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The objective of this study is to provide an overview of the Regenstrief Teaching Electronic Medical Record (tEMR), how the tEMR could be used, and how it is currently being used in health professions education. The tEMR is a derivative of a real-world electronic health record (EHR), a large, pseudonymized patient database, and a population health tool designed to support curricular goals. The tEMR has been successfully adopted at 12 health professional, public health, and health information technology (HIT) schools, with over 11 800 unique student users and more than 74 000 logins, for case presentation, to develop diagnostic and therapeutic plans, and to practice documentation skills. With the exponential growth of health-related data and the impact of HIT on work-life balance, it is critical for students to get early EHR skills practice and understand how EHR’s work. The tEMR is a promising, scalable, flexible application to help health professional students learn about common HIT tools and issues.

Objective Regenstrief Institute developed one of the seminal computerized order entry systems, the Medical Gopher, for implementation at Wishard Hospital nearly three decades ago. Wishard Hospital and Regenstrief remain committed to homegrown software development, and over the past 4 years we have fully rebuilt Gopher with an emphasis on usability, safety, leveraging open source technologies, and the advancement of biomedical informatics research. Our objective in this paper is to summarize the functionality of this new system and highlight its novel features. Materials and methods Applying a user-centered design process, the new Gopher was built upon a rich-internet application framework using an agile development process. The system incorporates order entry, clinical documentation, result viewing, decision support, and clinical workflow. We have customized its use for the outpatient, inpatient, and emergency department settings. Results The new Gopher is now in use by over 1100 users a day, including an average of 433 physicians caring for over 3600 patients daily. The system includes a wizard-like clinical workflow, dynamic multimedia alerts, and a familiar ‘e-commerce’-based interface for order entry. Clinical documentation is enhanced by real-time natural language processing and data review is supported by a rapid chart search feature. Discussion As one of the few remaining academically developed order entry systems, the Gopher has been designed both to improve patient care and to support next-generation informatics research. It has achieved rapid adoption within our health system and suggests continued viability for homegrown systems in settings of close collaboration between developers and providers.

Objective: We tested a novel, web-based teaching electronic medical record to teach and assess residents’ ability to enter appropriate admission orders for patients admitted to the intensive care unit. The primary objective was to determine if this tool could improve the learners’ ability to enter an evidence-based, comprehensive initial care plan for critically ill patients. Methods: The authors created three modules using de-identifed real patient data from selected patients that were admitted to the intensive care unit. All senior residents (113 total) were invited to participate in a dedicated two-hour educational session to complete the modules. Learner performance was graded against gold standard admission order sets created by study investigators based on the latest evidence-based medicine and guidelines. Results: The session was attended by 39 residents (34.5% of invitees). There was an average improvement of at least 20% in users’ scores across the three modules (Module 3-Module 1 mean difference 22.5%; p = 0.001 and Module 3-Module 2 mean difference 20.3%; p = 0.001). Diagnostic acumen improved in successive modules. Almost 90% of the residents reported the technology was an effective form of teaching and would use it autonomously if more modules were provided. Conclusions: In this pilot project, using a novel educational tool, users’ patient care performance scores improved with a high level of user satisfaction. These results identify a realistic and well-received way to supplement residents’ training and assessment on core clinical care and patient management in the face of duty hour restrictions.

For the purpose of a nationwide surveillance of the antimicrobial susceptibility of bacterial respiratory pathogens in patients in Japan, the Japanese Society of Chemotherapy conducted their second year survey, during the period from January to August, 2007. A total of 1178 strains were collected from clinical specimens obtained from adult patients with well-diagnosed respiratory tract infections. Susceptibility testing was evaluable for 1108 strains (226 Staphylococcus aureus, 257 Streptococcus pneumoniae, 6 Streptococcus pyogenes, 206 Haemophilus influenzae, 120 Moraxella catarrhalis, 122 Klebsiella pneumoniae, and 171 Pseudomonas aeruginosa). A total of 44 antibacterial agents, including 26 beta-lactams (four penicillins, three penicillins in combination with beta-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), three aminoglycosides, four macrolides (including ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standards Institute (CLSI). The incidence of methicillinresistant Staphylococcus aureus (MRSA) was high, at 59.7%, and the incidences of penicillin-intermediateresistant and -resistant Streptococcus pneumoniae (PISP and PRSP) were 30.4% and 5.1%, respectively. Among Haemophilus influenzae strains, 19.9% of them were found to be beta-lactamase-non-producing ampicillin (ABPC)-intermediately-resistant (BLNAI), 29.1% to be beta-lactamasenon-producing ABPC-resistant (BLNAR), and 6.7% to be beta-lactamase-producing ABPC-resistant (BLPAR) strains. Extended-spectrum beta-lactamase-producing Klebsiella pneumoniae was not isolated. Two isolates (1.2%) of Pseudomonas aeruginosa were found to be metallo-beta-lactamase-producing strains, including one (0.6%) suspected multidrug-resistant strain showing resistance to imipenem, amikacin, and ciprofloxacin. These data will be a useful reference for future periodic surveillance studies and for investigations to control resistant infections as well. Continued surveillance is required to prevent the further spread of these antimicrobial resistances.

