PRD Group Research Articles

The Effect of Probiotic Supplementation on Morphine Preference in Rats: Possible Antioxidative/Oxidative Signaling Pathway

Background: Many studies have revealed various aspects of the relationship between the stomach and the brain, but there has been no systematic study of the role of gut microbiota in drug addiction to date. This investigation is based on the novel concept that gut dysbiosis plays an important role in addiction disorders. Probiotic supplements (PBS) are thought to be a useful therapy method for opiate addiction and substance misuse. Therefore, it is postulated that changes in gut flora can play a significant part in the addiction process. Objectives: The aim of this study was to observe whether PBS, through the gut-brain axis in drug addiction, can decrease morphine (Mor) tendency in rats by affecting oxidative stress (OS) markers, using a conditioned place preference (CPP) paradigm. Methods: Forty-two rats (weight 180 - 200 g) were divided into six groups (n = 7 in each). The effective dose of morphine (Mor) was 7.5 mg/kg. Two probiotic supplements were used: Prodigest (Prd) containing Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium longum, and Prokid (Prk) containing Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus rhamnosus, and Bifidobacterium bifidum. These were administered via gavage for 14 days. The animals were given PBS after each conditioning session in the conditioned place preference (CPP) model. The animals' locomotor activity was then evaluated using an open field apparatus. The brain was tested for malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (TAC), and thiol levels. Results: Only the Prd group, but not the Prk group, significantly increased the time spent in the Mor chamber (the location preference index) during the acquisition phase (P < 0.05). The anti-oxidation/oxidation profiles (MDA, NO, CAT, SOD, TAC, and thiol) were altered by PBS. Conclusions: Given the elevated location preference index generated by Mor, it may be argued that PBS influences mood and behavior via antioxidative/oxidative signaling, thereby potentiating the effect of Mor.

Postoperative Nausea and Vomiting following Endoscopic Sinus Surgery under the Guidance of Adequacy of Anesthesia or Pupillometry with Intravenous Propofol/Remifentanil.

Postoperative nausea and vomiting (PONV) constitutes an adverse event after endoscopic sinus surgery (ESS) under general anesthesia (GA) with intravenous opioids, such as remifentanil (RMF). Monitoring the nociception/antinociception balance using the surgical pleth index (SPI) or pupillary dilatation reflex (PRD) helps guide intravenous RMF infusion. We aimed to investigate whether their employment could help reduce the incidence of PONV in patients undergoing ESS. The data of 30 patients from the GA group, 31 from the SPI group, and 28 from the PRD group were analyzed. The initial RMF infusion rate of 0.25 µg/kg body weight/minute was increased by 50% when the SPI, PRD, or Boezaart Bleeding Scale (BBS) were elevated by >15, >5%, or >2 points, respectively, until they normalized. PONV was present in 7/89 patients (7.9%): 2/31 patients (6.5%) of the SPI group, 1/30 patients (3.3%) of the GA group, and 4/28 patients (14.3%) of the PRD group. Neither PRD nor SPI guidance for RMF administration reduced the incidence of PONV compared to standard practice. Further studies are required in order to investigate the possibility of PONV eradication in patients undergoing ESS under GA when it is possibly combined with paracetamol/metamizole preventive analgesia, as well as those using antiemetic prophylaxis based on the Apfel Score and premedication with midazolam.

Pharyngeal Structure and Dysphagia in Patients with Parkinson's Disease and Related Disorders.

Pharyngeal muscle changes occur in patients with Parkinson's disease and related disorders (PRD); however, the association between the structural alterations in the pharynx and the symptoms of dysphagia remains unclear. We assessed structural changes and contractile forces by measuring pharyngeal wall thickness and width. We aimed to define the pharyngeal measurements and determine their value as diagnostic tools for dysphagia.The pharyngeal wall thickness (PWT), pharyngeal width at rest (PWR), and shortest pharyngeal width at swallowing (PWS) were measured using lateral neck roentgenograms and videofluoroscopic swallowing study. We compared the PWR and PWT between the PRD and control groups using an independent t-test. The Kendall correlation test was performed on the radiological data of the pharynx (PWT, PWR and PWS), dysphagia scales (Penetration-Aspiration scale [PAS] and Dysphagia Outcome and Severity Scale [DOSS]), and Hoehn and Yahr scale (HY scale).The PWT was smaller and the PWR greater in the PRD than in the control group (p < 0.05). The dysphagia scales (PAS and DOSS) were correlated with the radiological data (PWT and PWS) and the HY scale (p < 0.05). The HY scale score also correlated with the PWT (p < 0.05). The optimal cutoff points of the PWT and PWR for predicting aspiration were 4.05 and 16.05mm in the PRD group, respectively.Using the PWT, PWR and PWS, muscle atrophy and contractile strength of the pharynx can be estimated. The combination of the PWT and PWR can be a simple indicator for predicting swallowing disorders at the bedside.

