Rapamycin reduces orofacial nociceptive responses and microglial p38 mitogen-activated protein kinase phosphorylation in trigeminal nucleus caudalis in mouse orofacial formalin model

The mammalian target of rapamycin (mTOR) plays a role in various cellular phenomena, including autophagy, cell proliferation, and differentiation. Although recent studies have reported its involvement in nociceptive responses in several pain models, whether mTOR is involved in orofacial pain processing is currently unexplored. This study determined whether rapamycin, an mTOR inhibitor, reduces nociceptive responses and the number of Fos-immunoreactive (Fos-ir) cells in the trigeminal nucleus caudalis (TNC) in a mouse orofacial formalin model. We also examined whether the glial cell expression and phosphorylated p38 (p-p38) mitogen-activated protein kinases (MAPKs) in the TNC are affected by rapamycin. Mice were intraperitoneally given rapamycin (0.1, 0.3, or 1.0 mg/kg); then, 30 min after, 5% formalin (10 l) was subcutaneously injected into the right upper lip. The rubbing responses with the ipsilateral forepaw or hindpaw were counted for 45 min. High-dose rapamycin (1.0 mg/kg) produced significant antinociceptive effects in both the first and second phases of formalin test. The number of Fos-ir cells in the ipsilateral TNC was also reduced by high-dose rapamycin compared with vehicle-treated animals. Furthermore, the number of p-p38-ir cells the in ipsilateral TNC was significantly decreased in animals treated with high-dose rapamycin; p-p38 expression was co-localized in microglia, but not neurons and astrocytes. Therefore, the mTOR inhibitor, rapamycin, reduces orofacial nociception and Fos expression in the TNC, and its antinociceptive action on orofacial pain may be associated with the inhibition of p-p38 MAPK in the microglia.

Rapamycin reduces orofacial nociceptive responses and microglial p38 mitogen-activated protein kinase phosphorylation in trigeminal nucleus caudalis in mouse orofacial formalin model

The mammalian target of rapamycin (mTOR) plays a role in various cellular phenomena, including autophagy, cell proliferation, and differentiation. Although recent studies have reported its involvement in nociceptive responses in several pain models, whether mTOR is involved in orofacial pain processing is currently unexplored. This study determined whether rapamycin, an mTOR inhibitor, reduces nociceptive responses and the number of Fos-immunoreactive (Fos-ir) cells in the trigeminal nucleus caudalis (TNC) in a mouse orofacial formalin model. We also examined whether the glial cell expression and phosphorylated p38 (p-p38) mitogen-activated protein kinases (MAPKs) in the TNC are affected by rapamycin. Mice were intraperitoneally given rapamycin (0.1, 0.3, or 1.0 mg/kg); then, 30 min after, 5% formalin (10 l) was subcutaneously injected into the right upper lip. The rubbing responses with the ipsilateral forepaw or hindpaw were counted for 45 min. High-dose rapamycin (1.0 mg/kg) produced significant antinociceptive effects in both the first and second phases of formalin test. The number of Fos-ir cells in the ipsilateral TNC was also reduced by high-dose rapamycin compared with vehicle-treated animals. Furthermore, the number of p-p38-ir cells the in ipsilateral TNC was significantly decreased in animals treated with high-dose rapamycin; p-p38 expression was co-localized in microglia, but not neurons and astrocytes. Therefore, the mTOR inhibitor, rapamycin, reduces orofacial nociception and Fos expression in the TNC, and its antinociceptive action on orofacial pain may be associated with the inhibition of p-p38 MAPK in the microglia.

Bee venom stimulation of a lung meridian acupoint reduces inflammation in carrageenan-induced pleurisy: an alternative therapeutic approach for respiratory inflammation

