1.Research progress of live-attenuated Salmonella-based carrier vaccine
Xinyu LIU ; Wenjin ZHANG ; Yaolin CHEN ; Xiaoping BIAN ; Qing LIU ; Qingke KONG
Chinese Journal of Veterinary Science 2025;45(9):2075-2085
Salmonella has demonstrated considerable potential as a vaccine vector,exhibiting robust immunogenicity,ease of oral administration,and cost-effective production.Live attenuated Salmo-nella carrying heterologous antigens can induce both localized mucosal immunity and systemic a-daptive immune responses in hosts after successfully reaching the intestinal tract via oral delivery.Recent advances such as permanent deletion of virulence genes,regulated-delayed attenuation and lysis systems,have initially achieved a balance between the safety and immunogenicity of these vaccine platforms.Nevertheless,practical applications of such vaccine vectors remain constrained by challenges related to gastrointestinal barrier obstruction,inefficient antigen delivery,and im-mune tolerance.With the rapid advancement of multidisciplinary technologies,these limitations are anticipated to be progressively addressed.This review presented a comprehensive summary and dis-cussion of the immune mechanisms,development strategies,current applications,advantages,and challenges associated with oral live attenuated Salmonella vaccine vectors.It also delineated the fu-ture direction of research and development,with a view to providing theoretical references for re-lated research.
2.Research progress of live-attenuated Salmonella-based carrier vaccine
Xinyu LIU ; Wenjin ZHANG ; Yaolin CHEN ; Xiaoping BIAN ; Qing LIU ; Qingke KONG
Chinese Journal of Veterinary Science 2025;45(9):2075-2085
Salmonella has demonstrated considerable potential as a vaccine vector,exhibiting robust immunogenicity,ease of oral administration,and cost-effective production.Live attenuated Salmo-nella carrying heterologous antigens can induce both localized mucosal immunity and systemic a-daptive immune responses in hosts after successfully reaching the intestinal tract via oral delivery.Recent advances such as permanent deletion of virulence genes,regulated-delayed attenuation and lysis systems,have initially achieved a balance between the safety and immunogenicity of these vaccine platforms.Nevertheless,practical applications of such vaccine vectors remain constrained by challenges related to gastrointestinal barrier obstruction,inefficient antigen delivery,and im-mune tolerance.With the rapid advancement of multidisciplinary technologies,these limitations are anticipated to be progressively addressed.This review presented a comprehensive summary and dis-cussion of the immune mechanisms,development strategies,current applications,advantages,and challenges associated with oral live attenuated Salmonella vaccine vectors.It also delineated the fu-ture direction of research and development,with a view to providing theoretical references for re-lated research.
3.Partial translocation of flexor carpi radialis tendon for treatment of traumatic dislocation of first carpometacarpal joint.
Yaolin CHEN ; Yong YANG ; Zhenzhong WANG ; Yang WANG
Chinese Journal of Reparative and Reconstructive Surgery 2025;39(6):668-672
OBJECTIVE:
To explore the effectiveness of partial translocation of flexor carpi radialis tendon in the treatment of traumatic dislocation of the first carpometacarpal joint.
METHODS:
The clinical data of 6 patients with traumatic dislocation of the first carpometacarpal joint who met the selection criteria between March 2020 and June 2024 were retrospectively analyzed. There were 3 males and 3 females with an average age of 33.5 years (range, 16-42 years). All the 6 cases were treated with plaster immobilization for 4-6 weeks, and the time from injury to operation was 6-12 weeks, with an average of 8.8 weeks. All patients underwent reconstruction of the metacarpophalangeal anterior oblique ligament and dorsal posterior oblique ligament of the first carpometacarpal joint with partial translocation of flexor carpi radialis tendon. The pain relief was evaluated by visual analogue scale (VAS) score before and after operation, and the pinch force, palmar abduction and radial abduction angles of the affected side and the healthy side were recorded before and after operation, and the ratio of the above indexes between the affected side and the healthy side was calculated to evaluate the effectiveness.