The discipline of clinical informatics endeavors to improve the process and outcomes of health care by enabling efficient access to information. Care providers can then use this information, both in the form of medical knowledge and in the form of patient data collected during clinical practice, to make decisions and comply with appropriate standards of care. The Regenstrief Institute began work on clinical information systems in 1972, when Dr. Clement McDonald and colleagues conceptualized and began construction of a computerized patient management system for outpatient diabetes care, developed to meet three primary goals: first, it was built to eliminate the problems inherent in paper records by making clinical data available to authorized users “just-in-time” as medical decisions are made; second, it was designed to aid in the recognition of diagnoses and adoption of pertinent care practices by assisting clinicians during their record-keeping activities; third, the system was designed to aggregate and analyze clinical information to be used in health care support systems, such as those for public health, health services research, and quality improvement. The first installation of the Regenstrief Medical Record System (RMRS) at Wishard Memorial Hospital occurred in 1974 and, over the next few years, the use of this system expanded outside of the diabetic clinic into a few of the hospital’s many general medicine clinics. From early in its history, the Regenstrief system has included mechanisms for tailoring rules based on the data, to generate reminders and alerts to care providers. This chapter provides a history of the development and growth of the RMRS into a region-wide source of clinical data, the Indiana Network for Patient Care (INPC), and a summary of the research on the decision support interventions themselves, made possible by this infrastructure. Additionally, lessons learned throughout the more than 30 years of experience in both building and maintaining this system are detailed, alongside some reflections that may be useful for future system builders.

The annual multicenter studies on isolated bacteria from infections in general surgery and their antimicrobial susceptibility have been conducted in Japan since July 1982. This paper describes the results obtained in fiscal 1998 (from April 1998 to March 1999). The number of cases investigated as objectives was 225 for one year. A total of 429 strains (121 strains from primary infections and 308 strains from postoperative infections) were isolated from 183 cases (81.3% of total cases). In primary infections, the isolation rates of anaerobes and Escherichia coli were higher than in postoperative infections, while in postoperative infections, those of Gram-positive aerobes and Pseudomonas aeruginosa were higher than in primary infections. On the whole, among Gram-positive aerobes, the isolation rate of Enterococcus faecalis was the highest, followed by Staphylococcus aureus with high frequency in isolation from postoperative infections. Among Gram-positive anaerobes, Peptostreptococcus spp. and Streptococcus spp. were predominantly isolated. Among Gram-negative aerobes, E. coli, P. aeruginosa, Klebsiella pneumoniae and Enterobacter cloacae were frequently isolated. Among Gram-negative anaerobes, Bacteroides fragilis group was the majority of isolates. In primary infections, the percentage of Gram-negative aerobes has gradually increased since fiscal 1995 or 1996 with these years as the turning point, while those of Gram-positive and Gram-negative anaerobes have gradually declined. In postoperative infections, the percentage of Gram-negative anaerobes has increased continuously since the mid-1980s. The percentage of MRSA among S. aureus rose to 89.7%, which was the highest level since the beginning of this study. The susceptibilities of B. fragilis, which did not show apparent changes, were recognized to have decreased against cephems in fiscal 1998. Among other bacteria in B. fragilis group, development of resistance to cephems has continued on a long-term basis since the mid-1980s. E. coli and K. pneuminiae have obviously not changed in susceptibilities, however, the susceptibilities of isolated strains in fiscal 1998 against high-generation cephems, oxacephems and monobactams have declined. We found neither vancomycin-resistant nor teicoplanin-resistant strains of S. aureus and Enterococcus spp.

Vancomycin was used increasingly for treating methicillin-resistant Staphylococcus aureus(MRSA) infection. Recently MRSA strains which showed low-level resistance to vancomycin were isolated. Vancomycin-intermediate Staphylococcus aureus(VISA) show a vancomycin minimum inhibitory concentration(MIC) of 8 micrograms/ml. VISA appear to be rare. The vancomycin resistance phenotype is reported to be unstable in such isolates. To detect heterogeneously resistant VRSA(hetero-VRSA. MIC 1 to 4 micrograms/ml), we need to use population analysis and growth on Mu3 agar plate, because MIC cannot confirm hetero-VRSA. Hetero-VRSA is not so rare(about 0-47%). Hetero-VRSA may be responsible for failure of vancomycin therapy, but its mechanism remains unclear. Until it becomes better understood, the clinical relevance cannot be assessed.

