Aberrant Regeneration Research Articles

Delayed-onset post-craniotomy headache responsive to botulinum toxin A: a case series.

We report here the case of four patients presenting with delayed-onset temporal pain after pterional craniotomy. They reported similar symptoms: attacks of pain over the temporal region, ipsilateral to the operative site, irradiating around the eye and lasting from 10min to 1 h. All patients had hypertrophy of at least one part of the temporalis muscle. All responded dramatically to botulinum toxin A injection (25 to 50 Botox® units) into the temporalis muscle. We suggest that the headaches were caused by aberrant nerve regeneration following surgical injury to the frontal branch of the facial nerve.

Defining the Balance between Regeneration and Pathological Ossification in Skeletal Muscle Following Traumatic Injury.

Heterotopic ossification (HO) is characterized by the formation of bone at atypical sites. This type of ectopic bone formation is most prominent in skeletal muscle, most frequently resulting as a consequence of physical trauma and associated with aberrant tissue regeneration. The condition is debilitating, reducing a patient's range of motion and potentially causing severe pathologies resulting from nerve and vascular compression. Despite efforts to understand the pathological processes governing HO, there remains a lack of consensus regarding the micro-environmental conditions conducive to its formation, and attempting to define the balance between muscle regeneration and pathological ossification remains complex. The development of HO is thought to be related to a complex interplay between factors released both locally and systemically in response to trauma. It develops as skeletal muscle undergoes significant repair and regeneration, and is likely to result from the misdirected differentiation of endogenous or systemically derived progenitors in response to biochemical and/or environmental cues. The process can be sequentially delineated by the presence of inflammation, tissue breakdown, adipogenesis, hypoxia, neo-vasculogenesis, chondrogenesis and ossification. However, exactly how each of these stages contributes to the formation of HO is at present not well understood. Our previous review examined the cellular contribution to HO. Therefore, the principal aim of this review will be to comprehensively outline changes in the local tissue micro-environment following trauma, and identify how these changes can alter the balance between skeletal muscle regeneration and ectopic ossification. An understanding of the mechanisms governing this condition is required for the development and advancement of HO prophylaxis and treatment, and may even hold the key to unlocking novel methods for engineering hard tissues.

Molecular Mechanisms of Immunomodulation Properties of Mesenchymal Stromal Cells: A New Insight into the Role of ICAM-1.

Mesenchymal stromal cells (MSC) control excessive inflammation and create a microenvironment for tissue repair protecting from chronic inflammation and tissue fibrosis. We examined the molecular mechanisms of MSC immunomodulatory function in mixed cultures of human adipose-derived MSC with lymphocytes. Our data show that MSC promote unstimulated lymphocyte survival potentially by an increase in antigen presentation. Under inflammatory conditions, mimicked by stimulation of TCR in lymphocytes, MSC suppress activation and proliferation of stimulated T cells. Immunosuppression is accompanied by downregulation of IL-2Rα that negatively affects the survival of activated T cells. MSC upregulate transcription of indolamine-2,3-dioxygenase (IDO) and inducible NO synthase (iNOS), which generate products negatively affecting T cell function. Both MSC and lymphocytes dramatically increase the surface ICAM-1 level in mixed cultures. Antibody-mediated blockage of surface ICAM-1 partially releases MSC-mediated immune suppression in vitro. Our data suggest that MSC have cell-intrinsic molecular programs depending on the inflammatory microenvironment. We speculate that MSC sense soluble factors and respond by surface ICAM-1 upregulation. ICAM-1 is involved in the control of T cell activation leading to immunosuppression or modest stimulation depending on the T cell status. Immunomodulation by MSC ranging from support of naive T cell survival to immunosuppression of activated T cells may affect the tissue microenvironment protecting from aberrant regeneration.

An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US.

