Comparison of survival of stage I-III colon cancer by travel distance and hospital volume.

BACKGROUND: Previous studies have demonstrated improved outcomes at high-volume colorectal surgery centers; however, the benefit for patients who live far from such centers has not been assessed relative to local, low-volume facilities. METHODS: The 2010-2015 National Cancer Database (NCDB) was queried for patients with stage I-III colon adenocarcinoma undergoing treatment at a single center. A 'local, low-volume' cohort was constructed of 12,768 patients in the bottom quartile of travel distance at the bottom quartile of institution surgical volume and a 'travel, high-volume' cohort of 11,349 patients in the top quartile of travel distance at the top quartile of institution surgical volume. RESULTS: In unadjusted analysis, patients in the travel cohort had improved rates of positive resection margins (3.7% vs. 5.5%, p < 0.001), adequate lymph-node harvests (92% vs. 83.6%, p < 0.001), and 30- (2.2% vs. 3.9%, p < 0.001) and 90-day mortality (3.7% vs. 6.4%, p < 0.001). On multivariable logistic regression analysis adjusting for patient demographic, tumor, and facility characteristics, the cohorts demonstrated equivalent overall survival (HR: 0.972, p = 0.39), with improved secondary outcomes in the 'travel' cohort of adequate lymph-node harvesting (OR: 0.57, p < 0.001), and 30- (OR 0.79, p = 0.019) and 90-day mortality (OR 0.80, p = 0.004). CONCLUSIONS: For patients with stage I-III colon cancer, traveling to high-volume institutions compared to local, low-volume centers does not convey an overall survival benefit. However, given advantages including 30- and 90-day mortality and adequate lymph-node harvest, nuanced patient recommendations should consider both these differences and the unquantified benefits to local care, including cost, travel time, and support systems.

The side of the primary tumor affects overall survival in colon adenocarcinoma: an analysis of the national cancer database.

BACKGROUND: Due to conflicting study results on the effect of laterality on overall survival in primary colon cancers, we sought to examine the impact of left compared to right-sided primary tumors on overall survival for stage I-III colon cancer using the largest dataset to date. METHODS: The 2006-2013 NCDB was queried for patients with single primary, stage I-III colon adenocarcinoma and grouped by stage and tumor location. RESULTS: For stage I-II tumors, 114,839 patients had resection (62% right:38% left). After adjustment, patients with right-sided tumors had superior survival ([HR right as reference]: 1.13, 95% CI 1.09-1.17, p < 0.001). For stage III tumors, 71,024 patients had resection, (59% right:41% left). After adjustment, patients with left-sided tumors had superior survival with chemotherapy (HR 0.85, p < 0.001) and no difference in survival without chemotherapy (HR 0.97, p = 0.18). CONCLUSIONS: The side of the primary tumor impacts overall survival across stages for colon adenocarcinoma. Patients with right-sided tumors have superior survival for stage I-II disease while patients with left-sided stage III disease demonstrate a survival advantage, suggesting an opportunity for investigators to use sidedness as a surrogate for prognosis and chemoresponsiveness.

Disparities in colostomy reversal after Hartmann's procedure for diverticulitis.

BACKGROUND: Hartmann's procedure for diverticulitis is a common procedure, with highly variable rates and timing of colostomy reversal. The aim of this study was to evaluate the impact of race and insurance coverage on reversal within 2 years of Hartmann's procedure for diverticulitis. METHODS: The Healthcare Cost and Utilization Project (HCUP) State Inpatient Database of five states (2007-2010) was queried for patients who had Hartmann's procedure in the setting of diverticulitis. Patients were grouped by race and insurance status, and multivariable adjustment was performed to evaluate rate and timing of colostomy takedown at 2 years. RESULTS: Among 11,019 patients who had Hartmann's procedure for diverticulitis, 6900 (69%) patients had colostomy reversal by 2 years, with a median time to reversal of 19 weeks. Compared to white patients with private insurance, combinations of black race and non-private insurance significantly reduced likelihood of colostomy reversal at 2 years across all combinations. Black patients without insurance had the lowest likelihood of reversal at 2 years (OR 0.27, 95% CI 0.14-0.51, p < 0.001). For patients who had colostomy reversal within 2 years, black patients without insurance had a significant delay in time to reversal (11 weeks, 95% CI 6-16, p < 0.001) compared to white patients with private insurance, and delays persisted across all other groups. CONCLUSIONS: Black patients and those without private insurance experienced significantly lower rates of, and delayed time to, colostomy reversal compared to white patients with private insurance. These disparities must be considered for allocation of resources in marginalized communities.

