Vaccination after spleen embolization: A practice management guideline from the Eastern Association for the Surgery of Trauma.

BACKGROUND: Angioembolization is an important adjunct in the non-operative management of adult trauma patients with splenic injury. Multiple studies have shown that angioembolization may increase the non-operative splenic salvage rate for patients with high-grade splenic injuries. We performed a systematic review and developed evidence-based recommendations regarding the need for post-splenectomy vaccinations after splenic embolization in trauma patients. METHODS: A systematic review and meta-analysis of currently available evidence were performed utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Nine studies were identified and analyzed. A total of 240 embolization patients were compared to 443 control patients who neither underwent splenectomy nor were embolized. There was no statistical difference between the splenic immune function of embolized and control patients. In addition, a total of 3974 splenectomy patients was compared with 686 embolization patients. Embolization patients had fewer infectious complications and a greater degree of preserved splenic immune function. CONCLUSION: In adult trauma patients who have undergone splenic angioembolization, we conditionally recommend against routine post-splenectomy vaccinations. STUDY TYPE: systematic review/meta-analysis Level of evidence: level III.

[Purpura in a young woman with hyperthyroidism]. / Purpura chez une jeune femme hyperthyroïdienne.

INTRODUCTION: Propylthiouracil (PTU) is a synthetic antithyroid drug that can induce ANCA-associated vasculitis. OBSERVATION: A 27-year-old woman diagnosed with Graves' disease was on PTU for the past 10 years. She developed purpuric lesions of the legs and on the tip of the nose diagnosed as vasculitis. ANCAs were positive, with anti-MPO and anti-PR3 on blood ELISA. After discontinuation of PTU, she was able to fully recover. CONCLUSION: All synthetic antithyroid drugs can induce ANCA-associated vasculitis, more often PTU. In most cases, antibodies are directed against MPO. Dual anti-MPO and anti-PR3 positivity is possible, but rare. The mechanism could be through an accumulation of PTU in neutrophils, altering the structure of MPO and making it immunogenic. PTU can also induce ANCA-free or lupus vasculitis, maculopapular rashes or urticaria. Many other drugs can induce ANCA-associated vasculitis.

Pre-existing chronic medical illnesses and follow up status among active pulmonary tuberculosis cases in a district population.

INTRODUCTION: The knowledge of pre-existing medical illnesses and their follow up status among active pulmonary tuberculosis (PTB) subjects can help in tuberculosis (TB) control programme. The aims of our study were to examine: the prevalence of pre-existing chronic medical illnesses, the follow up status of known pre-existing co-morbid and to distinguish between diagnosed and undiagnosed preexisting tuberculosis related chronic medical illnesses among our active PTB subjects. METHODS: We conducted a retrospective review of demographic and clinical data of active PTB subjects that were diagnosed between January 2015 and June 2017 in the district of Manjung, Perak, Malaysia. Among the 302 TB clinical notes reviewed, 253 patients were included. Subjects below the age of 18 years and whose follow up centres for their medical illnesses that were located outside of Manjung were excluded. Demographic and clinical data were collected using pre-tested data collection form by trained investigators. The data was analysed using SPSS Version 20.0. RESULTS: We identified diabetes mellitus as the most prevalent pre-existing co-morbid (77 cases) and almost 90% (68 cases) of these diabetic subjects were diagnosed prior to active PTB diagnosis. This was followed by Human Immunodeficiency Virus and Hepatitis C infection which accounted for 12.0% (30 cases) of the study populations. Among 132 subjects who had pre-existing chronic medical illnesses, only 74 subjects (29%) were under regular follow up at healthcare facilities in Manjung prior to PTB diagnosis. CONCLUSION: Overall, our research provides evidence on the existence of wide variation of clinical background among active PTB subjects.

On the rheology of pulmonary surfactant: Effects of concentration and consequences for the surfactant replacement therapy.

