RESUMEN
Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.
Asunto(s)
Lesiones Encefálicas/fisiopatología , Enfermedades Neurodegenerativas/fisiopatología , Accidente Cerebrovascular/fisiopatología , Factor de Necrosis Tumoral alfa/fisiología , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/terapia , Antiinflamatorios no Esteroideos/uso terapéutico , Encéfalo/fisiopatología , Lesiones Encefálicas/diagnóstico , Lesiones Encefálicas/terapia , COVID-19/diagnóstico , COVID-19/fisiopatología , COVID-19/terapia , Progresión de la Enfermedad , Etanercept/uso terapéutico , Paro Cardíaco/diagnóstico , Paro Cardíaco/fisiopatología , Paro Cardíaco/terapia , Humanos , Locus Coeruleus/fisiopatología , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/terapia , Norepinefrina/fisiología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Factores de Riesgo , SARS-CoV-2 , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapia , Sobrevivientes , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Introduction: The importance of excessive cerebral tumor necrosis factor (TNF) concentrations as one of the central tenets of the pathogenesis of the neurodegenerative diseases is now widely known, but variably accepted. Areas covered: Here we update the field by including material that is freely available on the large databases, particularly PubMed. We include the therapeutic outcomes with etanercept (a widely used specific anti-TNF biological), XPro1595 (a new double negative TNF inhibitor), 3,61-dithiothalidomide, implanted SB623 stem cells, maraviroc (a CCR5 inhibitor used to treat AIDS), MCC950 (an NLRP3 inhibitor), and changes in the hormone irisin. Expert opinion: Remarkably, considering the ample literature that links SB623 cells, maraviroc, MCC950 and irisin to TNF, these publications do not mention this cytokine, and therefore not their implicit involvement with controlling its cerebral levels. With regard to developments demonstrated by MCC950, we note that DAMPs and PAMPs recognize and activate both TLRs and inflammasomes in these disease states. Here, as in other illnesses, data suggests that preventing a pathogenic interaction could be achieved through shutting down either of these arms of innate immunity.
Asunto(s)
Fibronectinas , Compuestos Heterocíclicos de 4 o más Anillos , Maraviroc , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/cirugía , Trasplante de Células Madre , Sulfonas , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Animales , Furanos , Humanos , Indenos , SulfonamidasRESUMEN
While cytokines such as TNF have long been recognized as essential to normal cerebral physiology, the implications of their chronic excessive production within the brain are now also increasingly appreciated. Syndromes as diverse as malaria and lead poisoning, as well as non-infectious neurodegenerative diseases, illustrate this. These cytokines also orchestrate changes in tau, α-synuclein, amyloid-ß levels and degree of insulin resistance in most neurodegenerative states. New data on the effects of salbutamol, an indirect anti-TNF agent, on α-synuclein and Parkinson's disease, APOE4 and tau add considerably to the rationale of the anti-TNF approach to understanding, and treating, these diseases. Therapeutic advances being tested, and arguably useful for a number of the neurodegenerative diseases, include a reduction of excess cerebral TNF, whether directly, with a specific anti-TNF biological agent such as etanercept via Batson's plexus, or indirectly via surgically implanting stem cells. Inhaled salbutamol also warrants investigating further across the neurodegenerative disease spectrum. It is now timely to integrate this range of new information across the neurodegenerative disease spectrum, rather than keep seeing it through the lens of individual disease states.
Asunto(s)
Enfermedades Neurodegenerativas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Apolipoproteínas E/metabolismo , Humanos , Resistencia a la Insulina , Fosforilación , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismoRESUMEN
BACKGROUND: A hallmark symptom after psychological trauma is the presence of intrusive memories. It is unclear why only some moments of trauma become intrusive, and how these memories involuntarily return to mind. Understanding the neural mechanisms involved in the encoding and involuntary recall of intrusive memories may elucidate these questions. METHOD: Participants (n = 35) underwent functional magnetic resonance imaging (fMRI) while being exposed to traumatic film footage. After film viewing, participants indicated within the scanner, while undergoing fMRI, if they experienced an intrusive memory of the film. Further intrusive memories in daily life were recorded for 7 days. After 7 days, participants completed a recognition memory test. Intrusive memory encoding was captured by comparing activity at the time of viewing 'Intrusive scenes' (scenes recalled involuntarily), 'Control scenes' (scenes never recalled involuntarily) and 'Potential scenes' (scenes recalled involuntarily by others but not that individual). Signal change associated with intrusive memory involuntary recall was modelled using finite impulse response basis functions. RESULTS: We found a widespread pattern of increased activation for Intrusive v. both Potential and Control scenes at encoding. The left inferior frontal gyrus and middle temporal gyrus showed increased activity in Intrusive scenes compared with Potential scenes, but not in Intrusive scenes compared with Control scenes. This pattern of activation persisted when taking recognition memory performance into account. Intrusive memory involuntary recall was characterized by activity in frontal regions, notably the left inferior frontal gyrus. CONCLUSIONS: The left inferior frontal gyrus may be implicated in both the encoding and involuntary recall of intrusive memories.