Are all primary retinal detachments the same? Anatomic and functional differences between phakic and pseudophakic patients

BackgroundGiven differences in the pathogenic mechanisms underlying primary retinal detachment (RD) as a function of the status of the lens, the objective was to explore differences between pseudophakic and phakic patients with primary RD.MethodsA retrospective study including 821 patients who underwent surgery for RD [491 cases of phakic and 330 of pseudophakic RD (pRD and psRD, respectively)] in our hospital between 2012 and 2020.ResultsThe mean age was 58.24 ± 12.76 years in the pRD group and 66.87 ± 11.18 years in the psRD group (p = 0.001). There were more men in both groups (70% and 64.23% of pseudophakic and phakic patients, respectively; p = 0.07). The most common location for the RD was superior in both groups (43.94% and 51.93% of pseudophakic and phakic patients, respectively), rates of inferior and total RD were somewhat higher in the psRD group (31.82% and 13.33% in pseudophakic vs 25.25% and 11.0% in phakic patients, p = 0.001). In pseudophakic and phakic patients respectively, macular involvement in 69.09% and 62.73% of cases (p = 0.067). Proliferative vitreoretinopathy was significantly more common in the psRD group (7.88% vs 3.6% in phakic patients, p = 0.01).The rate of final anatomic reattachment differed markedly between groups, with a higher rate in phakic (94.03%) than pseudophakic (87.27%) patients (p = 0.001).ConclusionsThe specific pathogenic mechanism involved in psRD seems to be responsible for worse evolution characteristics which are associated with poorer final anatomic and functional outcomes in pseudophakic patients.

The effects of remifentanil-propofol combined with dexmedetomidine on cognitive dysfunction in elderly patients after ureteroscopic holmium laser lithotripsy: a double-blind randomized controlled trial

BackgroundA clinical study indicated that infusion of dexmedetomidine without a loading dose administered intraoperatively provided a smooth and hemodynamically stable emergence and improved the quality of recovery with fewer postoperative side effects and reduced analgesic requirements. The objective was to determine whether administering remifentanil-propofol combined with dexmedetomidine during general anesthesia would decrease the incidence and severity of postoperative emergence agitation, anxiety, and depression without affecting cognitive dysfunction in elderly patients.MethodsA total of 120 elderly patients scheduled for ureteroscopic holmium laser lithotripsy were randomly allocated to the PR group and administered normal saline, and the PRD group was administered dexmedetomidine 0.4 μg kg−1 h−1 intravenously after the induction of anesthesia and stopped 30 min before the end of surgery. The primary outcome was the Mini-Mental State Examination score. The secondary outcomes were the Richmond Agitation Sedation, the State-Trait Anxiety Inventory, and the Zung Self-Rating Depression Scale scores; the memory span for Arabic numerals; the duration of surgery; and the time to spontaneous respiration, recovery, and extubation.ResultsThe MMSE scores were lower at T1–2 in the two groups (P < 0.001). The dosage of propofol and remifentanil decreased more significantly in the PRD group than in the PR group (P < 0.001). Both the RASS scores and the incidence of emergence agitation (EA) in the PRD group were significantly lower than those in the PR group at t1–3 (P < 0.001). Compared to the PR group, the ZSDS scores and STAI scores at T1–2 were lower in the PRD group (P < 0.005). The number of the Arabic numbers that were accurately recalled from memory was lower at T2 in the PR group than in the PRD group (P < 0.001).ConclusionDexmedetomidine administration has no influence on postoperative cognitive dysfunction but could reduce both the dosage of remifentanil and propofol needed during ureteroscopic holmium laser lithotripsy and the incidence and severity of postoperative emergence agitation, anxiety, and depression in elderly patients.Trial registrationChinese Clinical Trial Registry ChiCTR1900021254. Registered on 3 February 2019

Adequacy of Anesthesia and Pupillometry for Endoscopic Sinus Surgery.

Inadequate intraoperative analgesia causes the deterioration of the condition of the surgical field (CSF) as a result of hemodynamic instability. Analgesia monitors are used to guide remifentanil) infusion to optimize intraoperative analgesia. The main aim of the current randomized controlled trial was to investigate the potential advantages of intraoperative analgesia monitoring using surgical Pleth index (SPI)- or pupillometry (PRD)-guided remifentanil administration for managing the volume of total intraoperative blood loss (TEIBL), CSF, and length of operation (LOP) in comparison with the standard practice in patients undergoing endoscopic sinus surgery (ESS). The 89 patients in our study were grouped as follows: 30 patients were assigned to the general analgesia (GA) group, 31 patients were assigned to the SPI group, and 28 patients were assigned to the PRD group. The speed of remifentanil infusion was accelerated by 50% when SPI, PRD, or BSS were increased by >15 points, >5%, or >2, respectively, in adjacent groups until their normalization. The SPI group showed significantly lower TEIBL in comparison to the GA group (165.2 ± 100.2 vs. 283.3 ± 193.5 mL; p < 0.05) and a higher mean arterial pressure (MAP; 73.9 ± 8 vs. 69.2 ± 6.8 mmHg; p < 0.05). In the PRD group, a shorter LOP compared with the GA group was observed (63.1 ± 26.7 min vs. 82.6 ± 33.1 min; p < 0.05). It was noted that the PRD group had a lower total remifentanil consumption than the SPI group (1.3 ± 1.4 vs. 1.8 ± 0.9 mg; p < 0.05). In ASA I-III patients undergoing ESS, intraoperative monitoring based on state entropy and SPI values can optimize the CSF and reduce TEIBL, whereas monitoring based on state entropy and PRD measurements can optimize the cost effectiveness of anesthetic drugs and the use of the operation room.