The role of pulmonary surfactant is to reduce the surface tension in the lungs and to facilitate breathing. Surfactant replacement therapy (SRT) aims at bringing a substitute by instillation into the airways, a technique that has proven to be efficient and lifesaving for preterm infants. Adapting this therapy to adults requires to scale the administered dose to the patient body weight and to increase the lipid concentration, whilst maintaining its surface and flow properties similar. Here, we exploit a magnetic wire-based microrheology technique to measure the viscosity of the exogenous pulmonary surfactant Curosurf® in various experimental conditions. The Curosurf® viscosity is found to increase exponentially with lipid concentration following the Krieger-Dougherty law of colloids. The Krieger-Dougherty behavior also predicts a divergence of the viscosity at the liquid-to-gel transition. For Curosurf® the transition concentration is found close to the concentration at which it is formulated (117 g L-1versus 80 g L-1). This outcome suggests that for SRT the surfactant rheological properties need to be monitored and kept within a certain range. The results found here could help in producing suspensions for respiratory distress syndrome adapted to adults. The present work also demonstrates the potential of the magnetic wire microrheology technique as an accurate tool to explore biological soft matter dynamics.

Sensitivity, completeness and agreement of the tuberculosis electronic system in Ho Chi Minh City, Viet Nam.

Setting: Since 2011, tuberculosis (TB) clinics in Ho Chi Minh City (HCMC), Viet Nam, have been entering data from a paper-based TB treatment register into an electronic database known as VITIMES (Viet Nam TB Information Management Electronic System), which is currently used in parallel with the paper system. Objective: To evaluate the sensitivity, completeness and agreement of data in VITIMES with that of paper-based registers among TB patients co-infected with the human immunodeficiency virus (HIV) being treated for TB in HCMC. Design: This was a retrospective data review of all TB-HIV patients receiving anti-tuberculosis treatment in each of the 24 district TB clinics in HCMC in 2013. Data were abstracted from the paper-based TB treatment registers at district level and extracted electronically at the provincial level. Records were matched based on name, age and address. The sensitivity, completeness and agreement of the electronic data were compared with data from the paper system. Results: The findings showed that the electronic system had high sensitivity (99.2%), high completeness (87-99%) and high agreement (κ 0.78-0.97) for all variables. Conclusion: The results of this study suggest that data are being correctly entered into VITIMES and that patient data can be directly entered into VITIMES instead of having a parallel, paper-based system.

Contexte : Depuis 2011, les centres antituberculeux (TB) de Ho Chi Minh City (HCMC) ont entré les données émanant d'un registre papier de traitement de la TB dans une base de données électronique appelée VITIMES (Viet Nam TB Information Management Electronic System), qui est actuellement utilisée en parallèle au système papier.Objectif : Evaluer la sensibilité, l'exhaustivité et l'accord des données de VITIMES avec celles des registres papier parmi les patients TB co-infectés par le virus de l'immunodéficience humaine (VIH) et traités pour la TB à HCMC.Schéma : Cette étude est une revue rétrospective des données de tous les patients TB-VIH bénéficiant d'un traitement de TB dans chacun des 24 centres TB de district de HCMC en 2013. Les données ont été tirées du registre papier de traitement de la TB au niveau de chaque district et extraites électroniquement au niveau provincial. Les dossiers ont été appariés sur le nom, l'âge et l'adresse. La sensibilité, l'exhaustivité et l'accord des données ont été évalués par comparaison avec les données du système papier.Résultats : Les résultats ont montré que le système électronique avait une sensibilité élevée (99,2%), une exhaustivité élevée (87­99%) et un degré d'accord élevé (κ 0,78­0,97) pour toutes les variables.Conclusion : Les résultats de cette étude suggèrent que les données sont entrées correctement sur VITIMES et que les données des patients peuvent y être entrées directement au lieu d'avoir un système papier en parallèle.

