Precision Measurement of the Beam-Normal Single-Spin Asymmetry in Forward-Angle Elastic Electron-Proton Scattering.

A beam-normal single-spin asymmetry generated in the scattering of transversely polarized electrons from unpolarized nucleons is an observable related to the imaginary part of the two-photon exchange process. We report a 2% precision measurement of the beam-normal single-spin asymmetry in elastic electron-proton scattering with a mean scattering angle of θ_{lab}=7.9° and a mean energy of 1.149 GeV. The asymmetry result is B_{n}=-5.194±0.067(stat)±0.082 (syst) ppm. This is the most precise measurement of this quantity available to date and therefore provides a stringent test of two-photon exchange models at far-forward scattering angles (θ_{lab}→0) where they should be most reliable.

Heavy metal pollution and co-selection for antibiotic resistance: A microbial palaeontology approach.

Frequent and persistent heavy metal pollution has profound effects on the composition and activity of microbial communities. Heavy metals select for metal resistance but can also co-select for resistance to antibiotics, which is a global health concern. We here document metal concentration, metal resistance and antibiotic resistance along a sediment archive from a pond in the North West of the United Kingdom covering over a century of anthropogenic pollution. We specifically focus on zinc, as it is a ubiquitous and toxic metal contaminant known to co-select for antibiotic resistance, to assess the impact of temporal variation in heavy metal pollution on microbial community diversity and to quantify the selection effects of differential heavy metal exposure on antibiotic resistance. Zinc concentration and bioavailability was found to vary over the core, likely reflecting increased industrialisation around the middle of the 20th century. Zinc concentration had a significant effect on bacterial community composition, as revealed by a positive correlation between the level of zinc tolerance in culturable bacteria and zinc concentration. The proportion of zinc resistant isolates was also positively correlated with resistance to three clinically relevant antibiotics (oxacillin, cefotaxime and trimethoprim). The abundance of the class 1 integron-integrase gene, intI1, marker for anthropogenic pollutants correlated with the prevalence of zinc- and cefotaxime resistance but not with oxacillin and trimethoprim resistance. Our microbial palaeontology approach reveals that metal-contaminated sediments from depths that pre-date the use of antibiotics were enriched in antibiotic resistant bacteria, demonstrating the pervasive effects of metal-antibiotic co-selection in the environment.

Preferential reduction of synaptic efficacy in the dentate gyrus of hippocampal slices from aged rats during reduced glucose availability.

Glutamatergic synaptic activity entails a high energetic cost. During aging, a variety of neural metabolic changes have been reported that could compromise the capacity of neural circuits to maintain synaptic transmission during periods of reduced extracellular glucose. Indeed, a preferential compromise in evoked synaptic activity has been observed in hippocampal CA1 with age during exposure to low-glucose solutions. Whether this aging-related compromise in synaptic activity is regionally specific is unclear, however. Data suggest that the dentate gyrus (DG) preferentially exhibits hypometabolism with age and this region plays a critical role in spatial pattern separation, which is compromised with age. Therefore, we assessed whether synaptic activity is also preferentially affected in the DG with age. In vitro extracellular field potential recordings were used to monitor orthodromic and antidromic evoked activity in the DG granule cell layer in hippocampal slices from adult (8-12 months) and aged (22-27 months) rats in aCSF containing 10mM glucose, followed by a reduced glucose aCSF containing 1mM glucose. In 10mM glucose-aCSF, orthodromic- and antidromic-evoked field potential activity was comparable between age groups. However, orthodromic-evoked population spike amplitude and field excitatory post-synaptic potential (EPSP) slope were preferentially decreased in slices from aged rats during exposure to 1mM glucose-aCSF. Antidromic population spike amplitude was not differentially affected in slices from aged versus adult rats, however. These data suggest that synaptic efficacy is preferentially compromised with age under reduced glucose availability and, combined with a decreased capacity of the periphery to provide glucose to the central nervous system (CNS) during metabolically challenging conditions, could contribute to aging-related hippocampal dysfunction and cognitive decline.