Thoracic Paravertebral Nerve Block with Ropivacaine and Adjuvant Dexmedetomidine Produced Longer Analgesia in Patients Undergoing Video-Assisted Thoracoscopic Lobectomy: A Randomized Trial.

Purpose This study evaluated the postoperative analgesic effect of ultrasound-guided single-point thoracic paravertebral nerve block (TPVB) combined with dexmedetomidine (DEX) in patients undergoing video-assisted thoracoscopic lobectomy. Methods Sixty adult patients of the American Society of Anesthesiologists (ASA) I–III were randomly assigned into three groups (n = 20 each). G group: patients received routine general anesthesia; PR group: patients received 0.5% ropivacaine; and PRD group: patients received 0.5% ropivacaine with 1 μg/kg DEX. TPVB was performed in the T5 space before surgery, and then, general anesthesia induction and video-assisted thoracoscopic lobectomy were performed. Analgesics were administered through the patient-controlled analgesia (PCA) device intravenously. The background infusion of each PCA device was set to administer 0.02 μg/kg/h sufentanil, with a lockout time of 15 min, and a total allowable volume is 100 ml. Results Compared to PR and G groups, the total sufentanil consumption after operation, the times of analgesic pump pressing, the pain score, and the incidence of postoperative nausea or vomiting in the PRD group were significantly reduced (p < 0.05). Also, the duration of first time of usage of the patient-controlled analgesia (PCA) was longer. The heart rate (HR) and mean arterial pressure (MAP) during operation were lower in the PRD group as compared with the other two groups in most of the time. However, hypotension and arrhythmia occurred in three groups with no statistically significant difference. Conclusions A small volume of TPVB with ropivacaine and DEX by single injection produced longer analgesia in patients undergoing video-assisted thoracoscopic lobectomy, reduced postoperative opioids consumption, and the incidence of side effects.

Effect of dexmedetomidine on evoked-potential monitoring in patients undergoing brain stem and supratentorial cranial surgery.

Dexmedetomidine is used as adjuvant in total intravenous anaesthesia (TIVA), but there have been few studies concerning its effect on intraoperative neurophysiological monitoring (IONM) during cranial surgery. Our aim was to study the effect of dexmedetomidine on IONM in patients undergoing brain stem and supratentorial cranial surgery. Two prospective, randomized, double-blind substudies were conducted. In substudy 1, during TIVA with an infusion of propofol and remifentanil, 10 patients received saline solution (SS) (PR group) and another 10 (PRD group) received dexmedetomidine (0.5mcg/kg/h). Total dosage of propofol and remifentanil, intensity, latency and amplitude of motor-evoked potentials following transcranial electrical stimulation (tcMEPs) as well as somatosensory-evoked potentials (SSEP) were recorded at baseline, 15, 30, 45minutes, and at the end of surgery. In order to identify differences in the same patient after dexmedetomidine administration, we designed substudy 2 with 20 new patients randomized to two groups. After 30minutes with TIVA, 10 patients received dexmedetomidine (0.5mcg/kg/h) and 10 patients SS. The same variables were recorded. In substudy 1, propofol requirements were significantly lower (P=.004) and tcMEP intensity at the end of surgery was significantly higher in PRD group, but no statistically significant differences were observed for remifentanil requirements, SSEP and tcMEP latency or amplitude. In substudy 2, no differences in any of the variables were identified. The administration of dexmedetomidine at a dosage of 0.5mg/kg/h may reduce propofol requirements and adversely affect some neuromonitoring variables. However, it can be an alternative on IONM during cranial surgeries. REDEX EudraCT: 2014-000962-23.

Mouse Modeling of Small for Gestational Age with Obese Metabolic Phenotypes in Adult Stage

