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Biomedical subjects

L Duncan

Publications and source records attributed to L Duncan.

At least 19 recordsLinked to original sources

Experimental vesicular stomatitis virus infection in horses: effect of route of inoculation and virus serotype.

Horses were inoculated with Vesicular stomatitis New Jersey and Indiana viruses by routes simulating contact and vector transmission. Clinical signs, lesions, antibody development, viral shedding and persistence, and viremia were monitored. Horses were infected with both viruses by all routes as confirmed by seroconversion. Salivation, primary lesions at inoculation sites, and secondary oral lesions were the most common clinical findings. Viral shedding was most often from the oral cavity, followed by the nasal cavity; titers were highest from oral cavity samples. Virus was rarely isolated from the conjunctival sac and never from feces or blood. Development of neutralizing antibody coincided with cessation of lesion development and detection of virus by isolation. Circulating virus-specific IgM, IgG, IgA, and neutralizing antibodies developed in most animals postinoculation (PI) days 6 to 12, depending on the route of inoculation. At postmortem (PI days 12 to 15), lesions were healing, were not vesicular, and did not contain detectable virus by isolation, reverse transcriptase polymerase chain reaction, or immunohistochemistry. Numerous infiltrating lymphocytes and plasma cells suggested that lesion resolution was partially due to local immunity. Detection of viral RNA from tonsil and lymph nodes of head at necropsy suggests that these tissues play a role in the pathogenesis of the disease; molecular techniques targeting these tissues may be useful for confirming infection in resolving stages of disease. The routes of inoculation used in this study reflect the diversity of transmission routes that may occur during outbreaks and can be used to further study contact and vector transmission, vaccine development, and clarify pathogenesis of the disease in horses.

Animals↗

Inhibition of system A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action.

Clozapine is an atypical antipsychotic with particular efficacy in schizophrenia, possibly related to potentiation of brain N-methyl-D-aspartate receptor (NMDAR) -mediated neurotransmission. NMDARs are regulated in vivo by glycine, which is regulated in turn by glycine transporters. The present study investigates transport processes regulating glycine uptake into rat brain synaptosomes, along with effects of clozapine on synaptosomal glycine transport. Amino-acid uptake of amino acids was assessed in rat brain P2 synaptosomal preparations using a radiotransport assay. Synaptosomal glycine transport was inhibited by a series of amino acids and by the selective System A antagonist MeAIB (2-methyl-aminoisobutyric acid). Clozapine inhibited transport of both glycine and MeAIB, but not other amino acids, at concentrations associated with preferential clinical response (0.5-1 microg/ml). By contrast, other antipsychotics studied were ineffective. The novel glycine transport inhibitor N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS) produced biphasic inhibition of [(3)H]glycine transport, with IC(50) values of approximately 25 nM and 25 microM, respectively. NFPS inhibition of [(3)H]MeAIB was monophasic with a single IC(50) value of 31 microM. Clozapine significantly inhibited [(3)H]glycine binding even in the presence of 100 nM NFPS. In conclusion, this study suggests first that System A transporters, or a subset thereof, may play a critical role in regulation of synaptic glycine levels and by extension of NMDA receptor regulation, and second that System A antagonism may contribute to the differential clinical efficacy of clozapine compared with other typical or atypical antipsychotics.

Amino Acid Transport System A↗

Choroidal dendritic cells require activation to present antigen and resident choroidal macrophages potentiate this response.

BACKGROUND/AIM: The uveal compartment of the eye contains extensive networks of resident macrophages and dendritic cells. These cells are now recognised to have a role in many ocular pathologies. The aim of this study was to isolate, characterise, and compare the function of ciliary body/choroid dendritic cells and macrophages from the normal eye. METHODS: Explants of rat and human ciliary body/choroid were cultured in vitro for various periods of time and cells harvested either from the supernatant fluid or from enzyme digested and washed explants. The cells were then phenotyped by microscopy and flow cytometry, examined by video time lapse photomicroscopy, and analysed functionally in a series of immunoassays. RESULTS: Two main types of dendritic cell were identified: large veil-like MHC class II(mid) motile but relatively non-translocatory cells and small MHC class II(hi) motile and rapidly translocating cells. Tissue macrophages mainly remained associated with the explants in culture but gradually lost their resident tissue marker (ED2) and detached from the explants as clusters of low density, large, CR3 (ED7)(+) cells, some of which underwent apoptosis. Video time lapse studies showed dendritic cells constantly interacting with large single cells and cell clusters by traversing the interstices of the cell clusters. In functional studies, freshly isolated dendritic cells were poor presenters of antigen and required activation by short term culture for acquisition of antigen presenting function. In contrast, dendritic cell depleted choroidal cell preparations containing macrophages and other cells failed to present antigen even after short term culture but augmented the antigen presenting function of dendritic cells when tested in co-culture. CONCLUSION: At least two types of dendritic cells are present in the normal ciliary body/choroid layer of the eye. It is likely that these cells have different functions based on their motility and potential to migrate to secondary lymphoid tissue either during normal physiological homeostatic processes or during an inflammatory response. The behaviour of resident tissue myeloid cells may decide the outcome of the organism's response to stress, foreign antigen, and ageing processes such as age related macular degeneration.

