Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers

Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61-4.48; P(trend) = 0.0002) and their mothers (OR 2.74; 95% CI 1.55-4.84; P(trend) = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.

A prospective study of the impact of air pollution on respiratory symptoms and infections in infants

Rationale: There is increasing evidence that short-term exposure to air pollution has a detrimental effect on respiratory health, but data from healthy populations, particularly infants, are scarce. Objectives: To assess the association of air pollution with frequency and severity of respiratory symptoms and infections measured weekly in healthy infants. Methods: In a prospective birth cohort of 366 infants of unselected mothers, respiratory health was assessed weekly by telephone interviews during the first year of life (19,106 total observations). Daily mean levels of particulate matter (PM10), nitrogen dioxide (NO2), and ozone (O3) were obtained from local monitoring stations. We determined the association of the preceding week's pollutant levels with symptom scores and respiratory tract infections using a generalized additive mixed model with an autoregressive component. In addition, we assessed whether neonatal lung function influences this association and whether duration of infectious episodes differed between weeks with normal PM10 and weeks with elevated levels. Measurements and Main Results: We found a significant association between air pollution and respiratory symptoms, particularly in the week after respiratory tract infections (risk ratio, 1.13 [1.02-1.24] per 10 μg/m(3) PM10 levels) and in infants with premorbid lung function. During times of elevated PM10 (>33.3 μg/m(3)), duration of respiratory tract infections increased by 20% (95% confidence interval, 2-42%). Conclusions: Exposure to even moderate levels of air pollution was associated with increased respiratory symptoms in healthy infants. Particularly in infants with premorbid lung function and inflammation, air pollution contributed to longer duration of infectious episodes with a potentially large socioeconomic impact.

Visual function in human ocular toxoplasmosis

AIM: To assess functional impairment in terms of visual acuity reduction and visual field defects in inactive ocular toxoplasmosis. METHODS: 61 patients with known ocular toxoplasmosis in a quiescent state were included in this prospective, cross-sectional study. A complete ophthalmic examination, retinal photodocumentation and standard automated perimetry (Octopus perimeter, program G2) were performed. Visual acuity was classified on the basis of the World Health Organization definition of visual impairment and blindness: normal (> or =20/25), mild (20/25 to 20/60), moderate (20/60 to 20/400) and severe (<20/400). Visual field damage was correspondingly graded as mild (mean defect <4 dB), moderate (mean defect 4-12 dB) or severe (mean defect >12 dB). RESULTS: 8 (13%) patients presented with bilateral ocular toxoplasmosis. Thus, a total of 69 eyes was evaluated. Visual field damage was encountered in 65 (94%) eyes, whereas only 28 (41%) eyes had reduced visual acuity, showing perimetric findings to be more sensitive in detecting chorioretinal damage (p<0.001). Correlation with the clinical localisation of chorioretinal scars was better for visual field (in 70% of the instances) than for visual acuity (33%). Moderate to severe functional impairment was registered in 65.2% for visual field, and in 27.5% for visual acuity. CONCLUSION: In its quiescent stage, ocular toxoplasmosis was associated with permanent visual field defects in >94% of the eyes studied. Hence, standard automated perimetry may better reflect the functional damage encountered by ocular toxoplasmosis than visual acuity.

Noninvasive monitoring of chest wall movement in infants using laser

Traditionally, non-invasive monitoring of tidal volume in infants has been performed using impedance plethysmography analyzed using a one or two compartment model. We developed a new laser system for use in infants, which measures antero-posterior movement of the chest wall during quiet sleep. In 24 unsedated or sedated infants (11 healthy, 13 with respiratory disease), we examined whether the analysis of thoracoabdominal movement based on a three compartment model could more accurately estimate tidal volume in comparison to V(T) measured at the mouth. Using five laser signals, chest wall movements were measured at the right and left, upper and lower ribcage and the abdomen. Within the tidal volume range from 4.6 to 135.7 ml, a three compartment model showed good short term repeatability and the best agreement with tidal volume measured at mouth (r(2) = 0.86) compared to that of a single compartment model (r(2) = 0.62, P < 0.0001) and a two compartment model (r(2) = 0.82, P < 0.01), particularly in the presence of respiratory disease. Three compartment modeling of a 5 laser thoracoabdominal monitoring permits more accurate estimates of tidal volume in infants and potentially of regional differences of chest wall displacement in future studies.

