Clinical Outcomes and Contributors in Contemporary Kidney Transplantation: Single Center Experience / 대한이식학회지

BACKGROUND: In recent years, introduction of novel immunosuppressive agents and its proper implementation for clinical practice have contributed to improving clinical outcomes of kidney transplantation (KT). Here, we report clinical outcomes of KTs and related risk factors. METHODS: From July 1998 to June 2016, 354 KTs (182 from living and 172 from deceased donors) have been performed at Ulsan University Hospital. We retrospectively reviewed the clinical characteristics and outcomes of KT recipients, then estimated graft and patient survival rate were estimated and analyzed risk factors using Cox-regression. RESULTS: The median follow-up period was 53 months (range; 3 to 220 months). The mean ages of recipients and donors were 45.0 years (SD, 12.5) and 44.7 years (SD, 13.6) years, respectively. During follow-up, 18 grafts were lost and 5- and 10-year death-censored graft survival was 96.7% and 91.5%, respectively. Biopsy-proven acute rejection (BPAR) occurred in 71 patients (55 cases of acute cellular rejection and 16 of antibody-mediated rejection). Cox-regression analysis showed that BPAR was a risk factor related to graft loss (hazard ratio [HR], 14.38; 95% confidence interval [CI], 3.79 to 54.53; P < 0.001). In addition, 15 patients died, and the 5- and 10-year patient survival was 97.2% and 91.9%, respectively. Age ≥60 years (HR, 6.03; 95% CI, 1.12 to 32.61; P=0.037) and diabetes (HR, 6.18; 95% CI, 1.35 to 28.22; P=0.019) were significantly related to patient survival. CONCLUSIONS: We experienced excellent clinical outcomes of KT in terms of graft failure and patient survival despite the relatively high proportion of deceased donors. Long-term and short-term clinical outcomes have improved in the last two decades.

Roles of IL-33 in Resistance and Tolerance to Systemic Candida albicans Infections

IL-33 is a multifunctional cytokine that is released in response to a variety of intrinsic and extrinsic stimuli. The role of IL-33 in Candida albicans infections is just beginning to be revealed. This cytokine has beneficial effects on host defense against systemic C. albicans infections, and it promotes resistance mechanisms by which the immune system eliminates the invading fungal pathogens; and it also elevates host tolerance by reducing the inflammatory response and thereby, potentially, tissue damage. Thus, IL-33 is classified as a cytokine that has evolved functionally to protect the host from damage by pathogens and immunopathology.

Impact of the Endoscopic Submucosal Dissection on Early Postoperative Outcome after Additional Gastric Resections for Early Gastric Cancer

PURPOSE: The aim of this study was to compare ESD only and subsequent Laparoscopy-assisted gastrectomy (LAG) patients for EGC through propensity score matching analysis. METHODS: This study was a retrospective review of the records of 46 consecutive patients with gastric cancer who underwent LAG after ESD from 2009, September to 2014, September, and propensity matching analysis was performed with 92 patients who underwent LAG without ESD as a control group. Subgroup analysis was performed with the interval of subsequent laparoscopic gastrectomy and endoscopic resection (within 2 weeks, 2~4 weeks, above 4 weeks). RESULTS: There were no significant differences in age, gender, body mass index, comorbidity, previous abdominal surgery, and location of the lesion or clinical stage between the two groups. Early postoperative outcomes including postoperative complications and postoperative hospital stay were not significantly different between the two groups. According to subgroup analysis with the interval of laparoscopic gastrectomy and endoscopic resection, there were no significant differences in early outcomes in three groups. However, only early postoperative complication rate was significantly higher in patients who received LAG more than 4 weeks after ESD (0 versus 4.76 versus 40 per cent; p=0.0032). CONCLUSION: We analyzed the influence of ESD on subsequent LAG using propensity score matching to reduce the bias. However, we found that ESD might induce inflammation for a significant duration, but ESD had little influence on early postoperative outcome of LAG.

