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A 60-year-old man complained of severe general fatigue on October 11, 1992. Pertinent laboratory findings were: aspantate aminotransferase (AST) 1920 IU, alanine aminotransferase (ALT) 2050 IU, and total bilirubin (T. Bil) 124 micromol/l (normal range, 0-17 micromol/l). Virological assay revealed that hepatitis B surface antigen (HBsAg), anti-hepatitis B e (HBe), anti-HBc, and immunoglobulin M (IgM) anti-HBc were positive, and anti-HBs, HBeAg, and anti-delta antibody were negative. A diagnosis of acute hepatitis due to hepatitis B virus was made. Despite a decrease in transaminase, jaundice worsened and prothrombin time was prolonged. On the 60th day of hospitalization, massive ascites developed, but the patient's consciousness was not impaired. Although, albumin and diuretics were given, the ascites further increased. Paracentesis of 2000 ml of ascitic fluid was performed twice a week. On the 120th day of hospitalization, the patient passed black stools and he exhibited renal failure 3 weeks later. Although severe jaundice persisted, he was still alert. On the 150th day of hospitalization, massive gastrointestinal bleeding occurred, due to hemorrhagic gastritis. Despite receiving intensive care, the patient died. Determination of the HBV DNA sequence revealed two point mutations in the pre-core region; these have not been reported elsewhere. [ABSTRACT FROM AUTHOR]

A 30-year-old female with chronic hepatitis C treated with recombinant alpha-interferon developed serious hemolytic anemia after receiving 10 million units a day for 4 weeks. The results of Coombs' tests were negative before and after interferon therapy. The hemolytic anemia gradually improved after the withdrawal of recombinant alpha-interferon and the administration of methyl-prednisolone. The clinical course suggested that the recombinant alpha-interferon had provoked the hemolytic anemia. [ABSTRACT FROM AUTHOR]

Presents a case study of hemobilia after percutaneous liver biopsy in a patient with pseudoaneurysm. Clinical history of the patient; Results of physical abd laboratory examinations performed on the patient; Treatment; Discussion.

The development of vaccines against infectious diseases requires a different approach from that of therapeutics, because vaccines are inoculated into healthy individuals and have a preventive effect by activating the immunity of the inoculated human. In Japan, "The Guideline for Clinical Trials of Vaccines for the Prevention of Infectious Diseases" was published in 2010 before changes occurred in the vaccine development environment in Japan, such as the introductions of foreign vaccines and simultaneous global development. This study aimed to identify current challenges in vaccine development through a questionnaire-based survey of pharmaceutical companies in Japan and by comparing the domestic and international guidelines and surveying review reports of 35 vaccines approved in Japan between April 2010 and December 2020. Identified challenges included the requirement for protective efficacy trials, efficacy evaluation of combination vaccines, development of multiregional and foreign clinical trials, and immunization of older adults and immunocompromised patients. We propose that new vaccines against infectious diseases should be evaluated for the protective efficacy, preferably through multiregional clinical trials. Additionally, differences in the incidence of infectious diseases or in epidemic virus strains between regions may affect the trials, when multiregional clinical trials are conducted, but immunogenicity-based studies can be conducted if a correlation between protective efficacy and immunogenicity has been established. We suggest that licensed combination vaccines can be used as comparators when an antigen is added to a licensed combination vaccine. We also proposed that the efficacy of a vaccine in non-major subjects, such as older adults or immunocompromised patients could be evaluated by comparing immunogenicity in major subjects with the confirmed protective effects of the vaccine. It is expected that these revisions will lead to the rapid advancement of vaccine development, which should contribute to the improvement of public health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflict of Interest Takashi Nakano receives honorarium from Daiichi Sankyo Co., ltd., Sanofi Co., ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., and Denka Co., ltd., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This report surveyed vaccination decisions during pregnancy based on the package inserts of vaccines approved in Japan, the USA, and Europe. Furthermore, it evaluates vaccination decision-making factors based on the characteristics of the target infections and the modality of the vaccines. Live vaccines known to cause fetal abnormalities are contraindicated for pregnant women, whereas vaccines for life-threatening infectious diseases are authorized for administration during pregnancy when the need is recognized, even for live vaccines. We compared the World Health Organization and European Medicines Agency guidelines on the development of vaccines for pregnant women and surveyed the details of the studies to collect information on SARS-CoV-2 vaccination during pregnancy. In compliance with the guidelines, for all SARS-CoV-2 vaccines, non-clinical reproductive and developmental toxicity studies and clinical trials including non-pregnant women of childbearing age were conducted prior to the vaccination of pregnant women. For all vaccines, information from registries on vaccination during pregnancy are used for post-marketing surveillance. While it is desirable to vaccinate women before pregnancy through planned immunization, whenever possible, pandemics such as H1N1 influenza and COVID-19 may require vaccination even during pregnancy. Necessary and sufficient studies for the decision of vaccination during pregnancy should be carried out promptly.

