Multicenter study on the immunogenicity and safety of two recombinant vaccines against hepatitis B

The immunogenicity and safety of a new recombinant hepatitis B vaccine from the Instituto Butantan (Butang®) were evaluated in a multicenter, double-blind, prospective equivalence study in three centers in Brazil. Engerix B® was the standard vaccine. A total of 3937 subjects were recruited and 2754 (70%) met all protocol criteria at the end of the study. All the subjects were considered healthy and denied having received hepatitis B vaccine before the study. Study subjects who adhered to the protocol were newborn infants (566), children 1 to 10 years old (484), adolescents from 11 to 19 years (740), adults from 20 to 30 years (568), and adults from 31 to 40 years (396). Vaccine was administered in three doses on the schedule 0, 1, and 6 months (newborn infants, adolescents, and adults) or 0, 1, and 7 months (children). Vaccine dose was intramuscular 10 µg (infants, children, and adolescents) or 20 µg (adults). Percent seroprotection (assumed when anti-HBs titers were > 10mIU/ml) and geometric mean titer (mIU/ml) were: newborn infants, 93.7% and 351.1 (Butang®) and 97.5% and 1530.6 (Engerix B®); children, 100% and 3600.0 (Butang®) and 97.7% and 2753.1 (Engerix B®); adolescents, 95.1% and 746.3 (Butang®) and 96% and 1284.3 (Engerix B®); adults 20-30 years old, 91.8% and 453.5 (Butang®) and 95.5% and 1369.0 (Engerix B®); and adults 31-40 years old, 79.8% and 122.7 (Butang®) and 92.4% and 686.2 (Engerix B®). There were no severe adverse events following either vaccine. The study concluded that Butang® was equivalent to Engerix B® in children, and less immunogenic but acceptable for use in newborn infants, adolescents, and young adults.

Evaluation of the GlideScope (R) for tracheal intubation in patients with cervical spine immobilisation by a semi-rigid collar

Application of cervical collars may reduce cervical spine movements but render tracheal intubation with a standard laryngoscope difficult if not impossible. We hypothesised that despite the presence of a Philadelphia Patriot (R) cervical collar and with the patient's head taped to the trolley, tracheal intubation would be possible in 50 adult patients using the GlideScope (R) and its dedicated stylet. Laryngoscopy was attempted using a Macintosh laryngoscope with a size 4 blade, and the modified Cormack-Lehane grade was scored. Subsequently, laryngoscopy with the GlideScope was graded and followed by tracheal intubation. All patients' tracheas were successfully intubated with the GlideScope. The median (IQR) intubation time was 50 s (43-61 s). The modified Cormack-Lehane grade was 3 or 4 at direct laryngoscopy. It was significantly reduced with the GlideScope (p < 0.0001), reaching grade 2a in most patients. Tracheal intubation in patients wearing a semi-rigid collar and having their head taped to the trolley is possible with the help of the GlideScope.

Aversive Stimuli and Functional Networks of Fear Learning in PTSD : 734

Background: One characteristic of post traumatic stress disorder is an inability to adapt to a safe environment i.e. to change behavior when predictions of adverse outcomes are not met. Recent studies have also indicated that PTSD patients have altered pain processing, with hyperactivation of the putamen and insula to aversive stimuli (Geuze et al, 2007). The present study examined neuronal responses to aversive and predicted aversive events. Methods: Twenty-four trauma exposed non-PTSD controls and nineteen subjects with PTSD underwent fMRI imaging during a partial reinforcement fear conditioning paradigm, with a mild electric shock as the unconditioned stimuli (UCS). Three conditions were analyzed: actual presentations of the UCS, events when a UCS was expected, but omitted (CS+), and events when the UCS was neither expected nor delivered (CS-). Results: The UCS evoked significant alterations in the pain matrix consisting of the brainstem, the midbrain, the thalamus, the insula, the anterior and middle cingulate and the contralateral somatosensory cortex. PTSD subjects displayed bilaterally elevated putamen activity to the electric shock, as compared to controls. In trials when USC was expected, but omitted, significant activations were observed in the brainstem, the midbrain, the anterior insula and the anterior cingulate. PTSD subjects displayed similar activations, but also elevated activations in the amygdala and the posterior insula. Conclusions: These results indicate altered fear and safety learning in PTSD, and neuronal activations are further explored in terms of functional connectivity using psychophysiological interaction analyses.

