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Background: Primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS) may reduce the risk of subsequent cardiovascular events but remains challenging. The study aim was to evaluate the clinical characteristics and long-term outcomes of patients undergoing primary PCI for STEMI with CS., Methods: We conducted an observational cohort study of patients with STEMI who underwent primary PCI between April 2004 and December 2017 at Juntendo University Shizuoka Hospital. The primary outcome was cardiovascular death (CVD) during the median 3-year follow-up. We performed a landmark analysis for the incidence of CVD from 0 day to 1 year and from 1 to 10 years., Results: Among the 1758 STEMI patients in the cohort, 212 (12.1 %) patients with CS showed significantly higher 30-day CVD rate on admission than those without (26.4 % vs 2.9 %). Landmark Kaplan-Meier analysis showed that CVD from day 0 to year 1 was significantly higher in the patients with CS (log-rank p < 0.0001). Multivariate Cox regression analysis showed that CS was significantly associated with higher cardiovascular mortality (adjusted hazard ratio, 11.8; 95%confidence intervals, 7.78-18.1; p < 0.0001), but the mortality rates from 1 to 10 years were comparable (log-rank p = 0.68)., Conclusion: The cardiovascular 1-year mortality rate for patients with STEMI was higher for those with CS on admission than without, but the mortality rates of >1 year were comparable. Surviving the early phase is essential for patients with STEMI and CS to improve long-term outcomes., Competing Interests: Disclosures None. Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In Abashiri, Hokkaido, northern Japan, composted sewage sludge (CSS) containing a large amount of zinc (Zn) and copper (Cu) is used as fertilizer in agriculture. The local environmental risks of Cu and Zn from such organic fertilizers were studied. The study area, especially the brackish lakes located near the farmlands, is important for inland fisheries. The risks posed by heavy metals to the brackish-water bivalve, Corbicula japonica, was therefore investigated as an example. First, the long-term effect of CSS application in agricultural fields was monitored. Second, using pot cultivation, factors influencing Cu and Zn availability in the presence of organic fertilizers were evaluated under different scenarios of SOM content. In addition, the mobility and availability of Cu and Zn in organic fertilizers were evaluated in a field experiment. In the pot cultivation, both organic and chemical fertilizers increased the availability of Cu and Zn with a decrease in pH, possibly caused by nitrification. However, this decrease in pH was inhibited by higher SOM content, i.e. SOM mitigated the heavy metal risk from organic fertilizer. In the field experiment, potato (Solanum tuberosum L.) was cultivated using CSS and pig manure (PM). As observed in the pot cultivation, the applied chemical and organic fertilizers increased the soil-soluble and 0.1 N HCl-extractable Zn with increased nitrate. Considering the habitat and the LC 50 values of C. japonica that were lower than the concentration of Cu and Zn in the soil solution phase, there is no significant risk from heavy metals in the organic fertilizers. However, the K d values for Zn were significantly lower for CSS or the PM-applied plot in the field experiment soil, indicating a higher Zn desorption rate from organically fertilized soil particles. The potential risk of heavy metals from agricultural lands under changing climate conditions must therefore be monitored carefully., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yasuo Mitsui Nakamaru reports financial support was provided by Tokyo University of Agriculture. Yasuo Mitsui Nakamaru reports a relationship with Tokyo University of Agriculture that includes: employment and funding grants. Yasuo Mitusi Nakamaru has patent pending to Yasuo Mitusi Nakamaru. Co-author Retsushi Matsuda previously studied at Tokyo University of Agriculture as a postgraduate student under the supervision of co-author Takeshi Sonoda., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Recent clinical trials have shown that percutaneous coronary intervention (PCI) for non-culprit lesions (NCLs) reduces the risk of adverse events in patients with ST-segment elevation myocardial infarction (STEMI), but the effect on long-term outcomes remains unclear in acute coronary syndrome (ACS) patients and a real-world clinical setting., Methods: A retrospective observational cohort study of ACS patients who underwent primary PCI between April 2004 and December 2017 at Juntendo University Shizuoka Hospital, Japan, was performed. The primary endpoint was the composite of cardiovascular disease death (CVD death) and non-fatal myocardial infarction (MI) during the mean follow-up period of 2.7 years, and a landmark analysis for the incidence of the primary endpoint from 31 days to 5 years between the multivessel PCI group and the culprit only PCI group was performed. Multivessel PCI was defined as PCI including non-infarct-related coronary arteries within 30 days after the onset of ACS., Results: Of the 1109 ACS patients with multivessel coronary artery disease of the current cohort, multivessel PCI was performed in 364 (33.2 %) patients. The incidence of the primary endpoint from 31 days to 5 years was significantly lower in the multivessel PCI group (4.0 % vs. 9.6 %, log-rank p = 0.0008). Multivariate Cox regression analysis showed that multivessel PCI was significantly associated with fewer cardiovascular events (HR 0.37, 95 % CI 0.19-0.67, p = 0.0008)., Conclusion: In ACS patients with multivessel coronary artery disease, multivessel PCI may reduce the risk of CVD death and non-fatal MI compared to culprit-lesion-only PCI., 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Nutritional status is an important factor affecting prognosis of cardiovascular diseases. We compared major cardiovascular and cerebrovascular events (MACCE) between the malnutrition (geriatric nutritional risk index <92) and non-malnutrition (geriatric nutritional risk index ≥92) groups in 500 stable coronary artery disease patients undergoing percutaneous coronary intervention and evaluated coronary calcification by intravascular ultrasound. Incidences of all-cause death and MACCE differed between the malnutrition and non-malnutrition groups (22% vs 5%, P < 0.001 and 24% vs 6%, P < 0.001). In multivariate Cox proportional hazards regression, malnutrition significantly correlated with all-cause death (P = 0.006) and MACCE (P = 0.010). The proportion of moderate/severe calcification differed between the malnutrition (64%) and non-malnutrition groups (33%, P < 0.001). Multivariate logistic analysis identified age (P < 0.001), malnutrition (P = 0.048), and hemodialysis (P < 0.001) as significantly related to moderate/severe calcification. Malnutrition was an independent risk factor for all-cause death and MACCE in coronary artery disease patients after percutaneous coronary intervention and was associated with moderately/severely calcified lesions., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to examine the clinical and histopathologic effects of neoadjuvant intra-arterial chemoradiotherapy (IACRT) using cisplatin in combination with oral S-1 (tegafur/gimeracil/oteracil potassium) on stage III and IV oral squamous cell carcinoma., Study Design: Thirty patients received infusions of superselective intra-arterial cisplatin 60 mg/m 2 by the Seldinger method and conventional external beam radiotherapy (total 40 Gy) combined with oral S-1 on the day of irradiation. Curative surgery and neck dissection were performed 4 to 6 weeks after IACRT. The clinical response of the primary lesion was evaluated approximately 4 weeks after IACRT. The surgically resected specimens were examined for histologic features according to the grading system for histologic evaluation and for residual tumor grade (RGrades)., Results: Histopathologic evaluation of the therapeutic effect was grade 2 in 10 patients and grade 3 in 16 patients. According to the distribution of RGrades, the remaining tumor cells were mostly in the central area of the primary lesion, as seen in 24 patients., Conclusions: These findings indicate that neoadjuvant IACRT with cisplatin and oral S-1 was an effective treatment, suggesting the possibility of reducing the extent of curative surgery based on RGrades., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Quantitative evaluation of passive tension of the intrinsic muscles of the hand is necessary to assess contracture of the intrinsic muscles accurately. The aim of this study was to evaluate the shear modulus, which is related to passive muscle tension, of the first dorsal interosseous (FDI) and first lumbrical (FL) muscles using shear wave elastography., Methods: Subjects were 18 healthy males. The shear modulus of the FDI and FL muscles was assessed at several proximal interphalangeal (PIP), distal interphalangeal (DIP), metacarpophalangeal (MCP), and wrist joint positions. The position in which the MCP joint was flexed 60° past 0° with PIP-DIP joint extension and that in which the MCP joint was extended 30° past 0° with PIP-DIP joint flexion were respectively defined as the slack and stretched positions. We analyzed whether the shear modulus was affected by finger position (slack or stretched), wrist position (30° flexion past 0° and 30° extension past 0°), and muscle (FDI or FL)., Results: Shear modulus in the stretched position was significantly higher than that in the slack position. The shear modulus of the FL muscle at 30° wrist extension was significantly higher than that at 30° flexion. The shear modulus of the FL muscle was significantly higher than that of the FDI muscle in the stretched position with the wrist at 30° flexion and extension, and in the slack position with the wrist at 30° extension., Conclusions: The shear modulus of the FDI and FL muscles increased with MCP joint extension and PIP-DIP joint flexion. The difference in the muscle characteristics between the FDI and FL muscles should be considered when evaluating or treating contractures of the intrinsic muscles., Clinical Relevance: Shear wave elastography can evaluate the condition of the intrinsic muscles of the hand quantitatively., (Copyright © 2019 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Pulsatile gonadotropin-releasing hormone (GnRH) secretion is indispensable for reproduction in mammals. Kisspeptin neurons in the hypothalamic arcuate nucleus (ARC), referred to as KNDy neurons because of the coexpression of neurokinin B and dynorphin A, are considered as components of the GnRH pulse generator that produces rhythmic GnRH secretion. The present study aimed to investigate if peripheral administration of PF-4455242, a κ-opioid receptor (KOR, a dynorphin A receptor) antagonist, facilitates pulsatile luteinizing hormone (LH) secretion and GnRH pulse generator activity in estrogen-treated ovariectomized Shiba goats to determine the possibility of using KOR antagonists to artificially control ovarian activities. PF-4455242 was intravenously infused for 4 h (1 or 10 μmol/kg body weight/4 h) or as a single subcutaneous injection (1 or 10 μmol/kg body weight). In a separate experiment, the same KOR antagonist (10 μmol/kg body weight/4 h) was intravenously infused during the recording of multiple