Pressure support ventilation combined with volume guarantee versus synchronized intermittent mandatory ventilation: a pilot crossover trial in premature infants in their weaning phase.

OBJECTIVE: To compare pressure support ventilation combined with volume guarantee (PSV-VG) to synchronized intermittent mandatory ventilation (SIMV) regarding safety, course of blood gases, and infant-ventilator interaction in premature infants. DESIGN: Prospective, two-treatment, crossover pilot study. SETTING: Tertiary care neonatal unit. PATIENTS: Twenty-five ventilated premature infants: median (range) gestational age 26.1 wks (23.1-35.7), birth weight 765 g (450-3170), age at study 5 days (2-27), in their weaning phase. INTERVENTIONS: Infants were studied for three 30-min periods, starting from SIMV, followed by PSV-VG, and back again to SIMV. After concluding the last period, all infants were switched back to PSV-VG. On the next day, infants were studied in the opposite direction. During each period, vital parameters, ventilation parameters, degree of physical activity, duration of rhythmic breathing, and the number of vital signs monitor alarms were recorded. MEASUREMENTS AND MAIN RESULTS: Nineteen infants (84%) could be successfully ventilated with PSV-VG till the next day. PSV-VG achieved a similar oxygenation level as SIMV but with significantly lower ventilation pressures. Comparable ventilation was achieved, but infants with strong respiratory drive were more liable to hyperventilation episodes during PSV-VG. Although infants breathed more rhythmically during PSV-VG, suggesting better infant-ventilator synchrony, the infants' behavioral state and the fluctuations in blood gases did not differ. CONCLUSIONS: The potentials of PSV-VG to improve infant-ventilator synchrony and to decrease pressure needed to ventilate premature lungs are promising, even though the changes were small. However, its benefits during acute illness and on the final outcome remain to be proven.

Benign course of central pontine myelinolysis in a patient with anorexia nervosa.

Central pontine myelinolysis is a rare neurologic disorder defined by symmetric demyelination of the central base of the pons. Until recently its outcome was considered invariably poor if not fatal. We report a 15-year-old female patient with severe anorexia nervosa who acutely developed a locked-in syndrome. Magnetic resonance imaging revealed a central pontine lesion. There was no serum sodium abnormality. The corticospinal and corticonuclear tracts were intact, as assessed by serial neurophysiologic studies. Finally, the patient recovered completely both clinically and radiologically. This article discusses these observations in the light of recent reports on similar benign outcomes of central pontine myelinolysis. Although electrolyte imbalances could be overestimated and the clinical significance of the radiologic lesion is uncertain, the functional assessment of the corticospinal and corticonuclear fibers might have prognostic value.

Severe metformin intoxication with lactic acidosis in an adolescent.

UNLABELLED: A 15-year-old healthy girl ingested 38.25 g (0.55 g/kg body weight) of metformin in a suicide attempt. Subsequently she developed lactic acidosis and moderate renal failure. An initial session of haemodialysis was able to treat the acidosis and reduce the toxic level of metformin. Nevertheless, a further increase in serum lactate was observed during and after the first dialysis treatment. A second session of haemodialysis was started 5 h after the end of the first session and resulted in a lowering of the lactate level and an almost total elimination of metformin. During the further clinical course, reversible acute renal failure with a maximum creatinine of 2.4 mg/dl was observed. CONCLUSION: Despite sufficient haemodialysis, the production of lactate can be greater than the elimination in the case of severe metformin intoxication. Therefore haemodialysis should be continued even in the situation of rising lactate levels during the treatment.

Complete remission of post-transplant FSGS recurrence by long-term plasmapheresis.

Focal segmental glomerulosclerosis (FSGS) is known to recur in approximately 30% of renal allografts with graft loss in about half of these cases. The exact etiology remains unclear, though a putative circulating permeability factor or loss of inhibitory substances is being discussed. Different therapeutic approaches have been used. We report on a 10-year-old Arabian boy with a recurrence of FSGS immediately after transplantation. In addition to intensifying immunosuppressive therapy with high-dose cyclosporin A and cyclophosphamide, plasmapheresis was initiated and remission was achieved after 8 months. Three weeks after cessation of plasmapheresis a relapse occurred. Plasmapheresis was resumed and remission was achieved again after four additional sessions. The interval between plasmapheresis treatments was then gradually increased and fourteen months after transplantation plasmapheresis was stopped again. Since then (1.5 years after cessation of treatment) the patient has been in complete remission without any further episode of proteinuria. In conclusion, complete and sustained remission with stable renal function was achieved in our patient by long-term plasmapheresis in combination with intensified immunosuppression. Therefore, continuation of plasmapheresis treatment should be considered even in the situation of initial non-response.

