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Background: The effect of hospital spending on the mortality rate of patients with sepsis has not yet been fully elucidated. We hypothesized that hospitals that consume more medical resources would have lower mortality rates among patients with sepsis. Methods: This retrospective study used administrative data from 2010 to 2017. The enrolled hospitals were divided into quartiles based on average daily medical cost per sepsis case. The primary and secondary outcomes were the average in-hospital mortality rate of patients with sepsis and the effective cost per survivor among the enrolled hospitals, respectively. A multiple regression model was used to determine the significance of the differences among hospital categories to adjust for baseline imbalances. Fractional polynomials and restricted cubic splines were used to determine the significance of the association between hospital spending and in-hospital mortality. Subgroup and sensitivity analyses were performed for the primary outcome. Results: Among 997 hospitals enrolled in this study, the crude in-hospital mortality rates were 15.7% and 13.2% in the lowest and highest quartiles of hospital spending, respectively. After adjusting for confounding factors, the highest hospital spending group demonstrated a significantly lower in-hospital mortality rate than the lowest hospital spending group (coefficient = − 0.025, 95% confidence interval [CI] − 0.034 to − 0.015; p

We aimed to investigate the impact of hospital volume on the mortality rate and medical costs in sepsis. This retrospective study used the administrative data from 2010 to 2017. The hospital volume categorization into quartiles was performed according to the annual number of sepsis cases. The primary and secondary outcome was in-hospital mortality and medical costs, respectively. A mixed-effects logistic model with a two-level hierarchical structure was used to adjust for baseline imbalances. Among 1,781,014 sepsis patients from 1,622 hospitals, the crude in-hospital mortality rate was 22.1% and 17.0% in the lowest and highest quartile of sepsis volume, respectively (p

Among adult and pediatric patients, concern is growing in regard to toxic shock syndrome (TSS) resulting from methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infection. We investigated the incidence and characteristics of this form of TSS in patients with burn injury who were admitted to our burn care units from January 2008 to December 2011. Of the 244 patients with nosocomial MRSA infection admitted during the study period, TSS occurred in 20 (8.2%) patients whose average age was 42.9 years, average total burn surface area (TBSA) was 31.7%, and average day of TSS appearance was 9.5 days after injury. There were no particular characteristics associated with age, TBSA or day of TSS appearance in these patients. All but 1 patient recovered from TSS within an average of 9.4 days. The incidence of TSS due to nosocomial MRSA infection in these burn patients was higher than expected. TSS due to nosocomial MRSA infection should be considered in burn care.

Background:Sepsis is the leading cause of death worldwide. Although the mortality of sepsis patients has been decreasing over the past decade, the trend of medical costs and cost-effectiveness for sepsis treatment remains insufficiently determined.Methods:We conducted a retrospective study using the nationwide medical claims database of sepsis patients in Japan between 2010 and 2017. After selecting sepsis patients with a combined diagnosis of presumed serious infection and organ failure, patients over the age of 20 were included in this study. The primary outcome was the annual trend of the effective cost per survivor, calculated from the gross medical cost and number of survivors per year. Subsequently, we performed subgroup and multiple regression analyses to determine the significant predictors contributing to an increase in medical cost.Results:Among 50,490,128 adult patients with claims, a total of 1,276,678 patients with sepsis were selected from the database. Yearly gross medical costs to treat sepsis gradually increased over the decade from $3.04 billion in 2010 to $4.38 billion in 2017 (rate = + $0.2 billion/year, p p p = 0.001). In the subgroup analysis, the gross medical cost of the late elderly (75 ≤ age) showed the highest coefficient throughout the time period, despite the lowest medical cost per person. While gender (male), number of chronic diseases, intensive care unit (ICU) admission, length of hospital stay, and site of infection (blood, heart, and meninges/brain/spinal cord) contributed to an increase in medical costs, an increase in age, admission year, and other types of infection (abdominal, bone and soft tissue, respiratory, and urogenital) were significant predictors of reduced medical costs.Conclusions:We demonstrated an increase in annual gross medical costs with an improvement in annual cost-effectiveness in patients with sepsis between 2010 and 2017. Among the various factors altering medical costs, gender (male), number of chronic diseases, ICU admission, length of hospital stay, and specific types of infection were associated with increased medical expenses.

