BP Treatment Research Articles

A randomized clinical trial of adjunctive ketamine anesthesia in electro-convulsive therapy for depression

BackgroundElectroconvulsive therapy (ECT) is a rapid acting and effective treatment for both major depressive disorder (MDD) and bipolar disorder (BP). Both propofol and ketamine are commonly used anesthetic agents but recent clinical studies suggest that ketamine has rapid-acting antidepressant properties, itself, at sub-anesthetic doses. MethodsA total of 77 inpatients (41 MDD and 36 BP) were randomly assigned to receive ECT with propofol (1mg/kg) anesthesia or with ketamine (0.5mg/kg) plus propofol (0.5mg/kg). Depressive symptoms were assessed with the 24-item Hamilton Depression Rating Scale (HAMD-24) and Montgomery–Asberg Rating Scale (MADRS), before and after 1, 2, 4, and 6 ECT treatments, and 1–4 weeks following the last treatment. The MATRICS Consensus Cognitive Battery (MCCB) was evaluated at baseline,after the sixth ECT, and 1–4 weeks following the final ECT. Adverse effects were assessed at baseline and 4 weeks after the last treatment. ResultsThere were no significant differences in depressive symptoms, MCCB performance, or adverse effects between the treatment groups at any time. The electrical dose required to generate seizures in the ketamine plus propofol group was lower than that of the propofol only group at every time point. The seizure energy index and seizure duration in the ketamine plus propofol group was higher and longer than those in the propofol only group. LimitationsThe diagnoses of MDD and BP were unevenly distributed across treatment groups. ConclusionsKetamine plus propofol anesthesia in the ECT treatment of MDD and BP was not superior on any measure to propofol alone.

BP Reduction, Kidney Function Decline, and Cardiovascular Events in Patients without CKD.

In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic BP treatment (target <120 mm Hg) was associated with fewer cardiovascular events and higher incidence of kidney function decline compared with standard treatment (target <140 mm Hg). We evaluated the association between mean arterial pressure reduction, kidney function decline, and cardiovascular events in patients without CKD. We categorized patients in the intensive treatment group of the SPRINT according to mean arterial pressure reduction throughout follow-up: <20, 20 to <40, and ≥40 mm Hg. We defined the primary outcome as kidney function decline (≥30% reduction in eGFR to <60 ml/min per 1.73 m2 on two consecutive determinations at 3-month intervals), and we defined the secondary outcome as cardiovascular events. In a propensity score analysis, patients in each mean arterial pressure reduction category from the intensive treatment group were matched with patients from the standard treatment group to calculate the number needed to treat regarding cardiovascular events and the number needed to harm regarding kidney function decline. In the intensive treatment group, 1138 (34%) patients attained mean arterial pressure reduction <20 mm Hg, 1857 (56%) attained 20 to <40 mm Hg, and 309 (9%) attained ≥40 mm Hg. Adjusted hazard ratios for kidney function decline were 2.10 (95% confidence interval, 1.22 to 3.59) for mean arterial pressure reduction between 20 and 40 mm Hg and 6.22 (95% confidence interval, 2.75 to 14.08) for mean arterial pressure reduction ≥40 mm Hg. In propensity score analysis, mean arterial pressure reduction <20 mm Hg presented a number needed to treat of 44 and a number needed to harm of 65, reduction between 20 and <40 mm Hg presented a number needed to treat of 42 and a number needed to harm of 35, and reduction ≥40 mm Hg presented a number needed to treat of 95 and a number needed to harm of 16. In the intensive treatment group of SPRINT, larger declines in mean arterial pressure were associated with higher incidence of kidney function decline. Intensive treatment seemed to be less favorable when a larger reduction in mean arterial pressure was needed to attain the BP target.

Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk.

