RESUMEN
The aim of the study is to understand in depth the meaning of "reentry", and to decipher if and how it can lead to malfunctions of the heart and possibly of the brain. A simple model is used to reveal the mechanism by which a single pulse of action potential rotating around a ring of excitable medium, the latter simulating a reentry circuit, can generate spirals (single and/or double) when the pulse can emerge from and develop outside the ring. Two mechanisms of spiral generation are demonstrated: (1) a mechanism in which a source of single spirals is created at the contact with the core soon after the pulse freeing action, their chirality being due to the sense of the preceding pulse rotation. Interestingly, these spirals, adhering to the core, become "double-spiral patterns" while leaving behind the seeds of the new single spirals. (2) A second possible mechanism, similar to the known "arms encountering methods", in which a double spiral (a figure of eight) is repeatedly created on the other side of the core. Similar procedures are assumed to occur in the heart, leading to tachycardia and fibrillation and possibly in the brain leading to epilepsy. The exact processes of the hitherto assumed spiral generations by reentry were established. The novel deep understanding of the mechanisms involved in these processes can lead to new methods of treating heart fibrillation (e.g., by judicial ablation).
Asunto(s)
Sistema de Conducción Cardíaco/fisiopatología , Modelos Cardiovasculares , Potenciales de Acción/fisiología , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Encéfalo/fisiopatología , Simulación por Computador , Epilepsia/etiología , Epilepsia/fisiopatología , Humanos , Conceptos Matemáticos , Modelos Neurológicos , Dinámicas no Lineales , Taquicardia/etiología , Taquicardia/fisiopatologíaRESUMEN
We state that the autonomic part of the brain controls the blood pressure (BP) and the heart rate (HR) via the baroreflex mechanism in all situations of human activity (at sleep, at rest, during exercise, fright etc.), in a way which is not, as was hitherto assumed, a mere homeostatic tool or even a resetting device, designed to bring these variables on the road to preset values. The baroreflex is rather a continuous feedback mechanism commanded by the autonomic part of the brain, leading to values appropriate to the situation at hand. Feasibility of this assertion is demonstrated here by using the Seidel-Herzel feedback system outside of its regular practice. Results show indeed that the brain can, and we claim that it does, control the HR and BP throughout life. New responses are demonstrated, e.g., to a sudden fear or apnea. In this event, large BP and HR overshoots are expected before the variables can relax to a new level. Response to abrupt downward change in the controlling parameter shows an undershoot in HR and just a gradual resetting in the BP. The relaxation from sudden external changes to various expected states are calculated and discussed and properties of the Rheos test are explained. Experimental findings for orthostatic tests and for babies under translations and rotations reveal complete qualitative agreement with our model and show no need to invoke the operation of additional body systems. Our method should be the preferred one by the Occam Razor approach. The outcomes may lead to beneficial clinical implication.
Asunto(s)
Barorreflejo/fisiología , Presión Sanguínea/fisiología , Encéfalo/fisiología , Frecuencia Cardíaca/fisiología , Humanos , Conceptos Matemáticos , Modelos Cardiovasculares , Modelos NeurológicosRESUMEN
Our progress of understanding how cellular and structural factors contribute to the arrhythmia is hampered in part because of controversies whether a fibrillating heart is driven by a single, several, or multiple number of sources, and whether they are focal or reentrant, and how to localize them. Here we demonstrate how a novel usage of the neutral singular value decomposition (SVD) method enables the extraction of the governing spatial and temporal modes of excitation from a rotor and fibrillatory waves. Those modes highlight patterns and regions of organization in the midst of the otherwise seemingly-randomly propagating excitation waves. We apply the method to experimental models of cardiac fibrillation in rabbit hearts. We show that the SVD analysis is able to enhance the classification of the heart electrical patterns into regions harboring drivers in the form of fast reentrant activity and other regions of by-standing activity. This enhancement is accomplished without any prior assumptions regarding the spatial, temporal or spectral properties of those drivers. The analysis corroborates that the dominant mode has the highest activation rate and further reveals a new feature: A transfer of modes from the driving to the passive regions resulting in a partial reaction of the passive region to the driving region.
