Tumour-associated macrophages correlate with poor prognosis in myxoid liposarcoma and promote cell motility and invasion via the HB-EGF-EGFR-PI3K/Akt pathways.

BACKGROUND: Myxoid liposarcoma (MLS) is the second most common subtype of liposarcoma, and metastasis occurs in up to one-third of cases. However, the mechanisms of invasion and metastasis remain unclear. Tumour-associated macrophages (TAMs) have important roles in tumour invasion, metastasis, and/or poor prognosis. The aim of this study was to investigate the relationship between TAMs and MLS. METHODS: Using 78 primary MLS samples, the association between clinical prognosis and macrophage infiltration was evaluated by immunochemistry. The effects of macrophages on cell growth, cell motility, and invasion of MLS cell lines were investigated in vitro. In addition, clinicopathological factors were analysed to assess their prognostic implications in MLS. RESULTS: Higher levels of CD68-positive macrophages were associated with poorer overall survival in MLS samples. Macrophage-conditioned medium enhanced MLS cell motility and invasion by activating epidermal growth factor receptor (EGFR), with the key ligand suggested to be heparin-binding EGF-like growth factor (HB-EGF). The phosphoinositide 3-kinase/Akt pathway was mostly involved in HB-EGF-induced cell motility and invasion of MLS. The expression of phosphorylated EGFR in MLS clinical samples was associated with macrophage infiltration. In addition, more significant macrophage infiltration was associated with poor prognosis even in multivariate analysis. CONCLUSIONS: Macrophage infiltration in MLS predicts poor prognosis, and the relationship between TAMs and MLS may be a new candidate for therapeutic targets of MLS.

Y-box binding protein-1 regulates cell proliferation and is associated with clinical outcomes of osteosarcoma.

BACKGROUND: Prognosis of osteosarcoma (OS) with distant metastasis and local recurrence is still poor. Y-box binding protein-1 (YB-1) is a multifunctional protein that can act as a regulator of transcription and translation and its high expression of YB-1 protein was observed in OS, however, the role of YB-1 in OS remains unclear. METHODS: Y-box binding protein-1 expression in OS cells was inhibited by specific small interfering RNAs to YB-1 (si-YB-1). The effects of si-YB-1 in cell proliferation and cell cycle transition in OS cells were analysed in vitro and in vivo. The association of nuclear expression of YB-1 and clinical prognosis was also investigated by immunohistochemistry. RESULTS: Proliferation of OS cell was suppressed by si-YB-1 in vivo and in vitro. The expression of cyclin D1 and cyclin A were also decreased by si-YB-1. In addition, si-YB-1 induced G1/S arrest with decreased cyclin D1 and cyclin A in OS cell lines. Direct binding of YB-1 in OS cell lines was also observed. Finally, the nuclear expression of YB-1 was significantly related to the poorer overall survival in OS patients. CONCLUSION: Y-box binding protein-1 would regulate cell cycle progression at G1/S and tumour growth in human OS cells in vitro and in vivo. Nuclear expression of YB-1 was closely associated with the prognosis of OS, thus, YB-1 simultaneously could be a potent molecular target and prognostic biomarker for OS.

Polypeptide N-acetylgalactosaminyl transferase 3 independently predicts high-grade tumours and poor prognosis in patients with renal cell carcinomas.

BACKGROUND: The polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) family of enzymes regulates the initial steps of mucin-type O-glycosylation. N-acetylgalactosaminyltransferases might show novel patterns of GalNAc-T glycosylation on tumour-derived proteins, which could influence cancer biology, but its mechanisms are unclear. We investigated the association of GalNAc-T3 and -T6 expressions with clinicopathological features and prognoses of patients with renal cell carcinomas (RCCs). METHODS: Expressions of GalNAc-T3/6 and cell-adhesion molecules were analysed immunohistochemically in 254 paraffin-embedded tumour samples of patients with RCC. RESULTS: Of 138 GalNAc-T3+ cases, 46 revealed significant co-expression with GalNAc-T6. N-acetylgalactosaminyltransferases-3+ expression showed a close relationship to poor clinical performance and large tumour size, or pathologically high Fuhrman's grading, and presence of vascular invasion and necrosis. The GalNAc-T3-positivity potentially suppressed adhesive effects with a significantly low ß-catenin expression. Univariate and multivariate analyses showed the GalNAc-T3+ group, but not the GalNAc-T6+ group, to have significantly worse survival rates. CONCLUSION: N-acetylgalactosaminyltransferases-3 expression independently predicts high-grade tumour and poor prognosis in patients with RCC, and may offer a therapeutic target against RCC.

