Coronavirus disease 2019-associated thrombotic microangiopathy treated with plasma exchange and antihypertensive therapy in a patient with HIV: A case report with literature review.

RATIONALE: Coronavirus disease 2019 (COVID-19) is an infectious disease that often causes complications in multiple organs and thrombosis due to abnormal blood coagulation. This case report aimed to describe the clinical course of COVID-19-associated thrombotic microangiopathy (TMA) and reviewed the comprehensive information on TMA, thrombotic thrombocytopenic purpura (TTP), and atypical hemolytic uremic syndrome associated with COVID-19 in the past literature. PATIENT CONCERNS: A 46-year-old Japanese man was diagnosed with human immunodeficiency virus infection 10 years ago and treated with antiretroviral therapy. The patient presented with fever, malaise, hematuria, and bilateral upper abdominal discomfort for the past 4 days. DIAGNOSES: COVID-19-associated TMA was diagnosed based on a positive polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 and laboratory findings such as thrombocytopenia, acute kidney injury, and hemolytic anemia. Malignant hypertension and human immunodeficiency virus infection were also considered as differential diagnoses of TMA. INTERVENTIONS: Considering the possibility of TTP, plasma exchange was performed, and glucocorticoids were administered. Hemodialysis was performed for acute kidney injury. Antihypertensive drugs were administered to control the high blood pressure. OUTCOMES: Platelet count and renal function improved, and hemodialysis was no longer required. The patient was in good general condition and was discharged from the hospital. LESSONS: COVID-19-associated TMA should be considered as a differential diagnosis during the COVID-19 epidemic. Excessive inflammation and severe COVID-19 are not essential for TMA development. Early intervention using conventional TMA treatments, such as plasma exchange and corticosteroids, might be important in improving prognosis while differentiating between TTP and atypical hemolytic uremic syndrome. Antihypertensive therapy may be helpful in the treatment of COVID-19-associated TMA.

Successful dual antiviral therapy with remdesivir and ensitrelvir in a case of prolonged COVID-19 following B-cell depleting immunotherapy for malignant lymphoma.

Prolonged COVID-19 following B-cell depleting immunotherapy for malignant lymphoma is characterized by repeated cycles of remission followed by symptom recurrence, persistent detection of SARS-CoV-2, and profound humoral immunodeficiency. To the best of our knowledge, the present report is the first to describe dual antiviral therapy with remdesivir and ensitrelvir for prolonged COVID-19 following B-cell depleting immunotherapy for malignant lymphoma. A 59-year-old, female patient with a history of follicular lymphoma treated with obinutuzumab and bendamustine contracted COVID-19 despite receiving a single course of standard remdesivir therapy. She received dual antiviral therapy with remdesivir following a five-day course of oral ensitrelvir, which improved her clinical symptoms and chest radiology findings and cleared SARS-CoV-2 from respiratory samples. Dual antiviral therapy with remdesivir and ensitrelvir may be sufficient to stop viral replication and promote clinical resolution in prolonged COVID-19 following B-cell depleting immunotherapy for malignant lymphoma.

Vertebral Osteomyelitis Caused by Mycobacterium arupense Mimicking Tuberculous Spondylitis: First Reported Case and Literature Review.

Mycobacterium arupense is a slow-growing, nontuberculous mycobacterium widely found in the environment and is known to cause tenosynovitis and osteomyelitis, mainly in the hands and wrists. We present the first case of vertebral osteomyelitis caused by M arupense in a 78-year-old man with renal cell carcinoma. The patient had a history of tuberculous pleuritis in childhood. Although the nucleic acid amplification test of the vertebral tissue for Mycobacterium tuberculosis was negative, we initiated tuberculosis treatment based on the history and pathological findings of auramine-rhodamine-positive organisms and epithelioid cell granulomas. Subsequently, the isolated mycobacterium was identified as M arupense by genome sequencing. Accordingly, the treatment regimen was changed to a combination of clarithromycin, ethambutol, and rifabutin. Owing to a subsequent adverse event, rifabutin was switched to faropenem, and the patient was treated for a total of 1 year. In previous literature, we found 15 reported cases of bone and soft tissue infections caused by M arupense, but none of them had vertebral lesions. Physicians should be aware that M arupense can cause vertebral osteomyelitis mimicking tuberculous spondylitis. In addition, molecular testing of isolated mycobacteria is essential for diagnosis, even if tuberculous spondylitis is suspected.

