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Wilfred Sellars appears in Bas C. van Fraassen’s The Scientific Imageas one of van Fraassen’s primary realist opponents. However, little attention has been paid to Sellars’s influence on van Fraassen’s constructive empiricism and van Fraassen’s criticisms of Sellarsian realism, despite the significant impact of The Scientific Imageon the realism debate and recent renewed interest in Sellars’s scientific realism. In the first half of this article, I argue that reading The Scientific Imageagainst a Sellarsian background helps clarify and justify van Fraassen’s controversial characterization of scientific realism. Sellars and van Fraassen each inhabit a recognizable position in the other’s description of the realism debate and can reciprocally recognize the other as inhabiting the opposing position. The second half of this article reconstructs van Fraassen’s objections to Sellarsian realism in The Scientific Imageand its precursors. I argue that van Fraassen’s criticisms of Sellarsian realism significantly developed between his 1975 paper, “Wilfrid Sellars on Scientific Realism” and his 1980 book.

Made-to-measure is making a comeback with the development of advanced CAD technology and EDI applications. MADE-TO-MEASURE has been used as a means of producing garments since the inception of clothing. [...]

Objective: To review data on efficacy and safety of osilodrostat (Isturisa), a novel oral steroidogenesis inhibitor for treatment of Cushing’s disease (CD), a life-threatening endocrine disorder.Data Sources: A PubMed/CINAHL search from inception to September 25, 2020, was performed using the following keywords: osilodrostat, 11-beta hydroxylase, pituitary, ACTH hypersecretion, and Cushing’s disease.Study Selection and Data Extraction: Phase 2 and 3 clinical trials and supplementary documents investigating osilodrostat were obtained from a primary literature search, the manufacturer’s website, and the Food and Drug Administration website. These articles evaluated the clinical pharmacology, efficacy, safety, adverse events, warnings, and precautions for osilodrostat.Data Synthesis: Osilodrostat was efficacious and safe in the treatment of CD in mostly middle-aged Caucasian women. A pivotal phase 3 study revealed a significant difference in 24-hour mean urinary free cortisol (primary end point) between osilodrostat and placebo (86% vs 29%; P< 0.001).Relevance to Patient Care and Clinical Practice: Osilodrostat provides a potent and consistent effect in reducing life-threatening supraphysiological levels of cortisol in patients with CD. Hypocortisolism adverse effects can be mitigated by slowly increasing osilodrostat’s dose at ≥2-week intervals. QT interval prolongation was noted; therefore, the QT interval must be monitored by the electrocardiogram. Increased levels of cortisol precursors during treatment with osilodrostat may increase the risk of hypokalemia, edema, and hypertension.Conclusions: Osilodrostat was efficacious in decreasing cortisol levels and safe in treating patients who have failed or are ineligible for pituitary surgery. Although risks exist, a pivotal clinical trial revealed efficacy in 86% of participants.

Objective To review data on efficacy and safety of peanut allergen powder-dnfp (PAP; Palforzia), a novel oral immunotherapy for peanut allergy, a common food allergy.Data Sources A PubMed/CINAHL search in English was performed from inception to June 30, 2020, using the search words peanut allergy, desensitization, ARA101, and peanut oral immunotherapy.Study Selection and Data Extraction Quantification Published phase 2 and 3 clinical trials, documents presented to the Food and Drug Administration, and supplemental study documentation were reviewed. Articles evaluated PAP’s pharmacology, pharmacokinetics, mechanism of action, efficacy, and safety.Data Synthesis PAP was efficacious and safe for treatment of peanut allergy in mostly Caucasian children, 4 to 17 years old. A key phase III clinical trial showed a statistically significant difference (primary end point) between PAP 600 mg and placebo groups (67.2% vs 4%; P< 0.001). During initial dose escalation and updosing phases, gastrointestinal and respiratory tract allergic reactions (ARs) were more common in the PAP group. More epinephrine rescue was used in the PAP group.Relevance to Patient Care and Clinical Practice Oral immunotherapy for desensitization of peanut allergy was shown to reduce the severity of reactions if accidental allergen exposure occurs. Risk evaluation and mitigation strategy certification is required for pharmacies, health care providers, and clinics. More data in real-world populations will enhance its effectiveness.Conclusions In patients 4 to 17 years old, PAP mitigated ARs, including anaphylaxis, that may occur with accidental peanut exposure. Although there are risks, it was efficacious in more than two-thirds of participants in phase 2 and phase 3 efficacy trials.

