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New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 and C-28. This resulted in the targeted molecules being produced in good yields. Some of the synthesized conjugates showed significantly relevant bioactivity against mammalian cells and in animal models of cancers. Selected UA conjugates were tested against bladder and breast cancer cell lines. The conjugates showed moderate to significantly enhanced antiproliferative activities against Triple Negative Breast Cancer (TNBC; MDA-MB 231), which is an aggressive tumor making up about 10-15 % of all breast cancers and bladder (T24 and 5637) cancer cell lines. These properties were superior to the parent UA. Among all the synthesized compounds, 18 c and 18 d have exhibited promising antiproliferative and cytotoxic properties against all tested cancer cell lines. However, 18 d has proved to be exceptionally selective for cancer cell lines, showing more cytotoxicity towards them than normal epithelial cells (MCF-12A). Compound 18 d has demonstrated cytotoxicity against tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy., (© 2024 Wiley-VCH GmbH.)

Merkel cell polyomavirus (MCPyV) is a double-stranded tumor virus that is the main causative agent of Merkel cell carcinoma (MCC). The MCPyV large T antigen (LT), an essential viral DNA replication protein, maintains viral persistence by interacting with host Skp1-Cullin 1-F-box (SCF) E3 ubiquitin ligase complexes, which subsequently induces LT's proteasomal degradation, restricting MCPyV DNA replication. SCF E3 ubiquitin ligases require their substrates to be phosphorylated to bind them, utilizing phosphorylated serine residues as docking sites. The MCPyV LT unique region (MUR) is highly phosphorylated and plays a role in multiple host protein interactions, including SCF E3 ubiquitin ligases. Therefore, this domain highly governs LT stability. Though much work has been conducted to identify host factors that restrict MCPyV LT protein expression, the kinase(s) that cooperates with the SCF E3 ligase remains unknown. Here, we demonstrate that casein kinase 1 alpha (CK1α) negatively regulates MCPyV LT stability and LT-mediated replication by modulating interactions with the SCF β-TrCP. Specifically, we show that numerous CK1 isoforms (α, δ, ε) localize in close proximity to MCPyV LT through in situ proximity ligation assays (PLA) and CK1α overexpression mainly resulted in decreased MCPyV LT protein expression. Inhibition of CK1α using short hairpin RNA (shRNA) and treatment of a CK1α inhibitor or an mTOR inhibitor, TORKinib, resulted in decreased β-TrCP interaction with LT, increased LT expression, and enhanced MCPyV replication. The expression level of the CSNK1A1 gene transcripts is higher in MCPyV-positive MCC, suggesting a vital role of CK1α in limiting MCPyV replication required for establishing persistent infection., Importance: Merkel cell polyomavirus (MCPyV) large tumor antigen is a polyphosphoprotein and the phosphorylation event is required to modulate various functions of LT, including viral replication. Therefore, cellular kinase pathways are indispensable for governing MCPyV polyomavirus infection and life cycle in coordinating with the immunosuppression environment at disease onset. Understanding the regulation mechanisms of MCPyV replication by viral and cellular factors will guide proper prevention strategies with targeted inhibitors for MCPyV-associated Merkel cell carcinoma (MCC) patients, who currently lack therapies., Competing Interests: The authors declare no conflict of interest.

Alkaloids found in multiple species, known as 'driver species', are more likely to be included in early-stage drug development due to their high biodiversity compared to rare alkaloids. Many synthetic approaches have been employed to hybridize the natural alkaloids in drug development. Click chemistry is a highly efficient and versatile reaction targeting specific areas, making it a valuable tool for creating complex natural products and diverse molecular structures. It has been used to create hybrid alkaloids that address their limitations and serve as potential drugs that mimic natural products. In this review, we highlight the recent advancements made in modifying alkaloids using click chemistry and their potential medicinal applications. We discuss the significance, current trends, and prospects of click chemistry in natural product-based medicine. Furthermore, we have employed computational methods to evaluate the ADMET properties and drug-like qualities of hybrid molecules.