Clinical impact and early prediction of carbapenem-resistant Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation recipients.

OBJECTIVE: Although antipseudomonal agents are administered in high-risk patients, no reports have focused on the risk of carbapenem-resistant (CR) Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. METHODS: We retrospectively studied a cohort of adult allo-HSCT recipients with P. aeruginosa bacteraemia, focusing on a comparison between carbapenem-sensitive (CS) and CR P. aeruginosa after initiating conditioning chemotherapy at our institute between January 2005 and December 2020. The incidence, all-cause 30-d mortality of P. aeruginosa bacteraemia, and risk factors for carbapenem resistance among patients with P. aeruginosa bacteraemia in allo-HSCT recipients were evaluated. RESULTS: Forty-eight patients with P. aeruginosa bacteraemia were included, with an incidence of 3.84/100 recipients (CS = 1.92 vs. CR = 1.92). The all-cause 30-d mortality was significantly higher in CR P. aeruginosa bacteraemia (CS = 4.2% vs. CR = 39.1%; P = 0.003). The factor significantly associated with CR P. aeruginosa bacteraemia was carbapenem use for at least 3 d within 30 d before the onset of bacteraemia (odds ratio = 8.92; 95% confidence interval: 1.35-58.90). Inappropriate antimicrobial selection was significantly more frequent in CR P. aeruginosa bacteraemia (CS = 0% vs. CR = 29.2%; P ˂ 0.009). CONCLUSION: Empirical combination therapy with reference to antimicrobial susceptibility profiles in each institution should be considered when CR P. aeruginosa bacteraemia is suspected in allo-HSCT recipients based on the risk of carbapenem exposure.

Ecthyma gangrenosum caused by Staphylococcus aureus in hematological malignancies: Case reports and literature review.

RATIONALE: Ecthyma gangrenosum (EG) is a potentially life-threatening, systemic infection generally caused by Pseudomonas aeruginosa. Data on EG caused by Staphylococcus aureus in patients with hematological malignancies are scarce. The present case report aimed to describe the clinical features of EG caused by S. aureus in patients with hematological malignancies and to provide a comprehensive review of previous studies on the topic. PATIENT CONCERNS: The first patient was a 61-year-old man with acute myeloid leukemia who presented fever and multiple lesions during chemotherapy. The second patient was a 47-year-old man with myelodysplastic syndrome who developed progressive erythematous necrotic plaques on his extremities and face. DIAGNOSIS: Both cases were diagnosed as EG caused by S. aureus. While the first patient had concurrent methicillin-resistant S. aureus (MRSA) bacteremia, the second patient had positive results only for tissue culture of the skin lesion isolated methicillin-sensitive S. aureus. INTERVENTIONS: Vancomycin was initiated with critical care to the first patient. Cefazolin was administered to the second patient for 3 weeks, followed by cephalexin for 1 week. OUTCOMES: The first patient died of a brain hemorrhage and multiple organ failure. The second patient was cured without relapse. LESSONS: Of 18 patients in the previous and current studies with EG caused by S. aureus, 6 (33%) had an underlying hematological malignancy, and 10 (56%) had EG caused by MRSA. While 28% of the patients had positive blood cultures, all tissue cultures were positive. All 3 fatalities had concurrent bacteremia (MRSA caused two). EG caused by MRSA with concurrent bacteremia can be fatal, especially in patients with hematological malignancies. Although S. aureus-associated EG in patients with hematological malignancies is relatively uncommon, tissue cultures with an initial gram stain smear are essential for selecting appropriate empirical antimicrobials, including the coverage of S. aureus.

Streptococcus gallolyticus subspecies pasteurianus bacteremia accompanied by acute pancreatitis.

