Cost modelling rehabilitation in the home for reconditioning in the Australian context.

BACKGROUND: Inpatient rehabilitation services are challenged by increasing demand. Where appropriate, a shift in service models towards more community-oriented approaches may improve efficiency. We aimed to estimate the hypothetical cost of delivering a consensus-based rehabilitation in the home (RITH) model as hospital substitution for patients requiring reconditioning following medical illness, surgery or treatment for cancer, compared to the cost of inpatient rehabilitation. METHODS: Data were drawn from the following sources: the results of a Delphi survey with health professionals working in the field of rehabilitation in Australia; publicly available data and reports; and the expert opinion of the project team. Delphi survey data were analysed descriptively. The costing model was developed using assumptions based on the sources described above and was restricted to the Australian National Subacute and Non-Acute Patient Classification (AN-SNAP) classes 4AR1 to 4AR4, which comprise around 73% of all reconditioning episodes in Australia. RITH cost modelling estimates were compared to the known cost of inpatient rehabilitation. Where weighted averages are provided, these were determined based on the modelled number of inpatient reconditioning episodes per annum that might be substitutable by RITH. RESULTS: The cost modelling estimated the weighted average cost of a RITH reconditioning episode (which mirrors an inpatient reconditioning episode in intensity and duration) for AN-SNAP classes 4AR1 to 4AR4, to be A$11,371, which is 28.1% less than the equivalent weighted average public inpatient cost (of A$15,820). This represents hypothetical savings of A$4,449 per RITH reconditioning substituted episode of care. CONCLUSIONS: The hypothetical cost of a model of RITH which would provide patients with as comprehensive a rehabilitation service as received in inpatient rehabilitation, has been determined. Findings suggest potential cost savings to the public hospital sector. Future research should focus on trials which compare actual clinical and cost outcomes of RITH for patients in the reconditioning impairment category, to inpatient rehabilitation.

Is communication key in stroke rehabilitation and recovery? National linked stroke data study.

BACKGROUND: Information on the characteristics or long-term outcomes of people with communication support needs post-stroke is limited. We investigated associations between communication gains in rehabilitation and long-term outcomes (quality-of-life [EuroQOL-ED-3 L], mortality) by post-stroke communication support need status. METHODS: Retrospective cohort study using person-level linked data from the Australian Stroke Clinical Registry and the Australasian Rehabilitation Outcomes Centre (2014-2017). Communication support needs were assessed using the Functional Independence Measure™ comprehension and expression items recorded on admission indicated by scores one (total assistance) to five (standby prompting). Multivariable multilevel and Cox regression models were used to determine associations with long-term outcomes. RESULTS: Of 8,394 patients who received in-patient rehabilitation after stroke (42% female, median age 75.6 years), two-thirds had post-stroke communication support needs. Having aphasia (odds ratio [OR] 4.34, 95% CI 3.67-5.14), being aged ≥65 years (OR 1.21, 95% CI 1.08-1.36), greater stroke severity (unable to walk on admission; OR 1.48, 95% CI 1.32-1.68) and previous stroke (OR 1.25, 95% CI 1.11-1.41) were associated with increased likelihoods of having communication support needs. One-point improvement in FIM™ expression was associated with reduced likelihood of self-reporting problems related to mobility (OR 0.85, 95% CI: 0.80-0.90), self-care (OR 0.79, 95% CI: 0.74-0.86) or usual activities (OR 0.84, 95% CI: 0.75-0.94) at 90-180 days. Patients with communication support needs had greater mortality rates within one-year post-stroke (adjusted hazard ratio 1.99, 95% CI: 1.65-2.39). CONCLUSIONS: Two-thirds of patients with stroke require communication support to participate in healthcare activities. Establishing communication-accessible stroke care environments is a priority.

The impact of dementia on rehabilitation outcomes following hip fracture.