Marco de referencia: Desde el 2011, en los consultorios de atención de la tuberculosis (TB) de la ciudad de Ho Chi Minh, los datos del registro de tuberculosis en papel se están ingresando en un formato informático denominado VITIMES (por Viet Nam TB Information Management Electronic System). En la actualidad se utilizan ambos sistemas en paralelo.Objetivo: Evaluar la sensibilidad, el carácter integral y la concordancia de los datos del sistema VITIMES con respecto a los registros en papel sobre los pacientes con diagnóstico de coinfección por el virus de la inmunodeficiencia humana (VIH) y el bacilo de la TB que reciben tratamiento antituberculoso en la ciudad de Ho Chi Minh.Método: Fue este un análisis retrospectivo de los datos de todos los pacientes coinfectados por el VIH y la TB que habían recibido tratamiento antituberculoso en cada uno de los 24 consultorios distritales en la ciudad en el 2013. Se extrajeron los datos de los registros de tratamiento de la TB mantenidos en papel a escala distrital y de los registros electrónicos a escala de la provincia. Se emparejaron los archivos a partir del nombre, la edad y la dirección. Se evaluó la sensibilidad, el carácter integral y la concordancia de los datos electrónicos con respecto a los datos del sistema en formato de papel.Resultados: Se observó que el sistema electrónico ofrecía una alta sensibilidad (99,2%) y un alto grado de integridad (de 87% a 99%), con una alta concordancia para todas las variables (κ de 0,78 a 0,97).Conclusión: Los resultados del presente estudio indican que los datos se han ingresado de manera correcta en el sistema VITIMES y que es posible captar la información directamente en este formato, sin conservar en paralelo el sistema en papel.

Fusion and Thermal Degradation Behavior of Symmetric Sulfur-Containing Quaternary Ammonium Bromides.

Quaternary ammonium salts are widely used in consumer products and industrial processes, where their instability at elevated temperatures limits their range of applications. In this work, the thermal behavior of a new class of quaternary ammonium salts was investigated using differential scanning calorimetry. These salts contain a sulfur atom in each chain at the fourth position from the central nitrogen and are thus termed thiaquats. The temperatures at which these salts melt and thermally degrade were determined, and enthalpies and entropies of fusion were evaluated. Their melting points increase with chain lengths, in contrast to the behavior of traditional quaternary ammonium salts. Furthermore, they exhibit enthalpies and entropies of fusion significantly lower than corresponding tetraalkyl analogues. These trends provide physical insight into the molecular-level behavior of these salts, suggesting that they do not fully dissociate upon melting. The thiaquats also exhibit thermal stability to markedly higher temperatures than traditional quaternary ammonium bromides, a phenomenon that can be explained in by strong pairing between the quaternary cation and bromide anion, which inhibits possible decomposition mechanisms. This enhanced thermal stability may enable applications of these salts in processes where traditional salts are not viable, such as phase-transfer-catalyzed systems performed at elevated temperatures.

Cost driver analysis of statin expenditure on Australia's Pharmaceutical Benefits Scheme.

INTRODUCTION: The Australian Pharmaceutical Benefits Scheme (PBS) provides universal access to subsidized medicines. In 2013, statins as a class had the highest expenditure on the PBS. OBJECTIVES: To assess the influence of policies and drivers affecting PBS statin utilization and expenditure between 1992 and 2013. METHODS: Analyses conducted from 1992 to 2013 and over three distinct time periods, including monthly expenditure/prescription, annual utilization (calculated as Defined Daily Doses/1000 inhabitants/day) and statin strengths dispensed. RESULTS: The major driver of increased PBS expenditure for statins was increased volumes. After adjusting for inflation, the average PBS expenditure on statin prescriptions was the major negative driver. Other influential drivers included the increased use of newer statins and increased strength of statins dispensed. DISCUSSION: Whilst the inflation-adjusted reimbursed price of statins decreased, increased utilization, including increased use of patented statins, increased total statin expenditure. Successful measures adopted by other countries could be applied to Australia to decrease total medicines expenditure.

A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response.

