Clinical evaluation of the measurement of serum procalcitonin: comparative study of procalcitonin and serum amyloid A protein in patients with high and low concentrations of serum C-reactive protein.

Levels of C-reactive protein (CRP) and serum amyloid A protein (SAA) in blood are increased as acute phase proteins in patients with inflammatory conditions. Most of the currently used inflammatory markers, such as erythrocyte sedimentation rate and CRP or SAA levels, are non-specific parameters. By contrast, procalcitonin (PCT) has been reported to be selectively induced by severe infection in systemic inflammatory response syndrome (SIRS) and also in sepsis or multiorgan dysfunction syndrome. PCT expression is induced only slightly, if at all, by viral infections, autoimmune disorders, neoplastic disorders and trauma arising from surgical intervention. Serum PCT and SAA levels were compared in 93 patients with a CRP concentration higher than 100 mg/L and in 26 patients with a CRP concentration lower than 1.5 mg/L. In patients with high levels of CRP, all patients with sepsis and severe bacterial infection showed a significantly increased PCT concentration of more than 1.0 microg/L and it was possible to differentiate between the patients with neoplastic disorders and those with other inflammatory diseases. In patients with low levels of CRP, the PCT concentration was less than 0.3 microg/L and an increased PCT level was not seen in patients with autoimmune disorders or viral and fungal infections. These results suggest that determining the serum PCT level may be useful in the differential diagnosis of severe infection.

[Assay for determination of the serum procalcitonin level: biochemical and clinical evaluation].

In patients with inflammatory conditions such as infection, cytokines induce the production of C-reactive protein(CRP) and serum amyloid A protein(SAA) in hepatic cells. It has been reported that upon viral infection, the serum SAA level increases by a greater degree than the serum CRP level. Procalcitonin (PCT), the precursor of calcitonin, is a new type of inflammatory marker that is specifically induced by bacterial infection, sepsis and lethal multiple organ failure, but not by viral infection, autoimmune diseases, tumors or surgical stress. To evaluate the immunoluminometric assay(LUMI test PCT; Brahms Diagnostics, Berlin, Germany) procedure for determining the PCT level and to study the clinical significance of the serum PCT level, we determined the serum levels of PCT, CRP and SAA in patients with various inflammatory diseases and normal subjects. The serum PCT level in the normal subjects was < 0.3 ng/ml. Among the patients with inflammatory disease who had a high CRP level(CRP > 20000 micrograms/dl), the PCT level was elevated only in those patients with severe bacterial infection. These results suggest that determining the PCT level may be useful in the differential diagnosis of severe bacterial infection. The patients who had a low CRP level(CRP < 150 micrograms/dl), had a PCT level within the normal range. The patients with autoimmune disease, viral infection, and fungal infection did not have an elevated PCT level.

Levels of three inflammation markers, C-reactive protein, serum amyloid A protein and procalcitonin, in the serum and cerebrospinal fluid of patients with meningitis.

The levels of C-reactive protein (CRP) and serum amyloid A protein (SAA) in blood are increased in patients with inflammatory diseases as acute phase proteins. Most of the presently used indicators of inflammation, such as body temperature, white cell count, erythrocyte sedimentation rate or CRP, are non-specific parameters. In contrast, procalcitonin (PCT) has been reported to be selectively induced by severe bacterial infection during the systemic inflammatory response syndrome (SIRS), and also in sepsis or multiorgan dysfunction syndrome. PCT expression is only slightly induced, if at all, by viral infections, autoimmune disorders, neoplastic diseases and trauma of surgical intervention. We measured the concentrations of CRP, SAA and PCT in the sera and cerebrospinal fluid (CSF) of 30 patients with bacterial, viral, or mycotic meningitis, and 12 patients with a noninflammatory central nervous system disease as controls. An extremely high CRP level in CSF of above 100 microg/L was seen in all seven bacterial meningitis patients and in only 10% of the viral meningitis patients. A high SAA level in CSF of greater than 10 microg/L was observed in all of the bacterial meningitis and mycotic meningitis patients, and in 95% of the viral meningitis patients. Among those with bacterial meningitis, the serum PCT level was more elevated in those with more serious bacterial meningitis. The PCT level in the CSF did not significantly differ among the patients with the three types of meningitis. However, the serum PCT level was very high above 0.1 microg/L in all seven bacterial meningitis patients, especially in the clinically serious cases.

