So Young Lim

Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome

Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.

Radiofrequency Volumetric Reduction for Masseteric Hypertrophy

Masseteric hypertrophy occurs frequently among Asians, including Koreans, because of racial characteristics and dietary habits. It is thought to be an unpleasant feature, especially because of its strong and masculine impression. Recently, the authors developed a method for the volumetric reduction of hypertrophied masseter muscles using radiofrequency energy to correct the squared facial appearance caused by the hypertrophy. This study was performed to investigate the effects of radiofrequency applied to reduce hypertrophied masseter muscles of patients who sought an aesthetic alternative for a slim, smooth, and feminine-looking lower facial contour. A total of 340 patients were treated. The patients usually recognized the volume change 3 to 6 weeks after treatment, and an objective volume reduction was observed within 3 months of the operation. The range of the reduction in the masseter thickness, as measured by ultrasonic examination at a 6-month postoperative follow-up visit, was 10% to 60% (mean, 27%). Most of the patients could eat a nearly normal diet after 4 weeks and were satisfied with the improved aesthetic contour lines of their lower face. Radiofrequency-induced coagulation tissue necrosis of the masseter did not cause any infections or limitations of mouth opening, and the clinical improvement was well maintained after the treatment.

Radiofrequency Volume Reduction of Gastrocnemius Muscle Hypertrophy for Cosmetic Purposes

Muscularly prominent calves, caused mainly by hypertrophy of the gastrocnemius muscle (GCM), are prevalent among Asian women, and this condition can be a significant factor leading to psychological stress. The authors have devised a method for contouring the calf using radiofrequency (RF) applications to the GCMs to correct thick, muscular legs. This study was performed to investigate the effects of RF energy in reducing enlarged GCMs for 250 patients (249 women and 1 man) who sought aesthetic consultation for problems such as thick, muscular, asymmetric, or bowed calves. The operations were performed from June 2004 to April 2006. The patients first received a local anesthetic and sedation. After application of RF current, the prominent muscular contours improved, and the GCMs were contoured to an appropriate proportional volume. The range of the reductions in the calf circumferences at their thickest levels was 1 to 6 cm (mean, 2.5 cm) during the follow-up visits 6 months after the procedures. Most of the patients could return to their activities of daily living, except for exercise, after 1 to 7 days, and they were satisfied with the improved aesthetic contour lines of their lower legs. Clinical photography and ultrasonic examination were performed, and the leg circumferences were measured. Radiofrequency-induced coagulation tissue necrosis of the muscles caused no functional disabilities, and the clinical improvement was well maintained after the treatments for up to 17 months of follow-up evaluation.

Estimation of eighth costal cartilage in surgical timing of microtia reconstruction.

AbstractThere is controversy over the optimal timing of microtia reconstruction. The eighth costal cartilage, which is used to shape the helix framework, can be one of the key factors determining surgical timing of microtia reconstruction. Nevertheless, it is difficult to predict the length of the eighth costal cartilage preoperatively. The aim of the present study was to suggest clinical predictors of the length of the eighth cartilage by assessing the correlation between the actual length of the eighth cartilage and preoperative measurements of the cartilage length using three-dimensional rib-cage computed tomography (3D rib-cage CT). A retrospective analysis was performed on a total of 97 patients who underwent preoperative 3D rib-cage CT and auricular reconstruction using a rib cartilage graft between January 2010 and February 2013. The length of the eighth costal cartilage on 3D rib-cage CT was measured preoperatively, and the length of the harvested eighth rib cartilage was measured intraoperatively. We analyzed the association between the preoperative and intraoperative measured length of the eighth rib, with patient age, height, weight, and body mass index. Preoperative measurement using 3D rib-cage CT showed a high correlation with actual cartilage length. Height and weight correlated more strongly with length than with age. This study describes the usefulness of 3D rib-cage CT for preoperative measurement of the length of the eighth costal cartilage. The measurement of the eighth rib cartilage on 3D rib-cage CT could be a useful aid for reconstructive surgeons in planning microtia reconstruction.