RESUMEN
Schizophrenia is a psychotic disorder that affects approximately 1% of the global population. However, the etiology of this illness remains a subject of debate. One of the proposed mechanisms underlying schizophrenia is the synaptic pruning mediated by microglia in the brains of individuals with schizophrenia, although the precise mechanisms of this process remain elusive. In this regard, we propose that the potential development of the disease stems from both a genetic predisposition leading to an excessive production of GABAergic neurons and an exaggerated effort to maintain the E/I (excitation/inhibition) balance in the brain.
RESUMEN
Atrial fibrillation (AF) is the commonest cardiac arrhythmia, affecting 3 million people in the USA and 8 million in the EU (according to the European Society of Cardiology). So, why is it that even with the best medical care, around a third of the patients are treatment resistant. Extensive research of its etiology showed that AF and its mechanisms are still debatable. Some of the AF origins are ascribed to functional and ionic heterogeneities of the heart tissue and possibly to additional triggering agents. But, have all AF origins been detected? Are all accepted origins, in fact, arrhythmogenic? In order to study these questions and specifically to check our new idea of intermittency as an arrhythmogenesis agent, we chose to employ a mathematical model which was as simple as possible, but which could still be used to observe the basic network processes of AF development. At this point we were not interested in the detailed ionic propagations nor in the actual shapes of the induced action potentials (APs) during the AF outbreaks. The model was checked by its ability to exactly recapture the basic AF developmental stages known from experimental cardiac observations and from more elaborate mathematical models. We use a simple cellular automata 2D mathematical model of N × N matrices to elucidate the field processes leading to AF in a tissue riddled with randomly distributed heterogeneities of different types, under sinus node operation, simulated by an initial line of briefly stimulated cells inducing a propagating wave, and with or without an additional active ectopic action potential pulse, in turn simulated by a transitory operation of a specific cell. Arrhythmogenic contributions, of three different types of local heterogeneities in myocytes and their collaborations, in inducing AF are examined. These are: a heterogeneity created by diffuse fibrosis, a heterogeneity created by myocytes having different refractory periods, and a new heterogeneity type, created by intermittent operation of some myocytes. The developmental stages (target waves and spirals) and the different probabilities of AF occurring under each condition, are shown. This model was established as being capable of reproducing the known AF origins and their basic development stages, and in addition has shown: (1) That diffuse fibrosis on its own is not arrhythmogenic but in combination with other arrhythmogenic agents it can either enhance or limit AF. (2) In general, combinations of heterogeneities can act synergistically, and, most importantly, (3) The new type of intermittency heterogeneity proves to be extremely arrhythmogenic. Both the intermittency risk and the fibrosis role in AF generation were established. Knowledge of the character of these arrhythmogenesis agents can be of real importance in AF treatment.
Asunto(s)
Fibrilación Atrial , Fármacos Cardiovasculares , Humanos , Nodo Sinoatrial , Trastorno del Sistema de Conducción Cardíaco , Células Musculares , Fármacos Cardiovasculares/metabolismo , Fibrosis , Atrios Cardíacos , Potenciales de Acción , Miocitos Cardíacos/metabolismoRESUMEN
The origin of post-ictal malfunctions is debatable. We want to propose a novel idea of a cause of these adverse results occurring following epileptic seizures and anesthesia. Previously we have put forward the idea that epileptic seizures termination is caused by the function of the glymphatic system in the brain. A new measurement shows that this system can be much faster than what was estimated before. Moreover, the method enabling this speeding was actually measured in brains of epilepsy subjects. So, the main objection to our model is relegated. As a possible consequence of the glymphatic process, there can be an excess cleaning of the brain's interstitial fluid. We discuss possible adverse results of this process. This over-cleaning (that can, to a lower extent, occur also during anesthesia) which results post-ictally from the previous overexpression of fluid materials by the neurons during their seizure operation, can reduce ingredients essential for regular neuronal functioning, thereby leading to function reduction and EEG suppression which last until those materials are replenished. We argue that this ingredients' scarcity is the cause of post-ictal generalized EEG suppression (PGES), of post-ictal immobility (PI) and possibly of Sudden Unexpected Death in Epilepsy Patients (SUDEP). Similarly, such cleaning can lead to morbidity and even mortality problems following anesthesia. If our assumption is correct, this understanding of the process of the problems' origin can lead to a method to remedy them by judicial supplement of the lost materials.
