β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment

OBJECTIVE

This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.

RESEARCH DESIGN AND METHODS

A group of experts participated in a conference on 14–16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.

RESULTS

The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.

CONCLUSIONS

β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.     

Effects of Medicated Diet to Eradicate Helicobacter spp. on Growth,Pathology, and Infection Status in Rag1–/– and Nude Mice

The use of a commercial 4-drug diet has been shown to eradicate Helicobacter spp. from immunocompetent mice and those with innate immunodeficiencies. However the efficacy of this diet has not been confirmed in mice with altered adaptive immunity. We hypothesized that an 8-wk treatment with medicated diet would eradicate H. hepaticus and H. typhlonius from young naturally infected nude and Rag1 mice lacking functional T cells (Foxn1^nu) or T and B cells (B6.129S7-Rag1^tm1Mom/J), respectively. We evaluated helicobacter status, body weight, and gross and histologic changes between medicated and control diet in groups of infected and uninfected mice throughout treatment and at 8 wk after treatment completion. Initial infection status was confirmed by fecal PCR at weaning and 3 wk later, with study initiation in 7-wk-old mice. PCR testing demonstrated that independent of strain and sex, all treated mice tested negative for Helicobacter spp. after 4 wk of treatment and remained negative for the duration of the study. Irrespective of infection status, nude and Rag1 mice fed 8 wk of medicated diet gained less weight than did their untreated controls. Both strains normalized body weight while on control diet for the 8 wk after treatment. Mice fed medicated diet developed severe gastroesophageal hyperkeratosis, suggestive of reduced feed consumption, and enlarged ceca. These conditions improved or resolved after the return to control diet. This report is the first to demonstrate the efficacy and physical effects of providing medicated diet for the eradication of Helicobacter spp. from mice with adaptive immune deficiencies.Abbreviation: IBD, inflammatory bowel disease; NU/J, Foxn1^nu1; Rag1^tm1Mom, B6.129S7- Rag1^tm1Mom/JDespite 2 decades of reports documenting Helicobacter-associated gastrointestinal disease in mice, infections continue to persist widely not only at academic institutions in the United States but also at commercial vendors in other regions of the world.^1,3,31,44 Within the academic setting, health monitoring and exclusion policies vary markedly between universities and even within different animal facilities at a single institution. Often these policies are based on financial factors (the costs of screening by PCR and the resources required to rederive infected animals) in addition to the potential for Helicobacter infections to confound research.Attempting to predict the overall effect of infection on research can also be problematic. The development and severity of gastrointestinal pathology can vary considerably by mouse strain, species of Helicobacter, and disease model. Some strains of mice, including A/JCr, BALB/cAnNCr, C3H/HeNCr, and SJL/NCr, are particularly susceptible and develop chronic enterohepatic disease of considerable severity.^{19,21,30,49,50} In addition, several immunodeficient strains of mice develop severe disease after chronic infection. C.B-17/Icr-Prkdc^scid (SCID/NCr) mice, which lack functional T and B cells, develop progressive hepatitis and proliferative typhlocolitis after natural infection with H. hepaticus.³⁰ IL10^−/− mice such as B6.129P2-IL-10^tm1Cgn/J develop severe typhlocolitis after infection with several Helicobacter spp.^51,52 In contrast to immunocompetent strains, immunodeficient mice may manifest clinical signs such as diarrhea, perianal bleeding and rectal prolapse of variable severity.^18,29,51The species of Helicobacter affects the severity of disease. Although H. hepaticus remains the most well-studied enterohepatic mouse species, other closely related Helicobacter spp. also result in gastrointestinal disease.^15,31 Natural and experimental monoinfection with H. typhlonius led to typhlocolitis in C57BL/6J IL-10^−/− and SCID/NCr mice.^18,22,23 H. mastomyrinus infection led to granulomatous typhlocolitis (inflammatory bowel disease, IBD) in telomerase-deficient C57BL/6J mice during crucial early-senescence studies.¹⁵ Interestingly, gastrointestinal disease was significantly more severe in mice infected with H. mastomyrinus than in those infected with H. hepaticus.¹⁵In addition, the research impact of Helicobacter infections varies with disease model in a complex dynamic resulting from interactions between host gastrointestinal immunity, microflora, diet, and environmental conditions. Mouse models of IBD highlight these complexities. Helicobacter spp. infection rather than genetic modification was found to be responsible for the susceptibility and pattern of IBD development in T cell receptor αβ mutant mice.^6,10 Intentional inoculation has been used to study Helicobacter spp.- associated alterations in resident intestinal microflora and induction and severity of IBD in immunodeficient mice.⁵¹Given the difficulties of predicting the research impact of Helicobacter spp. infection in mice, perhaps tolerance for enzootic infections should be reconsidered. Benefits to eradication include not only elimination of the agent as an experimental confounder but also as a means to improve welfare through reduced clinical disease.¹ Complete exclusion of infected animals may serve as the least labor intensive and most cost effective strategy. A 10-y institution-wide exclusion policy that required all imported mice to be either rederived by embryo transfer or purchased from an approved Helicobacter-free vendor resulted in either complete elimination or significant reduction in 4 facilities tested in 1999 and again in 2009.