RESUMEN
BACKGROUND: Coronavirus disease 19 (COVID-19) is the disease caused by SARS-CoV-2, a highly infectious member of the coronavirus family, which emerged in December 2019 in "Wuhan, China". It induces respiratory illness ranging from mild symptoms to severe disease. It was declared a "pandemic" by the World Health Organization (WHO) in March 2020. Since then, a vast number of clinical and experimental studies have been conducted to identify effective approaches for its prevention and treatment. MAIN BODY: The pathophysiology of COVID-19 represents an unprecedented challenge; it triggers a strong immune response, which may be exacerbated by "a cytokine storm syndrome". It also induces thrombogenesis and may trigger multi-organ injury. Therefore, different drug classes have been proposed for its treatment and prevention, such as antivirals, anti-SARS-CoV-2 antibody agents (monoclonal antibodies, convalescent plasma, and immunoglobulins), anti-inflammatory drugs, immunomodulators, and anticoagulant drugs. To the best of our knowledge, this review is the first to present, discuss, and summarize the current knowledge about the different drug classes used for the treatment of COVID-19, with special emphasis on their targets, mechanisms of action, and important adverse effects and drug interactions. Additionally, we spotlight the latest "October 2023" important guidelines (NIH, IDSA, and NICE) and FDA approval or authorization regarding the use of these agents in the management of COVID-19. CONCLUSION: Despite the wide array of therapeutic strategies introduced for the treatment of COVID-19, one of the most prominent therapeutic challenges is SARS-CoV-2 mutations and emerging new variants and subvariants. Currently, the anti-COVID-19 drug pipeline is continuously affording novel treatments to face this growing challenge.
Asunto(s)
Antivirales , COVID-19 , Humanos , Antivirales/uso terapéutico , Antivirales/farmacología , SARS-CoV-2 , Anticuerpos Antivirales , Anticuerpos MonoclonalesRESUMEN
Chemotherapy-induced cognitive impairment (CICI) is a general term describing cognitive dysfunction during/after treatment with chemotherapeutic agents. CICI represents a significant medical problem due to its increasing prevalence with the lack of robust therapeutic approaches. This study aimed at investigating the effects of chronic treatment with amisulpride (5 mg/kg/day) in the management of 5-fluorouracil (5-FU)-induced cognitive deficits in Wistar rats. Rats received 5 intraperitoneal injections of 5-FU (25 mg/kg every 3 days). 5-FU treatment induced impairments in spatial learning (reduction in object location discrimination ratio) and non-spatial learning (reduction in novel object recognition discrimination ratio). Moreover, 5-FU induced a decrease in the activity of the Wnt/GSK-3ß/ß-catenin pathway with a decrease in brain-derived neurotrophic factor (BDNF) level in the hippocampus. These changes were associated with an increase in the expression of the pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), in hippocampal tissue sections accompanied by a decrease in the number of Ki-67 positive cells (indicating a decrease in proliferative capacity), a decrease in the Nissl's granules optical density (denoting neurodegeneration), a decrease in the number of viable intact neurons with an increase in the expression of ß-amyloid and caspase-3. Amisulpride enhanced Wnt/GSK-3ß/ß-catenin signaling, increased BDNF levels, and abrogated 5-FU-induced neuroinflammation, apoptosis, ß-amyloid accumulation, and neurodegenerative changes with an improvement of cognitive performance. This study draws attention to the pro-cognitive effects of amisulpride in 5-FU-exposed rats that could be attributed to enhancing hippocampal Wnt/GSK-3ß/ß-catenin signaling pathway, and this could offer a promising therapeutic option for subjects with CICI.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Disfunción Cognitiva , Humanos , Ratas , Animales , Ratas Wistar , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Amisulprida/farmacología , Fluorouracilo/farmacología , beta Catenina/metabolismo , Vía de Señalización Wnt , Hipocampo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , CogniciónRESUMEN