unit activity (MUA) in the ARC that reflects the activity of the GnRH pulse generator to test the effects of KOR antagonist administration on GnRH pulse generator activity. Intravenous infusion and single subcutaneous injection of the KOR antagonist significantly increased the frequency of LH pulses compared with controls. Intravenous infusion of KOR antagonist also significantly increased the frequency of episodic bursts in the MUA. The present study demonstrates that peripherally administered KOR antagonist stimulates pulsatile LH secretion by acting on the GnRH pulse generator, and peripheral administration of PF-4455242 can be used to facilitate pulsatile LH secretion, which in turn facilitates ovarian activities in farm animals., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Rearranged during transfection (RET)-rearranged non-small-cell lung cancer (NSCLC) is relatively rare and the clinical and computed tomography (CT) image characteristics of patients with an advanced disease stage have not been well documented., Patients and Methods: We identified patients with advanced-stage RET-rearranged NSCLC treated in the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and analyzed the clinical and CT imaging characteristics., Results: In 21 patients with advanced RET-rearranged NSCLC, RET rearrangements were identified using fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. The fusion partner genes were identified as KIF5B (57%), CCDC6 (19%), and unknown (24%). CT imaging showed that 12 primary lesions (92%) were peripherally located and all were solid tumors without ground-glass, air bronchograms, or cavitation. The median size of the primary lesions was 30 mm (range, 12-63 mm). Of the 18 patients with CT images before initial chemotherapy, 12 (67%) showed an absence of lymphadenopathy. Distant metastasis included 13 with pleural dissemination (72%), 10 with lung metastasis (56%), 8 with bone metastasis (44%), and 2 with brain metastasis (11%)., Conclusion: Advanced RET-rearranged NSCLC manifested as a relatively small and peripherally located solid primary lesion with or without small solitary lymphadenopathy. Pleural dissemination was frequently observed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: We have previously reported that the low rate of osteoporosis patients treated with anti-osteoporotic drugs following surgical treatment for the first fragility fractures by orthopaedic surgeons during 3 years from 2000 to 2003 was only 13.1%. Ten years have now passed our previous study, and we hypothesized that the rate of appropriate pharmacologic treatment for the prevention of secondary fractures has improved., Methods: We studied 730 osteoporosis patients (102 men and 628 women; average age of 78 years, range 33-102 years) who underwent surgical treatment for fragility fractures, during 3-year period from 2010 to 2012. The 730 cases consisted of 489 hip fractures and 241 distal radius fractures. All patients were admitted and underwent surgical intervention in hospitals. Variables were examined to ascertain whether pharmaceutical treatment was performed after discharge. Based on these data, we compared results for patients in the present study with those from our previous study., Results: The rate of treatment with anti-osteoporosis medication in the present (16.2%) was slightly but significantly improved from that in our previous study (13.1%). The rate of pharmaceutical treatment following hip fractures increased significantly, while that following distal radius fractures showed no significant change. Regarding the categories of anti-osteoporotic drugs prescribed to the patients, the rate of treatment with bisphosphonate as a higher evidenced drug for the prevention of fractures in the present study was significantly higher than that in our previous study., Conclusion: We demonstrated that the rate of pharmacologic treatment by orthopaedic surgeons and the rate of more effective anti-osteoporotic drugs prescribed to the patients following surgical intervention for the first fragility fracture in the present study were improved in comparison with those of 10 years ago., (Copyright © 2017 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Introduction: Industry funding of surgical training programs poses a potential conflict of interest. With the recent implementation of the Sunshine Act, industry funding can be more accurately determined., Objective: To determine the financial relationship between faculty surgeons within colon and rectal fellowship programs and industry., Design: Review of industry funding based on the first reporting period (August-December, 2013) using the Centers for Medicare and Medicaid Services online database., Setting: ACGME certified colon and rectum surgical fellowship programs., Participants: Overall, 343 Faculty surgeons from 55 colon and rectum surgical fellowship programs were identified using the American Board of Colon and Rectum Surgery website. There was complete identification of faculty surgeons in 47 (85.5%) programs, partially complete identification (i.e., >80%) in 6 (10.9%) programs, and inadequate identification of faculty in 2 (3.6%) programs., Main Outcome: Industry funding as defined by the Sunshine Act included general payments (honorariums, consulting fees, food and beverage, and travel), research payments, and amount invested., Results: In all, 69.1% of program directors and 59.4% of other faculty received at least one payment during the reporting period (Δ9.7%, 95% CI: -4.4% to 23.8%, p = 0.18). Program directors received higher amounts of funding than other faculty ($7072.90 vs. $2,819.29, Δ$4,253.61, 95% CI: $1132-$7375, p = 0.008). Overall, 49 of 53 (93%) programs had surgeons receive funding, with a median of 3.5 surgeons receiving funding per program. A total of 65 companies made payments to surgeons, with 80.1% of the funding categorized as general payments, 16.2% as investments, and 3.7% as research payments., Conclusions: Industry funding was common. This financial relationship poses a potential conflict of interest in training fellows for future practice., (Copyright © 2016 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Malunion is a complication of distal radius fractures and may be associated with a nonunion of the ulnar styloid. We tested the null hypothesis that there is no difference in outcome between patients without ulnar styloid fracture and those with the ulnar styloid nonunion after corrective radial osteotomy for distal radius malunion., Methods: A total of 19 patients with dorsally angulated distal radius malunion who had simultaneous radial closing-wedge and ulnar shortening osteotomies were included. There were 16 women and 3 men with a mean age of 63 years. All patients were followed up for a minimum of 1 year. During surgery, the accompanying ulnar styloid nonunion was not internally fixed in any patient. Eight patients had no ulnar styloid fracture, and 11 had a nonunion of the ulnar styloid. Each group of patients was evaluated on the basis of objective radiographic measurements and functional outcomes as determined on the basis of clinical examination, including wrist motion, grip strength, pain-rating score, Mayo wrist score, and Disabilities of the Arm, Shoulder, and Hand score., Results: There were no differences in the demographic and preoperative radiographic measurements between the nonfracture and nonunion groups. Postoperative radiographic measurements and functional outcomes improved significantly compared with the preoperative status in both groups. There were no significant differences in postoperative radiographic measurements, motion, strength, pain scores, Mayo scores, or Disabilities of the Arm, Shoulder, and Hand scores between the 2 groups. Four of the 11 ulnar styloid nonunions were healed within 1 to 12 months after corrective radial osteotomy., Conclusions: An accompanying ulnar styloid nonunion in patients with distal radius malunion has no apparent adverse effect on outcome or function after corrective radial osteotomy. An accompanying nonunion of the ulnar styloid can heal following corrective radial osteotomy., (Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Diatom fossils from core sediments and living diatoms from water samples of Notoro Lagoon in northern Japan were examined to evaluate natural climate effects on lagoon environmental changes. In 1974, the artificial inlet was excavated. Immediately after, the anoxic bottom water in Notoro Lagoon began to disappear due to an increasing water exchange rate. However, chemical oxygen demand (COD) in the bottom water of Notoro Lagoon gradually increased, with fluctuations, during the last 30 years. In addition, the dominant diatom assemblages in Notoro Lagoon shifted to ice-related and spring bloom taxa after the excavation. The dominant taxa of each year in the sediment core were also strongly related to the timing of lagoon ice melting. This is because the COD in Notoro Lagoon was affected by the deposited volume of blooming diatoms, which was controlled by the duration of ice cover and the timing of ice discharge to the Okhotsk Sea likely due to an air pressure pattern change over the northern North Pacific like the Pacific Decadal Oscillation (PDO)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: In Japan, older adults are assessed by frailty checklist for care prevention. However, the effect of care prevention programs in community-dwelling frail older adults is still unclear., Objectives: The purpose of this study was to investigate whether the care prevention program would reduce care and disability and to measure its cost-effectiveness in frail older adults., Design: This is a prospective study using propensity score matching., Setting and Subjects: A total of 610 community-dwelling older adults were recruited in 2 cities of Japan., Intervention: Subjects in the exercise group (n = 305) attended physical exercise sessions once a week for 16 consecutive weeks. The exercise sessions were in a standardized format consisting of moderate-intensity aerobic exercise, progressive strength training, flexibility and balance exercises, and cool-down activities. The control group (n = 305) received only screening evaluation., Measurements: Primary outcome was long term care insurance requirement certification during the 1-year follow-up period. Secondary outcome measurements were changes of frailty checklist, and care and medical cost., Results: Twenty-five subjects (8.1%) in the exercise group and 55 (18%) in the control group were newly certified for long-term care insurance service requirement in 1 year after the intervention (RR = 2.16, 95% CI = 1.46-3.20). Consequently, the health care cost for the subjects in the exercise group was significantly lower than in the control group (P < .001). Moreover, subjects in the exercise group had significant improvements in total scores of the frailty checklist compared with the control group that worsened after 1 year (exercise group: from 7.41 ± 3.98 to 7.11 ± 4.00, control group: from 7.34 ± 4.27 to 8.02 ± 4.81, F = 12.84, P < .001)., Conclusion: These results suggested that physical exercise is effective in preventing the progression of frailty and further disability in older adults living in the community. We could save heath care costs by our care prevention program., (Copyright © 2012 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.)

