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The complement C1q plays a critical role in microglial phagocytosis of glutamatergic synapses and in the pathogenesis of neuroinflammation in Alzheimer's disease (AD). We recently reported that upregulation of metabotropic glutamate receptor signaling is associated with increased synaptic C1q production and subsequent microglial phagocytosis of synapses in the rodent models of AD. Here, we explored the role of astrocytic glutamate transporter in the synaptic C1q production and microglial phagocytosis of hippocampal glutamatergic synapses in a rat model of AD. Activation of astrocyte and reduction glutamate transporter 1 (GLT1) were noted after bilateral microinjection of amyloid-beta (Aβ1-40) fibrils into the hippocampal CA1 area of rats. Ceftriaxone is a β-lactam antibiotic that upregulates GLT1 expression. Bilateral microinjection of ceftriaxone recovered GLT1 expression, decreased synaptic C1q production, suppressed microglial phagocytosis of glutamatergic synapses in the hippocampal CA1, and attenuated synaptic and cognitive deficits in rats microinjected with Aβ1-40. In contrast, artificial suppression of GLT1 activity by DL-threo-beta-benzyloxyaspartate (DL-TBOA) in naive rats induced synaptic C1q expression and microglial phagocytosis of glutamatergic synapses in the hippocampal CA1 area, resulting in synaptic and cognitive dysfunction. These findings demonstrated that impairment of astrocytic glutamate transporter plays a role in the pathogenesis of AD.

Paclitaxel induces microglial activation and production of proinflammatory mediators in the dorsal horn, which contribute to the development and maintenance of central sensitization and pain behavior. MDA7, 1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl) piperidine, is a novel highly selective cannabinoid type 2 (CB2) agonist. We tested the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation, suppresses the overexpression of brain-derived neurotrophic factor (BDNF) in microglia in the dorsal horn, and attenuates the central sensitization and pain behavior induced by paclitaxel. For 4 consecutice days, groups of rats randomly received saline or 1.0 mg/kg of paclitaxel daily intraperitoneally for a total cumulative dose of 4 mg/kg. MDA7 15 mg/kg intraperitoneally or vehicle were administered 15 min before administering paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular studies were performed. Paclitaxel induced the expression of CB2 receptors and production of interleukin (IL)-6 in microglia in the dorsal horn. MDA7 attenuated the expression of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation of IRF8 and P2X purinoceptor 4 (P2X4) in microglia and subsequently increased the expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIα), transcriptional factors p-CREB and ΔFosB, leading to the overproduction of BDNF in microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits GluR1 and NR2B, decreased the expression of K+-Cl- cotransporter, and induced mechanical allodynia in rats. All of the aforementioned molecular changes were attenuated by MDA7. Our data show that MDA7 attenuated paclitaxel-induced molecular and behavioral changes in rats. Perspective: This study provides evidence that paclitaxel induced microglia dysregulation and epigenetically upregulated the microglial expression of BDNF, which led to sensitization of dorsal horn neurons and mechanical allodynia in rats. The CB2 agonist MDA7 alleviated these pathological processes. MDA7 represents an innovative therapeutic approach for treatment of chemotherapy-induced neuropathy.

Mars Polar Science is an integrated, compelling system that serves as a nearby analogue to numerous other planets, supports human exploration, and habitability. Mars possesses the closest and most easily accessible layered ice deposits outside of Earth, and accessing those layers to read the climate record would be a triumph for planetary science.

Duvelisib (IPI‐145) is an oral dual inhibitor of phosphoinositide‐3‐kinase (PI3K)‐δ and ‐γ in clinical development for the treatment of hematologic malignancies, including indolent non‐Hodgkin lymphoma (iNHL). In a Phase 1, open‐label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8‐100 mg BID) in a dose‐escalation phase (n = 31 evaluable patients). Two dose‐limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a response (19.4% complete, 35.5% partial, and 3.2% minor); median time to response was 1.84 months and duration of response was 16.9 months. Median progression‐free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis, acute respiratory failure, and fungal pneumonia. No iNHL patients experienced Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high‐risk, heavily pretreated, relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical development.

