Modelling acute myeloid leukaemia in a continuum of differentiation states.

Here we present a mathematical model of movement in an abstract space representing states of cellular differentiation. We motivate this work with recent examples that demonstrate a continuum of cellular differentiation using single cell RNA sequencing data to characterize cellular states in a high-dimensional space, which is then mapped into ℝ 2 or ℝ 2 with dimension reduction techniques. We represent trajectories in the differentiation space as a graph, and model directed and random movement on the graph with partial differential equations. We hypothesize that flow in this space can be used to model normal and abnormal differentiation processes. We present a mathematical model of hematopoeisis parameterized with publicly available single cell RNA-Seq data and use it to simulate the pathogenesis of acute myeloid leukemia (AML). The model predicts the emergence of cells in novel intermediate states of differentiation consistent with immunophenotypic characterizations of a mouse model of AML.

A duplication in a patient with 46,XX ovo-testicular disorder of sex development refines the SOX9 testis-specific regulatory region to 24 kb.

A custom CGH microarray that covers the SOX9 regulatory region. Log2 ratio scatterplot showing individual data points. Blue box highlights copy number gain with 3' breakpoint region magnified.

Exome sequencing in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.

DMRT1 is required for Müllerian duct formation in the chicken embryo.

DMRT1 is a conserved transcription factor with a central role in gonadal sex differentiation. In all vertebrates studied, DMRT1 plays an essential function in testis development and/or maintenance. No studies have reported a role for DMRT1 outside the gonads. Here, we show that DMRT1 is expressed in the paired Müllerian ducts in the chicken embryo, where it is required for duct formation. DMRT1 mRNA and protein are expressed in the early forming Müllerian ridge, and in cells undergoing an epithelial to mesenchyme transition during duct morphogenesis. RNAi-mediated knockdown of DMRT1 in ovo causes a greatly reduced mesenchymal layer, which blocks caudal extension of the duct luminal epithelium. Critical markers of Müllerian duct formation in mammals, Pax2 in the duct epithelium and Wnt4 in the mesenchyme, are conserved in chicken and their expression disrupted in DMRT1 knockdown ducts. We conclude that DMRT1 is required for the early steps of Müllerian duct development. DMRT1 regulates Müllerian ridge and mesenchyme formation and its loss blocks caudal extension of the duct. While DMRT1 plays an important role during testis development and maintenance in many vertebrate species, this is the first report showing a requirement for DMRT1 in Müllerian duct development.

The molecular genetics of ovarian differentiation in the avian model.

In birds as in mammals, sex is determined at fertilization by the inheritance of sex chromosomes. However, sexual differentiation - development of a male or female phenotype - occurs during embryonic development. Sex differentiation requires the induction of sex-specific developmental pathways in the gonads, resulting in the formation of ovaries or testes. Birds utilize a different sex chromosome system to that of mammals, where females are the heterogametic sex (carrying Z and W chromosomes), while males are homogametic (carrying 2 Z chromosomes). Therefore, while some genes essential for testis and ovarian development are conserved, important differences also exist. Namely, the key mammalian male-determining factor SRY does not exist in birds, and another transcription factor, DMRT1, plays a central role in testis development. In contrast to our understanding of testis development, ovarian differentiation is less well-characterized. Given the presence of a female-specific chromosome, studies in chicken will provide insight into the induction and function of female-specific gonadal pathways. In this review, we discuss sexual differentiation in chicken embryos, with emphasis on ovarian development. We highlight genes that may play a conserved role in this process, and discuss how interaction between ovarian pathways may be regulated.

Does performance in selection processes predict performance as a dental student?

OBJECTIVE: This study investigated associations between the performance of dental students in each of the three components of the selection procedure [academic average, Undergraduate Medicine and Health Sciences Admission Test (UMAT) and structured interview], socio-demographic characteristics and their academic success in an undergraduate dental surgery programme. MATERIALS AND METHODS: Longitudinal review of admissions data relating to students entering dental education at the University of Otago, New Zealand, between 2004 and 2009 was compared with academic performance throughout the dental programme. RESULTS AND DISCUSSION: After controlling for variables, pre-admission academic average, UMAT scores and interview performance did not predict performance as a dental student. Class place in second year, however, was a strong predictor of class place in final year. Multivariate analysis demonstrated that the best predictors of higher class placement in the final year were New Zealand European ethnicity and domestic (rather than international) student status. Other socio-demographic characteristics were not associated with performance. These interim findings provide a sound base for the ongoing study. CONCLUSION: The study found important socio-demographic differences in pre-admission test scores, but those scores did not predict performance in the dental programme, whether measured in second year or in final year.

Self-reported occupational health of general dental practitioners.