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases.

Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system.

Aging Affects Bone Marrow Macrophage Polarization: Relevance to Bone Healing.

Macrophages are an important component of the inflammatory cascade by initiating and modulating the processes leading to tissue regeneration and bone healing. Depending on the local environment, macrophages can be polarized into M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes. In order to assess the effects of aging on macrophage function, bone marrow macrophage polarization using primary bone marrow macrophages (BMMs) from young (8 weeks old) and aged (72 weeks old) wild-type male C57BL/6J mice was analyzed. Fluorescence-activated cell sorting (FACS) analysis (CD11b, iNOS, CD206), qRT-PCR (iNOS, TNF-α, CD206, Arginase 1), and ELISA (TNF-α, IL-1ra) were performed to compare the M1 and M2 phenotypic markers in young and aged mouse macrophages. Once M1 and M2 macrophage phenotypes were confirmed, the results showed that TNF-α mRNA was significantly upregulated in aged M1s after interferon gamma (INF-γ) exposure. Arginase 1 and CD206 mRNA expression were still upregulated with IL4 stimulation in aged macrophages, but to a lesser extend than those from younger animals. TNF-α secretion was also significantly increased in aged M1s compared to young M1s, following lipopolysaccharide (LPS) exposure. However, the IL-1ra secretion did not increase accordingly in aged mice. The results demonstrate that, compared to younger animals, aging of bone marrow derived macrophages increases the resting levels of oxidative stress, and the ratios of pro- to anti-inflammatory markers. These age-related changes in macrophage polarization may explain in part the attenuated response to adverse stimuli and delay in processes such as fracture healing seen in the elderly. LAY SUMMARY: Bone healing is a complex process that involves both biological and mechanical factors. Macrophages are key cells that regulate the events involved in bone healing, especially the initial inflammatory phase. In this biological cascade of events, macrophages present as different functional phenotypes including uncommitted (M0), pro-inflammatory (M1), and anti-inflammatory (M2), a process called macrophage polarization. A clear understanding of the effects of aging on macrophage polarization is critical to modulating adverse events such as fractures, atraumatic bone loss, and tissue regeneration in an aging population.

Ethylidene glucose-substituted new analogue of streptozotocin cannot induce diabetes: study on the basis of structure and activity relationship.

4,6-O-Ethylidene glucose (ethylidene glucose), a specific inhibitor at the outer surface of a glucose transporter in the cell membranes, substituted analogue of streptozotocin was newly synthesized. This compound did not induce diabetes in rats and also did not show cytotoxic effect on pancreatic beta cells of neonatal rats in a monolayer culture system. The reasons why such a molecule was designed and why it showed no biological effects are discussed on the basis of a structure-activity relationship. Our results afford positive evidence for the presence of a glucose transport system or a glucose transporter on pancreatic beta cells and its involvement in the action of streptozotocin on beta cells.

Role of central ATP-sensitive potassium channels in the analgesic effect and spinal noradrenaline turnover-enhancing effect of intracerebroventricularly injected morphine in mice.

Glibenclamide is one of the most potent sulfonylurea-derived antidiabetic drugs which block the adenosine triphosphate-sensitive potassium (KATP) channels. In the present study, we found that none of morphine, U-50,488H (a selective kappa agonist) and baclofen (a selective GABAB agonist) added to the incubation medium at concentrations up to 10(-4) M had appreciable effect on the specific binding of [cyclohexyl-2,3-3H(N)]glibenclamide ([3H]glibenclamide) to the isolated mouse brain microsomes. The analgesic activity induced by intracerebroventricular injection (i.c.v.) of morphine but not U-50,488H was antagonized by pretreatment with either i.c.v. glibenclamide or beta-funaltrexamine (beta-FNA; a selective mu antagonist) in mice. Furthermore, the increasing effect of i.c.v. morphine on the spinal noradrenaline (NA) turnover was greatly antagonized by i.c.v. pretreatment with either beta-FNA or glibenclamide. From these results, we demonstrated that KATP channels play an important role as indirect modulators of the supraspinal analgesia induced by mu agonist but not kappa agonist in mice, and the activation of descending noradrenergic system induced by i.c.v. morphine appears to be suppressed by the blockade of KATP channels.

