Cell-mediated immune responses to artificial food additives in chronic urticaria

In some cases of chronic urticaria it is suspected that food additives such as tartrazine and sodium benzoate or salicylates may play a role in the pathogenesis of the condition. Since, at times, chronic urticaria may appear histologically similar to a mild cell-mediated immune response, the release of the T cell-derived lymphokine leucocyte inhibitory factor (LIF), in response to incubation with these additives and with acetylsalicylic acid (ASA), was measured in vitro using cells from normal controls, from patients with chronic urticaria with or without clinically associated additive sensitivity and from patients with asthma with or without associated ASA sensitivity. It was found that significant production of LIF occurred in response to tartrazine and sodium benzoate in those individuals with chronic additive induced urticaria. In addition, tartrazine caused LIF release from mononuclear cells of ASA-sensitive asthmatics. These results may indicate a possible role for additive-induced cell-mediated immune responses in the pathogenesis of some cases of chronic urticaria and suggest a potential diagnostic test for this condition.     

Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney

We evaluated the effect of age on CYP3A expression and function in the liver, intestine, and kidney from young (3-4 months), intermediate (13-14 months), and old (25-26 months) male Fischer-344 rats. The biotransformation of triazolam to its primary hydroxylated products, 4-OH-TRZ (triazolam) and alpha-OH-TRZ, was used as a marker of CYP3A activity in rat liver and intestine. Immunoactive CYP3A expression was evaluated by Western blot analysis in the rat intestine, liver, and kidney. Since testosterone and NADPH reductase levels may modulate CYP3A activity, we also examined free plasma testosterone concentrations and NADPH reductase expression in these rats. The effect of age on CYP3A expression was tissue-specific. Although both CYP3A activity and expression were reduced by approximately 50 to 70% in the old livers compared with the young animals, intestinal CYP3A activity and expression did not change significantly with age. The expression of one CYP3A isoform was increased by 1.5-fold in the old kidneys. NADPH reductase expression was reduced by 23 to 36% with age in all tissues; this reached statistical significance only in the liver. Plasma testosterone levels declined by 74% in the old animals. This study suggests that the effect of age on CYP3A expression and function is tissue-specific. In addition, changes in testosterone levels and NADPH reductase expression may contribute to age-related differences in hepatic CYP3A activity.     

Dopamine Function in Cigarette Smokers: An [18F]-DOPA PET Study

Tobacco addiction is a global public health problem. Addiction to tobacco is thought to involve the effects of nicotine on the dopaminergic system. Only one study has previously investigated dopamine synthesis capacity in cigarette smokers. This study, exclusively in male volunteers, reported increased dopamine synthesis capacity in heavy smokers compared with non-smokers. We sought to determine whether dopamine synthesis capacity was elevated in a larger sample of cigarette smokers that included females. Dopamine synthesis capacity was measured in 15 daily moderate smokers with 15 sex- and age-matched control subjects who had never smoked tobacco. Dopamine synthesis capacity (indexed as the influx rate constant K_i^cer) was measured with positron emission tomography and 3,4-dihydroxy-6-[¹⁸F]-fluoro-l-phenylalanine. There was no significant group difference in dopamine synthesis capacity between smokers and non-smoker controls in the whole striatum (t₂₈=0.64, p=0.53) or any of its functional subdivisions. In smokers, there were no significant relationships between the number of cigarettes smoked per day and dopamine synthesis capacity in the whole striatum (r=−0.23, p=0.41) or any striatal subdivision. These findings indicate that moderate smoking is not associated with altered striatal dopamine synthesis capacity.     

Killer cell immunoglobulin receptor profile on CD4+ CD28− T cells and their pathogenic role in non‐dialysis‐dependent and dialysis‐dependent chronic kidney disease patients

There is a progressive increase in cardiovascular disease with declining renal function, unexplained by traditional risk factors. A CD4⁺ T-cell subpopulation (CD4⁺ CD28⁻), activated by human heat-shock protein 60 (hHSP 60), expands in patients with acute coronary syndrome and is associated with vascular damage. These cells exhibit cytotoxicity via expression of activating killer cell-immunoglobulin-like receptor KIR2DS2, mainly in the absence of inhibitory KIR2DL3. We investigated expansion of these cells and the pathogenic role of the KIR in non-dialysis-dependent chronic kidney disease (NDD-CKD) and end-stage haemodialysis-dependent renal disease (HD-ESRD) patients. CD4⁺ CD28⁻ cells were present in 27% of the NDD-CKD and HD-ESRD patients (8–11% and 10–11% of CD4⁺ compartment, respectively). CD4⁺ CD28⁻ cells were phenotyped for KIR and DAP12 expression. Cytotoxicity was assessed by perforin and pro-inflammatory function by interferon-γ expression on CD4⁺ CD28⁻ clones (NDD-CKD n = 97, HD-ESRD n = 262). Thirty-four per cent of the CD4⁺ CD28⁻ cells from NDD-CKD expressed KIR2DS2 compared with 56% in HD-ESRD patients (P = 0·03). However, 20% of clones expressed KIR2DL3 in NDD-CKD compared with 7% in HD-ESRD patients (P = 0·004). DAP12 expression in CD28⁻ 2DS2⁺ clones was more prevalent in HD-ESRD than NDD-CKD (92% versus 60%; P < 0·001). Only 2DS2⁺ 2DL3⁻ DAP12⁺ clones were cytotoxic in response to hHSP 60. CD4⁺ CD28⁻ cells exhibited increased KIR2DS2, reduced KIR2DL3 and increased DAP12 expression in HD-ESRD compared with NDD-CKD patients. These findings suggest a gradual loss of expression, functionality and protective role of inhibitory KIR2DL3 as well as increased cytotoxic potential of CD4⁺ C28⁻ cells with progressive renal impairment. Clonal expansion of these T cells may contribute to heightened cardiovascular events in HD-ESRD.     

