Granulocyte colony-stimulating factor and azole antifungal therapy in murine aspergillosis: role of immune suppression

Outbred ICR mice were immune suppressed either with hydrocortisone or with 5-fluorouracil and were infected intranasally with Aspergillus fumigatus. Beginning 3 days before infection some groups of mice were given recombinant human granulocyte colony-stimulating factor (G-CSF), SCH56592 (an antifungal triazole), or both. Corticosteroid-pretreated mice responded to SCH56592 and had reduced counts in lung tissue and prolonged survival. In these mice, G-CSF strongly antagonized the antifungal activity of SCH56592. Animals treated with both agents developed large lung abscesses with polymorphonuclear leukocytes and large amounts of Aspergillus. In contrast, mice made neutropenic with 5-fluorouracil and then infected with A. fumigatus conidia benefited from either G-CSF or triazoles, and the effect of the combination was additive rather than antagonistic. Host predisposing factors contribute in different ways to the outcome of growth factor therapy in aspergillosis.     

The effects of dietary yeast on the cellular immune response of Drosophila melanogaster against the larval parasitoid, Leptopilina boulardi

The role of dietary yeast in Drosophila melanogaster cellular immunity was investigated. Host larvae deprived of yeast immediately after parasitization by the cynipid wasp Leptopilina boulardi encapsulated a significantly lower percentage of the parasitoid's eggs than hosts transferred to a medium with yeast. When the transfers of hosts were made 24 hr after exposure to the parasite, diet had no effect on the immune response that had commenced prior to the transfers. This study demonstrates for the first time the effect of a specific dietary component on the immune responsiveness of Drosophila against a larval parasitoid.     

Trade-off associated with selection for increased ability to resist parasitoid attack in Drosophila melanogaster

Costs of resistance are widely assumed to be important in the evolution of parasite and pathogen defence in animals, but they have been demonstrated experimentally on very few occasions. Endoparasitoids are insects whose larvae develop inside the bodies of other insects where they defend themselves from attack by their hosts' immune systems (especially cellular encapsulation). Working with Drosophila melanogaster and its endoparasitoid Leptopilina boulardi, we selected for increased resistance in four replicate populations of flies. The percentage of flies surviving attack increased from about 0.5% to between 40% and 50% in five generations, revealing substantial additive genetic variation in resistance in the field population from which our culture was established. In comparison with four control lines, flies from selected lines suffered from lower larval survival under conditions of moderate to severe intraspecific competition.     

Organochlorine pesticide-induced oxidative stress and immune suppression in rats

OBJECTIVE: To investigate the different responses to antiretroviral treatment including zidovudine, of patients harbouring HIV with primary resistance to zidovudine, serum viral load, and CD4+ cell counts, for 24 weeks in a group of antiretroviral-naive patients with the codon 215 mutation of the HIV pol gene and in a control group at the start of treatment. DESIGN: A case-control retrospective study (1989-1996). METHOD: Nineteen out of 210 patients previously studied harboured the codon 215 mutation, had a self-reported compliance with treatment, a minimum follow-up of 24 weeks, and were treated with zidovudine alone or in combination with other nucleoside analogues. These patients were matched with 19 patients with wild-type strains at entry by initial CD4+ cell counts, clinical status, and antiretroviral treatment. RESULTS: During the first 12 weeks, CD4+ cell counts increased (76+/-26 and 64+/-26 x 10(6)/l in wild-type and mutant virus-infected groups, respectively), decreasing slightly until week 24, although no significant differences were found between the two groups studied. Serum viral load decreased in both groups (change in serum viral load of 0.80+/-0.11 log10 and 0.87+/-0.26 log10 copies/ml, wild-type and mutant virus-infected, respectively), although no significant differences were found between groups. CONCLUSION: No significant differences were found between patients with the primary mutation to zidovudine and control patients harbouring wild-type virus in terms of short-term response measured by serum viral load and CD4+ cell counts.     

Genetic controls of meiotic recombination and somatic DNA metabolism in Drosophila melanogaster

Recombination-defective meiotic mutants and mutagen-sensitive mutants of D. melanogaster have been examined for their effects on meiotic chromosome behavior, sensitivity to killing by mutagens, somatic chromosome integrity, and DNA repair processes. Several loci have been identified that specify functions that are necessary for both meiotic recombination and DNA repair processes, whereas mutants at combination and DNA repair processes, whereas mutants at other loci appear to be defective in only one pathway of DNA processing.     