Objective: To evaluate intravenous immune globulin (IVIG) for autoimmune heparin-induced thrombocytopenia (aHIT), including platelet recovery, IVIG dose, dosing weight, IVIG product used, and complications reported.Data Sources: PubMed and EMBASE were searched from inception through June 21, 2020. Search terms included heparin-induced thrombocytopenia, HIT, intravenous immune globulin, IVIG, autoimmune HIT, aHIT, and immune globulin.Study Selection and Data Extraction: Patients administered IVIG for HIT and diagnosed by immunoassay (optical density ≥2) or positive activation assay were included.Data Synthesis: Twenty-four cases were reviewed; 92% had persistent aHIT. Time to IVIG administration post–nonheparin anticoagulant initiation was 9 days (median). Most common IVIG cumulative dose was 2 g/kg (dosed as 1 g/kg/d for 2 consecutive days); 75% had a favorable platelet increase (≥50 × 109/L) within 5 days of initial IVIG dosing.Relevance to Patient Care and Clinical Practice: aHIT is characterized by critically low platelets, thrombosis, and a persistent delay in platelet recovery despite treatment with a nonheparin anticoagulant. An immunoassay and subsequent confirmatory activation assay (at low, high, and 0 IU/mL unfractionated heparin levels) is recommended to confirm diagnosis. Patients nonresponsive to nonheparin anticoagulants within 5 days of initiation should be evaluated for IVIG treatment (2 g/kg cumulative dose). More data are needed to clarify appropriate IVIG dosing weight, although based on current published literature, it is recommended to use actual body weight.Conclusions: Data reported support use of IVIG as adjunctive therapy for patients with aHIT. Judicious IVIG use based on key clinical and laboratory findings is critical.

Objective: To evaluate glucagon-like peptide 1 receptor agonists (GLP-1 RAs), dipeptidyl-peptidase IV (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT) inhibitors to treat nondiabetic and type 2 diabetes mellitus (T2DM) nonalcoholic fatty liver disease (NAFLD) as it relates to improvement in hepatosteatosis (HS) or steatohepatitis (SH).Data Sources: MEDLINE and CINAHL were searched from inception through May 1, 2020. Search terms included nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, fatty liver, dipeptidyl-peptidase IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose transporter 2 inhibitors.Study Selection and Data Extraction: Full-text observational and randomized controlled studies in English were included. Patients diagnosed with NAFLD, treated with GLP-1 RAs, DPP-4 inhibitors, and SGLT2 inhibitors, with measures to evaluate HS or SH were evaluated.Data Synthesis: Eight GLP-1 RA trials were reviewed; 7 GLP-1 RA trials showed improvement in HS. Two studies demonstrated improvement in liver histology in patients with SH. Seven SGLT2 inhibitor studies were reviewed; 6 studies demonstrated improvements in NAFLD. Five studies showed improvements in HS, whereas 1 displayed improvement in liver histology in NASH. Six studies that included DPP-4 inhibitors were evaluated, and only 2 demonstrated improvement in NASH.Relevance to Patient Care and Clinical Practice: Based on evidence reviewed, GLP-1 RAs and SGLT2 inhibitors decreased HS and SH in NAFLD patients, whereas DPP-4 inhibitor therapy was not effective for patients with HS.Conclusions: Based on study data utilizing imaging studies and biopsy results, GLP-1 RAs or SGLT2 inhibitors can benefit NAFLD T2DM patients. Clinical trials with larger patient populations may augment these results.

Depression is the most common psychiatric sequela after traumatic brain injury (TBI) and poses a variety of treatment challenges. There is a lack of clinical trials focused on biological interventions used to manage TBI depression.

Professional identity formation (PIF) is the transformative process by which an individual, “thinks, feels and acts” in accordance with professional norms. In the pharmacy academy, institutions are required to support students on this transformative journey, however the most efficient and effective way to do so has yet to be determined. Interprofessional Education (IPE) in pharmacy programs typically consist of activities and assessments across most of the professional years. These IPE activities designed in accordance with the Interprofessional Education Collaborative (IPEC) Core Competencies include key elements of PIF such as, individual growth opportunities, socialization and “pivotal” moments that can propel an individual’s professional identity development. In light of curricular overload and attempt for curricular efficiency, pharmacy programs might consider using already existing IPE programming to help augment student PIF.

Objective: To review the literature leading to the Food and Drug Administration (FDA) approval of the first medication, resmetirom, for the treatment of nonalcoholic steatohepatitis (NASH), including the pharmacology, pharmacokinetics, clinical studies, dosing, and adverse effects. Relevant data will be used to discuss how resmetirom impacts clinical practice.Data sources: A literature search was conducted using MEDLINE from database inception to May 12, 2024. Keywords included non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, and resmetirom. Study selection, data extraction and all English-language studies involving the use of resmetirom for nonalcoholic fatty liver disease (NAFLD)/NASH were included.Data synthesis: Resmetirom, a thyroid hormone receptor agonist, is administered at daily doses of either 80 mg or 100 mg. The drug was shown to provide NASH resolution as assessed by the NAFLD activity score, 80 mg-24.2%, 100 mg-25.9% compared to 14.2% with the placebo group (P< 0.001). Resmetirom, improved liver fibrosis, 80 mg-25.9%, 100 mg-29.9% compared to 9.7% with the placebo group (P< 0.001). Resmetirom’s ability to improve fibrosis in patients with F2-F3 fibrosis offers valuable benefit for patients at risk of progressing to cirrhosis.Relevance to patient care and clinical practice: Resmetirom expands the medication options available to treat patients with NASH which can be given alongside other medications to optimize metabolic factors such as glucagon-like peptide-1 and hydroxymethylglutaryl-coenzyme A reductase inhibitors. Resmetirom was well tolerated in studies.Conclusion: Resmetirom serves as an attractive option in patients diagnosed with NASH with evidence of advanced fibrosis (F2-F3) in combination with exercise, diet, and other multimodal therapies targeting metabolic risk factors.

