Comparison of the Length of Stay and Medical Expenditures among Japanese Hospitals for Type 2 Diabetes Treatments: The Box-Cox Transformation Model under Heteroscedasticity

In this paper, we analyzed length of stay (LOS) in hospitals and medical expenditures for type 2 diabetes patients. LOS was analyzed by the power Box-Cox transformation model when variances differed among hospitals. We proposed a new test and consistent estimator. We rejected the ho-moscedasticity of variances among hospitals, and then analyzed the LOS of 12,666 type 2 diabetes patients hospitalized for regular medical treatments collected from 60 general hospitals in Japan. The variables found to affect LOS were age, number of comorbidities and complications, introduced by another hospital, one-week hospitalization, 2010 revision, specific-hospitalization-period (SHP), and principal diseases E11.5, E11.6 and E11.7. There were surprisingly large differences in ALOS among hospitals even after eliminating the influence of characteristics and conditions of patients. We then analyzed daily medical expenditure (DME) by the ordinary least squares methods. The variables that affected DME were LOS, number of comorbidities and complications, acute hospitalization, hospital’s own outpatient, season, introduced by another hospital, one-week hospitalization, 2010 revision, SHP, time trend, and principal diseases E11.2, E11.4 and E117. The DME did not decrease after the SHP. After eliminating the influences of characteristics and conditions of patients, the differences among hospitals were relatively small, 12% of the overall average. LOS is the main determinant of medical expenditures, and new incentives to reduce LOS are needed to control Japanese medical expenditures. Since at least 99% of patients require medical care after leaving the hospital, systems that take proper care of patients for long periods of time after hospitalization are absolutely necessary for efficient treatment of diabetes.

Did the Revision of the Japanese Medical Payment System Work Properly?—An Analysis of Averages and Variances of Length of Hospital Stay for Type 2 Diabetes Patients by Individual Hospital

We evaluated the effects of the 2010 revision of the medical payment system on the length of stay (LOS). In this analysis, we assessed not only the average length of stay (ALOS), but also variance of LOS at individual hospitals. We used a dataset of 18,641 type 2 diabetes patients collected from 51 general hospitals. The variables found to affect LOS were age, comorbidities, complications, acute hospitalization, introduced by other hospitals, winter, one-week hospitalization, specific hospitalization period, and principal diseases coded E11.5, E11.6 and E11.7. Although the effect was marginal, the 2010 revision did reduce ALOS, and the reduction was larger as ALOS became longer. On the other hand, we did not find that the variance of LOS within hospitals became smaller. The results of the study suggest that new incentives and assistance to hospitals to help them make efficient use of medical information are needed.

Cardiac Arrest Cases and Automated External Defibrillator Use in Railroad Stations in Tokyo

Objective: Nationwide dissemination of public-access defibrillation (PAD) contributed to an increase of survival rate in Japan. We analysed cardiac arrests (CAs) that occurred in railroad stations in Tokyo to evaluate PAD in the metropolis. Methods: We collected Utstein data from the Tokyo Fire Department (TFD) and analysed CA cases that occurred in stations. In total, 245 non-traumatic CAs from January 1, 2007 to March 31, 2008 were analysed;CAs in children under 8 years were excluded. Results: The rates of pre-hospital return of spontaneous circulation (ROSC) were 41 out of 145 witnessed CA patients (28.3%) and 12 ROSC out of 100 unwitnessed CA patients (12%). Of 245 CA cases, bystander cardiopulmonary resuscitation (CPR) performed in 156 (63.7%), automated external defibrillator (AED) used in 117 (47.8%) and shock delivered in 65 (26.5%). Rates of ROSC were 31.6% (37/117) with AED use significantly higher than those of 12.5% (16/128) without AED use (P < 0.001). Most CAs occurred on platforms;the use of AEDs on platforms increased from 18/31 (58.1%) in 2007 to 32/43 (74.4%) in 2008 and ROSC rates increased from 8 (25.8%) to 14 (32.6%), respectively. On train CAs: ROSC cases were very few, 1 case each year (8.3%;7.7%) while the use of AED increased from 8/12 (66.7%) in 2007 to 10/13 (76.9%) in 2008. Conclusion: Bystander CPR and the use of AED at railroad stations improved ROSC for out-of-hospital cardiac arrest (OHCA) patients. AED location and strategies for dealing with CAs on trains should be re-evaluated.

