Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients.

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease with heightened disease severity in children. The incomplete understanding of the precise cellular and molecular events that drive disease activity pose a significant hurdle to the development of targeted therapeutic agents. Here, we performed single-cell phenotypic and functional characterization of pediatric SLE patients and healthy controls blood via mass cytometry. We identified a distinct CD14hi monocyte cytokine signature, with increased levels of monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1ß (Mip1ß), and interleukin-1 receptor antagonist (IL-1RA). This signature was shared by every clinically heterogeneous patient, and reproduced in healthy donors' blood upon ex-vivo exposure to plasma from clinically active patients only. This SLE-plasma induced signature was abrogated by JAK1/JAK2 selective inhibition. This study demonstrates the utility of mass cytometry to evaluate immune dysregulation in pediatric autoimmunity, by identification of a multi-parametric immune signature that can be further dissected to delineate the events that drive disease pathogenesis.

Haemoglobinopathy screening in an maternity hospital.

Recent changes in population movement mean that an increasing number of mothers who deliver in Ireland and their infants are at risk of haemoglobinopathies, in particular sickle cell anaemia. Early detection of sickle cell anaemia improves outcome. For this reason, many hospitals have established antenatal and neonatal screening programmes targeting high-risk ethnic groups. We audited the provision rate of one such programme operated in the National Maternity Hospital in 2003. Using the hospital's databases, we estimated the number of mothers from high-risk ethnic groups, and how many were appropriately screened. We then calculated the neonatal screening provision rate to those infants at risk of homozygous haemoglobinopathies. In 2003, 1231 (14.9%) women from high-risk ethnic groups delivered in the National Maternity Hospital. Nine hundred and ninety one (80.5%) were screened appropriately. One hundred and thirty of these women had abnormal antenatal screens, resulting in 131 infants delivered at risk of homozygous haemoglobinopathy. Fifty eight of these infants (45%) were screened in the neonatal period. The screening programme audited did not achieve a satisfactory provision rate either antenatally or neonatally.

Neonatal transportation: the effects of a national neonatal transportation programme.

BACKGROUND: The transport of critically ill newborns by specialised transport teams has been shown to be associated with a significant improvement in their clinical condition on arrival at the receiving hospital. AIM: To determine if the National Neonatal Transport Programme introduced in 2001 improved clinical condition of newborns at the end of transfer. METHODS: A retrospective study of all 176 patients transported by the National Neonatal Transport Programme between March 2001 and March 2002. RESULTS: Before transfer, 17% of patients were hypothermic, 2% hypoglycaemic and 11% acidotic as were 7%, 3% and 5% respectively at the end of transfer. A review of 172 neonatal transports between 1987 and 1989 revealed that 21% of patients were hypothermic, 13% hypoglycaemic and 20% acidotic at the end of transfer. CONCLUSIONS: The National Neonatal Transport Programme has resulted in improved clinical condition of newborns at the end of transfer when compared to their condition before transfer and compared to outcomes prior to the introduction of the programme.

Predicting the rate of cognitive decline in aging and early Alzheimer disease.

OBJECTIVES: To determine prognostic factors affecting the course of Alzheimer disease (AD) and to determine the role of region-specific brain volumes as predictors of cognitive decline. METHODS: Longitudinal data from 166 normal elderly individuals and 59 early AD patients were analyzed. Brain volumes were extracted from MRI scans using semiautomated recursive segmentation methods. Prognostic factors were considered significant if they had a significant effect on the rate of cognitive decline. RESULTS: In multivariate analysis, higher Clinical Dementia Rating Scale (CDR) score at entry was a significant prognostic factor for an increased rate of cognitive decline. Significant prognostic factors within the baseline CDR = 0 group were base rate of progression and percent total high signal intensity (HSI), percent ventricular, and percent CSF volumes. Base rate of progression, family history, and percent ventricular volume were significant prognostic factors within the CDR = 0.5 group and APOE had a marginally significant effect on the rate of cognitive decline in the CDR = 1 group. CONCLUSIONS: Percent total HSI, ventricular, and total CSF volume measures can independently predict the rate of cognitive decline and improve the predictive power of statistical models that use only clinical data. Brain volumetric measures from MRI can be used to estimate the rate of cognitive decline even among normal elderly individuals and thus may aid in the prediction of time of onset of disease.

Outcome of infants born to hepatitis C infected women.