Host immune suppression after small bowel/liver transplantation in rats

Biopsy samples from seven patients with acquired immunodeficiency syndrome were screened for Mycoplasma fermentans, M. pneumoniae and M. genitalium infection by the polymerase chain reaction. M. fermentans DNA was detected in four patients. Various tissues were evaluated and the mycoplasma were mainly detected from lymph nodes. Moreover, mycoplasma genus-specific DNA was isolated from peripheral blood mononuclear cells of asymptomatic human immunodeficiency virus(HIV)-infected individuals (two of 31 HIV-infected individuals). These data suggest that mycoplasma infection in AIDS patients is not uncommon.     

Hedgehog directly controls initiation and propagation of retinal differentiation in the Drosophila eye

Patterning of the compound eye begins at the posterior edge of the eye imaginal disc and progresses anteriorly toward the disc margin. The advancing front of ommatidial differentiation is marked by the morphogenetic furrow (MF). Here we show by clonal analysis that Hedgehog (Hh), secreted from two distinct populations of cells has two distinct functions: It was well documented that Hh expression in the differentiating photoreceptor cells drives the morphogenetic furrow. Now we show that, in addition, Hh, secreted from cells at the posterior disc margin, is absolutely required for the initiation of patterning and predisposes ommatidial precursor cells to enter ommatidial assembly later. These two functions of Hh in eye patterning are similar to the biphasic requirement for Sonic Hh in patterning of the ventral neural tube in vertebrates. We show further that Hh induces ommatidial development in the absence of its secondary signals Wingless (Wg) and Dpp and that the primary function of Dpp in MF initiation is the repression of wg, which prevents ommatidial differentiation. Our results show that the regulatory relationships between Hh, Dpp, and Wg in the eye are similar to those found in other imaginal discs such as the leg disc despite obvious differences in their modes of development.     

Frizzled signalling controls orientation of asymmetric sense organ precursor cell divisions in Drosophila

During metazoan development, cell-fate diversity is brought about, in part, by asymmetric cell divisions. In Drosophila, bristle mechanosensory organs are composed of four different cells that originate from a single precursor cell, pI, after two rounds of asymmetric division. At each division, distinct fates are conferred on sister cells by the asymmetric segregation of Numb, a negative regulator of Notch signalling. Here we show that the orientation of the mitotic spindles and the localization of the Numb crescent follow a stereotyped pattern. Mitosis of pI is orientated parallel to the anteroposterior axis of the fly. We show that signalling mediated by the Frizzled receptor polarizes pI along this axis, thereby specifying the orientation of the mitotic spindle and positioning the Numb crescent. The mitoses of the two cells produced by mitosis of pI are orientated parallel and orthogonal, respectively, to the division axis of pI. This difference in cell-division orientation is largely independent of the identity of the secondary precursor cells, and is regulated by Frizzled-independent mechanisms.     

The sex-ratio trait in Drosophila simulans: genetic analysis of distortion and suppression

The sex-ratio trait described in several Drosophila species is a type of naturally occurring X-linked meiotic drive that causes males bearing a sex-ratio X chromosome to produce progenies with a large excess of females. We have previously reported the occurrence of sex-ratio X chromosomes in Drosophila simulans. In this species, because of the co-occurrence of drive suppressors, the natural populations and the derived laboratory strains show an equal sex-ratio even when sex-ratio X chromosomes are present at a high frequency. The presence of sex-ratio X chromosomes is established via crosses with a standard strain that is devoid of drive suppressors. In this article, we show first that the sex-ratio trait in D. simulans results from the action of several X-linked loci. Second we describe drive suppressors on each major autosome as well as on the Y chromosome. The Y-linked factors suppress the drive partially whereas the autosomal suppression can be complete.     