[Responses in a questionnaire by medical school students who participated in the new curriculum of the clinical learning in clinical pathology].

The clinical learning taken by medical students are an important part of their medical education. To develop a new, effective curriculum for the clinical learning in Clinical Pathology, the instructors defined clear general instructional objectives and specific behavioral objectives, and discussed the learning strategies and evaluation methods. The medical students at our medical school took this new curriculum in Clinical Pathology in 1999. As an evaluation method of this new curriculum, we asked all students to fill out a questionnaire that asked their opinions about the length of each component in the Clinical Pathology rotation, the content of the rotation, etc. Over 80% of the respondents answered that the rotation in Clinical Pathology was useful. Ninety-six percent of the students felt that the experience and knowledge they gained in this Clinical Pathology rotation will be useful in the clinical learning in other departments. Based on the high percentage of favorable responses from the students, we concluded that the new curriculum, which was developed after intensive planning, was successful. In summary, the feedback from students who took the new curriculum in Clinical Pathology showed that this new course was well-accepted by the students and that it created an excellent relationship between the instructors and students. Some of the responses in the questionnaires will be used to improve the Clinical Pathology rotation in the future.

[Development of gamma-heavy chain disease during the course of diabetic nephropathy].

We reported a rare case of gamma-heavy chain disease. A 63-year-old man had been given a diagnosis of diabetes mellitus at the age of 30 and had received hemodialysis since the age of 55. The patient presented with swollen lymph nodes in the neck. Lymph node biopsy findings suggested immunoblastic lymphadenopathy. The patient was admitted to Kitasato University hospital. Serum protein electrophoresis showed an increase of beta-fraction peak, and immunoelectrophoresis revealed an increase of gamma-heavy chain protein. Further studies of the gamma-heavy chain protein showed that it contained three different components and that the molecular weight of the main component was 34,000 Da. The patient died on the 11th day of hospitalization. The diagnosis at autopsy was unclassified malignant lymphoma.

[A role of clinical pathologists in Laboratory Information (Consulting) Center].

In the 21st Century, laboratory scientists must change their concepts and attitude in order to supply services and information of great value. The laboratory tests comprise an increasing volume, and medical workers frequently need consultation on these tests. Effective utilization of laboratory data are important aspects of evidence-based medicine, and will also contribute to the efficiency of hospital practice and management. Clinical Laboratory of Kitasato University Hospital opened the "Clinical Laboratory Information (Consulting) Center" in July 1995 to respond to the increasing demand for consultation. It has been supporting medical care and research. The Center is located on the second floor of the Clinical Laboratory building of Kitasato University Hospital, and is staffed by one medical technologist and a clinical pathologist specialized in laboratory medicine. The Center staff consults by telephone from 9 am to 5 pm on weekdays, and get inquiries after-work hours and during weekends either by e-mail or fax. The Center aims to improve medical care by providing accurate and up-to-date information on clinical laboratory tests and interpretations. The clinical pathologist of the Center attempts to advise physicians regarding appropriate tests for particular patients. This avoids the ordering of unnecessary tests, which benefits the patient, the physician, and the hospital. The clinical pathologist should keep abreast of new findings on a wide array of clinical laboratory tests. The clinical pathologist should respond immediately to requests and complaints, thereby always seeking to improve oneself and the Center. Our Center is the first clinical laboratory in Japan staffed by both a clinical pathologist and a medical technologist, and our Center could be a pilot study for a new service of hospital clinical laboratories.

[The possibility of acute inflammatory reaction affects the development of pressure ulcers in bedridden elderly patients].

