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Recent studies suggest that both high and low levels of vitamin B12 (vitB12) may have negative health impacts. We measured VitB12 in patients with the Neurodevelopmental disorders (ND) (n = 222), comprised of Autism Spectrum Disorders, specific Developmental disorders, and Intellectual Disability (aged 2-53 years), schizophrenia (n = 401), and healthy controls (HC) (n = 483). Age-and gender-adjusted vitB12 z-scores were calculated by comparisons with a reference population (n = 76 148). We found higher vitB12 in ND (median 420 pmol/L, mean z-score: 0.30) than in HC (316 pmol/L, z-score: 0.06, P < .01) and schizophrenia (306 pmol/L, z-score: -0.02, P < .001), which was significant after adjusting for age, gender, vitB12 supplement, folate, hemoglobin, leukocytes, liver, and kidney function (P < .02). In ND, 20% (n = 44) had vitB12 above 650 pmol/L, and 1% (n = 3) had below 150 pmol/L (common reference limits). In 6.3% (n = 14) of ND, vitB12 was above 2SD of mean in the age-and gender-adjusted reference population, which was more frequent than in HC (n = 8, 1.6%), OR: 4.0, P = .001. Low vitB12 was equally frequent as in HC, and vitB12 z-scores were equal across the age groups. To conclude, vitB12 was higher in ND than in HC and schizophrenia, suggesting a specific feature of ND, which warrants further studies to investigate the underlying mechanisms.

In the fetus, the cardiac neural crest gives rise to both the thymus and the conotruncus of the heart. In newborn screening for severe T-cell lymphopenia neonates with congenital heart defects may be detected. In this study, we investigated the occurrence of T-cell lymphopenia in neonates with or without 22q11.2 deletion syndrome (del) suffering from heart defects. This retrospective cohort study included 125 patients with heart defects. T-cell receptor excision circles (TRECs), a measure for T-cell lymphopenia, were quantified by RT-PCR using stored newborn screening blood spots. Three patient groups were compared: non-conotruncal defects (n = 57), conotruncal defects (n = 42), and 22q11.2 del with conotruncal defects (n = 26). Significantly lower TREC values were detected in patients with 22q11.2 del and conotruncal heart defects compared to those with non-syndromic conotruncal (p p p = 0.152). Low TREC levels were obtained in neonates treated with heart surgery/intervention within 2 weeks after birth and in those with a fatal outcome (p = 0.02) independent of patient group. A correlation was found between low TREC numbers and oxygen saturation, SpO2 below 95% (p = 0.017). The SpO2 was significantly lower in the non-syndromic conotruncal group compared to non-conotruncal (p p = 0.015). No correlation was found between low neonatal TRECs and infections needing hospitalization later in life (p = 0.135). Patients with 22q11.2 del and conotruncal defects have significantly lower TREC levels compared to patients with heart defects without this syndrome.

Aim To evaluate health-related quality of life, mental health and treatment-related stress responses in children with primary antibody deficiency and both their parents. Methods Children and their parents completed the standardised questionnaires Pediatric Quality of life Inventory, Strength and Difficulties Questionnaire and Impact of Event Scale. Parents also completed standardised questionnaires regarding their own mental health and quality of life. The results were compared to those of healthy children, kidney transplanted children and children in remission from acute lymphoblastic leukaemia. Results Children with primary antibody deficiency reported a poorer health-related quality of life compared to healthy children and children in remission from acute lymphoblastic leukaemia. They reported poorer mental health compared with healthy children. Mothers of children with primary antibody deficiency reported poorer mental health compared to mothers of healthy children but comparable to mothers of chronically ill children. Parents reported a similar quality of life as the general Norwegian population. Treatment with subcutaneous immunoglobulin infusions at home is generally well tolerated, but some report severe treatment-related stress. Conclusion Primary antibody deficiency has a significant impact on quality of life and mental health of affected children. Patients and parents with severe treatment-related stress should be identified and helped.

Immunodeficiency is one of the key features of 22q11.2 deletion syndrome (del), and it is seen in approximately 75% of the patients. The degree of immunodeficiency varies widely, from no circulating T cells to normal T cell counts. It has been hypothesized that the low number of T cells may at least in part be due to increased apoptosis of T cells. Increased spontaneous T cell apoptosis has been reported in one patient with 22q11.2del, but this has not been further investigated. A national cohort of patients with a proven heterozygous deletion of chromosome 22q11.2 diagnosed by FISH or MLPA and a group of age and sex matched controls were studied. Spontaneous and activation-induced apoptosis, in addition to FAS expression on lymphocytes, were measured using flow cytometry. Serum levels of FASL were analyzed using ELISA. There was no increased spontaneous apoptosis in patients with 22q11.2del. Upon activation, anti-FAS-induced apoptosis was significantly increased in patients compared to those in controls, while there was no difference in activation induced cell death or activated cell autonomous death. We also found a significant increase in expression of FAS on freshly isolated lymphocytes from patients, while there was no difference in serum levels of FASL. Patients with congenital heart defects (CHD) had significantly higher serum levels of FASL compared to non-CHD patients. We have shown increased FAS expression on lymphocytes from patients with 22q11.2del as well as increased levels of FASL in patients with CHD. Those changes may contribute to the pathophysiology of the 22q11.2del.

Horizontal transfer of antibiotic resistance determinants contributes to dissemination of antibiotic resistance. Such transfer of resistance genes within the human gut has been documented in some in vivo studies. The present study investigated seven blaCTX-M-1-carrying Escherichia coli isolates from three consecutive faecal samples collected from one cystic fibrosis patient in a nine-months period, by analysing whole genome sequencing data. The analyses showed that the seven E. coli isolates represented three genetically diverse strains. All isolates contained blaCTX-M-1-carrying Incl1 plasmids that shared a common 101 kb backbone differing by only four SNPs. The plasmids harboured by the three different E. coli strains varied within limited regions suggestive of recombination events, according to the phylogenetic topology of the genomes of the isolates harbouring them. The findings strongly suggest that horizontal transfer of a blaCTX-M-1-carrying plasmid had occurred within the patient´s gut. The study illustrates the within-host diversity of faecally carried resistant E. coli isolates and highlights the value of collecting multiple bacterial colonies from longitudinally collected samples to assess faecal carriage of resistant enterobacteria. The clustering of the plasmids with the corresponding E. coli strains carrying them indicates that the plasmids appear to have adapted to their respective E. coli hosts.

