Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome.

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS. Depleting leukocytes with a colony-stimulating factor 1 receptor inhibitor disrupted disease progression, including suppression of CNS lesion formation and a substantial extension of survival. Leukocyte depletion rescued diverse symptoms, including seizures, respiratory center function, hyperlactemia, and neurologic sequelae. These data reveal a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement is causal in disease. This work has important implications for the mechanisms of mitochondrial disease and may lead to novel therapeutic strategies.

Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy.

Genetic mitochondrial diseases are the most frequent cause of inherited metabolic disorders and one of the most prevalent causes of heritable neurological disease. Leigh syndrome is the most common clinical presentation of pediatric mitochondrial disease, typically appearing in the first few years of life, and involving severe multisystem pathologies. Clinical care for Leigh syndrome patients is difficult, complicated by the wide range of symptoms including characteristic progressive CNS lesion, metabolic sequelae, and epileptic seizures, which can be intractable to standard management. While no proven therapies yet exist for the underlying mitochondrial disease, a ketogenic diet has led to some reports of success in managing mitochondrial epilepsies, with ketosis reducing seizure risk and severity. The impact of ketosis on other aspects of disease progression in Leigh syndrome has not been studied, however, and a rigorous study of the impact of ketosis on seizures in mitochondrial disease is lacking. Conversely, preclinical efforts have identified the intracellular nutrient signaling regulator mTOR as a promising therapeutic target, with data suggesting the benefits are mediated by metabolic changes. mTOR inhibition alleviates epilepsies arising from defects in TSC, an mTOR regulator, but the therapeutic potential of mTOR inhibition in seizures related to primary mitochondrial dysfunction is unknown. Given that ketogenic diet is used clinically in the setting of mitochondrial disease, and mTOR inhibition is in clinical trials for intractable pediatric epilepsies of diverse causal origins, a direct experimental assessment of their effects is imperative. Here, we define the impact of dietary ketosis on survival and CNS disease in the Ndufs4(KO) mouse model of Leigh syndrome and the therapeutic potential of both dietary ketosis and mTOR inhibition on seizures in this model. These data provide timely insight into two important clinical interventions.

Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics.

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood ß-hydroxybutarate (ß-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. ß-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of ß-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.

Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease.

Leigh Syndrome (LS) is a mitochondrial disorder defined by progressive focal neurodegenerative lesions in specific regions of the brain. Defects in NDUFS4, a subunit of complex I of the mitochondrial electron transport chain, cause LS in humans; the Ndufs4 knockout mouse (Ndufs4(KO)) closely resembles the human disease. Here, we probed brain region-specific molecular signatures in pre-symptomatic Ndufs4(KO) to identify factors which underlie focal neurodegeneration. Metabolomics revealed that free amino acid concentrations are broadly different by region, and glucose metabolites are increased in a manner dependent on both region and genotype. We then tested the impact of the mTOR inhibitor rapamycin, which dramatically attenuates LS in Ndufs4(KO), on region specific metabolism. Our data revealed that loss of Ndufs4 drives pathogenic changes to CNS glutamine/glutamate/α-ketoglutarate metabolism which are rescued by mTOR inhibition Finally, restriction of the Ndufs4 deletion to pre-synaptic glutamatergic neurons recapitulated the whole-body knockout. Together, our findings are consistent with mTOR inhibition alleviating disease by increasing availability of α-ketoglutarate, which is both an efficient mitochondrial complex I substrate in Ndufs4(KO) and an important metabolite related to neurotransmitter metabolism in glutamatergic neurons.

Comparative effectiveness of different antiplatelet agents at reducing TNF-driven inflammatory responses in a mouse model.