Long-term outcomes of surgical treatment for dermatofibrosarcoma protuberans according to width of gross resection margin

BACKGROUND Controversy exists regarding appropriate surgical treatment for dermatofibrosarcoma protuberans (DFSP). The purpose of this study was to propose treatment recommendations based on long-term outcomes of surgical treatments for DFSP. METHODS A total of 63 patients who underwent surgical resection for primary DFSP were retrospectively reviewed from 1999 to 2011. They were classified into three groups based on the width of the gross resection margins: group I with marginal excision (14 patients); group II with resection margins < 3 cm (21 patients); and group III with resection margins ≥ 3 cm (28 patients) (group II and group III had wide local excision). RESULTS The median follow-up period was 65 months (range 31-190 months). The marginal excision group showed a significantly higher recurrence rate than the wide excision group (35.7% vs. 0%, p < 0.001). Among wide excision groups, group III showed a significantly higher requirement for reconstructive surgery than group II (82.7% vs. 52.4%, p = 0.011), yet both groups had no recurrence and pathologic margin status was comparable. The accuracy rate of frozen section analyses was 100% for the margin status in the wide excision group. Adjuvant radiation was significantly associated with a reduced recurrence in the marginal excision group (0% vs. 60%, p = 0.016). CONCLUSIONS Wide local excision with margins of 1.5-2 cm along with frozen biopsy is recommended for DFSP. Either re-excision or adjuvant radiation therapy can serve as a treatment option for patients with positive margins.

Evaluating the effectiveness of cryopreserved acellular dermal matrix in immediate expander-based breast reconstruction: a comparison study.

Background CGCryoDerm was first introduced in 2010 and offers a different matrix preservation processes for freezing without drying preparation. From a theoretical perspective, CGCryoDerm has a more preserved dermal structure and more abundant growth factors for angiogenesis and recellularization. In the current study, the authors performed a retrospective study to evaluate freezing- and freeze-drying-processed acellular dermal matrix (ADM) to determine whether any differences were present in an early complication profile. Methods Patients who underwent ADM-assisted tissue expander placement for two stage breast reconstruction between January of 2013 and March of 2014 were retrospectively reviewed and divided into two groups based on the types of ADM-assisted expander reconstruction (CGDerm vs. CGCryoDerm). Complications were divided into four main categories and recorded as follows: seroma, hematoma, infection, and mastectomy skin flap necrosis. Results In a total of 82 consecutive patients, the CGCryoDerm group had lower rates of seroma when compared to the CGDerm group without statistical significance (3.0% vs. 10.2%, P=0.221), respectively. Other complications were similar in both groups. Reconstructions with CGCryoDerm were found to have a significantly longer period of drainage when compared to reconstructions with CGDerm (11.91 days vs. 10.41 days, P=0.043). Conclusions Preliminary findings indicate no significant differences in early complications between implant/expander-based reconstructions using CGCryoderm and those using CGDerm.