Background Four patients from three Norwegian families presented with a common skin phenotype of warts, molluscum contagiosum, and dermatitis since early childhood, and various other immunological features. Warts are a common manifestation of human papilloma virus (HPV), but when they are overwhelming, disseminated and/or persistent, and presenting together with other immunological features, a primary immunodeficiency disease (PIDD) may be suspected. Methods and results The four patients were exome sequenced as part of a larger study for detecting genetic causes of primary immunodeficiencies. No disease‐causing variants were identified in known primary immunodeficiency genes or in other disease‐related OMIM genes. However, the same homozygous missense variant in CARMIL2 (also known as RLTPR) was identified in all four patients. In each family, the variant was located within a narrow region of homozygosity, representing a potential region of autozygosity. CARMIL2 is a protein of undetermined function. A role in T‐cell activation has been suggested and the mouse protein homolog (Rltpr) is essential for costimulation of T‐cell activation via CD28, and for the development of regulatory T cells. Immunophenotyping demonstrated reduced regulatory, CD4+ memory, and CD4+ follicular T cells in all four patients. In addition, they all seem to have a deficiency in IFN γ ‐synthesis in CD4+ T cells and NK cells. Conclusions We report a novel primary immunodeficiency, and a differential molecular diagnosis to CXCR4‐,DOCK8‐,GATA2‐,MAGT1‐,MCM4‐,STK4‐,RHOH‐,TMC6‐, and TMC8‐related diseases. The specific variant may represent a Norwegian founder variant segregating on a population‐specific haplotype.

Aim: To find out if subjects with 22q11.2 deletion syndrome (DS) have a different velopharyngeal anatomy which could cause velopharyngeal insufficiency (VPI). Methods: A prospective study of 16 subjects >16 years of age with 22q11.2 DS, without overt cleft palate and without previous VPI surgery, and 48 healthy controls >18 years of age were included in the study. Speech was recorded and scored blindly by two independent senior speech therapists. All 64 individuals had MRI scans, which were analyzed blindly by a consultant radiologist. Results: Subjects with 22q11.2 DS had a mild degree of weak pressure consonants (mean score); borderline to mild degree of hypernasality and audible nasal emission (mean score). All controls had normal speech. When comparing subjects (22q11.2 DS) to controls, we found the subjects to have the following: A shorter distance between left and right points of origin of the levator veli palatini muscle (LVP) (p

Newborns with severe T-cell lymphopenia, including those with 22q11.2 deletion syndrome (DS), have low numbers of T-cell receptor excision circles (TRECs). The aim of this study was to determine a possible correlation between neonatal TRECs in 22q11.2DS and the development of different phenotypes to elucidate the prognostic value of TREC in this disease.In this national survey including 46 patients with 22q11.2DS born after 2005, TREC levels were determined using stored newborn screening blood spots on filter cards. Patients were grouped into quartiles according to their TREC values, except the two infants with thymus aplasia.The two patients with thymic aplasia had no detectable TREC. The rest had no severe clinical immunodeficiency. There was a significant correlation between low TRECs and the proportion of patients with CD3(+)CD4(+)T-cells below the 5th percentile of healthy infants (p = 0.027) as well as the proportion with an abnormal thymus feature either no thymus or remnant thymus as observed during heart surgery (p = 0.022). Significantly lower TRECs (p = 0.019) were found in patients with cardiac defects compared to no such defects. Patients within the lowest quartile of TREC values (71 TRECs/μL, n = 11) had more frequent severe cardiac defects than the other quartiles (p = 0.010). Eight of these patients in the lowest quartile needed an operation/intervention within two weeks after birth or died because of a cardiac defect.The low TREC values not only correlate with decreased T-cell immunity, but also with the occurrence of heart defects in the patients.

Aim We evaluated a strict strategy that aimed to avoid fluctuations in glucose infusion rates (GIRs) and assessed the independent effects of maximal daily GIRs on the hyperglycaemia risk among extremely low birth weight (ELBW) infants receiving early enhanced parenteral nutrition. Methods This study comprised all ELBW infants admitted to the neonatal intensive care unit of Oslo University Hospital Rikshospitalet, Norway, before (2007-2009) and after (2012-2013) implementing a strict GIR strategy. Severe hyperglycaemia was defined as two consecutive blood glucose values over 12 mmol/L. Maximum daily GIRs (mg/kg/min) were categorised into low ( 7.0). Mixed effects logistic regression modelling for repeated measurements was applied to investigate independent determinants of hyperglycaemia. Results We included 1293 treatment days for 195 infants. The maximum daily GIR decreased (6.3 versus 5.8 mg/kg/min), while mean daily glucose and energy intakes were maintained in the post-strategy period. The prevalence of severe hyperglycaemia (48% versus 23%), insulin use (39% versus 16%) and mortality (26% versus 10%) fell. Intermediate GIR (odds ratio 2.11) and high GIR (odds ratio 2.85) were significant independent predictors of severe hyperglycaemia compared to low GIR. Conclusion A strict GIR strategy reduced the risk of severe hyperglycaemia and adverse outcomes.

Background Respiratory syncytial virus (RSV) infection is an important cause of hospitalization in previously healthy infants. Immunological mechanisms predisposing infants to severe disease are poorly understood. Early biomarkers for disease severity may assist clinical decisions. We investigated T-cell receptor excision circles (TREC), episomal DNA made during thymic T-cell receptor rearrangement, and a marker for thymus activity, both during disease and in neonatal screening cards as a risk factor for RSV disease severity. Methods One hundred thirteen patients hospitalized with RSV infection

WOS: 000393996800025, PubMed: 27577878, Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes., South-Eastern Norway Health Authority; American Women's club of Oslo; National Human Genome Research InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); National Heart, Lung, and BloodUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [U54HG006542]; Jeffrey Modell Foundation; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI-120989], Funding for the work performed in Oslo was provided by the South-Eastern Norway Health Authority, and A. S.-P. received research scholarship from the American Women's club of Oslo. The BHCMG is supported by the National Human Genome Research Institute and the National Heart, Lung, and Blood (U54HG006542). Funding was also provided by the Jeffrey Modell Foundation and NIH AI-120989 (to J.S.O.).