Optimized temperature and deadspace correction improve analysis of multiple breath washout measurements by ultrasonic flowmeter in infants

BACKGROUND: Assessment of lung volume (FRC) and ventilation inhomogeneities with ultrasonic flowmeter and multiple breath washout (MBW) has been used to provide important information about lung disease in infants. Sub-optimal adjustment of the mainstream molar mass (MM) signal for temperature and external deadspace may lead to analysis errors in infants with critically small tidal volume changes during breathing. METHODS: We measured expiratory temperature in human infants at 5 weeks of age and examined the influence of temperature and deadspace changes on FRC results with computer simulation modeling. A new analysis method with optimized temperature and deadspace settings was then derived, tested for robustness to analysis errors and compared with the previously used analysis methods. RESULTS: Temperature in the facemask was higher and variations of deadspace volumes larger than previously assumed. Both showed considerable impact upon FRC and LCI results with high variability when obtained with the previously used analysis model. Using the measured temperature we optimized model parameters and tested a newly derived analysis method, which was found to be more robust to variations in deadspace. Comparison between both analysis methods showed systematic differences and a wide scatter. CONCLUSION: Corrected deadspace and more realistic temperature assumptions improved the stability of the analysis of MM measurements obtained by ultrasonic flowmeter in infants. This new analysis method using the only currently available commercial ultrasonic flowmeter in infants may help to improve stability of the analysis and further facilitate assessment of lung volume and ventilation inhomogeneities in infants.

Deadspace estimation from CO2 versus molar mass measurements in infants

BACKGROUND: Estimation of respiratory deadspace is often based on the CO2 expirogram, however presence of the CO2 sensor increases equipment deadspace, which in turn influences breathing pattern and calculation of lung volume. In addition, it is necessary to correct for the delay between the sensor and flow signals. We propose a new method for estimation of effective deadspace using the molar mass (MM) signal from an ultrasonic flowmeter device, which does not require delay correction. We hypothesize that this estimation is correlated with that calculated from the CO2 signal using the Fowler method. METHODS: Breath-by-breath CO2, MM and flow measurements were made in a group of 77 term-born healthy infants. Fowler deadspace (Vd,Fowler) was calculated after correcting for the flow-dependent delay in the CO2 signal. Deadspace estimated from the MM signal (Vd,MM) was defined as the volume passing through the flowhead between start of expiration and the 10% rise point in MM. RESULTS: Correlation (r = 0.456, P < 0.0001) was found between Vd,MM and Vd,Fowler averaged over all measurements, with a mean difference of -1.4% (95% CI -4.1 to 1.3%). Vd,MM ranged from 6.6 to 11.4 ml between subjects, while Vd,Fowler ranged from 5.9 to 12.0 ml. Mean intra-measurement CV over 5-10 breaths was 7.8 +/- 5.6% for Vd,MM and 7.8 +/- 3.7% for Vd,Fowler. Mean intra-subject CV was 6.0 +/- 4.5% for Vd,MM and 8.3 +/- 5.9% for Vd,Fowler. Correcting for the CO2 signal delay resulted in a 12% difference (P = 0.022) in Vd,Fowler. Vd,MM could be obtained more frequently than Vd,Fowler in infants with CLD, with a high variability. CONCLUSIONS: Use of the MM signal provides a feasible estimate of Fowler deadspace without introducing additional equipment deadspace. The simple calculation without need for delay correction makes individual adjustment for deadspace in FRC measurements possible. This is especially important given the relative large range of deadspace seen in this homogeneous group of infants.

