Objective

To examine the effects of human leukocyte antigen (HLA) alleles on HIV-1-related disease progression and central nervous system (CNS) impairment in children.

Design

572 HIV-1-infected children, identified as disease progressors or non-progressors, were selected from PACTG P152 and P300 through a case-cohort sampling scheme. Study endpoints were HIV-1-related disease progression-free survival and time to CNS impairment.

Methods

DNA was genotyped for HLA alleles using a Luminex 100 platform. Weighted Kaplan-Meier methods and Cox proportional hazards models were used to assess the effects of HLA alleles on study endpoints.

Results

Presence of the B-27 allele (n=20) was associated with complete protection against disease progression and CNS impairment over the median follow-up of 26 months (P<0.0001 for both). These findings held in multivariate analyses controlling for baseline covariates including race, gender, age, log HIV-1 RNA, CD4+ lymphocyte count and percent, weight for age z-score and treatment, and for other genotypes shown to affect HIV-1-related disease progression. Also, while the Cw-2 allele protected against disease progression (HR, 0.48; 95% CI: 0.28–0.81; P= 0.006), the A-24 allele was associated with more rapid CNS impairment (HR: 2.01; 95% CI: 1.04–3.88; P= 0.04). The HLA class II DQB1-2 allele was associated with a delayed disease progression (HR: 0.66; 95% CI: 0.47–0.92; P= 0.01) and CNS impairment (HR: 0.58; 95% CI: 0.36–0.93; P= 0.02).

Conclusions

Presence of B-27, Cw-2, or DQB1-2 alleles was associated with delayed HIV-1 disease progression, while B-27, A-24, and DQB1-2 alleles were associated with altered progression to CNS impairment in children.

Objective

To develop a multivariate prediction model for major adverse cardiac events (MACE) after percutaneous coronary interventions (PCIs) by using the North West Quality Improvement Programme in Cardiac Interventions (NWQIP) PCI Registry.

Setting

All NHS centres undertaking adult PCIs in north west England.

Methods

Retrospective analysis of prospectively collected data on 9914 consecutive patients undergoing adult PCI between 1 August 2001 and 31 December 2003. A multivariate logistic regression analysis was undertaken, with the forward stepwise technique, to identify independent risk factors for MACE. The area under the receiver operating characteristic (ROC) curve and the Hosmer‐Lemeshow goodness of fit statistic were calculated to assess the performance and calibration of the model, respectively. The statistical model was internally validated by using the technique of bootstrap resampling.

Main outcome measures

MACE, which were in‐hospital mortality, Q wave myocardial infarction, emergency coronary artery bypass graft surgery, and cerebrovascular accidents.

Results

Independent variables identified with an increased risk of developing MACE were advanced age, female sex, cerebrovascular disease, cardiogenic shock, priority, and treatment of the left main stem or graft lesions during PCI. The ROC curve for the predicted probability of MACE was 0.76, indicating a good discrimination power. The prediction equation was well calibrated, predicting well at all levels of risk. Bootstrapping showed that estimates were stable.

Conclusions

A contemporaneous multivariate prediction model for MACE after PCI was developed. The NWQIP tool allows calculation of the risk of MACE permitting meaningful risk adjusted comparisons of performance between hospitals and operators.

Objective: To compare two dosing regimens for caffeine citrate in the periextubation period for neonates born at less than 30 weeks gestation in terms of successful extubation and adverse effects.

Design: A multicentre, randomised, double blind, clinical trial.

Setting: Four tertiary neonatal units within Australia.

Patients: Infants born less than 30 weeks gestation ventilated for more than 48 hours.

Interventions: Two dosing regimens of caffeine citrate (20 v 5 mg/kg/day) for periextubation management. Treatment started 24 hours before a planned extubation or within six hours of an unplanned extubation.

Main outcome measure: Failure to extubate within 48 hours of caffeine loading or reintubation and ventilation or doxapram within seven days of caffeine loading.