PURPOSE: Although adoptive cell therapy can be highly effective for the treatment of patients with melanoma, the application of this approach to the treatment of other solid tumors has been limited. The observation that the cancer germline (CG) antigen NY-ESO-1 is expressed in 70% to 80% and in approximately 25% of patients with synovial cell sarcoma and melanoma, respectively, prompted us to perform this first-in-man clinical trial using the adoptive transfer of autologous peripheral blood mononuclear cells that were retrovirally transduced with an NY-ESO-1-reactive T-cell receptor (TCR) to heavily pretreated patients bearing these metastatic cancers. EXPERIMENTAL DESIGN: HLA-*0201 patients with metastatic synovial cell sarcoma or melanoma refractory to standard treatments and whose cancers expressed NY-ESO-1 received autologous TCR-transduced T cells following a lymphodepleting preparative chemotherapy. Response rates using Response Evaluation Criteria in Solid Tumors (RECIST), as well as immunologic correlates of response, are presented in this report. RESULTS: Eleven of 18 patients with NY-ESO-1(+) synovial cell sarcomas (61%) and 11 of 20 patients with NY-ESO-1(+) melanomas (55%) who received autologous T cells transduced with an NY-ESO-1-reactive TCR demonstrated objective clinical responses. The estimated overall 3- and 5-year survival rates for patients with synovial cell sarcoma were 38% and 14%, respectively, whereas the corresponding estimated survival rates for patients with melanoma were both 33%. CONCLUSIONS: The adoptive transfer of autologous T cells transduced with a retrovirus encoding a TCR against an HLA-A*0201 restricted NY-ESO-1 epitope can be an effective therapy for some patients bearing synovial cell sarcomas and melanomas that are refractory to other treatments.

Time and geographical variations in utilization of endocrine therapy for breast cancer in Australia.

BACKGROUND: Endocrine therapies, aromatase inhibitors and tamoxifen, are commonly used as an adjuvant treatment in women with breast cancer. AIMS: This study examined the trends in use of endocrine therapies in Australia between 1996 and 2008, including a comparison between Australian states. METHODS: Prescription and expenditure data for tamoxifen and aromatase inhibitors (1996-2008) were obtained from the Drug Utilisation Sub-Committee. We converted prescription data to defined daily doses (DDD)/1000 population/day, the international unit of drug utilization. Utilization data in each state/territory (2003-2008) were adjusted for female population and age-standardized incidence rates of breast cancer. RESULTS: Total utilization of endocrine therapies increased by 30% from 1.66 to 2.14 DDD/1000/day between 1996 and 2008. Over this period, there was a shift in use from tamoxifen to aromatase inhibitors which became the highest used products in 2008. Anastrozole was the most used aromatase inhibitor and its use increased markedly after being listed on Australia's national Pharmaceutical Benefits Scheme (PBS) for early breast cancer in 2005 (average increase of 0.14 DDD/1000/day per annum between 2005 and 2008). PBS expenditure for endocrine therapies increased by 265% from $16 million to $58 million between 1996 and 2008. Utilization of endocrine therapies was overall comparable between regions except that it was substantially lower in the Northern Territory. CONCLUSIONS: Use of aromatase inhibitors has overtaken use of tamoxifen in 2008. Further real-world effectiveness data are required to evaluate whether large associated increases in expenditures partly because of the higher costs of aromatase inhibitors are actually justified.

Thalamic and caudate volumes in monozygotic twins discordantfor schizophrenia.