Purpose: A recent anatomical study has suggested that considerable contact between the undersurface of the extensor carpi radialis brevis (ECRB) and the lateral edge of the capitellum is the cause of tendon injury in lateral epicondylosis. We hypothesized that this contact might concurrently induce cartilage injuries of the capitellum. The purpose of the present study was to determine the prevalence, location, and severity of cartilage lesions of the radiocapitellar joint accompanying lateral epicondylosis and to identify their correlation with ECRB status., Methods: Arthroscopic assessment of the articular cartilage was performed for 31 elbows in 31 patients with lateral epicondylosis who had surgery. The study group consisted of 18 women and 13 men with a mean age of 50 years (range, 35 to 67 y). The relationship between the presence of the cartilage lesions and patient demographics, preoperative pain visual analog scale score, number of cortisone injections, and surgical findings including ECRB tears were investigated., Results: Cartilage injuries of the capitellum were found in 20 (65%) and cartilage injuries of the radial head were found in 25 (81%) of 31 elbows. Most of the lesions were located on the lateral aspect of the capitellum and radial head. Multivariate logistic regression analysis revealed that the absence of ECRB tears was independently associated with a higher risk of cartilage injuries of the capitellum., Conclusions: Cartilage injury was frequently found in the lateral edge of the capitellum and radial head. Lesions of the capitellum were related to the absence of ECRB tears., Type of Study/level of Evidence: Prognostic IV., (Copyright © 2012 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to evaluate surgical outcomes of arthroscopic débridement for lateral epicondylitis using a validated, patient-assessed scoring system as well as conventional outcome measures. We also wanted to identify potential predictive factors that may be associated with the outcomes., Methods: A total of 20 elbows in 18 patients with chronic lateral epicondylitis who underwent arthroscopic surgery were included. There were nine men and nine women with a mean age of 54 years (range 42-71 years). Operative treatment consisted of débridement of the extensor carpi radialis brevis (ECRB) origin and resection of the radiocapitellar synovial plica interposed in the joint. Outcomes were assessed using a patient rating, visual analogue scale (VAS) pain score, the Japanese Orthopaedic Association (JOA) elbow score, and the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire. The average length of follow-up was 28 months (range 24-40 months)., Results: After surgery, according to the patients' reports, 14 of 20 elbows were much better, and 6 elbows were better. A mean preoperative VAS pain score at rest of 3.9 points improved to 0.3 points (P < 0.0001), and that during activity improved from 7.8 points to 0.9 points (P < 0.0001). The mean preoperative JOA elbow score of 29 points was improved to 90 points (P < 0.0001). The mean postoperative DASH score was 10.6 (range 0-50). Absent of T2-weighted high signal focus of the ECRB origin on preoperative magnetic resonance imaging (MRI) (P = 0.02) and receiving public assistance (P = 0.01) were significantly associated with worse DASH scores., Conclusions: Arthroscopic release was a satisfactory procedure for chronic lateral epicondylitis. Preoperative MRI of the ECRB origin and socioeconomic factors were significantly associated with postoperative residual symptoms evaluated with the DASH score.