PURPOSE OF REVIEW: This narrative review summarizes recent insights into the role of the CB2 receptor as potential therapeutic target in neuropathic pain and neurodegenerative conditions. RECENT FINDINGS: The cannabinoid system continues to receive attention as a therapeutic target. The cannabinoid type 2 (CB2) receptor is primarily expressed only when there is active inflammation and appears to be devoid of undesired psychotropic effects or addiction liability. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases with limited or no currently approved therapies, such as neuropathic pain and neurodegenerative conditions such as Alzheimer’s disease. SUMMARY: The functional involvement of CB2 receptor in neuropathic pain and other neuroinflammatory diseases highlights the potential therapeutic role of drugs acting at the CB2 receptor.

Silent glutamatergic synapses lacking functional AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate) receptors exist in several brain regions including the hippocampus. Their involvement in the dysfunction of hippocampal glutamatergic transmission in the setting of Alzheimer’s disease (AD) is unknown. The present study demonstrated a decrease in the percentage of silent synapses in rats microinjected with amyloid fibrils (Aβ(1–40)) into the hippocampal CA1. Also, pairing low-frequency electric stimuli failed to induce activation of the hippocampal silent synapses in the modeled rats. Immunoblotting studies revealed a decreased expression of GluR1 subunits in the hippocampal CA1 synaptosomal preparation, indicating a potential reduction in the GluR1 subunits anchoring in postsynaptic density in the modeled rats. We also noted a decreased expression of phosphorylated cofilin, which regulates the function of actin cytoskeleton and receptor trafficking, and reduced expression of the scaffolding protein PSD95 in the hippocampal CA1 synaptosome in rats injected with Aβ(1–40). Taken together, the present study illustrates dysfunction of hippocampal silent synapse in the rodent model of AD, which might result from the impairments of actin cytoskeleton and postsynaptic scaffolding proteins induced by amyloid fibrils.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuroinflammation, extensive deposits of amyloid-β aggregates, and loss of memory and cognitive abilities. The brains of patients with AD show increased expression of cannabinoid receptor type 2 (CB2) receptors and glial markers. CB2 receptors act as a negative feedback regulator; when activated by a CB2 agonist, they can help limit the extent of the neuroinflammatory response and the subsequent development of neuronal damage in the central nervous system. In a double transgenic APP/PS1 mice model of AD, we evaluated the effect of MDA7, a CB2 agonist, on several neuropathological conditions of AD including amyloid deposition, inflammatory reaction, Sox2 (sex-determining region Y-box 2) expression, and spatial memory. Activation of microglia CB2 receptors by MDA7 suppressed neuroinflammation, demonstrated by decreased immunosignal of Iba1 in the hippocampal CA1 and dentate gyrus (DG) areas, promoted clearance of amyloid plaques in the DG area, restored Sox2 expression, and promoted recovery of the neuronal synaptic plasticity in hippocampal CA1. In addition, treatment with MDA7 improved the behavioral performance in the Morris water maze in APP/PS1mice. Collectively, these findings suggest that MDA7 has a potential therapeutic effect in the setting of AD.

Microglia and complements appear to be involved in the synaptic and cognitive deficits in Alzheimer's disease (AD), though the mechanisms remain elusive. In this study, utilizing two types of rodent model of AD, we reported increased complement C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses, which led to synaptic and cognitive deficits. We also found increased activity of the metabotropic glutamate receptor 1 (mGluR1) in hippocampal CA1 in the modeled rodents. Artificial activation of mGluR1 signaling promoted dephosphorylation of fragile X mental retardation protein (FMRP) and facilitated the local translation machinery of synaptic C1q mRNA, thus mimicking the C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses and synaptic and cognitive deficiency in the modeled rodents. However, suppression of mGluR1 signaling inhibited the dephosphorylation of FMRP and repressed the local translation of synaptic C1q mRNA, which consequently alleviated microglial phagocytosis of synapses and restored the synaptic and cognitive function in the rodent models. These findings illustrate a novel molecular mechanism underlying C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses in AD.

Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n = 179), patients with indolent non-Hodgkin lymphoma (iNHL), chronic lymphocytic leukemia (CLL), or T-cell lymphoma (TCL) were treated with 25 or 75 mg duvelisib twice daily continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration, 1-2 hours), with a half-life of 5.2 to 10.9 hours. PD results showed inhibition of phospho-AKT (S473) in CLL tumor cells following a single dose and near-complete inhibition of CLL proliferation (Ki-67) by cycle 2. Clinical responses were seen across a range of doses and disease subtypes: iNHL overall response rate, 58% (n = 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n = 55) with 1 CR; peripheral TCL, 50% (n = 16) with 3 CR; and cutaneous TCL, 32% (n = 19). Median time to response was ∼1.8 months. Severe (grade ≥3) adverse events occurred in 84% of patients: neutropenia (32%), alanine transaminase increase (20%), aspartate transaminase increase (15%), anemia and thrombocytopenia (each 14%), diarrhea (11%), and pneumonia (10%). These data support further investigation of duvelisib in phase 2 and 3 studies. This trial was registered at clinicaltrials.gov as #NCT01476657.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuroinflammation, extensive deposits of amyloid-β aggregates, and loss of memory and cognitive abilities. The brains of patients with AD show increased expression of cannabinoid receptor type 2 (CB

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.

Aim We examine the regional dominance of California as a beachhead for marine biological invasions in western North America and assess the relative contribution of different transfer mechanisms to invasions over time.

Given that preoperative hyperglycemia is associated with poor outcomes and many non-diabetic patients have high plasma glucose (PG) levels, the purpose of our study was to estimate the prevalence of undiagnosed diabetes among non-cardiac surgery patients and to identify predictors of hyperglycemia in non-diabetics.We included all non-cardiac surgery patients with complete records in the Clinical Database of the Anesthesiology Institute at the Cleveland Clinic during January 2007 to April 2009, and we estimated the prevalence of undiagnosed diabetes and impaired fasting glucose (IFG) among the non-diabetic patients. The mean glucose levels for known diabetics and undiagnosed diabetics were compared using two-tailed Student's t tests, and we assessed the association between PG levels and demographic variables within the non-diabetics.Of the 39,434 patients analyzed, 5,511 (14%) were known diabetics. Of the 33,923 known non-diabetics, 3,426 (10 %) were undiagnosed diabetics and another 3,549 (11%) had IFG. Thus, 6,975 patients (21%) of the non-diabetic patients presented with abnormally high glucose. Previously undiagnosed diabetics had higher preoperative glucose levels compared with known diabetics, with a mean ± standard deviation (SD) of 161 ± 48 vs 146 ± 67 mg·dL⁻¹ (8.9 ± 2.7 vs 8.1 ± 3.7 mmoL·L⁻¹), respectively. The difference remained highly significant after adjusting for body mass index, age, sex, and American Society of Anesthesiologists (ASA) physical status (P0.001). Among non-diabetics, older age, obesity, male sex, and a higher ASA physical status were collectively significant predictors of hyperglycemia, with a c-statistic (95% confidence interval) of 0.67 (0.66-0.68).A significant proportion of non-cardiac surgery patients have previously undiagnosed diabetes and pre-diabetes. Previously undiagnosed patients have higher fasting glucose levels compared with diabetic patients. Further studies should be conducted to identify the implications of these findings on patient outcomes.

The impact of inflammation on variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs should be considered in the design, analysis, and interpretation of clinical pharmacology studies. Data suggest that the metabolism and transport of drugs, as well as the expression of receptors, may change in the presence of inflammation. The clinical implications of these changes are not straightforward; they may vary depending on whether the inflammation is active or controlled and may change with time and successful treatment of the inflammation.

