Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged to be one of the world's greatest health threats. However, not only have recent decades shown a steady decline in the number of approved antimicrobial agents but a disappointing discovery also void. The development of novel antibiotics to treat MDR Gram-negative bacteria has been stagnated over the last half century. Though few compounds have shown activities in vitro, in animal models or even in clinical studies, the global antibiotic pipeline is not encouraging. There are a plethora of unexpected challenges that may arise and cannot always be solved to cause promising drugs to fail. This review intends to summarize recent research and development activities to meet the inevitable challenge in restricting the proliferation of MDR Gram-negative bacteria, with focus on compounds that have entered into clinical development stage. In addition to new analogues of existing antibiotic molecules, attention is also directed to alternative strategies to develop antibacterial agents with novel mechanisms of action.
Aminoglycosides ; pharmacology ; therapeutic use ; Animals ; Anti-Bacterial Agents ; pharmacology ; therapeutic use ; Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Drug Discovery ; Drug Resistance, Multiple, Bacterial ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Ferrous Compounds ; pharmacology ; therapeutic use ; Gram-Negative Bacteria ; drug effects ; Gram-Negative Bacterial Infections ; drug therapy ; Humans ; Peptides ; pharmacology ; therapeutic use ; Peptidomimetics ; pharmacology ; therapeutic use ; Tetracyclines ; pharmacology ; therapeutic use ; beta-Lactamase Inhibitors ; beta-Lactams ; pharmacology ; therapeutic use

A strain of P. Aeruginosa,which was seperated from clinical environment,shows a special characteristic. It keeps normal short rod shape when cultured at 37℃, however,it forms filament without pyocyanin producing when cultured at 25℃ overnight. The filaments will divide and form short rods, simultaneously, produce pyocyanin when culture time is prolonged to over 72h or culture temperature is raised to 37℃. The preliminary study indicates that this phenomenin has nothing to do with nutritive conditions and could the inbluenced by inoculating density and irradiating with ultraviolet rays The absence of pyocyanin was not the cause of filamentous formation by the test results.

BACKGROUNDCongestive heart failure (CHF) is a major cause of morbidity and mortality worldwide and angiotensin converting-enzyme inhibitor (ACEI) is the cornerstone in its treatment. However, CHF continues to progress despite this therapy, perhaps because of production of angiotensin II (Ang II) by alternative pathways. The present study was conducted to examine the combined effects of a chronic ACEI, ramipril, and a chronic Ang II type 1 receptor blocker, TCV116, on rat CHF after myocardial infarction (MI).

METHODSCongestive heart failure was caused by MI in rats, which was induced by ligating the left anterior descending coronary artery. The experiment protocol included sham-operated rats (Sham), MI-control rats (MI-control), MI rats treated with ramipril 3 mg/kg (MI-ramipril) or TCV116 2 mg/kg (MI-TCV116) per day, half dosage (MI-1/2R&T) or full dosage (MI-R&T) combination of the two. At 22 weeks, cardiac hemodynamic parameters such as mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), maximal rate of left ventricule pressure development and decline (LV dP/dtmax) and left ventricular end diastolic pressure (LVEDP), and cardiac morphometric parameters such as heart weight (HW), left ventricular weight (LVW) and left ventricular cavity area (LVCA) were measured, mRNA expressions of cardiac molecule genes such as beta myosin heavy chain (betaMHC), B-type natriuretic peptide (BNP), transforming growth factor-beta1 (TGF-beta1), collagen I and III were quantified with reverse transcription polymerase chain reaction (RT-PCR) in the surviving septum myocardium, and survival rates were calculated.

RESULTSThere were no significant differences in MI sizes (%) among each MI related experimental groups (33 +/- 13, 34 +/- 14, 33 +/- 13, 35 +/- 13 and 33 +/- 14 for MI-control, MI-ramipril, MI-TCV116, MI-1/2R&T and MI-R&T, respectively, no statistical significance for all). Compared with sham-operated rats, MI rats without therapy showed significant increases in morphometric parameters as well as in mRNA expressions of cardiac molecule genes (P < 0.01); while their hemodynamic parameters were significantly impaired (P < 0.01), and in terms of spontaneous deaths survival rate shortened (P < 0.05). Compared with MI rats without therapy, MI rats treated with each single drug showed significant attenuation of mRNA expressions of cardiac molecule genes (P < 0.01); while their hemodynamic parameters were significantly improved (P < 0.05 or P < 0.01), and in terms of spontaneous deaths survival rate prolonged (P < 0.05). Both half and full dosage combined treatments exerted more powerful effects on improvement of cardiac phenotypic changes and on attenuation of betaMHC, BNP mRNA expressions (P < 0.05 vs monotherapy); while LVEDP was further lowered (P < 0.05 vs monotherapy). However, the total death in MI rats with full dosage combined treatment was more though there were no significant differences when compared with other treatments.

