Differentiation of radioligand delivery and binding in the brain: validation of a two-compartment model for [11C]flumazenil

We recently developed a two-compartment, two-parameter tracer kinetic model to estimate the in vivo ligand transport rate (K1) and distribution volume (DV) for the benzodiazepine antagonist [11C]flumazenil (FMZ) as measured by positron emission tomography (PET). The aim of the present study was to validate that this simplified model provides a stable measure of regional benzodiazepine receptor availability even when ligand delivery is altered. Six young normal volunteers underwent two PET studies subsequent to intravenous injections of [11C]FMZ. Each FMZ study was immediately preceded by measurements of CBF following injection of [15O]water. One set of scans (water/FMZ) was acquired under resting conditions and the other set during audiovisual stimulation. Six additional volunteers underwent two FMZ studies under identical resting conditions. Parametric images were analyzed and a comparison of test-retest studies in the stimulation group revealed a significant increase of CBF and K1 of FMZ in the occipital cortex evoked by visual activation, whereas no regional changes were noted for the DV of FMZ. No significant changes were noted for either K1 or DV of FMZ when comparing studies in the rest-rest setting. The results indicate that the use of a simple two-compartment model for the tracer kinetic analysis of [11C]FMZ makes it possible to separate high-affinity binding from altered radio-ligand delivery to the human brain.     

Comparative efficacy of erythromycin-sulfisoxazole, cefaclor, amoxicillin or placebo for otitis media with effusion in children.

We randomly assigned children with otitis media with effusion to receive either erythromycin-sulfisoxazole, cefaclor, amoxicillin or placebo for a 2-week period, primarily to determine whether either erythromycin-sulfisoxazole or cefaclor would have greater short term efficacy than that found previously for amoxicillin, and secondarily to supplement earlier data on outcomes in placebo-treated subjects. Interim analyses showed no statistically significant (P less than 0.05) differences between the three antimicrobial treatment groups in the primary outcome measures, i.e. the prevalence of middle-ear effusion 2 and 4 weeks after entry, and indicated that postulated differences favoring the erythromycin-sulfisoxazole and cefaclor groups over the amoxicillin group were unlikely to be found even if the originally calculated sample size were attained. Subject accrual was therefore terminated. Final analysis showed no significant between-group differences in other outcome measures as well. In antimicrobial vs. placebo comparisons neither erythromycin-sulfisoxazole nor cefaclor gave more favorable outcomes than placebo, whereas more children were effusion-free in the amoxicillin group than in the placebo group at 2 weeks (31.6% vs. 14.1%, P = 0.007), but not at 4 weeks. We conclude that when antimicrobial treatment for otitis media with effusion is deemed advisable, neither erythromycin-sulfisoxazole nor cefaclor should replace amoxicillin as first line treatment.     

Increased Sensitivity of a New Coagglutination Test for Rapid Identification of Haemophilus influenzae Type b

A newly developed rapid coagglutination test for identifying Haemophilus influenzae type b organisms isolated from clinical specimens correlated 100% with the slide agglutination test but was 100- to 200-fold more sensitive.     

Continuous dose furosemide as a therapeutic approach to acute respiratory distress syndrome (ARDS)

BACKGROUND: Acute respiratory distress syndrome (ARDS) is seen in a variety of clinical settings in critically ill patients. ARDS has been defined as a clinical syndrome characterized by progressive hypoxemia, tachypnea, and generalized patchy bilateral pulmonary infiltrates in the absence of cardiac failure. Furosemide has been shown to improve pulmonary gas exchange and intrapulmonary shunt in animal models of ARDS by preferential perfusion of nonedematous lung units. We hypothesized that continuous dose furosemide would improve lung injury during resuscitation from oleic acid-induced lung injury in canines. METHODS: Ten mongrel dogs were anesthetized and given intravenous oleic acid (0.1 mg/kg) to induce lung injury. Once lung injury was established (2 h) the control animals (n = 6) were continued on standard supportive therapy, and the study animals (n = 4) were started on continuous dose furosemide at 0.2 mg/kg/h. Cardiac filling pressures were maintained in all animals by infusion of isotonic saline solution. Data collected included lung injury score (LIS), cardiac index (CI), stroke volume index (SVI), pulmonary capillary wedge pressure (PCWP), urine output (UO), volume of resuscitation (VR), and pulmonary shunt fraction (Qs/Qt). Data were collected at baseline, established lung injury (2 h), and end of protocol (6 h). Data were compared between groups at various stages of the model using one-way analysis of variance with repeated measures. RESULTS: All 10 animals survived the protocol. There was no difference between the experimental and control groups at baseline or established lung injury (2 h) for CI, SVI, PCWP, or VR. There was a significant improvement in PO2/FIO2 and reduction of PEEP values in the furosemide group. There was also a statistically significant difference between experimental and control groups in LIS, Qs/Qt, and urine volumes. CONCLUSIONS: Continuous dose furosemide therapy improves LIS, PO2/FIO2, and Qs/Qt and decreases PEEP requirements in this oleic acid model of ARDS.     

