ABSTRACT
BACKGROUND: We aimed to investigate whether the change in methemoglobin levels (ΔMHb) predicts oxygenation response to inhaled nitric oxide (iNO) in persistent pulmonary hypertension of the newborn (PPHN) with lung disease, with or without pulmonary hypoplasia. METHODS: In this prospective observational study, infants were categorized based on ΔMHb and oxygenation response (ΔPaO2/FiO2) following iNO: ΔMHb ≤0 or ΔMHb>0, and ΔPaO2/FiO2â<â20âmmHg (Non-responder) or≥20âmmHg (Responder). ΔMHb levels were compared among infants with or without pulmonary hypoplasia. RESULTS: Among infants with pulmonary hypoplasia (nâ=â28), ΔMHb was not associated with an oxygenation response to iNO or survival without ECMO. Among infants without hypoplasia (nâ=â29), subjects with ΔMHb>0 following iNO (nâ=â21) had a greater ΔPaO2/FiO2 (median, 64âmmHg; IQR, 127; pâ<â0.01) and 100% survival without extracorporeal membrane oxygenation (ECMO) when compared to infants with ΔMHb ≤0 (nâ=â8; median 10âmmHg; IQR, 33). CONCLUSIONS: PPHN secondary to lung disease without hypoplasia with increased ΔMHb following iNO was associated with better oxygenation response and survival without ECMO compared to subjects without an increase in MHb.
Subject(s)
Endothelium-Dependent Relaxing Factors/therapeutic use , Methemoglobin/metabolism , Nitric Oxide/therapeutic use , Persistent Fetal Circulation Syndrome/drug therapy , Administration, Inhalation , Female , Hernias, Diaphragmatic, Congenital/complications , Humans , Infant, Newborn , Kidney/abnormalities , Lung/abnormalities , Male , Meconium Aspiration Syndrome/complications , Oligohydramnios , Persistent Fetal Circulation Syndrome/blood , Persistent Fetal Circulation Syndrome/complications , Pneumonia/complications , Pregnancy , Prognosis , Prospective Studies , Respiratory Distress Syndrome, Newborn/complicationsABSTRACT
OBJECTIVE: To compare neurodevelopmental outcomes in linear growth-restricted (LGR) infants born <29 weeks with and without weight gain out of proportion to linear growth. STUDY DESIGN: We compared 2-year neurodevelopmental outcomes between infants with and without LGR and between LGR infants with and without weight gain out of proportion to linear growth. The outcomes were Bayley-III cognitive, motor, and language scores, cerebral palsy, Gross Motor Function Classification System (GMFCS) level ≥ 2, and neurodevelopmental impairment. RESULT: In total, 1227 infants were analyzed. LGR infants were smaller and less mature at birth, had higher BMI, and had lower Bayley-III language scores (82.3 vs. 85.0, p < 0.05). Among infants with LGR, infants with high BMI had lower language scores compared with those with low-to-normal BMI (80.8 vs. 83.3, p < 0.05), and were more likely to have GMFCS level ≥2 and neurodevelopmental impairment. CONCLUSION: Among infants with LGR, weight gain out of proportion to linear growth was associated with poorer neurodevelopmental outcomes.
Subject(s)
Infant, Extremely Premature/growth & development , Neuropsychological Tests , Weight Gain , Cerebral Palsy/diagnosis , Cognition Disorders/diagnosis , Databases, Factual , Developmental Disabilities/diagnosis , Female , Humans , Infant , Infant, Newborn , Language Development Disorders/diagnosis , Male , Motor Disorders/diagnosis , National Institute of Child Health and Human Development (U.S.) , Retrospective Studies , United StatesABSTRACT
OBJECTIVE: We hypothesized that, among parents of potential neonatal research subjects, an accompanying cover sheet added to the permission form (intervention) would increase understanding of the research, when compared to a standard form (control). STUDY DESIGN: This pilot study enrolled parents approached for one of two index studies: one randomized trial and one observational study. A one-page cover sheet described critical study information. Families were randomized 1:1 to receive the cover sheet or not. Objective and subjective understanding and satisfaction were measured. RESULTS: Thirty-two parents completed all measures (17 control, 15 intervention). There were no differences in comprehension score (16.8±5.7 vs 16.3±3.5), subjective understanding (median 6 vs 6.5), or overall satisfaction with consent (median 7 vs 6.5) between control and intervention groups (all P>0.50). CONCLUSION: A simplified permission form cover sheet had no effect on parents' understanding of studies for which their newborns were being recruited.