BACKGROUND: Limited information is available regarding the occupational health status of dentists (particularly in New Zealand), although previous research suggests that stress, hand dermatoses and musculoskeletal symptoms are common. AIMS: To determine the occupational health status of New Zealand dentists. METHODS: A nationwide postal survey of a representative sample of 750 dentists. RESULTS: There was a response rate of 77%. Most dentists (71%) reported their general health as very good or excellent; 43% rated their physical fitness as excellent or very good and 64% were happy and interested in life. Workplace bullying had been experienced by 19% and was higher for female and employee dentists and 29% had experienced a violent or abusive incident at work. Almost half of the sample (47%) had experienced at least one dermatitis-type condition in the previous 12 months. The most commonly reported sites for musculoskeletal problems experienced in the previous year were the neck (59%), lower back (57%) and shoulders (45%). Women had a higher prevalence of several occupational health problems, but were more satisfied with their overall health than male dentists. CONCLUSIONS: The majority of dentists had good general health, but physical fitness levels were not ideal. The prevalence of hand dermatoses and musculoskeletal problems are high and impact significantly on dentists' daily lives. Interventions such as reducing weight and training in optimal working methods to reduce musculoskeletal problems and injuries (such as eye or needlestick incidents) might improve the health of this workforce but further research is required.

Job stressors of New Zealand dentists and their coping strategies.

BACKGROUND: Dentistry is understood to be a stressful profession. Although there has been recent research about stress and dentistry in the UK and the Netherlands, little is known about the job stressors and coping strategies of New Zealand dentists. AIM: To investigate job stressors and coping strategies among New Zealand dentists. METHODS: A nationwide postal survey of a representative sample of 700 dentists. RESULTS: The response rate was 65%. The most commonly reported stressors were treating difficult children (52%), constant time pressure (48%) and maintaining high levels of concentration (43%). The strategies most utilized for managing work-related stress included interactions with people (78%), sports (64%) and forgetting about work (59%). Dentists who had graduated overseas reported more sources of stress than New Zealand graduates. There were differences in the strategies used by male and female practitioners to manage stress. CONCLUSIONS: There is considerable variation in the number of stressors experienced by dentists. Overseas-qualified dentists appear to be under more stress than New Zealand-trained dentists and may need greater professional support. Dentists should be encouraged to make greater use of active coping strategies.

Darbepoetin alfa for treatment of anaemia in a case of chronic renal failure during pregnancy--case report.

Oral haematinics are frequently, if not ubiquitously, used to supplement dietary iron in pregnancy. A 21-year-old patient attended the antennal clinic because she suffered from nephritic syndrome due to focal segmental glomerulosclerosis. Despite treatment with oral haematinics, her haemoglobin level continued to fall. After a blood transfusion, her renal function deteriorated. She was started on darbepoetin alfa, a long-acting erythropoietin, for treat the anaemia caused by renal failure.

The working practices and career satisfaction of dental therapists in New Zealand.

OBJECTIVE: To describe the working practices and level of career satisfaction of dental therapists in New Zealand. DESIGN: Postal survey of dental therapists identified from the New Zealand Dental Council's dental therapy database. One mailing with one follow-up. PARTICIPANTS: Questionnaires were sent to 683 registered dental therapists. Replies were received from 566 (82.9%). OUTCOME MEASURES: Current working practice, career breaks, continuing education, career satisfaction. RESULTS: Respondents had a high career satisfaction, but were much less satisfied with their remuneration. After controlling for age and income satisfaction, therapists who felt that they were valued members of the dental community had over four times the odds of having higher overall job satisfaction. There were no differences in the mean career satisfaction scale score by age, but respondents aged 45 and over had a lower mean income satisfaction scale score than their younger counterparts (p<0.05). Older respondents were more likely to report regularly placing fissure sealants (p<0.05), participating in peer review (p<0.05), and playing a role in team management/coordination (p<0.05) than younger respondents. Most therapists (412; 82.2%) had taken at least one career break, usually for child rearing. A mean of 6.5 years (SD 5.9; range six weeks to 25 years) had been taken in career breaks. Younger therapists were more interested in moving into private practice than their older colleagues (p<0.05). More than half of respondents planned to retire from dental therapy within 10 years. CONCLUSION: Urgent action is required to improve the recruitment and retention of dental therapists in the New Zealand School Dental Service. Measures to reduce the time taken in career breaks could increase the productivity of this workforce. Remuneration and career progression are key issues; therapists need to feel that they are valued members of the dental profession.

Dental caries experience and use of dental services among preschool children in Ajman, UAE.

