Immune responses in hookworm infections

Hookworms infect perhaps one-fifth of the entire human population, yet little is known about their interaction with our immune system. The two major species are Necator americanus, which is adapted to tropical conditions, and Ancylostoma duodenale, which predominates in more temperate zones. While having many common features, they also differ in several key aspects of their biology. Host immune responses are triggered by larval invasion of the skin, larval migration through the circulation and lungs, and worm establishment in the intestine, where adult worms feed on blood and mucosa while injecting various molecules that facilitate feeding and modulate host protective responses. Despite repeated exposure, protective immunity does not seem to develop in humans, so that infections occur in all age groups (depending on exposure patterns) and tend to be prolonged. Responses to both larval and adult worms have a characteristic T-helper type 2 profile, with activated mast cells in the gut mucosa, elevated levels of circulating immunoglobulin E, and eosinoophilia in the peripheral blood and local tissues, features also characteristic of type I hypersensitivity reactions. The longevity of adult hookworms is determined probably more by parasite genetics than by host immunity. However, many of the proteins released by the parasites seem to have immunomodulatory activity, presumably for self-protection. Advances in molecular biotechnology enable the identification and characterization of increasing numbers of these parasite molecules and should enhance our detailed understanding of the protective and pathogenetic mechanisms in hookworm infections.

Effect of Fusobacterium nucleatum on the T and B cell responses to Porphyromonas gingivalis in a mouse model

T cell cytokine profiles and specific serum antibody levels in five groups of BALB/c mice immunized with saline alone, viable Fusobacterium nucleatum ATCC 25586, viable Porphyromonas gingivalis ATCC 33277, F. nucleatum followed by P. gingivalis and P. gingivalis followed by F nucleatum were determined. Splenic CD4 and CD8 cells were examined for intracytoplasmic interleukin (IL)-4, interferon (IFN)-gamma and IL-10 by dual colour flow cytometry and the levels of serum anti-F. nucleatum and anti-P. gingivalis antibodies determined by an ELISA. Both Th1 and Th2 responses were demonstrated by all groups, and while there were slightly lower percentages of cytokine positive T cells in mice injected with F. nucleatum alone compared with the other groups immunized with bacteria., F nucleatum had no effect on the T cell production of cytokines induced by P gingivalis in the two groups immunized with both organisms. However, the percentages of cytokine positive CD8 cells were generally significantly higher than those of the CD4 cells. Mice immunized with F nucleatum alone had high levels of serum anti-E nucleatum antibodies with very low levels of P. gingivalis antibodies, whereas mice injected with P gingivalis alone produced anti-P. gingivalis antibodies predominantly. Although the levels of anti-E nucleatum antibodies in mice injected with E nucleatum followed by P. gingivalis were the same as in mice immunized with F nucleatum alone, antibody levels to P. gingivalis were very low. In contrast, mice injected with P. gingivalis followed by F nucleatum produced equal levels of both anti-P. gingivalis and anti-F nucleatum antibodies, although at lower levels than the other three groups immunized with bacteria, respectively. Anti-Actinobacillus actitiomycetemcomitans, Bacteroides forsythus and Prevotella intermedia serum antibody levels were also determined and found to be negligible. In conclusion, F nucleatum immunization does not affect the splenic T cell cytokine response to P. gingivalis. However, F nucleatum immunization prior to that of P. gingivalis almost completely inhibited the production of anti-P gingivalis antibodies while P. gingivalis injection before F. nucleatum demonstrated a partial inhibitory effect by P. gingivalis on antibody production to F. nucleatum. The significance of these results with respect to human periodontal disease is difficult to determine. However, they may explain in part differing responses to P. gingivalis in different individuals who may or may not have had prior exposure to F. nucleatum. Finally, the results suggested that P. gingivalis and F. nucleatum do not induce the production of cross-reactive antibodies to other oral microorganisms.

Route of administration of chimeric BPV1VLP determines the character of the induced immune responses

To examine the mucosal immune response to papillomavirus virus-like particles (PV-VLP), mice were immunized with VLP intrarectally (i.r.), intravaginally (i.va.) or intramuscularly (i.m.) without adjuvant. PV-VLP were assembled with chimeric BPV-1 L1 proteins incorporating sequence from HIV-1 gp 120, either the V3 loop or a shorter peptide incorporating a known CTL epitope (HIVP18I10). Antibody specific for BPV-1 VLP and P18 peptide was detected in serum following i.m., but not i.r. or i.va. immunization. Denatured VLP induced a much reduced immune response when compared with native VLP, Immune responses following mucosal administration of VLP were generally weaker than following systemic administration. VLP specific IgA was higher in intestine washes following i.r. than i.va. immunization, and higher in vaginal washes following i.m. than i.r. or i.va. immunization. No differences in specific antibody responses were seen between animals immunized with BPV-1 P18 VLP or with BPV-1 V3 VLP. Cytotoxic T lymphocyte precursors specific for the P18 CTL epitope were recovered from the spleen following i.m., i.va. or i.r. immunization with P18 VLP, and were similarly detected in Peyer's patches following i.m. or i.r. immunization. Thus, mucosal or systemic immunization with PV VLP induces mucosal CTL responses and this may be important for vaccines for mucosal infection with human papillomaviruses and for other viruses.

