The central face high-energy avulsive injury has been frequently encountered and predictably managed at the R Adams Cowley Shock Trauma Center. However, despite significant surgical advances and ...multiple surgical procedures, the ultimate outcome continues to reveal an inanimate, insensate, and suboptimal aesthetic result.
To effectively address this challenging deformity, a comprehensive multidisciplinary approach was devised. The strategy involved the foundation of a basic science laboratory, the cultivation of a supportive institutional clinical environment, the innovative application of technologies, cadaveric simulations, a real-time clinical rehearsal, and an informed and willing recipient who had the characteristic deformity.
After institutional review board and organ procurement organization approval, a total face, double jaw, and tongue transplantation was performed on a 37-year-old man with a central face high-energy avulsive ballistic injury.
This facial transplant represents the most comprehensive transplant performed to date. Through a systematic approach and clinical adherence to fundamental principles of aesthetic surgery, craniofacial surgery, and microsurgery and the innovative application of technologies, restoration of human appearance and function for individuals with a devastating composite disfigurement is now a reality.
Therapeutic, V.
With the transplantation of more extensive facial vascularized composite allografts, fundamental craniofacial and aesthetic principles become increasingly important. In addition, computer-assisted ...planning and intraoperative navigation may improve precision and efficiency in these complex procedures.
Ten mock face transplants were performed in 20 cadavers. The vascularized composite allograft consisted of all facial skin, mimetic muscles, the tongue, the midface by means of a Le Fort III osteotomy, and the mandible by means of sagittal split osteotomies. Craniofacial computed tomographic scans were obtained before and after the mock transplants. Surgical planning software was used to virtually plan the osteotomies, and a surgical navigation system guided the osteotomies intraoperatively. Cephalometric analyses were compared between the virtually planned transplants and the actual postoperative results.
The combination of preoperative computerized planning and intraoperative guidance consistently produced a vascularized composite allograft that could be easily fixated to the prepared recipient, with only minimal burring of osteotomy sites necessary. Satisfactory occlusion was maintained, and postoperative computed tomography confirmed accurate skeletal fixation. Insignificant differences with regard to cephalometric analyses were noted when predicted and actual postoperative data were compared.
The authors' experience treating severe craniofacial injury allowed consistent transfer of facial vascularized composite allografts, maintaining proper occlusion. Preoperative computer planning and intraoperative navigation ensured precise osteotomies and a good donor-recipient skeletal match, which greatly reduced the need for intraoperative adjustments and manipulation. This total facial vascularized composite allograft represents one of the most extensive described and is intended to represent a typical central facial demolition pattern.
Transplantation of a facial vascularized composite allograft is a highly complex procedure that requires meticulous planning and affords little room for error. Although cadaveric dissections are an ...essential preparatory exercise, they cannot simulate the true clinical experience of facial vascularized composite allograft recovery.
After obtaining institutional review board approval to perform a facial vascularized composite allograft research procurement, a 66-year-old, brain-dead donor was identified. The family graciously consented to donation of a total face, double jaw, and tongue allograft and multiple solid organs.
A craniofacial computed tomographic angiogram was obtained preoperatively to define the vascular anatomy and facilitate virtual computerized surgical planning. The allograft was procured in 10 hours, with an additional 2 hours required for an open tracheostomy and silicone facial impression. The donor was coagulopathic throughout the recovery, resulting in an estimated blood loss of 1500 ml. Fluorescence angiography confirmed adequate perfusion of the entire allograft based on lingual and facial arterial and external jugular and thyrolinguofacial venous pedicles. The solid organ transplant team initiated abdominal organ isolation while the facial allograft procurement was in progress. After completion of allograft recovery, the kidneys and liver were recovered without complication.
Before conducting a clinical face transplant, adequate preparation is critical to maximize vascularized composite allotransplantation outcomes and preserve solid organ allograft function. As more centers begin to perform facial transplantation, research procurement of a facial vascularized composite allograft offers a unique educational opportunity for the surgical and anesthesia teams, the organ procurement organization, and the institution.
Use of the ulnar forearm flap (UFF) is limited by concerns for ulnar nerve injury and impaired perfusion in the donor extremity. Twenty UFFs were performed over a 6-year period. All patients ...underwent postoperative bilateral upper extremity arterial duplex studies. A subset of postoperative patients (n = 10) also had bilateral upper extremity sensory and motor evaluations, and functional evaluation via the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH). Motor function was tested by digital and key grip dynamometry. Ulnar nerve sensation was tested by evaluation of one- and two-point perceived pressure thresholds and two-point discrimination using the Pressure-Specified Sensory Device (Sensory Management Services, LLC, Baltimore, MD). All UFFs were viable postoperatively. Mean follow-up was 28.8 months for vascular studies and 45.3 months for motor, sensory, and QuickDASH evaluations. Although mid and distal radial artery flow velocities were significantly higher in donor versus control extremities evaluated at less than 1 year postoperatively, there was no significant difference in extremities evaluated at later time points. Digital pressures, grip strength, key pinch strength, and ulnar sensation were equivalent between donor and control extremities. The mean QuickDASH score was 17.4 ± 23.8. The UFF can be harvested reliably and long-term follow-up shows no evidence of impaired vascular, motor, or sensory function in the donor extremity.
