A. De Cata

Immune system alterations in lung cancer patients

The immune system plays an important role in the defense against neoplastic disease and immune responses show temporal changes related to circadian variations of antibodies, total lymphocytes in the peripheral blood and cell mediated immune responses. In this study we evaluate, lymphocyte subpopulations and interleukin-2 (IL-2) serum levels in peripheral blood samples collected at four-hour intervals for 24-hours starting at 06.00h from ten healthy subjects aged 65–79 years (mean age ± S.E. 67.28 ±3.11) and from ten subjects suffering from untreated non small cell lung cancer aged 65–78 years (mean age ± S.E. 68.57 ± 1.81). Areas under the curve, mean diurnal levels (mean of 06.00–10.00–14.00 h) and mean nocturnal levels (mean of 18.00–22.00–02.00 h) were calculated, and the presence of circadian rhythmicity was evaluate. When we compared AUC values there was a decrease in CD8bright (T suppressor subset) and an increase in CD16 (natural killer cells) and of IL-2 serum levels in cancer patients. When we compared mean diurnal levels, CD8 (T suppressor/cytotoxic subset) and CD8bright levels were lower, and CD16 levels were higher in cancer patients. When we compared mean nocturnal levels, CD16 and CD25 (T and B activated lymphocytes with expression of the a chain of IL-2 receptor) levels were higher, while CD8, CD8bright, CD20 (total B-cells), TcRd1 (epitope of the constant domain of d chain of T-cell receptor 1) and dTcS1 (epitope of the variable domain of d chain of T-cell receptor1) levels were lower in cancer patients. A clear circadian rhythm was validated for the time-qualified changes in CD4, CD20, HLA-DR with acrophase at night, and CD8, CD8bright, CD8dim, CD16, TcRd1 and dTcS1 with acrophase in the morning in the control group. A clear circadian rhythm was validated for the time-qualified changes in CD4 with acrophase at night, in the group of cancer patients. Results obtained in our study show that lung cancer is associated with anomalies of proportion and circadian variations of lymphocyte subsets that must be considered when adoptive immunotherapy has to be planned.

Circadian variations of cortisol, melatonin and lymphocyte subpopulations in geriatric age

A number of age-related changes in the 24-hour hormonal and non-hormonal rhythms have been found in older human beings. Lymphocyte subpopulations present circadian variation of some of their subsets and this variation may influence magnitude and expression of the immune responses. Numerous interactions exist among the nervous, endocrine and immune systems, mediated by neurotransmitters, hormones and cytokines. The aim of this study is to evaluate circadian variations of some endocrine and immune factors in older adults. Cortisol and melatonin serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from ten healthy young and middle-aged subjects and from ten healthy elderly subjects. There was a statistically significant difference between the groups in the observed values of CD20 (higher in young and middle-aged subjects) and CD25 and DR+ T cells (higher in elderly subjects). In the group of young and middle-aged subjects a clear circadian rhythm was validated for the time-qualified changes of all the factors studied. In the group of elderly subjects a number of rhythms were absent or altered. The results of the current study show that aging is associated with enhanced responsiveness of T cell compartment and alterations of circadian rhythmicity.

Ultrasound signs of pulmonary fibrosis in systemic sclerosis as timely indicators for chest computed tomography

Objectives: Systemic sclerosis (SSc) patients in the early stages of pulmonary fibrosis (PF) often have few or no symptoms, normal to borderline pulmonary function tests, and negative chest X-ray (CXR); high-resolution computed tomography (HRCT) is the only reliable means of detecting the early signs of PF. However, thoracic ultrasound (TUS) enables detection of pleural thickening, pleural/subpleural nodules, and other subpleural lung abnormalities across 70% of the subpleural surface. We reassessed concordance between TUS abnormalities and HRCT findings in SSc patients, to see whether TUS pleural line thickness (normally < 3.0 mm) could be used to earmark those with asymptomatic PF for timely HRCT assessment. Method: In total, 175 SSc patients (nine males, 166 females), aged 46.46 ± 15.33 years, were given CXR, TUS, HRCT, echocardiography, and pulmonary function tests. Results: In the 26 patients without HRCT signs of PF, pleural line thickness was ≤ 3.0 mm. In diffuse SSc, 97/137 patients showed pleural line thickening (between 3.0 and 5 mm) and subpleural nodules in 32/97; and 35/137 showed major pleural line thickening (≥ 5.0 mm) with nodules, with good concordance with HRCT patterns indicating lung fibrosis severity. HRCT was normal in 5/137, with pleural line thickness ≤ 3.0 mm. Conclusions: TUS imaging of pleural/subpleural structures can detect ultrasonographic signs of initial PF prior to the onset of respiratory symptoms and function test abnormalities and, together with current criteria, could thereby enable exclusion of PF in SSc patients. Indicating some patients for selective referral to HRCT can thereby delay unwarranted procedures, provided that pulmonary function and TUS images are stable.