To test the hypothesis that acute inflammatory reaction associates with the development of pressure ulcers in bedridden elderly patients, 40 hospitalized elderly patients suffering from bacterial pneumonia, cerebrovascular disease, and femoral bone fracture were enrolled in this study. All of them were divided into two groups with pressure ulcers (group P; 17 patients) and without one (group N; 23 patients). The blood samples were taken from them within 5 days after the patients being bedridden. Although no significant difference exist in pressure ulcer risk factors (age, gender, Braden scale, underlying diseases, blood pressure, and heart rate) between the two groups, white blood cell, plasma C-reactive protein and fibrinogen in group P increased significantly as compared with those in group N. Besides number of platelets and maximum platelet aggregation rate were significantly higher in group P than in group N. Serum albumin and hemoglobin of both groups decreased after being bedridden, especially hemoglobin in group P was significantly lower than that in group N. While the concentration of serum IL-6 did not indicate a significant difference between both the groups, serum IL-1 beta increased significantly in group P. In conclusion, we suggested that acute inflammatory reaction releasing proinflammatory cytokines affected the development of pressure ulcer in bedridden elderly patients.

[Quantitative levels of serum amyloid A protein and other proteins in cerebrospinal fluid and serum of patients with meningitis].

Serum amyloid A protein (SAA), a putative precursor of the AA protein which constitutes amyloid fibrils in secondary amyloidosis, is evaluated as a sensitive acute-phase reactant in serum. At present, SAA concentration in serum is determined by latex nephelometry, but this assay cannot detect SAA in the low concentration range lower than 10 ng/ml. We have developed a sensitive enzyme immunoassay (EIA) for determining low concentrations of SAA. The assay is reproducible, reliable and requires no pretreatment of specimen prior to assay. We measured levels of SAA by this EIA in both cerebrospinal fluid (CSF) and serum of patients with suspected meningitis, measured also levels of albumin, alpha 2 macroglobulin and C-reactive protein (CRP) to investigate if these protein levels are useful for differential diagnoses of meningitis and for indicators damage of blood-CSF barrier. The SAA reference value in CSF is 3.99 +/- 1.74 ng/ml (mean +/- SD for nonmeningitis patients). The CRP concentration in CSF in bacterial meningitis was much higher than in viral meningitis, but CRP in CSF was also high in bacterial infection other than meningitis. On the other hand, SAA concentration in CSF in these patients with any meningitis are significantly higher than the reference values of SAA (p < 0.001). However, the differences in SAA concentrations among the three types (bacterial, viral and mycotic meningitis) of meningitis were not significant.

[Consultation on laboratory information--from the perspectives of clinical pathologists and medical technologists].

There is increasing demand for consultation on clinical laboratory test results. To respond to this demand, the Clinical Laboratory of Kitasato University Hospital opened the "Clinical Laboratory Information (Consulting) Center" in July 1995, which has been supporting medical care and research. The Center is located on the second floor of the Clinical Laboratory building of Kitasato University Hospital, and is staffed by one medical technologist and a clinical pathologist specialized in clinical laboratory medicine. The Center staff consults by telephone from 9 am to 5 pm on weekdays, and get inquiries after work hours and during weekends either by e-mail or fax. Since January 1998, the Center has been open to physicians belonging to the Japanese Medical Association, in the area surrounding Kitasato University Hospital. The Center aims to improve medical care by providing accurate and up-to-date information on clinical laboratory test and the interpretation. The staff of the Center attempts to advise physicians thus regarding appropriate tests for particular patients. This avoids the ordering of unnecessary tests, and benefits the patient, the physician, and the hospital. The staff should keep abreast of new findings on a wide array of clinical laboratory tests. The Center staff should respond immediately to requests and complaints, thereby always seeking to improve the Center. Since physicians who receive training in Clinical Pathology at this hospital must do a rotation in the Internal Medicine Department for at least two years, the clinical pathologist at the Center can provide not only interpretation of the test result but also clinical advice. More than 80% of the inquiries can be answered by medical technologists. It is important that the Center staff answer every question in a courteous and polite manner. Establishment of this Center increased the efficiency of the clinical laboratories at this hospital, as the other medical technologists were freed from answering questions over the telephone. Our Center is the first such clinical laboratory in Japan that is staffed by both a clinical pathologist and a medical technologist, and our Center could be a pilot program for a new service of hospital clinical laboratories.