Postoperative ileus (POI), a transient cessation of coordinated bowel function after surgery, is an important health care problem. The etiology of POI is multifactorial and related to both the surgical and anesthetic pathways chosen. Opioids used to manage surgical pain can exacerbate POI, delaying gastrointestinal (GI) recovery. Peripherally acting mu-opioid receptor (PAM-OR) antagonists are designed to mitigate the deleterious effects of opioids on GI motility. This new class is investigational for POI management with the goal of accelerating the recovery of upper and lower GI tract function after bowel resection. In this review, we summarize the mechanisms by which POI occurs and the role of opioids and opioid receptors in the enteric nervous system, discuss the mechanism of action of PAM-OR antagonists, and review clinical pharmacology and Phase II/III POI trial results of methylnaltrexone and alvimopan. Finally, the role of anesthesiologists in managing POI in the context of a multimodal approach is discussed.

BACKGROUND: Strategies to limit adverse cardiac events after vascular surgery continue to evolve. Early recognition and treatment of myocardial ischemia may be a key to improving postoperative survival rates. Cardiac troponin I (cTnI) screening is an effective means of surveillance for postoperative myocardial ischemic injury and has long-term prognostic value. METHODS: We designed a Markov-based decision analysis model to determine the cost-effectiveness of routine surveillance with cTnI on postoperative Days 0, 1, 2, and 3, with an aim to institute tight heart rate control (60–65 bpm) with close monitoring and coronary care in the intensive care unit for 5 days in patients with cTnI 1.5 ng/mL. The key input variables obtained from published literature were as follows: probability of myocardial infarction, 0.049; cost of cTnI surveillance, $357; cost and efficacy of interventions, $13,145 and 0.55, respectively. The time horizon was lifetime and the target population being individuals aged 65 yr (median) undergoing elective open abdominal aortic surgery. The perspective for analysis was third-party payer. RESULTS: The incremental cost-effectiveness ratio for cTnI surveillance was $12,641 per quality-adjusted life year compared with standard care without cTnI surveillance. During one-way sensitivity analysis, probability of myocardial infarction and efficacy of interventions were found to influence the cost-effectiveness. Multivariate sensitivity analysis with second-order Monte Carlo simulation revealed that cTnI surveillance was favored in 90.75% of simulations at a commonly used threshold of $50,000 per quality-adjusted life year. CONCLUSIONS: In patients presenting for elective open abdominal aortic surgery, intensive surveillance with cTnI and early institution of aggressive -blockade is cost-effective. (Anesth Analg 2007;105:1346‐56)

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis in most subtypes. Diagnosis of this rare disease by expert hematopathologists improves accuracy of subtyping, and referral to academic or specialty centers is recommended. Many patients, however, will receive treatment in the community, and knowledge of approved agents is key to optimizing therapeutic approaches for all patients. There is no current standard of care for patients with PTCL and no approved therapies for first-line treatment. Although many patients initially respond to induction chemotherapy, responses are often brief, and many patients relapse or become treatment refractory. For patients with relapsed or refractory PTCL, achievement of durable responses is challenging, and there are few treatment options. Romidepsin is a histone deacetylase inhibitor approved by the U.S. Food and Drug Administration for the treatment of patients with cutaneous T-cell lymphoma who have received one prior systemic therapy or more and patients with PTCL who have received one prior therapy or more. Approval of romidepsin for PTCL was based on a pivotal phase II study of patients with relapsed or refractory PTCL (n = 131) that demonstrated an objective response rate of 25% including 15% with complete response; responses lasted a median of >2 years. Long-term responses to romidepsin were achieved in patients regardless of baseline characteristics, including subtype, heavy pretreatment, response to prior therapy, or advanced disease. Common adverse events included hematologic abnormalities, gastrointestinal or asthenic conditions, and infections; romidepsin was not correlated with clinically meaningful QT prolongation or electrocardiogram abnormalities. Implications for Practice: Due to the rarity, severity, and heterogeneous nature of peripheral T-cell lymphoma (PTCL), diagnosis by expert hematopathologists is preferred, and referral to specialty centers is recommended. Many patients, however, will receive treatment in the community, and community oncologists play a key role in the recognition and treatment of PTCL. Knowledge of approved agents is key for optimizing therapeutic approaches. This review provides an overview of PTCL and an in-depth examination of romidepsin, a histone deacetylase inhibitor approved for the treatment of relapsed or refractory PTCL, and highlights difficulties of diagnosis and optimization of treatment modalities for patients with PTCL.

