Yersinia enterocolitica infections associated with improperly pasteurized milk products: southwest Pennsylvania, March-August, 2011.

In July 2011, a cluster of Yersinia enterocolitica infections was detected in southwestern Pennsylvania, USA. We investigated the outbreak's source and scope in order to prevent further transmission. Twenty-two persons were diagnosed with yersiniosis; 16 of whom reported consuming pasteurized dairy products from dairy A. Pasteurized milk and food samples were collected from this dairy. Y. enterocolitica was isolated from two products. Isolates from both food samples and available clinical isolates from nine dairy A consumers were indistinguishable by pulsed-field gel electrophoresis. Environmental and microbiological investigations were performed at dairy A and pasteurization deficiencies were noted. Because consumption of pasteurized milk is common and outbreaks have the potential to become large, public health interventions such as consumer advisories or closure of the dairy must be implemented quickly to prevent additional cases if epidemiological or laboratory evidence implicates pasteurized milk as the outbreak source.

The Effects of the Paleo Diet on Autoimmune Thyroid Disease: A Mixed Methods Review.

The aim of this systematic review was to examine the characteristics of Paleolithic diet (PD) interventions designed for adult patients with autoimmune thyroid disease (AITD) in order to determine if diet elements have the potential to successfully reduce thyroid antibodies (Ab) such as thyroglobulin (Tg), thyroid peroxidase (TPO), and thyroid stimulating hormone receptor (TSHR), and improve thyroid hormones (thyroxine (T4), triiodothyronine (T3) and thyroid stimulating hormone (TSH)) or resolve AITD pathogenesis. Randomized controlled trials (RCTs) with an adult population of 18 years and older, diagnosed with Hashimoto's thyroiditis (HT) or Graves' disease (GD) (Basedow's), who were placed on a diet of Paleolithic or ancestral nature, and achieved reduction of AITD Abs, improvement of thyroid hormones, and, or resolution of AITD were searched. Various electronic databases were used. Bias was assessed using critical appraisal tools from the Scottish Intercollegiate Guidelines Network (SIGN) and Joanna Briggs Institute (JBI). Studies were excluded according to exclusion criteria and results analyzed. One randomized controlled trial (RCT), a pilot study, and six case studies were found. In total, eight AITD studies focusing on Paleolithic or ancestral interventions were located. In highlight, females were the predominant gender. Case studies solely focused on AITD with protocols ranging from 8-60 weeks. All studies showed clinical improvements, one had significant improvement, two showed AITD resolution. After structured evaluation of nutritional interventions utilizing the PD on the effects of AITD, it was concluded foods of ancestral nature along with the addition of specific supplements, food components, exercise and mindfulness meditation, and exclusion of modern day foods have a considerable impact on thyroid Ab and hormones. The relevant studies suggest while this dietary protocol can be useful in clinical practice, larger-scale studies need to be conducted. Key teaching pointsThere are currently no dietary interventions recommended for the treatment of autoimmune thyroid disease. The Paleo diet has been documented to improve AITD antibodies and thyroid hormones in both Hashimoto's thyroiditis and Graves' disease.The Paleo diet can provide a natural source of nutrients similar to supplemental nutrients that have shown positive results on AITD.The paleo diet provides specific macronutrient percentages that may be beneficial in reducing AITD antibodies, while improving thyroid hormones.Methylation supplementation may be useful in AITD cases.

Comparative Pharmacokinetics and Local Tolerance of Tenofovir Alafenamide (TAF) From Subcutaneous Implant in Rabbits, Dogs, and Macaques.