INTRODUCTION: While Streptococcus gallolyticus subsp. gallolyticus has a well-known association with colorectal cancer, an epidemiological association between S. gallolyticus subsp. pasteurianus (SGSP) and hepatobiliary diseases has been suggested. Here we described a case of gallstone pancreatitis and SGSP bacteremia in which species-identification by Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF MS) helped to diagnose the biliary etiology. CASE REPORT: A 61-year-old Japanese man without history of alcohol consumption was hospitalized for acute pancreatitis. His past medical history included endoscopically treated familial adenomatous polyposis. A blood culture grew gram-positive cocci, identified to be SGSP by MALDI-TOF MS. A contrast-enhanced computed tomography scan showed pancreatic enlargement and increased fatty tissue concentration around the perirenal and pararenal space. He was diagnosed with acute pancreatitis and subsequently recovered after appropriate antimicrobial therapy and supportive care. Subsequent magnetic resonance cholangiopancreatography showed gallstones in the gallbladder neck, suggesting the cause of the acute pancreatitis. Seven months after admission, cholecystectomy was performed for cholelithiasis. CONCLUSION: This case highlights that the identification of subspecies enabled by MALDI-TOF MS supports the diagnosis of the underlying etiology from the microbiological point of view.

Central nervous system mucormycosis in a patient with hematological malignancy: A case report and review of the literature.

Invasive mucormycosis is a refractory fungal infection. Central nervous system (CNS) mucormycosis is a rare complication caused by infiltration from the paranasal sinuses or hematogenous dissemination. Here, we present a case of a brain abscess, due to mucormycosis, diagnosed using burr craniotomy. A 25-year-old Japanese woman with relapsed-refractory acute lymphoblastic leukemia underwent cord blood transplantation (CBT). The patient experienced prolonged and profound neutropenia, and oral voriconazole was administered as primary antifungal prophylaxis. The patient received a conditioning regimen on day -11 and complained of aphasia and right hemiparesis on day -6. Magnetic resonance imaging (MRI) revealed a T2-weighted high-intensity area in the left frontal cortex. A brain abscess was suspected, and liposomal amphotericin B (L-AMB) administration was started. The patient underwent CBT as scheduled and underwent neutrophil engraftment on day 14. Although the patient achieved complete remission on day 28, her consciousness level gradually deteriorated. MRI revealed an enlarged brain lesion with a midline shift sign, suggesting brain herniation. Craniotomy was performed to relieve intracranial pressure and drain the abscess on day 38, and a diagnosis of cerebral mucormycosis was confirmed. The L-AMB dose was increased to 10 mg/kg on day 43. Although the patient's consciousness level improved, she died of hemorrhagic cystitis and aspiration pneumonia. Cerebral mucormycosis should be suspected if neurological symptoms are observed in stem cell transplant recipients. Prompt commencement of antifungal therapy and debridement are crucial because mucormycosis has a poor prognosis.

Theoretical Study of the Mechanism of Ribosomal Peptide Bond Formation Using the ONIOM Method.

Peptide bond formation in living cells occurs at the peptidyl transferase center (PTC) of the large ribosomal subunit and involves the transfer of the peptidyl group from peptidyl-tRNA to aminoacyl-tRNA. Despite numerous kinetic and theoretical studies, many details of this reaction -such as whether it proceeds via a stepwise or concerted mechanism- remain unclear. In this study, we calculated the geometry and energy of the transition states and intermediates in peptide bond formation in the PTC environment using the ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) method. The calculations indicated that the energy of the transition states of stepwise mechanisms are lower than those of concerted mechanisms and suggested that the reaction involves a neutral tetrahedral intermediate that is stabilized through the hydrogen-bonding network in the PTC environment. The results will lead to a better understanding of the mechanism of peptidyl transfer reaction, and resolve fundamental questions of the steps and molecular intermediates involved in peptide bond formation in the ribosome.

Development of a Risk Prediction Score to Identify High-Risk Groups for the Critical Coronavirus Disease 2019 (COVID-19) in Japan.

Coronavirus disease 2019 (COVID-19) emerged in mid-December 2019 and has rapidly spread worldwide. We conducted a retrospective analysis of data from patients with COVID-19 to construct a simple risk prediction score to be implemented in prehospital settings. Patients were classified into critical and non-critical groups based on disease severity during hospitalization. Multivariate analysis was performed to identify independent risk factors and develop a risk prediction score. A total of 234 patients were included in the study. The median age of the critical group was significantly older than that of the non-critical group (68.0 and 44.0 years, respectively), and the percentage of males in the critical group was higher than that in the non-critical group (90.2% and 60.6%, respectively). Multivariate analysis revealed that factors such as age ≥ 45 years, male sex, comorbidities such as hypertension and cancer, and having fever and dyspnea on admission were independently associated with the critical COVID-19 infection. No critical events were noted in patients with a total risk factor score of ≤ 2. Contrastingly, patients with a total risk factor score ≥ 4 were more likely to have critical COVID-19 infection. This risk prediction score may be useful in identifying critical COVID-19 infections.