Asunto(s)
Anestesia , Epilepsia , Muerte Súbita e Inesperada en la Epilepsia , Anestesia/efectos adversos , Electroencefalografía , Epilepsia/complicaciones , Humanos , ConvulsionesRESUMEN
In the last several years, quite a few papers on the joint question of transport, tortuosity and percolation have appeared in the literature, dealing with passage of miscellaneous liquids or electrical currents in different media. However, these methods have not been applied to the passage of action potential in heart fibrosis (HF), which is crucial for problems of heart arrhythmia, especially of atrial tachycardia and fibrillation. In this work we address the HF problem from these aspects. A cellular automaton model is used to analyze percolation and transport of a distributed-fibrosis inflicted heart-like tissue. Although based on a rather simple mathematical model, it leads to several important outcomes: (1) It is shown that, for a single wave front (as the one emanated by the heart's sinus node), the percolation of heart-like matrices is exactly similar to the forest fire case. (2) It is shown that, on the average, the shape of the transport (a question not dealt with in relation to forest fire, and deals with the delay of action potential when passing a fibrotic tissue) behaves like a Gaussian. (3) Moreover, it is shown that close to the percolation threshold the parameters of this Gaussian behave in a critical way. From the physical point of view, these three results are an important contribution to the general percolation investigation. The relevance of our results to cardiological issues, specifically to the question of reentry initiation, are discussed and it is shown that: (A) Without an ectopic source and under a mere sinus node operation, no arrhythmia is generated, and (B) A sufficiently high refractory period could prevent some reentry mechanisms, even in partially fibrotic heart tissue.
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Potenciales de Acción , Fibrilación Atrial , Simulación por Computador , Modelos Cardiovasculares , Miocardio/metabolismo , Animales , Fibrilación Atrial/metabolismo , Fibrilación Atrial/fisiopatología , Fibrosis , Humanos , Taquicardia Atrial Ectópica/metabolismo , Taquicardia Atrial Ectópica/fisiopatologíaRESUMEN
We present a model from which the observed morphology of the inner mitochondrial membrane can be inferred as minimizing the system's free energy. In addition to the usual energetic terms for bending, surface area, and pressure difference, our free energy includes terms for tension that we hypothesize to be exerted by proteins and for an entropic contribution due to many dimensions worth of shapes available at a given energy. We also present measurements of the structural features of mitochondria in HeLa cells and mouse embryonic fibroblasts using three-dimensional electron tomography. Such tomograms reveal that the inner membrane self-assembles into a complex structure that contains both tubular and flat lamellar crista components. This structure, which contains one matrix compartment, is believed to be essential to the proper functioning of mitochondria as the powerhouse of the cell. Interpreting the measurements in terms of the model, we find that tensile forces of â¼20 pN would stabilize a stress-induced coexistence of tubular and flat lamellar cristae phases. The model also predicts a pressure difference of -0.036 ± 0.004 atm (pressure higher in the matrix) and a surface tension equal to 0.09 ± 0.04 pN/nm.
Asunto(s)
Entropía , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Forma de los Orgánulos , Animales , Células HeLa , Humanos , Ratones , Mitocondrias/ultraestructura , Membranas Mitocondriales/ultraestructura , Modelos Biológicos , Resistencia a la Tracción/fisiologíaRESUMEN
Two recent postictal EEG measurements demonstrate somewhat conflicting results of epileptic behavior clearance in different brain parts. Both measurements observed two modes of seizure cessation, an abrupt and a gradual one, with slightly different statistics. No explanations were given for the appearance of these modes. Both measurements differ also in assessing the postictal brain activity or lack thereof, specifically the gamma activity. Using our G-Lymphatic clearance hypothesis, these results can be explained theoretically. The presence of two modes can be related to the order of ISF-CSF cleaning of brain parts. The reduced activity can be ascribed to neuronal ingredients deficiency brought about by the seizure related excess brain activity and by an over cleaning by the G-Lymphatic system.
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Ondas Encefálicas , Epilepsia , Encéfalo , Electroencefalografía , Humanos , ConvulsionesRESUMEN
The transfer of 6-carboxyfluorescein between islet cells in monolayer culture was observed by fluorescence microscopy, and the endocrine cells involved in this transfer were identified by immunohistochemistry and electron microscopy. The results show that carboxyfluorescein was directly exchanged between homologous B-cells and also between B- and A- or D-cells. Successive microinjections of the probe into different cells of the same cluster showed the existence of separate territories, each formed by 2-8 communicating cells. Intercellular communication was not observed after every dye microinjection, and communicating and noncommunicating islet cells were found to coexist within the same cluster. The data indicate that the exchange of exogenous cytoplasmic molecules occurs between different types of endocrine islet cells. However, within a single cluster, all islet cells are not metabolically coupled to one another, at a given time.