The efficacy and safety of vaccines for the prevention of infectious diseases are mostly evaluated based on the induction of an immune response against antigens, and do not necessarily depend on the dose administered. Therefore, there are some specific aspects that need to be considered in the development of vaccines and have been described in "The Guidelines for the non-clinical studies of vaccines for the prevention of infectious disease" in Japan. Recent changes in the vaccine development field, such as the introduction of vaccines developed overseas in Japan and vaccine development on a global scale have increased the need for revision of these guidelines. In this study, we identified the current challenges in the development of vaccines through comparison of Japanese and international guidelines. We conducted a questionnaire-based survey of pharmaceutical industries in Japan, and found issues related to non-clinical studies, such as the necessity of safety pharmacology studies and repeated-dose toxicity studies for each route of administration. We examined international guidelines on these issues as well as review reports by regulatory authorities, and determined that the results of repeated-dose toxicity studies can be used to decide whether safety pharmacology studies are required, and that studies to evaluate toxicity due to systemic effects may not be necessary for both intramuscular and subcutaneous administration. We propose revision of the guidelines for the non-clinical studies of vaccines in Japan taking international harmonizaion into account. We expected that the revised guidelines will promote smooth and rational vaccine development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: [Takashi Nakano receives honorarium from Daiichi Sankyo Co., Ltd., Sanofi Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., and Denka Co., Ltd.]., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Bipartite patella has been recognized as an incidental radiographic finding. However, symptomatic bipartite patella is occasionally diagnosed in adolescents and young athletes. The incidence of bipartite patella has been reported at 0.2-1.7, and 1-2 % of these cases are symptomatic. The purpose of this review article was to discuss current concepts relevant to developmental anomaly of ossification type patella partita., Methods: A PubMed database search using the key words "bipartite patella" was performed. Clinical papers reporting the bipartite patella were included. Four German-language studies were also included, three for incidence of bipartite patella and one for classification., Results: A new classification of developmental anomaly of ossification type patella partita based on location and number of fragment was recently proposed. It is simple and useful and applicable to all types of bipartite or tripartite patella. Several imaging studies have reportedly been used to evaluate symptomatic bipartite patella. MRI is currently the most appropriate method used to assess patients with bipartite patella. Although surgical procedures have been developed that reduce excessive traction force by the vastus lateralis muscle on the bipartite fragment, there is not sufficient evidence to support their use for routine treatment of painful bipartite patella., Conclusion: In most symptomatic cases, movement at the interface between the bipartite fragment and the body of the patella presumably causes the pain. Therefore, the existence of apparent motion at the interface should be confirmed by specific imaging studies before surgery. Magnetic resonance imaging findings may provide such evidence by demonstrating a fluid bright signal across the segmentation, typical of pseudoarthrosis., Level of Evidence: V.