Relationship of XIST expression and responses of ovarian cancer to chemotherapy

Expression profiling to characterize cancer pharmacology has become a new approach to discover novel molecular targets for prognostic markers and cancer therapy. In a study to compare the global RNA expression profiles between primary and recurrent ovarian tumors from the same patient, we have identified XIST (inactive X chromosome-specific transcripts) as the most differentially expressed gene that was down-regulated in the recurrent tumor. XIST encodes a spliced noncoding polyadenylated transcript that is unique in being expressed exclusively from the inactive X chromosome and is involved in the X-inactivation process. Subsequent characterization of XIST expression in a panel of female cancer cell lines showed that the expression level of XIST correlates significantly with Taxol sensitivity. The clinical relevance of this observation is demonstrated by the strong association between XIST RNA levels and disease-free periods of ovarian cancer patients in a group of 21 ovarian cancer cases with Taxol in the therapeutic regiments. Cytogenetic studies on ovarian cancer cell lines indicated that loss of inactive X chromosome is one mechanism for the loss of XIST transcripts in the cell lines. Our data suggest that XIST expression may be a potential marker for chemotherapeutic responses in ovarian cancer.

Testing the beneficial acclimation hypothesis

Recent developments in evolutionary physiology have seen many of the long-held assumptions within comparative physiology receive rigorous experimental analysis. Studies of the adaptive significance of physiological acclimation exemplify this new evolutionary approach. The beneficial acclimation hypothesis (BAH) was proposed to describe the assumption that all acclimation changes enhance the physiological performance or fitness of an individual organism. To the surprise of most physiologists, all empirical examinations of the BAH have rejected its generality. However, we suggest that these examinations are neither direct nor complete tests of the functional benefit of acclimation. We consider them to be elegant analyses of the adaptive significance of developmental plasticity, a type of phenotypic plasticity that is very different from the traditional concept of acclimation that is used by comparative physiologists.

Responses to a clinical test of mechanical provocation of nerve tissue in whiplash associated disorder

Involvement of nerve tissue may contribute to the persistence of pain following a whiplash injury. This study aimed to investigate responses to the brachial plexus provocation test (BPPT) in 156 subjects with chronic whiplash associated disorder (WAD) with and without associated arm pain and 95 asymptomatic control subjects. The range of elbow extension (ROM) and visual analogue scale (VAS) pain scores were measured. Subjects with chronic WAD demonstrated significantly less ROM and higher VAS scores with the BPPT than the asymptomatic subjects (P

Enterohepatic circulation - Physiological, pharmacokinetic and clinical implications

Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation. Cycling is often associated with multiple peaks and a longer apparent half-life in a plasma concentration-time profile. Factors affecting biliary excretion include drug characteristics (chemical structure, polarity and molecular size), transport across sinusoidal plasma membrane and canniculae membranes, biotransformation and possible reabsorption from intrahepatic bile ductules. Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria. Bioavailability is also affected by the extent of intestinal absorption, gut-wall P-glycoprotein efflux and gut-wall metabolism. Recently, there has been a considerable increase in our understanding of the role of transporters, of gene expression of intestinal and hepatic enzymes, and of hepatic zonation. Drugs, disease and genetics may result in induced or inhibited activity of transporters and metabolising enzymes. Reduced expression of one transporter, for example hepatic canalicular multidrug resistance-associated protein (MRP) 2, is often associated with enhanced expression of others, for example the usually quiescent basolateral efflux MRP3, to limit hepatic toxicity. In addition, physiologically relevant pharmacokinetic models, which describe enterohepatic recirculation in terms of its determinants (such as sporadic gall bladder emptying), have been developed. In general, enterohepatic recirculation may prolong the pharmacological effect of certain drugs and drug metabolites. Of particular importance is the potential amplifying effect of enterohepatic variability in defining differences in the bioavailability, apparent volume of distribution and clearance of a given compound. Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling.