Orientation and conformation of anti-CD34 antibody immobilised on untreated and plasma treated polycarbonate.

The conformation and orientation of proteins immobilised on synthetic materials determine their ability to bind their antigens and thereby the sensitivity of the microarrays and biosensors employing them. Plasma immersion ion implantation (PIII) of polymers significantly increases both their wettability and protein binding capacity. This paper addresses the hypothesis that a PIII treated polymer surface modifies the native protein conformation less significantly than a more hydrophobic untreated surface and that the differences in surface properties also affect the protein orientation. To prove this, the orientation and conformation of rat anti-mouse CD34 antibody immobilized on untreated and PIII treated polycarbonate (PC) were investigated using ToF-SIMS and FTIR-ATR spectroscopy. Analysis of the primary structure of anti-CD34 antibody and principal component analysis of ToF-SIMS data were applied to detect the difference in the orientation of the antibody attached to untreated and PIII treated PC. The difference in the antibody conformation was analysed using deconvolution of the Amide I peak (in FTIR-ATR spectra) and curve-fitting. It was found that compared to the PIII treated sample, the antibody immobilized on the untreated PC sample has a secondary structure with a lower fraction of ß-sheets and a higher fraction of α-helices and disordered fragments. Also, it was found that anti-CD34 antibody has a higher tendency to occur in the inactive 'tail-up' orientation when immobilized on an untreated PC surface than on a PIII treated surface. These findings confirm the above hypothesis.

Radiofrequency ablation resulting in left lobe hypertrophy and improved resectability.

Surgical resection for colorectal liver metastases may only be considered when an adequate functional residual volume can be preserved. Selective portal venous embolisation may be used to increase this volume, whilst chemotherapy and radiofrequency ablation (RFA) can be used to treat inoperable lesions. A 73-year-old man with liver metastasis proceeded to surgery, with the intention to perform a right hemi-hepatectomy. Unexpectedly at laparotomy, despite adequate pre-operative imaging, both the right and middle hepatic veins were involved. At that time extended right hemi-hepatectomy was contraindicated by insufficient residual volume and RFA was performed. Follow-up imaging revealed atrophy of the lesion. Significantly, there was also left lateral lobe hypertrophy sufficient to permit resection, which was performed without complication. Thrombosis of intra-hepatic portal veins is a recognised complication of RFA but here it appears to have been beneficial. The case highlights the need for regular review of unresectable hepatic disease by a liver surgeon and could suggest new modalities of portal embolisation.

Developmental regulation and neuroprotective effects of striatal tonic GABAA currents.

Striatal neurons are known to express GABA(A) receptor subunits that underlie both phasic and tonic inhibition. Striatal projection neurons, or medium spiny neurons (MSNs), are divided into two classes: MSNs containing the dopamine D1 receptor (D1-MSNs) form the direct pathway to the substantia nigra and facilitate movement while MSNs expressing the dopamine D2 receptor (D2-MSNs) form the pallidal pathway that inhibits movement. Consequently, modulating inhibition in distinct classes of MSNs will differentially impact downstream network activity and motor behavior. Given the powerful role of extrasynaptic inhibition in controlling neuronal excitability, we examined the nature of striatal tonic inhibition and its potential role in preventing excitotoxicity. Consistent with earlier studies in young (P16-P25) mice, tonic GABA currents in D2-MSNs were larger than in D1-MSNs. However, with age (>P30 mice) the tonic GABA currents increased in D1-MSNs but decreased in D2-MSNs. These data demonstrate a developmental switch in the MSN subtype expressing larger tonic GABA currents. Compared to wild-type, MSNs from adult mice lacking the GABA(A)R delta subunit (Gabrd(-/-) mice) had both decreased tonic GABA currents and reduced survival following an in vitro excitotoxic challenge with quinolinic acid. Furthermore, muscimol-induced tonic GABA currents were accompanied by reduced acute swelling of striatal neurons after exposure to NMDA in WT mice but not in Gabrd(-/-) mice. Our data are consistent with a role for tonic inhibition mediated by GABA(A)R delta subunits in neuroprotection against excitotoxic insults in the adult striatum.