Characteristics and outcomes of coronavirus disease 2019 (COVID-19) patients with cancer: a single-center retrospective observational study in Tokyo, Japan.

BACKGROUND: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of coronavirus disease 2019 (COVID-19), data on the clinical characteristics of COVID-19 patients with cancer are limited. This study aimed to evaluate the clinical characteristics and outcomes including mortality and viral shedding period in COVID-19 patients with cancer in Japan. METHODS: We retrospectively analyzed 32 patients with a history of cancer who were referred to our hospital between January 31, 2020 and May 25, 2020. We evaluated the association between clinical outcomes and potential prognostic factors using univariate analyses. RESULTS: The median age was 74.5 (range 24-90) years and 22 patients (69%) were men. A total of 11 patients (34%) died. Our analyses demonstrated that the mortality was significantly associated with lymphocyte count, albumin, lactate dehydrogenase, serum ferritin, and C-reactive protein on admission. The median period between illness onset and the first effective negative SARS-CoV-2 PCR result was 22 days (interquartile range 18-25) in survivors. Of four patients with hematological malignancy who developed COVID-19 within the rest period of chemotherapy, three died and the other patient, who received bendamustine plus rituximab therapy, had the longest duration of viral shedding (56 days). CONCLUSION: Our study suggested that the risk factors for mortality previously reported in general COVID-19 patients, including lymphocytopenia, were also effective in cancer patients. Patients who received cytotoxic chemotherapy recently or were treated with chemotherapy, which can lead to lymphocyte reduction, had poor prognosis and prolonged periods of viral shedding.

Nontuberculous mycobacterial bloodstream infections after allogeneic hematopoietic stem cell transplantation.

Non-tuberculous mycobacteria (NTM) bacteremia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare, and limited data exist. We described the features of NTM bacteremia following allo-HSCT recipients in our hospital with a comprehensive review of the literature. Among the four cases of NTM bacteremia after allo-HSCT recipients in our hospital, two were catheter-related bloodstream infections (CRBSI), one was disseminated, and one was an unknown source of infection. Based on our report and the past literature, the incidence rate of NTM bacteremia was 0.1-1.3%. CRBSI (57%) was more common than disseminated infection (29%). Most cases with CRBSI were caused by rapidly growing mycobacteria (88%) and showed good prognoses under appropriate antimicrobial therapies. In contrast, slowly growing mycobacteria (71%) was more common than rapidly growing mycobacteria in disseminated NTM bacteremia. Although disseminated NTM bacteremia can remain stable with appropriate long-term management, three out of seven cases died of multi-organ failure. Background immunodeficiency after allo-HSCT and transplant-related comorbidities may be attributable to subsequent poor prognosis.

Unusual manifestation of disseminated herpes simplex virus type 2 infection associated with pharyngotonsilitis, esophagitis, and hemophagocytic lymphohisitocytosis without genital involvement.

BACKGROUND: Herpes simplex virus (HSV) has various presentations, depending on the patient's immune status, age, and the route of transmission. In adults, HSV type 1 is found predominantly in the oral area, and HSV type 2 (HSV-2) is commonly found in the genital area. HSV-2 infection without genital lesions is uncommon. Herein we report a unique case of pharyngotonsillitis as an initial manifestation of disseminated HSV-2 infection without genital involvement. CASE PRESENTATION: A 46-year-old male was admitted to our hospital with a 1-week history of fever and sore throat. His past medical history included hypereosinophilic syndrome diagnosed at age 45 years. Physical examination revealed throat congestion, bilaterally enlarged tonsils with exudates, tender cervical lymphadenopathy in the left posterior triangle, and mild epigastric tenderness. The laboratory data demonstrated bicytopenia, elevated liver enzyme levels, and hyperferritinemia. A bone marrow smear showed hypocellular marrow with histiocytes and hemophagocytosis. The diagnosis of HLH was confirmed, and the patient was treated with methylprednisolone pulse therapy on days 1-3. On day 5, despite initial improvement of the fever and sore throat, multiple, new, small bullae developed on the patient's face, trunk, and extremities. Additional testing showed that he was positive for HSV-specific immunoglobulin M and immunoglobulin G. Disseminated HSV infection was suspected, and intravenous acyclovir (10 mg/kg every 8 h) was begun. A subsequent direct antigen test of a bulla sample was positive for HSV-2. Moreover, tonsillar and esophageal biopsies revealed viral inclusion bodies. Immunohistochemical staining and a quantitative real-time polymerase chain reaction (PCR) assay confirmed the presence of HSV-2. Disseminated HSV-2 infection with multiple bullae, tonsillitis, esophagitis, and suspected hepatic involvement was diagnosed. After a 2-week course of intravenous acyclovir, his hematological status and liver function normalized, and his cutaneous skin lesions resolved. He was discharged on day 22 in good general health and continued taking oral valacyclovir for viral suppression due to his immunosuppressed status. CONCLUSION: Disseminated HSV-2 infection should be considered as one of the differential diagnoses in patients with pharyngotonsillitis and impaired liver function of unknown etiology even if there are no genital lesions.