Source at https://doi.org/10.1371/journal.pone.0187618 We prospectively studied the consequences of extensive antibiotic treatment on faecal carriage of antibiotic-resistant enterobacteria in a cohort of children with cystic fibrosis (CF) and a cohort of children with cancer compared to healthy children with no or low antibiotic exposure. The study was conducted in Norway in a low resistance prevalence setting. Sixty longitudinally collected faecal samples from children with CF (n = 32), 88 samples from children with cancer (n = 45) and 127 samples from healthy children (n = 70) were examined. A direct MIC-gradient strip method was used to detect resistant Enterobacteriaceae by applying Etest strips directly onto agar-plates swabbed with faecal samples. Whole genome sequencing (WGS) data were analysed to identify resistance mechanisms in 28 multidrug-resistant Escherichia coli isolates. The prevalence of resistance to third-generation cephalosporins, gentamicin and ciprofloxacin was low in all the study groups. At inclusion the prevalence of ampicillin-resistant E. coli and trimethoprim-sulfamethoxazole-resistant E. coli in the CF group compared to healthy controls was 58.6% vs. 28.4% (p = 0.005) and 48.3% vs. 14.9% (p = 0.001), respectively, with a similar prevalence at the end of the study. The prevalence of resistant enterobacteria was not significantly different in the children with cancer compared to the healthy children, not even at the end of the study when the children with cancer had been treated with repeated courses of broad-spectrum antibiotics. Children with cancer were mainly treated with intravenous antibiotics, while the CF group mainly received peroral treatment. Our observations indicate that the mode of administration of antibiotics and the general level of antimicrobial resistance in the community may have an impact on emergence of resistance in intestinal enterobacteria during antibiotic treatment. The WGS analyses detected acquired resistance genes and/or chromosomal mutations that explained the observed phenotypic resistance in all 28 multidrug-resistant E. coli isolates examined.

Human phosphoglucomutase 3 (PGM3) catalyzes the conversion of N-acetyl-glucosamine (GlcNAc)-6-phosphate into GlcNAc-1-phosphate during the synthesis of uridine diphosphate (UDP)-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways. We identified three unrelated children with recurrent infections, congenital leukopenia including neutropenia, B and T cell lymphopenia, and progression to bone marrow failure. Whole-exome sequencing demonstrated deleterious mutations in PGM3 in all three subjects, delineating their disease to be due to an unsuspected congenital disorder of glycosylation (CDG). Functional studies of the disease-associated PGM3 variants in E. coli cells demonstrated reduced PGM3 activity for all mutants tested. Two of the three children had skeletal anomalies resembling Desbuquois dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability. However, these additional features were absent in the third child, showing the clinical variability of the disease. Two children received hematopoietic stem cell transplantation of cord blood and bone marrow from matched related donors; both had successful engraftment and correction of neutropenia and lymphopenia. We define PGM3-CDG as a treatable immunodeficiency, document the power of whole-exome sequencing in gene discoveries for rare disorders, and illustrate the utility of genomic analyses in studying combined and variable phenotypes.

Background There are no previous blinded studies for comparison of preoperative versus postoperative perceptual speech assessments when using a pharyngeal flap for treating velopharyngeal insufficiency (VPI) in patients diagnosed with 22q11.2 deletion syndrome. The aim of the study was to evaluate the effect of superiorly based pharyngeal flap surgery on speech in these patients using blinded judgments of experienced speech therapists. Methods A retrospective study of 12 consecutive patients who had undergone pharyngeal flap surgery for treatment of VPI between 2002 and 2009 was conducted. Seven girls and 5 boys between 4 and 15 (median, 6) years old at the time of surgery were included in the study. Six patients were born with a submucous cleft palate (including 2 occult), and 1 patient, with an overt cleft palate. The remaining 5 patients had no signs of a palatal pathology. All palatal clefts had been repaired before pharyngeal flap surgery except in 2 patients with occult submucous cleft palate. Preoperative and postoperative audio recordings were blinded for scoring independently by 3 senior speech therapists. Results There was a significant improvement in hypernasality (P = 0.002), audible nasal emission (P = 0.033), weak pressure consonants (P = 0.008), and speech intelligibility (P = 0.021) after pharyngeal flap surgery. Hyponasality did not develop significantly with surgery. One patient was diagnosed with obstructive sleep apnea. Conclusions Superiorly based pharyngeal flap resulted in a significant speech improvement in 12 consecutive patients with 22q11.2 deletion syndrome having VPI.

The aims of the study were to examine tooth and enamel disturbances in individuals with 22q11.2 deletion syndrome and to analyze associations with medical conditions, birth characteristics and blood values of calcium and PTH.Fifty individuals participated in the study (27 females, median age 10 years, range 1.5-44). Congenital absence of teeth was studied on orthopantomograms; 1148 teeth were examined, both clinically and radiologically, and enamel hypomineralizations and hypoplasias were recorded. Medical history and findings were recorded as part of a larger study on the manifestations of 22q11.2-deletion syndrome in Norway.Tooth agenesis was observed in 15% of study participants. Sixty-six percent of the participants and 26.0% of teeth presented with enamel disturbances. Of these, 12 individuals (24.0%) and 215 teeth (18.7%) had hypomineralizations and four individuals (8.0%) and 86 teeth (7.5%) had hypoplasias. Seventeen participants (34.0%) presented with both types of disturbance, but rarely in the same tooth. Only two teeth (0.17%) had both types of disturbance. Hypomineralizations were twice as frequent in permanent as in primary teeth. No correlations were found to medical conditions, except that participants with congenital cardiac anomalies presented with fewer total enamel disturbances and hypomineralizations in permanent teeth than those without.Enamel disturbances were frequently seen. There were more hypomineralizations than hypoplasias. Hypoparathyroidism and/or hypocalcemia are not clear etiological factors for enamel disturbances and there were no major correlations between medical conditions and enamel disturbances.