Objective: To review efficacy and safety data of valoctocogene roxaparvovec (Roctavian) and etranacogene dezaparavovec (Hemgenix), novel gene therapies for the treatment of the life-threatening bleeding disorders hemophilia A and B, respectively.Data Sources: A PubMed/Google Scholar search from inception through August 11, 2023 was conducted using the following keywords: gene therapy, hemophilia A, hemophilia B, etranacogene dezaparavovec, valoctocogene roxaparvovec, and bleeding.Study Selection and Data Extraction: Data, including phase 1 to 3 clinical trials (non-comparator), were obtained from primary literature and package inserts. These reports evaluated clinical pharmacology, efficacy, safety, adverse events, warnings, and precautions.Data Synthesis: Valoctocogene phase 3 study in males (n = 134): 87% had factor VIII (FVIII) levels that at least met criteria for mild hemophilia. Etranacogene phase 3 study in males (n = 54): within 3 weeks of infusion, mean factor IX (FIX) levels had reached 26.8 IU/dL. Both therapies provided clinically and statistically significant decreases in bleeding events and prophylactic factor infusions. Most common adverse event was elevations in liver function tests that were treated with glucocorticoids.Relevance to Patient Care and Clinical Practice in Comparison with Existing Drugs: The endogenous production of clotting factors mimics physiological production while decreasing morbidity and mortality related to bleeding events similar to the effects of existing replacement strategies. Gene therapy was also shown to increase patient quality of life.Conclusion: Valoctocogene and etranacogene provide another treatment for selected patients with hemophilia. Treatment for the patient with hemophilia (gene therapy vs replacement strategy) must be personalized as new clinical data are published being cognizant of drug affordability.

Objective:To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosage, and administration of omadacycline, a new tetracycline antibiotic. Data Sources:A literature search through PubMed, Google Scholar, and clinicaltrials.govwas conducted (2008 to October 2018) using the search terms omadacyclineand PTK-0796. Abstracts presented at recent conferences, prescribing information and information from the FDA and the manufacturer’s website were reviewed. Study Selection and Data Extraction:Preclinical data and published phase 1, 2, and 3 studies were evaluated. Data Synthesis:Omadacycline displays in vitro activity against a wide range of bacteria. Clinical trials have shown that omadacycline is noninferior to linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP). A loading dose of 200 mg intravenously (IV) once or 100 mg IV twice or 450 mg orally for two days is recommended followed by a maintenance dose of 100 mg IV or 300 mg orally once daily. No dosage adjustment is needed in patients with renal or hepatic impairment. Omadacycline is well tolerated, with nausea being a common adverse effect, but is associated with food and drug interactions. Relevance to Patient Care and Clinical Practice:Omadacycline is active against staphylococci, including methicillin-resistant strains, and streptococci, including tetracycline-resistant strains, as well as atypical bacteria. Omadacycline provides clinicians with an additional parenteral and oral option for the treatment of adults with ABSSSI and CABP. Conclusion:Omadacycline is an alternative treatment option for ABSSSI and CABP.

Immunization is the best strategy to protect individuals from influenza; however, older adults tend to respond less favorably to vaccines because of immunosenescence. The Centers for Disease Control and Prevention states that any licensed, recommended, and age-appropriate influenza vaccine may be used in older adults despite reasonable evidence suggesting that the high-dose and, to a lesser extent, the adjuvanted and recombinant influenza vaccines provide better protection than the standard-dose vaccines in this vulnerable population. In this era of precision medicine, clinicians can preferentially recommend these contemporary vaccines to equip their older patients with the best possible protection against influenza.

Ketamine and other glutamatergic drugs have been slowly gaining traction in the psychiatric realm for the treatment of multiple conditions. Although monoamine modulators remain the stalwarts of pharmacologic treatment, glutamatergic agents are becoming options for those patients with treatment-refractory obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and other disorders that have been associated with dysfunctional glutamatergic pathways. To date, medications such as ketamine, lamotrigine, memantine, and D-cycloserine, among others, have demonstrated some efficacy for PTSD and OCD, although mostly in small studies for conditions not approved by the US Food and Drug Administration. Other disorders, such as traumatic brain injury, autistic spectrum disorders, and eating disorders, may benefit from glutamate modulators; however, the literature on these applications is currently limited. Ketamine and other glutamatergic drugs have been slowly gaining traction in the psychiatric realm for the treatment of multiple conditions. Although monoamine modulators remain the stalwarts of pharmacologic treatment, glutamatergic agents are becoming options for those patients with treatment-refractory obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and other disorders that have been associated with dysfunctional glutamatergic pathways. To date, medications such as ketamine, lamotrigine, memantine, and D-cycloserine, among others, have demonstrated some efficacy for PTSD and OCD, although mostly in small studies for conditions not approved by the US Food and Drug Administration. Other disorders, such as traumatic brain injury, autistic spectrum disorders, and eating disorders, may benefit from glutamate modulators; however, the literature on these applications is currently limited. [[Psychiatr Ann.2018;48(4):184–188.]

