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PubMed2006

Role played by brainstem neurons in regulating testosterone secretion via a direct neural pathway between the hypothalamus and the testes.

We previously reported anatomical and functional evidence for a direct, inhibitory neural pathway that regulates testosterone (T) secretion independently of the pituitary. This pathway is activated by the intracerebroventricular (icv) administration of agents that stimulate stress responses, such as IL-1beta, corticotropin-releasing factor (CRF), and norepinephrine (NE), which results in a blunted T response to the administration of human chorionic gonadotropin (hCG). Blunting of the T response is mediated by central beta-adrenergic receptor stimulation. CRF, but not ethanol (EtOH) or IL-1beta, acts directly on the paraventricular nucleus of the hypothalamus to activate the pathway. Here we explored the role played by brain areas hypothesized to be part of this pathway, such as neurons in the dorsal pons [including the locus coeruleus (LC) of the brainstem], where NE is produced. Microinfusion of EtOH or IL-1beta, but not CRF, into these neurons activated the pathway. Electrolytic lesions of this region significantly reversed the inhibitory effect of icv-administered EtOH on hCG-induced T release, while having no effect on the ability of IL-1beta or CRF to do so. However, the icv administration of IL-1beta, EtOH, or CRF, in doses that rapidly inhibit the T response to hCG, all caused a significant depletion of NE from the LC. Collectively, these results indicate that in addition to the paraventricular nucleus, the brainstem area containing the LC is part of a neural pathway that connects the brain to the testes independently of the pituitary. We also speculate that EtOH may stimulate this pathway through NE-dependent activation of the dorsal pons.

Animals↗
PubMed1997

Psychophysical signatures associated with magnocellular and parvocellular pathway contrast gain.

Physiological data have revealed characteristic contrast gain and temporal integration signatures of the magnocellular (MC) and the parvocellular (PC) pathways. The goal in this study was to find psychophysical correlates of these signatures. Psychophysical forced-choice, luminance pedestal discrimination data were collected with a stimulus-surround display. A 2.05 degrees four-square stimulus array was varied from 73 to 182 trolands (Td) in a larger 115-Td surround. When the stimulus array was pulsed briefly, discrimination thresholds showed a minimum at the surround retinal illuminance, increasing in a V shape when the stimulus array was incremental or decremental to the surround. When the stimulus array was presented continuously as a steady pedestal within the constant 115-Td surround, discrimination thresholds increased monotonically with stimulus array retinal illuminance, obeying a slope of unity. Exposure duration variation showed temporal summation to extend to longer durations for the pulse increments and decrements than for the steady pedestal condition. Discrimination thresholds for pulsed medium-sized contrast steps showed the contrast pedestal paradigm showed the temporal signature of the MC pathway. Discrimination thresholds for small pedestal steps of the stimulus array from a steady pedestal showed the contrast gain signature of the MC pathway. The data suggested a difference in the spatiotemporal control of adaptation of the two pathways: The MC pathway adapted locally to the stimulus array, while the PC pathways showed little evidence of local adaptation. The experiments show that characteristic signatures of MC- and PC-pathway processing can be demonstrated by use of psychophysical procedures.

Adaptation, Physiological↗
PubMed1988

Age-related changes in the central visual field for short-wavelength-sensitive pathways.

The sensitivity of short-wavelength-sensitive (SWS) cone pathways throughout the central 30-deg visual field was determined in both eyes of 62 normal volunteers between the ages of 20 and 72 years. We found an average SWS cone pathway sensitivity decrease with age of approximately 0.15 log unit per decade. The sensitivity reduction was approximately linear, with a slightly larger decrease beyond the age of 50 years. The age-related SWS cone pathway sensitivity reductions also became larger as a function of increasing stimulus eccentricity. Measurements of ocular-media absorption characteristics in each eye revealed that 30-40% of the age-related sensitivity loss could be attributed to reductions in transmission of short-wavelength light by the ocular media. After corrections for preretinal media transmission loss, the decrease in the sensitivity of SWS cone pathways with age was approximately 0.09 log unit per decade. This age-related loss is greater than age-related sensitivity decreases in the middle-wavelength-sensitive and/or long-wavelength-sensitive cones (approximately 0.06 to 0.07 log unit per decade). In the age group older than 60 years, there was an inverse relationship between media-corrected SWS cone pathway sensitivity and media absorption characteristics (i.e., media-corrected SWS cone pathway sensitivity was higher in eyes with lower media transmission of short wavelengths). This relationship was not so evident for younger subjects. A similar inverse relationship between transmission loss in the ocular media and SWS cone pathway sensitivity was found between left and right eyes of the same individual.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Step training-dependent plasticity in spinal cutaneous pathways.

