SUMOylation-mediated PSME3-20S proteasomal degradation of transcription factor CP2c is crucial for cell cycle progression.

Transcription factor CP2c (also known as TFCP2, α-CP2, LSF, and LBP-1c) is involved in diverse ubiquitous and tissue/stage-specific cellular processes and in human malignancies such as cancer. Despite its importance, many fundamental regulatory mechanisms of CP2c are still unclear. Here, we uncover an unprecedented mechanism of CP2c degradation via a previously unidentified SUMO1/PSME3/20S proteasome pathway and its biological meaning. CP2c is SUMOylated in a SUMO1-dependent way, and SUMOylated CP2c is degraded through the ubiquitin-independent PSME3 (also known as REGγ or PA28)/20S proteasome system. SUMOylated PSME3 could also interact with CP2c to degrade CP2c via the 20S proteasomal pathway. Moreover, precisely timed degradation of CP2c via the SUMO1/PSME3/20S proteasome axis is required for accurate progression of the cell cycle. Therefore, we reveal a unique SUMO1-mediated uncanonical 20S proteasome degradation mechanism via the SUMO1/PSME3 axis involving mutual SUMO-SIM interaction of CP2c and PSME3, providing previously unidentified mechanistic insights into the roles of dynamic degradation of CP2c in cell cycle progression.

A Cell-Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer-Specific Synthetic Lethality.

Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof-of-principle evidence is presented that a cell-penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene-addicted cancer cells through transcription activity-independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2-p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome-wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C-resistant cancers. This study enhances the understanding of ACP52C-induced cancer-specific apoptosis induction and supports the use of ACP52C in anticancer drug development.

Usefulness of the acromioclavicular joint cross-sectional area as a diagnostic image parameter of acromioclavicular osteoarthritis.

BACKGROUND: Acromioclavicular joint (ACJ) space narrowing has been considered to be an important diagnostic image parameter of ACJ osteoarthritis (ACJO). However, the morphology of the ACJ space is irregular because of osteophyte formation, subchondral irregularity, capsular distention, sclerosis, and erosion. Therefore, we created the ACJ cross-sectional area (ACJCSA) as a new diagnostic image parameter to assess the irregular morphologic changes of the ACJ. AIM: To hypothesize that the ACJCSA is a new diagnostic image parameter for ACJO. METHODS: ACJ samples were obtained from 35 patients with ACJO and 30 healthy individuals who underwent shoulder magnetic resonance (S-MR) imaging that revealed no evidence of ACJO. Oblique coronal, T2-weighted, fat-suppressed S-MR images were acquired at the ACJ level from the two groups. We measured the ACJCSA and the ACJ space width (ACJSW) at the ACJ on the S-MR images using our imaging analysis program. The ACJCSA was measured as the cross-sectional area of the ACJ. The ACJSW was measured as the narrowest point between the acromion and the clavicle. RESULTS: The average ACJCSA was 39.88 ± 10.60 mm2 in the normal group and 18.80 ± 5.13 mm2 in the ACJO group. The mean ACJSW was 3.51 ± 0.58 mm in the normal group and 2.02 ± 0.48 mm in the ACJO group. ACJO individuals had significantly lower ACJCSA and ACJSW than the healthy individuals. Receiver operating characteristic curve analyses demonstrated that the most suitable ACJCSA cutoff score was 26.14 mm2, with 91.4% sensitivity and 90.0% specificity. CONCLUSION: The optimal ACJSW cutoff score was 2.37 mm, with 88.6% sensitivity and 96.7% specificity. Even though both the ACJCSA and ACJSW were significantly associated with ACJO, the ACJCSA was a more sensitive diagnostic image parameter.

The value of the peroneus brevis tendon cross-sectional area in early diagnosing of peroneus brevis tendinitis: The peroneus brevis tendon cross-sectional area.