Association between neoadjuvant chemoradiation and survival for patients with locally advanced rectal cancer.

AIM: To examine the overall survival differences for the following neoadjuvant therapy modalities - no therapy, chemotherapy alone, radiation alone and chemoradiation - in a large cohort of patients with locally advanced rectal cancer. METHOD: Adults with clinical Stage II and III rectal adenocarcinoma were selected from the National Cancer Database and grouped by type of neoadjuvant therapy received: no therapy, chemotherapy only, radiotherapy only or chemoradiation. Multivariable regression methods were used to compare adjusted differences in perioperative outcomes and overall survival. RESULTS: Among 32 978 patients included, 9714 (29.5%) received no neoadjuvant therapy, 890 (2.7%) chemotherapy only, 1170 (3.5%) radiotherapy only and 21 204 (64.3%) chemoradiation. Compared with no therapy, chemotherapy or radiotherapy alone were not associated with any adjusted differences in surgical margin positivity, permanent colostomy rate or overall survival (all P > 0.05). With adjustment, neoadjuvant chemoradiation vs no therapy was associated with a lower likelihood of surgical margin positivity (OR 0.74, P < 0.001), decreased rate of permanent colostomy (OR 0.77, P < 0.001) and overall survival [hazard ratio (HR) 0.79, P < 0.001]. When compared with chemotherapy or radiotherapy alone, chemoradiation remained associated with improved overall survival (vs chemotherapy alone HR 0.83, P = 0.04; vs radiotherapy alone HR 0.83, P < 0.019). CONCLUSION: Neoadjuvant chemoradiation, not chemotherapy or radiotherapy alone, is important for sphincter preservation, R0 resection and survival for patients with locally advanced rectal cancer. Despite this finding, one-third of patients in the United States with locally advanced rectal cancer fail to receive stage-appropriate chemoradiation.

A simple scoring system for risk-stratifying rectal cancer patients prior to radical resection.

BACKGROUND: Various predictors of perioperative risk for patients with rectal cancer undergoing radical resection have been well described, but no simple scoring system for surgeons to estimate this risk currently exists. The objective of this study was to develop a system for more accurate preoperative evaluations of competing risks and more informed shared decision-making with patients diagnosed with rectal cancer. METHODS: The National Surgical Quality Improvement Program-Participant Use Data File for 2005-2011 was used to retrospectively identify patients undergoing radical resection for rectal cancer. A forward-stepwise multivariable logistic regression model was used to create a dynamic scoring system to preoperatively estimate a patient's risk of major complications. RESULTS: A total of 6,847 patients met study inclusion criteria. Thirteen risk factors were identified, and using these predictive variables, a scoring system was derived to stratify major complication risk after radical resection. CONCLUSIONS: The risk of a major complication after radical resection for rectal cancer is dependent on multiple preoperative variables. This study provides surgeons with a simple but effective tool for estimating major complication risk in rectal cancer patients prior to radical resection. This risk-stratification score serves as a patient-centered resource for discussing perioperative risks and assisting with the shared decision-making of operative planning.

Minimally invasive surgery for diverticulitis.

The realm of minimally invasive surgery now encompasses the majority of abdominal operations in the field of colorectal surgery. Diverticulitis, a common pathology seen in most colorectal practices, poses unique challenges to surgeons implementing laparoscopic surgery in their practices due to the presence of an inflammatory phlegmon and distorted anatomical planes, which increase the difficulty of the operation. Although the majority of colon resections for diverticulitis are still performed through a standard laparotomy incision, laparoscopic techniques are becoming increasingly common. A large body of literature now supports laparoscopic surgery to be safe and effective as well as to provide significant advantages over open surgery for diverticular disease. Here, we review the most current literature supporting laparoscopic surgery for elective and emergent treatment of diverticulitis.

