Molecular mechanisms and therapeutic interventions in sarcopenia

Sarcopenia is the degenerative loss of muscle mass and function with aging. Recently sarcopenia was recognized as a clinical disease by the International Classification of Disease, 10th revision, Clinical Modification. An imbalance between protein synthesis and degradation causes a gradual loss of muscle mass, resulting in a decline of muscle function as a progress of sarcopenia. Many mechanisms involved in the onset of sarcopenia include age-related factors as well as activity-, disease-, and nutrition-related factors. The stage of sarcopenia reflecting the severity of conditions assists clinical management of sarcopenia. It is important that systemic descriptions of the disease conditions include age, sex, and other environmental risk factors as well as levels of physical function. To develop a new therapeutic intervention needed is the detailed understanding of molecular and cellular mechanisms by which apoptosis, autophagy, atrophy, and hypertrophy occur in the muscle stem cells, myotubes, and/or neuromuscular junction. The new strategy to managing sarcopenia will be signal-modulating small molecules, natural compounds, repurposing of old drugs, and muscle-specific microRNAs.

CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors

CTHRC1 (collagen triple-helix repeat-containing 1), a protein secreted during the tissue-repair process, is highly expressed in several malignant tumors, including pancreatic cancer. We recently showed that CTHRC1 has an important role in the progression and metastasis of pancreatic cancer. Although CTHRC1 secretion affects tumor cells, how it promotes tumorigenesis in the context of the microenvironment is largely unknown. Here we identified a novel role of CTHRC1 as a potent endothelial activator that promotes angiogenesis by recruiting bone marrow-derived cells to the tumor microenvironment during tumorigenesis. Recombinant CTHRC1 (rCTHRC1) enhanced endothelial cell (EC) proliferation, migration and capillary-like tube formation, which was consistent with the observed increases in neovascularization in vivo. Moreover, rCTHRC1 upregulated angiopoietin-2 (Ang-2), a Tie2 receptor ligand, through ERK-dependent activation of AP-1 in ECs, resulting in recruitment of Tie2-expressing monocytes (TEMs) to CTHRC1-overexpressing tumor tissues. Treatment with a CTHRC1-neutralizing antibody-abrogated Ang-2 expression in the ECs in vitro. Moreover, administration of a CTHRC1-neutralizing antibody to a xenograft mouse model reduced the tumor burden and infiltration of TEMs in the tumor tissues, indicating that blocking the CTHRC1/Ang-2/TEM axis during angiogenesis inhibits tumorigenesis. Collectively, our findings support the hypothesis that CTHRC1 induction of the Ang-2/Tie2 axis mediates the recruitment of TEMs, which are important for tumorigenesis and can be targeted to achieve effective antitumor responses in pancreatic cancers.

Pulmonary Resection for Multidrug-Resistant Tuberculosis / 대한흉부외과학회지

BACKGROUND: Treatment outcome with only chemotherapy for multi-drug resistant tuberculosis is usually considered not to be satisfactory. However, the combined therapy of chemotherapy with surgical treatment has been producing higher sputum AFB negative conversion and longer survival rates, and this treatment strategy is expected to be a set-up for the patients with multi-drug resistant tuberculosis. MATERIAL AND METHOD: A retrospective review was performed with the medical records and laboratory findings in 49 patients with multi-drug resistant tuberculosis of 130 patients who underwent pulmonary resection for pulmonary tuberculosis between January 1995 and December 1999 at National Masan Tuberculosis Hospital. RESULT: A mean number of the resistant drugs was 4.5 with a mean age of 35 years. Cavitary lesions on plain chest x-ray were shown in 43 patients of 49(87.8%). Thirty one had positive sputum cultures preoperatively(63.3%). Operative techniques were as follows; 12 pneumonectomies, 28 lobectomies, 7 lobectomies with segmentectomies or wedge resections, one wedge resection and a cavernoplasty. Sputum AFB negative conversion rate was 93.5 % with continuous postoperative chemotherapy. There was no death after operation. Air leakage over a week, postoperative bleeding and wound disruption were developed as postoperative complications. CONCLUSION: We experienced the higher effectiveness of postoperative chemotherapy with pulmonary resection on multi-drug resistant tuberculosis. Although there are several different ideas about operative indications, postoperative drug regimens and length of postoperative medications, pulmonary resection should be considered actively as a effective combination measure with chemotherapy to give a treatment for multi-drug resistant pulmonary tuberculosis.