Although graft-versus-host disease (GVHD) is a life-threatening complication of hematopoietic stem-cell transplantation (HSCT), its current diagnosis depends mainly on clinical manifestations and invasive biopsies. Specific biomarkers for GVHD would facilitate early and accurate recognition of this grave condition. Using proteomics, we screened for plasma proteins specific for GVHD in a mouse model. One peak with 8972-Da molecular mass (m/z) retained a discriminatory value in 2 diagnostic groups (GVHD and normal controls) with increased expression in the disease and decreased expression during cyclosporin A treatment, and was barely detectable in syngeneic transplantation. Purification and mass analysis identified this molecule as CCL8, a member of a large chemokine family. In human samples, the serum concentration of CCL8 correlated closely with GVHD severity. All non-GVHD samples contained less than 48 pg/mL (mean +/- SE: 22.5 +/- 5.5 pg/mL, range: 12.6-48.0 pg/mL, n = 7). In sharp contrast, CCL8 was highly up-regulated in GVHD sera ranging from 52.0 to 333.6 pg/mL (mean +/- SE: 165.0 +/- 39.8 pg/mL, n = 7). Strikingly, 2 patients with severe fatal GVHD had extremely high levels of CCL8 (333.6 and 290.4 pg/mL. CCL8 is a promising specific serum marker for the early and accurate diagnosis of GVHD.

