Efficacy and adverse effects of insulin versus plasmapheresis in patients with hypertriglyceridemia-3-induced acute pancreatitis: a systematic review and meta-analysis.

Background: Hypertriglyceridemia is a common cause of acute pancreatitis (AP). This literature review compared the effectiveness and adverse events of insulin therapy, with or without heparin, and plasmapheresis, in reducing triglyceride levels in patients with hypertriglyceridemia-induced AP. Methods: Systematic reviews, meta-analyses, evidence syntheses, editorials, commentaries, protocols, abstracts, theses and preprints were excluded. Review Manager was used to conduct the meta-analysis. The literature search yielded 2765 articles, but only 5 were included in the systematic review and meta-analysis and the total number of participants in the review was 269. Results: From this study's analysis, insulin ± heparin was more successful in reducing triglyceride levels than plasmapheresis (standardized mean difference -0.37, 95% confidence interval [CI] 0.99 to 0.25; P=0.25). Insulin ± heparin therapy had a lower mortality rate than plasmapheresis (risk ratio [RR] 0.70, 95%CI 0.25-1.95). Hypotension, hypoglycemia, and acute renal failure were less common in the plasmapheresis therapy group than in insulin ± heparin therapy (RR 1.13, 95%CI 0.46-2.81, RR 3.90, 95%CI 0.45-33.78, and RR 0.48, 95%CI 0.02-13.98 for hypotension, hypoglycemia, and acute renal failure, respectively). Conclusions: This study found no significant difference in mortality between insulin ± heparin therapy and plasmapheresis used for the reduction in triglyceride levels. It is notable that no substantial differences were observed in the most common side-effects encountered during these therapies, thus indicating non-inferiority.

Lack of improvement in anorectal manometry parameters after implementation of a pelvic floor/anal sphincter biofeedback in persons with motor-incomplete spinal cord injury.

BACKGROUND: Effect of biofeedback on improving anorectal manometric parameters in incomplete spinal cord injury is unknown. A short-term biofeedback program investigated any effect on anorectal manometric parameters without correlation to bowel symptoms. METHODS: This prospective uncontrolled interventional study comprised three study subject groups, Group 1: sensory/motor-complete American Spinal Injury Association Impairment Scale (AIS) A SCI (n = 13); Group 2 (biofeedback group): sensory incomplete AIS B SCI (n = 17) (n = 3), and motor-incomplete AIS C SCI (n = 8), and AIS D SCI (n = 6); and Group 3: able-bodied (AB) controls (n = 12). High-resolution anorectal manometry (HR-ARM) was applied to establish baseline characteristics in all subjects for anorectal pressure, volume, length of pressure zones, and duration of sphincter squeeze pressure. SCI participants with motor-incomplete SCI were enrolled in pelvic floor/anal sphincter bowel biofeedback training (2 × 6-week training periods comprised of two training sessions per week for 30-45 min per session). HR-ARM was also performed after each of the 6-week periods of biofeedback training. RESULTS: Compared to motor-complete or motor-incomplete SCI participants, AB subjects had higher mean intra-rectal pressure, maximal sphincteric pressure, residual anal pressure, recto-anal pressure gradient, and duration of squeeze (p < 0.05 for each of the endpoints). No significant difference was evident at baseline between the motor-complete and motor-incomplete SCI groups. In motor-incomplete SCI subjects, the pelvic floor/anal sphincter biofeedback protocol failed to improve HR-ARM parameters. CONCLUSION: Biofeedback training program did not improve anal manometric parameters in subjects with motor-incomplete or sensory-incomplete SCI. Biofeedback did not change physiology, and its effects on symptoms are unknown. INFERENCES: Utility of biofeedback is limited in patients with incomplete spinal cord injury in terms of improving HR-ARM parameters.

Effects of Angiotensin Receptor-Neprilysin Inhibitors Versus Enalapril or Valsartan on Patients With Heart Failure: A Systematic Review and Meta-Analysis.