Results: A total of 234 neonates were enrolled. A significant reduction in failure to extubate was shown for the 20 mg/kg/day dosing group (15.0% v 29.8%; relative risk 0.51; 95% confidence interval (CI) 0.31 to 0.85; number needed to treat 7 (95% CI 4 to 24)). A significant difference in duration of mechanical ventilation was shown for infants of less than 28 weeks gestation receiving the high dose of caffeine (mean (SD) days 14.4 (11.1) v 22.1 (17.1); p  =  0.01). No difference in adverse effects was detected in terms of mortality, major neonatal morbidity, death, or severe disability or general quotient at 12 months.

Conclusions: This trial shows short term benefits for a 20 mg/kg/day dosing regimen of caffeine citrate for neonates born at less than 30 weeks gestation in the periextubation period, without evidence of harm in the first year of life.

AIMS—To compare the perinatal mortality and morbidity of infants with twin-twin transfusion syndrome (TTTS) with those of gestation matched twin controls and to assess the neurodevelopmental outcome of surviving twins with TTTS.
METHODS—A cohort of 17 consecutive pregnancies with TTTS was enrolled over three years together with gestation matched twin pregnancies unaffected by TTTS. Serial amnioreduction for the TTTS pregnancies was performed as appropriate. Perinatal death and neonatal morbidities were recorded for both the TTTS cohort and controls. The TTTS survivors had neurodevelopmental follow up to at least 2 years of age.
RESULTS—In 12 of the pregnancies, serial amniocenteses were performed, but, in five, the infants were born before intervention. The mean gestational age at delivery was 29.1 weeks (range 23-36). There were five intrauterine deaths in the TTTS cohort and six neonatal deaths (survival 68%). In the control group, there was one intrauterine death and five neonatal deaths (survival 82%). Infants in the TTTS group had a greater requirement for inotropes (p = 0.04) and a higher incidence of renal failure (p = 0.005). Periventricular leucomalacia and cerebral atrophy were seen in 17% of the TTTS group, but none of the controls (p = 0.03). The 23 surviving TTTS infants were all followed up, with 22% having significant neurological morbidity: cerebral palsy and global developmental delay.
CONCLUSIONS—Twins with TTTS have high perinatal mortality and neonatal morbidity, and long term neurodevelopmental morbidity in survivors is high. Further investigation into the pathogenesis and management of TTTS is required.



AIM—To determine the outcome of preterm infants born to mothers with hypertension during pregnancy, and preterm controls.
METHODS—107 infants of 24-32 weeks gestation, born to hypertensive mothers, and 107 controls matched for gestational age, sex, and multiple pregnancy, born to normotensive mothers, were prospectively enrolled over 2 years. Information on maternal complications and medication was obtained and neonatal mortality and morbidities recorded. Survivors were followed up to at least 2 years, corrected for prematurity.
RESULTS—One third of the hypertensive mothers were treated with antihypertensive drugs, while 18% received convulsion prophylaxis with phenytoin. Magnesium sulphate was not prescribed. Both groups had a mean gestational age of 29.9 weeks, with the study infants having a significantly lower birthweight than the controls. Four study and three control infants died in the neonatal period. Cerebral palsy was not diagnosed in any infant of a hypertensive mother compared with five of the controls. The mean general quotient for the two groups was very similar and no difference in the incidence of minor neuromotor developmental problems was shown.
CONCLUSIONS—Maternal hypertension seems to protect against cerebral palsy in preterm infants without increasing the risk of cognitive impairment. This was independent of the use of maternally administered magnesium sulphate.