Neuroendocrine Differentiation of Primary Mucinous Carcinoma of the Cheek Skin

Primary mucinous carcinoma of the skin (MCS) is a rare sweat gland tumor, with approximately 175 cases reported in the literature since the first case was described by Lennox et al. [1] in 1952. Although MCS is usually slow growing, it often shows locally aggressive behavior and a high rate of local recurrence following simple excision. The clinical appearance and differential diagnosis of MCS vary, but histopathologically MCS is similar to metastatic carcinomas, specifically of the breast and colon. The recognition of MCS is essential for preventing an erroneous diagnosis of metastatic carcinoma. In Korea, to our knowledge, only 1 of 9 cases that have been reported was diagnosed as neuroendocrine differentiation [2]. Kim et al. [2] reported a case of primary mucinous carcinoma with neuroendocrine differentiation, focusing on its clinical and histologic features. In the present study, we report a case of MCS with neuroendocrine differentiation on the cheek that was treated with wide excision and a rotation advancement cheek flap, which showed favorable results. This article is focused on the distinctive pathological findings, the surgical approach, and the postoperative evaluation process of neuroendocrine differentiation of MCS. A 72-year-old man presented with a 3-year history of an asymptomatic 15×20 mm, well-demarcated, erythematous nodule growing on his left cheek (Fig. 1). He had first noticed this lesion 3 years prior and became concerned as it slowly enlarged. An incisional biopsy demonstrated mucinous eccrine carcinoma with positive margins. Under general anesthesia, the tumor was excised with 2 cm margins, according to oncological principles, as a full-thickness specimen. The regional lymph nodes were not involved. The surgical defect measured 5.5×6.0 cm (Fig. 2). Although he was an elderly patient, his skin laxity was limited. Therefore, extensive undermining was performed in the surrounding facial region in the subcutaneous plane and stopped at the lower border of the mandible; there was no undermining in the cervical region. The rotation flap was progressively elevated until there was adequate flap mobilization to cover the defect area and tension-free closure was possible (Fig. 3). The histologic examination revealed aggregates of glandular epithelioid cells floating in mucinous pools that were defined by thin, fibrous septa. The pools of mucin stained positive for Alcian blue at pH 2.5 and periodic acid-Schiff. Immunohistochemical staining demonstrated positive reactions to synaptophysin (Fig. 4), estrogen receptors (ER), progesterone receptors (PR), and cytokeratin 7, and a negative reaction to cytokeratin 20, which met the description of markers positive for neuroendocrine differentiation. A full metastatic workup was performed, including computed tomography (CT) and positron emission tomography (PET) scans, without evidence of another primary type of cancer. Two years after surgery, the patient remains in good health without recurrence, showing good aesthetic results (Fig. 5). Fig. 1 Preoperative view: a 72-year-old man with a mucinous carcinoma of the skin on the left cheek. Fig. 2 Intraoperative view: the outline for tumor resection and the rotation advancement flap design. Fig. 3 Immediate postoperative view. Fig. 4 Immunohistochemical findings of the neuroendocrine marker: synaptophysin ×400; positive staining was observed. Fig. 5 View at postoperative 2 years. Histologically, MCS may appear similar to other sweat gland tumors and metastatic carcinomas. Immunohistochemical staining of MCS cells with Alcian blue, which shows positive at a pH of 2.4, but