RESULTS:
All the incisions healed by first intention after operation, and there was no complication related to operation such as neurovascular injury. All patients were followed up 6-19 months (mean, 12.7 months). The range of motion of the thumb on the affected side was the same as that on the healthy side, the first carpometacarpal joint was stable without recurrent dislocation and pain. At last follow-up, the VAS score, the pinch force of the affected side, the abduction angle of the palmar side of the affected thumb, the abduction angle of the radial side of the affected thumb, and the pinch force ratio, the palmar abduction angle ratio of the thumb, and the radial abduction angle ratio of the thumb of the affected side to the healthy side significantly improved when compared with those before operation ( P<0.05).
CONCLUSION
Partial translocation of the flexor carpi radialis tendon to reconstruct the metacarpophalangeal and dorsal radial ligaments for the treatment of traumatic dislocation of the first carpometacarpal joint is a reliable surgical method.
Humans
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Carpometacarpal Joints/surgery*
;
Male
;
Female
;
Adult
;
Adolescent
;
Retrospective Studies
;
Joint Dislocations/surgery*
;
Young Adult
;
Tendons/surgery*
;
Tendon Transfer/methods*
;
Plastic Surgery Procedures/methods*
;
Treatment Outcome
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Range of Motion, Articular
;
Ligaments, Articular/injuries*
4.Efficacy of cannulated screw internal fixation combined with quadratus femoris bone flap with preservation of the posterior superior retinaculum for femoral neck fracture in young and middle-aged patients
Huan LUO ; Tianhua ZHOU ; Chuan LI ; Luqiao PU ; Xingbo CAI ; Teng WANG ; Chen MENG ; Yaolin ZHANG ; Yongqing XU
Chinese Journal of Trauma 2025;41(1):65-71
Objective:To compare the efficacy of cannulated screw internal fixation combined with quadratus femoris bone flap with preservation of the posterior superior retinaculum and cannulated screw internal fixation alone in the treatment of femoral neck fracture in young and middle-aged patients.Methods:A retrospective cohort study was conducted to analyze the clinical data of 83 young and middle-aged patients with femoral neck fracture admitted to the 920th Hospital of Joint Logistic Support Force of PLA from January 2018 to January 2023, including 56 males and 27 females, aged 28-55 years [(42.7±3.2)years]. According to Garden classification, the fractures were classified as type III in 22 patients and type IV in 61. Based on Pauwels classification, the fractures were classified as type I in 15 patients, type II in 38 and type III in 30. Forty patients were treated with cannulated screw internal fixation combined with modified quadratus femoris bone flap (cannulated screw combined with bone flap group) and 43 with cannulated screw internal fixation alone (cannulated screw group). The two groups were compared in terms of the operation time, intraoperative blood loss, time to weight-bearing, length of hospital stay, and wound healing. The visual analogue scale (VAS) scores and Harris hip function scores at 1, 3, 6, 12 months after surgery and at the last follow-up. The postoperative complication rate was detected.Results:All the patients were followed up for 20-70 months [(40.0±1.2)months]. The operation time and intraoperative blood loss were (105.2±2.7)minutes and (100.6±16.3)ml in the cannulated screw combined with bone flap group, which were longer or more than (92.4±4.7)minutes and (92.5±14.6)ml in the cannulated screw group ( P<0.01). The time to weight-bearing was (12.1±1.4)weeks in the cannulated screw combined with bone flap group, shorter than (23.6±1.2)weeks in the cannulated screw group ( P<0.01). There was no statistically significant difference in the length of hospital stay between the two groups (P>0.05). The incisions in both groups were healed by first intention. At 1 month after surgery, no statistically significant difference was observed in VAS scores between the two groups ( P>0.05); at 3, 6, 12 months after surgery and at the last follow-up, the VAS scores were (6.6±0.2)points, (4.5±0.3)points, (3.2±0.5)points, and (2.6±0.4)points in the cannulated screw combined with bone flap group, lower than (7.0±0.1)points, (5.2±0.2)points, (3.9±0.4)points, and (3.3±0.1)points in the cannulated screw group ( P<0.05 or 0.01). At 1 and 3 months after surgery, no statistically significant difference was observed in the Harris hip function scores between the two groups ( P>0.05); at 6, 12 months after surgery and at the last follow-up, the Harris hip function scores were (82.2±1.7)points, (90.0±1.4)points, and (91.6±1.0)points in the cannulated screw combined with bone flap group, higher than (75.2±1.7)points, (83.4±1.9)points, and (85.2±0.7)points in the cannulated screw group ( P<0.01). At the last follow-up, in the cannulated screw combined with bone flap group, the Harris hip function was rated excellent in 32 patients, good in 5, and fair in 3, with an excellent and good rate of 92.5%, while in the cannulated screw group, the Harris hip function was rated excellent in 20 patients, good in 13, and fair in 10, with an excellent and good rate of 76.7% ( P<0.05). The postoperative complication rate was 5.0% (2/40) in the cannulated screw combined with bone flap group, significantly lower than 23.2% (10/43) in the cannulated screw group ( P<0.05). Conclusion:Compared with cannulated screw internal fixation alone, cannulated screw internal fixation combined with quadratus femoris bone flap with preservation of the posterior superior retinaculum has the advantages of earlier weight-bearing, less pain, better recovery of hip joint function, and lower incidence of postoperative complications in the treatment of femoral neck fracture in young and middle-aged patients, despite longer operation time and more intraoperative blood loss.