BACKGROUND: Hepatitis C virus (HCV) can be transmitted vertically from mother to infant, either late in pregnancy or at delivery. AIMS: To determine the outcome of infants born to HCV infected women, to characterise epidemiology and to design an appropriate infant monitoring schedule. METHODS: Three hundred and fourteen infants, born to 296 HCV positive women between 1994 and 1999 were monitored for a median of 18 months (range 1-52). RESULTS: Forty per cent of infants were small for age and 46% had neonatal abstinence syndrome (NAS). Of 173 infants of defined status, 11 were infected (vertical transmission rate [VTR] 6.4%, 95% CI 2.8-10). Infected infants were diagnosed at a median of three months (range 0.5-10). Liver transaminases elevation was documented in 8% of uninfected infants. A negative HCV PCR test before one month of age did not exclude infection but all infected patients had detectable HCV RNA when next tested (range 2-10 months). CONCLUSIONS: 94% of infants born to HCV antibody positive women are not HIV infected. Liver transaminase elevation in exposed infants is not always indicative of infection. A minimum monitoring schedule of testing (PCR and antibody) at six to eight weeks, six and 18 months allows early diagnosis while detecting late seroconversions.

An atypical case suggesting the possibility of overlap between Malpuech and Juberg-Hayward syndromes.

Malpuech syndrome and Juberg-Hayward syndrome are considered to be distinct disorders of orofacial clefting. We present details of a patient whose clinical presentation closely resembles the profile of Malpuech syndrome, but whose radiological features are more in keeping with published observations in Juberg-Hayward patients.

The use of silver-stained "comets" to visualize DNA damage and repair in normal and Xeroderma pigmentosum fibroblasts after exposure to simulated solar radiation.

The alkaline and neutral comet assays have been widely used to assess DNA damage and repair in individual cells after in vivo or in vitro exposure to chemical or physical genotoxins. Cells processed under neutral conditions generate comets primarily from DNA double strand breaks, whereas under alkaline conditions, comets arise from DNA single and double strand breaks and alkali-labile lesions. A modified version of the alkaline comet assay, as described here, used silver stain to visualize the comets and a Gelbond base to facilitate the manipulation and processing of samples. To demonstrate how these modifications improve the assay, fibroblasts derived from both normal and Xeroderma pigmentosum (Xp) individuals were exposed to simulated solar radiation and the resulting DNA damage and repair evaluated and compared with results from the relevant literature. Comets from normal fibroblasts reached their maximum length at about an hour after irradiation. Dose-dependent increases in comet length were observed up to at least 360 mJ/cm2. In contrast, comet lengths from repair deficient Xp fibroblasts were shorter than normal cells reflecting their reduced capacity to generate single strand breaks by the excision of DNA dimers. For incubation times of more than 1 h, comet lengths from normal fibroblasts underwent a time-dependent decrease, supporting the contention that this change was related to the ligation step in the DNA repair process. These changes were compatible with the model of DNA damage and repair established by others for ultraviolet radiation.

Hepatitis C infection in an Irish antenatal population.

BACKGROUND: Hepatitis C infection (HCV) has an estimated seroprevalence of 1-2% in women of child-bearing age and vertical transmission rate of 5-15%. AIMS: To characterise the current trends of HCV in an Irish antenatal population. METHODS: Infants of HCV seropositive women, born 1994 to 1999, were referred to the Paediatric Infectious Diseases service. Maternal details were collected retrospectively. RESULTS: 296 HCV seropositive women were studied. 244 (82%) were infected through intravenous drug use (IVDU), 25 (8%) through heterosexual contact and 13 (7%) via blood products. Nine women had no identifiable risk factors. Coinfection with other blood borne viruses was uncommon (4.7% HIV, 3.4% hepatitis B). Of 84 women tested for HCV-RNA, 46 (55%) were positive. Eighty three (26%) delivered prematurely; the caesarean section rate was 11%. CONCLUSIONS: HCV is increasingly detected in antenatal clinics. Heterosexual contact is a mode of spread. Maternal HCV viraemia can be variable in pregnancy. Further study of HCV in pregnancy is needed to define the impact of pregnancy on HCV, accurately predict infant outcome and selectively target interventions to women at greatest risk of transmission.

Quantifying aggregation of IgE-FcepsilonRI by multivalent antigen.

Aggregation of cell surface receptors by multivalent ligand can trigger a variety of cellular responses. A well-studied receptor that responds to aggregation is the high affinity receptor for IgE (FcepsilonRI), which is responsible for initiating allergic reactions. To quantify antigen-induced aggregation of IgE-FcepsilonRI complexes, we have developed a method based on multiparameter flow cytometry to monitor both occupancy of surface IgE combining sites and association of antigen with the cell surface. The number of bound IgE combining sites in excess of the number of bound antigens, the number of bridges between receptors, provides a quantitative measure of IgE-FcepsilonRI aggregation. We demonstrate our method by using it to study the equilibrium binding of a haptenated fluorescent protein, 2,4-dinitrophenol-coupled B-phycoerythrin (DNP25-PE), to fluorescein isothiocyanate-labeled anti-DNP IgE on the surface of rat basophilic leukemia cells. The results, which we analyze with the aid of a mathematical model, indicate how IgE-FcepsilonRI aggregation depends on the total concentrations of DNP25-PE and surface IgE. As expected, we find that maximal aggregation occurs at an optimal antigen concentration. We also find that aggregation varies qualitatively with the total concentration of surface IgE as predicted by an earlier theoretical analysis.