Members of Cryptosporidium species, which are protozoan parasites, are prevalent worldwide and can cause diarrhoea in both humans and animals, including dogs. In addition, the Cryptosporidium species harboured in dogs have the potential for zoonotic transmission. The purpose of the present study was to determine the prevalence of Cryptosporidium species infection and perform molecular characterization of isolates in household dogs, pet shop puppies, and dogs kept in a school of veterinary nursing in Japan. Fresh faecal samples were collected once from 529 household dogs (aged from 2 months to 18 years old, from 9 veterinary clinics located in 6 different regions), 471 pet shop puppies (≤ 3 months old, from 4 pet shops located in 2 different regions), and 98 dogs (aged from 2 to 11 years old) kept in a veterinary nursing school. A nested polymerase chain reaction (PCR) assay targeting the 18S rRNA gene was employed for the detection of Cryptosporidium species, and 111 random samples of PCR amplicons (approximately 500-bp) were sequenced for the molecular characterization of the isolates. The prevalences of Cryptosporidium species in household dogs, pet shop puppies, and veterinary nursing school dogs were 7.2%, 31.6%, and 18.4%, respectively. In household dogs, no significant correlation was observed between the prevalence of Cryptosporidium species and the age (≤ 6 months vs. >6 months), living conditions (indoor vs. outdoor), faecal conditions (formed vs. unformed), and location of residence. In pet shop puppies, the prevalence of Cryptosporidium species was not related to faecal condition; however, the prevalence significantly differed among the pet shops. All of the 111 sequence samples (26 from household dogs, 75 from pet shop puppies, and 10 from veterinary nursing school dogs) were identified as Cryptosporidium canis. The present study demonstrates a high prevalence of Cryptosporidium species infections in pet shop puppies and dogs of a veterinary nursing school in Japan. However, because Cryptosporidium hominis and Cryptosporidium parvum are the most common causes of human infections, it is likely that the risk of zoonotic transmission of Cryptosporidium species from dogs to humans is low., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The purposes of this study were to report clinical features of the developmental anomaly of ossification type bipartite or tripartite patella using a large series and to propose a new classification for the developmental anomaly of ossification type bipartite or tripartite patella. The first author prospectively examined 111 patients with symptomatic or asymptomatic bipartite (131 knees) or tripartite (8 knees) patellae. Eighty-six (77%) were male and 25 (23%) were female. Forty-three patients (39%) showed right knee involvement and 40 (36%) showed left, while 28 (25%) showed involvement in both knees. Forty-six bipartite and 4 tripartite patellae (36%) were symptomatic and 85 bipartite and 4 tripartite patellae (64%) were asymptomatic at initial examination. The median age at onset of pain of symptomatic patients (50 knees) was 15.6 ± 8.1 years (range, 10-51 years). The most common symptom was pain at the separated fragments during or after strenuous activity in all 50 knees. Physical examination revealed localized tenderness over the separated fragments in all 50 knees. Bipartite or tripartite patellae were classified by evaluating location and number of fragments. One hundred fifteen knees (83%) were classified as supero-lateral bipartite type, 16 (12%) were lateral bipartite type, 6 (4%) were supero-lateral and lateral tripartite type, and 2 (1%) were supero-lateral tripartite type. For the developmental anomaly of ossification type bipartite or tripartite patella, a classification based on both location and number of fragments is simple and easy to understand and applicable to all types of bipartite or tripartite patella.

The trochlea of the femur is a very unusual site for chondral fracture. Little is known of the mechanism of injuries confined to the articular cartilage of the trochlea of the femur. A very unusual case of chondral fracture of the lateral trochlea of the femur occurring in an adolescent is reported here. The mechanism by which this injury occurred could be evaluated in this patient. The cartilage on the convex surface of the lateral trochlea was likely avulsed proximally by shear force of the patella during rapid extension of the weight-bearing knee from a flexed position. From a viewpoint of mechanism, this injury differs from the more usual osteochondral or chondral fractures of the weight bearing area of the femoral condyle, which are usually accompanied by twisting forces.

This study was performed to assess the diagnostic value of bone scintigraphy to differentiate symptomatic bipartite patella from asymptomatic bipartite patella. Thirty-seven bipartite patellae (15 symptomatic and 22 asymptomatic) were evaluated by bone scintigraphy. Bone scintigraphic activity in bipartite patella was classified into the following four groups. Group A: Eleven bipartite patellae (10 symptomatic and 1 asymptomatic) demonstrated physiological and marked uptake at the epiphysio-metaphysial junction of the distal femur in bone scintiscans. Therefore, high scintigraphic uptake in the bipartite patella was difficult to distinguish from such uptake due to overlap. Group B: Five bipartite patellae (4 symptomatic and 1 asymptomatic) demonstrated both physiologically high scintigraphic uptake at the epiphysio-metaphysial junction of the distal femur and high scintigraphic uptake in the bipartite patella. Group C: Seventeen bipartite patellae (1 symptomatic and 16 asymptomatic) demonstrated abnormally high scintigraphic uptake in the bipartite patella. Group D: Four asymptomatic bipartite patellae did not demonstrate an abnormally high scintigraphic uptake. After excluding Group A, the proportion of positive bone scans in bipartite patella was 84.6% (22 of 26 patellae). Similarly, after excluding Group A, the proportion of positive bone scans in symptomatic bipartite patella was 100% (5 of 5 patellae) and in asymptomatic bipartite patella 81.0% (17 of 21 patellae). Statistical analysis using Fisher's exact test showed no significant differences in the proportion of positive bone scans between both groups (P = 0.5457). In conclusion, abnormally high scintigraphic uptake is frequent findings in both symptomatic and asymptomatic bipartite patella, and bone scintigraphy is not useful to differentiate between them. Therefore, surgical treatment should not be considered based only on scintigraphic findings.

