Metabolic Connection of Inflammatory Pain: Pivotal Role of a Pyruvate Dehydrogenase Kinase-Pyruvate Dehydrogenase-Lactic Acid Axis.

Pyruvate dehydrogenase kinases (PDK1-4) are mitochondrial metabolic regulators that serve as decision makers via modulation of pyruvate dehydrogenase (PDH) activity to convert pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Metabolic dysregulation and inflammatory processes are two sides of the same coin in several pathophysiological conditions. The lactic acid surge associated with the metabolic shift has been implicated in diverse painful states. In this study, we investigated the role of PDK-PDH-lactic acid axis in the pathogenesis of chronic inflammatory pain. Deficiency of Pdk2 and/or Pdk4 in mice attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivities. Likewise, Pdk2/4 deficiency attenuated the localized lactic acid surge along with hallmarks of peripheral and central inflammation following intraplantar administration of CFA. In vitro studies supported the role of PDK2/4 as promoters of classical proinflammatory activation of macrophages. Moreover, the pharmacological inhibition of PDKs or lactic acid production diminished CFA-induced inflammation and pain hypersensitivities. Thus, a PDK-PDH-lactic acid axis seems to mediate inflammation-driven chronic pain, establishing a connection between metabolism and inflammatory pain. SIGNIFICANCE STATEMENT: The mitochondrial pyruvate dehydrogenase (PDH) kinases (PDKs) and their substrate PDH orchestrate the conversion of pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Lactate, the predominant end product of glycolysis, has recently been identified as a signaling molecule for neuron-glia interactions and neuronal plasticity. Pathological metabolic shift and subsequent lactic acid production are thought to play an important role in diverse painful states; however, their contribution to inflammation-driven pain is still to be comprehended. Here, we report that the PDK-PDH-lactic acid axis constitutes a key component of inflammatory pain pathogenesis. Our findings establish an unanticipated link between metabolism and inflammatory pain. This study unlocks a previously ill-explored research avenue for the metabolic control of inflammatory pain pathogenesis.

Expression of the Nrf2-system at the blood-CSF barrier is modulated by neonatal inflammation and hypoxia-ischemia.

Transcription factor NF-E2-related factor-2 (Nrf2) is a key regulator of endogenous anti-oxidant systems shown to play a neuroprotective role in the adult by preserving blood-brain barrier function. The choroid plexus, site for the blood-CSF barrier, has been suggested to be particularly important in maintaining brain barrier function in development. We investigated the expression of Nrf2- and detoxification-system genes in choroid plexus following systemic LPS injections, unilateral cerebral hypoxia-ischemia (HI) as well as the combination of LPS and HI (LPS/HI). Plexuses were collected at different time points after LPS, HI and LPS/HI in 9-day old mice. mRNA levels of Nrf2 and many of its target genes were analyzed by quantitative PCR. Cell death was analyzed by caspase-3 immunostaining and TUNEL. LPS caused down-regulation of the Nrf2-system genes while HI increased expression at earlier time points. LPS exposure prior to HI prevented many of the HI-induced gene increases. None of the insults resulted in any apparent cell death to choroidal epithelium. These data imply that the function of the inducible anti-oxidant system in the choroid plexus is down-regulated by inflammation, even if choroid cells are not structurally damaged. Further, LPS prevented the endogenous antioxidant response following HI, suggesting the possibility that the choroid plexus may be at risk if LPS is united with an insult that increases oxidative stress such as hypoxia-ischemia.

Laboratory medicine in neonatal sepsis and inflammation.

The high incidence of neonatal sepsis worldwide and the considerably high mortality rate of severe sepsis and septic shock call for an earlier diagnosis and more accurate monitoring of the disease. Conventional laboratory tests, such as white blood cell count (WBC) and differential count, micro-erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have a number of limitations associated with their limited sensitivity in the early phase of the disease and their non-specific increase in the course of various severe neonatal clinical conditions like asphyxia, meconium aspiration and prolonged rupture of membranes. Next-generation biomarkers encompass new molecular tests, accurate measurement of the proteins and enzymes mainly involved in the innate immunity biochemical pathways, application of proteomics and metabolomics for risk stratification and prognosis, and the clinical use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the identification of various bacteria and yeasts. The availability of sophisticated biochemical and molecular tests and of innovative technologies can significantly improve baby outcomes in terms of earlier and more accurate diagnosis, tailored therapeutic treatment, shorter hospitalization and thus minimized complications, and ultimately can prevent and monitor nosocomial and healthcare-associated infections. As a consequence, costs can be significantly reduced over a full cycle of care by investing in high quality laboratory medicine.

Epidural analgesia and maternal fever: a clinical and research update.