³¹ Although effective, this method has the potential to interfere with the ability of individual investigators to receive mice from collaborating institutions that maintain facilities of unknown or positive infection status. In addition, this strategy would be ineffective for inhouse breeding colonies of genetically modified mice. In such cases, rederivation by in vitro fertilization, embryo transfer, and postpartum cross-fostering have all been proven successful. Although often effective, embryo transfer can be impeded by factors such as insufficient response to superovulation, unavailability of stud males, inadequate yield of fertilized eggs, unsuccessful embryo transfer, and the need for genotyping—all of which delay the initiation of research.⁴⁷ Furthermore, the detection of H. typhlonius from sex organs of both female and male Hsd:Athymic Nude-Foxn1^nu mice has demonstrated the potential for transmission from vasectomized male and recipient female mice.³⁸Rederivation by cross fostering has been used to eliminate enzootic Helicobacter spp. infections.^1,46 This technique is less costly and labor intensive and requires less expertise than embryo transfer.^1,42,46 One study comparing 2 cross fostering paradigms to eliminate Helicobacter spp., murine norovirus, mouse hepatitis virus and Syphacia obvelata found success was dependent on both pup age at the time of transfer and bedding changing patterns.¹ Pups transferred within 24 h of birth from cages that underwent bedding changes every 24 h tested negative more frequently than did pups transferred within 48 h of birth from cages containing up to 7-d-old dirty bedding.¹ However neither paradigm was completely successful in Helicobacter elimination, as evidenced by follow-up PCR testing of cross-fostered offspring.¹ Furthermore, isolation of H. hepaticus from the viscera of several late-stage C.B-17/Icr-Prkdc^scid (SCID/NCr) embryos belonging to an infected dam suggests that transplacental transmission is possible in immunodeficient mice.³⁰The administration of antibiotics to eliminate Helicobacter spp. in rodents has evolved considerably since first used to prevent chronic active hepatitis and colitis in young male SCID/NCr mice naturally infected with H. hepaticus.³⁶ In that initial report, various combinations of amoxicillin, bismuth, metronidazole, neomycin, and tetracycline were either added to the drinking water or administered orally 3 times daily for 14 d.³⁶ Although clearly labor-intensive, the cited study³⁶ determined that H. hepaticus could be eliminated by using all treatment regimens that included amoxicillin. A similar dosing regimen using either amoxicillin or tetracycline-based triple therapy was used to eliminate H. hepaticus from infected A/JCr mice.¹⁶ The first medicated diet formulation intended to eliminate infection in mice was a triple therapy of amoxicillin, metronidazole, and bismuth.¹⁷ When fed continuously for 2 wk to 6- to 10-mo-old DBA/J mice, the diet successfully eliminated chronic H. hepaticus infection as confirmed by posttreatment culture and PCR testing 1 mo later.¹⁷ Despite this success, the same amoxicillin-based triple combination diet fed for an unspecified duration failed to eliminate H. hepaticus from an immunodeficient breeding colony of Rag1 ^−/− mice.^16,51 When administered to a SCID (Prkc^scid/Tpr53^tm1tyi on a B6.129/Sv × C.B17 background) breeding colony severely affected by diarrhea associated with H. rodentium and H. bilis coinfection, the triple therapy reduced clinical illness during treatment period but did not eliminate infection or persistent diarrhea.⁴¹Although a newer medicated diet containing amoxicillin, clarithromycin, metronidazole, and omeprazole has been available for a decade, reports of efficacy are still quite limited. One study demonstrated successful eradication of H. hepaticus and H. bilis from a colony of 129 × 1/SvJ desmin-null and heterozygotic mice after 8 wk of continual treatment and 19 mo of PCR follow-up testing.²⁸ In addition, the 4-drug therapy was successful in eliminating Helicobacter spp. from several genetically modified rat strains whereby infected male rats were medicated for 3-two week cycles and pregnant rat dams and offspring were fed continuously from day 7 of gestation through weaning.²⁶ Posttreatment follow-up testing for 8 mo by fecal PCR confirmed that all treated rats remained negative.²⁶ More recently, we have reported the successful eradication of H. hepaticus, H. bilis, and H. rodentium from 2 strains of mice with innate immune deficiencies.⁹Questions remain, however, regarding the broad applicability of medicated diet for the elimination of Helicobacter spp., particularly with regard to strains with modifications of the immune system. The 4-drug medicated diet was unable to eradicate Helicobacter spp. from in B6.129P2-IL10^tm1Cgn/J mice,⁴⁰ and there is no information regarding efficacy in mice with deficiencies in adaptive immunity. Given the widespread use of these mice in gastrointestinal cancer and IBD research, evaluation of medicated diet to eradicate Helicobacter spp. from such strains is warranted. Although many immunodeficient inbred strains are available Helicobacter-free from commercial vendors, these strains often are genetically modified further, maintained, and imported from collaborating institutions with endemic Helicobacter spp. infections that need to be eliminated in a timely manner. We therefore conducted a prospective controlled study to evaluate the potential of the 4-drug medicated diet to eradicate H. hepaticus and H. typhlonius from young, naturally infected nude and Rag1 mice lacking functional T cells (Foxn1^nu) or T and B cells (B6.129S7-Rag1^tm1Mom/J), respectively. We also evaluated the physical effect of both Helicobacter infection and medicated diet in growing mice by weekly recordings of body weight and assessment of gross and histologic changes between medicated and control diet in groups of infected and uninfected mice after an 8-wk treatment course and again 8 wk after treatment completion.     