negative at a pH of 4.0, can differentiate MCS from other sweat gland tumors [3]. Gastrointestinal carcinomas contain sulfomucin, while sialomucin is present in MCS [3]. Cytokeratin 20 is common in gastrointestinal neoplasms, but absent in MCS [3]. Cytokeratin 7 and p63 can be found in MCS, but are rarely found in metastatic tumors [3]. Positive immunohistochemical staining for synaptophysin, cytokeratin 7, ER, and PR with a negative reaction to cytokeratin 20, indicates neuroendocrine differentiation [3]. Since 1980, neuroendocrine differentiation of mucinous carcinoma of the breast has been reported according to a type A (without neuroendocrine differentiation), type B (with neuroendocrine differentiation), and type AB (intermediate form) classification [4]. Two previous studies have shown that good prognosis was found in mucinous carcinoma of the breast showing neuroendocrine differentiation [4]. The exact component ratio of neuroendocrine differentiation among mucinous cutaneous carcinoma has not been reported yet [2]. A full oncologic evaluation to search for other primary cancer sites is required for all patients with sweat gland tumors to distinguish MCS from metastatic tumors. MCS is unresponsive to chemotherapy and is radiation-resistant. Given the high rate of local recurrence and the low rate of distant metastases, the gold standard treatment is excision of the tumor. Although local excision with narrow 2 mm margins is sometimes sufficient for superficial tumors, local recurrence has been reported following excision with a 1 cm margin in at least one case. There has been one case report with no evidence of recurrence or metastasis for 10 months postoperatively following resection with 1.5 cm to 2.0 cm margins [5]. For small cheek skin defects (less than 4 cm), the cheek rotation flap described by Mustarde generally allows for easy coverage without complications. When there is no skin laxity, a more extensive undermining in the facial region is necessary to cover the defect [5]. Cervicofacial flaps are helpful for larger cheek skin defects with a wider flap elevation and undermining. However, the resultant closure often has tension when occurring on the cheek, requiring larger incisions and undermining, which can result in compromised vascularity and vulnerability to ischemic necrosis on the distal end of the flap. For the 6 cm cheek defect in our case, the rotation advancement cheek flap with subcutaneous undermining only to the mandible border while preserving the cervical region allowed for good coverage without complications. The flap color and texture was well matched with the surroundings without flap loss. The slow growing and clinically asymptomatic features of MCS can delay the diagnosis, and to rule out other sources of metastatic mucin-secreting carcinomas to the skin, an imaging scan (CT, magnetic resonance imaging [MRI] or PET) is always required. Due to the locally aggressive behavior and high rate of local recurrence of MCS, surgical excision with a wide safety margin is required, and an annual follow-up with detailed systemic examination is recommended. For MCS with local recurrence and lymph node metastasis, whole-body CT and MRI is necessary. In conclusion, MCS is a rare sweat gland malignancy, and only one case was previously reported in Korea with neuroendocrine differentiation. To rule out other sources of metastatic mucin-secreting carcinomas to the skin mimicking MCS, a full metastatic workup is necessary. Due to the locally aggressive behavior and high rate of local recurrence of MCS, surgical excision with a wide safety margin is required, and an annual follow-up with detailed systemic examination is recommended.

