Cytokines and chronic rejection: a study in kidney transplant long-term survivors

BACKGROUND: In part, the long-term survival of kidney transplants depends on the efforts to perform grafts with good human leukocyte antigen (HLA) compatibility, but there are other mechanisms that must induce some sort of tolerance and impair the anti-graft immune reaction. Because cytokines are one of the main components of immune response, we evaluated single nucleotide polymorphisms (SNPs) of several cytokine genes that may influence the production of a given cytokine and therefore the features of immune reactions. METHODS: A total of 416 first cadaveric kidney transplants were monitored for HLA matching. After 10 years, the graft was still functional in 171 of 416 patients; 102 of 171 patients were also typed for cytokine polymorphisms. RESULTS: The mismatch distributions in patients who underwent transplantation were not statistically different from the entire group of patients who underwent transplantation during the same time period. Moreover, it seems that almost all of the HLA class I incompatible long-term survivors are homozygous for GG at the -1082 interleukin (IL)-10 or CC at the -33IL4. CONCLUSIONS: We observed that a match for class I and class II HLA antigens apparently does not favor the long-term survival of transplanted kidneys. In fact, matched grafts are lost before 10 years in the same proportion as the mismatched grafts. We also demonstrated (1) that patients who are homozygous for GG at the SNP -1082IL10 (high IL-10 producers) and HLA class I mismatched (but matched for class II) are protected from chronic rejection, and (2) that patients who are homozygous for CC at the SNP -33IL4 (low IL-4 producers) and HLA class I mismatched (regardless of matching for class II) are protected from chronic rejection.     

Antibiotic therapy in the elderly: features and problems

Bacterial infections cause 30% of deaths in the elderly and are the most frequent cause of hospitalization in elderly patients. Diagnosis of infection can be difficult because aged patients may have neither fever nor leucocytosis; most patients present unusual symptoms such as changes in mental status. The clinician must be cognizant of the frequent noncompliance with drug regimens because lack of elderly adherence to a prescribed antibiotic therapy has the potential to result in treatment failure and to foster the emergence of drug-resistant bacteria. Elderly frequently are taking other drugs such as antiarrhythmics and antihypertensives; ignorance of potential antibiotic-drug interaction can result in ineffective treatment or enhanced toxicity. Aging is associated with changes in physiological processes; the age-related decline in renal function influences the excretion of some antibiotics (aminoglycosides, vancomycin, ofloxacin). The increased potential for toxicity of antimicrobial agents requires a careful drug selection as well as clinical and laboratory monitoring. The most frequent infections occurring in the elderly are pneumonia, urinary tract infection, intra-abdominal infection and soft tissue infection; prevalence and incidence of bacterial meningitis, bacterial endocarditis and bacteraemia are increasing with a mortality rate of 20 to 40%. These bacterial infections have different microbial causes and require different therapeutic approaches according to sites involved, elderly's salient features and overall susceptibility of the bacteria in the ecosystem. Appropriate empirical antibiotic treatment reduces mortality also in bacteraemic old patients.     

Dissociation between respiratory effort and dyspnoea in a subset of patients with stroke

Dyspnoea is not a prominent complaint of resting patients with recent hemispheric stroke (RHS). We hypothesized that, in patients with RHS presenting abnormalities in respiratory mechanics, increased respiratory motor output could translate into an increased perception of dyspnoea. We studied eight wheelchair-bound patients with RHS (mean age 62.4 years), previously evaluated by computerized tomography scanning, and a control group of normal subjects, matched for age and sex. We assessed routine spirometry, inspiratory and expiratory muscle pressures, breathing pattern and dyspnoea using a modified Borg scale. In six patients, we also measured oesophageal pressure during the maximal sniff manoeuvre and tidal inspiratory swing, and mechanical characteristics of the lung in terms of dynamic elastance during both quiet breathing and a hypercapnic/hyperoxic rebreathing test. During room air breathing, ventilation and tidal volume were similar in patients and controls, while tidal inspiratory swings of oesophageal pressure, an index of inspiratory motor output, were greater in patients ( P =0.005). Patients also exhibited a greater dynamic elastance ( P =0.013). During rebreathing, dynamic elastance remained higher ( P =0.01) and a greater than normal inspiratory motor output was found ( P =0.03). Responses of ventilation and tidal volume to carbon dioxide tension were normal, and in all patients but one a lower Borg score for the unit change in carbon dioxide tension and ventilation was found. In conclusion, a higher than normal inspiratory motor output was unexpectedly associated with a blunted perception of dyspnoea in this subset of RHS patients. This is likely to be due to the modulation of the integration process of respiratory sensation.     

A single-blind, partial crossover clinical trial of the effects of inhaled fluticasone propionate and nedocromil sodium on airway hyperresponsiveness to methacholine

Background: Airway inflammation plays a central role in the pathogenesis of asthma, even in the mildest forms and at the earliest stages. Therapeutic strategies now aim to relieve bronchoconstriction as well as focus primarily on controlling the underlying inflammatory process. Clinical trials of children and adults with asthma have demonstrated that inhaled corticosteroids and cromones (such as nedocromil sodium [NS]) improve symptoms and lung function, as well as decrease nonspecific bronchial hyperresponsiveness.Objective: The aim of this study was to compare the effects of various anti-inflammatory therapeutic regimens using inhaled fluticasone propionate (FP) and/or NS on airway hyperresponsiveness to methacholine.Methods: Patients with mild, persistent asthma, who tested positive to a Dermatophagoides pteronyssinus skin prick test, were randomly assigned to 1 of 4 treatment groups: (1) FP for 16 weeks; (2) FP for 8 weeks, followed by NS for 8 weeks; (3) NS for 8 weeks, followed by FP for 8 weeks; or (4) NS for 16 weeks. Each patient was evaluated every 4 weeks.Results: Thirty-two patients with asthma (16 men and 16 women; age range, 18-48 years) were included in the study; 8 patients were randomly assigned to each of the 4 treatment groups. During treatment with FP alone, the provocative dose of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second (PD₂₀) was significantly higher than that recorded during treatment with NS alone (P < 0.05 at weeks 12 and 16). However, both drugs induced progressive increases in PD₂₀ versus baseline values throughout the study. Moreover, when FP was administered as the second drug (after NS), a further increase in PD₂₀ compared with the values at week 8 occurred at both week 12 (P < 0.01) and week 16 (P < 0.001). In contrast, when NS was administered after 8 weeks of treatment with FP, methacholine PD₂₀ decreased significantly compared with week 8 (P < 0.001 and P < 0.01 at weeks 12 and 16, respectively).Conclusions: Our results suggest that, in this limited population of asthmatic patients who were treated for 16 weeks, FP was effective in increasing the PD₂₀ and that NS exerted an effective, progressive protective action against bronchial hyperresponsiveness to methacholine, thereby partially limiting the negative consequences of FP withdrawal on airway inflammation.