Asunto(s)
Memoria Episódica , Recuerdo Mental , Corteza Prefrontal/fisiopatología , Trauma Psicológico/fisiopatología , Lóbulo Temporal/fisiopatología , Adolescente , Adulto , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos por Estrés Postraumático/psicología , Reino Unido , Adulto JovenRESUMEN
This review concerns how the primary inflammation preceding the generation of certain key damage-associated molecular patterns (DAMPs) arises in Alzheimer's disease (AD). In doing so, it places soluble amyloid ß (Aß), a protein hitherto considered as a primary initiator of AD, in a novel perspective. We note here that increased soluble Aß is one of the proinflammatory cytokine-induced DAMPs recognized by at least one of the toll-like receptors on and in various cell types. Moreover, Aß is best regarded as belonging to a class of DAMPs, as do the S100 proteins and HMBG1, that further exacerbate production of these same proinflammatory cytokines, which are already enhanced, and induces them further. Moreover, variation in levels of other DAMPs of this same class in AD may explain why normal elderly patients can exhibit high Aß plaque levels, and why removing Aß or its plaque does not retard disease progression. It may also explain why mouse transgenic models, having been designed to generate high Aß, can be treated successfully by this approach.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Animales , Humanos , Ácido Láctico , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismoRESUMEN
Persistent and severe fatigue is a common part of the presentation of a diverse range of disease processes. There is a growing body of evidence indicating a common inflammatory pathophysiology underlying many conditions where fatigue is a primary patient concern, including chronic fatigue syndrome. This review explores current models of how inflammatory mediators act on the central nervous system to produce fatigue and sickness behaviour, and the commonality of these processes in conditions as diverse as surgical trauma, infection, various cancers, inflammatory bowel disease, connective tissue diseases and autoimmune diseases. We also discuss evidence indicating chronic fatigue syndrome may have important pathophysiological similarities with cytokine mediated sickness behaviour, and what lessons can be applied from sickness behaviour to chronic fatigue syndrome with regards to the diagnosis and management.
Asunto(s)
Citocinas/fisiología , Fatiga , Conducta de Enfermedad/fisiología , Mediadores de Inflamación/fisiología , Enfermedades Autoinmunes/complicaciones , Fatiga/diagnóstico , Fatiga/inmunología , Fatiga/fisiopatología , Síndrome de Fatiga Crónica/diagnóstico , Síndrome de Fatiga Crónica/inmunología , Síndrome de Fatiga Crónica/fisiopatología , HumanosRESUMEN
The aetiological and pathophysiological basis of chronic fatigue syndrome (CFS) remains a controversial field of inquiry in the research community. While CFS and similar disease conditions such as fibromyalgia (FM) and post-infectious encephalopathy have been the focus of intense scrutiny for the past 20 years, results of research were often contradictory and a cohesive pathological model has remained elusive. However, recent developments in understanding the unique immunophysiology of the brain may provide important clues for the development of a truly comprehensive explanation of the pathology of CFS. We argue that CFS pathogenesis lies in the influence of peripheral inflammatory events on the brain and the unique immunophysiology of the central nervous system. There is also evidence that CFS patients have a relative immunodeficiency that predisposes to poor early control of infection that leads to chronic inflammatory responses to infectious insults. The neurological and endocrine changes have been described in CFS patients support the view that CFS has an inflammatory pathogenesis when considered as a whole. An inflammatory model of disease also provides an explanation for the marked female sex bias associated with CFS. This review therefore posits the hypothesis that CFS as a disease of long-term inflammatory processes of the brain. We will also provide an investigative framework that could be used to justify the use of anti-TNF biological agents as a reliable and effective treatment approach to CFS, a syndrome that to date remains frustratingly difficult for both patients and health care professionals to manage.