Objective: To compare clinical outcomes between patients for whom their participation in inpatient rehabilitation was and was not impacted by dementia through matching patients reporting dementia (dementia group) with those not reporting dementia (non-dementia group). Methods: Prospectively collected data held by the Australasian Rehabilitation Outcome Centre (AROC) were analyzed for patients aged 65 years or older receiving inpatient rehabilitation in public hospitals in Australia following a hip fracture and discharged between July 1, 2014, and June 30, 2019. Patients reported as having dementia impacting their rehabilitation program were matched to patients not reporting dementia based on age, admission motor Functional Independence Measure (FIM) score, and accommodation prior to rehabilitation. The matched cohorts were compared in relation to clinical outcomes (motor and cognitive FIM improvement, FIM efficiency, length of stay, and discharge destination) following participation in hospital-based rehabilitation using univariate analysis. Results: Patients with dementia had significantly lower cognitive FIM scores on commencing rehabilitation (17.6 and 26.9, respectively, P < 0.001) and their median length of stay was 2 days shorter than those without dementia (21 and 23 days, respectively, P < 0.001). Relative change in FIM score and FIM efficiency (per week) were lower in the dementia group [relative FIM score change of dementia vs non-dementia, respectively, 26.2% vs. 44.0% (P < 0.001) and FIM efficiency, 6.5 vs. 8.9 (P < 0.001)]. Discharge destination between the two groups was statistically different, with 35.7% of patients with dementia being discharged to residential aged care facilities (RACFs) compared to 21.7% of those without dementia (P < 0.001). More patients with dementia had carers in their private residence in the post-rehabilitation phase, 82.2% vs. 57.6% (P < 0.001). Conclusion: Patients with dementia who sustain a fractured hip benefit from inpatient rehabilitation, although their clinical outcomes are not as good as those without dementia. FIM change and FIM efficiency were lower in the dementia group. Length of stay in the hospital for patients with dementia was shorter due to earlier recognition for the need for placement in either an RACF or at home with carer support. The need for placement in an RACF or carer support in a private residence was significantly greater in the dementia group.

Developing a model for rehabilitation in the home as hospital substitution for patients requiring reconditioning: a Delphi survey in Australia.

BACKGROUND: Reconditioning for patients who have experienced functional decline following medical illness, surgery or treatment for cancer accounts for approximately 26% of all reported inpatient rehabilitation episodes in Australia. Rehabilitation in the home (RITH) has the potential to offer a cost-effective, high-quality alternative for appropriate patients, helping to reduce pressure on the acute care sector. This study sought to gain consensus on a model for RITH as hospital substitution for patients requiring reconditioning. METHODS: A multidisciplinary group of health professionals working in the rehabilitation field was identified from across Australia and invited to participate in a three-round online Delphi survey. Survey items followed the patient journey, and also included items on practitioner roles, clinical governance, and budgetary considerations. Survey items mostly comprised statements seeking agreement on 5-point Likert scales (strongly agree to strongly disagree). Free text boxes allowed participants to qualify item answers or make comments. Analysis of quantitative data used descriptive statistics; qualitative data informed question content in subsequent survey rounds or were used in understanding item responses. RESULTS: One-hundred and ninety-eight health professionals received an invitation to participate. Of these, 131/198 (66%) completed round 1, 101/131 (77%) completed round 2, and 78/101 (77%) completed round 3. Consensus (defined as ≥ 70% agreement or disagreement) was achieved on over 130 statements. These related to the RITH patient journey (including patient assessment and development of the care plan, case management and program provision, and patient and program outcomes); clinical governance and budgetary considerations; and included items for initial patient screening, patient eligibility and case manager roles. A consensus-based model for RITH was developed, comprising five key steps and the actions within each. CONCLUSIONS: Strong support amongst survey participants was found for RITH as hospital substitution to be widely available for appropriate patients needing reconditioning. Supportive legislative and payment systems, mechanisms that allow for the integration of primary care, and appropriate clinical governance frameworks for RITH are required, if broad implementation is to be achieved. Studies comparing clinical outcomes and cost-benefit of RITH to inpatient rehabilitation for patients requiring reconditioning are also needed.

Effect of comorbidities on inpatient rehabilitation outcomes following non-traumatic lower limb amputations in Australia and New Zealand.