Repaglinide, a meglitinide insulinotropic antidiabetic, was unraveled as a promising therapeutic agent for Huntington's disease by targeting the neuronal calcium sensor downstream regulatory element antagonist modulator (DREAM). However, its mechanistic profile in Parkinson's disease (PD) especially its impact on endoplasmic reticulum (ER) stress, mitophagy, and their interconnections is poorly elucidated. This study is the first to examine the neuroprotective potential of repaglinide in rotenone-induced PD in rats by exploring its effects on DREAM, BiP/ATF6/CHOP ER stress pathway, apoptosis, mitophagy/autophagy, oxidative stress, astrogliosis/microgliosis, and neuroinflammation. Male Wistar rats were randomly assigned to four groups: groups 1 and 2 received the vehicle or repaglinide (0.5 mg/kg/day p.o). Groups 3 and 4 received rotenone (1.5 mg/kg/48 h s.c) for 21 days; meanwhile, group 4 additionally received repaglinide (0.5 mg/kg/day p.o) for 15 days starting from day 11. Interestingly, repaglinide lessened striatal ER stress and apoptosis as evidenced by reduced BiP/ATF6/CHOP and caspase-3 levels; however, it augmented striatal DREAM mRNA expression. Repaglinide triggered the expression of the mitophagy marker PINK1 and the autophagy protein beclin1 and alleviated striatal oxidative stress through escalating catalase activity. In addition, repaglinide halted astrocyte/microglial activation and neuroinflammation in the striatum as expressed by reducing glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor protein 1 (Iba1) immunostaining and decreasing interleukin (IL)-6 and IL-1ß levels. Repaglinide restored striatum morphological alterations, intact neuron count, and neurobehavioral motor performance in rats examined by an open field, grip strength, and footprint gait analysis. Conclusively, repaglinide modulates the DREAM-ER stress BiP/ATF6/CHOP cascade, increases mitophagy/autophagy, inhibits apoptosis, and lessens oxidative stress, astrocyte/microglial activation, and neuroinflammation in PD.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Masculino , Ratas , Factor de Transcripción Activador 6/metabolismo , Factor de Transcripción Activador 6/farmacología , Apoptosis , Calcio/metabolismo , Estrés del Retículo Endoplásmico , Proteínas de Interacción con los Canales Kv/metabolismo , Mitofagia , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/metabolismo , Ratas Wistar , Rotenona/toxicidad , Factor de Transcripción CHOP/metabolismoRESUMEN
Empagliflozin, a selective sodium-glucose co-transporter-2 inhibitor, has been demonstrated to provide additional non-glycemic benefits, including neuroprotection. Endoplasmic reticulum (ER) stress is a key player in neurodegeneration and occurs at the crossroads of other pathologic mechanisms; however, its role in the pathogenesis of Parkinson's disease (PD) is still elusive. miR-211-5p regulates neuronal differentiation and viability and was predicted to target CHOP, a downstream effector in the ER stress pathway. For the first time, this study investigated the possible neuroprotective effect of empagliflozin in a rotenone-induced rat model of PD from the perspective of ER stress. Rotenone (1.5 mg/kg) was administered subcutaneously every other day for 3 weeks. Meanwhile, the treated group received empagliflozin 10 mg/kg/day orally for 15 consecutive days post-PD induction. On the molecular level, the ER stress pathway components; GRP78, total and phosphorylated PERK, eIF2α and CHOP, along with miR-211-5p expression were upregulated in the striatum of rotenone-injected rats. Concurrently, the untreated rats showed elevated striatal α-synuclein levels along with diminished autophagy and the proteasome system as evidenced by reduced beclin-1 protein and ELF2/NERF mRNA expression levels. The rotenone-induced striatal oxidative stress and neuroinflammation were expressed by reduced catalase activity and elevated interleukin (IL)-1ß levels. miR-211-5p was positively correlated with PERK/eIF2α/CHOP, IL-1ß and α-synuclein, while negatively correlated with ELF2/NERF, beclin-1 and catalase activity. Empagliflozin treatment showed a restorative effect on all biochemical alterations and improved the motor function of rats tested by open field, grip strength and footprint gait analysis. In the histopathological examination, empagliflozin increased the intact neuron count and attenuated astrogliosis and microgliosis by reducing the glial fibrillary acidic protein and ionized calcium-binding adaptor protein 1 immunostaining. Conclusively, these results emphasize the neurotherapeutic impact of empagliflozin in PD by moderating the GRP78/PERK/eIF2α/CHOP ER stress pathway, downregulating miR-211-5p, resolving oxidative stress, lessening astrocyte/microglial activation and neuroinflammation, along with augmenting autophagy.
