Oxidative stress markers in patients with hereditary angioedema.

Introduction: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) or with normal C1-INH is characterized by recurrent swellings due to uncontrolled production of vasoactive mediators, among which bradykinin (BK) is crucial. Through the binding and activation of the two human BK-receptors, kinins may have dual beneficial and deleterious effects in vascular and inflammation physiopathology by inducing oxidative stress. We aimed to assess the serum concentrations of advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) in patients affected by HAE. Material and methods: Blood samples were collected to measure the serum concentrations of AGEs and AOPPs by spectrofluorimetric and spectrophotometric methods in patients affected by C1-INH-HAE and FXII-HAE during the remission state. Results: We showed that the circulating levels of AOPPs observed on control group (0.94 (0.36) nmol/mg) were significantly lower than those observed on the C1-INH-HAE group (1.68 (0.47) nmol/mg; p = 0.002) and FXII-HAE (1.50 (0.27) nmol/mg; p = 0.001). Moreover, the circulating levels of AGEs were significantly higher in C1-INH-HAE group (211.58 (151.05) AU/g; p = 0.02) than the FXII group (141.48 (89.59) AU/g), thus demonstrating a state of heightened oxidative stress. Conclusions: Our observations show additional underlying events involved in HAE and are of central importance for further investigations of differences in bradykinin receptors signaling among the two disease subgroups.

Distinctive metabolomic fingerprint in scleroderma patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) in systemic sclerosis (SS) identifies a poor prognosis subset of patients. Recent studies suggested a "metabolic theory" on the development of pulmonary arterial hypertension. On this basis we performed a metabolomic study in order to evaluate whether differences in pulmonary arterial blood metabolites were identifiable in SS patients with increased pulmonary vascular resistance (PVR). METHODS: We studied 18 SS patients (age 58.7±15.6years) free of pulmonary fibrosis who underwent a right heart catheterization (RHC). A blood sample was collected during the RHC in the distal peripheral circulation of the pulmonary arteries to perform the metabolomic analysis. RESULTS: Based on PVR we divided the population into Group A (n=8; PVR=1.16±0.23WU) and Group B (n=10; PVR=2.67±0.67WU; p<0.001 vs Group A). No significant differences were identified in terms of anthropometric, clinical, echo and therapeutic characteristics. At RHC the 2 groups showed a difference in mean pulmonary pressure values (Group A: 20±4mmHg; Group B: 27±3.4mmHg; p=0.03), with mild PAH in Group B. We applied an OSC-PLS-DA with a clear clusterization; SSc patients with PAH showed an increase in acetate, alanine, lactate, and lipoprotein levels and a decrease in γ-aminobutyrate, arginine, betaine, choline, creatine, creatinine, glucose, glutamate, glutamine, glycine, histidine, phenylalanine, and tyrosine levels CONCLUSIONS: Our results suggest that, despite similar clinical and disease-related parameters, SSc patients who develop PAH have an unfavorable metabolic profile able to cause an impaired production of metabolites with protective effects on endothelial cells.

The asthma-anxiety connection.