Subject(s)
Comprehension , Health Knowledge, Attitudes, Practice , Parental Consent/psychology , Adult , Female , Humans , Infant, Newborn , Linear Models , Male , Multivariate Analysis , New York , Pilot Projects , Research , Single-Blind Method , Young AdultABSTRACT
OBJECTIVE: To compare neurodevelopmental outcomes in postnatal growth-restricted infants born <29 weeks with and without postnatal head-sparing (PHS). STUDY DESIGN: We analyzed developmental outcomes at 2 years of age among postnatally growth-restricted infants with and without head-sparing. The primary outcome was Bayley III cognitive composite score; secondary outcomes included Bayley III motor composite score, moderate/severe cerebral palsy, gross motor functional classification scale level⩾2, and presence or absence of neurodevelopmental impairment (NDI). RESULTS: Of 1098 infants evaluated at 18 to 22 months, 658 were postnatally growth restricted, of whom 301 had head-sparing. In the multivariate model including independent risk factors for poor growth and poor developmental outcome, infants with head-sparing had higher adjusted motor composite scores (mean difference 4.65, P<0.01), but no differences in other neurodevelopmental outcomes. CONCLUSION: PHS is associated with improved neurodevelopmental outcome in extremely preterm infants, specifically Bayley III motor scores, but whether beneficial effects of PHS persist later in life is unknown.
Subject(s)
Child Development , Developmental Disabilities/diagnosis , Infant, Extremely Premature/growth & development , Case-Control Studies , Child, Preschool , Female , Fetal Growth Retardation/therapy , Humans , Infant , Infant, Low Birth Weight , Intellectual Disability/diagnosis , Male , Motor Skills , Prospective StudiesABSTRACT
OBJECTIVE: To assess whether the adequate antibody response observed in former extremely premature infants after the primary series of immunizations is sustained after the first booster vaccines. SUBJECTS AND METHODS: Sixteen former extremely premature (<29 weeks, <1000 g at birth) and 17 former full-term (>37 weeks) infants had sera obtained for antibody titer measurement at 3 to 4 years of age. All had received the primary series and first booster vaccines for diphtheria, pertussis, tetanus, polio, and Haemophilus influenzae type b. Twelve preterm and 14 full-term children had completed the hepatitis B vaccine series. RESULTS: At 3 to 4 years of age, former preterm and full-term children had similar geometric mean titer (GMT) values of antibodies to tetanus, diphtheria, and pertussis. Preterm children had a lower GMT value of Haemophilus polyribosylribitol phosphate (PRP) antibody than did full-term children (0.99 vs 3.06 microg/mL). Fifty percent of preterm and 88% of full-term children had PRP antibody >1.0 microg/mL; 100% of preterm and 94% of full-term children had anti-PRP titers >0.15 microg/mL. GMT values of neutralizing antibodies to polio serotypes 1 and 2 were similar, with 94% to 100% of both groups above protective levels (>/=1:8). The difference in GMT values of polio serotype 3 approached significance (29 vs 73); fewer preterm children had protective titer values (75% vs 100%). Among children vaccinated against hepatitis B, 75% of preterm and 71% of full-term children were protected (10 mIU/mL). CONCLUSIONS: Preterm children immunized at the recommended chronological ages displayed antibody responses similar to those for full-term children for most immunizing antigens. Responses to PRP and polio serotype 3 were less robust than those of full-term children.