Respiratory inflammation is a frequent and fatal pathologic state encountered in veterinary medicine. Although diluted bee venom (dBV) has potent anti-inflammatory effects, the clinical use of dBV is limited to several chronic inflammatory diseases. The present study was designed to propose an acupoint dBV treatment as a novel therapeutic strategy for respiratory inflammatory disease. Experimental pleurisy was induced by injection of carrageenan into the left pleural space in mouse. The dBV was injected into a specific lung meridian acupoint (LU-5) or into an arbitrary non-acupoint located near the midline of the back in mouse. The inflammatory responses were evaluated by analyzing inflammatory indicators in pleural exudate. The dBV injection into the LU-5 acupoint significantly suppressed the carrageenan-induced increase of pleural exudate volume, leukocyte accumulation, and myeloperoxidase activity. Moreover, dBV acupoint treatment effectively inhibited the production of interleukin 1 beta, but not tumor necrosis factor alpha in the pleural exudate. On the other hand, dBV treatment at non-acupoint did not inhibit the inflammatory responses in carrageenan-induced pleurisy. The present results demonstrate that dBV stimulation in the LU-5 lung meridian acupoint can produce significant anti-inflammatory effects on carrageenan-induced pleurisy suggesting that dBV acupuncture may be a promising alternative medicine therapy for respiratory inflammatory diseases.

Development of an easy-to-handle murine model for the characterization of radiation-induced gross and molecular changes in skin

BACKGROUND: Radiation-induced skin injury is a dose-limiting complication of radiotherapy. To investigate this problem and to develop a framework for making decisions on treatment and dose prescription, a murine model of radiation-induced skin injury was developed. METHODS: The dorsal skin of the mice was isolated, and irradiation was applied at single doses of 15, 30, and 50 Gy. The mice were followed for 12 weeks with serial photography and laser Doppler analysis. Sequential skin biopsy samples were obtained and subjected to a histological analysis, immunostaining against transforming growth factor beta (TGF-β), and Western blotting with Wnt-3 and β-catenin. Increases in the levels of TGF-β, Wnt, and β-catenin were detected after irradiation. RESULTS: All tested radiation doses caused progressive dermal thickening and fibrosis. The cause of this process, however, may not be radiation alone, as the natural course of wound healing may elicit a similar response. The latent appearance of molecular and histological markers that induce fibrosis in the 15 Gy group without causing apparent gross skin injuries indicates that 15 Gy is an appropriate dose for characterizing the effects of chronic irradiation alone. Thus, this model best mimics the patterns of injury that occur in human subjects. CONCLUSIONS: This animal model can be used to elucidate the gross and molecular changes that occur in radiation-induced skin injury and provides an effective platform for studying this adverse effect without complicating the process of wound healing.

Therapeutic Dose Range of Valproate-Induced Hyperammonemic Encephalopathy: A Case Report / 대한정신약물학회지

We report a case of a 34-year-old woman who was in temporary delirium and hyperammonemia during treatment of bipolar affective disorder with valproate. Patient showed delirium after 20 days of treatment, while the serum valproate level was within the therapeutic range without any sign of hepatic insufficiency. However, the patient had increased serum ammonia level (121 microg/mL), and valproate was discontinued due to suspicion of valproate-induced hyperammonemic encephalopathy (VHE). Serum valproate level was normalized with reduced delirium after valproate has been discontinued. Few VHE in psychiatric literature has been documented, because of possible confusion between VHE and preexisting psychiatric symptoms. Clinicians should be cautious about the potential risk for hyperammonemic encephalopathy caused by valproate medication.

Follow-Up on Medication Adherence of Dementia Patients : After Diagnosed through the Nationwide Project for Early Detection of Dementia

OBJECTIVE: This study examined medication adherence rate and associated factors with medication adherence in patients who had been diagnosed as having dementia through the nationwide project for early detection of dementia in South Korea. METHODS: This study enrolled a total of 131 patients, who were diagnosed as having dementia through utilization of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet at the Namgu Dementia Center in Incheon, from January 1, 2012 through December 31, 2012. Telephone interview was done with principal caregivers of dementia patients at least 18 months after they had been diagnosed. RESULTS: Out of 131 patients, 83 caregivers of patients completed telephone interview. 62 (72.9%) patients were currently being treated with antidementia drugs, and the proportion of patients being treated at the psychiatric clinic was 54.8%. Sociodemographic variables and clinical rating scales included in the study had no statistically significant effect on the medication adherence. The most common cause of nonadherence was a misconception of dementia diagnosis and treatment (28.6%). CONCLUSION: The major cause of nonadherence was a misconception of dementia diagnosis and treatment, therefore, education on misconception may enhance a patient's medication adherence. Sociodemographic variables and clinical rating scales included in the study had no statistically significant effect on the medication adherence.