OBJECTIVE: The thalamus and caudate nucleus are key subcortical structures in the fronto-striato-thalamic pathways that have been implicated in the pathogenesis of schizophrenia. Previous studies have been inconsistent in identifying structural and functional abnormalities in these structures. However, methodologies in these studies have been unreliable and some have not adequately matched patients and controls. METHODS: Using algebraically-manipulated double-echomagnetic resonance (MR) images, we developed a reliable method to estimate caudate and thalamic volumes in a group of 13 monozygotic(MZ) twins; eight discordant for schizophrenia and five normal.Initially, volumes were measured on four image types: proton density(PD), T2-weighted, summed (PD + T2) and subtracted (PD-T2) to determine the most reliable method. RESULTS: There was a significant method by region interaction, where caudate volumes measured on PD images were significantly larger than those measured on T2-weighted images, while the opposite was found for thalamic volumes. However, there was no interaction of method by diagnosis. Test-retest reliability was highest for the summed images. Using summed images to measure the volumes of the caudate and thalamus in each twin, we found significantly increased caudate volumes in affected twins compared to their unaffected cotwins,but no significant difference in thalamic volume. CONCLUSIONS: Our results in a small sample of MZ twins discordant for schizophrenia do not support the presence of structural abnormalities in the thalamus. The findings in the caudate are consistent with previously reported effects of antipsychotic medication. We also report a reliable method for assessing the volumes of subcortical structures. However, volumetric estimates of brain structures may be dependent on which method is used and the structure being assessed. Such interactions need to be considered in future studies investigating brain structural abnormalities in schizophrenia and other disorders.

Farnesol is utilized for isoprenoid biosynthesis in plant cells via farnesyl pyrophosphate formed by successive monophosphorylation reactions.

The ability of Nicotiana tabacum cell cultures to utilize farnesol (F-OH) for sterol and sesquiterpene biosynthesis was investigated. [(3)H]F-OH was readily incorporated into sterols by rapidly growing cell cultures. However, the incorporation rate into sterols was reduced by greater than 70% in elicitor-treated cell cultures whereas a substantial proportion of the radioactivity was redirected into capsidiol, an extracellular sesquiterpene phytoalexin. The incorporation of [(3)H]F-OH into sterols was inhibited by squalestatin 1, suggesting that [(3)H]F-OH was incorporated via farnesyl pyrophosphate (F-P-P). Consistent with this possibility, N. tabacum proteins were metabolically labeled with [(3)H]F-OH or [(3)H]geranylgeraniol ([(3)H]GG-OH). Kinase activities converting F-OH to farnesyl monophosphate (F-P) and, subsequently, F-P-P were demonstrated directly by in vitro enzymatic studies. [(3)H]F-P and [(3)H]F-P-P were synthesized when exogenous [(3)H]F-OH was incubated with microsomal fractions and CTP. The kinetics of formation suggested a precursor-product relationship between [(3)H]F-P and [(3)H]F-P-P. In agreement with this kinetic pattern of labeling, [(32)P]F-P and [(32)P]F-P-P were synthesized when microsomal fractions were incubated with F-OH and F-P, respectively, with [gamma-(32)P]CTP serving as the phosphoryl donor. Under similar conditions, the microsomal fractions catalyzed the enzymatic conversion of [(3)H]GG-OH to [(3)H]geranylgeranyl monophosphate and [(3)H]geranylgeranyl pyrophosphate ([(3)H]GG-P-P) in CTP-dependent reactions. A novel biosynthetic mechanism involving two successive monophosphorylation reactions was supported by the observation that [(3)H]CTP was formed when microsomes were incubated with [(3)H]CDP and either F-P-P or GG-P-P, but not F-P. These results document the presence of at least two CTP-mediated kinases that provide a mechanism for the utilization of F-OH and GG-OH for the biosynthesis of isoprenoid lipids and protein isoprenylation.

Aging and glucocorticoids: effects on cell signaling mediated through adenylyl cyclase.