Senescent cells accumulate in the host during the aging process and are associated with age-related pathogeneses, including cancer. Although persistent senescence seems to contribute to many aspects of cellular pathways and homeostasis, the role of senescence in virus-induced human cancer is not well understood. Merkel cell carcinoma (MCC) is an aggressive skin cancer induced by a life-long human infection of Merkel cell polyomavirus (MCPyV). Here, we show that MCPyV large T (LT) antigen expression in human skin fibroblasts causes a novel nucleolar stress response, followed by p21-dependent senescence and senescence-associated secretory phenotypes (SASPs), which are required for MCPyV genome maintenance. Senolytic and navitoclax treatments result in decreased senescence and MCPyV genome levels, suggesting a potential therapeutic for MCC prevention. Our results uncover the mechanism of a host stress response regulating human polyomavirus genome maintenance in viral persistency, which may lead to targeted intervention for MCC.

Merkel cell carcinoma (MCC) is a rare but aggressive form of skin cancer predominantly caused by the human Merkel cell polyomavirus (MCPyV). Treatment for MCC includes excision and radiotherapy of local disease, and chemotherapy or immunotherapy for metastatic disease. The schweinfurthin family of natural compounds previously displayed potent and selective growth inhibitory activity against the NCI-60 panel of human-derived cancer cell lines. Here, we investigated the impact of schweinfurthin on human MCC cell lines. Treatment with the schweinfurthin analog, 5'-methylschweinfurth G (MeSG also known as TTI-3114), impaired metabolic activity through induction of an apoptotic pathway. MeSG also selectively inhibited PI3K/AKT and MAPK/ERK pathways in the MCPyV-positive MCC cell line, MS-1. Interestingly, expression of the MCPyV small T (sT) oncogene selectively sensitizes mouse embryonic fibroblasts to MeSG. These results suggest that the schweinfurthin family of compounds display promising potential as a novel therapeutic option for virus-induced MCCs.

Viral infections are among the most complex medical problems and have been a major threat to the economy and global health. Several epidemics and pandemics have occurred due to viruses, which has led to a significant increase in mortality and morbidity rates. Natural products have always been an inspiration and source for new drug development because of their various uses. Among all-natural sources, plant sources are the most dominant for the discovery of new therapeutic agents due to their chemical and structural diversity. Despite the traditional use and potential source for drug development, natural products have gained little attention from large pharmaceutical industries. Several plant extracts and isolated compounds have been extensively studied and explored for antiviral properties against different strains of viruses. In this review, we have compiled antiviral plant extracts and natural products isolated from plants reported since 2015.

Merkel cell polyomavirus (MCPyV) large tumor (LT) antigen is a DNA binding protein essential for viral gene transcription and genome replication. MCPyV LT interacts with multiple E3 ligases in a phosphorylation-dependent manner, limiting its own viral replication by enhancing LT protein degradation, which is a unique mechanism for MCPyV latency. Thus, identifying LT ubiquitination sites is an important step toward understanding the biological role of these virus-host interactions that can potentially result in viral oncogenesis. The ubiquitin (Ub) attachment sites in LT were predicted by using Rapid UBIquitination (RUBI), a sequence-based ubiquitination web server. Using an immunoprecipitation approach, the lysine (Lys, K) 585 residue in LT is identified as the ubiquitin conjugation site. Lysine 585 is deleted from tumor-derived truncated LTs (tLTs), resulting in stable expression of tLTs present in cancers. Substitution of lysine 585 to arginine (Arg, R) increased LT protein stability, but impaired MCPyV origin replication, due to a loss of ATP hydrolysis activity. These findings uncover a never-before-identified ubiquitination site of LT and its importance not only in the regulation of protein turnover, but also in MCPyV genome replication.

