The Effectiveness of Serial Casting in the Treatment of Recurrent Equinovarus in Children With Arthrogryposis.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is characterized by joint contractures in 2 or more body areas, often resulting in clubfoot deformities that are typically stiffer than those seen in idiopathic clubfoot deformities. While surgery is routinely used to treat clubfoot in AMC, it has a high rate of recurrence and complications. Current literature suggests serial casting (SC) could be useful in treating clubfoot in AMC, though evidence of its effectiveness is limited. METHODS: Passive range of motion (PROM), dynamic foot pressure, parent-reported Pediatric Outcomes Data Collection Instrument, brace tolerance, and the need for post-casting surgery were evaluated retrospectively in children with AMC treated with SC to address clubfoot deformities. Analysis of variance or paired t tests were used as appropriate on pre-casting, short-term (within 6 mo after SC) and/or longer-term (6 to 18 mo after SC) parameters to determine the effectiveness of SC. Brace tolerance before and after SC was analyzed using the Global Test for Symmetry, and medical records were reviewed to determine the need for surgery post-SC. RESULTS: Forty-six children (6.1±3.1 y old) were cast an average of 2.5±1.9 times, resulting in 206 SC episodes. PROM showed improvement in ankle dorsiflexion and forefoot abduction in the short term (P<0.05), returning to baseline measurements in the long term (P=0.09). Brace tolerance improved after casting (P<0.05). Only 15% of feet required surgery at follow-up at 10.3±5.5 years. There were no significant changes in dynamic foot pressure or Pediatric Outcomes Data Collection Instrument results after SC, except for an increase in the pain subtest (P<0.05). CONCLUSIONS: Serial casting in children with AMC can be effective in temporarily improving PROM and improving brace tolerance, but it does not impact dynamic barefoot position. Positive impact of conservative management in children with AMC can potentially delay or reduce the need for invasive surgical intervention by improving PROM and brace tolerance. LEVEL OF EVIDENCE: Level III, Retrospective Comparative Study.

Lower Limb Deformity Correction: Analysis and Preoperative Planning.

Lower limb deformities have a wide range of presentations and require significant preparation and planning from the surgeon to correct. It is important to provide a clear and systematic approach to preoperative planning for these cases and to detail three well-established correction techniques: external fixation, plate fixation, and intramedullary nail fixation. In using a simple mnemonic that lays out the systematic analysis of various axis lines and joint angles from proximal to distal in the lower extremity, deformities can be readily identified, and correction strategies can be effectively used to produce a successful deformity correction that restores colinear alignment to the lower limb. Additional pearls and pitfalls for these techniques are also provided to assist with some of the nuances that exist in the field.

Has the Threshold for Epiphysiodesis Versus Lengthening Changed in the Era of Magnetically Controlled Nails?

INTRODUCTION: Limb length discrepancy (LLD) is common in both the pediatric and adult population. Length inequalities can be due to a multitude of etiologies including congenital, developmental, and acquired causes. There has been little consensus on the morbidity of LLD and, as a result, the threshold necessary for treatment of LLD to prevent morbidity. Advances in magnetically controlled lengthening devices achieve greater accuracy and patient satisfaction and create an opportunity to lower the threshold for limb lengthening. DISCUSSION: Asymptomatic LLD is relatively common in both pediatric and adult populations. Only ~10% of the population has equal leg length. LLD of <5 cm may lead to long-term morbidities such as scoliosis, lower back pain, gait abnormalities, stress on hip or knee joint, and lower extremity symptomatic versus asymptomatic osteoarthritis. The teaching in most orthopaedic textbooks is to adjust the shoe if symptomatic for discrepancies up to 2 cm; consider an orthotic, epiphysiodesis, or skeletal shortening for 2.5 to 5 cm; and possible limb reconstruction for >5 cm. The assumption is that there are no long-term consequences of mild LLD. However, data in recent literature show that small discrepancies may contribute to pathologic changes such as pain, gait abnormalities, and osteoarthritis. Major advances have been made in limb lengthening over the past 40 years. The increased accuracy and superior patient satisfaction of the magnetically controlled lengthening nail versus external fixation methods argue for including lengthening for LLD of <5 cm. CONCLUSION: If mild LLD can cause long-term pathology, it is important to counsel families on the full range of options for limb equalization no matter the size of the discrepancy. The evolution in technology and understanding of limb lengthening has provided additional safe surgical options. Therefore, the historic treatment protocol for addressing limb differences may need to include lengthening for smaller discrepancies even <2 cm.

