Investigating the role connective tissue fibroblasts play in the altered muscle anatomy associated with the limb abnormality, Radial Dysplasia.

Radial dysplasia (RD) is a congenital upper limb birth defect that presents with changes to the upper limb anatomy, including a shortened or absent radius, bowed ulna, thumb malformations, a radially deviated hand and a range of muscle and tendon malformations, including absent or abnormally shaped muscle bundles. Current treatments to address wrist instability caused by a shortened or absent radius frequently require an initial soft tissue distraction intervention followed by a wrist stabilisation procedure. Following these surgical interventions, however, recurrence of the wrist deviation remains a common, long-term problem following treatment. The impact of the abnormal soft connective tissue (muscle and tendon) anatomy on the clinical presentation of RD and the complications following surgery are not understood. To address this, we have examined the muscle, fascia and the fascial irregular connective tissue (ICT) fibroblasts found within soft connective tissues, from RD patients. We show that ICT fibroblasts isolated from RD patients are functionally abnormal when compared to the same cells isolated from control patients and secrete a relatively disordered extracellular matrix (ECM). Furthermore, we show that ICT fibroblast dysfunction is a unifying feature found in RD patients, even when the RD clinical presentation is caused by distinct genetic syndromes.

Aesthetic Considerations in Pollicisation Using the Buck-Gramcko Technique.

The Buck-Gramcko (BG) technique of pollicisation has stood the test of time and provides good to excellent prehensile function in thumb hypoplasia. Proponents of the technique favour it because it provides good exposure to the palmar neurovascular structures. However, the skin flap design may occasionally lead to a 'finger-like' appearance with a sharp interdigital cleft and a triphalangeal form. In this report, we describe some of the important aspects of the operative technique so that the outcome is aesthetically pleasing in addition to providing good function. Level of Evidence: Level V (Therapeutic).

Thin and superthin free flaps: An innovative approach to pediatric extremity reconstruction.

INTRODUCTION: Published standards for the management of open extremity fractures have improved limb salvage, fracture union, and deep infection rates, but the aesthetic and functional importance of our flap choices has been overlooked. Thin and superthin free flaps exhibit advantages over traditional free flaps in some situations but have seldom been reported in children. The aim of this paper is to present our experience of thin and superthin free flaps in pediatric extremity reconstruction. METHODS: Children (≤13 years) who underwent soft tissue reconstruction using a thin and superthin free flap following major extremity trauma are presented. RESULTS: Five patients (5 flaps) met the inclusion criteria. The median age was 9 (range 6-13). There were 3 Gustilo IIIB open fractures and 2 multiplanar degloving injuries. The median mangled extremity severity score (MESS) was 4 (range 2-6). The median time from injury to definitive soft tissue closure was 72 h (range 28-120 h). Four anterolateral thigh (ALT) flaps were raised as thin flaps, and 1 superficial circumflex iliac artery perforator (SCIP) was raised as a superthin flap. There was one re-exploration owing to venous congestion, and a second venous anastomosis was performed to enhance flap drainage. The same ALT flap exhibited necrosis at one margin, which was debrided and grafted before discharge. There were no other flap complications. No flap-related secondary surgeries were required. CONCLUSION: Thin and superthin free flaps are viable options in pediatric extremity reconstruction. They exhibit excellent aesthetic and functional contouring when a slender fasciocutaneous flap is needed, especially when body habitus renders traditional options unfavorable.

PolliRS: A 3D-printed Pollicization Retractor System that Improves Access and Autonomy during the Surgical Procedure.

We demonstrate the design, manufacture, and deployment of the first custom-made 3-dimensional (3D)-printed hand retractor for the pollicization procedure. Radiological images of the patient's hand were taken preoperatively to measure anatomical dimensions and guide the design of the device in a patient-precise manner. The 3D-printed, sterilizable, device was autoclaved and successfully used on a patient that underwent a pollicization procedure in our unit. The radiolucency of the device and the fluency enabled by the ability to exchange between different positions demonstrated the potential of this device in increasing the overall autonomy afforded to the lead-surgeon during the operation and demonstrated the potential of rapid-prototyping techniques such as 3D printing for producing patient-precise tools on-the-fly that taken account the specific needs of the patient.

Cenani-Lenz syndactyly in siblings with a novel homozygous LRP4 mutation and recurrent hypoglycaemia.