Recent studies have focused on treating heart failure, primarily mitigating symptoms and reducing the risk of mortality and other cardiovascular complications. A promising new treatment approach involves using LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI) comprising sacubitril and valsartan. This treatment is superior to the conventional drugs enalapril or valsartan in patients diagnosed with heart failure. A systematic search was conducted on PubMed, the Cochrane Library, and Elsevier's ScienceDirect databases to identify studies comparing sacubitril/valsartan with other drugs in heart failure patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The analyses were conducted using the random-effects model. The study's primary outcomes included all-cause mortality, death from cardiovascular causes, first hospitalization for heart failure, congestive heart failure, and changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical score. The pooled analysis showed that treatment with the sacubitril/valsartan combination was associated with a significantly decreased rate of first hospitalization for heart failure (RR: 0.86; 95% CI: 0.79, 0.98, p: 0.03; I2: 57%) and significantly increased KCCQ clinical score (WMD: 2.20; 95% CI: 0.33, 4.06, p: 0.02; I2: 100%). However, the two groups had no significant difference in all-cause mortality (RR: 0.90; 95% CI: 0.80, 1.01, p: 0.08; I2: 20%), death from cardiovascular causes (RR: 0.96; 95% CI: 0.87, 1.05, p: 0.34; I2: 0%), or congestive heart failure (RR: 0.97; 95% CI: 0.75, 1.25, p: 0.19; I2: 38%). The research findings suggest that sacubitril/valsartan (LCZ696) reduces hospitalizations due to heart failure and improves KCCQ clinical scores. This treatment also reduces the decline in renal function and side effects associated with enalapril or valsartan. Nonetheless, further high-quality randomized controlled trials with large sample sizes are needed to assess other impacts of this therapy on heart failure patients. Overall, the use of LCZ696 represents a promising new approach to the treatment of heart failure.

Ondansetron-induced QT prolongation among various age groups: a systematic review and meta-analysis.

BACKGROUND: Ondansetron is a selective 5-hydroxytryptamine type 3 serotonin-receptor antagonist with antiemetic properties used inadvertently in the emergency department for controlling nausea. However, ondansetron is linked with a number of adverse effects, including prolongation of the QT interval. Therefore, the purpose of this meta-analysis was to assess the occurrence of QT prolongation in pediatric, adult, and elderly patients receiving oral or intravenously administered ondansetron. METHODS: A thorough electronic search was conducted on PubMed (Medline) and Cochrane Library from the databases' inception to August 10, 2022. Only those studies were considered in which ondansetron was administered orally or intravenously to participants for the treatment of nausea and vomiting. The prevalence of QT prolongation in multiple predefined age groups was the outcome variable. Analyses were conducted using Review manager 5.4 (Cochrane collaboration, 2020). RESULTS: A total of 10 studies involving 687 ondansetron group participants were statistically analyzed. The administration of ondansetron was associated with a statistically significant prevalence of QT prolongation in all age groups. An age-wise subgroup analysis was conducted which revealed that the prevalence of QT prolongation among participants younger than 18 years was not statistically significant, whereas it was statistically significant among participants aged 18-50 years and among patients older than 50 years. CONCLUSIONS: The present meta-analysis provides further evidence that oral or intravenous administration of Ondansetron may lead to QT prolongation, particularly among patients older than 18 years of age.

Knowledge and Awareness About Diabetes Mellitus Among Urban and Rural Population Attending a Tertiary Care Hospital in Haryana.