Rapid-onset, acute hypernatremia caused by sodium overload is a rare, life-threatening condition. Although experts recommend rapid correction of sodium concentration [Na] based on pathophysiological theories, only a few reports have documented the specific details of sodium correction methods. The objective of this study was to systematically review the reported treatment regimens, achieved [Na] correction rates, and treatment outcomes.PubMed, Ichushi-database, and references without language restrictions, from inception to January 2021, were searched for studies that described ≥1 adult (aged ≥18 years) patients with rapid-onset hypernatremia caused by sodium overload, whose treatment was initiated ≤12 hours from the onset. The primary outcome of interest was the [Na] correction rate associated with mortality.Eighteen case reports (18 patients; median [Na], 180.5 mEq/L) were included. The cause of sodium overload was self-ingestion in 8 patients and iatrogenic sodium gain in 10 patients; baseline [Na] and symptoms at presentation were comparable for both groups. Individualized rapid infusion of dextrose-based solutions was the most commonly adopted fluid therapy, whereas hemodialysis was also used for patients already treated with hemodialysis. The correction rates were more rapid in 13 successfully treated patients than in 5 fatal patients. The successfully treated patients typically achieved [Na] ≤160 within 8 hours, [Na] ≤150 within 24 hours, and [Na] ≤145 within 48 hours. Hyperglycemia was a commonly observed treatment-related adverse event.The limited empirical evidence derived from case reports appears to endorse the recommended, rapid, and aggressive sodium correction using dextrose-based hypotonic solutions.

Background Trends in the incidence and outcomes of sepsis using a Japanese nationwide database were investigated. Methods This was a retrospective cohort study. Adult patients, who had both presumed serious infections and acute organ dysfunction, between 2010 and 2017 were extracted using a combined method of administrative and electronic health record data from the Japanese nationwide medical claim database, which covered 71.5% of all acute care hospitals in 2017. Presumed serious infection was defined using blood culture test records and antibiotic administration. Acute organ dysfunction was defined using records of diagnosis according to the international statistical classification of diseases and related health problems, 10th revision, and records of organ support. The primary outcomes were the annual incidence of sepsis and death in sepsis per 1000 inpatients. The secondary outcomes were in-hospital mortality rate and length of hospital stay in patients with sepsis. Results The analyzed dataset included 50,490,128 adult inpatients admitted between 2010 and 2017. Of these, 2,043,073 (4.0%) patients had sepsis. During the 8-year period, the annual proportion of patients with sepsis across inpatients significantly increased (slope = + 0.30%/year, P P = 0.0001), accounting for 7.8 deaths per 1000 inpatients in 2017. The in-hospital mortality rate and median (interquartile range) length of hospital stay significantly decreased (P Conclusions The Japanese nationwide data indicate that the annual incidence of sepsis and death in inpatients with sepsis significantly increased; however, the annual mortality rates and length of hospital stay in patients with sepsis significantly decreased. The increasing incidence of sepsis and death in sepsis appear to be a significant and ongoing issue.

We encountered a patient with rapidly progressive acute necrotizing encephalopathy associated with influenza A falling into coma from lucidity within 10 min., Background Among the influenza‐associated encephalopathies, acute necrotizing encephalopathy (ANE) has a particularly poor prognosis. While it usually progresses within 48 h, we encountered a rapidly evolving case with the patient falling into coma from lucidity within 10 min. Case Presentation A 71‐year‐old man was found unconscious after taking a 10‐min bath and brought to the emergency room. The head computed tomography (HCT) was normal, and he was diagnosed with heatstroke as a complication of influenza A. Despite effective therapy to correct his temperature, his consciousness did not improve, and within 24 h he progressed to multiple organ injury. Repeat HCT and subsequent magnetic resonance imaging revealed irreparably progressed ANE. Conclusion To effectively treat ANE, early recognition and diagnosis are critical. Our case suggests that ANE should be considered and added to the differential diagnosis for adult patients with rapid cognitive deterioration.

It is rare for children to be in serious condition or die from coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) except for those with underlying diseases such as chronic lung disease (including asthma), cardiovascular disease, and immunosuppressive disease. Recently, patients with hyperinflammatory shock have been identified among children who are confirmed to have or are suspected of having SARS-CoV-2 infection. The presenting signs and symptoms are characterized by prolonged fever, abdominal pain, and cardiac involvement without any signs of pneumonia on chest computed tomography. However, it is uncertain at this time whether SARS-CoV-2 infection affects this syndrome. Compared with adults, quite a few children are asymptomatic even when infected with SARS-CoV-2, which could make these children serious sources of infection at home or in medical institutions. Considering these characteristics, it is important to take appropriate precautions during medical examinations and perform infection control in emergency departments to save the lives of both the children and adult patients. Most healthy children are suffering from huge stress due to restrictions against going outside and school closures as social means to control infection. It is possible that children are socially isolated when they come to the emergency department, and they might require mental or social support even if they are only complaining about their physical condition. Health-care providers are required to examine the children's circumstances carefully and cooperate with workers in other professions appropriately.