Animals↗

Systemic CD4(+) T cell phenotype and activation status in intermediate uveitis.

AIM: To investigate peripheral blood lymphocyte phenotype in patients with intermediate uveitis using CD69, chemokine receptor, and cytokine expression. METHODS: Peripheral blood lymphocytes of 18 patients with idiopathic intermediate uveitis and 6 patients with presumed sarcoid intermediate uveitis were evaluated for CD4(+) T cell expression of CD69, CCR4, CCR5, CXCR3 and the intracellular cytokines IFNgamma, TNFalpha, and interleukin (IL)-10 by flow cytometry, and for IL-2, IL-4, IL-5, IL-10, IFNgamma, and TNFalpha production following unstimulated and activated culture using cytokine bead array and compared with healthy control subjects. RESULTS: The expression of CD69 and TNFalpha by peripheral blood CD4(+) lymphocytes of patients with idiopathic intermediate uveitis and presumed sarcoid intermediate uveitis was significantly higher than control subjects (p = 0.002 and p<0.05, respectively). The ratios of the concentrations of IL-2:IL-5 and IFNgamma:IL-5 in supernatants of activated peripheral blood lymphocyte cultures were significantly higher in patients with presumed sarcoid intermediate uveitis than control subjects. CONCLUSIONS: This study implicates TNFalpha in the pathogenesis of intermediate uveitis, highlighting the potential role of anti-TNF treatments for this disease. Studies of Th1:Th2 cytokine ratios suggested polarisation of the immune response towards Th1 in presumed sarcoid intermediate uveitis despite clinically quiescent systemic disease.

Adolescent↗

A serial longitudinal quantitative MRI study of cerebral changes in first-episode schizophrenia using image segmentation and subvoxel registration.

Lateral ventricular enlargement is the most consistently replicated brain abnormality found in schizophrenia. This article reports a first episode, longitudinal study of ventricular volume using high-resolution serial magnetic resonance imaging (MRI) and recently developed techniques for image registration and quantitation. Baseline and follow-up (on average 8 months later) MRI scans were carried out on 24 patients and 12 controls. Accurate subvoxel registration was performed and subtraction images were produced to reveal areas of regional brain change. Whereas there were no differences between patients and controls with respect to the mean change in ventricular volume, the patients were much more variable in this respect and showed larger increases and decreases. The percentage increase in ventricular size was greater than one standard deviation of control values for 14 patients and the percentage decrease exceeded one standard deviation in eight patients. Although the finding of progressive ventricular enlargement in a proportion of patients supports other studies indicating an ongoing neuropathological process in the early stages of schizophrenia, the reduction of ventricular size in the remaining patients is more difficult to explain. It is suggested that this may reflect improvement in nutrition and hydration following treatment.

Adult↗

CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines.

The 70 kDa mycobacterial heat shock protein (Mtb HSP70) stimulates mononuclear cells to release CC-chemokines. We now show that this function of Mtb HSP70, but not human HSP70, is dependent on the cell surface expression of CD40. Deletion of the CD40 cytoplasmic tail abolished, and CD40 antibody inhibited, Mtb HSP70 stimulation of CC-chemokine release. Mtb HSP70 stimulated THP1, KG1 cells, and monocyte-derived dendritic cells to produce RANTES. Specific binding of CD40-transfected HEK 293 cells to Mtb HSP70 was demonstrated by surface plasmon resonance. Coimmunoprecipitation of Mtb HSP70 with CD40 indicates a physical association between these molecules. The results suggest that CD40 is critical in microbial HSP70 binding and stimulation of RANTES production.

Bacterial Proteins↗

Perceptions of human immunodeficiency virus and sexually transmitted disease risk among low-income adults: a pilot study.