A thickened peroneus brevis tendon has been considered to be an important morphologic parameter of peroneus brevis tendinitis (PBT). Previous researchers have found that the peroneus brevis tendon thickness (PBTT) is correlated with inflammation of the peroneus brevis tendon. However, inflammatory hypertrophic change is different from simple thickness. Thus, we devised the peroneus brevis tendon cross-sectional area (PBTCSA) as a new diagnostic parameter to analyze the hypertrophy of the whole PBT. We assumed that the PBTCSA is a major morphologic parameter useful for early PBT diagnosis. Peroneus brevis tendon images were collected from 22 patients with PBT and from 22 normal subjects who underwent ankle-magnetic resonance imaging and revealed no evidence of PBT. The T1-weighted axial ankle-magnetic resonance imaging images were evaluated at the ankle level from all participants. The PBTT was measured as the thickest point at the transverse image of the peroneus brevis tendon. The PBTCSA was measured as the cross-sectional ligament whole area of the peroneus brevis tendon that was most hypertrophied in the axial A-MR images. The average PBTT was 2.22 ± 0.29 mm in the normal group and 2.85 ± 0.36 mm in the PBT group. The average PBTCSA was 6.98 ± 1.54 mm2 in the normal group and 13.11 ± 2.45 mm2 in the PBT group. PBT patients had significantly greater PBTT (P < .001) and PBTCSA (P < .001) than the normal group did. A receiver operating characteristic curve analysis revealed that the most suitable cutoff value of the PBTT was 2.51 mm, with 81.8% sensitivity and 81.8% specificity, and an AUC for the score was 0.93. The most suitable cutoff value of the PBTCSA was 10.08 mm2, with 90.9% sensitivity and 90.9% specificity, and AUC for the score was 0.98. Even though the PBTT and PBTCSA were both significantly associated with PBT, the PBTCSA was a more sensitive diagnostic parameter.

Delayed human neutrophil apoptosis by Trichomonas vaginalis lysate.

Neutrophils play an important role in the human immune system for protection against such microorganisms as a protozoan parasite, Trichomonas vaginalis; however, the precise role of neutrophils in the pathogenesis of trichomoniasis is still unknown. Moreover, it is thought that trichomonal lysates and excretory-secretory products (ESP), as well as live T. vaginalis, could possibly interact with neutrophils in local tissues, including areas of inflammation induced by T. vaginalis in humans. The aim of this study was to investigate the influence of T. vaginalis lysate on the fate of neutrophils. We found that T. vaginalis lysate inhibits apoptosis of human neutrophils as revealed by Giemsa stain. Less altered mitochondrial membrane potential (MMP) and surface CD16 receptor expression also supported the idea that neutrophil apoptosis is delayed after T. vaginalis lysate stimulation. In contrast, ESP stimulated-neutrophils were similar in apoptotic features of untreated neutrophils. Maintained caspase-3 and myeloid cell leukemia-1 (Mcl-1) in neutrophils co-cultured with trichomonad lysate suggest that an intrinsic mitochondrial pathway of apoptosis was involved in T. vaginalis lysate-induced delayed neutrophil apoptosis; this phenomenon may contribute to local inflammation in trichomoniasis.

Prediction of all-cause mortality after liver transplantation using left ventricular systolic and diastolic function assessment.

Although pretransplant cardiac dysfunction is considered a major predictor of poor outcomes after liver transplantation (LT), the ability of left ventricular (LV) systolic/diastolic function (LVSF/LVDF), together or individually, to predict mortality after LT is poorly characterized. We retrospectively evaluated pretransplant clinical and Doppler echocardiographic data of 839 consecutive LT recipients from 2009 to 2012 aged 18-60 years. The primary endpoint was all-cause mortality at 4 years. The overall survival rate was 91.2%. In multivariate Cox analysis, reduced LV ejection fraction (LVEF, P = 0.014) and decreased transmitral E/A ratio(P = 0.022) remained significant prognosticators. In LVSF analysis, patients with LVEF≤60% (quartile [Q]1) had higher mortality than those with LVEF>60% (hazard ratio = 1.90, 95% confidence interval = 1.15-3.15, P = 0.012). In LVDF analysis, patients with an E/A ratio<0.9(Q1) had a 2.19-fold higher risk of death (95% confidence interval = 1.11-4.32, P = 0.024) than those with an E/A ratio>1.4(Q4). In combined LVDF and LVSF analysis, patients with an E/A ratio<0.9 and LVEF≤60% had poorer survival outcomes than patients with an E/A ratio≥0.9 and LVEF>60% (79.5% versus 93.3%, P = 0.001). Patients with an early mitral inflow velocity/annular velocity (E/e' ratio)>11.5(Q4) and LV stroke volume index (LVSVI)<33mL/m2(Q1) showed worse survival than those with an E/e' ratio≤11.5 and LVSVI ≥33mL/m2(78.4% versus 92.2%, P = 0.003). A combination of LVSF and LVDF is a better predictor of survival than LVSF or LVDF alone.