Outcome of Chemotherapy with Pulmonary Tuberculosis Resistant to Isoniazid and Rifampin / 결핵

BACKGROUND: The treatment for multi-drug resistant tuberculosis(MDRTB) is encountered to be important clinically, but there are still a few reports about it all over the world. So, we evaluated the outcomes of only chemotherapy for the pulmonary MDRTB retrosptctively. METHOD: We reviewed the clinical courses of 63 patients with pulmonary disease due to M.tuberculosis resistant to rifampin and isoniazid who were under follow-up between March 1996 and June 1996 after hospitalization at our hospital between January 1993 and January 1996. We performed cohort retrospective study for all these patient's records. Their regimens were selected individually and preferably included four medications that they had not been given previously and to which the strain was fully susceptible. RESULTS: The 63 patients(mean age, 43.2 years) had previously received a median 5.1drugs. Fifty two(82.5%) patients responded to chemotherapy(as indicated by negative sputum cultures for at least three consecutive months); eleven patients(17.5%) had no response, as shown by continually positive cultures. In a univariate analysis, an unfavorable response was significantly associated with greater number of resistant drugs before the current courses of therapy(relative risk 21.5; 95 percent confidence interval, 1.2-3.0; p<0.05). The mean period of follow-up was seventeen months. There was no relapse subsequently among the patients with responses. There was no death related to tuberculosis. CONCLUSION: In this report from National Masan Tuberculosis Hospital in Korea, multi-drug resistant pulmonary tuberculosis responded relatively well to carefully selected regimens.

Clinical Finding of MDR Tuberculosis and Frequency of MOTT / 결핵

BACKGROUND: The frequency of MOTT has risen as the prevalence of tuberculosis has been declining. Our country has been also. The most of MOTT was resistant to the major anti-tuberculous drugs. METHOD: To compare clinical characteristics and frequencies of MDR tuverculosis with MOTT, the author studied 65 patients showing AFB culture positive with sputum. The data were collected from 176 patients who had been admitted at the National Masan Tuberculosis Hospital from May to June, 1997 to April, 1998. RESULTS: The frequency of MDR tuberculosis was 43.1% and that of MOTT was 9.2%. Among 65 isolated my-cobacteria, 3 cases were M. intracellulare, 2 cases were M. fortuitum, and 1 case was unidentified MOTT. The most frequent age group in 65 culture positive patients was 4th decade and the mean age was 44. The mean age was 61 in MOTT and 42 in M. tuberculosis and bad significant difference(p<0.01). The numbers with past history of treatment were 2.3 in MDR tuberculosis and 1.7 in non-MDR tuberculosis and had significant difference(p<0.05). At the time of admisson, the most frequent regiment for the theatment of MDR tuberculosis was 24 months regimen(85.7%) with the 2nd line anti-tuberculosis drugs. For non-MDR tuberculosis, 9 or 12 months regimen (72.9%) with the 1st line anti-tuberculosis drugs and had significant difference(p<0.01). At the time of admission, the symptom of weight loss was shown in 84.7% of M. tuberculosis and 50.0% in MOTT and there was significant difference(p<0.05) between them. All of the MOTT were identified to be resistant against INH and PAS. Drug resistane rates to INH, OFX(p<0.01) and PAS(p<0.05) in MOTT were higher than in MDR. All of three M. intracellulare strains were resistant to INH, RFP, PAS and OFX. All of two M. fortuitum strains were resistant to most anti-tuberculosis drugs. And the other MOTT was resistant to INH, EMB and PAS. CONCLUSION: MOTT was more common in elderly patients than M. tuberculosis. MOTT cases should be considered to be the probability of multiple drug resistance and treatment failure during the 1st treatment because they showed more resistance to anti-tuberculosis drugs than M. tuberculosis cases. Therefore, there should be more careful investigations for clinical characteristics, natural history of disease, and efficient management for MOTT.