Antiplatelet drugs are conventionally used as treatments because of their anti-coagulation functions. However, their pleiotropic effects are of great significance to the treatment of ischaemic cardiovascular diseases. Many studies have reported that an excessive amount of inflammation driven by tumour necrosis factor (TNF) is closely related to the prevalence of atherosclerosis. As the drug selection criteria and evaluation methods related to the anti-TNF activity of antiplatelet drugs remain limited, our investigation of these drugs should prove beneficial. In this study, we compared the anti-TNF activity of three antiplatelet agents, namely clopidogrel, sarpogrelate, and cilostazol, using the TNF-induced inflammatory mouse model. After the oral administration of these drugs, acute inflammation was induced via injection of lipopolysaccharide (LPS) or D-galactosamine (D-gal) and TNF. Serum TNF levels, and the mRNA and protein expression levels of TNF in mouse heart tissue, macrophage accumulation in aortic lesions, and mouse survival were analysed to compare the anti-TNF effects of the three antiplatelet agents. Of the three antiplatelet agents, cilostazol significantly reduced the different levels under the most effective observation. In addition, cilostazol was found to attenuate the TNF-stimulated phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) p65 in the aortic vascular smooth muscle cell line, MOVAS-1 and the D-gal plus TNF-challenged heart tissue of mouse. Therefore, cilostazol is the most ideal of the three antiplatelet drugs for the treatment of TNF-mediated inflammatory disorders.

A Comparison of the Anti-Inflammatory Effects of Four Combined Statin and Antiplatelet Therapies on Tumor Necrosis Factor-Mediated Acute Inflammation in vivo.

BACKGROUND: Combination therapy has been administered to patients with chronic or complex diseases due to its improved therapeutic effects compared with the results of monotherapy. Due to the pleiotropic effects of statins and antiplatelets, these drugs have been studied in combination with other drugs, but not all combinations exerted obvious beneficial effects compared with individual drugs. In this study, we aimed to compare the anti-inflammatory effects of 4 different combination therapies of statins and antiplatelets on the tumor necrosis factor (TNF)-mediated inflammation in vivo. METHODS: Mice were orally administered cilostazol plus pravastatin (CILOP) or cilostazol plus rosuvastatin (CILOR), clopidogrel plus pravastatin (CLOP), or clopidogrel plus rosuvastatin (CLOR); then, acute inflammation was induced by the injection of lipopolysaccharide (LPS) or TNF. Serum TNF levels, macrophage accumulation in the lesioned aortas, and mouse mortality were observed to be comparable to the anti-inflammatory effects of the combination therapies. RESULTS: In mice with LPS-induced inflammation, CILOP and CILOR substantially reduced macrophage infiltration of aortic lesions and the serum TNF levels compared with CLOP and CLOR. Moreover, among the 4 combinations, CILOP significantly improved the survival rate of mice with TNF-mediated acute lethal inflammation. CONCLUSIONS: The combination therapy comprising cilostazol and statins, particularly pravastatin, exerted the best anti-TNF effect compared with clopidogrel and statin therapy; thus, a suitable combination therapy, such as CILOP, can be a potential remedy to cure TNF-related diseases.

Beneficial anti-inflammatory effects of combined rosuvastatin and cilostazol in a TNF-driven inflammatory model.

BACKGROUND: Due to anti-inflammatory and anti-thrombotic functions, statins and antiplatelets are widely used for patients with cardiovascular-related or coronary artery diseases. Patients with systemic or complex diseases are commonly prescribed multiple targeted medications; thus, a proper combination of two or more drugs for beneficial efficacy is considered in clinical therapy. Recent studies have suggested that combinational therapy with statins and other medications accelerates their single effect to suppress inflammatory responses. However, the therapeutic efficacy and underlying mechanism of combination treatment with rosuvastatin and cilostazol have been poorly studied. METHODS: Mice were administered rosuvastatin alone, cilostazol alone or rosuvastatin and cilostazol in combination, and then injected with LPS or TNF to induce acute inflammation. The serum TNF level, macrophage infiltration of the lesioned aortas and mice mortality were observed in the acute inflammation model. The phosphorylation of MAPK was analyzed in TNF-stimulated HeLa cells. RESULTS: Compared to the treatment with cilostazol alone, the combination treatment with rosuvastatin and cilostazol significantly reduced not only the levels of TNF in the sera but also macrophage infiltration in aortic lesions. In addition, the combination therapy decreased TNF-mediated phosphorylation of the MAPK signaling pathway and improved the survival rate in the TNF-driven inflammatory mice model. CONCLUSION: Rosuvastatin combined with cilostazol therapy can greatly improve the anti-inflammatory effect of monotherapies, resulting in reduced mortality of mice; thus, we propose the potential of use of this combination therapy as anti-TNF agent.