A single point mutation controls the cholesterol dependence of Semliki Forest virus entry and exit

Hypergastrinaemia-associated changes of non-antral argyrophil cells in man are of increasing interest, because of the development of potent inhibitors of gastric acid secretion. Using an antibody against chromogranin A, we identified micronodular endocrine cell hyperplasia of the oxyntic mucosa in gastric biopsy specimens of patients with hypergastrinaemia of different backgrounds. Consecutive ultrathin sections were examined at the electron-microscopical level. Endocrine cell types within the (extraepithelial) micronodules closely resembled those in the adjacent mucosa. Micronodules were classified into two groups. The first group was composed of endocrine cells only and predominated in patients with drug-induced hypergastrinaemia and/or chronic gastritis, and in a gastrinoma/MEN I patient. The second group represented "neuroendocrine complexes", showing a close intermingling of non-myelinated nerve fibres with endocrine cells, and was found predominantly in pernicious anaemia. Micronodular argyrophil cell growth in man is therefore heterogeneous and depends on the background of the hypergastrinaemia.     

Integration of the head and trunk segmentation systems controls cephalic furrow formation in Drosophila

Genetic and molecular analyses of patterning of the Drosophila embryo have shown that the process of segmentation of the head is fundamentally different from the process of segmentation of the trunk. The cephalic furrow (CF), one of the first morphological manifestations of the patterning process, forms at the juxtaposition of these two patterning systems. We report here that the initial step in CF formation is a change in shape and apical positioning of a single row of cells. The anteroposterior position of these initiator cells may be defined by the overlapping expression of the head gap gene buttonhead (btd) and the primary pair-rule gene even-skipped (eve). Re-examination of the btd and eve phenotypes in live embryos indicated that both genes are required for CF formation. Further, Eve expression in initiator cells was found to be dependent upon btd activity. The control of eve expression by btd in these cells is the first indication of a new level of integrated regulation that interfaces the head and trunk segmentation systems. In conjunction with previous data on the btd and eve embryonic phenotypes, our results suggest that interaction between these two genes both controls initiation of a specific morphogenetic movement that separates two morphogenetic fields and contributes to patterning the hinge region that demarcates the procephalon from the segmented germ band.     

Brain vasopressin is involved in stress-induced suppression of immune function in the rat

A well-designed, adequately funded clinical trial based on sound science and conducted by experienced investigators and staff can falter if participating trial clinics are not managed well. Ten commandments for successful trial clinic management address key organizational and operational issues. Commandment I: Thou shalt know and follow thy rules. Commandment II: Thou shalt know and fulfill thy roles. Commandment III: Thou shalt meet thy commitments. Commandment IV: Thou shalt collaborate. Commandment V: Thou shalt communicate. Commandment VI: Thou shalt document. Commandment VII: Thou shalt honor thy participants. Commandment VIII: Thou shalt keep thy participants' secrets. Commandment IX: Thou shalt revere thy data. Commandment X: Thou shalt know and accept thy limitations. This report puts these commandments into context by providing concrete examples in the clinical trial setting. These commandments could serve as guidelines to the spectrum of personnel involved in the operations of a trial clinic, namely, principal investigators and co-investigators, trial coordinators, data managers, technicians, administrators, and support staff.     

A natural cytokine mixture (IRX-2) and interference with immune suppression induce immune mobilization and regression of head and neck cancer

Prior studies indicate that combination immunotherapy of squamous cell cancer (SCC) of head and neck (H&N) with cytokines is feasible (Hadden et al., 1994). To induce immune regression of H&N SCC 20 stage II-IV patients received 3 weeks prior to surgery low dose cyclophosphamide (300 mg/M2), then 10 daily perilymphatic injections of a natural cytokine mixture (IRX-2)(150 units of IL-2 equivalence) and daily oral indomethacin and zinc. Tumor responses, T-lymphocyte and subset counts, and toxicity were monitored. Six patients had major clinical responses (both complete [CR] and partial [PR]) without major toxicity. Five of 20 patients were lymphocytopenic (1242 +/- 88 mm3) prior to treatment and the immunotherapy induced marked significant increases in total lymphocyte counts, CD3+ T-cells, and both CD4+ and CD8+ T-cells as well as a population of CD3+, CD4-, and CD8- lymphocytes. The post treatment specimen of 18/20 patients showed histologically tumor fragmentation, overall reduction and diffuse infiltration with lymphocytes and plasma cells. Histologic tumor reductions in these patients averaged 44% and the lymphoid infiltration increased 4.7 fold from 9-42%. The immune infiltration of the tumor reflects varying degrees of both T- and B-cells and indicates immunization to the tumor. The immunization achieved may improve clinical control of H&N SCC by improving the possibility that surgical resection of advanced loco-regional disease will leave no viable tumor.     