BPs are the most widely used treatment for postmenopausal osteoporosis. The optimal treatment duration, however, remains unclear. The purpose of this study was to evaluate the fracture risk in postmenopausal women with osteoporosis after discontinuing BP treatment (BP "drug holiday"). A retrospective analysis was performed at Lille University Hospital (LUH) on postmenopausal women with osteoporosis who had taken a "drug holiday" or continued treatment after first-line BP therapy (3 to 5years). The occurrence of new clinical fractures during follow-up was also explored. Cox proportional hazards models were used to investigate the relationships between BP "drug holiday" and the occurrence of clinical fractures, while controlling for confounding factors. Survival without new clinical fractures was analyzed using Kaplan-Meier curves and log-rank tests. One hundred eighty-three women (mean age: 61.8years; SD: 8.7) who had previously undergone BP treatment for 3 to 5years were enrolled in our study. The patients had received alendronate (n=81), risedronate (n=73), zoledronic acid (n=20), and ibandronate (n=9). In 166 patients ("drug holiday" group: n=31; continuous-treatment group: n=135), follow-up ranged from 6 to 36months (mean duration: 31.8months; SD: 8.2). The incidences of new clinical fractures during follow-up were 16.1% (5/31) and 11.9% (16/135). After full adjustment, the hazard ratio of new clinical fractures among "drug holiday" patients was 1.40 (95% CI: 1.12-1.60; p=0.0095). After first-line BP therapy in postmenopausal women with osteoporosis, the risk of new clinical fractures was 40% higher in subjects who took a bisphosphonate drug holiday.

Abstract 149: Impact of Baseline 10-year Cardiovascular Risk on Benefit and Harm of Intensive Treatment in SPRINT

We investigated the impact of baseline CV risk on outcomes in SPRINT. Using the ACC/AHA CVD risk algorithm, we stratified the SPRINT population into quartiles of baseline 10-year CV risk. Within each quartile, Cox proportional hazards models were used to examine the effect of intensive treatment vs. standard of care on the SPRINT CV outcomes, all-cause mortality and serious adverse events (SAEs). Number needed to treat (NNT) and number needed to harm (NNH) were calculated for each quartile. There were 9,323 participants with available baseline ACC/AHA 10-year risk scores. In each quartile of risk, the hazard ratio (HR) favored intensive treatment. For CV outcomes, NNT decreased from 91 in the 1 st quartile to 38 in the 4 th quartile. For all-cause mortality, NNT decreased from 333 in the 1 st quartile to 45 in the 4 th quartile. Although incidence of all SAEs increased with each quartile in both treatment groups (p for trend &lt;0.0001), there was no difference in incidence of SAEs between the treatment groups in each quartile. However, SAEs classified as hypotension were more frequent in the 4 th quartile for the intensive treatment group (incremental increase 1.8%, NNH = 55) and SAEs classified as acute kidney injury or acute renal failure were significantly more frequent in the 2 nd , 3 rd and 4 th quartiles for the intensively treated group (incremental increase 1.7%, 2.4% and 2.1%; NNH 59, 42 and 48, respectively). Therefore, those with greatest baseline CVD risk got the most benefit from intensive BP treatment but were at greater risk for hypotension and renal injury. This analysis may help providers and patients make decisions regarding the intensity of BP treatment to prevent death and CV events.

OP.1A.02] INNATE IMMUNITY AND CARDIO-RENAL RISK IN STAGE 2-5 CKD PATIENTS

Objective: The soluble form of urokinase-type plasminogen activator (suPAR) is a powerful marker for immune activation that accurately predict clinical outcomes in patients with sepsis or infectious diseases. Alterations in innate immunity and Inflammation are major risk factors for the high risk for cardiovascular disease in patients with chronic kidney disease (CKD) but whether suPAR predicts cardiovascular and renal complications independently of established risk factors in CKD is still unknown. Design and method: We measured plasma suPAR levels (ELISA) and a series of traditional and CKD-specific risk factors in 753 stage G2-5 CKD patients. We estimated the risk for GFR loss (>30%) or kidney failure, time to death and first cardiovascular event by multivariate Cox regression analysis adjusting for traditional risk factors and a large series of CKD-specific risk factors. Results: suPAR was gender-dependent and associated with lower GFR and higher proteinuria, older age, diabetes, higher systolic BP, C Reactive Protein (CRP), phosphate, PTH, FGF23, ADMA and lower Hb, 25OH vitD and 1,25OH2 vitD (all P < 0.001). Over a 31 +/− 10 months follow-up 42 patients died and 95 had a renal event. suPAR was a strong predictor of the combined end-point death and cardiovascular events [HR (500pg/ml): 1.09, 95%CI: 1.04–1.14] in a Cox's regression analysis adjusting for a large series of potential confounders including background cardiovascular disease, the GFR, proteinuria, age, gender, smoking, diabetes, systolic BP and anti-hypertensive treatment, phosphate, Hb, serum albumin, BMI, CRP, ADMA and FGF23. Separate analyses of time to death and time to first CV event were both highly significant (P < 0.01) in crude and adjusted analyses. Conclusions: Elevated suPAR levels robustly predict incident cardiovascular events and death in CKD patients. These findings go along with biological knowledge documenting a strong role of suPAR in atherosclerosis and support the contention that suPAR is causally implicated in cardiovascular disease in CKD patients.

