Unrelated donor bone marrow transplantation: influence of HLA A and B incompatibility on outcome

We have studied the outcome of 211 consecutive unrelated donor (URD) bone marrow transplants (BMT) performed at the University of Minnesota (Minneapolis, MN) between May 1985 and December 1992. Ninety patients (43%) received marrow matched serologically at HLA A, B, and DR loci; 86 (41%) received marrow with a major and 32 (15%) marrow with a minor serologic mismatch at the HLA A or B locus. Multivariate analysis revealed that older age had an adverse effect on survival. In younger (age less than 18 years) recipients, survival after fully matched (A, B, and DR sub-type) or major mismatched (A or B locus), DR subtype- matched donor BMT was not significantly different (P = .4; survival: 53% v 41%, respectively, at 3 years). For adults, survival after matched donor BMT was significantly better than that with mismatched donors (P < .01; survival: 30% v 10%, respectively, at 3 years). Formal quality of life assessment by telephone interview demonstrated similar functional status in survivors of URD and related donor (RD) BMT at least 2 years post-BMT. URD BMT provides effective therapy for a variety of lethal hematopoietic diseases that rivals outcome of RD transplant in some cases. Use of URD marrow with a major mismatch at one HLA A or B locus is well tolerated in young, but not in older, recipients. These observations should be used to improve donor selection and counseling for URD BMT candidates.     

糖皮质激素在炎症性肠病中的应用

炎症性肠病(IBD)是糖皮质激素(简称激素)治疗的适应证.IBD包括溃疡性结肠炎(UC)和克罗恩病(CD).对UC患者,激素可经静脉、口服、直肠灌注或栓剂给药.直肠灌注或栓剂的成分可以是传统使用的激素、布地奈德或人体生物利用度低的其他激素.对CD患者,传统使用的激素可以口服给药,亦可静脉给药.布地奈德可以口服.     

Modelling the force of infection for hepatitis B and hepatitis C in injecting drug users in England and Wales

Background  

Injecting drug use is a key risk factor, for several infections of public health importance, especially hepatitis B (HBV) and hepatitis C (HCV). In England and Wales, where less than 1% of the population are likely to be injecting drug users (IDUs), approximately 38% of laboratory reports of HBV, and 95% of HCV reports are attributed to injecting drug use.     

Carbon monoxide is a rapid modulator of recombinant and native P2X2 ligand-gated ion channels

Background and purpose:

Carbon monoxide (CO) is a potent modulator of a wide variety of physiological processes, including sensory signal transduction. Many afferent sensory pathways are dependent upon purinergic neurotransmission, but direct modulation of the P2X purinoceptors by this important, endogenously produced gas has never been investigated.

Experimental approach:

Whole-cell patch-clamp experiments were used to measure ATP-elicited currents in human embryonic kidney 293 cells heterologously expressing P2X₂, P2X₃, P2X_2/3 and P2X₄ receptors and in rat pheochromocytoma (PC12) cells known to express native P2X₂ receptors. Modulation was investigated using solutions containing CO gas and the CO donor molecule, tricarbonyldichlororuthenium (II) dimer (CORM-2).

Key results:

CO was a potent and selective modulator of native P2X₂ receptors, and these effects were mimicked by a CO donor (CORM-2). Neither pre-incubation with 8-bromoguanosine-3′,5′-cyclomonophosphate nor 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (a potent blocker of soluble guanylyl cyclase) affected the ability of the CO donor to enhance the ATP-evoked P2X₂ currents. The CO donor caused a small, but significant inhibition of currents evoked by P2X_2/3 and P2X₄ receptors, but was without effect on P2X₃ receptors.

Conclusions and implications:

These data provided an explanation for how CO might regulate sensory neuronal traffic in physiological reflexes such as systemic oxygen sensing but also showed that CO could be used as a selective pharmacological tool to assess the involvement of homomeric P2X₂ receptors in physiological systems.     

Histamine H1 receptor blockade predominantly impairs sensory processes in human sensorimotor performance

Background and purpose:

Centrally active antihistamines impair cognitive performance, particularly sensorimotor performance. The aim of the present study was to further elucidate the scarcely studied subprocesses involved in sensorimotor performance, which may be affected by H₁ receptor blockade. Better knowledge about the cognitive deficits associated with histamine dysfunction can contribute to better treatment of clinical disorders in which histamine hypofunction may be a contributing factor, such as in schizophrenia.

Experimental approach:

Interactions of dexchlorpheniramine with specific task manipulations in a choice reaction time task were studied. Task demands were increased at the level of sensory subprocesses by decreasing stimulus quality, and at the level of motor subprocesses by increasing response complexity. A total of 18 healthy volunteers (9 female) aged between 18 and 45 years participated in a three-way, double-blind, crossover design. Treatments were single oral doses of 4 mg dexchlorpheniramine, 1 mg lorazepam and placebo. Behavioural effects were assessed by measuring reaction times and effects on brain activity by event-related potentials.

Key results:

Dexchlorpheniramine significantly slowed reaction times, but did not significantly interact with task manipulations. However, it did significantly interact with stimulus quality, as measured by event-related potentials. Lorazepam slowed reaction times and interacted with perceptual manipulations, as shown by effects on reaction times.

Conclusions and implications:

The results confirm that the histamine system is involved in sensory information processing and show that H₁ blockade does not affect motoric information processing. Histamine hypofunction in clinical disorders may cause impaired sensory processing, which may be a drug target.     

Age differences in target detection and interference resolution in working memory: an event-related potential study

There is growing consensus that a decline in attentional control is a core aspect of cognitive aging. We used event-related potentials to examine the time course of attentional control in older and younger adults as they attempted to resolve familiarity-based and response-based interference during a working memory task. Accuracy was high for both groups but their neural response to targets and to distracters was markedly different. Young adults' early target selection was evident by 300 msec in a differentiated P3a and they responded to interference by generating a medial frontal negativity (MFN) to distracters by 450 msec that was largest when the need for interference resolution was greatest. Dipole source analyses revealed a temporal coactivation of the inferior frontal and anterior cingulate cortex in younger adults, suggesting that these regions may interact during interference resolution. Older adults did not show the early target-selective P3a effect and failed to subsequently produce the MFN in response to distracting stimuli. In fact, older adults showed a large frontal positivity in place of the MFN but, rather than serve a compensatory role, this frontal activation was associated with poorer behavioral performance. These data suggest that aging interferes with a dynamic interplay of early target selection followed by later suppression of distracter-related neural activity--a process central to the efficient control of attention.     

Design and pharmacological activity of phosphinic acid based NAALADase inhibitors.

A novel series of phosphinic acid based inhibitors of the neuropeptidase NAALADase are described in this work. This series of compounds is the most potent series of inhibitors of the enzyme described to date. In addition, we have shown that these compounds are protective in animal models of neurodegeneration. Compound 34 significantly prevented neurodegeneration in a middle cerebral artery occlusion model of cerebral ischemia. In addition, in the chronic constrictive model of neuropathic pain, compound 34 significantly attenuated the hypersensitivity observed with saline-treated animals. These data suggest that NAALADase inhibition may provide a new approach for the treatment of both neurodegenerative disorders and peripheral neuropathies.