Current status of the diagnosis of chronic pancreatitis by ultrasonographic elastography

Chronic pancreatitis (CP) is pathologically characterized by the loss of exocrine pancreatic parenchyma, irregular fibrosis, cellular infiltration, and ductal abnormalities. Diagnosing CP objectively is difficult because standard diagnostic criteria are insufficient. The change of parenchymal hardness is the key factor for the diagnosis and understanding of the severity of CP. The ultrasonography (US) or endoscopic ultrasonography (EUS) elastography have been used to diagnose pancreatic diseases. Both strain elastography (SE) and shear wave elastography are specific diagnostic techniques for measuring tissue hardness. Most previous studies were conducted with SE. There are three methods of interpreting SE; the method of recognizing the patterns in SE distribution images in the region of interest, the method of using strain ratio to compare the hardness of adipose tissue or connective tissue with that of the lesion, and the method of evaluating the hardness distribution of a target by histogram analysis. These former two methods have been used primarily for neoplastic diseases, and histograms analysis has been used to assess hardness distribution in the evaluation of CP. Since the hardness of the pancreas increases with aging, it is necessary to consider the age in the diagnosis of pancreatic disorders using US or EUS elastography.

A Case of Axillofemoral Bypass Graft Stump Syndrome Occurring in Both the Upper and Lower Extremities / 日本心臓血管外科学会雑誌

Acute ischemia due to thromboembolism caused by occluded prosthetic graft after axillary-femoral artery bypass has been reported as axillofemoral bypass graft stump syndrome (AxSS). AxSS usually occurs in the upper extremities and it is rare that it occurs in the lower extremities. We encountered a rare case of a 76-year-old woman with acute right upper and lower extremities ischemia 4 years after right axillary-external iliac artery bypass grafting. The graft and the native arteries of the right upper and lower limbs were occluded. In addition, the right axillary artery and proximal anastomotic site were deformed. We diagnosed acute limb ischemia due to AxSS and immediately performed thrombectomy. Because we considered the thrombosis to originate from the axillary-iliac artery bypass graft, we disconnected the occluded graft from the native arteries. Six months after surgery, she was doing well without recurrence of thromboembolism. We report here the successful treatment of a case of AxSS that developed in both the upper and lower extremities.

Ureteral Peritonitis after an Abdominal Aortic Aneurysm Repair / 日本心臓血管外科学会雑誌

An 84-year-old man electively underwent abdominal aortic open repair for an abdominal aortic aneurysm. During the operation, the ureter was not confirmed when manipulating the iliac arteries. Subsequently, intestinal paralysis occurred on the fifth day after surgery and a drainage tube of the intestinal tract was inserted. Liquid retention around the left iliopsoas muscle, and left renal nephropathy were recognized on performing enhanced computed tomography (CT) on postoperative day 11. An initial diagnosis of an iliopsoas abscess was considered. Simple CT imaging was performed on the 13th day after surgery without symptomatic improvement. This scan revealed that the contrast agent had remained in the cavity since the previous CT scan, which had been misdiagnosed as an abscess. Ureteral injury was now suspected. Retrograde ureterography revealed an urinoma caused by left ureter injury. We diagnosed paralytic ileus due to urinoma. For drainage of the urine, a percutaneous renal fistula was constructed. He was discharged from the hospital on the 56th postoperative day, and by six months after the operation, the urinary tract problem had disappeared. In conclusion, we report a case of delayed ureteral injury that occurred after abdominal aortic open repair surgery.

Improvement Effects of Drink Containing Ampelopsis glandulosa Extract on Knee Joint Discomfort / 日本補完代替医療学会誌

The prevalence of joint diseases in Japan is increasing yearly and it causes the need of nursing care and reduces quality of life. Therefore, there is an urgent need for the development of approaches to prevent and treat the diseases. In the present study, we investigated the effective, healthy food material focusing on the metabolism of joint cartilage. Ampelopsis glandulosa (A. g. ) extract improved exacerbation of hyaluronic acid metabolism and NFκB nuclear translocation caused by inflammatory cytokines, and it suppressed the onset of collagen-induced arthritis in mice. Moreover, intake of the drink containing A. g. extract for three months improved discomfort, pain, and bending angle of knee joint in activities of daily living. These results suggest that A. g. extract improves hyaluronic acid metabolism of joint cartilage, and it is expected to prevent and improve joint disease by long-term intake of the drink containing A. g. extract.

