilateral to that of occlusion. The largest number of Fos-labeled neurons was found in the T11 DRG. In the spinal cord the largest number of Fos-labeled neurons was found in the ipsilateral dorsal horn of spinal segments T11-T12, predominantly in a cluster near the dorsomedial edge of laminae I-II. A few additional Fos-labeled neurons were observed in laminae IV and V. After RAO Fos-labeled neurons were found in the ipsilateral DRG of spinal segments similar to those observed to contain neurons after RVO. However, most of the Fos-labeled neurons were observed within the T12-L1 DRG. In the spinal cord Fos-labeled neurons were scattered throughout lamina I-II of the ipsilateral dorsal horn of spinal segments T8-L2, although the largest number was observed at the T13 level. Additionally, a distinct cluster of Fos-labeled neurons was observed predominantly in the region of the ipsilateral intermediolateral cell column, although a few neurons were found scattered throughout the nucleus intercalatus, central autonomic areas, and laminae IV and V of the cord bilaterally. No Fos labeling was observed in the complementary contralateral DRG or dorsal horns after either RVO or RAO. In addition, renal nerve transection prevented Fos labeling in the ipsilateral DRG and dorsal horns after RVO or RAO. Taken together, these data suggest that functionally different renal afferent fibers activate DRG neurons that may have distinct projections in the spinal cord.

Experiments were done in the conscious and unrestrained rat to identify central structures activated by electrical stimulation of afferent renal nerves (ARN) using the immunohistochemical detection of Fos-like proteins. Fos-labelled neurons were found in a number of forebrain and brainstem structures bilaterally, but with a contralateral predominance. Additionally, Fos-labelled neurons were found in the lower thoracolumbar spinal cord predominantly ipsilateral to the side of ARN stimulation. Within the forebrain, neurons containing Fos-like immunoreactivity after ARN stimulation were primarily found along the outer edge of the rostral organum vasculosum of the laminae terminalis, in the medial regions of the subfornical organ, in the median preoptic nucleus, in the ventral subdivision of the bed nucleus of the stria terminalis, along the lateral part of the central nucleus of the amygdala, throughout the deeper layers of the dysgranular insular cortex, in the parvocellular component of the paraventricular nucleus of the hypothalamus (PVH), and in the paraventricular nucleus of the thalamus. Additionally, a smaller number of Fos-labelled neurons was observed in the supraoptic nucleus, in the magnocellular component of the PVH and along the lateral border of the arcuate nucleus. Within the brainstem, Fos-labelled neurons were found predominantly in the commissural and medial subnuclei of the nucleus of the solitary tract and in the external subnucleus of the lateral parabrachial nucleus. A smaller number were observed near the caudal pole of the locus coeruleus, and scattered throughout the ventrolateral medullary and pontine reticular formation in the regions known to contain the A1, C1 and A5 catecholamine cell groups. The final area observed to contain Fos-labelled neurons in the central nervous system was the thoracolumbar spinal cord (T9-L1) which contained cells in laminae I-V of the dorsal horn ipsilateral to side of stimulation and in the intermediolateral cell column at the same levels bilaterally, but with an ipsilateral predominance. Few, if any Fos-labelled neurons were observed in the same structures of control animals in which the ARN were stimulated, but the renal nerves proximal to the site of stimulation were transected, or in the sham operated animals. These data indicate that ARN information originating in renal receptors is conveyed to a number of central areas known to be involved in the regulation of body fluid balance and arterial pressure, and suggest that this afferent information is an important component of central mechanisms regulating these homeostatic functions.