Anti-TNF effect of combined pravastatin and cilostazol treatment in an in vivo mouse model.

Objectives: Pravastatin and cilostazol are used as lipid-lowering and antiplatelet agents, respectively. Regarding their well-known anti-inflammatory effects, the additive effect of the two drugs on anti-TNF functions has not yet been investigated. In the present investigation, the beneficial effect of combined pravastatin and cilostazol on their anti-TNF activities was assessed using an in vivo mouse model. Methods: Mice were pretreated with pravastatin and/or cilostazol (40 mg/kg of each), orally once two hour prior to an LPS (5 mg/kg, i.p.) challenge. One hour post challenge, blood and descending aorta were collected for serum TNF levels and immune cell infiltration analyses. For survival analysis, pravastatin and/or cilostazol (40 mg/kg of each) were administered 30 minutes prior to d-galactosamine administration (700 mg/kg, i.p.) and TNF (10 µg/kg, i.p.) challenge and mice survival was monitored. We also examined the effect of either drug or the combination of drugs on TNF-mediated MAPK and NF-κB signaling, using Western blot analysis. Results: Combined treatment of pravastatin and cilostazol significantly decreased serum TNF release and immune cell infiltration in the descending aorta following LPS administration, compared to each single treatment. Additionally, the combined drugs significantly decreased TNF-mediated mouse mortality and downregulated TNF-induced MAPK and NF-κB activation. Conclusions: These findings suggest that combined pravastatin and cilostazol is more effective for reducing TNF-driven inflammation through their anti-TNF activity than monotherapy.

Combination therapy with cilostazol and pravastatin improves antiatherogenic effects in low-density lipoprotein receptor knockout mice.

AIMS: Despite the therapeutic efficacy of statins and antiplatelet agents for atherosclerosis, monotherapy with each drug alone is often insufficient to achieve the patient's therapeutic goals. We previously showed that combined statin/antiplatelet agent/anti-tumor necrosis factor (TNF) agent therapy (pravastatin/sarpogrelate/etanercept) reduces atherosclerotic lesions by inhibiting TNF, an atherogenic cytokine that contributes to the progression of arteriosclerosis. In addition, our previous study showed that combined treatment with pravastatin and cilostazol is effective for reducing TNF-driven inflammation through anti-TNF activity. Therefore, in the present study, we evaluated the additive effects of combined pravastatin and cilostazol therapy on atherosclerotic progression using low-density lipoprotein receptor (LDLR) knockout (KO) mice. METHODS: Ten-week-old LDLR KO mice were fed a high-fat, high-cholesterol diet and orally administered pravastatin and cilostazol alone or in combination. Body weight, plasma lipid levels, and the levels of intracellular adhesion molecules and inflammatory cytokines were analyzed. In addition, aortas and aortic roots were stained with Oil Red O, and atherosclerotic plaques were quantified. RESULTS: The atherosclerotic plaques in the combined pravastatin and cilostazol treatment groups were significantly reduced compared to those in each drug monotherapy group. The combination therapy group also showed the downregulation of ICAM-1, MOMA-2, TNF, interleukin (IL)-6, triglyceride, total cholesterol, and low-density lipoprotein levels and the upregulation of high-density lipoprotein levels compared to those of the pravastatin- or cilostazol-treated groups. CONCLUSIONS: Our results suggest that combination therapy with pravastatin and cilostazol exerts beneficial effects by decreasing atherosclerotic lesion progression and improving the pro-inflammatory state in the vascular endothelium. These effects are mediated by the reduction in adhesion molecule expression, immune cell infiltration, and cytokine levels and the antiatherosclerotic modulation of serum cholesterol levels. Therefore, we conclude that combined treatment with pravastatin and cilostazol may be a more effective antiatherosclerotic strategy than treatment with either agent alone.