Stenosis or Occlusion of the Right Subclavian and Common Carotid Arteries Is More Common than That of the Innominate Artery in Takayasu Arteritis

PURPOSE: The aim of this study was to introduce the phenomenon that stenosis or occlusion occurs less frequently in the innominate artery than in the right subclavian and common carotid arteries, which are not first-order branches of the aorta, in Takayasu arteritis (TA). MATERIALS AND METHODS: We retrospectively reviewed the medical records and image findings of all patients who were diagnosed with TA from 2006 to 2014. Two vascular surgeons and two radiologists interpreted the images by disease character, location, and extent of occlusion based on computed tomography angiography, magnetic resonance angiography, or digital subtraction arteriography. We have also reviewed the literature on arterial involvement in TA. RESULTS: A total of 42 patients were diagnosed with TA. The mean age was 43.9 years, and 83.3% (35/42) of the patients were women. The left subclavian artery was the most common stenosis or occlusion site (17, 40.5%) among the aortic branches. The innominate artery was a less common site (3, 7.1%) than the right subclavian artery (4, 9.5%) and the right common carotid artery (9, 21.4%). All innominate artery cases were found after endovascular procedures of the right subclavian or common carotid arteries. CONCLUSION: The innominate artery might develop stenosis or occlusion less frequently than the right subclavian and common carotid arteries in Korean TA patients.

Integration of the Innate and Adaptive Immunity by CD137-CD137L Bidirectional Signals: Implications in Allograft Rejection / 대한이식학회지

Two-signal models are useful in explaining various types of immune responses. In particular, secondary, so-called costimulatory, signals are critically required for the process of T-cell activation, survival, differentiation, and memory formation. Early studies in rodent models showed that targeting T-cell costimulatory pathways elicits immunological tolerance, providing a basis for development of costimulatory therapeutics in allograft rejection. However, as the classic definition of T-cell costimulation continues to evolve, simple blockade of costimulatory pathways has limitations in prevention of allograft rejection. Furthermore, functions of costimulatory molecules are much more diverse than initially anticipated and beyond T cells. In this mini-review, we will discuss CD137-CD137L bidirectional signals as examples showing that two-signals can be applicable to multiple phases of immune responses.

Safety and Efficacy of Conversion from Twice-Daily Tacrolimus to Once-Daily Tacrolimus One Month after Transplantation: Randomized Controlled Trial in Adult Renal Transplantation

PURPOSE: The purpose of this study was to compare once-daily tacrolimus with twice-daily tacrolimus in terms of safety, efficacy, and patient satisfaction. MATERIALS AND METHODS: This prospective, randomized, open-label, multicenter study was conducted at three institutes. Patients in the investigational group were converted from tacrolimus twice daily to the same dose of extended-release tacrolimus once daily at 1 month post-transplantation, while patients in the control group were maintained on tacrolimus twice daily. The efficacies, safeties, and patient satisfaction for the two drugs at 6 months post-transplantation were compared. RESULTS: Sixty patients were enrolled and randomized to the investigational group (28 of 29 patients completed the study) or the control group (26 of 31 patients completed the study). At 6 months post-transplantation, composite efficacy failure rates including the incidences of biopsy-confirmed acute rejection in the investigational and control groups were 0% and 10.7%, respectively; patient survival was 100% in each group. No difference in estimated glomerular filtration rate values were observed at 6 months post-transplantation (p=0.97). The safety and satisfaction profile (immunosuppressant therapy barrier scale) of once-daily tacrolimus was comparable with that of twice-daily tacrolimus (p=0.35). CONCLUSION: Conversion from twice-daily tacrolimus to once-daily tacrolimus one month after transplantation is safe and effective.

Optimal Level of Tacrolimus to Minimize Nephrotoxicity in Liver Transplantation / 대한이식학회지

BACKGROUND: Calcineurin inhibitor-induced nephrotoxicity is the main cause of renal dysfunction after liver transplantation (LT). The aims of this study were to investigate the changes in kidney function after LT and to determine the optimal tacrolimus level in order to minimize nephrotoxicity at various time points after LT. METHODS: We enrolled 37 LT recipients with a preoperative estimated glomerular filtration rate (eGFR) > or =60 mL/min/1.73 m2 and all received immunosuppression including tacrolimus. Renal function was assessed by eGFR. eGFR and tacrolimus level were estimated at 2 weeks, 1, 3, 6, and 12 months after LT. Multivariate regression analysis was applied for determination of mean tacrolimus level minimizing the decrease in eGFR at those time periods. Age, sex, presence of diabetes or hypertension, and use of Simulect were the covariates. RESULTS: Mean eGFR showed a decrease from 88 to 58 mL/min/1.73 m2 by 3 months after LT. Thereafter, eGFR remained stationary until 1 year. By multivariate regression analysis, mean tacrolimus level minimizing the decrease in eGFR could be obtained. Decrease of eGFR was lower in 12 patients with a mean tacrolimus level below 7.96 ng/mL compared to 25 patients with a mean tacrolimus level above 7.96 ng/mL (0.29 mL/min/1.73 m2 vs. 23.38 mL/min/1.73 m2; P=0.008). CONCLUSIONS: Kidney function had declined by three months after LT. However, thereafter, it was stationary until 1 year. Renal dysfunction could be decelerated by optimizing tacrolimus level at various time points.