BACKGROUND: Diabetes mellitus (DM) is one of the fastest-growing public health problems in the twenty-first century. The ignorance among people about their disease may be related to their low socioeconomic status and lack of quality education available to them about the disease. It is a serious condition leading to several complications if the individual does not follow up regularly for check-ups and blood sugar monitoring. Lifestyle modifications such as a healthy diet, regular exercise, reducing weight, stress management, and smoking cessation can play a critical role in managing diabetes and improving the health and well-being of diabetic patients. Thus, through this study, we want to assess and create awareness among diabetic patients. METHODOLOGY: It is a hospital-based cross-sectional study conducted at a tertiary care hospital on diagnosed cases of DM. The patients aged 18 years or above of either gender who had already been diagnosed with DM type 1 and type 2 were included, and patients with gestational DM were excluded from the study. Informed consent was taken from the patients, and all the required details were obtained using a well-structured questionnaire. After obtaining all the answers, the level of knowledge and awareness was analyzed, and the data was entered into an MS Excel sheet (Microsoft, Redmond, Washington) and analyzed by Statistical Package for the Social Sciences (SPSS) version 22.0 (IBM Corp., Armonk, NY). RESULTS: In our study, the maximum prevalence of diabetes was seen in males (55.5%) than females (44.5%), and the mean age of our study population was 53.3 ± 16.4 years. In our study, participants from rural areas made up the majority (59%) compared to those from urban areas (41%), and the majority of participants had a high school education. Among 211 diabetics, about 84%, 79%, and 41% of the patients knew about diabetes, symptoms of diabetes, and complication of diabetes. Only 18% of the patients were aware of the symptoms of hypoglycemia, and 38% of the patients possess their own glucometers and monitor their blood sugar levels on a regular basis. Merely 38% of the diabetics were aware of the various DM treatment choices. About 52% of patients had some awareness of insulin therapy. Out of 211 patients, about half skipped their antidiabetic prescriptions, and of those, 22% took a double dose the next day. A total of 121 patients (57%) combined the use of alternative and allopathic medications, and among these, 22% of patients had replaced the allopathic with alternative medicines. Almost 53% of patients had a positive family history of diabetes; 54% of patients believe that obesity is unrelated to diabetes, and 79% of diabetics are aware of the lifestyle changes that must be done for diabetes. Almost 67% of the patients believed that diabetes could be permanently treated, and 84% of patients believed that eating too much sugar caused their diabetes. CONCLUSION: In our study, a significant number of patients suffering from diabetes had less knowledge and awareness about it. The prevalence of myths about the onset of diabetes was noticeably higher among diabetic patients. It was observed that a greater number of patients were shifting to alternative medications instead of allopathic ones, and in the long run, it can lead to various complications. Therefore, there is an immediate need to promote awareness about diabetes among the general population.

Beyond Scrubs: Understanding the Root Causes of Violence Against Doctors.

Workplace violence (WPV) against doctors is a growing epidemic in India, with at least two-thirds of doctors facing some form of abuse during their careers. Verbal abuse is common, but doctors are also subjected to brutal attacks that endanger their lives. This review lists abusive incidents reported by the media since 2021. Despite increased respect for healthcare professionals during the COVID-19 pandemic, doctors in India are under significant stress due to inadequate medical infrastructure, mismanagement of young doctors, increasing mistrust between doctors and patients, a shortage of doctors, and overworked healthcare workers, leading to delays in attention and treatment. Additional factors contributing to the situation include the lack of proper insurance coverage, weak primary healthcare with overburdened tertiary care, the lack of an effective grievance redressal system, and the poor state of medical education. To combat this epidemic, collaborative efforts are needed between doctors, hospitals, the government, and society. Improving communication skills and treating patients with empathy are essential for healthcare workers. Meanwhile, hospitals should implement an efficient security system, a transparent billing system, and an active complaint system to prevent incidents. Unbiased reporting and adequate documentation are required to further investigate this occupational health hazard. The government should focus on building better medical facilities and passing a strict law against violence against doctors to ensure the safety of medical professionals. This review presents some solutions, along with the current legal coverage provided to healthcare professionals regarding WPV.

Leigh's disease, a fatal finding in the common world: A case report.

Leigh syndrome is a neurodegenerative mitochondrial disorder of childhood characterized by symmetrical spongiform lesions in the brain. The clinical presentation of Leigh's syndrome can vary significantly. However, in the majority of cases, it usually presents as a progressive neurological disease involving motor and cognitive development. It is common to see signs and symptoms of the midbrain and brainstem involvement. Limited data are present on the brain processes occurring in Leigh's syndrome which can be attributed to fatal respiratory failure. Raised lactate levels in the blood and/or cerebrospinal fluid are noted. Magnetic resonance imaging (MRI) findings such as necrotic, symmetrical lesions in the BG/brain stem are helpful in arriving at the diagnosis of Leigh's syndrome. It's of utmost importance to determine whether fatal respiratory failure can be predicted based on clinical characteristics and findings on MRI. In our report, we presented 3 cases from rural India, including a 2-year-old male child presenting with UMN lesion signs, a 3-month-old female infant with delayed developmental milestones with lab results suggestive of Leigh's disease, and a 12-year-old female child with epistaxis and generalized weakness. As discussed above, all 3 cases presented differently with a variety of signs and symptoms and would have gone undiagnosed without the use of brain imaging. The study concluded with the impression that while MRI is essential to the initial diagnosis of Leigh's disease, MRI alone cannot be used to predict fatal respiratory failure in patients with Leigh's disease. In any dilemma regarding diagnosis even with MRI, molecular studies remain the gold standard.