PURPOSE OF REVIEW: Maternal fever following epidural analgesia complicates up to one-third of nulliparous labors. Although generally benign, maternal fever is associated with both excess healthcare costs and an increased risk of adverse maternal and neonatal outcomes; therefore, this topic is of interest to anesthesiologists, obstetricians and pediatricians alike. The purpose of this review is to examine the latest research on the topic of epidural-related maternal fever, with special focus on the clinical relevance of new information. RECENT FINDINGS: Research over the past 18 months has increased our understanding of the cause of epidural-related fever and brought additional supportive evidence that proactive labor management may decrease risk. Additionally, there were innovative investigations of potential pharmacologic interventions to reduce maternal, and potentially fetal, risk. SUMMARY: Significant research advances were made in the last 18 months around the topic of epidural-related fever, but major gaps in knowledge persist especially with understanding the precise mechanism. The most pressing area of research is the development of well tolerated and effective prophylactic interventions to prevent maternal and fetal exposure to hyperthermia and inflammation.

Leptin and interleukin-6 alter the function of mesolimbic dopamine neurons in a rodent model of prenatal inflammation.

Maternal inflammation during critical stages of gestation is thought to underlie the link between prenatal infection and several neurodevelopmental psychiatric disorders in the offspring, including schizophrenia. Increased activity of mesolimbic dopamine (DA) neurons, a hallmark of psychosis, is found in offspring of rodents exposed to a prenatal inflammatory challenge but it is unclear how this effect is elicited. Using an experimental model of localized aseptic inflammation with turpentine oil (TURP) we sought to establish whether circulating interleukin-6 (IL-6) and leptin play a role in the effects of prenatal inflammation on DA neurons. Both mediators are involved in the systemic inflammatory response to immunogens, with IL-6 mediating the early phase, followed by leptin in the late phase of the response. Maternal treatment with TURP at gestational day (GD) 15 enhanced the locomotor response to the DA indirect agonist, amphetamine (AMPH), increased the expression of tyrosine hydroxylase (TH), an enzyme involved in DA synthesis, DA levels and the expression of the post-synaptic protein spinophilin in the nucleus accumbens (NAcc) in the adult offspring. All of these alterations were totally abolished by co-treating the pregnant dams with a neutralizing IL-6 antiserum. Neutralization of maternal leptin prevented the enhanced behavioral sensitization and elevation of DA and spinophilin in the NAcc but spared other changes regulated by IL-6, such as increased NAcc TH levels and acute locomotor response to AMPH. Our results provide novel evidence to suggest that prenatal surges in both maternal circulating IL-6 and leptin contribute to the appearance of sensitized DA function in the adult offspring.

Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune nonobese diabetic mice: cellular and molecular characterization of tertiary lymphoid structures in pancreatic islets.

A pivotal role for tertiary lymphoid structures (TLSs) in promoting Ag-specific humoral responses during chronic inflammation is emerging in several autoimmune conditions, including rheumatoid arthritis, Sjogren's syndrome, and autoimmune thyroiditis. However, there is limited evidence on the cellular and molecular mechanisms underlying TLS formation and their contribution to autoimmunity in the pancreas during autoimmune insulitis. In this study, we performed a detailed and comprehensive assessment of the evolution of TLSs during autoimmune insulitis in 126 female NOD mice from 4 to 38 wk of age. We demonstrated that during progression from peri- to intrainsulitis in early diabetic mice, T and B cell infiltration follows a highly regulated process with the formation of lymphoid aggregates characterized by T/B cell segregation, follicular dendritic cell networks, and differentiation of germinal center B cells. This process is preceded by local upregulation of lymphotoxins alpha/beta and lymphoid chemokines CXCL13 and CCL19, and is associated with infiltration of B220(+)/IgD(+)/CD23(+)/CD21(-) follicular B cells expressing CXCR5. Despite a similar incidence of insulitis, late diabetic mice displayed a significantly reduced incidence of fully organized TLSs and reduced levels of lymphotoxins/lymphoid chemokines. Upon development, TLSs were fully functional in supporting in situ autoreactive B cell differentiation, as demonstrated by the expression of activation-induced cytidine deaminase, the enzyme required for Ig affinity maturation and class switching, and the presence of CD138(+) plasma cells displaying anti-insulin reactivity. Overall, our work provides direct evidence that TLSs are of critical relevance in promoting autoimmunity and chronic inflammation during autoimmune insulitis and diabetes in NOD mice.

Immaturity, perinatal inflammation, and retinopathy of prematurity: a multi-hit hypothesis.