Successful Reuse of a Kidney Allograft from a Brain-Dead Donor into a Second Recipient: A Case Report / 대한이식학회지

The limited donor organ supply is a main problem for transplant surgeons in Korea, and forces them to use organs from extended sources. In one such case, we reused a transplanted kidney allograft in August 2012. This was the first successful case involving the reuse of a transplanted kidney allograft in Korea. The kidney donor was a 44-year-old man brain-dead due to spontaneous subdural hemorrhage. He received a kidney transplant from his sister in 2006. The second recipient was a 59-year-old man who had been receiving hemodialysis for 11 years. There were full human leukocyte antigen (HLA) matches between the first donor and the first recipient, and two HLA mismatches between the first donor and the second recipient. Fortunately, we were able to perform a crossmatch test between the first donor and the second recipient as well as the first recipient and the second recipient (with the first donor's agreement). We used the left iliac artery for perfusion instead of the aorta during organ procurement. The cold ischemic time was 4 hours and the initial kidney function was excellent. The patient has been doing well, without any significant complications or rejections, for 3 weeks. His last serum creatinine level was 0.91 mg/dL. Our case shows that the reuse of kidney allografts could be a possible solution for the shortage of donor kidneys. However, this method requires careful consideration and an agreement among participants before its performance.

Role of surgical treatment for peripheral arterial disease in endovascular era / 대한외과학회지

PURPOSE: The purpose of this study is to review the roll changes of surgical treatment for peripheral artery disease in endovascular era. METHODS: One hundred and twelve surgically treated cases of peripheral artery disease at a single institution during the period from 2006 to 2011 were studied retrospectively. The cases were divided into two groups of different time periods, one before 2009 (surgical period group) and the other from 2009 onward (endovascular period group). We analyzed the type and location of surgery as well as clinical characteristics of patients and treatment results. RESULTS: Fifty-three cases were for the surgical period group and 59 cases for the endovascular group. No difference in the demographic characteristics and the distribution of major atherosclerosis risk factors was found between the two groups. Additionally, the technical and functional success rate was similar in both groups. However, it is found that there were more acute cases in the endovascular period group than in the surgical period group. The number of cases in need of suprainguinal or below knee exposure was similar in both groups. In hybrid cases, suprainguinal or below knee exposures were more frequently needed during the former period than the latter period. CONCLUSION: The role of surgical treatment is currently in the process of changing. Surgical treatment seems to be a complementary alternative to endovascular treatment for chronic limb ischemia. However, it still seems to play a major role for acute limb ischemia.

The Influence of Operative Approach on Food Retention after Open and Laparoscopy-Assisted Distal Gastrectomy (LADG) for Gastric Cancer

PURPOSE: Laparoscopy-assisted distal gastrectomy (LADG) has gained wide acceptance for minimally invasive treatment of early gastric cancer (EGC). The aim of this study was to see the relationship between the operative approach of a distal subtotal gastrectomy and food retention of the remnant stomach. METHODS: A retrospective review of the records of 321 consecutive patients with gastric cancer who underwent a distal subtotal gastrectomy between 2001 and 2008 was conducted. A total of 233 patients who revisited the same surgeon's outpatient clinic and received regular endoscopic examination using the same protocol were finally included in this study. Reconstruction was performed using the Billroth I procedure. Mechanical-stapled anastomosis (MSA) was performed in 112 patients and conventional hand-sutured anastomosis (HA) was performed in 121 patients. RESULTS: According to results of multivariate analysis, the anastomosis method (MSA) was the only independent risk factor for accumulation of food residue. At six and 12 months after surgery, the incidence of food retention was higher in patients who had undergone MSA (22.3%, 13.4%) than in those who had undergone HA (9.1%, 2.5%) (p=0.006, p=0.002, respectively). However, the incidence of food residue at 24 months after surgery did not differ statistically between MSA and HA (p=0.266). CONCLUSION: Our results showed that the laparoscopic approach was not influenced on the accumulation of food residue. Mechanical-stapled anastomosis was the only independent risk factor for food retention. During the early postoperative period, although more food retention was observed in patients who underwent MSA than in those who underwent HA, in the long term, this anastomosis method did not influence food retention after a distal gastrectomy.