Intraoperative pelvic brachytherapy for treatment of locally advanced or recurrent colorectal cancer.

BACKGROUND: The aim of this study was to evaluate the efficacy and morbidity of intraoperative radiation therapy (IORT) for advanced colorectal cancer. METHODS: All patients undergoing IORT for locally advanced rectal cancer from 2001-2009 were reviewed for cancer recurrence, survival, and procedure-related morbidity. Cumulative event rates were estimated using the method of Kaplan and Meier. RESULTS: Twenty-nine patients with locally advanced (n = 8) or recurrent (n = 21) rectal cancers were treated with IORT and resection. Surgical interventions included low anterior resection, abdominoperineal resection, pelvic exenteration, and a variety of non-anatomic resections of pelvic recurrences. R(0) resections were achieved in 16 patients, while R(1) resections were achieved in 10, and margins were grossly positive in 3 patients. IORT was delivered to all patients over a median area of 48 (42-72) cm(2) at a median dose of 12 (12-15) Gy. Local and overall recurrence rates were 24 % (locally advanced group) and 45 % (recurrent group). Median disease-free and overall survival were 25 and 40 months respectively at a median follow-up of 26 (18-42) months. The short-term (≤30 days) complication rate was 45 %. Eight patients developed local wound complications, 5 of which required operative intervention. Four patients developed intra-abdominal abscesses requiring drainage. Long-term (>30 days) complications were identified in 11 patients (38 %) and included long-term wound complications (n = 3), ureteral obstruction requiring stenting (n = 1), neurogenic bladder (n = 3), enteric fistulae (n = 2), small bowel obstruction (n = 1), and neuropathic pain (n = 1). CONCLUSIONS: Intraoperative brachytherapy is a viable IORT option during pelvic surgery for locally advanced or recurrent colorectal cancer but is associated with high postoperative morbidity. Whether intraoperative brachytherapy can improve local recurrence rates for locally advanced or recurrent colorectal cancer will require further prospective investigation.

Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation.

In vivo somatosensory stimuli evoked the release of substance P from primary afferent neurons that terminate in the spinal cord and stimulated endocytosis of substance P receptors in rat spinal cord neurons. The distal dendrites that showed substance P receptor internalization underwent morphological reorganization, changing from a tubular structure to one characterized by swollen varicosities connected by thin segments. This internalization and dendritic structural reorganization provided a specific image of neurons activated by substance P. Thus receptor internalization can drive reversible structural changes in central nervous system neurons in vivo. Both of these processes may be involved in neuronal plasticity.

Localization of specific binding sites for atrial natriuretic factor in peripheral tissues of the guinea pig, rat, and human.

Specific, high affinity atrial natriuretic factor (ANF) binding sites were identified and localized by autoradiographic techniques in peripheral tissues of the guinea pig, rat, and human. In the guinea pig kidney, high concentrations of ANF binding sites were located in the glomerular apparatus, outer medulla, and small renal arteries. Other peripheral tissues containing ANF binding sites included the zona glomerulosa of the adrenal cortex, the smooth muscle layer of the aorta and gallbladder, the lung parenchyma, the posterior lobe of the pituitary, the ciliary body of the eye, and the leptomeninges and choroid plexus of the brain. The distribution of ANF binding sites in the rat and human kidney was nearly identical to those seen in the guinea pig kidney; high concentrations were present in the glomerular apparatus, outer medulla, and small renal arteries. These results are consistent with earlier physiological and pharmacological studies that suggested that ANF plays a functional role in the regulation of extracellular fluid volume and blood pressure. There appears to be little species variation in the location and concentration of renal ANF binding sites, suggesting that, at least in the kidney, the results in experimental animals are relevant to the actions of ANF in humans. The finding that ANF binding sites were stable and present in high concentrations in human postmortem kidneys further suggests that these tissues may be amenable to testing for the involvement of ANF receptor dysfunction in diseases such as hypertension and congestive heart failure.

Calcitonin gene-related peptide-alpha receptor binding sites in the gastrointestinal tract.