Critical role of TNF inhibition in combination therapy for elderly mice with atherosclerosis.

AIMS: We have previously shown that the combination of pravastatin and sarpogrelate is synergistically beneficial for atherosclerosis. In this study, we investigated whether the pravastatin-sarpogrelate combination was sufficient for treatment in an old mouse model of atherosclerosis or if additional intervention would be needed to address the newly included aging factor and its complex pathophysiological impact on the atherosclerogenic state. We added an anti-TNF biological to the combination treatment cocktail because of the known pathologic roles of TNF in the aging process. METHODS: Sixty-week-old low-density lipoprotein receptor knockout mice were fed a high-fat, high-cholesterol diet and treated with the sarpogrelate and pravastatin combination, etanercept alone, or the triple combination. RESULTS: Although, etanercept alone did not significantly reduce aortic root and atherosclerotic plaque areas, the pravastatin-sarpogrelate combination, and pravastatin-sarpogrelate-etanercept triple therapy significantly reduced the plaque areas. Surprisingly, TNF inhibition was critically required to reduce the plaque areas of aortic roots and the expression of ICAM-1, MOMA-2, and TNF. More importantly, a lipid-lowering effect by pravastatin was observed only in the triple therapy group and not in the pravastatin and sarpogrelate combination group. CONCLUSIONS: These results suggest that TNF-inhibitory intervention should be added to the conventional therapy as a novel strategy for treating the elderly patients with atherosclerosis.

Comparing the Postoperative Complications, Hospitalization Days and Treatment Expenses Depending on the Administration of Postoperative Prophylactic Antibiotics to Hysterectomy.

PURPOSE: This study was conducted to compare postoperative complications, hospitalization days and treatment expenses to postoperative prophylactic antibiotics administrated to hysterectomy or not. METHODS: A retrospective survey study was performed with 128 cases in which elective hysterectomy had undergone. They were divided into two groups by identifying whether postoperative prophylactic antibiotics was administered for hysterectomy: a) one group who received postoperative prophylactic antibiotics and; b) those who did not. Data were collected using the electric medical record at a hospital and analyzed by SPSS 23.0 for χ2 test, t-test and ANCOVA. RESULTS: Postoperative complications including wound infection (p=1.000), pneumonia (p=.496), hematoma (p=.530), and pneumoperitoneum (p=.496) showed no significant differences between two groups. Hospitalization days for the prophylactic antibioticsadministrated group were significantly longer than the non-administered for prophylactic antibiotics (p=.004). The treatment expenses of the prophylactic antibiotics-administrated group were significantly higher than those of the non-administered prophylactic antibiotics (F=4.31, p=.040). CONCLUSION: These results can be provided for the evidence of administrating postoperative prophylactic antibiotics to hysterectomy. Additionally, it can contribute to decreasing the medication errors caused by infrequently administrating postoperative prophylactic antibiotics as well as to lessening likelihood of infection of intravenous injection site.

Pravastatin and Sarpogrelate Synergistically Ameliorate Atherosclerosis in LDLr-Knockout Mice.

Pravastatin is a lipid-lowering agent that attenuates atherosclerosis. However, the multifactorial pathogenesis of atherosclerosis requires other drugs with different anti-atherogenic mechanisms. We chose sarpogrelate as an anti-platelet agent and a novel component of a complex drug with pravastatin due to its high potential but little information on its beneficial effects on atherosclerosis. Low-density lipoprotein receptor-knockout mice were fed a high-fat, high-cholesterol diet and treated with pravastatin alone, sarpogrelate alone, or a combination of both drugs. Although sarpogrelate alone did not significantly reduce atherosclerotic plaque areas, co-treatment with pravastatin significantly decreased aortic lesions compared to those of the pravastatin alone treated group. The combined therapy was markedly more effective than that of the single therapies in terms of foam cell formation, smooth muscle cell proliferation, and inflammatory cytokine levels. These results suggest that pravastatin and sarpogrelate combined therapy may provide a new therapeutic strategy for treating atherosclerosis.