Group B streptococcus (GBS) colonisation among expectant Irish mothers.

Group B streptococci (GBS) have been recognised for more than three decades as a serious cause of perinatal morbidity and neonatal mortality. The aim of this study was to accurately determine the prevalence of GBS carriage and the serotype distribution among pregnant Irish women. 504 women attending antenatal clinics had two swabs (one perianal and one low vaginal) taken in the last four weeks of their pregnancy. These were placed in Todd Hewitt broth and then subcultured onto solid media. Serotyping of the isolates was performed by the Central Public Health Laboratory, London. GBS colonised women were treated with prophylactic antibiotics in labour and their infants received prophylaxis for 48 hours. 129 women (25.6%) were found to be asymptomatically colonised with GBS. Dual site screening (low-vaginal and perianal) identified 5% more GBS carriers than one site would have done. Serotypes identified included types I (30%), II (17%), III (30%), IV (1%) and V (9%). GBS colonisation is very common in Irish pregnant women and therefore a strategy for management in pregnancy ought to be developed in order to reduce the recognised occurrence of neonatal morbidity and mortality caused by this organism.

Herniated intervertebral disc without pain.

The diagnosis of herniated intervertebral disc is often made in cases of radicular pain in the low back, the neck, or sciatica or brachialgia. Practitioners often call upon radiologic imaging to confirm this diagnosis. But on radiologic examination, such a herniation may consist of a bulge, protrusion, prolapse, extension, extrusion or sequestration of this disc. We define and illustrate these terms from the literature. We then review the radiologic studies of normal controls, who have never had sciatica, brachialgia or pain in the low back or neck. In over one-quarter of these controls, studies using the plain x-ray, CT scan, myelogram, and MRI show various radiologic signs of a herniated intervertebral disc. We therefore recommend that practitioners should not exclusively rely on radiologic imaging to confirm the clinical diagnosis of a herniated intervertebral disc.

The Dublin outcome for low birth-weight infants.

This report describes outcomes for all infants with birth weight 501-1750 grams born in the three major maternity hospitals in Dublin between 1.1.90 to 31.12.91. 37,958 mothers delivered 38,498 infants during this period, consisting of approximately 36% of all deliveries in Ireland. 633 (1.6%) of all infants born weighed 501-1750 grms. 102 (16%) were stillborn and 28 of the 531 live born infants had lethal malformations. 30% of women received two or more doses of antenatal steroids before delivery and a highly significant negative correlation occurred between the need for ventilation after birth and antenatal steroids. 56.4% of babies were delivered by caesarean section as compared with 10.8% of the hospital population. Of 503 liveborn infants without lethal malformation. 426 (85%) survived to 28 days and 419 (83%) to discharge home. 15% were growth retarded. 46% of infants were ventilated, mean duration of ventilation was 7 days. 25% of infants had an intraventricular haemorrhage, 10% necrotising enterocolitis and 19% culture proven sepsis. 15% of survivors developed broncho pulmonary dysplasia and 12% retinopathy of prematurity. This paper describes important information for mortality, morbidity and interventions among a large population of low birth weight infants in Ireland and can be used as a basis against which to compare future alterations in practice. It demonstrates a clear benefit for antenatal steroids in decreasing the need for ventilation and the importance of ensuring their utilisation antenatally where possible.

Auditory affect perception in a dichotic listening paradigm as a function of verbal fluency classification.

This study evaluated cerebral asymmetry for affect perception as a function of fluency classification. After being assigned to a fluency category using scores on the FAS test (Borkowski, Benton, & Spreen, 1967), forty-five right-handed subjects with normal auditory acuity listened to the Bryden and MacCrae (1989) Dichotic Emotional Words Tape. Subjects higher in fluency exhibited significantly greater right and left ear advantages than subjects lower in fluency. Conversely, REA scores for words were significantly greater than REA scores for affect, while LEA scores for affect were significantly greater than LEA scores for words.

Benign aging or Alzheimer disease?

We show that in benign aging, normally functioning elders have minor neurobehavioral deficits in activities of daily living, and in their neurologic, motor and sensory status; hearing is peripherally and centrally impaired. Also, depression appears in 25%. Gentle physical exercise improves mobility, prevents falls, diminishes pain, wards off depression, reduces mortality, and increases cerebral blood flow and cognition. Diagnosis of Alzheimer disease consists of (1) proof of dementia, (2) meeting established clinical criteria, and (3) staging of severity. We describe dementia, giving tables to identify it and distinguish it from depression, and cite some reversible dementias. We report the accepted clinical inclusion criteria and exclusion criteria for this disease. We show, also with tables, the staging of severity of both dementia and Alzheimer disease as mild, moderate, or severe.