Background Small for gestational age (SGA) in human is defined as the newborns with birth weight below the 10th percentile, whose prevalence continues to increase due to advanced maternal age. SGA children have a higher risk of developing metabolic disorders including obesity and diabetes later in adult life. Reliable SGA mouse models are needed to study their pathophysiology. Previous reports have suggested various SGA mouse models through dietary restriction of pregnant dams, but their low reproducibility is no small limitation. Therefore, we attempted to improve SGA mouse models with high reproducibility by modifying the dietary restriction. We aimed to model SGA with a smaller height and weight at birth followed by phenotypes of metabolic disorders including glucose tolerance and fatness in adult stages. Methods The 8-week-old C57BL6/J mice were given a normal Chow diet and protein-restricted diet (PRD, 6% protein by kcal) during pregnancy or pregnancy plus lactation. In the PRD group, frequent cannibalism and neglect occurred, so the foster mother system was introduced to minimize the mortality rate. Body weight and nasal-anal length were measured to define SGA. Intraperitoneal glucose tolerance test and body composition (fatness) were measured as metabolic variables. Results By PRD during pregnancy (~3 week), significantly smaller height (30.1±0.2 vs 22.4±0.4 mm, p<0.0001) and weight [1.42±0.02 vs 0.83±0.02 g, p<0.0001 (n=19~37)] and weight at birth were achieved. However, the survival rate in PRD group after postnatal day (PND) 1 was very low (38.1%) due to cannibalism and neglect from dams. We supposed that a golden time exists to rescue newborns to the foster mother to increase the survival, and the survival rate of PND 1 was increased up to 70% by rigorous care before 9am on e19.5 day (plus 1pm and 5pm if needed): fast delivery to the foster mother immediately after birth was most important for the survival. Most PRD group caught up with the height and weight of control group in the first week (PND 7), and there was no difference in body fat mass or glucose tolerance tests in 32 weeks of age. To induce metabolic phenotypes and failure of catch-up growth, PRD period was extended from pregnancy to even lactation period (~6 week). With this extended protocol, the differences in height were maintained until 12 weeks of age and there was a significant difference in body mass index (BMI) [male 0.30±0.01 vs 0.36±0.01 g/cm2, p<0.0001 (n=6~10); female 0.25±0.01 vs 0.31±0.01 g/cm2, p<0.0001 (n=7 for each)] in 12 weeks of age. Conclusion Sufficient duration of protein restriction (pregnancy ~ lactation) yields better phenotype of SGA with high adult BMI with improved survival rate of SGA pups by the rigorous care. Various metabolic parameters are regularly being measured further to confirm metabolic derangement, and if appropriate, this method can be effectively used in future studies.

Impact of the Timing of Rocuronium Injection after Propofol Administration on Temporal Summation of Pain in Gynecologic Laparoscopic Surgery: A Prospective and Controlled Study

Purpose Temporal summation of pain, which is defined as the perception of greater pain evoked by repetitive painful stimuli, varies among individuals. This study aimed at determining the impact of the timing of rocuronium after induction with propofol on the temporal summation of pain. Methods One hundred patients aged 19–60 years underwent gynecologic laparoscopic surgery. Patients were randomly assigned to one of the two groups: group PRi received immediate injections of rocuronium after propofol administration and group PRd received rocuronium injections when the bispectral index score (BIS) decreased to <60 after propofol administration. The grade of rocuronium-induced withdrawal movement (RIWM) according to the timing of propofol injection, the incidence and severity of propofol injection pain (PIP), rescue analgesics, visual analog scale (VAS) score after surgery for postoperative pain, patient-controlled analgesia (PCA) opioid consumption, association between PIP and the grade of RIWM, and associations between PIP, the grade of RIWM, and postoperative pain outcomes were measured. Results The differences between the incidence and severity of PIP in the two groups were not significant. The grade of the RIWM in the PRd group was significantly reduced compared with the PRi group. Rescue analgesics, severity for postoperative pain, and PCA opioid consumption were not significant. Correlations between the incidence and severity of PIP and the grade of RIWM were weakly negative. Correlations between the grade of RIWM and pain outcomes were moderately positive, but correlations between the severity for PIP and the postoperative pain outcomes were negligible. Conclusion The timing of rocuronium administration after propofol injection played a role in reducing RIWM. The grade of RIWM was significantly related to pain outcomes compared with the severity of PIP. Therefore, delayed rocuronium injection after induction with propofol reduced temporal summation of pain.

Inhalation of low-dose desflurane prevents the hemodynamic instability caused by target-controlled infusion of remifentanil and propofol during laparoscopic gynecological surgery: A randomized controlled trial.

The objective of the present study was to determine whether the addition of inhaled desflurane is superior to remifentanil-propofol total intravenous anesthesia (TIVA) alone in patients undergoing laparoscopic gynecological surgery. A total of 60 patients who were scheduled to undergo laparoscopic gynecological surgery were prospectively enrolled and randomly allocated to receive either propofol-remifentanil (PR group; n=30) or combined propofol-remifentanil and low-dose desflurane (PRD group; n=30) for the maintenance of anesthesia. Hemodynamics [mean arterial pressure (MAP); heart rate (HR)], recovery parameters and complications were recorded. The results of the present study indicated that the addition of desflurane significantly reduced the amount of propofol and remifentanil that was administered in the PRD group, compared with that in the PR group. MAP and HR were significantly higher at T3 (5 min post-pneumoperitoneum), but significantly lower at T4 (removal of pneumoperitoneum needle) and T5 (post-operation immediately) in the PR group, compared with the PRD group. Moreover, MAP and HR were significantly altered at multiple time points within the PR group; however, they were relatively stable in the PRD group. There were no significant differences in the recovery parameters and complications between the two groups. In conclusion, combining low-dose desflurane with PR may represent an efficient anesthesia regimen to prevent the hemodynamic instability of TIVA in patients undergoing laparoscopic gynecological surgery.