Pulmonary Resection in the Treatment of Multidrug-Resistant Tuberculosis / 결핵

BACKGROUND: Recent outbreaks of pulmonary disease due to drug-resistant strains of Mycobacterium Tuber-culosis have resulted in significant morbidity and mortality in patients worldwide. We reviewed our experience to evaluate the effects of pulmonary resection on the managenent of multidrug-resistant tuberculosis. METHOD: A retrospective review was performed of 41 patients undergoing pulmonary resection for multidrug-resistant tuberculosis between January 1993 and December 1997. We divided these into 3 groups according to the radiologic findigs : (1) patients who have reasonably localized lesion ( Localized Lesion Group ; LLG) (2) patients who have cavitary lesion after pulmonary resection on chest roentgenogram (Remained Cavity Group : RCG). (3) patients who have Remained infiltrative lesions postoperatively (Remained infiltrative group : RIG). We evaluated the negative conversion rate after resection and overall response rate of the groups. Then they were compared with the results of the chemotherapy on the multidrug-resistant tuberculosis which has been outcome by Goble et al. Goble et al reported that negative conversion rate was 65% and overall response rate, 56% over a mean period of 5.1 months. RESULTS: Seventy five point six percent were men and 24.4% woment with a median age of 31 years (range, 16 to 60 years). Although the patients were treated preoperatively with multidrug regimens in an effort to reduce the mycobacterial burden, 22 of 41 were still sputum culture positive at the time of surgery. 20 of 22 patients (90.9%, p<0.01) responded which is defined as negative sputum cultures within 2 months postoperative. Of 26 patients with the sufficient follow up data, 19 have Remained sputum culture negative for a mean duration of 25.7 months (73.1%, p<0.05). The bulk of the disease was manifest in one lung, but lesser amounts of contralateral disease were demonstrated in 15, consisted of 8 in RIG and 7 in RCG, of 41. 12 of 12 patients (100%, p<0.01) who were sputum positive at the time of surgery in LLG converted successfully. 14 of 15 patients (93.3%, p<0.05) with the follow up have completed treatment and not relapsed for a mean period of 25.7 months. The mean length of postoperative drug therapy off LLG was 12.2 months. In RIG, postoperative negative conversion rate was 83.3% which was not significant statistically. There was a statistical significance in overall response rate (100%, p<0.05) of RIG for a mean period of 24.4 months with a mean length of postoperative chemotherapy, 11.8 months. In RCG a statistically lower overall response rate (14.3%, p<0.01) has been revealed for a mean duration of follow up, 24.2 months. A negative conversion rate of RCG was 75% which was not significant statistically. CONCLUSION: Surgery plays an important role in the management of patients with multidrug-resistant Mycobacterium tuberculosis infection. Aggressive pulmonary resection should be performed for resistant Mycobacterium tuberculosis infection to avoid treatment failture or relapse. Especially all cavitary lesions on preoperative chest roentgenogram should be resected completely. If all them could not be resected perfectly, you should not open the thorax.

A Comparative Study of Effect of Secondary Anti-tuberculosis Drugs in the Retreatment of Pulmonary Tuberculosis / 결핵

BACKGROUND: In the management of patients whose primary chemotherapy has failed, careful assessment is essential. It is important to find out as accurate a chemotherapy history as possible. Preferably it should contain the drugs which has never used before. The purpose of present study is establishment of retreatment regimen for pulmonary tuberculosis. The present report concerns the results of retreatment of pulmonary tuberculosis patients treated at National Masan Tubersulosis Hospital. METHOD: Retrospective cohort study was made 104 drug-resistant pulmonary tuberculosis patients who were treated by five regimens between Jan. 1994 and Now. 1996. All the patients taken medicine for second anti-tuberculosis regimens for the first time. We separated the patients by three groups(Group l : OFX+PTA+CS+PAS+Aminoglycoside, Group ll : PZA+PTA+CS+PAS+Aminoglycoside, Group lll : PZA+OFX+PTA+PAS+Aminoglycoside). RESULTS: The age distribution was most frequent in fourth decade(36patients, 34.6%) and the mean age was 42.6 year. The sex distribution was most frequent in the males(81patients, 85.7%). There was 31 patients(29.8%) with combined diseaes, 18 patients with complication and 24 patients(27.9%) with family history. Primary chemotherapy regaimens were HERAZ(S or K) in 48 patients (46.2%), HER(S or K) in 41 patients (39.4%) and others in 15 patients(14.4%). Result of drug sensivivity test showed that the resistance to INH and RFP is in 68 patients(65.4%), RFP is in 12 patients(11.5%), INH s in 3 patients(2.9%) and all sensitive to INH and RFP is 3 patients(2.9%). The clinical symptoms on admission were coughing(89.4%), sputum(69.2%), dyspenea on exertion(37.5%), weight loss(33.7%) blood tinged sputum (15.4%) and otheres. The extent of disease on the radiograph was far-advanced in 73 patients (70.2%), moderate in 28 patients(26.9%) and minimal in 3 patients(2.8%). The side effects for drugs were gastrointestinal troubles in 31 patients(29.8%), arthralgai in 22 patients(21.2%), skin rash in 12 patients(11.5%) and others. The negative conversion rate on sputum AFB smear was 85.6%(87.5% in Group l, 80% in Group ll and 90.5% in Group lll). The average negative conversion time on sputum was 4 month(4.0 month in Group l, 4.6 month in Group ll and 3.0 month in Group III). CONCLUSION: In the retreatment of pulmonary tuberculosis, ofloxacin is useful drug for the patients who are not available to use PZA and combination of PZA and OFX can be use effectively substively substituting for CS.