Sexual risk-taking research and subsequent intervention programs have focused almost exclusively on adolescents and men who have sex with men. In comparison, less research has been conducted into adult heterosexual risk-taking behavior. The purposes of this pilot study were to test a survey instrument, assess how low-income adults perceive their risk of human immunodeficiency virus (HIV) and sexually transmitted disease (STD) infection, and determine the degree to which condom use is a function of age. The Health Belief Model was used to guide the development of the survey instrument. In the Health Belief Model, age is a mediating factor that influences a person's likelihood to take action to change his or her lifestyle. Respondents perceived that their vulnerability to infection declined because of increased age and decreased frequency of coitus. Condom use was found to significantly decline as the age of the respondents increased. Although this is only a pilot study, the findings highlight the need for HIV and STD education for all age groups and genders.

Adult↗

Screening for renal disease using serum creatinine: who are we missing?

BACKGROUND: Appropriate management and timely referral of patients with early renal disease often depend on the identification of renal insufficiency by primary care physicians. Serum creatinine (SCr) levels are frequently used as a screening test for renal dysfunction; however, patients can have significantly decreased glomerular filtration rates (GFR) with normal range SCr values, making the recognition of renal dysfunction more difficult. This study was designed to estimate the prevalence of patients who have significantly reduced GFR as calculated by the Cockcroft-Gault (C-G) formula, but normal-range SCR: METHODS: The study included 2781 outpatients referred by community physicians to an urban laboratory network for SCr measurement. GFR was estimated using the C-G formula. Patients were grouped according to the concordance of SCr level abnormalities (abnormal >130 micromol/l) with significantly abnormal C-G values (abnormal </=50 ml/min). The C-G value of < or =50 ml/min was chosen to reflect substantial renal impairment in all age groups. A further analysis of historical laboratory data was undertaken to determine if there were previously documented changes in renal function parameters in those patients who had overt renal dysfunction during the study period. RESULTS: Of the 2781 outpatients referred, 2543 (91.4%) had normal SCr levels. Of these patients, 387/2543 (15.2%) had C-G calculated GFR < or =50 ml/min, representing substantially impaired renal function. Among patients with normal SCr, abnormal C-G values were identified in 47.3% > or =70 years old, 12.6% 60-69 years old, and 1.2% 40-59 years old. Analysis of historical available laboratory data for patients with abnormal SCr and abnormal C-G values showed that 2 years prior to the study period, 72% of this group had abnormal SCr, while 18% had normal SCr with abnormal C-G values, and 10% had normal SCr with normal C-G values. CONCLUSIONS: This study documents the substantial prevalence of significantly abnormal renal function among patients identified by laboratories as having normal-range SCR: Including calculated estimates of GFR in routine laboratory reporting may help to facilitate the early identification of patients with renal impairment.

Adolescent↗

Central and peripheral adverse hemodynamic changes during laparoscopic surgery and their reversal with a novel intermittent sequential pneumatic compression device.

OBJECTIVE: To study the influence of a novel intermittent sequential pneumatic compression device (Lympha-press) on the adverse cardiac and peripheral hemodynamic changes induced by positive-pressure pneumoperitoneum (PPPn) in laparoscopic surgery. SUMMARY BACKGROUND DATA: Creation of PPPn is known to cause adverse central and peripheral hemodynamic changes. An intrasubject observational study was undertaken to quantitate these adverse changes and to assess the influence of an intermittent sequential pneumatic compression system on these adverse hemodynamic changes during laparoscopic surgery with PPPn. METHODS: The study involved 16 consecutive patients undergoing laparoscopic surgery with PPPn of 12 mmHg and 30 degrees head-up tilt position. The following peripheral hemodynamic recordings were made using Doppler ultrasound: peak systolic velocity (PSV), end diastolic velocity (EDV), and cross-sectional area of the femoral vein. Central monitoring included cardiac output and stroke volume by transesophageal Doppler, blood pressure, and pulse. The hemodynamic state based on these parameters was assessed before induction of PPPn with the anesthetized patient in the supine position, after induction of PPPn and head-up tilt position with Lympha-press off, and during PPPn and head-up tilt position with Lympha-press on, and after desufflation with the patient in the supine position under general anesthesia. RESULTS: Positive-pressure pneumoperitoneum and the head-up tilt position resulted in a 33% reduction in PSV, a 21% reduction in EDV, and a 29% increase in cross-sectional area of the femoral vein. This was associated with a 20% reduction in cardiac output and an 18% reduction in stroke volume. Activation of Lympha-press during PPPn and the head-up tilt position resulted in a 129% increase in PSV and a 55% increase in EDV by 55%. It also increased the cardiac output by 27% and stroke volume by 16%, with no effect on cross-sectional area. Compared with the pre-PPPn stage, there was no difference in cardiac output or stroke volume, but the PSV was higher by 78% and the EDV by 32%. After abdominal desufflation in the supine position, the cardiac output and stroke volume were restored to the pre-PPPn level, but persistent and significant elevations were observed during the period of study in PSV, EDV, and cross-sectional area. CONCLUSIONS: Significant and individually variable central and peripheral hemodynamic changes are encountered during laparoscopic surgery with PPPn and the head-up tilt position. These are reversed by intermittent sequential pneumatic compression using Lympha-press.