Background Non-traumatic lower limb amputation rates are rising worldwide, resulting in increased hospitalisations and use of rehabilitation services. This study aimed to identify key comorbidities associated with prolonged length of stay or decreased functional gain for episodes receiving inpatient rehabilitation following non-traumatic lower limb amputation. Methods Prospectively collected data submitted to the Australasian Rehabilitation Outcomes Centre were analysed. The cohort comprised episodes for patients (aged ≥18 years) discharged from inpatient rehabilitation between 1 July 2013 and 30 June 2018 following a non-traumatic lower limb amputation. Results The cohort included 5074 episodes with an average age of 66.3 years and the majority being male (71.7%). Comorbidities affecting the ability to participate in rehabilitation were reported for 65.4% of episodes, most commonly diabetes mellitus (50.3%), cardiac disease (33.5%), and respiratory disease (10.1%). These comorbidities were associated with a prolonged length of stay and reduced functional improvement. Conclusion This study showed comorbidities contribute to prolonged length of stay and poorer functional outcomes among those undergoing inpatient rehabilitation following non-traumatic lower limb amputation. Future research should focus on strategies to address these comorbidities to help improve patient outcomes and reduce healthcare costs.

Rehabilitation outcomes of survivors of cardiac arrest admitted to ICUs in Australia and New Zealand (ROSC ANZ): A data linkage study.

INTRODUCTION: Rehabilitation outcomes in cardiac arrest survivors are largely unknown, with no data comparing out-of-hospital cardiac arrests (OHCA) and in-hospital cardiac arrests (IHCA). This study aimed to describe and compare inpatient rehabilitation outcomes in these patients who were admitted from intensive care units (ICU). METHODS: A retrospective linkage and analysis of cardiac arrest patients in the Australian and New Zealand Intensive Care Society Adult Patient Database and the Australasian Rehabilitation Outcomes Centre inpatient dataset discharged to inpatient rehabilitation between January 2017 and June 2018. Primary outcome was the functional improvement during rehabilitation (difference between the Functional Independence Measurement (FIM) score on admission and discharge). Multivariate regression analyses were performed to determine factors associated with functional improvement. RESULTS: In the 240 (84 OHCA and 156 IHCA) patients included, the median length of inpatient rehabilitation was 15 days [1st-3rd quartile (Q1-Q3): 9-24]. OHCA patients were more likely to be admitted to rehabilitation for neurological issues (41.7%) and IHCA for medical reasons (51.9%). Median (Q1-Q3) change in total FIM scores was similar between the two groups (24.5[10-37]) vs 21[11-31], adjusted p = 0.20), with most of the FIM change seen in the motor items, and this was only associated with a lower admission FIM score. The majority of OHCA and IHCA patients were discharged home (91.5% and 89.7%, respectively), although with an increased need for a carer at home compared to baseline (27.2% to 55.6%). CONCLUSION: Patients discharged from ICU following OHCA and IHCA achieved reasonable and similar functional improvement during inpatient rehabilitation.

Increased Relative Functional Gain and Improved Stroke Outcomes: A Linked Registry Study of the Impact of Rehabilitation.

OBJECTIVES: It is unclear how acute care influences patient outcomes in those who receive rehabilitation. We aimed to determine the associations between acute stroke therapies, outcomes during inpatient rehabilitation and self-reported outcomes at 90-180 days after stroke. MATERIALS AND METHODS: Patient-level data from adults with acute stroke registered in the Australian Stroke Clinical Registry (AuSCR, 2014-2017) were linked with data from the Australasian Rehabilitation Outcomes Centre (AROC). The main outcome was relative function gain (RFG), which is a measure of the FIM change achieved between admission to discharge as a proportion of the total gain possible based on admission FIM, relative to the maximum achievable score. Multilevel logistic/median regression analyses were used to investigate the association between RFG achieved in rehabilitation and (1) acute stroke therapies; (2) 90-180 day outcomes (health-related quality of life using EuroQoL-5D-3L; independence according to modified Rankin Scale (score 0-2) and self-reported hospital readmission). RESULTS: Overall, 8397/8507 eligible patients from the AuSCR were linked with corresponding AROC data (95% linkage rate; median age 75 years, 43% female); 4239 had 90-180 days survey data. Receiving thrombolysis (16% of the cohort) had a minimal association with RFG in rehabilitation (coefficient: 0.03; 95% Confidence Interval [CI]: 0.01, 0.05). Greater RFG achieved whilst in in-patient rehabilitation was associated with better longer-term HR-QoL (coefficient 21.77, 95% CI 17.8, 25.8) including fewer problems with mobility, self-care, pain, usual activities and anxiety/depression; greater likelihood of independence (adjusted Odds Ratio: 10.66; 95% CI 7.86, 14.45); and decreased odds of self-reported hospital readmission (adjusted Odds Ratio: 0.53; 95% CI 0.41, 0.70) within 90-180 days post-stroke. CONCLUSIONS: Stroke survivors who achieved greater RFG during inpatient rehabilitation had better HR-QoL and were more likely to be independent at follow-up. Acute care processes did not appear to impact RFG or long-term outcomes for those who accessed inpatient rehabilitation.