The relationship between genetic variability and the susceptibility of Biomphalaria alexandrina snails to Schistosoma mansoni infection

In the present study, Biomphalaria snails collected from five Egyptian governorates (Giza, Fayoum, Kafr El-Sheikh, Ismailia and Damietta), as well as reference control Biomphalaria alexandrina snails from the Schistosome Biological Supply Center (SBSC) (Theodor Bilharz Research Institute, Egypt), were subjected to species-specific polymerase chain reaction (PCR) assays to identify the collected species. All of the collected snails were found to be B. alexandrina and there was no evidence of the presence of Biomphalaria glabrata. Randomly amplified polymorphic DNA (RAPD)-PCR assays showed different fingerprints with varying numbers of bands for the first generation (F1) of B. alexandrina snail populations (SBSC, Giza, Fayoum, Kafr El-Sheikh, Ismailia and Damietta). The primer OPA-1 produced the highest level of polymorphism and amplified the greatest number of specific bands. The estimated similarity coefficients among the B. alexandrina populations based on the RAPD-PCR profiles ranged from 0.56 (between SBSC and Ismailia snails) to 0.72 (between Ismailia and Kafr El-Sheikh snails). Experimental infection of the F1 of progeny from the collected snails with Schistosoma mansoni (SBSC strain) showed variable susceptibility rates ranging from 15% in the Fayoum snail group to 50.3% in SBSC snails. A negative correlation was observed between the infection rates in the different snail groups and the distances separating their corresponding governorates from the parasite source. The infection rates of the snail groups and their similarity coefficients with SBSC B. alexandrina snails were positively correlated. The variations in the rates of infection of different B. alexandrina groups with S. mansoni, as well as the differences in the similarity coefficients among these snails, are dependent not only on the geographical distribution of the snails and the parasite, but also on the genetic variability of the snails. Introduction of this variability into endemic areas may reduce the ability of the parasite to infect local hosts and consequently reduce schistosomiasis epidemiology.

Sandflies (Diptera: Psychodidae) in a focus of visceral leishmaniasis in White Nile, Sudan

Visceral leishmaniasis (VL) has been known to occur since the 1980s on the western bank of the White Nile River (Central Sudan), 150 km south of Khartoum, and has resulted in high mortality. The most recent outbreak of the disease in this area began in 2006. Entomological surveys were carried out during May 2008, June 2010 and May and July 2011 in the White Nile area. Sandflies were collected using Centers for Disease Control light traps and sticky oil traps in the village of Kadaba and the nearby woodland. Phlebotomus females were dissected for the presence of Leishmania promastigotes. A total of 17,387 sandflies, including six species of Phlebotomus and 10 species of Sergentomyia, were identified. The Phlebotomus species recorded were Phlebotomus orientalis, Phlebotomus papatasi, Phlebotomus bergeroti, Phlebotomus duboscqi, Phlebotomus rodhaini and Phlebotomus saevus. P. orientalis was collected in both habitats. The relative abundance of P. orientalis in the woodland habitat was higher than that recorded in the village habitat. In the woodland habitat, there was a notable increase in the relative abundance of P. orientalis during the surveys conducted in 2008 and 2010 compared to 2011. None of the 311 P. orientalis females dissected were infected with Leishmania promastigotes, although relatively high parous rates were recorded in both habitats. Based on the distribution of P. orientalis recorded in this study, this species is the most likely vector of VL in the endemic focus in the White Nile area. Further investigation is required to elucidate the seasonal abundance and distribution of the vector, as well as the transmission season of VL in both habitats so that appropriate control strategies for the vector can be designed.

Genetics and molecular epidemiology of multiple myeloma: the rationale for the IMMEnSE consortium (review).

There is strong evidence suggesting the presence of a genetic component in the aetiology of multiple myeloma (MM). However no genetic risk factors have been unequivocally established so far. To further our understanding of the genetic determinants of MM risk, a promising strategy is to collect a large set of patients in a consortium, as successfully done for other cancers. In this article, we review the main findings in the genetic susceptibility and pharmacogenetics of MM and present the strategy of the IMMEnSE (International Multiple Myeloma rESEarch) consortium in contributing to determine the role of genetic variation in pharmacogenetics and in MM risk.

Effect of myrrh and thyme on Trichinella spiralisenteral and parenteral phases with inducible nitric oxide expression in mice

Trichinellosis is a serious disease with no satisfactory treatment. We aimed to assess the effect of myrrh (Commiphora molmol) and, for the first time, thyme (Thymus vulgaris L.) against enteral and encysted (parenteral) phases of Trichinella spiralis in mice compared with albendazole, and detect their effect on inducible nitric oxide synthase (iNOS) expression. Oral administration of 500 mg/kg of myrrh and thyme led to adult reduction (90.9%, 79.4%), while 1,000 mg/kg led to larvae reduction (79.6%, 71.3%), respectively. Administration of 50 mg/kg of albendazole resulted in adult and larvae reduction (94.2%, 90.9%). Positive immunostaining of inflammatory cells infiltrating intestinal mucosa and submucosa of all treated groups was detected. Myrrh-treated mice showed the highest iNOS expression followed by albendazole, then thyme. On the other hand, both myrrh and thyme-treated groups showed stronger iNOS expression of inflammatory cells infiltrating and surrounding encapsulated T. spiralis larvae than albendazole treated group. In conclusion, myrrh and thyme extracts are highly effective against both phases of T. spiralis and showed strong iNOS expressions, especially myrrh which could be a promising alternative drug. This experiment provides a basis for further exploration of this plant by isolation and retesting the active principles of both extracts against different stages of T. spiralis.