BP treatment adherence influenced by conversations with provider

BP treatment adherence influenced by conversations with provider

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts.

The rising prevalence of primary pediatric hypertension and its tracking into adult hypertension point to the importance of determining its pathogenesis to gain insights into its current and emerging management. Considering that the intricate control of BP is governed by a myriad of anatomical, molecular biological, biochemical, and physiological systems, multiple genes are likely to influence an individual's BP and susceptibility to develop hypertension. The long-term regulation of BP rests on renal and non-renal mechanisms. One renal mechanism relates to sodium transport. The impaired renal sodium handling in primary hypertension and salt sensitivity may be caused by aberrant counter-regulatory natriuretic and anti-natriuretic pathways. The sympathetic nervous and renin-angiotensin-aldosterone systems are examples of antinatriuretic pathways. An important counter-regulatory natriuretic pathway is afforded by the renal autocrine/paracrine dopamine system, aberrations of which are involved in the pathogenesis of hypertension, including that associated with obesity. We present updates on the complex interactions of these two systems with dietary salt intake in relation to obesity, insulin resistance, inflammation, and oxidative stress. We review how insults during pregnancy such as maternal and paternal malnutrition, glucocorticoid exposure, infection, placental insufficiency, and treatments during the neonatal period have long-lasting effects in the regulation of renal function and BP. Moreover, these effects have sex differences. There is a need for early diagnosis, frequent monitoring, and timely management due to increasing evidence of premature target organ damage. Large controlled studies are needed to evaluate the long-term consequences of the treatment of elevated BP during childhood, especially to establish the validity of the current definition and treatment of pediatric hypertension.

The Elusive Search for Optimal Blood Pressure Targets.

BP treatment thresholds/targets determine when to initiate treatment and to what level BP should be reduced. The Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) recommended a target of <140/90 for most patients and a target <130/80mmHg for patients with diabetes or chronic kidney disease. Subsequently, meta-analyses, retrospective studies relating on-treatment BP to clinical outcomes and two large, randomized clinical trials (RCTs) have re-evaluated BP targets. In Action to Control Cardiovascular Risk in Diabetes (ACCORD), a systolic blood pressure (SBP) <120mmHg was found not to be superior to SBP <140mmHg in diabetics. In SPRINT (Systolic Blood Pressure Intervention Trial) which studied a different population, the lower target resulted in a 25% cardiovascular event reduction. Despite unresolved issues, certain recommendations can be made with confidence. SBP >160mmHg should, with rare exceptions, be treated. The historical threshold/target of 140/90mmHg remains reasonable in most patients in identifying "treatable" risk, i.e., risk high enough to justify treatment and for which available treatment is effective enough to result in significant endpoint reduction. Above 140/90mmHg, most low-to-moderate risk people should be treated and this target is also appropriate for the majority of high-risk individuals with diabetes, CKD, and/or CAD. The advisability of initiating or intensifying treatment with BPs in the 130s remains equivocal. The next steps in the search for more precise BP targets should include (1) standardization of BP measurement techniques and (2) well-designed RCTs evaluating a treatment target of SBP <130 in carefully categorized patient populations.

Stimulatory effects of curcumin and quercetin on posttranslational modifications of p53 during lung carcinogenesis.

Lung cancer is responsible for increase in mortality due to cancer-related deaths, and new approaches are being explored for the betterment of the situation. In the present study, chemopreventive efficacy of curcumin and quercetin was investigated against benzo(a)pyrene (BP)-induced lung carcinogenesis. The mice were segregated into five groups, which included normal control, BP-treated, BP + curcumin-treated, BP + quercetin-treated, and BP + curcumin + quercetin-treated groups. The morphological and histological analyses of tumor nodules confirmed lung carcinogenesis22 weeks after weeks single intraperitoneal injection of BP at a dose of 100 mg/kg body weight to mice. Curcumin and quercetin when administered individually as well as in combination significantly elevated the expression of acetylated-p53, which was otherwise depressed due to BP treatment. Also, both the phytochemicals significantly reduced the BP-inflicted increased levels of phosphorylated-p53. Furthermore, observed increase in the number of apoptotic cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), assay and increased activities of caspase 3 and 9 confirmed the induction of apoptosis by curcumin and quercetin. Moreover, the histological slides also showed noticeable improvement in the histoarchitecture of lungs by phytochemicals. The present study concludes that prophylactic treatment with curcumin and quercetin induces apoptosis in the lungs by modulation of p53 posttranslational modifications.