Usefulness of patellar cartilage cross-sectional area for knee tibiofemoral osteoarthritis in elderly.

PURPOSE: Knee tibiofemoral osteoarthritis (KOA) is a major health problem, affecting approximately 30% of elderly. Several studies have reported that the loss of patellar cartilage is associated with an increased risk of KOA. However, no study has reported the optimal cut off value of patellar cartilage cross-sectional area (PCA) in KOA. We hypothesize that PCA is a new sensitive morphologic parameter in the diagnosis of KOA. The purpose of this study was to determine whether PCA could be used as an important adjuvant morphological parameter in the diagnosis of KOA. PATIENTS AND METHODS: Data regarding PCA were collected from 88 subjects with KOA. A total of 77 subjects in the control group underwent knee MRI as part of nonsymptomatic medical examination. T2-weighted axial images were acquired from both groups. Using a picture archiving communications system, we analyzed the cross-sectional area of the patellar cartilage on MRI. RESULTS: The average PCA was 98.66±22.18 mm2 in the control group, which was significantly (p<0.001) higher than that (59.43±16.11 mm2) in the KOA group. Receiver operator haracteristic curve analysis was computed to determine the validity of PCA as a predictor of KOA. In the KOA group, the optimal cut offpoint was 76.06 mm2, with sensitivity of 83.0%, specificity of 83.1%, and AUC of 0.94 (95% CI: 0.90-0.97). CONCLUSIONS: Lower PCA values were associated with a higher possibility of KOA. The optimal cutoff score of PCA might be used to facilitate the evaluation of patients with KOA.

Optimal Cut-Off Value of the Superior Articular Process Area as a Morphological Parameter to Predict Lumbar Foraminal Stenosis.

Background. We devised a new morphological parameter called the superior articular process area (SAPA) to evaluate the connection between lumbar foraminal stenosis (LFS) and the superior articular process. Objective. We hypothesized that the SAPA is an important morphologic parameter in the diagnosis of LFS. Methods. All patients over 60 years of age were included. Data regarding the SAPA were collected from 137 patients with LFS. A total of 167 control subjects underwent lumbar magnetic resonance imaging (MRI) as part of a routine medical examination. We analyzed the cross-sectional area of the bone margin of the superior articular process at the level of L4-L5 facet joint in the axial plane. Results. The average SAPA was 96.3 ± 13.6 mm2 in the control group and 128.1 ± 17.2 mm2 in the LFS group. The LFS group was found to have significantly higher levels of SAPA (p < 0.001) in comparison to the control group. In the LFS group, the optimal cut-off value was 112.1 mm2, with 84.4% sensitivity, 83.9% specificity, and AUC of 0.94 (95% CI: 0.91-0.96). Conclusions. Higher SAPA values were associated with a higher possibility of LFS. These results are important in the evaluation of patients with LFS.

Dural sac area is a more sensitive parameter for evaluating lumbar spinal stenosis than spinal canal area: A retrospective study.