PP2A-dependent disruption of centrosome replication and cytoskeleton organization in Drosophila by SV40 small tumor antigen.

Viruses of the DNA tumor virus family share the ability to transform vertebrate cells through the action of virus-encoded tumor antigens that interfere with normal cell physiology. They accomplish this very efficiently by inhibiting endogenous tumor suppressor proteins that control cell proliferation and apoptosis. Simian virus 40 (SV40) encodes two oncoproteins, large tumor antigen, which directly inhibits the tumor suppressors p53 and Rb, and small tumor antigen (ST), which interferes with serine/threonine protein phosphatase 2A (PP2A). We have constructed a Drosophila model for SV40 ST expression and show that ST induces supernumerary centrosomes, an activity we also demonstrate in human cells. In early Drosophila embryos, ST also caused increased microtubule stability, chromosome segregation errors, defective assembly of actin into cleavage furrows, cleavage failure, a rise in cyclin E levels and embryonic lethality. Using ST mutants and genetic interaction experiments between ST and PP2A subunit mutations, we show that all of these phenotypes are dependent on ST's interaction with PP2A. These analyses demonstrate the validity and utility of Drosophila as a model for viral oncoprotein function in vivo.

Catecholamine response to methamphetamine is related to glucocorticoid levels but not to pleasurable subjective response.

INTRODUCTION: Corticosteroids may modulate addiction. We previously described subjective, physiological, and endocrine effects of 0.5 mg/kg of intravenous methamphetamine after augmenting cortisol level with hydrocortisone or blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone in a double-blind, balanced crossover study. Although the pharmacologic manipulations produced the expected hormonal changes, pleasurable subjective effects of methamphetamine were unchanged. Metyrapone was followed by frequent premature ventricular complexes (PVCs) in two subjects during methamphetamine administration. In order to better understand these results, we examined changes in two plasma catecholamine metabolites, homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and their relationship to the previously reported hormonal changes and physiological and subjective responses. METHODS: Plasma from 10 methamphetamine subjects from the earlier study was assayed for HVA and MHPG by high performance liquid chromatography. RESULTS: HVA levels were greater after hydrocortisone or metyrapone pretreatment compared to placebo, and MHPG levels were greater after metyrapone pretreatment. Hydrocortisone pretreatment diminished HVA and MHPG increases after methamphetamine (perhaps explaining the lack of expected increase in pleasurable effects), but metyrapone did not. HVA and MHPG concentrations were not correlated with pleasurable drug effects but were inversely related to reports of "Bad Drug Effect." Increases in MHPG and DHEA concentrations were positively correlated. Metyrapone pre-treated subjects with PVCs had lower HVA and MHPG concentrations. CONCLUSION: Raising cortisol concentration and blocking cortisol synthesis did not produce opposite effects, perhaps because of metyrapone's effect on the hypothalamic-pituitary-adrenal axis, its stress-like effects, and its effects on neurosteroids.

Differential expression of ryanodine receptors in the rat cochlea.

This study examined the localization and functional expression of ryanodine receptors (RyR) within the cochlea using a combination of reverse transcription-polymerase chain reaction, immunolabeling techniques, and confocal Ca2+ imaging. All three RyR isoform mRNA transcripts were detected in the adult rat cochlea. Immunoperoxidase and immunofluorescence labeling showed that the three isoforms were differentially expressed. The most pronounced RyR protein expression, involving all three isoforms, occurred in the cell bodies of the spiral ganglion neurons. RyR3 labeling extended to the synaptic terminals innervating the inner and outer hair cells. RyR2 expression also occurred in the inner hair cells and supporting cells of the organ of Corti, while cells associated with ion homeostasis in the cochlea, such as the interdental cells of the spiral limbus (RyR1), and the epithelial cells of the spiral prominence and basal cells of the stria vascularis (RyR2 and RyR3), were also immunopositive. The functionality of RyR-gated Ca2+ stores in the spiral ganglion neurons was shown by confocal calcium imaging of fluo-4 fluorescence in rat cochlear slices. Caffeine (5 mM) evoked an increase in intracellular Ca2+ concentration in the cell bodies of the spiral ganglion neurons which occurred inthe absence of external Ca2+. Ryanodine (50 nm-1 microM) evoked comparable increases in intracellular Ca2+ concentration. These findings suggest that RyR-mediated Ca2+ release may be involved in auditory neurotransmission, sound transduction, and cochlear electrochemical homeostasis.