Synthesis and Evaluation of 13N-Labelled Azo Compounds for β-Amyloid Imaging in Mice

Purpose

The aim of the present study was to develop short half-lived tools for in vitro and in vivo β-amyloid imaging in mice, for which no suitable PET tracers are available.

Procedures

Five ¹³N-labelled azo compounds (1–5) were synthesized using a three-step process using cyclotron-produced [¹³N]NO₃ ^?. Biodistribution studies were performed using positron emission tomography–computed tomography (PET–CT) on 20-month-old healthy, wild-type (WT) mice. In vivo and in vitro binding assays were performed using PET-CT and autoradiography, respectively, on 20-month-old healthy (WT) mice and transgenic (Tg2576) Alzheimer's disease model mice.

Results

¹³N-labelled azo compounds were prepared with decay corrected radiochemical yields in the range 27?±?4 % to 39?±?4 %. Biodistribution studies showed good blood–brain barrier penetration for compounds 1 and 3–5; good clearance data were also obtained for compounds 1–3 and 5. Compounds 2, 3 and 5 (but not 1) showed a significant uptake in β-amyloid-rich structures when assayed in in vitro autoradiographic studies. PET studies showed significant uptake of compounds 2 and 3 in the cortex of transgenic animals that exhibit β-amyloid deposits.

Conclusions

The results underscore the potential of compounds 2 and 3 as in vitro and in vivo markers for β-amyloid in animal models of Alzheimer's disease.     