Plasticity after spinal cord injury can be initiated by specific patterns of sensory feedback, leading to a reorganization of spinal networks. For example, proprioceptive feedback from limb loading during the stance phase is crucial for the recovery of stepping in spinal-injured animals and humans. Our recent results showed that step training modified transmission from group I afferents of extensors in spinal cats. However, cutaneous afferents are also activated during locomotion and are necessary for proper foot placement in spinal cats. We therefore hypothesized that step training would also modify transmission in cutaneous pathways to facilitate recovery of stepping. We tested transmission in cutaneous pathways by comparing intracellular responses in lumbar motoneurons (n = 136) in trained (n = 11) and untrained (n = 7) cats spinalized 3-5 weeks before the acute electrophysiological experiment. Three cutaneous nerves were stimulated, and each evoked up to three motoneuronal responses mediated by at least three different pathways. Overall, of 71 cutaneous pathways tested, 10 were modified by step training: transmission was reduced in 7 and facilitated in 3. Remarkably, 6 of 10 involved the medial plantar nerve innervating the plantar surface of the foot, including two of the facilitated pathways. Because the cutaneous reflexes are exaggerated after spinalization, we interpret the decrease in most pathways as a normalization of cutaneous transmission necessary to recover locomotor movements. Overall, the results showed a high degree of specificity in plasticity among cutaneous pathways and indicate that transmission of skin inputs signaling ground contact, in particular, is modified by step training.

Adrenergic alpha-Agonists↗
PubMed2006

Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis.

Activation of each complement initiation pathway (classical, alternative, and lectin) can lead to the generation of bioactive fragments with resulting inflammation in target organs. The objective of the current study was to determine the role of specific complement activation pathways in the pathogenesis of experimental anti-type II collagen mAb-passive transfer arthritis. C57BL/6 mice were used that were genetically deficient in either the alternative pathway protein factor B (Bf(-/-)) or in the classical pathway component C4 (C4(-/-)). Clinical disease activity was markedly decreased in Bf(-/-) compared with wild-type (WT) mice (0.5 +/- 0.22 (n = 6) in Bf(-/-) vs 8.83 +/- 0.41 (n = 6) in WT mice (p < 0.0001)). Disease activity scores were not different between C4(-/-) and WT mice. Analyses of joints showed that C3 deposition, inflammation, pannus, cartilage, and bone damage scores were all significantly less in Bf(-/-) as compared with WT mice. There were significant decreases in mRNA levels of C3, C4, CR2, CR3, C3aR, and C5aR in the knees of Bf(-/-) as compared with C4(-/-) and WT mice with arthritis; mRNA levels for complement regulatory proteins did not differ between the three strains. These results indicate that the alternative pathway is absolutely required for the induction of arthritis following injection of anti-collagen Abs. The mechanisms by which these target organ-specific mAbs bypass the requirements for engagement of the classical pathway remain to be defined but do not appear to involve a lack of alternative pathway regulatory proteins.

Animals↗
PubMed1997

A critical pathway for management of patients with acute chest pain who are at low risk for myocardial ischemia: recommendations and potential impact.