The psychological effects of Hurricane Andrew on ethnic minority and Caucasian children and adolescents: a case study.

The impact of Hurricane Andrew on 212 African American, Caucasian, and Hispanic elementary and middle school children was examined at 6 months postdisaster. Using self-report instruments, this case study examined the predictive utility of several hypothesized mediators of children's reactions to disaster. Results showed higher levels of intrusive symptomatology for girls and for elementary school children as compared with their middle school counterparts. No differences were found with reference to race. The lack of findings concerning race is addressed, as well as implications for future studies.

Fear in children and adolescents: relations with negative life events, attributional style, and avoidant coping.

In this study, we explored relations among negative life events, negative attributional style, avoidant coping, and level of fear in 99 children who had survived residential fires. Overall, negative life events, negative attributional style, and avoidant coping were found to be predictive of levels of fear. However, the relation between negative life events and fear was moderated by mother's level of education such that this prediction was obtained only for those children whose mothers were low in education level. Age, ethnicity, and sex did not moderate these relations. In addition, negative attributional style and avoidant coping were related to levels of fear in those children whose mothers were high in education levels but not those whose mothers were low in education level. Results are discussed within a stress and coping framework.

Cardiovascular effects of 3,4-methylenedioxymethamphetamine. A double-blind, placebo-controlled trial.

BACKGROUND: The psychoactive stimulant 3, 4-methylenedioxymethamphetamine (MDMA), also known as "ecstasy," is widely used in nonmedical settings. Little is known about its cardiovascular effects. OBJECTIVE: To evaluate the acute cardiovascular effects of MDMA by using transthoracic two-dimensional and Doppler echocardiography. DESIGN: Four-session, ascending-dose, double-blind, placebo-controlled trial. SETTING: Urban hospital. PATIENTS: Eight healthy adults who self-reported MDMA use. INTERVENTION: Echocardiographic effects of dobutamine (5, 20, and 40 microg/kg of body weight per minute) were measured in a preliminary session. Oral MDMA (0.5 and 1.5 mg/kg of body weight) or placebo was administered 1 hour before echocardiographic measurements in three weekly sessions. MEASUREMENTS: Heart rate and blood pressure were measured at regular intervals before and after MDMA administration. Echocardiographic measures of stroke volume, ejection fraction, cardiac output, and meridional wall stress were obtained 1 hour after MDMA administration and during dobutamine infusions. RESULTS: At a dose of 1.5 mg/kg, MDMA increased mean heart rate (by 28 beats/min), systolic blood pressure (by 25 mm Hg), diastolic blood pressure (by 7 mm Hg), and cardiac output (by 2 L/min). The effects of MDMA were similar to those of dobutamine, 20 and 40 microg/kg per minute. Inotropism, measured by using meridional wall stress corrected for ejection fraction, decreased after administration of dobutamine, 40 microg/kg per minute, but did not change after either dose of MDMA. CONCLUSIONS: Modest oral doses of MDMA increase heart rate, blood pressure, and myocardial oxygen consumption in a magnitude similar to dobutamine, 20 to 40 microg/kg per minute. In contrast to dobutamine, MDMA has no measurable inotropic effects.

Self-reported marijuana effects and characteristics of 100 San Francisco medical marijuana club members.

