[New techniques in the operative treatment of calcaneal fractures]. / Neue Techniken in der operativen Versorgung von Calcaneusfrakturen.

The ideal treatment of displaced intra-articular calcaneal fractures is still controversially discussed. Because of the variable fracture patterns and the vulnerable soft tissue coverage an individual treatment concept is advisable. In order to minimize wound edge necrosis associated with extended lateral approaches, selected fractures may be treated percutaneously or in a less invasive manner while controlling joint reduction via a sinus tarsi approach. Fixation in these cases is achieved with screws, intramedullary locking nails or modified plates that are slid in subcutaneously. A thorough knowledge of the three dimensional calcaneal anatomy and open reduction maneuvers is a prerequisite for good results with less invasive techniques. Early functional follow-up treatment aims at early rehabilitation independent of the kind of fixation. Peripheral fractures of the talus and calcaneus frequently result from subluxation and dislocation at the subtalar and Chopart joints. They are still regularly overlooked and result in painful arthritis if left untreated. If an exact anatomical reduction of these intra-articular fractures is impossible, resection of small fragments is indicated.

Microfluidics enables multiplex evaluation of the same cells for further studies.

OBJECTIVE: The continuous discovery of biomarkers and their evolving use for the diagnosis and guidance of therapy for patients with cancer has increased awareness of the need to triage biospecimens properly. On occasion, cytology samples are the only type of biospecimen available for analysis. Often, the current approach for these latter specimens is cytopathology-centric, with cells limited to examination by bright field microscopy. When specimens are paucicellular, there is often insufficient material for ancillary testing. Therefore, a need exists to develop an alternative approach that allows for the multiplexed analysis of cells when they are limited in number. In recent previous publications, we demonstrated that clinically derived cells from tissue are suitable for evaluation in a microfluidic device. In our current endeavour, we seek to expand upon those findings and determine if those same cells can be recovered for further analysis. METHODS: A microfluidic channel was designed, fabricated and tested using cytology specimens generated from tissue specimens. The cytological features of the cells tested were examined prior to entering the channel; they were then compared to similar cells while in the channel, and upon recovery from the channel. Recovery of DNA and proteins were also tested. RESULTS: The morphology of the tested cells was not compromised in either the channel or upon recovery. More importantly, the integrity of the cells remained intact, with the recovery of proteins and high molecular weight DNA possible. CONCLUSIONS: We developed and tested an alternative approach to the processing of cytopathology specimens that enables multiplexed evaluation. Using microfluidics, cytological examination of biopecimens can be performed, but in contrast to existing approaches, the same cells examined can be recovered for downstream analysis.

Exercise training improves activity in adolescents with congenital heart disease.

OBJECTIVES: To ascertain if motivational techniques and a structured exercise programme can increase activity in adolescents afflicted with congenital heart disease (CHD). DESIGN: Prospective randomised controlled trial. SETTING: One hundred and forty-three patients aged 12-20 years attending the tertiary centre for paediatric cardiology in Northern Ireland. MAIN OUTCOME MEASURES: Increase in exercise capacity as assessed by duration of exercise stress test, and number of minutes spent in moderate to vigorous physical activity (MVPA) per day. RESULTS: Eighty-six patients were men (60%), mean age was 15.60 ± 2.27 years. Seventy-three percent were considered to have major CHD. Seventy-two participants were randomised to the intervention group. Following intervention, duration of exercise test increased by 1 min 5 s for the intervention group (p value 0.02) along with increase in predicted VO2Max (p value 0.02). There was a significant increase in minutes of MVPA per day for the intervention group from baseline to reassessment (p value <0.001) while MVPA remained much the same for the control group. Fourteen patients met the current recommendation for more than 60 min MVPA per day at baseline. This doubled to 29 participants at reassessment. There were no adverse effects or mortalities reported. CONCLUSIONS: Exercise training is safe, feasible and beneficial in adolescents with CHD. Psychological techniques can be employed to maximise the impact of interventions. TRIAL REGISTRATION NUMBER: ISRCTN27986270.

Primitive hepatic venous plexus in a child with scimitar syndrome and pulmonary sequestration.