The role of citizen science in addressing grand challenges in food and agriculture research.

The power of citizen science to contribute to both science and society is gaining increased recognition, particularly in physics and biology. Although there is a long history of public engagement in agriculture and food science, the term 'citizen science' has rarely been applied to these efforts. Similarly, in the emerging field of citizen science, most new citizen science projects do not focus on food or agriculture. Here, we convened thought leaders from a broad range of fields related to citizen science, agriculture, and food science to highlight key opportunities for bridging these overlapping yet disconnected communities/fields and identify ways to leverage their respective strengths. Specifically, we show that (i) citizen science projects are addressing many grand challenges facing our food systems, as outlined by the United States National Institute of Food and Agriculture, as well as broader Sustainable Development Goals set by the United Nations Development Programme, (ii) there exist emerging opportunities and unique challenges for citizen science in agriculture/food research, and (iii) the greatest opportunities for the development of citizen science projects in agriculture and food science will be gained by using the existing infrastructure and tools of Extension programmes and through the engagement of urban communities. Further, we argue there is no better time to foster greater collaboration between these fields given the trend of shrinking Extension programmes, the increasing need to apply innovative solutions to address rising demands on agricultural systems, and the exponential growth of the field of citizen science.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Assessing the value of matrix metalloproteinase 9 (MMP9) in improving the appropriateness of referrals for colorectal cancer.

BACKGROUND: A blood test may be an effective means of improving the appropriateness of referrals for symptomatic patients referred to specialist colorectal clinics. We evaluated the accuracy of a serum matrix metalloproteinase (MMP9) test in indicating colorectal cancer or its precursor conditions in a symptomatic population. METHODS: Patients aged over 18, referred urgently or routinely to secondary care following primary care presentation with colorectal symptoms completed a questionnaire and provided a blood sample for serum MMP9 estimation. Univariate analysis and logistic regression modelling investigated the association between presenting symptoms, MMP9 measurements and the diagnostic outcome of patient investigations, in order to derive the combination of factors which best predicted a high risk of malignancy. RESULTS: Data were analysed for 1002 patients. Forty-seven cases of neoplasia were identified. Age, male gender, absence of anal pain, diabetes, blood in stools, urgent referral, previous bowel polyps and previous bowel cancer were significantly associated with neoplasia. Matrix metalloproteinase 9 measurements were not found to be associated with significant colorectal pathology. CONCLUSION: This study, despite robust sampling protocols, showed no clear association between MMP9 and colorectal neoplasia. Matrix metalloproteinase 9 therefore appears to have little value as a tool to aid referral decisions in the symptomatic population.

Oxaliplatin/capecitabine vs oxaliplatin/infusional 5-FU in advanced colorectal cancer: the MRC COIN trial.

BACKGROUND: COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC). METHODS: Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment. RESULTS: In total, 64% of 2397 patients received OxCap(± cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (± cetuximab) was associated with more mucositis and infection whereas OxCap(± cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50-80 ml min(-1) on OxCap(± cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function. CONCLUSIONS: Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50-80 ml min(-1) on both regimens require close toxicity monitoring.

Transpupillary collagen photocrosslinking for targeted modulation of ocular biomechanics.

The central vision-threatening event in glaucoma is dysfunction and loss of retinal ganglion cells (RGCs), thought to be promoted by local tissue deformations. Here, we sought to reduce tissue deformation near the optic nerve head by selectively stiffening the peripapillary sclera, i.e. the scleral region immediately adjacent to the optic nerve head. Previous scleral stiffening studies to treat glaucoma or myopia have used either pan-scleral stiffening (not regionally selective) or regionally selective stiffening with limited access to the posterior globe. We present a method for selectively stiffening the peripapillary sclera using a transpupillary annular light beam to activate methylene blue administered by retrobulbar injection. Unlike prior approaches to photocrosslinking in the eye, this approach avoids the damaging effects of ultraviolet light by employing red light. This targeted photocrosslinking approach successfully stiffened the peripapillary sclera at 6 weeks post-treatment, as measured by whole globe inflation testing. Specifically, strain was reduced by 47% when comparing treated vs. untreated sclera within the same eye (n = 7, p=0.0064) and by 54% when comparing the peripapillary sclera of treated vs. untreated eyes (n = 7, p<0.0001). Post-treatment characterization of RGCs (optic nerve axon counts/density, and grading), retinal function (electroretinography), and retinal histology revealed that photocrosslinking was associated with some ocular toxicity. We conclude that a transpupillary photocrosslinking approach enables selective scleral stiffening targeted to the peripapillary region that may be useful in future treatments of glaucoma.