Enzymatic activity monitoring of caspases, which are a class of cysteine protease, was performed by using peptide arrays based on surface plasmon resonance (SPR) imaging. The strategy of the detection is straightforward, using streptavidin to amplify the SPR signals of the surface-immobilized substrate peptides labeled with biotin at the C termini. Thus, the cleavage of the substrate peptides by caspases was detected as a signal decrease. Using this method, we succeeded in monitoring the activities of purified caspases and caspases in cell lysates. The SPR imaging-based peptide array would be applicable to cell-based drug screening and biochemical studies to reveal signal transduction processes.

We examined associations between nutritional and other lifestyle factors and the prevalence of prostate cancer in a case-control study of Japanese men. Two hundred patients and 200 age-matched controls (+/-5 y) were selected from 3 geographic areas of Japan. BMI, physical activity, occupation, family history of prostate cancer, and medical history were not associated with prostate cancer risk. Isoflavones and their aglycones (genistein and daidzein) were significantly associated with decreased risk. The odds ratio for the highest category (> or = 89.9 mg/d) compared with the lowest category (<30.5 mg/d) of isoflavone intake was 0.42 (95% CI = 0.24-0.72) and the linear trend was significant (P < 0.01). PUFA, (n-6) fatty acids, and magnesium were significantly associated with decreased risk but not after adjustment for isoflavone intake. Isoflavone intake was correlated with the intake of PUFA (r = 0.68, P < 0.001), (n-6) fatty acids (r = 0.69, P < 0.001), and magnesium (r = 0.56, P < 0.001), because soy products contain high levels of these nutrients. On the other hand, isoflavone significantly decreased the risk of prostate cancer regardless of adjustment by PUFA, (n-6) fatty acids or magnesium. In conclusion, our findings indicate that isoflavones might be an effective dietary protective factor against prostate cancer in Japanese men.

The glutamate receptor delta2 (GluRdelta2) is selectively expressed in cerebellar Purkinje cells and plays an important role in motor learning, motor coordination, and long-term depression. Delphilin is identified as a GluRdelta2-interacting protein, selectively expressed in Purkinje cell-parallel fiber synapses, and specifically interacts with the GluRdelta2 C-terminus via its PDZ domain. Here, surface plasmon resonance analyses showed that Delphilin PDZ bound to GluRdelta2 C-terminal peptide (DPDRGTSI), but not to its phosphopeptides (DPDRGphosphoTSI and DPDRGTphosphoSI). We showed the incorporation of phosphate into threonine at -2 (-2T) and serine at -1 (-1S) of GluRdelta2 C-terminus by cAMP-dependent protein kinase (PKA) in vitro. In the experiments using heterologous expression system, Delphilin coimmunoprecipitated with GluRdelta2 was dramatically decreased under the condition with forskolin and isobutylmethylxanthine, which led to cAMP-dependent phosphorylation by PKA. Thus, phosphorylation of -2T and/or -1S of GluRdelta2 C-terminus by PKA may regulate the binding of GluRdelta2 to its scaffolding protein, Delphilin.

A bacterial strain AM7, isolated from soil and identified as Bacillus circulans, produced two kinds of novel cyclic oligosaccharides. The cyclic oligosaccharides were produced from amylose using a culture supernatant of the strain as the enzyme preparation. The major product was a cyclomaltopentaose cyclized by an alpha-(1-->6)-linkage, cyclo-{-->6)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->}. The other minor product was cyclomaltohexaose cyclized by an alpha-(1-->6)-linkage, cyclo-{-->6)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->}. We propose the names isocyclomaltopentaose (ICG5) and isocyclomaltohexaose (ICG6) for these novel cyclic maltooligosaccharides having one alpha-(1-->6)-linkage. ICG5 was digested by alpha-amylase derived from Aspergillus oryzae, cyclomaltodextrin glucanotransferase (CGTase) from Bacillus stearothermophilus, and maltogenic alpha-amylase. On the other hand, ICG6 was digested by CGTase from B. stearothermophilus and B. circulans, and maltogenic alpha-amylase. This is the first report of enzymatically produced cyclomaltopentaose and cyclomaltohexaose, which have an alpha-(1-->6)-linkage in their molecules.

Protease nexin-1, a serine protease inhibitor, is expressed specifically in the dermal papilla (DP) of anagen hair follicles and is suggested to be one of the modulators of the cyclic growth of hair follicles. Accumulating evidence has shown that protease nexin-1 plays its biologic role by inhibiting thrombin action in various systems other than the hair follicle. Thrombin has various physiologic functions including blood coagulation cascade, mostly via activation of protease-activated receptors (PAR). In this study, we investigated the expression of PAR mRNA using RT-PCR in dissected human hair follicles. We showed that PAR-1 mRNA was expressed specifically in the mesenchymal portions, including DP and connective tissue sheath, of anagen hair follicles. Furthermore, immunoreactivity for PAR-1 was detected in the DP and lower portion of connective tissue sheath in the anagen and catagen phases and in the DP of telogen hair follicles. Because only a pharmacologic level (100 nM) of thrombin significantly stimulated cell proliferation and DNA synthesis of the cultured dermal papilla cells, thrombin does not seem to have a mitogenic effect on dermal papilla cells physiologically. These results raise the possibility that thrombin is involved in the cyclic hair growth through its receptor of PAR-1.

Hair follicle formation and maintenance involve intimate interactions between follicular epithelial cells and a group of specialized mesenchymal cells known as the dermal papilla. Using the random primer polymerase chain reaction, we have identified an approximately 1.4 kb osteopontin mRNA that is present in large quantities in cultured rat vibrissa dermal papilla cells but undetectable in cultured rat skin fibroblasts. In situ hybridization showed that the osteopontin gene is expressed in dermal papilla cells of pelage follicles during catagen but not in anagen or telogen. As an acidic glycosylated RGD-containing extracellular matrix protein, osteopontin can function both as a cell attachment protein and as a soluble cytokine playing roles in signaling, cell migration, tissue survival, anti-inflammation, and T-cell-mediated cellular immunity. Our results indicate that the comparison of the mRNA of cultured dermal papilla cells and fibroblasts can lead to the identification of not only anagen-specific genes (e.g., nexin 1), but also a catagen-specific gene. We have thus provided evidence that specific genes are turned on during catagen, which is therefore not simply a passive "degenerative" phase. The functional role of osteopontin in catagen is unclear but it may promote the formation of a tightly aggregated dermal papilla, and/or protect the dermal papilla cells from apoptosis induced by cytokines or hypoxia during catagen.