The administration of antiretrovirals (ARVs) for HIV pre-exposure prophylaxis (PrEP) is highly efficacious and may benefit from new long-acting (LA) drug delivery approaches. This paper describes a subcutaneous, reservoir-style implant for the LA delivery of tenofovir alafenamide (TAF) and documents the preclinical assessment of implant safety and pharmacokinetics (PK) in New Zealand White (NZW) rabbits (3 groups of n = 5), beagle dogs (2 groups of n = 6), and rhesus macaques (2 groups of n = 3). Placebo implants were placed in rabbits (n = 10) and dogs (n = 12). Implant parameters, including selection of the TAF form, choice of excipient, and PCL formulation were tuned to achieve targeted concentrations of the active anabolite of TAF, tenofovir diphosphate (TFV-DP), within peripheral blood mononuclear cells (PBMCs) and mucosal tissues relevant to HIV transmission. Sustained concentrations of TFV-DP in PBMCs over 100 fmol/106 cells were achieved in all animal species indicating that the implants effectively delivered TAF for 3-6 months. Unlike placebo implants without TAF, all active implants resulted in local adverse events (AEs) proximal to the implant ranging in severity from mild to moderate and included dermal inflammation and necrosis across all species. Despite these AEs, the implant performed as designed and achieved a constant drug release profile, supporting the continued development of this drug delivery platform.

Circulating omega-7 fatty acids are differentially related to metabolic dysfunction and incident type II diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA).

AIM: Determine whether plasma omega-7 vaccenic acid and palmitoleic acid levels are related to homeostasis model of insulin resistance scores and incident type II diabetes, and whether race/ethnicity modifies these associations. METHODS: Plasma phospholipid fatty acids were measured by gas chromatography with flame-ionization detection in Multi-Ethnic Study of Atherosclerosis participants. Linear regression determined associations of vaccenic acid and palmitoleic acid with log-transformed homeostasis model of insulin resistance scores (n=5689), and Cox regression determined associations with incident type II diabetes (n=5413, 660 cases). Race-interactions were tested. RESULTS: Adjusting for typical risk factors, higher levels of plasma vaccenic acid were found to be inversely associated with insulin resistance scores across all four race/ethnicities, and a significant race-interaction was observed between Hispanics and Caucasians (P for interaction=0.03). Vaccenic acid was related to 17%, 32%, and 39% lower risks of incident type II diabetes in Black, Hispanic, and Chinese American participants, respectively. Differences in associations between races were detected (P for interactions<0.05). By contrast, higher levels of plasma palmitoleic acid were related to greater insulin resistance scores in Blacks (P<0.001) and Hispanics (P<0.001); significant race-based differences between associations were detected (P for interactions<0.05). Palmitoleic acid was correspondingly related to a 21% greater risk of incident type II diabetes in Black individuals. CONCLUSIONS: Results suggest that plasma vaccenic acid and palmitoleic acid are markers of metabolic health and dysfunction, respectively. Coupled with previous evidence and the significant race-interactions, our findings have implications for future studies of the race-based differences in omega-7 fatty acids and their regulation in the context of deteriorating metabolic health.

The Hin dimer interface is critical for Fis-mediated activation of the catalytic steps of site-specific DNA inversion.

BACKGROUND: Hin is a member of an extended family of site-specific recombinases--the DNA invertase/resolvase family--that catalyze inversion or deletion of DNA. DNA inversion by Hin occurs between two recombination sites and requires the regulatory protein Fis, which associates with a cis-acting recombinational enhancer sequence. Hin recombinase dimers bind to the two recombination sites and assemble onto the Fis-bound enhancer to generate an invertasome structure, at which time they become competent to catalyze DNA cleavage and strand exchange. In this report, we investigate the role of the Hin dimer interface in the activation of its catalytic functions. RESULTS: We show that the Hin dimer is formed at an interface that contains putative amphipathic alpha-helices in a manner that is very similar to gamma delta resolvase. Certain detergents weakened cooperative interactions between the subunits of the Hin dimer and dramatically increased the rate of the first chemical step of the reaction--double-strand cleavage events at the center of the recombination sites. Amino-acid substitutions within the dimer interface led to profound changes in the catalytic properties of the recombinase. Nearly all mutations strongly affected the ability of the dimer to cleave DNA and most abolished DNA strand exchange in vitro. Some amino-acid substitutions altered the concerted nature of the DNA cleavage events within both recombination sites, and two mutations resulted in cleavage activity that was independent of Fis activation in vitro. Disulfide-linked Hin dimers were catalytically inactive; however, subsequent to the addition of the Fis-bound enhancer sequence, catalytic activity was no longer affected by the presence of oxidizing agents. CONCLUSIONS: The combined results demonstrate that the Hin dimer interface is of critical importance for the activation of catalysis and imply that interactions with the Fis-bound enhancer may trigger a conformational adjustment within the region that is important for concerted DNA cleavage within both recombination sites, and possibly for the subsequent exchange of DNA strands.