β-Catenin Preserves the Stem State of Murine Bone Marrow Stromal Cells Through Activation of EZH2

During bone marrow stromal cell (BMSC) differentiation, both Wnt signaling and the development of a rigid cytoskeleton promote commitment to the osteoblastic over adipogenic lineage. β-catenin plays a critical role in the Wnt signaling pathway to facilitate downstream effects on gene expression. We show that β-catenin was additive with cytoskeletal signals to prevent adipogenesis, and β-catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. β-catenin also prevented osteoblast commitment in a cytoskeletal-independent manner, with β-catenin knockdown enhancing lineage commitment. Chromatin immunoprecipitation (ChIP)-sequencing demonstrated binding of β-catenin to the promoter of enhancer of zeste homolog 2 (EZH2), a key component of the polycomb repressive complex 2 (PRC2) complex that catalyzes histone methylation. Knockdown of β-catenin reduced EZH2 protein levels and decreased methylated histone 3 (H3K27me3) at osteogenic loci. Further, when EZH2 was inhibited, β-catenin's anti-differentiation effects were lost. These results indicate that regulating EZH2 activity is key to β-catenin's effects on BMSCs to preserve multipotentiality. © 2020 American Society for Bone and Mineral Research.     

Electronic Cigarettes: Smoke-Free Laws,Sale Restrictions,and the Public Health

Consumer use of e-cigarettes is rising despite a lack of rigorous safety testing, manufacturing controls, and a well-understood risk profile. Many states and municipalities have prohibited e-cigarette sale to minors or amended their smoke-free laws to restrict public use. I discuss the public health impact of e-cigarettes and the current lack of Food and Drug Administration regulation, and advocate that states and localities reexamine their smoke-free laws and sale restrictions to appropriately regulate public use and youth access.Smoking consistently accounts for nearly 5.4 million deaths worldwide1 and approximately 443 000 in the United States each year.2 Heeding the significant health warnings and deadly statistics, smokers are increasingly turning to a new mode of nicotine intake: the electronic cigarette, or e-cigarette. Public awareness and use of e-cigarettes is skyrocketing as a result of targeted marketing tactics.3 The Centers for Disease Control and Prevention (CDC) report that e-cigarette use quadrupled in a 1-year period and continues to rise.4 Twenty-one percent of adult smokers in the United States have used e-cigarettes, 6% of all adults have tried e-cigarettes, and general awareness of e-cigarettes has risen to 60% of all adults, up from 40% the previous year.4 The CDC also report that use among US youths is staggering, having doubled among high-school students between 2011 and 2012.5 This most recent figure has led many nonsmoking advocates and health officials to question whether a troubling gateway effect of e-cigarettes for subsequent youth cigarette smoking is emerging after decades of decline in cigarette use by minors.6A core feature of the e-cigarette is that it looks and feels like a cigarette, satisfying psychological and behavioral stimuli for users who smoke. E-cigarettes, however, are smokeless, consisting of a replaceable nicotine cartridge, an atomizer that vaporizes the nicotine when the user inhales, and a battery that powers the device. The nicotine cartridge contains nicotine and various secondary chemical ingredients. When screwed together, the nicotine liquid from the cartridge contacts the atomizer and is carried to a metal coil heating element. The intake of air triggers a current from the battery through the atomizer, which heats up the nicotine liquid. Often, a light-emitting diode at the base mimics the burning ash at the end of traditional cigarette as the user inhales. Many products resemble a traditional cigarette, yet some are marketed in the shape of other household accessories such as pipes, pens, and lipstick. A single cartridge can hold the nicotine equivalent of an entire pack of cigarettes or more, and there is tremendous variation in the composition, strengths, and flavoring of the nicotine liquid.7E-cigarette advertisements, and the celebrities that frequent them, have emphasized the freedom to smoke anywhere; a lack of smell, tar, smoke, or toxic chemicals; an absence of social stigma; cost savings; and health advantages, often specifically reaching out to smokers aiming to quit or cut down.8 Some distributors also advertise their products as not emitting secondhand smoke or as ecologically friendly.8 The accuracy of these claims is unclear and contested. In fact, the Food and Drug Administration (FDA) and health care professionals alike have raised concern about the novel method of nicotine delivery, product ingredients, nicotine levels, safety of the various mechanical and electrical parts, dearth of data on product performance, and both explicit and implicit messages to users regarding health benefits.9 Scientific and clinical publications have only begun to target issues related to e-cigarette use.Consumer use, marketing and promotional claims, and technological characteristics of e-cigarettes have also raised decades-old questions of when the FDA can assert authority over particular products as drugs or medical devices. The 2010 DC Circuit case of Sottera v. FDA limited the FDA’s authority to regulate e-cigarettes as drugs or medical devices to instances where the manufacturer makes explicit health or disease-prevention claims for its products.10 Examining the language and congressional intent of the Family Smoking Prevention and Tobacco Control Act of 2009 (TCA), the court held that e-cigarettes fall within the literal definition of tobacco products because nicotine is “derived from tobacco,” as set forth in the TCA definitions. The FDA declined to appeal that decision and is currently assessing appropriate regulation and enforcement activities; the agency has issued a statement that it plans to assert regulatory authority over e-cigarettes as tobacco products.11While the FDA struggles to determine how to regulate these products at the federal level, state and local governments also have a role to play. The TCA, coupled with previous legislative authority, gives broad latitude to states and localities to enact laws and regulations relating to the sale, distribution, possession, and use of tobacco products.12 State and local regulatory efforts have focused on smoke-free laws and restrictions on use and sale. Thirty-six states and 3931 municipalities have laws in place restricting or prohibiting smoking in public places and workplaces.13 The scope of the laws varies, commonly directed at a combination of locations such as nonhospitality workplaces, restaurants and bars, and public areas. The overwhelming majority of the laws were drafted with cigarettes and traditional tobacco products in mind, with many specifically using the word “smoke” or “smoking” to define the restricted or prohibited action. However, e-cigarettes do not produce smoke; they produce vapor. States and localities must reexamine their smoke-free laws and access restrictions to appropriately regulate the use of e-cigarettes.As of September 2013, 27 states and localities have amended their smoke-free laws to explicitly include e-cigarettes within the ban on smoking in public places.14 For example, the New Jersey Smoke-Free Air Act prohibits smoking in indoor public places, workplaces, and in buildings or grounds of any public or nonpublic elementary or secondary school. It was amended in 2010 to include within the scope of smoking “the inhaling or exhaling of smoke or vapor from an electronic smoking device.”15 An electronic smoking device is further defined as “an electronic device that can be used to deliver nicotine or other substances to the person inhaling from the device, including, but not limited to, an electronic cigarette, cigar, cigarillo, or pipe.”15 Likewise, New York bans e-cigarette use within 100 feet of entrances and exits to public or private schools.16 In addition to the state laws, Somerset, Massachusetts; King County, Washington; Madison County, Kentucky; Savannah, Georgia; and Petaluma, California, are just a few cities and counties, among others, that have passed ordinances explicitly including e-cigarettes within the scope of their smoking bans.14 Both California and Oregon have settled in court with leading e-cigarette manufacturers and distributors, making the sale of their specific e-cigarette products unlawful in those states.14Thirty-four states and municipalities have also enacted laws banning sales of e-cigarettes to minors, although the age limitations vary from younger than 18 to younger than 21 years.14 Dozens of states include both a ban on smoking in public settings and a ban on sale to minors, and other laws contain individual nuances.14 For example, Hawaii prohibits the sale of e-cigarettes to minors younger than 18 years, and also requires in-person sales rather than sales through the Internet.14 Tacoma–Pierce County, Washington, includes a ban on free sampling unless within an e-cigarette retail store.14 In a September 2013 letter to the FDA, lawmakers joined the call, urging the agency to act swiftly at the federal level to address the epidemic of youths’ use of e-cigarettes.17 Federal legislators have also advocated hearings on the health risks and scope of FDA authority.17These state and local laws are merely a stopgap measure and fail to establish a uniform national policy for e-cigarettes. The best outcome to ensure the protection of the public health, and youths in particular, would be for the FDA to initiate rulemaking proceedings to deem e-cigarettes within the definitional scope of the TCA. This would allow the FDA to develop manufacturing requirements, reporting mechanisms, product standardization, ingredient listings, limitations on marketing claims, and various other procedures to install proper oversight of product development and distribution. As with any effort at content regulation, First Amendment challenges may arise. However, states and local governments also have a role in regulation and should proactively reassess their existing smoking bans, sale to minors, and other restrictions and decide whether to amend the language to include e-cigarettes. Failing to include a clear statutory definition leaves use and access to e-cigarettes as a significant loophole, and may thwart even the most well-intended public health laws.     

Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial.

To determine the efficacy of amoxicillin prophylaxis and of tympanostomy tube insertion in preventing recurrences of acute otitis media, we randomized 264 children 7 to 35 months of age who had a history of recurrent otitis media but were free of middle ear effusion to receive either amoxicillin prophylaxis, bilateral tympanostomy tube insertion or placebo. The average rate of new episodes per child year of either acute otitis media or otorrhea was 0.60 in the amoxicillin group, 1.08 in the placebo group and 1.02 in the tympanostomy tube group (amoxicillin vs. placebo, P less than 0.001; tubes vs. placebo, P = 0.25). The average proportion of time with otitis media of any type was 10.0% in the amoxicillin group, 15.0% in the placebo group and 6.6% in the tympanostomy tube group (amoxicillin vs. placebo, P = 0.03; tubes vs. placebo, P less than 0.001). At the 2-year end point, the rate of attrition was 42.2% in the amoxicillin group, 45.5% in the placebo group and 26.7% in the tympanostomy tube group. Adverse drug reactions occurred in 7.0% of the amoxicillin group and persistent tympanic membrane perforations developed in 3.9% of the tympanostomy tube group. The observed degree of efficacy of amoxicillin prophylaxis and of tympanostomy tube insertion must be viewed in light of the fact that study subjects proved not to have been at as high risk for acute otitis media as had been anticipated and in view of the differential attrition rates.(ABSTRACT TRUNCATED AT 250 WORDS)