The purpose of this study was to clarify the etiology of painful bipartite patella in adolescents by histopathological examination of excised specimens. We performed excision of a fragment of painful bipartite or tripartite patella from six patients (six knees). The articular cartilage, interposed tissue, bone, and bone marrow of the excised specimens were histologically examined. The articular cartilage was intact in all but two patellae. The predominant composition of the interposed tissue was fibrous tissue in one patient; fibrous tissue and fibrocartilage in four patients; and fibrous tissue, fibrocartilage, and hyaline cartilage in one patient. In the interposed tissue, diffuse degenerative and necrotic fibrocartilage was observed in four patients and focal necrotic fibrocartilage was seen in two patients. In all patients, the central region of the interposed tissue almost completely lacked blood vessels. Other histological features of the interposed tissue included necrosis of the trabecular bone in three patients, irregularly shaped spicules of immature bone in three patients, and fragments of hyaline cartilage in two patients. In all patients the bone marrow adjacent to the interposed tissue showed numerous small blood vessels, and trabecular bone surfaces and the fibrocartilage surface adjacent to this bone marrow was scalloped and lined with numerous osteoclasts. The striking histopathological features of the interposed tissue were fibrous tissue and necrosis of the fibrocartilage. These abnormalities may ultimately lead to the failure of an accessory ossification center to unite with the main portion of the patella.

We report a case of myopathic form of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency with adolescent onset which presented with recurrent rhabdomyolysis and was diagnosed by immunostain of biopsy muscle. She was an 18-year-old woman who showed recurrent episodes of rhabdomyolysis after exercise since the age of 15. The diagnosis was made by the immunostain using anti-VLCAD antibody and the measurement of acyl-CoA dehydrogenase activity for the biopsy muscle. Her elder sister had also showed recurrent episodes of rhabdomyolysis at least two times. The analysis of genomic DNA on blood samples of the patient and her sister was performed and the same mutations were identified. Hence, these sister were revealed to have VLCAD deficiency. We should keep in mind this disorder for those presenting with recurrent rhabdomyolysis. In addition, as far as we know, this is the first report that a correct diagnosis was obtained by immunostain. Immunostain is probably a useful diagnostic procedure to identify an uncommon myopathy.

To determine changes in cervical muscle strength after laminoplasty and to evaluate the relation between muscle strength and neck pain, we measured maximum isometric muscle strength using a handheld dynamometer. We also investigated neck pain before surgery and every month after surgery in 21 subjects who had undergone French-door laminoplasty. Muscle strength decreased particularly 1 month after surgery, the extensor muscles being affected more than the flexors. The strength of both muscle groups increased gradually; and at 1 year after surgery they had regained their presurgical status. All of the subjects complained of severe neck pain after 1 month. Their complaints began to decrease a few months after surgery, although they were still present in nine patients at 1 year after surgery. The correlation between muscle strength and neck pain was strongly negative for extension and flexion in men and for extension in women. No correlation was found between flexor muscle strength and neck pain in women. The extension/flexion ratio was significantly high in the neck pain group 1 year after surgery. Our results suggest that symptoms within a few months after surgery are due to surgical trauma to the soft tissues but that chronic neck pain derives from an imbalance of the two muscle strengths.