Antibiotic resistance of urinary tract pathogens and rationale for empirical intravenous therapy.

Empirical antibiotic treatment in urinary tract infection (UTI) in children must rely on surveillance data on the epidemiology and resistance patterns of common uropathogens. A retrospective analysis of bacteria isolated from children with UTI irrespective of underlying disease or pre-treatment was performed at the University Hospital of Freiburg, Germany, in 1997, and from 1999 to 2001. In the first study period, 261 positive urine samples and in the second period 684 positive samples were analyzed. Escherichia coli (57.2%) was the leading uropathogen followed by Enterococcus spp. (13.7%), Pseudomonas aeruginosa (7.0%), Proteus spp. (5.9%), Klebsiella spp. (4.7%), and Enterobacter/Citrobacter spp. (4.3%). Almost 50% of the E. coli isolates were resistant to ampicillin, but effectively no resistance against cephalosporins, aminogylcosides, ciprofloxacin, nitrofurantoin, and imipenem was observed. In Enterococcus spp. the resistance to ampicillin was about 15% and 40% to netilmicin, while none of the latter showed high-level aminoglycoside resistance. In P. aeruginosa, there was no resistance to aminoglycosides. No difference in resistance patterns between the two study periods was observed. We conclude that an empirical combination treatment of ampicillin and gentamicin, netilmicin, or tobramycin is appropriate in children with UTI independent of pre-treatment or underlying disease. This therapy should be clinically efficacious, well tolerated, and cost effective, and should prevent unnecessary development of antimicrobial resistance.

Cytokine expression of cord and adult blood mononuclear cells in response to Streptococcus agalactiae.

Neonatal bacterial sepsis is often characterized by a fulminant clinical course and highly elevated plasma levels of proinflammatory cytokines. To evaluate in vitro activation of the neonatal immune system by specific infectious stimuli, cord blood cells from healthy neonates were examined for expression of tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, and IL-8 in response to Streptococcus agalactiae (GBS), lipopolysaccharide (LPS), and lipoteichoic acid (LTA). Cytokine-expression was compared in mononuclear cells from cord and adult peripheral blood. TNF-alpha and IL-6 levels in the supernatant of cord blood cell cultures were significantly higher after stimulation with heat-killed GBS (10(7)/mL) than with LPS (2 microg/mL) or LTA (2 microg/mL) (TNF-alpha: 2215 versus 267.5 versus 40 pg/mL, p = 0.001; IL-6: 9667 versus 4909 versus 919 pg/mL, p = 0.006). mRNA expression of TNF-alpha, IL-1beta, IL-6, and IL-8 was equally pronounced after stimulation with either GBS, LPS, or LTA in cord or adult blood cells at various times. A MAb directed against the monocyte receptor molecule CD14 did not inhibit the release of cytokines in cord blood mononuclear cells after stimulation with GBS. In summary, activation of cord blood cells by infectious stimuli is comparable to the adult immune response in terms of expression of proinflammatory cytokines. GBS in particular proves to be a potent activator of the neonatal immune system when compared with LPS and LTA. CD14 seems not to be a crucial molecule for activation of cord blood cells by GBS.

Polymorphisms in the cell wall-spanning domain of the C protein beta-antigen in clinical Streptococcus agalactiae isolates are caused by genetic instability of repeating DNA sequences.

The C protein alpha- and beta-antigens are immunodominant components of the surface of Streptococcus agalactiae, the most frequent cause of neonatal sepsis. Both proteins are thought to contribute significantly to virulence of S. agalactiae. They are mainly expressed by serotypes Ia, Ib, and II. The C protein beta-antigen (Cbeta-protein) binds to the Fc portion of human IgA and seems to be of importance in bacterial resistance to mucosal immune defense mechanisms. In this study, PCR analysis of S. agalactiae isolates obtained from 189 neonates and 112 pregnant women revealed the presence of the Cbeta-protein gene in 19% and 22% of the isolates, respectively. Size polymorphisms of the PCR products within the gene region encoding the cell wall-spanning domain indicated a high degree of genetic variability. Thirteen different variants of the amplified region were differentiated among the 60 Cbeta-protein-positive isolates by sequence analysis. In all variants, the polymorphisms were caused by insertions and deletions of repetitive DNA elements that did not alter the open reading frame. Comparison of the Cbeta-protein gene polymorphisms showed a significantly higher rate of isolates carrying deletions >50 bp in serotype Ib than in serotype II isolates (p = 0.001); this was also true for neonatal isolates analyzed separately (p = 0.01). Neonatal isolates carried a higher rate of large deletions when compared with maternal isolates; this difference, however, did not reach statistical significance (p = 0.08). We hypothesize that polymorphisms in the cell wall-spanning domain of the Cbeta-protein are of functional relevance with regard to maternofetal transmission of the pathogen.