Asunto(s)
Compuestos de Bencidrilo , Estrés del Retículo Endoplásmico , Glucósidos , MicroARNs , Enfermedad de Parkinson , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Beclina-1/metabolismo , Compuestos de Bencidrilo/farmacología , Catalasa , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Factor 2 Eucariótico de Iniciación/metabolismo , Glucósidos/farmacología , Proteínas de Choque Térmico/metabolismo , MicroARNs/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ratas , Rotenona/toxicidad , Factor de Transcripción CHOP/metabolismo , alfa-Sinucleína , eIF-2 Quinasa/metabolismoRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder of heterogenous etiology exhibiting a challenge in understanding its exact neuro-pathophysiology. Recently, peroxisome proliferator activated receptor (PPAR)-α activation was found to play a fundamental role in neuroprotection and improving autistic-like-behaviors in experimental animal models of ASD through alleviating neuroinflammation, oxidative-stress, astrocyte reactivity, tauopathy in addition to its favorable role in metabolic regulation, thus attracting attention as a possible target in treatment of ASD. This study aimed to investigate the role of PPAR-α, astrocytic dysfunction and tauopathy in ASD and detect the possible neuroprotective effects of metformin (MET), through PPAR-α activation, and risperidone (RIS) either monotherapy or in combination in alleviating autistic-like-changes at behavioral and neurobiological levels in male Wistar rats. Pregnant female Wistar rats received valproic-acid (VPA) to induce autistic-like-behavioral and neurobiological alterations in their offspring. Chronic intra-peritoneal MET (100 mg/kg/day) and RIS (1 mg/kg/day) either monotherapy or in combination started from postnatal day (PND) 24 till PND61 (38 days). Prenatal VPA exposure simulated the autistic core behaviors associated with neurochemical and histopathological neurodevelopmental degenerative changes. Both MET and RIS either monotherapy or in combination were able to reverse these changes. The effect of MET was comparable to RIS. Moreover, MET was able to alleviate the RIS induced weight gain and improve cognitive functions highlighting its promising adjunctive role in alleviating ASD pathophysiology. Our study highlighted the favorable effects of MET and RIS both in monotherapy and in combination in alleviating the autistic-like-changes and proposed PPAR-α activation along with restoring astrocytes homeostasis as promising targets in novel therapeutic strategies in ASD.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Metformina , Efectos Tardíos de la Exposición Prenatal , Tauopatías , Animales , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/inducido químicamente , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Masculino , Metformina/efectos adversos , Receptores Activados del Proliferador del Peroxisoma/efectos adversos , Embarazo , Ratas , Ratas Wistar , Risperidona/farmacología , Risperidona/uso terapéutico , Ácido Valproico/farmacologíaRESUMEN
Despite the increasing prevalence of autism spectrum disorder (ASD), there is still a deficiency in understanding its exact pathophysiology and treatment, therefore validation of translational ASD animal model is warranted. Although strong evidences support the valproic acid (VPA) model of autism, yet a controversy exists regarding the best timing of exposure whether prenatal or postnatal. Accordingly, this study was designed to compare the time dependent effects of VPA exposure as regard its ability to induce autistic like changes in male Wistar rats. In this study, two different protocols of VPA exposure (prenatal and postnatal) were compared at different levels (behavioral, neurochemical and histopathological). Results of this study revealed that both prenatal and postnatal VPA exposures induced autistic-like behaviors manifested by reduced social interaction, increased repetitive stereotyped behavior and anxiety, cognitive dysfunction, lowered sensitivity to pain, and neurodevelopmental delay. Furthermore, inflammatory cytokines and oxidative/nitrosative stress markers were elevated in prefrontal cortex and hippocampal homogenates. Likewise, histopathological and immunohistochemical assessment confirmed the neurodegenerative and the apoptotic changes in prefrontal cortex, hippocampus and cerebellum exhibited by decreased viable cells number and Nissl's granules optical density, and increased caspase-3 immunoreactivity respectively. Interestingly, ASD core symptoms and histopathological changes were significantly (P < 0.05) altered in prenatal VPA model compared to postnatal VPA model. Additionally, postnatal mortality in prenatal model (4.3%) was much lower compared to the postnatal model (22.7%). In conclusion, our study overweighs the ability of prenatal VPA model over postnatal VPA model to induce behavioral and neuropathological alterations that simulate those observed in autistic individuals with a lower postnatal animal mortality, highlighting the privilege of prenatal over postnatal VPA exposure as a translational model for understanding pathophysiology and developing novel targets for management of ASD.