Specific repression of the yeast silent mating locus HMR by an adjacent telomere.

The yeast silent mating loci HML and HMR are located at opposite ends of chromosome III adjacent to the telomeres. Mutations in the N terminus of histone H4 have been previously found to derepress the yeast silent mating locus HML to a much greater extent than HMR. Although differences in the a and alpha mating-type regulatory genes and in the cis-acting silencer elements do not appear to strongly influence the level of derepression at HMR, we have found that the differential between the two silent cassettes is largely due to the position of the HMR cassette relative to the telomere on chromosome III. While HML is derepressed to roughly the same extent by mutations in histone H4 regardless of its chromosomal location, HMR is affected to different extends depending upon its chromosomal positioning. We have found that HMR is more severely derepressed by histone H4 mutations when positioned far from the telomere (cdc14 locus on chromosome VI) but is only minimally affected by the same mutations when integrated immediately adjacent to another telomere (ADH4 locus on chromosome VII). These data indicate that the degree of silencing at HMR is regulated in part by its neighboring telomere over a distance of at least 23 kb and that this form of regulation is unique for HMR and not present at HML. These data also indicate that histone H4 plays an important role in regulating the silenced state at both HML and HMR.

Steroids, steroid precursors, and neuroactive steroids in critically ill equine neonates.

Hypothalamic-pituitary-adrenal axis (HPAA) dysfunction has been associated with sepsis and mortality in foals. Most studies have focused on cortisol, while other steroids have not been investigated. The objectives of this study were to characterise the adrenal steroid and steroid precursor response to disease and to determine their association with the HPAA response to illness, disease severity, and mortality in hospitalised foals. All foals (n=326) were classified by two scoring systems into three categories: based on the sepsis score (septic, sick non-septic [SNS] and healthy) and the foal survival score (Group 1: 3-18%; Group 2: 38-62%; Group 3: 82-97% likelihood of survival). Blood concentrations of adrenocorticotropic hormone (ACTH) and steroids were determined by immunoassays. ACTH-cortisol imbalance (ACI) was defined as a high ACTH/cortisol ratio. Septic foals had higher ACTH, cortisol, progesterone, 17α-OH-progesterone, pregnenolone, and androstenedione concentrations as well as higher ACTH/cortisol, ACTH/progesterone, ACTH/aldosterone, and ACTH/DHEAS ratios than SNS and healthy foals (P<0.01). Foals with DHEAS of 0.4-5.4ng/mL were more likely to have ACI (OR=2.5). Foals in Group 1 had higher ACTH, aldosterone, progesterone, and cortisol concentrations as well as ACTH/cortisol, ACTH/progesterone, and ACTH/DHEAS ratios than foals in Groups 2 and 3 (P<0.01). High progesterone concentrations were associated with non-survival and the cutoff value below which survival could be predicted was 23.5ng/mL, with 75% sensitivity and 72% specificity. In addition to cortisol, the response to the stress of illness in foals is characterised by the release of multiple adrenal steroids. DHEAS and progesterone were good predictors of HPAA dysfunction and outcome in hospitalised foals.

Luteinizing hormone in the cat. I. Tonic secretion.