A Fixed Nitrous Oxide and Oxygen Mixture for Analgesia in Children With Leukemia With Lumbar Puncture–induced Pain: A Randomized,Double-blind Controlled Trial

ContextLeukemia is the most common cancer in the childhood population. Lumbar puncture (LP) plays central role in the diagnosis and treatment process, but options for analgesia are limited.ObjectivesThe present study aims to evaluate the efficacy of a fixed N₂O/O₂ mixture to reduce pain in children with leukemia during LP as compared with placebo.MethodsA double-blind, placebo-controlled, and randomized clinical trial involving children who needed LP for diagnosis or treatment was conducted in the pediatrics department of the General Hospital of Ningxia Medical University. Eligible patients were randomly assigned to inhale either a fixed N₂O/O₂ mixture or O₂. The primary endpoint was the maximal pain level felt by the patient during the procedure measured using a numerical rating scale (0–10).ResultsOne-hundred fourteen consecutive patients were enrolled in this study and randomized. Pain scores during the procedure showed a significant decrease in N₂O/O₂ mixture–treated patients to 1.05 ± 1.40 versus 8.00 ± 2.13 in controls (P < 0.01). No serious adverse effects were attributed to N₂O/O₂ mixture inhalation. Analysis of the satisfaction of patients receiving N₂O/O₂ mixture indicated that medical staff were satisfied with this treatment.ConclusionsThis study demonstrated that self-administered fixed N₂O/O₂ is efficient to reduce pain related to LP in children with leukemia.     

Cell Membrane–associated Heparan Sulfate Is a Receptor for Prototype Foamy Virus in Human,Monkey, and Rodent Cells

Foamy viruses (FVs) (spumaretroviruses) are good alternative to retroviruses as gene therapy vector. Despite four decades since the discovery of FV, its receptor molecule is still unknown. FV vector transduction of human CD34⁺ cells was inhibited by culture with fibronectin. Because fibronectin contains heparin-binding domain, the interactions of fibronectin with heparan sulfate (HS) on cells might be inhibitory to FV transduction. These observations led us to investigate whether HS is a receptor for FV. Two mutant CHO cell lines (but not parental wild type) lacking cell surface HS but not chondroitin sulfate (CS) were largely resistant to FV attachment and transduction. Inhibition of HS expression using enzymes or chemicals greatly reduced FV transduction in human, monkey, and rodent cells. Raji cells, which lack HS and were largely resistant to FV, were rendered more permissive through ectopic expression of syndecan-1, which contains HS. In contrast, mutant syndecan-1-expressing cells were largely resistant to FV. Our findings indicate that cellular HS is a receptor for FV. Identifying FV receptor will enable better understanding of its entry process and optimal use as gene therapy vector to treat inherited and pathogenic diseases.     

Mechanisms: what are they evidence for in evidence‐based medicine?

Even though the evidence‐based medicine (EBM) movement labels mechanisms a low quality form of evidence, consideration of the mechanisms on which medicine relies, and the distinct roles that mechanisms might play in clinical practice, offers a number of insights into EBM itself. In this paper, I examine the connections between EBM and mechanisms from several angles. I diagnose what went wrong in two examples where mechanistic reasoning failed to generate accurate predictions for how a dysfunctional mechanism would respond to intervention. I then use these examples to explain why we should expect this kind of mechanistic reasoning to fail in systematic ways, by situating these failures in terms of evolved complexity of the causal system(s) in question. I argue that there is still a different role in which mechanisms continue to figure as evidence in EBM: namely, in guiding the application of population‐level recommendations to individual patients. Thus, even though the evidence‐based movement rejects one role in which mechanistic reasoning serves as evidence, there are other evidentiary roles for mechanistic reasoning. This renders plausible the claims of some critics of EBM who point to the ineliminable role of clinical experience. Clearly specifying the ways in which mechanisms and mechanistic reasoning can be involved in clinical practice frames the discussion about EBM and clinical experience in more fruitful terms.     

β-Cell Mass and Turnover in Humans: Effects of obesity and aging

OBJECTIVE

We sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age.

RESEARCH DESIGN AND METHODS

We examined human autopsy pancreas from 167 nondiabetic individuals 20–102 years of age. The effect of obesity on β-cell mass was examined in 53 lean and 61 obese subjects, and the effect of aging was examined in 106 lean subjects.

RESULTS

β-Cell mass is increased by ∼50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably preserved. There is minimal β-cell replication or apoptosis in lean humans throughout life with no detectable changes with obesity or advanced age.