Copper chaperone is an essential cytosolic factor that maintains copper homeostasis in living cells. Cytosolic metallochaperones have been recently identified in plant, yeast, rodents, and human cells. During our investigation, we found a new member of the copper chaperone family for copper/zinc superoxide dismutase, which was cloned from rats. The new copper chaperone was named rCCS (rat Copper Chaperone for Superoxide dismutase). The cDNA of rCCS was found to have a length of 1094 bp, and the protein analyzed from the cDNA was deduced to contain 274 amino acids. The amino acid sequence of rCCS consists of three domains: A metal binding domain, which has a MXCXXC motif in domain I, a homolog of the Cu/Zn SOD in domain II, and a CXC motif in domain III. The binding of rCCS to Cu/Zn SOD was analyzed by GST column binding assay, and the domain II of rCCS was found to be essential for binding to Cu/Zn SOD, which in turn activates Cu/Zn SOD., (Copyright 2000 Academic Press.)

Protease nexin-1, an inhibitor of serine proteases, plays important parts in the regulation of the growth, differentiation, and death of cells by modulating proteolytic activity. The mRNA for protease nexin-1 accumulates in rat dermal papilla cells in a hair cycle-dependent fashion and its levels are well correlated with the ability of dermal papilla cells to support hair growth. In an attempt to characterize the potential role of protease nexin-1 as a modulator of hair growth in humans, we investigated the steady-state level of protease nexin-1 mRNA in cultured human dermal papilla cells using a semiquantitative technique that involved reverse transcription and polymerase chain reaction, as well as the localization of this mRNA in vivo using dissected hair follicles. Protease nexin-1 mRNA was expressed in all dermal papilla cells examined, and it was also identified in the lower part of the connective tissue sheath. Moreover, we found that levels of protease nexin-1 mRNA were depressed by dihydrotestosterone, the most potent androgen, in cultured dermal papilla cells obtained from balding scalp. Our results suggest that protease nexin-1 might be a key molecule in the control of hair growth in humans and, moreover, that the androgen-mediated downregulation of the synthesis of protease nexin-1 might be associated with the progression of male-pattern baldness.

Analysis of the proportion of cell types in native wood is important for understanding the environmental stresses including an increasing atmospheric CO2 concentration on the structure of wood, especially for the management of plantation forests which will reduce our reliance on natural forests. The conventional method for determining the proportion of cell types is a quantitative microscopy, which is one of the image analyzing systems using a light microscope combined with a microcomputer. However, it is a lengthy multistep procedure. We have examined the feasibility of using Fourier transform Raman spectroscopy for rapid determination of proportion of cell types (fiber, ray parenchyma, vessels, and axial parenchyma) in native wood with using wood meals of two Eucalyptus species, including samples of various ages and colors. By the application of second derivative transformation of Raman spectroscopic data and the partial least-squares regression, we have successfully obtained highly significant correlations between microscopically measured and Raman predicted values for all traits except vessels with correlation coefficients of >0.9 and 0.8, respectively, in the calibration and in the prediction. This method is valid for all traits since vessels can be calculated by the rest of three traits, and will help to solve the effect of the environmental issues on trees and the supplement of renewable raw materials., (Copyright 1999 Academic Press.)

Minoxidil is known to induce hair growth in male pattern baldness, for which development androgen plays a central role. We studied the effect of minoxidil on testosterone metabolism by cultured dermal papilla cells from balding or nonbalding scalp and dermal fibroblasts. In all three groups, 17beta-hydroxysteroid dehydrogenase activity was much higher than 5alpha-reductase activity. Minoxidil increased 17beta-hydroxysteroid dehydrogenase activity by nearly 40% (P < 0.001) in dermal papilla cells of balding scalp, whereas the effect was less marked in dermal papilla cells from nonbalding scalp and dermal fibroblasts. 5alpha-Reductase activity was also slightly increased by minoxidil in dermal papilla cells from balding scalp. Again, the effect on 5alpha-reductase activity was insignificant in the other two groups of cells. Whether such modification of testosterone metabolism in dermal papilla cells of balding scalp by minoxidil is related to its therapeutic effect remains unknown.

In order to examine the relationship between activation of an antipain-sensitive protease and suppression of mutability in UV (UVC)-irradiated human cells, a human cell variant with the high protease activity induced by UV was established and characterized for its susceptibility to UV-induced mutagenicity. Cells of a hypermutable cell strain, RSa, were mutagenized with ethyl methanesulfonate and irradiated with 10 J/m2 UV, followed by exposure to 20 mM antipain for 34 h. Whereas the combined treatment was totally lethal to RSa cells not treated with ethyl methanesulfonate, one surviving clone was isolated from the mutagenized cells and designated UVAP-1. When fibrinolytic protease activity was measured from extracts of the cell, it was found that the protease activity was elevated promptly after UV irradiation, reaching the maximum at 10 min post-irradiation. This protease activity was inhibited by antipain. After UV irradiation the phenotypic mutation frequencies of UVAP-1 cells were much lower than those of the parent RSa cells, as evaluated by the generation of clones resistant to ouabain-killing. Furthermore, mutation at the K-ras codon 12 in genomic DNA was detected in RSa cells but not in UVAP-1 cells. Thus, the protease activation was correlated with the decreased levels of UV-mutagenicity in UVAP-1 cells, supporting the possible involvement of the antipain-sensitive protease activity in the regulation of cellular mutability following UV irradiation.

DNA synthesis activity was examined in fibroblasts and isolated nuclei derived from patients with nevoid basal cell carcinoma syndrome (NBCCS) upon exposure to X-ray and ultraviolet (UV). The DNA synthesis activity in NBCCS fibroblasts increased after X-ray irradiation, i.e., to twice that on mock-irradiation, while it decreased in healthy donor-derived fibroblasts. The DNA synthesis activity in isolated nuclei of X-ray irradiated NBCCS fibroblasts also increased, i.e., more than twice that on mock-irradiated. In the experiments using synchronized cells, DNA synthesis activity showed the most marked increase when the fibroblasts at S phase were irradiated with X-rays. In contrast, UV-irradiated NBCCS fibroblasts showed no such increase in DNA synthesis. These results revealed that DNA synthesis is abnormally induced in X-ray irradiated NBCCS cells and that this abnormality might be related with the tendency of tumorigenesis in NBCCS patients after exposure to X-ray.