CONCLUSIONSThe results suggest that treatment with appropriate dosage combination of a chronic ACEI and a chronic ARB may further improve cardiac remodeling and cardiac function after MI.

Angiotensin-Converting Enzyme Inhibitors ; administration & dosage ; Animals ; Benzimidazoles ; administration & dosage ; Biphenyl Compounds ; administration & dosage ; Blood Pressure ; drug effects ; Drug Therapy, Combination ; Heart Failure ; drug therapy ; pathology ; physiopathology ; Male ; Myocardial Infarction ; complications ; Myocardium ; pathology ; Ramipril ; administration & dosage ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1 ; drug effects ; Tetrazoles ; administration & dosage ; Ventricular Function, Left ; drug effects

OBJECTIVETo investigate the effect of puerarin on the neural function and the histopathological changes after ischemic spinal cord injury in rabbits.

METHODSThirty male New Zealand white rabbits were randomly divided into three groups as follows: puerarin group (n=10) receiving intravenous infusion of 30 mg/kg puerarin for 10 minutes, control group (n=10) receiving intravenous infusion of the same volume of normal saline as puerarin for 10 minutes, and sham operation group (n=10) undergoing only the surgical exposure of the abdominal aorta. Temporary spinal cord ischemia was induced by infrarenal aortic occlusion for 20 minutes and followed by reperfusion. The neural status was scored with the Tarlov criteria at 8, 12, 24 and 48 hours after reperfusion. All the animals were killed at 48 hours after reperfusion and the spinal cords (L5) were removed immediately for histopathological study.

RESULTSThe neural function scores at 8, 12, 24 and 48 hours after reperfusion were higher in the puerarin group and sham operation group than those in the control group (P<0.05). More normal motor neurons in the anterior horn of spinal cord were present in the puerarin group and sham operation group than those in the control group (P<0.01). There was a strong correlation between the final neural function scores and the number of normal motor neurons in the anterior horn of spinal cord (r=0.839, P<0.01).

CONCLUSIONSPuerarin can significantly ameliorate the neural function and the histopathological damages after transient spinal cord ischemia in rabbits.

Animals ; Isoflavones ; pharmacology ; Male ; Motor Neurons ; pathology ; Rabbits ; Spinal Cord Ischemia ; drug therapy ; pathology ; physiopathology ; Vasodilator Agents ; pharmacology

Objective:To observe the effects of electroacupuncture (EA) of three different frequencies (2 Hz,80 Hz and 2 Hz/80 Hz) on the free radicals in hippocampus of vascular dementia (VD) model mice.Methods:A total of 100 Kunming mice were randomly divided into a sham operation group,a model group,a 2 Hz EA group,an 80 Hz EA group and a 2 Hz/80 Hz EA group,with 20 mice in each group.The ischemia-reperfusion VD model was established by repeated blockade of bilateral common carotid arteries.Mice in EA groups began EA treatment on the 4th day after the operation.Baihui (GV 20),Dazhui (GV 14),Geshu (BL 17) and Zusanli (ST 36) were punctured and then connected to EA instrument,with different waves of 2 Hz,80 Hz or 2 Hz/80 Hz (10 min/time) applied accordingly,once a day.During the jumping stand experiment,the learning performance,memory performance and hippocampal calcitonin gene-related peptide (CGRP),nitric oxide synthase (NOS),malondialdehyde (MDA),changes in superoxide dismutase (SOD) and true choline esterase (TChE) were observed.In hippocampus,the CGRP level was determined by radioimmunoassay;the MDA level was determined by thiobarbituric acid colorimetric method;the activities of NOS and TChE were determined by spectrophotometry;the activity of SOD was determined by xanthine oxidase method.Results:Compared with the sham operation group,the performances of learning and memory decreased significantly in the model group (P＜0.01);in hippocampus,the CGRP level decreased,the MDA level increased,the activities of NOS and TChE increased,and the activity of SOD decreased in the model group.Compared with the model group,the learning and memory performances of the EA groups were significantly improved (P＜0.05 or P＜0.01);in hippocampus,the CGRP level increased,the MDA level decreased,the NOS and TChE activities decreased,and the SOD activity increased (P＜0.05 or P＜0.01).Among EA groups,the 2 Hz/80 Hz EA group was superior to the 2 Hz EA group and the 80 Hz EA group (P＜0.05 or P＜0.01).Conclusion:EA can improve the cognitive impairment of mice with ischemia-reperfusion VD.The mechanism may be related to the improvement of cerebral blood circulation,regulation of the central neurotransmitters,fighting lipid peroxidation and promoting nerve cell repair.The therapeutic effects of EA with different frequencies were different,and the intervention effect by EA at 2 Hz/80Hz is the most significant.