CONCLUSIONS

β-Cell mass in human obesity increases by ∼50% by an increase in β-cell number, the source of which is unknown. β-Cell mass is well preserved in humans with advanced aging.The incidence of type 2 diabetes increases with obesity and aging (1). There is a deficit in β-cell mass with increased β-cell apoptosis in type 2 diabetes (2). Although there are numerous studies of changes in β-cell mass and turnover in rodents, inevitably the data is much more limited in humans. As there is an increasing appreciation that regulation of β-cell mass in humans and rodents can be quite different, additional studies in humans, where possible, is important. In the current study, we addressed the following questions.First, is β-cell mass adaptively increased in obese humans, and if so, is this through increased β-cell replication as widely reported in rodents? It has been reported that β-cell mass increases with obesity in age-matched individuals but β-cell replication was not reported (3). Second, is β-cell apoptosis increased with obesity? The increased β-cell apoptosis in type 2 diabetes (2) has been ascribed to lipotoxicity, based on increased β-cell apoptosis in rodents with obesity due to deficient leptin signaling (4). Since the relative fat content (fat-to-acinar ratio) accumulates in the pancreas in humans with obesity (5), if this is sufficient to induce increased β-cell apoptosis, then it would be anticipated that humans with marked obesity would have increased β-cell apoptosis.Third, we questioned if β-cell mass adaptively decreases with aging, and if so, is this due to increased β-cell apoptosis? β-Cell function declines in humans with aging (6). The exocrine pancreas undergoes marked atrophy after 60 years of age, but there is limited data available about the changes in β-cell mass with aging, with one study reporting a marginal decline with age (3) but providing no measure of β-cell turnover.     

Quinolone Resistance Mechanisms in Salmonella enterica Serovars Hadar,Kentucky, Virchow,Schwarzengrund, and 4,5,12:i:?, Isolated from Humans in Switzerland,and Identification of a Novel qnrD Variant,qnrD2, in S. Hadar

Human isolates of Salmonella enterica serovars Hadar, Kentucky, Virchow, Schwarzengrund, and the monophasic variant of S. Typhimurium, Salmonella enterica subsp. enterica serovar 4,5,12:i:− were examined for mutations within the quinolone resistance target genes gyrA, gyrB, parC, and parE and for plasmid-mediated resistance genes. Differences were observed among the serovars. A novel variant of qnrD, qnrD2, was detected in an S. Hadar isolate.     

Effects of a brief and economical intervention in preparing patients for surgery: does coping style matter?

The objective of this study was to examine the effects of a brief and economical procedure in the preparation of surgical patients. More specifically, the study was intended to test whether patient's monitoring style (high vs. low) makes any difference to the benefits of a relaxation technique. Ninety-two patients scheduled for hysterectomy with double oophorectomy were assessed for preferred coping style and randomly assigned to one of two conditions: (a) relaxation training and (b) attention control. It was hypothesized that low monitors would report less pain, less analgesic use and a higher activity level when trained in relaxation than low monitor controls or than high monitors trained in relaxation. Results showed no differences between individuals with different coping styles. On the other hand, however, statistically significant differences were observed between trained patients and controls. Namely, individuals trained in relaxation experienced less pain along the surgical process, pain interfered less with their daily activities, and performed a higher activity level three weeks after surgery, compared to non trained patients.     

Antinociceptive Effects of (1→3),(1→6)-Linked β-Glucan Isolated From Pleurotus pulmonarius in Models of Acute and Neuropathic Pain in Mice: Evidence for a Role for Glutamatergic Receptors and Cytokine Pathways

The present study evaluated the antinociceptive effect of (1→3),(1→6)-linked β-glucan (GL) isolated from Pleurotus pulmonarius (Fr.) Quel. in mice and its possible mechanism of action. Intraperitoneal administration of GL inhibited glutamate-induced licking with an ID₅₀ of 0.34 mg/kg and inhibition of 96% ± 3%. The treatment of animals with GL (1 mg/kg i.p.) inhibited nociception induced by intrathecal injection of N-methyl-D-aspartic acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate and interleukin -1β in 67% ± 13%, 89% ± 11%, 74% ± 9%, and 75% ± 7%, respectively, but not the nociceptive response induced by (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, substance P, and tumor necrosis factor-α. Moreover, GL (30 mg/kg i.p.) also reduced mechanical allodynia caused by partial sciatic nerve ligation for 2 hours, with inhibition of 47% ± 10% observed 0.5 hours after treatment. When given chronically (twice a day) over 7 days, GL reversed the mechanical allodynia caused by partial sciatic nerve ligation (inhibition of 45% ± 13% to 60% ± 8%). Interestingly, GL did not affect the locomotor activity of mice in an open field test with doses that produce antinociceptive effects. Our findings show that GL inhibits acute and neuropathic pain in mice through mechanisms that involve the inhibition of ionotropic glutamate receptors and the interleukin -1β pathway.     