[This corrects the article DOI: 10.1371/journal.pone.0187618.].

Patients with the 22q11.2 deletion syndrome display a wide phenotypic variation that is important for clinical follow-up. In this national survey of 60 patients (ages 1 to 54 years) diagnosed by Fluorescence in situ hybridization test, data were collected from medical records, a physical examination, and a semistructured interview. Ultrasound investigation of the kidneys was also performed. In addition, multiplex ligation probe amplification assay was performed to detect deletion size. Phenotypic features leading to the genetic diagnosis were noted. The patients showed a variety of organ malformations including 39 with heart anomalies. Only 20 individuals had been diagnosed with 22q11.2 DS in the first year of life. Four patients had renal and five males had genital malformations. The increased infection susceptibility (excluding otitis media) and most feeding difficulties subsided during early childhood. Speech difficulties started early and were a major problem for many patients at least until 10 years of age. Ten patients developed kyphoscoliosis in late childhood. In teenagers and adults, abnormal social behavior, learning disabilities, and psychiatric symptoms dominated. Our study which also includes adult patients emphasizes a marked change in challenges in individuals with the 22q11.2 deletion syndrome with increasing age.

Cell suspensions containing an average of 78% lymphocytes were obtained from synovial tissues of 26 patients with rheumatoid arthritis and 10 patients with juvenile rheumatoid arthritis. These cells were shown to mediate cytotoxicity against 51Cr-labeled chicken erythrocytes sensitized with a rabbit anti-chicken erythrocyte antiserum. Nylon column filtration of the cells increased the proportion of lymphocytes and usually also the cytotoxicity, which suggested that at least some of the effector cells were lymphocytes. The cytotoxic activity of the cells obtained from rheumatoid synovial tissue was always lower than that obtained with the patients' peripheral blood lymphocytes. No significant change in cytotoxicity of normal peripheral blood lymphocytes was observed after these cells had been treated in the same manner as the rheumatoid synovial tissues.

A controlled intervention study was performed in a paediatric hospital in Russia to improve antibiotic use and to see whether improvements persisted. During October-December 2002, clinical and microbiological data, antibiotic use, costs and outcome were recorded at two wards for gastrointestinal infections (GIIs) and two wards for respiratory tract infections (RTIs). Guidelines for diagnosis and treatment of infections were developed and implemented at one ward for GIIs and one ward for RTIs in 2003. The other two wards served as controls. The same data were recorded during the same 3-month periods in 2003 and 2004. At the intervention ward, the percentage of patients with GII who received antibiotics decreased from 94% in 2002 to 41% in 2003, but increased to 73% in 2004. In RTI patients these percentages were 90% in 2002, 53% in 2003 and 83% in 2004. The proportions of patients who received antibiotics in 2004 were still lower than in 2002: risk difference (RD)=0.217 (P

OBJECTIVE. The purpose of this work was to assess the annual incidence of arthritis in children and describe early disease and patient characteristics, microbiologic features, and immunogenetic factors in children with different subgroups of childhood arthritis.PATIENTS AND METHODS. A population-based multicenter study was performed in southeastern Norway between June 1, 2004, and May 31, 2005. The total population of children under 16 years of age was 255303. Physicians were asked to refer their patients with suspected arthritis to the local department of pediatrics or rheumatology. The children were assessed on the basis of clinical, radiologic, and laboratory examinations at inclusion and followed up at 6 weeks, 6 months, and thereafter as long as clinically indicated. A chart review was performed to identify patients with arthritis who had not been included prospectively.RESULTS. The total annual incidence of arthritis was 71 per 100000 children. Transient arthritis, juvenile idiopathic arthritis, postinfectious arthritis, and infectious arthritis were found in 43, 14, 9, and 5 of 100000 children, respectively. The incidence was higher in children under the age of 8 years than in older children (107 vs 34 per 100000). Arthritis occurred more frequently in boys than in girls before the age of 8 years but not thereafter. The median age of onset was lower in children with infectious arthritis than in those with other types of arthritis. Monarthritis was less frequent in patients with juvenile idiopathic arthritis than in the other subgroups (64% vs 83%–100%). Ten percent of the patients had poststreptococcal reactive arthritis, and only 1 had enteropathic arthritis. Autoantibodies and the presence of HLA-B27 were associated with juvenile idiopathic arthritis.CONCLUSIONS. The annual incidence of childhood arthritis was 71 per 100000 children. We found several factors that may help in differentiating between subgroups of arthritis.

Background Atypical mycobacteria can cause systemic infections in patients with certain types of immunodeficiency. Methods Clinical samples were decontaminated and cultured to assess the presence of mycobacterial species. Gene sequencing was performed to reveal interferon-gamma receptor 1 (IFN-gamma R1) deficiency. Results The index patient received a diagnosis of dominant IFN-gamma R1 deficiency during treatment for a serious infection due to atypical mycobacteria. She belongs to a Norwegian multiplex family comprising 3 generations and 5 patients with dominant IFN-gamma R1 deficiency. Four of these patients have been treated with tuberculostatics because of extensive infection due to atypical mycobacteria, such as Mycobacterium avium-intracellulare, Mycobacterium scrofulaceum, Mycobacterium bovis (bacille Calmette-Guerin), Mycobacterium bohemicum, and Mycobacterium gordonae. Two of the patients have also received subcutaneous injections of IFN-gamma. One family member with the deficiency has not received treatment and is still healthy at 13 years of age. Conclusions Serious infection due to atypical mycobacteria should initiate a search for primary immunodeficiencies, particularly IFN-gamma R1 deficiency. Treatment with IFN-gamma should be started when serious infection due to atypical mycobacteria is verified and dominant partial IFN-gamma R1 deficiency is suspected.