Narrowing of the dural sac cross-sectional area (DSCSA) and spinal canal cross-sectional area (SCCSA) have been considered major causes of lumbar central canal spinal stenosis (LCCSS). DSCSA and SCCSA were previously correlated with subjective walking distance before claudication occurs, aging, and disc degeneration. DSCSA and SCCSA have been ideal morphological parameters for evaluating LCCSS. However, the comparative value of these parameters is unknown and no studies have evaluated the clinical optimal cut-off values of DSCSA and SCCSA. This study assessed which parameter is more sensitive.Both DSCSA and SCCSA samples were collected from 135 patients with LCCSS, and from 130 control subjects who underwent lumbar magnetic resonance imaging (MRI) as part of a medical examination. Axial T2-weighted MRI scans were acquired at the level of facet joint from each subject. DSCSA and SCCSA were measured at the L4-L5 intervertebral level on MRI using a picture archiving and communications system.The average DSCSA value was 151.67 ±â€Š53.59 mm in the control group and 80.04 ±â€Š35.36 mm in the LCCSS group. The corresponding average SCCSA values were 199.95 ±â€Š60.96 and 119.17 ±â€Š49.41 mm. LCCSS patients had significantly lower DSCSA and SCCSA (both P < .001). Regarding the validity of both DSCSA and SCCSA as predictors of LCCSS, Receiver operating characteristic curve analysis revealed an optimal cut-off value for DSCSA of 111.09 mm, with 80.0% sensitivity, 80.8% specificity, and an area under the curve (AUC) of 0.87 (95% confidence interval, 0.83-0.92). The best cut off-point of SCCSA was 147.12 mm, with 74.8% sensitivity, 78.5% specificity, and AUC of 0.85 (95% confidence interval, 0.81-0.89).DSCSA and SCCSA were both significantly associated with LCCSS, with DSCSA being a more sensitive measurement parameter. Thus, to evaluate LCCSS patients, pain specialists should more carefully investigate the DSCSA than SCCSA.

The effect of polydeoxyribonucleotide prolotherapy on posterior tibial tendon dysfunction after ankle syndesmotic surgery: A case report.

RATIONALE: Ankle syndesmotic injuries occasionally require long-term therapy for recovery and can result in tendon injury. Posterior tibial tendon dysfunction (PTTD) is an acquired deformity that can cause flatfoot deformity. The current nonoperative management of PTTD includes nonsteroidal antiinflammatory drugs (NSAIDs), orthopedic devices. Although various treatment options have been attempted, optimal treatments for each stage of the condition are debated. Polydeoxyribonucleotide (PDRN) is effective in healing of chronic wounds associated with tissue damage by attracting tissue growth factors. PATIENT CONCERNS: A 67-year-old woman who presented at our pain clinic with pain on the inside of ankle. She had a syndesmotic screw fixation 3 years prior. Her ankle pain had persisted after the removal of screws and edema for about 1 month resulting from long-term NSAIDs administration. DIAGNOSES: The origin of the pain was possibly tibialis posterior muscle and posterior tibial tendon and she was diagnosed as PTTD after syndesmosis surgery. INTERVENTIONS: Sono guided prolotherapy with PDRN was carried out. OUTCOMES: Patient showed improvement in the arch of the foot, experienced pain relief, and was able to wear regular shoes without any orthopedic device. LESSONS: This case report highlights that PDRN prolotherapy is a safe and efficient therapeutic option for the treatment of PTTD.

Thalamic Pain Misdiagnosed as Cervical Disc Herniation.

Thalamic pain is a primary cause of central post-stroke pain (CPSP). Clinical symptoms vary depending on the location of the infarction and frequently accompany several pain symptoms. Therefore, correct diagnosis and proper examination are not easy. We report a case of CPSP due to a left acute thalamic infarction with central disc protrusion at C5-6. A 45-year-old-male patient experiencing a tingling sensation in his right arm was referred to our pain clinic under the diagnosis of cervical disc herniation. This patient also complained of right cramp-like abdominal pain. After further evaluations, he was diagnosed with an acute thalamic infarction. Therefore detailed history taking should be performed and examiners should always be aware of other symptoms that could suggest a more dangerous disease.

The secretory products of Trichomonas vaginalis decrease fertilizing capacity of mice sperm in vitro.