A Survey of Patients whose Consciousness Levels have been Judged as 1 on the Japan Coma Scale by Emergency Life-saving Technicians / 日本プライマリ・ケア連合学会誌

<p><b>Introduction: </b>We retrospectively examined the grounds for judging the consciousness level as 1 on the Japan Coma Scale (JCS) made by emergency life-saving technicians (ELSTs).</p><p><b>Methods: </b>The survey involved the sick and injured who were transferred to the hospital by ambulance during the 25-month period from July 1st, 2011, and who were able to respond to questions asked by hospital staff to make records after ELSTs had judged their consciousness level as 1 on the JCS.</p><p><b>Result: </b>A survey involving 105 cases was conducted to examine grounds for judgment of consciousness level of the sick and injured as 1 on the JCS. "Vacant or blank expression", "delay in reactions" or "delay in responses" were cited as the grounds by 61.0 and 47.6%, respectively.</p><p><b>Conclusion: </b>When ELSTs judged the consciousness level of the sick and injured as 1 on the JCS, they made the above observations of the patients. Although these factors are useful for evaluating the status of consciousness, they are not certain. In some cases, ELSTs may have judged the consciousness level as 1 when it should have been judged as 2 or 3 on the JCS. Therefore, it is suspected that some ELSTs may not recognize disorientation appropriately.</p>

A Surgical Case of Residual Axillary Artery Aneurysm Associated with Kawasaki Disease / 日本心臓血管外科学会雑誌

<p>We herein report on a case in which we conducted bypass surgery for occlusion of a left axillary artery aneurysm with ischemic symptoms 21 years after the contraction of Kawasaki disease and achieved symptomatic improvement. The case involved a 22-year-old man who had been suffering from Kawasaki disease since the age of one. He had been undergoing antiplatelet therapy for bilateral axillary artery aneurysms by orally taking aspirin for 20 years. He suffered from symptoms of upper limb ischemia 21 years after receiving a diagnosis of peripheral aneurysms and occlusion of a left axillary artery aneurysm upon 3DCTA. We conducted aneurysmotomy, plication, and bypass surgery between the axillary and brachial arteries via the autologous vein. Pathological examination revealed due to the formation of atheroma in the tunica intima and disarrangement of the layer structure in the tunica media : thickening of the tunica media was partially observed. His fatigue upon exertion of his left upper extremity remarkably improved following surgery. Although peripheral aneurysms associated with Kawasaki disease are rare, as seen in this case, peripheral arterial disease remains and progresses even after long periods of time. It is believed necessary to carry out long term follow-up and examine the approaches to therapy including surgery in accordance with the site and degree of the disease.</p>

A Case of One-Stage Surgical Treatment for Chronic Mesenteric Ischemia Associated with Severe Aortic Valve Regurgitation and Stenosis / 日本心臓血管外科学会雑誌

<p>We report a case of chronic mesenteric ischemia associated with severe aortic valve regurgitation and stenosis (ASR). The patient was a 76-year-old man who had been given a diagnosis of ASR in his 40s. He gradually developed heart failure and chronic kidney disorder due to deterioration of ASR. He had started hemodialysis 1 year before admission and had complained of abdominal pain after meals and weight loss during that period. He was admitted to the Department of Cardiology in our hospital for evaluation of ASR. Severe ASR with low output syndrome (C. I. 2.00 L/min/m²) were confirmed by cardiac catheter examination. In addition, abdominal angiography revealed total occlusion of the superior mesenteric artery (SMA) and severe stenosis of the celiac artery (CA). We considered that low cardiac output due to severe ASR had exacerbated the mesenteric ischemia. We performed AVR and abdominal aorta-SMA bypass at the same time to prevent acute mesenteric ischemia in the perioperative period. The combination of valvular disease and CMI is very rare. This is the first report in Japan of simultaneous valve replacement and mesenteric artery revascularization.</p>

A Case of Minimally Structural Deterioration in Starr-Edwards Caged-Disk Valve 39 Years after Implantation / 日本心臓血管外科学会雑誌