Coagulase-negative staphylococci (CoNS) are the major cause of nosocomial bacteraemia in neonates. The aim of this study was to investigate whether persistent strains of CoNS possess specific bacterial characteristics as compared with sporadic non-cluster isolates. In total, 180 blood culture isolates (95 contaminants and 85 invasive isolates) obtained from a single neonatal unit over a 12-year period were studied. Pulsed-field gel electrophoresis (PFGE) identified 87 persistent CoNS strains (endemic clones). The two largest PFGE clusters belonged to a single clonal complex according to multilocus sequence typing. Patients colonised or infected with endemic clones were of lower gestational age than those infected with non-cluster strains. One Staphylococcus haemolyticus cluster appeared to selectively colonise and infect the most extreme pre-term infants. Endemic clones were characterised by high levels of antibiotic resistance and biofilm formation. All 51 isolates belonging to the two largest PFGE clusters were ica operon-positive. Genes encoding Staphylococcus epidermidis surface protein B and the production of phenol-soluble modulins (PSMs) were also more prevalent among endemic clones than among non-cluster strains. However, endemic clones were not more prevalent among invasive isolates than among contaminants. These findings indicate that multiple selective factors, including antibiotic resistance, biofilm formation, surface proteins with adhesive properties, and PSMs regulated by agr, increase the ability of CoNS to persist in a hospital environment. It may be more prudent, when searching for new therapeutic targets, to focus on ubiquitous components of CoNS instead of putative virulence factors that do not clearly contribute to increased invasive capacity.

The elevated serum alpha fetoprotein (AFP) concentration in ataxia–telangiectasia (A–T) patients has been known for decades, but the individual variation of AFP levels over time has not been studied. We have followed 12 patients (five girls and seven boys) for 1–12 years (mean 5.5 years) measuring in each patient AFP 2–8 (mean 4) times. Serum AFP levels were increased in all patients, mean 168.7 (range 40–373) kU/L, and without significant differences between the patients. There was a significant age related difference in the serum AFP level. A positive linear relationship (r ¼ 0.61, p ¼ 0.04) could be found between AFP level and age. Albumin levels were within normal range and did not change with age. Four patients had slightly increased aspartate aminotransferase (AST) levels. None of the patients had serological evidence of infectious hepatitis, and none had increased levels of carcinoembryonic antigen. Repeated standardized observations of gait function revealed no major difference in neurological deterioration between our patients. All had classical A–T disease and mainly truncating mutations; 21 out of 24 possible mutations were either frameshift or nonsense. Four were homozygous for the Norwegian ATM founder mutation. No correlation between serum AFP levels and the different ATM genotypes could be found. We conclude that serum AFP is not only elevated, but also is continuously increasing with age in patients with classical A–T disease.

Aim: To present a possible association between cerebral venous thrombosis (CVT) and infection with Escherichia coli. Methods: Four neonates with deep CVT occurring during an E. coli infection are presented. Results: In these patients the thrombotic disease was found by Doppler ultrasonography. The thrombosis involved at least the sagittal sinus and the transverse sinus according to subsequent MRI scans. The E. coli strains did not produce verotoxin or haemolysin. Disseminated intravascular coagulation was not demonstrated. Three patients presented with seizures. At discharge, all of the patients had signs of neurological damage, but two of them have improved significantly since then. None of the patients has had recurrent (venous) thrombosis. Conclusion: E. coli infections in neonates may predispose to CVT, a finding that has clinical implications.

The 22q11.2 deletion syndrome (22q11.2 DS), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:4000 births. These patients may suffer from affection of many organ systems with cardiac malformations, thymic hypoplasia or aplasia, hypoparathyroidism, palate anomalies and psychiatric disorders being the most frequent. The incidence of autoimmune diseases is increased in older patients. The aim of the present study was to examine a cytokine profile in patients with 22q11.2 DS by measuring a broad spectrum of serum cytokines. Patients with a proven deletion of chromosome 22q11.2 (n = 55) and healthy individuals (n = 54) recruited from an age- and sex-comparable group were included in the study. Serum levels of 27 cytokines, including chemokines and growth factors, were analysed using multiplex technology. Interferon-inducible protein 10 (IP-10) was also measured by ELISA to confirm the multiplex results. The 22q11.2 DS patients had distinctly and significantly raised levels of pro-inflammatory and angiostatic chemokine IP-10 (P

Importance Efforts to optimize early parenteral nutrition (PN) in extremely low-birth-weight (ELBW) infants to promote growth and development may increase hyperglycemia risk. Recent studies have identified an association between early hyperglycemia and adverse outcomes in ELBW infants. Objectives To examine the prevalence of early hyperglycemia and clinical outcomes among ELBW infants before (2002-2005) and after (2006-2011) the implementation of an early enhanced PN protocol and to assess the independent effects of early enhanced PN and early hyperglycemia on mortality. Design, Setting, and Participants Observational cohort study in a level III neonatal intensive care unit. Prospectively collected clinical data in the neonatal intensive care unit’s medical database, nutritional information, and blood glucose levels were merged for analysis. All ELBW infants born between January 1, 2002, and December 31, 2011, without lethal malformations and still alive at 12 hours of life were eligible for inclusion in the study. Main Outcomes and Measures Mortality was the main outcome measure. Severe hyperglycemia was defined as 2 consecutive blood glucose levels exceeding 216 mg/dL at least 3 hours apart. A multivariable logistic regression model was applied to determine the independent effects of early enhanced PN and hyperglycemia on mortality. Results In total, 343 infants were included in the study, 129 in a historical comparison group before the enhanced PN protocol and 214 in the early enhanced PN group. Baseline characteristics were similar between the study groups. After the introduction of early enhanced PN, the prevalence of severe hyperglycemia during the first week of life was higher in the early enhanced PN group (11.6% [15 of 129] vs 41.6% [89 of 214], P P = .003). When adjusting for background characteristics, treatment, and nutritional data, early severe hyperglycemia remained a strong independent risk factor for death (odds ratio, 4.68; 95% CI, 1.82-12.03), together with gestational age (odds ratio, 0.62; 95% CI, 0.49-0.79). Conclusions and Relevance The implementation of an enhanced PN protocol was correlated with an increased prevalence of severe hyperglycemia and higher mortality. In the multivariable analysis, an enhanced PN regimen per se was not predictive of mortality, whereas early severe hyperglycemia remained strongly predictive of death. To avoid detrimental effects on outcomes in ELBW infants, the optimal composition of early PN to avoid postnatal growth failure must be carefully balanced against hyperglycemia risk.