We have used a RIA system for measuring LH in the plasma of domestic cats and characterized the component of LH secretion which is controlled by negative feedback inhibition. Blood samples were collected at 6- to 10-min intervals from animals with chronically indwelling venous cannulae. The inhibitory influence (negative feedback) of gonadal secretion was evidenced by the increased plasma concentrations of LH seen 24 h after castration in 9 animals and within 5 days in all 15 cats. Restoration of negative feedback by either short or long term administration of 17 beta-estradiol reduced LH concentrations to precastration levels. In castrated animals of both sexes, the plasma concentrations of LH fluctuated episodically, with increases occurring at intervals of 20-30 min, presumably a reflection of intermittent periods of LH release. The dynamics of this pattern of LH release were simulated by the iv injection of gonadotropin-releasing hormone. In combination with our additional observation that plasma concentrations of LH decreased rapidly after treatment with four different anesthetic agents, the observations are suggestive of episodic secretion of gonadotropin-releasing hormone in the absence of negative feedback. The mechanisms regulating tonic LH secretion in this reflex ovulator appear to be more sensitive to neural stimuli but qualitatively similar to those previously described for other species in which ovulation occurs spontaneously.

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides.

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure--activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 2. Indole-3-acetamides with additional functionality.

As reported in our previous paper, a series of indole-3-acetamides which possessed potency and selectivity as inhibitors of human nonpancreatic secretory phospholipase A2(hnps-PLA2) was developed. The design of these compounds was based on information derived from x-ray crystal structures determined for complexes between the enzyme and its inhibitors. We describe here the further implementation of this structure-based design strategy and continued SAR development to produce indole-3-acetamides with additional functionalities which provide increased interaction with important residues within the enzyme active site. These efforts led to inhibitors with substantially enhanced potency and selectivity.

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides.

The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.

Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives.

A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.

Implication of alpha4 phosphoprotein and the rapamycin-sensitive mammalian target-of-rapamycin pathway in prolactin receptor signalling.

A prolactin (PRL)-responsive 3'-end cDNA encoding rat alpha4 phosphoprotein was previously isolated from a rat lymphoma cDNA library. Rat alpha4 is a homologue of yeast Tap42 and is a component of the mammalian target-of-rapamycin (mTOR) signalling pathway that stimulates translation initiation and G1 progression in response to nutrients and growth factors. In the present study, the full-length rat alpha4 cDNA was obtained by 5'-RACE and the 1023 bp open reading frame predicted a 340 amino acid protein of 39.1 kDa. The alpha4 mRNA was expressed in quiescent PRL-dependent Nb2 lymphoma cells deprived of PRL for up to 72 h but expression was downregulated within 4 h of PRL treatment. In contrast, PRL-independent Nb2-Sp cells showed constitutive expression of alpha4 that was not affected by PRL. Western analysis of Nb2 cell lysates or of V5-tagged-alpha4 expressed in COS-1 cells detected a single immunoreactive band of approximately 45 kDa. Enzymatic deglycosylation of affinity-purified 45 kDa alpha4 yielded the predicted 39 kDa protein. Phosphorylation of Nb2 alpha4 was induced by PRL or 2-O-tetradecanoyl-phorbol-13-acetate (TPA) and further enhanced by a combination of PRL and TPA. The Nb2 alpha4 associated with the catalytic subunit of protein phosphatase 2A and localized predominantly in Nb2 nuclear fractions with trace amounts in the cytosol. The immunosuppressant drug rapamycin inhibited proliferation of Nb2 cells in response to PRL or interleukin-2, but had no effect on Nb2-Sp cells. Furthermore, transient overexpression of alpha4 in COS-1 cells inhibited PRL stimulation of the immediate-early gene interferon regulatory factor-1 promoter activity. Therefore, PRL downregulation of alpha4 expression and/or PRL-inducible phosphorylation of alpha4 may be necessary for PRL receptor (PRLr) signalling to the interferon regulatory factor-1 promoter in the Nb2 cells and, furthermore, implicates cross-talk between the mTOR and PRLr signalling cascades during Nb2 cell mitogenesis.