Multicenter Clinical Investigation for the Safety and Efficacy of Advagraf(R) (Extended Release Tacrolimus) versus Prograf(R) (Tacrolimus) in De Novo Kidney Recipients after 1 Month of Transplantation: Preliminary Results / 대한이식학회지

BACKGROUND: Compliance from kidney transplant recipients might improve with less frequent doses of immunosuppressant drugs. We describe the development of an extended-release formulation of tacrolimus that enables taking the drug just once a day, instead of the current twice a day tacrolimus formulation. METHODS: We performed a prospective, open-label, 1:1 randomized, and multicenter study. Patients received Prograf(R) (Astellas Inc.) twice a day for 1 month post-transplantation. The patients of the investigational group converted to a dose of Advagraf(R) (Astellas Inc.) given once a day. We evaluated the efficacy, safety, and patient satisfaction of both groups. RESULTS: Within 5 months after conversion to Advagraf, the incidence of biopsy-confirmed acute rejection was 0%, while patient and graft survival was 100%. We could not find differences of the patients' estimated glomerular filtration rate (eGFR) between the Prograf and Advagraf treated groups 1~6 months post-transplantation. The safety profile and satisfaction profiles (immunosuppressant therapy barrier scale) were also equivalent between the treated groups. CONCLUSIONS: The preliminary results of this study support the safety, efficacy, and patient satisfaction from a single daily formulation of tacrolimus (Advagraf(R)).

Extrinsic compression of left iliac vein does not predict the development of post thrombotic syndrome in left side deep venous thrombosis / 대한외과학회지

PURPOSE: Left side deep venous thrombosis (DVT) is associated with May-Thurner's anatomical variation and is often instigated by invasive treatment. The aim of this study is to analyze the influence of left iliac vein narrowness on incidence of post thrombotic syndrome (PTS) that developed after left side DVT. METHODS: Forty-one left side DVT cases that were followed up for more than 1 year were enrolled. The iliac vein narrowness was measured by the shortest distance from the right iliac artery to the 5th lumbar vertebra overlying left iliac vein in computed tomography (CT) scan. The incidence of PTS was measured by phone-call history taking for specific symptoms of PTS. The means of the shortest distance were compared by independent t-test. RESULTS: The number of PTS cases was eleven (26.8%). The level of thrombus, demographic data and other risk factors were similar in both PTS and non-PTS groups except the mean risk factor score. The mean of the shortest distance of PTS group and non-PTS group were 5.56 mm and 5.89 mm, respectively. CONCLUSION: The degree of left iliac vein narrowness measured by the shortest distance from the right iliac artery and the 5th lumbar vertebral body was not a predictive factor for PTS.

Role of Protein Kinase C-delta in Atherosclerosis / 대한혈관외과학회지

PURPOSE: Protein kinase C (PKC) has been implicated in a wide variety of cellular processes. Although PKC-delta is implicated in cell growth inhibition, as well as in cell differentiation, apoptosis, and tumor suppression, its role in atherosclerosis remains unclear. This study aimed to identify the mechanism of PKC-delta in the development of atherosclerosis. METHODS: To induce atherosclerosis, we performed allograft transplantations on aortas in mice. At 2, 4, and 6 weeks after transplantation, grafted aortas were obtained to compare the degree of atherosclerosis between wild type and PKC-delta (-/-) aorta. Alloantibody levels in the recipient mice's blood were measured. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to quantitatively measure chemokine and cytokine mRNA expression of the inflammation from the harvested aorta. RESULTS: Atherosclerosis was more severe in the PKC-delta (-/-) aorta than in the wild type aorta. Alloantibody levels were higher in the mice grafted with aorta from the PKC-delta (-/-) mice than in the mice grafted with aorta from the wild type mice. RT-PCR revealed higher expressions of MRP-2, MCP-1, MIP-1alpha, and IL-2 in the mice grafted with aorta from the PKC-delta (-/-) mice than the wild type mice. CONCLUSION: Aorta allograft transplantation is a useful modality for inducing atherosclerosis. PKC-delta may be a negative regulator of atherosclerosis.