Clinical and genetic evaluation of familial steroid-responsive nephrotic syndrome in childhood.

Steroid-responsive idiopathic nephrotic syndrome (SSINS) is the most common form of nephrotic syndrome in childhood. This article reports a cohort of familial SSINS with disease onset in childhood. The clinical course in terms of age at onset, symptoms during the initial phase, renal morphology, and outcome was evaluated. Furthermore, linkage to NPHS2, the gene for autosomal-recessive steroid-resistant INS on chromosome 1, was examined. Two families with haplotypes consistent with linkage to NPHS2 were evaluated for mutations in the NPHS2 gene. Familial SSINS (32 patients from 15 families, minimal change NS in 12 of 12 biopsies) was found to be a clinically homogeneous entity. Interfamilial and intrafamilial variability with respect to the age at disease onset was low, indicating a strong genetic influence on disease onset. By linkage studies and mutational analysis, familial SSINS was found to be genetically distinct from NPHS2. This is the first report of a large cohort of familial SSINS. Exclusion of linkage to NPHS2 makes likely the existence of a distinct gene locus for SSINS.

Circadian variation of exhaled nitric oxide and urinary eosinophil protein X in asthmatic and healthy children.

Asthmatic symptoms and the frequency of admissions to hospital because of acute asthma tend to increase in the early morning hours, and it is therefore possible that airway inflammation increases during the night. To elucidate the hypothetical circadian variation of airway inflammation, we measured concentrations of exhaled nitric oxide (FeNo), urinary eosinophil protein X excretion (EPX), and forced expiratory volume in the first second (FEV1) in 20 asthmatic and 6 nonatopic nonasthmatic children every 3 h during a 21-h period. Compared with control subjects, asthmatic subjects had higher FeNo (median, 22.7 versus 10.3 ppb, p = 0.016) and lower FEV1 % predicted (median, 91.0 versus 101.9%, p = 0.045), but did not differ significantly in EPX (median, 153.8 versus 148.7 microg/mmol creatinine, p = 0.83) at 7 AM. However, differences in gender and age do not allow direct comparisons between asthmatic and control children. FeNo and EPX demonstrated a cosinelike circadian rhythm (log FeNo, p = 0.0001; log EPX, p = 0.0001) with lowest levels at 7 PM and highest at 7 AM. This was also the case for FEV1 % (p = 0.01). No difference in the amplitude of circadian rhythm was observed between asthmatic and healthy control children for log FeNo (p = 0.35), log EPX (p = 0.57), and FEV1 % (p = 0.17). A stratified analysis showed a significant circadian rhythm in the control group for log FeNo (p = 0.014) and log EPX (p = 0.0001). Our results therefore suggest a circadian rhythm of inflammatory markers, which peaks in the early morning. Rhythmicity of EPX excretion and FeNo in healthy children suggests a physiologic mechanism; however, pathologic effects during the night might occur under conditions of asthma-specific inflammation.

Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia.

Human airway epithelia express Ca2+-activated Cl- channels (CaCC) that are activated by extracellular nucleotides (ATP and UTP). CaCC is preserved and seems to be up-regulated in the airways of cystic fibrosis (CF) patients. In the present study, we examined the role of basolateral K+ channels in CaCC-mediated Cl- secretion in native nasal tissues from normal individuals and CF patients by measuring ion transport in perfused micro Ussing chambers. In the presence of amiloride, UTP-mediated peak secretory responses were increased in CF compared with normal nasal tissues. Activation of the cAMP pathway further increased CaCC-mediated secretion in CF but not in normal nasal mucosa. CaCC-dependent ion transport was inhibited by the chromanol 293B, an inhibitor of cAMP-activated hKvLQT1 K+ channels, and by clotrimazole, an inhibitor of Ca2+-activated hSK4 K+ channels. The K+ channel opener 1-ethyl-2-benzimidazolinone further increased CaCC-mediated Cl- secretion in normal and CF tissues. Expression of hSK4 as well as hCACC-2 and hCACC-3 but not hCACC-1 was demonstrated by reverse transcriptase PCR on native nasal tissues. We conclude that Ca2+-activated Cl- secretion in native human airway epithelia requires activation of Ca2+-dependent basolateral K+ channels (hSK4). Co-activation of hKvLQT1 improves CaCC-mediated Cl- secretion in native CF airway epithelia, and may have a therapeutic effect in the treatment of CF lung disease.