OS after Allogeneic HSCT for AML Stratified at the Time of Transplant By CIBMTR and IWG Response Criteria

Introduction Disease Status of AML patients at the time of HSCT is an important factor in predicting their survival. We hypothesize that MLFS (as per IWG criteria) identifies a group of patients that have better outcome than PIF (as per CIBMTR criteria). Objectives • To identify group of patients previously categorized as PIF by CIBMTR pretransplant that may have favorable outcome with HSCT. • To assess the outcome of patients with primary refractory disease by IWG criteria with HSCT. Methods We retrospectively analyzed 78 patients with AML who underwent allogeneic HSCT between June 2008 and December 2017 at our institution. We assessed the disease status at time of transplant as per CIBMTR criteria as complete remission (CR) defined as 1000, platelets >100,000 with transfusion independence, and primary induction failure (PIF) defined as not achieved CR or CRi. We also assessed the patients at time of transplant as per IWG criteria as CR (similar to CR as per CIBMTR but does not require normal maturation), morphologic leukemic-free state (MLFS) defined as 5%. We compared the OS at one year for the above groups. The patients received myeloablative conditioning with FBT or reduced intensity conditioning with FB2. Results Per IWG criteria, The OS at 1 year was 62 % in the CR group (n=29), 65% in the MLFS group (n=17) and 22% in the PRD group (n= 32). Our analysis revealed an overall statistically significant difference between CR v PRD, p=0.0009 and MLFS v PRD, p=0.0006. When we used the CIBMTR criteria, both MLFS and PRD were reclassified into the PIF group with OS of 34% (n=49). Conclusion Disease status prior to transplant is a predictor of outcome after allogeneic HSCT. Our analysis shows better survival for patients who achieved MLFS prior to transplant according to IWG criteria as compared to patients who were classified as primary induction failure by CIBMTR criteria. We intend to prospectively use the IWG criteria pre-transplant in our patients to help predict their survival at one year.

PR deviation as a risk marker for cardiac events in patients with Takotsubo syndrome

PR segment deviation (PRD: defined as PR elevation in aVR and PR depression in lead II/III) on electrocardiography is frequently observed in patients with acute pericarditis; however, there have been few studies that explore the occurrence of PRD in patients with Takotsubo syndrome (TTS). The clinical significance of PRD in TTS is not clearly elucidated. A total of 52 consecutive patients with TTS in sinus rhythm (73.9 ± 13.8 years, nine males) were enrolled in the study. The major cardiac events were defined as sustained ventricular tachycardia or ventricular fibrillation, Killip class 4 heart failure, and cardiac death within 30 days. PRD in the hyperacute phase (within 48 h from the onset of TTS) was observed in 15 patients (29%), and all PRDs disappeared or diminished at 1 week later. The PRD (+) group had a higher value of C-reactive protein level (median: 1.80mg/dL [0.31-3.26] vs 0.20mg/dL [0.06-0.81], P=0.013) and creatine kinase-muscle/brain isoenzyme (median: 60IU/L [28-75] vs 17IU/L [13-26], P<0.001) and a lower level of left ventricular ejection fraction (42.7 ± 7.2% vs 48.8 ± 9.4%, P=0.041) than the PRD (-) group. Multivariate analysis showed that PRD was a significant and independent predictor for major cardiac events (odds ratio=21.0, 95% confidence interval=1.18-273). TTS patients with PRD in the hyperacute phase showed a high incidence of major cardiac events. Therefore, PRD may help to identify TTS patients at high risk for cardiac event.

Blood pathway analyses reveal differences between prediabetic subjects with or without dyslipidaemia. The Cardiovascular Risk in Young Finns Study.

Prediabetes often occurs together with dyslipidaemia, which is paradoxically treated with statins predisposing to type 2 diabetes mellitus. We examined peripheral blood pathway profiles in prediabetic subjects with (PRD ) and without dyslipidaemia (PR0 ) and compared these to nonprediabetic controls without dyslipidaemia (C0 ). The participants were from the Cardiovascular Risk in Young Finns Study, including 1240 subjects aged 34 to 49years. Genome-wide expression data of peripheral blood and gene set enrichment analysis were used to investigate the differentially expressed genes and enriched pathways between different subtypes of prediabetes. Pathways for cholesterol synthesis, interleukin-12-mediated signalling events, and downstream signalling in naïve CD8+ T-cells were upregulated in the PR0 group in comparison with controls (C0 ). The upregulation of these pathways was independent of waist circumference, blood pressure, smoking status, and insulin. Adjustment for CRP left the CD8+ T-cell signalling and interleukin-12-mediated signalling event pathway upregulated. The cholesterol synthesis pathway was also upregulated when all prediabetic subjects (PR0 and PRD ) were compared with the nonprediabetic control group. No pathways were upregulated or downregulated when the PRD group was compared with the C0 group. Five genes in the PR0 group and 1 in the PRD group were significantly differentially expressed in comparison with the C0 group. Blood cell gene expression profiles differ significantly between prediabetic subjects with and without dyslipidaemia. Whether this classification may be used in detection of prediabetic individuals at a high risk of cardiovascular complications remains to be examined.