Seroepidemiology of hepatitis C virus infection in hemodialysis patients and the general population in Fukuoka and Okinawa, Japan.

In 1992, a seroepidemiologic study was carried out among hemodialysis patients and the general population in Fukuoka and Okinawa, Japan to determine the presence of hepatitis C virus (HCV) infection and HCV viremia. The markers used were antibody to HCV, determined by second-generation assay (anti-HCV), and HCV RNA, determined by the polymerase chain reaction. The prevalence of anti-HCV in Fukuoka was 3.3%, 73 per 2237 persons, significantly (P < 0.001) higher than the 0.4%, 5 per 1295, in Okinawa. The prevalence of anti-HCV in hemodialysis patients in Fukuoka was 51.9% (161 of 310 patients), significantly (P < 0.001) higher than the 9.1% (13 of 143 patients) in Okinawa. The ratio of HCV RNA-positive to anti-HCV-positive persons was significantly higher in hemodialysis patients (147/174, 84.5%) than in the general population (49/78, 62.8%) (P < 0.001). Elimination of HCV among hemodialysis patients appears to be difficult, as such patients have lower immune responses than the general population. In Fukuoka, but not in Okinawa, blood used for transfusion was supplied by paid donors at commercial blood banks from 1953 to 1969. This may explain why HCV infection is endemic in Fukuoka and not in Okinawa. Differences between the prevalence of anti-HCV in the hemodialysis patients in Fukuoka and Okinawa reflect differences in the prevalence in the general population in these two areas of Japan.

[Reduction of medical resources utilization by influenza vaccination for hospitalized elderly patients].

In order to evaluate the economic efficacy of influenza vaccination for the elderly inpatients, we have investigated the health insurance fee of elderly inpatients in Japan. It was revealed that the health insurance fee varied by patients largely, ranging from 7,000 yen to 90,000 yen. Primary reason of this variation was due to the existence of the same effective drugs with variant prices and there were no rules concerning the period of drug medication. Thus, it was found that it would be improper to use the medication fee as a measure in evaluating the effects of influenza vaccinations. In this study, we used the length of days of testing and medication such as oral antibiotics, blood cell count, etc. as a measure to evaluate the effect of influenza vaccination. We compared these measures among elderly hospitalized patients with influenza vaccination or without influenza vaccination by ADL. Mean length of days of oral antibiotics was 2.64 (+/- 6.40) days for those with vaccination, and 3.92 (+/- 7.31) days for those without vaccination. Mean length of days of injection antibiotics was 2.52 (+/- 5.53) days for those with vaccination, and 8.82 (+/- 15.1) days for those without vaccination. Mean length of days of cells blood counter was 2.63 (+/- 2.22) days for those with vaccination, and 4.44 (+/- 3.20) days for those without vaccination. Mean length of days of chest X-ray was 1.30 (+/- 2.07) days for those with vaccination, and 2.56 (+/- 3.49) days for those without vaccination. These results suggest that influenza vaccination reduces medical utilization of resources. It was also revealed that influenza vaccination is most effective when elderly patients who are bed-bound are vaccinated.

[An outbreak of influenza A (H3N2) among hospitalized geriatric patients].