Leg ulcers in patients with sickle cell disease [see comments]

During the entry examination, leg ulcers were present in 2.5% of 2,075 patients 10 years of age and older with sickle cell disease who entered into the Cooperative Study of Sickle Cell Disease (CSSCD) between 1979 and 1986. Prevalence rates were highest among patients with sickle cell anemia and sickle cell anemia with thalassemia genotypes. Among sickle cell anemia patients free of ulcers at entry, the overall incidence was 5.73 per 100 person years in those having associated alpha-thalassemia and 9.97 for those without. Among sickle cell anemia patients with two alpha genes, the estimated incidence of leg ulcers is 2.38 per 100 person years and 6.12 per 100 person years among sickle cell anemia patients with three alpha genes (P less than .05). In both groups, the incidence was highest among those patients over 20 years of age and considerably higher among males than females (P less than .001). Leg ulcers were nonexistent in patients with sickle beta plus thalassemia and sickle hemoglobin C disease. Low steady-state hemoglobin is associated with a higher incidence of ulcer formation (P less than .0001) in sickle cell anemia patients. The protective effect of hemoglobin F is apparent at all levels of total hemoglobin among sickle cell anemia patients and those with associated alpha-thalassemia.     

A circumscribed refractory access disorder: A verbal semantic impairment sparing visual semantics

Abstract

We report the case of a patient (AZ) with a semantic refractory access dysphasia. On matching-to-sample tests assessing comprehension of the spoken word, AZ shows all the hallmarks of a refractory access disorder, namely inconsistent performance on repeated testing and sensitivity to both presentation rate and the semantic similarity between competing responses. However, on tasks examining her visual knowledge, such as matching two structurally different exemplars of the same item, AZ's performance is quantitatively and qualitatively different. In a series of experiments testing her knowledge of animate and inanimate items, AZ demonstrated significantly worse performance with verbal-visual matching than with visual-visual matching. Furthermore, response accuracy was observed to decrease with successive probing of an item in the verbal conditions but not the visual conditions. We also demonstrate that this discrepancy cannot be explained on the basis of either task difficulty or presentation rate. We attribute our results to a build-up of refractoriness in the systems mediating verbal comprehension whilst those underlying visual comprehension remain unaffected. We argue that our data speak against a unitary amodal semantic system and in favour of at least partially separate verbal and visual semantic processing.     

Different patterns of spoken and written word comprehension deficit in aphasic stroke patients

This study presents neuropsychological evidence for differences in the semantic representations underpinning spoken and written word comprehension. Potential modality-based discrepancies in the semantic system were examined by testing whether spoken word (auditory–verbal input) and written word (visual–verbal input) comprehension exhibited the same effect profile on variables typically used to distinguish so-called access and storage disorders (e.g., response consistency, sensitivity to item frequency). The study was based on the premise that damage to a common set of semantic representations should have an equivalent impact upon comprehension performance irrespective of input modality, whereas damage to partially dissociable semantic representations may give rise to different qualities of deficit (access/storage) in the comprehension of stimuli presented in different input modalities (spoken/written). The study involved two patients with global aphasia following left middle cerebral artery stroke (F.B.I. and H.O.P.). The two patients showed matched performance on conventional tests of single word comprehension with clear evidence of semantic impairment for stimuli presented in both the spoken and written input modalities. However, in H.O.P., spoken and written word comprehension was affected in the same way by variations in stimulus category, frequency, and multiple stimulus presentations, whilst in F.B.I., there were clear differences between input modalities with all three variables. More specifically, F.B.I.'s written word comprehension was significantly affected by category (living?>?nonliving) and frequency (high?>?low) but not multiple presentations (single?=?multiple), more consistent with degradation of stored representations (storage deficit). By contrast, his spoken word comprehension was unaffected by category (living?=?nonliving) and frequency (high?=?low) but was affected by multiple presentations (single?>?multiple; serial position effects), more consistent with impaired access to stored representations (access deficit). These spoken/written input modality differences were observed on tasks matched closely for output modality, stimulus identity, and executive control requirements. It is argued that subtle differences in comprehension performance for stimuli presented in different input modalities may reflect damage to multimodal representations, which are intermediate between unimodal and amodal representations on a continuum of convergence within the semantic system. These ideas are discussed in the context of existing “distributed-only”, “distributed-plus-convergence”, or “distributed-plus-hub” models of conceptual knowledge.