A comparison of patients managed in specialist versus non-specialist inpatient rehabilitation units in Australia.

Aim: To compare the rehabilitation of patients with brain and spinal cord injury in specialist rehabilitation units and non-specialist rehabilitation units in Australia over a 10-year period.Method: A retrospective cohort study design was used. Epidemiological descriptive analysis was used to examine inpatient rehabilitation data held in the Australasian Rehabilitation Outcomes Centre Registry Database at four discrete time points: 2007, 2010, 2013 and 2016. Data sets included patient demographics, length of stay and the Functional Independence Measure. Data sets were examined for differences between specialist and non-specialist rehabilitation units.Results: Over the 10-year study period, compared to patients admitted to non-specialist rehabilitation units patients admitted to specialist rehabilitation units: (1) were younger and more likely to be male; (2) had a longer time between onset of illness/injury and rehabilitation admission; (3) had a longer median rehabilitation length of stay; (4) had a higher burden of care on admission to rehabilitation; however (5) had a greater functional gain. Patients in specialist rehabilitation units had a lower relative functional efficiency per day of rehabilitation, but higher percentage of Functional Independence Measure gain. In 2016, 66% of brain injury and 51% of spinal cord injury patients were not rehabilitated in specialist rehabilitation units.Conclusion: There are differences in the characteristics of patients admitted to specialist versus non-specialist rehabilitation units. Patients admitted to specialist rehabilitation units have greater functional gain. A noteworthy proportion of brain and spinal cord injury patients are not being rehabilitated in specialist rehabilitation units, particularly patients with non-traumatic injuries.Implications for rehabilitationPatients with a brain or spinal cord injury rehabilitated in specialist rehabilitation units achieve a greater functional gain than those in non-specialist units.Development of best practice admission guidelines would better enable the right care for the right patient in the right setting at the right time.There is a need for longitudinal examination of patient outcomes to better understand the long-term benefits of being rehabilitated in specialist rehabilitation units compared to non-specialist rehabilitation units.

Examination of the dependency and complexity of patients admitted to in-patient rehabilitation in Australia.

Objective The aim of this study was to determine whether there has been a measurable change in the dependency and complexity of patients admitted to in-patient rehabilitation in Australia between 2007 and 2016. Methods A retrospective cohort study design was used to examine in-patient rehabilitation data held in the Australasian Rehabilitation Outcomes Centre Registry Database for the period 2007-16. Epidemiological descriptive analysis was used to examine datasets for difference between four discrete years (2007, 2010, 2013 and 2016). Datasets included patient demographics, length of stay (LOS), comorbidities, complications and the Functional Independence Measure (FIM™). Results Between 2007 and 2016, rehabilitation in-patients as a whole: (1) had a mean decrease in total admission FIM score; (2) became more complex, as evidenced by the increased proportion of particular comorbidities impacting on rehabilitation, namely cardiac and respiratory disease, dementia, diabetes and morbid obesity; and (3) had a mean decrease in total discharge FIM score. However, there was an increase in the proportion of patients discharged home from rehabilitation (from 86.5% to 92%) and decreases in onset and rehabilitation LOS of 2.2 and 2.5 days respectively. Conclusion The dependency and complexity of patients admitted to in-patient rehabilitation in Australia has increased between 2007 and 2016. What is known about the topic? Anecdotal reports suggest that rehabilitation patients in Australia have become more complex, necessitating increased active management of their presenting health condition and comorbid health conditions. However, to date, no systematic investigation has been undertaken to examine trends in rehabilitation in-patient dependency and complexity over time. What does this paper add? This study provides measurable evidence of increased dependency and complexity in patients admitted to rehabilitation in Australia. Further, compared with 2007, rehabilitation in-patients as a whole had an increased burden of care on discharge from rehabilitation in 2016. What are the implications for practitioners? The changes in patient dependency and complexity reported in this study have implications for rehabilitation service delivery. This is because the increased need for illness or injury and comorbidity management may result in increased potential for acute complications and health deterioration, and compensatory care for patients during rehabilitation. Clinicians may need to widen their skill set to include more acute and chronic illness management.