A Rare Giant Cell Tumor of the Tendon Sheath of the Dorsal Hand in a Child

Giant cell tumors of the tendon sheath (GCTTS) are benign soft tissue neoplasms of the synovial lining. The peak incidence occurs in the third to fifth decades of life with a slight female predominance, and is very rarely reported in children under the age of 10 years [1]. GCTTS occurs as a firm, nodular mass, most commonly on the volar aspects of the fingers and hands [2]. In this article, we report a rare case of a child who developed a GCTTS in the dorsal aspect of the hand. An 8-year-old boy presented to our clinic with a painless swelling on the dorsum of the right hand (Fig. 1). Medical history indicated that he had been healthy and had no underlying diseases. The mass was first noted one year prior to presentation, and had grown progressively since. At the first visit, the mass protruded from the metacarpal area of the right hand dorsum, and was approximately 2 cm in diameter (Fig. 1). The mass was firm, not freely movable, and was not tender. Magnetic resonance imaging (MRI) was performed to evaluate the characteristics and boundaries of the mass. MRI revealed a 2.8×3.3 cm lobulated subcutaneous soft tissue mass that was in contact with extensor digitorum tendon of the right hand, located dorsal to the second to fourth metacarpal bones (Fig. 2). It showed intermediate or dark signal intensity on both T1-weighted and T2-weighted images, and mild homogenous enhancement on contrast images. The mass was strongly suspected to be a giant cell tumor or fibroma originating from the tendon sheath. Fig. 1 Preoperative clinical photograph of the patients hand. Fig. 2 (A) A T1-weighted axial image shows a lobulated mass with intermediate signal intensity, adjacent to the extensor digitorum tendon. (B) A T2-weighted axial image shows a mass with dark signal intensity. Based on clinical findings and imaging, we decided to perform surgical excision of the mass with a suspicion of giant cell tumor or fibroma of the tendon sheath. The operation was performed under general anesthesia with surgical tourniquet. After making an incision in the middle of the swelling, we performed subcutaneous dissection. A poorly encapsulated mass was also successfully dissected and excised without sacrificing any tendons or neurovascular structures (Fig. 3). After irrigation and hemostasis, the incision was closed and a Penrose drain placed. The drain was removed on the second postoperative day, and the wound healed uneventfully. Cytological assays were negative for malignant cells and hemosiderin-laden macrophages, which would have implied previous hemorrhage. Pathologic findings revealed a 2.5×1.5 cm giant cell tumor of the tendon sheath (Fig. 4). The patient underwent an uneventful one-year course of postoperative follow-up without recurrence. Fig. 3 Intraoperative findings showing resected specimen of a poorly encapsulated mass. Fig. 4 Histology showing a giant cell tumor of the tendon sheath (H&E, ×200). GCTTS is a slow-growing soft tissue mass that develops over a period of months to years. The common clinical presentation is a painless, firm mass. Its radiological appearance is usually subtle, consisting only of soft tissue shadowing. Bony pressure erosions are reported to be more likely in recurrent cases [1]. GCTTS has many other names, including pigmented villonodular tenosynovitis, fibrous xanthoma, xanthogranuloma, and localized nodular synovitis, because its exact pathologic nature is unknown. Trauma, inflammation, metabolic disease, and neoplastic etiology are considered etiological factors [3]. It is the second most common tumor of the hand, but it is very uncommon in children under 10 years of age [1,3]. Morphologically, GCTTS can be classified into a localized nodular type seen more commonly in the hand, and a diffuse type usually seen in larger joints [2]. Al-Qattan [4] classified GCTTS into two main types: Type I GCTTS is surrounded by one pseudocapsule, while type II is not surrounded by one pseudocapsule. The tumor in our case can be classified as type II GCTTS based upon the intraoperative findings. Histologically, GCTTS is characterized by a diverse cell population, including round stromal cells, multinucleated giant cells, and lipid-laden foam cells with deposits of hemosiderin [2]. GCTTS has high propensity for local recurrence, with reported recurrence rates varying widely from 4% to 44%. The morphological factors associated with higher risk of recurrence include diffuse, poorly encapsulated lesions, presence of satellite lesions, involvement of tendon and joint, and intraosseous involvement [2]. There is consensus that recurrence is associated with incomplete excision. Thus, complete local excision remains the mainstay of GCTTS treatment [3,5]. All surrounding tissues should be examined for satellite lesions, and such lesions and connections to these lesions should be excised with the assistance of an operating microscope or a magnifying loupe. Local irradiation has been applied as an adjuvant therapy to prevent recurrence. In the present study, we describe a rare case of GCTTS of the dorsal aspect of the hand in a child. As there is a high tendency for local recurrence, complete excision and prolonged follow-up is recommended when treating patients with GCTTS [1].