[Establishment of a laboratory information office in response to the expanding need for consultation--actual situation of the laboratory information room, Clinical Laboratory Department, Kitasato University Hospital].

Due to the advancement, segmentation and specialization of the medical care, laboratory examinations covered by the National Health Insurance (NHI) tariff have exceeded several hundred, and it is not possible for medical staff to be familiar with all of these and to utilize them appropriately. There is an urgent need for laboratory information for physicians, nurses, and other health professionals. Accordingly, our Clinical Laboratory Department, Kitasato University Hospital, established a "Laboratory Information (Consultation) Office" in July 1995 to provide consultations on clinical laboratory tests to those engaged in daily clinical practice and in medical research. The office is situated on the second floor of the Laboratory Building of the Kitasato University Hospital. One laboratory technician and one laboratory physician (clinical pathologist) are stationed there. They are available for telephone consultations from 9:00 to 17:00 on weekdays, except for holidays, and from 9:00 to 13:00 on the first, third and fifth Saturdays. In addition, since January 1997, this office also has been open to members of medical associations in various cities in our area. To cope with requests for laboratory information, including whether an examination is covered the NHI tariff, selection of appropriate screening examinations and availability of new laboratory tests, consultations by fax are accepted at any time, even after regular working hours. As a post-graduate education program, the clinical laboratory physicians study specimen handling analytical methods and interpretation of results. At medical staff meeting, personnel from the Laboratory Information Office provide clarification on the types of consultations offered, address complex questions and find resolutions for rarely encountered and difficult laboratory issues. At these meetings, a summary of new laboratory examinations also is presented. This system of an information office where full-time laboratory physicians and laboratory technicians are stationed is the first such attempt in Japan. It may be considered a pilot project to determine if such a system may be applied to other laboratory departments in the future.

[Production of inflammatory markers by HepG 2 cells stimulated with monocyte conditioned media: the effects of corticosteroid and other immunosuppressants].

Both C-reactive protein (CRP) and serum amyloid A protein (SAA) are determined as an indicator of inflammation and tissue damage. We found that CRP decreased extremely after administration of corticosteroid but SAA did not. However, the mechanism of the CRP decrease by corticosteroid therapy is unclear. In this study we have examined the effects of some immunosuppressive drugs and cytokines on the production of CRP and SAA by human hepatoma cells (HepG 2). A corticosteroid prednisolone did not enhance the production of CRP by HepG 2 cells but enhanced that of SAA, which indicate that prednisolone had no direct effect on the CRP production. Some immunosuppressants other than corticosteroids suppressed the SAA production but had no effect on the CRP production. IL-1 beta induced both CRP and SAA production but only in the co-presence of IL-6. A cytokine IL-6 induced the CRP production in the presence of IL-1 beta, but did not affect the constitutive production of SAA. Then we have examined the cytokine production by monocytes stimulated by lipopolysaccharide. Prednisolone inhibited the production of IL-1 alpha, IL-1 beta, IL-6 and TNF alpha.

[Variations of serum amyloid A protein and interleukin-6 in patients with low concentration of serum C-reactive protein].

Both C-reactive protein (CRP) and Serum amyloid A protein(SAA) are determined as an indicator of inflammation and tissue damage. But serum CRP in the range less than 10 micrograms/dl was not correlated with SAA. We determined CRP, SAA and interleukin-6(IL-6) in sera of patients who had received corticosteroid therapy. CRP decreased extremely after administration of more than 50 mg/day corticosteroid. However, SAA and IL-6 levels changed independently from CRP levels. In the patients under long-term corticosteroid therapy, CRP decreased rapidly to the level below the reference range and remained low, while SAA decreased but to the level in the reference range, and IL-6 levels was unchanged. When they were complicated with infectious disease during the corticosteroid therapy, CRP increased to or above the reference level but not so markedly, however, SAA increased markedly and exceeded the upper reference range three or four days earlier than the day of CRP increase. It is suggested that serial SAA monitoring will be reliable for the early diagnosis of infection if the patients is taking corticosteroid therapy.