We report a case of scimitar syndrome with pulmonary sequestration, persistent primitive hepatic venous plexus and stenosis of the inferior vena cava in a child presenting with failure to thrive. Such associations are rare but may have implications when planning interventions for patients with complex congenital heart disease.

LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial.

Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.

Congenital hydrocephalus in genetically engineered mice.

There is evidence that genetic factors play a role in the complex multifactorial pathogenesis of hydrocephalus. Identification of the genes involved in the development of this neurologic disorder in animal models may elucidate factors responsible for the excessive accumulation of cerebrospinal fluid in hydrocephalic humans. The authors report here a brief summary of findings from 12 lines of genetically engineered mice that presented with autosomal recessive congenital hydrocephalus. This study illustrates the value of knockout mice in identifying genetic factors involved in the development of congenital hydrocephalus. Findings suggest that dysfunctional motile cilia represent the underlying pathogenetic mechanism in 8 of the 12 lines (Ulk4, Nme5, Nme7, Kif27, Stk36, Dpcd, Ak7, and Ak8). The likely underlying cause in the remaining 4 lines (RIKEN 4930444A02, Celsr2, Mboat7, and transgenic FZD3) was not determined, but it is possible that some of these could also have ciliary defects. For example, the cerebellar malformations observed in RIKEN 4930444A02 knockout mice show similarities to a number of developmental disorders, such as Joubert, Meckel-Gruber, and Bardet-Biedl syndromes, which involve mutations in cilia-related genes. Even though the direct relevance of mouse models to hydrocephalus in humans remains uncertain, the high prevalence of familial patterns of inheritance for congenital hydrocephalus in humans suggests that identification of genes responsible for development of hydrocephalus in mice may lead to the identification of homologous modifier genes and susceptibility alleles in humans. Also, characterization of mouse models can enhance understanding of important cell signaling and developmental pathways involved in the pathogenesis of hydrocephalus.

Examination of the physical and psychosocial determinants of health behaviour in 4-5-year-old children with congenital cardiac disease.

OBJECTIVES: To assess the general health and activity levels of 4- and 5-year-old children after intervention for congenital cardiac disease. METHODS: Health behaviour outcomes were assessed in 91 children who had surgery or catheter intervention for congenital cardiac disease. The children were classified into four groups according to severity. The main parameters of classification were the presence of residual symptoms, frequency of visits to general practitioner or the Accident and Emergency Department, and ability to participate in physical activity according to a calculated "activity score". RESULTS: Children had very few residual symptoms after "corrective surgery". Those with complex congenital cardiac disease post-Fontan-type repair still had symptoms on average 18.2 days per month. Surprisingly, the complex group had fewer days "sick" from non-cardiac causes and had fewer visits to general practitioner or Accident and Emergency Departments. Regression analysis indicates that three variables had significant relevance to the general practitioner or Accident and Emergency visits: complex congenital cardiac disease, fewer visits; Townsend score - more deprivation - more visits; and maternal worry - higher maternal worry score - more visits. Regression analysis indicates that lower activity score is significantly related to complex cardiac disease and higher maternal worry score. CONCLUSIONS: The majority of this group of 4- and 5-year-old children had few residual symptoms and had good exercise tolerance. Maternal worry is a significant factor in influencing both activity levels and frequency of unscheduled health service demands - general practitioner or Accident and Emergency visits.

Impact of a regional training program in fetal echocardiography for sonographers on the antenatal detection of major congenital heart disease.

OBJECTIVES: The aims of this study were to ascertain the effect of a regional training program in fetal echocardiography for obstetric radiographers on the antenatal detection of major congenital heart disease (CHD) and to document short-term outcomes for major CHD. METHODS: All 87 obstetric radiographers in Northern Ireland were invited to attend 2.5 days of training during a 1-year period. Data were collected before and after the training, over a 5-year study period, to assess the effect of training on the antenatal detection of CHD in the population. RESULTS: The antenatal detection of major CHD rose significantly, from 28% (72/262) pretraining to 43% (36/84) in the year of training (P = 0.008). Antenatal diagnosis of four-chamber-view defects rose significantly (from 38% to 54%; P = 0.04), as did detection of outflow-tract-view defects (from 8% to 21%; P = 0.05). Twelve per cent (13/108) of cases died spontaneously in utero and 8% (9/108) were terminated. Only 78% (67/86) of live-born cases in which CHD had been diagnosed antenatally survived the neonatal period, compared to 93% (221/238) with a postnatal diagnosis of CHD (P < 0.001). CONCLUSIONS: Even with a relatively simple training program, significant improvements can be made in the antenatal detection of CHD. With training, obstetric sonographers can successfully assess outflow tracts. Antenatally diagnosed cases have more complex CHD and this probably contributes to poor neonatal survival.

