Space-time clustering analyses of type 1 diabetes in children from north-east England: support for an infectious aetiology?

Background

The aetiology of type 1 diabetes in children is uncertain. A number of recent studies have suggested an infectious aetiology. It has been postulated that an infectious agent may be involved. Support for this hypothesis may be provided by a finding of space-time clustering. The aims of this study were: (i) to determine whether there was space-time clustering in cases of childhood diabetes from north-east England; and to test for differences in space-time clustering: (ii) due to age at diagnosis; (iii) between the sexes and (iv) between levels of residential population density.

Methods

We studied incidence of type 1 diabetes diagnosed in children aged 0-14 years and diagnosed during the period 1990-2007. All cases were resident in a defined geographical region of north-east England (Northumberland, Newcastle upon Tyne and North Tyneside). We applied a second-order procedure based on K-functions to test for global clustering. Locations were residential addresses at time of diagnosis. Tests were repeated using nearest neighbour thresholds to allow for variable population density, providing the primary result for each analysis. Differences between sexes and between levels of population density were assessed.

Results

We analysed 457 cases of type 1 diabetes. Overall, there was marginally significant evidence of global space-time clustering (P = 0.089). There was statistically significant clustering amongst pairs of cases that contained at least one female (P = 0.017), but not amongst pairs of cases that contained at least one male (P = 0.190). Furthermore, there was significant clustering amongst pairs of cases that contained at least one from a more densely populated area (P = 0.044), but not amongst pairs of cases that contained at least one from a less densely populated area (P = 0.226).

Conclusion

Although the analyses have only found marginally significant evidence of global space-time clustering for cases of type 1 diabetes diagnosed in north-east England, there were two notable findings. First, there was evidence of clustering amongst females and secondly clustering was confined to cases from more densely populated areas. These findings are consistent with a possible aetiological involvement of an infectious agent.

     

“Why doesn't she seek help for partner abuse?” An exploratory study with South Asian immigrant women

This study explores why South Asian immigrant women with experiences of partner abuse delay seeking help from professionals. Three focus groups were conducted in Hindi language with South Asian immigrant women in Toronto. Twenty-two women participated with a mean age of 46 years (range 29–68 years). Thematic analysis was conducted on the transcribed data using constant comparison techniques within and across the groups. We found that three major themes emerged from the discussions: reasons for delayed help-seeking, turning points and talking to professionals. Women expressed delaying help-seeking to the point when “Pani sar se guzar jata he” (water crosses over your head). Their dominant reasons for delayed help-seeking were social stigma, rigid gender roles, marriage obligations, expected silence, loss of social support after migration and limited knowledge about available resources and myths about partner abuse. Women usually turned for help only after experiencing pronounced mental and physical health problems.     

Ataque de nervios: relationship to anxiety sensitivity and dissociation predisposition

We investigated the relative importance of "fear of arousal symptoms" (i.e., anxiety sensitivity) and "dissociation tendency" in generating ataque de nervios. Puerto Rican patients attending an outpatient psychiatric clinic were assessed for ataque de nervios frequency in the previous month, and they completed the Anxiety Sensitivity Index (ASI) and the Dissociation Experiences Scale (DES). ASI scores were especially high in the ataque-positive group (M=41.6, SD=12.8) as compared with the ataque-negative group (M=27.2, SD=11.7), t(2, 68)=4.6, P<.001. Among the whole sample (N=70), in a logistic regression analysis, the ASI significantly predicted (odds ratio=2.6) the presence of ataque de nervios, but the DES did not. In a linear regression analysis, ataque severity was significantly predicted by both the ASI (beta=.46) and the DES (beta=.29). The theoretical and clinical implications of the strong relationship of the ASI to ataque severity are discussed.     

Examination of gender effect in birth weight and miscarriage associations with childhood cancer (United Kingdom)

Background Higher birth weight and maternal history of miscarriage has been associated with an increased risk of childhood leukemia. The possibility that this association may be sex-specific has not been explored in detail in previous studies. Methods In a retrospective case-control study, 732 childhood (≤14 years) cancer cases from a population-based Registry in Northern England whose hospital birth records could be accessed and 3,723 controls matched for date and hospital of birth to the cases were compared. We examined birth weight for sex-specific associations with childhood cancer. Conditional logistic regression analysis was used for statistical evaluation of associations. Results In acute lymphoblastic leukemia (ALL) (225 cases and 1,163 matched controls), birth weight and sex showed a strong interaction (P = 0.003). In boys with ALL, but not in girls, there was a nonlinear association with birth weight (P for trend = 0.008; OR = 3.05 for the highest quintile compared to the second lowest quintile, 95% CI = 1.40–6.64; P = 0.005). When birth weights were adjusted using UK standards for gestational age and sex, the risk associations were similar in statistical significance and magnitude. Maternal history of miscarriage showed an association with all cancers and individually with ALL. The miscarriage association with ALL was statistically significant in boys only (OR = 1.91, 95% CI = 1.07–3.42; P = 0.03). A multivariable model for ALL containing other examined maternal and reproductive variables confirmed the independence of the birth weight and miscarriage associations. There was no birth weight or miscarriage associations in other cancers. Conclusions This study confirmed the risk associations with birth weight and miscarriages in childhood ALL. Statistically significant association of size at birth suggested marked differences in etiology between girls and boys.     