BACKGROUND: The literature reports a significant association between various mental disorders and asthma, in particular depression and/or anxiety, with some more robust data regarding anxiety disorders. However, the nature of this association remains largely unclear. OBJECTIVES: (1) To test the hypothesis of a specific association of anxiety and depressive disorder (according to the DSM-IV) with asthma and (2) to test the bidirectional hypothesis of causality between asthma and psychiatric disorders. METHODS: Ninety-six adults were compared with 96 control subjects matched according to main socio-demographic variables (i.e., gender, age, marital status, cohabiting/non-cohabiting, and BMI). Subjects with asthma were divided according to GINA and ACT classifications. All subjects underwent Structured Clinical Interviews for DSM-IV Axis I (SCID-I) diagnosis. RESULTS: Significant association between asthma and lifetime anxiety disorders emerged (OR 3.03; p = 0.003); no significant association with other psychiatric diagnosis emerged. Moreover, lifetime and current anxiety were associated with asthma severity levels (p < 0.01 and p = 0.001 based on age). Asthma preceded anxiety in 48% of cases; in 52% of cases, anxiety preceded asthma, without significant group differences. The risk of asthma, particularly of severe, uncontrolled forms (p < 0.01), resulted higher in lifetime anxiety disorder patients (p = 0.003 and p = 0.001 based on age at onset). Current anxiety increased the risk of asthma, and that of an uncontrolled form (p < 0.05). Asthma increased the risk of lifetime anxiety disorders (p = 0.002 and p = 0.018 using ages). Intermittent asthma increased the risk of lifetime and current anxiety disorders (p < 0.01). CONCLUSIONS: Anxiety disorders, in particular Lifetime Anxiety Disorders, represent the only psychiatric disorder significantly associated with asthma, with a possible bidirectional, anxiety-asthma relationship, each of which can be caused or result from the other.

Response to First-Line Ritonavir-Boosted Protease Inhibitors (PI/r)-Based Regimens in HIV Positive Patients Presenting to Care with Low CD4 Counts: Data from the Icona Foundation Cohort.

BACKGROUND: There are no data comparing the response to PI/r-based regimens in people presenting for care with low CD4 counts or AIDS (LC). AIM: To compare the response to LPV/r-, DRV/r- or ATV/r-based cART regimens in LC initiating cART from ART-naive. METHODS: We included people enrolled in Icona with either CD4 counts ≤350 cells/mm3 (low CD4-LC) or CD4 counts ≤200 cells/mm3 (very low CD4-VLC) and/or AIDS, starting their first PI/r-based regimen after 2008. Initial regimens were compared by intention-to-treat: i) time to viral failure (VF) (first of 2 consecutive VL>200 copies/mL after≥6 months); II) time to PI/r discontinuation/switching for any cause (TD) and for toxicity (TDT); III) treatment failure (TF) (VF or TD). Kaplan-Meier and Cox analyses were used. RESULTS: 1,362 LC patients were included (DRV/r 607; ATV/r 552; LPV/r 203); 813 VLC. In a median of 18 months (IQR:7-35), the 1-year probability of VF and TF were 2.8% (1.9-3.8) and 21.1% (18.7-23.4). In the adjusted analysis, patients initiating ATV/r had a 53% lower chance, and those initiating DRV/r a 61% lower chance of TD, as compared to LPV/r; the risk of TF was more likely in people starting LPV/r. Results were similar among VLC; in this subgroup LPV/r including regimens demonstrated a lower chance of VF. CONCLUSIONS: We confirmed in LC a low chance of virological failure by 1 year, with small differences according to PI/r. However, larger differences were observed when comparing longer-term endpoints such as treatment failure. These results are important for people presenting late for care.

SAPHO Syndrome: Current Developments and Approaches to Clinical Treatment.

SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare autoimmune disease which, due to its clinical presentation and symptoms, is often misdiagnosed and unrecognized. Its main features are prominent inflammatory cutaneous and articular manifestations. Treatments with immunosuppressive drugs have been used for the management of SAPHO with variable results. To date, the use of anti-TNF-α agents has proved to be an effective alternative to conventional treatment for unresponsive or refractory SAPHO cases. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 ß, IL-6, and IL-8, involved in inflammation, acute-phase response induction, and chemotaxis. IL-1 inhibition strategies with anakinra have shown efficacy as first and second lines of treatment. In this review, we will describe the main characteristics of biological drugs currently used for SAPHO syndrome. We also describe some of the promising therapeutic effects of ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and anakinra. We discuss the use and impact of the new anti-IL-1 antagonists involved in the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases.

A Case of SAPHO Syndrome with Endodontic Implications and Treatment with Biologic Drugs.