This study examined the utility of PET scans for assessing prognosis and response to treatment in patients with relapsed/refractory PTCL receiving romidepsin. For patients with stable disease or partial response by conventional criteria, PET status better differentiated durability of response than conventional response category. Routine PET use may aid in treatment planning in patients with PTCL., Background For patients with peripheral T-cell lymphoma (PTCL), the value of 18fluoro-deoxyglucose positron emission tomography (FDG-PET) scans for assessing prognosis and response to treatment remains unclear. The utility of FDG-PET, in addition to conventional radiology, was examined as a planned exploratory end point in the pivotal phase 2 trial of romidepsin for the treatment of relapsed/refractory PTCL. Patients and methods Patients received romidepsin at a dose of 14 mg/m2 on days 1, 8, and 15 of 28-day cycles. The primary end point was the rate of confirmed/unconfirmed complete response (CR/CRu) as assessed by International Workshop Criteria (IWC) using conventional radiology. For the exploratory PET end point, patients with at least baseline FDG-PET scans were assessed by IWC + PET criteria. Results Of 130 patients, 110 had baseline FDG-PET scans, and 105 were PET positive at baseline. The use of IWC + PET criteria increased the objective response rate to 30% compared with 26% by conventional radiology. Durations of response were well differentiated by both conventional radiology response criteria [CR/CRu versus partial response (PR), P = 0.0001] and PET status (negative versus positive, P < 0.0001). Patients who achieved CR/CRu had prolonged progression-free survival (PFS, median 25.9 months) compared with other response groups (P = 0.0007). Patients who achieved PR or stable disease (SD) had similar PFS (median 7.2 and 6.3 months, respectively, P = 0.6427). When grouping PR and SD patients by PET status, patients with PET-negative versus PET-positive disease had a median PFS of 18.2 versus 7.1 months (P = 0.0923). Conclusion(s) Routine use of FDG-PET does not obviate conventional staging, but may aid in determining prognosis and refine response assessments for patients with PTCL, particularly for those who do not achieve CR/CRu by conventional staging. The optimal way to incorporate FDG-PET scans for patients with PTCL remains to be determined. Trial registration NCT00426764.

backgroundaims: Opiate bowel dysfunction is a significant clinical problem. Our aim was to evaluate the ability of a peripheral mu-opioid antagonist, alvimopan, to reverse the effect of codeine on gastric, small-bowel, and colonic transit time in healthy volunteers.Seventy-four healthy participants (43 women) were randomized in a double-blind, placebo-controlled manner to 1 of 4 groups: alvimopan 12 mg twice daily in the presence and absence of codeine sulfate 30 mg 4 times/day, or codeine or placebo alone. Gastric emptying, small-bowel, and colonic transit were measured by scintigraphy using a 99m-labeled technetium egg meal and 111-labeled indium charcoal delivered to the proximal colon via a delayed-release capsule. The primary end points for colonic transit were geometric center of the colonic counts at 24 hours and time for 50% ascending colon emptying. Analysis of covariance was used to assess the significance of the primary and secondary end points.Codeine delayed gastric, small-bowel, proximal, and overall colonic transit (P.05). Alvimopan reversed codeine's effect on small bowel and colon (ascending colon and overall colonic transit). Alvimopan also accelerated overall colonic transit compared with placebo. Thus, the mean colonic geometric center at 24 hours was 2.33 with placebo/placebo, 3.25 with alvimopan/placebo (P.05), 1.5 with placebo/codeine (P.05), and 2.63 with alvimopan/codeine. Alvimopan did not reverse codeine's delay of gastric emptying.Alvimopan reverses codeine's inhibitory effect on small-bowel and colon transit and has potential for treatment of opiate bowel dysfunction. Alvimopan alone accelerates colonic transit, suggesting that mu-opiate mechanisms participate in the physiologic control of colonic transit.

