Primary dysmenorrhoea in adolescents and young women: A twin family study of maternal transmission, genetic influence and associations.

AIMS: The extent to which maternal transmission of primary dysmenorrhoea is genetically determined in adolescents and young women has yet to be determined. We aimed to assess heritability and associations relevant to primary pain syndromes using a twin family study. METHODS: Participants were young menstruating female twins, and their oldest sisters and mothers, whose families were registered with Twins Research Australia and previously participated in a twin family study of primary paediatric pain disorders. Questionnaire packs were mailed, assessing current maximum and average menstrual pain intensity, current pain interference with activities and retrospective dysmenorrhea secondary symptoms. RESULTS: The sample comprised 206 twin individuals (57 monozygous (MZ) and 46 dizygous (DZ) pairs) aged 10-22 years, eldest siblings (n = 38) aged 13-28 years and mothers (n = 101) aged 32-61 years. The estimated regression coefficient of the relationship between mother-daughter and twin-sibling dyads indicated significant associations for the measures of dysmenorrhea and supported heritability. Adjusted for age, the within twin-pair correlation for MZ twins was generally more than twice that of DZ twins. Heritability estimates were maximal pain intensity 0.67 (P = 3.8 × 10-11 ), average pain intensity 0.63 (P = 3.7 × 10-10 ), pain interference 0.57 (P = 1.8 × 10-8 ) and retrospective symptoms 0.57 (P = 1.8 × 10-8 ). Twin individuals with a lifetime (three-month) history of iron deficiency and those with painless restless legs syndrome (RLS) were significantly more likely to have more intense pain associated with menstruation. CONCLUSION: Primary dysmenorrhea in adolescents and young women was shown to be relatively strongly genetically influenced and associated especially with a history of iron deficiency and painless RLS which have potential therapeutic implications.

Improved definition of growing pains: A common familial primary pain disorder of early childhood.

Background: Commonly applied diagnostic criteria for growing pains (GP) have evolved without determination by an authoritative representative body. GP and restless legs syndrome (RLS) share anatomical, distributional, temporal, and other clinical features and are associated in individuals over time, in families, and in population samples. In this study, we tested the hypothesis that GP, diagnosed by widely used criteria, is confounded by cases of painful restless legs syndrome (RLS-Painful). Methods: A twin family study of genetic influence and associations of GP using questionnaires was administered by Twins Research Australia. Twins (3-18 years; monozygous 503, dizygous 513), their oldest siblings, mothers, and fathers were randomly selected from the twin registry. Family members completed the questionnaires assessing lifetime prevalence of GP by commonly applied criteria and covariates including the history of iron deficiency and pediatric pain disorders. A GP-Specific phenotype was defined as GP without urge to move the legs. We determined similarities in twin pairs for the GP and GP-Specific phenotypes, family associations, and estimated familial and individual-specific associations for each phenotype. Results: Lifetime prevalence was one-third lower for GP-Specific than for GP among the twin and family members. Monozygous twin pairs were more similar than dizygous twin pairs for GP and for the derived GP-Specific phenotype by three methods, consistent with genetic influence. There were familial associations, but the essential evidence for genetic influence was the twin-cotwin data. GP was associated, in multivariable analyses, with migraine, headaches, recurrent abdominal pain, and iron deficiency, while GP-Specific associations were limited to migraine and headaches. Conclusions: GP is hybrid, one-third of cases having symptoms and associations of RLS, necessarily RLS-Painful. GP-Specific (without symptoms and associations of RLS) could have a genetic etiology. We propose new criteria to facilitate etiological and therapeutic research.

Somatosensory Testing in Pediatric Patients with Chronic Pain: An Exploration of Clinical Utility.

We aimed to evaluate the utility of clinical somatosensory testing (SST), an office adaptation of laboratory quantitative sensory testing, in a biopsychosocial assessment of a pediatric chronic somatic pain sample (N = 98, 65 females, 7-18 years). Stimulus-response tests were applied at pain regions and intra-subject control sites to cutaneous stimuli (simple and dynamic touch, punctate pressure and cool) and deep pressure stimuli (using a handheld pressure algometer, and, in a subset, manually inflated cuff). Validated psychological, pain-related and functional measures were administered. Cutaneous allodynia, usually regional, was elicited by at least one stimulus in 81% of cases, most frequently by punctate pressure. Central sensitization, using a composite measure of deep pressure pain threshold and temporal summation of pain, was implied in the majority (59.2%) and associated with worse sleep impairment and psychological functioning. In regression analyses, depressive symptoms were the only significant predictor of pain intensity. Functional interference was statistically predicted by deep pressure pain threshold and depressive symptoms. Manually inflated cuff algometry had comparable sensitivity to handheld pressure algometry for deep pressure pain threshold but not temporal summation of pain. SST complemented standard biopsychosocial assessment of pediatric chronic pain; use of SST may facilitate the understanding of disordered neurobiology.