Purpose: Deep phenotyping is an emerging trend in precision medicine for genetic disease. The shape of the face is affected in 30-40% of known genetic syndromes. Here, we determine whether syndromes can be diagnosed from 3D images of human faces., Methods: We analyzed variation in three-dimensional (3D) facial images of 7057 subjects: 3327 with 396 different syndromes, 727 of their relatives, and 3003 unrelated, unaffected subjects. We developed and tested machine learning and parametric approaches to automated syndrome diagnosis using 3D facial images., Results: Unrelated, unaffected subjects were correctly classified with 96% accuracy. Considering both syndromic and unrelated, unaffected subjects together, balanced accuracy was 73% and mean sensitivity 49%. Excluding unrelated, unaffected subjects substantially improved both balanced accuracy (78.1%) and sensitivity (56.9%) of syndrome diagnosis. The best predictors of classification accuracy were phenotypic severity and facial distinctiveness of syndromes. Surprisingly, unaffected relatives of syndromic subjects were frequently classified as syndromic, often to the syndrome of their affected relative., Conclusion: Deep phenotyping by quantitative 3D facial imaging has considerable potential to facilitate syndrome diagnosis. Furthermore, 3D facial imaging of "unaffected" relatives may identify unrecognized cases or may reveal novel examples of semidominant inheritance.

Sensing invading pathogens early in infection is critical for establishing host defense. Two cytosolic RIG-like RNA helicases, RIG-I and MDA5, are key to type I interferon (IFN) induction in response to viral infection. Mounting evidence suggests that another viral RNA sensor, protein kinase R (PKR), may also be critical for IFN induction during infection, although its exact contribution and mechanism of action are not completely understood. Using PKR-deficient cells, we found that PKR was required for type I IFN induction in response to infection by vaccinia virus lacking the PKR antagonist E3L (VVΔE3L), but not by Sendai virus or influenza A virus lacking the IFN-antagonist NS1 (FluΔNS1). IFN induction required the catalytic activity of PKR, but not the phosphorylation of its principal substrate, eIF2α, or the resulting inhibition of host translation. In the absence of PKR, IRF3 nuclear translocation was impaired in response to MDA5 activators, VVΔE3L and encephalomyocarditis virus, but not during infection with a RIG-I-activating virus. Interestingly, PKR interacted with both RIG-I and MDA5; however, PKR was only required for MDA5-mediated, but not RIG-I-mediated, IFN production. Using an artificially activated form of PKR, we showed that PKR activity alone was sufficient for IFN induction. This effect required MAVS and correlated with IRF3 activation, but no longer required MDA5. Nonetheless, PKR activation during viral infection was enhanced by MDA5, as virus-stimulated catalytic activity was impaired in MDA5-null cells. Taken together, our data describe a critical and non-redundant role for PKR following MDA5, but not RIG-I, activation to mediate MAVS-dependent induction of type I IFN through a kinase-dependent mechanism.

The life cycle of several viruses involves host or virally encoded small noncoding RNAs, which play important roles in posttranscriptional regulation. Small noncoding RNAs include microRNAs (miRNAs), which modulate the transcriptome, and small interfering RNAs (siRNAs), which are involved in pathogen defense in plants, worms, and insects. We show that insect and mammalian poxviruses induce the degradation of host miRNAs. The virally encoded poly(A) polymerase, which polyadenylates viral transcripts, also mediates 3' polyadenylation of host miRNAs, resulting in their degradation by the host machinery. In contrast, siRNAs, which are protected by 2'O-methylation (2'OMe), were not targeted by poxviruses. These findings suggest that poxviruses may degrade host miRNAs to promote replication and that virus-mediated small RNA degradation likely contributed to 2'OMe evolution., (Copyright © 2012 Elsevier Inc. All rights reserved.)

microRNAs (miRNAs) represent a class of noncoding RNAs that fine-tune gene expression through post-transcriptional silencing. While miRNA biogenesis occurs in a stepwise fashion, initiated by the nuclear microprocessor, rare noncanonical miRNAs have also been identified. Here we characterize the molecular components and unique attributes associated with the processing of virus-derived cytoplasmic primary miRNAs (c-pri-miRNAs). RNA in situ hybridization and inhibition of cellular division demonstrated a complete lack of nuclear involvement in c-pri-miRNA cleavage while genetic studies revealed that maturation still relied on the canonical nuclear RNase III enzyme, Drosha. The involvement of Drosha was mediated by a dramatic relocalization to the cytoplasm following virus infection. Deep sequencing analyses revealed that the cytoplasmic localization of Drosha does not impact the endogenous miRNA landscape during infection, despite allowing for robust synthesis of virus-derived miRNAs in the cytoplasm. Taken together, this research describes a unique function for Drosha in the processing of highly structured cytoplasmic RNAs in the context of virus infection.

