Defects in regulation of apoptosis in caspase-2-deficient mice

During embryonic development, a large number of cells die naturally to shape the new organism. Members of the caspase family of proteases are essential intracellular death effectors. Herein, we generated caspase-2-deficient mice to evaluate the requirement for this enzyme in various paradigms of apoptosis. Excess numbers of germ cells were endowed in ovaries of mutant mice and the oocytes were found to be resistant to cell death following exposure to chemotherapeutic drugs. Apoptosis mediated by granzyme B and perforin was defective in caspase-2-deficient B lymphoblasts. In contrast, cell death of motor neurons during development was accelerated in caspase-2-deficient mice. In addition, caspase-2-deficient sympathetic neurons underwent apoptosis more effectively than wild-type neurons when deprived of NGF. Thus, caspase-2 acts both as a positive and negative cell death effector, depending upon cell lineage and stage of development.     

Prevalences, genotypes, and risk factors for HIV transmission in South America

HIV cross-sectional studies were conducted among high-risk populations in 9 countries of South America. Enzyme-linked immunosorbent assay screening and Western blot confirmatory testing were performed, and env heteroduplex mobility assay genotyping and DNA sequencing were performed on a subset of HIV-positive subjects. HIV prevalences were highest among men who have sex with men (MSM; 2.0%-27.8%) and were found to be associated with multiple partners, noninjection drug use (non-IDU), and sexually transmitted infections (STIs). By comparison, much lower prevalences were noted among female commercial sex workers (FCSWs; 0%-6.3%) and were associated mainly with a prior IDU and STI history. Env subtype B predominated among MSM throughout the region (more than 90% of strains), whereas env subtype F predominated among FCSWs in Argentina and male commercial sex workers in Uruguay (more than 50% of strains). A renewed effort in controlling STIs, especially among MSM groups, could significantly lessen the impact of the HIV epidemic in South America.     

Effect of two thymosin fraction 5 polypeptides on human peripheral blood lymphocytes

Thymosin fraction 5 polypeptides beta 4 and alpha 1 were tested for their ability to affect certain immunological parameters of human peripheral blood lymphocytes (PBL). PBL were cultured with various concentrations of the peptides for 24 hours. Thymosin beta 4 was found to induce a significant decrease in the expression of the Fc alpha receptors of PBL, as well as in their ability to express antibody dependent cellular cytotoxic (ADCC) activity. In addition, this peptide had the ability to increase the percentage of T4 lymphocytes in normal and immunosuppressed donors and to decrease the percentage of T8 positive cells in normal donors. Finally, beta 4 peptide caused a small increase in the capacity of peripheral blood lymphocytes to form sheep red blood cell (SRBC) rosettes (ER). In parallel experiments thymosin alpha 1 was found inactive. The results presented here indicate that thymosin beta 4 may be used as an immunoregulatory molecule in patients with immunodeficiencies.     

Killing of Aspergillus fumigatus by alveolar macrophages is mediated by reactive oxidant intermediates

Phagocytosis and mechanisms of killing of Aspergillus fumigatus conidia by murine alveolar macrophages (AM), which are the main phagocytic cells of the innate immunity of the lung, were investigated. Engulfment of conidia by murine AM lasts 2 h. Killing of A. fumigatus conidia by AM begins after 6 h of phagocytosis. Swelling of the conidia inside the AM is a prerequisite for killing of conidia. The contributions of NADPH oxidase and inducible nitric oxide synthase to the conidicidal activity of AM were studied using AM from OF1, wild-type and congenic p47phox(-/-) 129Sv, and wild-type and congenic iNOS(-/-) C57BL/6 mice. AM from p47phox(-/-) mice were unable to kill A. fumigatus conidia. Inhibitors of NADPH oxidase that decreased the production of reactive oxidant intermediates inhibited the killing of A. fumigatus without altering the phagocytosis rate. In contrast to NADPH oxidase, nitric oxide synthase does not play a role in killing of conidia. Corticosteroids did not alter the internalization of conidia by AM but did inhibit the production of reactive oxidant intermediates and the killing of A. fumigatus conidia by AM. Impairment of production of reactive oxidant intermediates by corticosteroids is responsible for the development of invasive aspergillosis in immunosuppressed mice.     