Prolactin, interleukin-2 and FGF-2 stimulate expression, nuclear distribution and DNA-binding of rat homolog of pombe Cdc5 in Nb2 T lymphoma cells.

Pombe and human Cdc5 have been implicated in G2/M progression, but recently Cdc5 was identified as a component of a multiprotein complex essential for pre-mRNA splicing. We have previously isolated a prolactin (PRL)-inducible partial cDNA (1907 bp) encoding rat Cdc5. In the present study, the full length rCdc5 sequence (2847 bp) was obtained by 5'-RACE and cytokine regulation of Cdc5 expression was examined. PRL and interleukin-2 (IL2) act as mitogens in Nb2 T-lymphoma cells. Fibroblast growth factor (FGF-2) is not mitogenic in Nb2 cells but inhibits apoptosis of PRL-deprived cells. This study showed that PRL, IL-2 and FGF-2 rapidly increased Nb2 Cdc5 expression (3.4 kb mRNA) to reach 2-3-fold above controls at 4 h, and Cdc5 mRNA levels remained elevated at 24 h. There was a corresponding 2-3-fold increase in Cdc5 protein (105 kDa) levels at 24 h. Immunoblotting and fluorescent confocal microscopy showed predominant nuclear/perinuclear Cdc5 in quiescent Nb2 cells. PRL or FGF-2 treatment transiently increased nuclear Cdc5-specific immunofluorescence at 4 h but IL-2 gave maximal nuclear accumulation of Cdc5 at 24 h. The deduced rCdc5 protein has approximately 98% amino acid identity with human Cdc5. Like other Cdc5 family members, the N-terminus of rCdc5 contains two repeats of a DNA-binding domain found in a-, b- and c-Myb. Gel shift assays using (32)P-labeled Myb consensus oligonucleotides revealed two Myb-specific DNA-protein complexes in Nb2 nuclear extracts. Formation of both complexes was increased by PRL or FGF-2 at 1-5 and at 20 h and was partially inhibited by anti-Myb or anti-Cdc5 antibodies. In summary, rapid activation of Cdc5 in response to mitogenic and non-mitogenic stimuli suggests a complex role for Cdc5 in cellular regulation and this may not be restricted to mitotic entry or G2/M progression as previously supposed.

Palmitate potentiation of glucose-induced insulin release: a study using 2-bromopalmitate.

The mechanisms whereby fatty acids (FA) potentiate glucose-induced insulin secretion from the pancreatic beta cell are incompletely understood. In this study, the effects of palmitate on insulin secretion were investigated in isolated rat islets. Palmitate did not initiate insulin secretion at nonstimulatory glucose concentrations, but markedly stimulated insulin release at concentrations of glucose > or = 5.6 mmol/L. At concentrations of palmitate > or =0.5 mmol/L, the important determinant of the potency of the FA was its unbound concentration. At total concentrations < or = 0.5 mmol/L, both the total and unbound concentrations appeared important. Surprisingly, 2-bromopalmitate did not affect palmitate oxidation, but significantly diminished palmitate esterification into cellular lipids. Neither methyl palmitate, which is not activated into a long-chain acyl-CoA ester, nor 2-bromopalmitate affected glucose-stimulated insulin release. Further, 2-bromopalmitate partly inhibited the potentiating effect of palmitate. These results support the concept that FA potentiation of insulin release is mediated by FA-derived signals generated in the esterification pathway.

Airway changes in relationship to mandibular posturing.

Comparison of posterior airway space was evaluated radiographically on patients with sleep apnea in a mandibular reposed position vs. a mandibular protruded position. This was performed at the Santa Barbara Sleep Disorders Medical Center to simulate the effect of anterior orthotic appliances on these patients. The overall effect of forward mandibular posturing was a mean increase of posterior airway space (PAS) by approximately 56%, but wide variations were seen.