Subject(s)
Antibodies, Viral/blood , Infant, Premature/immunology , Vaccines/immunology , Child, Preschool , Diphtheria-Tetanus-Pertussis Vaccine , Follow-Up Studies , Haemophilus Vaccines , Hepatitis B Vaccines , Humans , Poliovirus Vaccine, Oral , Reference ValuesABSTRACT
OBJECTIVE: To determine whether extremely premature infants have immunologic responses to tetanus toxoid, Haemophilus influenzae type b polysaccharide and polio vaccines similar to those of full-term infants. INFANTS AND METHODS: Sixteen extremely premature (< 29 weeks, < 1000 g at birth) infants received separate diphtheria-tetanus-pertussis and H influenzae type b oligosaccharide-CRM197-conjugated (HbOC) vaccines at 2, 4 and 6 months of chronologic age, enhanced potency inactivated polio vaccine at 2 months, and oral polio vaccine at 4 months. Serum was obtained for anti-tetanus toxoid (TT), anti-Haemophilus b polysaccharide (HbPs) and polio neutralizing antibody assays before the 2-month vaccination and 4 to 6 weeks after the 6-month vaccination. Comparison sera were obtained from full-term infants immunized with the same lots of diphtheria-tetanus-pertussis (n = 46) and HbOC (n = 66) vaccines or the same sequence of polio vaccines (n = 10). RESULTS: Preterm and full-term infants had similar geometric mean titers of anti-TT antibodies, anti-HbPs antibodies, and neutralizing antibodies to polio serotypes 1, 2, and 3 after the completion of the primary series of vaccines. After vaccination, similar proportions of preterm and full-term infants had protective levels of antibody to TT (preterm 100% vs full-term 100% with levels > 0.01 IU/mL), HbPS (82% vs 87%, > 1.0 microgram/mL), and polio serotypes 1 (85% vs 80%, > or = 1:8) and 2 (100% vs 100%, > or = 1:8). Preterm infants were less likely than full-term infants to have protective levels of neutralizing antibody to polio serotype 3 (31% vs 90%, > or = 1:8). CONCLUSIONS: Extremely premature infants have adequate antibody responses to tetanus and HbOC antigens but may have diminished responsiveness to serotype 3 polio vaccine.
Subject(s)
Bacterial Proteins/immunology , Haemophilus Vaccines/immunology , Infant, Premature/immunology , Poliovirus Vaccine, Oral/immunology , Tetanus Toxoid/immunology , Vaccines, Synthetic/immunology , Antibodies, Bacterial/blood , Antibodies, Viral/blood , Bacterial Proteins/administration & dosage , Haemophilus Vaccines/administration & dosage , Haemophilus influenzae/immunology , Humans , Infant, Low Birth Weight/immunology , Infant, Newborn , Poliovirus/immunology , Poliovirus Vaccine, Oral/administration & dosage , Tetanus Toxin/immunology , Tetanus Toxoid/administration & dosage , Vaccines, Synthetic/administration & dosageABSTRACT
OBJECTIVE: To determine, in the postsurfactant era, the incidence and clinical characteristics of infants with atypical versus traditionally defined bronchopulmonary dysplasia (BPD) among premature infants with birth weights <1251 g. DESIGN: Retrospective cohort study. SETTING: A single regional neonatal intensive care unit (level III/IV). PATIENTS: Two hundred thirty-two premature infants <1251 g at birth consecutively admitted during a 2-year period. MAIN OUTCOME MEASURE: Incidence of classic BPD and atypical chronic lung disease (CLD) (occurring without preceding respiratory distress or after recovery from respiratory distress). RESULTS: Among 177 infants <1251 g who survived to 28 days, 27 (15%) had atypical CLD and 61 (34.5%) had classic BPD. Atypical CLD infants were significantly heavier and more mature than classic BPD infants (mean birth weights, 922 +/- 152 g vs 854 +/- 173 g; and mean gestational age, 26.8 +/- 1.3 weeks vs 26.1 +/- 1.6 weeks). Median duration of ventilator support (31 days; range, 2 to 127 vs 42 days; range, 4-145 days) and oxygen therapy (30 days; range, 11 to 163 vs 48 days; range, 19-180 days) were shorter in atypical CLD infants than in classic BPD infants. CONCLUSION: Atypical CLD comprised 31% of total cases of CLD. Atypical CLD appears to be less severe than classic BPD. These data suggest that initial, acute lung injuries are not the sole antecedents of neonatal CLD.