OBJECTIVETo explore the role of HOXB2 gene in the proliferation of primary human umbilical vein endothelial cells (HUVECs) and the protective effects of VEGF on the endothelia against radiation injury.

METHODSHUVECs were isolated, cultured, subcultured and identified. (1) Liposome coated oligodeoxynucleotide (odn) and homeoboxB2 antisense oligodeoxyncleotide (HOXB2asodn) were prepared prepared in the concentrations of 0.25, 0.5, 1.0 and 2.5 mg/L for the stimulation of HUVEC. (3)H-TdR incorporation test and MTT method were employed to determine the proliferation activity of HUVECs after activation. The cell cycle analysis of HUVECs was determined by flow cytometry. The expression level of HOXB2mRNA within HUVECs was detected by RT-PCR (reverse transcription polymerase chain reaction). (2) HUVECs were separately treated with the addition of VEGF in concentration of 50 microg/L, by radiation in the dose of 6 Gy or 12 Gy (60)Co gamma gamma ray, or radiation with 12 Gy (60)Co gamma gamma ray followed by the addition of VEGF in dose of 50 microg/L. The cellular morphology was observed and the cellular proliferation activity was determined by MTT method.

RESULTS(1) The proliferation activity of HUVECs could be markedly inhibited by liposome coated HOXB2asodn in comparison to liposome-odn (P < 0.05 or 0.001), and the inhibition effect was positively correlated with the increase in asodn concentration. The cell ratio in S phase and the expression level of the HOXB2mRNA could be lowered by asodn in dose of 2.5 mg/L (P < 0.05 or 0.001). (2) Radiation by (60)Co gamma ray could lead to the nuclear enlargement, vacuolation in the cytoplasm, multiplicity of nucleus and nuclear swelling. The proliferative activity of HUVECs was increased from 0.365 +/- 0.047 and 0.487 +/- 0.022 without radiation to 0.557 +/- 0.042 and 0.648 +/- 0.021 24 and 48 hours after 6 Gy radiation However it was decreased to 0.263 +/- 0.038 and 0.306 +/- 0.024 (P < 0.01) after 12 Gy (60)Co gamma ray radiation. Nevertheless, the cell morphology was obviously improved and the proliferation was enhanced by the addition of VEGF after 12 Gy radiation.

CONCLUSIONHOXB2 gene played important roles in the biological activities of HUVECs. Small dose (6 Gy) gamma-radiation could promote, but large dose (12 Gy) could decrease the mRNA expression of HOXB2 gene in HUVECs. In addition, VEGF could protect HUVECs against radiation injury.

Cell Proliferation ; drug effects ; radiation effects ; Cells, Cultured ; Endothelial Cells ; drug effects ; radiation effects ; Endothelium, Vascular ; cytology ; drug effects ; radiation effects ; Genes, Homeobox ; genetics ; Homeodomain Proteins ; genetics ; Humans ; Liposomes ; pharmacology ; Oligonucleotides, Antisense ; genetics ; Radiation Injuries ; Transcription Factors ; genetics ; Umbilical Veins ; cytology ; Vascular Endothelial Growth Factors ; pharmacology

BACKGROUNDPatellar fracture and cruciate ligament injury are a common consequence of traumatic knee injury. Patellar fracture combined with cruciate ligament injury is rarely reported, although the mechanisms of two things are similar. This study aimed to evaluate the incidence of closed patella fracture combined with cruciate ligament injury.

