Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

Aims Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury.Methods Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg·kg^–1·day^–1) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg·kg^–1·day^–1 for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor , -inducible gene-h3 and nephrin were also quantitated.Results Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGF and ig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs.Conclusion/Interpretation These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease.Abbreviations ACEi angiotensin converting enzyme inhibitor - AII angiotensin II - ig-h3 -inducible gene-h3 - GSI glomerulosclerotic index - NEP neutral endopeptidase - Oma omapatrilat - Per perindopril - PRA plasma renin activity - RAS renin-angiotensin system - SBP systolic blood pressure - TIA tubulointerstitial area - VPI vasopeptidase inhibitor     

A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes

The formation of advanced glycation end products (AGEs) on extracellular matrix components leads to accelerated increases in collagen cross linking that contributes to myocardial stiffness in diabetes. This study determined the effect of the crosslink breaker, ALT-711 on diabetes-induced cardiac disease. Streptozotocin diabetes was induced in Sprague-Dawley rats for 32 weeks. Treatment with ALT-711 (10 mg/kg) was initiated at week 16. Diabetic hearts were characterized by increased left ventricular (LV) mass and brain natriuretic peptide (BNP) expression, decreased LV collagen solubility, and increased collagen III gene and protein expression. Diabetic hearts had significant increases in AGEs and increased expression of the AGE receptors, RAGE and AGE-R3, in association with increases in gene and protein expression of connective tissue growth factor (CTGF). ALT-711 treatment restored LV collagen solubility and cardiac BNP in association with reduced cardiac AGE levels and abrogated the increase in RAGE, AGE-R3, CTGF, and collagen III expression. The present study suggests that AGEs play a central role in many of the alterations observed in the diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads to attenuation of diabetes-associated cardiac abnormalities in rats. This provides a potential new therapeutic approach for cardiovascular disease in human diabetes.     

Are Nonpharmacologic Pain Interventions Effective at Reducing Pain in Adult Patients Visiting the Emergency Department? A Systematic Review and Meta‐analysis

Objectives

Pain is a common complaint in the emergency department (ED). Its management currently depends heavily on pharmacologic treatment, but evidence suggests that nonpharmacologic interventions may be beneficial. The purpose of this systematic review and meta‐analysis was to assess whether nonpharmacologic interventions in the ED are effective in reducing pain.

Methods

We conducted a systematic review of the literature on all types of nonpharmacologic interventions in the ED with pain reduction as an outcome. We performed a qualitative summary of all studies meeting inclusion criteria and meta‐analysis of randomized controlled studies measuring postintervention changes in pain. Interventions were divided by type into five categories for more focused subanalyses.

Results

Fifty‐six studies met inclusion criteria for summary analysis. The most studied interventions were acupuncture (10 studies) and physical therapy (six studies). The type of pain most studied was musculoskeletal pain (34 studies). Most (42 studies) reported at least one improved outcome after intervention. Of these, 23 studies reported significantly reduced pain compared to control, 24 studies showed no difference, and nine studies had no control group. Meta‐analysis included 22 qualifying randomized controlled trials and had a global standardized mean difference of –0.46 (95% confidence interval = –0.66 to –0.27) in favor of nonpharmacologic interventions for reducing pain.

Conclusion

Nonpharmacologic interventions are often effective in reducing pain in the ED. However, most existing studies are small, warranting further investigation into their use for optimizing ED pain management.

     

High‐Fiber Orange Juice as a Nutrition Supplement in Women

Background: The daily consumption of dietary fiber is frequently below suggested recommendations. Using a double‐blind, controlled, randomized study, we assessed the efficiency and tolerance of a fiber‐enriched orange juice to supplement fiber intake in women. Materials and Methods: After 1 week of noninterventional observation, 192 healthy adult women ingested 400 mL of orange juice for 21 days, which either was not (placebo group) or was enriched with fiber (fiber group). Orange juice ingestion was registered daily and controlled for each week during the study period. Macronutrient, fiber, and energy intake were determined using a 3‐day food record, validated food chemical composition databases, and the “Pro Diet” software. Gastrointestinal symptoms were self‐evaluated daily by scoring 4 grades of symptom intensity and using a visual analog scale to grade pain severity. Results: No changes were observed for macronutrient and energy ingestion. For the placebo group (n = 97), the total fiber intake record was under the daily recommended value. In contrast, the fiber group (n = 95) displayed higher comparative values of total and soluble fiber consumption (P ≤ .001), achieving the daily recommended values of fiber intake. Both groups reported an increased frequency of slight bloating and rumbles over time (P ≤ .05). The fiber group also experienced a higher frequency of slight flatulence over time (P = .002). Conclusion: Consumption of fiber‐enriched orange juice was efficient to achieve the daily fiber intake recommendation for women, was not accompanied by intense adverse events, and may represent a suitable method to supplement fiber intake in woman.     