Subject(s)
Infant, Premature, Diseases/epidemiology , Infant, Very Low Birth Weight , Lung Diseases/epidemiology , Bronchopulmonary Dysplasia/epidemiology , Bronchopulmonary Dysplasia/therapy , Chronic Disease , Cohort Studies , Female , Humans , Incidence , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/therapy , Intensive Care Units, Neonatal , Lung Diseases/therapy , Male , Regression Analysis , Retrospective StudiesABSTRACT
In the ideal situation, the evaluation for sepsis in the young infant should include collection of multiple blood cultures before the institution of antibiotics. Unfortunately, in some infants, it may not be possible to obtain more than a single blood culture at the time of initial evaluation. If this single culture ultimately grows coagulase-negative staphylococci and the infant has been treated with antimicrobial therapy in the interim, it is often difficult to determine whether the positive culture represents true infection or contamination. Our data suggest that peripheral blood cultures yielding high colony counts most likely represent infection. Furthermore, in this high-risk patient population, low colony-count growth should not be ignored as contamination, particularly if there are significant clinical findings or if the infant has a central catheter or hematologic abnormality. Future studies should examine these important issues.
Subject(s)
Coagulase/isolation & purification , Staphylococcal Infections/enzymology , Blood Specimen Collection , Colony Count, Microbial , Diagnosis, Differential , Equipment Contamination , Humans , Infant , Intensive Care Units, Neonatal , Medical Records , Staphylococcal Infections/diagnosis , Staphylococcus epidermidis/growth & developmentABSTRACT
BACKGROUND: We previously demonstrated improved survival and early outcomes in a pilot trial of 2 doses of intravenous dexamethasone for infants with surfactant-treated respiratory distress syndrome. (1) A multicenter, randomized, double-blind trial was undertaken to confirm these results. METHODS: Infants <30 weeks' gestation were eligible if they had respiratory distress syndrome, required mechanical ventilation at 12 to 18 hours of age, and had received at least 1 dose of exogenous surfactant. Infants were excluded if sepsis or pneumonia was suspected or if congenital heart disease or chromosomal abnormalities were present. A total of 384 infants were enrolled-189 randomized to dexamethasone (.5mg/kg birth weight at 12-18 hours of age and a second dose 12 hours later) and 195 to an equal volume of saline placebo. RESULTS: No differences were found in the dexamethasone versus placebo groups, respectively, regarding the primary outcomes of survival (79% vs 83%), survival without oxygen at 36 weeks' corrected gestational age (CGA; both 59%), and survival without oxygen at 36 weeks' CGA and without late glucocorticoid therapy (46% vs 44%). No significant differences between the groups in estimates from Kaplan-Meier survival analyses were found for median days on oxygen (50 vs 56 days), ventilation (20 vs 27 days), days to regain birth weight (15.5 vs 14 days), or length of stay (LOS; 88 vs 89 days). Infants given early dexamethasone were less likely to receive later glucocorticoid therapy for bronchopulmonary dysplasia during their hospitalization (27% vs 35%). No clinically significant side effects were noted in the dexamethasone group, although there were transient elevations in blood glucose and blood pressure followed by a return to baseline by study day 10. Among infants who died (40 vs 33), there were no differences in the median days on oxygen, ventilation, nor LOS. However, in survivors (149 vs 162), the following were observed: median days on oxygen 37 versus 45 days, ventilation 14 versus 19 days, and LOS 79 versus 81 days, for the dexamethasone versus placebo groups, respectively. CONCLUSIONS: This dose of early intravenous dexamethasone did not reduce the requirement for oxygen at 36 weeks' CGA and survival was not improved. However, early dexamethasone reduced the use of later prolonged dexamethasone therapy, and among survivors, reduced the median days on oxygen and ventilation. We conclude that this course of early dexamethasone probably represents a near minimum dose for instituting a prophylactic regimen against bronchopulmonary dysplasia.