Adult↗

Total dose and frequency of administration critically affect success of nasal mucosal tolerance induction.

AIMS: Nasal tolerance induction with autoantigens can effectively protect against a variety of experimental models of autoimmune disease. The aims of this study were to characterise the dosage and kinetics of inhibition of experimental autoimmune uveoretinitis (EAU) via intranasal administration of the uveitogenic antigen interphotoreceptor retinal binding protein (IRBP) in the murine model of IRBP induced EAU. METHODS: B10RIII mice were tolerised by intranasal administration of IRBP either with a long term multiple low dose or a short term/high dosing regimen before subcutaneous immunisation with IRBP in complete Freund's adjuvant (CFA). On day 15 post-immunisation, mice were killed and eyes were removed for histological examination and quantification of inflammatory cell infiltration and degree of target organ (rod outer segment, ROS) destruction. RESULTS: Nasal administration of multiple low doses of IRBP (1 microg or 3 microg IRBP per mouse per day for 10 days) significantly protected mice from IRBP induced EAU. Short term/high dose regimens were only effective when given either as a single or, at most, as two consecutive doses (40 microg per dose). Multiple doses in the range of 45-120 microg over 3 days afforded no protection. CONCLUSIONS: These results indicate that both dose and frequency of intranasal antigen administration are pivotal to tolerance induction and subsequent suppression of T cell mediated autoimmune disease.

Administration, Intranasal↗

Ex vivo adenovirus mediated gene transfection of human conjunctival epithelium.

AIM: To investigate the efficacy of "ex vivo" adenoviral vector mediated gene transfection of human conjunctival epithelial cell as a possible route for gene therapy for the distribution of anti-inflammatory agents for the potential treatment of immune mediated ocular inflammatory disorders. METHODS: Human conjunctival cells (HCs) were cultured with various concentrations of recombinant adenoviral vectors carrying a reporter gene LacZ, GFP, or an immunomodulating cytokine vIL-10. vIL-10 in culture supernatant was detected by sandwich ELISA and biological activity was assessed by suppression of ConA stimulated splenocyte proliferation. X-gal and GFP expression was assessed by histochemistry. RESULTS: The extent of adenoviral vector mediated transfer of both reporter genes and vIL-10 was dose dependent. LacZ expression could be detected for at least 50 day after infection with multiple of infection (MOI) 200. Following AdCMVvIL-10 transduction, vIL-10 protein expression occurred between 4-6 days post-transduction, and was maintained at a detectable level for at least 1 month. Secreted vIL-10 showed biological activity, significantly inhibiting Con A induced splenocyte proliferation. Additionally, transfection of HCs with two Adv vectors, one carrying LacZ and the other carrying GFP, resulted in co-expression within a single cell. CONCLUSION: These results confirm previous successful adenoviral vector mediated gene transfer to HCs and further show that expression can be maintained. Furthermore the data show HCs can secrete biologically active vIL-10 that could be developed as a strategy to suppress immune mediated disorders. The successful co-transduction of HCs as described for other tissues, opens avenues to develop a multiple target gene therapy locally.

Adenoviridae↗

Older female inpatients in Arkansas.

