Accelerated calcium influx and hyperactivation of neutrophils in chronic granulomatous disease

The relationship between activation of NADPH-oxidase, alterations in membrane potential and triggering of Ca2+ fluxes in human phagocytes has been investigated using neutrophils from four subjects with chronic granulomatous disease (CGD). Cytosolic Ca2+ and membrane potential were measured by spectrofluorimetry, and net efflux and influx of Ca2+ by radiometric procedures. Exposure of normal neutrophils to the chemotactic tripeptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 1 microM) was accompanied by an abrupt increase in cytosolic Ca2+ coincident with membrane depolarization and efflux of the cation. These events terminated at around 30 s after the addition of FMLP and were followed by membrane repolarization and store-operated influx of Ca2+, both of which were superimposable and complete after about 5 min. Activation of CGD neutrophils was also accompanied by an increase in cytosolic Ca2+, which, in spite of an efficient efflux response, was prolonged in relation to that observed in normal cells. This prolonged increase in cytosolic Ca2+ in activated CGD neutrophils occurred in the setting of trivial membrane depolarization and accelerated influx of Ca2+, and was associated with hyperactivity of the cells according to excessive release of elastase and increased activity of phospholipase A2. Treatment of CGD neutrophils with the type 4 phosphodiesterase inhibitor, rolipram (1 microM) restored Ca2+ homeostasis and attenuated the increase in elastase release. These findings support the involvement of NADPH-oxidase in regulating membrane potential and Ca2+ influx in activated neutrophils, and may explain the disordered inflammatory responses and granuloma formation which are characteristic of CGD.     

Pre-migration trauma and HIV-risk behavior

This study examined the relationship between pre-migration trauma and HIV-risk behavior in refugees from sub-Saharan Africa. The sample comprised 122 persons who had emigrated from sub-Saharan Africa and were currently residing in Sweden. Qualitative methods including individual interviews, focus groups, and interviews with key informants addressed questions regarding trauma experience and HIV-risk behavior. A history of pre-migration trauma was found to be associated with HIV-risk behavior. According to the participants, symptoms associated with post-traumatic stress disorder, depression, adjustment disorder, and substance use mediated the relationship between pre-migration trauma and sexual risk behavior. In contrast, a minority of the participants who reported pre-migration trauma but not psychological sequelae, or experienced post-traumatic growth, reported safer sexual practices. It appears that for some individuals, pre-migration trauma resulted in psychiatric sequelae, which may increase an individual's risk to be infected with HIV. Interventions targeted at individuals at increased risk (i.e. pre-migration trauma with unresolved psychiatric symptomatology) may facilitate the prevention of HIV and other sexually transmitted diseases in this population. Integration of multiple psychosocial and health issues is recommended for comprehensive treatment and prevention programs.     

A randomized trial of two public health nurse follow-up programs after early obstetrical discharge: an examination of breastfeeding rates,maternal confidence and utilization and costs of health services

OBJECTIVES: To determine whether the outcomes of routine home visiting by public health nurses (PHN) after early obstetrical discharge differ from those of a screening telephone call designed to identify mothers who need further intervention. METHODS: Primiparas delivering a singleton infant and eligible for postpartum follow-up were randomized to a home visit or screening telephone call. Data were collected by telephone from 733 participants located at two tertiary care centres in Ontario. Outcomes included maternal confidence at two weeks, health problems of the infants between discharge and four weeks postpartum, breastfeeding rates at six months and costs of the two models. RESULTS: Differences between the samples at the two sites necessitated stratified analyses. No differences were detected between the groups in maternal confidence (p = 0.96), health problems of infants (p = 0.87), or rates of breastfeeding at six months (p = 0.22). However, at both sites the cost of routine home visits was found to be higher than that of screening by telephone. CONCLUSION: Although universal access to postpartum support is important, the results suggest that a routine home visit is not always necessary to identify the women who need it. These results can be generalized only to low-risk women and infants.     

