Magnetization Transfer and T2 Relaxation Components in Tissue

T₂ relaxation makes an important contribution to tissue contrast in magnetic resonance (MR) imaging. Many tissues are known to exhibit multicomponent T₂ relaxation that suggests some compartmental segregation of mobile protons on a T₂ timescale. Magnetization transfer (MT) is another relaxation mechanism that can be used to produce tissue contrast in MR imaging. The MT process depends strongly on water-macromolecular interactions. To investigate the relationship between multicomponent T₂ relaxation and the MT process, multiecho T₂ measurements have been combined with MT measurements for freshly excised samples of cardiac muscle, striated muscle, and white matter. For muscle, short T₂ components show greater MT than long T₂ components, consistent with the belief that they represent distinct water environments. For white matter, quantitative MT measurements were identical for the two major T₂ components, apparently because of exchange between the T₂ compartments on a timescale characteristic of the MT experiment. Implications for accurate modeling of MT in tissue and the use of MT for MR image contrast are discussed.     

Detection of chromosomes and estimation of aneuploidy in human spermatozoa using fluorescence in-situ hybridization

The development and application of fluorescence in-situ hybridization (FISH) has opened the way for comprehensive studies on numerical chromosome abnormalities in human spermatozoa. FISH can be rapidly applied to large numbers of spermatozoa and thus overcomes the major limitation of karyotyping spermatozoa after penetration of zona-free hamster oocytes. The simultaneous hybridization of two or more chromosome-specific probes to spermatozoa and subsequent detection of the bound probes using different fluorescent detection systems enables two or more chromosomes to be localized simultaneously in the same spermatozoon and provides a technique for undertaking reasonable estimates of aneuploidy. The most commonly used probes are those which bind to the centromeric region of specific chromosomes. Most studies to date have concentrated on estimating aneuploidy in spermatozoa from normospermic men, although reports are beginning to appear on aneuploidy in spermatozoa from subfertile and infertile men. Multi- probe FISH studies have generally reported disomy (hyperhaploidy) estimates of 0.05-0.2% per chromosome. There is preliminary evidence that some chromosomes such as X, Y and 21 are predisposed towards higher rates of non-disjunction during spermatogenesis. There are also suggestions of inter-donor variability in aneuploidy frequencies for specific chromosomes, although this requires confirmation in larger studies. While FISH is clearly a powerful technique that has many applications in reproductive medicine, it must also be realized that it does have limitations and the technology itself is still evolving and has yet to be fully validated on spermatozoa.      

Reactions of Musca domestica L. (Diptera: Muscidae) to parasitism by Aphaereta pallipes (Say) (Hymenoptera: Braconidae), with special reference to host diet and parasitoid toxin

Summary Varying host reaction of the house fly, Musca domestica L., to parasitism by the braconid Aphaereta pallipes (Say) was chiefly correlated with the diet of the host. Some evidence was found that implicated the strain of the host, the rearing temperatures, the ages of the parasitoid and the host, and the site of oviposition. Though development of A. pallipes embryos was inhibited before they became encapsulated with melanin within the host, the presence of the parasitoid and (or) the effect of its paralyzing toxin that was injected into the host just before oviposition prevented normal larval, pupal, or adult development of the six house fly strains tested. A considerable increase of parasitoid survival occurred when M. domestica larvae were reared on a chemically defined diet.

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Zusammenfassung Musca domestica L. reagierte unterschiedlich auf die Parasitierung durch die Braconide Aphaereta pallipes (Say). Die verschiedenen Reaktionen waren im wesentlichen mit der Art der Wirtsnahrung korreliert. Daneben finden sich Hinweise, daß auch der Wirtsstamm, dessen Zuchttemperatur, das Alter von Parasit und Wirt und der Eiablageort des Parasiten die Reaktionen beeinflussen. Obgleich die Entwicklung von Parasitenembryonen bereits gehemmt war, ehe sie innerhalb des Wirtes von Melanin eingeschlossen wurden, so verhinderten doch die Parasiten-embryonen und/oder die Wirkung der vor der Eiablage abgegebenen Paralysierungstoxine die normale Entwicklung der Wirte aus sechs Fliegenstämmen. Eine beträchtliche Steigerung der Überlebensrate der Parasiten trat ein, wenn M. domestica-Larven in einem Gemisch chemisch genau definierter Nahrung gezogen wurden.

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With 8 Figures in the Text

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Formerly National Research Council Postdoctorate Fellow, Research Institute, Belleville, Ontario.     