Asunto(s)
Sistema Nervioso Central/fisiopatología , Síndrome de Fatiga Crónica/inmunología , Modelos Biológicos , Síndrome de Fatiga Crónica/fisiopatología , HumanosRESUMEN
This is a personal account of how tumour necrosis factor (TNF) the prototype of a group of host-origin mediators, often known as pro-inflammatory cytokines, came into parasitology, and was subsequently realised to be central to the pathogenesis of most disease pathology. This contribution summarizes an example of how a curiosity-driven outsider, with initially no intention of heading this way, and no relevant experience, and with no more than the simplest of plans but an ambition to read as widely as it takes, and (most importantly) allowed to follow his head, can be what is required to give fresh insight into understanding a disease. It also gives the author's views on aspects of how the field of malaria disease pathogenesis seems to be developing. The hope is to inspire another generation to follow a similarly original course.
Asunto(s)
Eritrocitos/parasitología , Interacciones Huésped-Parásitos , Malaria Cerebral/fisiopatología , Plasmodium falciparum , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Interacciones Huésped-Parásitos/inmunología , Malaria Cerebral/inmunología , Malaria Cerebral/parasitología , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Malaria Falciparum/fisiopatología , Plasmodium falciparum/inmunología , Plasmodium falciparum/patogenicidad , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
High mobility group box 1 (HMGB1) protein, a DNA-binding protein that can also act as a pro-inflammatory cytokine if released from cells, is an important amplification signal in various forms of inflammation. The concentration of HMGB1 in serum taken at admission was increased in falciparum malaria in sixteen African children, more so in fatal cases than in those who subsequently recovered (P<0.001). Serum from both non-fatal (P=0.0048) and fatal (P<0.001) cases contained significantly more circulating HMGB1 than did serum from healthy Caucasian adults. These data provide an additional argument that malaria is fundamentally a systemic inflammatory state. In keeping with its developing role in sepsis, HMGB1 may enhance and prolong the inflammatory processes, and thus illness, in malaria.
Asunto(s)
Proteína HMGB1/sangre , Malaria Cerebral/sangre , Malaria Falciparum/sangre , Transducción de Señal/fisiología , Niño , Preescolar , Femenino , Humanos , Lactante , Inflamación/sangre , Malaria Cerebral/etiología , Malaria Cerebral/mortalidad , Malaria Falciparum/etiología , Malaria Falciparum/mortalidad , MasculinoRESUMEN
Heterologous immunity, or protection by one invading organism against another across phylogenetic divides, has been recognised for decades. It was initially thought to operate largely through enhancement of phagocytosis, but this explanation became untenable when it was realised it worked extremely well against intraerythrocytic protozoa and killed them while they were free in the circulation. Clearly a soluble mediator was called for. This review summarises the logic that arose from this observation, which led to a wider appreciation of the roles of pro-inflammatory cytokines, and then nitric oxide, in the host's response against invaders, as well as the ability of these mediators to harm the host itself if they are generated too enthusiastically. This has led to a discernable pattern across heterologous immunity as a whole, and its lessons influence a range of areas, including vaccine development.
Asunto(s)
Citocinas/inmunología , Malaria Falciparum/inmunología , Óxido Nítrico/inmunología , Plasmodium falciparum/inmunología , Animales , Babesia/inmunología , Babesiosis/complicaciones , Babesiosis/inmunología , Citocinas/biosíntesis , Humanos , Malaria Falciparum/complicaciones , Malaria Falciparum/parasitología , Óxido Nítrico/biosíntesis , Vacunas Antiprotozoos , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
As the mortality rate of 20-30% for severe falciparum malaria under even the best clinical conditions testifies, access to antimalarial drugs is not sufficient to prevent an appreciable mortality from this disease. Understanding the cause of death at a cellular level is essential if additional rational treatments are to be developed. Here, Ian Clark and Louis Schofield discuss recent work presented at the Molecular Approaches to Malaria conference, Lorne, Australia, 2-5 February 2000, that updates the cytokine-based concept of malarial disease.