Abstract 498: Attenuation of polycyclic aromatic hydrocarbon (PAH)-mediated pulmonary carcinogenesis in mice by omega-3-fatty acids

Abstract 3-Methylcholanthrene (MC) and benzo[a]pyrene (BP) are potent polycyclic aromatic hydrocarbons (PAHs) carcinogens. PAHs are present in cigarette smoke, diesel exhausts, and charcoal broiled meats, etc. Cytochrome P450 (CYP) 1A/1B1 enzymes play key roles in the activation of PAHs to carcinogenic metabolites, which initiate carcinogenesis by binding covalently to DNA, and the adducts, if not repaired, could lead to tumorigenesis. In this study we tested the hypothesis that pre-treatment of mice with omega-3-fatty acids, i.e. [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) will lead to attenuation of PAH-mediated pulmonary DNA adduct formation and pulmonary tumorigenesis. Twelve week old male and female A/J mice received EPA (60 mg/kg) and DHA (40 mg/kg) from day 1 to day 24. Control mice were treated with vehicle corn oil. On day 3, mice were treated with BP (40 µmol/kg) or 3-methylcholanthrene (MC, 40 µmol/kg) by i.p. In the short-term experiment (DNA adduct studies), 3-5 mice from each group were terminated at day 10 (7 days after BP or MC treatment). EPA/DHA significantly suppressed formation of BP-DNA and MC-DNA adducts in lung and liver of both male and female mice. In the long-term experiment (tumor studies), 8 mice for each group continued to receive EPA/DHA twice per week till end of experiment (16 weeks). Pulmonary tumor incidence and multiplicity was significantly suppressed in mice given EPA+DHA, compared to those given the PAHs, BP or MC alone. These studies suggest that the omega 3-fatty acids could be developed as novel candidates for the prevention of PAH-mediated lung cancers in humans. Citation Format: Bhagavatula Moorthy, Weiwu Jiang, Lihua Wang, Sudha R. Kondraganti, Guodong Zhou. Attenuation of polycyclic aromatic hydrocarbon (PAH)-mediated pulmonary carcinogenesis in mice by omega-3-fatty acids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 498. doi:10.1158/1538-7445.AM2017-498

Use of an innovative Technology Enabled Care service (TECS) 'Florence' to empower patients and enhance adherence to BP treatments in diabetes

Use of an innovative Technology Enabled Care service (TECS) 'Florence' to empower patients and enhance adherence to BP treatments in diabetes

N-butylidenephthalide treatment prolongs life span and attenuates motor neuron loss in SOD1G93A mouse model of amyotrophic lateral sclerosis.

To evaluate the therapeutic effects of n-butylidenephthalide (BP) in SOD1G93A mouse model of amyotrophic lateral sclerosis and explore the possible mechanisms. The SOD1G93A mice were treated by oral administration of BP (q.d., 400mg/kgd) starting from 60days of age and continuing until death. The rotarod test was performed to assess the disease onset. The expression levels of apoptosis-related proteins, inflammatory molecules, and autophagy-associated proteins were determined. The number of apoptotic motor neurons and the extent of microglial and astroglial activation were also assessed in the lumbar spinal cords of BP-treated mice. Grip strength test, hematoxylin-eosin staining, nicotinamide adenine dinucleotide hydrogen staining, and malondialdehyde assay were conducted to evaluate the muscle function and pathology. Although BP treatment did not delay the disease onset, it prolonged the life span and thereafter extended the disease duration in SOD1G93A mouse model of ALS. BP treatment also reduced the motor neuron loss through inhibiting apoptosis. We further demonstrated that the neuroprotective effects of BP might be resulted from the inhibition of inflammatory, oxidative stress, and autophagy. Our study suggests that BP may be a promising candidate for the treatment of ALS.