Modulation of Higher-Order Olfaction Components on Executive Functions in Humans.

The prefrontal (PFC) and orbitofrontal cortex (OFC) appear to be associated with both executive functions and olfaction. However, there is little data relating olfactory processing and executive functions in humans. The present study aimed at exploring the role of olfaction on executive functioning, making a distinction between primary and more cognitive aspects of olfaction. Three executive tasks of similar difficulty were used. One was used to assess hot executive functions (Iowa Gambling Task-IGT), and two as a measure of cold executive functioning (Stroop Colour and Word Test-SCWT and Wisconsin Card Sorting Test-WCST). Sixty two healthy participants were included: 31 with normosmia and 31 with hyposmia. Olfactory abilities were assessed using the ''Sniffin' Sticks'' test and the olfactory threshold, odour discrimination and odour identification measures were obtained. All participants were female, aged between 18 and 60. Results showed that participants with hyposmia displayed worse performance in decision making (IGT; Cohen's-d = 0.91) and cognitive flexibility (WCST; Cohen's-d between 0.54 and 0.68) compared to those with normosmia. Multiple regression adjusted by the covariates participants' age and education level showed a positive association between odour identification and the cognitive inhibition response (SCWT-interference; Beta = 0.29; p = .034). The odour discrimination capacity was not a predictor of the cognitive executive performance. Our results suggest that both hot and cold executive functions seem to be associated with higher-order olfactory functioning in humans. These results robustly support the hypothesis that olfaction and executive measures have a common neural substrate in PFC and OFC, and suggest that olfaction might be a reliable cognitive marker in psychiatric and neurologic disorders.

Development of a retrospective job exposure matrix for PCB-exposed workers in capacitor manufacturing

Objectives: Polychlorinated biphenyls (PCBs) are considered probable human carcinogens by the International Agency for Research on Cancer and one congener, PCB126, has been rated as a known human carcinogen. A period-specific job exposure matrix (JEM) was developed for former PCB-exposed capacitor manufacturing workers (n=12,605) (1938-1977). Methods: A detailed exposure assessment for this plant was based on a number of exposure determinants (proximity, degree of contact with PCBs, temperature, ventilation, process control, job mobility). The intensity and frequency of PCB exposures by job for both inhalation and dermal exposures, and additional chemical exposures were reviewed. The JEM was developed in nine steps: (1) all unique jobs (n=1,684) were assessed using (2) defined PCB exposure determinants; (3) the exposure determinants were used to develop exposure profiles; (4) similar exposure profiles were combined into categories having similar PCB exposures; (5) qualitative intensity (high-medium-low-baseline) and frequency (continuous-intermittent) ratings were developed, and (6) used to qualitatively rate inhalation and dermal exposure separately for each category; (7) quantitative intensity ratings based on available air concentrations were developed for inhalation and dermal exposures based on equal importance of both routes of exposure; (8) adjustments were made for overall exposure, and (9) for each category the product of intensity and frequency was calculated, and exposure in the earlier era was weighted. Results: A period-specific JEM modified for two eras of stable PCB exposure conditions. Conclusions: These exposure estimates, derived from a systematic and rigorous use of the exposure determinant data, lead to cumulative PCB exposure-response relationships in the epidemiological cancer mortality and incidence studies of this cohort. [Authors]

Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging.

Adult hippocampal neurogenesis results in the formation of new neurons and is a process of brain plasticity involved in learning and memory. The proliferation of adult neural stem or progenitor cells is regulated by several extrinsic factors such as experience, disease or aging and intrinsic factors originating from the neurogenic niche. Microglia is very abundant in the dentate gyrus (DG) and increasing evidence indicates that these cells mediate the inflammation-induced reduction in neurogenesis. However, the role of microglia in neurogenesis in physiological conditions remains poorly understood. In this study, we monitored microglia and the proliferation of adult hippocampal stem/progenitor cells in physiological conditions known to increase or decrease adult neurogenesis, voluntary running and aging respectively. We found that the number of microglia in the DG was strongly inversely correlated with the number of stem/progenitor cells and cell proliferation in the granule cell layer. Accordingly, co-cultures of decreasing neural progenitor/glia ratio showed that microglia but not astroglia reduced the number of progenitor cells. Together, these results suggest that microglia inhibits the proliferation of neural stem/progenitor cells despite the absence of inflammatory stimulus.