Comparison Between Beers Criteria and Screening Tool of Older Person's Prescriptions as a Screening Tool for the Detection of Potentially Inappropriate Medicines and Adverse Drug Events in the Elderly Patients

BACKGROUND: Beers criteria are used to identify the potentially inappropriate medications (PIMs) in elderly patients. However, the criteria have limitations such as lacking consideration of drug-drug and duplicated prescriptions. The aim of this study is to compare the efficacy of newly developed screening tool of older person's prescriptions (STOPP) with Beers criteria in identifying PIMs and adverse drug events (ADEs) in elderly patients. METHODS: We included 115 elderly patients older than 65 years who visited the outpatients' clinic or have been hospitalized for medical illness. Comprehensive geriatric assessments including medication review by the pharmacists were performed by the multidisciplinary team. Beers criteria and STOPP were used to find out PIMs. The association between PIMs defined by both criteria with ADEs was also evaluated. RESULTS: A total of 59 patients (50.4%) by Beers criteria and 76 patients (65.0%) by STOPP had been prescribed with PIMs. Compared with Beers criteria, STOPP had advantage in identifying more PIMs. In addition, STOPP could identify more ADEs related medications than Beers criteria. STOPP was also useful to detect duplicate drug class prescription and nonsteroidal anti-inflammatory drugs for renal impaired patients. CONCLUSION: STOPP criteria PIMs can detect more duplicated prescription and are significantly associated with avoidable ADEs in older individuals compared with that of Beers criteria PIMs.

Antinociceptive Effect of Cyperi rhizoma and Corydalis tuber Extracts on Neuropathic Pain in Rats

In this study, we examined the antinociceptive effect of Cyperi rhizoma (CR) and Corydalis tuber (CT) extracts using a chronic constriction injury-induced neuropathic pain rat model. After the ligation of sciatic nerve, neuropathic pain behavior such as mechanical allodynia and thermal hyperalgesia were rapidly induced and maintained for 1 month. Repeated treatment of CR or CT (per oral, 10 or 30 mg/kg, twice a day) was performed either in induction (day 0~5) or maintenance (day 14~19) period of neuropathic pain state. Treatment of CR or CT at doses of 30 mg/kg in the induction and maintenance periods significantly decreased the nerve injury-induced mechanical allodynia. In addition, CR and CT at doses of 10 or 30 mg/kg alleviated thermal heat hyperalgesia when they were treated in the maintenance period. Finally, CR or CT (30 mg/kg) treated during the induction period remarkably reduced the nerve injury-induced phosphorylation of NMDA receptor NR1 subunit (pNR1) in the spinal dorsal horn. Results of this study suggest that extracts from CR and CT may be useful to alleviate neuropathic pain.

Factors Affecting Subjective Quality of Life of Hospice Volunteers / 한국호스피스완화의료학회지

PURPOSE: This study tested a model of hospice volunteer's motivations and outcomes to encourage more volunteer workers to participate in hospice care. METHODS: This included 200 volunteers who attended the Autumn Conference in 2007 and 132 volunteers from five hospice organizations. RESULTS: Volunteers' existential well-being affected an endogenous variable of volunteers' participation in volunteer activities. The durability of volunteer activity was affected by value motivation, the level of participation in volunteer activities and the level of job satisfaction. For volunteers' job satisfaction level, valid endogenous variables included existential well-being, social motivation, understanding motivation and value motivation. The durability of volunteer activities was indirectly affected through three different paths. Volunteers' existential well-being determined the level of their participation in volunteer activities, which in turn affected the durability of such activities. Social motivation influenced volunteers' job satisfaction, and then the durability of volunteer activities. Volunteers' understanding of motivation also influenced their job satisfaction, and then the durability of volunteer activities. CONCLUSION: Based on these results, this study proposes that the durability of volunteers activities could be improved by developing a program to improve volunteers' well-being and by providing volunteers with education on altruistic values, encouraging them to seek intellectual growth, and advocating them to continue volunteer activities based on close relationships with other volunteers.

