Acute flaccid myelitis in childhood: a retrospective cohort study.

BACKGROUND AND PURPOSE: Clusters of acute limb weakness in paediatric patients have been linked to outbreaks of non-polio enteroviruses, termed acute flaccid myelitis (AFM). Outside these clusters, in countries where polio is not endemic, this poliomyelitic-like illness is rare in childhood and its natural history is not well defined. We describe presenting features, investigation findings and long-term outcome of a series of children with AFM. METHODS: This was a retrospective cohort study. RESULTS: Eight children (six females) aged 3 months to 8 years (median age 5 years) met case criteria. Initial symptoms were pain (n = 7) followed by limb weakness with hypotonia (n = 8). Flaccid paralysis occurred in only three patients. Two had cranial nerve dysfunction. Magnetic resonance imaging of the spinal cord demonstrated grey matter involvement particularly affecting the anterior cord, with longitudinally extensive changes in three children. Cerebrospinal fluid examination showed pleocytosis in six children with raised cerebrospinal fluid protein in five. Nerve conduction and electromyography findings were consistent with a motor neuronopathy. Residual deficits were common, with moderate to severe weakness seen in five patients. Median follow-up was 28 months (range 17-108 months, 30.4 patient years in total). CONCLUSIONS: Acute flaccid myelitis is an uncommon condition in childhood with a high rate of significant long-term morbidity. AFM should be considered in children presenting with acute limb pain and weakness.

Muscle wound healing in rainbow trout (Oncorhynchus mykiss).

We followed the progression of healing of deep excisional biopsy punch wounds over the course of 365 days in rainbow trout (Oncorhynchus mykiss) by monitoring visual wound healing and gene expression in the healing muscle at regular intervals (1, 3, 7, 14, 38 and 100 days post-wounding). In addition, we performed muscle texture analysis one year after wound infliction. The selected genes have all previously been investigated in relation to vertebrate wound healing, but only few specifically in fish. The selected genes were interleukin (IL)-1ß, IL-6, transforming growth factor (TGF)-ß1 and -ß3, matrix metalloproteinase (MMP) -9 and -13, inducible nitric oxide synthase (iNOS), fibronectin (FN), tenascin-C (TN-C), prolyl 4-hydroxylase α1-chain (P4Hα1), lysyl oxidase (LOX), collagen type I α1-chain (ColIα1), CD41 and CD163. Wound healing progressed slowly in the presented study, which is at least partially due to the low temperature of about 8.5 °C during the first 100 days. The inflammation phase lasted more than 14 days, and the genes relating to production and remodeling of new extracellular matrix (ECM) exhibited a delayed but prolonged upregulation starting 1-2 weeks post-wounding and lasting until at least 100 days post-wounding. The gene expression patterns and histology reveal limited capacity for muscle regeneration in rainbow trout, and muscle texture analyses one year after wound infliction confirm that wounds heal with fibrosis. At 100 dpw epidermis had fully regenerated, and dermis partially regenerated. Scales had not regenerated even after one year. CD163 is a marker of "wound healing"-type M2c macrophages in mammals. M2 macrophage markers are as yet poorly described in fish. The pattern of CD163 expression in the present study is consistent with the expected timing of presence of M2c macrophages in the wound. CD163 may thus potentially prove a valuable marker of M2 macrophages - or a subset hereof - in fish. We subjected a group of fish to bathing in an immunomodulatory ß-glucan product during wound healing, but found this to have very limited effect on wound healing in contrast to a previously published study on common carp.

Effectiveness of offering healthy labelled meals in improving the nutritional quality of lunch meals eaten in a worksite canteen.

Healthier meal selections at restaurants and canteens are often limited and not actively promoted. In this Danish study the effectiveness of a healthy labelling certification program in improving dietary intake and influencing edible plate waste was evaluated in a quasi-experimental study design. Employees from an intervention worksite canteen and a matched control canteen were included in the study at baseline (February 2012), after completing the certification process (end-point) and six month from end-point (follow-up) (total n=270). In order to estimate nutrient composition of the consumed lunch meals and plate waste a validated digital photographic method was used combining estimation of food intake with food nutrient composition data. Food satisfaction was rated by participants using a questionnaire. Several significant positive nutritional effects were observed at the intervention canteen including a mean decrease in energy density in the consumed meals from 561kJ/100g at baseline to 368 and 407kJ/100g at end-point and follow-up, respectively (P<0.001). No significant changes were seen with regard to food satisfaction and plate waste. In the control canteen no positive nutritional effects were observed. The results of the study highlight the potential of using healthy labelling certification programs as a possible driver for increasing both the availability and awareness of healthy meal choices, thereby improving dietary intake when eating out.