Implant positioning in total hip arthroplasty: influence of horizontal and vertical offset on functionality of prosthetic hip joint.

PURPOSE: To analyze the effect of implant position measured in terms of offset on patient reported outcomes (PRO) following hip arthroplasty (THA). METHODS: A total of 243 patients of the total hip replacement who had a one year follow-up were included in the study. Standard both hips radiograph was used to asses post-surgery implant position in terms of horizontal offset and vertical offset, and correlated with functional outcome which was evaluated as change in PRO. i.e., Harris hip score (HHS) post-op. With center of hip rotation as reference, horizontal offset was calculated as sum of distance, of centre, from proximal femoral shaft axis and a vertical line through ipsilateral teardrop, and vertical offset as limb length discrepancy. Post-op patients were classified into three groups depending on the measurement of horizontal offset of the operated hip. The patients having operated hip horizontal offset within 5 mm of the normal hip were grouped as restored offset (RO); those having shorter or higher offset by more than 5 mm compared to normal hip were labeled as decreased (DO) or increased offset (IO) group respectively. The groups were further subdivided into suboptimal and optimal function groups based on HHS, and among these groups, limb length discrepancy was evaluated. RESULTS: Post follow-up mean HHS (78.23 ± 9.96) improved significantly in all three groups (p < 0.0001). The difference in post-operative HHS among DO, RO, and IO groups was significant, with their averages being 72.5 ± 4.7, 82.1 ± 6.5, and 75.2 ± 4.8 respectively (p = .01). Limb length discrepancy was significantly more common in patients with suboptimal functional scores in all three groups. CONCLUSION: This study concluded that both horizontal offset and vertical offset should be reconstructed in patients operated with unilateral THR due to hip pathology, since both factor demonstrated a comparable additive effect on clinical outcome.

Internal stenting across the pancreaticojejunostomy anastomosis and main pancreatic duct after pancreaticoduodenectomy.

BACKGROUND: Postoperative pancreatic fistula is associated with high morbidity and mortality. Studies have reported internal stenting of the pancreaticojejunostomy anastomosis to reduce postoperative pancreatic fistula, but it is still controversial. MATERIALS AND METHODS: Fifty patients undergoing elective pancreaticoduodenectomy, were included. Patients were divided into 2 groups in randomized fashion; Group A (n-25) without internal stenting across the pancreaticojejunostomy anastomosis and Group B (n-25) with internal stenting of the pancreaticojejunostomy anastomosis. Primary endpoint was the occurrence of postoperative pancreatic fistula. RESULT: Both the groups were comparable in demographics, co morbidities, pathologies, pancreatic texture and pancreatic duct diameter. Out of 50 patients studied, total 23(46.0%) patients developed postoperative pancreatic fistula. Ten (40%) in group A and 13 (52%) in group B (p 0.156). Sixteen patients (32%) developed Grade A and 7 (14%) patients had Grade B postoperative pancreatic fistula. In group A, 6 patients developed grade A and 4 patients developed grade B postoperative pancreatic fistula. In group B, 10 patients developed grade A and 3 patients developed grade B postoperative pancreatic fistula. There was no Grade C fistula. All patients had satisfactory recovery on conservative management. Eight patients (16%) developed delayed gastric emptying [5 in group A and 3 in group B; p-0.366]. Six patients developed superficial surgical site infection (2 in group A and 4 in group B; p-0.445). The length of hospital stay was comparable in two groups. There was no mortality. CONCLUSION: Internal stenting of pancreaticojejunostomy anastomosis does not decrease the rate of postoperative pancreatic fistula after pancreaticoduodenectomy.

Extended Thromboprophylaxis With Betrixaban or Rivaroxaban for Acutely Ill Hospitalized Medical Patients: Meta-Analysis of Prespecified Subgroups.