BACKGROUND: Use of resources for patients with acute chest pain may be improved with clinical strategies that integrate research, Bayesian analysis, and expert opinion. OBJECTIVES: To 1) develop a critical pathway for management of patients with acute chest pain who are at low risk for complications of ischemic heart disease and 2) assess the potential effects of implementation of the pathway on patient safety and resource use. DESIGN: Evidence-based consensus and prospective cohort study. SETTING: Urban teaching hospital. PATIENTS: Patients at least 30 years of age who were seen in the emergency department for chest pain and who did not have a history of trauma or abnormalities on radiologic study. INTERVENTION: Physician-opinion leaders defined criteria for patient inclusion in the pathway and for remaining on the pathway after 6 or 12 hours of observation. Criteria were defined for appropriateness of direct admission, direct discharge, or 6 hours of observation followed by exercise treadmill testing. MEASUREMENTS: Number of patients admitted to the hospital, number of days that patients were hospitalized, and clinical outcome. RESULTS: 2898 of 4585 patients (63%) were admitted to the hospital; of the 2898, 1152 (40%) were classified as potentially eligible for the pathway and 1068 (93%) had a benign clinical course during the initial observation period. The 1068 patients had a mean length of stay of 2.8 +/- 4.8 days. If 47% of these patients had been discharged after observation and exercise testing, implementation of the pathway would have reduced the number of admissions by 505 (17%) and days of hospitalization by 1407 (11%). CONCLUSIONS: Retrospective analysis suggests that a critical pathway for patients with acute chest pain may substantially reduce resource use. Prospective study is needed to ensure increased efficiency without increased adverse outcomes.

Acute Disease↗
PubMed1995

Cancer care critical pathways: implementing a successful program.

Change in any form creates stress on systems, yet there is growing awareness within the health care field that change must come as cost-conscious insurers and employers refuse to pay for overextended processes that grew out of the charge-based reimbursement era. Short-term solutions, such as discounted charges and staff cuts, are not the answer when the entire system needs an overhaul. The cost of care escalates and the quality of patient care suffers because the system lacks the appropriate mechanisms to reduce redundancy, eliminate waste, improve effectiveness, and provide the high-quality care that a community expects from its hospital. The outcomes-based critical pathway approach discussed here has been used with great success and differs from classic pathway writing in that only elements related to the specific outcome are allowed on the order set. The critical pathway process starts with a review of historical patient records, which yields information about both historical practice patterns and the provider team. Using this information, a work group is formed and patient goals or outcomes are established for the population in question. The entire system is informed and educated, with special attention given to the medical staff, clinical outcome and financial data are developed and provided to individuals in the process, and a feedback loop is established. Cancer care is an attractive target for critical pathways, because it is an area with high cost and expensive technology, and physician practice patterns and patient outcomes can vary widely. On the flip side, the historically multidisciplinary nature of cancer care offers a good starting point for the collaborative culture needed to successfully implement critical pathways. When done right, critical pathways can decrease morbidity and mortality, reduce redundancy and cost, increase patient satisfaction, and improve patient outcomes. Shifting practice and eliminating variation in practice patterns, without regard to best practices and outcomes, could leave an organization compromised by group norms. Few things will sustain the energy needed to keep the hospital culture moving forward. This is not to say that it cannot be done, because it can. The critical pathway process has noticeable energy cycle levels--periods of high energy and low energy. The two hospitals discussed here reveal their painstaking effort to maintain and invigorate a process that would rather wait another day. Carefully selected work group members, reminders to keep individuals from returning to old practice habits, and an established, firm connection between cost and quality will help carry an organization through periods of low energy.(ABSTRACT TRUNCATED AT 400 WORDS)

California↗
PubMedDate not supplied

A patient pathway to renal replacement therapy: implementation in the progressive renal insufficiency population.

Care paths and patient pathways are collaborative interdisciplinary tools developed to provide quality care. One goal in progressive renal insufficiency (PRI) care is to provide patients and family members with relevant and timely information to help them cope with medical therapy and lifestyle changes required to slow the progression of renal insufficiency. At Halton Healthcare Services, clinical and patient pathways have been widely used with success. Recognizing the potential benefits of a patient pathway for the PRI population, our interdisciplinary team developed a pathway that outlines the journey to renal replacement therapy. The pathway provides the patient with some insight into the future, as their disease process continues to have impact on their life. Reviewed by a patient within our PRI program during the development process, we have tailored this pathway to meet the needs of this unique population. We predict this patient pathway will have positive impact on the patient's understanding of the role of the PRI clinic and the partnership between the team members, the patient, and the family.