Pentoxifylline During Steroid Window At Induction To Remission Increases Apoptosis In Childhood Acute Lymphoblastic Leukemia

IntroductionAcute lymphoblastic leukemia (ALL) is the most common cancer diagnostic in children, and it represents the second death cause in this population. Despite advances in the treatment of childhood ALL, there are small portion of patients whom still succumb to this disease.A reduced apoptosis in cells plays an important role in carcinogenesis. This phenomenon is an important component in the cytotoxicity induced by anticancer drugs. A currently challenge is the chemotherapy resistance of tumor cells, inhibiting the apoptosis induced by chemotherapy.Pentoxifylline, (PTX) has been studied for its role on increase of apoptosis on cancer cells by different pathways. Our group has reported its efficacy in vitro and ex vivo in increasing apoptosis induced by chemotherapy drugs such as adriamycin and cisplatin in fresh leukemic human cells, lymphoma murine models and cervical cancer cells. We conducted a phase 1 controlled randomized trial to evaluate the efficacy of adding PTX to the steroid window during the remission induction phase in new diagnosed children with ALL. MethodsWe included all children from both sexes from 9 months to 17 years old during October 2011 to December 2012. Patients were divided into 3 groups, the first one as a non-malignant control group (NL group) included children with a non-hematology disease in which bone marrow aspiration (BMA) was mandatory in order to reach the diagnosis. The second one, the ALL control group whom received prednisone (PRD group) for the steroid window at 40mg/m2/day PO from day -7 to day 0; and then the third one (PTX group), the study group which included children receiving the steroid phase with PRD as early described, plus PTX at 10mg/kg/day IV divided in 3 doses, at the same days as recommended in our treatment protocol (Total Therapy XV). For all 3 groups a BMA was performed at diagnosis, for PRD group as well as PTX group, a second BMA was also collected at day 0. Apoptosis was evaluated by means of Annexin V Apoptosis Detection Kit FITC/PI (eBioscience¨, San Diego, CA, USA) in 1×106 bone marrow mononuclear cells. We measured minimal residual disease (MRD) by flow cytometry at day 14 to demonstrate complete remission in leukemic patients. Statically analysis was performed by U Man Whitney. ResultsWe enrolled 32 patients: 10 in NL group; 11 in PRD group; and 11 in PTX group. The median age of all groups was 6 years (range 9 months-17 years). In PRD group, patient 1 abandoned treatment after administration of day 0, nevertheless the second BMA sample was collected. Patient number 7 died at day 4 due to complications from tumor lysis syndrome. Consequently, in these patients we were not able to measure MRD and BM aspiration at day 14. Except one patient in PRD group, all achieved complete remission at day 14. We did not find any significant difference between NL group and PRD and PTX groups before intervention (U=32 p=0.7; U=28.5 p=0.48 respectively). There was no significant difference between treatment groups before intervention (U= 37 p=0.79). However, after treatment we found an important difference between PRD and PTX groups, we observed an increase in apoptosis in PTX group in comparison with PRD group (U=17.5 p=0.04). There were no adverse effects during treatment. ConclusionsThe present study is the first one that shows the efficacy of PTX in increasing apoptosis induced by PRD in new ALL diagnosed children, whom have not received any treatment yet. This might be helpful, not only in patients with relapse, but to increase the overall cure rate in ALL. Further studies are needed to prove this hypothesis. With this objective, our study group is already planning a second trial were PTX will be given during all remission induction phase. Experimental reports strongly suggest that PTX induces inhibition of the transcription factor NF-ĸB, by inhibiting survival gens and facilitating apoptosis. To prove it, we are currently processing these patients' samples to know their genetic expression. Disclosures:No relevant conflicts of interest to declare.

Effects of PRD supermicropowder on mitochondrial pathway of retinal neuron apoptosis in diabetic rat