Oral Health Management of Three Head and Neck Cancer Patients Performed by Dental Hygienists

Introduction: Oral health management is often difficult in patients after surgical tumor resection and/or radiotherapy due to defects, bulky flaps, limitation of tongue movement, and trismus. In addition, patients who have undergone radiotherapy have serious disabilities such as oral mucositis, mucosal weakening, soft tissue fibrosis, salivary gland disorder, and osteoradionecrosis. Dental hygienists must understand the characteristics of patients after surgical tumor resection and/or radiotherapy. In this report, the oral health management of three patients after maxillectomy, mandibulectomy, and radiotherapy was shown. Case Description: Case 1: A 53-year-old male patient visited our clinic after chemotherapy, radiotherapy, and partial maxillectomy for cancer of the right maxillary gingiva. Case 2: A 65-year-old male patient visited our clinic after radiotherapy for a right-sided tongue cancer, partial mandibulectomy of the right tongue to the oropharynx, a right-sided segmental mandibulectomy and a speech aid and a mandibular prosthesis were provided. Case 3: A 36-year-old female visited our clinic for radiotherapy for left-sided tongue cancer. Dental hygienists provided oral health management to the patients. In oral health management, it was suggested that intervention before cancer treatment, oral hygiene instructions tailored to patients’ symptoms, and frequent professional care are important. Conclusion: Oral health management by dental hygienists is extremely important for patients undergoing maxillofacial cancer treatment to maintain their quality of life in the long term.

An Econometric Analysis of Hospital Length of Stay for Cataract Operations in Japan by the Box-Cox Transformation Model and Hausman Tests: Evaluation of the 2010 Revision of the Medical Payment System

The Japanese medical costs for cataract treatments reached 270 billion yen in fiscal year 2012. Since the length of stay (LOS) in hospital is much longer than other major countries, controlling the medical costs by reducing LOS becomes an important issue in Japan. In this paper, we evaluated the effects of the 2010 revision of the Japanese medical payment system (DPC/PDPS) on LOS for cataract operations. The Box-Cox transformation model, Nawata’s estimators and Hausman tests were used in the analysis. To evaluate the effects, we analyzed a dataset obtained from 34 DPC hospitals (Hp1-34) where one-eye cataract operations were performed both before (April 2008-March 2010) and after (April 2010-March 2012) the 2010 revision and there were more than 500 patients. The dataset contained information from 32,593 patients. We did not admit the effect of the 2010 revision in this study, and there were large differences LOS among hospitals, even after removing the influences of factors such as patient characteristics and types of principal diseases.

Dental Implant Patients Grouped by the Brinkman Index: Their Attitude toward Smoking, Nicotine Dependence, and Knowledge of Peri-Implantitis

Purpose: This study investigated the attitude of patients, grouped by the Brinkman index, towards smoking by using the Kano Test for Social Nicotine Dependence (KTSND) and their knowledge of peri-implantitis. Methods: The participants were 3093 new patients who visited the Tokyo Medical and Dental University Hospital from January 2012 to December 2013 for an oral implant. The methodology included a questionnaire about sex, age, smoking status, daily average number of cigarettes, years of smoking, knowledge of peri-implantitis, and the KTSND. The patients were grouped according to their smoking status by calculating their Brinkman index (over 200 or not): current smokers with the possibility of nicotine dependence (BI(+)CS), current smokers with no possibility of nicotine dependence (BI(-)CS), ex-smokers (ES), and non-smokers (NS). The Brinkman index is obtained by multiplying one’s daily average number of cigarettes by the number of years they have been smoking. Results: Data were collected from 2182 respondents (response rate = 71%). The KTSND scores of BI(+)CS (16.89 ± 4.26) were significantly higher than the scores of ES (11.99 ± 4.52) and NS (11.53 ± 5.01). In current smokers, there were no significant differences between BI(+)CS and BI(-)CS. The patients replied “I don’t know” about peri-implantitis most often in all groups;however, there were no significant differences between the groups. Discussion: BI(+)CS were more dependent on nicotine in social situations than the other groups were. In Japan, a Brinkman index over 200 is required for a nicotine-dependence management fee to be instituted for health insurance treatment. This is a major concern for young smokers, who may be excluded from treatment because their years of smoking are substantially less. Results revealed that there were no significant differences between BI(+)CS and BI(-)CS. Therefore, it was suggested that the Brinkman index did not sufficiently group the participants.