In order to investigate the mode of action of testosterone (T) on human hair follicles we studied the metabolism of T and localization of androgen receptors in outer root sheath cells (ORSC) and dermal papilla cells (DPC) from different body sites. T was principally metabolized to androstenedione (delta 4) even in beard ORSC as well as epidermal keratinocytes (EK), and the ratio of apparent 5 alpha-reductase (5 alpha-R) to 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) did not differ between these two kinds of cells. The 5 alpha-R activity in beard DPC was 3 times as high as that in occipital scalp and axillary DPC. The 5 alpha-R of beard DPC exhibited a narrow optimum pH of 5.5, which is characteristic of type 2 enzyme present in androgen target cells. In contrast, 5 alpha-R of DPC from axillary and occipital scalp hair showed a broad optimum pH range between 6.5-9.0 corresponding to type 1 5 alpha-R. Androgen receptors were detected in the DPC of beard and axillary hair follicles, but not in those of occipital scalp hair follicles using immunohistochemical staining with polyclonal anti-androgen receptor antibody. Epithelial cells of the hair bulb were not stained by the antibody. Androgen receptors were also detected in the nuclei of cultured beard and axillary DPC, but the DPC from occipital scalp hair follicles showed little staining with the antibody. We also examined the effects of T on the DNA synthesis and proliferation of cultured ORSC and DPC. T did not have a proliferative effect on either type of cell when cultured alone.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to elucidate the mechanism of action of androgen in human hair follicles, we studied testosterone metabolism by cultured beard outer root sheath cells in comparison with that of epidermal keratinocytes. When cells were incubated as a monolayer in serum-free keratinocyte growth medium with physiological concentrations (25 nM) of [3H]testosterone, the major metabolite was androstenedione in either type of cells. Small amounts of androstanedione, dihydrotestosterone and androsterone were also formed. The ratio of apparent 5 alpha-reductase to 17 beta-hydroxy-steroid dehydrogenase activities ranged from 0.11 to 0.81 and did not differ between these two kinds of cells. After these cells were cultured in the presence of 10% fetal calf serum for 10 days, the activities of both metabolic pathways markedly increased without significant changes of the ratio of activities of these two enzymes. Thus, testosterone was rather converted to weak androgens even in beard outer root sheath cells under the experimental conditions.

The concentrations of 5 alpha-dihydrotestosterone (DHT) and testosterone were measured by radioimmunoassay (RIA) in the crude nuclear and cytoplasmic fractions of facial skin containing large sebaceous glands. The data obtained were compared with those obtained with specimens from non-target areas. The intranuclear levels of DHT and testosterone in facial skin were 0.03 +/- 0.3 pg/micrograms DNA and 0.35 +/- 0.03 pg/micrograms DNA, respectively levels in genital skin. By contrast, both androgens were below detection by RIA in non-target skin. There was no significant difference between men and women with respect to the intranuclear androgen levels in facial skin. These findings support the view that the sebaceous gland is a typical androgen target organ irrespective of sex.

In order to gain a deeper insight into the role of 5 alpha-reductase in the growth of beards in men, we studied some kinetic properties of the enzyme in cell homogenates of cultured human dermal papilla cells from beard and occipital scalp hair. When cell homogenates were incubated with [3H]-testosterone, the 5 alpha-reductase of beard dermal papilla cells exhibited an optimum activity at pH 5.5, whereas the enzyme of dermal papilla cells from occipital scalp hair showed a broad and low plateau between pH 6.0 and 9.0, without a sharp peak. The apparent Michaelis constant of 5 alpha-reductase was 3.3 x 10(-7) M in dermal papilla cells from beard and 2.4 x 10(-5) M in those cells from occipital scalp hair. The apparent Km of 5 alpha-reductase for NADPH was 2.8 x 10(-5) M and 7.6 x 10(-4) M in beard and occipital scalp hair dermal papilla cells, respectively. There were no significant differences in the substrate specificity between these two types of cells. The 5 alpha-reductase activity was recovered mainly in the nuclear fraction of beard dermal papilla cells. By contrast, it was widely distributed among the individual subcellular fractions of dermal papilla cells from occipital scalp hair. These results strongly suggest that these two kinds of dermal papilla cells have different types of 5 alpha-reductase, and that the enzyme in beard dermal papilla cells is similar in characteristics to that in the androgen target organs such as prostate.

This study was performed to evaluate the effect of IUD-bearing uterine secretions on peri-implantation mouse embryo. 83% of blastocysts degenerated by 96 hr after co-culture with uterine fluids from the IUD-bearing uterus. This degeneration rate was contrasted to 78% after heat treatment (56 degrees C for 30 min) of the IUD-bearing uterine secretions. These results suggest that embryotoxic agents are present in the fluid of the IUD-bearing uterus, especially in the supernatant component and that these agents may be related to the presence of macrophage or a chemical mediator produced by macrophage.

Concentration of mast-cell precursors in hematopoietic tissues of mouse embryos was evaluated by a limiting dilution method. Cells from yolk sacs, livers, and bodies of (WB x C57BL/6)F1 (hereafter called WBB6F1)- +/+ embryos were injected directly into the skin of adult WBB6F1-W/Wv mice which were genetically depleted of tissue mast cells. Concentration of mast-cell precursors was calculated from the proportion of injection sites at which mast cells did not appear. Since the concentration of mast-cell precursors in the yolk sac was about 30 times as great as that of embryonic body at Day 9.5 of the pregnancy, the mast-cell precursors seemed to be generated within the yolk sac. The concentration in the yolk sac reached the maximum level at Day 11, and then dropped markedly at Day 13. In contrast, mast-cell precursors increased from Day 11 to Day 15 in the fetal liver. As a result, the concentration of 11-day yolk sacs was comparable to that of 15-day fetal liver. Although intravenous injection of 15-day fetal liver cells (2 x 10(6)) rescued the general mast-cell depletion of WBB6F1-W/Wv mice, the intravenous injection of the same number of 11-day yolk sac cells did not rescue it. In contrast with fetal livers, yolk sacs scarcely contained hematopoietic stem cells which were measured by spleen colony formation. Therefore, the mast-cell precursors of the yolk sac may not originate from such stem cells.