Neuropathic pain (NeuP) is a syndrome that results from damaged nerves and/or aberrant regeneration. Common etiologies of neuropathy include chronic illnesses and medication use. Chronic disorders, such as diabetes and alcoholism, can cause neuronal injury and consequently NeuP. Certain medications with antineoplastic effects also carry an exquisitely high risk for neuropathy. These culprits are a few of many that are fueling the NeuP epidemic, which currently affects 7%–10% of the population. It has been estimated that approximately 10% and 7% of US adults carry a diagnosis of diabetes and alcohol disorder, respectively. Despite its pervasiveness, many physicians are unfamiliar with adequate treatment of NeuP, partly due to the few reviews that are available that have integrated basic science and clinical practice. In light of the recent Centers for Disease Control and Prevention guidelines that advise against the routine use of μ-opioid receptor-selective opioids for chronic pain management, such a review is timely. Here, we provide a succinct overview of the etiology and treatment options of diabetic and alcohol- and drug-induced neuropathy, three different and prevalent neuropathies fusing the combined clinical and preclinical pharmacological expertise in NeuP of the authors. We discuss the anatomy of pain and pain transmission, with special attention to key ion channels, receptors, and neurotransmitters. An understanding of pain neurophysiology will lead to a better understanding of the rationale for the effectiveness of current treatment options, and may lead to better diagnostic tools to help distinguish types of neuropathy. We close with a discussion of ongoing research efforts to develop additional treatments for NeuP.

Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease.

Skeletal muscle atrophy and impaired muscle function are associated with lower health-related quality of life, and greater disability and mortality risk in those with chronic kidney disease (CKD). However, the pathogenesis of skeletal dysfunction in CKD is unknown. We used a slow progressing, naturally occurring, CKD rat model (Cy/+ rat) with hormonal abnormalities consistent with clinical presentations of CKD to study skeletal muscle signaling. The CKD rats demonstrated augmented skeletal muscle regeneration with higher activation and differentiation signals in muscle cells (i.e. lower Pax-7; higher MyoD and myogenin RNA expression). However, there was also higher expression of proteolytic markers (Atrogin-1 and MuRF-1) in CKD muscle relative to normal. CKD animals had higher indices of oxidative stress compared to normal, evident by elevated plasma levels of an oxidative stress marker, 8-hydroxy-2' -deoxyguanosine (8-OHdG), increased muscle expression of succinate dehydrogenase (SDH) and Nox4 and altered mitochondria morphology. Furthermore, we show significantly higher serum levels of myostatin and expression of myostatin in skeletal muscle of CKD animals compared to normal. Taken together, these data show aberrant regeneration and proteolytic signaling that is associated with oxidative stress and high levels of myostatin in the setting of CKD. These changes likely play a role in the compromised skeletal muscle function that exists in CKD.

Surgical management of third nerve palsy

Third nerve paralysis has been known to be associated with a wide spectrum of presentation and other associated factors such as the presence of ptosis, pupillary involvement, amblyopia, aberrant regeneration, poor bell's phenomenon, superior oblique (SO) overaction, and lateral rectus (LR) contracture. Correction of strabismus due to third nerve palsy can be complex as four out of the six extraocular muscles are involved and therefore should be approached differently. Third nerve palsy can be congenital or acquired. The common causes of isolated third nerve palsy in children are congenital (43%), trauma (20%), inflammation (13%), aneurysm (7%), and ophthalmoplegic migraine. Whereas, in adult population, common etiologies are vasculopathic disorders (diabetes mellitus, hypertension), aneurysm, and trauma. Treatment can be both nonsurgical and surgical. As nonsurgical modalities are not of much help, surgery remains the main-stay of treatment. Surgical strategies are different for complete and partial third nerve palsy. Surgery for complete third nerve palsy may involve supra-maximal recession - resection of the recti. This may be combined with SO transposition and augmented by surgery on the other eye. For partial third nerve, palsy surgery is determined according to nature and extent of involvement of extraocular muscles.

Tensor fascia lata interposition for treatment of Frey's syndrome: a forgotten surgical technique?

Frey’s syndrome which manifests clinically as unilateral facial sweating and flushing on salivary stimulation and mastication, is postulated to result from aberrant regeneration of sectioned autonomic nerve fibers. Many surgical and non-surgical treatment modalities have been described with varying degrees of success to relive the symptoms. In this case report, we describe the surgical technique of tensor fascia lata interposition as a simple and reliable treatment option for Frey’s syndrome.