A randomized, multicenter, double-blind, parallel-group study was conducted in order to evaluate the hormonal kinetics, pharmacokinetics, efficacy and safety of TAP-144-SR (3M) a three-month sustained-release injectable preparation of leuprorelin acetate, a highly active luteinizing hormone-releasing hormone (LH-RH) derivative by comparing the treatment with two subcutaneous doses of the test medication TAP-144-SR (3M) and the treatment with six subcutaneous doses of the reference medication TAP-144-SR (1M), a 1-month sustained-release injectable preparation. Study participants were 103 patients with prostate cancer in whom a stable anti-tumor effect had been obtained with Leuplin Injection 3.75. The hormonal kinetics revealed that the proportion of the patients "maintaining the castration level of serum testosterone (maximum serum testosterone level during treatment below the castration level [100 ng/dl])" was 100% in both treatment groups. With regard to the efficacy, the proportions of the patients in whom the anti-tumor effects (> or = Stable) of the baseline treatment prior to the initiation of the treatment with the study medication were maintained during the study treatment period (6 months) were comparable; 84.0% with TAP-144-SR (1M) and 80.4% with TAP-144-SR (3M). On evaluation of the pharmacokinetics, the mean value of AUC1-12w of the serum TAP-144 concentration (including the metabolite M-I) for the treatment with TAP-144-SR (3M) was 77.0% that of the treatment with TAP-144-SR (1M). Adverse events were similar in the subjects on TAP-144-SR (3M) and in those on TAP-144-SR (1M). There existed no big differences in kind, incidence or time of occurrence of adverse events between two groups. TAP-144-SR (3M) showed no clinically relevant findings in particular. These results indicate that one dose of TAP-144-SR (3M) is comparable to three doses of the already approved Leuplin injection 3.75 in serum testosterone level-inhibitory effect, efficacy and safety. Hence, it is considered that TAP-144-SR (3M) is a drug suitable for treatment of prostate cancer over a prolonged period of time.

Treatment for acute rectal bleeding from rectal varices in a patient with liver cirrhosis is often difficult. Herein, we report an elderly male with cirrhosis who successfully underwent endoscopic sclerotherapy for rectal bleeding from rectal varices. He had a history of esophageal varices, which were treated by endoscopic sclerotherapy. Three years after the treatment of esophageal varices, he developed massive bright red rectal bleeding. Taking into consideration the risk of treating rectal varices by surgery, we decided to try endoscopic sclerotherapy of the rectal varices. In this case, we injected 16.4 mL of 5% ethanolamine oleate with iopamidole to the rectal varices for the purpose of confirmation of the feeding vein for the varices. After six months, the rectal varices had disappeared. We believe endoscopic sclerotherapy might be an effective therapeutic modality for rectal varices with cirrhosis.

Background: Adenosquamous/squamous cell carcinoma of the gallbladder generally has been considered a lethal disease. The objective of this study was to clarify the effectiveness of resection for patients with adenosquamous/squamous cell carcinoma of the gallbladder., Methods: Twenty-nine patients who underwent resection for either adenosquamous carcinoma (n = 28 patients) or squamous cell carcinoma (n = 1 patient) were analyzed retrospectively. Sixteen patients underwent radical resection, whereas the other patients underwent primary tumor resection alone. To elucidate the factors that influenced postresectional survival, 10 variables (age, gender, presence or absence of gallstones, size of the primary tumor, lymphatic vessel invasion, blood vessel invasion, perineural invasion, TNM stage, residual tumor status, and type of resection) were examined., Results: Twenty-three patients (79.3%) were categorized with T3 or T4 tumors that invaded adjacent organs. The outcome after undergoing radical resection (cumulative 5-year survival rate, 48.6%) was significantly better compared with the outcome of patients after undergoing primary tumor resection alone (cumulative 3-year survival rate, 7.7%; P = 0.004). The outcome after undergoing resection was better in 14 patients who had no residual tumor (cumulative 5-year survival rate, 62.9%) compared with the outcome in 15 patients who had residual tumor (cumulative 5-year survival rate, 0%; P < 0.001). Univariate analysis revealed that residual tumor status (P < 0.001), type of resection (P = 0.004), patient age (P = 0.012), and blood vessel invasion (P = 0.017) were significant prognostic factors. Residual tumor status (P = 0.026) was the only significant independent prognostic factor., Conclusions: Adenosquamous/squamous cell carcinoma of the gallbladder warrants resection only if potentially curative (R0) resection is feasible., (Copyright 2002 American Cancer Society.)

Summary: The purpose of this article is to describe a new and simple technique for arthroscopic suture fixation of avulsion fractures of the intercondylar eminence of the tibia using surgical steels as both suture passers and suture. The looped ends of 2 folded surgical steels being used as suture passers were inserted through 2 tibial drill holes and through the reduced bone fragment into the knee joint cavity and pulled out through the anteromedial portal in front of the knee joint. Outside the knee joint, a third unbent surgical steel to be used as a suture was tied to the 2 small loops of the folded surgical steels very easily. The ends of the folded surgical steels outside the tibia were then retracted back through the tibial drill holes, thereby automatically bringing the third surgical steel through the holes while making a loop over the avulsed fragment. The advantage of this technique is that the suture can be tied to the suture passers outside of the knee joint.