Relation of white matter anisotropy to visual memory in 17 healthy subjects

We performed a Rey visual design learning test (RVDLT) in 17 subjects and measured intervoxel coherence (IC) by DTI as an indication of connectivity to investigate if visual memory performance would depend on white matter structure in healthy persons. IC considers the orientation of the adjacent voxels and has a better signal-to-noise ratio than the commonly used fractional anisotropy index. Voxel-based t-test analysis of the IC values was used to identify neighboring voxel clusters with significant differences between 7 low and 10 high test performers. We detected 9 circumscribed significant clusters (p< .01) with lower IC values in low performers than in high performers, with centers of gravity located in left and right superior temporal region, corpus callosum, left superior longitudinal fascicle, and left optic radiation. Using non-parametric correlation analysis, IC and memory performance were significantly correlated in each of the 9 clusters (r< .61 to r< .81; df=15, p< .01 to p< .0001). The findings provide in vivo evidence for the contribution of white matter structure to visual memory in healthy people.

Higher cord blood levels of mannose-binding lectin-associated serine protease-2 in infants with necrotising enterocolitis

Necrotising enterocolitis (NEC) causes significant morbidity and mortality in premature infants. The role of innate immunity in the pathogenesis of NEC remains unclear. Mannose-binding lectin (MBL) recognizes microorganisms and activates the complement system via MBL-associated serine protease-2 (MASP-2). The aim of this study was to investigate whether MBL and MASP-2 are associated with NEC. This observational case-control study included 32 infants with radiologically confirmed NEC and 64 controls. MBL and MASP-2 were measured in cord blood using ELISA. Multivariate logistic regression was performed. Of the 32 NEC cases (median gestational age, 30.5 wk), 13 (41%) were operated and 5 (16%) died. MASP-2 cord blood concentration ranged from undetectable (<10 ng/mL) to 277 ng/mL. Eighteen of 32 (56%) NEC cases had higher MASP-2 levels (> or =30 ng/mL) compared with 22 of 64 (34%) controls (univariate OR 2.46; 95% CI 1.03-5.85; p = 0.043). Higher cord blood MASP-2 levels were significantly associated with an increased risk of NEC in multivariate analysis (OR 3.00; 95% CI 1.17-7.93; p = 0.027). MBL levels were not associated with NEC (p = 0.64). In conclusion, infants later developing NEC had significantly higher MASP-2 cord blood levels compared with controls. Higher MASP-2 may favor complement-mediated inflammation and could thereby predispose to NEC.

A semi-structured interview to assess visual hallucinations in older people

OBJECTIVE: Visual hallucinations are under-reported by patients and are often undiscovered by health professionals. There is no gold standard available to assess hallucinations. Our objective was to develop a reliable, valid, semi-structured interview for identifying and assessing visual hallucinations in older people with eye disease and cognitive impairment. METHODS: We piloted the North-East Visual Hallucinations Interview (NEVHI) in 80 older people with visual and/or cognitive impairment (patient group) and 34 older people without known risks of hallucinations (control group). The informants of 11 patients were interviewed separately. We established face validity, content validity, criterion validity, inter-rater agreement and the internal consistency of the NEVHI, and assessed the factor structure for questions evaluating emotions, cognitions, and behaviours associated with hallucinations. RESULTS: Recurrent visual hallucinations were common in the patient group (68.8%) and absent in controls (0%). The criterion, face and content validities were good and the internal consistency of screening questions for hallucinations was high (Cronbach alpha: 0.71). The inter-rater agreements for simple and complex hallucinations were good (Kappa 0.72 and 0.83, respectively). Four factors associated with experiencing hallucinations (perceived control, pleasantness, distress and awareness) were identified and explained a total variance of 73%. Informants gave more 'don't know answers' than patients throughout the interview (p = 0.008), especially to questions evaluating cognitions and emotions associated with hallucinations (p = 0.02). CONCLUSIONS: NEVHI is a comprehensive assessment tool, helpful to identify the presence of visual hallucinations and to quantify cognitions, emotions and behaviours associated with hallucinations.