Prolonged remission of neuro-Behcet disease following autologous transplantation

Two young male patients with severe progressive Behcets disease with neurological involvement (N-BD) were treated by high-dose immunosuppressive chemotherapy (HIC) followed by autologous CD34+ selected peripheral blood stem cell transplantation (APBSCT). Neurological impairment and disability were quantified by means of Expanded Disability Status Scale (EDSS). Neuroimaging included spine and brain MRI and brain SPECT by radiolabeling technetium (Tc99m) Ethyl Cisteynate Dimer (ECD). Disease progression halted after treatment in both patients. At 48 months of follow-up they were therapy-free and one showed neurological status and disability improvement. Brain MRI findings were unchanged in both patients, but SPECT-ECD showed an increase of blood flow in the hypoperfused cerebral areas in the ameliorated patient. Immune ablation followed by APBSCT can modify the course of severe N-BD. Because of the high risk and the transplant-related mortality, these cases have to be carefully selected.

Digital ulcers in scleroderma patients: A retrospective observational study.

Background: The guidelines for digital ulcers (DUs) management in systemic sclerosis (SSc) indicate the use of iloprost to induce wound healing and bosentan to prevent the onset of new DU. The aim of our study was to evaluate whether the combination treatment may surmount the effect of the single drug. Methods: We analyzed data regarding 34 patients with SSc and at least one active DU persisting despite 6 months of iloprost therapy, and treated for other 6 months with a combination therapy, i.e. iloprost plus bosentan. Results: Overall, patients initially presented 69 DUs (58 on the fingers and 11 on the legs). At the end of the study 34 (49.3%) DUs were completely healed (responding, R), 18 (26.1%) started the healing process (partially responding, PR), and 17 (24.6%) did not respond (NR) to therapy. No new DU was recorded and the ulcers localized on the legs did not respond to the combination therapy. Finally, data have been analyzed by dividing the patients in two groups according to the fibrosis level on the finger. In the group with mild fibrosis, 83.4% of DUs resulted with showing complete healing while, in the group with severe fibrosis, only 18% of DUs were healed (P = 0.024). Conclusion: The treatment with iloprost plus bosentan is effective in determining healing of DUs in SSc patients with mild digital skin fibrosis. Conversely, the severity of skin fibrosis strongly influences the healing process of DUs. The study confirmed the efficacy of bosentan to prevent onset of new DUs.

Change of γδTCR-expressing T cells in healthy aging.

A mature T-cell lineage with the capacity to proliferate in response to receptor-mediated signals and to display non-major histocompatibility complex (MHC)-restricted cytolysis expresses a CD3-associated heterodimer made up of the protein encoded by the T-cell receptor (TCR) gamma-gene. We investigated the possible differences in lymphocyte subpopulations between healthy young-middle-aged and elderly subjects, focusing attention on y8-TCR-expressing cells. The study was carried out on fifteen healthy young-middle-aged male subjects (age range 36–55 years) and fifteen healthy elderly male subjects (age range 67–79 years). Lymphocyte subpopulations were analyzed in blood samples collected every four hours for 24 hours. The presence of circadian rhythmicity on absolute counts was validated to evaluate the periodicity of variation, and the fractional variation between single time point values was calculated to evaluate the dynamics of variation. In the group of young and middle-aged subjects a clear circadian rhythm was validated for the time-qualified changes of all the lymphocyte subpopulations (CD3, CD4, CD4/CD8 ratio, CD20, CD25 and HLA-DR with acrophase at night, CD8, CD16 and TcRγδ with acrophase at noon). In the group of elderly subjects a clear circadian rhythm was validated for the nyctohemeral changes of CD3, CD8, CD4/CD8 ratio, CD 16, CD25. There was a statistically significant difference for the Midline Estimating Statistic of Rhythm (MESOR) of CD3 (p=0.001), CD25 (p=0.003) and γδ-TCR- expressing cells (p=0.004), higher in the elderly, and for the MESOR of HLA-DR (p=0.002) and CD20 (p=0.002) higher in the young and middle-aged subjects. There was a statistically significant difference between the groups in the fractional variation of TcRγδ-expressing cells between 18:00h and 22:00h values (higher in elderly subjects, p=0.007). In conclusion, specific lymphocyte subsets present different levels and different profiles of nyctohemeral changes in healthy young-middle aged in respect to elderly subjects, since B cells are decreased, whereas CD25 and γδ-TCR-bearing cells are higher in the elderly, but the rhythm and the dynamics of variation of this lymphocyte subset is severely altered and this phenomenon might contribute to the onset of age-related variations of the immune responses.