Contrasting painless and painful phenotypes of pediatric restless legs syndrome: a twin family study.

OBJECTIVE: This study was designed to investigate painless and painful subsets of pediatric restless legs syndrome (RLS) for genetic influence and for associations with iron deficiency and common pediatric pain disorders. METHODS: In a twin family study, twins (3-18 years) and their oldest siblings, mothers and fathers completed questionnaires, assessing lifetime prevalence of RLS using current criteria, as well as history of iron deficiency and pediatric pain disorders. Subsets were categorized as RLS-Painless or RLS-Painful. Within twin pair analyses were conducted to assess familial and potential genetic effects for the defined subsets. Penalized maximum likelihood logistic regression was used to test familial associations. Random-effects logistic regression modeling was used in the total pediatric sample to investigate univariate and multivariate associations with the subsets. RESULTS: Data were available for 2033 twin individuals (1007 monozygous (MZ), 1026 dizygous (DZ); 51.7% female), 688 siblings, 1013 mothers and 921 fathers. Odds ratios, correlations and casewise concordance were significantly higher in MZ than in DZ twins only for RLS-Painful. RLS-Painless, though familial (co-twin and mother), was not genetically influenced, but was independently associated with female sex (OR 0.52, p = 0.003), iron deficiency (OR 4.20, p < 0.001) and with persistent pain disorders (OR 2.28, p = 0.02). RLS-Painful was familial and was probably genetically influenced; was independently associated with non-migraine headaches (OR 2.70, p = 0.02) and recurrent abdominal pain (OR 2.07, p = 0.04). CONCLUSIONS: Pediatric RLS was heterogeneous and was categorized into contrasting painless and painful phenotypes. RLS-Painless was associated with iron deficiency while RLS-Painful accounted for the heritability of RLS.

Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma.

Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.

Developing the Comfort Care Case: An End-of-Life Resource for Pediatric Patients, Their Families, and Health Professionals.

Caring for a child in hospital who is approaching death, in the terminal phase, requires a focus on caring for the physical, emotional, and spiritual needs of the child and family. Health professionals caring for these children and families may need to shift their focus from a treatment-focused approach aimed at cure or maintaining life to a comfort-focused approach. The Comfort Care Case (CCC) is a collection of resources designed for use in hospital to ease suffering and facilitate comfort within a pediatric end-of-life (EOL) context. The resources are intended to support the child, the family, and the health professionals involved in EOL care. This article describes the development, implementation, and education associated with the CCC in a tertiary pediatric hospital.

Safety and long-term efficacy of fractional CO2 laser treatment in women suffering from genitourinary syndrome of menopause.

OBJECTIVES: To evaluate the safety and long-term efficacy of fractional CO2 laser treatment in reducing the severity of symptoms of genitourinary syndrome of menopause (GSM) in menopausal women. STUDY DESIGN: 102 women presenting with symptomatic GSM were treated with the fractional CO2 laser (MonaLisa Touch, DEKA) system across a series of treatments delivered at intervals of six or more weeks. The Australian Pelvic Floor Questionnaire was used to gather data on sexual function and side-effects at three time-points across the study period (prospective panel design study). Wilcoxon signed-rank tests were used to detect statistically and clinically significant changes in sexual function and side-effects occurring from pre- to post-treatment. The primary outcome of this study was an improvement of the symptoms of GSM. The secondary outcome included bladder function and prolapse symptoms. RESULTS: A total of 102 women suffering from moderate to severe GSM were recruited. Eighty-four percent experienced significant improvement in their symptoms after CO2 laser treatment. Scores on measures of sexual function, dyspareunia, and bothersomeness of sexual issues were improved from pre-treatment to long-term (12-24 month) follow-up. Furthermore, there were improvements on measures of bladder function (P=0.001), prolapse (P=0.001), vaginal sensation (P=0.001), vaginal lubrication (P<0.001) and urge incontinence (P=0.003) from the pre-treatment assessment to the second assessment (i.e. after the third treatment). CONCLUSIONS: In this study, fractional microablative CO2 laser treatment was associated with an improvement in symptoms of GSM and sexual function.