Effects of metformin and rosiglitazone on peripheral insulin resistance and β-cell function in obesity: a double-blind, randomized, controlled study

Metformin and rosiglitazone combination therapy is known to improve insulin resistance and postpone diabetes mellitus development in subjects with impaired glucose tolerance. This double-blind, randomized, controlled study assessed this combination therapy for preventing type 2 diabetes in obese subjects with hyperinsulinaemia. Subjects received metformin (500 mg three times daily, orally) plus either rosiglitazone (4 mg once daily, orally; n = 94) or placebo (n = 95) and were followed for 6 months. Blood pressure, body fat, body mass index (BMI), lipid and insulin levels were recorded pre- and post-treatment. Metformin plus rosiglitazone significantly decreased blood pressure, lipids, BMI, and fasting and postmeal insulin levels. Metformin plus placebo led to a significant decrease in blood pressure, BMI and lipid levels, but fasting and postmeal insulin levels were unchanged. Adverse events were similar between the two groups. The metformin and rosiglitazone combination increased insulin sensitivity and β-cell function recovered. This approach may represent a therapeutic option for preventing development of type 2 diabetes in obese subjects with hyperinsulinaemia.     

Effects of dopamine,norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best?

OBJECTIVE: To assess the effects of different doses of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in patients with septic shock. DESIGN: Prospective, randomized, open-label study. SETTING: A 31-bed, medicosurgical intensive care unit of a university hospital. PATIENTS: Convenience sample of 20 patients with septic shock, separated into two groups according to whether (moderate shock group, n = 10) or not (severe shock, n = 10) dopamine alone was able maintain mean arterial pressure >65 mm Hg. INTERVENTIONS: Dopamine was progressively withdrawn and replaced successively by norepinephrine and then epinephrine (the order of the two agents was randomly determined) to maintain mean arterial pressure constant (moderate shock) or to increase mean arterial pressure above 65 mm Hg (severe shock). MEASUREMENTS AND MAIN RESULTS: Systemic circulation (pulmonary artery catheter) and splanchnic circulation (indocyanine green dilution and hepatic vein catheter) and gastric mucosal Pco(2) (gas tonometry) were measured during dopamine (moderate shock only), norepinephrine, and epinephrine administration (both groups). Data were analyzed with nonparametric tests and are presented as median [percentiles 25-75]. In moderate shock, cardiac index was similar to dopamine and norepinephrine (3.1 [2.7-3.8] vs. 2.9 [2.7-4.1] L/min.m2, p = nonsignificant) but greater with epinephrine (4.1 [3.5-4.4] p <.01 vs. dopamine and norepinephrine). Splanchnic blood flow was similar with the three agents (732 [413-1483] vs. 746 [470-1401] vs. 653 [476-1832] mL/min.m, p = nonsignificant). The gradient between mixed-venous and hepatic venous oxygen saturations was lower with dopamine than with norepinephrine and epinephrine, but the Pco(2) gap was similar with the three agents. In severe shock, cardiac index was higher, but splanchnic blood flow was lower, with epinephrine than with norepinephrine (4.6 [3.7-5.3] vs. 3.4 [3.0-4.1] L/min.m2, p <.01 and 860 [684-1334] vs. 977 [806-1802] mL/min.m2, p <.05, respectively). Epinephrine increased the mixed-venous and hepatic venous oxygen saturation gradient but did not alter Pco(2) gap. CONCLUSIONS: Dopamine and norepinephrine have similar hemodynamic effects, but epinephrine can impair splanchnic circulation in severe septic shock.     

Making sense of refractive surgery in 2001: why, when, for whom, and by whom?