Experiments were done to investigate the distribution of neurons within the nucleus of the solitary tract (NTS) that projected directly to the subfornical organ (SFO) and to determine whether these neurons were components of the catecholaminergic cell groups in the dorsal medial medulla. Microinjection of the fluorescent tract-tracers fluorogold or rhodamine latex micro-beads were made into the SFO of the rat. Brainstem sections were then processed immunocytochemically for the identification of neuronal cell bodies containing the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH) or phenylethanolamine-N-methyltransferase (PNMT). Retrogradely labelled cell bodies that projected to the SFO were found in the NTS, bilaterally, extending from approximately the level of the rostral aspect of the area postrema (obex) caudally to the calamus scriptorius. These neurons were located predominantly in the medial, lateral and dorsolateral subdivisions of NTS. Approximately one-third of these retrogradely labelled neurons were immunoreactive to TH and DBH. On the other hand, less than 7% of the retrogradely labelled neurons were found to contain TH and PNMT immunoreactivity. These data have demonstrated that noradrenergic neurons of the A2 cell group in the caudal NTS innervate the SFO and suggest that these neurons may be involved in relaying cardiovascular afferent information directly to a forebrain circumventricular organ involved in arterial pressure and body fluid homeostasis.

Experiments were done in urethane anesthetized rats to investigate the effect of electrical and glutamate stimulation of arcuate nucleus (Arc) on the discharge rate of subfornical organ (SFO) neurons that responded to either plasma hypernatremia or angiotensin II (ANG II). Extracellular recordings were made from 253 histologically verified single neurons in SFO. Of these, 40.3% (102/253) responded with excitation and 10% (25/253) with inhibition to Arc stimulation. Thirty-five (34.3%) of the units excited by Arc were also excited by intracarotid infusion of hypertonic (0.5 M) NaCl. In addition, 37 (36.3%) of the units excited by Arc were also excited by intracarotid infusion of ANG II. Furthermore, 10 (40.0%) of the units inhibited by Arc were found to be excited by ANG II. None of the units inhibited by Arc stimulation were responsive to plasma hypernatremia. These data indicate that inputs from Arc neurons converge onto SFO neurons that alter their discharge rate during changes in plasma concentration of Na+ or ANG II. These results suggest that Arc may be involved in body fluid balance and circulatory regulation by modulating the activity of SFO neurons that function in the detection of blood-borne signals from the depletion of intra- and extra-cellular fluid volumes.

Two series of experiments were done in the rat to investigate whether neurons in arcuate nucleus of the hypothalamus (Arc) containing neurotensin (NT)-like immunoreactivity projected to subfornical organ (SFO). In the first series, the anterograde tract-tracer Phaseolus vulgaris leucoagglutinin (PHA-L) was microiontrophoresed into the region of Arc that contains NT neurons. After a 9-12 day survival period the animals were sacrificed and forebrain sections that contained SFO were processed for combined PHA-L and NT immunoreactivity. In the second series of experiments, unilateral or bilateral electrolytic lesions of Arc were made and after a 10-17 day survival period SFO was examined to determine the relative contribution of NT Arc neurons to NT immunoreactivity within SFO. PHA-L labelled fibers with terminal-like boutons were found in SFO primarily on the side ipsilateral to the site of injection. A small number of the PHA-L labelled fibers in the lateral aspect of SFO was also immunoreactive to NT. Unilateral lesions reduced, whereas bilateral lesions of Arc eliminated most of the NT-like immunoreactivity within SFO. These data demonstrate the existence of a direct pathway from Arc to SFO that contains the putative neurotransmitter NT. These results suggest that this pathway may function in the modulation of neural and/or humoral events related to cardiovascular regulation and body fluid homeostasis by influencing the activity of SFO neurons.

Experiments were done in urethane anesthetized rats to investigate the effect of glutamate (Glu) stimulation of arcuate nucleus of the hypothalamus (Arc) on the discharge rate of subfornical organ (SFO) neurons during changes in plasma sodium concentration and angiotensin II (ANG II) levels. Extracellular recordings were made from 67 histologically verified single neurons within SFO. Of these, 17 (25.4%) were excited by intracarotid infusion of hypertonic NaCl and 21 (31.3%) by intracarotid ANG II infusion. Five (29.4%) of the units excited by hypertonic NaCl were also excited by Glu stimulation of Arc. Similarly, seven (33.3%) of the units excited by ANG II were also excited by Arc stimulation. Additionally, four (19.0%) of the units excited by ANG II were inhibited by Glu stimulation of Arc. The remaining SFO units did not alter their discharge rate to activation of Arc neurons. The response of units to hypertonic NaCl or to ANG II was attenuated during simultaneous activation of Arc. These data suggest that Arc may be involved in modulating the activity of SFO neurons that function in the detection of blood-borne signals from the depletion of intra- and extracellular fluid volumes.

