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Abstract: Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine N = 235, skeletal muscle N = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine (R2 = 0.61–0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G‐harbouring individuals; increasing age and heteroplasmy contribute (R2 = 0.27, P < 0.001). In muscle, heteroplasmy, age and mtDNA copy number explain a higher proportion of variability in disease burden (R2 = 0.40, P < 0.001), although activity level and disease severity are likely to affect copy number. Whilst our data indicate that age‐corrected blood m.3243A>G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence disease severity. [ABSTRACT FROM AUTHOR]

Aim: This study investigated annual and seasonal death trends for infants of <1 year of age in Hungary between 1963 and 2012 and analysed commonly accepted risk factors. Methods: Data on the numbers of live births and infant deaths were obtained from the published nationwide population register. Negative binomial regression was applied to investigate the yearly trends in rates and also the effect of possible risk factors - low birthweight, maternal education and sex - on infant mortality. Cyclic trends were investigated using logistic regression. Results: Annual infant mortality declined significantly (p<0.001) from 42.9 to 4.9 per 1000 live births per year during the study period and significantly increased (p<0.001) in the low birthweight group and lower maternal education groups. A significant (p<0.001) cyclic trend in mortality was revealed, with a peak in deaths in late February for all infants and a double peak, in May and November, in the group of cases who died during the early neonatal period. Conclusion: This Hungarian study suggests that there was a significant seasonal effect on neonatal and infant mortality at the end of winter between 1963 and 2012. We speculate that this may have been related to respiratory infections. [ABSTRACT FROM AUTHOR]

A letter to the editor about cutaneous malignant melanoma in teenagers and young adults is presented.

Basta NO, James PW, Craft AW, McNally RJQ. Season of birth and diagnosis for childhood cancer in Northern England, 1968–2005. Paediatric and Perinatal Epidemiology 2010; 24: 309–318. The aim of this study was to investigate seasonal variation in the incidence of cancer in children aged 0–14 years. Details of 2959 primary malignant cases (1659 males, 1300 females), diagnosed during the period 1968–2005, were extracted from a specialist registry (the Northern Region Young Persons' Malignant Disease Registry). Seasonal variation was analysed with respect to month of birth and diagnosis. The chi-squared heterogeneity test was used to test for non-uniform variation. Poisson regression analysis was used to fit sinusoidal (harmonic) models to the data, using month of birth and month of diagnosis, respectively, as covariates in separate models. There was significant sinusoidal variation based on month of birth for acute lymphoblastic leukaemia (ALL) aged 1–6 years ( P = 0.04; peak in March). For 0- to 14-year-old boys, there was statistically significant sinusoidal variation in month of birth for acute non-lymphocytic leukaemia ( P = 0.04; peak in September) and astrocytoma ( P = 0.03; peak in October). Based on month of diagnosis, there was statistically significant sinusoidal variation in girls for all lymphomas ( P = 0.048; peak in March) and Hodgkin lymphoma (HL) ( P = 0.005; peak in January), and in boys for osteosarcoma ( P = 0.049; peak in October). This study confirms previous findings of seasonal variation around the month of birth for childhood ALL (at the peak ages) and provides further evidence of seasonal variation around month of birth for astrocytoma and around month of diagnosis for HL. The results are consistent with a role for environmental factors in the aetiology of these diagnostic groups. Further studies are needed to examine putative candidate agents. [ABSTRACT FROM AUTHOR]

Objective Hypoglycaemia may be a frequent occurrence in young GH deficient patients and so we studied the response to fasting in children and adolescents with GH and/or cortisol deficiency. Methods A total of 20 patients (2–18 years) fasted for 14 h (22·00–12·00 h) on two occasions as part of a randomized cross-over study. Fourteen had pituitary hormone deficiency (PHD) including GH deficiency (GHD). Of the 14 patients, seven were ACTH sufficient (PHDC+) and seven ACTH deficient (PHDC–). Six had primary adrenal failure (PAF). Subjects administered or omitted their normal dose of evening GH and/or morning hydrocortisone. Glucose, insulin, GH, cortisol, ketones and catecholamines were measured at 04·00 h and regularly from 07·00 to 12·00 h. Insulin sensitivity was assessed by HOMA and hypoglycaemia defined as a blood glucose (BG) ≤ 3·3 mmol/l. Results BG was related to age and body mass index on treatment but no subject became hypoglycaemic on or off therapy prior to 07·00 h. Five children (aged 3, 4, 7, 8 and 11 years) were hypoglycaemic between 07·00 and 12·00 h off treatment. There was a positive relationship between GH AUC and minimum BG in patients with PHD on treatment ( r2 = 0·45, P = 0·012) with increased insulin sensitivity off treatment. Increased cortisol levels were seen in PHDC+ patients off GH ( P < 0·001). A negative relationship was observed between minimum BG and adrenaline ( r2 = 0·37, P = 0·01), ketone bodies ( r2 = –0·20, P = 0·05) and NEFA ( r2 = –0·35, P = 0·02). Noradrenaline levels were reduced in patients with PHDC–. Low BMI (on treatment) and young age (off treatment) were determinants of low BG levels in a multiple regression model. Conclusions Unrecognized overnight hypoglycaemia in children and adolescents on pituitary hormone replacement is uncommon but BG levels quickly become abnormal when treatment and meals are omitted. The insulin antagonistic actions of GH are important in preventing hypoglycaemia. Patients with PHD have altered sympathetic nerve activity. [ABSTRACT FROM AUTHOR]

There are three current hypotheses concerning infectious mechanisms in the aetiology of childhood leukaemia: exposure in utero or around the time of birth, delayed exposure beyond the first year of life to common infections and unusual population mixing. No specific virus has been definitively linked with childhood leukaemia and there is no evidence to date of viral genomic inclusions within leukaemic cells. The case–control and cohort studies have revealed equivocal results. Maternal infection during pregnancy has been linked with increased risk whilst breast feeding and day care attendance in the first year of life appear to be protective. There is inconclusive evidence from studies on early childhood infectious exposures, vaccination and social mixing. Some supportive evidence for an infectious aetiology is provided by the findings of space-time clustering and seasonal variation. Spatial clustering suggests that higher incidence is confined to specific areas with increased levels of population mixing, particularly in previously isolated populations. Ecological studies have also shown excess incidence with higher population mixing. The marked childhood peak in resource-rich countries and an increased incidence of the childhood peak in acute lymphoblastic leukaemia (ALL) (occurring at ages 2–6 years predominantly with precursor B-cell ALL) is supportive of the concept that reduced early infection may play a role. Genetically determined individual response to infection may be critical in the proliferation of preleukaemic clones as evidenced by the human leucocyte antigen class II polymorphic variant association with precursor B-cell and T-cell ALL. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about a study on the increased likelihood of malignancy in young patients with a thyroid nodule in Northern England.

Focuses on letters to the editors published in the 1999 'Clinical Endocrinology' journal. Cortisol response in short synacthen tests; Obesity in the Prader-Labhart-Willi syndrome; Kallman's syndrome; Neoplasia in patients with pitutary adenomas.

Comments on the report of increased incidence of neoplasia in patients with pituitary adenomas. Errors and substantial limitations of the report; Summary of the report.

Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.