The article discusses the naming tradition of the family author John Dougherty. Topics include the family background of John James Dougherty from Ireland in 1830 during potato famine in Inishowen Peninsula; their Jesuit education, Carrer, job life and importance of the shared names in his son's life focusing on the journeys of the family, the hardships faced by family.

IMPORTANCE: Microglia, the resident immune cells of the central nervous system, play an important role in the brain’s response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury. OBJECTIVE: To measure translocator protein 18 kDa (TSPO), a marker of activated glial cell response, in a cohort of National Football League (NFL) players and control participants, and to report measures of white matter integrity. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, case-control study included young active (n = 4) or former (n = 10) NFL players recruited from across the United States, and 16 age-, sex-, highest educational level–, and body mass index–matched control participants. This study was conducted at an academic research institution in Baltimore, Maryland, from January 29, 2015, to February 18, 2016. MAIN OUTCOMES AND MEASURES: Positron emission tomography–based regional measures of TSPO using [11C]DPA-713, diffusion tensor imaging measures of regional white matter integrity, regional volumes on structural magnetic resonance imaging, and neuropsychological performance. RESULTS: The mean (SD) ages of the 14 NFL participants and 16 control participants were 31.3 (6.1) years and 27.6 (4.9) years, respectively. Players reported a mean (SD) of 7.0 (6.4) years (range, 1-21 years) since the last self-reported concussion. Using [11C]DPA-713 positron emission tomographic data from 12 active or former NFL players and 11 matched control participants, the NFL players showed higher total distribution volume in 8 of the 12 brain regions examined (P &lt; .004). We also observed limited change in white matter fractional anisotropy and mean diffusivity in 13 players compared with 15 control participants. In contrast, these young players did not differ from control participants in regional brain volumes or in neuropsychological performance. CONCLUSIONS AND RELEVANCE: The results suggest that localized brain injury and repair, indicated by higher TSPO signal and white matter changes, may be associated with NFL play. Further study is needed to confirm these findings and to determine whether TSPO signal and white matter changes in young NFL athletes are related to later onset of neuropsychiatric symptoms.

Context:Proliferation of the use of psychopharmacologic drugs for the treatment of individuals with attention and behavior disorders has promoted discussion of the illicit use of such drugs to enhance academic performance. Previous research has focused on the use of such drugs by undergraduate students; however, inquiry into the nonmedical use of prescription stimulants by medical students is warranted because of the unique qualities of the medical school environment (including academic pressure, stress, and competition with peers) and the demographic characteristics common to many medical students.

Context:Practitioners of manipulative medicine have long sought to prove the intra- and interexaminer reliability of palpatory examinations in assessing somatic dysfunction. However, decades of research have yet to achieve the level of reproducibility needed to satisfy evidence-based criteria.

The article discusses the agreement between Elling Halvorson, owner of Papillon Helicopters and his partners Percassi Group and Gruppo Stilo USA to transform the town of Tusayan, Arizona into a world-class destination resort. It states that Halvorson and his partners are negotiating a zonign and development agreement. It also mentions that their plan coincides with the plan of the Arizona Department of Transportation to expand the local airport of Arizona.

The anterior cruciate ligament (ACL) of the knee and the function of its anteromedial (AM) and posterolateral (PL) bundles are a focus of orthopedic research. Because of the probability that third-year and fourth-year osteopathic medical students will encounter ACL injuries during clinical rotations, it is of paramount importance that students fully understand the functions of the AM and PL bundles as 2 distinct functional components of the ACL. The authors assess the degree to which the AM and PL bundles are discussed within basic science curricula at colleges of osteopathic medicine (COMs). In September 2008, a 6-question survey addressing various aspects of ACL education was mailed to instructors of lower-extremity anatomy at all 28 COMs that existed at that time. Nine of the 21 responding institutions (42.9%) indicated that both the AM and PL bundles of the ACL are discussed within their basic science curricula. Four of these 9 COMs indicated that their instruction mentions that the bundles are parallel in extension and crossed in flexion. Nine of the 21 responding COMs (42.9%) indicated that they instruct students that the AM bundle is a major anterior-posterior restrictor, and 12 (57.1%) indicated that they instruct students that the PL bundle is the major rotational stabilizer of the ACL. In 7 of the 21 responding COMs (33.3%), the AM and PL bundles are identified via direct visualization during anatomic dissection of the ACL. The authors conclude that their findings suggest the need for enhanced presentation of the AM and PL bundles within the basic science curricula at COMs to provide osteopathic medical students with a more comprehensive education in anatomy.

The article focuses on the proposal to develop the Superstition Mountains into a real estate area in Phoenix, Arizona. Having the plans for development of the Superstition Mountains, the author explores the advantages and disadvantages of the real estate development towards the wildlife and environment of Phoenix. He also makes a reference on the possibility for the Superstition Mountains to be like the crowded and polluted image of Superstition Vistas. In addition, he examines the proposals made by the state government for Superstition Mountains, targeting to preserve the wildlife in the city. Furthermore, the author suggests on the need to plan better for the utilization of the land, projecting its transformation into a sustainable area.