Background Ventilator-associated pneumonia (VAP) is a common and serious problem in intensive care units (ICUs). Several studies have suggested that the Gram stain of endotracheal aspirates is a useful method for accurately diagnosing VAP. However, the usefulness of the Gram stain in predicting which microorganisms cause VAP has not been established. The purpose of this study was to evaluate whether a Gram stain of endotracheal aspirates could be used to determine appropriate initial antimicrobial therapy for VAP. Methods Data on consecutive episodes of microbiologically confirmed VAP were collected from February 2013 to February 2016 in the ICU of a tertiary care hospital in Japan. We constructed two hypothetical empirical antimicrobial treatment algorithms for VAP: a guidelines-based algorithm (GLBA) based on the recommendations of the American Thoracic Society-Infectious Diseases Society of America (ATS-IDSA) guidelines and a Gram stain-based algorithm (GSBA) which limited the choice of initial antimicrobials according to the results of bedside Gram stains. The GLBA and the GSBA were retrospectively reviewed for each VAP episode. The initial coverage rates and the selection of broad-spectrum antimicrobial agents were compared between the two algorithms. Results During the study period, 219 suspected VAP episodes were observed and 131 episodes were assessed for analysis. Appropriate antimicrobial coverage rates were not significantly different between the two algorithms (GLBA 95.4% versus GSBA 92.4%; p = 0.134). The number of episodes for which antimethicillin-resistant Staphylococcus aureus agents were selected as an initial treatment was larger in the GLBA than in the GSBA (71.0% versus 31.3%; p

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines., other authors: Satoru Hashimoto,Daisuke Hasegawa,Junji Hatakeyama,Naoki Hara,Naoki Higashibeppu,Nana Furushima,Hirotaka Furusono,Yujiro Matsuishi,Tasuku Matsuyama,Yusuke Minematsu,Ryoichi Miyashita,Yuji Miyatake,Megumi Moriyasu,Toru Yamada,Hiroyuki Yamada,Ryo Yamamoto,Takeshi Yoshida,Yuhei Yoshida,Jumpei Yoshimura,Ryuichi Yotsumoto,Hiroshi Yonekura,Takeshi Wada,Eizo Watanabe,Makoto Aoki,Hideki Asai,Takakuni Abe,Yutaka Igarashi,Naoya Iguchi,Masami Ishikawa,Go Ishimaru,Shutaro Isokawa,Ryuta Itakura,Hisashi Imahase,Haruki Imura,Takashi Irinoda,Kenji Uehara,Noritaka Ushio,Takeshi Umegaki,Yuko Egawa,Yuki Enomoto,Kohei Ota,Yoshifumi Ohchi,Takanori Ohno,Hiroyuki Ohbe,Kazuyuki Oka,Nobunaga Okada,Yohei Okada,Hiromu Okano,Jun Okamoto,Hiroshi Okuda,Takayuki Ogura,Yu Onodera,Yuhta Oyama,Motoshi Kainuma,Eisuke Kako,Masahiro Kashiura,Hiromi Kato,Akihiro Kanaya,Tadashi Kaneko,Keita Kanehata,Ken-ichi Kano,Hiroyuki Kawano,Kazuya Kikutani,Hitoshi Kikuchi,Takahiro Kido,Sho Kimura,Hiroyuki Koami,Daisuke Kobashi,Iwao Saiki,Masahito Sakai,Ayaka Sakamoto,Tetsuya Sato,Yasuhiro Shiga,Manabu Shimoto,Shinya Shimoyama,Tomohisa Shoko,Yoh Sugawara,Atsunori Sugita,Satoshi Suzuki,Yuji Suzuki,Tomohiro Suhara,Kenji Sonota,Shuhei Takauji,Kohei Takashima,Sho Takahashi,Yoko Takahashi,Jun Takeshita,Yuuki Tanaka,Akihito Tampo,Taichiro Tsunoyama,Kenichi Tetsuhara,Kentaro Tokunaga,Yoshihiro Tomioka,Kentaro Tomita,Naoki Tominaga,Mitsunobu Toyosaki,Yukitoshi Toyoda,Hiromichi Naito,Isao Nagata,Tadashi Nagato,Yoshimi Nakamura,Yuki Nakamori,Isao Nahara,Hiromu Naraba,Chihiro Narita,Norihiro Nishioka,Tomoya Nishimura,Kei Nishiyama,Tomohisa Nomura,Taiki Haga,Yoshihiro Hagiwara,Katsuhiko Hashimoto,Takeshi Hatachi,Toshiaki Hamasaki,Takuya Hayashi,Minoru Hayashi,Atsuki Hayamizu,Go Haraguchi,Yohei Hirano,Ryo Fujii,Motoki Fujita,Naoyuki Fujimura,Hiraku Funakoshi,Masahito Horiguchi,Jun Maki,Naohisa Masunaga,Yosuke Matsumura,Takuya Mayumi,Keisuke Minami,Yuya Miyazaki,Kazuyuki Miyamoto,Teppei Murata,Machi Yanai,Takao Yano,Kohei Yamada,Naoki Yamada,Tomonori Yamamoto,Shodai Yoshihiro,Hiroshi Tanaka,Osamu Nishida, Guidelines