Summary The soluble branched yeast β-1,3-D-glucan (SBG) belongs to a group of carbohydrate polymers known to exert potent immunomodulatory effects when administered to animals and humans. A new oral solution of SBG has been developed for local application to the oropharyngeal and oesophageal mucosa in order to strengthen the defence mechanisms against microbial and toxic influences. In the present study oral administration of SBG has been investigated primarily for assessment of safety and tolerability in an early phase human pharmacological study (phase I). Eighteen healthy volunteers were included among non-smoking individuals. The study was an open 1 : 1 : 1 dose-escalation safety study consisting of a screening visit, an administration period of 4 days and a follow-up period. Groups of six individuals received SBG 100 mg/day, 200 mg/day or 400 mg/day, respectively, for 4 consecutive days. The dose increase was allowed after a careful review of the safety data of the lower dose group. No drug-related adverse event, including abnormalities in vital signs, was observed. By inspection of the oral cavity only minor mucosal lesions not related to the study medication were seen in seven subjects. Repeated measurements of β-glucan in serum revealed no systemic absorption of the agent following the oral doses of SBG. In saliva, the immunoglobulin A concentration increased significantly for the highest SBG dose employed. SBG was thus safe and well tolerated by healthy volunteers, when given orally once daily for 4 consecutive days at doses up to 400 mg.

Objectives. To investigate the incidence, causes, predictors, and outcomes of septicemia in the first week of life in a national cohort of extremely premature infants. Methods. A prospective study of survival of all infants with gestational age of Results. Of 462 included infants, VEOS occurred for 15 (32.5 per 1000 population) and EOS for 15 (35.5 per 1000 population). The most prevalent bacteria were Escherichia coli in VEOS (n = 9) and staphylococci (coagulase-negative staphylococci and Staphylococcus aureus) (n = 15) in EOS. Case fatality rates were 40% and 13%, respectively. Independent predictive factors for VEOS were clinical chorioamnionitis (odds ratio [OR]: 10.5; 95% confidence interval [CI]: 3.3-33.4) and high maternal age (OR: 1.2; 95% CI: 1.0–1.3), whereas not receiving systemic antibiotic therapy within 2 days of age (OR: 13.6; 95% CI: 3.7–50.2) and receiving nasal continuous positive airway pressure (n-CPAP) support at 24 hours of age (OR: 9.8; 95% CI: 2.5–38.4) independently predicted septicemia after the first day of life. Conclusions. Whereas vertically transmitted septicemia was dominated by Gram-negative bacteria, with predictors being exclusively of maternal origin, EOS was dominated by typically nosocomial flora, with n-CPAP treatment at 24 hours of age being a powerful predictor. Early n-CPAP treatment, as opposed to mechanical ventilation, as a powerful predictor of septicemia in the early neonatal period, even with adjustment for early systemic antibiotic treatment, is a new observation among extremely premature infants that warrants additional study.

We report on a family with three stillborn males, three affected males who were small for gestational age and died within 8 months, and one male who died at age 5 years. This boy had cone-shaped teeth and oligoodontia. He had serious bacterial infections and inflammatory bowel disease. Mutations in the NF-kappaB essential modulator (NEMO) gene have recently been shown to be the cause of a group of ectodermal dysplasia and immunodeficiency disorders (EDA-ID). Analysis of the NEMO gene revealed a nucleotide change in the consensus sequence of the splicing donor site of exon 6 IVS6 + 5G --> A(1027 + 5G --> A), which has not previously been described in EDA-ID. RT-PCR analysis of fibroblast RNA from an aborted affected male fetus demonstrated a skipping of exons 4, 5, and 6 which resulted in a truncated protein of about 35 kDa revealed by NEMO antibody. The skipping of exons 4, 5, and 6 did not affect the ORF of the C-terminal of NEMO encoded by exons 7, 8, 9, and 10, which contains a coiled-coil motif (CC2), a leucin-zipper (LZ), and a zinc finger motif (ZF) sub-domains of NEMO. IkappaBalpha degradation was strongly impaired in the fetal fibroblasts, suggesting an impaired NF-kappaB signaling. One healthy carrier had a completely skewed X-inactivation pattern with the normal X active, whereas the two other carriers had a random X-inactivation pattern. This family may represent a new phenotype within the EDA-ID disorders. From the heterogeneity in X-inactivation phenotype, we conclude that this mutation is not deleterious enough to be lethal for peripheral blood cells.

Fungal infections by molds like Aspergillus fumigatus are an increasing health problem which can be fatal in immuno-compromised patients. In healthy individuals, these infections are easily eliminated by the innate and acquired immune system. Complement factor 3 (C3) has a key place within the complement cascade and C3 RNA expression can therefore be used to monitor an impending immune response. Employing a liver cell line (HepG2) as a model system, we have examined their responses to A. fumigatus or beta-glucan, a major component of the fungal wall. C3 RNA expression was increased after stimulation with both LPS and A. fumigatus as well as after incubation with beta-glucan, although with different kinetics. C3 protein release into the supernatant followed an inverse bell-shaped curve when cells were incubated with A. fumigatus or beta-glucan while during LPS stimulation, the release was more stable. HepG2 cells also express Toll-like receptors (TLRs) and both for TLR2 and TLR4, an expression increase was found. These data demonstrate that liver cells are able to react specifically to a fungal pathogen without the help of Kupffer cells.