Background: Lymph node spread is the most common pattern of progression in gallbladder carcinoma (GBC) and is a prognostic factor. The purpose of this study was to determine the prevalence of lymph node metastases in patients with resected advanced GBC, and to evaluate the curative effects of radical surgery for patients with lymph node metastasis., Methods: One hundred and eleven consecutive patients who had undergone radical surgery for GBC were included in this study. The pattern of lymph node metastases was examined histopathologically, using the TNM staging of the American Joint Committee on Cancer., Results: There was no neurovascular invasion or lymph node involvement in 15 patients with pT1 tumors. Sixty of 96 patients with pT2-4 tumors had lymph node metastases. The pericholedochal lymph node was the most common metastatic lymph node, followed by the cystic lymph node. The frequency of metastases in retroportal, posterosuperior pancreaticoduodenal, and interaorticocaval lymph nodes was >15% in all cases. pT3-4 tumors had significantly more lymph node involvement (79%) and significantly higher N2:N1 ratios (2.5) than pT2 tumors (46% and 0.6, respectively). There was no difference in 5-year survival between N0 and N1 groups in pT2-4 tumors (66% in N0 and 53% in N1). Patients with N2 disease had a significantly worse prognosis, but 4 patients survived >5 years., Conclusions: The cystic and pericholedochal lymph nodes are the initial site of spread from GBC. The frequency of lymph node involvement is strongly influenced by the depth of invasion of the primary tumor. GBC limited to such lymph node metastases can be cured by surgery in >50% of such cases.

Current histopathological evidence suggests that gall-bladder cancer has two main morphological pathways for its development: de novo (ab initio) origin and adenoma-carcinoma sequence. In order to investigate the genetic difference between them, APC mutations were examined by RNase protection analysis, K-ras mutations by nested polymerase chain reaction-restriction fragment length polymorphism analysis, and p53 gene overexpression by immunohisto-chemical analysis in both tumors and benign lesions of the gall-bladder. Overexpression of the p53 gene was detected in 105 of 164 (64%) de novo carcinomas regardless of size and depth of invasion, but not in 16 tumors of carcinoma-in-pyloric-gland-type adenoma, or in 51 adenomas (47 pyloric gland-type and 4 intestinal-type). K-ras codon 12 mutation was detected in 4 of 40 (10%) de novo carcinomas, all four being associated with p53 gene overexpression, but not in 12 tumors of carcinoma in adenoma or 16 adenomas (14 pyloric gland-type and 2 intestinal-type). APC mutation was not found in 16 de novo carcinomas or the one pyloric gland-type adenoma examined. These results suggest that there are two distinct genetic pathways in gall-bladder carcinogenesis; that is, de novo carcinoma develops from a predominant p53 alteration with low K-ras mutation, and carcinoma-in-pyloric-gland-type adenoma develops from p53-, K-ras-, and APC-gene-unrelated, as yet unknown, alteration.

The expression of p53 protein was studied in formalin-fixed paraffin-embedded specimens of 41 well-differentiated adenocarcinomas of the gall-bladder, six cases of acute cholecystitis and 23 cases of chronic cholecystitis, using a monoclonal p53 (PAb 1801) antibody and streptavidin-biotin. p53 staining was divided into diffuse, focal or sporadic patterns. The relationship between the p53 Labeling Index (p53 LI) and cellular proliferation was also investigated using monoclonal Ki-67 (MIB1) antibody. Twenty-four of the 41 carcinomas (58.5%) had a diffuse staining pattern with a high p53 LI (47-93%) and 9.8% (4/41) had a focal staining pattern with an intermediate p53 LI (22-34%), with no relation to pT stage, tumor size, histologic type or grade of cytologic atypia. The p53 LI was higher than the Ki-67 LI in these tumors except for one. On the other hand, p53 staining was completely sporadic in the non-neoplastic specimens with a low p53 LI (0.2-2.8%). The p53-positive cells in these specimens were located only within areas of Ki-67-positive cells. In conclusion, p53-protein overexpression occurs as an early event in approximately 70% of well-differentiated adenocarcinomas of the gall-bladder, and this alteration is maintained during progression from intramucosal to invasive carcinoma. p53 immunostaining can distinguish malignant from benign lesions of the gall-bladder.