Collaboration can maximize limited resources of universities, school systems, and public health departments by offering learning from experience. Polvika's theoretical model and principles from Community-Campus Partnerships for Health guided development of a service-learning partnership among a university, a county health department, and an alternative school in a large public school district. Of three commonly identified patterns of service-learning, this partnership demonstrated the pattern that equally emphasizes service to a community or agency, and mutual learning by all participants. All organizations in the partnership share a common goal to optimize the health of children in schools, and to provide quality learning for professional students. The partnership is in its fourth year. Formal interagency agreements now exist among all partners. Individuals continue to demonstrate flexibility and mutual awareness of strengths and limitations of respective organizations. Public school students receive more services, many high-risk children achieve better learning outcomes, school nurses offer expanded services in many schools with the help of nursing students, and undergraduate and graduate nursing students gain meaningful learning experiences. Some nursing students state that school nursing has become a career goal. The partnership continues to evolve to meet changing needs of the partners. Members remain satisfied with the collaboration.

PURPOSE: To determine the extent of posttraumatic stress and acculturation in Vietnamese and Hmong mothers and identify their relationship to maternal sensitivity. DESIGN: Descriptive correlational research design. METHODS: A sample of 30 mothers was evenly divided between Hmong and Vietnamese who had lived in the United States 2 to 21 years, had healthy children under 30 months, and had varied education and literacy levels. Data were collected in the home using a script. The mother's sensitivity to her infant was measured by Ainsworth's Sensitivity vs. Insensitivity to the Baby's Communication, degree of acculturation by the Suinn-Lew Self-identity Acculturation Scale (SL-ASIA), and posttraumatic stress by the Hopkins Symptom Checklist-25 (HSCL-25). RESULTS: Depression and anxiety correlated highly with posttraumatic stress (PTS), and thus were substituted for PTS. Almost half (43%) were clinically depressed or anxious, with less acculturated mothers tending to be more anxious and depressed. One third had considered suicide in the previous week. Mothers found it difficult to communicate their distress to primary providers. In spite of high depression and anxiety rates, maternal sensitivity was high, and was not significantly correlated to any variable. CLINICAL IMPLICATIONS: Nurses should incorporate screening for depression and anxiety into routine assessments or discharge planning for foreign-born mothers, then refer stressed mothers to appropriate resources. It is important to not assume diminished sensitivity in depressed or anxious mothers and to consider the coaching role of the grandmother. Language: en

Patients presenting for vascular surgery frequently have multiple coexisting diseases. To meet the goal of providing a safe anesthetic with optimum resource use, we must ex amine the impact of each of these conditions on the patient and how the data from a particular evaluation or test will impact our anesthetic plan. Existing guidelines may be valu able if adapted to institution-specific circumstances. Con sultants represent a relatively high-cost resource, which can be optimized when used with clear goals in sight. Finally, we may be able to modify our evaluation based on the antici pated procedure, as these patients are exposed to a range of potential hemodynamic stresses.

BACKGROUND Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. METHODS This trial consisted of two studies: a pilot study and a controlled study. The lactulose hydrogen breath test was used to measure the oral-cecal transit time. RESULTS In the pilot study with three subjects, an oral dose of 6.4 mg/kg enteric-coated methylnaltrexone effectively reversed the effects of morphine, producing transit times shorter than baseline levels. Subsequently, in the controlled study with another nine subjects, the transit time increased after intravenous morphine administration in all nine subjects, and the lower dose (3.2 mg/kg) of enteric-coated methylnaltrexone completely prevented the morphine-induced change in oral-cecal transit time in all nine subjects. Morphine significantly increased oral-cecal transit time from baseline level of 96.7 +/- 54.1 minutes (mean +/- SD) to 155.0 +/- 53.6 minutes (P = .014). After enteric-coated methylnaltrexone and morphine, the transit time returned to the baseline level (93.3 +/- 56.0 minutes; P = .55 compared with placebo). Plasma concentrations after 6.4 mg/kg and 3.2 mg/kg enteric-coated methylnaltrexone were substantially lower compared with those after 6.4 mg/kg of the uncoated formulation. CONCLUSION Our results suggest that there is a prevailing direct and local luminal effect of enteric-coated methylnaltrexone and that the enteric-coated formulation exerts its gut pharmacologic actions more efficiently than the uncoated formulation.