The discovery of microRNAs (miRNAs) revealed an unappreciated level of post-transcriptional control used by the cell to maintain optimal protein levels. This process has represented an attractive strategy for therapeutics that is currently limited by in vivo delivery constraints. Here, we describe the generation of a single-stranded, cytoplasmic virus of negative polarity capable of producing functional miRNAs. Cytoplasmic RNA virus-derived miRNAs accumulated to high levels in vitro, generated significant amounts of miRNA star strand, associated with the RNA-induced silencing complex (RISC), and conferred post transcriptional gene silencing in a sequence-specific manner. Furthermore, we demonstrate that these vectors could deliver miRNAs to a wide range of tissues, and sustain prolonged expression capable of achieving measurable knockdown of physiological targets in vivo. Taken together, these results validate noncanonical processing of cytoplasmic-derived miRNAs and provide a novel platform for small RNA delivery.

Dengue virus (DENV) is a mosquito-borne pathogen for which no vaccine or specific therapeutic is available. Although it is well established that dendritic cells and macrophages are primary sites of DENV replication, it remains unclear whether non-hematopoietic cellular compartments serve as virus reservoirs. Here, we exploited hematopoietic-specific microRNA-142 (miR-142) to control virus tropism by inserting tandem target sites into the virus to restrict replication exclusively in this cell population. In vivo use of this virus restricted infection of CD11b+, CD11c+, and CD45+ cells, resulting in a loss of virus spread, regardless of the route of administration. Furthermore, sequencing of the targeted virus population that persisted at low levels, demonstrated total excision of the inserted miR-142 target sites. The complete conversion of the virus population under these selective conditions suggests that these immune cells are the predominant sources of virus amplification. Taken together, this work highlights the importance of hematopoietic cells for DENV replication and showcases an invaluable tool for the study of virus pathogenesis.

Objective: To investigate the efficacy of 1550-nm (Fraxel SR1500 RE:Store; Solta Medical, Hayward, California) nonablative laser treatment of facial surgical scars., Methods: In this prospective clinical study, a volunteer sample of 13 adults with Fitzpatrick skin types I to III and facial surgical scars with a postoperative duration longer than 6 months were enrolled. Subjects were treated once every 4 weeks for a total of 4 treatments. Initial settings for the 1550-nm nonablative laser were at energy level 40 mJ and treatment level 4 and were subsequently increased on each visit according to the patients' tolerance level. Using a previously validated Patient and Observer Scar Assessment Scale (POSAS), the study subject and an independent evaluator completed assessments of the scar at each visit., Results: According to the Friedman test on ratings across all occasions after the first treatment to the last evaluation, there was a statistically significant improvement in the patient's assessment of the color, stiffness, thickness, and irregularity of the scar but not for pain or itching. For the observer's ratings, there was a statistically significant improvement in pigmentation, thickness, relief, and pliability but not for vascularization., Conclusions: Preliminary data suggest improved aesthetic results, demonstrating the potential use of fractional photothermolysis as a scar revision technique. Future studies with a longer follow-up period could elucidate the role of fractional photothermolysis in more permanent scar improvements.

Cellular utilization of RNA interference (RNAi) as a mechanism to combat virus infection is thought to be restricted to plants and invertebrates. In vertebrates, antiviral defenses are largely dependent on interferons (IFNs), with the use of small RNAs restricted to microRNA (miRNA)-mediated targeting of host transcripts. Here we demonstrate that incorporation of a primary miRNA into a cytoplasmic virus results in the formation of a Dicer-dependent, DGCR8-independent, mature miRNA capable of conferring RNAi-like activity. Processing of the viral mirtron-like product (virtron) is indistinguishable from endogenous miRNA maturation and elicits post-transcriptional gene silencing, albeit at a reduced level. Furthermore, virtrons impose Dicer-dependent, microprocessor-independent, and IFN-independent interference on virus replication in a sequence-specific manner. Taken together, these results suggest the existence of a noncanonical, small-RNA-based activity capable of processing cytoplasmic hairpins and perhaps contributing to the cell's antiviral arsenal.