BACKGROUND: Betrixaban and rivaroxaban are the direct anticoagulants approved in the United States for extended venous thromboembolism (VTE) prophylaxis among acutely ill medical patients. The efficacy and safety in specific subgroups remain unclear. METHODS: A meta-analysis of 3 randomized trials involving extended thromboprophylaxis with betrixaban or rivaroxaban versus enoxaparin for medically ill patients was performed to compare VTE (composite of asymptomatic proximal and symptomatic deep vein thrombosis, pulmonary embolism, or VTE-related death) and major bleeding in subgroups by baseline D-dimer, age, sex, and major medical illness on hospitalization. Risk difference (RD) was computed with the Mantel-Haenszel method by fitting a fixed-effect model. Heterogeneity of treatment effect across subgroups was examined using the nominal thresholds of P < 0.05 and I2 > 75%. RESULTS: Compared with enoxaparin, extended betrixaban or rivaroxaban reduced VTE (RD = -1.51% [95% CI, -2.32% to -0.69%]; P = 0.0003) without excess major bleeding (RD = 0.12% [-0.05% to 0.29%]; P = 0.16). A significant effect modification was observed in the subgroups by D-dimer (P = 0.004) and age (P = 0.04). Patients with D-dimer >2× upper limit of normal (ULN) experienced a greater VTE reduction (RD = -2.39% [-3.57% to -1.21%]; P < 0.0001) than those with ≤2×ULN (RD = -0.26% [-1.08% to 0.56%]; P = 0.53). Similarly, patients aged ≥75 years had a greater VTE reduction (RD = -2.29% [-3.49% to -1.09%]; P = 0.0002) than those aged <75 years (RD = -0.63% [-1.70% to 0.44%]; P = 0.25). Treatment effect was consistent across the remaining subgroups. CONCLUSIONS: A more favorable efficacy and comparable safety outcome associated with extended betrixaban or rivaroxaban were observed among medical inpatients with D-dimer >2×ULN or aged ≥75 years. D-dimer and advanced age may assist in decision-making on pharmacological thromboprophylaxis for hospitalized medical patients.

Delivery of neostigmine and glycopyrrolate by iontophoresis: a nonrandomized study in individuals with spinal cord injury.

STUDY DESIGN: Phase I Clinical Trial. OBJECTIVES: In this proof-of-principle study, the effectiveness and safety of transdermal administration of neostigmine/glycopyrrolate to elicit a bowel movement was compared to intravenous administration in patients with spinal cord injury. SETTING: James J. Peters Veterans Affairs Medical Center (Bronx, NY). METHODS: Individuals were screened for responsiveness (Physical Response) to intravenous neostigmine (0.03 mg/kg)/glycopyrrolate (0.006 mg/kg). Intravenous neostigmine/glycopyrrolate responders (Therapeutic Response) were administered low-dose transdermal neostigmine/glycopyrrolate [(0.05 mg/kg)/(0.01 mg/kg)] by iontophoresis. Non-responders to low-dose transdermal neostigmine/glycopyrrolate were administered high-dose transdermal neostigmine/glycopyrrolate [(0.07 mg/kg)/(0.014 mg/kg)] by iontophoresis. Bowel movement, bowel evacuation time, and cholinergic side effects were recorded. Visits were separated by 2 to 14 days. RESULTS: Eighteen of 25 individuals (72.0%) had a bowel movement (20 ± 22 min) after intravenous neostigmine/glycopyrrolate. Of these 18 individuals, 5 individuals experienced a bowel movement with low-dose transdermal neostigmine/glycopyrrolate. Another five individuals had a bowel movement after high-dose transdermal neostigmine/glycopyrrolate administration. Fewer side effects were observed in individuals who received neostigmine/glycopyrrolate transdermally compared to those who were administered intravenous neostigmine/glycopyrrolate. CONCLUSIONS: Transdermal administration of neostigmine/glycopyrrolate by iontophoresis appears to be a practical, safe, and effective approach to induce bowel evacuation in individuals with spinal cord injury.

Bronchodilator effects of ipratropium bromide and albuterol sulfate among subjects with tetraplegia.

OBJECTIVE: In addition to lung volume restriction, persons with chronic tetraplegia demonstrate obstructive airway physiology evinced by pharmacologically-induced bronchodilation. We previously found independent evidence that anticholinergic agents (ipratropium bromide; IB) and beta-2 adrenergic agonists (albuterol sulfate; AS) were associated with significant bronchodilation in subjects with tetraplegia as determined via spirometry or body plethysmography. Direct comparison of these two classes of agents has received little attention. METHODS: Twelve subjects with chronic tetraplegia completed single dose treatment on alternate days with nebulized IB or AS. Patients underwent pre- and 30-minute post-bronchodilator spirometry, body plethysmography, and impulse oscillation system (IOS) in accordance with established protocols. RESULTS: Spirometry and specific airway conductance revealed significant bronchodilator responsiveness following both IB and AS. As determined by increases in specific airway conductance post-bronchodilator, IB tended toward greater bronchodilation than AS (71% vs. 47%). IOS revealed a greater reduction in central airway resistance (R20) following IB compared to AS (22% vs. 9%, P < 0.01). A greater number of subjects exhibited a clinically significant reduction in R20 following IB compared to AS (58% vs. 8%, P < 0.01). CONCLUSION: Among subjects with tetraplegia, both IB and AS elicit significant bronchodilation, although the magnitude of the bronchodilator response is greater following IB. This lends support to theory of overriding cholinergic airway tone in tetraplegia. The IOS findings further suggest that the predominant site of action of IB is upon the larger central airways congruent with findings in able-bodied subjects.