The neurodevelopmental outcome of 78 infants with bronchopulmonary dysplasia (BPD) was compared with that of 78 control infants matched for birthweight. To determine the effect of the severity of BPD, 62 infants requiring oxygen at 36 weeks' postmenstrual age (sBPD) were compared with their matched controls. Infants were followed up to 2 years of age, corrected for prematurity, and were classified for neurological impairment, developmental delay, and neurodevelopmental disability. Seventy six (98%) BPD infants and 71 (91%) controls had follow up data available to two years. Neurological impairment, developmental delay, and neurodevelopmental disability occurred more frequently in infants with BPD than in controls but this was not significant. For infants with sBPD, the increased incidence of neurological impairment and definite developmental delay was not significant when compared with the controls, though neurodevelopmental disability occurred more frequently (odds ratio (OR) 3.6: 95% confidence intervals (CI) 1.1-11.8). Predictors of disability in infants with sBPD included periventricular haemorrhage (OR 19.4: 95% CI 4.3-86.6), ventricular dilatation (OR 12.8: 95% CI 2.9-57.3), and sepsis (OR 5.0: 95% CI 1.3-19.4). Adjusting for the presence of these factors, the association between BPD and disability was no longer apparent (OR 0.9: 95% CI 0.2-3.6). The findings suggest that BPD is not independently associated with adverse neurodevelopmental outcome.

Insulin-like growth factor I has similar mitogenic effects to insulin, a growth factor required by most cells in culture, and it can replace insulin in serum-free formulations for some cells. Chinese Hamster Ovary cells grow well in serum-free medium with insulin and transferrin as the only exogenous growth factors. An alternative approach to addition of exogenous growth factors to serum-free medium is transfection of host cells with growth factor-encoding genes, permitting autocrine growth. Taking this approach, we constructed an IGF-I heterologous gene driven by the cytomegalovirus promoter, introduced it into Chinese Hamster Ovary cells and examined the growth characteristics of Insulin-like growth factor I-expressing clonal cells in the absence of the exogenous factor. The transfected cells secreted up to 500 ng/106 cells/day of mature Insulin-like growth factor I into the conditioned medium and as a result they grew autonomously in serum-free medium containing transferrin as the only added growth factor. This growth-stimulating effect, observed under both small and large scale culture conditions, was maximal since no further improvement was observed in the presence of exogenous insulin.

A panel of primary syncytium-inducing (SI) human immunodeficiency virus type 1 isolates that infected several CD4+ T-cell lines, including MT-2 and C8166, were tested for infection of blood-derived macrophages. Infectivity titers for C8166 cells and macrophages demonstrated that primary SI strains infected macrophages much more efficiently than T-cell line-adapted HIV-1 strains such as LAI and RF. These primary SI strains were therefore dual-tropic. Nine biological clones of two SI strains, prepared by limiting dilution, had macrophage/C8166 infectivity ratios similar to those of their parental viruses, indicating that the dual-tropic phenotype was not due to a mixture of non-SI/macrophage-tropic and SI/T-cell tropic viruses. We tested whether the primary SI strains used either Lestr (fusin) or CCR5 as coreceptors. Infection of cat CCC/CD4 cells transiently expressing Lestr supported infection by T-cell line-adapted strains including LAI, whereas CCC/CD4 cells expressing CCR5 were sensitive to primary non-SI strains as well as to the molecularly cloned strains SF-162 and JR-CSF. Several primary SI strains, as well as the molecularly cloned dual-tropic viruses 89.6 and GUN-1, infected both Lestr+ and CCR5+ CCC/CD4 cells. Thus, these viruses can choose between Lestr and CCR5 for entry into cells. Interestingly, some dual-tropic primary SI strains that infected Lestr+ cells failed to infect CCR5+ cells, suggesting that these viruses may use an alternative coreceptor for infection of macrophages. Alternatively, CCR5 may be processed or presented differently on cat cells so that entry of some primary SI strains but not others is affected.

Granulocyte colony stimulating factor (G-CSF) treatment was successfully used in three preterm infants with alloimmune neonatal neutropenia (AINN). Two infants had persistent neutropenia despite treatment with intravenous immunoglobulin and random donor granulocyte transfusions for presumed sepsis. Neutrophil counts returned to normal with G-CSF treatment; the response was least convincing in one infant with fulminant necrotising enterocolits. It is suggested that treatment with G-CSF be considered early for the treatment of infants with AINN.

Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase is an autosomal recessive syndrome that has been associated with severe asthma in Japanese children. Acquired deficiency has been described in several human diseases usually associated with severe inflammation. PAF acetylhydrolase catalyzes the degradation of PAF and related phospholipids, which have proinflammatory, allergic, and prothrombotic properties. Thus, a deficiency in the degradation of these lipids should increase the susceptibility to inflammatory and allergic disorders. Miwa et al. reported that PAF acetylhydrolase activity is absent in 4% of the Japanese population, which suggests that it could be a common factor in such disorders, but the molecular basis of the defect is unknown. We show that inherited deficiency of PAF acetylhydrolase is the result of a point mutation in exon 9 and that this mutation completely abolishes enzymatic activity. This mutation is the cause of the lack of enzymatic activity as expression in E. coli of a construct harboring the mutation results in an inactive protein. This mutation as a heterozygous trait is present in 27% in the Japanese population. This finding will allow rapid identification of subjects predisposed to severe asthma and other PAF-mediated disorders.

The prevalence of eye disease and uncorrected refractive errors in a group of 167 elderly members of the Bangladeshi community which resides in the London Borough of Tower Hamlets was studied. Of the subjects screened 24.6% were found to have a significant and potentially treatable cause of visual loss and a further 32.3% were visually handicapped through the presence of uncorrected refractive errors. A high prevalence (53.3%) of cataract was found in the elderly Bengalis. The high prevalence of eye disease in this ethnic minority group, has important implications for health service planning.

Multifocal intraocular lenses allow pseudophakic patients to obtain good near and distance visual acuities without an additional near correction. We report our experiences in implanting diffractive multifocal intraocular lenses in prepresbyopic patients with acquired unilateral cataracts and assess their postoperative visual acuities and stereoscopic vision. Accommodative function in patients following cataract surgery is discussed.

Capillary heel prick plasma elastase alpha 1-proteinase inhibitor (E alpha 1-PI) measured by an immunoassay (using commercially available reagents) was examined as an early indicator of neonatal sepsis. Fifty five infants were studied within 24 hours of birth; 60 (including 10 studied on the first day of life) were examined between two and 30 days after birth. Reference ranges for the neonatal period were developed. Raised E alpha 1-PI concentrations (range 440-2600 micrograms/l) were found at the outset of each of the 24 infectious episodes including five with concomitant neutropenia. On the first day of life, obstetric and neonatal complications were also associated with high concentrations (range 190-2400 micrograms/ml). In infants who survived infection, E alpha 1-PI normalised with antibiotic treatment. It is concluded that capillary heel prick plasma is suitable for E alpha 1-PI testing and raised concentrations provide a sensitive but non-specific index of infection in the first 24 hours after birth. Sequential testing may provide early warning of infectious complications and serve as a guide to the cessation of antibiotic treatment.

At least two species-specific gene products are required for signal transduction by interferon gamma (IFN-gamma). The first is the IFN-gamma receptor, which binds ligand with high affinity in a species-specific manner. The second is an undetermined species-specific signal transducer(s). To determine whether the human IFN-gamma receptor (hIFN-gamma R) interacts directly with this signal transducer(s) and, if so, with what functional domain(s), we constructed expression vectors for the hIFN-gamma R and three hybrid human-murine IFN-gamma receptors. The hybrid receptors contained the extracellular, human IFN-gamma (hIFN-gamma) binding domain of the hIFN-gamma R, either the human or murine transmembrane domain, and either the human or murine intracellular domain. The vectors encoding these receptors were stably transfected into two mouse cell lines, one of which (SCC-16-5) contains a single copy of human chromosome 21. The resulting cell lines were treated with hIFN-gamma, and murine major histocompatibility complex class I antigen expression was analyzed by immunofluorescence flow cytometry. All transfected cell lines lacking human chromosome 21 remained insensitive to hIFN-gamma. However, all four of the IFN-gamma receptors were able to signal when expressed in the cell line containing human chromosome 21. We conclude that the extracellular domain of the IFN-gamma receptor is involved not only in the species specificity of IFN-gamma binding but also in signalling through interaction with an as yet unidentified species-specific factor(s) encoded by a gene(s) on human chromosome 21.

