Coming to grips with complex disorders: genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics.

We previously proposed and provided proof of principle for the use of a complementary approach, convergent functional genomics (CFG), combining gene expression and genetic data, from human and animal model studies, as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach [Le-Niculescu et al., 2009b]. CFG provides a fit-to-disease prioritization of genes that leads to generalizability in independent cohorts, and counterbalances the fit-to-cohort prioritization inherent in classic genetic-only approaches, which have been plagued by poor reproducibility across cohorts. We have now extended our previous work to include more datasets of GWAS, and more recent evidence from other lines of work. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder. Biological pathway analyses identified top canonical pathways, and epistatic interaction testing inside these pathways has identified genes that merit future follow-up as direct interactors (intra-pathway epistasis, INPEP). Moreover, we have put together a panel of best P-value single nucleotide polymorphisms (SNPs), based on the top candidate genes we identified. We have developed a genetic risk prediction score (GRPS) based on our panel, and demonstrate how in two independent test cohorts the GRPS differentiates between subjects with bipolar disorder and normal controls, in both European-American and African-American populations. Lastly, we describe a prototype of how such testing could be used to categorize disease risk in individuals and aid personalized medicine approaches, in psychiatry and beyond.

Meteorite nanoparticles as models for interstellar grains: synthesis and preliminary characterisation.

Dust particles and their interaction with gases play important roles in star formation and in solar nebulae. Appropriate model dust grains are needed for the laboratory simulation of gas-grain interactions. Nanoparticles formed from carbonaceous meteorites may be particularly suitable, as these particles are formed from materials that were formed originally from interstellar/nebula dust. Extending our previous studies with grounded meteorite powders, we demonstrate here the production of nanoparticles formed from meteorites using the laser desorption/controlled condensation method developed in our laboratory. The product nanoparticle aggregates have porous, web-like morphologies similar to interstellar dust grains, indicating that they can present large specific surface areas for gas/grain interactions. In this paper, we present polarisation modulation reflection-absorption infrared spectra (PM-RAIRS) of supported thin films and compare these spectra with the known silicate bands in the spectra of interstellar dust recorded during the ISO mission. We also report an ultrahigh vacuum (UHV) temperature programmed desorption (TPD) study of the adsorption of CO on the supported nanoparticle films. The latter allow us to estimate the CO binding energy on the meteorite nanoparticles as 13.5 +/- 3.0 kJ mol(-1), cf. a value of 9.8 +/- 0.2 kJ mol(-1) for CO binding to a water ice substrate. Such thermochemical data can be useful for computational modelling of gas-grain interactions under the diverse conditions in interstellar clouds and solar nebulae.

Massive infectious soft-tissue injury: diagnosis and management of necrotizing fasciitis and purpura fulminans.

LEARNING OBJECTIVES: After studying the article, the participant should be able to: 1. Describe the most common bacteriology of necrotizing fasciitis and purpura fulminans. 2. Describe the "finger test" in the diagnosis of necrotizing fasciitis. 3. Discuss the three presentation patterns of necrotizing fasciitis. 4. Discuss the pathophysiology of acute infectious purpura fulminans. 5. Discuss the treatment strategies for necrotizing fasciitis and purpura fulminans, including the use of artificial skin substitutes. Necrotizing fasciitis and purpura fulminans are two destructive processes that involve skin and soft tissues. The plastic and reconstructive surgeon may frequently be called on for assistance in the diagnosis, treatment, and/or reconstruction of patients with these conditions. Understanding the natural history and unique characteristics of these processes is essential for effective surgical management and favorable patient outcome. A comprehensive review of the literature pertaining to these two conditions is presented, outlining the different pathophysiologies, the patterns of presentation, and the treatment strategies necessary for successful management of these massive infectious soft-tissue diseases.

Genetic heterogeneity of HIV type 1 subtypes in Kimpese, rural Democratic Republic of Congo.