Impact of Distance from the Right Iliac Artery to the Lumbar Vertebra in Left Side Deep Venous Thrombosis / 대한혈관외과학회지

PURPOSE: The aim of this study is to evaluate how much influence iliac vein compression exerts on the clinical feature of deep venous thrombosis (DVT). METHODS: One hundred five cases of lower extremity DVT were enrolled. The cases were grouped by location of the thrombus, left/right and inferior vena cava, iliac vein (IV), femoral vein (FV), popliteal vein, and calf vein. The estimated frequency was calculated by means of that the numbers of each goup were divided by the group's mean of DVT risk score. The minor distance from the right iliac artery to the fifth lumbar vertebral body overlying the left iliac vein was measured in computed tomography. Correlation of the severity and the minor distance was evaluated. RESULTS: Left, right, and bilateral DVT were represented in 66, 26, and 13 cases, respectively. Estimated frequencies were 2, 6.47, 5.47, 2.08, and 0.96 in the left side and 2, 1.44, 2.5, 1.33, and 1 in the right, respectively. Statistics significance was seen at the IV and FV levels. The means of minor distances in millimeters were 4.88, 3.98, 6.13, 6.20, and 4.20 in the left and 2.50, 7.00, 5.20, 7.33, and 6.50 in the right, respectively. Significance was seen only at the IV level. DVT severity and the minor distance could not be correlated with statistical significance. CONCLUSION: We consider that May-Thurner's anatomical changes impacts the DVT prevalence only at the proximal vein. We also suggest that the compression of the left iliac vein might be a contributing factor for developing DVT but not for severity of the DVT.

Recombinant TAT-CD137 Ligand Cytoplasmic Domain Fusion Protein Induces the Production of IL-6 and TNF-alpha in Peritoneal Macrophages

BACKGROUND: The ligand for CD137 (CD137L; also called 4-1BBL) is mainly expressed on activated APCs such as dendritic cells, B cells and macrophages. Even though CD137L functions as a trigger of the CD137 signaling pathway for T cell activation and expansion, engagement of CD137L can deliver a signal leading to the production of proinflammatory cytokines in macrophages. METHODS: We generated cell-permeable TAT-CD137L cytoplasmic domain fusion protein (TAT-CD137Lct) and examined its ability to initiate the CD137L reverse signaling pathway. RESULTS: Treatment of TAT-CD137Lct induced the production of high levels of IL-6 and TNF-alpha mRNAs and proteins in peritoneal macrophages. TAT-CD137Lct increased phosphorylation of Erk, p38 MAPK and Jnk, and activated transcription factors C/EBP and CREB. However, TAT-CD137Lct did not visibly affect the degradation of the inhibitor of NF-kB (IkBalpha). We further demonstrated that JNK activation was required for TAT-CD137Lct-induced production of TNF-alpha, while activation of Erk and p38 MAPK were involved in IL-6 and TNF-alpha production. CONCLUSION: Our results suggest that TAT-CD137Lct is an effective activator for the CD137L reverse signaling pathway.

Anti-CD137 mAb Deletes Both Donor CD4+ and CD8+ T Cells in Acute Graft-versus-host Disease

We previously demonstrated that in vivo engagement of CD137, a member of TNF receptor superfamily, can delete allorective CD4+ T cells through the induction of activation-induced cell death (AICD) in chronic graft-versus-host disease (cGVHD) and subsequently reverse established cGVHD. In this study, we further showed that agonistic anti-CD137 mAb was highly effective in triggering AICD of donor CD8+ T cells as well as donor CD4+ T cells in the C57BL/6-->unirradiated (C57BL/6 x DBA/2)F1 acute GVHD model. Our results suggest that strong allostimulation should facilitate AICD of both alloreactive CD4+ and CD8+ T cells induced by CD137 stimulation. Therefore, depletion of pathogenic T cells using agonistic anti-CD137 mAb combined with potent TCR stimulation may be used to block autoimmune or inflammatory diseases mediated by T cells.