The Frequency of BRAF Mutation in Very Small Papillary Thyroid Carcinomas

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid and BRAF (V600E) is the most frequent genetic alteration in PTCs. The aim of this study was to investigate the frequency of BRAF mutation, especially in very small PTCs. METHODS: We analyzed the presence of the BRAF mutation in PTCs in subgroups defined by tumor size (0.5 cm intervals). RESULTS: Of 140 patients, 85 (60.7%) showed a BRAF mutation. The frequency of BRAF mutation in the subgroup was: 45/70 (64.3%) in tumors less than 0.5 cm in size, 18/28 (64.3%) in 0.6-1 cm tumors, 10/22 (45.5%) in 1.1-1.5 cm tumors, and 12/20 (60.0%) in 1.6-2 cm tumors. There was no statistically significant association between BRAF mutation and tumor size (p = 0.44). Similarly, BRAF mutation was not statistically related to age, sex, stage, perithyroidal extension or lymph node metastasis. On multivariate logistic regression analysis, tumor sizes larger than 0.5 cm were associated with lymph node metastasis (odds ratio, 3.79; 95% confidence interval, 1.81 to 7.91; p < 0.01). CONCLUSIONS: The BRAF mutation is not related to tumor size even in very small PTCs. The similar frequency of BRAF mutation in very small PTCs suggests that the BRAF mutation is a very early event in the tumorigenesis of PTCs.

Factors Related to Bone Mineral Content Among Adolescents in Seoul

The purpose of this study was to investigate factors related to bone mineral contents (BMC) at os calcis of adolescents. The subjects were 604 students (327 boys and 277 girls) between 7th and 9th grade in Seoul, Korea. The mean age was 14.2 +/- 0.9 years. General characteristics were collected by a questionnaire, bone mineral contents (BMC) were measured in os calcis by Duel Energy X-ray Absorptiometry (PIXI, General Electronics, USA) and height and weight were measured by bioelectrical impedance analysis method (Inbody 4.0, Biospace Co. Ltd, Seoul, Korea). Mean BMC of os calsis were 2.241 g. Height (p < .0001), weight (p < .0001), BMC (p < .0001) of boys were higher than those of girls. Percent body fat of girls, however, was higher than that of boys (p < .0001). Anthropometric measurement, pocket money, sibling, experience of fracture, pubertal stage, intake of supplements, physical or outdoors activity, and eating habit had significant influence on BMC of boys. Anthropometric measurement, physical or outdoors activity, and eating habit had significant influence on BMC of girls. Multivariate regression with adjustment for sex and age showed that BMC was associated positively with height, BMI, frequency of regular activity, and intake of spinach or radish leaves (all p < 0.05), and negatively with percent body fat (p < .0001) and Korean traditional diet pattern (p = 0.01). On the basis of these results, it is recommended to develop nutrition education and physical activity program for adolescents to improve BMC and prevent osteoporosis.

Topical application of epidermal growth factor accelerates wound healing by myofibroblast proliferation and collagen synthesis in rat

Recombinant human epidermal growth factor (rhEGF) stimulates the proliferation and migration of epithelial cells in human cell culture systems and animal models of partial-thickness skin wounds. This study investigated the effect of a topical rhEGF ointment on the rate of wound healing and skin re-epithelialization in a rat full thickness wound model, and verified whether or not the rhEGF treatment affected both myofibroblast proliferation and collagen synthesis in the dermis. When rhEGF (10 microgram/g ointment) was applied topically twice a day for 14 days, there was significantly enhanced wound closure from the 5th to the 12th day compared with the control (ointment base treatment) group. A histological examination at the postoperative 7th day revealed that the rhEGF treatment increased the number of proliferating nuclear antigen immunoreactive cells in the epidermis layer. In addition, the immunoreactive area of alpha-smooth muscle actin and the expression of prolyl 4-hydroxylase were significantly higher than those of the control group. Overall, a topical treatment of rhEGF ointment promotes wound healing by increasing the rate of epidermal proliferation and accelerating the level of wound contraction related to myofibroblast proliferation and collagen deposition.