A relatively low and stable seroprevalence of HIV-1 was previously reported among pregnant women attending for antenatal care between 1988 and 1993 in Kimpese, a rural town in the Democratic Republic of Congo (DRC, formerly Zaire). To characterize the HIV-1 subtypes circulating in this area, we have examined a 330-bp fragment of the p17 region of the gag gene of HIV-1 strains obtained from 70 patients (55 mothers, 15 children), of whom 61 were epidemiologically unlinked. Phylogenetic analyses revealed the existence of at least seven HIV-1 subtypes within the Kimpese region. Among the 61 epidemiologically unlinked patients, subtype A was predominant and found in 29 (47.5%) individuals. Other subtypes cocirculating in this rural part of DRC include subtypes C (1.6%), D (9.8%), F (3.2%), G (6.5%), H (21.3%), and J (4.9%). Sequences from four patients did not cluster with any of the currently documented HIV-1 subtypes, in analyses of fragments of both the gag (247 to 330 bp, 197 bp, and 310 bp) and env (340 bp) genes. Overall, comparisons of the gag(p17) gene regions revealed high pairwise divergences (mean, 19.9%; range, 1 to 46%). This level of gag(p17) gene variation in the DRC is considerably greater than previously appreciated. These results are relevant for the molecular epidemiology of HIV-1 in Africa and for the design of a future vaccine against HIV-1 in this region.

Clinical definition for invasive Salmonella infection in African children.

BACKGROUND: Invasive salmonellosis is common among children in tropical Africa, typically presenting as a nonspecific febrile illness that is difficult to distinguish clinically from malaria. This study examines the performance of a clinical definition devised to aid its recognition among children ages 1 to 15 years presenting to a mission hospital in rural Zaire. METHODS: Invasive salmonellosis was defined by: (1) illness requiring admission to hospital in the opinion of an experience pediatrician; (2) history of fever for 5 or more days; (3) no focus of infection on clinical examination; and (4) negative or only scanty positive thick film for malarial parasites. Children fulfilling all these criteria were treated with ciprofloxacin after culture of blood and feces. The primary outcome measure was blood culture-confirmed salmonellosis. Secondary measures were final clinical diagnosis and serologic evidence of recent salmonellosis. RESULTS: Of 120 children fulfilling the definition, 55 (46%) were bacteremia; in 46 (38%) Salmonella species were isolated. In the majority of the nonbacteremic children no definite cause for the fever could be found. Salmonella serology supported invasive salmonellosis as the diagnosis in 62% of the nonbacteremic children. CONCLUSION: Salmonella serology suggested that invasive salmonellosis without detectable bacteremia was common. The addition of blood culture-proved and serologically diagnosed cases indicates that the definition has a specificity of at least 60%.

Indications and restrictions of fluoroquinolone use in children.

Fluoroquinolones (FQs) have a proven record in adults against a wide range of organisms, but their use in children has been restricted because of the potential for causing damage to joints. Accumulated evidence suggests that FQs are effective, well tolerated and do not cause arthropathy in children.

How valuable are IgA and IgM anti-HIV tests for the diagnosis of mother-child transmission of HIV in an African setting?

BACKGROUND: Babies born to HIV-infected mothers retain anti-HIV of maternal origin until 15-18 months of age. Because of this, HIV proviral DNA and p24 antigen measurements have become the methods of choice for timely diagnosis of HIV infection in infancy. They are, however, too expensive for widespread use in the developing world. OBJECTIVE: To evaluate a simple, inexpensive serological method for diagnosing mother-child transmission of HIV, in an African population, which takes account of the effects of placental transfer of maternal antibody and continued exposure to HIV through breast-feeding. STUDY DESIGN: Plasma specimens for a prospective study of mother-to-infant transmission of HIV in rural Zaire were collected at birth, 3, 6, 9, 12, 18 and 24 months from 21 infected infants (PP group), 21 uninfected infants (PN group) born to seropositive mothers and 21 control infants (NN group) born to uninfected mothers. The specimens were retrospectively tested for IgG, IgM and IgA anti-HIV by immunoglobulin class-specific capture EIAs, and by a commercial anti-HIV EIA. RESULTS: In neonatal specimens, IgA and IgM anti-HIV were present, respectively, in 13 of 14 (97%) and 8 of 14 (57%) of the PP group and in 6 of 11 (55%) and 2 of 11 (18%) of the PN group. Later, at 3 months and older, IgA and IgM anti-HIV were only detected in the PP group. They peaked at 18 months (93%) and 24 months (67%) respectively. Of the 21 PP group children, 8 (38%) were transiently IgG anti-HIV-negative in the first year, indicating that infection had probably taken place after birth; four of the 8 had no detectable IgA anti-HIV during the first year. None of the specimens collected from the NN group babies were reactive for IgA, IgM or IgG anti-HIV. CONCLUSIONS: IgA and IgM anti-HIV may be passively transferred across the placenta. Where breast-feeding is prevalent, about half of the transmissions may occur after birth, thus delaying the diagnosis of mother-child transmission. Nevertheless, this simple, cheap IgA anti-HIV, EIA identified 65% of transmissions by 9 months of age, and 93% at 18 months of age. It is a more useful marker than IgM anti-HIV, and gave a much more rapid answer than did tests for IgG anti-HIV seroreversion.