Pulmonary Mucosa-associated Lymphoid Tissue Lymphoma with Spontaneous Regression after Computed Tomography-guided Needle Biopsy: A Case Report and Summary of 8 Reported Cases.

A 72-year-old woman was admitted to our hospital with a solitary right lung nodule. She had no symptoms and no abnormal physical findings except for bladder cancer. Tumor markers were mildly elevated but no other abnormal laboratory data were found. The nodule was diagnosed to be pulmonary mucosa-associated lymphoid tissue lymphoma on computed tomography-guided needle biopsy. Thereafter, she first underwent surgery for bladder cancer. The lung nodule was found to have slightly increased at three months and then disappeared at 15 months after the biopsy. The notable clinical course of this rare disease suggests the effectiveness of a non-interventional treatment strategy.

Occurrence of Donor Cell-derived Lymphoid Blast Crisis 24 Years Following Related Bone Marrow Transplantation for Chronic Myeloid Leukemia.

We herein report a unique case of donor cell leukemia (DCL), as donor cell-derived lymphoid blast crisis of chronic myeloid leukemia (CML) was observed 24 years after related bone marrow transplantation for CML in the chronic phase. Short tandem repeat testing of the leukemic blast sample revealed full donor chimerism, strongly indicative of DCL. The original donor is healthy with a normal complete blood cell count for the past 24 years. This rare case may provide a precious opportunity to consider not only the underlying mechanism of DCL, but also the pathogenesis of CML.

Repeated anesthetic management for a patient with Klippel-Feil syndrome.

Klippel-Feil syndrome (KFS) is a rare disease characterized by a classic triad comprising a short neck, a low posterior hairline, and restricted motion of the neck due to fused cervical vertebrae. We report repeated anesthetic management for orthognathic surgeries for a KFS patient with micrognathia. Because KFS can be associated with a number of other anomalies, we therefore performed a careful preoperative evaluation to exclude them. The patient had an extremely small mandible, significant retrognathia, and severe limitation of cervical mobility due to cervical vertebral fusion. As difficult intubation was predicted, awake nasal endotracheal intubation with a fiberoptic bronchoscope was our first choice for gaining control of the patient's airway. Moreover, the possibility of respiratory distress due to postoperative laryngeal edema was considered because of the surgeries on the mandible. In the operating room, tracheotomy equipment was always kept ready if a perioperative surgical airway control was required. Three orthognathic surgeries and their associated anesthetics were completed without a fatal outcome, although once the patient was transferred to the intensive care unit for precautionary postoperative airway management and observation. Careful preoperative examination and preparation for difficult airway management are important for KFS patients with micrognathia.

Effect of some naturally occurring iron ion chelators on the formation of radicals in the reaction mixtures of rat liver microsomes with ADP, Fe and NADPH.

In order to clarify the mechanism by polyphenols of protective effects against oxidative damage or by quinolinic acid of its neurotoxic and inflammatory actions, effects of polyphenols or quinolinic acid on the radical formation were examined. The ESR measurements showed that some polyphenols such as caffeic acid, catechol, gallic acid, D-(+)-catechin, L-dopa, chlorogenic acid and L-noradrenaline inhibited the formation of radicals in the reaction mixture of rat liver microsomes with ADP, Fe(3+) and NADPH. The ESR measurements showed that α-picolinic acid, 2,6-pyridinedicarboxylic acid and quinolinic acid (2,3-pyridinedicarboxylic acid) enhanced the formation of radicals in the reaction mixture of rat liver microsomes with Fe(3+) and NADPH. Caffeic acid and α-picolinic acid had no effects on the formation of radicals in the presence of EDTA, suggesting that the chelation of iron ion seems to be related to the inhibitory and enhanced effects. The polyphenols may exert protective effects against oxidative damage of erythrocyte membrane, ethanol-induced fatty livers, cardiovascular diseases, inflammatory and cancer through the mechanism. On the other hand, quinolinic acid may exert its neurotoxic and inflammatory effects because of the enhanced effect on the radical formation.