The purpose of this study was to examine age and Major Diagnostic Categories (MDCs) and compare the variables to mortality and length of stay among inpatient women age 50 and over. Archival statistical data were obtained for 2,238 inpatients in a private, nonprofit hospital in 1998. The ages ranged from 50 to 107 years old, with a mean age of 71.21 years. Quantitative analyses were conducted to examine the data from a private, nonprofit hospital and determine if there were significant relationships between age, major diagnostic category, length of stay, and mortality in older women. The MDC distribution indicated that the highest frequency of diseases and disorders were in the following three systems: circulatory system, musculoskeletal system and connective tissue, and the digestive system. The average length of stay was 8.01 days. The 30-day readmission percentage and the 365-day readmission percentage were 12.24% and 28.02%, respectively. The mortality rate was 6%. In addition, 63.97% went home after discharge, and 67.07% were Medicare recipients. The risk of musculoskeletal diseases and disorders increased with age (p = .0001). The conditional probability of death was nearly nine times higher for the diseases of the nervous system, myeloproliferative diseases and disorders, poorly differentiated neoplasms and respiratory diseases. As age increased, the probabilities of a long hospital stay decreased. The mortality analyses found that the lowest probabilities of survival were in categories of myeloproliferative diseases and disorders, poorly differentiated neoplasms, and infectious and parasitic diseases. According to current health statistics, our society is getting older. Not only are people living longer, they are accessing more health care (American Association for World Health, 1999). Overall, the average life expectancy at birth has been identified at 76.5 years. The female has a longer life expectancy than the male, averaging 5.8 years longer. The highest life expectancy has been identified in the white female, who can expect to live to 79. The black woman has the second-highest life expectancy, 74.7 years. Peters, Kochanek, and Murphy reported an all-time-low age-adjusted death rate for the United States and a continuing trend in the decline in mortality for all age groups. With a growing number of people living longer, there is a need to know about the most common health issues that affect quality of life. The top three national causes of death in older Americans were diseases of the heart, malignant neoplasms, and cerebrovascular diseases/stroke. Arkansas health statistics mirror the national statistics. In April 1999, the Arkansas Department of Health reported that 30.5% percent of all female deaths were caused by heart disease. Malignant neoplasms were responsible for 20.1%, followed by cerebrovascular diseases at 10.8%. Other than three Connecticut hospital studies that explored the relationship of diagnosis code, mortality, and readmission, research is meager in this area. There is a need for hospital-based research that addresses the diagnosis categories and the relationship to age and other variables.

Age Factors↗

JAM-2, a novel immunoglobulin superfamily molecule, expressed by endothelial and lymphatic cells.

Cell-cell contacts are essential for morphogenesis and tissue function and play a vital role in mediating endothelial cohesion within the vascular system during vessel growth and organization. We identified a novel junctional adhesion molecule, named JAM-2, by a selective RNA display method, which allowed identification of transcripts encoding immunoglobulin superfamily molecules regulated during coculture of endothelial cells with tumor cells. The JAM-2 transcript is highly expressed during embryogenesis and is detected in lymph node and Peyer's patches RNA of adult mice. Accordingly, antibodies specific for JAM-2 stain high endothelial venules and lymphatic vessels in lymphoid organs, and vascular structures in the kidney. Using real time video microscopy, we show that JAM-2 is localized within minutes to the newly formed cell-cell contact. The role of the protein in the sealing of cell-cell contact is further suggested by the reduced paracellular permeability of cell monolayer transfected with JAM-2 cDNA, and by the localization of JAM-2 to tight junctional complexes of polarized cells. Taken together, our results suggest that JAM-2 is a novel vascular molecule, which participates in interendothelial junctional complexes.

Amino Acid Sequence↗

A randomized placebo-controlled double-blind trial of lipid-lowering strategies in patients with renal insufficiency: diet modification with or without fenofibrate.

BACKGROUND: Renal insufficiency is characterized by lipoprotein abnormalities including elevated triglyceride levels. PATIENTS AND METHODS: The safety and efficacy of micronized fenofibrate as a treatment for dyslipidemia in patients with progressive renal insufficiency was evaluated in a randomized, placebo-controlled double-blind study comparing fenofibrate and dietary modification to dietary modification alone. Patients were evaluated following a 3-month pre-randomization period of dietary counseling. Twenty-eight patients with moderate renal insufficiency and triglyceride levels 2.3 mmol/l or LDL/HDL ratio 5 were randomized to placebo (n = 12) or fenofibrate (n = 16) therapy. Treatment and dietary counseling continued for 6 months. RESULTS: Ten of 16 patients (63%) treated with fenofibrate achieved a 30% reduction in triglyceride levels or LDL/HDL ratio reduction < 5 compared to 2 of 17% in the placebo group (p = 0.015). Triglyceride levels were significantly reduced in the fenofibrate group (-31%) versus placebo (+1.3%, p = 0.003). In compliant patients (n = 25) there was also a significantly greater increase in HDL cholesterol levels in the fenofibrate group (+19.9%) compared to placebo (-4.7%, p = 0.001). Changes in measured creatinine clearance were not significantly different between the groups and there were no serious adverse effects of treatment. CONCLUSION: Fenofibrate therapy combined with dietary modification effectively reduced triglyceride levels in renal insufficiency patients without serious adverse effects.