Benefits and Harms of Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older: A Systematic Review and Meta-analysis.

Recent guidelines recommend a systolic blood pressure (SBP) goal of less than 150 mm Hg for adults aged 60 years or older, but the balance of benefits and harms is unclear in light of newer evidence. To systematically review the effects of more versus less intensive BP control in older adults. Multiple databases through January 2015 and MEDLINE to September 2016. 21 randomized, controlled trials comparing BP targets or treatment intensity, and 3 observational studies that assessed harms. Two investigators extracted data, assessed study quality, and graded the evidence using published criteria. Nine trials provided high-strength evidence that BP control to less than 150/90 mm Hg reduces mortality (relative risk [RR], 0.90 [95% CI, 0.83 to 0.98]), cardiac events (RR, 0.77 [CI, 0.68 to 0.89]), and stroke (RR, 0.74 [CI, 0.65 to 0.84]). Six trials yielded low- to moderate-strength evidence that lower targets (≤140/85 mm Hg) are associated with marginally significant decreases in cardiac events (RR, 0.82 [CI, 0.64 to 1.00]) and stroke (RR, 0.79 [CI, 0.59 to 0.99]) and nonsignificantly fewer deaths (RR, 0.86 [CI, 0.69 to 1.06]). Low- to moderate-strength evidence showed that lower BP targets do not increase falls or cognitive impairment. Data relevant to frail elderly adults and the effect of multimorbidity are limited. Treatment to at least current guideline standards for BP (<150/90 mm Hg) substantially improves health outcomes in older adults. There is less consistent evidence, largely from 1 trial targeting SBP less than 120 mm Hg, that lower BP targets are beneficial for high-risk patients. Lower BP targets did not increase falls or cognitive decline but are associated with hypotension, syncope, and greater medication burden. U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO 2015: CRD42015017677).

Optimising BP measurement and treatment before elective surgery: taking the pressure off

Optimising BP measurement and treatment before elective surgery: taking the pressure off

HOPE-‑3, BP treatment, milestones in CV prevention. Dr. Salim Yusuf in aninterview with Dr. Akbar Panju and Dr. Roman Jaeschke.

HOPE-‑3, BP treatment, milestones in CV prevention. Dr. Salim Yusuf in aninterview with Dr. Akbar Panju and Dr. Roman Jaeschke.

Burkholderia pseudomallei-derived miR-3473 enhances NF-κB via targeting TRAF3 and is associated with different inflammatory responses compared to Burkholderia thailandensis in murine macrophages.

Background Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a kind of tropical disease. Burkholderia thailandensis (Bt), with a high sequence similarity to Bp, is thought to be an avirulent organism. Since there are numerous similarities between Bp and Bt, their differences in pathogenesis of host response and related mechanism are still undermined. In recent years, microRNAs have been researched in many diseases, but seldom involved in bacterial infection, bacteria-host interaction or explaining the differences between virulent and avirulent species.ResultsWe found that Bp and Bt had similar phenotypes in terms of intracellular replication, dissemination (reflected by multinucleated giant cell formation), TNF-α release and apoptosis in RAW264.7 macrophages or TC-1 pulmonary cell but in different level. Especially, at the late infection phases (after 12 h post infection), Bp showed faster intracellular growth, stronger cytotoxicity, and higher TNF-α release. After microRNA array analysis, we found some microRNAs were significantly expressed in macrophages treated by Bp. miR-3473 was one of them specifically induced, but not significantly changed in Bt-treated macrophages. In addition, TargetScan suggested that miR-3473 possibly target TRAF3 (TNF receptor-associated factor 3), a well-known negative regulator of the NF-κB pathway, which was probably involved in the TNF-α induction and apoptosis in cells with Bp infection. In vivo, it was found that miR-3473 expression of total lungs cells from Bp-treated was higher than that from Bt-treated mice. And miR-3473 inhibitor was able to decrease the TNF-α release of mice and prolong the survival of mice with Bp infection.ConclusionIn sum, miR-3473 plays an important role in the differential pathogenicity of Bp and Bt via miR-3473-TRAF3-TNF-α network, and regulates TNF-α release, cell apoptosis and animal survival after Bp treatment. In this study, we have found a specific microRNA is related to bacterial virulence and provide insight into the mechanism for host-bacteria interaction, which suggests that potential oligonucleotides should be applied against bacterial infection.