<p>The durability of the Starr-Edwards (SE) mitral caged-disk valve, model 6520, is not clearly known. We reported that SE mitral caged-disk valves implanted ＞20 years previously should be carefully followed up, and that SE caged-disk valves implanted ＞30 years previously should be electively replaced with modern prosthetic valves in our experience. We found the removed valve 39 years after implantation, which seemed minimal structural deterioration. The patient was discharged on the 10th postoperative day without any complications.</p>

Popliteal Artery Adventitia Cyst / 日本心臓血管外科学会雑誌

<p>A 60 year old man presented with a history of right leg claudication which occurred after walking a distance of 200 m. He had no history of cardiovascular risk factors or trauma in the lower extremities. Palpation disclosed no right popliteal or pedal pulse. Ankle-brachial pressure index (ABI) was 0.60 on the affected side. Computed tomography (CT) demonstrated the presence of a highly stenotic lesion in the right popliteal artery due to compression from periarterial polycystic masses. Magnetic resonance imaging (MRI) revealed no communication to the knee joint bursa. Further, angiography showed a beak-like severe stenosis on the knee of the right popliteal artery. Based on the results of these three imaging techniques we confirmed the diagnosis of cystic adventitial disease (CAD). The patient underwent a surgical exploration of his popliteal artery through a posterior approach. Evacuation of all cysts by longitudinal incision of his adventitia yielded yellow mucoid gelatinous material. The popliteal artery was replaced using the great saphenous vein because the previous imaging showed thrombus formation at the cyst site. He had an uneventful postoperative recovery with ABI of 1.10.</p>

A Case of Aortic Subannular Left Ventricular Aneurysm with Bicuspid Aortic Valve Stenosis / 日本心臓血管外科学会雑誌

<p>A 69-year-old woman was given a diagnosis of moderate aortic stenosis (AS) associated with congenital bicuspid valve in 2011. In 2014, surgery was indicated because of progression of AS and dilatation of the sinus of Valsalva and ascending aorta. Preoperative contrast-enhanced CT and echocardiography showed the saccular space (2×2 cm) located at the left ventricular outflow tract just below the aortic annulus. At surgery, the saccular aneurysm was located just below the aortic annulus of the noncoronary cusp. We resected the aneurysm and closed the orifice with interrupted sutures from the inside of the LV and the outside. Aortic subannular left ventricular aneurysm is a very rare malformation with only 25 reported cases and its natural course is largely unknown. Rupture of aneurysms, infection, thrombus formation, arrhythmia, and heart failure etc. has been reported as complications. We reported a case of aortic subannular left ventricular aneurysm with bicuspid aortic valve stenosis with a literature review.</p>

Survey of Package Inserts for Cautionary Statements about Hypersensitivity Caused by Drug Moieties Similar to Sulfonamide / 医薬品情報学

<b>Objective: </b>The aim of this study was to review cautionary statements regarding hypersensitivity to drugs with a moiety similar to sulfonamide on Japanese package inserts.<br><b>Methods: </b>From approved drugs listed as of March 2015, we selected those with a moiety similar to sulfonamide and examined their therapeutic categories, together with the presence or absence, location, and wording of cautionary statements regarding usage, and matters pertaining to a history of drug hypersensitivity that was not limited to sulfonamide, on the package inserts.<br><b>Results: </b>We extracted 73 drugs (65 components) that included a moiety similar to sulfonamide.  Their therapeutic categories were diverse, and 39 (53.4%) had cautionary statements about hypersensitivity caused by a moiety similar to sulfonamide.  Among these 39 drugs, the cautionary statements were located in different sections (Contraindication 31, Careful Administration 4, and Important Precautions 4).  The cautionary statements showed differences in wording according to the individual drugs or positions.  For 10 of the drugs, information pertaining to a history of drug hypersensitivity not limited to sulfonamide was provided.<br><b>Conclusion: </b>Medical staff should recognize that package inserts are not standardized with regard to cautionary statements about hypersensitivity caused by moieties similar to sulfonamide, and that it is necessary to predict or judge the likelihood of cross-hypersensitivity reaction to such moieties on the basis of their chemical structure.  In addition, it is necessary to carefully observe the clinical condition of individual patients who are receiving drugs that have a moiety similar to sulfonamide.