Situs inversus in Dpcd/Poll-/-, Nme7-/- , and Pkd1l1-/- mice.

Situs inversus (SI) is a congenital condition characterized by left-right transposition of thoracic and visceral organs and associated vasculature. The usual asymmetrical positioning of organs is established early in development in a transient structure called the embryonic node. The 2-cilia hypothesis proposes that 2 kinds of primary cilia in the embryonic node determine left-right asymmetry: motile cilia that generate a leftward fluid flow, and immotile mechanosensory cilia that respond to the flow. Here, we describe 3 mouse SI models that provide support for the 2-cilia hypothesis. In addition to having SI, Dpcd/Poll(-/-) mice (for: deleted in a mouse model of primary ciliary dyskinesia) and Nme7(-/-) mice (for: nonmetastatic cells 7) had lesions consistent with deficient ciliary motility: Hydrocephalus, sinusitis, and male infertility developed in Dpcd/Poll(-/-) mice, whereas hydrocephalus and excessive nasal exudates were seen in Nme7(-/-) mice. In contrast, the absence of respiratory tract lesions, hydrocephalus, and male infertility in Pkd1l1(-/-) mice (for: polycystic kidney disease 1 like 1) suggested that dysfunction of motile cilia was not involved in the development of SI in this line. Moreover, the gene Pkd1l1 has considerable sequence similarity with Pkd1 (for: polycystic kidney disease 1), which encodes a protein (polycystin-1) that is essential for the mechanosensory function of immotile primary cilia in the kidney. The markedly reduced viability of Pkd1l1(-/-) mice is somewhat surprising given the absence of any detected abnormalities (other than SI) in surviving Pkd1l1(-/-) mice subjected to a comprehensive battery of phenotype-screening exams. However, the heart and great vessels of Pkd1l1(-/-) mice were not examined, and it is possible that the decreased viability of Pkd1l1(-/-) mice is due to undiagnosed cardiovascular defects associated with heterotaxy.

A controlled trial of early interventions to promote maternal adjustment and development in infants born with severe congenital heart disease.

Abstract Background Congenital heart disease can have a negative impact on both infant development and maternal adjustment. This study considered the impact of a new programme of early psychosocial interventions on such outcomes, following the birth of a child with severe congenital heart disease. Methods Seventy infants and their mothers were assigned to an intervention or control group based on order of presentation to the unit. Interventions aimed at bolstering mother-infant transactions, through psychoeducation, parent skills training and narrative therapy techniques were implemented. Results Clinically and statistically significant gains were observed at 6-month follow-up on the mental (but not the psychomotor) scale of the Bayleys-II. Positive gains were also manifested on feeding practices, maternal anxiety, worry and appraisal of their situation. Conclusions A programme of generalizable psychosocial interventions is shown to have a positive impact on the infant with severe congenital heart disease and the mother.

Assessing ASDs prior to device closure using 3D echocardiography. Just pretty pictures or a useful clinical tool?

AIMS: To determine the usefulness of three-dimensional transthoracic echocardiography (3D echo) in assessment of secundum atrial septal defects (ASDs) considered for device closure. To compare the findings from 3D echo with those from two-dimensional transoesophageal echocardiography (TOE) regarding dimensions, morphology and suitability for device closure. METHODS AND RESULTS: Twenty-four patients were enrolled in this prospective, crossover study. Three-dimensional echo and TOE data were collected, analysed and compared, assessing quantitative data including maximum defect diameter, area and circumference. Qualitative morphology such as the presence of fenestrations and the defect margins were noted, and an assessment of the suitability for device closure was made using each modality. Eighteen (75%) of the 3D data sets produced usable data for analysis. In each case the maximum diameter of the defect was larger on 3D echo than on TOE (mean difference = 0.34 cm, P < 0.001). On three occasions suitability for device closure could not be determined using 3D echo. On the other 15 occasions there was agreement between the TOE and 3D echo data. CONCLUSIONS: Three-dimensional echo provides comparable data with TOE when attempting to predict suitability for device closure without the need for general anaesthetic or sedation. It also provides useful additional dynamic and morphological information.