The locus coeruleus (LC) was anatomically separated from the periventricular gray substance (PVG) by means of knife cuts in the adult female rat presenting regular estrous cycling. This resulted in a transient suppression of the estrous cycling that lasted 10-13 days after surgery. After this period, irregular or regular cycling activity was observed. The regular cycling was restored 30-45 days after the knife cuts. Golgi impregnation of some of the brains of these rats revealed regenerative elements in the knife-cut-insulted area. Thus, blood vessels, macrophagic-like elements, and glial-like elements were observed in close relation with the knife-cut pathway. Additionally, well-defined stained neurons typical of the LC and PVG were observed in close proximity to the knife-cut pathway. Dendritic and axon projections towards the insulted area were observed. Well defined axons were seen across the knife-cut pathway. These data support, first, that the LC-PVG communication is part of a circuitry for the modulation of gonadotropic activity, and second, that in the restoration of the estrous cyclicity after the knife cut, regenerative processes leading to a LC-PVG functional reconnection occurred after the knife cut.

Experiments were done in conscious rats to investigate the effect of i.c.v. infusions of hypertonic NaCl solutions on the induction of the protein Fos in the arcuate nucleus (Arc). Neurons containing Fos-like immunoreactivity were observed throughout the rostrocaudal extent of Arc after i.c.v. infusions of hypertonic saline solutions (337-744 mM). However, most of the labelled neurons were confined to the middle third of the nucleus, in the region of the dorsomedial and ventromedial subnuclei. Few, if any Fos-labelled neurons were observed in Arc of animals that received i.c.v. infusions of isotonic (142 mM) or mild hypertonic (173 mM) saline solutions or a hyperosmotic (660 mOsm/kg) saline solution of mannitol. No Fos-labelled neurons were found in the subfornical organ, although a few were observed scattered throughout the organum vasculosum laminae terminalis (OVLT) in all the animals studied. The density nor the distribution pattern of Fos-labelled neurons in OVLT was altered in animals receiving i.c.v. infusions of hypertonic saline or hyperosmotic solutions. These data demonstrate that Arc neurons are activated during a hypertonic saline challenge and suggest that Arc may function as a sodium-sensitive structure that is involved in body-fluid and circulatory homeostasis.

Experiments were done in urethane anesthetized rats to investigate the effect of activation of the arcuate nucleus (Arc) on the discharge rate of single units in the subfornical organ (SFO). Extracellular recordings were made from 51 spontaneously active neurons histologically verified in the SFO. Of these units, 19 (37%) were inhibited (mean latency 7.3 +/- 1.1 ms) and 14 (28%) were excited (mean latency 12.8 +/- 3.2 ms) during electrical stimulation of the Arc. The remaining 18 units did not alter their firing frequency during stimulation of the Arc. These data suggest that the Arc may be involved in the modulation of neural and humoral events related to body fluid homeostasis and cardiovascular regulation by altering the activity of SFO neurons.

The present study was aimed at observing the diuretic and natriuretic responses after a water load (2% body weight) in four groups of young consenting volunteers submitted previously, during three days, to a hypersodic (500 mEq Na/day), hyposodic (35 mEq Na/day), and normosodic (200 mEq Na/day) diet, or treated with furosemide (Lasix, 40 mg/day). During the treatment urine was collected each day. On the fourth day, in the morning, the bladder was emptied, the water load was ingested, and the urine collected during 10 periods of 20 min each. The urinary, sodium, and chloride flows were determined. The four groups displayed diuretic curves following a similar pattern. In contrast, the natriuretic curves of the four groups were completely different; totally flat with low values for the furosemide group and a large initial natriuretic curve for the hypersodic group with a gradual decrease but maintaining high values. The results indicate that the way the organism compensates for the excess of water by means of urinary water loss is independent of the body sodium content, whereas the way in which sodium loss is accomplished is determined by its body content and is independent of the way in which the water is lost.

A technique for the implantation of a permanent polyethylene catheter into the bladder is described. The procedure permits collecting the subject's urine in arbitrary periods of time during at least four to six weeks.