Synthesis of stable isotope‐labeled epothilone D using a degradation–reconstruction approach

The stabilization of microtubules using epothilones represents a novel mechanism of action to treat Alzheimer's disease. Epothilone D is one such microtubule‐stabilizing drug that has been investigated by Bristol‐Myers Squibb. An important step in the development process was the synthesis of a stable isotope‐labeled analog for use in bioanalytical assays to accurately quantify the concentration of the drug in biological samples. A novel synthetic route to stable isotope‐labeled epothilone D is described. The synthetic route was based on a strategy to degrade epothilone B and then use that key intermediate to reconstruct stable isotope‐labeled epothilone D. Epothilone B was treated with potassium osmate and sodium periodate. The thiazole moiety in epothilone B was efficiently cleaved to give (1S,3S,7S,10R,11S,12S,16R)‐3‐acetyl‐7,11‐dihydroxy‐8,8,10,12,16‐pentamethyl‐4,17‐dioxabicyclo[14.1.0]heptadecane‐5,9‐dione. The epoxide in the macrocyclic ring of that intermediate was cleanly removed by treatment with tungsten hexachloride and n‐butyllithium to give the corresponding olefin (4S,7R,8S,9S,16S,Z)‐16‐acetyl‐4,8‐dihydroxy‐5,5,7,9,13‐pentamethyloxacyclohexadec‐13‐ene‐2,6‐dione. Bis(triethylsilyl) protection produced (4S,7R,8S,9S,16S,Z)‐16‐acetyl‐5,5,7,9,13‐pentamethyl‐4,8‐bis(triethylsilyloxy)‐oxacyclohexadec‐13‐ene‐2,6‐dione. This intermediate was coupled to a stable isotope‐labeled thiazole using a Wittig reaction as the key step to provide ¹³C₅, ¹⁵N‐labeled epothilone D. In summary, the synthesis was completed in nine total steps, only six of which involved isotopically labeled reagents. A total of 168 mg of ¹³C₅, ¹⁵N‐labeled epothilone D was prepared in an 8% overall yield from ¹³C₂, ¹⁵N‐labeled thioacetamide and ¹³C₃‐labeled ethyl bromopyruvate.     

Cor triatriatum sinister, not mitral stenosis, in an adult with previous Sydenham's chorea: diagnosis and preoperative assessment by cross sectional echocardiography.

In cor triatriatum sinister, one of the rarest congenital cardiac anomalies, a membrane divides the left atrium into a pulmonary venous component above and the vestibule below. The importance of the anomaly lies in the effects of the resultant pulmonary venous obstruction that usually present in the first year of life and can mimic obstructed total anomalous venous drainage or congenital mitral stenosis. A case presented as mitral stenosis in the third decade of life, ten years after a well documented episode of Sydenham's chorea. The diagnosis was made rapidly by transthoracic echocardiography and transoesophageal echocardiography was used for complete assessment. Cardiac catheterisation added nothing to the non-invasive diagnosis or the preoperative assessment. Uncomplicated corrective surgery was undertaken.     

Bloody needles: the volumes of blood transferred in simulations of needlestick injuries and shared use of syringes for injection of intravenous drugs.

Residual HIV-infected blood in needles and syringes is a source of HIV infection. Using radiolabelled blood we have stimulated needlestick injuries and sharing of syringes by intravenous drug users and quantified the volumes of blood which could be transferred to recipients in these situations. Up to 0.75 microliters of blood was transferred in needlestick simulations, but there was a large variation. In simulations of needlesharing, seven to ten times more blood was transferred from the index user to the first sharer when 2 ml syringes were used compared with 1 ml syringes. Washing with water was not effective in removing 'infected' blood from a syringe.     

Hyperoxia in patients with cardiogenic shock after myocardial infarction supported with venoarterial extracorporeal membrane oxygenation

BackgroundVenoarterial extracorporeal membrane oxygenation (V-A ECMO) improves perfusion and oxygenation in patients with cardiogenic shock. However, it can also result in supranormal oxygen exposure. Recent evidence suggests hyperoxia may be harmful, particularly in critically ill patients. The aim of this study was to describe oxygen exposure in patients receiving V-A ECMO after acute myocardial infarction and to investigate the association between hyperoxia and in-hospital mortality.Methods and designWe conducted a retrospective, cohort study of consecutive patients receiving V-A ECMO at a single tertiary level ECMO centre. We compared the mean and peak arterial oxygen tensions over the first 72 h after V-A ECMO initiation (n = 30) with those from a convenience sample of patients treated with an intra-aortic balloon pump (IABP) (n = 30) for cardiogenic shock.ResultsSixty patients admitted between January 2012 and March 2018 were included in the study. Patients on V-A ECMO had significantly higher arterial oxygen tensions during the first three days than those with an IABP, at 0–24 h; V-A ECMO: 286.51 mmHg (135.76) vs IABP: 103.48 mmHg (15.22), p < 0.01.Thirteen of 30 (44.8%) patients in the V-A ECMO cohort manifested extreme hyperoxia (PaO₂ ≥300 mmHg) in the first 24 hrs, compared with none in the IABP population. Within the V-A ECMO group, there was no significant association between extreme hyperoxia and in-hospital mortality (P = 0.19), duration of mechanical ventilation (P = 0.63), or troponin levels (P = 0.16) in the first 24 hrs.ConclusionSevere hyperoxia is common in patients receiving V-A ECMO after acute myocardial infarction, and this continues for at least 72 h. We found no association between extreme hyperoxia and clinical outcomes.