METHODSFrom 2012 March 1 to June 30, magnetic resonance images of 60 patients with unilateral closed patellar fracture were studied in our institution. The mean age of the patients at presentation was 40.2 years (range, 13-64 years) and 48 patients were men. First, patients were divided according to the cause of injury. Twenty-eight patients had high-energy trauma from a falling injury or motor vehicle accident, and 32 patients had low-energy trauma resulting from a tumbling injury. Second, according to the fracture pattern, 31 patients had a transverse fracture and 29 patients had a comminuted fracture.

RESULTSWe found seven cases of closed patellar fracture combined with cruciate ligament injury among 60 patients, including two cases of a completely ruptured posterior cruciate ligament, two with a partially torn posterior cruciate ligament, and three with a partially torn anterior cruciate ligament. The percentage of this combined injury was 11.6% (7/60). The incidence of a combined injury of the cruciate ligament with a comminuted fracture (6/29, 20.7%) was significantly higher than that with a transverse fracture (1/31, 3.2%, P < 0.05). The most common mechanism of injury in patellar fracture combined with cruciate ligament injury was high-energy trauma from road traffic accidents (94%), whereas in the patellar fracture alone, it was tumbling (62%). The incidence of combined injury with high-energy trauma (6/28, 21.4%) was significantly higher than that with low-energy trauma (1/32, 3.1%, P < 0.05).

CONCLUSIONSThese data suggest that high-energy trauma often results in a comminuted patellar fracture, which is often combined with cruciate ligament injury. Traffic accidents are the main risk factor for this combined injury. Understanding the relationship between patellar fracture and cruciate ligament injury for diagnosis and treatment is important.

Adolescent ; Adult ; Anterior Cruciate Ligament Injuries ; Case-Control Studies ; Female ; Fractures, Closed ; diagnosis ; Humans ; Knee Injuries ; diagnosis ; Knee Joint ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Patella ; injuries ; Young Adult

OBJECTIVETo determine the spatio-temporal expression of p70S6k activation in hippocampus in mesial temporal lobe epilepsy.

METHODSTemporal lobe epilepsy model was established by stereotaxically unilateral and intrahippocampal injection of kainite acid (KA) in adult male C57BL/6 mice. Latent and chronic epileptogenesis were represented by mice 5 days after KA injection (n = 5) and mice 5 weeks after KA injection (n = 8), respectively. Control mice (n = 5) were injected with saline. Immunohistochemical assays were performed on brain sections of the mice.

RESULTSHippocampus both ipsilateral and contralateral to the KA injection displayed significantly up-regulated pS6 immunoreactivity in dispersed granule cells in 5-day and 5-week model mice.

CONCLUSIONThe activation of p70S6k is mainly located in the dentate gyrus in KA-induced mouse model of temporal lobe epilepsy, indicating that the activation may be related with the disperse degree and hypertrophy of granule cells.

Animals ; Epilepsy, Temporal Lobe ; enzymology ; Hippocampus ; enzymology ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; Ribosomal Protein S6 Kinases, 70-kDa ; analysis ; metabolism

OBJECTIVETo investigate the early outcome of vertical expandable prosthetic titanium rib (VEPTR) technique in treating early-onset scoliosis.

METHODSThis study recruited 11 early-onset scoliosis patients (8 boys and 3 girls) who received VEPTR treatment from December 2006 to July 2011 with a minimum follow-up of 12 months. The average age at initial surgery was (7 ± 3) years (range, 3.1 to 9.8 years). VEPTR device, either rib to rib or rib to lumbar, was implanted at initial surgery. During the regular post-operative follow-ups, expansion surgeries were scheduled at an interval of 6 to 12 months. Measurements of primary curve magnitude, apical vertebral translation, thoracic height and T(1)-S(1) height were performed on radiographs, and were compared between those of preoperatively, postoperatively, and at latest follow-up through paired-t tests.