Subject(s)
Bronchopulmonary Dysplasia/prevention & control , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Lung Diseases, Obstructive/prevention & control , Respiratory Distress Syndrome, Newborn/drug therapy , Bronchopulmonary Dysplasia/mortality , Dexamethasone/adverse effects , Female , Glucocorticoids/adverse effects , Humans , Infant , Infant, Newborn , Length of Stay , Lung Diseases, Obstructive/mortality , Male , Oxygen Inhalation Therapy , Respiratory Distress Syndrome, Newborn/mortality , Survival RateABSTRACT
OBJECTIVE: To examine the relative levels of gamma-aminobutyric acid (GABA), glutamate, and vascular endothelial growth factor (VEGF) in the vitreous of nondiabetic and diabetic patients. METHODS: Undiluted vitreous samples were obtained from 22 patients with proliferative diabetic retinopathy (PDR) and 28 patients without diabetes who underwent pars plana vitrectomy. Simultaneous venous blood samples also were obtained. Amino acid concentrations were determined using sensitive high-performance liquid chromatography, and VEGF levels by quantitative enzyme-linked immunosorbent assay. Hemoglobin concentrations in the blood and vitreous were determined using spectrophotometry. RESULTS: The level of GABA in the vitreous of patients with PDR, 29.4 +/- 7.8 mumol/L, was significantly higher than in controls (18.4 +/- 5.5 mumol/L) (P = .004). The vitreous concentration of glutamate was higher in patients with PDR (24.7 +/- 14.0 mumol/L) compared with controls (9.1 +/- 5.1 mumol/L) (P < .001). Vitreous VEGF level was significantly higher in patients with PDR (1759 +/- 1721 pg/mL) compared with controls (27 +/- 65 pg/mL) (P < .001). There were moderately strong correlations between GABA and VEGF levels (r = 0.68) and glutamate and VEGF levels (r = 0.43). Elevated GABA, glutamate, and VEGF levels also correlated strongly with the presence of PDR. Correcting for possible introduction of these molecules by vitreous hemorrhage did not significantly alter these findings. CONCLUSIONS: Levels of glutamate potentially toxic to retinal ganglion cells are found in the vitreous of patients with PDR. Elevated vitreous GABA may reflect amacrine cell dysfunction and underlie electroretinographic oscillatory potential abnormalities seen in diabetic retinopathy. The correlations of glutamate and GABA levels with an elevated VEGF level provide biochemical support for ischemia-induced neovascularization in patients with PDR. These findings present opportunities for novel therapeutic modalities in the treatment of PDR.
Subject(s)
Diabetic Retinopathy/metabolism , Endothelial Growth Factors/metabolism , Glutamic Acid/metabolism , Lymphokines/metabolism , Vitreous Body/metabolism , gamma-Aminobutyric Acid/metabolism , Chromatography, High Pressure Liquid , Diabetic Retinopathy/surgery , Enzyme-Linked Immunosorbent Assay , Female , Hemoglobins/analysis , Humans , Male , Middle Aged , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , VitrectomyABSTRACT
OBJECTIVES: To determine the long-term neurologic, cognitive, and educational outcomes of Navajo children who survived Haemophilus influenzae type b meningitis. DESIGN: Retrospective cohort study, with 3.6- to 15.0-year follow-up. SETTING: Navajo Indian reservation. PARTICIPANTS: Population-based cohort of 76 Navajo children with Haemophilus meningitis at less than 5 years of age between 1975 and 1986, with 41 (54%) consenting to undergo follow-up in 1990. Each case was matched to one nearest-age sibling and one unrelated age-matched control. MAIN OUTCOME MEASURES: Standard intelligence test scores, neurologic abnormalities, and school performance. RESULTS: The mean IQ for cases was lower than that for siblings (79 vs 87, P = .006) or age-matched controls (79 vs 95, P < .001). Twenty-nine percent of cases had severe neurologic sequelae, including mental retardation (24%), severe hearing loss (5%), cerebral palsy (7%), and seizure disorder (12%). Eight percent of siblings (relative risk for cases vs siblings, 8.0; P = .05) and 2% of age-matched controls (relative risk vs cases, 10.0; P = .01) had mental retardation. No siblings or age-matched controls had any other severe neurologic sequela. Twenty-nine percent of cases, 23% of siblings (relative risk, 2.5; P = .45), and 0% of age-matched controls (P = .001) required special education services, while 42% of cases, 23% of siblings (relative risk, 3.3; P = .10), and 11% of age-matched controls (relative risk, 4.0; P = .005) had been retained in a grade in school. CONCLUSIONS: Navajo survivors of Haemophilus meningitis suffer more long-term neurologic, cognitive, and school-related disability than siblings or age-matched controls. They may also suffer higher morbidity than Haemophilus meningitis survivors in the general population.