OBJECTIVE: The aim of this study was to estimate the prevalence and severity of dental caries in the primary dentition of young children in Ajman, UAE, and investigate its association with sociodemographic characteristics and use of dental services. METHODS: A cluster-sampling approach was used to randomly select children aged 5 or 6 years who were enrolled in public or private schools. Clinical examinations for caries were conducted by a single examiner using World Health Organization criteria. Parents completed questionnaires seeking information on socioeconomic background and dental service utilization. Zero-inflated negative binomial (ZINB) regression modelling was used to identify risk markers and risk indicators for caries experience. RESULTS: The prevalence of dental caries in the sample was high 76.1%. The average dmfs score 10.2. Caries severity was greater among older children and among male children of less educated mothers. Emirati (local) children had higher caries severity than others. Children who had higher level of caries visited the dentist more frequently than other children whose visits were for check-up only. CONCLUSIONS: Dental caries prevalence and severity in young children in Ajman are high, and socioeconomic characteristics and dental utilization are important determinants of their dental caries experience. There is an urgent need for oral health programmes targeted at the treatment and underlying causes of dental caries in these children.

Socioeconomic inequalities in oral health in childhood and adulthood in a birth cohort.

OBJECTIVES: To determine whether adult oral health is predicted by (a) childhood socioeconomic advantage or disadvantage (controlling for childhood oral health), or (b) oral health in childhood (controlling for childhood socioeconomic advantage or disadvantage), and whether oral health in adulthood is affected by changes in socioeconomic status (SES). METHODS: Participants in a longstanding cohort study underwent systematic dental examination for dental caries and tooth loss at ages 5 and 26 years. The examination at age 26 years included the collection of data on periodontal attachment loss and plaque level. Childhood SES was determined using parental occupation, and adult SES was determined from each study member's occupation at age 26 years. Regression models were used to test the study hypotheses. RESULTS: Complete data were available for 789 individuals (47.4% female). After controlling for childhood oral health, those who were of low SES at age 5 years had substantially greater mean DFS and DS scores by age 26 years, were more likely to have lost a tooth in adulthood because of caries, and had greater prevalence and extent of periodontitis. A largely similar pattern was observed (after controlling for childhood SES) among those with greater caries experience at age 5 years. For almost all oral health indicators examined, a clear gradient was observed of greater disease at age 26 years across socioeconomic trajectory groups, in the following order of ascending disease severity and prevalence: 'high-high', 'low-high' (upwardly mobile), 'high-low' (downwardly mobile) and 'low-low'. CONCLUSION: Adult oral health is predicted by not only childhood socioeconomic advantage or disadvantage, but also by oral health in childhood. Changes in socioeconomic advantage or disadvantage are associated with differing levels of oral health in adulthood. The life-course approach appears to be a useful paradigm for understanding oral health disparities.

The involvement of New Zealand dentists in smoking cessation interventions.

OBJECTIVES: To determine the attitudes and practices of dentists towards smoking cessation interventions (SCI), to identify perceived barriers to providing SCI, and to determine the level of interest in future training in smoking cessation for dental staff. DESIGN: Self-administered questionnaire. SUBJECTS AND METHODS: 204 NZDA members in Wellington, Otago, and Southland completed a self-administered questionnaire about SCI. RESULTS: There has been little change in attitudes and practices of dentists towards SCI over the last decade. Few are actively involved in providing these services for their patients. Most dentists believe that there are significant barriers to providing SCI in their daily practice. CONCLUSION: Dentists require greater access to appropriate forms of training in SCI, and increased support (including resources) in order to increase the level of SCI provided in the dental setting.

Is attention-deficit hyperactivity disorder a risk factor for dental caries? A case-control study.

Experience in practice has suggested that children with attention-deficit hyperactivity disorder (ADHD) tend to have higher numbers of diseased, missing and filled teeth (DMFT score) than children without the condition. To date, however, this impression has not been systematically investigated. A case-control study of children in Otago, New Zealand (case DMFT > or = 5; control DMFT <5; case status determined from School Dental Service dental records) was conducted by postal survey and reference to the School Dental Service records. Cases and controls were matched on age, sex, ethnicity, and school socio-economic status. The purpose of the study was to assess whether having ADHD was associated with higher odds of having high caries experience. Questionnaires were returned for a total of 128 case-control pairs. Conditional logistical regression analysis showed that, after controlling for fluoride history, medical problems, diet, and self-reported oral hygiene, children with ADHD had nearly 12 times the odds of having a high DMFT score than children who did not have ADHD (OR = 11.98; 95% CI 1.13, 91.81). No other factors were significant predictors. Dental practitioners and parents should consider ADHD to be a condition that may affect children's dental caries experience.

Evidence for allelic association on chromosome 3q25-27 in families with autism spectrum disorders originating from a subisolate of Finland.

Recent molecular studies on autism and related disorders have supported a multilocus etiology for the disease spectrum. To maximize genetic and cultural homogeneity, we have focused our molecular studies to families originating from a subisolate of Central Finland. Genealogical studies enabled the identification of a megapedigree comprising of 12 core families with autism and Asperger syndrome (AS). We analyzed two chromosomal regions on Iq and 3q showing highest lod scores in our genome-wide scan, as well as the AUTS1 locus on chromosome 7q. For markers on 3q25-27, more significant association was observed in families from subisolate compared to families from the rest of Finland. In contrast, no clear evidence for association on AUTS1 locus was obtained. The wide interval showing association, in particular, on chromosome 3q suggests a locus for autism spectrum of disorders on this chromosomal region.