Electroretinographic anomalies in mice with mutations in Myo7a, the gene involved in human Usher syndrome type 1B

PURPOSE. In humans, mutations in the gene encoding myosin VIIa can cause Usher syndrome type 1b (USH1B), a disease characterized by deafness and retinitis pigmentosa. Myosin VIIa is also the gene responsible for the inner ear abnormalities at the shaker1 (sh1) locus in mice. To date, none of the sh1 alleles examined have shown any signs of retinal degeneration. In the present study, electroretinograms (ERGs) were recorded from sh1 mice to determine whether they have any physiological abnormalities. METHODS. ERGs were recorded from mice homozygous for one of nine mutant alleles of Myo7a ranging in age from postnatal day (P)20 to approximately 1 year. All mice were dark adapted for 30 minutes, and all the mutant mice were paired with an appropriately age- and strain-matched control animal. A presumptive null allele of myosin VIIa, Myo7a(4626SB), was used to determine whether mice without myosin VIIa had an increased threshold, as assessed by the light level required to elicit a 15-microV b-wave. RESULTS. At the maximum light intensity used, five of the nine alleles examined had significantly reduced a- and b-wave amplitudes. For example, Myo7a(4626SB) mutant mice had a 20% reduction in a-wave amplitude at the maximum light intensity, and this reduction was the same for mice ranging in age from P20 through 7 months. The b-wave thresholds of the Myo7a(4626SB) mutant mice were not significantly different from those of the control mice. Furthermore, whereas most of the alleles' a-wave implicit times were the same in mutant and control mice, mutant mice with two of the alleles had significantly faster a-wave implicit times. CONCLUSIONS. Mutations in myosin VIIa in mice can lead to decreased ERG amplitudes while threshold remains normal. This is the first report of a physiological anomaly in a mouse model with a mutation in the same gene as involved in USH1B.     

The mental health implications of detaining asylum seekers

The possible mental health impact on asylum seekers of Australia's policy of mandatory detention is an issue of special relevance to health professionals and the public. Independent commissions of inquiry in Australia have found varying degrees of mental distress to be common in detained asylum seekers. Research studies in Australia and elsewhere suggest that detained asylum seekers may have suffered greater levels of past trauma than other refugees, and this may contribute to their mental health problems, with their detention providing a retraumatising environment. Studies are urgently required to examine the mental health consequences of detention, and to determine the effect of detention on acculturation and adaptation for asylum seekers subsequently released into the community.     

Young dyspeptic patients: with a test-and-treat policy, are the benefits of decreased symptom severity and oesophago-gastric-duodenoscopy workload sustained?

OBJECTIVES: To examine the symptom severity and requirement for oesophago-gastro-duodenoscopy (OGD) in young dyspeptic patients 2 years after serological testing for Helicobacter pylori, and to compare the outcomes of seronegative patients with those of seropositive patients. DESIGN: Long-term follow-up study of 232 participants from our previous trial. METHODS: Telephone assessment of patients' symptom severity, scored using a previously validated questionnaire; return of patients for OGD determined using local patient administration system (PAS); and review of medical case notes. RESULTS: Dyspepsia symptom severity of both seronegative and seropositive patients remained reduced compared with initial scores at time of trial recruitment. Symptom severity of seropositive patients was significantly lower than that of seronegative patients (P< 0.001). Seventeen additional patients returned for OGD between six months and two years after the start of the serological study. As 61 of the original 232 study patients returned for OGD within the first six month follow-up period, a total of 78 individuals (34%) had OGD during the two years following the study. Thus, 66% of the original participants avoided OGD. CONCLUSIONS: This study of non-invasive testing for H. pylori in young dyspeptic patients has demonstrated an improvement in symptom severity and a substantial reduction in OGD workload over a 2-year period.     

Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase

delta(1)-pyrroline-5-carboxylate synthase (P5CS), a bifunctional ATP- and NADPH-dependent mitochondrial enzyme, catalyzes the reduction of glutamate to delta(1)-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine. Recently, we reported the cloning and expression of human and murine P5CS cDNAs. Previously, we showed that mammalian P5CS undergoes alternative splicing to generate two isoforms differing only by a 2 amino acid insert at the N-terminus of the gamma-glutamyl kinase active site. The short isoform has high activity in the gut, where it participates in arginine biosynthesis and is inhibited by ornithine. The long isoform, expressed in multiple tissues, is necessary for the synthesis of proline from glutamate and is insensitive to ornithine. Here, we describe a newly recognized inborn error due to the deficiency of P5CS in two siblings with progressive neurodegeneration, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Their metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia. Both are homozygous for the missense mutation, R84Q, which alters a conserved residue in the P5CS gamma-glutamyl kinase domain. R84Q is not present in 194 control chromosomes and dramatically reduces the activity of both P5CS isoforms when expressed in mammalian cells. Additionally, R84Q appears to destabilize the long isoform. This is the first documented report of an inborn error of P5CS and suggests that this disorder should be considered in the differential diagnosis in patients with neurodegeneration and/or cataracts and connective tissue disease.