Analysis of Facial Asymmetry in Deformational Plagiocephaly Using Three-Dimensional Computed Tomographic Review

Background Infants with deformational plagiocephaly (DP) usually present with cranial vault deformities as well as facial asymmetry. The purpose of this study was to use three-dimensional anthropometric data to evaluate the influence of cranial deformities on facial asymmetry. Methods We analyzed three-dimensional computed tomography data for infants with DP (n=48) and without DP (n=30, control). Using 16 landmarks and 3 reference planes, 22 distance parameters and 2 angular parameters were compared. This cephalometric assessment focused on asymmetry of the orbits, nose, ears, maxilla, and mandible. We then assessed the correlation between 23 of the measurements and cranial vault asymmetry (CVA) for statistical significance using relative differences and correlation analysis. Results With the exception of few orbital asymmetry variables, most measurements indicated that the facial asymmetry was greater in infants with DP. Mandibular and nasal asymmetry was correlated highly with severity of CVA. Shortening of the ipsilateral mandibular body was particularly significant. There was no significant deformity in the maxilla or ear. Conclusion This study demonstrated that the cranial vault deformity in DP is associated with facial asymmetry. Compared with the control group, the infants with DP were found to have prominent asymmetry of the nose and mandible.

Leiomyoma of the Forehead

Leiomyoma is a benign proliferation of smooth muscle cells that may be found in various anatomical locations. Leiomyoma of the uterus is the most common, and there have been a few case reports of extra-uterine leiomyomas including on the hand, foot, esophagus, trachea, heart, and even in vessels. However, there have been no reports of leiomyoma of the frontalis muscle. We present a case of leiomyoma of the frontalis muscle that was excised using an endoscopic method. A 5-year-old boy was referred to our hospital with a palpable mass on his left forehead. It was first observed when he was 4-year-old (Fig. 1). Computed tomography revealed a nonspecific soft tissue lesion on his left forehead. Except for the lesion, there were no other abnormalities on his skull, ventricle, or brain parenchyma. The patient revisited the hospital 1 year after the first visit because the size of the mass had increased. Fig. 1 Preoperative photograph showing bulging of the left forehead due to the mass. The mass was 1 cm in diameter and non-tender, and the patient did not experience any discomfort. The mass was somewhat firm and movable. There were no clinical signs suggesting an inflammatory lesion such as an epidermal cyst. We initially suspected a lipoma. The mass was excised using an endoscopic approach under general anesthesia. Anesthesia and hydrodissection were performed by injecting an excessive amount of lidocaine mixed with epinephrine between the galea and the periosteum, to ease the performance of the dissection. Two incisions of 1.5 cm in length were made 1 cm behind the hairline for less visible scarring and to create the shortest distance and easiest approach to the lesion. The endoscope with a retractor and other surgical instruments were inserted through these incisions. We dissected the muscle using a Freer elevator with palpation (Fig. 2). The mass was identified intramuscularly, and was completely excised without any remnant lesion. It was solid with a fibrous capsule (Fig. 3). Fig. 2 Intraoperative endoscopic image showing the mass (black arrow) in the frontalis muscle. Fig. 3 Excised specimen showing a solid mass with a fibrous capsule. Pathologically, the mass showed the characteristics of a leiomyoma, and a definite diagnosis was confirmed based on the immunohistochemistry showing desmin positivity (Fig. 4), because desmin is a specific protein that is expressed in smooth and skeletal muscle myocytes and is also expressed in neoplasms with smooth or skeletal muscle differentiation. Fig. 4 Desmin stained histology of the patient, showing that the origin of this mass was the smooth muscle (×100). Usually, leiomyomas originate from the muscle of the uterus and alimentary tract, but it is rare for a neoplasm to originate from the soft tissue of the head or neck. Benign smooth muscle tumors that arise from the forehead are rare, and this is the first case of leiomyoma in the forehead [1-3]. Among the soft tissue tumors in the head and neck area, 96% are known to be benign [4], and leiomyomas comprise only 1.3% of them; no cases of forehead leiomyoma have been published. A relationship between leiomyoma and trauma has been discussed in a previous study [1]. In our case, however, there was no history of trauma in the years just before the tumor was recognized. A precise pathological examination is required before surgery in forehead leiomyoma cases, even if the tumor is believed to be benign, because the examination can precisely represent the character of the lesion. A specimen is assumed to be malignant if an average of one or more mitoses in every five high-power fields is identified. Moreover, if mitoses are found in every high-power field, the specimen is considered to be definitely malignant [3]. The pathologic study of this case demonstrated an average of less than one mitosis in every five high-power fields; therefore, the specimen had a high likelihood of being a benign leiomyoma. The definitive treatment for subcutaneous leiomyomas of the forehead and other body parts is complete excision of the lesion. However, the choice of surgical method, approach, and extent may vary according to the site in which the tumor is involved. In our case, total excision of the mass was achieved via an endoscopic approach. Because the procedure is minimally invasive, the patient was discharged on postoperative day 1 with a mild compressive dressing to minimize the swelling, and the wound healed uneventfully; the scars were almost unidentifiable (Fig. 5). Fig. 5 Follow-up photograph at 10 days postoperatively. Leiomyoma is a benign proliferation of smooth muscle cells that may be found in various anatomical locations. The disease is not rare, but most cases are focused on the uterus. An extra-uterine leiomyoma typically presents as a small, painless mass. This article is meaningful in that it shows leiomyoma can occur on the frontalis muscle. Magnetic resonance imaging may be helpful for diagnosis, but a definite diagnosis is confirmed by pathology [5]. Simple excision yields excellent results, but to minimize scarring, an endoscopic approach should be used. In addition, because cases of multiple metastasizing leiomyoma have been reported, regular follow-up should be considered.