The annual multicenter studies on isolated bacteria from infections in general surgery and their antimicrobial susceptibility have been conducted in 19 facilities in Japan since July 1982. This paper describes the results obtained during the period from April 1997 to March 1998. The number of cases investigated as objectives was 215 for one year. A total of 420 strains (170 strains from primary infections and 250 strains from postoperative infections) were isolated from 174 cases (80.9% of total cases). In primary infections, the isolation rate of anaerobic bacteria was higher than in postoperative infections, while in postoperative infections, those of aerobic Gram-positive bacteria and Pseudomonas aeruginosa were higher than in primary infections. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus faecalis was the highest, followed by Staphylococcus aureus, which was frequently isolated from postoperative infections. Among anaerobic Gram-positive bacteria, Peptostreptococcus spp. and Streptococcus spp. were commonly isolated from both types of infections. Among aerobic Gram-negative bacteria, Escherichia coli was most predominantly isolated from primary infections, followed by P. aeruginosa, Klebsiella pneumoniae in this order, and from postoperative infections, P. aeruginosa was most predominantly isolated, followed by E. coli and K. pneumoniae. Among anaerobic Gram-negative bacteria, Bacteroides fragilis group was the majority of isolates from both types of infections. We found neither vancomycin nor arbekacin resistant strains of S. aureus, and found no vancomycin resistant strains of Enterococcus spp. The susceptibility of P. aeruginosa against carbapenems did not decline in the year 1997, while resistance of B. fragilis group against cephems advanced increasingly.

In major systemic inflammation such as severe peritonitis, various pro-inflammatory cytokines, such as TNF-alpha, IL-1 beta and IL-6, play important roles in the development of multiple organ dysfunction syndrome (MODS). The purpose of this study was to investigate the outflow of pro-inflammatory and anti-inflammatory cytokines from the efferent mesenteric lymphatic vessels under peritonitis. Mesenteric lymph samples were collected from adult male rats at 2, 4, 6, 8 and 10 hr after an intraperitoneal injection of zymosan at a dosage of 0.1 mg/g (non-lethal dose) or 0.5 mg/g (lethal dose). Blood samples were obtained at 10 hr after zymosan administration. The amounts of drained TNF-alpha and IL-6 in the lymph peaked at 2-4 hr and 4-8 hr after zymosan administration, respectively. The amounts of drained IL-10 in the lymph gradually increased until 10 hr. The amounts of drained TNF-alpha and IL-10 in the mesenteric lymph were significantly correlated with the dosage of zymosan. In conclusion, under intraperitoneal inflammation, pro-inflammatory cytokines (TNF-alpha and IL-6) increased in the mesenteric lymph and were drained into circulation. IL-10, one of the anti-inflammatory cytokines, also increased in the mesenteric lymph after several hours' delay and its increase was remarkable in several inflammations. These findings suggested that the gut might be one of the pro-inflammatory and anti-inflammatory cytokine-generating organs under peritonitis. The lymph-drained amounts of each cytokine under peritonitis are considered to differ with the time or severity of inflammation, which may cause different conditions in patients due to the imbalance of pro-inflammatory and anti-inflammatory cytokines.

The intrinsic resistance of methicillin-resistant Staphylococcus aureus (MRSA) is frequently explained by the production of an additional penicillin-binding protein (PBP), which is encoded by the mecA gene. The mec regulator genes, mecR1 and mecI, was identified in mecA-carrying Staphylococcus aureus N315. Between February and March, 1993, 179 clinical MRSA isolates were collected from institutions in Hiroshima prefecture. According to serological types of coagulase, enterotoxins, and toxic shock syndrome toxin-1 (TSST-1) productions, these strains were classified into 6 groups. In 53 strains chosen from all groups, mec regulatory gene distributions were divided into two groups; one with whole regulatory genes and another with the lacking region, including 3'-partial region of the mecR1 gene and mecI gene. This same deletion was detected across the different groups, suggesting that the deletion occurred at the ancestral strain before branching according to coagulase or enterotoxin productions. The strains with this lacking region showed a high-level of resistance to methicillin, while the strains with whole regulatory genes consisted of low and high levels of resistant strains. The highly resistant strains with whole regulatory genes were found to harbor a point mutation in the mecI gene. The basal levels of mecA gene transcription were elevated in the strains with the lacking region or the mecI point mutations. These data suggest that deletion or mutation of the mecI gene, the repressor on the mecA gene, might play an important role in methicillin resistance in clinical isolates of MRSA.

The purpose of this study was to assess the point at which the postoperative infection has occurred in order to decide upon the proper duration of prophylactic antibiotic use. Another goal of this study was to determine whether prediction for the development of postoperative infections in major surgery such as esophagectomy should be the same as that in routine gastroenterological surgery. Twenty-five patients who underwent transthoracic esophagectomy and 127 patients who underwent gastrectomy were studied. On the third day after gastric surgery, the body temperature of patients who developed an infection was higher than that of the patients who did not develop an infection. The relative changes in peripheral white blood count (WBC), and C-reactive protein (CRP) concentration on the third and fourth days were more predictive of the development of infection than the absolute values. Almost all patients with systemic inflammatory response syndrome (SIRS) on the third day after gastric surgery developed an infection. On the other hand, the incidence of SIRS in patients who did not develop an infection was high on both the third and fourth days after esophageal surgery. It was nearly impossible to predict who would develop an infection in esophageal surgery. The high incidence of postoperative infections, and their significant consequences justify planned successive postoperative antibiotic use in esophageal surgery.