Cenani-Lenz syndactyly (CLS) is a rare autosomal recessive syndrome characterized by disorganized oligosyndactyly of upper and lower limbs as well as radioulnar synostosis. Structural renal abnormalities are also common. We report two affected brothers, born to orthodox Jewish parents, in whom we found a novel homozygous missense variant c.4910G>A; p.(Cys1637Tyr) in LRP4 situated in an EGF-like domain between the fourth beta-propeller and transmembrane domains. Both brothers have had recurrent ketotic hypoglycaemia which has not been associated previously. We present 3D computed tomographic imaging illustrating the limb abnormalities in detail.

Vascular anomalies of the upper limb.

Vascular anomalies are common in the upper extremities, but there continues to be a relative paucity of information about them in publications dealing with surgery in the hands and upper limbs. The wide spectrum of pathology and an inconsistent use of terminology make vascular anomalies susceptible to incorrect diagnosis and as a result, to misdirected management. This article aims to provide an update on vascular anomalies relevant to the upper limbs, focusing on significant advances in pathogenesis and genetics, classification systems, diagnosis and treatment.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

Correction of "Wrist" Deformity in Radial Dysplasia: A Systematic Review and Meta-Analysis.

BACKGROUND: Radial dysplasia affects 1 in 6,000 to 8,000 births, classically presenting with a shortened, bowed ulna and radially deviated hand. The optimal treatment remains unclear, with several opposing approaches advocated. This review aims to clarify the long-term outcomes of nonsurgical and surgical treatment of the "wrist" deformity. METHODS: The Embase, MEDLINE, PubMed, Cochrane Central, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (ICTRP) databases were searched for published and unpublished studies reporting long-term outcomes of surgical or nonsurgical treatment of children with radial dysplasia. Results were not restricted by date or language. Primary outcomes were hand-forearm angle, ulnar length, and "wrist" active range of motion (ROM). Studies were assessed using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) criteria. Data for the change in hand-forearm angle were pooled using random-effects meta-analysis, and mean differences and 95% confidence intervals were obtained. Primary outcome data at last follow-up were pooled, and means and standard deviations were obtained. The PROSPERO registration of this study was CRD42016036665. RESULTS: Of 104 studies identified, 12 were included in this review. Five were retrospective cohort studies and 7 were case series. No randomized studies were found. Study quality was low or very low according to the GRADE criteria. The hand-forearm angle of nonsurgically treated patients worsened during childhood, from 66° to 84°, whereas "wrist" active ROM, at 61°, was better than that for most surgically treated patients. Ulnar length with nonsurgical treatment was predicted to be 64% of normal, but was not directly reported. Isolated soft-tissue release provided a modest reduction in hand-forearm angle compared with nonsurgical treatment. Soft-tissue distraction with centralization or radialization achieved the best hand-forearm angle correction (16° radial deviation). Radialization maintained better "wrist" active ROM (46°) and ulnar length than centralization. Microvascular second metatarsophalangeal joint transfer yielded better reported "wrist" active ROM (83°) and good ulnar length compared with other surgical techniques, but a slightly worse hand-forearm angle (28°). CONCLUSIONS: There was low-quality evidence that soft-tissue distraction plus centralization or radialization achieved the best correction of the hand-forearm angle for children with radial dysplasia. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Considerations in surgical management of a Buschke-Lowenstein tumor in Netherton syndrome: A case report.

Netherton syndrome is an autosomal recessive ichthyosis caused by mutations in SPINK5, with the classic triad of linearis circumflexa, trichorrhexis invaginata, and atopy. There are few reports of surgical management in individuals with Netherton syndrome and clinicians may be reluctant to operate for fear of wound-healing complications. This report describes a pediatric case of a Buschke-Lowenstein tumor of the natal cleft in a patient with Netherton syndrome that had failed to respond to medical management. We reviewed the literature for previous cases of surgery in individuals with Netherton syndrome using MEDLINE and PubMed searches. Our patient underwent surgery to remove the lesion without complication. Using conventional dressings and topical negative-pressure therapy, the wound was managed and healed within a reasonable time frame despite the underlying skin condition. This case indicates that surgery and topical negative-pressure therapy is a safe and reasonable treatment for individuals with Netherton syndrome.

A morphometric study of the human ear.

