Insulin tightly regulates glucose levels within a narrow range through its action on muscle, adipose tissue and the liver. The activation of insulin receptors activates multiple intracellular ...pathways with different functions. Another tightly regulated complex system in the body is acid-base balance. Metabolic acidosis, defined as a blood pH < 7.35 and serum bicarbonate < 22 mmol/L, has clear pathophysiologic consequences including an effect on insulin action. With the ongoing intake of typical acid-producing Western diets and the age-related decline in renal function, there is an increase in acid levels within the range considered to be normal. This modest increase in acidosis is referred to as "acid stress" and it may have some pathophysiological consequences. In this article, we discuss the effects of acid stress on insulin actions in different tissues.
The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive ...regimen using the antileukocyte functional antigen‐1 antibody efalizumab which permits long‐term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single‐islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long‐term follow‐up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid‐free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long‐term islet allograft survival.
An immunosuppressive regimen based on the anti‐LFA‐1 antibody efalizumab showed some promising results in eight islet transplant recipients. See Editorial by Oberholzer et al 1725.
The effects of single doses of intravenous (IV) ciprofloxacin and rifampin and of multiple doses of rifampin on glyburide exposure and blood glucose levels were investigated in nine healthy ...volunteers. A single IV dose of rifampin significantly increased the area under the concentration–time curve (AUC) of glyburide and its metabolite. Blood glucose levels were significantly lower than those observed after dosing with glyburide alone. Multiple doses of rifampin induced an increase in liver enzyme levels, leading to a marked decrease in glyburide exposure and blood glucose levels. When IV rifampin was administered after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect; however, the relative changes in AUC for glyburide and its hydroxyl metabolite were similar to those seen under noninduced conditions. The studies reported here demonstrate how measurements of the levels of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug–drug induction and inhibition effects and in characterizing enzymatic vs. transporter mechanisms.
Clinical Pharmacology & Therapeutics (2008); 85, 1, 78–85 doi:10.1038/clpt.2008.186
Purpose
The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced ...elevations in gastric pH.
Methods
This open-label cross over clinical study (NCT02758015) included 9 subjects who were randomly assigned to one of 16 possible, 4-period cross-over sequences to determine the impact and relationship of food and gastric pH with acid supplementation. Subjects were administered various doses (1500 mg, 3000 mg and 4500 mg) of betaine hydrochloride (BHCl) to determine the ability of acid supplementation to reacidify gastric pH after the elevation of gastric pH caused by the ingestion of food.
Results
Following the administration of food and the resulting elevation in gastric pH, time to return to baseline gastric pH levels without acid supplementation was 49.7 ± 14.0 min. Administering 4500 mg of BHCl acid in capsules was able to reacidify gastric pH levels back to baseline following the administration of food in approximately 17.3 ± 5.9 min. AUC
pH
of each treatment were similar and not statistically different. Mean max pH following the administration of food was 3.20 ± 0.55.
Conclusion
The ability of food to elevate and maintain gastric pH levels in the presence of acid supplementation was made evident throughout the study. A 4500 mg dose of BHCl was required to reacidify gastric pH after the administration of food. This study details the difficulty faced by clinicians in dosing a poorly soluble, weakly basic drug to patients receiving acid reducing agents where administration with food is recommended to avoid gastric side effects.
Trial Registration:
https://clinicaltrials.gov/ct2/show/NCT02758015
High dietary phosphorus intake (P-In) and high acid loads may adversely affect kidney function. In animal models, excessive phosphorus intake causes renal injury, which, in humans, is also inducible ...by chronic metabolic acidosis. We thus examined whether habitually high P-In and endogenous acid production during childhood and adolescence may be early indicators of incipient renal inflammatory processes later in adulthood. P-In and acid-base status were longitudinally and exclusively determined by biomarker-based assessment in 277 healthy children, utilizing phosphate and net acid excretion (NAE) measurements in 24 h urine samples repeatedly collected between the ages of 3 and 17 years. Standard deviation scores (by sex and age) were calculated for anthropometric data and for the urinary biomarkers available within age range 3-17 years. Multivariable linear regression was used to analyze the relations of phosphate excretion and NAE with the adulthood outcome circulating interleukin-18 (IL-18), a marker of inflammation and kidney dysfunction. After adjusting for growth- and adulthood-related covariates and pro-inflammatory biomarkers to rule out confounding by non-renal inflammatory processes, regression models revealed a significant positive relationship of long-term NAE (
= 0.01), but not of long-term phosphate excretion with adult serum IL-18. Similar significant positive regression results were obtained after replacing NAE with 24 h urinary ammonium excretion as the exposition variable. Our results suggest that even moderate elevations in renal ammonia production, as caused by habitually higher acid loading during growth, may affect the intrarenal pro-inflammatory system in the long-term, known to be boosted by acidosis-induced raised ammoniagenesis.