Self-reported effects of cold temperature exposure in persons with tetraplegia.

OBJECTIVE: Cervical spinal cord injury (tetraplegia) is known to interrupt sympathetic vasculature control, thereby preventing shunting of blood from the periphery to central organs when exposed to cold temperatures. As a result, persons with tetraplegia are at risk to develop hypothermia. However, information regarding the discomfort experienced during the cooler months (late fall, winter, early spring) is overwhelmingly anecdotal. It is not known, with any certainty, how those with tetraplegia perceive cold and if discomfort in colder environments restricts them from performing activities that they routinely would perform. DESIGN: Prospective, two-group, self-report surveys. SETTING: VA Medical Center and Kessler Institute for Rehabilitation. PARTICIPANTS: Forty-four subjects with tetraplegia; 41 matched non-SCI controls. OUTCOME MEASURES: Tetraplegic and control groups responded "yes" or "no" when asked whether cold seasonal temperatures allowed comfort or negatively affected participation in routine activities. RESULTS: Percentage of responses of tetraplegia compared to controls was different as to whether they felt cold when others in the same room were comfortable (82 vs. 24%; χ2 = 28.2, P < 0.0001), felt comfortable outdoors (17 vs. 43%; χ2 = 6.8, P = 0.009), or whether cold negatively affected bathing routines (55 vs. 15%; χ2 = 14.8, P = 0.0001), keeping physician appointments (46 vs. 12%; χ2 = 11.3, P = 0.0008), thinking clearly (41 vs. 7%; χ2 = 12.9, P = 0.0003), and completing usual work duties (46 vs. 10%; χ2 = 13.3, P = 0.0003). CONCLUSION: Cold seasonal temperatures have a reported greater negative impact on personal comfort and ability to perform vital activities in persons with tetraplegia than that of non-SCI controls. These findings highlight the need to address thermoregulatory impairment in persons with tetraplegia.

Impact of timing from blood sampling to pharmacodynamic assessment on measures of platelet reactivity in patients treated with P2Y12 receptor inhibitors.

Several platelet function tests (PFT) are available to assess the pharmacodynamic (PD) effects of P2Y12 inhibitors. However, there are technical variances between PFT, and P2Y12 inhibitors differ in pharmacological properties. Manufactures of PFT recommend a time-frame within which assessments needs to be executed. However, if the timing from blood sampling to processing affects PD results is unknown. We conducted a prospective study assessing the impact of timing from blood sampling to processing on PD measures using three different PFT. We studied 60 aspirin-treated patients with coronary artery disease (CAD) on maintenance P2Y12 inhibiting therapy [clopidogrel 75 mg/day (n=20), prasugrel 10 mg/day (n=20) and ticagrelor 90 mg bid (n=20)]. PD assessments (trough levels) were performed by VerifyNow P2Y12 (VN), light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein (VASP) at 30 minutes, 2 and 4 hours post-sampling; VASP was also performed at 24 hours. P2Y12 reaction units (PRU) by VN significantly decreased over time with all P2Y12 inhibitors (clopidogrel p<0.001; prasugrel p=0.016; ticagrelor p<0.001). PRU at 30 minutes and 2 hours were similar, but decreased at 4 hours. LTA showed consistent findings with VN. Conversely, PD measures as assessed by VASP were stable over time (p>0.1 for all P2Y12 inhibitors). In conclusion, in CAD patients on maintenance therapy with P2Y12 inhibitors, timing from blood sampling to processing significantly influences PD measures as assessed by VN and LTA, but not by VASP.

A head-to-head pharmacodynamic comparison of prasugrel vs. ticagrelor after switching from clopidogrel in patients with coronary artery disease: results of a prospective randomized study.