Gene duplication is an important source of phenotypic change and adaptive evolution. We leverage a haploid hydatidiform mole to identify highly identical sequences missing from the reference genome, ...confirming that the cortical development gene Slit-Robo Rho GTPase-activating protein 2 (SRGAP2) duplicated three times exclusively in humans. We show that the promoter and first nine exons of SRGAP2 duplicated from 1q32.1 (SRGAP2A) to 1q21.1 (SRGAP2B) ∼3.4 million years ago (mya). Two larger duplications later copied SRGAP2B to chromosome 1p12 (SRGAP2C) and to proximal 1q21.1 (SRGAP2D) ∼2.4 and ∼1 mya, respectively. Sequence and expression analyses show that SRGAP2C is the most likely duplicate to encode a functional protein and is among the most fixed human-specific duplicate genes. Our data suggest a mechanism where incomplete duplication created a novel gene function—antagonizing parental SRGAP2 function—immediately “at birth” 2–3 mya, which is a time corresponding to the transition from Australopithecus to Homo and the beginning of neocortex expansion.
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► Missing SRGAP2 human-specific genes sequenced by using haploid hydatidiform mole DNA ► SRGAP2 duplicated three times in the human lineage ∼1.0–3.4 million years ago ► One duplicate is expressed in the brain and is fixed in copy number in all humans ► The incomplete initial duplication likely antagonized the parent gene at birth
A series of incomplete duplications of an ancestral neuronal gene that took place only in the human lineage generated truncated genes, likely to encode new functions immediately upon “birth.” The appearance of these human-specific genes coincides with the emergence of an expanded neocortex.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or ...related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.
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▸ Mechanisms of epigenetic and transcriptional regulation implicated in autism ▸ Balanced chromosomal abnormality breakpoints harbor individual strong-effect genes ▸ Dosage-sensitive loci confer risk to autism from a spectrum of mutational mechanisms ▸ Different alterations in a gene are associated with diverse clinical outcomes
Sequencing of balanced chromosomal abnormalities, combined with convergent genomic studies of gene expression, copy-number variation, and genome-wide association, identifies 22 new loci that contribute to autism and related neurodevelopmental disorders. These data support a polygenic risk model for autism and provide new insight into how different types of mutations of the same genes can lead to variable disease phenotypes that manifest at different stages of life.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal ...insufficiency showed improved survival without BPD at 36 weeks' postmenstrual age, particularly in infants exposed to histologic chorioamnionitis.
Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks' postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation > or =90%).
Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect.
Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.
Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen, but the ...full range of potential noncancer health effects from exposure to PCBs has not been systematically summarized and evaluated. We used systematic review methods to identify and screen the literature using combined manual review and machine learning approaches. A protocol was developed that describes the literature search strategy and Populations, Exposures, Comparators, and Outcomes (PECO) criteria used to facilitate subsequent screening and categorization of literature into a systematic evidence map of PCB exposure and noncancer health endpoints across 15 organs/systems. A comprehensive literature search yielded 62,599 records. After electronic prioritization steps, 17,037 studies were manually screened at the title and abstract level. An additional 900 studies identified by experts or supplemental searches were also included. After full-text screening of 3889 references, 1586 studies met the PECO criteria. Relevant study details such as the endpoints assessed, exposure duration, and species were extracted into literature summary tables. This review compiles and organizes the human and mammalian studies from these tables into an evidence map for noncancer health endpoints and PCB mixture exposure to identify areas of robust research as well as areas of uncertainty that would benefit from future investigation. Summary data are available online as interactive visuals with downloadable metadata. Sufficient research is available to inform PCB hazard assessments for most organs/systems, but the amount of data to inform associations with specific endpoints differs. Furthermore, despite many years of research, sparse data exist for inhalation and dermal exposures, which are highly relevant human exposure routes. This evidence map provides a foundation for future systematic reviews and noncancer hazard assessments of PCB mixtures and for strategic planning of research to inform areas of greater uncertainty.
•A wide variety of endpoints have been assessed with PCB exposure.•For each organ/system examined, at least 45 studies were identified.•Reproductive, hepatobiliary, and nervous system effects were the most studied.•Sparse data exist for PCB inhalation and dermal exposures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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