The psychometric properties of a modified client-centred rehabilitation questionnaire in an Australian population.

Purpose: To identify the face validity of the Client-Centred Rehabilitation Questionnaire (CCRQ) and to determine the internal consistency reliability and factorial validity of a modified CCRQ.Materials and methods: This study was conducted in 2 phases. Phase 1 consisted of 5 focus groups to examine the face validity of the CCRQ, resulting in the development of a modified CCRQ. Phase 2 consisted of a multi-site cross sectional survey, involving 408 rehabilitation inpatients, to examine the internal consistency reliability and factorial validity of the modified CCRQ. Chronbach's coefficient alpha, composite reliability coefficients, and single factor congeneric models with maximum likelihood confirmatory factor analysis were used.Results: Based on feedback from the focus groups the CCRQ was modified with the word 'rehabilitation' replacing 'program' throughout. The three negatively worded items had poor item-to-total correlations of <0.3. Removing these items resulted in subscale alphas of 0.74-0.86 and composite reliability coefficients of 0.66-0.87. Six of the seven sub-scales had good model fit and the other one had moderate fit following removal of the negatively worded item.Conclusions: This study supports the underlying structure and internal consistency of the modified CCRQ.Implications for RehabilitationPerson-centredness is an important characteristic of effective rehabilitation service delivery that warrants measurement.A modified Client-Centered Rehabilitation Questionnaire has been found to have good face validity, internal consistency reliability and construct validity in an Australian sample of inpatient rehabilitation patients.Use of a modified Client-Centered Rehabilitation Questionnaire incorporating the 7 sub-scales in the original Client-Centered Rehabilitation Questionnaire is supported for use in inpatient rehabilitation.Both sub-scale and item level responses to the modified Client-Centered Rehabilitation Questionnaire provide detailed feedback to rehabilitation service providers looking for opportunities to make their services more person-centred.

Record linkage is feasible with non-identifiable trauma and rehabilitation datasets.

OBJECTIVES: 1) Describe probabilistic linkage (PL) for road trauma and rehabilitation records in New South Wales (NSW) Australia. 2) Determine the accuracy of linkage for these records. METHODS: Data were extracted from the NSW Trauma Registry for all road trauma admissions for the years 2009-2012 and from Australasian Rehabilitation Outcomes Centre for January 2009 to June 2013. PL was performed using: age; sex; residential postcode; and date of acute discharge = date of admission to rehabilitation. False matches were cases that linked but were not true matches; they were determined by manual review. Reasons for incomplete linkages were explored. The benefits and limitations of the linked study dataset are described. RESULTS: Of 3,256 road trauma records, 683 were matched to rehabilitation records. Using the field of 'discharge destination' from the trauma records, 265 patients with unmatched records were discharged to inpatient rehabilitation (missed matches). This gave an overall 72% linkage rate (or sensitivity) using PL. There were 16 cases of false matches, giving a specificity of 99%. CONCLUSION: It was feasible to use PL to link road trauma and rehabilitation datasets in the absence of identifiers. However, this needed to be combined with careful manual review before the linked dataset could be used to make inferences on trauma rehabilitation outcomes. IMPLICATION: PL may be a cost-effective way to capture inpatient rehabilitation outcomes of multi-trauma patients.