Exacerbation of tumor necrosis factor-induced vascular leak syndrome by aging.

Aging is associated with upregulation of tumor necrosis factor (TNF) and increased vascular inflammation. TNF is a major proinflammatory cytokine that contributes to both vascular inflammation and vascular leak syndrome (VLS). The purpose of this study was to investigate whether the aging affects TNF-induced VLS. Vascular leak, histology, and cytokine assays were performed in young and aged groups of wild-type and TNF overexpressing transgenic (Tg) mice. An aged group of TNF Tg mice showed substantially amplified VLS compared with young Tg mice. Age-related amplification of TNF-induced VLS appears to be related to local vascular fibrosis and the systemic upregulation of TNF and MCP-1 levels in older TNF Tg mice. Our finding suggests that chronic high-grade TNF exposure could mediate the severe vascular pathogenicity of VLS.

A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor ß Subunit, Glycoprotein 130.

IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-α production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6Rα, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6Rα complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.

Induction of vascular leak syndrome by tumor necrosis factor-alpha alone.

Although TNF-α possesses promising anticancer activity, clinical application is limited partly due to cardiovascular toxicities. TNF-α effects on vessels are likely related to vascular toxicity, but much remains poorly understood. Similarly, IL-2 is an attractive treatment option for cancers but its clinical use is limited by the side effect of vascular leak syndrome (VLS). We report here that TNF-α alone can trigger VLS. Administration of recombinant TNF-α induced VLS in normal mice and TNF-α transgenic mice exhibited VLS. Perivascular infiltrates in the lungs and specific cytokines in serum were observed in VLS-induced mice. This study shed a new light on the critical role of the TNF-α in IL-2-induced or non IL-2-induced VLS and provides important points to TNF-α therapy.

Comparing Nutrition Knowledge, Eating Habits, and Neonatal Health Status of Primipara for Pregnant Women of Advanced Maternal Age Compared to Those of Younger Ages.

PURPOSE: The aim of this study was to examine differences in nutrition knowledge, eating habits during pregnancy, and neonatal health status between primipara for pregnant women of advanced maternal age in comparison to those under the age of 35. METHODS: This study used a comparative survey design. Data were collected through self-report questionnaires and patients medical records. A total of 127 participants, mothers after delivery were recruited from metropolitan city B. RESULTS: Primipara in advanced maternal age (n=32) reported significantly higher scores of eating habits (Z=-2.96, p=.003) than younger ages (n=95). There were no significant differences in scores of pregnancy nutrition knowledge (Z=-0.44, p=.660), duration of gestation (Z=-0.28, p=.778), neonatal birth height (Z=-0.10, p=.924), neonatal birth weight (Z=-0.28, p=.777), Apgar score 1 minute (Z=-0.53, p=.599) and 5 minutes (Z=-0.23, p=.816) between two groups. CONCLUSION: It concludes that age is not the obstacle to the best nutritional status of women and their newborns.

Factors influencing the confidence in core clinical skills among hospital nurses.

The purpose of this study was to examine the confidence to perform 20 clinical skills and identify factors influencing the confidence of hospital nurses. A descriptive, cross-sectional study was conducted with 550 hospital nurses at four hospitals in B city, Korea. The confidence to perform, frequency of performance and educational needs on 20 clinical skills identified by Korean Accreditation Board of Nursing were measured with a self-reported questionnaire. Data were analysed by SPSS 19.0 (IBM Corporation, Armonk, New York, USA). Participants were 27 years old on average, and 49.5% had less than 3 years of total working experience. The most confident skill was measuring vital signs, whereas the least confident skill was using defibrillator. In results of stepwise regression, confidence to perform was associated with educational needs, total working experience, frequency of performance and position. It is necessary to give opportunities to practice clinical skills at both schools and clinics for producing well-prepared nurses.