Trichomonas vaginalis infection is one of the most prevalent sexually transmitted infections in humans and is now recognized as an important cause of infertility in men. There is little information about the effect of extracellular polymeric substances (EPS) from T. vaginalis on sperm, but previous reports do not provide a conclusive description of the functional integrity of the sperm. To investigate the impact of EPS on the fertilizing capacity of sperm, we assessed sperm motility, acrosomal status, hypo-osmotic swelling, and in vitrofertilization rate after incubating the sperm with EPS in vitrousing mice. The incubation of sperm with EPS significantly decreased sperm motility, viability, and functional integrity in a concentration and time-dependent manner. These effects on sperm quality also resulted in a decreased fertilization rate in vitro. This is the first report that demonstrates the direct negative impact of the EPS of T. vaginalis on the fertilization rate of sperm in vitro. However, further study should be performed using human sperm to determine if EPS has similar negative impact on human sperm fertilizing capacity in vitro.

Midazolam protects B35 neuroblastoma cells through Akt-phosphorylation in reactive oxygen species derived cellular injury.

BACKGROUND: Soman, a potent irreversible acetylcholinesterase (AChE) inhibitor, induces delayed neuronal injury by reactive oxygen species (ROS). Midazolam is used in patients with pathologic effects of oxidative stresses such as infection, hemodynamic instability and hypoxia. We investigated whether midazolam protects the Central Nervous System (CNS) from soman intoxication. The present study was performed to determine whether midazolam protects B35 cells from ROS stress for the purpose of exploring an application of midazolam to soman intoxication. METHODS: Glucose oxidase (GOX) induced ROS stress was used in a B35 neuroblastoma cell model of ROS induced neuronal injury. To investigate the effect of midazolam on cell viability, LDH assays and fluorescence activated cell sorting (FACS) analysis was performed. Western blotting was used for evaluating whether Akt-phosphorylation is involved in cell-protective effects of midazolam. RESULTS: GOX derived ROS injury decreased cell viability about 1.6-2 times compared to control; midazolam treatment (5 and 10 µg/ml) dose-dependently increased cell viability during ROS injury. On western blots, Akt-phosphorylation was induced during pretreatment with midazolam; it was diminished during co-treatment with LY-294002, an inhibitor of Akt-phosphorylation. FACS analysis confirmed that the cell protective effect of midazolam is mediated by an anti-apoptotic effect. GOX-induced apoptosis was inhibited by midazolam and the finding was diminished by LY-294002. CONCLUSIONS: Midazolam protects neuronal cells from GOX-induced ROS injury; this effect is mediated by an anti-apoptotic effect through Akt-phosphorylation. This shows that midazolam may be useful in soman intoxication.

Acute hypertensive pulmonary edema after Cesarean section in a patient with an antepartum myocardial infarction -A case report-.

We report a case of 29-year-old, morbidly obese, diabetic primigravida who had undergone previously primary percutaneous coronary intervention with stent placement for an inferior wall myocardial infarction at 10 weeks of gestation. She remained asymptomatic with medication during the remainder of her pregnancy, but preoperative echocardiography revealed left ventricular dilation and a restrictive diastolic dysfunction with a preserved ejection fraction (46%). She developed acute pulmonary edema associated with hypertension after an elective Cesarean delivery under continuous epidural anesthesia despite the meticulous restriction of fluid.

Pleural effusion and atelectasis during continuous interscalene brachial plexus block -A case report-.

An interscalene brachial plexus block is an effective means of providing anesthesia-analgesia for shoulder surgery. However, it has a multitude of potential side effects such as phrenic nerve block. We report a case of a patient who developed atelectasis of the lung, and pleural effusion manifested as chest discomfort during a continuous interscalene brachial plexus block for postoperative analgesia.

Identification of the L4-5 interspinous space using difference in heights of two consecutive spinous processes.