Continuity of Patient Care↗
PubMed2002

Beneficial impact of a clinical care pathway in patients with testicular cancer undergoing retroperitoneal lymph node dissection.

PURPOSE: Since 1997, we have used a clinical collaborative care pathway for patients undergoing retroperitoneal lymph node dissection. We examined its impact on perioperative care and outcome. MATERIALS AND METHODS: We examined the records of all patients with germ cell carcinoma who underwent retroperitoneal lymph node dissection from July 1990 to July 2001. Variables examined included clinical/pathological stage, hospital stay, postoperative care and the complication rate. RESULTS: A total of 118 patients underwent retroperitoneal lymph node dissection for germ cell carcinoma during this period, including 46 (39%) before pathway implementation in 1997 and 72 patients (61%) after pathway implementation. Of the 118 patients 40 (34%) underwent the procedure after chemotherapy. This rate remained fairly constant in the period before and after pathway initiation (31% and 36%, respectively). After pathway implementation fewer patients received a nasogastric tube (94% versus 5%, p <0.001) and had complications (26% versus 16%, p = 0.036). Mean hospital stay decreased after pathway implementation in all primary and post-chemotherapy retroperitoneal lymph node dissection cases (4.2 versus 6.4 days, p <0.005). Although patients who underwent the procedure after chemotherapy were more likely to have complications than those who underwent a primary procedure, the difference was not statistically significant (p = 0.09). CONCLUSIONS: Our collaborative clinical care pathway safely and efficiently outlines routine postoperative care and significantly decreased hospital stay.

Adult↗
PubMed2004

Classifying clinical pathways.

BACKGROUND: Clinical pathways are commonly developed for homogenous patient groups. We were wondering if the traditional patient classification systems could be used for classifying clinical pathways. METHODOLOGY: To examine the utility of patient classification systems for clinical pathways, a sample of 13 clinical pathways was analyzed, involving a total of 412 patients. Three classification systems were tested: International Classification of Diseases, Ninth Revision (ICD9-CM), Clinical Coding System (CCS) data and All-Patient Redefined Diagnosis Related Groups (APR-DRG). RESULTS: Categorization with ICD9-CM and CCS shows rather wide variation. However, when restricting for the principal codes, CCS classification shows an almost homogeneous relationship with clinical pathways. APR-DRG's are already corrected for secondary procedures and are difficult to assess. Categorization with the Risk Of Mortality (ROM) is more homogeneous than with the Severity Of Illness (SOI). CONCLUSION: Patient groups in clinical pathways are rather heterogeneous. When restricting for the principal procedures, the strongest relationship seems to exist between clinical pathways and CCS. Further research is needed to refine this relationship.

Belgium↗
PubMed2006

Magnocellular and parvocellular visual pathways have different blood oxygen level-dependent signal time courses in human primary visual cortex.

PURPOSE: The magnocellular and parvocellular pathways (M and P pathways) are the major pathways of the visual system, with distinct histologic and physiologic properties that may also have different metabolic characteristics. We hypothesize that the differences of the 2 visual pathways would also manifest as differences in the signal time course of blood oxygen level-dependent functional MR imaging (BOLD fMRI). The differences in BOLD signal time course may provide insight into the metabolic requirements of the 2 pathways. METHODS: Eleven fMRI sessions on 6 subjects were performed using stimuli that preferentially activated the 2 pathways. Regions commonly activated by both the M and P stimuli in the primary visual cortex (V1) were determined, and the contrast elicited by the stimulus, time-to-peak (TTP), and the full width at half maximum (FWHM) of the BOLD signal time course were measured. RESULTS: The functional stimuli activated cortical regions described previously in the literature, such as V1, V4, and V5. Within V1, the TTP of the signal time course of the 2 stimuli were statistically different, with the P stimulus generating TTPs that were on average 12% faster than the M stimulus (P = .0037). CONCLUSION: We have demonstrated the ability to functionally differentiate the M and P stimuli in a commonly activated anatomic region. Because the BOLD response is dependent on the ratio of oxyhemoglobin and deoxyhemoglobin in the blood, the difference in the BOLD time course between the 2 stimuli suggests that the oxygen demand of the 2 pathways may be different.