Meningococcal meningitis and carriage in western Zaire: a hypoendemic zone related to climate?

An analysis of bacteria recovered from cerebrospinal fluid over a 16-year period at a rural hospital in western Zaire showed that Neisseria meningitidis accounted for only five (2.2%) isolates. A survey of naso-pharyngeal colonisation with N. meningitidis in 378 healthy children was undertaken to distinguish whether this low frequency was due to lack of carriage or, by inference, lack of the co-factors necessary to permit invasive disease. N. meningitidis was recovered from only three (0.78%) of the children. All isolates were non-typable strains of low pathogenicity. A review of studies examining the aetiology of bacterial meningitis and the geographical location of epidemics of meningococcal meningitis in and around Zaire reveals a 'hypoendemic zone', the limits of which correlate well with the area in which mean absolute humidity remains above 10 g m-3 of air throughout the year. Continuous high absolute humidity appears to reduce the transmission of meningococci.

A preliminary evaluation of the cognitive and motor effects of pediatric HIV infection in Zairian children.

Fourteen asymptomatic HIV-infected Zairian children under 2 years of age displayed social and motor developmental deficits on the Denver Developmental Screening Test when compared with 20 HIV-negative cohorts born to HIV-infected mothers and 16 control children. In a second study, 11 infected children over 2 years of age had sequential motor and visual-spatial memory deficits on the Kaufman Assessment Battery for Children and motor development deficits on the Early Childhood Screening Profiles. HIV infection affects central nervous system structures mediating motor and spatial memory development, even in seemingly asymptomatic children. Furthermore, maternal HIV infection compromises the labor-intensive provision of care in the African milieu and undermines global cognitive development in even uninfected children.

PIP: Language and motor skill deficits have been noted for HIV-infected children when tested with Stanford-Binet. With the McCarthy Scales of Children's Abilities, quantitative, verbal, and memory ability deficits have also been documented with infected children and are particularly significant for those children with accompanying neurological impairment from the virus. Deficits of visual-spatial integrative ability and memory have also been identified with the Kaufman Assessment Battery for Children. This paper reports results from a direct comparison of differences in cognitive and motor skills development between HIV-1-seropositive and HIV-1-seronegative children born to infected African mothers. Both subgroups were subsequently compared to a third group of HIV-negative children born to noninfected mothers in order to better assess some of the second-order effects of the epidemic upon the development of children who are not themselves infected, but who bear the consequences of the disease in the form of illness of the primary caregiver, and the hardship which that imposes upon the entire family. Such factors are most likely especially severe for nonaffluent families in developing countries. 14 asymptomatic HIV-infected Zairian children under 2 years old displayed social and motor developmental deficits on the Denver Developmental Screening Test when compared with 20 HIV-negative cohorts born to HIV-infected mothers and 16 control children. In the second study, 11 infected children over 2 years old had sequential motor and visual-spatial memory deficits on the Kaufman Assessment Battery for Children and motor development deficits on the Early Childhood Screening Profiles. The authors conclude that HIV infection affects central nervous system structures mediating motor and spatial memory development, even in seemingly asymptomatic children. Moreover, maternal HIV infection compromises the labor-intensive provision of care in the African milieu and undermines global cognitive development in even uninfected children.

The treatment of neonatal meningitis due to gram-negative bacilli with ciprofloxacin: evidence of satisfactory penetration into the cerebrospinal fluid.

We describe two cases of neonatal meningitis due to Gram-negative bacilli treated successfully with ciprofloxacin. Examination of serial samples of cerebrospinal fluid indicated the effect of meningeal inflammation on penetration of this drug into the CSF.

Salmonella bacteraemia among young children at a rural hospital in western Zaire.