Impact of changes in metabolic control on progression to photocoagulation for clinically significant macular oedema: a 20 year study of type 1 diabetes.

AIMS/HYPOTHESIS: Although increasing hyperglycaemia, arterial hypertension and longer duration of diabetes raise the risk of progression of diabetic retinopathy, short-term benefits in terms of improved metabolic control and lowered blood pressure have not been demonstrated. We therefore examined the effect of changes in glycaemia and arterial blood pressure on the incidence of clinically significant macular oedema in a population of diabetic patients. METHODS: We performed a retrospective review of all patients with type 1 diabetes who attended the retinopathy screening clinic at the Steno Diabetes Center from 1988 to 2008, using the endpoint referral to first photocoagulation treatment for clinically significant diabetic macular oedema. The analysis included 1,878 patients (median observation, 8 years). Changes were defined as the inter-visit change; in the case of an event the last event-free interval before referral, where the median screening interval was 6 months. RESULTS: Risk of progression to photocoagulation for macular oedema increased with duration of diabetes (p < 0.001), current HbA1c (p < 0.0001) and with the magnitude of changes in HbA1c (p = 0.0002) and systolic blood pressure (p < 0.0001) in a multiple regression model. A recent decrease of ≥ 0.5 percentage points or an increase in HbA1c of >0.5 percentage points per 6 months was associated with HRs of 3.04 and 1.28, respectively, compared with lesser changes in HbA1c. CONCLUSIONS/INTERPRETATION: In this study, large recent changes in metabolic control and systolic blood pressure, irrespective of direction, were independent risk factors for progression to photocoagulation for diabetic macular oedema. The effects of metabolic and haemodynamic stability on diabetic retinopathy should be examined in prospective studies.

Trimethoprim use in early pregnancy and the risk of miscarriage: a register-based nationwide cohort study.

The antibiotic trimethoprim acts as a folate antagonist. Since trophoblasts are very sensitive to drugs that interfere with the folic acid cycle and thereby inhibit DNA synthesis, use of trimethoprim during the first trimester could be associated with miscarriage. A nationwide cohort study including all women in Denmark with a registered pregnancy between 1997 and 2005 was conducted. We used nationwide registers to identify all women giving birth, having a record of miscarriage or induced abortion. Data on exposure to trimethoprim were obtained from the National Prescription Register. Cox proportional hazard regression analysis with exposure to trimethoprim as a time-dependent variable was used to estimate the risk of miscarriage. The adjusted hazard ratio of having a miscarriage after exposure to trimethoprim in the first trimester compared to non-exposure was 2∙04 (95% confidence interval 1∙43-2∙91). Our results indicate that trimethoprim exposure in the first trimester is associated with a doubling of the hazard of miscarriage.

Germ cell numbers in human embryonic and fetal gonads during the first two trimesters of pregnancy: analysis of six published studies.

BACKGROUND: The number of germ cells in human embryonic and fetal ovaries in relation to age is currently based on volumetric estimations from one study including a total of 12 ovaries. Six recent publications present stereological estimations of the number of germ cells in ovaries and testes for the first two trimesters. METHODS: Germ cell numbers from 103 human first and second trimester gonads aged 37-133 days post-conception (p.c.), obtained after legal termination of pregnancy, were collected from six independent studies that all used similar validated stereological methods for estimating germ cell numbers as well as somatic cell numbers. RESULTS: Statistically, the six studies estimated similar number of germ cells (P > 0.05) and no interaction between the studies and age was found (P > 0.05), indicating that the increase in cell numbers in relation to age was of comparable magnitude in each study. The number of germ cells increased from a mean of 7200 to 4,933,000 in fetal ovaries and from 3700 to 1,417,000 in fetal testes, from week 5 to week 19 p.c. A higher rate of increase was found for female germ cells as compared with males (P = 0.004). During the same period, the number of somatic cells increased from a mean of 158,000 to 1,017,000 in ovaries and from 154,000 to 2,035,000 in testes, respectively. CONCLUSIONS By the use of validated stereological methods, this study provides more accurate and improved information on human germ and somatic cell numbers in ovaries and testes during the first two trimesters of pregnancy.