Abnormalities of hypothalamus-pituitary-adrenal axis regulation are common in the elderly and excess glucocorticoids have been implicated in the loss of neural function in aging. In the current study, we examined cell signaling mediated through adenylyl cyclase in brain regions, heart and liver of young and aged rats given continuous infusions of dexamethasone (10 or 50 micrograms/kg/day) for 26 days. Aged control animals showed significant deficits in total adenylyl cyclase activity (assessed with forskolin-Mn++) in the brain regions and the heart; superimposed on this change, the striatum and the heart displayed interference with the response mediated either at the level of G-protein coupling to cyclase (striatum) or neurotransmitter receptor coupling to G-proteins (heart). Administration of dexamethasone to young rats did not reproduce the effects of aging on any of the measures of adenylyl cyclase, despite the fact that the higher dose produced Cushingoid effects. The same dexamethasone regimens given to aged rats produced alterations in G-protein coupling mechanisms in the cortex and in serotonergic-mediated cyclase responses in the striatum, and also decreased basal enzyme activity in the heart. In contrast to the brain regions and the heart, the liver showed unique effects of aging and dexamethasone. Total adenylyl cyclase activity, the enzymatic response to beta adrenergic stimulation and the number of beta adrenergic receptors were all elevated in aged animals as compared to the younger cohort. Dexamethasone decreased both hepatic beta receptor numbers and isoproterenol responsiveness in young animals, but increased receptor binding in aged animals. These data indicate that the defects associated with aging in the central nervous system and the cardiac cell signaling mediated through adenylyl cyclase are not a result of glucocorticoid excess; however, central and peripheral tissues respond differently to glucocorticoids in aged vs. young animals. Given the high incidence of hypothalamus-pituitary-adrenal axis dysregulation in the elderly, and particularly in elderly depression, effects of glucocorticoids on cell signaling may contribute to disruption of cell function and to hypo- or hyper-reactivity to drugs, such as antidepressants, that act by altering synaptic transmission.

Dexamethasone and forskolin synergistically increase [Met5]enkephalin accumulation in mixed brain cell cultures.

Possible synergistic effects of the glucocorticoid dexamethasone (DEX, 10(-7) M) and the adenylate cyclase agonist forskolin (FSK, 10(-5) M) on [Met5]enkephalin (ME) accumulation were examined in enriched rat glial cultures and in mixed neuronal/glial cultures. In enriched glial cultures, DEX and FSK each stimulated the accumulation of ME 2-3-fold over basal media levels, but there was little additional stimulation when these agonists were combined. In contrast, mixed neuronal/glial cultures showed only weak responses to DEX or FSK alone, but the combination of these agonists produced a pronounced synergistic effect on media ME accumulation (6-10-fold over basal levels). The DEX effect was mediated via a classical glucocorticoid receptor, since DEX was potent (acting over a concentration range of 10(-11)-10(-7) M), mimicked by corticosterone (10(-6) M), and blocked by the glucocorticoid receptor antagonist RU486. There was a pronounced time lag (2 days) for the synergistic effects of DEX + FSK to develop. In situ hybridization and immunocytochemical studies suggested that astrocytes were the major source for the increased ME production in all mixed neuronal/glial cultures examined. Creating a mixed culture by plating fetal neurons onto confluent, enriched P7 glial cultures inhibited accumulation of ME in the media. DEX + FSK, but neither agonist alone, overcame this neuronal inhibition and increased accumulation of media ME to levels identical to levels in stimulated enriched glial cultures. The net effect was a 6-fold increase in ME accumulation in the mixed neuronal/glial cultures relative to a 2.5-fold increase in the enriched glial cultures. Neuronal inhibition of basal glial ME production could explain the similar synergistic effects of DEX + FSK observed in all mixed neuronal/glial cultures examined, and may be important in suppressing ME production by astrocytes in the brain.

Atypical regulation of hepatic adenylyl cyclase and adrenergic receptors during a critical developmental period: agonists evoke supersensitivity accompanied by failure of receptor down-regulation.