The effects of recombinant human gamma interferon (rHuIFN-gamma; two identical monomers of 140 residues in length) and of two re-engineered C-terminal variants, rHuIFN-gamma Tetra-Ser (residues 129 to 132 replaced by serine) and rHuIFN-gamma 125 (two identical monomers of 125 residues each with the last 14 residues plus an additional alanine from the C terminus deleted), were compared in terms of several in vitro biological activities. By using three different human cell lines (HeLa 229, HEp-2, and A549), the interferons were tested for their ability to inhibit: (i) growth of Chlamydia trachomatis; (ii) replication of encephalomyocarditis virus; and (iii) cell growth. rHuIFN-gamma restricted the growth of chlamydiae to 50% of the non-IFN-treated control at concentrations ranging from 0.01 to 0.05 ng/ml, depending on the cell type assayed. One of the modified proteins, rHuIFN-gamma Tetra-Ser, also decreased the growth of chlamydiae, but it required a concentration of approximately 0.5 ng/ml to produce 50% inhibition. rHuIFN-gamma 125 had the lowest antichlamydial activity of the three IFN-gamma variants tested; concentrations of 1 to 20 ng/ml were needed to reduce the growth of C. trachomatis to 50% of that of the control. The relative antiviral and antiproliferative activities of the three IFN-gamma preparations paralleled their antichlamydial activities in these three cell lines. The antiencephalomyocarditis virus activities of rHuIFN-gamma Tetra-Ser and rHuIFN-gamma 125 were reduced by approximately 10-fold and 10(2)- to 10(3)-fold, respectively, compared with the antiviral activity of rHuIFN-gamma. Proliferation of the three cell lines was restricted to approximately 50% of the control with 0.5 to 10 ng of rHuIFN-gamma per ml. Inhibition of cell growth by rHuIFN-gamma Tetra-Ser was significant only at concentrations equal to or greater than 30 ng/ml, and the rHuIFN-gamma 125 variant did not significantly decrease the growth of any of the three cell lines at the concentrations tested. These results suggest that the C-terminal portion of rHuIFN-gamma is critical for maintaining the conformation necessary for inducing the antichlamydial, antiviral, and antiproliferative activities of the molecule.

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A notes survey was undertaken by a group of eight general practitioners in seven Southampton practices to study the mode of presentation and follow-up of the diabetic patients on the lists of 24 doctors. The 431 known diabetic patients were classified as non-insulin-dependent (67%), insulin-dependent (20%), or, if they had commenced their insulin more than a month after the diagnosis had been made, 'insulin-treated' (13%). This classification allowed characterization of the truly insulin-dependent and non-insulin-dependent patients.

Non-insulin-dependent diabetics were older than insulin-dependent diabetics and had first presented at a greater age. Most patients in each treatment group presented with classical diabetic symptoms, diabetes-related infections, or recognized complications. The majority of these were diagnosed in general practice. However, over half of the asymptomatic non-insulin-dependent diabetic patients had been diagnosed by routine blood or urine testing in hospital. After 1979 fewer non-insulin-dependent diabetic patients were referred to hospital for follow-up at diagnosis than before 1975.

Most non-insulin-treated diabetics were followed up in general practice whereas most patients treated with or dependent on insulin were followed up in hospital clinics. Twenty-two per cent of all patients received diabetic care from both their general practitioner and hospital outpatient departments but 20% received no regular diabetic follow-up at all. One year after the initial study, 4% of patients were still without regular review, and 27 more patients had been identified who would have qualified for the original audit.