Orthopedic Manifestations of Bruck Syndrome: A Case Series with Intermediate to Long-term Follow-Up.

The aim of this study was to evaluate the association of contractures, fractures, and deformities in four patients with Bruck syndrome treated in our facility. Data were collected from medical records, radiographs, dual-energy X-ray absorptiometry (DEXA) scans, genetic tests, and gait analysis. All had contractures at birth and genotypic findings including mutations in PLOD2 or FPKB10. Three cases were treated with bisphosphonates with improvement in bone density verified by DEXA. In Bruck syndrome, orthopedic deformities include the following sequential aspects: contractures, characterized by upper and lower extremity contractures such as clubfeet; fractures, characterized by multiple diaphyseal fractures in the long bones of the extremities; and deformities, characterized by malalignment of extremities and the spine. Physical therapy and bracing proved helpful for the contractures to try to stop progression. Bone fragility needs to be considered when deciding to attempt cast correction. Surgeries in the soft tissues can be performed to retain joint movement. In fractures with angulation, intramedullary nail fixation was useful, and in cases without deformity, casting alone was successful. We suggest monitoring the bone density with DEXA, nutrition support with vitamin D and calcium, and treatment with bisphosphonates. Spine deformities were successfully treated by spinal fusion and instrumentation.

Viability and apoptosis of human chondrocytes in osteochondral fragments following joint trauma.

Post-traumatic arthritis is a frequent consequence of articular fracture. The mechanisms leading to its development after such injuries have not been clearly delineated. A potential contributing factor is decreased viability of the articular chondrocytes. The object of this study was to characterise the regional variation in the viability of chondrocytes following joint trauma. A total of 29 osteochondral fragments from traumatic injuries to joints that could not be used in articular reconstruction were analysed for cell viability using the fluorescence live/dead assay and for apoptosis employing the TUNEL assay, and compared with cadaver control fragments. Chondrocyte death and apoptosis were significantly greater along the edge of the fracture and in the superficial zone of the osteochondral fragments. The middle and deep zones demonstrated significantly higher viability of the chondrocytes. These findings indicate the presence of both necrotic and apoptotic chondrocytes after joint injury and may provide further insight into the role of chondrocyte death in post-traumatic arthritis.

The signal for a leaky UAG stop codon in several plant viruses includes the two downstream codons.

Expression of the RNA replicase domain of tobacco mosaic virus (TMV) and certain protein-coding regions in other plant viruses, is mediated by translational readthrough of a leaky UAG stop codon. It has been proposed that normal tobacco tyrosine tRNAs are able to read the UAG codon of TMV by non-conventional base-pairing but recent findings that stop codons can also be bypassed as a result of extended translocational shifts (tRNA hopping) have encouraged a re-examination. In light of the alternatives, we investigated the sequences flanking the leaky UAG codon using an in vivo assay in which bypass of the stop codon is coupled to the transient expression of beta-glucuronidase (GUS) reporter genes in tobacco protoplasts. Analysis of GUS constructions in which codons flanking the stop were altered allowed definition of the minimal sequence required for read through as UAG-CAA-UUA. The effects of all possible single-base mutations in the codons flanking the stop indicated that 3' contexts of the form CAR-YYA confer leakiness and that the 3' context permits read through of UAA and UGA stop codons as well as UAG. Our studies demonstrate a major role for the 3' context in the read through process and do not support a model in which teh UAG is bypassed exclusively as a result of anticodon-codon interactions. No evidence for tRNA hopping was obtained. The 3' context apparently represents a unique sequence element that affects translation termination.

The Hox-2 homeo box gene complex on mouse chromosome 11 is closely linked to Re.

Restriction fragment length polymorphisms have been identified between inbred strains of mice for the homeo box gene complex Hox-2. These genetic markers were used to follow the segregation of different Hox-2 alleles among recombinant inbred strains of mice and among the progeny of a three point genetic cross. The results place the Hoax-2 locus approximately 1 cM from the rex (Re) locus on mouse chromosome 11.