5.Efficacy of cannulated screw internal fixation combined with quadratus femoris bone flap with preservation of the posterior superior retinaculum for femoral neck fracture in young and middle-aged patients
Huan LUO ; Tianhua ZHOU ; Chuan LI ; Luqiao PU ; Xingbo CAI ; Teng WANG ; Chen MENG ; Yaolin ZHANG ; Yongqing XU
Chinese Journal of Trauma 2025;41(1):65-71
Objective:To compare the efficacy of cannulated screw internal fixation combined with quadratus femoris bone flap with preservation of the posterior superior retinaculum and cannulated screw internal fixation alone in the treatment of femoral neck fracture in young and middle-aged patients.Methods:A retrospective cohort study was conducted to analyze the clinical data of 83 young and middle-aged patients with femoral neck fracture admitted to the 920th Hospital of Joint Logistic Support Force of PLA from January 2018 to January 2023, including 56 males and 27 females, aged 28-55 years [(42.7±3.2)years]. According to Garden classification, the fractures were classified as type III in 22 patients and type IV in 61. Based on Pauwels classification, the fractures were classified as type I in 15 patients, type II in 38 and type III in 30. Forty patients were treated with cannulated screw internal fixation combined with modified quadratus femoris bone flap (cannulated screw combined with bone flap group) and 43 with cannulated screw internal fixation alone (cannulated screw group). The two groups were compared in terms of the operation time, intraoperative blood loss, time to weight-bearing, length of hospital stay, and wound healing. The visual analogue scale (VAS) scores and Harris hip function scores at 1, 3, 6, 12 months after surgery and at the last follow-up. The postoperative complication rate was detected.Results:All the patients were followed up for 20-70 months [(40.0±1.2)months]. The operation time and intraoperative blood loss were (105.2±2.7)minutes and (100.6±16.3)ml in the cannulated screw combined with bone flap group, which were longer or more than (92.4±4.7)minutes and (92.5±14.6)ml in the cannulated screw group ( P<0.01). The time to weight-bearing was (12.1±1.4)weeks in the cannulated screw combined with bone flap group, shorter than (23.6±1.2)weeks in the cannulated screw group ( P<0.01). There was no statistically significant difference in the length of hospital stay between the two groups (P>0.05). The incisions in both groups were healed by first intention. At 1 month after surgery, no statistically significant difference was observed in VAS scores between the two groups ( P>0.05); at 3, 6, 12 months after surgery and at the last follow-up, the VAS scores were (6.6±0.2)points, (4.5±0.3)points, (3.2±0.5)points, and (2.6±0.4)points in the cannulated screw combined with bone flap group, lower than (7.0±0.1)points, (5.2±0.2)points, (3.9±0.4)points, and (3.3±0.1)points in the cannulated screw group ( P<0.05 or 0.01). At 1 and 3 months after surgery, no statistically significant difference was observed in the Harris hip function scores between the two groups ( P>0.05); at 6, 12 months after surgery and at the last follow-up, the Harris hip function scores were (82.2±1.7)points, (90.0±1.4)points, and (91.6±1.0)points in the cannulated screw combined with bone flap group, higher than (75.2±1.7)points, (83.4±1.9)points, and (85.2±0.7)points in the cannulated screw group ( P<0.01). At the last follow-up, in the cannulated screw combined with bone flap group, the Harris hip function was rated excellent in 32 patients, good in 5, and fair in 3, with an excellent and good rate of 92.5%, while in the cannulated screw group, the Harris hip function was rated excellent in 20 patients, good in 13, and fair in 10, with an excellent and good rate of 76.7% ( P<0.05). The postoperative complication rate was 5.0% (2/40) in the cannulated screw combined with bone flap group, significantly lower than 23.2% (10/43) in the cannulated screw group ( P<0.05). Conclusion:Compared with cannulated screw internal fixation alone, cannulated screw internal fixation combined with quadratus femoris bone flap with preservation of the posterior superior retinaculum has the advantages of earlier weight-bearing, less pain, better recovery of hip joint function, and lower incidence of postoperative complications in the treatment of femoral neck fracture in young and middle-aged patients, despite longer operation time and more intraoperative blood loss.