Analyses of fugu hoxa2 genes provide evidence for subfunctionalization of neural crest cell and rhombomere cis-regulatory modules during vertebrate evolution.

Hoxa2 gene is a primary player in regulation of craniofacial programs of head development in vertebrates. Here we investigate the evolution of a Hoxa2 neural crest enhancer identified originally in mouse by comparing and contrasting the fugu hoxa2a and hoxa2b genes with their orthologous teleost and mammalian sequences. Using sequence analyses in combination with transgenic regulatory assays in zebrafish and mouse embryos we demonstrate subfunctionalization of regulatory activity for expression in hindbrain segments and neural crest cells between these two fugu co-orthologs. hoxa2a regulatory sequences have retained the ability to mediate expression in neural crest cells while those of hoxa2b include cis-elements that direct expression in rhombomeres. Functional dissection of the neural crest regulatory potential of the fugu hoxa2a and hoxa2b genes identify the previously unknown cis-element NC5, which is implicated in generating the differential activity of the enhancers from these genes. The NC5 region plays a similar role in the ability of this enhancer to mediate reporter expression in mice, suggesting it is a conserved component involved in control of neural crest expression of Hoxa2 in vertebrate craniofacial development.

Use of live interactive webcasting for an international postgraduate module in ehealth: case study evaluation.

BACKGROUND: Producing "traditional" e-learning can be time consuming, and in a topic such as eHealth, it may have a short shelf-life. Students sometimes report feeling isolated and lacking in motivation. Synchronous methods can play an important part in any blended approach to learning. OBJECTIVE: The aim was to develop, deliver, and evaluate an international postgraduate module in eHealth using live interactive webcasting. METHODS: We developed a hybrid solution for live interactive webcasting using a scan converter, mixer, and digitizer, and video server to embed a presenter-controlled talking head or copy of the presenter's computer screen (normally a PowerPoint slide) in a student chat room. We recruited 16 students from six countries and ran weekly 2.5-hour live sessions for 10 weeks. The content included the use of computers by patients, patient access to records, different forms of e-learning for patients and professionals, research methods in eHealth, geographic information systems, and telehealth. All sessions were recorded-presentations as video files and the student interaction as text files. Students were sent an email questionnaire of mostly open questions seeking their views of this form of learning. Responses were collated and anonymized by a colleague who was not part of the teaching team. RESULTS: Sessions were generally very interactive, with most students participating actively in breakout or full-class discussions. In a typical 2.5-hour session, students posted about 50 messages each. Two students did not complete all sessions; one withdrew from the pressure of work after session 6, and one from illness after session 7. Fourteen of the 16 responded to the feedback questionnaire. Most students (12/14) found the module useful or very useful, and all would recommend the module to others. All liked the method of delivery, in particular the interactivity, the variety of students, and the "closeness" of the group. Most (11/14) felt "connected" with the other students on the course. Many students (11/14) had previous experience with asynchronous e-learning, two as teachers; 12/14 students suggested advantages of synchronous methods, mostly associated with the interaction and feedback from teachers and peers. CONCLUSIONS: This model of synchronous e-learning based on interactive live webcasting was a successful method of delivering an international postgraduate module. Students found it engaging over a 10-week course. Although this is a small study, given that synchronous methods such as interactive webcasting are a much easier transition for lecturers used to face-to-face teaching than are asynchronous methods, they should be considered as part of the blend of e-learning methods. Further research and development is needed on interfaces and methods that are robust and accessible, on the most appropriate blend of synchronous and asynchronous work for different student groups, and on learning outcomes and effectiveness.

Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II.

A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. Set1/COMPASS was the founding member and is the only H3K4 methylase in Saccharomyces cerevisiae; however, in mammals, at least six H3K4 methylases, Set1A and Set1B and MLL1 to MLL4, are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation patterns in wild-type Mll1(+/+) and Mll1(-)(/)(-) mouse embryonic fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes, show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/MLL4 and/or the Set1 complexes has little to no effect on the H3K4 methylation of Hox loci or their expression levels in these MEFs. Together these data provide insight into the redundancy and specialization of COMPASS-like complexes in mammals and provide evidence for a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation.