Intraparotid Location of the Great Auricular Nerve: A New Anatomical Basis for Gustatory Sweating Syndrome.

Gustatory sweating syndrome (also known as Frey syndrome or auriculotemporal nerve syndrome) is thought to result from a lesion of the auriculotemporal nerve. A lesion of this nerve can lead to aberrant regeneration of nerve fibers to the sweat glands and blood vessels. The occurrence of signs outside the region of the auriculotemporal nerve prompted the author to search for another anatomical basis for this syndrome. The author dissected 46 great auricular nerves from their origin to the parotid gland and in the infratemporal fossa. The author investigated the different connections of the great auricular nerve with the facial nerve and the auriculotemporal nerve. The great auricular nerve was found to essentially be a parotid nerve. There was a set of intraparotid nerve connections on 14 of the 46 half-heads that were dissected. The author was able to discern three types of parotid great auricular nerve connections, which he designates as either type 1, connection with the trunk of the facial nerve and its branches; type 2, connection with the auriculotemporal nerve; or type 3, connection with the auriculotemporal nerve and the facial nerve with the formation of an intraparotid nerve circle. Having clearly established the nerve connections of the great auricular nerve, the author believes that it is primarily this nerve that is responsible for gustatory sweating syndrome. This allows for a better understanding of the sympathetic nervous system features and the manifestation of the syndrome outside the region of the auriculotemporal nerve.

Endoscopic Thoracodorsal Neurectomy for Correction of Animation Deformity following Latissimus Dorsi-Based Breast Reconstruction.

Sir: Painful muscular contractions, involuntary twitching, tightness, and/or dynamic displacement of the breast affect a high percentage of patients (41 percent) undergoing innervated latissimus dorsi–based breast reconstruction.1 These sequelae can limit physical activity, jeopardize satisfaction, and diminish quality of life for individuals who have otherwise achieved a favorable aesthetic result. Studies evaluating the impact of surgical denervation of the latissimus dorsi muscle demonstrate significantly reduced pain and animation; comparable preservation of volume, shape, and symmetry; and improved satisfaction following thoracodorsal neurectomy.2,3 It is therefore our preference to perform primary nerve resection during immediate or delayed breast reconstruction, which is readily accomplished through an open axillary or dorsal approach and eliminates the need for a second-stage procedure. Nevertheless, plastic surgeons must also be familiar with treatment strategies for patients who present with secondary contractile deformities. In such cases, chemical denervation with botulinum toxin type A offers a temporary solution; however, results with this approach are unpredictable, and the need for repeated injections over time increases the risk of implant leakage and/or rupture.4 Alternatively, delayed proximal resection of the thoracodorsal nerve may offer the best available option for symptomatic relief. Although high success rates have been reported using an axillary approach (90 percent), sectioning of the latissimus dorsi muscle to access the thoracodorsal nerve is excessively destructive and may alter muscle tropism and contour without guaranteeing successful denervation.1 Furthermore, scarring and/or fibrosis, which are often encountered during secondary revisions, increase the risk and complexity of dissection and the need for more extensive incisions.4 In this communication, we propose a minimally invasive, endoscopic approach to thoracodorsal neurectomy that minimizes incisions, bypasses axillary scarring, and eliminates dynamic abnormalities through selective denervation of the latissimus dorsi muscle. With the patient in lateral decubitus position, endoscopic visualization of the thoracodorsal neurovascular hilus is achieved using carbon dioxide insufflation (10 mmHg) through a 3-mm trocar inserted along the posterior axillary line. Two additional trocars placed distal to the dorsocaudal border of the latissimus dorsi permit unobstructed dissection through the nonirradiated, dorsal submuscular plane. Once identified on the undersurface of the muscle, the thoracodorsal nerve is isolated proximal to the point of divergence from the vascular pedicle and clipped (Fig. 1). Proximal resection of at least 4 cm of extramuscular nerve is then performed under endoscopic guidance, following confirmation of latissimus dorsi contraction on nerve stimulation (Fig. 2).Fig. 1: Endoscopic view of the thoracodorsal neurovascular bundle in situ. The nerve (arrow) is traced proximal to the point of divergence from the vascular pedicle, isolated, and clipped to prevent nerve sprouting and/or aberrant regeneration from adjacent nerve fibers following segmental resection.Fig. 2: A minimum of 4 cm of extramuscular nerve is routinely excised, proximal to the neurovascular hilus, to minimize the risk of latissimus dorsi reinnervation along the vascular pedicle.It is important to note that both muscular reinnervation and incomplete/distal nerve transection may contribute to compromised results and/or persistent animation.4 Technical error can be prevented through segmental resection of the main thoracodorsal nerve trunk—proximal to the neurovascular hilus—using a dorsal approach to avoid injuring the latissimus dorsi muscle and any structures embedded within the scarred axillae. As recommend by Schroegendorfer et al., at least 4 cm of thoracodorsal nerve is resected to achieve permanent sufficient denervation.5 We routinely clip the proximal/distal ends to prevent nerve sprouting and/or aberrant regeneration from adjacent nerve fibers. As with other minimally invasive techniques, improved scarring, reduced pain, and earlier postoperative recovery can be expected following endoscopic thoracodorsal neurectomy for correction of latissimus dorsi–based contractile deformities. DISCLOSURE The authors have no financial interest to declare in relation to the content of this article. Michael V. DeFazio, M.D. Troy A. Pittman, M.D. Department of Plastic Surgery Medstar Georgetown University Hospital Washington, D.C.

Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration.

SummaryPostnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Previous studies have demonstrated that certain embryonic development programs are reactivated aberrantly in adult organs to drive repair and regeneration1–3, it is not well understood how quiescence is maintained in organs such as the lung which displays a remarkably low level of cellular turnover4,5. We now demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signaling. Epithelial-specific deletion of sonic hedgehog during postnatal homeostasis in the lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signaling is initially down-regulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signaling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintains postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.

Therapeutic strategies for preventing skeletal muscle fibrosis after injury.

Skeletal muscle repair after injury includes a complex and well-coordinated regenerative response. However, fibrosis often manifests, leading to aberrant regeneration and incomplete functional recovery. Research efforts have focused on the use of anti-fibrotic agents aimed at reducing the fibrotic response and improving functional recovery. While there are a number of mediators involved in the development of post-injury fibrosis, TGF-β1 is the primary pro-fibrogenic growth factor and several agents that inactivate TGF-β1 signaling cascade have emerged as promising anti-fibrotic therapies. A number of these agents are FDA approved for other conditions, clearing the way for rapid translation into clinical treatment. In this article, we provide an overview of muscle's host response to injury with special emphasis on the cellular and non-cellular mediators involved in the development of fibrosis. This article also reviews the findings of several pre-clinical studies that have utilized anti-fibrotic agents to improve muscle healing following most common forms of muscle injuries. Although some studies have shown positive results with anti-fibrotic treatment, others have indicated adverse outcomes. Some concerns and questions regarding the clinical potential of these anti-fibrotic agents have also been presented.

Cranial nerve palsies in childhood.

We review ocular motor cranial nerve palsies in childhood and highlight many of the features that differentiate these from their occurrence in adulthood. The clinical characteristics of cranial nerve palsies in childhood are affected by the child's impressive ability to repair and regenerate after injury. Thus, aberrant regeneration is very common after congenital III palsy; Duane syndrome, the result of early repair after congenital VI palsy, is invariably associated with retraction of the globe in adduction related to the innervation of the lateral rectus by the III nerve causing co-contraction in adduction. Clinical features that may be of concern in adulthood may not be relevant in childhood; whereas the presence of mydriasis in III palsy suggests a compressive aetiology in adults, this is not the case in children. However, the frequency of associated CNS abnormalities in III palsy and the risk of tumour in VI palsy can be indications for early neuroimaging depending on presenting features elicited through a careful history and clinical examination. The latter should include the neighbouring cranial nerves. We discuss the impact of our evolving knowledge of congenital cranial dysinnervation syndromes on this field.