The article focuses on the emergence of endangered Mexican gray wolf in the grasslands, mountains and streams of western New Mexico and eastern Arizona. The government's reintroduction rulebook states that a rancher cannot shoot a wolf simply because it threatens the livestocks however, the federal officers may kill or capture the wolf unless it kills three cows or sheep or other domestic animals in a single year. Allegedly, some ranchers said that environmentalists are using the wolf as a terrorist tactic to force ranchers off public lands they have controlled for decades.

The article presents an investigation on the murder of Japanese tourist Tomomi Hanamure near the Havasu Falls, a mile away from the Supai village in Arizona on July 11, 2006. Hanamure was reportedly traveling along the waterfalls to celebrate her 34th birthday alone on May 8, 2006. She was said to be an experienced world traveler who had been hiking the canyon before. Investigations revealed that such murder involves an 18-year-old Randy Redtail Wescogame, who allegedly killed Hanamure during a robbery by stabbing her 29 times in the head, neck, and back. Her dead body was discovered submerged in Havasu Creek, indicating no sexual assault. The murderer was found to have been involved in a methamphetamine abuse, whose father has been convicted of sexual abuse while serving as a policeman.

The article discusses the developments of the once-quiet homeland of the Tohono O'odham Nation in Arizona which was now turned into a police state. Due to illegal drugs and the surge of immigrants from Mexico, the U.S. decided to assign Border Patrol officer. Before, it was only a barbed-wire fence that separates the U.S. and Mexico and no U.S. law enforcement group or Tohono O'odham tribal police are delegated to check documents as people travel in and out at a crossing, the San Miguel Gate. O'odham tribal members, through the San Miguel Gate, enter Mexico to shop at their flea market rather than travel far. Border Patrol officials said some smugglers just drive through the gate, hoping they can enter far enough to deliver narcotics or human.

OBJECTIVE To review recent advances in the prevention of venous thromboembolism (VTE) in acutely ill nonsurgical inpatients.DATA SOURCES A MEDLINE search (1966–March 2005) was done to identify relevant articles relating to prevention of VTE in acutely ill nonsurgical inpatients.STUDY SELECTION AND DATA EXTRACTION Four major prophylaxis trials, one registry, one guideline, and supporting articles representative of the subject matter from the last few years were included.DATA SYNTHESIS Enoxaparin, dalteparin, fondaparinux, and unfractionated heparin 5000 units every 8 hours are effective in reducing the risk of VTE in acutely ill medical patients, but such prophylaxis is currently underused. Barriers to be overcome include recognition of the importance of VTE in this population, definition of the optimal strategy to assess risks, optimal timing of the risk assessment, optimal prophylactic regimen for a given level of risk or disease state, and optimal duration of prophylaxis. We recommend that acutely ill medical inpatients should be risk-stratified early in their hospitalization. At this time, the specific risk-assessment protocol should be derived from the trial(s) of the available formulary agent(s). Decisions about providing prophylaxis must also be made considering anticoagulant contraindications and renal function. Mechanical methods of prophylaxis should be considered as monotherapy only if an anticoagulant contraindication exists. The optimal duration of prophylaxis is not known, but 14 days was used in recent studies.CONCLUSIONS Prophylaxis of VTE in acutely ill medical inpatients is underused. Data provide some guidance for increasing awareness and optimizing patient care.

Focuses on the actions and defenses of school district teachers from liability case in the U.S. Discussion on sovereign immunity; Information on the Paul D. Coverdell Teacher Liability Protection Act under the No Child Left Behind in the country; Discussion on the negligence of employees from liability case.

Focuses on education tort cases in the U.S. Information on the Phillips v. Lincoln County School District case; Discussion on assault and battery as intentional torts; Definition of defamation in tort cases.

OBJECTIVE: To describe the pathogenesis of chronic obstructive pulmonary disease (COPD) and mechanisms of benefit, formulations available, drug costs, pharmacokinetic profiles, and pertinent clinical studies for long-acting β2-agonists.DATA SOURCES: A MEDLINE search was conducted from July 1966 through October 2002.STUDY SELECTION AND DATA EXTRACTION: Pertinent articles related to COPD and long-acting β2-agonists.DATA SYNTHESIS: The incidence and subsequent morbidity and mortality of COPD have increased during the last 4 decades, prompting worldwide initiatives to formulate guidelines to decrease the burden of this disease. COPD is a progressive, irreversible disease state characterized by chronic cough, dyspnea, sputum production, and wheezing, in which no medication has been shown to decrease mortality, excluding oxygen supplementation. Bronchodilators have been a mainstay of COPD treatment through their ability to work by both smooth- and non–smooth-muscle mechanisms. Long-acting β2-agonists (i.e., formoterol, salmeterol) dosed twice daily provide more convenient dosing than 4-times-daily regimens of traditional short-acting bronchodilators. Both formoterol and salmeterol have acceptable adverse event profiles when used at recommended doses. There have been no direct clinical outcome studies comparing formoterol and salmeterol, but both have shown some benefits over ipratropium and theophylline in improving the symptoms, spirometric indices, exacerbations, and quality of life of patients with COPD.CONCLUSIONS: Based on current evidence, long-acting β2-agonists are acceptable first-line agents for patients with COPD.

