Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis

Protection from cytomegalovirus (CMV) disease in immunocompromised hosts has been shown to correlate with recovery of the host virus- specific CD8+ T-cell response. The administration of ganciclovir to immunosuppressed transplant recipients as antiviral prophylaxis has reduced the early risk of CMV disease, but late disease is observed with increased frequency, suggesting that recovery of the CMV-specific T-cell responses necessary for protective immunity may be delayed in these patients. Therefore, we evaluated reconstitution of CMV-specific T-cell responses in 47 bone marrow transplant (BMT) recipients entered on a randomized placebo-controlled study of ganciclovir. The study drug was initiated at a mean of 24 days after BMT. At day 30 to 40, a minority of patients had recovery of T-cell immunity to CMV and the frequency of reconstitution was equivalent in patients randomized to ganciclovir or placebo. The failure of ganciclovir to effect early reconstitution may reflect the short duration of treatment. Early recovery was associated with the infusion of BM from a CMV seropositive donor (P = .07 for CD8+ cytotoxic T cell (CTL), P = .04 for CD4+ Th). Between day 40 and day 90, recovery of deficient CD8+ and CD4+ CMV- specific T-cell responses occurred in the majority of individuals that received placebo, but in a minority of ganciclovir recipients. Two cases of late-onset CMV disease occurred in ganciclovir recipients. In all patients, the presence of a CTL response to CMV conferred protection from subsequent CMV disease (P = .005), and these protective CTL responses are shown to be specific for structural virion proteins similar to the responses in immunocompetent CMV seropositive individuals. These data confirm the importance of CMV-specific T-cell responses and suggest that a delay in recovery of these responses as a result of ganciclovir prophylaxis may contribute to the occurrence of late CMV disease.     

Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood

A newly recognized family of proteins that inhibit cyclin-dependent kinases (CDKs) termed cyclin-dependent kinase inhibitors (CDKI) have an important role in regulation of cell-cycle progression. A subfamily of these CDKIs (p15INK4B/MTS2, p16INK4/MTS1, and p18) have a high degree of structural and functional homology and are candidate tumor- suppressor genes. We evaluated the mutational status of the p15, p16, and p18 genes in 103 childhood acute lymphoblastic leukemia (ALL) samples and correlated these results with both their clinical data and additional results concerning their loss of heterozygosity in the region of the p15/p16 genes. Homozygous deletions of the p16 gene occurred extremely frequently in T-ALLs (17/22; 77%), and it was also frequent in precursor-B ALLs (12/81; 15%). Homozygous deletions of the p15 gene were also very frequent in T-ALLs (9/22; 41%), and it occurred in 5 of 81 (6%) precursor-B ALL samples. No deletions of p18 was found in any of the 103 ALL samples. Also, no point mutations of the p15, p16, and p18 genes were detected. We correlated p15/p16 alterations at diagnosis with their clinical characteristics as compared with 2,927 other patients treated similarly. Those with p15/p16 alterations were older; had higher white blood cell counts, often with T-cell ALL phenotype; and more frequently had a mediastinal mass at presentation; but they had the same nonremission, relapse, and survival rates at 5 years as did those patients whose blast cells did not have a p15/p16 deletion. To better understand the extent of alterations affecting chromosome 9p21 (location of the p15/p16 genes), loss of heterozygosity (LOH) was examined at D9S171, which is about 1 megabase proximal to the p15/p16 genes. LOH was detected in 15 of 37 (41%) informative samples. Interestingly, of the 24 informative samples that had no detectable alteration of the p15/p16 genes, 7 samples (29%) had LOH at D9S171. In summary, we show in a very large study that p15 and p16, but not p18, CDKI genes are very frequently altered in ALL; those with p15/p16 alterations are more frequently older children, have higher white blood cells at presentation, and often have a T-cell ALL phenotype. The LOH analysis suggests that another tumor-suppressor gene important in ALL also is present on chromosome 9p21.     

Proline metabolism in N2-fixing root nodules: energy transfer and regulation of purine synthesis.

N2-fixing root nodules of soybean (Glycine max L. Merr.) convert atmospheric N2 to ammonia(um) in an energy-intensive enzymatic reaction. These nodules synthesize large quantities of purines because nitrogen fixed by bacteria contained within this tissue is transferred to the shoots in the form of ureides, which are degradation products of purines. In animal systems, it has been proposed that proline biosynthesis by pyrroline-5-carboxylate reductase (P5CR) is used to generate the NADP+ required for the synthesis of the purine precursor ribose 5-phosphate. We have examined the levels, properties, and location of P5CR and proline dehydrogenase (ProDH) in soybean nodules. Nodule P5CR was found in the plant cytosol. Its activity was substantially higher than that reported for other animal and plant tissues and is 4-fold higher than in pea (Pisum sativum) nodules (which export amides). The Km for NADPH was lower by a factor of 25 than the Km for NADH, while the Vmax with NADPH was one-third of that with NADH. P5CR activity was diminished by NADP+ but not by proline. These characteristics are consistent with a role for P5CR in supporting nodule purine biosynthesis rather than in producing proline for incorporation into protein. ProDH activity was divided between the bacteroids and plant cytosol, but less than 2% was in the mitochondria-rich fractions. The specific activity of ProDH in soybean nodule bacteroids was comparable to that in rat liver mitochondria. In addition, we propose that some of the proline synthesized in the plant cytosol by P5CR is catabolized within the bacteroids by ProDH and that this represents a novel mechanism for transferring energy from the plant to its endosymbiont.     