The deterministic condition for the ground reaction force acting point on the combined knee valgus and tibial internal rotation moments in early phase of cutting maneuvers in female athletes

Background:Combined knee valgus and tibial internal rotation(VL+IR)moments have been shown to stress the anterior cruciate ligament(ACL)in several in vitro cadaveric studies.To utilize this knowledge for non-contact ACL injury prevention in sports,it is necessary to elucidate how the ground reaction force(GRF)acting point(center of pressure(CoP))in the stance foot produces combined knee VL+IR moments in risky maneuvers,such as cuttings.However,the effects of the GRF acting point on the development of the combined knee VL+IR moment in cutting are still unknown.Methods:We first established the deterministic mechanical condition that the CoP position relative to the tibial rotational axis differentiates the GRF vector’s directional probability for developing the combined knee VL+IR moment,and theoretically predicted that when the CoP is posterior to the tibial rotational axis,the GRF vector is more likely to produce the combined knee VL+IR moment than when the CoP is anterior to the tibial rotational axis.Then,we tested a stochastic aspect of our theory in a lab-controlled in vivo experiment.Fourteen females performed 60˚cutting under forefoot/rearfoot strike conditions(10 trials each).The positions of lower limb markers and GRF data were measured,and the knee moment due to GRF vector was calculated.The trials were divided into anterior-and posterior-CoP groups depending on the CoP position relative to the tibial rotational axis at each 10 ms interval from 0 to 100 ms after foot strike,and the occurrence rate of the combined knee VL+IR moment was compared between trial groups.Results:The posterior-CoP group showed significantly higher occurrence rates of the combined knee VL+IR moment(maximum of 82.8%)at every time point than those of the anterior-CoP trials,as theoretically predicted by the deterministic mechanical condition.Conclusion:The rearfoot strikes inducing the posterior CoP should be avoided to reduce the risk of non-contact ACL injury associated with the combined knee VL+IR stress.

Effect of Wearing a Maxillofacial Prosthesis on Masticatory Rhythm Improvement in Mandibulectomy Patients

Background: Recording jaw movement rhythms in patients with jaw defects is challenging using conventional tracking devices. However, masticatory rhythm is crucial for masticatory performance and nutritional intake. This study aimed to explore the impact of using a maxillofacial prosthesis to restore masticatory rhythm in mandibulectomy patients with a novel wearable device. Methods: Twelve patients who underwent mandibulectomy and were rehabilitated with maxillofacial prosthesis were recruited. Chewing rate, cycle durations, coefficient of variation of cycle durations (CV), changing times of skin morphology on the back of the ear pinna area (SM), and masticatory performance were measured during gum chewing without and with a denture using a wearable jaw movement rhythm tracking device. A paired t-test and the Pearson correlation coefficient were used for statistical analysis. Results: The chewing rate increased by 8.6 cycles/min with dentures (P P = 0.01). The CV and SM decreased with dentures (P = 0.004 and P = 0.01, respectively). Significant correlations were found between the CV and SM without dentures (P = 0.004). Conclusion: 1. Wearing maxillofacial prostheses can improve masticatory rhythm in patients who undergo mandibulectomy with Eichner B2 occlusal supports. 2. The wearable device is available for measuring masticatory rhythm in patients with jaw defects in clinics. 3. Changing times of the skin morphology on the back of the ear pinna indicate jaw movement stability through a simpler process than the coefficient of variation of cycle durations.

E2FBP1 antagonizes the p16^(INK4A)-Rb tumor suppressor machinery for growth suppression and cellular senescence by regulating promyelocytic leukemia protein stability

Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16INK4A and promyelocytic leukemia protein （PML） in normal cells. E2F-binding protein 1 （E2FBP1）, a transcription regulator for E2F, induces PML reduction and suppresses the formation of PML-nuclear bodies, whereas the down-regulation of E2FBP1 provokes the PML-dependent premature senescence in human normal fibroblasts. Here we report that the depletion of E2FBP1 induces the accumulation of PML through the Ras-dependent activation of MAP kinase signaling. The cellular levels of p16INK4A and p53 are elevated during premature senescence induced by depletion of E2FBP1, and the depletion of p16INK4A, but not p53 rescued senescent cells from growth arrest. Therefore, the premature senescence induced by E2FBP1 depletion is achieved through the pl6INK4A-Rb pathway. Similar to human normal fibroblasts, the growth inhibition induced by E2FBP1 depletion is also observed in human tumor cells with intact p16INK4A and Rb. These results suggest that E2FBP1 functions as a critical antagonist to the pI6INK4A-Rb tumor suppressor machinery by regulating PML stability.