Assisting the transition from hospital to home for children with major congenital heart disease by telemedicine: a feasibility study and initial results.

Parents of children hospitalized with major congenital heart disease often state that the weeks following discharge from hospital are particularly difficult. There is a sudden change from 24-h medical supervision and care to outpatient reviews. Videoconferencing not only gives the family an opportunity to have visual and audio contact with staff but also allows clinicians to visually assess the patient. We have investigated the feasibility of using videoconferencing to provide support for families at home. We also report the early results of a randomized control trial comparing videoconference support with regular telephone support and the current clinic review follow-up.

Determinants of neuropsychological and behavioural outcomes in early childhood survivors of congenital heart disease.

AIMS: To evaluate the relative effect of cyanosis, surgical interventions and family processes on neuropsychological and behavioural outcomes in 4-year-old survivors of serious congenital heart disease (CHD). METHODS: 90 children with a range of cyanotic and acyanotic conditions, who underwent either corrective or palliative surgery, completed a neuropsychological and behavioural evaluation. Families of participants were also profiled by evaluation of maternal mental health, worry, social support, parenting style and family functioning. RESULTS: Compromised neuropsychological outcomes were associated with a combination of cyanotic conditions and open-heart surgery, but this was not exacerbated by having a complex, palliative, status. Both cyanotic and acyanotic conditions were associated with specific sensorimotor delays, regardless of method of the correction. Only children with complex conditions and palliative interventions seemed at risk of poor behavioural outcomes; indeed, children with cyanosis with complete repair showed favourable behavioural outcomes compared with controls. Multivariate analyses highlighted the sometimes greater relevance of family processes (eg parenting style, maternal mental health and worry), rather than disease or surgical factors, in predicting especially behavioural outcomes. CONCLUSIONS: The findings (1) suggest a more complex relationship between cyanosis, surgical methods of correction, neuropsychological and behavioural outcomes than previously charted, (2) highlight that family processes may be aetiologically more important than disease and surgical factors, and (3) indicate specific targets for secondary prevention programmes for this at-risk population.

Suitability of human juvenile pancreatic islets for clinical use.

AIMS/HYPOTHESIS: The limited availability of deceased donor pancreases suitable for pancreas and islet transplantation calls for a broader utilisation of donor tissue for transplantation purposes. Young donors, representing, fortunately, a minor but significant pool of individuals, have been largely under-employed, mainly because of anatomical and functional incompatibilities with potential recipients. For islet transplantation, the isolation of pancreatic islets from young donors rarely occurs, because of technical problems. As a result of the peculiar characteristics of young donor pancreases, the standard isolation procedure does not allow efficient separation of the islets from the surrounding exocrine tissue, and favours the generation of mantled islets. Nonetheless, young donor islets offer high qualitative and clinically appealing characteristics. SUBJECTS AND METHODS: We standardised a modified methodology to obtain purified and mantle-free human islets from young donors. This method principally involves efficient delivery of isolation enzyme with reduced mechanical disruption of the pancreas combined with additional filtration steps. RESULTS: We were able to obtain purified and mantle-free human islets from donors as young as 6 months of age with good morphological and functional properties. The good qualitative characteristics of the islets, evidenced in vitro, were proven in vivo, as they were qualitatively superior to islets of older donors in transplantation studies. CONCLUSIONS/INTERPRETATION: This study justifies the utilisation of islets derived from young donors for islet transplantation.

Supporting families of critically ill children at home using videoconferencing.