Myostatin blockade improves function but not histopathology in a murine model of limb-girdle muscular dystrophy 2C

Myostatin is a negative regulator of skeletal muscle growth. Myostatin mutations and pharmacological strategies increase muscle mass in vivo, suggesting that myostatin blockade may prove useful in diseases characterized by muscle wasting, such as the muscular dystrophies. We subjected the gamma-sarcoglycan-deficient (Sgcg(-/-)) mouse model of limb-girdle muscular dystrophy (LGMD) 2C to antibody-mediated myostatin blockade in vivo. Myostatin inhibition led to increased fiber size, muscle mass, and absolute force. However, no clear improvement in muscle histopathology was evident, demonstrating discordance between physiological and histological improvement. These results and previous studies on the dyw/dyw mouse model of congenital muscular dystrophy and in the late-stage delta-sarcoglycan-deficient (Sgcd(-/-)) mouse model of LGMD2F document disease-specific limitations to therapeutic strategies based on myostatin blockade in the more severe mouse models of different muscular dystrophies.     

Grade progression and regression in recurrent urothelial cancer

PURPOSE: Recurrent urothelial cancers are reported to have characteristics similar to those of the primary tumor, with 10% to 25% of low grade tumors recurring as high grade disease. We determined how often grade progression and regression occur and whether abnormalities in p53 protein expression in original tumors are preserved in recurrences. MATERIALS AND METHODS: Two groups of patients treated for recurrent stages Ta/T1 urothelial bladder cancers with at least 1 tumor-free examination between the index and recurrent tumors were reviewed. Group 1 included 115 patients in whom the first available tumor was compared with the last recurrence and group 2 included 42 in whom the initial tumor was compared with the first recurrence. Immunohistochemical analysis of p53 expression was performed on a subset of 34 tumor pairs. RESULTS: In group 1, 33 grade 3 tumors (45%) recurred as grade 1 or 2 tumors, while 9 of 82 grades 1 and 2 tumors (11%) recurred as grade 3 tumors. Five of 7 group 2 grade 3 tumors (71%) recurred as grade 1 or 2 disease, while 1 of 35 grades 1 and 2 tumors (3%) recurred as grade 3 disease. In the 34 pairs studied immunohistochemically 6 of 14 grade 3 tumors recurred at lower grades. Nuclear p53 over expression occurred in 21 index tumors (12 of 14 grade 3, 8 of 17 grade 2 and 1 of 3 grade 1) and in 9 recurrences (6 of 10 grade 3, 2 of 17 grade 2 and 1 of 7 grade 1). Only 7 of 21 p53 positive and 2 of 12 p53 negative index tumors were p53 positive on recurrence. CONCLUSIONS: While progression from low to high grade occurred in less than 15% of patients, grade regression was observed in almost 50%. The loss of p53 positivity in regressing tumors indicates that these recurrences are molecularly distinct from the corresponding initial tumor.     

Volition and alcohol-risk reduction: the role of action orientation in the reduction of alcohol-related harm among college student drinkers

The present study examined the role of action orientation in health behavior change. Eighty-six binge drinking college students completed measures of alcohol use, alcohol-related consequences (e.g., driving drunk), motivation to change drinking, and action orientation. Alcohol use and consequences were reassessed 1 month later. Results showed that, although there was no significant change in alcohol quantity per occasion, students reported a significant decline in alcohol-related problems over time. Hierarchical regression analyses were conducted to examine whether action orientation was associated with changes in alcohol involvement. Controlling for alcohol problems and motivation to change at Time 1, those with higher dispositional action orientation showed fewer alcohol-related consequences at Time 2. These results suggest that those who are low in action orientation may have more difficulty enacting intentions to modify harmful health behaviors. The findings underscore the importance of volitional skills in interventions to promote change in health behavior.     

Anxiety sensitivity in agoraphobics

This study further validated the "Reiss-Epstein-Gursky Anxiety Sensitivity Index" (ASI) as a measure of the fear of anxiety. Agoraphobics scored high on the ASI before, but not after, behavioral treatment. Residual anxiety sensitivity, however, did not predict resurgence of agoraphobic avoidance at six months follow-up. Indeed, anxiety sensitivity continued to decline during the follow-up period. Multiple regression analyses indicated that the ASI predicted the number of fears in agoraphobics beyond that predicted by the level of general anxiety. This finding supports the hypothesis that high anxiety sensitivity enhances fear acquisition; it also suggests that the ASI measures a construct different from that measured by general anxiety scales. Empirical similarities and differences were found between the ASI and two other "fear of fear" measures: the Agoraphobic Cognitions Questionnaire and the Body Sensations Questionnaire.     