Facial analysis is an integral part of the surgical planning process. Clinical photography has long been an invaluable tool in the surgeon's practice not only for accurate facial analysis but also for enhancing communication between the patient and surgeon, for evaluating postoperative results, for medicolegal documentation, and for educational and teaching opportunities. From 35-mm slide film to the digital technology of today, clinical photography has benefited greatly from technological advances. With the development of computer imaging software, objective facial analysis becomes easier to perform and less time consuming. Thus, while the original purpose of facial analysis remains the same, the process becomes much more efficient and allows for some objectivity. Although clinical judgment and artistry of technique is never compromised, the ability to perform objective facial photograph analysis using imaging software may become the standard in facial plastic surgery practices in the future., (Copyright 2010 Elsevier Inc. All rights reserved.)

The dendritic cell (DC) is a master regulator of immune responses. Pathogenic viruses subvert normal immune function in DCs through the expression of immune antagonists. Understanding how these antagonists interact with the host immune system requires knowledge of the underlying genetic regulatory network that operates during an uninhibited antiviral response. To isolate and identify this network, we studied DCs infected with Newcastle disease virus, which is able to stimulate innate immunity and DC maturation through activation of RIG-I signaling, but lacks the ability to evade the human IFN response. To analyze this experimental model, we developed a new approach integrating genome-wide expression kinetics and time-dependent promoter analysis. We found that the genetic program underlying the antiviral cell-state transition during the first 18 h postinfection could be explained by a single convergent regulatory network. Gene expression changes were driven by a stepwise multifactor cascading control mechanism, where the specific transcription factors controlling expression changed over time. Within this network, most individual genes were regulated by multiple factors, indicating robustness against virus-encoded immune evasion genes. In addition to effectively recapitulating current biological knowledge, we predicted, and validated experimentally, antiviral roles for several novel transcription factors. More generally, our results show how a genetic program can be temporally controlled through a single regulatory network to achieve the large-scale genetic reprogramming characteristic of cell-state transitions.

The ability of a cell to combat an intracellular pathogen requires a mechanism to recognize the threat and elicit a transcriptional response against it. In the context of virus infection, the cell must take measures to inhibit viral replication, meanwhile, convey warning signals to neighboring cells of the imminent threat. This immune response is predominantly mediated by the production of cytokines, notably, interferon beta (IFNβ). IFNβ signaling results in the transcriptional induction of over one hundred antiviral gene products whose timely expression renders infected cells more capable of inhibiting virus replication, while providing the uninfected cells with the reinforcements to generate a less permissive cellular environment. Induction of IFNβ and many aspects of the antiviral response pivot on the function of the IKK and IKK-related kinases. Despite sharing high levels of homology and some degree of functional redundancy, the classic IKK kinases: IKKα and IKKβ, and the IKK-related kinases: TBK1 and IKKɛ, perform distinct roles in regulating the host antiviral defense. These kinases serve as molecular operators in their cooperative ability to integrate incoming cellular cues and act on a range of essential antiviral transcription factors to reshape the cellular transcriptome during infection.

Influenza A virus leads to yearly epidemics and sporadic pandemics. Present prophylactic strategies focus on egg-grown, live, attenuated influenza vaccines (LAIVs), in which attenuation is generated by conferring temperature sensitivity onto the virus. Here we describe an alternative approach to attenuating influenza A virus based on microRNA-mediated gene silencing. By incorporating nonavian microRNA response elements (MREs) into the open-reading frame of the viral nucleoprotein, we generate reassortant LAIVs for H1N1 and H5N1 that are attenuated in mice but not in eggs. MRE-based LAIVs show a greater than two-log reduction in mortality compared with control viruses lacking MREs and elicit a diverse antibody response. This approach might be combined with existing LAIVs to increase attenuation and improve vaccine safety.