A randomized controlled trial on the effect of montelukast on sputum eosinophil cationic protein in children with corticosteroid-dependent asthma.

Previous adult studies demonstrated the clinical efficacy of an additional treatment with leukotriene receptor antagonists on steroid-dependent asthma, but there is little knowledge about anti-inflammatory add-on effects within the lung. In this study, we hypothesized that steroid-treated children exhibit a decrease in bronchial inflammation in induced sputum under additional treatment with montelukast. Twenty-five asthmatic children aged 6 to 14 y, who had been taking inhaled corticosteroids (400-800 microg/d budesonide) regularly for at least 12 wk, were randomized to receive additional treatment with either montelukast (5 mg orally, once daily) or placebo over a 4-wk period. As primary efficacy variable, eosinophil cationic protein (ECP) in induced sputum as direct measurement of bronchial inflammation was assessed before and after treatment. To assure a baseline level of inflammation, an ECP concentration above 100 microg/L was required. Sputum eosinophil count, concentration of exhaled nitric oxide, urinary excretion of eosinophil protein X, and quality-of-life items were considered as secondary outcome variables. After treatment with montelukast, ECP in sputum was significantly reduced (montelukast: median -975 microg/L [5 to 95% confidence interval: -4295 to 583 microg/L]; placebo: 561 microg/L [-1335 to 3320 microg/L]; p < 0.01) and the quality-of-life score had significantly improved (p < 0.05) compared with placebo. Partly explained by low baseline levels, no statistically significant change in concentration of exhaled nitric oxide (p > 0.05), urinary excretion of eosinophil protein X (p > 0.05), or eosinophil count (p > 0.05) was found. In conclusion, add-on treatment with montelukast can suppress sputum ECP in children with steroid-dependent asthma, while at the same time an improvement in quality of life items occurs.

Successful (?) therapy of hemolytic-uremic syndrome with factor H abnormality.

We report a patient with continuously recurring hemolytic-uremic syndrome due to factor H deficiency. First at the age of 3 months he showed signs of hemolytic anemia, thrombocytopenia and renal insufficiency, often recurring concomitantly with respiratory tract infections, despite weekly to twice weekly plasma substitution (20 ml/kg body weight). Now at the age of 3.5 years glomerular filtration rate is approximately 50 ml/min/1.73 m(2) and psychomotoric development is normal. Since factor H is mainly synthesized in the liver, hepatic transplantation has been proposed as curative treatment. Before justification of liver transplantation as the ultimate treatment for these patients, an international registry should be developed to optimize and standardize therapeutic alternatives.

Identification of a gene locus for Senior-Løken syndrome in the region of the nephronophthisis type 3 gene.

Senior-Løken syndrome is an autosomal recessive disease with the main features of nephronophthisis (NPH) and Leber congenital amaurosis. The gene for adolescent nephronophthisis (NPHP3) was recently localized to chromosome 3q21-q22. The hypothesis was tested that Senior-Løken syndrome (SLS) might localize to the same region by studying a kindred of German ancestry with extended consanguinity and typical findings of SLS. Twenty highly polymorphic markers located in the vicinity of the NPHP3 genetic region were tested. Haplotype analysis revealed homozygosity by descent in affected individuals, and linkage analysis yielded a parametric maximum multipoint logarithm of likelihood of odds (LOD) score of 3.14, thus identifying the first locus for SLS. The SLS1 locus is flanked by D3S1587 and D3S621 and contains a 14-cM interval that contains the whole critical NPHP3 region. Three additional families with SLS were studied, and evidence for genetic heterogeneity in one of them was found. Localization of a SLS locus to the region of NPHP3 opens the possibilities of both diseases arising by mutations within the same pleiotropic gene or two adjacent genes.