AIMS: We examined variations in the shape of the human ear according to age, sex and ethnic group with particular attention to ear prominence. METHODS: 420 volunteers were recruited. Measurements included; head height and length, ear height and axis, antihelix taken off angle, earlobe length and width, ear width at the helical root and tragus. Prominence was measured at the helical root and tragus (conchomastoid angle, conchal bowl depth and helical-mastoid distance). RESULTS: Good symmetry was shown for all measurements. Ethnically Indian volunteers had the largest ears (both length and width), followed by Caucasians, and Afro-Caribbeans. This trend was significant in males (p<0.001), but not significant in females (p=0.087). Ears increased in size throughout life. Subjectively, only 2% of volunteers felt their ears were prominent compared to 10% in the opinion of the principal investigator. No objective measurements were identified that accurately predicted subjective perceptions of prominence. CONCLUSIONS: We found consistent trends in ear morphology depending on ethnic group, age and sex. Our study was unable to define an objective method for assessing ear prominence. Decisions about what constitutes a prominent ear should be left to personal and aesthetic choice.

Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is characterised by invasion of cartilage, bone and tendon by inflamed synovium. Previous studies in our laboratory have shown that hypoxia is a feature of RA synovitis. In the present study, we investigated the consequences of hypoxia on angiogenesis and synovial fibroblast migration in RA. METHODS: Synovial tissue was harvested from RA patients, and synovial membrane cells were cultured under conditions either of hypoxia (1% oxygen) or normoxia (21% oxygen). Protein levels of matrix metalloproteinases (MMPs) and angiogenic factors were measured, while RNA was extracted for PCR quantification of MMPs/tissue inhibitors of MMP (TIMPs) and angiogenic factors. Migration of RA synovial fibroblasts through collagen, and the effect of RA synovial cell supernatants in an in vitro angiogenesis assay, were utilised to determine the functional relevance of changes in mRNA/protein. RESULTS: We observed upregulation under hypoxic conditions of MMPs responsible for collagen breakdown, specifically collagenase MMP-8, and the gelatinases MMP-2 and MMP-9, at both mRNA and protein levels. Increased MT1-MMP mRNA was also observed, but no effect on TIMP-1 or TIMP-2 was detected. RA fibroblast migration across collagen was significantly increased under hypoxic conditions, and was dependent on MMP activity. Furthermore, expression of angiogenic stimuli, such as vascular endothelial growth factor (VEGF), and VEGF/placental growth factor heterodimer, was also increased. Crucially, we show for the first time that hypoxia increased the angiogenic drive of RA cells, as demonstrated by enhanced blood vessel formation in an in vitro angiogenesis assay. CONCLUSIONS: Hypoxia may be responsible for rendering RA synovial lining proangiogenic and proinvasive, thus leading to the debilitating features characteristic of RA.

Angiogenesis and plastic surgery.

SUMMARY: Angiogenesis, the formation of new blood vessels from an existing vascular bed, is a normal physiological process which also underpins many--apparently unrelated--pathological states. It is an integral factor in determining the success or failure of many procedures in plastic and reconstructive surgery. As a result, the ability to control the process would be of great therapeutic benefit. To appreciate the potential benefits and limitations of recent advances in our understanding of angiogenesis, it is important to comprehend the basic physiology of blood vessel formation. This review aims to summarise current knowledge of the way in which angiogenesis is controlled and to look at how disordered vessel development results in pathology relevant to plastic surgery. Through this we hope to provide a comprehensive overview of the recent advances in angiogenesis as they relate to plastic surgery, particularly the promotion of flap survival, tendon healing, nerve regeneration, fracture healing and ulcer treatments.

Synovial hypoxia as a cause of tendon rupture in rheumatoid arthritis.

PURPOSE: Hypoxia and angiogenesis are now recognized as being important events in the perpetuation of joint destruction in rheumatoid arthritis (RA). In 50% of patients with RA, however, the disease also involves inflammation of the synovial tissue surrounding the tendons, which is associated with multiple ruptures and poor prognosis for long-term hand function. The aim of this study was to determine whether hypoxia and angiogenesis may also play a role in RA tendon disease. METHODS: Matched in vivo synovial oxygen measurements (invasive and encapsulating tenosynovium and joint synovium) were taken intraoperatively using a microelectrode technique in patients having elective hand surgery for RA. Patients having elective hand surgery for indications other than inflammatory synovitis were recruited as controls. In parallel, RA synovial tissue was harvested and stained for vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-2alpha. Tissue was also cultured under either hypoxic (1% O(2)) or normoxic (21% O(2)) conditions to investigate the effect of hypoxia on the expression of VEGF and its soluble receptor, as well as on the key cytokines interleukin (IL)-6, IL-8, IL-10 and the chemokine monocyte chemoattractant protein-1. RESULTS: Invasive tenosynovium was observed to be significantly more hypoxic than either noninvasive tenosynovium or joint synovium in the same patients. Furthermore, RA tenosynovium was shown to be more hypoxic than tenosynovium in patients without RA. This hypoxia was accompanied by expression of VEGF and hypoxia-inducible factor-2alpha. Using in vitro joint synovial cell cultures, upregulation of VEGF expression was shown to be a consequence of this in vivo hypoxia. Furthermore, hypoxia downregulated release of monocyte chemoattractant protein-1 and the immunoregulatory cytokine IL-10. CONCLUSIONS: These data demonstrate that hypoxia is a feature of rheumatoid tendon disease and differentially regulates angiogenesis and the inflammatory cascade in RA.