Adult↗

IFN-gamma and LPS-mediated IL-10-dependent suppression of retinal microglial activation.

PURPOSE: Human retinal microglia (MG) express constitutively major histocompatability complex (MHC) class II molecules and have thus been highlighted as potential immunocompetent antigen-presenting cells (APCs). This study was undertaken to characterize microglial expression of coaccessory molecules and the functional changes in antigen expression, cytokine production, migration, and phagocytosis after proinflammatory stimulation. METHODS: Fresh donor retinal MG were obtained and isolated using a percoll density gradient technique. Phenotypic characteristics used for isolating rodent microglia were applied and modified. Coaccessory molecule expression and intracellular cytokine production were assessed using three-color flow cytometric analysis in both freshly isolated and interferon (IFN)gamma-lipopolysaccharide (LPS)-stimulated MG. Using five-millimeter retinal explants in culture, microglial migratory behavior, changes in cell surface antigen expression and phagocytic activity were documented. RESULTS: MG could be clearly defined by the flow cytometric phenotype CD45low CD11b+ MHC class II+ CD86low CD40low. Freshly isolated MG showed mannose receptor-mediated uptake of dextran-FITC. MG migrated from explants, were adherent, and upregulated MHC class II expression. After IFNgamma-LPS stimulation of single-cell suspension of MG isolates, MHC class II expression was reduced, with an increase occurring in MG intracellular interleukin (IL)-10 and IL-10 production. Microglial migration from explants was reduced after IFNgamma-LPS stimulation. CONCLUSIONS: These results highlight both phenotypic and behavioral characteristics that support an antigen-processing and -presenting capability of freshly isolated MG. However, proinflammatory stimulation with IFNgamma-LPS induces an IL-10-mediated downregulation of cell surface antigen expression and loss of migratory and phagocytic activity. Therefore, although equipped to act as APCs, MG are able to rapidly modulate their own function and behavior and as a result may have the potential to limit inflammation.

Aged↗

Regional differences in the sympathetic innervation of the guinea pig large intestine by neuropeptide Y- and tyrosine hydroxylase-immunoreactive nerves of divergent extrinsic origin.

Region-specific patterns of nerves with immunoreactivity to neuropeptide Y (NPY) have been described previously in the submucous plexus of guinea pig large intestine. Because these may have functional significance, the possibility of similar, characteristic variations of NPY-like immunoreactivity (NPY-ir) in the myenteric plexus was explored. Regional differences were found in the occurrence and pattern of distribution of NPY-ir in the myenteric plexus of the guinea pig large intestine. NPY-ir was present rarely within neuron somata in any region of the large intestine, and NPY-ir nerve fibers were present only within the distal large intestine, increasing progressively in density from the distal spiral to the rectum. Lesion of the colonic nerves, but not the hypogastric, intermesenteric, or lumbar splanchnic nerves, resulted in a loss of NPY-ir in the distal spiral and transverse colon but not in the descending colon or rectum. Ring myotomies in the descending colon resulted in a loss of NPY-ir proximal to the lesion. Dual-labeling immunohistochemical studies revealed that the NPY-ir nerve fibers rarely contained immunoreactivity for tyrosine hydroxylase (TH). Extrinsic nerve lesions resulted in an unequivocal reduction in NPY-ir in intraganglionic fibers of the submucosal plexuses of the transverse colon and a partial loss in the distal spiral and descending colon: the rectum was unaffected; in only a minority of guinea pigs, however, was any decrease in the NPY-ir innervation of submucosal blood vessels detected. The principal projections of NPY-ir nerves were from and through the inferior mesenteric ganglion; however, NPY-ir was not colocalized with TH-ir. It is proposed that nonnoradrenergic, NPY-containing neurons located in the inferior mesenteric ganglion project through the colonic nerves and that these proximally directed fibers innervate the transverse colon and the distal spiral. Nonnoradrenergic, NPY-ir neurons lying in the pelvic ganglia or sacral sympathetic chain may make an important contribution to the innervation of the myenteric plexus of the rectum and the descending colon.

Animals↗