SAPHO syndrome (SS) is an autoinflammatory disease characterized by synovitis, acne, pustulosis, hyperostosis, and osteitis. Among the sites affected by the osteoarticular manifestations of SS are the anterior chest wall and the mandible. The etiology of SS is still unknown; theories advocate a genetic predisposition and an infectious cause in association with disorders of the immune system. We report a case of SS in which there was the involvement of the mandible with a lesion of endodontic origin. A 44-year-old white woman diagnosed with SS at the university hospital was referred to the Department of Conservative Dentistry and Endodontics for a consultation. She reported spontaneous pain localized to the periapical area of tooth #19 with a history of multiple restorative and endodontic treatments. It was diagnosed as a previously treated tooth with symptomatic apical periodontitis (AP) at the time of the endodontic evaluation. A second retreatment was then performed in 1 appointment under local anesthesia. During retreatment, a separated instrument and a ledge were found in the mesiobuccal canal, and attempts to bypass it were not successful; the canal was then obturated to the reachable length. Within the same month, the patient was also administered an anti-tumor necrosis factor alpha biologic medication in association with a disease-modifying antirheumatic drugs for the treatment of SS. Within 3 months, the overall therapy had led to a marked improvement of the systemic and mandibular symptoms, and a periapical radiograph showed almost complete healing of the lesion. Medical examinations have shown a total remission of signs and symptoms starting 6 months after the initiation of treatment. After 5 years, the disease is under control, and tooth #19 is symptom free and shows absence of AP. The endodontists need to be aware of the existence of SS and the possible effects of the use of disease-modifying antirheumatic drugs and biologic medications on the treatment of persistent AP.

Characterization of patients with angioedema without wheals: the importance of F12 gene screening.

Sporadic and familiar forms of non-histaminergic angioedema and normal C1 inhibitor encompass a group of disorders possibly caused by bradikinin. We aimed to study the subgroups of hereditary angioedema with FXII mutation (FXII-HAE), unknown genetic defect (U-HAE) and idiopathic non-histaminergic acquired angioedema (InH-AAE). We screened the F12 locus in our cohort and delineated the clinical, laboratory and genetic features. Four families carried the p.Thr309Lys mutation in F12 gene. Haplotyping confirmed the hypothesis of a common founder. Six families were affected by U-HAE and 13 patients by sporadic InH-AAE. C4 levels were significantly lower in FXII-HAE than in InH-AAE. In the FXII-HAE group, none had attacks exclusively in high estrogenic states; acute attacks were treated with icatibant. Prophylaxis with tranexamic acid reduced the attack frequency in most patients. Our study provides new data on the diagnosis, clinical features and treatment of non-histaminergic angioedema, underlying the role of the screening for F12 mutations.

The salivary proteome profile in patients affected by SAPHO syndrome characterized by a top-down RP-HPLC-ESI-MS platform.

SAPHO syndrome is a rare and often unrecognized disease with prominent inflammatory cutaneous and articular symptoms characterized by musculoskeletal manifestations (synovitis, hyperostosis, osteomyelitis) associated with dermatological conditions (severe acne and pustulosis). The acidic soluble fraction of whole saliva from 10 adult women affected by SAPHO syndrome and from a group of 28 healthy women was analysed by RP-HPLC-ESI-MS with the aim of discovering salivary biomarkers of the disorder. The levels of the oral proteins and peptides were correlated with clinical data. The following proteins showed a significant decreased concentration in saliva of SAPHO subjects with respect to controls: cystatin S1 and SN, histatins, the major acidic PRPs, P-C and P-B peptides. The cystatin SN abundance lowered according to the disease duration and histatins showed positive correlations with the C reactive protein. Statistical analysis performed excluding one patient with a different pattern of salivary proteins/peptides highlighted a positive relationship between cystatin S1, histatins 3, histatin 5, and the neutrophil count. Moreover, histatin 3 correlated positively with the total white cell count and negatively with the erythrocyte sedimentation rate. Levels and frequency of S100A12 protein showed a trend to increase in SAPHO patients. The high expression of this pro-inflammatory protein is probably related to the inflammatory response and to the altered neutrophil responses to functional stimuli that characterize SAPHO syndrome suggesting a possible application as a salivary biomarker.