Toxic shock syndrome (TSS) caused by methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infection is a growing concern in both adult and pediatric patients. The reason why TSS appears in only some patients with MRSA infection remains unclear. In this study, we analyzed serial TSS toxin-1 (TSST-1) antibody in patients with burn injury to investigate the mechanisms of TSS caused by MRSA nosocomial infection. This study comprised of patients with burn injury in our burn care unit from September, 2010 to August, 2011. Serum samples were collected serially on admission, at 48 to 72 hours after injury, on the day MRSA infection appeared, and on the day MRSA infection resolved. TSST-1 antibody was measured by enzyme-linked immunosorbent assay (ELISA). TSS was diagnosed according to the criteria of the Centers for Disease Control. Serial serum samples were collected from 24 patients and nosocomial MRSA infection was detected in 12 patients. In these 12 patients, TSS occurred in five patients (TSS+ group) but did not occur in the other seven patients (TSS- group). TSST-1 antibody level was significantly lower in the TSS+ group than TSS- group on admission and on the day MRSA infection appeared. All patients in the TSS+ group received intravenous immune globulin when TSS was diagnosed, and no patients died of TSS. Patients suffering from TSS had a lower level of TSST-1 antibody than patients not suffering from TSS. Testing for TSST-1 antibody in the clinical setting might help to predict and prevent the appearance of TSS caused by nosocomial MRSA infection.

A 40-year-old woman withuntreated type II diabetes mellitus was discovered withcardiopulmonary arrest in her room. On admission, she had ventricular fibrillation. After cardiopulmonary resuscitation, her own pulse restarted. The plasma glucose was 722 mg/dl and venous PH was 6.704. Abdominal computed tomography revealed gas within the parenchyma of the left kidney. We diagnosed her with emphysematous pyelonephritis and conducted emergency nephrectomy. Urinary and blood cultures were positive for Escherichia coli. Antibiotic therapy was initiated with doripenem and she was restrictively treated with intravenous insulin to control her plasma glucose. On the 8th day of hospital stay, she underwent resection of the small intestine because of necrosis. After multidisciplinary therapy, she was discharged with complete resolution of the infection.

Bone marrow mesenchymal stem cells (MSCs) have been used for bone tissue engineering due to their osteogenic differentiation capability, but their application is controversial. To enhance their capability, we prepared biodegradable gelatin sponges incorporating β-tricalcium phosphate ceramics (GT sponge), which has been shown to possess excellent controlled drug-release properties. The GT sponge was used as a carrier for both rat MSCs and bone morphogenetic protein-2 (BMP-2) and osteogenic differentiation was assessed by subcutaneous implantation of four different kinds of implants, i.e. GT-alone, MSC-GT composites, BMP-GT composites and BMP-GT composites supplemented with MSCs (BMP-MSC-GT) in rats. Two weeks after implantation, histological sections showed new bone formation in the peripheral parts of the BMP-GT and in almost the total volume of the BMP-MSC-GT implants. After 4 weeks, histology as well as microCT analyses demonstrated extensive bone formation in BMP-MSC-GT implants. Gene expression and biochemical analyses of both alkaline phosphatase and bone-specific osteocalcin confirmed the histological findings. These results indicate that the combination of MSCs, GT and BMP synergistically enhances osteogenic capability and provides a rational basis for their clinical application in bone reconstruction.