Osteoarthritis and meniscus disorders of the knee as occupational diseases of miners.

AIM: To determine whether kneeling or squatting for prolonged periods is sufficiently causally associated with an increased risk of injury or degenerative disease of the knee joint as to meet the classic criteria to be considered an occupational disease of coal miners for whom these are or have been routine working postures. METHOD: Systematic literature searches were made for studies relating to kneeling and squatting as part of the working environment of coal mines and the role of these postures in causation of knee disorders in coal miners, analogous occupations, populations, and communities. The working environment and potentially damaging forces on the knee when kneeling or squatting were described. Papers on the incidence or prevalence of knee disorders in occupational and other groups were scored against five criteria independently by each author, and from this a single consensus score representing the overall strength of evidence given by the research was awarded. The evidence was then weighed against the criteria for an occupational disease. RESULTS: Nineteen published papers were scored, the majority of which focussed on osteoarthritis as the outcome of interest. Few of the studies found focussed specifically on miners, and those that did tended to involve small numbers of subjects and were carried out before 1960, when the mining population was at its largest but epidemiological evidence of the risk factors for knee disorders was not well established. The non-mining studies in the review represent groups of workers with a similar or lesser kneeling content in their work. CONCLUSION: The papers reviewed provide sufficient evidence to conclude that work involving kneeling and/or squatting is causally associated with an increased risk of osteoarthritis of the knee. In some of the more recent epidemiologically sound studies, frequent or prolonged kneeling or squatting doubles the general risk of osteoarthritis of the knees found in the general population. This may be of particular importance in welfare and medico-legal situations. There was also evidence to suggest that lifting, in combination with kneeling/squatting, an activity also performed by miners in the course of their work, is associated with an excess risk of osteoarthritis above that attributed to kneeling/squatting alone.

Heterodimerization between the glucocorticoid receptor and the unrelated DNA-binding protein, Xenopus glucocorticoid receptor accessory factor.

The adrenal steroid hormones, glucocorticoids, control many physiological responses to trauma, including elevated synthesis of fibrinogen, a major blood-clotting protein. Glucocorticoid regulation of the gamma-fibrinogen subunit gene in Xenopus laevis is mediated by a binding site for Xenopus glucocorticoid receptor accessory factor (XGRAF) and a contiguous glucocorticoid response element (GRE) half-site. Here, we characterize the protein:DNA complex formed by a cooperative interaction between XGRAF, GR, and the DNA. We demonstrate that the complex contains XGRAF by competition in a gel shift assay. The presence of GR is established by two criteria: 1) size dependence of the XGRAF:GR:DNA complex on the size of the GR component and 2) interference with complex formation by GR antibody. Cooperative binding of XGRAF and GR to the DNA was quantitated, showing that GR favors binding to XGRAF:DNA compared with free DNA by a factor of 30. The cooperative interaction between XGRAF and GR can occur on nicked DNA but is disrupted when 1 bp is inserted between the XGRAF binding site and half-GRE. Significantly, this loss of physical association in vitro correlates with loss of XGRAF amplification of GR activity in transiently transfected primary Xenopus hepatocytes. The simplest explanation for cooperativity between XGRAF and GR is formation of a DNA-bound heterodimer of these two proteins. This mechanism represents a new mode of transcriptional regulation in which GR and a nonreceptor protein form a heterodimer, with both partners contacting their specific DNA sites simultaneously.

Prediction of in-hospital cardiopulmonary arrest outcome.

Clinical and demographic characteristics of 122 patients undergoing cardiopulmonary resuscitation were retrospectively collected to develop a predictive model for immediate success of resuscitation (restoration of pulse and blood pressure). The project focused on objective measurement of parameters available before resuscitation was performed. Variables included age, diagnoses, objective severity of illness, laboratory data, and clinical course variables. A four-variable model was developed using logistic regression to predict resuscitation success immediately after resuscitation. The four predictive before arrest factors were age between 40 and 70 years, scheduled for surgery, location of arrest in an intensive care unit, and before arrest PO2 greater than 8 mm Hg. The model had an accuracy of 69%, sensitivity of 76%, and specificity of 61%.

Impact of continued geriatric outpatient management on health outcomes of older veterans.