Phenotype of tumor lymphatic vessels is a prognostic factor in human tongue squamous cell carcinoma.

Tumor metastasis to lymph nodes occurs through the lymphatic vessels located in the tumor circumference. However, few studies have focused on the phenotypes of lymphatic vessels around these tumors. We investigated the characteristics of the lymph vessels of tongue squamous cell carcinoma (SCC) and compared them to clinicopathological characteristics. A total of 43 patients diagnosed as having tongue SCC consulted Hokkaido University Hospital were examined. The lymphatic vessels were identified by antibody D2-40 and the number and diameter of tumor lymphatic vessels were measured. The proliferative activity of lymphatic endothelial cells was also examined by immunostaining using antibody MIB-1. We then measured the DNA density of lymphatic endothelial cells in normal and tumor tissues. The number of tumor lymphatic vessels significantly increased in highly metastatic cases of tongue SCC, particularly in cases with a large number of micro lymphatic vessels. A significant correlation was found between the metastatic and proliferative activity of tumor lymphatic endothelial cells. Moreover, the DNA density of tumor lymphatic endothelial cells increased compared to normal tissues. These results suggest that the phenotypes of tumor lymphatic endothelial cells are an indicator of lymph node metastasis of tongue SCC.

Recovery of dynamic balance after general anesthesia with sevoflurane in short-duration oral surgery.

PURPOSE: Recovery of dynamic balance, involving adjustment of the center of gravity, is essential for safe discharge on foot after ambulatory anesthesia. The purpose of this study was to assess the recovery of dynamic balance after general anesthesia with sevoflurane, using two computerized dynamic posturographies. METHODS: Nine hospitalized patients undergoing oral surgery of less than 2 h duration under general anesthesia (air-oxygensevoflurane) were studied. A dynamic balance test, assessing the ability of postural control against unpredictable perturbation stimuli (Stability System; Biodex Medical), a walking analysis test using sheets with foot pressure sensors (Walk Way-MG1000; Anima), and two simple psychomotor function tests were performed before anesthesia (baseline), and 150 and 210 min after the emergence from anesthesia. RESULTS: Only the double-stance phase in the walking analysis test showed a significant difference between baseline and results at 150 min. None of the other variables showed any differences among results at baseline and at 150 and 210 min. CONCLUSION: The recovery times for dynamic balance and psychomotor function seem to be within 150 min after emergence from general anesthesia with sevoflurane in patients undergoing oral surgery of less than 2-h duration.

Recovery of dynamic balance after additional small divided doses of midazolam given intravenously for sedation.

We have previously reported that a dynamic balance test with perturbation stimuli and computerised dynamic posturography sensitively reflected the inhibitory effect on balance of intravenous midazolam sedation given intravenously as a single dose, and recovery time was within 80 min. The purpose of this study was to investigate the recovery of dynamic balance after additional doses of midazolam. Eighteen young adult male volunteers were sedated with midazolam given intravenously. The initial dose was given until the Wilson sedation score reached 3, and an additional dose was given until the same score was obtained 40 min later. They were tested with perturbation stimuli 40, 80, 100, and 120 min after the additional doses had been given. Their recovery time was recorded. The mean (S.D.) initial dose of midazolam was 0.07 (0.005) mg kg(-1), and additional doses were 41 (7)% of the initial dose. The serial changes in bispectral index after initial and additional doses were similar. The recovery time for the dynamic balance test (within 80 min) was the same as that recorded in the previous single-dose study. The recovery time of the psychomotor function test was within 75 min. Additional doses of midazolam aiming for a Wilson sedation score of 3 at a dose about 40% of the initial dose and given 40 min after the initial dose are valid in terms of the maintenance of sedation and recovery of dynamic balance. Complete recovery time, including psychomotor function, was within 80 min of the additional dose of the drug.