6.Outcomes of autologous osteo-periosteal cylinder graft transplantation for Hepple Ⅴ osteochondral lesions of the talus
Qinwei GUO ; Yu MEI ; Chen JIAO ; Dong JIANG ; Jianing WANG ; Yuping YANG ; Yaolin HU
Chinese Journal of Orthopaedics 2013;(4):342-347
Objective To study the outcomes of autologous osteo-periosteal cylinder graft transplantation for Hepple V osteochondral lesions of the talus (OLT) with large subchondral cyst.Methods The data of 27 consecutive patients of OLT with subchondral cyst was retrospectively analyzed who were treated by autologous osteo-periosteal cylinder graft transplantation from October 2007 to September 2011.There were 26 males and 1 female with an average age of 35.8 years (range,22-53 years).Visual analogue score (VAS) for pain during daily activities,the American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot score,and subjective satisfaction were investigated.The plain radiographs,magnetic resonance imaging (MRI) of the ankle,and second look arthroscopy were analyzed.Results All the 26 patients were followed up for 22.4 months.At the last follow-up,the VAS score decreased from 5.4±1.0 points preoperatively to 0.8±0.8 points postoperatively,and the mean (50%) AOFAS score improved from 73.9±3.1 points preoperatively to 93.0±6.5 points postoperatively.In 26 cases,the radiolucent area of cysts disappeared on plain radiographs.The mean magnetic resonance observation of cartilage repair tissue (MOCART) score was 57.2,though small subchondral bone cyst was still found in 3 cases on postoperative MRI.The mean (50%) ICRS arthroscopic score of cartilage repair was 9.2 points according to second look arthroscopy of 18 cases.There were 16 cases receiving excellent effect,8 good and 2 fair.The excellent and good rate was 92.3% (24/26).There were no major complications.Conclusion Autologous osteo-periosteal cylinder graft transplantation could repair the osteochondral defects.It yields satisfactory results,and is suitable for treating OLT with large subchondral cyst.
7.The role of vasoactive substances in hyperhemodynamics after orthotopic liver transplantation in cirrhotic rats.
Hui CAO ; Zhiyong WU ; Xiaojie ZHANG ; Haiying ZHANG ; Zhiping CHEN ; Yaolin KUANG
Chinese Medical Journal 2003;116(3):405-409
OBJECTIVETo evaluate the role of endogenous vasoactive substances in hyperdynamic circulation after orthotopic liver transplantation (OLT) in cirrhotic rats.
METHODSMale SD rats were randomly divided into 4 groups: normal controls (NL, n = 10), rats with intrahepatic portal hypertension (IHPH, n = 10), normal rats with OLT (NL-OLT, n = 9), and IHPH rats with OLT (IHPH-OLT, n = 16). IHPH-OLT rats were divided into 2 subgroups: Group A (3 days after OLT, n = 9) and Group B (7 days after OLT, n = 7). IHPH was induced by injection of CCI(4) and OLT was performed using cuffs for the anastomosis of suprahepatic inferior vena cava, infrahepatic vena cava and portal vein. Radioactive microsphere method was used for hemodynamic study. The concentrations of plasma glucagon (Glu), nitric oxide (NO), prostaglandin (PGI(2)), thromboxaneA(2) (TXA(2)) and endothelin (ET) were measured by radioimmunoassay.