Surgical alteration of the focusing or refractive properties of the eye has been performed on millions of patients. An array of procedures to correct myopia, hyperopia, astigmatism, and presbyopia have been introduced over the past 25 years with varying degrees of success. Improved technology has increased patient and physician satisfaction and enthusiasm. Currently available surgical procedures can be categorized as incisional, surface-altering, lamellar, and intraocular. The choice of procedure depends on individual patient indications and contraindications based on results of ocular examinations, eg, corneal pachymetry to measure corneal thickness, keratometry to measure the corneal curvature, basal tear secretory rate, and dark-adapted pupil size. The postoperative uncorrected visual acuity depends, in large part, on the quality of the preoperative evaluation and refraction. Before scheduling a patient for surgery, the ophthalmologist must ensure that the patient understands the potential risks of the procedure and has realistic expectations for the postoperative level and quality of uncorrected visual acuity. Postoperative complications include corneal flap displacement, undercorrection and overcorrection, and epithelial ingrowth under the corneal flap and inflammatory keratitis. Postoperative dry eye, infection, and inflammation are usually treated medically. Ongoing technological innovations to customize the surgical approach to an individual patient's eye continue to improve outcomes.     

Faster,higher, stronger? Evidence for formulation and efficacy for ibuprofen in acute pain

A Cochrane review of ibuprofen in acute pain suggested that rapidly absorbed formulations of salts, or features to speed absorption, provided better analgesia than standard ibuprofen as the free acid. We examined several lines of evidence to investigate what benefit derived from fast-acting formulations. A systematic review of the kinetics of oral ibuprofen (30 studies, 1015 subjects) showed that median maximum plasma concentrations of fast-acting formulations occurred before 50 min (29–35 min for arginine, lysine, and sodium salts) compared with 90 min for standard formulations. An updated analysis of clinical trials (over 10,000 patients) showed that fast-acting formulations produced significantly better analgesia over 6 h and fewer remedications than standard formulations in both indirect and direct comparisons. In dental studies, 200-mg fast-acting ibuprofen (number needed to treat 2.1; 95% confidence interval 1.9–2.4) was as effective as 400 mg standard ibuprofen (number needed to treat 2.4; 95% confidence interval 2.2–2.5), with faster onset of analgesia. Individual patient data analysis in dental pain demonstrated a strong correlation between more rapid reduction of pain intensity over 0–60 min and better pain relief over 0–6 h. Rapid initial reduction of pain intensity was also linked with reduced need for remedication. Fast-acting formulations of ibuprofen demonstrated more rapid absorption, faster initial pain reduction, good overall analgesia in more patients at the same dose, and probably longer-lasting analgesia, but with no higher rate of patients reporting adverse events. Achieving a better analgesic effect with fast-acting nonsteroidal anti-inflammatory drug formulations has important implications for safety. Formulation chemistry is of potential importance for analgesics.     

Action of Phα1β, a Peptide From the Venom of the Spider Phoneutria nigriventer,on the Analgesic and Adverse Effects Caused by Morphine in Mice

Opioids are standard therapy for the treatment of pain; however, adverse effects limit their use. Voltage-gated calcium channel blockers may be used to increase opioid analgesia, but their effect on opioid-induced side effects is little known. Thus, the goal of this study was to evaluate the action of the peptide Phα1β, a voltage-gated calcium channel blocker, on the antinociceptive and adverse effects produced by morphine in mice. A single administration of morphine (3–10 mg/kg) was able to reduce heat nociception as well as decrease gastrointestinal transit. The antinociception caused by a single injection of morphine was slightly increased by an intrathecal injection of Phα1β (30 pmol/site). Repeated treatment with morphine caused tolerance, hyperalgesia, withdrawal syndrome, and constipation, and the Phα1β (.1–30 pmol/site, intrathecal) was able to reverse these effects. Finally, the effects produced by the native form of Phα1β were fully mimicked by a recombinant version of this peptide. Taken together, these data show that Phα1β was effective in potentiating the analgesia caused by a single dose of morphine as well as in reducing tolerance and the adverse effects induced by repeated administration of morphine, indicating its potential use as an adjuvant drug in combination with opioids.PerspectiveThis article presents preclinical evidence for a useful adjuvant drug in opioid treatment. Phα1β, a peptide calcium channel blocker, could be used not only to potentiate morphine analgesia but also to reduce the adverse effects caused by repeated administration of morphine.