The incidence of postoperative infections, especially due to multi-drug resistant strains such as Pseudomonas sp., Enterococcus sp., and Methicillin resistant Staphylococcus aureus (MRSA), is high in compromised hosts. Among them, respiratory infection, catheter sepsis, and drug-associated enteritis are frequently observed and respiratory infection is liable to fall into serious illness. These infections have characteristics in causative organisms. Pseudomonas aeruginosa or MRSA are frequently isolated in respiratory infections and Candida or coagulase-negative staphylococcus are frequently isolated in catheter sepsis. G-test in addition to blood culture is necessary for early diagnosis of Candida sepsis, vancomycin should be administered in early phase of antibiotic-associated enteritis, since this infection is usually caused by MRSA or Clostridium difficile and frequently falls into serious illness. The patients with protein-calorie malnutrition, liver cirrhosis, renal failure, diabetes melitis, administration of anticancer drugs and/or radiation therapy, serious injury, or severe operative stress are considered to be compromised hosts in surgical field, and the adequate perioperative managements according to these disorders should be carried out against postoperative infections.

To identify high-risk patients with heart disease by using data stored in an electronic medical record system to predict six-year mortality.Retrospective cohort study.Academic primary care general internal medicine practice affiliated with an urban teaching hospital with a state-of-the-art electronic medical record system.Of 2,434 patients with evidence of ischemic heart disease or heart failure or both who visited an urban primary care practice in 1986, half were used to derive a proportional hazards model, and half were used to validate it.Mortality from any cause within six years of inception date. Model discrimination was assessed with the C statistic, and goodness-of-fit was measured with a calibration curve and Hosmer-Lemeshow statistic.Of these patients 82% had evidence of ischemic heart disease, 53% heart failure, and 35% both conditions. Mean survival among the 653 (27%) who died was 2.8 years; mean follow-up among survivors was 5.0 years. Those with both heart conditions had the highest mortality rate (45% at 6 years), followed by isolated heart failure (39%) and ischemic heart disease (18%). Of 300 potential predictive characteristics, 100 passed a univariate screen and were submitted to maltivariable proportional hazards regression. Twelve variables contributed independent predictive information: age, weight, more than one previous hospitalization for heart failure, and nine conditions indicated on diagnostic tests and problem lists. No drug treatment variables were independent predictors. The model C statistic was 0.76 in the derivation sample of patients and 0.74 in a randomly selected validation sample, and it was well calibrated. Patients in the lowest and highest quartiles of risk differed more than five-fold in their average risk.Routine clinical data stored in patients electronic medical records are capable of predicting mortality among patients with heart disease. This could allow increasingly scarce health care resources to be focused on those at highest mortality risk.

5-Fluorouracil (5-FU) is useful as an adjunct treatment for glaucoma filtering surgery. However, efficacy depends upon maintaining sustained drug levels, currently achieved by repeated daily injections of the drug for several days. To overcome this limitation, we designed a biodegradable implant for the sustained release of 5-FU.The implant (0.79 mm diameter, 6 mm long, 2.2 mg weight) contains 0.66 mg of 5-FU and is loaded in a needle coupled to a custom-made instrument to permit subconjonctival insertion of the implant through a 2 mm wide snip incision. The in vitro and in vivo pharmacokinetics as well as the biocompatibility studies of the implants were assessed in the rabbit.No infection, inflammatory reaction or extrusion occurred. The implant released the drug at a constant rate of 1.20 micrograms/hr for over 18 days and totally biodegraded in less than 86 days.Implantation of the device, after laser sclerostomy or conventional trabeculectomy shows great potential for the treatment of glaucoma. To determine the implant's efficacy, additional studies in the cat are underway.

The aim of this study was to evaluate the characteristics of the polymorphonuclear leukocyte (PMN) function after surgical stress. We investigated Mac-1 expression and superoxide generation by peripheral PMNs and serum granulocyte-colony stimulating factor (G-CSF) concentrations in 15 patients who underwent either gastrectomy (n = 8) or esophagectomy (n = 7). The serum G-CSF rapidly increased within 24 hours after operation. The maximum levels of serum G-CSF in the cases of esophagectomy were about 5-8 fold those of gastrectomy, although the increases in PMN counts within 24 hours of esophagectomy were lower than those after gastrectomy. Mac-1 expression and superoxide generation by PMN counts and serum G-CSF. After esophagectomy, Mac-1 expression on peripheral PMNs remained elevated through the 7th day after operation, while superoxide generation by PMNs in response to PMA declined to below preoperative levels after the 3rd day. These results suggest that, after major surgery such as esophagectomy, there is a discrepancy between Mac-1 expression and superoxide generation by the peripheral PMN despite a high level of serum G-CSF.