SUMMARY Eleven Norwegian patients (aged 2–33 years, seven males and four females) with Ataxia-telangiectasia (A-T) and their parents were investigated. Five of the patients were homozygous for the same ATM mutation, 3245delATCinsTGAT, a Norwegian founder mutation. They had the lowest IgG2 levels; mean (95% confidence interval) 0·23 (0·05–0·41) g/l versus 0·91 (0·58–1·26) g/l in the other patients (P = 0·002). Among the 11 A-T patients, six had IgG2 deficiency, six had IgA deficiency (three in combination with IgG2 deficiency) and seven had low/undetectable IgE values. All patients had very low levels of antibodies to Streptococcus pneumoniae 0·9 (0·4–1·4) U/ml, while normal levels were found in their parents 11·1 (8·7–13·4) U/ml (P

Item does not contain fulltext The release of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10 upon stimulation with non-viable conidia and hyphal fragments from Aspergillus fumigatus was investigated in an ex vivo whole-blood model. In healthy volunteers, high numbers of conidia (between 10(6) and 3 x 10(8)/ml) induced a moderate release of TNF-alpha and IL-6. Hyphal fragments (2.5 x 10(5)/ml) were more potent in stimulating the release of these pro-inflammatory cytokines. Although some IL-10 release was observed upon stimulation with either conidia or hyphal fragments, it was not significantly different from that in unstimulated controls. In comparison, in whole blood obtained from 4 patients with chronic granulomatous disease (CGD), a high release of pro-inflammatory cytokines together with a significantly higher IL-10 release than in the healthy controls was seen after stimulation with A. fumigatus. In conclusion, A. fumigatus can trigger the release of pro-inflammatory cytokines in a human whole-blood system, which is likely to be central to the activation of antifungal defence mechanisms. In contrast, A. fumigatus stimulates a higher release of anti-inflammatory cytokines in CGD patients, which may suggest that a dysregulation between pro- and anti-inflammatory cytokines contributes to the increased susceptibility to invasive aspergillosis in this patient group.

Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.

Inflammation elicits an acute phase response, which includes changes in plasma concentrations of a number of cytokines, reflecting changes in their gene transcription in the liver. In this study, the induction of complement factor 3 (C3) was investigated in HepG2 cells, a human hepatoma cell line often used as a model system for cytokine-dependent expression of acute phase proteins of the liver. By using a very sensitive RT-PCR assay, the amount of mRNA for C3 was measured after induction with lipopolysaccharide (LPS) and interleukin-6 (IL-6). Both substances were found to up-regulate C3 gene expression. C3 mRNA level was lower in LPS-treated cells compared to IL-6 induction and also reached maximum expression at an earlier time point. These findings suggest a coordinate stimulation of C3 expression in the hepatocytes, which then maintains the host response to infectious agents.

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of primary immunodeficiencies, a proportion of which are due to mutations in either of the 2 recombination activating genes (RAG)-1 and -2, which mediate the process of V(D)J recombination leading to the assembly of antigen receptor genes. It is reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one allele and maintain partial V(D)J recombination activity, which accounts for the generation of residual, oligoclonal T-lymphocytes; (3) in a third group of patients, findings were only partially compatible with OS, and these patients, who also carried at least one missense mutation, may be considered to have atypical SCID/OS; (4) patients with engraftment of maternal T cells as a complication of a transplacental transfusion represented a fourth group, and these patients, who often presented with a clinical phenotype mimicking OS, may be observed regardless of the type of RAG gene mutation. Analysis of the RAG genes by direct sequencing is an effective way to provide accurate diagnosis of RAG-deficient as opposed to RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone.

This study represents the first national epidemiological survey of primary immunodeficiency diseases in Norway. Uniform questionnaires were sent out in April 1998 to all hospital departments considered relevant. As of February 1999, a total of 372 patients have been registered, of whom 69 patients are deceased. With a population of 4.45 million people, the total prevalence of primary immunodeficiency diseases in Norway February 1, 1999 is 6.82 per 100.000 inhabitants. Distribution between the main immunodeficiency diagnoses is (a) antibody deficiencies 50.8%, (b) combined deficiencies included other immunodeficiency syndromes 12.4%, (c) complement deficiencies 21.0%, (d) phagocytic disorders 6.7%, (e) and immunodeficiency associated with other congenital diseases 9.1%. Compared to previous reports from other European countries, there is a smaller proportion of antibody deficiencies due to few IgA deficiencies registered and a large proportion of complement deficiencies due to many patients with hereditary angioedema.

C-reactive protein (CRP) is an unreliable diagnostic tool in the early diagnosis of neonatal septicaemia. However, serial measurements have been shown to be useful in monitoring the effectiveness of treatment. The aim of the present study was to investigate whether a specific CRP response pattern to different groups of pathogens could be identified during treatment of neonatal septicaemia. Serial CRP measurements from day 1 to 4 in monomicrobial blood culture-proven episodes of septicaemia were reviewed. In 4416 admissions, 180 out of 206 positive blood cultures were monomicrobial; 121 monomicrobial septic episodes were eligible for final analysis of the CRP response during treatment. A low median (M) value (day 1 to 4) was identified in coagulase-negative staphylococci (CONS) (M=23 mg/l), contrasting with high median values in Staphylococcus aureus (M=58 mg/l), group B streptococci (M=51 mg/l), Escherichia coli (M=51 mg/l) and Candida species (M=76 mg/l) (p

We describe two brothers of consanguineous Pakistani parents who lived in Norway and had disseminated infections due to nontuberculous mycobacteria. The first boy developed clinical signs of disseminated BCG infection after vaccination. He was successfully treated with antimycobacterial agents. Two and one-half years later, he developed disseminated Mycobacterium avium complex infection and died at 6 years of age. The second boy, born 5 years after the death of his brother, did not receive BCG vaccine. At 2 years of age, he developed disseminated M. avium complex infection. Because he responded only partly to specific chemotherapy, empirical interferon gamma treatment was added to the antimycobacterial regimen. After 2 years of combined therapy, his condition is stable. Studies of peripheral blood mononuclear cells from the second boy demonstrated reduced surface expression of the ligand binding chain of interferon gamma receptor 1. This defect explains the increased susceptibility to mycobacterial disease in the two brothers.