Receptor-blocking factor present in immune serum resembling auto-anti-idiotype antibody

Previous studies have shown that rabbit antibody-forming cells in the primary and secondary response possess cell-associated antigen-binding receptors. In the present study, we demonstrate that a factor appears in the serum of rabbits following immunization which inhibits the antigen binding of up to 60% of the receptor-bearing antibody-forming cells in both the primary and secondary response. These observations were made on lymph node cells from rabbits primed with either sheep red blood cells (SRBC)3 or 3-nitro-4-hydroxy-5-iodophenylacetic acid coupled to keyhole limpet hemocyanin (NIP-KLH). The inhibitory activity is not associated with anti-SRBC or anti-NIP antibody. In the primary response to SRBC, the antigen binding by day 6 antibody-forming cells is inhibited by the autologous days 7 to 10 inactivated and absorbed serum. In the secondary response to SRBC, the inhibitory factor peaks in the serum around day 10. Later, in both the primary and secondary immune response to SRBC, the inhibitory activity of the serum decreases rapidly. In the primary response to NIP-KLH, the inhibitory activity of the immune sera increased from day 7 through day 14. The receptor-inhibiting factor is antigen specific since the serum from SRBC-primed rabbits inhibits SRBC binding by anti-SRBC antibody-forming cells, but it does not inhibit NIP binding by anti-NIP antibody-forming cells. Similarly, serum from NIP-KLH-primed rabbits inhibits NIP binding by anti-NIP antibody-forming cells, but does not inhibit the SRBC receptor on the anti-SRBC antibody-forming cells. The inhibition is not due to the presence of antihapten or anti-SRBC antibody competing with receptor sites, since the immune sera from one SRBC-primed animal inhibit antigen binding of its own antibody-forming cells, but do not inhibit the antigen binding of antibody-forming cells from other SRBC-primed rabbits.     

A single risk factor measurement predicts 35-year mortality from cardiovascular disease

Two Italian rural cohorts of men aged 40-59 years, were examined in 1960 within the Seven Countries Study of Cardiovascular Diseases and a total of 1712 men were enrolled (participation rate 98.8%). Cardiovascular risk factors were measured and 35-year follow-up made for vital status, mortality and cause of death. Cardiovascular diseases represented the first cause of death (46.2%), cancer the second (29.9%). The association between risk factors measured at baseline and the occurrence of cardiovascular deaths was tested by the use of multivariate functions (proportional hazards model in particular) which predict an event as a function of many possible factors. The predicted fatal events were, among men initially free of cardiovascular disease, coronary heart disease-restricted criteria (CHD-RC), coronary heart disease-broad criteria (CHD-BC), strokes (STR), and all cardiovascular diseases (CVD). The predicting variables were 21 risk factors of different nature. All models were highly discriminant between cases and non-cases. The predictivity of risk factors was assessed by testing the statistical significance of their multivariate coefficients, and by computing relative risks (expressed as hazards ratios) for standard differences in their levels. Age and systolic blood pressure produced significant coefficients and large hazards ratios in solutions for all end-points; cholesterol and cigarette smoking in three (not for STR); vital capacity (inverse relationship) and gerontoxon in two; physical activity (inverse relationship), forced expiratory volume (inverse relationship), urine glucose, family history of heart attack, and xanthelasma in one each. Marital status, family history of hypertension or diabetes, body mass index, skinfold thickness, arm circumference, shoulder-pelvis shape, laterality-linearity index, trunk-height ratio, and heart rate never provided a significant contribution to prediction. As an example, a difference of 20 mmHg in systolic blood pressure corresponds to a relative risk (excess risk) of 1.50 for CHD-RC, 1.46 for CHD-BC, 1.42 for STR and 1.43 for CVD; a difference of 40 mg/dl of serum cholesterol corresponds to relative risks of 1.38, 1.33, 1.13 and 1.25 respectively for the four end-points; a difference of 10 cigarettes smoked per day corresponds to relative risks of 1.19, 1.21, 1.06 and 1.17 respectively for the four end-points. The findings indicate that some cardiovascular risk factors measured once in middle age retain a long term association with prediction of future cardiovascular events, up to 35 years follow-up.