Increasing amounts of medical knowledge, clinical data, and patient expectations have created a fertile environment for developing and using clinical practice guidelines. Electronic medical records have provided an opportunity to invoke guidelines during the everyday practice of clinical medicine to improve health care quality and control costs. In this paper, efforts to incorporate complex guidelines [those for heart failure from the Agency for Health Care Policy and Research (AHCPR)] into a network of physicians' interactive microcomputer workstations are reported. The task proved difficult because the guidelines often lack explicit definitions (e.g., for symptom severity and adverse events) that are necessary to navigate the AHCPR algorithm. They also focus more on errors of omission (not doing the right thing) than on errors of commission (doing the wrong thing) and do not account for comorbid conditions, concurrent drug therapy, or the timing of most interventions and follow-up. As they stand, the heart failure guidelines give good general guidance to individual practitioners, but cannot be used to assess quality or care without extensive "translation" into the local environment. Specific recommendations are made so that future guidelines will prove useful to a wide range of prospective users.

Resistance patterns against various antimicrobial agents including beta-lactams, aminoglycosides, tetracyclines, fluoroquinolones, macrolides were examined for 58 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated at Hiroshima University Hospital from April to November 1992. All the MRSA strains produced type II-coagulase but not beta-lactamase. Regarding aminoglycoside-modifying enzymes, 7 strains (12%) appeared to be producing aminoglycoside 4',4"-adenyltransferase AAD(4',4") encoded by aadD without coproduction of bifunctional aminoglycoside 6'-acetyltransferase/2"-phosphotransferase AAC(6')/APH(2") encoded by aacA-aphD (referred to as tobramycin-resistant type, TOBr). The remaining 51 strains (88%) were phenotypically producers of both enzymes (i.e., mix-resistant type, Mixr). AAD(4',4"), encoded by aadD which was reported to be closely linked with bleomycin (BLM)-resistance determinant, could be seen in 100% MRSA strains and ca. 90% strains expressed AAC(6')/APH(2"). BLM endowed Mixr-type but not TOBr-type MRSA strain with enhanced resistance to arbekacin (ABK) dose-dependently, presumably by modifying the production of AAC(6')/APH(2"). The manifestation of ABK-resistant phenotype by Mixr-type MRSA required the coexistence of BLM. Therefore, ABK must be administered carefully to cure MRSA infection in patients who have been treated with BLM.

To clarify defection mechanisms in those with total colectomy, we performed comparative studies of intestinal motility in two groups of straight and J-pouch ileorectal anastomosis. In the straight group, 98 percent of the interdigestive migrating contractions (IMC) reached the anastomosis and 48 percent of the defecations were affected by the contractions. In the J-pouch group, 16 percent of the contractions reached the anastomosis and only 8 percent of the defecations were related to the contractions. We conclude that transmission of IMC to the rectum is related to the frequency of defecation after total colectomy and that the disappearance of IMC in the J-pouch anastomosis reduced the frequency of defecations in those instances.

The objective of this study was to investigate nosocomial infections by the comparison of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. We made a serological classification of 262 strains of Pseudomonas aeruginosa between 1983 and 1991. Group E strains were prevalent in 1987 and group F strains after 1990. Both these groups strains were resistant to several antibiotics, and were scarcely detected from the appendix contents in appendicitis that originated outside the hospital. Therefore we presumed these were nosocomial pathogens. With the countermeasures to nosocomial infections from 1987 on the isolation rate of enterotoxin type B and C MRSA strains decreased. Following this MRSA change, almost group E strains disappeared in Pseudomonas aeruginosa. Whereas type AC MRSA began to isolated abruptly from 1990, and the isolation of group F strains increased simultaneously. Type B and C strains still remained high sensitivity to minocycline. Type AC which have already gotten resistance to minocycline took the place of type B and C and prevalented. Similarly group F in Pseudomonas aeruginosa took the place of group E as soon as the former acquired resistance to carbapenem.

Gel Injection Adjustable Keratoplasty (GIAK) is a technique previously described by G. Simon for the correction of myopia. Following pachometry, a 0.8 mm wide, 80% deep linear incision is performed 2.5 mm from the apex. Using a guide, a 1 mm wide, 5 mm diameter annular spatula is introduced to dissect an interlamellar canal and the crosslinked polyethylene oxide hydrogel is injected with a modified 23 gauge needle. The biocompatibility to 13 PEO batches was studied on 21 albino rabbits (Follow up 15 to 135 days). In nineteen, the cornea remained perfectly transparent. Two animals presented an infection at POD 1. Histopathology showed no endothelial deterioration, no anomaly of the thickness or of the cellular morphology around the injected zone. However some mononuclear cells were noticed surrounding the hydrogel in some rabbits together with thinning of the corneal epithelium anterior to the injected zone. A pilot refractive study was conducted on 5 cats using 2 PEO gels. One cat developed an infection following surgery. A second developed an inflammatory response with corneal neovascularization at POD 8. Thus, these animals were not included in the follow-up study which ranged from 6 to 28 months. Immediately after surgery, the refractive effect, measured with the Canon SK-1 digital autokeratometer, was 5.22 +/- 0.46 D (SD) of flattening. The long term effect (26 months) of the GIAK procedure appears to be stable and safe when using sterile PEO gels made of highly purified materials.