Asunto(s)
Citocinas/fisiología , Malaria Cerebral/inmunología , Malaria Cerebral/fisiopatología , Malaria Falciparum/inmunología , Malaria Falciparum/fisiopatología , Adulto , Animales , Niño , Glicosilfosfatidilinositoles/fisiología , Humanos , Óxido Nítrico/metabolismo , Plasmodium falciparum/inmunologíaRESUMEN
Here, Ian Clark and Bill Cowden summarize new evidence suggesting that nitric oxide (NO) generated by inducible NO synthase (iNOS) provides a functional link between the previously competing approaches to malarial disease pathogenesis: ischaemic hypoxia and NO. When combined with the newly recognized roles of iNOS in renal and pulmonary function and glucose metabolism, synergy between inflammatory cytokines and hypoxia in iNOS induction provides a framework to help explain, at a molecular level, the differences in the pathology seen in falciparum and vivax malaria. Thus sequestration, through localized hypoxia, might contribute to pathology by enhancing cytokine-induced iNOS. Generalized hypoxia might have the same effect.
Asunto(s)
Malaria Falciparum/fisiopatología , Malaria Vivax/fisiopatología , Óxido Nítrico/biosíntesis , Plasmodium falciparum/patogenicidad , Plasmodium vivax/patogenicidad , Animales , Citocinas/inmunología , Glucólisis , Humanos , Hipoxia/fisiopatología , Malaria Cerebral/etiología , Malaria Cerebral/fisiopatología , Malaria Falciparum/complicaciones , Malaria Falciparum/enzimología , Malaria Vivax/complicaciones , Malaria Vivax/inmunología , Óxido Nítrico/inmunología , Óxido Nítrico Sintasa/inmunología , Óxido Nítrico Sintasa de Tipo II , Edema Pulmonar/parasitología , Edema Pulmonar/fisiopatología , Insuficiencia Renal/parasitología , Insuficiencia Renal/fisiopatología , VirulenciaRESUMEN
CD4+ T cells have been implicated in immunity to the blood stages of malaria and cytokines associated with both monocyte and T cell activation have been implicated in disease. To determine whether specific T cells capable of inhibiting parasite growth can also mediate pathology we have transfused populations of Plasmodium berghei-specific T cells into normal and immunodeficient naive mice. We observed that they could inhibit parasite growth but were unable to save the animals which exhibited significantly greater anaemia and weight loss than control infected animals receiving either no T cells or T cells specific for ovalbumin. T cell-dependent tomour necrosis factor (TNF)alpha was a critical component in both parasite killing and disease promotion. Experiments with blocking antibodies demonstrated that all T-cell mediated antiparasitic immunity and all T-cell mediated weight loss was TNF-dependent. Blocking TNF-alpha in mice that received parasite-specific T cells prolonged the survival of the mice. Nitric oxide demonstrated no antiparasite effect, but was involved in the regulation of T-cell mediated weight loss. The data thus show that while parasite-specific CD4+ T cells can significantly limit parasite growth, such an effect need not be beneficial to the host, and that TNF-alpha and nitric oxide are critical effector molecules operating downstream of parasite-specific T cells in both immunity and disease.
Asunto(s)
Malaria/inmunología , Parasitemia/inmunología , Plasmodium berghei/inmunología , Linfocitos T/inmunología , Células TH1/inmunología , Animales , Citocinas/biosíntesis , Femenino , Citometría de Flujo , Activación de Linfocitos , Malaria/parasitología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratones SCID , Óxido Nítrico/metabolismo , Parasitemia/parasitología , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Serum levels of reactive nitrogen intermediates (RNI; nitrate + nitrite), interferon gamma (IFN gamma) and tumour necrosis factor (TNF) were measured in 177 Papua New Guinean children with different clinical manifestations of malaria. The groups investigated were asymptomatic parasitaemic, mild malaria, cerebral malaria survivors and cerebral malaria non-survivors. The levels of TNF were highest among the cases of cerebral malaria who died and lowest among the asymptomatic parasitaemic children (mean log TNF levels 2.183 pg/mL vs. 1.455 pg/mL; P = 0.001). Similarly, the levels of IFN gamma were highest among the cerebral and lowest among the asymptomatic patients (mean log TNF levels 0.338 pg/mL vs 0.054 pg/mL; P < 0.0001). RNI levels were high among both the asymptomatic parasitaemic group and those who died due to cerebral malaria (mean log RNI levels 1.56 microM vs. 1.412 microM; P = 0.18). The ratio of RNI to TNF, however, was significantly higher among the asymptomatic parasitaemic children and lowest among those who died due to cerebral malaria (mean log (RNI:TNF) ratio 0.118 vs. -0.789; P < 0.001). We concluded that the ratio of serum RNI to serum TNF is a more useful indicator of outcome of falciparum malaria in this population than the absolute levels of either alone.