OBJECTIVE: To evaluate the role of risedronate in corticosteroid-induced osteoporosis.DATA SOURCES: Clinical literature was accessed through MEDLINE (1966–February 2001). Key search terms included risedronate, corticosteroid, osteoporosis, and bisphosphonate.DATA SYNTHESIS: Corticosteroid-induced osteoporosis (CIO) is clinically challenging and can lead to fractures. Risedronate, an oral bisphosphonate, has been studied for use in CIO. Trials focusing on the use of risedronate in these patients were reviewed.CONCLUSIONS: Risedronate 5 mg/d increased bone mineral density at lumbar, femoral neck, and trochanter skeletal sites in patients recently initiated on or receiving long-term corticosteroid therapy. Further investigation is needed to determine risedronate's effects on fracture prevention. The drug was well tolerated.

1Presynaptic varicosities of the model neuronal cell line NG108–15, a cholinergic neuroblastoma cell × glioma cell hybrid capable of innervating striated myotubes, were examined for the presence of inositol 1,4,5‐trisphosphate (IP3)‐sensitive and Ca2+‐activated (ryanodine‐sensitive) Ca2+stores using confocal microscopic imaging of Ca2+‐sensitive fluorescent dye loaded into the cells.2Initial demonstration of the presence of IP3receptors and ryanodine receptors in the NG108–15 varicosities was obtained using immunocytochemistry.3Treatment of NG108–15 cells with bradykinin (0.1 μM), whose receptor is linked to IP3generation, and separately, caffeine (10 mM), an activator of endoplasmic reticulum ryanodine receptors, resulted in substantial increases in [Ca2+]iin the varicosities.4K+‐evoked changes in [Ca2+]iin the varicosities were reduced (52 %) after emptying the ryanodine‐sensitive Ca2+store using caffeine (10 mM), but were not affected by prior depletion of the IP3‐sensitive Ca2+store using thapsigargin (1 μM).5Bradykinin‐induced changes in [Ca2+]iwere abolished following depletion of the IP3‐sensitive Ca2+store using thapsigargin (1 μM) and were reduced (72 %) by prior emptying of the ryanodine‐sensitive Ca2+store with caffeine (10 mM).6The same results were obtained when the varicosities of the NG108–15 cells had formed synaptic junctions with co‐cultured rat hindlimb myotubes.7Taken together, the results suggest that, in the varicosities, activation of the IP3pathway evoked the release of Ca2+from the IP3‐sensitive store, which, in turn, secondarily induced the release of Ca2+from the ryanodine‐sensitive store via Ca2+‐induced Ca2+release, and that depolarization‐induced Ca2+entry evoked Ca2+‐induced Ca2+release only from the ryanodine‐sensitive store. Thus, functional internal Ca2+stores are inherent components of presynaptic varicosities in this neural cell line.

Fas ligand (FasL)-dependent apoptosis has been implicated in the control of tissue-damaging inflammatory responses in several immune privileged sites. Here, we present data demonstrating that FasL is expressed on human trophoblast cells throughout pregnancy and transduces growth inhibitory/death signals in cells bearing its receptor, Fas (CD95). Immunohistochemical analysis detected FasL-positive staining in the trophoblast layer of villi of first- and second-trimester and term (no labor) placental tissues, as well as in freshly isolated cytotrophoblasts representing these gestational ages. In contrast, term placental tissues and cytotrophoblasts from labor-associated deliveries exhibited significantly reduced FasL expression, suggesting that parturition altered the characteristics of trophoblast cells. FasL-specific immunoblotting of cytotrophoblast cell lysates further confirmed these results. To assess the functionality of FasL expressed on cytotrophoblasts, we co-cultured these cells with Fas-bearing Jurkat T cells. Cytotrophoblasts from early pregnancy, or term with no labor, significantly inhibited growth in Jurkat cells, evident even at a 11 effectortarget cell ratio, as determined by the incorporation of 3Hthymidine. Similar results were obtained when a FasL-positive colon carcinoma cell line, SW620, was used in place of cytotrophoblasts. In contrast, term cytotrophoblasts from labor deliveries exhibited poor FasL expression and were quantitatively much less proficient in inhibiting 3Hthymidine incorporation in Jurkat cells. These data indicate that FasL could participate in modulating the inflammatory responses associated with labor and suggest intrinsic molecular differences in the placental microenvironment before and after labor .

Recent data suggesting complex I dysfunction in Parkinson's disease (PD) arises from mitochondrial DNA (mtDNA) mutation does not conclusively answer whether the responsible genetic lesion is inherited (primary) or somatic (secondary). To address this question, we identified a family in which multiple members over three generations are affected with PD through exclusively maternal lines. Cytoplasmic hybrids (cybrids) were created for 15 family members over two generations by trnsferring each individual's mtDNA to mtDNA‐depleted human neuroblastoma cells. Eight of the 15 cybrid lines contained mtDNA obtained from maternally descended family members and seven contained mtDNA from paternally descended family members. After 6 weeks of culture, cybrid cell lines were assayed for complex I activity and oxidative stress, and mitochondrial morphology was analyzed by electron microscopy. Compared with the cybrid lines containing mtDNA from paternal descendants, cybrid lines containing mtDNA from maternal descendants had lower complex I activity, increased reactive oxygen species production, increased radical scavenging enzyme activities, and more abnormal mitochondrial morphologic features. These findings were present in cybrid lines containing mtDNA from maternal descendants with PD as well as in currently asymptomatic young maternal descendants, and support a precedent for inherited mtDNA mutation in some persons with PD.