Resistance patterns against 25 antimicrobial agents consisting of beta-lactams, aminoglycosides, tetracyclines, fluoroquinolones, macrolides and etc. were examined for 69 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated at Hiroshima University Hospital from July 1991 to April 1992. Regarding overall resistance (the percentage of highly and moderately resistant strains), the following antimicrobial agents were no more effective chemotherapeutics for MRSA infections (%resistance): methicillin (100), flomoxef (100), kanamycin (100), tobramycin (100), amikacin (100), isepamicin (100), gentamicin (78), dibekacin (100), ofloxacin (99), levofloxacin (99), temafloxacin (99), erythromycin (100), clarithromycin (100), tetracycline (93), minocycline (93) and fosfomycin (100). Further spread of arbekacin-resistant strain, which was isolated in April 1991, into a clinical environment could not be recognized during the period covered in the present study. All the MRSA strains were resistant either constitutively (26 strains) or inducibly (43 strains) to macrolide-lincosamide-streptogramin B (MLS) antibiotics. When expression is constitutive, the strains are resistant to all MLS antibiotics. In contrast, 16-membered macrolide (i.e., jasamycin), lincomycin and mikamycin B escape resistance in the strains with a typical inducible resistance overcome in the presence of 14-membered macrolides by a translational attenuation mechanism. Three of 4 beta-lactamase-positive strains, however, can not be classified in these two resistance groups, being exclusively resistant to mikamycin B. The strains grown in the presence of any inducing MLS antibiotic became susceptible to mikamycin B even in the inducer-free culture.

Resistance patterns against 24 antimicrobial agents were examined for 50 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated at Hiroshima University Hospital during the period October 1990 and July 1991. Overall resistance (the percentage of highly and moderately resistant strains) to the antimicrobial agents is summarized as follows: methicillin 100%, flomoxef 100% (beta-lactams); kanamycin 94%, tobramycin 94%, amikacin 100%, isepamicin 94%, gentamicin 80%, dibekacin 94%, arbekacin 2% (basic oligosaccharide group/aminocyclitols); ofloxacin 96%, temafloxacin 96%, levofloxacin 96% (fluoroquinolones); erythromycin 98%, clarithromycin 98%, josamycin 30% (macrolides); vancomycin 0% (glycopeptide); tetracycline 94%, minocycline 94% (tetracyclines); fosfomycin 100%; mikamycin B 30%, nosiheptide 0% (peptide); rifampicin 2% (ansamycin); streptomycin 2% (basic oligosaccharide group); chloramphenicol 2%. Arbekacin resistance was observed in one case: the cross resistance was complete among the aminocyclitol antibiotics tested in this study and streptomycin, probably due to the ribosomal alteration.

Resistance patterns against 23 antimicrobial agents were examined for 42 strains of methicillin-resistant Staphylococcus aureus (MRSA). Thirty-four strains were isolated at Hiroshima University Hospital during 1984-1990 and 8 strains were collected in Tokushima city in 1986. Overall resistance to the antimicrobial agents in clinical use is summarized as follows: methicillin 100%, flomoxef 93% (beta-lactams); kanamycin 98%, tobramycin 88%, amikacin 83%, isepamicin 81%, gentamicin 60%, dibekacin 64%, arbekacin 0% (aminocyclitol aminoglycosides); ofloxacin 31%, TA-167 33% (fluoroquinolones); erythromycin 100%, clarithromycin 100%, josamycin 71% (macrolides); vancomycin 0% (glycopeptide); tetracycline 43%, minocycline 31% (tetracyclines); fosfomycin 93%. The MRSA strains remained susceptible to the non-clinical peptide group of antibiotics except for mikamycin B: mikamycin A 2%, mikamycin B 69%, nosiheptide 0%, bottromycin A2 0%, bottromycin D-1 0%, bottromycin D-2 0%. Since April 1990, the MRSA strains isolated at Hiroshima University Hospital showed a tendency to acquire resistance to tetracyclines and fluoroquinolones and to lose mikamycin B-resistance. As of August 1990, none of the MRSA strains isolated at Hiroshima University Hospital was resistant to vancomycin and arbekacin.

A study of the pathogenicity of the Enterococcus and Methicillin resistant S. aureus (MRSA) was made of 781 cases with gastroenterological surgery. The results obtained were summarized as follows. In this study 215 strains were isolated from clinical specimens. In these strains 13% was isolated from the postoperative mixed infection and only 7% occurred in single infection. Most of the single infections by the Enterococcus occurred in the cases with changes in host resistance, such as terminal cancer, disorder of the glucose tolerance, malnutrition and/or organ failures. Seventy-three strains were isolated from clinical specimens. In these strains 10% were the postoperative mixed infection and 40% were single infection. Incidence of the infection by the MRSA was significantly high compared with that by the Enterococcus. Single infection by the MRSA occurred even in the cases with normal host resistance. Strains producing enterotoxin C (single or plus A) were frequently isolated in MRSA enteritis or pneumonia. However, 60 percent of the patients in whom MRSA were detected in their abdominal drains had no signs of infection. These results suggest that the occurrence and severity of the MRSA infection relate with site of the infection and production of the exotoxin.