Commentary on Pharmacotherapy of Hypertension in Patients on Chronic Dialysis.

Introduction This comprehensive review by Agarwal and Georgianos summarizes results of numerous clinical trials of antihypertensive medications in patients on chronic dialysis (1). The authors note the unique challenges of such studies in this patient population. For example, the effect of widely used, nonpharmacologic approaches to BP control, such as increased ultrafiltration and dietary sodium restriction, could easily outweigh the more modest effects on BP of pharmacologic treatments. Furthermore, there is enormous variability of BP across the interdialytic period, and uncertainty regarding the most appropriate or optimal timing of BP measurement on which to guide treatment. Acknowledging these challenges and limitations, upon their review the authors note the following key findings: Most clinical trials were open-label without blinding of treatment assignment. No trials in patients on maintenance dialysis compared different BP goals of antihypertensive pharmacologic treatment. Most trials utilized a placebo or “usual care” control comparator group; very few trials directly compared two or more classes of antihypertensive medications. Most prior trials involved small samples of patients and examined the effects on change in cardiac structure, vascular function, and/or BP. Only a few trials examined the effects of treatment on cardiovascular morbidity/mortality. In some trials of patients on hemodialysis with left ventricular hypertrophy or dilated cardiomyopathy, beta-blockers reduced the incidence of cardiovascular morbidity/mortality. Some trials demonstrated a reduction in adverse cardiovascular events with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, but other trials found no such reduction in risk with this class of antihypertensives. There is insufficient evidence to support the preferential use of one class of antihypertensive medications over another class. Evaluating Clinical Trials One useful systematic approach for evaluating clinical trials is to focus on three characteristics of study design: the study population, the intervention, and the outcome. The study population in a clinical trial typically balances internal validity (the ability of a study to accurately answer a scientific question), with external validity (the extent to which study results can be applied to other individuals with the same general disease condition). For example, a clinical trial comparing calcium channel blockers to angiotensin-converting enzyme inhibitors might exclude dialysis patients who are obese, have obvious signs of volume overload, or are nonadherent. Such exclusions could improve internal validity by removing extraneous factors to enhance focus on the inherent biologic effects of the medications. However, excluding patients on dialysis who are obese, have clinical edema, or miss some dialysis sessions would preclude understanding of the risks and benefits of the study medications among these relatively common groups, diminishing clinical application. Because large randomized trial designs effectively balance participant characteristics across treatment groups, large pragmatic trials of BP treatments that employ broad entry criteria and simple monitoring strategies would maintain internal validity while providing the greatest impact on clinical care. Clinical trials of medications must carefully consider the dosage and duration of the intervention to provide clear separation of treatment groups while maintaining patient safety. The numerous trials cited in this review provide ample preliminary data for choosing the correct dose and length of treatment for future large-scale clinical trials. Ideally, trials assess the impact of a treatment on outcomes that are important to patients, such as the development of major diseases, mortality, symptoms, and quality of life. Surrogate end points are substitutes for direct measurements of how a patient feels, functions, or survives. To qualify as a surrogate end point, a characteristic or measurement must be shown to change in response to treatment in a manner that is consistent with clinical benefit. For example, in the general population, BP is an accepted surrogate end point for cardiovascular disease because antihypertensive medications lower BP while reducing the risks of stroke and heart failure. Simply demonstrating associations of a characteristic with disease risk is not sufficient to establish a surrogate end point for the purposes of clinical trials. For example, higher serum phosphate or hemoglobin levels are associated with greater risk of cardiovascular disease and death in patients with CKD; however, they would not be considered surrogate end points for studies of treatment of hyperphosphatemia or anemia with the intention of reducing morbidity/mortality. In fact, there are repeated examples of clinical trials in nephrology and other disciplines that demonstrated beneficial effects of an intervention on a biomarker, only to find null or harmful effects on clinical outcomes (2,3). Uncertainties regarding optimal BP targets and the most accurate methods to measure BP in patients on dialysis temper the use of BP as a surrogate end point in studies of ESRD. Future BP trials that directly assess clinical outcomes among patients on chronic dialysis would have the greatest impact on clinical care. Disclosures None.