A case with extra-adrenal pheochromocytoma, which was found by chance in the course of renovascular hypertension, is reported. The tumor was on the stenotic portion of the right renal artery. The results of examinations for pheochromocytoma were not conclusive, that is, inconsistent elevation of plasma catecholamines and urinary catecholamine excretion, equivocal results of pharmacological tests for pheochromocytoma, and negative results in [131I]metaiodobenzylguanidine scintigraphy. The stenosis of the right renal artery disappeared, the blood pressure was normalized by surgical resection of the tumor, and the extra-adrenal pheochromocytoma was finally diagnosed by pathohistological findings. Renovascular hypertension appeared to be the primary cause of this hypertension, judging from the significant decrease in blood pressure induced by an angiotensin II analog and a renal vein renin ratio of 7.3. Even in the case of obvious renovascular hypertension, the possibility of this unusual coexistence with pheochromocytoma should be considered.

We treated a patient in whom hepatocellular and cholangiocellular cancer nodules in the liver were of independent occurrence. A 57-year-old Japanese male was admitted with a diagnosis of liver tumour, detected by a scan on a follow-up study of chronic liver disease. Computed tomography and hepatic angiography demonstrated two nodules located on different sites of the right lobe of the liver and which were suggestive of primary liver cancers. He underwent hepatic resection and each tumour was histologically proved to arise independently from hepatocellular and bile duct origins. This may be the first report of patient surgically treated for two different types of carcinoma in the liver.

Concentration of mast-cell precursors in the skin and liver of mouse embryos was evaluated by the limiting dilution analysis. The concentration of mast-cell precursors in the liver of (WB X C57BL/6)F1 (hereafter WBB6F1)-+/+ embryos reached the maximum level at Day 15 of the pregnancy, whereas the concentration in the skin at Day 17. The concentration of 17-day skin was about 10 times as high as that of 15-day liver. Appearance of morphologically identifiable mast cells in the skin followed the increase in concentration of the skin precursors. Concentrations of mast-cell precursors in the skin and liver of mutant embryos of Sl/Sld genotype were also measured to clarify the mechanism of mast-cell depletion in this mutant. Although the concentration of mast-cell precursors in the liver of WBB6F1-Sl/Sld embryos was comparable to that of the WBB6F1-+/+ embryos, the concentration in the skin of the Sl/Sld embryos was about 1% that of the +/+ embryos. Moreover, the concentration of morphologically identifiable mast cells in the skin of the Sl/Sld embryos was about 0.1% that of the +/+ embryos. Thus, mast-cell production in Sl/Sld embryos seemed to be suppressed at two stages; (1) during deficient invasion of liver-derived precursors into the skin, or the decreased proliferation of these cells, or both of these causes, (2) during differentiation of the precursors into mast cells.

The effects of the application of 7,12-dimethylbenz(alpha)anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on the differentiation of tissue mast cells were investigated. Giant granules of beige (C57BL/6-bgJ/bgJ, Chédiak-Higashi syndrome) mice were used to distinguish different populations of mast cells. In the normal C57BL/6 mice that had been irradiated and injected with bone marrow cells of beige C57BL/6 mice (bgJ/bgJ leads to +/+ chimeras), mast cells in the skin remained normal in type and mast cell precursors in the bone marrow and peripheral blood were of the beige type. When DMBA was painted onto the skin of such bgJ/bgJ leads to +/+ chimeras, the number of beige mast cells increased, but the number of normal mast cells did not change. On the other hand, the number of both normal and beige mast cells increased when TPA was applied to the bgJ/bgJ leads to +/+ chimeras. Autoradiographic study showed that beige mast cells proliferated more than normal mast cells after DMBA applications, whereas the proliferations was comparable in both types of mast cells after TPA applications. The present results indicate that the effects of DMBA applications on differentiation of mast cells are different from those of TPA applications.

In order to obtain biochemical indicators for histopathological, biological and clinical malignancy of renal cell carcinoma (RCC), concentrations of protein, RNA, DNA and polyamines in 14 samples of RCC were measured and examined on their histopathological properties and clinical malignancies. The concentration of spermidine in RCC was significantly higher than that in normal renal tissue and a statistically significant difference was not detected between the concentrations of the other compounds in RCC and normal tissue. The concentration of spermidine and the ratio of spermidine/spermine were found to increase in the order of normal tissue, the well-differentiated type and the poorly-differentiated type of RCC while no significant difference was detected between the concentrations of the other compounds in these types. There was no difference in the concentrations of the compounds examined among the non-metastasis and istant-metastasis groups of RCC.

A novel gamma-glutamyl transpeptidase was found in a renal carcinoma tissue. This enzyme electrophoresed more quickly than that of normal kidney, but more slowly than normal liver enzyme. Their Rf values are 0.46, 0.33, and 0.52 for the renal carcinoma, normal kidney and normal liver enzyme, respectively. After treatment of the renal carcinoma and normal kidney enzyme with neuraminidase, the renal carcinoma gamma-glutamyl transpeptidase still electrophoresed slightly faster than that of normal kidney. The catalytic properties of the renal carcinoma gamma-glutamyl transpeptidase were almost the same as those of normal kidney except for molecular weight; the molecular weight for the renal carcinoma was estimated to be about 130 000, while that of normal kidney was about 90 000. These results may mean that the enzyme of the renal carcinoma is different from that of normal kidney in chemical constituents other than sialic acid. Of 10 patients with renal carcinoma examined electrophoretically, 5 posessed this novel enzyme in their renal carcinoma tissues.

The course and treatment of a life-threatening hemorrhagic episode in a patient with hemophilia A whose plasma contained a high concentration of an inhibitor of factor VIII activity is presented. The inhibitor of factor VIII was localized to the most anodal fractions of immunoglobulin G on electrophoresis, and was thus presumed to be an antibody directed against factor VIII. No therapeutic benefit occurred with infusions of massive amounts of fresh blood and factor VIII concentrates, or with a brief course of immunosuppressive therapy. Administration of standard and activated prothrombin complex concentrates resulted in reduction of the partial thromboplastin time to almost normal values and control of hemorrhage. Eight months later, another hemorrhagic episode occurred. Although a higher titer of inhibitor of factor VIII activity was still present in the patient's plasma, a beneficial therapeutic response was again achieved with standard prothrombin complex infusions.