Contractile reserve in systemic sclerosis patients as a major predictor of global cardiac impairment and exercise tolerance.

Several studies have evidenced high prevalence of myocardial systolic and diastolic dysfunction among patients with systemic sclerosis (SSc). Exercise echocardiography has shown a diagnostic and prognostic role in identifying early left ventricular (LV) dysfunction in several myocardial pathological settings. The aim of our study was to evaluate early signs of LV impairment under exercise and their correlation to patient's exercise tolerance. Forty-five patients (age 60.4 ± 10.3 years) with SSc and 20 age and sex comparable controls were enrolled in the study. All patients underwent clinical evaluation, 2D echocardiography associated with Tissue Doppler and speckle tracking to evaluate LV deformation indexes, and an exercise echocardiography to evaluate left ventricle contractile reserve (LVCR) and exercise pulmonary pressures. Finally, a 6-minute walking test (6MWT) to evaluate exercise tolerance was also performed. Compared to controls, SSc patients showed an impaired diastolic function (E/E' 10.9 ± 3.7 vs 8.36 ± 2.01; p < 0.01) associated with larger left atrial dimensions (LAVI 28.4 ± 8.7 vs 19.3 ± 4.6 mL/m(2); p < 0.01). During exercise echocardiography, a reduced global longitudinal strain at peak exercise (S-GLS) was highlighted compared to controls (15.7 ± 3.6 vs 18.2 ± 2.2; p = 0.001). A S-GLS cutoff <18%, identified by ROC analysis, identified SSc patients with a reduced diastolic function, exercise tolerance at the 6MWT and higher pulmonary pressures. Our data show that in SSc patients a reduced LVCR characterizes the patients with a more extensive cardiovascular impairment in terms of LV diastolic function, pulmonary pressures and exercise tolerance. These data underline the importance of exercise echocardiography for the preclinical screening of the LV impairment in this population.

Cognitive Impairment and Age-Related Vision Disorders: Their Possible Relationship and the Evaluation of the Use of Aspirin and Statins in a 65 Years-and-Over Sardinian Population.

Neurological disorders (Alzheimer's disease, vascular and mixed dementia) and visual loss (cataract, age-related macular degeneration, glaucoma, and diabetic retinopathy) are among the most common conditions that afflict people of at least 65 years of age. An increasing body of evidence is emerging, which demonstrates that memory and vision impairment are closely, significantly, and positively linked and that statins and aspirin may lessen the risk of developing age-related visual and neurological problems. However, clinical studies have produced contradictory results. Thus, the intent of the present study was to reliably establish whether a relationship exist between various types of dementia and age-related vision disorders, and to establish whether statins and aspirin may or may not have beneficial effects on these two types of disorders. We found that participants with dementia and/or vision problems were more likely to be depressed and displayed worse functional ability in basic and instrumental activities of daily living than controls. Mini mental state examination scores were significantly lower in patients with vision disorders compared to subjects without vision disorders. A closer association with macular degeneration was found in subjects with Alzheimer's disease than in subjects without dementia or with vascular dementia, mixed dementia, or other types of age-related vision disorders. When we considered the associations between different types of dementia and vision disorders and the use of statins and aspirin, we found a significant positive association between Alzheimer's disease and statins on their own or in combination with aspirin, indicating that these two drugs do not appear to reduce the risk of Alzheimer's disease or improve its clinical evolution and may, on the contrary, favor its development. No significant association in statin use alone, aspirin use alone, or the combination of these was found in subjects without vision disorders but with dementia, and, similarly, none in subjects with vision disorders but without dementia. Overall, these results confirm the general impression so far; namely, that macular degeneration may contribute to cognitive disorders (Alzheimer's disease in particular). In addition, they also suggest that, while statin and aspirin use may undoubtedly have some protective effects, they do not appear to be magic pills against the development of cognitive impairment or vision disorders in the elderly.

Biological treatments for SAPHO syndrome: an update.

Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome is a rare and often unrecognized disease with prominent inflammatory cutaneous and articular manifestations. Since the identification of the syndrome many immunosuppressive drugs have been used for the management of SAPHO, with variable results. The use of anti- TNF-α agents as a therapeutic option for SAPHO cases unresponsive or refractory to conventional drugs, demonstrated their efficacy for bone, skin and joints manifestations. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 ß , IL-6 and IL-8, involved in inflammation, acute-phase response induction and chemotaxis. IL-1 inhibition strategies with Anakinra have proven their efficacy as first and second line treatment. We herein review the literature concerning the use of biological drugs in patients with SAPHO syndrome. In addition, we describe for the first time the use of Ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and Anakinra. This anti-IL12/IL23 agent could be a promising therapeutic option, also considering the opportunity to interfere with the IL23/TH17 pathway, which we recently found disturbed. Furthermore, a rationale emerges for the use of the new anti-IL-1 antagonists or the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases.

TH17 cells are increased in the peripheral blood of patients with SAPHO syndrome.

To assess whether the immune derangement previously observed in SAPHO syndrome could be linked to variations in blood TH1, TH2 or TH17 lymphocytes frequency. Seven SAPHO patients with a protracted course of the disease were studied ex-vivo for intracellular cytokines production by means of flow-cytometry and compared with matched groups of Psoriatic Arthritis patients and healthy controls. The Kruskal-Wallis test on the median of the three categories showed that there is a significant association between the TH17 levels and the category (p value = 0.02474). The mean and variance for the proportion of IL-17 producing CD4+ cells were compared between groups showing significant differences between SAPHO versus PsA subgroup (p = 0.05) and SAPHO versus healthy controls (p = 0.008). Interestingly, activation of TH17 axis, but not of TH1 and TH2, has been found, and can be observed both in patients with different activity of the disease or treated with different drugs. The TH17 increase in peripheral blood of our SAPHO subjects resembles the one recently found in patients with different AIDs. Novel therapeutic options in these patients may therefore include IL-17 blockade.

Identification of a novel and recurrent mutation in the SERPING1 gene in patients with hereditary angioedema.

Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is an autosomal dominant disorder caused by mutations in SERPING1 gene. More than 200 different mutations are known, with high genetic heterogeneity and high frequency of private familial mutations. We analyzed for genetic mutations the C1-INH locus in 11 Sardinian families, revealing in seven subjects from four unrelated families the novel nonsense mutation S318X. This mutation, detected with unexpected high frequency, accounts for over a third of the here reported Sardinian families affected by HAE. The recurrence of a pathogenic mutation within the same geographical area is a unique finding, previously unreported in HAE due to C1-INH deficiency.

Response to raltegravir-based salvage therapy in HIV-infected patients with hepatitis C virus or hepatitis B virus coinfection.

OBJECTIVES: To define the impact of coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) on viroimmunological response to raltegravir-based salvage regimens that also include new HIV inhibitors such as maraviroc, darunavir and etravirine. METHODS: We used data from a national observational study of patients starting raltegravir-based regimens to compare virological suppression and CD4 cell change from baseline in patients with and without concomitant HBV or HCV infection. RESULTS: Overall, 275 patients (107 coinfected and 168 non-coinfected) were evaluated. Coinfected patients were more commonly former intravenous drug users and had a longer history of HIV infection and higher baseline aminotransferase levels. Both HIV-RNA and CD4 response were similar in the two groups. Mean time to first HIV-RNA copy number <50 copies/mL was 4.1 months (95% CI 3.5-4.6) in non-coinfected patients and 3.9 months (95% CI 3.3-4.5) in coinfected patients (hazard ratio 1.039, 95% CI 0.761-1.418, P = 0.766, log-rank test). The risk of developing new grade 3-4 hepatic adverse events was significantly higher in coinfected patients (hazard ratio 1.779, 95% CI 1.123-2.817, P = 0.009). The two groups of coinfected and non-coinfected patients had similar rates of interruption of any baseline drug (hazard ratio 1.075, 95% CI 0.649-1.781, P = 0.776) and of raltegravir (hazard ratio 1.520, 95% CI 0.671-3.447, P = 0.311). Few AIDS-defining events and deaths occurred. CONCLUSIONS: Viroimmunological response to regimens based on raltegravir and other recent anti-HIV inhibitors is not negatively affected by coinfection with HBV or HCV. Liver toxicity, either pre-existing or new, is more common in coinfected patients, but with no increased risk of treatment interruption.