Ordinarily, beta-adrenergic receptors and responses linked to the receptors increase with development but in the liver, beta-receptors are higher in the fetus and neonate than in adulthood. We examined how hepatic beta-receptor signaling mediated through adenylyl cyclase is regulated in rats of different ages. In each case, animals were pretreated with isoproterenol for 4 d, and on the 5th d, hepatic membrane preparations were examined for adenylyl cyclase activity and receptor binding capabilities. Uniquely in 6-d-old animals, the cyclase response to isoproterenol was enhanced by chronic pretreatment, caused by heterologous sensitization mediated through effects on total catalytic activity (increased response to forskolin-Mn2+) and on G-protein coupling (enhanced effect of fluoride and increased GTP dependence of basal activity). Isoproterenol pretreatment failed to cause beta-receptor down-regulation in 6-d-old animals, but by 15 d of age, down-regulation was detected along with slight desensitization of the cyclase response. However, at 25 d, neither effect was present. In adulthood, repeated isoproterenol administration failed to cause cyclase desensitization but did reduce beta-receptor numbers; the loss of receptors was still unusual in that beta-receptor down-regulation could be achieved with either isoproterenol or with methoxamine, an alpha-receptor agonist. The results indicate that, early in development, hepatic beta-receptor-mediated responses are enhanced, not desensitized, after chronic stimulation. These effects would foster responsiveness of hepatic gluconeogenesis in the face of the massive adrenergic stimulation associated with the transition from fetal to neonatal life. In adulthood, when receptor numbers are far lower than in the neonate, the inability to desensitize the signaling cascade despite receptor down-regulation would serve to maintain the response to catecholamines.

The regulation of hippocampal dynorphin by neural/neuroendocrine pathways: models for effects of aging on an opioid peptide system.

Previous research has demonstrated increased messenger RNA expression and peptide content in an opioid system localized to hippocampal dentate granule cells in aged rats. This altered regulation of dynorphin was correlated with the emergence of an age-related impairment in spatial learning. Considerable evidence exists for additional effects of aging on systems that provide input to the dynorphin-containing dentate granule cells. Such changes have been well documented for loss of perforant path innervation from entorhinal cortex, deterioration in septohippocampal cholinergic neurons, and high amounts of glucocorticoids that have, among their targets, receptors located in the dentate gyrus. Similar to the effects of aging on hippocampal dynorphin, age-related changes in each of these systems correlate with the severity of spatial learning impairment in aged rats. This raises the possibility that dysregulation of dynorphin in the aged brain is a reactive response to antecedant change(s) in this circuitry, a hypothesis that was examined by separately manipulating in young rats the three neural/neuroendocrine systems identified above. Of the three models examined only removal of the perforant path reproduced the effect of aging on dynorphin in the hippocampal formation. An immunotoxin was used in Experiment 1 to selectively remove septo-hippocampal cholinergic neurons in young rats. No alteration in hippocampal opioid peptides was produced by this treatment. Experiment 2 examined effects of exposure to excess corticosterone. Adrenalectomized rats exhibited a significant decrease in hippocampal dynorphin-A (1-8) content, which was reversed by corticosterone replacement at a concentration approximating normal basal levels. Dynorphin-A (1-8) content, however, was not reliably increased by exposure to excess corticosterone. In contrast, perforant path removal was found to reproduce the effect of aging on dynorphin content; either aspiration of the entorhinal cortex or knife-cut transections of the perforant path reliably increased hippocampal dynorphin content. These results support the conclusion that age-related deterioration in the septohippocampal cholinergic system and evaluated exposure to corticosterone are not sufficient to induce an elevation in hippocampal dynorphin content. Only removal of the perforant path innervation was found to reproduce the elevation in hippocampal dynorphin content observed in aged rats with hippocampal-dependent learning impairment.

A nontoxic cholera enterotoxin (CT) analog is chimeric with regard to both epitypes of CT-B subunits, CT-B-1 and CT-B-2.

The gene encoding a nontoxic analog, CT-2*, of cholera enterotoxin (CT) with attenuating codon substitutions in the A subunit was introduced into the attenuated Vibrio cholerae classical biotype mutant candidate vaccine strain CVD103, which produces the B subunit (but not the A subunit) of CT-1. The recombinant strain produces a chimeric nontoxic analog holotoxin containing both CT-B-1 and CT-B-2 subunits. This offers potential advantages over CVD103 in the induction of immunity against E1 Tor biotype and V. cholerae O139 strains which produce CT-B-2. The recombinant protein may also be useful in polysaccharide-protein conjugate vaccines against both O1 and O139 serovars of V. cholerae.

Th1/Th2-like immunity and resistance to herpes simplex labialis.