An outbreak of influenza A (H3N2) in a hospital where almost 90% of the inpatients are aged over 70 years is described. An increase of febrile episodes was seen during the period from January 29th to March 17th, 1992 in two of six wards paired sera, at the onset of fever and more than two weeks later, were obtained from patients in sixty-five episodes. Serum antibody titer to influenza A (H3N2) elevated over four times in 39 (60%) of 65. Influenza A (H3N2) virus was also isolated from seven patients. These results indicated an outbreak of influenza A (H3N2) in this population. Maximum body temperature was over 39 degrees C in 18 patients (46.2%) with influenza, and were significantly higher than that of the non-influenza patients. The duration of fever in 12 patients of 39 was longer than 8 days in 12 patients, and significantly longer than that of non-influenza cases. Bronchopneumonia was found in ten patients (25.6%). These results suggest that the influenza infection causes a high grade fever in geriatric patients and lasts longer than is commonly seen in patients with fever not associated with influenza. Influenza infection also frequently induces bronchopneumonia and may contribute to increase mortality in the elderly, especially in patients over 70 years old.

[A case of an elderly patient with dementia and gait disturbance associated with influenza].

We report a case of progressive dementia and prolonged gait disturbance correlated with influenza A/H3N2 infection in 91-year-old female patient, admitted because of in ability to take care of herself due to aging and cerebral infarction. At admission, conversation and comprehension were not significantly impaired, and she was able to walk by herself. Flu symptoms such as high grade fever, chills, arthralgia, and cough appeared after a short stay at home. Influenza A/ H3N2 was confirmed serologically. Delirium occurred on the sixth day after influenza onset, persisted for three weeks, followed by recovery. Dementia symptoms such as memory defects and disorientation continued and did not improve. Due to this febrile episode, she was unable to walk unassisted. The results of computed tomography performed before and after the influenza episode were unremarkable for additional cellebro-vascular events during the observed period. Influenza infection may be an important risk factor for reducing the quality of life in the elderly. In geriatric cases, influenza should not be treated as a mere transient illness, but rather one which has important consequences for the elderly population, including the possibility of life threatening complications.

[The clinical feature of febrile episodes].

Institutionalized elderly patients are at risk of nosocomial infection because of their compromised status by aging. To clarify the relationship between fever and disease in elderly patients, we analyzed 1,105 febrile episodes, the etiology of which were already diagnosed, of 443 patients (136 men, 307 women). All patients who were 65 years of age or older and who had been admitted to the hospital for more than 7 days had fevers above 37.5 degrees C recorded. The etiologies of the 1,105 febrille episodes were respiratory tract infection in 381 (34.5%), urinary tract infection in 263 (23.8%), other diseases in 164 (14.8%) and in 297 (26.9%) unknown. The episodes were categorized into two groups by the degree of initial fever: group A, 559 episodes (50.6%) of 37.5-38.0 degrees C and group B, 546 episodes (49.4%) of above 38.0 degrees C. Of the episodes, 41.0% were one-day fevers, 21.4% two-day fevers, and 14.0% three-day fevers. The frequency of two-or-more-day fevers was significantly higher in group B (69.0%) than in group A (49.2%) (p < 0.001). In group B, respiratory tract infection (44.3%) was more frequent than urinary tract infection (16.1%) (p < 0.001). Of the respiratory tract infections, 63.5% were in group B and, in contrast, 66.5% of the urinary tract infections were in group A. The white blood cell count and C-reacting protein levels were significantly higher in group B than in group A (p < 0.001). The degree of initial fever is an important predictive marker of severity of disease in elderly patients.

[Amantadine usage for influenza A during an influenza outbreak in a nursing home].

An outbreak of an influenza like illness was found in a nursing home in Fukuoka in January, 1999. Results of hemagglutinin inhibition tests with paired sera of patients and rapid diagnosis kit for influenza A indicated that an influenza A (H3N2) outbreak had occurred. A total of 15 patients with influenza like illness from one residential area of the nursing home were administered amantadine, 100 mg per day for five days. Clinical records of 264 residents were surveyed retrospectively from the tenth to the thirty-first of January, 1999. Influenza like illness was found in 112 residents (42.4%). The incidence of influenza like illness differed by residential area, ranging from 27.6% to 54.0%. The mean duration of fever was 3.6 days among patients administered amantadine. The mean duration was 4.4 days for patients not administered amantadine. The incidence of influenza like illness decreased rapidly after amantadine administration in the residential area where amantadine administration was done. These results suggest that amantadine is effective in mitigating influenza symptoms in the elderly. Amantadine may be useful for diminishing the influence of influenza A outbreaks in nursing homes.