OBJECTIVE: To explore the relationship among markers of infection/inflammation in their association with retinopathy of prematurity (ROP). METHODS: We studied clinical characteristics and 4 single nucleotide polymorphisms in infection/inflammation-associated genes in a group of 73 children with a gestational age<32 weeks. Forty-four children (60%) had ROP, of whom 13 (30% of those with ROP) progressed to stage 3 ROP. No child had grade 4 or 5 ROP. We employed both descriptive and analytic statistical methods. RESULTS: Clinical variables of infection/inflammation were consistently associated with an increased risk of ROP. Among infants with ROP, they were also associated with progression to ROP grade 3. Genetic markers were not associated with ROP occurrence, but with progression to high grade disease. In tri-variable analyses exploring the effects of gestational age <29 weeks, clinical chorioamnionitis (CAM) and neonatal systemic inflammatory response syndrome (SIRS) on ROP occurrence, low gestational age was the most important antecedent, while additional individual or joint exposure to SIRS and CAM add appreciably to this risk of progression to high grade disease. CONCLUSION: Both antenatal and neonatal exposure to inflammation appear to contribute to the increased ROP risk in preterm infants.

Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes.

Chronic infantile neurological cutaneous and articular (CINCA) syndrome is a severe chronic inflammatory disease of early onset, characterized by cutaneous symptoms, central-nervous-system involvement, and arthropathy. In the present study, we report, in seven unrelated patients with CINCA syndrome, distinct missense mutations within the nucleotide-binding site of CIAS1, a gene encoding cryopyrin and previously shown to cause Muckle-Wells syndrome and familial cold urticaria. Because of the severe cartilage overgrowth observed in some patients with CINCA syndrome and the implications of polymorphonuclear cell infiltration in the cutaneous and neurological manifestations of this syndrome, the tissue-specific expression of CIAS1 was evaluated. A high level of expression of CIAS1 was found to be restricted to polymorphonuclear cells and chondrocytes. These findings demonstrate that CIAS1 missense mutations can result in distinct phenotypes with only a few overlapping symptoms and suggest that this gene may function as a potential inducer of apoptosis.

MEDICACION CON PRODUCTOS NATURALES EN INFLAMACIONES PULPARES

Las soluciones farmacéuticas demostraron su potencia farmacológica (acción analgésica-antiinflamatoria) demostraron su rapidez de acción que fueron comprobados clínicamente, por la inmediata mejoría clínica con supresión del dolor y el proceso inflamatorio. Las soluciones farmacéuticas naturales, tiene una activa y segura respuesta terapéutica y son preferentemente toleradas por los pacientes. La dosificación es aceptable, sin producir efectos colaterales ni tóxicos en la pulpa inflamada. El costo en la preparación de estas soluciones farmacéuticas naturales es accesible a nuestra realidad. Puede ser patentada e incorporada al uso diario odontológico de nuestra clínica como terapéutica(dirigida y/o específica)

[Severe, refractory neonatal inflammatory syndrome as the manifestation of a systemic multivisceral and meningeal syndrome]. / Syndrome inflammatoire néonatal grave, rebelle, d'expression systémique multiviscérale et méningée.

A neonate presented with an inflammatory syndrome with multisystemic manifestations. There was no remission until age 6 years, despite anti-inflammatory treatments. Neonatal onset and neuromeningeal manifestations identified a peculiar rare inflammatory syndrome, whose relationship with juvenile rheumatoid arthritis is discussed. In the case reported, renal, abdominal, deep lymphatic and cranial involvements were present: these have not been previously reported.

Congenital diarrhea with intestinal inflammation and epithelial immaturity.

We report an interesting case of congenital inflammatory bowel disease and intestinal epithelial immaturity that presented as secretory diarrhea. No infectious, metabolic, or anatomical basis for these findings was identified. As differentiated from previous reports of neonatal enteropathies, this infant demonstrated involvement of both the small and large intestine with histopathologic findings of acute and chronic inflammation, extensive submucosal fibrosis, and "flat" small intestine mucosa. In addition, this patient had a polyamine deficiency (a primary or secondary phenomenon), which may have contributed to delayed epithelial maturation. These findings suggest that the inflammatory bowel disease and altered epithelial maturation contributed to a fatal intractable diarrhea.

Cranial fasciitis of childhood.

Nine cases of fibroblastic lesions occurring in the cranium of young children were reviewed. The age of the patients at the time of initial treatment ranged from three weeks to six years (median 18 months), with the lesions being congenital in two cases. There was 2:1 male predominance. The size of the lesions averaged 2.5 cm in greatest dimension with the largest being 9.0 cm. All cases presented as rapidly growing masses with a preoperative duration of only two months. The lesions presented as soft-tissue masses deep in the scalp with involvement of the underlying cranium in all eight of the cases in which roentgenograms or operative reports were available for review. Characteristically, there was erosion of only the outer table of the skull, although in three cases the lesion extended through the inner table to attach to the underlying dura mater. It was not possible to detect the exact site or origin, although origin from one of the deep fascial layers of the scalp or the underlying periosteum seems most likely. Microscopically, the lesion appeared to be a proliferation of loosely arranged fibroblasts which most closely resembled nodular fasciitis. Mitotic figures as well as foci of osseous metaplasia were present. Treatment consisted of excision of the mass with local resection or curettage of the affected underlying bone in some cases. Followup revealed a benign clinical course with no recurrent or aggressive behavior.