In this era of medical technology assessment and evidence-based medicine, evaluating new methods to measure physiologic variables is facilitated by standardization of reporting results. It has been proposed that assessing repeatability be followed by assessing agreement with an established technique. If the “limits of agreement” (mean bias 6 2sd) are not clinically important, then one could use two measurements interchangeably. Generalizability to larger populations is facilitated by reporting confidence intervals. We identified 44 studies that compared methods of clinical measurement published during 1996 to 1998 in seven anesthesia journals. Although 42 of 44 (95.4%) used the limits of agreement methodology for analysis, several inadequacies and inconsistencies in reporting the results were noted. Limits of agreement were defined a priori in 7.1%, repeatability was evaluated in 21.4%, and relationship (pattern) between difference and average was evaluated in 7.1%. Only one of the articles reported confidence intervals. A computer macro for the Minitab statistical package (State College, PA) is described to facilitate reporting of Bland and Altman analysis with confidence intervals. We propose standardization of nomenclature in clinical measurement comparison studies. Implications: A literature review of anesthesia journals revealed several inadequacies and inconsistencies in statistical reports of results of comparison studies with regard to interchangeability of measurement methods. We encourage journal editors to evaluate submissions on this subject carefully to ensure that their readers can draw valid conclusions about the value of new technologies.

Morphine and related opioids are widely used medications that are associated with a number of limiting side effects. In the last three decades significant progress has been achieved in our understanding of the mechanisms of action of these opioids; however, these advances have yielded few new approaches to the management of opioid side effects. Methylnaltrexone, the first peripheral opioid antagonist currently under clinical investigation, has the potential to prevent or treat opioid-induced peripherally mediated side effects without interfering with analgesia. This article reviews data obtained from preclinical and clinical studies on methylnaltrexone that focus on the antagonism of opioid-induced constipation. Other potential clinical applications of the compound are also discussed. Drug Dev. Res. 50:133–141, 2000. © 2000 Wiley-Liss, Inc.

Background The authors hypothesized that myoclonus after etomidate is dose-related, could be suppressed when small doses of etomidate were administered before induction, and is unassociated with seizure-like activity on electroencephalogram (EEG). Methods Three studies were performed. In the first study, 36 men were randomly assigned to receive 0.025, 0.050, 0.075, 0.100, 0.200, or 0.300 mg/kg of etomidate. In a second crossover study, eight men were randomly allocated to receive either a pretreatment dose of 0.050 mg/kg etomidate or placebo 50 s before 0.300 mg/kg etomidate was injected. EEG was recorded for subjects in the first two studies. In a third study, 60 patients were randomly allocated to one of three pretreatment doses of etomidate: 0.030, 0.050, or 0.075 mg/kg before 0.300 mg/kg was given. Results In Study 1, myoclonus was not observed after 0.025 or 0.050 mg/kg etomidate. One volunteer had myoclonus after 0.075 mg/kg and another after 0.100 mg/kg etomidate; three had myoclonus after 0.200 mg/kg; and five after 0.300 mg/kg. Incidence of myoclonus was dose-related (P < or = 0.01). In Study 2, two volunteers (25%) with etomidate pretreatment had mild myoclonus compared to six (75%) with placebo pretreatment (P < or = 0.05). EEG changes, other than delta waves, were not seen during myoclonic epochs. In Study 3, myoclonus was less likely after the small pretreatment doses (0.030 or 0.050 mg/kg) than after the large dose (0.075 mg/kg, P < or = 0.01). Conclusions Incidence and intensity of myoclonus after induction with etomidate are dose-related, suppressed by pretreatment, and unassociated with seizure-like EEG activity.