Summary Healthcare-associated infection by meticillin-resistant Staphylococcus aureus (MRSA) is still a great concern in an intensive care unit (ICU). Our surveillance data in the ICU revealed that intubated patients were at eight times higher risk of acquiring MRSA than non-intubated patients, so we hypothesised that pre-emptive contact precautions for all intubated patients would prevent healthcare-associated infection by MRSA in the ICU. Patients staying in our ICU for >2 days were included in this study. The study period was divided into two periods. During 2004 (1st period), contact precautions were performed only for patients with MRSA. During 2005–2007 (2nd period), contact precautions were applied to all intubated patients regardless of MRSA infection status. Patients were defined as MRSA-positive on admission when MRSA was detected by surveillance or clinical culture on enrolment. Other MRSA-positive results were defined as healthcare-associated MRSA (HA-MRSA) transmission. HA-MRSA infection was diagnosed according to the National Nosocomial Infections Surveillance Manual. The 1st period comprised 415 patients, and the 2nd period comprised 1280 patients. In intubated patients, HA-MRSA infection rate decreased significantly in the 2nd period (1st period 12.2%, 2nd period 5.6%; P = 0.015). HA-MRSA infection of all patients decreased from 3.6 to 2.3 incidents per 1000 patient-days (P

Background The gut is an important target organ of injury during critically ill conditions. Although Gram staining is a common and quick method for identifying bacteria, its clinical application has not been fully evaluated in critically ill conditions. Aims This study’s aims were to identify patterns of Gram-stained fecal flora and compare them to cultured bacterial counts and to investigate the association between the patterns and septic complications in patients with severe systemic inflammatory response syndrome (SIRS). Methods Fifty-two patients with SIRS were included whose Gram-stained fecal flora was classified into three patterns. In a diverse pattern, large numbers of multiple kinds of bacteria completely covered the field. In a single pattern, one specific kind of bacteria or fungi predominantly covered the field. In a depleted pattern, most bacteria were diminished in the field. Results In the analysis of fecal flora, the numbers of total obligate anaerobes in the depleted pattern was significantly lower than those in the diverse pattern and single pattern (p

Background and purpose The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] 10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc. This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine. Methods Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members. Results A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs. Conclusions Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals. Electronic supplementary material The online version of this article (10.1186/s40560-017-0270-8) contains supplementary material, which is available to authorized users.

The aim of the current study was to examine in vitro osteogenic capability and in vivo bone formation of mesenchymal stromal cells (MSCs) on two kinds of calcium phosphate ceramics. MSCs derived from human bone marrow were seeded on either hydroxyapatite (HA) ceramic or beta-tricalcium phosphate (beta-TCP) ceramic and then cultured in a medium supplemented with a donor's serum, vitamin C, beta-glycerophosphate, and dexamethasone. The culture revealed the expression of alkaline phosphatase activity, indicating the osteogenic differentiation of the MSCs on the ceramics (fabrication of tissue-engineered construct). The constructs were then implanted subcutaneously into nude rats for 8 weeks. New bone formation was observed in both types of ceramics, and human-specific Alu sequence was detected by in situ hybridization analysis. Quantitative microcomputed tomography showed that the volume of the new bone in the HA ceramic was greater than that in the beta-TCP ceramic in six of seven cases. These results suggest that human MSCs cultured on ceramics could retain their osteogenic capability even after ectopic implantation and provide a rationale for the use of tissue-engineered constructs derived from a patient's MSCs and calcium phosphate ceramics in bone tissue regeneration.

The purpose of this study was to evaluate if synbiotic therapy can correct the deteriorated gut flora and environment in patients with severe systemic inflammatory response syndrome (SIRS). Twenty-nine SIRS patients, who fulfilled a serum C-reactive protein (CRP) level >10 mg/dl, received synbiotics (Bifidobacterium breve, Lactobacillus casei, and galactooligosaccharides) (S group) and were compared with previous observations in 26 patients without synbiotics (NS group). Analysis of fecal flora confirmed that patients in the S group had significantly greater levels of beneficial Bifidobacterium, Lactobacillus, and total organic acids (particularly short-chain fatty acids) than those in the NS group. The incidence of infectious complications such as enteritis, pneumonia, and bacteremia was significantly lower in the S group than in the NS group. Synbiotics maintain the gut flora and environment and decrease the incidence of septic complications in patients with severe SIRS. Further randomized controlled study is necessary to determine the effects of synbiotics.