Asunto(s)
Comunicación Celular , Islotes Pancreáticos/fisiología , Animales , Células Cultivadas , Fluoresceínas , Islotes Pancreáticos/citología , Islotes Pancreáticos/ultraestructura , Microscopía Electrónica , RatasRESUMEN
Single islet cells in monolayer cultures of neonatal rat pancreas were microinjected with fluorescein and scanned topographically by microfluorometry. Fluorescein spread from an injected islet cell directly into neighboring islet cells, and, in the presence of 16.7 millimolar glucose, significantly more islet cells communicated with the injected cell than in glucose-free medium. Islet cells were also microinjected with glycolytic substrates and activators that produced transient changes in cellular levels of reduced pyridine nucleotides-nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate [NAD(P)H]. Changes in NAD(P)H fluorescence were observed in islet cells incubated first for 18 hours in very low glucose concentrations and then in a glucose-free medium and injected with glycolytic substrates and activators; however, little change of fluorescence occurred in adjacent islet cells. In contrast, after adding 16.7 millimolar glucose to the medium, injection of glycolytic substrates and activators produced transient changes in NAD(P)H fluorescence in the injected cell and in neighboring cells.
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Comunicación Celular , Islotes Pancreáticos/fisiología , Animales , Comunicación Celular/efectos de los fármacos , Fluoresceínas , Glucosa/farmacología , Glucólisis , Islotes Pancreáticos/citología , Cinética , NAD/metabolismo , NADP/metabolismo , Ratas , Espectrometría de FluorescenciaRESUMEN
A consistent explanation for the abrupt appearance of the mist zone in high velocity brittle fractures is given. The dependence of the boundary on flaw sizes is calculated. For low velocity fractures a gradual mirror-mist transition is demonstrated.
RESUMEN
The shape of Escherichia coli is approximately that of a cylinder with hemispherical caps. Since its size is not much larger than optical resolution, it has been difficult to quantify deviations from this approximation. We show that one can bypass this limitation and obtain the cell shape with subpixel accuracy. The resulting contours are shown to deviate from the hemisphere-cylinder-hemisphere shape. In particular, the cell is weakly asymmetric. Its two caps are different from each other and the sides are slightly curved. Most cells have convex sides. We discuss our results in light of several mechanisms that are involved in determining the shape of cells.
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Fenómenos Fisiológicos Bacterianos , Biofisica/métodos , Escherichia coli/fisiología , Interpretación de Imagen Asistida por Computador/métodos , Modelos Biológicos , Algoritmos , Forma de la Célula , Escherichia coli/metabolismo , Procesamiento de Imagen Asistido por Computador , Luz , Microscopía Fluorescente , Microscopía de Contraste de Fase/métodos , Modelos Estadísticos , Reproducibilidad de los ResultadosRESUMEN
In a previous study, we observed that combination therapy of nonobese diabetic (NOD) mice with epidermal growth factor (EGF) and gastrin partially restored pancreatic islet beta-cell mass and reversed hyperglycemia without the use of immunotherapy. Herein we have studied the effects of EGF plus gastrin on recurrent autoimmune responses in diabetic NOD mice transplanted with syngeneic islets. EGF (10 microg/kg) plus gastrin (30 microg/kg) given intraperitoneally (i.p.) once daily to diabetic NOD mice (blood glucose, 23 +/- 2 mmol/L) significantly prolonged the median survival time of NOD islet grafts to 60 days (n = 10 mice) measured as the days until hyperglycemia recurrence (blood glucose > or =12 mmol/L; versus EGF alone to 36 days (n = 10), or gastrin alone, 19 days (n = 10), or vehicle, 11 days (n = 9). At 7-14 days after transplantation insulin-stained beta-cells were much more numerous in islet grafts of EGF plus gastrin-treated mice (13.0 +/- 0.9 x 10(5) cells) versus grafts in vehicle-treated mice (1.0 +/- 0.3 x 10(5) cells). CD45+ leukocytes were significantly reduced in number and surrounded but did not destroy the beta cells in the islets of EGF plus gastrin-treated mice (29 +/- 2 x 10(5) cells) versus those in vehicle-treated mice (57 +/- 3 x 10(5) cells). We concluded that the EGF plus gastrin combination therapy inhibited the recurrent autoimmune response and delayed rejection of syngeneic islet grafts, suggesting a therapeutic role for these peptides in islet transplantation.