Objective: To examine the potential efficacy of Crosseal (the human protein, bovine component-free fibrin sealant) (OMRIX Biopharmaceuticals, Ltd, Brussels, Belgium) to reduce ecchymoses and hematoma formation in patients undergoing rhytidectomy., Methods: Before initiation of the study, approval was obtained from the US Food and Drug Administration for an Investigational New Drug Application and off-label use of Crosseal and from the Institutional Review Board of the University of California, Davis. Patients undergoing rhytidectomy with or without concomitant procedures were voluntarily enrolled without compensation in the study (N = 9). Patients were randomized according to which side of the rhytidectomy the tissue sealant was placed. In all patients in the study, 1 side of the rhytidectomy was treated with Crosseal; the other, untreated side was used as a control. Before closure of the skin, 2 mL of Crosseal was sprayed through a pressure regulator under the skin flap of the dissected area of the rhytidectomy only on 1 side. The skin was pretrimmed before placement and closed in standard fashion. A pressure dressing was left in place for 3 days before removal. Nine patients were originally enrolled in the study. On postoperative days 3 and 7, photographs were taken of the patients. The photographs were judged by 5 independent reviewers who were blinded as to which side had been treated with Crosseal. The judges rated the degree of ecchymoses on a scale of 1 (minimal) to 10 (severe) and were asked their opinion as to which side of the facelift had been treated with Crosseal. These results were compared using statistical analysis. Also on days 3 and 7, patients were examined for seroma or hematoma formation on each side of the face., Results: Our study demonstrated efficacy of Crosseal in reducing ecchymoses and swelling in all patients. The mean score for ecchymosis on the Crosseal-treated side was 4.5 and on the untreated (control) side was 6.2 (P < .01, Wilcoxon rank sum test). The rate of hematoma or seroma formation was 22% (2 of 9 patients) for the untreated side vs 0% (0 of 9 patients) for the treated side. This did not reach statistical significance (P = .43, Fisher exact test). Small hematomas developed in 2 patients on the control side, which were needle aspirated. There were no known long-term complications from either the use of Crosseal or the rhytidectomy., Conclusion: Crosseal is efficacious in reducing ecchymoses after rhytidectomy.

Objectives: Giant fibrovascular polyps of the esophagus are rare benign tumors originating from the proximal esophagus. These pedunculated lesions can grow to "giant" proportions. Asphyxiation from aspiration of the regurgitated polyp is a well-described cause of death. Traditional excision has involved a transcervical vertical esophagotomy. This report describes the successful endoscopic removal of a giant fibrovascular polyp of the esophagus., Results: A 63-year-old man with dwarfism and obstructive sleep apnea was referred for evaluation of an esophageal mass that was intermittently regurgitated into the hypopharynx. Office esophagoscopy demonstrated a 10-cm giant fibrovascular polyp originating just below the cricoid cartilage. During endoscopic removal, the base of the lesion was exposed with a Weerda bivalved laryngoscope. Bipolar cautery combined with a snare was used to transect the base with excellent hemostasis. No esophageal leak was noted on an esophagogram on postoperative day 3. The patient then resumed a liquid diet and was discharged home, resuming a regular diet within a week., Conclusions: Giant fibrovascular polyps of the esophagus are life-threatening because of potential airway obstruction. This report describes the successful endoscopic removal of a giant fibrovascular polyp, avoiding the potential morbidity associated with a transcervical vertical esophagotomy.