General pharmacological profiles of bee venom and its water soluble fractions in rodent models

Recently, the antinociceptive and anti-inflammatory efficacy of bee venom (BV, Apis mellifera) has been confirmed in rodent models of inflammation and arthritis. Interestingly, the antinociceptive and anti-inflammatory effect of whole BV can be reproduced by two water-soluble fractions of BV (>20 kDa:BVAF1 and<10 kDa: BVAF3). Based on these scientific findings, BV and its effective water-soluble fractions have been proposed as potential anti-inflammatory and antinociceptive pharmaceuticals. While BV's anti-inflammatory and antinociceptive properties have been well documented, there have been no careful studies of potential, side effects of BV and its fractions when administered in the therapeutic range (BV, 5 microgram/kg; BVAF1, 0.2 microgram/kg: BVAF3, 3 microgram/kg; subcutaneous or intradermal). Such information is critical for future clinical use of BV in humans. Because of this paucity of information, the present study was designed to determine the general pharmacological/physiological effects of BV and its fractions administration on the rodent central nervous, cardiovascular, respiratory and gastrointestinal system. Subcutaneous BV and its fractions treatment did not produce any significant effects on general physiological functions at the highest dose tested (200-fold and 100-fold doses higher than that used clinically, respectively) except writhing test. These results demonstrate that doses of BV or BV subfractions in the therapeutic range or higher can be used as safe antinociceptive and anti-inflammatory agents.

Clinicopathological Study of Cutaneous Involvement from Breast Cancer / 대한피부과학회지

BACKGROUND: Cutaneous involvement from breast cancer is rarely seen in dermatologic clinics although the breast is the most common source of cutaneous metastasis in women. OBJECTIVE: Our purpose was to study the clinical and histopathological characteristics of cutaneous involvement from breast cancer in our hospital. METHODS: A clinical and histopathological observation was made analyzing 42 cases of cutaneous involvement from breast cancer during the last 13 years from 1990 to 2002 in Asan Medical Center. RESULTS & CONCLUSION: The mean age at diagnosis of breast cancer was 45.8 years. The most common histologic type was infiltrating ductal carcinoma(39 cases), followed by infiltrating lobular carcinoma(1 case) and malignant cystosarcoma phyllodes(1 case). The patterns of cutaneous manifestations were nodular(22 cases), lymphadenopathic(10 cases), inflammatory(5 cases), indurated(3 cases), and zosteriform(2 cases). The sites of locoregional recurrence(LRR) were as follows: the chest wall(28 cases), the ipsilateral supraclavicular node(8 cases), the axillary node(2 cases). The sites of distant skin metastasis were as follows: the contralateral chest wall(6 cases), the scalp(5 cases), the arm(3 cases), the abdomen(1 case), the finger(1 case). LRR or distant skin metastasis appeared within the first decade after treatment in all patients.

Clinicopathological Study of Cutaneous Involvement from Breast Cancer / 대한피부과학회지

BACKGROUND: Cutaneous involvement from breast cancer is rarely seen in dermatologic clinics although the breast is the most common source of cutaneous metastasis in women. OBJECTIVE: Our purpose was to study the clinical and histopathological characteristics of cutaneous involvement from breast cancer in our hospital. METHODS: A clinical and histopathological observation was made analyzing 42 cases of cutaneous involvement from breast cancer during the last 13 years from 1990 to 2002 in Asan Medical Center. RESULTS & CONCLUSION: The mean age at diagnosis of breast cancer was 45.8 years. The most common histologic type was infiltrating ductal carcinoma(39 cases), followed by infiltrating lobular carcinoma(1 case) and malignant cystosarcoma phyllodes(1 case). The patterns of cutaneous manifestations were nodular(22 cases), lymphadenopathic(10 cases), inflammatory(5 cases), indurated(3 cases), and zosteriform(2 cases). The sites of locoregional recurrence(LRR) were as follows: the chest wall(28 cases), the ipsilateral supraclavicular node(8 cases), the axillary node(2 cases). The sites of distant skin metastasis were as follows: the contralateral chest wall(6 cases), the scalp(5 cases), the arm(3 cases), the abdomen(1 case), the finger(1 case). LRR or distant skin metastasis appeared within the first decade after treatment in all patients.