This study tested the hypothesis that the pacing of suggestions to phases of the breathing cycle can enhance responding in hypnosis. Ninety-six subjects at three levels of hypnotizability responded to suggestions for coolness/numbness and arm lightness/levitation both paced and counter-paced to the phase of breathing (inhalation) claimed to enhance responding to them. As a test of pacing as a technique for indirect hypnosis, the covert pacing of such suggestions was compared to overt pacing. Results failed to demonstrate a relationship between the pacing of the phases of breathing and its hypothesized effects. Responding to suggestions was related to level of hypnotizability and an interaction was noted between overtness/covertness of pacing and level of hypnotizability.

The metabolic fate of 2,4-dichlorophenoxyacetic acid (2,4-D)-n-butyl ester in rats has not been extensively studied. Upon subcutaneous administration of a 100 mg/kg dose of 2,4-D butyl ester to four male Wistar rats, urine samples were analyzed by three analytical techniques for the presence of the butyl ester and metabolites. Thin layer chromatography (TLC), gas chromatography using an electron capture detector (GC-ECD), and gas chromatography-mass spectroscopy (GC-MS) were the techniques employed. 2,4-D butyl ester was rapidly hydrolyzed in the body to form 2,4-D acid. Ninety-five percent of the administered dose was excreted into the urine as the free acid within 48 h of injection, while only a small fraction (5%) was excreted over an additional 48 h. No amino acid conjugates or the parent 2,4-D butyl ester could be detected in the urine of treated rats. A minor metabolite (=2% of dose) was detected by GC-MS analysis of urine samples. This compound appears to be a side chain metabolite of the 2,4-D butyl ester. Some chemical properties of the metabolite were characterized, and a 2,4-D hydroxyethyl ester structure proposed. The mechanism of this minor metabolic formation remains unknown.

The problem: How to get the most for the electric utility industry's research and development dollar. The answer, an ambitious and innovative one, was initiated by the utilities themselves when they founded the Electric Power Research Institute (EPRI) in 1973. EPRI's charter — to develop new and improved technology for environmentally acceptable production, transmission, and distribution of electric power to help the utility industry meet present and future electric energy needs.

As teachers demand, and receive, in creased compensa tion for sponsorship of extracurricular activities the need becomes greater to evaluate their work. Some considerations are discussed here.

A comparison of the benthic fauna found in two shallow lakes in the New Jersey Pinelands (USA) illustrated the impact of elevated pH and nutrients caused by residential and agricultural disturbance on a naturally acidic, poorly buffered aquatic environment. Detailed community analysis suggested that change in community composition was a better indicator of response to disturbance than biological diversity indices. Chironomidae (insecta) were the predominant components of the benthic macroinvertebrate assemblage of both undisturbed Oswego Lake (low pH, low nutrients) and Nescochague Lake (fluctuating pH, elevated nutrients). The genera Procladius, Tribelos, and Pagastiella dominated Oswego Lake, where as Zalutschia zalutschicola, Procladius, Dicrotendipes, and Tanytarsus dominated Nescochague Lake. Glyptotendipes was a common and unique member of the Nescochague Lake assemblage. Cluster analysis indicated that the chemical differences between lakes were the most important community determinants, although, within each lake, depth and substrate affected the local communities. Oswego Lake exhibited a depauperate nonchironomid benthic fauna typical of low nutrient, acid lakes. In turn, Nescochague Lake exhibited an enriched nonchironomid fauna including mollusks and planaria which were not found in Oswego Lake.

The Ah receptor binds aryl hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with high affinity. After binding aryl hydrocarbons, the receptor releases the 90-kDa heat shock protein and forms a dimer with the Arnt protein capable of binding at xenobiotic-responsive elements (XREs) and stimulating the transcription of genes involved in the metabolism of aryl hydrocarbons. The activity of the Ah receptor/Arnt dimer can be decreased by treatments causing the down-regulation of protein kinase C and decreasing the nuclear accumulation of the receptor. Incubation with acid phosphatase or with alkaline phosphatase has been reported to block XRE binding. Thus the literature suggests that phosphorylation regulates Ah receptor activity by affecting DNA binding and/or nuclear transport. A reporter plasmid containing two XREs was used to investigate the effects of phosphatase inhibitors on TCDD-dependent transcription by the Hepa-1 mouse liver cell line. The inhibitors calyculin A and okadaic acid caused two- to threefold increases in TCDD-dependent transcription at concentrations capable of selectively inhibiting protein phosphatase 1 and protein phosphatase 2A . The inhibitor cyclosporin A doubled TCDD-dependent transcription at a concentration capable of selectively inhibiting protein phosphatase 2B. All three of the phosphatase inhibitors increased TCDD-dependent transcription without affecting transcription in the absence of TCDD. Nuclear extracts were prepared from cells treated with concentrations of okadaic acid or cyclosporin A which substantially stimulated TCDD-dependent transcription. Neither of the inhibitors significantly increased the level of TCDD-dependent XRE binding in the extracts. GAL4–Arnt fusion proteins were used to further investigate whether the phosphatase inhibitors affected a step other than DNA binding. Okadaic acid treatment specifically increased the ability of a GAL4 fusion protein containing the Arnt PAS and transactivation domains to stimulate transcription. These results suggest that serine/threonine-specific protein phosphatases can act at a level subsequent to XRE binding to inhibit the ability of the Ah receptor/Arnt dimer to stimulate transcription.