In the African country of Zimbabwe, a variety of socioeconomic factors have contributed to a lack of specialty care and resources for the indigent population. Although cleft lip and palate has a lower incidence in Africa (0.67 per 1000 births) than in Latin America or Asia, access to reconstructive surgery is often difficult to obtain. A surgical team worked with Zimbabweans at the Harare Central Hospital, Harare, to perform cleft surgery for 39 patients. We review the epidemiology of cleft deformities in Africa, our experience with 39 patients with cleft lip and palate, and the techniques used to address 2 patients with midfacial clefts. To our knowledge, this retrospective case review and epidemiologic literature review is the first review of cleft care in Zimbabwe. Poverty in Zimbabwe, caused in part by the highest inflation rate in the world, has contributed to the emigration of a large number of specialists to other countries. In addition, the health care system is overwhelmed by a high prevalence rate of human immunodeficiency virus (25%), leading to a drastically reduced parental life expectancy (mean life expectancy, 36 years). Primary and secondary cleft lip and palate repairs were completed without complications. Children requiring care beyond the scope of this mission were referred to the Republic of South Africa. The cooperation among the Zimbabwean administration, physicians, and nurses was integral to the organization and successful execution of this reconstructive surgical mission. Ultimately, until the socioeconomic conditions improve in Zimbabwe, training and continuing education of local physicians are imperative to advance the care of children with cleft lip and palate.

Purpose: Recent advances in computer-modeling software allow reconstruction of facial symmetry in a virtual environment. This study evaluates the use of preoperative computer modeling and intraoperative navigation to guide reconstruction of the maxillofacial skeleton., Methods: Three patients with traumatic maxillofacial deformities received preoperative, thin-cut axial CT scans. Three-dimensional reconstructions, virtual osteotomies, and bony reductions were performed using MIMICS planning software (Materialise, Ann Arbor, MI). The original and "repaired" virtual datasets were then imported into an intraoperative navigation system and used to guide the surgical repair., Results: Postoperative CT scans and photographs reveal excellent correction of enophthalmos to within 1 mm in patient 1, significant improvement in symmetry of the nasoethmoid complex in patient 2, and reconstruction of the zygomaticomaxillary complex location to within 1 mm in patient 3., Conclusion: Computer modeling and intraoperative navigation is a relatively new tool that can assist surgeons with reconstruction of the maxillofacial skeleton.

Purpose: Surgeons have recently started to use computer-aided surgery (CAS) to assist with maxillofacial reconstructive surgery. This study evaluates four different CAS registration strategies in the maxillofacial skeleton., Materials and Methods: Fifteen fiducial markers were placed on each of four cadaveric heads. Four registration protocols were used: 1) group 1-invasive markers, 2) group 2-skin surface, 3) group 3-bony landmark, 4) group 4-intraoral splint. Two observers registered each head twice with each of the four protocols and measured the target registration error (TRE). The process was repeated on two different navigation systems for confirmation., Results: The mean TRE values were: invasive, 1.13 +/- 0.05 mm (P < 0.05); skin, 2.03 +/- 0.07 mm (P < 0.05); bone, 3.17 +/- 0.10 mm (P < 0.05); and splint, 3.79 +/- 0.13 mm (P < 0.05). The TRE values were consistent across CAS systems., Conclusion: Of the techniques tested for CAS registration, invasive fiducial markers are the most accurate. Skin surface landmarks, bony landmarks, and an intraoral splint are incrementally less accurate.

Purpose: Injury to the male external genitalia is rare and, therefore, there are little data in the literature regarding the options for nonoperative management and outcome. To assist in defining the indications for nonoperative management the usefulness of the American Association for the Surgery of Trauma (AAST) organ injury scales for these injuries was examined., Materials and Methods: We retrospectively reviewed the medical records of 116 male patients with trauma to the external genitalia in a 10-year period and classified injuries according to the organ injury severity scales (scrotum, testis, penis and urethra) of the AAST. Based on AAST grading management and outcome was reviewed., Results: Mean patient age was 28 years and 79% of the injuries were due to gunshot wounds. A total of 87 patients (75%) underwent surgery, while 27 penile injuries and 8 scrotal/testicular injuries were managed nonoperatively. There were 54 scrotal explorations, 33 testicular injuries and 20 orchiectomies (bilateral in 1) for a testicular salvage rate of 39%. Documented followup by the trauma or genitourinary service was achieved in 47 of 110 survivors. No patient reported impotence or difficulty with fertility., Conclusions: The AAST grading for male external genital trauma readily characterizes patients with high grade injuries that require operative management as well as select patients in whom injury can be safely managed nonoperatively.