Infected Abdominal Aortic Aneurysm with a Previous History of Coronary Artery Bypass Grafting with the Right Gastroepiploic Artery / 日本心臓血管外科学会雑誌

We report a case of successful anatomical reconstruction with omentopexy of an infected abdominal aortic aneurysm (AAA) in a patient with a previous history of coronary artery bypass grafting with the right gastroepiploic artery. A 60-year-old man was referred to our institute because of fever and abdominal pain during hemodialysis for chronic renal failure. Antibiotic therapy was started after computed tomography revealed an infected abdominal aortic aneurysm. After infection control, surgical treatment was scheduled. At surgery, left axillo-bifemoral bypass was performed first, because it was unclear whether the omentum was large enough for omentopexy. At laparotomy, adequate omentum and infective AAA were confirmed. AAA repair using a rifampicin-soaked graft, and omentopexy were performed. <i>Enterobacter aerogenes </i>was detected from the resected aortic wall. After the operation, intravenous antibiotic was used for 25 days until CRP was normalized. One year follow-up showed no sign of re-infection.

A Case of Type A Acute Aortic Dissection in an Elderly Woman with Immune Thrombocytopenia Who Underwent Replacement of the Ascending Aorta and Aortic Arch and Later Required Aortic Root Replacement for Redissection of the Aortic Root / 日本心臓血管外科学会雑誌

We report a case of type A acute aortic dissection in an elderly woman with immune thrombocytopenia (ITP) who underwent replacement of the ascending aorta and aortic arch and later required aortic root replacement for redissection of the aortic root one month after her initial surgery. She was an 86-year-old woman with severe mitral regurgitation, and surgery was contraindicated because of her age and ITP. In October 2014, the patient presented with back pain. Computed tomography confirmed the diagnosis of her condition as type A acute aortic dissection, and she was immediately transferred to our hospital. Because echocardiography showed severe aortic regurgitation, severe mitral regurgitation, and moderate tricuspid regurgitation, we performed replacement of the ascending aorta and aortic arch, mitral valve repair, and tricuspid annuloplasty. We used Bioglue to fuse the false lumen of the type A acute aortic dissection and used a Teflon felt sandwich for the proximal anastomosis technique. Respiratory support was discontinued 91 h after her first operation ; however, 30 days after surgery, she developed a to-and-fro murmur-a sign of the progression of heart failure. Echocardiography showed aggravation of aortic regurgitation, and computed tomography showed aortic root redissection ; therefore, 39 days after the initial surgery, we performed aortic root replacement. During the operation, we found the entry under the proximal anastomosis with an almost semicircle form at the right coronary cusp to the noncoronary cusp, and the dissection extended close to the right coronary artery ; thus, we performed bypass to the right coronary artery. Pathologic findings did not establish a causal association between the redissection and Bioglue, and we believed the fragility of the tissue and the selection of the surgical procedure to be the cause of redissection. The patient was transferred to another hospital when she was able to walk and eat, which was 121 days after her first operation. The patient required 50 units of platelet transfusion during her first and second operations, but her bleeding was easily controlled during surgery. She needed two procedures of pericardium drainage for pericardiac effusion and cardiac tamponade, which may relate to ITP. The diagnosis of redissection of the aortic root was made 30 days after the patient's first operation, on the basis of exacerbation of the to-and-fro murmur. Here, we emphasize the clinical importance of basic observations over time, such as auscultation, that are liable to be overlooked in the intensive care unit.

A Suspected Case of Heyde Syndrome with Bleeding of the Small Intestine before Aortic Valve Replacement for Severe Aortic Valve Stenosis / 日本心臓血管外科学会雑誌

The patient was a 74-year-old woman who had undergone mitral valve replacement with a mechanical valve for rheumatic mitral valve stenosis at age 60. She was scheduled for aortic valve replacement for severe aortic stenosis. However, she had significantly worsening anemia before the operation. Capsule endoscopy showed angiodysplasia with bleeding in her small intestine, which was considered the cause of the anemia. Because of progressive anemia, we tried embolization under angiography. However, there was no evidence of extravasation. Neither melena nor exacerbation of anemia was observed, and she underwent aortic valve replacement. She was discharged on postoperative day 22 without gastrointestinal bleeding. Heyde syndrome is aortic valve stenosis associated with gastrointestinal bleeding induced by von Willebrand disease and angiodysplasia in small intestine. Molecular multimeric analysis of von Willebrand factor and the existence of angiodysplasia with hemorrhage of the digestive tract are important for definitive diagnosis. Capsule endoscopy, which is a general examination, is more useful for diagnosis than molecular multimeric analysis of von Willebrand factor. Aortic valve replacement is the only therapeutic option for Heyde syndrome. It is important to decide the appropriate timing of AVR with cardiopulmonary bypass.