Asunto(s)
Interferón gamma/sangre , Malaria Falciparum/diagnóstico , Óxido Nítrico/sangre , Factor de Necrosis Tumoral alfa/análisis , Biomarcadores/sangre , Preescolar , Femenino , Humanos , Masculino , Papúa Nueva Guinea , PronósticoRESUMEN
Clinical Confusion between human babesiosis and malaria is often reported in the literature. Headache, fever, chills, nausea, vomiting, myalgia, altered mental status, disseminated intravascular coagulation, anaemia with dyserythropoiesis, hypotension, respiratory distress, and renal insufficiency are common to both diseases. This remarkable similarity is not restricted to the human host. In the mouse, for example, the histological changes wrought by fatal malaria (Plasmodium vinckei) and babesiosis (Babesia rhodaini) are identical, and parasites of both genera cross-protect. Malarial disease pathogenesis is now generally associated with excessive production of pro-inflammatory cytokines , such as tumour necrosis factor. While this concept has not yet been examined in babesiosis, indirect evidence arises from noting the parasite density at which illness occurs in primary infections caused by either organism. Naive mice tolerate high loads of malarial or babesial parasites before they become ill, and are also tolerant to endotoxicity, which is mediated by these same cytokines. In contrast, humans require very much smaller loads of Plasmodium or Babesia spp. before becoming ill, and likewise are very sensitive to endotoxin, the harmful effects of which are mediated by the pro-inflammatory cytokines. For these reasons, as discussed in this review, the diseases caused by these two genera of intra-erythrocytic protozoan parasites will probably prove to be conceptually identical.
Asunto(s)
Babesiosis/parasitología , Malaria/parasitología , Animales , Babesiosis/sangre , Babesiosis/complicaciones , Citocinas/metabolismo , Enfermedades de los Perros/sangre , Perros , Humanos , Tolerancia Inmunológica , Malaria/sangre , Malaria/complicaciones , Ratones , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In this review we summarise the arguments that inflammatory cytokines, triggered by material released from the parasite at schizogony (malarial toxin), might induce the illness and pathology seen in malaria. These pro-inflammatory cytokines can generate inducible nitric oxide synthase and cause nitric oxide to be released, as can low concentrations of malarial toxin itself provided interferon-gamma, which has only low activity in the absence of malarial toxin, is present. We suggest here that recently described hypermetabolic functions of these mediators provide a much more plausible explanation for malarial hyperlactataemia and hypoglycaemia, the chief prognostic indicators in falciparum malaria, than does hypoxia secondary to mechanical blockage of vessels by sequestering parasites, which is the dominant current theory. We also review the arguments that rationalise, through these mediators, the reversibility of the coma of cerebral malaria. Although not yet tested at a cellular level, the proposal that nitric oxide generated in cerebral vascular walls contributes to this coma continues to gather indirect support. In addition, new evidence incriminating nitric oxide in the mechanism of tolerance to endotoxin rationalises the raised nitric oxide generation seen in malarial tolerance.
Asunto(s)
Malaria/etiología , Animales , Metabolismo de los Hidratos de Carbono , Citocinas/fisiología , Humanos , Hipoglucemia/etiología , Tolerancia Inmunológica , Mediadores de Inflamación/fisiología , Ácido Láctico/sangre , Malaria/inmunología , Malaria/fisiopatología , Malaria Cerebral/etiología , Óxido Nítrico/fisiologíaRESUMEN
Serum from 41 of 92 children admitted to Madang Hospital, Papua New Guinea, with cerebral malaria, previously assessed for serum levels of reactive nitrogen intermediates (RNI: nitrate plus nitrite), were re-assessed for creatinine levels on the day of admission. Further analysis of RNI levels on day 21 compared to day 0 was carried out. Children with the highest RNI levels on admission, and with the longest duration of coma, did not have elevated creatinine levels. The highest levels of creatinine occurred among those with the lightest coma and creatinine levels were similar in those with short (< 48 h) and long (> 48 h) duration of coma. Between days 0 and 21, RNI decreased in 30 of 57 children, increased in 23, and did not change in 4. There was a significant relationship between the decrease in RNI relative to the level of RNI on admission and the duration of coma. For children with a coma duration < 48 h (48/57), there was no difference between the numbers showing an increase or a decrease in RNI level, but 6 of the 9 children with coma duration > 48 h showed a decrease in RNI greater than 50% of the RNI levels on admission. None of these 9 children had elevated creatinine levels. Elevated RNI levels in severe cases were thus not associated with renal function in these children in Papua New Guinea.