[Development and effectiveness of a drug dosage calculation training program using cognitive loading theory based on smartphone application].

PURPOSE: This study was done to develop and evaluate a drug dosage calculation training program using cognitive loading theory based on a smartphone application. Calculation ability, dosage calculation related self-efficacy and anxiety were measured. METHODS: A nonequivalent control group design was used. Smartphone application and a handout for self-study were developed and administered to the experimental group and only a handout was provided for control group. Intervention period was 4 weeks. Data were analyzed using descriptive analysis, χ²-test, t-test, and ANCOVA with the SPSS 18.0. RESULTS: The experimental group showed more 'self-efficacy for drug dosage calculation' than the control group (t=3.82, p<.001). Experimental group students had higher ability to perform drug dosage calculations than control group students (t=3.98, p<.001), with regard to 'metric conversion' (t=2.25, p=.027), 'table dosage calculation' (t=2.20, p=.031) and 'drop rate calculation' (t=4.60, p<.001). There was no difference in improvement in 'anxiety for drug dosage calculation'. Mean satisfaction score for the program was 86.1. CONCLUSION: These results indicate that this drug dosage calculation training program using smartphone application is effective in improving dosage calculation related self-efficacy and calculation ability. Further study should be done to develop additional interventions for reducing anxiety.

[Development of a coping scale for families of patients with schizophrenia].

PURPOSE: The purpose of this study was to develop and evaluate a coping scale for families of patients with schizophrenia(CSFPS). METHODS: Item construction was derived from literature reviews and interviews with family members and psychiatric nurses. Content validity was tested by experts. Each item was scored on a four-point Likert scale. The preliminary questionnaire was administered to 188 family members of patients with schizophrenia. The data were analyzed using item analysis, factor analysis, Pearson correlation coefficients, and Cronbach's alpha. RESULTS: From the factor analysis, 32 items in five factors were derived. The factors were named active coping strategies, avoidance coping strategies, hospital treatment-oriented coping strategies, emotional coping strategies, and suppressive coping strategies for problematic behaviors. The five factors explained 49.7% of the total variance, Cronbach's alpha of the total items was .83 and the factors ranged from .66 to .86. CONCLUSION: The results of this study suggest that CSFPS is a reliable and valid instrument to measure coping in families of patients with schizophrenia.

Effects of a problem-solving counseling program to facilitate intensified walking on Koreans with type 2 diabetes.

AIM: This study aimed to evaluate the immediate and long-term effects of a 12 week problem-solving (PS) counseling program to facilitate intensified walking with machinery monitoring on persons with type 2 diabetes mellitus in Korea. METHODS: The study used a quasi-experimental design. The participants were 57 patients with diabetes from three endocrinology or internal medicine clinics in an urban city of South Korea. Moderate-intensity walking and PS counseling were recommended to both groups. The difference between the two groups was whether the intensity of the exercise was monitored by an ambulatory heart rate monitor (experimental group) or was self-regulated (comparison group). Those programs were evaluated in relation to BMI, glycemic control (blood glucose level, glycosylated hemoglobin [HbA1c]), a vascular complication index (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, tissue plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], Parma Cardiovascular Risk Index), and coping strategies at 3 and 6 months. RESULTS: The experimental group members showed dramatic decreases in their glucose and HbA1c levels at 3 months. The values of t-PA decreased significantly at baseline, compared to at 3 months. The levels of PAI-1 continuously declined and the Parma Cardiovascular Risk Index score did not change significantly from baseline to at 3 months, but showed significant effects at 6 months. CONCLUSION: A combined program of intensified walking, using a heart rate monitor, with PS counseling is more helpful to prevent complications than self-regulated exercise for persons with type 2 diabetes in Korea.