Hox genes and segmentation of the hindbrain and axial skeleton.

Segmentation is an important process that is frequently used during development to segregate groups of cells with distinct features. Segmental compartments provide a mechanism for generating and organizing regional properties along an embryonic axis and within tissues. In vertebrates the development of two major systems, the hindbrain and the paraxial mesoderm, displays overt signs of compartmentalization and depends on the process of segmentation for their functional organization. The hindbrain plays a key role in regulating head development, and it is a complex coordination center for motor activity, breathing rhythms, and many unconscious functions. The paraxial mesoderm generates somites, which give rise to the axial skeleton. The cellular processes of segmentation in these two systems depend on ordered patterns of Hox gene expression as a mechanism for generating a combinatorial code that specifies unique identities of the segments and their derivatives. In this review, we compare and contrast the signaling inputs and transcriptional mechanisms by which Hox gene regulatory networks are established during segmentation in these two different systems.

Novel gene ashwin functions in Xenopus cell survival and anteroposterior patterning.

The novel gene ashwin was isolated in a differential display screen for genes activated or up-regulated early in neural specification. ashwin is expressed maternally and zygotically, and it is up-regulated in the neural ectoderm after the midgastrula stage. It is expressed in the neural plate and later in the embryonic brain, eyes, and spinal cord. Overexpression of ashwin in whole embryos leads to anterior truncations and other defects. However, a second Organizer does not form, and the secondary axial structures may result from splitting of the Organizer, rather than axis duplication. Morpholino oligonucleotide-mediated reduction in ashwin expression leads to lethality or abnormalities in gastrulation, as well as significant apoptosis in midgastrula embryos. Apoptosis is also observed in midgastrula embryos overexpressing ashwin. Coexpression of ashwin with the bone morphogenetic protein-4 antagonist noggin has a synergistic effect on neural-specific gene expression in isolated animal cap ectoderm. Ashwin has no previously characterized domains, although two nuclear localization signals can be identified. Orthologues have been identified in the human, mouse, chicken, and pufferfish genomes. Our results suggest that ashwin regulates cell survival and anteroposterior patterning.

Evidence for antagonism of BMP-4 signals by MAP kinase during Xenopus axis determination and neural specification.

We have previously shown that mitogen-activated protein (MAP) kinase activity is required for neural specification in Xenopus. In mammalian cells, the BMP-4 effector Smad1 is inhibited by phosphorylation at MAP kinase sites (Kretzschmar et al., 1997). To test the hypothesis that MAP kinase inhibits the BMP-4/Smad1 pathway during early Xenopus development, we have generated a Smad1 mutant lacking the MAP kinase phosphorylation sites (M4A-Smad1) and compared the effects of wild-type (WT)- and M4A-Smad1 on axial pattern and neural specification in Xenopus embryos. Although overexpression of either WT- or M4A-Smad1 produced ventralized embryos, at each mRNA concentration, M4A-Smad1 had a greater ventralizing effect than WT-Smad1. Interestingly, overexpression of either form of Smad1 in ventral blastomeres disrupted posterior pattern and morphogenesis; again, more severe defects were produced by expression of M4A-Smad1 than by equal amounts of WT-Smad1. Ectodermal expression of M4A-Smad1 disrupted expression of the anterior neural gene otx2 in vivo and inhibited neural specification in response to endogenous signals in mesoderm-ectoderm recombinates. In contrast, overexpression of WT-Smad1 at identical levels had little effect on either neural specification or otx2 expression. Comparisons of protein levels following overexpression of either WT- or M4A-Smad1 indicate that WT-Smad1 may be slightly more stable than M4A-Smad1; thus, differences in stability cannot account for the increased effectiveness of M4A-Smad1. Our results demonstrate that mutations disrupting the MAPK phosphorylation sites act collectively as a gain-of-function mutation in Smad1 and that inhibitory phosphorylation of Smad1 may be a significant mechanism for the regulation of BMP-4/Smad1 signals during Xenopus development.