Anticipation of a non-aversive reaction time task facilitates the blink startle reflex

The conditions under which blink startle facilitation can be found in anticipation of a reaction time task were investigated to resolve inconsistent findings across previous studies. Four groups of participants (n = 64) were presented with two visual stimuli, one predicting a reaction time task (S+) and the second presented alone (S-). Participants were asked to make a speeded response to the offset of the S+ (S1 paradigm) or were asked to respond to a tactile stimulus presented at the offset of the S+ (S1-S2 paradigm). Half of the participants in each paradigm condition received performance feedback. Overall, blink latency shortening and magnitude facilitation were larger during S+ than during S-. More detailed analyses, however, found these differences to be reliable only in the Feedback conditions. Ratings of S+ pleasantness did not change across the experiment. Electrodermal responses to S+ were larger than to S- in all groups with differential electrodermal responding emerging earlier in the S1 paradigm. Taken together, the data support the notion that startle facilitation can occur during non-aversive Pavlovian conditioning. (C) 2002 Elsevier Science B.V. All rights reserved.

Lead stimulus modality change and the attentional modulation of the acoustic and electrical blink reflex

Two experiments investigated the effects of the sensory modality of the lead and of the blink-eliciting stimulus during lead stimulus modality change on blink modulation at lead intervals of 2500 and 3500 ins. Participants were presented with acoustic, visual, or tactile change stimuli after habituation training with lead stimuli from the same or a different sensory modality. In Experiment 1, latency and magnitude of the acoustic blink were facilitated during a change to acoustic or visual lead stimuli, but not during a change to tactile lead stimuli. After habituation to acoustic lead stimuli, blink magnitude was smaller during tactile change stimuli than during habituation stimuli. The latter finding was replicated in Experiment 2 in which blink was elicited by electrical stimulation of the trigeminal nerve. The consistency of the findings across different combinations of lead stimulus and blink-eliciting stimulus modalities does not support a modality-specific account of attentional blink modulation. Rather, blink modulation during generalized orienting reflects modality non-specific processes, although modulation may not always be found during tactile lead stimuli. (C) 2002 Elsevier Science B.V. All rights reserved.

Probing the time course of nonlinear discriminations during human electrodermal conditioning

Animal-based theories of Pavlovian conditioning propose that patterning discriminations are solved using unique cues or immediate configuring. Recent studies with humans, however, provided evidence that in positive and negative patterning two different rules are utilized. The present experiment was designed to provide further support for this proposal by tracking the time course of the allocation of cognitive resources. One group was trained in a positive patterning; schedule (A-, B-, AB+) and a second in a negative patterning schedule (A+, B+, AB-). Electrodermal responses and secondary task probe reaction time were measured. In negative patterning, reaction times were slower during reinforced stimuli than during non-reinforced stimuli at both probe positions while there were no differences in positive patterning. These results support the assumption that negative patterning is solved using a rule that is more complex and requires more resources than does the rule employed to solve positive patterning. (C) 2001 Elsevier Science (USA).

Effect of instructed extinction on verbal and autonomic indices of Pavlovian learning with fear-relevant and fear-irrelevant conditional stimuli

We investigated the effects of conditional stimulus fear-relevance and of instructed extinction on human Pavlovian conditioning as indexed by electrodermal responses and verbal ratings of conditional stimulus unpleasantness. Half of the participants (n = 64) were trained with pictures of snakes and spiders (fear-relevant) as conditional stimuli, whereas the others were trained with pictures of flowers and mushrooms (fear-irrelevant) in a differential aversive Pavlovian conditioning procedure. Half of the participants in each group were instructed after the completion of acquisition that no more unconditional stimuli were to be presented. Extinction of differential electrodermal responses required more trials after training with fear-relevant pictures. Moreover, there was some evidence that verbal instructions did not affect extinction of second interval electrodermal responses to fear-relevant pictures. However, neither fear-relevance nor instructions affected the changes in rated conditional stimulus pleasantness. This dissociation across measures is interpreted as reflecting renewal of Pavlovian learning.

Spontaneous and reflexive eye activity measures of mental workload

Measures of eye activity, such as blink rate and scanning patterns, have been used extensively as psychophysiological indices of mental workload. In a review of measures derived from spontaneous eye activity it is shown that different measures are differentially sensitive to specific aspects of mental workload. A less well-known measure of non-spontaneous eye activity, the blink reflex, is also reviewed. Experiments using discrete punctuate stimuli and continuous tasks analogous to real-world systems show that blink reflexes are modulated by attention and that this modulation reflects modality-specific attentional engagement. Future research should examine the utility of the blink reflex according to the desirable properties of sensitivity, diagnosticity, validity, reliability, ease of use, unobtrusiveness, and operator acceptance.