RESULTSAll patients had a mean follow-up of (32 ± 11) months. Totally 41 surgeries were performed, averagely 3.7 surgeries per patient; and 30 expansion surgeries were carried out, averagely 2.7 surgeries per patient. The average interval for each expansion surgery was 8 months. From preoperatively to latest follow-up, the Cobb angle of primary curves was averagely corrected from 78° ± 18° to 55° ± 11° (t = 4.931, P < 0.05), and apical vertebral translation and thoracic kyphosis displayed slight improvement. Average thoracic height increased from (13.3 ± 2.0) cm to (17.2 ± 2.4) cm (t = 8.365, P < 0.001), and average T(1)-S(1) height from (24.4 ± 3.8) cm to (32.5 ± 5.3) cm (t = 9.080, P < 0.001). After initial surgery with VEPTR instrumented, gains in thoracic height and T(1)-S(1) height per expansion surgery averaged (0.8 ± 0.3) cm and (1.8 ± 0.4) cm, respectively. Eight complications occurred in 6 patients, including rib cradle dislodgements, displayed infection, intraoperative pleura rupture and loosening of lumbar pedicle screws.

CONCLUSIONSVEPTR technique proves to be an effective way of preventing curve progression in early-onset scoliosis patients while allowing growth of spine and chest. Yet, indications for such a technique need to be strictly selected because of the relatively high complication rate.

Age of Onset ; Bone Substitutes ; therapeutic use ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Humans ; Male ; Postoperative Complications ; epidemiology ; Ribs ; Scoliosis ; surgery ; Spine ; anatomy & histology ; surgery ; Titanium ; Treatment Outcome

OBJECTIVESTo investigate the incidence of thoracic curve decompensation or proximal adding-on phenomenon after anterior selective fusion of thoracolumbar or lumbar curve in Lenke type 5 adolescent idiopathic scoliosis (AIS), and to identify its risk factors.

METHODSFrom June 2001 to December 2008, 130 Lenke type 5 AIS patients with a Cobb angle of 40° - 73° treated with anterior selective thoracolumbar or lumbar fusion, and with a minimum 2-year postoperative regular follow-up were recruited in this study. The average age, Cobb angle and Risser sign of all patients was 14.8 ± 1.6 years, 46° ± 6° of major thoracolumbar or lumbar curve (TL or L), 25° ± 7° of proximal thoracic curve and 0-5, respectively. The patients were grouped according to the relationship between the upper instrumented vertebrae (UIV) and the upper end vertebrae (UEV), the patients' Risser sign and the relationship between UIV and C(7) plumb line (C(7)PL). The radiographic data of the patients were compared between patients with and without proximal adding-on by using t test, and the incidence of proximal adding-on was analyzed in terms of determination of UIV and Risser sign to identify the risk factors of this phenomenon by using Fisher's exact test.

RESULTSEleven patients were identified with proximal adding-on, thus the incidence of it was 8.5%. At last follow-up postoperatively, the average Cobb angle of TL or L and proximal thoracic curve was 9° ± 4° and 11° ± 5°, respectively. Moreover, the incidence of adding-on in Rissex sign grade 0 to 1 (3/8) was higher than that of grade 2 to 3 (12.1%) and grade 4 to 5 (4.5%). In addition, the incidence of adding-on in UIV lower than UEV group (20.6%) was obviously higher than that of UIV higher than or equal to UEV group (4.2%). The incidence of adding-on for patients with C(7)PL falls away from UIV (19.5%) were obviously higher than that of patients with C(7)PL falls between the pedicle and lateral margin of UIV (3.6%) and between bilateral pedicles of UIV (3.0%). Each group showed significant difference for the incidence of adding-on by Fisher's exact test (P < 0.05).

CONCLUSIONSThere exists the risk of proximal thoracic curve decompensation, with a not low rate, after anterior selective fusion for major TL or L curve AIS. The determination of UIV relative to UEV and the skeletal maturity of the patient are the two factors closely associated with the presence of such a phenomenon.

Adolescent ; Child ; Female ; Follow-Up Studies ; Humans ; Male ; Postoperative Complications ; etiology ; Retrospective Studies ; Risk Factors ; Scoliosis ; surgery ; Spinal Fusion ; adverse effects ; methods ; Thoracic Vertebrae ; surgery ; Treatment Outcome