Changes in EEG activity and hypothalamic temperature as indices for non-REM sleep to REM sleep transitions

A shift of physiological regulations from a homeostatic to a non-homeostatic modality characterizes the passage from non-NREM sleep (NREMS) to REM sleep (REMS). In the rat, an EEG index which allows the automatic scoring of transitions from NREMS to REMS has been proposed: the NREMS to REMS transition indicator value, NIV [J.H. Benington et al., Sleep 17 (1994) 28-36]. However, such transitions are not always followed by a REMS episode, but are often followed by an awakening. In the present study, the relationship between changes in EEG activity and hypothalamic temperature (Thy), taken as an index of autonomic activity, was studied within a window consisting of the 60s which precedes a state change from a consolidated NREMS episode. Furthermore, the probability that a transition would lead to REMS or wake was analysed. The results showed that, within this time window, both a modified NIV (NIV(60)) and the difference between Thy at the limits of the window (Thy(D)) were related to the probability of REMS onset. Both the relationship between the indices and the probability of REMS onset was sigmoid, the latter of which saturated at a probability level around 50-60%. The efficacy for the prediction of successful transitions from NREMS to REMS found using Thy(D) as an index supports the view that such a transition is a dynamic process where the physiological risk to enter REMS is weighted at a central level.     

Contribution of HLA class II genes to susceptibility in achalasia

Abstract: Achalasia is a motor disorder of the esophagus resulting in functional obstruction. The cause of the lesion is unknown although genetic and immunologic factors have been suggested. An association with serological HLA epitopes has been previously reported. In this study, we have further examined this HLA class II association with susceptibility to achalasia by DNA based methods. Achalasia patients ( n =40) and healthy controls ( n = 275), all Caucasians and unrelated, were included in the analysis. The strongest associations were with HLA-DQAl*0101 and two HLA-DQαβ heterodimers having their a chain encoded by this allele. Moreover, relative risk was significantly higher in DQAl*0101 homozygotes as compared to heterozygotes and results suggested that DQB1*02 may have a protective role.     

Presynaptic control of group Ia afferents in relation to acquisition of a visuo-motor skill in healthy humans

Sensory information continuously converges on the spinal cord during a variety of motor behaviours. Here, we examined presynaptic control of group Ia afferents in relation to acquisition of a novel motor skill. We tested whether repetition of two motor tasks with different degrees of difficulty, a novel visuo-motor task involving the ankle muscles, and a control task involving simple voluntary ankle movements, would induce changes in the size of the soleus H-reflex. The slope of the H-reflex recruitment curve and the H-max/M-max ratio were depressed after repetition of the visuo-motor skill task and returned to baseline after 10 min. No changes were observed after the control task. To elucidate the mechanisms contributing to the H-reflex depression, we measured the size of the long-latency depression of the soleus H-reflex evoked by peroneal nerve stimulation (D1 inhibition) and the size of the monosynaptic Ia facilitation of the soleus H-reflex evoked by femoral nerve stimulation. The D1 inhibition was increased and the femoral nerve facilitation was decreased following the visuo-motor skill task, suggesting an increase in presynaptic inhibition of Ia afferents. No changes were observed in the disynaptic reciprocal Ia inhibition. Somatosensory evoked potentials (SEPs) evoked by stimulation of the tibial nerve (TN) were also unchanged, suggesting that transmission in ascending pathways was unaltered following the visuo-motor skill task. Together these observations suggest that a selective presynaptic control of Ia afferents contributes to the modulation of sensory inputs during acquisition of a novel visuo-motor skill in healthy humans.     

Primary gastroesophageal-ileal hodgkin lymphoma

Primary Hodgkin lymphoma of the gastrointestinal tract is exceedingly rare to the point that some authors regard with skepticism the existence of this entity. Cases of gastrointestinal Hodgkin lymphoma have been reported previously; however, most of these cases represented secondary involvement of the digestive tract in the context of systemic disease. Other cases have been reclassified in retrospective studies as non-Hodgkin lymphomas after the application of immunohistochemical techniques. We report a case of primary Hodgkin lymphoma of the gastrointestinal tract in a patient who presented with obstructive symptoms at the site of a gastroileal bypass; the bypass had been performed years earlier because of morbid obesity. Some non-Hodgkin lymphomas may morphologically mimic Hodgkin lymphoma and vice versa; therefore, an accurate pathologic diagnosis is important, since the therapeutic approach and prognostic implications differ significantly for these diseases. In this context, immunohistochemistry should be used to confirm or to exclude the histologic diagnosis of Hodgkin lymphoma.