Inflammation is an interesting phenomenon that crosses many disciplines as part of the host response to disease, whether it is the acute response to an infectious, traumatic, or surgical event or the more chronic responses to systemic disease such as malignancy, rheumatoid arthritis, asthma, inflammatory bowel disease, or diabetes. The impact of inflammatory states on the variability in drug response should be an integral part of research conducted across disciplines within clinical pharmacology.

Opioid compounds are commonly used analgesics. After opioid administration, troublesome subjective effects, such as dysphoria, dizziness, nausea, and pruritus, have been reported. While some if not all of these are believed to occur due to central nervous system effects of opioids, the anecdotal reports heard from volunteers in our other studies suggest that a peripheral opioid antagonist reduced some of these effects. In this double-blind randomized placebo-controlled study, we evaluated the efficacy of oral methylnaltrexone, a selective peripheral opioid receptor antagonist, to decrease subjective effects after administering morphine to normal human volunteers. After intravenous morphine injection (0.05 mg/kg), significant increases in subjective ratings were obtained on 'nauseous', 'skin itch', 'stimulated', and 'flushing'. Oral methylnaltrexone 19.2 mg/kg significantly decreased these four ratings. Plasma methylnaltrexone concentrations at two different oral doses were also measured to correlate between pharmacological effects of the compound and its plasma levels. Our results suggested that methylnaltrexone has a potential therapeutic value in decreasing some undesirable subjective effects associated with opioid medications.

This study was conducted to survey gut motility and transit in 19 volunteers receiving methadone maintenance who were opioid-dependent, and to measure the oral-cecal transit time in these individuals using the lactulose hydrogen breath test. None of these patients reported constipation problems before use of illicit drugs. During current long-term methadone therapy, 58% of patients experienced some degree of constipation, and two of these 19 patients reported that constipation was a very serious problem. Mean +/- standard deviation (SD) oral-cecal transit time in these individuals was 159+/-49.2 minutes, which is significantly longer than the transit time recorded in two previous studies of healthy volunteers (P < 0.01). These results indicate that tolerance to opioids does not appear to extend to gastrointestinal motility and transit. It seems that patients receiving long-term methadone therapy are a good model for use in evaluating gastrointestinal effects of opioid antagonists.

N-methylnaltrexone bromide (methylnaltrexone) is a quaternary opioid antagonist with a limited ability to cross the blood-brain barrier. In animal models it reverses at peripheral receptors such side effects of opioids as decreased gastrointestinal motility, emesis, and cough suppression without affecting the desired analgesic effect mediated by central nervous system receptors. Methylnaltrexone thus may be a clinically useful compound for the prevention and treatment of opioid-induced side effects. This study was designed to examine the safety and tolerance of methylnaltrexone in healthy human participants over a range of doses and to identify any adverse effects or toxicity associated with methylnaltrexone and the doses at which these adverse effects occur. Healthy male volunteers received intravenous methylnaltrexone in six ascending doses with a placebo randomly inserted into the sequence. Each participant was observed for subjective and hemodynamic changes. Electrocardiogram and laboratory studies were also performed. The dose-limiting adverse effect of methylnaltrexone was orthostatic hypotension at 0.64 mg/kg (n = 3) or 1.25 mg/kg (n = 5), which was transient and self-limiting. Plasma levels of methylnaltrexone in excess of 1,400 ng/mL were observed to be associated with orthostatic hypotension. There were no significant subjective changes, no release of histamine, and no changes in physical examination or laboratory studies during the course of the study. Pharmacokinetic analysis revealed an elimination half-life of 117.5 minutes (+/-53.2), and a clearance of 38.8 L/hr (+/-17.4) with a methylnaltrexone dose of 0.64 mg/kg. Our results indicate that methylnaltrexone is well tolerated at doses of 0.32 mg/kg in healthy humans.