Geschlechterunterschiede in der neuropsychiatrischen Pharmakotherapie

At least half of all patients with psychiatric disorders are female. Depressive disorders occur twice as often in women than in men. Despite the need for a gender-specific approach in treating psychiatric disorders, little is known about gender issues in psychopharmacology. It has been recognized that women respond better than men to serotonin-modulating substances but that this effect is reversed after menopause. Furthermore, women develop gynecological complications under medication with certain psychopharmacological agents which calls the use of these drugs into question. Side effects such as weight gain, hyperglycemia, cardiac arrhythmias, and sexual dysfunction also occur more frequently in women than in men. Pregnancy is a particularly sensitive aspect. The risk that a mother with a psychiatric disorder could relapse if the drug is discontinued has to be weighed against the risk of the child being born with an anomaly or developing prenatal complications.     

Abrupt tectonics and rapid slab detachment with grain damage

A simple model for necking and detachment of subducting slabs is developed to include the coupling between grain-sensitive rheology and grain-size evolution with damage. Necking is triggered by thickened buoyant crust entrained into a subduction zone, in which case grain damage accelerates necking and allows for relatively rapid slab detachment, i.e., within 1 My, depending on the size of the crustal plug. Thick continental crustal plugs can cause rapid necking while smaller plugs characteristic of ocean plateaux cause slower necking; oceanic lithosphere with normal or slightly thickened crust subducts without necking. The model potentially explains how large plateaux or continental crust drawn into subduction zones can cause slab loss and rapid changes in plate motion and/or induce abrupt continental rebound.Subduction of tectonic plates is widely recognized as the manifestation of a convecting mantle, i.e., where the cold convective thermal boundary layer at the Earth’s surface becomes heavy enough to sink (e.g., refs. 1 and 2). Subduction is similarly recognized for being the primary driving force for tectonic motions (3, 4) as well as controlling vertical displacements of continents in convergent margins (5, 6). Subducting slabs, however, can become detached from their originating plate, possibly by either a necking instability or by plastic or brittle failure (see refs. 7 and 8). Such detachment has been invoked to explain seismicity gaps and pinched tomographic features in slab structures (9, 10). However, slab detachment also has significant geodynamic consequences and may help account for precipitous tectonic events that are not readily explained by mantle convective motions (11). In particular, rapid loss of a slab from its connected plate could cause a sudden change in plate forces and hence abrupt change in plate motion. Likewise, slab loss below continents could account for instances of rapid uplift. In both cases, horizontal or vertical adjustments occur on the order of a few million years, which is much more rapid than the typical 10- to 100-My timescale for changes in convective circulation (i.e., typical transit times across the mantle).The trigger for slab loss must also be reasonably rapid and induce a change in the subducting system that causes it to neck or break off rather than continue subducting. One plausible trigger is the arrival of thick buoyant crust swept into the subduction zone, which would likely have little influence until its actual arrival; this would potentially impede subduction and introduce tensile stresses that could initiate detachment. This process could, for example, be associated with the arrival of thick oceanic plateaux (or midocean ridges) at subduction zones and subsequent changes in plate motion. For example, the collision of the Ontong Java Plateau with the Melanesian arc possibly curtailed subduction and caused a rotation of the Pacific plate at 6 Ma (12). Although highly speculative, ingestion of a plateau into the Aleutian trench at 50 Ma may have abruptly disrupted plate forces, causing the sudden change in plate motion associated with the Emperor-Hawaiian bend. Moreover, when thick continental crust is entrained into a subduction zone, the slab can also detach (13), and this is possibly associated with a rapid isostatic uplift of the overriding plate. This process is apparent in the correlation between the tectonic evolution of various margins with tomographic images of slabs (e.g., ref. 9). Slab detachment has thus been invoked to explain the topographic and tectonic changes at Vanuatu (14), the Alps and the Aegean (13), the Dabie shan (15), the Pannonian Basin (16), Central America (10), Borneo (17), Anatolia (18, 19), Taiwan (20), East Timor (21), the Appenines (22), and during the Messinian Event (23, 24).The first numerical models of slab detachment, based on diffusion and dislocation creep rheologies for olivine, found that the slab was too cold and stiff to detach in the short timescale implied by geological observations (25). More recent studies, however (7, 8), were able to obtain more rapid detachment, but required a power-law behavior in excess of normal dislocation creep, and/or a combination of multiple lithologic layers with various self-weakening effects (non-Newtonian behavior, shear heating, brittle failure, and sediment ingestion).We propose a simple model for rapid slab detachment that combines triggering by entrainment of buoyant crust, and a rapid necking mechanism facilitated by the coupling of grain-sensitive rheology and grain-size evolution with damage (26–31). In particular, grain reduction and weakening by the combination of damage and Zener pinning in a multiphase mineralogical assemblage, which is consistent with field and laboratory observations of polycrystalline rocks (27), allows rapid necking and thus abrupt detachment. The stress drop in the slab during detachment also provides an estimate for how quickly the slab decouples from the surface and changes plate forces and/or loading for continental subsidence. With a sufficiently large buoyant crustal plug and substantial damage, rapid necking occurs on the order of 1 My; this suggests that the introduction of large ocean plateaux or continental crust into convergent margins can trigger precipitous detachment, and thus abrupt horizontal or vertical changes in tectonic motion.     

Phylogenetic analysis of <Emphasis Type="Italic">Wheat dwarf virus</Emphasis> isolates from Iran

Wheat dwarf virus (WDV) adversely affects cereal production in Asia, Europe, and North Africa. In this study, sequences of several WDV isolates from Iran which is located in the Fertile Crescent were analyzed. Analysis revealed a new geographic cluster for WDV-Wheat from Iran. Recombination analysis demonstrated the existence of several breakpoints in different regions of the viral genome. Data analysis demonstrated that WDV-Barley has an older history and lower diversity than WDV-Wheat. Sequence analysis identified a rare occasion of a co-infection of wheat with WDV-Wheat and WDV-Barley.