Noncovalent Functionalization of Black Phosphorus

AbstractBlack phosphorus (BP) was functionalized with organic moieties on the basis of liquid exfoliation. The treatment of BP with electron‐withdrawing 7,7,8,8‐tetracyano‐p‐quinodimethane (TCNQ) led to electron transfer from BP to the organic dopant. On the other hand, the noncovalent interaction of BP with a perylene diimide was mainly due to van der Waals interactions but also led to considerable stabilization of the BP flakes against oxygen degradation.

Ultrastructural changes during lung carcinogenesis-modulation by curcumin and quercetin.

The aim of the present study was to examine the effectiveness of curcumin and quercetin in modulating ultrastructural changes during lung carcinogenesis. A total of 24 male laka mice were divided into the normal control, benzo[a]pyrene (BP)-treated, BP+curcumin-treated, BP+quercetin- treated, and BP+curcumin+quercetin-treated groups (n=6 per group). Lung carcinogenesis was induced by a single intraperitoneal injection of BP [100 mg/kg of body weight (b.wt.)]. Curcumin was supplemented to mice at a dose level of 60 mg/kg of b.wt. in drinking water and quercetin was given at a dose level of 40 mg/kg of b.wt. in drinking water. The ultrastructure of BP-treated mice revealed disruptions in cellular integrity together with nuclear deformation and premature mitochondrial aging. Notably, supplementation with phytochemicals individually resulted in improvement of the ultra-histoarchitecture of BP-treated mice although the improvement was much greater with combined supplementation of phytochemicals. Furthermore, BP treatment revealed alterations in lung histoarchitecture, which, however, were improved appreciably following combined supplementation with curcumin and quercetin. The results of the present study show that, combined supplementation with curcumin and quercetin effectively preserved the histoarchitecture as well as ultra-histoarchitecture during BP-induced lung carcinogenesis in mice.

Syndrome métabolique et troubles bipolaires : le sommeil est-il le chaînon manquant ?

ObjectiveTo examine the pathophysiologic mechanisms that may link circadian disorder and metabolic syndrome in bipolar disorder (BP). MethodA systematic review of the literature was conducted from January 2013 to January 2015, using the Medline and Cochrane databases, using the keywords “metabolic syndrome”, “obesity”, “leptin” and “circadian disorders”, “sleeping disorders” and cross-referencing them with “bipolar disorder”. The following types of publications were candidates for review: (i) clinical trials; (ii) studies involving patients diagnosed with bipolar disorder; (iii) studies involving patients with sleeping disorder; or (iv) data about metabolic syndrome. ResultsForty articles were selected. The prevalence of metabolic syndrome in BP was significantly higher compared to the general population (from 36 to 49% in the USA [Vancampfort, 2013]), and could be explained by several factors including reduced exercise and poor diet, genetic vulnerability, frequent depressive episodes, psychiatric comorbidity and psychotropic treatment. This high frequency of metabolic syndrome worsens the prognosis of these patients, increasing morbidity and mortality. Secondly, patients with BP experienced circadian and sleep disturbance, including modification in melatonin secretion. These perturbations are known to persist in periods of mood stabilization and are found in patients’ relatives. Circadian disturbances are factors of relapse in bipolar patients, and they may also have a role in the metabolic comorbidities of these patients. Recent studies show that in populations of patients with bipolar disorder, a correlation between circadian disturbance and metabolic parameters are found. To identify the pathophysiological pathway connecting both could lead to a better comprehension of the disease and new therapeutics. In the overall population, mechanisms have been identified linking circadian and metabolic disorder involving hormones like leptin and ghrelin. These hormones are keys to regulation of energy balance in the organism, via their action on the hypothalamus, and are also regulated by sleep. We have hypothesized that these pathways could be implicated in the vulnerability of bipolar patients to metabolic syndrome. This hypothesis is supported by several studies showing dysregulation in leptin and ghrelin secretion in multiple psychiatric disorders, including bipolar disorder, as well as genetic variations of leptin and ghrelin genes in these diseases. We also assume that other mechanisms may be at stake to explain this link, such as melatonin dysregulation and inflammation. ConclusionsCircadian and sleeping disorder may have a role in the prevalence of metabolic syndrome in BP. Hormones like leptin and ghrelin could be the link between these perturbations. Prevention and treatment of circadian disorder in BP may greatly reduce the occurrence of MetS in these patients. Being aware of this statement and taking care of these troubles should be a big step forward for treatment of BP.