An inverse relationship between baseline fixed-interval response rate and the effects of a tandem response requirement.

Previous experiments examining the effects of adding a tandem fixed-ratio response requirement on fixed-interval schedule performance have reported inconsistent results. One variable that may account for such inconsistencies is the baseline response rate in the fixed-interval condition. This possibility was investigated in the present study. Rats were given histories with either interresponse times greater than 11 s or fixed-ratio 40 schedules of reinforcement, which engendered either relatively low or high rates of responding, respectively, in the subsequent fixed-interval condition. A tandem ratio response requirement (fixed-ratio 9) was then introduced. The effects of adding this tandem response requirement were inversely related to the baseline fixed-interval response rates; low rates of responding in the fixed-interval condition were markedly increased, whereas high rates of responding were relatively unaffected. This inverse relationship appears to be similar to the rate-dependent relations observed in behavioral pharmacology. These results may provide an explanation for the inconsistent findings reported in previous studies on tandem fixed-interval fixed-ratio schedules and suggest that principles of behavioral pharmacology research may be applicable to the study of the effects of nonpharmacological variables on schedule-controlled behavior.

The effects of schedule history and the opportunity for adjunctive responding on behavior during a fixed-interval schedule of reinforcement.

The effects of schedule history and the availability of an adjunctive response (polydipsia) on fixed-interval schedule performance were investigated. Two rats first pressed levers under a schedule of food reinforcement with an interresponse time greater than 11 s, and 2 others responded under a fixed-ratio 40 schedule. All 4 were then exposed to a fixed-interval 15-s schedule. Water was continuously available under these conditions, but after responding became stable on the fixed-interval schedule, access was experimentally manipulated. With water freely available, subjects did not display characteristic fixed-interval response rates and patterns (i.e., scalloping or break-and-run). Instead, they exhibited predictable, stable patterns of behavior as a function of their schedule histories: Subjects with the interresponse-time history exhibited low response rates, and those with the fixed-ratio history exhibited high rates. Manipulating the amount of water available resulted in marked changes in response rates for rats with the interresponse-time history but not for those with the fixed-ratio history. The results illustrate the multiple causation of behavior by its previous and current schedules of reinforcement and other concurrent factors.

Pharmacokinetic and pharmacodynamic properties of conventional and CD-formulated diltiazem in cats.

The i.v. and apparent steady-state kinetics of diltiazem HCI (DLT) and slow-absorption long-acting diltiazem (CD) given p.o. were investigated in cats. The effects of p.o. diltiazem on heart rate and PR interval were also studied. Plasma diltiazem concentrations were determined by ultraviolet high-performance liquid chromatography (UV-HPLC), using verapamil as the internal standard. Heart rate and PR interval determinations were evaluated over a 24-hour period for the PO formulations and compared with values under diltiazemfree conditions. The mean systemic clearance and apparent volume of distribution of i.v. diltiazem were 15.0 mL/min/kg and 2.70 L/kg, respectively. The elimination half-life of diltiazem after i.v. and p.o. DLT administration were approximately 120 minutes. In contrast, the terminal half-life of CD was 460 minutes. The mean apparent bioavailability of DLT p.o. was 71%, which was significantly higher than that observed with CD (36%). Heart rate and PR intervals in cats receiving the 2 formulations at steady-state were not different from those measured in the drug-free state. We conclude that DLT at 1 mg/kg p.o. tid and CD at 10 mg/kg p.o. sid provide plasma concentrations that are known to have pharmacodynamic effects in other species.

Cases from the aerospace medicine residents' teaching file. Case H56. Pilot incapacitation of psychiatric etiology (PIPE)

A case is presented which involves a fighter pilot with anxiety disorder and in-flight panic attacks. The initial presentation, clinical course, evaluation, and aeromedical disposition are all discussed.