Calcitonin gene-related peptide-alpha (CGRP alpha) is a putative neurotransmitter in the brain and in peripheral tissues. Quantitative receptor autoradiography was used to localize and quantify the distribution of specific binding sites for radiolabeled human CGRP alpha in the canine gastrointestinal tract. The canine gastrointestinal tract was chosen as a model since it is similar in both size and structure to the human gastrointestinal tract. In the stomach CGRP alpha binding sites were localized to smooth muscle cells in the muscularis mucosa and muscularis externa, the smooth muscle and endothelium of medium and small arteries, neurons in the myenteric plexus, mucosal epithelial cells and the germinal centers of lymph nodules. In the intestines, the prominent cells types expressing CGRP alpha receptors were myenteric neurons and the germinal centers of lymph nodules. Since previous studies have demonstrated that CGRP-containing sensory neurons innervate the muscularis externa in the stomach and since CGRP alpha receptors are expressed by smooth muscle cells in the muscularis externa, these results suggest that sensory neurons may directly regulate gastric motility by releasing CGRP. In correlation with previous physiological data, the present study suggests that CGRP is involved in the regulation of a variety of gastrointestinal functions including gastric motility, mucosal ion transport, hemodynamics, digestive enzyme secretion, neuronal excitability, and the inflammatory and immune response.

Receptor binding sites for substance P and substance K in the canine gastrointestinal tract and their possible role in inflammatory bowel disease.

The mammalian tachykinins, substance P, substance K (neurokinin A) and neuromedin K (neurokinin B), are putative peptide neurotransmitters in both the brain and peripheral tissues. We used quantitative receptor autoradiography to localize and quantify the distribution of binding sites for radiolabeled substance P, substance K and neuromedin K in the canine gastrointestinal tract. Substance P binding sites were localized to smooth muscle cells in the muscularis mucosa and muscularis externa, the smooth muscle and endothelium of arterioles and venules, neurons in the myenteric plexus, mucosal epithelial cells, exocrine cells and lymph nodules. Substance K binding sites were distributed in a pattern distinct from substance P binding sites and were localized to smooth muscle cells in the muscularis mucosa and muscularis externa, the smooth muscle and endothelium of arterioles and venules, and neurons of the myenteric plexus. Neuromedin K binding sites were not observed in any area of the canine gastrointestinal tract although they were localized with high specific/non-specific binding ratios in the canine spinal cord. These results indicate that there are at least two distinct types of tachykinin receptor binding sites in the canine gastrointestinal tract, one of which probably recognizes substance P and the other substance K as endogenous ligands. In correlation with previous physiological data, these substance P and substance K receptor binding sites appear to be involved in the regulation of a variety of gastrointestinal functions including gastric motility, mucosal ion transport, hemodynamics, digestive enzyme secretion and neuronal excitability. In addition these results demonstrate that receptor binding sites for substance P and substance K are expressed by cells involved in mediating inflammatory and immune responses. These data, together with our studies on surgical specimens from patients with inflammatory bowel disease, suggest that in a pathophysiological state tachykinins and their receptors may play a role in inflammatory bowel disease and should permit a rational approach to designing neuropeptide antagonists which may prove effective in treating inflammatory diseases.

Vasoactive intestinal polypeptide receptor binding sites in the human gastrointestinal tract: localization by autoradiography.

Vasoactive intestinal polypeptide (VIP) is a putative neurotransmitter in both the brain and peripheral tissues. To define possible target tissues of VIP we have used quantitative receptor autoradiography to localize and quantify the distribution of [125I]VIP receptor binding sites in histologically normal human surgical specimens. While the distribution of VIP binding sites was different for each gastrointestinal segment examined, specific vasoactive intestinal polypeptide binding sites were localized to the mucosa, the muscularis mucosa, the smooth muscle of submucosal arterioles, the circular and longitudinal smooth muscle of the muscularis externa, the myenteric plexus, and lymph nodules. In most segments, the mucosal layer expressed the highest concentration of VIP binding sites, with the duodenal and jejunal mucosa showing the highest density of receptors. These results identify putative VIP target tissues in the human gastrointestinal tract. In correlation with physiological data, VIP binding sites appear to be involved in the regulation of a variety of gastrointestinal functions including mucosal ion transport, gastric secretion, hemodynamic regulation, gastric and intestinal motility, neuronal excitability, and modulation of the immune system.