Background: Ventilator-associated pneumonia (VAP) is one of the major complications in the intensive care unit. VAP sometimes results in acute respiratory distress syndrome (ARDS), and the associated mortality is high. We hypothesized that preemptive antibiotic therapy based on results of bedside gram staining would reduce the incidence of VAP. Methods: Patients who were endotracheally intubated in our intensive care unit for more than 72 hours were included. Patients younger than 16 years of age or patients died because of brain death were excluded. The study was divided into two periods. During the first period, we used antibiotics according to the American Thoracic Society guidelines. During the second period, antibiotics were given according to the results of bedside gram staining even before radiographic infiltrate appeared. Results: One hundred twenty-eight patients and 133 patients were included in the first and second periods, respectively. The incidence of VAP was significantly decreased in the second period (first period, 22%; second period, 9%, p < 0.01). The incidence of ARDS was also decreased significantly in the second period (first period, 11%; second period, 3%, p < 0.01). The duration and total amount of antibiotics administered did not increase in the second period. VAP associated mortality was significantly lower in the second period (first period, 5%; second period, 0.8%, p < 0.05). Conclusion: Early diagnosis and treatment of respiratory infection based on results of gram staining significantly reduced the incidences of VAP and ARDS without an increase in the use of antibiotics.

To investigate the cascade of matrix mineralization, cells expressing high and low alkaline phosphatase (ALP) were separated from human osteoblast-like (HOS) cells by fluorescence-activated cell sorting with an ALP antibody. After these cells had been recloned from single cells and then cultured under osteogenic conditions, high-ALP-expressing HOS (H-HOS) cells showed matrix mineralization, but low-ALP-expressing HOS (L-HOS) cells did not. The interaction among osteogenic-related genes, such as runt-related transcription factor 2 (RUNX2), collagen type I alpha1 chain (COL1A1), tissue non-specific ALP, and osteocalcin (OCN), is well known as being related to matrix mineralization. Quantitative real-time polymerase chain reaction revealed that the gene expression of ALP was higher in H-HOS cells than in L-HOS, whereas the gene expression of RUNX2, COL1A1, and OCN was lower in H-HOS cells than in L-HOS cells. When small interfering RNAs (siRNAs) of these osteogenic-related genes were introduced into H-HOS cells by transfection, only ALP siRNA inhibited matrix mineralization. Furthermore, the expression of not only the ALP gene, but also the COL1A1 and RUNX2 genes was influenced by the inhibition of ALP, although the expression of OCN was not affected by the inhibition of ALP. We have been able to confirm that the ALP gene is a strong candidate as the trigger of matrix mineralization. These results indicate the usefulness of cloned osteogenic cells in investigating the molecular mechanisms of matrix mineralization, the function of which can be modulated by using a variety of siRNAs.

Hydroxyapatite (HA) ceramics together with various kinds of osteogenic cells have been used in bone tissue engineering. It is well known that the ceramics structure and composition affect cell proliferation / differentiation. In this study, three different types of HA ceramics were used to investigate initial cell attachment followed by osteoblastic differentiation of human mesenchymal stromal cells (MSCs). The results indicated that micro-pore affected the cell attachment and porosity (pore diameter and inter-pore connection) was the key to allow spacious distribution of the viable cells in the ceramics. This study also confirmed that surface pore areas of HA ceramics support the differentiation of human MSCs and thus the ceramics have the capability to regenerate damaged bone tissue.

Since 2001, we have started tissue engineered approach for hard tissue repair using mesenchymal stromal cells (MSCs) derived from patient’s bone marrow. MSCs were culture expanded on culture dish, then applied on various ceramics including hydroxyapatite (HA) ceramics. The MSCs on the ceramics were further cultured in osteogenic media to induce osteognenic differentiation. The differentiation resulted in appearance of bone forming osteoblasts as well as bone matrix on the ceramics, thus we could fabricate the tissue engineered bone. We have reported that the tissue engineered bone is effective for treatment of large bone defect, which is difficult to repair only with artificial materials such as HA ceramics. The present study focused on osteogenic capability of cryopreserved human MSCs derived from patients who already were treated by the tissue engineered bone. The MSCs showed high alkaline phosphatase activity together with abundant bone matrix formation when cultured in osteogenic media. The MSCs also showed in vivo new bone formation when implanted at subcutaneous sites of athymic nude rats. Based on the results, we concluded that the tissue engineering approach is a reliable method to be used in hard tissue regeneration.