To investigate potential immunologic mechanisms of resistance to recurrent herpes simplex labialis, we assayed serum antibody titers and cultured peripheral blood mononuclear cell (PBMC) cytokine production among patients with a history of frequent episodes (H+S+), herpes simplex virus (HSV)-seropositive individuals without a history of herpes labialis (H-S+) and HSV-seronegative persons (H-S-). In addition, H+S+ patients were exposed to experimental ultraviolet radiation (UVR) on the lips and the immunologic assay results compared among those who developed experimental lesions and those who did not. H+S+ patients were found to have higher median serum titers of HSV antibody and trends to lower levels of HSV-specific PBMC IFN-gamma and IL-2 than H-S+ control patients (123 vs 66, P = 0.04; 424 vs 548 pg/ml, P = 0.08; 14 vs 26 pg/ml, P = 0.14, respectively). Correlation of the results with the occurrence of experimental lesions showed the inverse: the subgroup of H+S+ patients with UVR-induced lesions had lower titers of antibody and trends to higher levels of IFN-gamma and IL-2 than H+S+ patients who could not be induced (93 vs 149, P = 0.02; 501 vs 347 pg/ml, P = NS; 26 vs 11 pg/ml, P = NS, respectively). The size and duration of UVR-induced lesions showed positive correlations with IFN-gamma and IL-2 levels (r = 0.60-0.67, P = 0.02-0.04). Although the small number of patients limited the power of this study, the overall pattern of the findings suggests that a Th1-like cytokine response (IFN-gamma and IL-2 production) may be associated with resistance to naturally occurring episodes of herpes labialis. The development and severity of experimental UVR-induced herpes labialis appears to be regulated differently and may involve an immunopathologic mechanism.

The dopaminergic, glutamatergic, GABAergic bases for the action of amphetamine and cocaine.

The present experiments were designed to evaluate pharmacologically the role of three neuroanatomically related systems--dopamine, glutamate and GABA--in the motor-stimulant response to amphetamine and cocaine. The data indicate that stimulant-induced stereotypy is blocked by antagonists of all three systems and that agonists of all three systems administered into the striatum induce stereotypy. Furthermore, the interaction among them occurs in the striatum; and the reaction sequence, as determined by the effect of the relatively selective antagonists on agonist-induced stereotypy, appears to be a dopaminergic activation of a glutamatergic system which in turn activates a GABAergic system. Because the GABAergic system represents the major efferents from the striatum, the evidence suggests that the motor-stimulatory effects of amphetamine and cocaine result from a disinhibition of inhibitory systems in the thalamus, resulting in facilitation of excitation in the cortex.

A dopaminergic-glutamatergic basis for the action of amphetamine and cocaine.

The behavioral effects of amphetamine and cocaine are generally considered to be the result of their indirect dopaminergic activity. Recent reports, however, suggest that the activity of the psychomotor stimulants involves not only the dopaminergic but also the glutamatergic system. In the present study the role of the glutamate system in the action of the stimulants was investigated in mice with the use of glutamatergic agonists and antagonists administered either intraperitoneally or intracranially into the striatum. CPP, an NMDA-type glutamate antagonist, given systemically or intrastriatally, blocked stereotypy induced by either amphetamine or cocaine. These results represent pharmacological evidence that the glutamate system is an essential component in the expression of the stereotypic effect of the psychomotor stimulants, and that a locus of this action of glutamate is in the striatum. These conclusions were supported further by the observation that NMDLA administered focally into the striatum caused stereotypy which was indistinguishable from that produced by either amphetamine or dopamine. Stereotypy induced by amphetamine injected into the striatum was blocked by CPP or sulpiride administered either systemically or directly into the striatum; in contrast, stereotypy induced by NMDLA given into the striatum was blocked by CPP but not by sulpiride, regardless of whether the antagonists were presented systemically or into the striatum. The data suggest that stereotypy induced by amphetamine or cocaine is mediated by a dopaminergic activation of a glutamatergic system within the striatum.