Angiogenesis as a therapeutic target in arthritis: lessons from oncology.

Rheumatoid arthritis (RA) is a chronic disabling autoimmune inflammatory disease of unknown aetiology with a prevalence of about 1% in most parts of the world. As a result of the debilitating nature of the disease, sufferers struggle with the simple activities of daily living and frequently fail to remain in full time employment. Furthermore, the mortality associated with the disease is equivalent to that seen in triple vessel coronary artery disease. Over the 10-15 years, advances in understanding the mechanisms of RA pathogenesis based on studies of human cells and animal models of arthritis have led to the identification of new targets for therapeutic intervention. Despite these advances, a significant proportion of patients continue to exhibit disease which is refractory to such therapy. As an alternative to anti-cytokine therapy, formation of new blood vessels ('angiogenesis') represents a potentially attractive target for therapy in RA. Angiogenesis has been a putative target in cancer since it was first linked to tumour growth and metastases in the 1970s. A number of significant advances have been made in the development of anti-cancer therapy using such an approach. This review focuses on the potential for targeting angiogenesis in RA, building upon the experience of angiogenesis inhibition in the oncological setting. Through this we hope to emphasise the potential value of anti-angiogenic therapy in RA and identify future directions for optimising treatment of this disabling disease.

Intra-lesional injections of collagenase are ineffective in the treatment of keloid and hypertrophic scars.

The treatment of keloid and hypertrophic scars remains difficult. Enzymatic digestion of keloid scars has been previously proposed as an effective treatment strategy for reducing the volume of keloid scars. To test this, we administered intra-lesional injections of pure collagenase (between 600 and 4500 units for each scar) into the keloid and hypertrophic scars of seven human volunteers (five keloid and two hypertrophic scars). Five patients (three keloid and two hypertrophic) received more than one injection of collagenase. The treatment resulted in a temporary reduction in scar volume for three of the patients with keloid scars. However, scar volumes for these three patients returned to the same (or greater) levels after 6 months of follow-up. Treatment with collagenase produced no change in scar volume for the two patients with hypertrophic scar. Side effects were numerous and severe including; pain, swelling, blistering, ulceration and ecchymosis at the site of injection. One patient required admission to hospital for 48 h after the first injection. Maximum length of follow-up was 6 months. None of the seven patients completed the study and returned for final follow-up at 2 years. This pilot study suggests that treatment of keloid and hypertrophic scars with intra-lesional injections of collagenase is ineffective.

Immunotherapy of rheumatoid arthritis: past, present and future.

Rheumatoid arthritis (RA) is a chronic autoimmune disease, characterized by inflammation of the synovial lining of joints, and the destruction of cartilage and bone. Seminal studies demonstrating that pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFalpha), are expressed in RA, has resulted in the approval of anti-TNFalpha biological therapies for its treatment. Although groundbreaking in themselves, these studies have also paved the way for further research to determine whether the targeting of other cytokines and immune pathways might aid in development of the next generation of drugs for the treatment of RA.

Modulating angiogenesis: more vs less.

The concept of manipulation of the vascular bed to either increase or decrease the number of blood vessels has attracted considerable interest. This review focuses on angiogenesis as a therapeutic target, particularly in the context of cancer and arthritis, as well as on promoting angiogenesis in cardiovascular disease and the healing of bone fractures. Although once touted almost as a panacea for treatment of tumors, as well as other diseases associated with angiogenesis, such as diabetic retinopathy or rheumatoid arthritis, it is now clear that such enthusiasm was somewhat premature. Similarly, some clinical trials of therapeutic angiogenesis for the management of cardiovascular disease have been disappointing. Nevertheless, this exciting field of research holds promise for more targeted therapies.