Successful treatment of chronic mucocutaneous candidiasis caused by azole-resistant Candida albicans with posaconazole.

Refractory or recurrent infections of skin, nails, and the mucous membranes are clinical signs of chronic mucocutaneous candidiasis, frequently associated with immunological defects. Here we describe a 39-years-old female patient, with familial CMC, that presented with an extensive infection caused by an azole-resistant Candida albicans isolate, successfully treated with posaconazole.

IRAK-M is involved in the pathogenesis of early-onset persistent asthma.

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF- kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.

HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients.

BACKGROUND: Hypersensitivity reaction to nevirapine, which in some cases can be fatal, shows a higher prevalence in Sardinia in comparison with other Italian regions. OBJECTIVE: This study demonstrates that hypersensitive reaction to nevirapine in Sardinian HIV-infected patients is associated with the HLA Cw8-B14 haplotype. These two HLA class I antigens are in strong linkage disequilibrium in the Sardinian population. METHODS: Forty-nine Sardinian HIV-positive patients treated with nevirapine were studied. Thirteen (26%), developed a hypersensitive reaction thus requiring the drug to be discontinued. HLA class I and II molecular typing was performed in both nevirapine-hypersensitive and nevirapine-tolerant patients. To avoid biased representation of the allele frequencies in the two groups of treated patients, molecular typing was also performed in 82 HIV-positive patients who had not been treated with nevirapine. RESULTS: Considerable overlap was observed for the clinical, immunological and demographic characteristics of the 13 hypersensitive patients and 36 tolerant patients. Clinical parameters included viral load, status of HIV infection, CD4 and CD8 cell counts, hepatitis C virus/hepatitis B virus co-infections. Forty-six percent (6/13) of the nevirapine-hypersensitive subjects had the HLA-Cw8 and HLA-B14(65) antigens compared with 5% (2/36) of the nevirapine-tolerant group (P = 0.004; Pc = 0.05). CONCLUSION: In agreement with other recent reports, the utility of HLA typing in HIV patients to identify genetic factors that may confer susceptibility to drug-induced hypersensitive reaction was confirmed. A careful choice of antiretroviral therapy in susceptible individuals should significantly reduce the risk of severe hypersensitive reaction.

Lack of reduction of thymidine kinase activity in stavudine-treated HIV-infected patients.

It has been demonstrated that prolonged in vivo or in vitro treatment with some nucleosides analogs may favor the selection of cells with a reduced activity of enzymes involved in the phosphorylation of these drugs leading to a reduced sensitivity to their antiretroviral action. The aim of this study was to evaluate the effect, in vivo, of zidovudine and stavudine treatment on thymidine kinase (TK) activity. The results obtained showed that TK levels in PBMC from naive patients and stavudine-treated patients did not significantly differ (naive TK = 4.16 +/- 1.19 U/mg protein; stavudine TK = 3.65 +/- 1.73 U/mg protein; p = 0.42), suggesting that the treatment with this nucleoside analog is not associated to a defect of TK activity. On the contrary, PBMC from zidovudine-treated patients showed a significant reduction in TK activity compared to naive patients (naive TK = 4.16 +/- 1.19 U/mg protein; zidovudine TK = 2.70 +/- 1.54; p = 0.014. Although the clinical significance of these results has to be established, we can speculate that stavudine and zidovudine, which are presumably phosphorylated by the same cellular kinases, might display a different ability to in vivo select cells with a resistant phenotype.