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

High frequency of functionally active Melan-a-specific T cells in a patient with progressive immunoproteasome-deficient melanoma.

Tumor-reactive T cells play an important role in cancer immunosurveillance. Applying the multimer technology, we report here an unexpected high frequency of Melan-A-specific CTLs in a melanoma patient with progressive lymph node metastases, consisting of 18 and 12.8% of total peripheral blood and tumor-infiltrating CD8+ T cells, respectively. Melan-A-specific CTLs revealed a high cytolytic activity against allogeneic Melan-A-expressing target cells but failed to kill the autologous tumor cells. Loading of the tumor cells with Melan-A peptide reversed the resistance to killing, suggesting impaired function of the MHC class I antigen processing and presentation pathway. Mutations of the coding region of the HLA-A2 binding Melan-A26-35 peptide or down-regulation of the MHC class I heavy chain, the antigenic peptide TAP, and tapasin could be excluded. However, PCR and immunohistochemical analysis revealed a deficiency of the immunoproteasomes low molecular weight protein 2 and low molecular weight protein 7 in the primary tumor cells, which affects the quantity and quality of generated T-cell epitopes and might explain the resistance to killing. This is supported by our data, demonstrating that the resistance to killing can be partially reversed by pre-exposure of the tumor cells to IFN-gamma, which is known to induce the immunoproteasomes. Overall, this is the first report of an extremely high frequency of tumor-specific CTLs that exhibit competent T-cell-effector functions but fail to lyse the autologous tumor cells. Immunotherapeutic approaches should not only focus on the induction of a robust antitumor immune response, but should also have to target tumor immune escape mechanisms.

Propofol anesthesia impairs the maturation and survival of adult-born hippocampal neurons.

BACKGROUND: Adult neurogenesis occurs in the hippocampus of most mammals, including humans, and plays an important role in hippocampal-dependent learning. This process is highly regulated by neuronal activity and might therefore be vulnerable to anesthesia. In this article, the authors investigated this possibility by evaluating the impact of propofol anesthesia on mouse hippocampal neurons generated during adulthood, at two functionally distinct maturational stages of their development. METHODS: Adult-born hippocampal neurons were identified using the cell proliferation marker bromodeoxyuridine or a retroviral vector expressing the green fluorescent protein in dividing cells and their progenies. Eleven or 17 days after the labeling procedure, animals (n = 3-5 animals per group) underwent a 6-h-long propofol anesthesia. Twenty-one days after labeling, the authors analyzed the survival, differentiation, and morphologic maturation of adult-born neurons using confocal microscopy. RESULTS: Propofol impaired the survival and maturation of adult-born neurons in an age-dependent manner. Anesthesia induced a significant decrease in the survival of neurons that were 17 days old at the time of anesthesia, but not of neurons that were 11 days old. Similarly, propofol anesthesia significantly reduced the dendritic maturation of neurons generated 17 days before anesthesia, without interfering with the maturation of neurons generated 11 days before anesthesia. CONCLUSIONS: These results reveal that propofol impairs the survival and maturation of adult-born hippocampal neurons in a developmental stage-dependent manner in mice.

Middle and late Cenomanian oceanic anoxic events in shallow and deeper shelf environments of western Morocco

The response of shallow-water sequences to oceanic anoxic event 2 and mid-Cenomanian events 1a and 1b was investigated along the west African margin of Morocco north of Agadir (Azazoul) and correlated with the deep-water sequence of the Tarfaya Basin (Mohammed Beach) based on biostratigraphy, mineralogy, phosphorus and stable isotopes. In the deeper Mohammed Beach section results show double peaks in delta 13C(org) for mid-Cenomanian events 1a and 1b (Rotalipora reicheli biozone, lower CC10a biozone), the characteristic oceanic anoxic event 2 delta 13C excursion (Rotalipora cushmani extinction, top of CC10a biozone) and laminated (anoxic) black shale. In the shallow environment north of Agadir, a fluctuating sea-level associated with dysoxic, brackish and mesotrophic conditions prevailed during the middle to late Cenomanian, as indicated by oyster biostromes, nannofossils, planktonic and benthonic foraminiferal assemblages. Anoxic conditions characteristic of oceanic anoxic event 2 (for example, laminated black shales) did not reach into shallow-water environments until the maximum transgression of the early Turonian. Climate conditions decoupled along the western margin of Morocco between mid-Cenomanian event 1b and the Cenomanian-Turonian boundary, as also observed in eastern Tethys. North of Agadir alternating humid and dry seasonal conditions prevailed, whereas in the Tarfaya Basin the climate was dry and seasonal. This climatic decoupling can be attributed to variations in the Intertropical Convergence Zone and in the intensity of the north-east trade winds in tropical areas.