Subject(s)
Indians, North American , Meningitis, Haemophilus/physiopathology , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Educational Status , Female , Humans , Intelligence , Male , Nervous System Diseases/physiopathology , Prognosis , Retrospective Studies , Time FactorsABSTRACT
PURPOSE: Vascular endothelial growth factor (VEGF) is elevated in the vitreous of patients with proliferative retinopathies (PR). Angiogenic factors like VEGF are elevated in the urine of subjects with cancers, including those distant from the genitourinary tract. We hypothesized that local increases in VEGF in the vitreous would be reflected in the urine of subjects with PR. METHODS: Urine samples were collected from adults with absent, mild, or severe (requiring laser photocoagulation) PR. VEGF was measured by enzyme linked immunosorbent assay. RESULTS: Of 42 subjects, 16 had no PR and 26 had PR (8 mild, 18 severe). Thirty subjects had diabetes mellitus; 24 of these had PR. Subjects with PR were older than controls. Subjects with PR tended to have higher urinary VEGF (median 123 pg/ml Cr, range 3--1738) than controls without PR (median 93 pg/ml Cr, range 2--200) (p = 0.08). None of 16 controls, but 11/15 subjects with PR had >200 mg VEGF/mg Cr (p = 0.003), yielding high specificity (100%), but poor sensitivity (42%) of elevated urinary VEGF for PR. Urinary VEGF was also modestly correlated with urinary protein excretion (r(2 ) = 0.23). Correction of VEGF values for urinary protein abrogated any correlation with PR. CONCLUSIONS: Urinary levels of VEGF are associated with PR, but this relationship may be caused by concurrent renal diseases that result in proteinuria and/or renal VEGF production. The insensitivity of the association may preclude its use in screening to avoid eye examinations.
Subject(s)
Diabetic Retinopathy/urine , Endothelial Growth Factors/urine , Lymphokines/urine , Retinal Neovascularization/urine , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Proteinuria/urine , Reproducibility of Results , Sensitivity and Specificity , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
OBJECTIVE: Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500 g,VLBWs) with and without blood stream infection (BSI) during their birth hospitalization. STUDY DESIGN: Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4 and 6 months after birth with blood drawn 4 to 6 weeks after third dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with BW groups and other confounding factors identified in the primary study. RESULT: In all, 244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody î¶0.35 µg ml(-1). CONCLUSION: BSI was not associated with reduced odds of World Health Organization-defined protective PCV7 responses in VLBWs.