Brain Mapping↗
PubMed1990

Identified primary motoneurons in embryonic zebrafish select appropriate pathways in the absence of other primary motoneurons.

Accurate pathfinding is a crucial step in formation of a functional nervous system. Individually identified zebrafish primary motoneurons undergo a stereotyped temporal sequence of axonal outgrowth and pathway selection during which their growth cones follow a common pathway to a "choice point" and then select divergent cell-specific pathways that lead to separate muscle territories. The characteristic sequence of cell-specific pathway selection raises the possibility that the sequence of growth cone arrival at the choice point might determine pathway selection. To test this idea, we ablated identified primary motoneurons by laser irradiation, labeled the remaining primary motoneuron in the same hemisegment with a fluorescent dye, and followed its development through the end of embryogenesis. We found that the growth cone of each primary motoneuron has an independent ability to pioneer the common pathway and select its appropriate cell-specific pathway, even in the absence of all other primary motoneurons in the same hemisegment.

Animals↗
PubMed1989

Operant conditioning of head-waving in Aplysia. III. Cellular analysis of possible reinforcement pathways.

Operant conditioning of the head-waving response in Aplysia, as well as conditioning of the electrical activity of identified neck muscles, can be induced readily when bright light is used as aversive reinforcement (Cook and Carew, 1986, 1989b). A cellular analysis of this type of operant conditioning requires an understanding of the neural circuitry that underlies the reinforcement pathways involved in the conditioning. In the present paper we describe a cellular analysis of possible reinforcement pathways that mediate the aversive effects of bright light in the CNS of Aplysia. Using a semi-intact "split-body" preparation, we explored the effects of bright light on the operant response pathway by recording intracellularly from identified pedal neck and body wall motor neurons, which contribute to the operant response. In these experiments we identified 2 light-sensitive pathways. One pathway, from the eyes and rhinophores, mediated functional inhibition of light-induced excitation of pedal motor neurons. The other pathway, from the oral veil (cerebral ganglion nerves C1-C3) mediated significant excitation of the same motor cells. Randomly occurring blank trials ruled out the possibility that the light-induced effects were due to sampling bias. Finally, surgical isolation of the CNS from the periphery showed that none of the effects of light were due to direct illumination of central neurons. This identification of candidate reinforcement pathways will facilitate a cellular analysis of operant conditioning of head-waving in Aplysia.

Animals↗
PubMed1986

Guidance of neuronal growth cones in the grasshopper embryo. III. Recognition of specific glial pathways.

In the previous 2 papers, we focused on the selective affinities that growth cones display for specific axonal pathways. Little is known, however, about how this orthogonal scaffold of axonal pathways in the CNS is established in the first place, and what, if any, role glia might play in these events. Here we show an important relationship between pioneering growth cones and primitive glial cells in the developing longitudinal connectives and peripheral nerve roots of the grasshopper embryo. We describe a preformed glial pathway for the formation of the intersegmental nerve, one of the major roots exiting the CNS. The growth cones that pioneer this nerve display a selective affinity for the segment boundary cell (SBC), a primitive glial cell that establishes the location of this nerve root. Similar glial cells are also found along the pathway where the longitudinal connectives form, and they too may play an important role in the formation of the first longitudinal axonal pathways. Experimental analysis shows that when the SBC is ablated, the growth cones that normally turn laterally to pioneer the intersegmental nerve do not do so, thus confirming the importance of the guiding role of this glial cell. We postulate that a simple orthogonal scaffold of primitive glia is involved in the initial patterning of axonal pathways within and exiting the insect CNS; this concept is remarkably similar to the blueprint hypothesis proposed by Singer et al. (1979) to explain the development of axon pathways in vertebrates.