RESULTSNo significant difference in hemodynamic changes was observed between NL-OLT and NL rats, except for mean arterial blood pressure. No significant changes in NO and PGI(2) were seen between NL-OLT and NL rats. Glu, ET and TXA(2) were significantly elevated in NL-OLT rats compared with NL rats (P < 0.05). Characteristics of systemic and splanchnic hyperdynamic circulatory states were observed in IHPH, IHPH-OLT A, IHPH-OLT B rats. Both the magnitude of hyperhemodynamics and increasing concentrations of Glu and NO occurred in the order of IHPH > IHPH-OLT A > IHPH-OLT B rats. The level of plasma PGI(2) in IHPH rats was significantly elevated compared with NL rats, while PGI(2) in IHPH-OLT A and B rats was found to be lower than in IHPH rats (P < 0.05). There was no obvious difference in PGI(2) between IHPH-OLT B and NL rats. Vasoconstrictors including ET and TXA(2) were found elevated in IHPH-OLT rats.
CONCLUSIONSOLT does not induce postoperative hyperhemodynamics per se. Vasodilators including NO and Glu, especially NO, play an important role in the hyperhemodynamics of IHPH and IHPH-OLT rats. The results of the present study demonstrate that the persistence of systemic and splanchnic hyperkinetic circulation in the early stages after OLT may result from those non-eliminated factors that caused hyperhemodynamics in liver cirrhosis patients with portal hypertension before OLT.
Animals ; Endothelins ; blood ; physiology ; Epoprostenol ; blood ; physiology ; Glucagon ; blood ; physiology ; Hemodynamics ; Liver Cirrhosis, Experimental ; physiopathology ; Liver Transplantation ; Male ; Nitric Oxide ; blood ; physiology ; Rats ; Rats, Sprague-Dawley ; Thromboxane A2 ; blood ; physiology
8.Expression of ET-1 mRNA in the lung of hepatopulmonary syndrome rats.
Xingzhi NI ; Zhiyong WU ; Zhiping CHEN ; Yaolin KUANG
Chinese Journal of Surgery 2002;40(2):142-145
OBJECTIVETo investigate the expression of ET-1 mRNA in the lung of rats with hepatopulmonary syndrome.
METHODSMale Sprague-Dawley rats were divided into four groups: SO, IHPH, PHPH and PCS. Two weeks after production of rat models, all measurements were performed. Arterial blood gas was analyzed. The concentrations of NO and ET-1 in lungs were measured by using radioimmunoassay. In situ hybridization, ET-1 mRNA expressions were detected in lung tissue sections with digoxin-labeled ET-1 oligonucleotide probes. Liver and lung tissues and all the results of in situ hybridization were analyzed by one pathologist. At a magnification of 10 x 40, percent areas of positive stains were detected to indicate the expressions of ET-1 mRNA in the arteries, capillaries and branches.
RESULTSArterial blood gas analysis showed that PaO(2) (mmHg) decreased more significantly in IHPH (73.85 +/- 6.51) rats than in PHPH (97.39 +/- 1.33), PCS (95.23 +/- 2.22) and SO rats (99.05 +/- 0.75). Alveolar-arterial oxygen gradient (A-aG) (mmHg) increased more significantly in IHPH rats (32.99 +/- 6.57) than in PHPH (4.98 +/- 1.69), PCS (6.51 +/- 2.04) and SO rats (3.23 +/- 0.81). Changes of vascular active substance in plasma and lung indicated that the level of lung NO of IHPH (19.78 +/- 5.33) was increased significantly more than that of PHPH (13.21 +/- 3.99) and PCS (13.89 +/- 3.16). These levels in lung homogenate increased more significantly than those SO (8.71 +/- 1.68). The levels of ET-1 in IHPH rats (195.1 +/- 36.2) was significantly lower than in PHPH (234.8 +/- 71.0), PCS (240.4 +/- 66.5) and SO rats (271.8 +/- 40.6). ET-1 mRNA in situ hybridization showed that there was no significant difference in positive expression of ET-1 mRNA in alveolar arteries and small bronchi. The expression of ET-1 mRNA was significantly lower in alveolar capillary endothelia (5.12 +/- 1.27) than in PHPH (7.43 +/- 0.83), PCS (7.07 +/- 0.86) and SO (7.81 +/- 1.98) rats.
CONCLUSIONThe low expressions of ET-1 mRNA in HPS rat alveolar capillary endothelia accompanied by decreased ET-1 levels in lung may play an important role in the mechanism of HPS.