Neuropathic pain after bilateral sagittal split osteotomy: management and prevention

Neuropathic pain is characterized by spontaneous and provoked pain and other signs reflecting neural damage. Aberrant regeneration following peripheral nerve lesions leaves neurons unusually sensitive and prone to spontaneous pathological activity, abnormal excitability and heightened sensitivity to stimuli. This review covers the current understanding of neuropathic pain after bilateral sagittal split osteotomy (BSSO) of the lower jaw. The reported incidence of neuropathic pain after mandibular osteotomies is less than 1%, while the incidence in patients with iatrogenic inferior alveolar nerve (IAN) injuries during BSSO can be as high as 45%. The factors which modulate the healing process toward neuropathic pain during or after nerve damage have not yet been elucidated. Patients at highest risk for developing post-BSSO neuropathic pain are older than 45 years and have undergone procedures involving IAN compression, partial severance, or complete discontinuity of the lingual nerve with a proximal stump neuroma, patients with nerve injury repair delayed longer than 12 months and patients with chronic illnesses that compromise healing or increase risk for peripheral neuropathy. Although neuropathic pain tends to be long-lasting, some patients can recover completely. Preventive measures include risk assessment prior to surgery, prevention of nerve damage during surgery, and early repair of nerve injury.

Chapter 33 - Post-traumatic epilepsy: clinical clues to pathogenesis and paths to prevention

Post-traumatic epilepsy (PTE) remains one of the most intractable consequences of traumatic brain injury (TBI) and its incidence and characteristics have remained relatively constant through the past century, in spite of significant advances in medical management. Survivors of military penetrating head injury (PHI) suffer by far the highest incidence of (PTE), ranging from 32% to 55%, and they are a particularly valuable group in which to study this complication. Clues to the high incidence of PTE in PHI survivors are likely related to dural penetration with free intracerebral blood, and perhaps to retained ferric metal fragments. The failure of well-reasoned and well-conducted trials evaluating conventional anticonvulsants for prevention of PTE also offers important clues and has forced us to reconsider our approach to management. Here we briefly review the clinical characteristics of PHI patients with PTE, with an emphasis on clues to pathogenesis that can generalize to other types of head injury; followed by a discussion of the pathogenetic mechanisms common to epilepsy, PHI, and TBI in general, with an eye to future neuroprotection and PTE prophylaxis. Future studies that more directly target the basic pathogenesis of TBI, including neuroinflammation and lipid peroxidation with their consequent excitotoxic mechanisms and aberrant regeneration, may ultimately prove to be more fruitful in the struggle to understand and control this especially stubborn complication of head injury.

Predictors of Good Motor and Sensory Outcomes Following Strabismus Surgery for Patients with Third Nerve Palsies

Strabismus from third nerve palsy (3NP) is difficult to treat. Our goal was to explore factors associated with successful surgical outcomes in 3NP. Institutional records of all adult patients (>18 years) from 1988 to 2012 with 3NP who underwent strabismus surgery or botulinum toxin injections were retrospectively reviewed. Success was defined as absence of diplopia, vertical deviation ≤2 prism dioptres (PD), and horizontal deviation ≤10 PD. Fifty-six patients from four surgeons were included. Thirty (54%) were female; mean age was 48 (range: 20–80). Forty-four (79%) had unilateral 3NP; 9 (16%) had other ocular motor nerve palsies. 3NP were complete in 24 (43%). Underlying aetiology was idiopathic/microvascular in 5 (9%), traumatic in 13 (23%), neoplastic in 12 (21%), aneurysmal in 10 (18%), and other central nervous system related in 16 (29%). Trauma was associated more frequently with aberrant regeneration than other aetiologies: 9/13 (69%) versus 4/43 (9%) (p < 0.01). Ten patients (18%) had >1 surgery. Surgical success was achieved in 28/56 (50%). Success rate was unaffected by aetiology, degree of palsy, pupillary involvement, presence of aberrant regeneration, or number of other cranial nerves involved. However, adjustable sutures were used in 27 patients (48%), and there was a trend toward higher success rates when adjustable versus nonadjustable sutures were used (63% versus 38%; p = 0.06). Unlike with sixth nerve palsies, the aetiology and degree of 3NP does not appear to affect the success rates or number of procedures performed. Strabismus surgeries for 3NP with adjustable sutures may be associated with better outcomes.

Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne Muscular Dystrophy.

BackgroundFibrosis, an excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues. Fibrosis is a hallmark of muscular dystrophies, including the lethal Duchenne muscular dystrophy (DMD), which remains incurable. Substitution of muscle by fibrotic tissue also complicates gene/cell therapies for DMD. Yet, no optimal models to study muscle fibrosis are available. In the widely used mdx mouse model for DMD, extensive fibrosis develops in the diaphragm only at advanced adulthood, and at about two years of age in the ‘easy-to-access’ limb muscles, thus precluding fibrosis research and the testing of novel therapies.MethodsWe developed distinct experimental strategies, ranging from chronic exercise to increasing muscle damage on limb muscles of young mdx mice, by myotoxin injection, surgically induced trauma (laceration or denervation) or intramuscular delivery of profibrotic growth factors (such as TGFβ). We also extended these approaches to muscle of normal non-dystrophic mice.ResultsThese strategies resulted in advanced and enhanced muscle fibrosis in young mdx mice, which persisted over time, and correlated with reduced muscle force, thus mimicking the severe DMD phenotype. Furthermore, increased fibrosis was also obtained by combining these procedures in muscles of normal mice, mirroring aberrant repair after severe trauma.ConclusionsWe have developed new and improved experimental strategies to accelerate and enhance muscle fibrosis in vivo. These strategies will allow rapidly assessing fibrosis in the easily accessible limb muscles of young mdx mice, without necessarily having to use old animals. The extension of these fibrogenic regimes to the muscle of non-dystrophic wild-type mice will allow fibrosis assessment in a wide array of pre-existing transgenic mouse lines, which in turn will facilitate understanding the mechanisms of fibrogenesis. These strategies should improve our ability to combat fibrosis-driven dystrophy progression and aberrant regeneration.

Why adult stem cell functionality declines with age? Studies from the fruit fly Drosophila melanogaster model organism.

Highly regenerative adult tissues are supported by rare populations of stem cells that continuously divide to self-renew and generate differentiated progeny. This process is tightly regulated by signals emanating from surrounding cells to fulfill the dynamic demands of the tissue. One of the hallmarks of aging is slow and aberrant tissue regeneration due to deteriorated function of stem and supporting cells. Several Drosophila regenerative tissues are unique in that they provide exact identification of stem and neighboring cells in whole-tissue anatomy. This allows for precise tracking of age-related changes as well as their targeted manipulation within the tissue. In this review we present the stem cell niche of Drosophila testis, ovary and intestine and describe the major changes and phenotypes that occur in the course of aging. Specifically we discuss changes in both intrinsic properties of stem cells and their microenvironment that contribute to the decline in tissue functionality. Understanding these mechanisms in adult Drosophila tissues will likely provide new paradigms in the field of aging.