Association between Diabetes Mellitus and Oral Health Status in Japanese Adults

Aim The objective of this study was to analyze the oral health among Japanese adults, with and without diabetes mellitus. Methodology The subjects were 518 community residents aged 20 to 91 years in Japan, who participated in the ＂Akita health and nutrition survey＂ and the ＂Akita dental disease survey＂, conducted in 2006. The surveys comprised a self-administered questionnaire, along with medical and dental examinations. Results Using the community periodontal index （CPI）, the mean numbers of sextants presenting codes 0, 1 and 2 were significantly lower in diabetics than non-diabetics among the 59 years or younger age group. Although the mean numbers of sextants with codes 0, 1 and 2 among the 60 to 69 years age group were lower, and sextants with a code X among the 59 years or younger age group were higher in diabetics than non-diabetics, no statistically significant differences were detected. The tendency of lower mean numbers of natural teeth and functional tooth units in diabetics than non-diabetics was observed, however no differences were statistically significant. Conclusion The outcome of periodontal disease seemed to be influenced by the diabetic state to some degree, but a clear association between diabetes and oral health status was not found.

VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis

Although VEGFR-3 deficiency disrupts blood vascular development during early embryogenesis, the underlying mechanism was not clear. To characterize its function in angiogenesis and lymphangiogenesis, we employed two genetically modified mouse models in this study, targeting the coding region for the ligand-binding domain （Vegfr△LBD） or the tyrosine kinase domain with an inactivation point mutation （Vegfr3^TKmat）. We show that lymphatic growth was disrupted in Vegfr3△LBD/△LBD and Vegfr3^TKmut3^TKmat mice, but blood vessels developed normally in both embryo and yolk sac. Interestingly, in Vegfr3△LBD/△LBD but not Vegfr3^TKmut3^TKmat mice, lymph sac was present but there was lack of iym- phangiogenic sprouting. We further demonstrate that both the wild-type and mutant forms of VEGFR-3 could form heterodimers with VEGFR-2, and decreased the level of phospho-VEGFR-2 and the downstream phospho-Erk1/2 in endothelial cells when they were treated with VEGF-A. These findings indicate that signaling mediated via VEGFR-3 activation by its cognate ligands （VEGF-C/-D） is not required for angiogenesis, and that VEGFR-3 may play a role in this process by modulating VEGFR-2-mediated signals.

Endocytoscopic narrow-band imaging efficiency for evaluation of inflammatory activity in ulcerative colitis

AIM:To assess the efficacy of endocytoscopic narrowband imaging(EC-NBI)for evaluating the severity of inflammation in ulcerative colitis(UC).METHODS:This retrospective study was conducted at a single tertiary care referral center.We included UC patients who underwent colonoscopy with endocytoscopy from July 2010 to December 2013.ECNBI was performed,and the images were evaluated by assessing visibility,increased vascularization,and the increased calibers of capillaries and were classified as Obscure,Visible or Dilated.Obscure was indicative of inactive disease,while Visible and Dilated were indicative of acute inflammation.This study received Institutional Review Board approval.The primary outcome measures included the diagnostic ability of EC-NBI to distinguish between active and inactive UC on the basis of histological activity.The conventional endoscopic images were classified according to the Mayo endoscopic score.A score of 0 or 1 indicated inactive disease,whereas a score of 2 indicated active disease.RESULTS:Fifty-two patients were enrolled.There was a strong correlation between the EC-NBI findings and the histological assessment(r=0.871,P<0.01).The sensitivity,specificity,positive predictive value,negative predictive value,and accuracy of EC-NBI for diagnosing acute inflammation were 84.0%,100%,87.1%,100%,and 92.3%,respectively,while those for the Mayo endoscopic score were 100%,40.7%,100%,61.0%,and 69.2%,respectively.Compared with conventional endoscopy,EC-NBI was superior in diagnostic specificity,negative predictive value,and accuracy(P<0.001,P=0.001 and P=0.047,respectively).CONCLUSION:The EC-NBI finding of capillaries in the rectal mucosa was strongly correlated with histological inflammation and aided in the differential diagnosis between active and inactive UC.