Monocyte deactivation is an important contributor to infectious susceptibility in critically ill patients. However, the mechanism of monocyte deactivation has not been fully elucidated. Recently, intracellular heme oxygenese-1 (HO-1), an anti-inflammatory heat-shock protein, was reported to be activated by Toll-like receptors (TLRs), and to inhibit inflammatory cytokine production such as that of TNF-alpha. In the present study, we evaluated the expression of intracellular HO-1 and TLRs in monocytes from patients with severe systemic inflammatory response syndrome (SIRS) and examined the role of HO-1 in monocyte deactivation.Twenty-seven patients who fulfilled the criteria for severe SIRS and had a serum C-reactive protein (CRP) level10 mg/dL were included in this study. The cause of SIRS was sepsis in 16 patients, trauma in 7, and other in 4. Expression of intracellular HO-1, surface TLR2 and TLR4, and intracellular cytokines (TNF-alpha, Interleukin-6) stimulated via TLR activation were measured in circulating monocytes by flow cytometry. Intracellular HO-1 expression was evaluated in normal monocytes stimulated with patient serum. Serum cytokine levels were also measured. Patient data were compared with data from healthy volunteers (n = 16).Cytoplasmic HO-1 was clearly detected by fluorescence microscopy. Expression of HO-1, TLR2, and TLR4 in monocytes was significantly enhanced in patients with severe SIRS compared with that in healthy volunteers, whereas intracellular TNF-alpha expression with peptidoglycan was significantly decreased (p0.05) in patients compared with that in healthy volunteers. HO-1 expression was significantly enhanced in normal monocytes stimulated with patient serum. Intracellular HO-1 levels were positively related to serum TNF-alpha levels in patients (r = 0.46).Expression of intracellular HO-1 and of TLRs was enhanced in deactivated monocytes from patients with SIRS. Increased production of intracellular HO-1 in response to serum factors may play a role in monocyte deactivation after systemic inflammation.

A novel approach to the treatment of bone tumors using tissue-engineered implants is reported in this study. The number of mesenchymal stem cells (MSCs) obtained from each patient's bone marrow cells was first increased, and the MSCs were forced to differentiate into osteoblasts followed by bone matrix formation on hydroxyapatite (HA) ceramics. The strong osteogenic ability of the implants, as evidenced by high osteoblastic activity, was confirmed. Consequently, the HA surface was covered with the patient's derived cultured osteoblast/bone matrix. The tissue-engineered HA was used to fill the patient's bone cavity after tumor curettage. Immediate healing potential was found by serial plain radiographs and computed tomograhy images, and no adverse reactions were noted in these patients. The results indicate that tissue-engineered osteogenic ceramics might be an alternative to autologous bone grafts.

腸管内には多彩な細菌群がバランスを保ち共存しており,腸内環境を整えると同時に生体へ豊富なシグナルを送り続けている。腸管は,侵襲時の主要な標的臓器(target organ)であり,腸内細菌叢の維持は腸上皮におけるバリア機能の維持と感染防御の点で極めて重要と考えられる。しかしながら,急性期重症病態の腸内細菌叢や腸内環境に関する検討はほとんどされていない。われわれは,SIRS患者の腸内細菌叢と腸内環境の変化を明らかにし,近年注目されているシンバイオティクス(synbiotics)療法(“善玉”生菌+増殖物質)の有効性を評価した。研究結果を含め,侵襲時の腸管機能と腸管内治療に関して総説する。(1) SIRS患者において,腸内細菌叢および腸内環境は著しく崩れる。「善玉菌」であるBifidobacteriumとLactobacillusは健常人の1/100-1000程度に減少し,「病原性」を有するブドウ球菌数は,健常人の100倍程度に増加した。腸内細菌叢の崩壊と同時に,短鎖脂肪酸の産生は減少し,腸管内pHは上昇した。このような腸内環境の悪化は腸内細菌叢をさらに崩す(“腸内環境の悪循環”)と考えられる。(2)シンバイオティクス療法は,SIRS患者の腸内細菌叢および腸内環境を維持し,経過中の感染合併症を減少させる。シンバイオティクス投与により,BifidobacteriumとLactobacillusが高く維持され,腸管内の短鎖脂肪酸,pHも保たれた。また腸炎の発生だけでなく,肺炎や菌血症の合併を有意に減らした。シンバイオティクス療法が感染症の合併を防止するメカニズムに関しては,今後の検討を要する。(3)現在,急性期重症病態に対する標準化された腸管内治療は存在しない。シンバイオティクス療法は,腸内細菌叢を保持し,腸内環境と腸管機能を保つ点で生理的であり,重症患者の臨床経過を改善する有望な腸管内治療法と考えられる。