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Diabetes Mellitus Tipo 1/prevención & control , Factor de Crecimiento Epidérmico/uso terapéutico , Gastrinas/uso terapéutico , Trasplante de Islotes Pancreáticos , Ratones Endogámicos NOD , Animales , Terapia Combinada , Quimioterapia Combinada , Femenino , Inmunohistoquímica , Células Secretoras de Insulina/patología , Trasplante de Islotes Pancreáticos/patología , Recuento de Leucocitos , Ratones , Ensayo de Capsula Subrrenal , Trasplante IsogénicoRESUMEN
We sought direct evidence for anti-islet cellular cytotoxicity in diabetic Bio-Breeding/Worcester (BB/W) rats by comparing the effects of splenic lymphoid cells from BB/W diabetic (D), diabetes-prone (DP), and diabetes-resistant (DR) rats on the release of 51Cr from damaged islet cells in vitro. D and DP splenic lymphoid cells were cytotoxic to major histocompatibility complex (MHC)-compatible Wistar-Furth (WF) rat islet cells and also to MHC-incompatible Lewis rat islet cells and a rat islet cell line (RIN 5F), whereas WF and Lewis rat spleen cells and a rat pituitary cell line (GH3) were not lysed by lymphoid cells from D or DP rats. The cytotoxic cells were identified as natural killer (NK) cells since NK-sensitive cells (G1-TC and YAC-1 cell lines) were lysed by D and DP spleen cells, YAC-1 cells competed for the lysis of RIN islet cells by D spleen cells, lysis of RIN cells was increased by using D spleen cells from the low density fraction (large lymphocytes/monocytes) of a Percoll density gradient, and incubation of D spleen cells with an antiserum to NK cells (anti-asialo GM1 serum) and complement decreased monoclonal antibody-defined subsets containing NK cells (W3/13+ OX19- and OX8+), and this was accompanied by similar decreases in cytotoxicity to YAC-1, RIN, and WF islet cells. These studies demonstrate that NK cell activity is increased in BB/W diabetic and DP rats, and that islet cells can serve as targets for these NK cells. The findings suggest that NK cells may participate in the islet-directed cellular cytotoxic response leading to beta cell destruction and diabetes.
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Diabetes Mellitus Experimental/inmunología , Inmunidad Celular , Islotes Pancreáticos/inmunología , Células Asesinas Naturales/inmunología , Animales , Anticuerpos Monoclonales , Enfermedades Autoinmunes/inmunología , Separación Celular , Citotoxicidad Inmunológica , Linfocitos/clasificación , Macrófagos/inmunología , Ratas , Ratas Mutantes , Bazo/inmunologíaRESUMEN
A possible role for cyclic adenosine 3',5'-monophosphate (cAMP) in islet B cell replication was examined in neonatal rat pancreatic monolayer cultures. Islet cells deteriorated and insulin release decreased during 12 d of culture in medium with 5.6 mM glucose, whereas the cells survived and insulin release increased during culture in medium with 5.6 mM glucose plus the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX, 0.1 mM), or in medium with 16.7 mM glucose with or without IBMX. IBMX also increased the mitotic index and stimulated dose-dependent increases in [(3)H]thymidine incorporation in nuclei of islet B cells in aldehydethionine stained radioautographs; maximal stimulation of B cell replication occurred with addition of 0.1 mM IBMX to 5.6 mM glucose (+170%, P < 0.001), and this increase was similar to that observed with 16.7 mM glucose (+185%, P < 0.001). Also, 8-bromo-adenosine-3',5-monophosphate, but not 8-bromo-guanosine-3',5'-monophosphate produced dose-dependent increases in islet B cell replication in medium with 5.6 mM glucose. Measurement of cAMP levels in the cultures revealed dissociations between effects on B cell replication and insulin release. Thus, addition of 0.1 mM IBMX, or 0.1 nM cholera toxin, to 5.6 mM glucose produced slightly greater increases in cAMP levels and B cell replication than did 16.7 mM glucose, whereas insulin release was increased significantly more with 16.7 mM glucose. Also, addition of 0.1 mM IBMX, or 0.1 nM cholera toxin, to 16.7 mM glucose stimulated further increases in cAMP levels and insulin release in the cultures, but no further increases in B cell replication. We conclude that (a) cAMP stimulates islet B cell replication, (b) cAMP may mediate the effects of glucose on B cell replication, and (c) mechanisms regulating B cell replication may be more sensitive to cAMP and/or different from those regulating insulin secretion.