Management of a simple anterior crossbite in a child with autism: a review and case report.

This case report describes a simple treatment used to correct an anterior crossbite in a child with autism. A review of autism and the treatment of simple anterior crossbite are given. It is possible for children with special needs to be managed in the general practice setting, although treatment plans may need to be modified to meet the capabilities of individual patients. Follow-up is required for cases of anterior crossbite treated in the early mixed dentition.

Risk indicators for tooth wear in New Zealand school children.

AIM: To investigate the prevalence and severity of tooth wear in the primary dentition of a representative sample of New Zealand school children and relate these to possible risk factors. DESIGN: A cross-sectional study. SETTING: Primary schools in Dunedin, New Zealand. PARTICIPANTS: 104 children of both sexes, aged between 5 and 8 years, randomly selected. METHODS: Clinical examinations of the buccal, occlusal/incisal and lingual surfaces of deciduous canines and molars. MAIN OUTCOME MEASURE: Degree of wear and the presence of dentinal cupping of teeth. Information on weaning and consumption of fruit-based drinks at bed time, frequency of consumption of fruits, yoghurt, pickled foods, fizzy and fruit-based drinks. RESULTS: The prevalence of tooth wear was similar in boys and girls and there were no significant differences between sides of the arches. A high percentage (82%) of children had at least one primary tooth with dentine exposed. While maxillary canines showed the greatest prevalence of dentine exposed, maxillary molars displayed the greatest prevalence of cupping. Severe tooth wear was less prevalent among children weaned after 12 months (14.3%) than those weaned earlier (27.9% P < 0.01). There were no statistically significant associations between wear and the consumption of fruit, yoghurt, pickled foods, fizzy drinks or fruit-based drinks. CONCLUSIONS: Tooth wear associated with dentine exposure is common in 5-8 year old children. This is not significantly associated with dietary factors, but appears to be related to early weaning from the breast.

Leukaemia in children. Part I: Orofacial complications and side-effects of treatment.

Significant orofacial complications of leukaemia in children include lymphadenopathy, spontaneous gingival bleeding, labial and lingual ecchymoses and mucosal petechiae, ulceration, gingival swelling, and infections. The dentist may be the first to notice signs of the illness. Treatment of leukaemia can result in serious orofacial problems which include oral mucositis and ulceration, infections, spontaneous gingival bleeding, neuropathy, xerostomia, and gingival hypertrophy. A prompt diagnosis leading to early intervention can decrease the morbidity and mortality of the disease and its treatment.

Mechanomyographic and electromyographic responses during fatigue in humans: influence of muscle length.

Mechanomyography (MMG) provides a measure of muscle mechanical changes during contractions. The purpose of this study was to quantify alterations in MMG signals during fatigue at two muscle lengths. Comparisons with electromyographic (EMG) recordings were made. A group of 13 subjects performed isometric dorsiflexions (50% of maximum for 60 s) at 40 degrees of plantarflexion (long, l(l)) and 5 degrees of dorsiflexion (short, l(s)). The mean power frequency of the EMG (f(EMG)) and MMG (f(MMG)) signals and the mean rectified MMG (rMMG) and EMG (rEMG) were determined over each 1-s period, normalized to the respective maximal value, regressed against time, and the resulting slopes (units = %max. s(-1)) were analyzed. The slopes were larger (P = 0.007) at l(l) compared to l(s) [mean l(l) 0.50 (SD 0.26), mean l(s) 0.27 (SD 0.16)], however there were no differences (P = 0.24) between mean fMMG slopes [l(l) -0.10 (SD 0.16), l(s) -0.16 (SD 0.11)]. Similarly, slopes were larger (P = 0.001) at l(l) versus l(s) [l(l) 0.26 (SD 0.13), l(s) 0.08 (SD 0.15)] and there were no differences (P=0.89) between mean fEMG slopes [l(l) -0.15 (SD 0.14), l(s) -0.14 (SD 0.12)]. At 5 s following the exercise to fatigue mean MVC (units = %max) were not significantly different between l(l) and l(s) [P = 0.08; l(l) 78.8 (SD 9.1), l(s) 85.2 (SD 6. 0)]. These results showed that during fatiguing contractions, MMG and EMG amplitudes increased while frequency characteristics decreased at both muscle lengths. The change in and was greater at l(l) but no differences in fMMG or fEMG slopes occurred between lengths. These results would suggest that larger increases in motor unit recruitment occur with time during fatigue at l(l) compared to l(s).