Home videoconferencing links for families of children recently discharged with complex congenital heart disease may be useful in monitoring potentially unstable patients. A randomized controlled trial was carried out comparing home videoconferencing with telephone contact. Patients were randomized to an interventional videoconferencing group (n = 14), or to one of two control groups: the first (n = 9) received the same ad hoc telephone support that was available to all patients; the second group (n = 13) received regular telephone calls with the same protocol as those in the videoconferencing group. The results from the trial are still being analysed. Our experience with commercial cable modem transmission quickly showed that this is an unsuitable modality. Preliminary results with ISDN videoconferencing are encouraging. Initial results and feedback from families strongly suggest that videoconferencing provides significant benefits over telephone follow-up.

Miliary neonatal hemangiomatosis with fulminant heart failure and cardiac septal hypertrophy in two infants.

Miliary neonatal hemangiomatosis is a rare, life-threatening condition associated with cutaneous and multiorgan involvement. We report two infants with this condition who had fulminant cardiac failure and cardiac septal hypertrophy. The first was a 5-day-old boy who presented with increasing numbers of cutaneous hemangiomata associated with worsening cardiac failure. Magnetic resonance imaging (MRI) showed extensive hepatic hemangioma. Despite treatment with systemic corticosteroids and subcutaneous interferon alfa-2b his disease progressed. Hepatic artery embolization was unsuccessful. The infant died of congestive cardiac failure at 6 weeks of age. Postmortem examination showed a massively enlarged cardiac interventricular septum and biventricular hypertrophy. The second patient was a 1-week-old girl who also had cutaneous hemangioma and cardiac decompensation. MRI showed extensive intrahepatic involvement. She was treated early with corticosteroids and interferon alpha, which resulted in involution of the cutaneous and hepatic lesions. Cardiac septal hypertrophy did not persist at late follow-up, and the association of miliary neonatal hemangiomatosis and cardiac septal hypertrophy has not yet been established.

Transcatheter occlusion of the patent ductus arteriosus: a comparison of two devices.

BACKGROUND: Transcatheter occlusion of the arterial duct is a safe and effective alternative to surgical closure. The Rashkind umbrella occluder and the Cook coil are two established devices, although the former is no longer manufactured. AIMS: To assess any difference in outcomes between the use of the Cook detachable coil and the Rashkind double umbrella in patent ductus arteriosus (PDA) occlusion. METHODS: A retrospective study of 77 patients in whom PDA occlusion was attempted using the Cook detachable PDA coil from March 1996 to March 2000. A comparison was carried out with patients in whom occlusion was attempted using the Rashkind double umbrella between 1989 and 1996. RESULTS: The rate of immediate complete occlusion was 24% compared with 29.9% for the Rashkind device. The figure for complete occlusion after 24 hours with the PDA coil was 63% compared with 61.5% in the Rashkind group (p > 0.1). The overall closure rate in the coil group was 72% versus 74.6% for umbrellas. CONCLUSION: The outcome in terms of complete duct closure using the Cook coil is comparable with figures obtained using the Rashkind umbrella. Both devices have a good safety profile in the short and medium-terms.

Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice.

SNF5/INI1 is a component of the ATP-dependent chromatin remodeling enzyme family SWI/SNF. Germ line mutations of INI1 have been identified in children with brain and renal rhabdoid tumors, indicating that INI1 is a tumor suppressor. Here we report that disruption of Ini1 expression in mice results in early embryonic lethality. Ini1-null embryos die between 3.5 and 5.5 days postcoitum, and Ini1-null blastocysts fail to hatch, form the trophectoderm, or expand the inner cell mass when cultured in vitro. Furthermore, we report that approximately 15% of Ini1-heterozygous mice present with tumors, mostly undifferentiated or poorly differentiated sarcomas. Tumor formation is associated with a loss of heterozygocity at the Ini1 locus, characterizing Ini1 as a tumor suppressor in mice. Thus, Ini1 is essential for embryo viability and for repression of oncogenesis in the adult organism.

In vivo drug target discovery: identifying the best targets from the genome.

A vast number of genes of unknown function threaten to clog drug discovery pipelines. To develop therapeutic products from novel genomic targets, it will be necessary to correlate biology with gene sequence information. Industrialized mouse reverse genetics is being used to determine gene function in the context of mammalian physiology and to identify the best targets for drug development.