BACKGROUND: The appropriate landmark of spinal puncture is important for preventing spinal cord injury. L4 spinous process (SP) is the largest in size and L5 is the smallest. In this study 'height of SP' is the longitudinal length of SP on lumbar AP view. The purpose of this study was to identify the L4-5 interspinous space (ISS) using difference between L4, 5 SP heights. METHODS: Sixty-six patients scheduled for spine surgery were enrolled. After induction of general anesthesia, patients were changed to a prone position. The lumbar vertebrae were palpated from the lowest point of the lumbar spine and cranially. We palpated the difference in spinous process heights and marked the point of step-off from L4 SP to L5 SP. The level was radiologically confirmed. Direction of estimation error and the effects of spondylolisthesis, sex, and obesity were also analyzed. RESULTS: The number of accurate identification of the L4-5 ISS in males was 36 (85.7%), in females was 17 (70.8%), and in total 53 (80.3%). The difference between L4 and L5 SP heights (DL4-5SPHs) and sex affect the results. DL4-5SPHs were larger in concordant patients than in discordant patients (7.2 +/- 4.9 mm: 5.0 +/- 1.6 mm, P < 0.05). Among errors, there were more cephalad identified cases compared to caudad identified ones (12.1%: 7.6%). CONCLUSIONS: The identification of L4-5 ISS using SP height difference was considerably accurate. So, we considered this might be a useful method for spinal anesthesia.

A clinical comparison of vertical infraclavicular brachial plexus block using 0.75% or 0.5% ropivacaine for upper limb surgery.

BACKGROUND: We performed a prospective, double blind study to compare the clinical effect of vertical infraclavicular brachial plexus block produced by 0.75% vs 0.5% ropivacaine for upper limb surgery. METHODS: We included 80 patients receiving upper limb surgery under infraclavicular brachial plexus block. The infraclavicular brachial plexus block was performed via the vertical technique with 30 ml of 0.75% or 0.5% ropivacaine. By observation, we determined nerve type was stimulated and scored the level of sensory block and motor block. The quality of blocks was assessed intra-operatively. The duration of sensory block and motor block and their complications were assessed. RESULTS: There were no significant differences in the frequency of stimulated nerve type, evolution of sensory and motor block quality, or success of block. There were no significant differences in the duration of sensory block and motor block. Vascular puncture was noted in 1 patient in the 0.75% ropivacaine. CONCLUSIONS: Both the 0.75% and 0.5% ropivacaine had similar effects in the vertical infraclavicular brachial plexus block.

Continuous epidural analgesia versus continuous intravenous analgesia with peri-articular infiltration following total knee arthroplasty in geriatric patients.

BACKGROUND: Postoperative continuous intravenous analgesia may not provide effective postoperative analgesia following total knee arthroplasty. This study was conducted to determine if combined continuous intravenous analgesia and peri-articular infiltration provided a better quality of analgesia following total knee arthroplasty than epidural analgesia. METHODS: A prospective, double-blind study involving 50 patients who had undergone total knee arthroplasty was conducted. Patients were divided into control group and an experimental group. Patients in the control group (n = 25) received peri-articular infiltration with 47 mL normal saline prior to closure of the wound and postoperative epidural analgesia for 48 hours. Patients in the experimental group (n = 25) received a mixture of peri-articular infiltration of 16 mL of 0.75% ropivacaine, 6 mg morphine, 0.2 mg of epinephrine and 25 mL normal saline prior to closure of the wound and postoperative continuous intravenous analgesia for 48 hours. The analgesic efficacy was then evaluated using the verbal numeric rating scale at 1, 2, 6, 12, 24, and 48 hours postoperatively. The side effects and the dosage of rescue analgesics were then recorded. RESULTS: The experimental group showed a significantly higher pain score than the control group 2 and, 6 hours postoperatively at rest and 2 hours postoperatively following passive knee movement (P < 0.05). In addition, the rescue analgesic requirement was higher for the experimental group during the first 24 hours following surgery than for the control group (P < 0.05). CONCLUSIONS: We found that combined continuous intravenous analgesia and peri-articular infiltration of a mixture of ropivacaine and, morphine injected into the peri-articular tissue provided minimal benefits for pain control during the early postoperative period when compared to epidural analgesia after total knee arthroplasty.