Background: The contemporary American diet figures centrally in the pathogenesis of numerous chronic diseases--'diseases of civilization'. We investigated in humans whether a diet similar to that ...consumed by our preagricultural hunter-gatherer ancestors (that is, a paleolithic type diet) confers health benefits. Methods: We performed an outpatient, metabolically controlled study, in nine nonobese sedentary healthy volunteers, ensuring no weight loss by daily weight. We compared the findings when the participants consumed their usual diet with those when they consumed a paleolithic type diet. The participants consumed their usual diet for 3 days, three ramp-up diets of increasing potassium and fiber for 7 days, then a paleolithic type diet comprising lean meat, fruits, vegetables and nuts, and excluding nonpaleolithic type foods, such as cereal grains, dairy or legumes, for 10 days. Outcomes included arterial blood pressure (BP); 24-h urine sodium and potassium excretion; plasma glucose and insulin areas under the curve (AUC) during a 2 h oral glucose tolerance test (OGTT); insulin sensitivity; plasma lipid concentrations; and brachial artery reactivity in response to ischemia. Results: Compared with the baseline (usual) diet, we observed (a) significant reductions in BP associated with improved arterial distensibility (-3.12.9, P=0.01 and +0.190.23, P=0.05);(b) significant reduction in plasma insulin vs time AUC, during the OGTT (P=0.006); and (c) large significant reductions in total cholesterol, low-density lipoproteins (LDL) and triglycerides (-0.80.6 (P=0.007), -0.70.5 (P=0.003) and -0.30.3 (P=0.01) mmol/l respectively). In all these measured variables, either eight or all nine participants had identical directional responses when switched to paleolithic type diet, that is, near consistently improved status of circulatory, carbohydrate and lipid metabolism/physiology. Conclusions: Even short-term consumption of a paleolithic type diet improves BP and glucose tolerance, decreases insulin secretion, increases insulin sensitivity and improves lipid profiles without weight loss in healthy sedentary humans.
Global seismographic networks (GSNs) emerged during the late nineteenth and early twentieth centuries, facilitated by seminal international developments in theory, technology, instrumentation, and ...data exchange. The mid‐ to late‐twentieth century saw the creation of the World‐Wide Standardized Seismographic Network (1961) and International Deployment of Accelerometers (1976), which advanced global geographic coverage as seismometer bandwidth increased greatly allowing for the recording of the Earth's principal seismic spectrum. The modern era of global observations and rapid data access began during the 1980s, and notably included the inception of the GEOSCOPE initiative (1982) and GSN (1988). Through continual improvements, GEOSCOPE and the GSN have realized near‐real time recording of ground motion with state‐of‐art data quality, dynamic range, and timing precision to encompass 180 seismic stations, many in very remote locations. Data from GSNs are increasingly integrated with other geophysical data (e.g., space geodesy, infrasound and Interferometric Synthetic Aperture Radar). Globally distributed seismic data are critical to resolving crust, mantle, and core structure; illuminating features of the plate tectonic and mantle convection system; rapid characterization of earthquakes; identification of potential tsunamis; global nuclear test verification; and provide sensitive proxies for environmental changes. As the global geosciences community continues to advance our understanding of Earth structure and processes controlling elastic wave propagation, GSN infrastructure offers a springboard to realize increasingly multi‐instrument geophysical observatories. Here, we review the historical, scientific, and monitoring heritage of GSNs, summarize key discoveries, and discuss future associated opportunities for Earth Science.
Plain Language Summary
Global seismographic networks (GSNs) record information‐rich ground motion signals that allow scientists and nations to identify and quantify global earthquakes and other seismic sources, and to rapidly assess their significance and impacts on society. In addition to providing a global standard for the monitoring and assessment of such events, these networks provide unique high‐quality data that are fundamental to revealing Earth's structure and dynamic behavior. Scientific applications of GSNs, supplemented by regional data, include imaging the deep interior of the Earth and its plate tectonic system, modeling the structure and dynamics of the inner core, imaging and understanding the rupture of earthquake faults, detecting, discriminating, and characterizing nuclear and other explosions, and improving our general understanding of Earth's ubiquitous seismic wavefield and the unique information that it conveys from the deep interior to the surface and atmosphere of the planet. Leveraging the extensive and hardened infrastructure at these global observatories facilitates the recording of other signals of geophysical interest, such as the magnetic field, low frequency sound waves, and meteorological observations. We review the heritage of GSNs, including their history and resulting scientific achievements, and summarize future opportunities for these networks to contribute further to improved advancements in Earth science.