The localization of sensory nerve fibers and receptor binding sites for sensory neuropeptides in canine mesenteric lymph nodes.

Previous work has established that the central nervous system can modulate the immune response. Direct routes through which this regulation may occur are the sympathetic and sensory innervation of lymphoid organs. We investigated the innervation of canine mesenteric lymph nodes using immunohistochemistry and the expression of binding sites for sensory neuropeptides using quantitative receptor autoradiography. The sympathetic innervation of lymph nodes was examined by immunohistochemical methods using an antiserum directed against tyrosine hydroxylase (TOH), the rate limiting enzyme in catecholamine synthesis. TOH-containing fibers were associated with 90% of the blood vessels (arteries, veins, arterioles and venules) in the hilus, medullary and internodular regions of lymph nodes and in trabeculae with no obvious relationship to blood vessels. The sensory innervation of lymph nodes was investigated using antisera directed against the putative sensory neurotransmitters calcitonin gene-related peptide (CGRP) and substance P (SP). CGRP- and SP-containing fibers were detected in the hilus, the medullary region, and the internodular region of lymph nodes usually in association with arterioles and venules. About 50% of the arterioles and venules exhibited a CGRP innervation and a smaller fraction (5-10%) were innervated by SP-containing fibers. Few if any TOH, CGRP, and SP nerve fibers were detected in the germinal centers of lymph nodes. Using quantitative receptor autoradiography we studied the distribution of receptor binding sites for the sensory neuropeptides CGRP, SP, substance K (SK), vasoactive intestinal peptide (VIP), somatostatin (SOM), and bombesin. Specific CGRP binding sites were expressed throughout lymph nodes by trabeculae, arterioles, venules and 25% of the germinal centers. SP receptor binding sites were localized to arterioles and venules in the T cell regions and 25-30% of the germinal centers. VIP binding sites were localized to the internodular and T cell regions, to medullary cords, and to 10-20% of germinal centers. SK, SOM, and bombesin binding sites were not detected in the lymph nodes, although receptor binding sites for these peptides were detected with high specific/nonspecific binding ratios in other canine peripheral tissues. Taken together with previous results these findings suggest that the sympathetic and sensory innervation of mesenteric lymph nodes appears to be involved with the regulation of their blood and lymph flow. The neuropeptide receptor binding sites in lymph node germinal centers may be expressed by lymphocytes upon activation by antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

Receptor binding sites for atrial natriuretic factor are expressed by brown adipose tissue.

To explore the possibility that atrial natriuretic factor (ANF) is involved in thermoregulation we used quantitative receptor autoradiography and homogenate receptor binding assays to identify ANF bindings sites in neonatal rat and sheep brown adipose tissue, respectively. Using quantitative receptor autoradiography were were able to localize high levels of specific binding sites for 125I-rat ANF in neonatal rat brown adipose tissue. Homogenate binding assays on sheep brown fat demonstrated that the radioligand was binding to the membrane fraction and that the specific binding was not due to a lipophilic interaction between 125I-rat ANF and brown fat. Specific binding of 125I-rat ANF to the membranes of brown fat cells was inhibited by unlabeled rat ANF with a Ki of 8.0 x 10(-9) M, but not by unrelated peptides. These studies demonstrate that brown fat cells express high levels of ANF receptor binding sites in neonatal rat and sheep and suggest that ANF may play a role in thermoregulation.

Substance P and substance K receptor binding sites in the human gastrointestinal tract: localization by autoradiography.

Quantitative receptor autoradiography was used to localize and quantify the distribution of binding sites for 125I-radiolabeled substance P (SP), substance K (SK) and neuromedin K (NK) in the human GI tract using histologically normal tissue obtained from uninvolved margins of resections for carcinoma. The distribution of SP and SK binding sites is different for each gastrointestinal (GI) segment examined. Specific SP binding sites are expressed by arterioles and venules, myenteric plexus, external circular muscle, external longitudinal muscle, muscularis mucosa, epithelial cells of the mucosa, and the germinal centers of lymph nodules. SK binding sites are distributed in a pattern distinct from SP binding sites and are localized to the external circular muscle, external longitudinal muscle, and the muscularis mucosa. Binding sites for NK were not detected in any part of the human GI tract. These results demonstrate that: 1) surgical specimens from the human GI tract can be effectively processed for quantitative receptor autoradiography; 2) of the three mammalian tachykinins tested, SP and SK, but not NK binding sites are expressed in detectable levels in the human GI tract; 3) whereas SK receptor binding sites are expressed almost exclusively by smooth muscle, SP binding sites are expressed by smooth muscle cells, arterioles, venules, epithelial cells of the mucosa and cells associated with lymph nodules; and 4) both SP and SK binding sites expressed by smooth muscle are more stable than SP binding sites expressed by blood vessels, lymph nodules, and mucosal cells.