Cigarette smoking during early pregnancy reduces the number of embryonic germ and somatic cells.

BACKGROUND: Cigarette smoking during pregnancy is associated with negative reproductive consequences for male fetuses in adult life such as reduced testicular volume and sperm concentration. The present study evaluates the number of germ and somatic cells present in human embryonic first-trimester gonads in relation to maternal smoking. METHODS: The study includes 24 human first-trimester testes, aged 37-68 days post-conception, obtained from women undergoing legal termination of pregnancy. A questionnaire was used to obtain information about smoking and drinking habits during pregnancy. Validated stereological methods were used to estimate gonadal cell numbers in histological sections. Results were also evaluated in the context of previously published data on ovaries from our laboratory. RESULTS: A significant reduction in the number of germ cells by 55% [95% confidence interval (CI) 74-21% reduction, P = 0.004] and somatic cells by 37% (95% CI 59-3%, P = 0.023) was observed in testes prenatally exposed to maternal cigarette smoking, compared with unexposed. The effect of maternal smoking was dose-dependent being higher in the heavy smokers and remained consistent after adjusting for possible confounders such as alcohol and coffee consumption (P = 0.002). The number of germ cells in embryonic gonads, irrespective of gender, was also significantly reduced by 41% (95% CI 58-19%, P = 0.001) in exposed versus non-exposed embryonic gonads. CONCLUSIONS: Prenatal exposure to maternal cigarette smoke reduces the number of germ and somatic cells in embryonic male and female gonads. This effect may have long-term consequences on the future fertility of exposed offspring. These findings may provide one potential cause of the reduced fertility observed during recent years.

Predictors of recurrence in affective disorder--analyses accounting for individual heterogeneity.

BACKGROUND: Previous studies suggest that gender, age at onset, and marital status act as risk factors for further recurrence initially during the course of affective disorder but not at a later stage. These studies did, however, not take the individual liability to recurrence into account. METHOD: The effect of predictors of recurrence was estimated with the use of generalised linear mixed models in a case register study including a random sample of all patients admitted with primary affective disorder in Denmark during 1971-1993. RESULTS: In total, 7047 first admission patients with a diagnosis of affective disorder, depressive or manic/circular type were included in the analyses. The study confirmed that the effect of the type of disorder, age at first admission, and never being married decreased during the course of illness even when the individual liability to recurrence was taken into account. No differences in the effect of gender and in the effect of a recent divorce were found between early and later episodes and the effect of a recent death of a spouse seemed to increase during the course of illness. The risk of recurrence increased with every new episode for all sub-groups of patients. CONCLUSION: The effect of some, but not all, predictors of recurrence decline during the course of affective illness. The number of previous episodes predicts recurrence in most subgroups of patients. LIMITATION: The data relate to re-admissions rather than recurrence. CLINICAL RELEVANCE: The study underscores the importance of the illness process itself.

High concordance of subtypes of childhood acute lymphoblastic leukemia within families: lessons from sibships with multiple cases of leukemia.

Polymorphic genes have been linked to the risk of acute lymphoblastic leukemia (ALL). Surrogate markers for a low burden of early childhood infections are also related to increased risk for developing childhood ALL. It remains uncertain, whether siblings of children with ALL have an increased risk of developing ALL. This international collaboration identified 54 sibships with two (N = 51) or more (N = 3) cases of childhood ALL (ages <18 years). The 5-year event-free survival for 61 patients diagnosed after 1 January 1990 was 0.83 ± 0.05. Ages at diagnosis (Spearman correlation coefficient, r(S) = 0.41, P = 0.002) were significantly correlated, but not WBCs (r(S) = 0.23, P = 0.11). In 18 sibships with successful karyotyping in both cases, six were concordant for high-hyperdiploidy (N = 3), t(12;21) [ETV6/RUNX1] (N = 1), MLL rearrangement (N = 1) or t(1;19)(q23/p13) (N = 1). Eleven sibships were ALL-subtype concordant, being T-cell ALL (T-ALL) (N = 5, of a total of six sibships, where the first-born had T-ALL) or B-lineage ALL belonging to the same cytogenetic subset (N = 6), a finding that differs significantly from the expected chance distribution (κ: 0.58; P < 0.0001). These data indicate strong genetic and/or environmental risk factors for childhood ALL that are restricted to specific ALL subtypes, which must be taken into account, when performing epidemiological studies to reveal etiological factors.