Fatal rupture of an inflammatory arterial aneurysm in a patient with Wegener's granulomatosis.

A 67-year-old man presented with a complaint of high-grade fever, up to 39.7‡C, rigors, myalgias, occasional bloody nasal discharge, a cough productive of a thick and blood-streaked sputum for several weeks, and no improvement after several courses of empirical antibiotic treatment. There was no risk factor for cardiovascular diseases, and his previous medical history was otherwise normal, except for a diagnosis of chronic paranasal sinusitis 11 months earlier. On admission, vital parameters were normal, and no physical abnormality was detected on respiratory, cardiovascular, abdominal, and genitourinary examinations. Laboratory studies included a Westergren erythrocyte sedimentation rate (ESR) of 97 mm/h, C-reactive protein (CRP) 81 mg/L, and raised white-cell count of 17.5|10/L with 14.5|10/L Dr Giuseppe Famularo, Department of Internal Medicine, San Camillo Hospital, Circonvallazione Gianicolense, 00152 Rome, Italy. E-mail: gfamularo@scamilloforlanini.rm.it

Intrarenal resistive index in patients with type 2 diabetes mellitus with and without microalbuminuria

Diabetic nephropathy affects a subset of about 30% of patients with type 1 Diabetes Mellitus (DM); it also develops in a less defined percentage (20–30%) of patients with type 2, after a period of 15–20 years. It is usually divided into stages. The aim of this study is to assess the usefulness of duplex sonography with Doppler wave form analysis in the evaluation of early diabetic nephropathy, in order to detect patients at risk for irreversible renal disease. 262 patients (61 males, 201 females; age range: 48–81 years) with type 2 diabetes mellitus were studied; 100 healthy volunteers with no evidence of diabetes mellitus (74 females, 26 males; age range: 50–80 years) composed the control group. All of them underwent duplex Doppler sonography of the kidneys; a scanner with a 3.5 MHz transducer (Toshiba 270 SSA) was used, Pulsatily Index (P.I.) and Resistive Index (R.I.) of Doppler waveform were obtained at the intrarenal arteries; the average value of 3 bilateral measurements was taken. Doppler sonography was done by the same authors without knowledge of the patient group (case or control). Both indexes (PI. and R.I.) resulted to be higher in patients with DM compared to controls in patients with microalbuminuria: PI. = 1.49 +/- 0.34 vs. 1.07 +/- 0.06, p< 0.05; R.I. = 0.79 +/- 0.15 vs 0.60 +/- 0.03, p<0.05. Even if our data have to be confirmed by further studies, they suggest that duplex Doppler sonography may be a useful complementary test in the evaluation of diabetic nephropathy, especially in the early stages, in order to identify more patients at risk of developing diabetic nephropathy.

Immunopathogenetic and Pharmacological Aspects of Interstitial Lung Diseases

Interstitial lung diseases (ILDs) are inflammatory diseases characterized by slow and progressive destruction of alveolar-capillary functional units, often leading to respiratory failure and death. A first stage of alveolitis and a following stage of fibrosis provoke an anatomical distortion of the peripheral airways and the interstitium, and for their smoldering evolution and non-specificity of symptoms ILDs may remain undiagnosed and untreated for a long time. In this review we exploited the immunopathogenetic aspects and the therapeutical approaches to this frequently unrecognized and severe disease.