[The efficacy of influenza vaccine among geriatric inpatients].

To investigate the efficacy of influenza vaccine in the elderly, hemagglutination inhibition (HI) antibody titer for the three types of influenza viruses were measured and the influenza infection rate was determined serologically in geriatric inpatients. Influenza vaccination was done for inpatients. For patients who had influenza vaccination in the year prior to the study, influenza vaccine was administered once or twice, and the number of injections were determined randomly. Influenza vaccine was injected twice to those had not received influenza vaccine in the previous year. Serum samples were collected from 166 vaccinated and 104 unvaccinated patients before and after 1996/1997 influenza season. In the vaccinees who had been vaccinated the previous year, 56 patients were injected once and 58 patient were injected twice. Fifty-two patients had not been vaccinated the previous year. Serologically diagnosed influenza infection rate in the 104 unvaccinated patients was 16.3% for influenza A/H3N2 and 8.7% for influenza B. The infection rate was 3.0% for influenza A/H3N2 and 0.6% for influenza B in the 166 vaccinated patients. The infection rates were significantly lower in the vaccinees than in the unvaccinated patients (p < 0.001 with A/H3N2 and p < 0.01 with B). There was no significant difference in the infection rate among the three vaccinated groups. These results suggest that the influenza vaccination had significant protective efficacy for influenza infection in the elderly. Prior vaccination did not diminish the efficacy of the influenza vaccine. The efficacy of a single influenza vaccine injection was equivalent to that of two injection.

[Cost of medication for influenza infected elderly inpatients].

Influenza vaccine is recommended for the elderly, a high-risk group for influenza infection. Unlike in many developed countries, the rate of influenza vaccination is extremely low in Japan. One of the primary reasons for this low level of vaccination use may be insufficient study on the cost-effectiveness of influenza vaccination in Japan. We determined the cost of medical tests and medications for inpatients with influenza in a referred hospital. We compared the medical costs by (1) level of daily life activity, (2) presence of pneumonia, and (3) living/dead status, 9 months after the infection. In addition, we set up a control group of patients for comparison of their medical costs to those of the influenza patients. Mean costs were 37,279 (+/- 26,784) yen for patients, and 2,361 (+/- 4,893) yen for controls. Mean costs were 32,424 (+/- 30,935) yen for inpatients without limitations to activity, 44,075 (+/- 20,937) yen for bed-bound inpatients, 44,614 (+/- 28,609) yen for inpatients with pneumonia, 27,009 (+/- 22,783) yen for inpatients without pneumonia, 57,624 (+/- 21,041) yen for inpatients who died within 9 months of the onset of influenza, and 16,934 (+/- 11,920) yen for inpatients who were alive 9 month after influenza infection.

[Febrile episodes in elderly inpatients--a one year survey to determine the causes of fever in hospital].

To determine the cause of nosocomial infections, all febrile episodes of hospitalized elderly patients aged 65 and older at a hospital in Fukuoka City were categorized between April 15 1994 and April 14 1995. A febrile episode was a temperature above 37.5 degrees C after 7 consecutive days of normal body temperature (below 37.5 degrees C). Various clinical tests including blood examination, urinalysis, chest radiography and bacterial culture were done on the first and 7th day of the fever. A total of 1105 episodes in 443 patients (male 136, female 307) fulfilled this criteria for fever. The fevers were mainly due to respiratory tract (381 cases, 34.5%) and urinary tract infections (263 cases, 23.8%). There were 135 infections (12.2%) of other kinds and 297 cases (26.9%) that were classified as unknown. Approximately 70% of the febrile episodes were caused nosocomial infections, suggesting increased risk of infection in the hospitalized elderly and the importance of early detection of febrile changes in elderly inpatients.

[Pleural washing with povidone-iodine for treatment of empyema].