BACKGROUND: Although previous trials have proved inpatient-based geriatric assessment to be beneficial, to our knowledge, the effectiveness of outpatient geriatric assessment has not been established. We examined the effectiveness of an outpatient geriatric evaluation and management (GEM) clinic. METHODS: Hospitalized veterans aged 65 years or older with impairment of activities of daily living, chronic disease, polypharmacy, or two or more hospitalizations in the previous year were randomized to an outpatient GEM team clinic (n = 60) or usual care (n = 68). After an initial comprehensive assessment, they received long-term management in the geriatric clinic. Principal outcomes included health status (mortality, hospitalizations, health perception, and medications), function (activities of daily living, instrumental ADL, and social activity), affect (Center for Epidemiologic Studies-Depression test score and life satisfaction), and cognition (Mini-Mental State examination score). RESULTS: At randomization, no significant differences were noted between the groups. The average age of the patients was 71 years (range, 65 to 93 years). At 1 year following randomization, GEM clinic patients compared with subjects receiving usual care had significantly improved health perception, took fewer medications despite increased number of diagnoses, reported greater social activity, had improved Center for Epidemiologic Studies-Depression scale scores, and had higher life satisfaction scores. There was a trend toward improved performance of activities of daily living for GEM clinic patients. The GEM clinic patients had a 54% lower mortality (6.8% vs 14.9%). Overall, no differences were observed in the total number of hospitalizations between the groups. CONCLUSIONS: The combination of long-term management following comprehensive outpatient assessment significantly improved aspects of health status (including health perception and medications), function (including social activity), and affect (including depression and life satisfaction) for older veterans and may influence mortality and function.

cDNA and amino-acid sequences and organization of the gene encoding the B beta subunit of fibrinogen from Xenopus laevis.

Fibrinogen, the major blood-clotting protein, is made up of three chains, A alpha, B beta and gamma, which are synthesized and secreted by the liver. In this communication, we describe the complete cDNA sequence, deduced amino acid (aa) sequence and organization of the gene encoding the B beta subunit of fibrinogen from Xenopus laevis (Xl). The cDNA representing the predominant form of the B beta mRNA comprises 2390 nucleotides (nt), with an open reading frame of 1467 nt coding for a 488-aa protein. The percent identity between Xl B beta and that of other animals ranges from 50% for lamprey to 66% for human. The Xl B beta gene consists of nine exons, one more than found in the human gene. The exon/intron boundaries in the frog and human B beta genes are in exactly conserved positions, except for junctions in the highly variable fibrinopeptide-encoding regions. Three of the exon/intron boundaries in the Xl B beta gene are also analogous to ones in A alpha and gamma genes of other species, supporting the notion of a close evolutionary relationship between the genes for all three subunits. This analysis of B beta from an amphibian provides the first complete description of the arrangement of exons and introns in any fibrinogen subunit gene from a non mammal and gives insight into the most highly conserved aspects of fibrinogen protein structure and gene organization.

Renal cortical neoplasms in long term survivors of solid organ transplantation.

BACKGROUND: Renal cortical neoplasms have been reported after organ transplantation, but the level of risk as well as the histological features are poorly defined. METHODS: A retrospective autopsy-based study was performed to evaluate renal neoplasms occurring in patients who underwent solid organ transplantation, died, and received an autopsy from 1981 to 1997 (383 liver, 125 heart, 52 lung, 39 heart/lung, 98 kidney, 4 bowel). Patients were divided into those with short (less than 101 days), medium (101 days to 5 years), and long-term survival (more than 5 years). The control group consisted of hospital autopsies on nontransplanted patients from the odd-numbered years, 1983 through 1997. RESULTS: Renal cortical neoplasms were identified in 32/1325 of nontransplanted patients and 15/701 transplanted patients. In transplanted patients, neoplasms were identified in 14 native and 1 allograft kidney: 2/391 in short-term survivors, 3/234 in medium, and 10/76 in long term survivors. While transplant patients with short and medium length survival had no increased risk for neoplasms, patients with long-term survival showed a 9-fold increase in cortical neoplasms. Transplant patients with neoplasms averaged 47 years of age at death, significantly younger than the average age of 70 for nontransplanted control patients with renal neoplasms. The neoplasms in transplanted patients were all tubulopapillary, except for one clear cell neoplasm and ranged in size from 0.1 to 2 cm. CONCLUSIONS: Long-term survivors of solid organ transplants have an 9-fold increased risk of developing tubulopapillary renal cortical neoplasms.