Animals↗
PubMed1985

Properties of glycans that activate the human alternative complement pathway and interact with the human monocyte beta-glucan receptor.

The glycans used in an earlier study to define the ligand specificity of the human monocyte phagocytic receptor for unopsonized particulate activators were assessed for their capacities to activate the proteins of the human alternative complement pathway. Normal human serum was preincubated with glycans under conditions of chelation to prevent activation of the classical complement pathway, and the activation-depletion of the alternative complement pathway was determined by the subsequent capacity of the serum to lyse rabbit erythrocytes (Er). When serum was preincubated at a 1/2 dilution in 8 mM EGTA/2 mM Mg with increasing numbers of yeast glucan or zymosan particles, and was evaluated at final serum dilutions of 1/8, its capacity to lyse Er was found to be reduced by 50% with 1.9 X 10(6)/ml yeast glucan particles and 1.4 X 10(6)/ml zymosan particles. At 2 mg/ml of serum diluted 1/2 in 8 mM EGTA/2 mM Mg, nonturbid preparations of mannan, laminarin, or pyrogen-free inulin and turbid suspensions of cellulose, Sephadex, agarose, or purified inulin failed to activate the alternative complement pathway. In contrast, activation-depletion of the alternative pathway was induced by turbid preparations of crude inulin, nigeran, pachyman, barley beta-glucan, and pustulan, which at 700 micrograms/ml, 500 micrograms/ml, 350 micrograms/ml, 60 micrograms/ml, and 27 micrograms/ml, respectively, effected 50% reductions in the subsequent lysis of Er. After centrifugation of 2 mg/ml suspensions of barley beta-glucan at 1100 X G for 5 min and at 15,000 X G for 15 min, the supernatants contained 90 to 92% and 65% of the barley beta-glucan, respectively, as determined by the anthrone method. On a weight basis, the 1100 X G supernatant exhibited the same capacity to activate the alternative pathway as the corresponding original suspension, whereas the 15,000 X G supernatants had less than 3% of the original anti-complementary activity. Preincubation of adherent human monocytes with increasing concentrations of barley beta-glucan suspensions, 100,000 X G supernatants containing 64% of the original beta-glucan, and laminarin all decreased subsequent ingestion of 1.25 X 10(6) zymosan particles in a dose-related fashion. The numbers of monocytes from three different donors phagocytosing zymosan were reduced by 50% after pretreatment with 30 to 65 micrograms/ml, 25 to 48 micrograms/ml, and 12 to 15 micrograms/ml of barley beta-glucan suspensions, 100,000 X G supernatants of barley beta-glucan, and laminarin, respectively, even though the latter two preparations were fully soluble and had no capacity to activate the alternative pathway.(ABSTRACT TRUNCATED AT 400 WORDS)

Complement Activation↗
PubMed1981

Inhibitory effect of C-reactive protein on alternative C pathway activation by liposomes and Streptococcus pneumoniae.

C-reactive protein (CRP) is an acute phase serum protein found associated with damaged tissue at sites of inflammation. CRP bound to multivalent phosphocholine-containing or polycationic ligands activates C by the classical pathway. We have previously described liposomes of a particular lipid composition that are able both to activate the alternative pathway of C and to bind CRP. In addition many strains of Streptococcus pneumoniae activate the alternative pathway. We have shown CRP binding to these bacteria as well. Because antibody to an activating surface in many cases enhances alternative pathway activation, we tested CRP for a similar function in these systems. Our results indicate that, in contrast to antibody, CRP inhibits alternative pathway activation. This inhibition by CRP is apparently restricted to surfaces that bind CRP. Thus, CRP binding to membrane or bacterial surfaces can convert them from alternative pathway activation to classical pathway activation.

Amines↗
PubMedDate not supplied

[Activation of the alternative complement pathway in pleural fluid of patients with pneumonia].