A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma

We examined the relationship between a functional polymorphism (667C-- >T, ala-->val) of the methylenetetrahydrofolate reductase gene (MTHFR) and the risk of colorectal adenomas in the prospective Nurses' Health Study. Among 257 incident polyp cases and 713 controls, the MTHFR val/val polymorphism [relative risk (RR) = 1.35, 95% confidence interval (CI) 0.84-2.17] was not significantly associated with risk of adenomas. This lack of association was observed for both small (RR = 1.36, 95% CI 0.76-2.45) and large (RR = 1.32, 95% CI 0.66-2.66) adenomas. Furthermore, there was no significant interaction between this polymorphism and consumption of either folate, methionine or alcohol. We also examined the relationship of a newly identified polymorphism (asp919gly) of the methionine synthase gene (MS) with the risk of colorectal adenomas in the same population. The MS gly/gly polymorphism was also not significantly associated with risk of colorectal adenomas (RR = 0.66, 95% CI 0.26-1.70). These results, which need to be confirmed in other studies, suggest that the MTHFR val/val polymorphism, which has been previously inversely associated with risk of colorectal cancer, plays a role only in a late stage (adenoma-- >carcinoma) of colorectal tumorigenesis, and/or may protect against malignant transformation in the subset of benign adenomas, which may progress to malignancy.      

Use of angiotensin-converting enzyme inhibitor therapy and dose-related outcomes in older adults with new heart failure in the community

OBJECTIVE: To evaluate the dose-related benefit of angiotensin-converting enzyme (ACE) inhibitor therapy among older adults with heart failure and to evaluate whether low-dose ACE inhibitor therapy is better than none. DESIGN: Observational cohort study. SETTING: Community-dwelling older adults in Ontario, Canada. PATIENTS/PARTICIPANTS: We identified 16539 adults 66 years or older who survived 45 days following their first heart failure hospitalization discharge. MEASUREMENT AND MAIN RESULTS: Multivariate techniques including propensity scores were used to study the association between the dose of ACE inhibitor therapy dispensed and 3 outcomes: survival, survival or heart failure rehospitalization, and survival or all-cause hospitalization at 1 year of follow-up. Logistic regression models explored the association between initial dose dispensed and subsequent dose reduction or drug cessation. Overall, 10793 (65.3%) of patients were dispensed ACE inhibitor therapy, with more than a third (3935; 36.5%) initiated on low-dose therapy. Relative to dispensing of low-dose ACE inhibitor therapy, nonuse was associated with increased mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.02 to 1.22). Dispensing medium-dose therapy provided a benefit similar to low-dose (HR, 0.94; CI, 0.86 to 1.03) and dispensing of high-dose therapy was associated with improved survival benefit (HR, 0.76; CI, 0.68 to 0.85). Relative to dispensing of low-dose ACE inhibitor therapy, dispensing high-dose conferred a benefit (HR, 0.87; CI, 0.80 to 0.95) on the composite outcome of 1-year mortality or heart failure hospitalization and the composite outcome of 1-year mortality or all-cause hospitalization (HR, 0.87; CI, 0.81 to 0.93). Relative to those dispensed low-dose ACE inhibitor therapy, those initially dispensed high-dose therapy were twice as likely to have their subsequent dose reduced or the therapy discontinued (odds ratio, 2.36; CI, 2.07 to 2.69). CONCLUSION: Our findings suggest that when possible, older adults should be titrated to the higher doses of ACE inhibitor therapy evaluated in clinical trials. If older adults cannot tolerate higher doses, then low-dose ACE inhibitor therapy is superior to none. High-dose ACE inhibitor therapy is not as well tolerated as lower doses.     

Transforming growth factor beta (TGF-beta), a potent inhibitor of erythropoiesis: neutralizing TGF-beta antibodies show erythropoietin as a potent stimulator of murine burst-forming unit erythroid colony formation in the absence of a burst-promoting activity

Transforming growth factor beta (TGF-beta) is a bifunctional regulator of the growth of myeloid progenitors and is here demonstrated to directly inhibit the growth of primitive erythroid progenitors by 95% to 100% regardless of the cytokines stimulating growth. Autocrine TGF- beta production of primitive hematopoietic progenitors has previously been reported. In the present study, a neutralizing TGF-beta antibody (anti-TGF-beta) added to serum-containing cultures, resulted in a 3-, 4- , and 25-fold increase in burst-forming unit erythroid (BFU-E) colony formation in response to interleukin-4 (IL-4) plus erythropoietin (Epo), SCF plus Epo, and IL-11 plus Epo, respectively. The growth of BFU-E progenitors has been suggested to require a burst-promoting activity in addition to Epo. Accordingly, we observed no BFU-E colony formation in serum-containing cultures in response to Epo alone. In contrast, 50 BFU-E colonies were formed when anti-TGF-beta was included in the culture. In serum-free cultures, Epo also stimulated BFU-E colony formation in the absence of other cytokines, whereas anti-TGF- beta had no effect on the number of colonies formed. Quantitation of TGF-beta 1 in serum by an enzyme-linked immunosorbent assay method showed predominantly the presence of precursor (latent) TGF-beta 1, but also showed active TGF-beta 1 at a concentration sufficient to potently inhibit erythroid colony formation. Thus, neutralization of active TGF- beta 1 in serum shows that Epo alone is sufficient to stimulate the growth of murine BFU-E progenitors.