Vasoactive intestinal peptide (VIP) receptors in the canine gastrointestinal tract.

Vasoactive intestinal peptide (VIP) is a putative neurotransmitter in both the brain and peripheral tissues. To define possible target tissues of VIP we have used quantitative receptor autoradiography to localize and quantify the distribution of 125I-VIP receptor binding sites in the canine gastrointestinal tract. While the distribution of VIP binding sites was different for each segment examined, specific VIP binding sites were localized to the mucosa, the muscularis mucosa, the smooth muscle of submucosal arterioles, lymph nodules, and the circular and longitudinal smooth muscle of the muscularis externa. These results identify putative target tissues of VIP action in the canine gastrointestinal tract. In correlation with physiological data, VIP sites appear to be involved in the regulation of a variety of gastrointestinal functions including epithelial ion transport, gastric secretion, hemodynamic regulation, immune response, esophageal, gastric and intestinal motility.

Bombesin/GRP-preferring and neuromedin B-preferring receptors in the rat urogenital system.

Bombesin binding sites were localized in the rat urogenital system by autoradiography of 125I-Tyr4-bombesin binding to frozen tissue sections. Saturable binding was observed in the bladder, seminal vesicle, uterus, and oviduct. In all organs, the binding sites corresponded to layers of smooth muscle. Radioligand binding studies were performed on homogenized membrane preparations from bladder, uterus, and seminal vesicle. Membrane binding was saturable, reversible, time- and temperature-dependent, and specific for bombesin and related peptides. Analysis of saturable equilibrium binding from all three organs yielded a best fit to a one-site model of high affinity binding with apparent KdS of 720 pM for bladder, 470 pM for uterus, and 700 pM for seminal vesicle. Neuromedin B was potent in displacing saturable 125I-Tyr4-bombesin binding from bladder and seminal vesicle but not uterus membranes. In order to characterize these binding sites further, the ability of these membranes to interact with a specific bombesin receptor antagonist, [Leu13-psi-CH2NH-Leu14]-bombesin, and with GTP-gamma-S was determined. [Leu13-psi-CH2NH-Leu14]-bombesin was much more potent in displacing saturable 125I-Tyr4-bombesin binding from uterus than from bladder and seminal vesicle membranes, further supporting the distinction between the uterus and the bladder/seminal vesicle binding sites as bombesin receptor subtypes. GTP-gamma-S inhibited saturable 125I-Tyr4-bombesin binding to membranes from all three organs, indicating that both receptor subtypes are linked to GTP-binding proteins. We conclude that smooth muscle in the rat urogenital system expresses bombesin receptors and that endogenous GRP and neuromedin B may regulate some reproductive and excretory functions. The bladder and seminal vesicle express the neuromedin B-preferring subtype and the uterus expresses the bombesin/GRP-preferring subtype of bombesin receptor.

Localization of specific binding sites for atrial natriuretic factor in the central nervous system of rat, guinea pig, cat and human.