Hybrid Treatment of the Intrathoracic Right Subclavian Artery Aneurysm / 日本心臓血管外科学会雑誌

Subclavian artery aneurysm (SCAA), a peripheral arterial aneurysm, is a rare entity. The surgical procedure and approach depend on the location of the aneurysm. We present a case of the endovascular therapy combined with cross axillary bypass. The patient was a 75-year-old man with a small abdominal aortic aneurysm. Multi-detector computed tomography (MDCT) revealed an intrathoracic right SCAA 38 mm in diameter. The operation was performed successfully under general anesthesia. After cross bypass of bilateral axillary artery, the orifice of the right subclavian artery was covered with a stent-graft inserted into the right common carotid artery-brachiocephalic artery and the right subclavian artery was occluded with coils distal to the aneurysm. Post operation angiogram showed complete exclusion of the SCAA and patency of the right common carotid and right vertebral artery. We thought this hybrid treatment for the intrathoracic SCAA could be a useful surgical strategy.

<b>Yokukansan Descriptions in the Original Texts</b> / 日本東洋医学雑誌

We investigated original texts for yokukansan, a familiar Kampo formula, focusing on the classical literature <i>Xue-shi yi-an</i> (薛氏医案) . Yokukansan was described in the <i>Bao-ying jin-jing-lu</i> (保嬰金鏡録) written by Xue ji (薛己) in 1550, the <i>Xiao-er yao-zheng zhi-jue</i> (小児薬証直訣) revised by Xue ji (薛己) in 1551,the <i>Bao-ying cuo-yao</i> (保嬰撮要) by Xue kai (薛鎧) in 1556, and the <i>Xiao-er dou-zhen fang-lun</i> (小児痘疹方論) in 1550. The phrase “one's own work” was used in “<i>Bao-ying jin-jing-lu</i> (保嬰金鏡録)” and in the <i>Xiao-er dou-zhen fang-lun</i> (小児痘疹方論) by Chen wen-zhong (陳文仲). However, there was no mention of “one's own work” in the same title, the <i>Xiao-er dou-zhen fang-lun</i> (小児痘疹方論), as summarized by Xiong zong-li (熊宗立).<br>Yokukansan was found only in the <i>Xiao-er yao-zheng zhi-jue</i> (小児薬証直訣) revised by Xue ji (薛己) in 1551, but not in the other copies of the same text. Therefore, it seems likely that yokukansan was created by Xue ji (薛己) himself.<br>Yokukansan was previously thought to have originated with the <i>Bao-ying cuo-yao</i> (保嬰撮要). However, based on use of the phrase “one's own work” in the classical literature, it appears that the original text for yokukansan should be the <i>Bao-ying jin-jing-lu</i> (保嬰金鏡録). Therefore, yokukansan seems to have been made by Xue ji (薛己), and not Xue kai (薛鎧), who was his father.