Highly methicillin-resistant Staphylococcus aureus (H-MRSA, MIC greater than 100 micrograms/ml) was prevalent from 1986 in our institution. The failure of povidone-iodine to reduce the prevalence of MRSA led us to choose chlorhexidine-ethanol solution as an antiseptic, and then the isolation frequency of H-MRSA decreased significantly in 1988. When H-MRSA began to increase again recently, we studied the resistance to antiseptics of MRSA in order to investigate the cause of this re-increase. Common antiseptics were tested against 45 strains of H-MRSA and 22 strains of methicillin sensitive S. aureus (MSSA, MIC less than 12.5 micrograms/ml). Dilute preparations (1:100) of povidone-iodine and chlorhexidine-ethanol solution were more effective on H-MRSA than the other antiseptics. Though there was no significant difference between H-MRSA and MSSA in their sensitivity to povidone-iodine, the killing of H-MRSA strains was more delayed than the killing of MSSA strains in chlorhexidine. Even after a 120-second exposure, 13.3% of H-MRSA strains were resistant to chlorhexidine (more than 1000 colonies were recovered). These highly chlorhexidine-resistant strains have been isolated since 1987 when we chose chlorhexidine-ethanol solution as the antiseptic in our institution. Therefore we suspect that the acquirement of resistance to antiseptics by H-MRSA caused the re-increase of this strain.

We have previously demonstrated that depletion of CD8+ T-cells by the use of a monoclonal anti-Lyt-2.2 antibody abolishes the curative effectiveness of low-dose melphalan (L-phenylalanine mustard; L-PAM) therapy for BALB/c mice bearing a large (greater than or equal to 20 mm) s.c. MOPC-315 tumor and extensive metastases (Mokyr et al., Cancer Res., 49: 4597-4606, 1989). Here we show that as a consequence of low-dose L-PAM therapy, CD8+ T-cells accumulate in the s.c. tumor nodules of MOPC-315 tumor bearers. Specifically, an 80-fold increase in the number of CD8+ T-cells was seen within 5 days after the chemotherapy. Treatment of MOPC-315 tumor bearers with low-dose L-PAM in conjunction with monoclonal anti-Thy-1.2 or anti-Lyt-2.2 antibody, in contrast to treatment with monoclonal anti-L3T4 antibody, prevented the appearance of the massive CD8+ T-cell infiltrate in the s.c. tumor nodules. Fresh CD8+ T-cells derived from s.c. MOPC-315 tumor nodules that were regressing as a consequence of low-dose L-PAM therapy exhibited a potent direct lytic activity against the MOPC-315 plasmacytoma in a short-term in vitro assay. The specificity of the lytic activity exhibited by the CD8+ T-cells was illustrated not only by the inability of the CD8+ T-cells to lyse two antigenically unrelated thymomas (the WEHI 22.1 and the EL-4) and a natural killer-sensitive lymphoma (the YAC-1), but also by their relatively weak lytic activity against an antigenically related plasmacytoma (the MOPC-104E). Thus, CD8+ T-cells that infiltrate the s.c. tumor nodules of MOPC-315 tumor bearers following low-dose L-PAM therapy most likely exploit a CTL-type lytic mechanism to eradicate at least part of the large tumor burden not eliminated by the direct antitumor effects of the drug.

Concomitant with the extensive use of antibiotics, the number of multiple antibiotic-resistant strains has been increasing. Since resistance is mainly mediated by R plasmids, we undertook to investigate the characteristics of R plasmid-determined beta-lactamase in 6 Gram-negative rods. The beta-lactamase produced by each organism was classified by its substrate: type P which attacks penicillins, type C which attacks cephalosporins, and type C/P which attacks both penicillins and cephalosporins. Though the chromosomally mediated beta-lactamase of almost all Gram-negative rods is classified as type C, R plasmid-mediated beta-lactamase is almost equally active against both penicillins and cephalosporins. Therefore, we suggest that type C/P beta-lactamase was mediated by R plasmids in Gram-negative rods which already produced chromosomally mediated type C beta-lactamase. The strains which produced type C/P beta-lactamase tended to be more resistant to antibiotics than the other beta-lactamase producing strains. Among type C/P strains, the sensitivity to cephalosporins varied with the bacterial species, whereas all these strains were highly resistant to penicillins. Even for piperacillin, which is stable to cephalosporinase, the MIC at which the cumulative percentage of strains inhibited was 50% (MIC50) was over 50 micrograms/ml in all strains tested.