Acute development of collateral circulation and therapeutic prospects in ischemic stroke

In acute ischemic stroke,collateral circulation plays an important role in maintaining blood flow to the tissue that is at risk of progressing into ischemia,and in increasing the successful recanalization rate without hemorrhagic transformation.We have reported that well-developed collateral circulation is associated with smaller infarct volume and better long-term neurological outcome,and it disappears promptly once the effective recanalization is achieved.Contrary to the belief that collateral vessels develop over time in chronic stenotic condition,there exists a phenomenon that collateral circulation develops immediately in acute stenosis or occlusion of the arteries and it seems to be triggered by fluid shear stress,which occurs between the territories of stenotic/occluded arteries and those fed by surrounding intact arteries.We believe that this acute development of collateral circulation is a target of novel therapeutics in ischemic stroke and refer our recent attempt in enhancing collateral circulation by modulating sphingosine-1-phosphate receptor 1,which is a known shear-stress mechanosensing protein.

Adenomyoepithelioma of the breast with malignant transformation and repeated local recurrence:A case report

BACKGROUND Adenomyoepithelioma(AME)of the breast is a rare type of benign breast tumor.Many AMEs show benign behavior,but reports of the malignant type are rare.We present the case of a patient with AME with repeated local recurrences and further malignant transformation.CASE SUMMARY A 53-year-old woman visited our hospital with a 16-mm palpable mass in the right breast.A core needle biopsy was performed.The pathological diagnosis was AME.Lumpectomy with a safety margin was performed without axillary lymph node dissection(ALND).Two years later,local recurrence developed,and the patient again underwent lumpectomy with a safety margin.The pathology showed malignant AME,and the margin was negative.Eight months later,local recurrence developed again in the same location,and a total mastectomy was performed without ALND.The pathological diagnosis was malignant AME.The patient was disease-free for three years posttreatment.CONCLUSION The treatment of AME requires caution,as it may exhibit repeated recurrences after local excision as well as malignant transformation.

Evaluation of Length of Hospital Stay Joining Educational Programs for Type 2 Diabetes Mellitus Patients: Can We Control Medical Costs in Japan?

Diabetes has become a growing concern in Japan, both medically and financially. The medical cost of diabetes was estimated at 1215 billion yen for fiscal year 2011. We analyzed the length of stay (LOS) in a hospital for type 2 diabetes mellitus patients who participated in educational programs to determine factors affecting LOS. Data on 991 patients obtained from 28 Red Cross hospitals in 2008 were used. For the analysis, we used the Box-Cox transformation model and Hausman test. The results revealed that patients aged 75 years and above and those with comorbidities and complications were prone to longer LOS. The analysis also revealed significant differences in LOS across the hospitals, even after controlling for patient characteristics. Finally, we applied the least squares method to determine the effects of hospital and regional factors and revealed that patients’ LOS was affected by the region’s average LOS. Regional corporations and networks appeared to be important in improving educational programs.

Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1αsignaling

Impaired locomotion has been extensively studied worldwide because those afflicted with it have a potential risk of becoming bedridden.Physical exercise at times can be an effective remedy for frailty,but exercise therapy cannot be applied in all clinical cases.Medication is safer than exercise,but there are no drugs that reinforce both muscle and bone when administered alone.Multiple medications increase the risk of adverse events;thus,there is a need for individual drugs targeting both tissues.To this end,we established a novel sequential drug screening system and identified an aminoindazole derivative,locamidazole(LAMZ),which promotes both myogenesis and osteoblastogenesis while suppressing osteoclastogenesis.Administration of this drug enhanced locomotor function,with muscle and bone significantly strengthened.Mechanistically,LAMZ induced Mef2c and PGC-1αin a calcium signaling–dependent manner.As this signaling is activated upon physical exercise,LAMZ mimics physical exercise.Thus,LAMZ is a promising therapeutic drug for locomotor diseases,including sarcopenia and osteoporosis.

A case of hemangiopericytoma of the soft palate with articulate disorder and dysphagia

We report a case of hemangiopericytoma of the soft palate of 60-year-old patient, who noticed a mass of the soft palate and experienced difficulty in speaking. We found a pediculate, hard, elastic mass measuring 38 mm （cross-sectional diameter）. Computed tomography （CT） scans and dynamic magnetic resonance imaging （MRI） confirmed irregularly shaped mass and revealed a heterogeneous internal composition, consistent with vascular tumors. We excised the tumor under general anesthesia. Histopathological diagnosis was based on positive immunoreactivity of CD99 and vimentin and weak, positive staining of CD34. Three and half years following tumor excision, there is no recurrence or metastasis.