In this paper, we report two successful cases of empyema treated by pleural washing with povidone-iodine solution. In these two cases, empyema was caused by secondary infection of multi-drug resistant Pseudomonas aeruginosa. First, we replaced intrathoracic drainage tube and washed intrathoracic space with 500-1000 ml saline containing antibiotics (tobramycin, aztreonam) every 8 hours for 10-14 days. But, cultural studies of pleural effusion were positive even after this treatment. So, we tried pleural washing with warm povidone-iodine solution 1:20 diluted with saline every 8 hours. Surprisingly, after 3 days treatment, cultural studies of the pleural effusion became negative. This pleural washing method with povidone-iodine was very effective for treatment of empyema patients.

[Clinical significance of peak body temperature, white blood cell count, and C-reactive protein level in febrile episodes among geriatric inpatients].

To investigate the clinical implication of peak body temperature, peripheral blood white blood cell (WBC) count, and serum C-reactive protein (CRP) level in febrile symptoms among geriatric hospitalized patients, they were analyzed in 968 febrile episodes obtained from 433 hospitalized patients in the referred hospital. Episodes of one day duration were most frequent (41.6%). WBC count was elevated over 8000/microliters in 475 episodes (49.1%) and CRP exceeded 1.0 mg/dl in 770 episodes (79.5%). Frequency of WBC elevation decreased and frequency of CRP elevation increased according to the time course. The mean value of CRP increased significantly according to the time course. The frequency of WBC count increase and CRP elevation and their averages correlated to the peak body temperature. The peak body temperature displayed the most striking correlation to the length of febrile episodes among three clinical indicators, peak body temperature, WBC count, and CRP level. These results indicate that the elevation of WBC count and/or CRP level is frequent in geriatric patients with febrile symptoms. Peak body temperature may serve as a clinical indicator of the severy of the febrile disease occurring in geriatric patients.

[Serum albumin level as a predictor of incidence of febrile episodes and mortality in hospitalized geriatric patients].

To investigate the relationship between serum albumin level and incidence of febrile episodes and mortality in the elderly, we studied 748 patients hospitalized for over one year. The subjects included 123 males and 355 females with a mean age 81.2 years. The average serum albumin level was 3.79 g/dl and levels of serum albumin decreased with advancing age. The incidence of febrile episodes was 1.8 per year in patients with serum albumin levels over 4.1 g/dl, increasing with decline of serum albumin levels. The incidence of febrile episodes was 5.3 per year in patients with serum albumin levels under 3.0 g/dl. Patients with serum albumin levels under 3.0 g/dl displayed a high incidence of febrile episodes irrespective of age. Age adjusted in-hospital mortality was 40.4% during the observed period in patients with serum albumin levels under 3.0 g/dl, significantly higher than that of the patients with serum albumin levels over 3.1 g/dl. Relative risk of febrile episode and mortality calculated using the patients with serum albumin levels over 4.1 g/dl as a control was 2.9 and 2.1, respectively, in the patients with serum albumin levels under 3.0 g/dl. These results indicate that serum albumin level is a simple, but strong, predictor of susceptibility of febrile episode and death. Patients with serum albumin levels under 3.0 g/dl may constitute a high risk group for febrile episode and death.

[Incidence and duration of febrile episodes in a hospitalized geriatric cohort].

Fever is a common and important clinical symptom observed among hospitalized geriatric patients. To investigate the frequency and duration of fever episodes, we surveyed fever episodes in a hospital where the frequency of patients over 60 years of age exceeds 90 per cent of the patients. Fever episodes with body temperature of over 37.5 degrees C were registered from May in 1991 to December in 1994, and 6809 episodes were subjected to analysis. The average incidences per month were 157.1, 165.3, 158.0, and 139.3 in 1991, 1992, 1993, and 1994, respectively. The numbers of episodes per month did not show any significant correlation with temperature or humidity. Average duration of the episodes were 8.0, 6.5, 7.6, and 6.7 days for 1991, 1992, 1993, and 1994, respectively. Episodes of one day duration were the most frequent in all months, and the frequencies of that ranged from 37.1% to 58.6% with a mean of 47.8%. The average duration of episodes and the frequency of one day episodes did not change significantly irrespective of a notable decrease in the total incidence. The high frequency of one day episodes and their consistency through the observed period suggest that fevers with one day duration are one of the characteristic features of the febrile symptoms in geriatric patients. Causality and prevention methods for these one day fever episodes should be investigated.