The gut is considered an important target organ of injury after severe insult such as sepsis, trauma, and shock. The impact of bacterial translocation or mesenteric lymph on systemic inflammatory response and multiple organ damage has been investigated in animals, but dynamic changes in the gut flora and environment have not been fully clarified in critically ill patients. In the present study, we quantitatively evaluated changes in the gut microflora and environment in patients with severe systemic inflammatory response syndrome (SIRS).Twenty-five patients with severe SIRS, who fulfilled the criteria for SIRS, had a serum CRP level10 mg/dL, and were treated in the intensive care unit for more than 2 days, were included in our study. SIRS was a result of sepsis in 18 patients, trauma in 6, and burn in 1. A fecal sample was used for quantitative evaluation of microflora (bacterial counts of 10 key groups including Bifidobacterium and Lactobacillus) by plate or tube technique and of the gut environment (pH and 9 organic acids by high speed liquid chromatography). Data obtained from patients were compared with corresponding data from healthy volunteers.Analysis of fecal flora confirmed that patients with severe SIRS had significantly lower total anaerobic bacterial counts (especially 2-4 log fewer "beneficial" Bifidobacterium and Lactobacillus) and 2 log higher "pathogenic" Staphylococcus and Pseudomonas group counts than those of healthy volunteers. Concentrations of total organic acids (especially "beneficial" short-chain fatty acids such as acetic acid, propionic acid, and butyric acid) in the feces were significantly decreased in the patients, whereas pH was markedly increased.The gut flora and environment are significantly altered in patients with severe SIRS. Abnormal gut flora and environment may affect systemic inflammatory response after severe insult.

Background: Hepatocyte growth factor (HGF) has a significant effect on the regeneration of epithelial and endothelial cells. Studies have also shown an important role of HGF in wound healing and organ regeneration. Because recent studies indicate that polymorphonuclear leukocytes (PMNLs) store HGF in their specific granules and that HGF can be degranulated in the inflammatory tissue in which activated PMNLs migrate, we evaluated the storage and release of HGF in PMNLs from patients with systemic inflammatory response syndrome (SIRS) and attempted to examine the role of HGF from PMNLs in the systemic inflammatory process. Methods: Twenty-four patients with SIRS (serum C-reactive protein, 20.2 ± 12.4 mg/dL [mean ± SD]) and 18 healthy volunteers were studied. HGF in PMNLs was measured by flow cytometry by using a monoclonal antibody to HGF. The oxidative activity in PMNLs was also measured by flow cytometry. Serum HGF, interleukin (IL)-6, and IL-8 levels in each patient were measured by enzyme-linked immunosorbent assay. HGF degranulation from PMNLs was evaluated in 10 patients. Results: Immunocytochemistry under fluorescence microscopy revealed enhanced expression of HGF in the granules of PMNLs. HGF in PMNLs significantly increased in patients with SIRS compared with PMNLs from healthy volunteers (SIRS, 171.0 ± 6.6 fluorescence/cell; control, 130.7 ± 3.8 fluorescence/cell). N-formylmethionyl-leucyl-phenylalanine and lipopolysaccharide stimulation induced further increase of HGF fluorescence in PMNLs from patients. HGF degranulation from PMNLs was also significantly enhanced in patients. Moreover, oxidative activity in PMNLs was significantly enhanced in patients with SIRS. Plasma HGF (pHGF) correlated positively with IL-6 and IL-8 levels in patients (pHGF and IL-6, y = 0.635, p < 0.05; pHGF and IL-8, y = 0.827, p < 0.01), but these values did not correlate with HGF in PMNLs. Conclusion: Activated PMNLs in SIRS patients increased HGF in their granules and demonstrate enhanced degranulation of HGF. The release of HGF from migrated PMNLs in the inflammatory tissue may play an important role in wound healing and organ regeneration under those conditions.