Diffusion MRI Microstructural Abnormalities at Term-Equivalent Age Are Associated with Neurodevelopmental Outcomes at 3 Years of Age in Very Preterm Infants

BACKGROUND AND PURPOSE:Microstructural white matter abnormalities on DTI using Tract-Based Spatial Statistics at term-equivalent age are associated with cognitive and motor outcomes at 2 years of age or younger. However, neurodevelopmental tests administered at such early time points are insufficiently predictive of mild-moderate motor and cognitive impairment at school age. Our objective was to evaluate the microstructural antecedents of cognitive and motor outcomes at 3 years'' corrected age in a cohort of very preterm infants.MATERIALS AND METHODS:We prospectively recruited 101 very preterm infants (<32 weeks'' gestational age) and performed DTI at term-equivalent age. The Differential Ability Scales, 2nd ed, Verbal and Nonverbal subtests, and the Bayley Scales of Infant and Toddler Development, 3rd ed, Motor subtest, were administered at 3 years of age. We correlated DTI metrics from Tract-Based Spatial Statistics with the Bayley Scales of Infant and Toddler Development, 3rd ed, and the Differential Ability Scales, 2nd ed, scores with correction for multiple comparisons.RESULTS:Of the 101 subjects, 84 had high-quality DTI data, and of these, 69 returned for developmental testing (82%). Their mean (SD) gestational age was 28.4 (2.5) weeks, and birth weight was 1121.4 (394.1) g. DTI metrics were significantly associated with Nonverbal Ability in the corpus callosum, posterior thalamic radiations, fornix, and inferior longitudinal fasciculus and with Motor scores in the corpus callosum, internal and external capsules, posterior thalamic radiations, superior and inferior longitudinal fasciculi, cerebral peduncles, and corticospinal tracts.CONCLUSIONS:We identified widespread microstructural white matter abnormalities in very preterm infants at term that were significantly associated with cognitive and motor development at 3 years'' corrected age.

Premature birth is associated with a significantly increased risk of brain abnormalities and long-term neurodevelopmental impairment. Injuries or maturational delays affecting the WM are observed in 50%–80% of very preterm infants.^1-3 These abnormalities are associated with serious neurodevelopmental impairment.^1,3,4 However, such abnormalities are challenging to detect using conventional MR imaging techniques alone. Fortunately, DTI, a specialized form of MR imaging that can sensitively query the brain''s microstructure, offers a novel approach for identifying these WM injuries. In preterm brains, the evolution of fractional anisotropy (FA) and mean diffusivity (MD), 2 metrics derived from DTI, varies from that of normative populations, and underlying brain injury may lead to neurodevelopmental impairment later in life.^4-6Functional MR imaging with the FMRIB Tract-Based Spatial Statistics (TBSS; http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/TBSS) tool uses observer-independent voxelwise statistical analysis to process the complex information contained within diffusion-weighted images.^4-16 TBSS can be used to identify specific WM tracts and structures in the infant brain that correlate with later developmental outcomes.^8,10,13-15 Previous studies have used TBSS to objectively assess WM microstructure following clinical events such as infection, sports injury, or preterm brain injury (eg, intraventricular hemorrhage) and to relate the associated WM alterations to outcomes.^9,11,16-19 In addition, studies have used TBSS to identify brain regions and tracts in which FA significantly correlates with cognitive and motor outcomes at 2 years of age or younger.^10,13,15 These studies have consistently concluded that higher FA is associated with better motor, cognitive, and language functioning.Past studies emphasizing the value of TBSS correlated DTI parameters with neurodevelopmental outcomes derived from the Bayley Scales of Infant and Toddler Development, 3rd ed (Bayley-III) collected at 2 years of age or younger. Such standardized assessments are administered between 18 and 24 months of age, representing the earliest time point at which cognitive, language, and motor development can be reliably ascertained. However, assessment at these earliest ages is not necessarily predictive of school age outcomes.^20-22 For example, the Bayley-III Motor subscale at 2 years of age significantly underestimates rates of motor impairment at 4 years of age in preterm infants.²² Spencer-Smith et al²³ showed that cognitive delay, as assessed by the Bayley-III administered at 2 years of age, was not strongly associated with cognitive impairment at 4 years of age as assessed by the Differential Ability Scales, 2nd ed (DAS-II).²⁴ We propose that correlating FA from term-equivalent age MR imaging with 3-year outcomes may provide a more robust understanding of the early changes in WM microstructure that are also significantly associated with cognitive development.Our objective was to test the hypothesis that WM microstructure, assessed using TBSS at term-corrected age (CA), is associated with neurodevelopmental performance at 3 years'' CA in a regional cohort of very preterm infants.