Animals ; Disease Models, Animal ; Endothelin-1 ; biosynthesis ; genetics ; Hepatopulmonary Syndrome ; metabolism ; pathology ; Image Processing, Computer-Assisted ; In Situ Hybridization ; Lung ; metabolism ; pathology ; Male ; Nitrates ; metabolism ; Nitrites ; metabolism ; RNA, Messenger ; biosynthesis ; Rats ; Rats, Sprague-Dawley
9.Role of vascular mediators in the pathogenesis of hepatopulmonary syndrome in rats
Xingzhi NI ; Zhiyong WU ; Zhiping CHEN ; Yaolin KUANG
Chinese Journal of General Surgery 2001;0(10):-
Objective To study the role of vascular mediators in the pathogenesis of hepatopulmonary syndrome in rats. Methods Male Sprague-Dawley (SD) rats were divided into four groups: SO (surgical control), IHPH (intrahepatic portal hypertension), PHPH (prehepatic) and PCS (portocaval shunt). Two weeks after pathological study, arterial blood gas and the concentrations of NO, glucagon, VIP and ET-1 in plasma and lung were determined. Results Lung structural alteration of rats induced by CCl 4 was of alveolar capillary dilation and angiogenesis, thickened alveolar septa and decreased alveolar capacity. There was no inflammation, edema, fibrosis, alveolar collapse and hyaline membrane formation in lung of all rats. PaO 2 ( mm?Hg)decreased more significantly in IHPH (73.85?6.51) rats than in PHPH (972?9?1.33), PCS (95.23?2.22) and SO rats (99.05?0.75). The level of lung NO of IHPH (19.78?5.33) was significantly increased than those of PHPH (13.21?3.99) and PCS (13.89?3.16) whose level in lung homogenate increased than those of SO (8.71?1.68). There was no difference of Glu and VIP levels in lung among all rats. The level of lung ET-1 in IHPH was significantly decreased than other rats. Conclusion Increased NO levels and decreased ET-1 levels in lung of HPS rats cause alveolar dilation and angiogenesis leading to mismatched ventilation-perfusion, and decrease of PaO 2.
10.Changes in systemic and splanchnic hemodynamics after orthotopic liver transplantation in cirrhotic rats
Hui CAO ; Zhiyoag WU ; Xiaojie ZHANG ; Haiying ZHANG ; Zhiping CHEN ; Yaolin KUANG
Chinese Medical Journal 2000;113(12):1108-1111
Objective To investigate early changes in systemic and splanchnic hemodynamics after orthotopic liver transplantation (OLT) in normal and cirrhotic rats. Methods Male Sprague-Dawley rats were divided into 4 groups:normal controls (NL,n=10),intrahepatic portal hypertension (IHPH, n=10) induced by injection of CCl4, normal rats with OLT (NL-OLT,n=9) and IHPH rats with OLT (IHPH-OLT,n=16). IHPH-OLT rots were divided into 2 subgroups: 3 days (Group A, n=9) and 7 days (Group B, n=7) after OLT. OLT was pedormed in rats using cuffs for the anastomosis of the suprahepatic inferior vena cava,infrahepatic vena cava and portal vein. Two weeks after production of IHPH rots, 7 days after NL-OLT rats, 3 days and 7 days after IHPH-OLT rats, radicective microspheres were used in a hemodynamic study. Results There were no significant differences in hemodynamic changes between NL-OLT and NL rets, except mean arterial blood pressure (MAP).The characteristies of systemic and splanchnic hyperdynamic circulatory slate,including increased cardiac output and splanchnic blood flow, decreased mean acterial blood pressure, total peripheral vascular resistance and splanchnic vascular resistance were ibserved in IHPH, IHPH-OLT A, and IHPH-OLT B rats,The magnitude of hyperhemodynamics was in the order of IHPH>IHPH-OLT A>IHPH-OLT B rats. Moreover, the derangement of splanchnic hyper hemodynamice was more significant than that of systemic hyperhemodynamics. Conclusioos The present study demonstrates that the persistence of early systemic and splanchnic hyperkinetic circulation after OLT may be the consequence of factors which maintain hyperhemo dynamics in liver cirrhosis, where portal hypertension is not completely eliminated. Hyperhemodynamics is not induced by OLT per se.

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