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1-Metil-3-Isobutilxantina/farmacología , AMP Cíclico/farmacología , Islotes Pancreáticos/efectos de los fármacos , Teofilina/análogos & derivados , Animales , División Celular/efectos de los fármacos , Supervivencia Celular , Células Cultivadas , Relación Dosis-Respuesta a Droga , Glucosa/farmacología , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/citología , RatasRESUMEN
The dose as well as the time kinetics of insulin and adenosine-3', 5' -monophosphate (cyclic AMP) responses to glucose were compared in pancreatic islets of fed and starved rats. There was a preferential impairment of the early phase of glucose-induced insulin release in perifused islets of rats starved for 16 and 48 h. Similarly, the accumulation of 3H cyclic AMP in islets prelabeled with 3H-2-adenine was less in islets of 48 h starved than fed rats, during the first 10-min of stimulation with 26.7 mM glucose in the presence of 0.1 mM of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, whereas at 30 and 60 min 3H cyclic AMP responses to glucose were similar in fed and starved islets. Also, in 10-min incubations with glucose 3.3, 6.7, 10.0, 13.3, and 26.7 mM without and with 0.1 mM and 1.0 mM 3-isobutyl-1-methylxanthine, insulin release correlated strongly with the accumulation of 3H cyclic AMP in the islets of fed as well as starved rats. The thresholds for glucose-induced insulin and 3H cyclic AMP responses were higher and the maximal responses were lower in starved than fed islets. Preincubation of islets of 48-h starved rats with 16.7 mM glucose for 60 min corrected the impaired insulin and 3H cyclic AMP responses to glucose. Starvation-induced impairment of insulin secretory responses to glucose, and their restoration by preincubation with glucose in vitro, may represent acute regulatory effects of glucose on the adenylate cyclase-cyclic AMP system in the pancreatic beta cell.
Asunto(s)
AMP Cíclico/metabolismo , Glucosa/farmacología , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Inanición/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Glucosa/administración & dosificación , Técnicas In Vitro , Secreción de Insulina , Masculino , Ratas , Estimulación QuímicaRESUMEN
The purpose of the present study was to evaluate the significance of immunogenetic factors on the survival of pancreatic allografts in beagle dogs. Donors and recipients were leukocyte antigen (DLA)-typed and mixed lymphocyte culture (MLC)-tested. Recipients were made diabetic by total pancreatectomy and immediately implanted intraperitoneally with a vascularized, free-draining (duct unligated) pancreatic segmental (FDPS) allograft. Two groups of dogs were studied. In group I consisting of donor-recipient littermates, recipients were immunosuppressed with prednisone and azathioprine (n = 16 dogs), or not immunosuppressed (n = 4). In group II, recipients were made specifically unresponsive by total body radiation, autologous marrow implantation, and kidney transplantation from DLA-MLC identical donors, 1 yr before FDPS transplantation from the corresponding original kidney donors. Survival of the FDPS grafts in group I was inversely related to pretransplant MLC reactivity, irrespective of DLA genotyped match between donor and recipient. Thus, immunosuppressed high MLC reactors (n = 8) rejected FDPS grafts between 7 and 14 d, whereas immunosuppressed low MLC reactors (n = 8) accepted grafts for 25 to 260+ days, and nonimmunosuppressed low MLC reactors (n = 4) accepted grafts for 9-55 d. Rejection (hyperglycemia) of FDPS grafts was sudden, permanent, and unpredictable despite weekly intravenous glucose tolerance tests with measurements of glucose disappearance rates and serum insulin responses. Nevertheless, serial in vitro cell-mediated lymphocytotoxicity (CML) assays revealed increases in CML before graft rejection in low MLC reactors, and decreases in both CML and MLC responses before graft rejection in high MLC reactors. FDPS graft survival was indefinite (>6 mo) in group II dogs, despite low-grade MLC reactivity (2:4 dogs) and CML responses (4:4 dogs). Biopsies of FDPS grafts at 6 mo in normoglycemic dogs showed disappearance of exocrine tissue and coalescence of islets in both groups I and II, but with less fibrosis in group I (immunosuppressed). These results indicate that (a) pancreatic islets in vascularized grafts (FDPS) may survive indefinitely in the presence of a good tissue match best predicted by MLC testing, (b) tissue specific histocompatibility factors appear to be common enough between kidney and pancreas to allow for long-term survival of both organs transplanted from the same donor, at least in appropriate recipients (group II), and (c) immunosuppression is associated with less fibrosis in FDPS allografts.