Surgical Results of Valvular Disease in Hemodialysis Patients / 日本心臓血管外科学会雑誌

<b>Background</b> : The Japanese Society for Dialysis Therapy in 2011 reports that the number of hemodialysis patients has been increasing and that there is an increase in long-term hemodialysis patients and the aging of hemodialysis induction. Therefore, it can be expected that the number of valve surgeries in chronic hemodialysis patients will increase. However, there are many problems between chronic hemodialysis and valve surgery. <b>Objectives</b> : To describe the results of valve surgery in chronic hemodialysis patients at our institution and evaluate the selection of prosthetic valve and associated problems. <b>Methods</b> : Between January 2001 and June 2011, a total of 29 patients on chronic hemodialysis including 3 patients for re-operation, underwent valve replacements. The average age was 67.3±9.3 years and 17 (65%) were men. The average dialysis duration was 7.9±6.4 years. The etiologies of renal failure were 8 for chronic glomerulonephritis (31%), 8 for nephrosclerosis (31%) and 3 for diabetic nephropathy (12%). <b>Results</b> : There were 2 (7.7%) in-hospital deaths, which resulted from ischemia of intestine and multiple organ failure due to heart failure. Twelve (46%) patients died during the follow-up period and the 5-year survival rate after surgery was as poor as another authors have reported previously (30.6%). However, the 5-year survival rate after hemodialysis introduction was 87.1%, which was better than the report of the Japanese Society for Dialysis Therapy in 2011 (60%). Average age was significantly higher in bioprosthetic valves than in mechanical valves (<i>p</i>=0.02). There was no significant difference in survival rate among mechanical and bioprosthetic valves (<i>p</i>=0.75). There was no significant difference in valve-related complication free rate among mechanical (27.5%) and bioprosthetic valves (23.4%) (<i>p</i>=0.9). Three patients with mechanical valves had cerebral hemorrhage, and 1 patient with bioprosthetic valve had structural valve deterioration. <b>Conclusions</b> : Surgical result of valvular disease in hemodialysis patients was as poor as another authors reported previously (5-year survival rate : 30.6%), but survival rate after hemodialysis introduction was not very poor (87.1%). There was no significant difference in survival rate among mechanical and bioprosthetic valves. Bioprosthetic valve has the risk of reoperation due to early structural valve deterioration, but there was no significant difference in valve-related complication free rates. Therefore, we should select prosthetic valve in consideration of individual cases.

Development of a Pseudoaneurysm of the Thoracic Aorta at the Cannulation Site : Our Experience with Three Cases / 日本心臓血管外科学会雑誌

A pseudoaneurysm of the thoracic aorta after cardiac surgery is a rare complication, but can be life-threatening when it is ruptured. The pseudoaneurysm itself presents no symptoms in many cases, or may be similar to an atherosclerotic aortic aneurysm. Therefore, it is usually found incidently during imaging studies. We encountered 3 cases of pseudoaneurysm of the thoracic aorta that developed during the long-term follow-up after congenital cardiac surgery. None of the patients experienced specific symptoms associated with the pseudoaneurysm, and were diagnosed by chest roentgenograms and computed tomography. Most patients who undergo surgery for congenital heart defects as adolescents are free from medical treatment, and do not regularly see a doctor after the surgery. It is important to consider the possibility of a pseudoaneurysm in patients having a history of cardiac surgery.

Giant Para-anastomotic Aneurysm after Thoracoabdominal Aortic Aneurysm Repair / 日本心臓血管外科学会雑誌

Para-anastomotic aneurysms may have dangerous complications such as rupture and thrombosis, with consequent loss of life. As these complications are associated with high mortality rates, early detection and prompt surgical treatment are important. Repair of para-anastomotic aneurysms may be challenging and the surgical approach should be carefully planned. A 66-year-old man had undergone thoracoabdominal aortic aneurysm repair 18 years previously. The diameter of the distal aortic anastomosis was gradually increasing. We comprehensively discussed the surgical approach preoperatively, including consideration of spinal cord protection. Abdominal aortic graft replacement was performed through a midline abdominal incision, with cross-clamping on the proximal side of the aneurysm, continuous intravenous infusion of naloxone, and segmental aortic clamping with distal aortic perfusion and selective visceral perfusion. The left renal artery was reconstructed, and the inferior mesenteric artery and lumbar arteries were preserved.

Aortic Valve-Sparing Operation in a 8 Years Old Boy with Loeys-Dietz Syndrome with Annuloaortic Ectasia / 日本心臓血管外科学会雑誌

An 8 year-old boy had a cardiac murmur pointed out on day three after birth and was given a diagnosis of ventricular septal defect (VSD). He underwent VSD patch closure at two months after birth. He was also found the having Loeys-Dietz syndrome on the basis of mutation of <i>TGFBR2 </i>and physical examination at the age of 2 years. He had been followed up at pediatrics clinic of our hospital since then, and was hospitalized for a 46.5-mm extension of valsalva sinus diameter and moderate aortic insufficiency. The aortic valve was three-cusped and had no abnormality. We performed valve-sparing aortic root replacement. He was discharged on day 18 after the operation without any problems in the postoperative course. Use of an artificial heart valve for the surgery of the aortic root lesion in childhood will probably cause reoperation in the future and difficulty in Warfarin anticoagulation control. A careful decision is needed in the choice of an operation method. Valve-sparing aortic root replacement is a useful operation for patients without aortic valve abnormality.