Eighteen-Point Abobotulinum Toxin A Upper Face Rejuvenation

To report the method and results of 18-point Abobotulinum toxin A (ABO-BTA, Dysport) upper face rejuvenation on 845 subjects. In a retrospective chart review, all subjects (the first cycle of injection) with ABO-BTA upper face rejuvenation from 2003 to 2009 were included. Excluded were subjects with facial spastic disorders, injection after upper face lifting, and aberrant regeneration of facial nerves. Upper face rejuvenation included 18 points of injection at forehead creases (4), frown lines (5), bunny line (1), crow's feet (4 on both sides), and lower eyelid crease (4 on both sides). They were revisited in 10 to 14 days for assessment of the effects and possible touch-up injection. Demographics, year of injection, topical anesthetic usage, touch-up injection, and adverse effects (AE) were recorded. There were 845 subjects (85.8% women) whose age was below 40 in 49.3%. All but 68 (8%) were happy with the touch-up visit, 10 to 14 days after injection. Touch-up injection was performed in 8% of subjects mainly for the eyebrow asymmetry. AE (22/845, 2.6%) were bruise (15/845, 1.8%), blepharoptosis (3/845, 0.3%), remained eyebrow asymmetry after touch-up injection (2/845, 0.2%), and headache (2/845, 0.2%). They were significantly more in subjects with touch-up injection, younger than 40 years, and in the first and second year of experience (especially for the bruise). Eighteen-point ABO-BTA upper face rejuvenation had a low rate of AE in this series in which majority was bruise at the lateral canthal area. They were significantly more in the first years of experience, subjects younger than 40, and who had touch-up injections.

Brain injury in premature neonates: A primary cerebral dysmaturation disorder?

With advances in neonatal care, preterm neonates are surviving with an evolving constellation of motor and cognitive disabilities that appear to be related to widespread cellular maturational disturbances that target cerebral gray and white matter. Whereas preterm infants were previously at high risk for destructive brain lesions that resulted in cystic white matter injury and secondary cortical and subcortical gray matter degeneration, contemporary cohorts of preterm survivors commonly display less severe injury that does not appear to involve pronounced glial or neuronal loss. Nevertheless, these milder forms of injury are also associated with reduced cerebral growth. Recent human and experimental studies support that impaired cerebral growth is related to disparate responses in gray and white matter. Myelination disturbances in cerebral white matter are related to aberrant regeneration and repair responses to acute death of premyelinating late oligodendrocyte progenitors (preOLs). In response to preOL death, early oligodendrocyte progenitors rapidly proliferate and differentiate, but the regenerated preOLs fail to normally mature to myelinating cells required for white matter growth. Although immature neurons appear to be more resistant to cell death from hypoxia-ischemia than glia, they display widespread disturbances in maturation of their dendritic arbors, which further contribute to impaired cerebral growth. These complex and disparate responses of neurons and preOLs thus result in large numbers of cells that fail to fully mature during a critical window in development of neural circuitry. These recently recognized forms of cerebral gray and white matter dysmaturation raise new diagnostic challenges and suggest new therapeutic directions centered on reversal of the processes that promote dysmaturation.

Redirection of Neurite Outgrowth by Coupling Chondroitin Sulfate Proteoglycans to Polymer Membranes

Upon nerve injury, the body creates an environment consisting of permissive and non-permissive cues that instruct the function of cells involved in nerve repair. Among other roles, the developing extracellular matrix (ECM) acts as an underlying substrate to guide the union of neurites extending from the proximal stump for bridging the nerve gap. Chondroitin sulfate proteoglycans (CSPGs) are present in the nerve ECM and inhibit axon growth, potentially providing molecular cues to prevent aberrant growth and direct regeneration. In this study, we examined the potential of CSPGs to guide dorsal root ganglia (DRG) neurite outgrowth when freely available in the media or presented from a polymeric membrane. Soluble CSPGs added to the media of DRG explant cultures inhibited neurite outgrowth without spatial bias, caused retraction of axons, and decreased neurite extension in a dose-dependent manner. Poly-L-lactic acid membranes were chemically treated to enhance adsorption of CSPGs to the surface. CSPGs bound to 1,6-hexanediamine-treated membranes directed the orientation of neurite outgrowth, as neurites avoided bound CSPGs and a higher number and percentage grew on treated membranes lacking CSPGs. DRG explants cultured on CSPG-coated membranes without 1,6-hexanediamine-treatment had a smaller number of neurites and decreased neurite outgrowth, suggesting CSPGs were not retained on the membrane and were released into the culture medium. Taken together, these data demonstrate the potential of CSPG presentation to guide axonal growth. This approach offers a strategy to improve upon existing nerve guidance conduits by incorporating axon guidance molecules to direct nerve regeneration.