Asunto(s)
Trastorno Autístico/inducido químicamente , Ácido Valproico/farmacología , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Trastorno Autístico/patología , Trastorno Autístico/psicología , Química Encefálica/efectos de los fármacos , Citocinas/análisis , Modelos Animales de Enfermedad , Femenino , Masculino , Prueba del Laberinto Acuático de Morris , Prueba de Campo Abierto , Estrés Oxidativo/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Ácido Valproico/administración & dosificaciónRESUMEN
Accumulating evidence indicates the role of microglial activation and sustained neuroinflammation in the pathogenesis of cognitive dysfunction, a common feature associated with depressive disorders. It also indicates the role of Wnt/ß-catenin pathway in regulation of microglia-mediated neuroinflammation. Amisulpride exhibits antidepressant and pro-cognitive activities in several clinical and experimental studies. Hitherto, the direct effects of amisulpride on Wnt/ß-catenin signaling and microglial activity have not been thoroughly studied. This study aimed at investigating the effects of chronic amisulpride treatment on Wnt/ß-catenin signaling and pro-inflammatory microglial activation and its role in alleviation of depressive-like behavior and cognitive deficits elicited by unpredictable chronic mild stress (UCMS). The effects of amisulpride (3â¯mg/kg/day) were investigated on behavioral/cognitive deficits, expression of Wnt/ß-catenin pathway and microglial activation in the prefrontal cortex (PFC) of UCMS-exposed male Wistar rats. UCMS induced depressive-like behavior with impairment of performance in novel object recognition test and attentional set-shifting task. These behavioral deficits were associated with decreased total ß-catenin and increased pro-inflammatory microglial activation. Amisulpride improved UCMS-induced behavioral/cognitive deficits, ameliorated Wnt/ß-catenin signaling dysregulation and pro-inflammatory microglial activation. This work highlights the antidepressant and pro-cognitive effects of amisulpride in UCMS-exposed rats that could be mediated by modulation of Wnt/ß-catenin pathway activity and amelioration of pro-inflammatory microglial activation in the prefrontal cortex. This could provide new insights into the putative mechanisms behind the antidepressant and pro-cognitive effects exerted by amisulpride.
Asunto(s)
Amisulprida/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Microglía/efectos de los fármacos , Nootrópicos/uso terapéutico , Corteza Prefrontal/efectos de los fármacos , Estrés Psicológico/psicología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Atención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Trastornos del Conocimiento/etiología , Depresión/prevención & control , Depresión/psicología , Encefalitis/tratamiento farmacológico , Encefalitis/psicología , Activación de Macrófagos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , beta Catenina/antagonistas & inhibidores , beta Catenina/biosíntesisRESUMEN
Two series of novel morpholinopyrimidine derivatives were synthesized and screened for their in-vitro cytotoxic activity against 60 tumor cell line by the National Cancer Institute, USA. The in-vitro cytotoxic IC50 values for the most active compounds 6e, 6g, and 6l against the most sensitive cell line leukemia SR were estimated (IC50 = 0.76, 13.59, and 4.37 uM, respectively). To investigate their PI3K enzyme inhibition activity, the assay was done on Class IA (α, ß, & δ) isoforms. The IC50 values were very promising: compound [6e = 11.73 (α), 6.09 (ß), 11.18 (δ)], compound [6g = 8.43 (α), 15.84 (ß), 30.62 (δ)], and compound [6l = 13.98 (α), 7.22 (ß), 10.94 (δ)], compared to the reference compound LY294002 = 6.28 (α), 4.51 (ß), 4.60 (δ) uM, respectively. Moreover, cell cycle analysis and annexin V-FITC staining were done on Leukemia SR, there was arrest at G2/M phase and apoptosis was induced. Finally, docking study was performed to analyze the interactive mode of these derivatives in PI3Kα ATP-binding site. These outcomes proved that compounds 6e, 6g, and 6l are potential leads for further optimization as antileukemic agents.
Asunto(s)
Apoptosis/efectos de los fármacos , Simulación del Acoplamiento Molecular/métodos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/síntesis química , Pirimidinas/uso terapéutico , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders around the world. Increasing evidence suggests that neurotransmitter Gamma-aminobutyric acid (GABA) is involved in the pathogenesis of PCOS through its central role in the hypothalamus. However, the peripheral role of GABA in PCOS has not been sufficiently investigated in spite of its existence in peripheral organs. First, the aim of this study is to, investigate serum GABA level in Egyptian PCOS patients. Second, to explore the correlation between serum GABA level with Body Mass Index (BMI), dyslipidemia, totaltestosterone and 25 (OH) vitamin D. METHODS: Eighty PCOS patients and eighty age-matched healthy females were included in this study. All parameters were assessed colourimetrically or with ELISA. RESULTS: PCOS patients exhibited significantly decreased serum GABA level compared to controls (p < 0.001). There was a significant positive correlation between serum GABA and 25(OH) vitamin D levels (r = 0.26, p = 0.018), and a significant negative correlation with total testosterone (r = - 0.3, p = 0.02), total cholesterol (TC) (r = - 0.31, p = 0.01) and LDL-Cholesterol (LDL-C) (r = - 0.23, p = 0.045), respectively. CONCLUSIONS: The findings of this study suggest that disrupted GABA level in the peripheral circulation is an additional contributing factor to PCOS manifestations. GABA deficiency was correlated with 25 (OH) vitamin D deficiency, dyslipidemia, and total testosterone. Further investigations for GABA adjustment might provide a promising means for better management of PCOS symptoms.