Huge carotid body paraganglioma / 대한외과학회지

A 33-year-old woman was admitted to our hospital with a slow-growing mass in the left side of her neck. The mass was found to be a huge (73 x 56 x 54 mm) carotid body paraganglioma. Another 21 mm-size tumor was incidentally detected at the right carotid bifurcation. She had hoarseness and Horner's syndrome of her left side. Both tumors were surgically removed. There were no cerebrovascular complications but some neurologic complications occurred when the left tumor was removed.

Roles of Host Nonhematopoietic Cells in Autoimmunity and Donor Cell Engraftment in Graft-versus-host Disease

BACKGROUND: Graft-versus-host disease (GVHD) is initiated when alloreactive donor T cells are primed by host APCs to undergo clonal expansion and maturation. Since there is a controversy regarding the role of nonhematopoietic cells in GVHD, we wanted to investigate the influence of MHC disparity on nonhematopoietic cells on the pathogenesis of GVHD in the MHC-haplomismatched C57BL/6 (H-2(b)) or DBA/2 (H-2(d))-->unirradiated (C57BL/6xDBA/2) F(1)(BDF(1); H-2(b/d)) murine model of acute GVHD (aGVHD) or chronic GVHD (cGVHD). METHODS: We generated (BDF(1)-->C57BL/6), (BDF(1)-->DBA/2), and (BDF(1)-->BDF(1)) chimeras and examined GVHD-related parameters and donor cell engraftment in those chimeras. RESULTS: Using this experimental system, we found that 1) severe aGVHD across MHC Ag barrier depends on the expression of nonhematopoietically rather than hematopoietically derived alloAgs for maximal GVHD manifestations; 2) host APCs were sufficient to break B cell tolerance to self molecules in cGVHD, whereas host APCs were insufficient to induce autoimmunity in aGVHD; 3) donor cell engraftment was greatly enhanced in the host with MHC-matched nonhematopoietic cells. CONCLUSION: Taken together, our results provide an insight into how MHC disparity on GVHD target organs contribute to the pathogenesis of GVHD.

The Usefulness of the Computed Tomography for Diagnosing DeepVenous Thrombosis of the Lower Extremities

PURPOSE: This study aims to access the usefulness of indirect computed tomographic venography (CTV) after performing computed tomographic pulmonary angiography (CTPA) to detect deep venous thrombosis. METHODS: Eighty six patients who were diagnosed with deep venous thrombosis (DVT) were retrospectively enrolled in this study. All the patients had CTPA & CTV performed within 24 hours after Doppler ultrasound (US). The CTV was compared with Doppler US for their ability to diagnose DVT. Pulmonary embolism (PE) and other findings that were detected by CTPA & CTV were analyzed. RESULTS: Among 86 patients, 83 had thrombi detected by Doppler US. CTV did not detect DVT in 11 of the 83 patients. Among the 11 patients, 8 had below the knee thrombosis, which was not in the scan area of CTV. In 2 patients, their Doppler US results could not be guaranteed. One case was a false positive result on Doppler US. The results for determining the thrombi level between Doppler US and CTV were roughly concordant. In addition to DVT or PE, 32 new lesions in 27 patients were incidentally detected by CTPA & CTV. CONCLUSION: Compared with Doppler US, CTPA & CTV are not inferior to detect DVT of the lower extremities and these modalities can also provide information about incidental disease, as well as pulmonary embolism.

Retroperitoneal Mucinous Cystadenoma

We present a case of a primary retroperitoneal mucinous cystadenoma, which is a relatively rare tumor found exclusively in women. This tumor is difficult to correctly diagnose preoperatively. Although there is little published information regarding the CEA levels in the cystic fluid of cystic tumors arising in the retroperitoneum, a high CEA level in the cystic fluid is a useful diagnostic marker for a primary retroperitoneal mucinous tumor. The appropriate management of retroperitoneal mucinous cystadenomas is the total removal of the cyst. The retroperitoneal approach for retroperitoneal cystic tumors is useful, has a lower risk of traumatizing the bowel than the intra-abdominal approach, and does not require compression of the other organs. We report the successful resection of a retroperitoneal mucinous cystadenoma through the retroperitoneal approach.