Familial risk of venous thromboembolism: a nationwide cohort study.

BACKGROUND: Venous thromboembolism has genetic determinants, but population-based data on familial risks are limited. OBJECTIVES: To examine the familial risk of venous thromboembolism. METHODS: We undertook a nationwide study of a cohort of patients with deep venous thrombosis or pulmonary embolism born after 1952. We used the Danish National Registry of Patients covering all Danish hospitals, for the years 1977 through 2009, to identify index cases of venous thromboembolism, and assessed the incidence among their siblings. We compared standardized incidence ratios (SIRs) of the observed and expected number of venous thromboembolism cases among siblings, using population-specific, gender-specific and age-specific incidence rates. RESULTS: We identified 30,179 siblings of 19,599 cases of venous thromboembolism. The incidence among siblings was 2.2 cases per 1000 person-years, representing a relative risk of 3.08 (95% confidence interval [CI] 2.80-3.39) as compared with the general population. The risk was higher for both men (SIR 3.36, 95% CI 2.96-3.82) and women (SIR 2.81, 95% CI 2.45-3.23). The risk was similar among siblings of index cases with venous thrombosis and those of index cases with pulmonary embolism. CONCLUSION: Venous thromboembolism has a strong familial component.

Increased incidence of affective disorders, anxiety disorders, and non-natural mortality in women after breast cancer diagnosis: a nation-wide cohort study in Denmark.

OBJECTIVE: To investigate whether breast cancer patients have increased incidence of psychiatric admission with affective disorders, anxiety disorders, or non-natural mortality compared with the general female population. METHOD: Register-linkage between nation-wide registries: The Danish Psychiatric Central Register, The Danish Cancer Registry, and The Danish National Register of Causes of Death. A total of 61 709 women registered with primary invasive breast cancer between 1970 and 1993 were included and 356 023 person-years were accrued. RESULTS: The standardized incidence ratio of first-ever psychiatric admission with affective disorder was 1.49 (95% CI: 1.35-1.63) and with anxiety disorder 1.25 (95% CI: 1.06-1.46). The standardized non-natural mortality ratio during the first year after breast cancer diagnosis was 1.54 (95% CI: 1.27-1.87). All analyses were adjusted for age, calendar period, and place of residence. CONCLUSION: Breast cancer patients have significantly increased incidence of psychiatric admission with affective disorders, anxiety disorders, and non-natural mortality.

Breast cancer risk among women with psychiatric admission with affective or neurotic disorders: a nationwide cohort study in Denmark.

There is a considerable interest in the possible relationship between psychosocial factors and the onset of breast cancer. This cohort study was based upon two nationwide and population-based central registers: The Danish Psychiatric Central Register, which contains all cases of psychiatric admissions, and The Danish Cancer Registry, which contains all cases of cancer. The register-linkage was accomplished by using a personal identification number. The study population comprised all women admitted to psychiatric departments or psychiatric hospitals in Denmark between 1969 and 1993 with an affective or a neurotic disorder. Overall, 66,648 women comprising 199,910 admissions and 775,522 person-years were included. The incidence of breast cancer in the cohort was compared with the national breast cancer incidence rates adjusted for age and calendar time. In all, 1270 women with affective or neurotic disorders developed breast cancer subsequent to the first admission as compared with the 1242 women expected, standardized incidence ratio (SIR) = 1.02 (95% confidence interval 0.97-1.08). None of the hypothetical risk factors: type of diagnosis, age or calendar period at cohort entry, age at breast cancer, alcohol abuse, alcohol/drug abuse without further specification, total number of admissions, total length of admissions, or time from first admission showed a statistically significant effect on the relative risk of breast cancer. We found no support for the hypothesis that women admitted to a psychiatric department with an affective or a neurotic disorder subsequently have an increased risk of breast cancer.