Clinical variability in 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency.

We report the identification of two new 7-year-old patients with 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency, a recently described inborn error of isoleucine metabolism. The defect is localized one step above 3-ketothiolase, resulting in a urinary metabolite pattern similar to that seen for deficiency of the latter. One patient has progressive neurodegenerative symptoms, whereas the clinical phenotype of the other patient is characterized by psychomotor retardation without loss of developmental milestones. A short-term biochemical response to an isoleucine-restricted diet was observed in both children.

Hemolytic uremic syndrome due to an altered factor H triggered by neonatal pertussis.

We report on a previously healthy newborn suffering from severe Bordetella pertussis infection who developed hemolytic uremic syndrome (HUS) a few weeks after the onset of whooping cough, with a fatal outcome. A factor H protein with abnormal mobility was found in the serum of the patient as analyzed by Western blotting, indicating that B. pertussis infection might have triggered HUS in a genetically predisposed patient.

Confirmation of the ATP6B1 gene as responsible for distal renal tubular acidosis.

Primary distal renal tubular acidosis (dRTA) type I is a hereditary renal tubular disorder, which is characterized by impaired renal acid secretion resulting in metabolic acidosis. Clinical symptoms are nephrocalcinosis, nephrolithiasis, osteomalacia, and growth retardation. Biochemical alterations consist of hyperchloremic metabolic acidosis, hypokalemia with muscle weakness, hypercalciuria, and inappropriately raised urinary pH. Autosomal dominant and rare forms of recessive dRTA are known to be caused by mutations in the gene for the anion exchanger AE1. In order to identify a gene responsible for recessive dRTA, we performed a total genome scan with 303 polymorphic microsatellite markers in six consanguineous families with recessive dRTA from Turkey. In four of these there was an association with sensorineural deafness. The total genome scan yielded regions of homozygosity by descent in all six families on chromosomes 1, 2, and 10 as positional candidate region. In one of these regions the gene ATP6B1for the ss1 subunit of the vacuolar H(+)-ATPase is localized, which has recently been identified as causative for recessive dRTA with sensorineural deafness. Therefore, we conducted mutational analysis in 15 families and identified potential loss-of-function mutations in ATP6B1in 8. We thus confirmed that defects in this gene are responsible for recessive dRTA with sensorineural deafness.

CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.

BACKGROUND & AIMS: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype-phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl- channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. METHODS: To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)-mediated Cl- secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non-DeltaF508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR-mediated Cl- secretion with patients in whom Cl- secretion was absent. RESULTS: Residual anion secretion was detected in 40% of CF patients, and was associated with later disease onset (P < 0.0001), higher frequency of PS (P < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of approximately 12%-54% of controls. CONCLUSIONS: Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR-mediated Cl- secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.

Human adolescent nephronophthisis: gene locus synteny with polycystic kidney disease in pcy mice.

In a large Venezuelan kindred, a new type of nephronophthisis was recently identified: Adolescent nephronophthisis (NPH3) is a late-onset recessive renal cystic disorder of the nephronophthisis/medullary cystic group of diseases causing end-stage renal disease at a median age of 19 yr. With the use of a homozygosity mapping strategy, the gene (NPHP3) was previously localized to chromosome 3q22 within a critical interval of 2.4 cM. In the current study, the NPHP3 genetic region was cloned and seven genes, eight expressed sequence-tagged sites, and seven microsatellites were physically localized within the critical disease interval. By human-mouse synteny analysis based on expressed genes, synteny between the human NPHP3 locus on chromosome 3q and the pcy locus on mouse chromosome 9 was clearly demonstrated, thus providing the first evidence of synteny between a human and a spontaneous murine renal cystic disease. By fluorescence in situ hybridization the chromosomal assignment of NPHP3 to chromosome 3q21-q22 was refined. Renal pathology in NPH3 was found to consist of tubular basement membranes changes, tubular atrophy and dilation, and sclerosing tubulointerstitial nephropathy. This pathology clearly resembled findings observed in the recessive pcy mouse model of late-onset polycystic kidney disease. In analogy to pcy, renal cyst development at the corticomedullary junction was found to be an early sign of the disease. Through cloning of the NPH3 critical region and mapping of expressed genes, synteny between human NPH3 and murine pcy was established, thus generating the hypothesis that both diseases are caused by recessive mutations of homologous genes.