It has been reported that the opsonic activity of pleural fluid is decreased in patients with pneumonia complicated by infected effusions (empyema) compared to those with sterile (metapneumonic) effusions. In this paper some parameters of complement activity in 12 patients with empyema and in 13 patients with metapneumonic effusions were compared. The hemolytic activity of the alternative pathway and of Factor B in empyemas (15 +/- 10% and 25+15%, respectively) was less than that measured in metapneumonic effusions (55 +/- 38% and 71 +/- 21%; p less than 0.01). Both parameters showed a significant correlation (r=0.76; p less than 0.01). The Ba fragment, a catabolic product of Factor B, was increased in empyema (125 +/- 59%) compared to that in metapneumonic effusions (49 +/- 24%; p less than 0.01). The levels of C3, protein of both, alternative and classical pathways, were decreased in empyema (17 +/- 29%) when compared with the levels in metapneumonic pleural effusion (42 +/- 20%; p less than 0.01). The levels of this protein were correlated with the activity of alternative complement pathway (r=0.68; p less than 0.01), as well as with those of Factor B (r=0.75; p less than 0.01). Finally, the hemolytic activity of C4, as a representative element of the classical pathway, has also shown to be decreased in empyema (6 +/- 6%) compared to metapneumonic fluids (27 +/- 28%; p less than 0.01). Significant correlations between the hemolytic activity of C4 and levels of C3 (r=0.75; p less than 0.01), the hemolytic activity of the alternative pathway (r=0.63; p less than 0.01) and the levels of Factor B (r=0.73; p less than 0.01) were demonstrated. This last suggest a simultaneous activation of both, classical and alternative pathways of complement. The complement decrease and particularly, the activation of the alternative pathway in patients with empyema could be a determinant factor of the deficient bacterial opsonization. This can explain the survival of bacteria in an empyema despite the large number of neutrophils present.

Complement Activation↗
PubMed1995

Type 4a metabotropic glutamate receptor: identification of new potent agonists and differentiation from the L-(+)-2-amino-4-phosphonobutanoic acid-sensitive receptor in the lateral perforant pathway in rats.

Before the discovery of the metabotropic glutamate receptors (mGluRs), the glutamate analogue L-2-amino-4-phosphonobutanoic acid (L-AP4) was identified as a potent presynaptic inhibitor of evoked synaptic transmission in the lateral perforant pathway in rats. The localization and L-AP4 sensitivity of the mGluR4a subtype of mGluRs were consistent with the hypothesis that this receptor mediates the synaptic depressant effects of L-AP4 in the lateral perforant pathway. In the present study, the pharmacology of mGluR4a expressed in baby hamster kidney 570 cells was characterized and compared with that previously reported for the lateral perforant pathway responses. The endogenous excitatory amino acid L-aspartate was inactive at mGluR4a, whereas L-homocysteic acid was only 5-fold less potent than L-glutamate. These data suggest that L-homocysteic acid may be an endogenous agonist at mGluR4a. Of the 30 L-AP4 analogues examined, several compounds were identified as agonists at mGluR4a. The cyclopropyl-AP4 analogue (Z)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid inhibited forskolin-stimulated cAMP production with an EC50 of 0.58 microM, which is comparable to that of L-AP4 (EC50 = 0.43 microM). Two other cyclic analogues of L-AP4 were approximately 10-fold less potent as agonists at mGluR4a, i.e., (+/-)-1-amino-3-(phosphonomethylene)cyclobutanecarboxylic acid (EC50 = 4.4 microM) and (E)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid (EC50 = 7.9 microM). Comparison of the potencies of the compounds for activation of mGluR4a with their potencies for inhibition of lateral perforant pathway responses demonstrates that some compounds have comparable activities in the two systems, whereas several compounds are at least 10-fold more potent in one of the systems. In addition, although the mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine blocked the effects of L-AP4 in the lateral perforant pathway, it did not block the effects of L-AP4 at the cloned receptor. These data provide evidence that mGluR4a does not mediate the effects of L-AP4 in the lateral perforant pathway, they provide new tools to identify the function of these receptors in the mammalian central nervous system, and they indicate that the effects of L-AP4 in the lateral perforant pathway are mediated by a (+)-alpha-methyl-4-carboxyphenylglycine-sensitive receptor.

Aminobutyrates↗