We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.

Complement biosynthesis in monocytes is stimulated by different microorganisms including Gram negative bacteria and yeasts. We have tested the effect of human cytomegalovirus (HCMV) on complement factor 3 (C3) production by cultured human monocytes. The monocytes were challenged with either a crude or a purified HCMV preparation obtained from the supernatant of HCMV-infected fibroblasts. When the monocytes were infected with 2 pfu/cell of virus and cultured for 2 days, the increase in C3 production compared to control ranged from 3% to 162%, median 62% (p < 0.01). However, crude HCMV was even more potent in stimulating C3 production, as the increase in C3 values ranged from 104% to 507%, median 247% (p = 0.001). This indicates the presence in the crude HCMV preparation of a substance which acts synergistically with HCMV on the C3 production. When monocytes were stimulated by lipopolysaccharide (LPS), a well known inducer of C3, infection with crude or purified HCMV did not further increase C3 production. Both HCMV and substances produced during the propagation of HCMV in fibroblasts are able to stimulate C3 production in monocytes. Complement production by inflammatory cells may be of importance in host resistance against viral infections.

Recently, considerable interest has arisen as to use cord blood (CB) as a source of hematopoietic stem cells for allogenic transplantation when bone marrow (BM) from a familial HLA-matched donor is not available. Because human cytomegalovirus (HCMV) has been shown to inhibit the proliferation of BM progenitors in vitro, it was important to examine whether similar effect could be observed in HCMV-infected CB cells. Therefore, the effect of HCMV challenge on the proliferation of myeloid progenitors from BM and CB was compared using both mononuclear cells (MNC) and purified CD34+ cells. A clinical isolate of HCMV inhibited the colony formation of myeloid BM progenitors responsive to granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, macrophage-CSF, interleukin-3 (IL-3) and the combination of IL-3 and stem cell factor (SCF). In contrast, colony growth of CB progenitors was not affected. In addition, HCMV inhibited directly the growth of purified BM CD34+ cells responsive to IL-3 and SCF in single cell assay by 40%, wheras the growth of CD34+ progenitors obtained from CB was not suppressed. The HCMV lower matrix structural protein pp65 and HCMV DNA were detected in both CB and BM CD34+ cells after in vitro challenge. However, neither immediate early (IE)-mRNA nor IE proteins were observed in infected cells. Cell cyclus examination of BM and CB CD34+ cells revealed that 25.7% of BM progenitors were in S + G2/ M phase wheras only 10.7% of the CB progenitors. Thus, a clinical isolate of HCMV directly inhibited the proliferation of myeloid BM progenitors in vitro wheras CB progenitors were not affected. This difference in the susceptibility of CB and BM cells to HCMV may partly be caused by the slow cycling rate of naive CB progenitors compared to BM progenitors at the time of infection.

Complement biosynthesis in monocytes is stimulated by different pathogens and modulated by a variety of cytokines, but little is known about the possible effect of transforming growth factor β (TGF-β) on this monocyte function. We therefore studied the effect of TGF-βl and TGF-β2 on constitutive, lipopolysaccharide (LPS)- and Candida albicans-induced monocyte biosynthesis of complement components C3 and factor B. Under all three conditions, both forms of TGF-β (20 ng/ml) induced a two- to fourfold increase in C3 concentration in monocyte supernatants harvested after 2 or 5 days of cell culture, an effect that was abrogated by cycloheximide. In contrast, constitutive and pathogen-induced production of factor B was suppressed by TGF-β. The effects of TGF-β on complement production were neutralized by a monoclonal anti-TGF-β antibody. Moreover, TGF-β suppressed the pathogen-induced release of granulocyte-macrophage colony-stimulating factor and down-regulated the expression of complement receptor 3 (CD11b/CD18), while the expression of CD11a/CD18, a related β 2 integrin, was unaffected. These novel effects of TGF-β emphasize the immunomodulatory significance of this cytokine. J. Leukoc. Biol. 57: 287–296; 1995.

Neonates are predisposed to serious infections such as meningitis, probably due to their immature host reaction to the pathogens. We have studied the intrathecal immune response in 2 newborns with Flavobacterium meningosepticum meningitis. They showed a significant elevation of immunoglobulin indices (> 1.0), also after the CSF had become sterile with a normalized cell count. In addition, an intrathecal increase and subsequent decrease of both C3dg and TCC (terminal complement complex) were observed in 1 patient. We conclude that immunoglobulin production and complement activation may occur in neonatal CSF.

ObjectiveTo characterize the endocrine and autoimmune disturbances with emphasis on parathyroid dysfunction in patients with 22q11.2 deletion syndrome (22q11.2 DS).DesignIn this nationwide survey; 59 patients (age 1–54 years) out of 86 invited with a 22q11.2 DS were recruited through all the genetic institutes in Norway.MethodsData was collected from blood tests, medical records, a physical examination and a semi-structured interview. We registered autoimmune diseases and measured autoantibodies, hormone levels and HLA types.ResultsTwenty-eight (47%) patients had hypoparathyroidism or a history of neonatal or transient hypocalcemia. Fifteen patients had neonatal hypocalcemia. Fourteen patients had permanent hypoparathyroidism including seven (54%) of those above age 15 years. A history of neonatal hypocalcemia did not predict later occurring hypoparathyroidism. Parathyroid hormone levels were generally low indicating a low reserve capacity. Twenty-eight patients were positive for autoantibodies. Six (10%) persons had developed an autoimmune disease, and all were females (PPConclusionsHypoparathyroidism and autoimmunity occur frequently in the 22q11.2 DS. Neonatal hypocalcemia is not associated with later development of permanent hypoparathyroidism. Hypoparathyroidism may present at any age, also in adults, and warrants regular measurement of calcium levels. Hypoparathyroidism and autoimmunity occur frequently together. Our findings of autoimmune diseases in 10% of the patients highlight the importance of stringent screening and follow-up routines.