AIMS: Pharmacodynamic (PD) studies comparing prasugrel and ticagrelor have reached inconsistent findings. Therefore, a comprehensive investigation comparing the PD effects of prasugrel vs. ticagrelor after switching from clopidogrel therapy, exploring both loading dose (LD) and maintenance dose (MD) regimens represented the aim of this study. METHODS AND RESULTS: Patients (n = 110) with coronary artery disease were randomized to prasugrel (60 mg LD/10 mg MD q.d.) or ticagrelor (180 mg LD/90 mg MD b.i.d) therapy for 1 week. Pharmacodynamic assessments were conducted using three assays (vasodilator-stimulated phosphoprotein, VerifyNow P2Y12, and light transmittance aggregometry, LTA) at baseline, 30 min, 2, 24 h, and 1 week. The impact of initiating ticagrelor MD 12 vs. 24 h after LD administration was also assessed. Switching clopidogrel-treated patients to an LD of prasugrel or ticagrelor was associated with a reduction in platelet reactivity at 30 min and was sustained at all time points up to 1 week with the MD (P < 0.001 for all assays). Platelet reactivity was similar with prasugrel and ticagrelor with all assays at 30 min, 2 h, and 1 week (P > 0.05 for all time points), with the exception of LTA at 30 min (lower with prasugrel; P = 0.003). At 24 h, platelet reactivity was lower among patients initiating ticagrelor MD after 12 vs. 24 h post-LD. Rates of high platelet reactivity (HPR) were markedly reduced and similar between groups. CONCLUSION: Prasugrel and ticagrelor exert similar levels of P2Y12 inhibition achieving more potent PD effects and reduced HPR rates compared with clopidogrel which are reached promptly following LD and sustained with MD. CLINICALTRIALSGOV IDENTIFIER: NCT01852175.

Biomarkers of inflammation in persons with chronic tetraplegia.

In addition to lung volume restriction, individuals with chronic tetraplegia exhibit reduced airway caliber and bronchodilator responsiveness similar to persons with asthma. In asthma, airflow obstruction is closely linked to airway inflammation. Conversely, little is known regarding the airway inflammatory response in tetraplegia. To compare levels of biomarkers of inflammation in exhaled breath condensate (EBC) and serum in subjects with chronic tetraplegia, mild asthma, and able-bodied controls.Prospective, observational pilot study. Thirty-four subjects participated: tetraplegia (n = 12), asthma (n = 12), controls (n = 10). Biomarkers in EBC [8-isoprostane (8-IP), leukotriene B4 (LT-B4), prostaglandin E2 (PG-E2), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6)] and serum (8-IP, LT-B4, TNF-α, IL-6) were determined using commercially available EIA kits (Cayman Chemical Company, Ann Arbor, MI). Separate, one-way ANOVA with Bonferroni's post-hoc analyses were performed to determine group differences in demographic and dependent variables [EBC and serum biomarkers, fractional exhaled nitric oxide (FeNO), pulmonary function parameters, and specific airway conductance (sGaw)]. The tetraplegia group had significantly elevated 8-IP levels in EBC compared to the asthma (68 ± 38 versus 21 ± 13 pg ml(-1); p < 0.001) and control groups (22 ± 13 pg ml(-1); p < 0.01), respectively. FeNO levels were significantly elevated in the asthma compared to the control group (26 ± 18 versus 11 ± 4 ppb; p < 0.05), and trended higher than levels in the tetraplegia group (15 ± 6; p = 0.08). Levels of serum biomarkers did not differ significantly among groups. Through analysis of EBC, levels of 8-IP were significantly elevated compared to levels found in individuals with mild asthma and healthy controls. Further studies are needed to extend upon these preliminary findings that suggest the presence of airway inflammation in subjects with chronic tetraplegia, and how this relates to pulmonary dysfunction in this population.

Inhibition of PTEN gene expression by oncogenic miR-23b-3p in renal cancer.