Specific, high-affinity binding sites for atrial natriuretic factor (ANF) were identified and localized in the rat and guinea pig central nervous system (CNS), the cat brainstem, and the rat, guinea pig, cat and human spinal cord using quantitative autoradiographic techniques. The radioligands tested were rat 125I-ANF(1-28) in guinea pig, rat, cat and human tissues, human 125I-ANF in rat and human, and rat [3H]atriopeptin III in rat. All 3 radioligands labeled essentially the same structures in the brain and spinal cord of all species in which they were tested. In guinea pig very high concentrations of ANF binding sites were observed in the olfactory bulb, lateral olfactory tract and the granule cell layer of the cerebellum, high concentrations were observed in the fasciculus retroflexus, interpeduncular nucleus and subfornical organ. Moderate concentrations were observed in the nucleus accumbens, dorsomedial and suprachiasmatic hypothalamic nuclei, paraventricular thalamic nuclei, primary olfactory cortex and the subcommissural organ. High concentrations of ANF binding sites were also observed in the choroid plexus and the leptomeninges. Low concentrations were observed in the pineal gland. In the rat the same structures were labeled as in the guinea pig except that suprachiasmatic and dorsomedial hypothalamic nuclei, paraventricular thalamus and cerebellum were unlabeled. In the lower brainstem of the cat and all levels of the rat, guinea pig, cat and human spinal cord, the only site where specific binding was observed was in the pia/arachnoid. These findings suggest that ANF binding sites constitute several functional classes in the CNS as well as in a variety of other tissues. Outside the blood-brain barrier binding sites are prominent in glandular tissues implicated in the production of hormones involved in fluid and electrolyte balance, e.g. adrenal glomerulosa, neurohypophysis and subfornical organ, unstratified epithelia involved in ion gradient exchange, e.g. renal glomerulus, ciliary body, choroid plexus and pia mater; crossing the blood-brain barrier are sites in the anterior hypothalamus, e.g. organum vasculosum, regions of the brain parenchyma associated with angiotensin II binding sites, e.g. dorsomedial nucleus of hypothalamus, some of which may be occupied by brain rather than cardiac synthesized ANF, regions of brain lacking an obvious role in fluid and ion exchange or regulation, e.g. cerebellum, although association with K+,Na+-ATPase in guinea pig cerebellum may be a relevant clue and brain regions possibly implicated in an integrative and/or indirect regulatory role in fluid and electrolyte balance.(ABSTRACT TRUNCATED AT 400 WORDS)

Calcitonin gene-related peptide (CGRP) in the rat central nervous system: patterns of immunoreactivity and receptor binding sites.

The distribution of immunoreactive (IR) axons and neurons in the rat central nervous system (CNS) has been studied with an antiserum directed against the C-terminal sequence of rat a-calcitonin gene-related peptide (CGRP) and a durable peroxidase reaction product for detailed analysis in relation to normal cytoarchitecture. These materials were studied and illustrated in the three principal axes in relation to cell-stained adjacent sections in normal as well as colchicine- and capsaicin-treated animals, although no fundamental differences in pattern were evident in neurotoxin-treated rats. The patterns of CGRP-IR were then compared with autoradiograms of specific, high affinity receptor binding sites for 125I-human a-CGRP. CGRP-IR labeling in motor systems includes the vast majority of motoneurons, enabling facile identification of isolated 'accessory' populations. Preganglionic parasympathetic nuclei revealed only labeling of a small proportion of neurons. By contrast, the sensory systems revealed a diversity of labeling patterns precluding simple generalizations. Peripheral input ranges from extensive labeling of thin somatic afferents, feeble to moderate gustatory and olfactory afferents to a total absence of auditory afferents, yet IR axons and neurons can be found in selective distribution within each of these sensory systems. Patterns of IR in various integrative centers, e.g. cerebellum, basal ganglia and hypothalamus, reveal selectivity that fails to conform to conventional descriptions of functional systems. Some regions display unexpected patterns, e.g. vertical stripes in cerebellar cortex. CGRP receptor binding sites (RB) are found in many of the sites where IR axons terminate and in some cases, e.g. motor neurons, which express intraneuronal IR. The main sensory systems reveal a variety of RB patterns, only a few of which can be related to sites of IR axon terminals. Many apparent 'mismatches' between IR and RB are illustrated and discussed in the context of functional peptide expression or in quasi-hormonal terms. It is suggested that the principle of CGRP-IR axon distribution in peripheral tissues, where synapses are lacking, might also apply to the CNS and that neither the locus of IR-axon terminals nor RB sites need indicate transmitter action for impulse information transfer. CGRP is a widely distributed neuromodulator probably subserving a role in both synaptic and metabolic regulation, depending on the specific requirements of the diverse distribution of its receptors.