Key Points
Long running globally distributed seismographic networks are fundamental to understanding Earth's interior structure and processes
Networks have expanded beyond initial mid‐twentieth century design which were focused on recording signals from earthquakes and explosions
Global seismic data combined with data from nearby geophysical instrumentation continue to facilitate new discoveries in Earth science
Solid organ transplantation in human immunodeficiency virus (HIV)‐infected individuals requiring concomitant use of immunosuppressants (IS) (e.g. cyclosporine CsA, sirolimus SrL, tacrolimus FK) and ...antiretrovirals (ARVs) (e.g. protease inhibitors PIs and/or nonnucleoside reverse transcriptase inhibitors NNRTIs) is complicated by significant drug interactions. To assist in appropriate clinical management, we describe the pharmacokinetics and dosing modifications in 35 patients (20 kidney, 13 liver and two kidney‐liver HIV‐infected subjects with end‐stage kidney or liver disease), on both IS and NNRTIs, PIs, and combined NNRTIs + PIs, in studies done at weeks 2–4 and/or 12 weeks after transplantation or after a change in IS or ARV drug regimen (n = 97 studies). CsA, SrL and FK concentrations were measured in whole blood by LC/MS. HIV‐infected transplant recipients using PIs with IS had marked increases in CsA, FK or SrL trough levels compared to those on NNRTIs alone or to patients not on ARVs, necessitating either a reduction in dose or an increase in dosing interval. Subjects on efavirenz (EFV) and CsA required much higher doses of CsA than those using any other ARV. Changes in antiretroviral therapy should be carefully managed to avoid insufficient immunosuppression or toxicity due to drug interactions.
Pharmacokinetics and initial dosing of immunosuppressants in HIV‐infected liver and kidney transplant patients on various antiretroviral regimens.
Normal adult humans eating Western diets have chronic, low-grade metabolic acidosis, the severity of which is determined in part by the net rate of endogenous noncarbonic acid production (NEAP), ...which varies with diet. To prevent or reverse age-related sequelae of such diet-dependent acidosis (eg, bone and muscle loss), methods are needed for estimating and regulating NEAP. Because NEAP is difficult to measure directly, we sought a simple method to estimate it from diet-composition data. We focused on protein and potassium contents because the production of sulfuric acid from protein metabolism and bicarbonate from dietary potassium salts of organic acids are the major variable components of NEAP. Using steady state renal net acid excretion (RNAE) as an index of NEAP in 141 normal subjects eating 20 different diets, we found by multiple linear regression analysis that RNAE mEq/d x 10460 kJ diet (mEq/d 2500 kcal) was predictable (R2 = 0.62) from protein g/d x 10460 kJ diet (g/d 2500 kcal); positive regression coefficient, P < 0.001 and potassium mEq/d x 10460 kJ diet (mEq/d x 2500 kcal): negative regression coefficient, P = 0.001 contents, which were not themselves correlated. Among diets, 71% of the variation in RNAE could be accounted for by the ratio of protein (Pro) to potassium (K) content: RNAE = 62Pro/K - 17.9 (r = 0.84, R2 = 0.71, P < 0.001). Thus, by considering both the acidifying effect of protein and the alkalinizing effect of potassium (organic anions), NEAP can be predicted with confidence from the readily available contents of only 2 nutrients in foods. Provisionally, these findings allow estimation and regulation of NEAP through diet modification.
Improvements in human immunodeficiency virus (HIV)‐associated mortality make it difficult to deny transplantation based upon futility. Outcomes in the current management era are unknown. This is a ...prospective series of liver or kidney transplant recipients with stable HIV disease. Eleven liver and 18 kidney transplant recipients were followed for a median of 3.4 years (IQR interquartile range 2.9–4.9). One‐ and 3‐year liver recipients’ survival was 91% and 64%, respectively; kidney recipients’ survival was 94%. One‐ and 3‐year liver graft survival was 82% and 64%, respectively; kidney graft survival was 83%. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999–2004 transplants in the national database. CD4+ T‐cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). The 1‐ and 3‐year cumulative incidence (95% confidence intervals CI) of rejection episodes for kidney recipients was 52% (28–75%) and 70% (48–92%), respectively. Two‐thirds of hepatitis C virus (HCV)‐infected patients, but no patient with hepatitis B virus (HBV) infection, recurred. Good transplant and HIV‐related outcomes among kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV‐infected patients cared for at centers with adequate expertise.
Good transplant and HIV‐related outcomes among HIV‐infected kidney recipients, and reasonable outcomes among liver transplant recipients, suggest that transplantation is an option for selected HIV‐infected patients cared for at centers with adequate expertise.
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