Background Research demonstrated that mitochondrial pathway plays a key role in cell apoptosis.Purendan supermicropowder(PRD),a traditional Chinese medicine,may be a potentially effective therapy for neuron apoptosis in diabetic retina.Objective This study was carried out to investigate the effects of PRD on aldose reductase(AR)activity,neuron apoptosis and mitochondrial pathway in retina of diabetic rat.Methods Thirty-six clean male Wistar rats were randomly divided into normal control group,diabetes model group,PRD treatment group randomly and 12 rats for each group.The diabetes models were established by intraperitoneal injection of 25 mg/(kg · d)streptozotocin(STZ)for 3 consecutive days,and blood glucose ≥ 16.7 mmol/L was taken as the standard.PRD solution of 1.8 g/(kg · d)was lavaged in 12 models for 3 months.The eyeballs were enucleated for the preparation of retinal tissue homogenate and slice.AR activity in the retina was detected by ultraviolet spectrophotometry,and neuron apoptosis in retina was assayed by TUNEL staining.Western blot was used to assess the expressions of bcl-2,bax,cyt-c and caspase-3 protein in the retina.The use of animals followed the Regulations for the Administration of Affair Concerning Experimental Animals by State Science and Technology Committee(Version 1988).Results Statistically significant differences were found in AR activity and AI among the normal control group,diabetic group and PRD groups(F=90.115,165.540,P＜0.01),and those of diabetic group were evidently higher than the normal control group and PRD group(P＜0.01,P＜0.01).The positive TUNEL cells mainly located in inner nuclear layer and retinal ganglion cell layer.The expressions of bax,cyt-c,caspase-3,bcl-2 and bcl-2/bax in retina were obviously different among these three groups(F =51.332,41.262,25.888,38.564,47.870,P＜0.01),and the expression of bax,cyt-c and caspase-3 protein in diabetic group evidently elevated in comparison with the normal control group and PRD group(t ＝ 10.32,11.04,6.91,P ＜ 0.01)and the expressions of bcl-2 protein and bcl-2/bax value were significantly lower in diabetic rats than in the normal control rats(t =18.05,12.23,P＜0.01).AR activity by AI of retina,the expressions of bax,cyt-c and caspase-3 proteins in retina were obviously lower in PRD group than in diabetes model rats(P ＜ 0.01),and the expression of bcl-2 protein and bcl-2/bax value were significantly higher in PRD group than in diabetes group(P＜0.01).Conclusions PRD can protect retina against the damage caused by high glucose by suppressing AR activity by downregulating the expressions of bax,cyt-c,caspase-3 proteins,increasing the expressions of bcl-2 protein in retina of diabetic rats and further inhibiting the mitochondrial pathway and reducing cell apoptosis in retina of diabetic rats. Key words: Traditional Chinese medicion/purendan supermicropowder; Retina/diabetic retinopathy; cell apoptosis; Mitochondria

Beneficial Effect of 3% Milled-Rice on Blood Glucose Level and Serum Lipid Concentrations in Spontaneously Non-Insulin-Dependent Diabetic Rats

Three percent milled-rice was evaluated for beneficial effect on blood glucose level and serum lipid concentrations in an experiment with Otsuka Long-Evans Tokushima Fatty (OLETF) rats, used as model animals for spontaneously non-insulin-dependent diabetes mellitus. The same experiment was carried out using Long-Evans Tokushima Otsuka (LETO) rats, the control of the OLETF rats. The results obtained from the rats given a diet containing 3% milled-rice (3% MRD) ad libitum were compared with those from rats given polished rice. During the feeding period of 140 d, body weight of the OLETF rats receiving the 3% MRD was significantly lower than that of the rats fed on the diet containing polished rice (PRD) from the 48th to the 124th days. The body weight of the LETO rats during the both periods of 90 to 104 d and 114 to 140 d was lower than that of the rats receiving the PRD. Though food intakes of the rats receiving 3% MRD were significantly lower in the OLETF and LETO rats during the two periods of days 48 to 124 and days 1 to 140 than in the rats of the PRD group, the feed efficiency of the OLETF or LETO rats did not show significant difference between the 3% MRD and the PRD groups during the same experimental periods. The excretion rate of feces of the OLETF rats receiving the 3% MRD was significantly higher than that of the rats receiving the PRD, both on the 126th day and during the period of days 129 to 131. The fasting blood glucose levels were significantly lower in the OLETF rats receiving the 3% MRD than the rats receiving the PRD on the 84th day, the 105th day and the 127th day, and also lower in the LETO rats receiving the 3% MRD on the 84th day and the 105th day. The incremental areas under the curve of blood glucose concentrations (IAUC-Glc) for 120 min after oral administration of glucose on the 133rd day was lower in the OLETF rats receiving 3% MRD than that of the PRD. The ratio of IAUC-Glc in the 3% MRD to PRD group, after ingestion of diets for 1 h after fasting for 18 h on the 138th day, was 0.89 in the OLETF rats, and 0.74 in the LETO rats. Compared with the PRD group, the amounts of cholesterol and bile acid in the feces of the OLETF rats in the 3% MRD group were significantly higher on days 129-131, and the cholesterol excretion was significantly higher on the 84th day in the OLETF rats in the 3% MRD group. The liver weight, the level of total lipids in liver, and the concentrations of triglyceride and total cholesterol in liver and serum of the OLETF rats on the 140th day were significantly lower in the 3% MRD than those of the PRD group. These results indicate that 3% milled-rice has beneficial effects on blood glucose level and serum lipid concentrations in spontaneously non-insulin-dependent diabetic rats.