In order to assess the relationships between medical marijuana users' reasons for use, side effects, and drug use patterns, 100 participants were recruited from the San Francisco Cannabis Cultivator's Club. Users, averaging 14 years pre-illness use, perceived marijuana to be more effective than other treatments and to have less severe side effects. Urine drug assays showed recent use of other drugs, particularly stimulants. History of substance abuse or dependence and other psychiatric disorders was common. Those with greater past dependence on other drugs thought marijuana to be more effective but also reported worse side effects and quality of life. Quality of life was associated more with marijuana side effects rating than effectiveness. Patients reported potentially serious marijuana side effects on some questionnaires but not others. Inconsistencies in reporting made interpretation of results difficult. Physician supervision of medical marijuana use would allow more effective monitoring of therapeutic and unwanted effects, some unrecognized by patients.

Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine.

Buprenorphine and naloxone sublingual (s.l.) dose formulations may decrease parenteral buprenorphine abuse. We evaluated pharmacologic interactions between 8 mg s.l. buprenorphine combined with 0, 4, or 8 mg of naloxone in nine opiate-dependent volunteers stabilized on 8 mg s.l. buprenorphine for 7 days. Combined naloxone and buprenorphine did not diminish buprenorphine's effects on opiate withdrawal nor alter buprenorphine bioavailability. Opiate addicts stabilized on buprenorphine showed no evidence of precipitated opiate withdrawal after s.l. buprenorphine-naloxone combinations. Buprenorphine and naloxone bioavailability was approximately 40 and 10%, respectively. Intravenous buprenorphine and naloxone produced subjective effects similar to those of s.l. buprenorphine and did not precipitate opiate withdrawal.

Nasal mucosal versus gastrointestinal absorption of nasally administered cocaine.

OBJECTIVE: Several xenobiotics, including cocaine, are dosed by the nasal route for systemic effects. The aim of this study was to estimate and compare cocaine input into the systemic circulation after oral and nasal dosing, and to determine the relevance of local absorption through the nasal mucosa. METHODS: Cocaine was administered to healthy volunteers through the intravenous, oral, and nasal routes. Cocaine serum concentrations were measured at frequent intervals. From these data, the gastrointestinal, nasal, and nasal mucosa input rate functions were determined using nonparametric, subject-specific population deconvolution. RESULTS: After oral dosing, cocaine input into systemic circulation increased slowly and peaked around 45 min after ingestion. The median systemic bioavailability after oral dosing was 33%. After nasal dosing, drug input was substantial even during the first minute and showed two peaks at 10 min and 45 min after ingestion. Since the second peak after nasal dosing closely resembled drug input after oral administration, we hypothesized that, after nasal administration, a part of the dose is swallowed and thereafter absorbed gastrointestinally. The data from the sessions with nasal cocaine administration were reanalyzed assuming the same shape for gastrointestinal drug input as after oral dosing. The fraction absorbed through the nasal mucosa was estimated to be 19% (95% CI: 11-26%). The fraction absorbed through the nasal mucosa contributed 31% (95% CI: 23-37%) of total systemic cocaine exposure. CONCLUSIONS: Our data suggest that the main reason addicts prefer nasal to oral cocaine dosing is faster absorption, enhancing the subjective effects rather than higher bioavailability.

Allergy to iguana.

BACKGROUND: Furry animals produce allergens that can cause allergic rhinitis and asthma. In contrast, scaly animals, such as lizards, are assumed not to be allergenic. OBJECTIVE: We sought to evaluate a 32-year-old man who complained of allergic rhinitis and asthma symptoms that occurred exclusively in his own home. He had dogs and cats at home but denied any increase in symptoms specifically associated with these pets. Skin prick testing initially performed to 42 common aeroallergens, including cat, dog, and house dust mite, elicited negative results. He later reported that the symptoms were worse on exposure to his pet iguanas. METHODS: Skin prick tests were subsequently performed to an extract made from scales from his pet iguana. Extracts were also prepared from several zoo reptiles. Immunoassays for IgE antibody, as well as IgE immunoblots, were performed by using these extracts and the patient's serum. RESULTS: The skin prick test result with the pet iguana scale extract was positive. The patient's serum contained IgE antibody to his own pet iguana and to a zoo iguana. CONCLUSION: Our patient's history, skin test results, and in vitro studies clearly demonstrate that he is allergic to iguana. Physicians should be aware that such allergy to scaly pets may occur and should not restrict history taking to questions about furry pets.