Subject(s)
Infant, Premature, Diseases/immunology , Infant, Very Low Birth Weight/immunology , Pneumococcal Vaccines/immunology , Sepsis/immunology , Female , Heptavalent Pneumococcal Conjugate Vaccine , Humans , Infant, Newborn , Male , Retrospective StudiesSubject(s)
Altitude Sickness/complications , Bronchiolitis/ethnology , Bronchiolitis/etiology , Hospitalization/statistics & numerical data , Indians, North American , Inuit , Alaska/epidemiology , Altitude Sickness/diagnosis , Bronchiolitis/diagnosis , Humans , Infant , Oximetry , Predictive Value of Tests , Southwestern United States/epidemiologySubject(s)
Infant, Premature , Pediatrics/standards , Vaccination/standards , Diphtheria-Tetanus-Pertussis Vaccine/administration & dosage , Haemophilus Vaccines/administration & dosage , Hepatitis B Vaccines/administration & dosage , Humans , Infant, Newborn , Poliovirus Vaccine, Inactivated/administration & dosageABSTRACT
Nephrocalcinosis has been reported only infrequently in Shwachman's syndrome. We describe a case in which nephrocalcinosis occurred and speculate that this may be due to increased urinary oxalate excretion.
Subject(s)
Bone Marrow Diseases/complications , Exocrine Pancreatic Insufficiency/complications , Nephrocalcinosis/etiology , Humans , Infant , Male , SyndromeABSTRACT
Oxygen is crucial to aerobic metabolism, but excesses of oxygen or reactive oxygen species (ROS) can injure cells. This minireview addresses two transcription factors that regulate several cellular responses to oxygen tension. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric protein activated by hypoxia. Levels of HIF-1 are regulated by removal of the HIF-1alpha subunit through ubiquination and proteasomal destruction under normoxic conditions. Hypoxia inhibits the ubiquination of HIF-1alpha, preventing its destruction and allowing it to bind to hypoxia-responsive elements in gene promoter, enhancer, and intronic sequences. HIF-1 induces the expression of the hypoxia responsive genes vascular endothelial growth factor and erythropoietin. Its dysregulation has been implicated in von Hippel-Lindau disease. Nuclear factor kappaB (NFkappaB) is a family of pleotropic, dimeric transcription factors, and has a complex pattern of regulation. Under normoxic conditions, NFkappaB is bound to one of several inhibitory proteins (e.g., IkappaB) that prevent its nuclear translocation. Hyperoxia or elevations of ROS cause the ubiquination and destruction of the inhibitory proteins, freeing NFkappaB and allowing it to bind to target gene promoters. Hyperoxia in cell and animal models and acute lung injury in humans induce the expression of multiple proinflammatory cytokines through NFkappaB-dependent mechanisms. Although HIF-1 and NFkappaB respond to changes in pO(2), the precise nature of the oxygen sensing and transduction pathways is unclear in both cases. Both heme-protein and redox-sensitive mechanisms have been proposed. Improved understanding of oxygen-sensitive gene regulation may suggest targeted therapies for human disease.
Subject(s)
Gene Expression Regulation/drug effects , Oxygen/pharmacology , Transcription Factors , Animals , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Humans , Hyperoxia/genetics , Hyperoxia/metabolism , Hypoxia/genetics , Hypoxia/metabolism , Hypoxia-Inducible Factor 1 , Hypoxia-Inducible Factor 1, alpha Subunit , Models, Biological , NF-kappa B/genetics , NF-kappa B/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Oxygen/toxicity , Reactive Oxygen Species/metabolismABSTRACT
Renal tubular function was assessed in seven patients with methylmalonic acidaemia not responsive to vitamin B12. Five patients failed to concentrate their urine normally and in these patients the glomerular filtration rate was also reduced. Fractional excretion of sodium was increased in four patients, fractional excretion of potassium in one patient and in three there was a decreased tubular reabsorption of phosphate. Although possibly representing primary tubular damage these findings were thought to be consistent with adaptive changes secondary to the reduced glomerular filtration rate. Two patients had evidence of a defect of urinary acidification and several had a degree of hyporeninaemic hypoaldosteronism suggesting type 4 renal tubular acidosis. In one patient with a mild variant no renal disease was detected. Decreased renal function and tubular abnormalities were common in patients with methylmalonic acidaemia. It is likely that they are linked and essentially secondary to the tubulo-interstitial nephritis that is histologically demonstrable on renal biopsy. The failure of urinary concentrating ability and the disturbed urine acidification will contribute to the metabolic derangement during episodes of decompensation.