The Decision to Use Topical Anesthetic for Intravenous Insertion in the Pediatric Emergency Department

Topical anesthetic creams to reduce the pain of intravenous (IV) placement may be more effectively used in the emergency setting if they are applied by nurses in the triage area of the emergency department or soon after the patient is placed into a room. This strategy requires accurate prediction of which patients will require IV placement. The objective of this study was to compare triage nurse judgment regarding IV placement in pediatric patients with a triage prediction rule using chief complaint, referral status, and high-risk medical history. A secondary objective was to evaluate whether the presence of the anesthetic cream placed in triage influenced the subsequent decision to place an IV and thus invalidate the prediction strategy. Triage nurses were randomly assigned to a prediction score group (PRD), classifying patients as "IV likely" if the prediction score was > or =2, or an "own judgment" (RN JDGMT) group, classifying any patient that he or she considered to have a > or =50% risk of receiving an IV. The rate of actual IV placement in the emergency department treatment rooms was compared between the triage prediction strategies. To assess the influence of the presence of lidocaine 2.5% and prilocaine 2.5% (EMLA cream) on the judgment to place an IV, only 75% of the "IV likely" patients had EMLA applied in triage; the IV placement rate was compared between "IV likely" patients who did or did not have EMLA applied. The authors enrolled 3,790 of 5,025 (75.4%) of eligible patients. The RN JDGMT group predicted 165 of 250 (66%; 95% confidence interval = 59% to 72%) of IVs placed, compared with 127 of 305 (41%; 95% CI = 36% to 47%) in the PRD group (p < 0.0001). Positive predictive values were 59% and 53% for the RN JDGMNT and PRD groups, respectively. There was no difference in IV placement rates in the "IV likely" patients who did and did not have EMLA applied. Triage nurse judgment to predict eventual IV placement had greater sensitivity and similar predictive value compared with a prediction model based on medical history and chief complaint. The triage placement of topical anesthetic in pediatric patients did not change the eventual rate of IV placement.

Repeated low level formaldehyde exposure produces enhanced fear conditioning to odor in male, but not female, rats

Multiple chemical sensitivity (MCS) is an ill-defined disorder in humans attributed to exposure to volatile organic compounds. This study draws on apparent parallels between individuals with posttraumatic stress disorder (PTSD) and panic disorder and a subset of those reporting MCS, using a conditioned fear task in rats. Male and female Sprague–Dawley rats were given repeated exposure to 2 ppm formaldehyde (Form) (1 h/day×5 days/week×4 week) or air, and after 2–3 weeks, rats were trained on the conditioned fear task. One half of Air and Form rats were given odor (orange oil, the conditioned stimulus, CS) paired with footshock (PRD) and the other half was given the same stimuli in an unpaired manner (UNP). After 24 h, rats were placed into the same context without the CS or footshock. Male and female PRD groups demonstrated contextual freezing 5–15% of the time, while the UNP groups showed freezing 30–50% of the time, with no effect of Air or Form pretreatment. For the next 5 days, rats were placed into a novel context and tested for freezing in the absence or presence of the CS. In male rats, Form pretreatment produced a significantly greater freezing response in both UNP and PRD groups in the presence of the CS, with no differences in freezing in the absence of the CS. In female rats, no significant differences between Form pretreated rats and Air controls were observed in either the PRD or UNP groups. The increase in conditioned fear responding to the CS after Form exposure in males suggests that repeated low-level Form may act as a stressor to produce sensitized responding within olfactory/limbic pathways, and may help explain the panic-like responses observed in a subset of individuals reporting MCS. Furthermore, the male/female differences suggest a gonadal hormonal contribution to this behavior.

Hypersexual Desire in Males: Are Males With Paraphilias Different From Males With Paraphilia-Related Disorders?

The assessment of current sexual behavior (fantasies, urges, and activities) and sexual preoccupation (measured in min/day) associated with both conventional (i.e., adult relationship-associated) or unconventional (paraphilia and paraphilia-related) sexual behavior were ascertained from a sample of 120 consecutively evaluated males with paraphilias (PA; n = 88, including sex offender paraphiliacs; n = 60) and paraphilia-related disorders (PRD; n = 32). In addition, an assessment of hypersexual desire, defined as the highest sustained period (at least 6 months minimum duration) of persistently enacted sexual behavior (total sexual outlet/week [TSO] after age 15) was assessed. In almost all measures, the PA and PRD groups were not statistically significantly different. The average PA or PRD reported a mean hypersexual TSO of 11.7 +/- 7.3, a mean age of 21.6 +/- 7.1 years at onset of peak hypersexual behavior, and a mean duration of 6.2 +/- 7.6 years of hypersexual TSO. When the sample was stratified into three subgroups on the basis of the lifetime number of PAs + PRDs as a proxy measure of the severity of sexual impulsivity, the "high" group, with at least 5 lifetime PAs and PRDs, consisted of all paraphilic males, predominantly sex offenders, who self-reported the highest hypersexual desire (14.3 +/- 7.9), the highest current TSO/week (9.9 +/- 8.1), the most current sexual preoccupation (2-4 hr/day), and the highest likelihood of incarceration secondary to paraphilic sex-offending behavior. Although hypersexual desire, a quantitative measure of enacted sexual behaviours, may be a meaningful construct for clinically derived samples, the incidence and prevalence of hypersexual desire in community samples of males with paraphilias and paraphilia-related disorders is unknown.