RESUMEN
Hepatitis C virus (HCV) infects primarily hepatocytes, leads to development of fibrosis and/or cirrhosis of the liver and is a significant factor for developing hepatocellular carcinoma (HCC). Evidence indicates that liver fibrosis contains uncontrolled inflammation as a part of its etiology. Normal cell-mediated immunity plays a central role in the mechanisms involved in viral clearance/persistence in the liver. In this context, cytokines modulate the immune system and exert direct anti-viral activity. To this end, this study investigated potential associations of serum IL-17 and IL-6 with exacerbation of hepatic damage in chronic HCV patients to determine their utility as prognostic markers for potential development of HCC. Chronic HCV-patients were recruited, divided into groups according to degree of liver damage, i.e. patients with peri-hepatic fibrosis, hepatic cirrhosis, or HCC, and had their blood collected for analysis of liver function and serum IL-6 and IL-17 levels. Interestingly, increases in serum IL-17 levels in the study groups were associated with aggravation of the clinical state from HCV to cirrhosis and then to HCC. Serum IL-6 levels followed a similar pattern. The association of both cytokines with progressive exacerbation of the initial HCV-induced liver damage was further confirmed by correlation analysis that revealed positive correlations between HCV RNA titer and IL-17 (+0.951, p < 0.05) and IL-6 (+0.85, p < 0.05). A receiver operating characteristics (ROC) analysis revealed their beneficial addition as promising biomarkers for a better prognostic profile of HCC. Interestingly, a significant progressive decline in the active vitamin D status was noted in all three clinical states, and these too were associated with progressive liver disease. This study confirms the necessity of adding screening for IL-6 and IL-17 and vitamin D to that of the classic marker AFP for patients with HCV and cirrhosis to hopefully permit clinicians to initiate measures that ultimately might mitigate/delay development of HCC in these infected patients.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico , Hepacivirus/inmunología , Hepatitis C Crónica/diagnóstico , Neoplasias Hepáticas/diagnóstico , Hígado/patología , Adulto , Anciano , Biomarcadores de Tumor/sangre , Carcinogénesis , Carcinoma Hepatocelular/inmunología , Progresión de la Enfermedad , Femenino , Hepacivirus/genética , Hepatitis C Crónica/inmunología , Humanos , Interleucina-17/sangre , Interleucina-6/sangre , Hígado/virología , Neoplasias Hepáticas/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , ARN Viral/análisis , Carga Viral , Vitamina D/sangreRESUMEN
Chlorinated pesticides (CP) are environmentally persistent pollutants that (prenatally through the placenta and post-natally via breastfeeding) are transferred from mother to child. Considering the significant bleeding tendency noted in infants of CP-intoxicated mothers in Egypt, this study aimed to investigate any correlation between levels of these xenobiotics in mothers' milk and bleeding tendencies of their infants, as well as a possible role of any related immunosuppression in this phenomenon. This study examined 180 newborns presenting with altered bleeding tendencies and their mothers, and 180 normal newborns and their mothers (serving as a controls), selected from the Breastfeeding Unit, Center for Social and Preventive Medicine at the Cairo University Pediatric Hospital. Chlorinated pesticides (e.g., hexachlorocyclohexane, DDT, hepta-chloroepoxide, α- and ß-endosulfan, aldrin, endrin, dieldrin) levels and their derivatives were measured in mothers' milk as well as in serum of neonates using gas chromatography/high resolution mass spectrometry. To link bleeding tendency with lactational intoxication of neonates by CP, newborns' blood was assessed for: platelet count, bleeding and prothrombin time, liver enzymes, Vitamin K, TNFα, and IL-10. Breast milk CP levels were associated with a higher incidence of bleeding in infants. Interference with the coagulation cascade was supported by changes in prothrombin time (prolonged), platelet counts (decreased), liver enzymes (increased), and serum vitamin K concentrations (decreased). Moreover, the significant decrease in WBC count and lymphocytes added to depressed cytokine secretion, i.e., TNFα and IL-10, suggested an organochlorine-induced immunotoxicity in infants developmentally exposed to the agents. We conclude that maternal transfer of CP, via breastfeeding or across the placenta, was sufficient to achieve similar CP levels in the serum of their infants; this correlated with a manifesting of altered bleeding tendencies and perturbed cytokine biology in these infants.