BACKGROUND: miR-23b is located on chromosome number 9 and plays different roles in different organs especially with regards to cancer development. However, the functional significance of miR-23b-3p in renal cell carcinoma (RCC) has not been reported. METHODS AND RESULTS: We measured miR-23b-3p levels in 29 pairs of renal cell carcinoma and their normal matched tissues using real-time PCR. The expression level of miR-23b-3p was correlated with the 5 year survival rate of renal cancer patients. In 15 cases (52%), miR-23b-3p expression was found to be high. All patients with moderate to low miR-23b-3p expression survived 5 years, while those with high miR-23b-3p expression, only 50% survived. After knocking down miRNA-23b-3p expression in RCC cell lines, there was an induction of apoptosis and reduced invasive capabilities. MiR-23b-3p was shown to directly target PTEN gene through 3'UTR reporter assays. Inhibition of miR-23b-3p induces PTEN gene expression with a concomitant reduction in PI3-kinase, total Akt and IL-32. Immunohistochemistry showed the lack of PTEN protein expression in cancerous regions of tissue samples where the expression of miR-23b-3p was high. We studied the in vitro effects of the dietary chemo preventive agent genistein on miR-23b-3p expression and found that it inhibited expression of miR-23b-3p in RCC cell lines. CONCLUSIONS: The current study shows that miR-23b-3p is an oncogenic miRNA and inhibits PTEN tumor suppressor gene in RCC. Therefore, inhibition of miR-23b-3p may be a useful therapeutic target for the treatment of renal cell carcinoma.

Up-regulation of microRNA-21 correlates with lower kidney cancer survival.

BACKGROUND: MicroRNA-21 is up-regulated in a variety of cancers like, breast, colorectal, lung, head and neck etc. However, the regulation of miR-21 in renal cell carcinoma (RCC) has not yet been studied systematically. METHODS AND RESULTS: We measured miR-21 levels in 54 pairs of kidney cancers and their normal matched tissues by real-time PCR. The expression level of miR-21 was correlated with 5 year survival and the pathological stage. Functional studies were done after inhibiting miR-21 in RCC cell lines. We studied in vitro and in vivo effects of the chemo preventive agent genistein on miR-21 expression. In 48 cases (90%), miR-21 was increased. All patients with low miR-21 expression survived 5 years, while with high miR-21 expression, only 50% survived. Higher expression of miR-21 is associated with an increase in the stage of renal cancer. Functional studies after inhibiting miRNA-21 in RCC cell lines show cell cycle arrest, induction of apoptosis and reduced invasive and migratory capabilities. Western blot analysis showed an increase in the expression of p21 and p38 MAP kinase genes and a reduction in cyclin E2. Genistein inhibited the expression of miR-21 in A-498 cells and in the tumors formed after injecting genistein treated A-498 cells in nude mice besides inhibiting tumor formation. CONCLUSIONS: The current study shows a clear correlation between miR-21 expression and clinical characteristics of renal cancer. Thus we believe that miR-21 can be used as a tumor marker and its inhibition may prove to be useful in controlling cancers with up-regulated miR-21.

MicroRNA-205 inhibits Src-mediated oncogenic pathways in renal cancer.

The Src family of protein kinases (SFK) plays key roles in regulating fundamental cellular processes, including cell growth, differentiation, cell shape, migration, and survival, and specialized cell signals in various malignancies. The pleiotropic functions of SFKs in cancer make them promising targets for intervention. Here, we sought to investigate the role of microRNA-205 (miR-205) in inhibition of Src-mediated oncogenic pathways in renal cancer. We report that expression of miR-205 was significantly suppressed in renal cancer cell lines and tumors when compared with normal tissues and a nonmalignant cell line and is correlated inversely with the expression of SFKs. miR-205 significantly suppressed the luciferase activity of reporter plasmids containing the 3'-UTR (untranslated region) sequences complementary to either Src, Lyn, or Yes, which was abolished by mutations in these 3'-UTR regions. Overexpression of miR-205 in A498 cells reduced Src, Lyn, and Yes expression, both at mRNA and protein levels. Proliferation of renal cancer cells was suppressed by miR-205, mediated by the phospho-Src-regulated ERK1/2 pathway. Cell motility factor FAK (focal adhesion kinase) and STAT3 activation were also inhibited by miR-205. Transient and stable overexpression of miR-205 in A498 cells resulted in induction of G0/G1 cell-cycle arrest and apoptosis, as indicated by decreased levels of cyclin D1 and c-Myc, suppressed cell proliferation, colony formation, migration, and invasion in renal cancer cells. miR-205 also inhibited tumor cell growth in vivo. This is the first study showing that miR-205 inhibits proto-oncogenic SFKs, indicating a therapeutic potential of miR-205 in the treatment of renal cancer.