A late phase II study of a new non-steroidal aromatase inhibitor CGS16949A was performed in postmenopausal patients with advanced or recurrent breast cancer. The drug was given orally, 1 mg twice daily for 12 weeks or more. Of 72 evaluable cases, there were 1-CR, 10-PR, 17-"long NC", 12 NC and 32-PD, with "long NC" defined as disease stabilization for more than 6 months. Median time to the onset of PR and median duration of objective tumor responses were 85 and 278 days, respectively. Maximum and median duration of long NC were 471 and 243 days, respectively. Adverse effects were observed in 5 (7.8%) of 64 cases. In laboratory evaluations, slight abnormalities were observed in 11 (17.2%) of 64 cases. No adverse effect and laboratory abnormality was found worse than Grade 1 toxicity. As for Global Utility Rating, treatment with CGS16949A was considered to be useful or better in 24 (32.9%) of 73 cases. Plasma estradiol and estrone concentrations at one month after initiation of the treatment decreased significantly in comparison with pre-treatment levels. Plasma cortisol, testosterone and androstenedione was not changed. Thus, CGS16949A showed good efficacy, tolerability and usefulness in postmenopausal patients with advanced or recurrent breast cancer.

We evaluated the activation of eosinophils in the airways of patients with acute asthma attacks by measuring the concentration of sputum eosinophil cationic protein (ECP) and changes in the electron densities of the eosinophil specific granules in sputum. In six hospitalized patients with asthmatic attacks, sputum samples were collected for seven consecutive days after admission and were used for the evaluation of eosinophil activation. The concentration of sputum ECP, the incidence of changes in the electron densities of eosinophil specific granules and the severity of asthma attacks were highest on the day of admission and decreased in association with each other after treatment. A significant correlation was found between the concentration of sputum ECP and the incidence of changes in the electron densities of eosinophil specific granules. These findings suggest that the eosinophils in the airways are markedly activated and degranulated in asthma attacks.

We examined silent myocardial ischemia in diabetics by treadmill exercise testing. There were 28 diabetic men and 64 diabetic woman without angina, with a mean age of 59 +/- 11 years. Symptom-limited treadmill exercise testing was performed, and we used the electrocardiogram during exercise and immediately after exercise for judgement. ST segment depression was defined as positive if there was at least 0.1 mV of ST depression 80 ms from the J point. It was defined as negative if max heart rate (HR) was more than 80% of target HR and there was no significant ST depression. It was defined as equivocal if there was no significant ST depression but max HR was less than 80% of target HR. In 92 diabetics, 21 patients (23%) showed positive ST depression, 35 (38%) showed negative ST depression, 36 (39%) showed equivocal ST depression. In 56 diabetics exclusive of treadmill equivocal patients, 38% of patients showed positive ST depression. Treadmill positive diabetics had a significantly higher rate of smokers, patients with hypertension, and a higher triglyceride level as compared with treadmill negative diabetics. Coronary arteriography, which was performed in six treadmill positive diabetics, revealed coronary stenosis of more than 75% in four patients.

Some sulfated polysaccharides, such as d-CGN, APS, and DSS, have carcinogenicity to the rat colorectum. These materials first induced colitis, secondly squamous metaplasia, and finally tumors at the colorectum. Initially, colitis was located in the columnar epithelium of the rectum and extended proximally thereafter. Squamous metaplasia persisted in almost all experimental rats and progressed irreversibly. The tumors were adenoma, adenocarcinoma, squamous cell papilloma, and squamous cell carcinoma. Macrophages containing these materials were observed in the lamina propria mucosa and submucosa of the colorectum. There were differences in the molecular weight of the substances and their tumor incidences. However, with regard to their carcinogenicity, these sulfated polysaccharides were inferred to be similar to each other in their target organs and process of tumor development. Consequently, these sulfated polysaccharides may be one entity of carcinogenic sulfates.

We have undertaken studies on carcinogenesis arising from precancerous lesions, such as squamous metaplasia and ulcerative lesions of the rat colorectum, after termination of degraded carrageenan administration. Rates of tumor incidence in groups that were given a 10% diet of degraded carrageenan for 2, 6 and 9 months were 5 rats out of 39 (12.8%), 8 out of 42 (19.0%) and 17 out of 42 (40.5%), respectively. The colorectal squamous metaplasia persisted in all rats and progressed irreversibly. Degraded carrageenan was deposited not only in the colorectal propria mucosa, but also in the other reticuloendothelial organs. These results show that, even with short-term degraded carrageenan administration, degraded carrageenan is carcinogenic to the colorectum of the rat after a prolonged period.