Financial Sustainability of the Japanese Medical Payment System: Analysis of the Japanese Medical Expenditure for Educational Hospitalization of Patients with Type 2 Diabetes

Japanese medical expenditures have increased rapidly in recent years and are predicted to continue rising. Indeed, it remains uncertain whether the current Japanese medical system can be sustained. In this paper, we analyzed the medical expenditures for educational hospitalization of patients with type 2 diabetes. A dataset of 6173 patients from 36 hospitals was used in the analysis. The sample period was from July 2008 to March 2012. We analyzed the medical expenditures in two ways. First, we analyzed the length of hospital stay (LOS). Next, we analyzed the daily expenditure per patient. The Box-Cox transformation model was used in the first analysis and the ordinary least squares method in the second. Comorbidities and complications prolonged LOS and increased daily expenditures. The LOS was significantly different among hospitals. On the other hand, the differences in daily expenditures among hospitals were relatively small, such that LOS was the main determinant of medical expenditures. Previous studies suggested that LOS could be shortened without degradation of medical quality. Moreover, LOS could be controlled by introducing proper critical paths and improving and standardizing educational programs. Hence, it would be possible to control the medical expenditures for this disease.

A novel equation and nomogram including body weight for estimating prostate volumes in men with biopsy-proven benign prostatic hyperplasia

Anthropometric measurements, e.g., body weight （BW）, body mass index （BMI）, as well as serum prostate-specific antigen （PSA） and percent-free PSA （%fPSA） have been shown to have positive correlations with total prostate volume （TPV）. We developed an equation and nomogram for estimating TPV, incorporating these predictors in men with benign prostatic hyperplasia （BPH）. A total of 1852 men, including 1113 at Tokyo Medical and Dental University （TMDU） Hospital as a training set and 739 at Cancer Institute Hospital （CIH） as a validation set, with PSA levels of up to 20 ng m1-1, who underwent extended prostate biopsy and were proved to have BPH, were enrolled in this study. We developed an equation for continuously coded TPV and a logistic regression-based nomogram for estimating a TPV grater than 40 mh Predictive accuracy and performance characteristics were assessed using an area under the receiver operating characteristics curve （AUC） and calibration plots. The final linear regression model indicated age, PSA, %fPSA and BW as independent predictors of continuously coded TPV. For predictions in the training set, the multiple correlation coefficient was increased from 0.38 for PSA alone to 0.60 in the final model. We developed a novel nomogram incorporating age, PSA, %fPSA and BW for estimating TPV greater than 40 mh External validation confirmed its predictive accuracy, with AUC value of 0.764. Calibration plots showed good agreement between predicted probability and observed proportion. In conclusion, TPV can be easily estimated using these four independent predictors.

Apaf-l-deficient fog mouse cell apoptosis involves hypopolarization of the mitochondrial inner membrane, ATP depletion and citrate accumulation

To explore how the intrinsic apoptosis pathway is controlled in the spontaneous fog （forebrain overgrowth） mutant mice with an Apafl splicing deficiency, we examined spleen and bone marrow cells from Apafl＋/＋ （＋/＋） and Apafl^fog/fog （fog/fog） mice for initiator caspase-9 activation by cellular stresses. When the mitochondrial inner membrane potential （△ψm） was disrupted by staurosporine, ＋/＋ cells but not fog/fog cells activated caspase-9 to cause apoptosis, indicating the lack of apoptosome （apoptosis protease activating factor 1 （Apaf-l）/cytochrome c/（d）ATP/procaspase-9） function in fog/fog cells. However, when a marginal （-20%） decrease in △ψm was caused by hydrogen peroxide （0.1 mM）, peroxynitrite donor 3-morpholinosydnonimine （0.1 mM） and UV-C irradiation （20 J/m^2）, both ＋/＋ and fog/fog cells triggered procaspase-9 auto-processing and its downstream cascade activation. Supporting our previous results, procaspase-9 pre-existing in the mitochondria induced its auto-processing before the cytosolic caspase activation regardless of the genotypes. Cellular ATP concentration significantly decreased under the hypoactive △ψm condition. Furthermore, we detected accumulation of citrate, a kosmotrope known to facilitate procaspase-9 dimerization, probably due to a feedback control of the Krebs cycle by the electron transfer system. Thus, mitochondrial in situ caspase-9 activation may be caused by the major metabolic reactions in response to physiological stresses, which may represent a mode of Apaf-l-independent apoptosis hypothesized from recent genetic studies.