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Supervivencia de Injerto , Histocompatibilidad , Trasplante de Páncreas , Animales , Perros , Femenino , Rechazo de Injerto , Antígenos de Histocompatibilidad , Terapia de Inmunosupresión , Islotes Pancreáticos/fisiología , Prueba de Cultivo Mixto de Linfocitos , Masculino , Páncreas/anatomía & histología , Trasplante HomólogoRESUMEN
Because successful allotransplantation of islets of Langerhans isolated by collagenase digestion has been difficult in many animal species, we asked whether isolated islet preparations might have tissue specific determinants conferring amplified immunogenicity in vitro. Lymphocyte proliferative responses ([(3)H]thymidine uptake) were studied in beagle dogs in mixed culture combinations of lymphocyte vs. lymphocyte (MLC) and lymphocyte vs. islet (MLIC). In five MLC responder and five nonresponder pairs, peripheral blood lymphocytes of dogs A and B were used as responding cells, and dog B x-irradiated lymphocytes (Bx), x-irradiated (or nonirradiated) islets (BI), or hepatic cells (BH) were used as stimulating cells in primary and secondary reactions. For the secondary reactions, A + Bx, A + BI, or B + BI were incubated for 9 d (A'B, A'BI, B'BI, respectively) before addition of new stimulating cells. The results showed that islets were autostimulatory, eliciting a tissue-specific lymphoproliferative response in a primary MLIC. Thus, B + BI reactivity was evident at 3,5, and 7 d in primary culture, whereas collagenase-digested liver cells, or lymphocytes obtained from collagenase-digested lymph nodes did not stimulate autologous lymphocytes. A separate reactivity was observed in the allogeneic A + BI combination in MLC responder pairs, and the peak response of A + BI at 9 d was markedly greater than that of B + BI, suggesting the presence of major histocompatibility complex lymphocyte-defined locus determinants in the islet preparations, in addition to islet-specific determinants. A secondary reaction was observed if lymphocytes were primed with islets and challenged with islets (A'BI + BI or B'BI + BI), but not if they were challenged with lymphocytes (A'BI + Bx, B'BI + Bx) or hepatic cells (A'BI + BH, B'BI + AH). Furthermore, priming of lymphocytes with autologous islets (B'BI) led to exclusion of any reactivity against allogeneic lymphocytes, i.e., B'BI suppressed A + Bx, and B'BI also markedly suppressed phytohemagglutinin-stimulated lymphoproliferative responses. Experiments were performed that excluded the possibility that the insulin levels present in the MLIC, the presence of passenger lymphocytes in the islets, or the maintenance of islets in tissue culture for 1-7 d affected the observations. These results provide evidence for the existence of alloantigens as well as tissue-specific antigens on collagenase-isolated islets of Langerhans.
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Islotes Pancreáticos/inmunología , Activación de Linfocitos , Animales , Células Cultivadas , Perros , Glucosa/metabolismo , Tolerancia Inmunológica , Memoria Inmunológica , Insulina/metabolismo , Trasplante de Islotes Pancreáticos , Isoantígenos/análisis , Prueba de Cultivo Mixto de LinfocitosRESUMEN
The dynamics of unidirectionally propagating pulses in a two-dimensional uniform excitable reaction-diffusion medium is investigated. It is shown that under weak diffusion coupling between medium points such a pulse can evolve into a pair of counter-rotating spirals (spiral pair). We analyze the drift of such a pair and examine the collisions between several drifting pairs. It is demonstrated that collisions can result in a special type of reflection or, alternatively, in new types of complex stationary spiral structures. A possible application of these findings for the diagnosis of cardiac arrhythmias is suggested.