An analysis of 206 cases of extra-intestinal Salmonella infection among children up to 60 months of age admitted to a rural hospital in western Zaire was undertaken. Most children presented with fever but without any focus of infection which was difficult to distinguish clinically from falciparum malaria. The majority (83%) of the infections were due to serotypes other than S. typhi. Infection with these serotypes was clinically indistinguishable from S. Typhi infection and was associated with a comparably high case fatality rate of 23%. Death was significantly associated with age under 6 months (relative risk 1.7), meningitis (RR 4.7), jaundice (RR 2.5), severe anaemia (RR 1.8), contracting disease in the late wet season when malnutrition peaks (RR 2.6) and infection with a chloramphenicol-resistant isolate (RR 3.2). The increasing prevalence of antibiotic resistance and HIV infection will complicate the management of this disease in the future.

PIP: Between 1982 and 1986 in western Zaire, a pediatrician collected data on 206 children under 5 years old presenting at the Institute Medical Evangelique, a 400-bed mission hospital (60 pediatric beds), in Kimpese with persisting fever despite chloroquine therapy for falciparum malaria, a negative or scanty positive thick film for malaria, and no clear localizing signs of infections. The pediatrician suspected that these cases had an extraintestinal Salmonella infection and took blood, synovial fluid, and/or cerebrospinal fluid samples for diagnostic analyses. Salmonella serotypes other than Salmonella typhi (non-S. typhi) were responsible for most bacteremia cases (83%). The clinical features of non-S. typhi and S. typhi infections were basically the same. The case fatality rate for non-S. typhi and S. typhi an S. typhi infections were 22.7% and 29.4%, respectively. Infants under 6 months old had a significantly higher case fatality rate than older children (relative risk [RR] = 1.7; p .0005; e.g., 66% and 100% for infants under 3 months old). Meningitis was significantly associated with increased mortality, regardless of age (RR = 4.68). Jaundice was the only clinical sign significantly linked to increased mortality (RR = 2.35), especially among children who had S. typhi infection (80%). Mortality occurred significantly more often when children fell ill with Salmonella bacteremia in the late rainy season, coinciding with the peak of malnutrition, than in the dry season (RR = 2.62). Chloramphenicol-resistant non-S. typhi isolated were significantly associated with increased mortality (RR = 3.19). Hemoglobin levels below 6 g (i.e. severe anemia) has a strong link to increased mortality (RR = 1.77). Salmonella bacteremia will become more difficult to treat as antibiotic resistance and the prevalence of HIV infection increases in African countries.

Lymphadenopathy and hepatosplenomegaly in the 1st year in children infected by HIV-1 in Zaire.

The children of 50 women positive for antibody to human immunodeficiency virus type 1 (HIV-1) and 42 children of antibody-negative mothers were examined for lymphadenopathy and hepatosplenomegaly at 3-month intervals during the 1st year of life. Lymphadenopathy was found to be significantly more frequent at 6 months (p less than 0.01), 9 months (p less than 0.001) and 12 months (p less than 0.01) in children who were subsequently shown to be infected with HIV-1. Hepatomegaly was seen more frequently (p less than 0.05) in the 1st year in HIV-1-infected children than in uninfected children. Splenomegaly was not more frequent in HIV-1-infected children in this area which is holoendemic for falciparum malaria.

Caring for children with HIV/AIDS in rural Zaire

HIV/AIDS presents a fascinating and major challenge to doctors working in developing countries such as Zaire. This challenge has to be met as part of the clinical work load because it is still true to say that more children are dying from malaria; respiratory diseases and diarrhea than from HIV infection at present. This may change and emphasises the need for intensive educational programmes now

Severe anaemia in pregnancy: a problem of primigravidae in rural Zaire.

Haemoglobin levels were measured in 2950 pregnant women attending antenatal clinics in Kimpese, Bas Zaire. 72% were suffering from moderate anaemia (haemoglobin (Hb) 7-11 g/dl) and 3.7% from severe anaemia (Hb less than 7 g/dl) at their first visit, before receiving any haematinics or anti-malarial prophylaxis. Haemoglobin levels rose with both increasing parity (P less than 0.001) and age. Multiple regression analysis revealed that parity was significant but age was not. The fall in haemoglobin early in the second trimester was greatest in primigravidae and diminished with successive pregnancies until the fourth. One in 6 primigravidae approached labour with a haemoglobin level less than 7.7 g/dl. Thick blood smears were examined from 379 women who presented in the first and second trimester. 70% of primigravidae had malaria parasitaemia, compared with 13% of multigravidae (P less than 0.001). Early malaria prophylaxis in the first 2 pregnancies is an important primary health care objective if the contribution of malaria to the significant fall in haemoglobin in the second trimester is to be averted.