Acquired immunity and epidemiology of Schistosoma haematobium

Human immune responses to schistosome infection have been characterized in detail. But there has been controversy over the relative importance of ecological factors (variation in exposure to infection) and immunological factors (acquired immunity) in determining the relationships between levels of infection and age typically found in areas where infection is endemic. Independent effects of exposure and age on the rates of reinfection with Schistosoma haematobium after chemotherapy have been demonstrated in the Gambia and Zimbabwe. This age effect could be the result of acquired immunity to infection. Indeed, allowing for variation in exposure and age, low rates of reinfection in the Gambia are correlated with high amounts of specific IgE antibodies--human IgE can kill S. mansoni schistosomulae in vitro. Further, animals can acquire immunologically mediated resistance to S. mansoni infection, although nonimmunological factors could also be involved. Acquisition of this immunity seems to be related to the cumulative effects of repeated infection and provides only partial protection. These characteristics are consistent with immuno-epidemiological data for both S. mansoni and S. haematobium infections of humans. We have now analysed age-prevalence data for human infection with S. haematobium, and find patterns of variation that are indeed consistent with the epidemiological effects of acquired immunity predicted by mathematical models.     

Cyclosporine is angiostatic

The systemic effect of the immunosuppressive drug cyclosporine (CS) on formation of new blood vessels was studied quantitatively in rats using the mesenteric-window assay. Angiogenesis was induced by i.p. injection of saline. CS at a s.c. dose of 4 mg/kg/day, which is in the range used clinically, suppressed angiogenesis (inhibiting branching or tortuosity more than spatial expansion), and appeared to be non-toxic. This is the first report on an apparently selective angiostatic effect of CS. The finding is likely to have implications for the clinical use of CS, not only in certain types of organ transplantation but possibly also in psoriasis and other angiogenesis-dependent diseases.     

Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.

The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.     

Age distribution of circulatingα-interferon

Summary A sensitive radioimmunoassay showed that circulating -interferon in the plasma of healthy individuals was low in children and reached the highest level in the young adult, then declined gradually with age. Circulating -interferon was 0.201±0.059 ng/ml in males (n=19) and 0.184±0.076 ng/ml in females (n=14) at ages 30–39 years old. It was noted that circulating -interferon was maintained up to a certain level even in elderly individuals.     

Failure of opioids to affect excitation and contraction in isolated ventricular heart muscle

Summary The opioid agonists morphine (selective for -receptors) and ethylketocyclazocine (selective for kappa-receptors), at concentrations evoking strong effects in neuronal structures, did not significantly affect the configuration of the intracellularly recorded action potential and the force of contraction in ventricular heart muscle isolated from guinea pigs, rabbits and man. These results suggest that any changes of heart functions in vivo in response to opioid-like drugs are probably not mediated postsynaptically at the myocardial cell membrane but rather presynaptically, influencing the release of noradrenaline and/or acetylcholine from the nerve terminals.     

Goniothalamicin and annonacin: Bioactive acetogenins fromGoniothalamus giganteus (Annonaceae)

Summary Using brine shrimp lethality for activity-directed fractionation, goniothalamicin (I), a new tetrahydroxy-mono-tetrahydrofuran fatty acid -lactone (acetogenin), has been isolated from ethanolic extracts of the stem bark ofGoniothalamus giganteus Hook. f., Thomas (Annonaceae). This novel compound was found to be cytotoxic and insecticidal and inhibited the formation of crown gall tumors on potato discs. Annonacin (II), the only other reported mono-tetrahydrofuran acetogenin, was also isolated; the previously reported 9ASK (astrocytoma reversal) activity ofII was confirmed, andII is now also found to be weakly active against 3PS murine leukemia.     

Pharmacodynamic profile of CQP 201-403, a novel 8α-amino-ergoline

Summary The profile of action in animals of CQP 201-403, a novel 8-amino-ergoline, is in most aspects that of a very potent dopaminomimetic, both as a prolactin secretion inhibitor, and at the levels of the CNS and the cardiovascular system. Qualitatively CQP 201-403 differs slightly from bromocriptine and apomorphine in its effects on the CNS (no influence on serotonin metabolism in the rat cortex; induction of masculine mounting behavior in rats) and the cardiovascular system of the dog (reflex tachycardia in response to a blood-pressure fall). In man the new compound proved to be highly active in lowering prolactin serum levels and to be more potent than bromocriptine (Parlodel^®).In memory of Dr Annemarie Closse, who died 14 June 1987.     

Definition of a consensus binding site for p53.

Recent experiments have suggested that p53 action may be mediated through its interaction with DNA. We have now identified 18 human genomic clones that bind to p53 in vitro. Precise mapping of the binding sequences within these clones revealed a consensus binding site with a striking internal symmetry, consisting of two copies of the 10 base pair motif 5'-PuPuPuC(A/T)(T/A)GPyPyPy-3' separated by 0-13 base pairs. One copy of the motif was insufficient for binding, and subtle alterations of the motif, even when present in multiple copies, resulted in loss of affinity for p53. Mutants of p53, representing each of the four "hot spots" frequently altered in human cancers, failed to bind to the consensus dimer. These results define the DNA sequence elements with which p53 interacts in vitro and which may be important for p53 action in vivo.     

Heterogeneous responses of canine basilar and middle cerebral arteries to serotonin at normal and high CO2 tension

The responses of basilar arteries (BAs) to serotonin were attenuated by high \(P_{CO_2 } \) (86±1 mm Hg) and the pH matched acidotic solution ( \(P_{CO_2 } \) 37±1 mm Hg), whereas the responses of middle cerebral arteries (MCAs) were not. High \(P_{CO_2 } \) decreased the basal tone of both arteries, and the changes in basal tone due to high \(P_{CO_2 } \) were not influenced by 3×10^?7 M imipramine, 10^?5 M pargyline or 10^?4 M aspirin. The responses of BAs to serotonin were attenuated by high \(P_{CO_2 } \) in the presence of imipramine, pargyline and aspirin. The responses of MCAs to serotonin were not influenced by high \(P_{CO_2 } \) in the presence of pargyline and aspirin, but attenuated by high \(P_{CO_2 } \) in the presence of imipramine.     

The life span of the biosphere revisited

A decade ago, Lovelock and Whitfield raised the question of how much longer the biosphere can survive on Earth. They pointed out that, despite the current fossil-fuel induced increase in the atmospheric CO2 concentration, the long-term trend should be in the opposite direction: as increased solar luminosity warms the Earth, silicate rocks should weather more readily, causing atmospheric CO2 to decrease. In their model, atmospheric CO2 falls below the critical level for C3 photosynthesis, 150 parts per million (p.p.m.), in only 100 Myr, and this is assumed to mark the demise of the biosphere as a whole. Here, we re-examine this problem using a more elaborate model that includes a more accurate treatment of the greenhouse effect of CO2, a biologically mediated weathering parameterization, and the realization that C4 photosynthesis can persist to much lower concentrations of atmospheric CO2(<10 p.p.m.). We find that a C4-plant-based biosphere could survive for at least another 0.9 Gyr to 1.5 Gyr after the present time, depending respectively on whether CO2 or temperature is the limiting factor. Within an additional 1 Gyr, Earth may lose its water to space, thereby following the path of its sister planet, Venus.