Eruptive Syringoma: Clinicopathologic Analysis of Thirteen Cases

BACKGROUND: Eruptive syringoma is a very rare variant of syringoma and arises most frequently on the anterior trunk of young people. Because eruptive syringoma represents clinically a very rare distinct entity, clinicopathologic studies rarely have been described in literature. OBJECTIVE: The aim of this study is to characterize clinical and histopathologic findings of eruptive syringomas which were diagnosed by histopathologic examination for a 10 year period in Asan medical center. METHODS: The hospital records, clinical history, and biopsy slides of 13 eruptive syringoma were reviewed retrospectively. RESULTS: There were 5 men(38%) and 8 women (62%) with the mean age of 31 years. The mean age of onset was 23 years and 3 patients(23%) presented the lesions before puberty. The most frequently involved sites were anterior trunk, axilla, upper extremities, neck, and face in descending order. The most common initial clinical diagnosis was verruca plana(38%). Most of the lesions did not show self-limiting course and several treatment modalities including oral isotretinoin or CO2 laser were not so effective. All cases showed characteristic histopathologic features of syringoma and 76% of them revealed increased basal melanin pigment or pigmentary incontinence. CONCLUSION: Eruptive syringoma should be included in the differential diagnosis of flat papular lesions by histopathologic examination and it may help to avoid inappropriate therapeutic approach.

A Case of Hair Follicle Nevus / 대한피부과학회지

Hair follicle nevus is a very rare hair follicle tumor and should be differentiated from other hair follicle hamartomas, such as trichofolliculoma, dilated pore of Winer, pilar sheath acanthoma, and trichodiscoma. We describe a 4-year-old female patient who presented erythematous papule on the face that was histopathologically diagnosed as hair follicle nevus.

A Case of Epidermolytic Palmoplantar Keratoderma / 대한피부과학회지

Palmoplantar keratodermas are divided into autosomal dominant and autosomal recessive groups by the mode of transmission. The autosomal dominantly transmitted group is further divided into epidermolytic and nonepidermolytic types according to the histological findings. Hereditary epidermolytic palmoplantar keratoderma manifests clinically as a localized thickening of the palms and soles. Herein we report a 29-year-old woman showing the typical clinical and histologic features of epidermolytic palmoplantar keratoderma without family history. This case could be spontaneous mutations that will later breed a true autosomal dominant trait.

The Antinociceptive and Anti-inflammatory Effect of Ethylacetate Extracts from Bang-Poong (Radix ledebouriellae) on the Freund's Adjuvant-Induced Arthritis in Rats

In this study, we aimed to determine the antinociceptive and/or anti-inflammatory effect of Bang-Poong (BP, Radix Ledebouriellae) on Freund's adjuvant-induced arthritis in rats. Traditionally, BP has been used to treat several inflammatory diseases such as arthritis. Whole BP is extracted into two fractions that were ethylacetate and hexane-soluble fractions. Adult Sprague-Dawley rats (n=30, 130-150 g) were subcutaneously administered by the Freund's complete adjuvant (FCA) into the plantar surface of right hindpaw. Twelve days after the injection of FCA, the rats initially showed typical inflammatory edema and arthritis-related symptoms on the contralateral side (i.e. left hindpaw). Both antinociceptive (evaluation of mechanical, thermal pain threshold and analysis of spinal Fos expression) and anti- inflammatory (evaluation of paw edema, serum interleukin-6 level and x-ray analysis) effect of BP extracts were examined. The ethylacetate fraction of BP (BPE) significantly suppressed the FCA-induced paw edema as well as the serum level of interleukin-6 and it alleviated the radiological changes. Moreover, both mechanical and thermal hyperalgesia were attenuated by the treatment of BPE. In addition, spinal Fos expression that was increased by FCA- injection was suppressed in BPE group. Therefore, this study showed that BPE produced significant both antinociceptive and anti-inflammatory effects on FCA- induced arthritis in rats, while hexane fraction of BP did not show these effects. In conclusion, it is suggested that the ethylacetate fraction of BP is recommended to alleviate the arthritis-related symptoms in human according to the results of this study.

A Case of Benign Symmetric Lipomatosis

Benign symmetric lipomatosis is characterized by diffuse symmetric deposits of nonencapsulated fat, generally affecting the cervical and upper dorsal regions. There is a history of alcohol abuse in nearly all the cases. It is rarely reported in non-drinkers. Herein we report a 63-year-old man presenting with one year's history of multiple ill-defined symmetric soft mass on posterior neck, upper trunk and upper extremities without the history of alcohol abuse. We ad-ministered corticosteroid orally due to osteoarthritis of the knee for a long time.