To determine whether the production of brain ischemia is modified by antiplatelet agents administered at the time of extracranial endothelial injury, we modified a four-vessel occlusion rat model so that an electrogenic platelet thrombus in one carotid artery produced cerebral ischemia. DC current was passed through an anode around the left carotid artery of 11 rats with preoccluded vertebral and contralateral carotid arteries. Five of six untreated rats became unresponsive because of carotid occlusion and resultant cerebral ischemia; none of five animals pretreated with indomethacin and infused with prostacyclin (PGI2) were clinically affected. Light-and electronmicroscopic studies showed arterial platelet-fibrin thrombi and ischemic brain damage in untreated rats. All rats had received radiolabeled platelets; radioactivity was increased in the electrogenically injured left carotid arteries from treated and untreated rats, but counts were reduced by more than 80 in indomethacin/ PGL2-treated rats (p< 0.01).

Male weanling rats were raised on diets based on torula yeast which were deficient in vitamin E and selenium, or supplemented with these substances. They were injected intraperitoneally with sodium selenite at 2 mg Se/kg or with sodium sulfite to give the same level of sodium. Following injection, lipid peroxidation in vivowas estimated by monitoring the production of ethane, a volatile product formed on the peroxidation of ω-3-unsaturated fatty acids. In the hour following injection, vitamin E- and selenium-deficient rats injected with selenite produced 15 times as much ethane as did controls injected with sulfite. All rats in this group died from 1 to 4 hr after injection. Rats fed diets supplemented with selenite showed only a two- to threefold stimulation of ethane production by selenite and 3/4 survived. Rats fed diets supplemented with vitamin E did not produce more ethane in response to selenite injection and 3/4 survived. All four rats supplemented with both vitamin E and selenium survived without showing increased ethane production. Thus, the increased vulnerability of vitamin E- and selenium-deficient rats to acute selenite toxicity may involve peroxidation in vivo.Rats fed diets supplemented with vitamin E could survive at least twice as much selenite as rats deficient in selenium and vitamin E. Seven-day survival figures for rats fed the basal diet and injected with selenite were: 1 mg Se/kg, 7/8; 2 mg Se/kg, 0/8. For rats supplemented with vitamin E the figures were 2 mg Se/kg, 7/8; 4 mg Se/kg, 2/8. When sodium selenate was injected into rats deficient in vitamin E and selenium at 3 mg Se/kg it caused acute mortality without increasing peroxidation in vivo.

Copper sulfate injected intraperitoneally at a dose of 2 mg Cu/kg into vitamin E-and selenium-deficient rats caused a sixfold increase in the formation in vivoof the lipid peroxidation product ethane, and caused acute mortality in 4/5 rats. Selenium supplementation of the diet at 0.5 ppm Se largely prevented the increase in ethane production caused by copper injection and reduced mortality to 1/5 rats. Vitamin E supplementation of the diet at 200 IU/kg fully eliminated the increase in ethane production caused by copper injection, and completely prevented mortality. Vitamin E-deficient rats injected with copper sulfate at 5 mg Cu/kg produced over 10 times the ethane produced by rats injected with sodium sulfate or left uninjected. The ethylene produced by the rats injected with copper sulfate was 5% of the ethane produced, and did not differ significantly from the ethylene produced by the controls. Adding copper sulfate at 5 ppm Cu to a liver homogenate stimulated the production of ethane but not of ethylene. The correlation of increased ethane production with increased mortality suggests that lipid peroxidation may be important in the increased toxicity of copper in vitamin E- and selenium-deficient rats.

We studied 10 patients who survived for 2 to 8 weeks in a vegetative state, including 8 with cardiopulmonary failure and 2 with subarachnoid hemorrhage. Within days of onset, they regained brainstem function and awoke, but none had evidence of cognitive awareness. All patients opened their eyes within 2 weeks, and eight had roving conjugate eye movements. Pupillary and corneal responses were intact within 1 week, and seven patients had tonic oculovestibular responses (OVR) within 24 hours. By the end of 1 day, only three patients failed to move limbs in response to noxious stimuli. At postmortem, all patients had widespread ischemic neuronal damage in the cerebral hemispheres. The brainstems lacked morphologic abnormality, except that one patient had a single microinfarct in the superior colliculus.

Of 217 patients with clinical diagnosis of acute stroke 23 had nonischemic lesions diagnosed by computed tomography (CT) or lumbar puncture (LP). CT demonstrated all 37 cases of intracerebral hemorrhagic lesions; 9 were detected by LP. CT failed to demonstrate 8 of 17 cases of subarachnoid hemorrhage, but only 1 of these lacked headache or stiff neck.