Assessment has been made, using MIC values and coagulase types, of 214 strains of Staphylococcus aureus isolated from the lesions of inpatients at the First Surgical Department, Hiroshima University, from 1983 to 1988. The obtained results are summarized below: 1. Frequency of MRSA among all the strains of S. aureus during a period from 1983 to 1987 was higher than 50%. 2. Highly methicillin-resistant strains (MIC of methicillin greater than 100 micrograms/ml) emerged in 1984 and thereafter, showed a trend of increase through 1987. 3. The highly methicillin-resistant strains are of coagulase II type strain and they are considered to be inhospital epidemic strains. 4. Both ofloxacin and minocycline (MINO) showed good activities against highly methicillin-resistant strains, but many resistant strains were resistant to beta-lactam and aminoglycoside agents. Based on the above basic assessment, chemotherapies mainly using MINO were performed on cases of MRSA infections experienced at the First Surgical Department, Hiroshima University in a period from July, 1987, to November, 1988, and the following results were obtained. 1. Drugs used were: single MINO in 2 cases; MINO+imipenem/cilastatin (IPM/CS) in 4 cases; MINO+IPM/CS+tobramycin in 1 case; MINO+cefmetazole (CMZ) in 1 cases; and MINO+fosfomycin+CMZ (changed to MINO+Amikacin) in 1 case, a total of 9 cases. Clinical result showed remarkable effectiveness of these therapies in 3 cases with some degrees of effectiveness in 6 cases, thus the therapies were all effective or better. 2. No particular abnormality was observed in subjective or objective symptoms or clinical laboratory tests, judged from values obtained before and after administration of MINO. The above results agreed with well those of the basic assessment, suggesting the possibility that the chemotherapies mainly using MINO would exhibit effectiveness on MRSA infections.

The pressure to improve health care and provide better care at a lower cost has generated the need for efficient capture of clinical data. Many data sets are now being defined to analyze health care. Historically, review and research organizations have simply determined what data they wanted to collect, developed forms, and then gathered the information through chart review without regard to what is already available institutionally in computerized databases. Today, much electronic patient information is available in operational data systems (for example, laboratory systems, pharmacy systems, and surgical scheduling systems) and is accessible by agencies and organizations through standards for messages, codes, and encrypted electronic mail. Such agencies and organizations should define the elements of their data sets in terms of standardized operational data, and data producers should fully adopt these code and message standards. The Health Plan Employer Data and Information Set and the Council of State and Territorial Epidemiologists in collaboration with the Centers for Disease Control and Prevention and the Association of State and Territorial Public Health Laboratory Directors provide examples of how this can be done.

We have previously shown that Sephadex G-10-adherent spleen cells from mice bearing a large MOPC-315 tumor can suppress the in vitro generation of a primary anti-MOPC-315 cytotoxic response. Here we show that following low dose melphalan (L-phenylalanine mustard; L-PAM) therapy of such tumor bearing mice their Sephadex G-10-adherent spleen cells no longer suppressed but actually brought about the generation of enhanced antitumor cytotoxicity when added to the immunization culture of normal spleen cells and MOPC-315 tumor cells. This immunopotentiating activity of the Sephadex G-10-adherent spleen cells from L-PAM treated MOPC-315 tumor bearers was attributed to T-cells which co-express the Lyt 2 and the L3T4 antigens based on results of experiments employing negative selection. Specifically, depletion of Lyt 2+ cells or of L3T4+ cells abolished the ability of the Sephadex G-10-adherent splenic cell population from L-PAM treated MOPC-315 tumor bearers to bring about the generation of enhanced antitumor cytotoxicity when added to the immunization culture of normal spleen cells. Moreover, the immunopotentiating activity was not restored when a population of Sephadex G-10-adherent spleen cells depleted of Lyt 2+ cells was admixed with a population of Sephadex G-10-adherent spleen cells depleted of L3T4+ cells. In light of the unusual phenotype of the immunopotentiating cells in the spleens of L-PAM treated MOPC-315 tumor bearing mice (i.e. Lyt 2+ L3T4+), and since the vast majority of thymocytes in normal adult BALB/c mice co-express the Lyt 2 and the L3T4 antigens, we evaluated the effect of low dose L-PAM therapy on the antitumor immune reactivity of thymocytes from MOPC-315 tumor bearing mice. A low dose of L-PAM was found to render thymocytes from MOPC-315 tumor bearers, but not from normal mice, capable of bringing about the generation of enhanced lytic activity when added to the immunization culture of normal spleen cells and MOPC-315 tumor cells. At the same time, the thymocytes from L-PAM treated MOPC-315 tumor bearers were unable to develop an antitumor cytotoxic response of their own when immunized in vitro in the absence of normal spleen cells. The possibility that the Lyt 2+ L3T4+ immunopotentiating cells in the spleens of L-PAM treated MOPC-315 tumor bearers represent immature cells that have been induced by the chemotherapy to migrate from the thymus into the spleen is discussed.