The Impact of COVID-19 Lockdown on Patients with Type 2 Diabetes Mellitus: A Brief Report.

BACKGROUND: The Italian population's habits changed dramatically during the "COVID- 19 lockdown" due to physical distancing and self-isolation. Moreover, medical consultations of patients with chronic diseases, such as type 2 diabetes (T2D), were suspended or postponed, unless urgent or semi-urgent, for several consecutive months. Thus, it is expected that the lockdown could have affected glucometabolic control in T2D. v Purpose: The aim of the study was to assess changes in glucometabolic control in a cohort of T2D patients before (T1) and after (T2) the COVID-19 lockdown (March-May 2020). METHODS: The study was approved by the Ethics Committee of the University of Bari, and all patients provided informed written consent to participate. Medical history, complete physical examination, and laboratory assessment were conducted as real-life clinical practice. Changes in clinical and laboratory variables between T1 and T2 were calculated. RESULTS: In detail, 13 patients were on metformin as monotherapy, 36 on GLP-1RA, 12 on sodiumglucose transporter 2 inhibitors (SGLT-2i), and 2 on dipeptidyl-peptidase 4 inhibitors (DPP4i). The mean age was 65.3 years (43-83). Study participants were mainly men (73%). The body weight (BW) ranged from 56 to 145 kg, and the waist circumference ranged from 88 to 146 cm. The mean HbA1c was 51.0 mmol/mol. At T2, no statistically significant changes were observed frombaseline except for BW [-1.6 (-2.60 to -0.62)] and HbA1c [-2.90 (-4.69; -1.12)]. CONCLUSION: We evaluated the effects of the COVID-19 lockdown on glucometabolic control in patients with background well-controlled T2D. We found that the lockdown had no adverse effects on metabolic profile regardless of background clinical characteristics and antihyperglycemic management. Despite limitations due to the nature of this study (sample size, retrospective observation, lack of data on lifestyle changes in our patients' everyday lives), T2D patients managed in our Diabetes Centers faced the lockdown-related restrictions without any detrimental consequence.

Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience.

We evaluated the clinical impact, in daily clinical practice, of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) therapies in patients with type 2 diabetes. Data from 500 unselected consecutive patients were retrospectively analyzed. Only those with a full assessment at baseline (T0) and after 3 (T3), 6 (T6), and 12 (T12) months of treatment with SGLT2i or GLP1RA were included in the study (n = 167). At baseline, patients had a high mean body weight (BW), abdominal circumference (AC), body mass index (BMI), and HOMA index. Despite normal C-peptide values, 39 patients were being treated with insulin (up to 120 IU/day). During therapy, a progressive improvement in BW, BMI, and AC was observed with both the molecules. Fasting glucose and glycated Hb decrease was already significant at T3 in all patients, while the HOMA index selectively improved with SGLT2i therapy. Renal function parameters remained stable regardless of the drug used. Finally, SGLT2i reduced serum uric acid and improved the lipid profile, while GLP1RA reduced serum levels of liver enzymes. Both the therapeutic regimens allowed a significant reduction or complete suspension of unnecessary insulin therapies. Our real life data confirm the results obtained from randomized clinical trials and should be taken as a warning against inappropriate use of insulin in patients with preserved ß-cell function.

Once-Weekly Semaglutide Induces an Early Improvement in Body Composition in Patients with Type 2 Diabetes: A 26-Week Prospective Real-Life Study.

BACKGROUND: Body weight (BW) loss is an essential therapeutic goal in type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists are effective in reducing BW, but their effect on body composition has not yet been fully explored. The study aim was to assess the impact of Semaglutide on body composition in patients with T2D. METHODS: Forty patients with T2D were treated with subcutaneous Semaglutide and evaluated at the baseline (T0) and after three (T3) and six (T6) months. Body composition was assessed by a phase-sensitive bioimpedance analyzer. Visceral adipose tissue (VAT) thickness was also measured with an ultrasonographic method (US-VAT). Anthropometric variables, muscular strength, and laboratory tests were analyzed and compared. RESULTS: A significant decrease in VAT, the fat mass index (FMI), and BW loss was observed at all observation times. US-VAT, the skeletal mass index (SMI), the fat-free mass index (FFMI), waist circumferences, and glycated hemoglobin had lessened after three months and remained stable at T6. No variations in muscle strength, the muscle quality index, and body water were found. DISCUSSION: In a real-life setting, Semaglutide provided significant weight loss mainly due to a reduction in the FMI and VAT, with non-clinically relevant changes in the SMI, the FFMI, and muscle strength. Most importantly, the results were obtained after three months of treatment and persisted thereafter.

When Inappropriate Use of Insulin is Dangerous: The Utility of C-Peptide Assay in the Era of Cardioprotective Antidiabetic Drugs.

INTRODUCTION: New antidiabetic drugs have simplified treatment regimens in patients with type-2 diabetes (T2D). More importantly, they have proven to reduce cardiovascular risk by lowering insulin-resistance, blood pressure and body weight, in addition to avoiding inappropriate insulin therapy, responsible for hypoglycemic episodes and weight gain. In this context, accurate assessment of the metabolic status of T2D patients becomes essential. The C-peptide assay is a simple but often overlooked test that can provide a fundamental contribution to the correct disease classification and optimal therapeutic management of diabetic patients. CLINICAL CASE: We report the case of a 72-year-old patient, treated with insulin for 26 years after a diagnosis of type-1 diabetes (T1D), resulting in inadequate glycemia control and a severe evolution of cardiovascular complications. After an accurate evaluation of the clinical history, phenotype and laboratory data, including the determination of C-peptide serum levels, a diagnosis was made of T2D not T1D. Considering the patient's very high cardiovascular risk and dysmetabolic profile, insulin therapy was discontinued and more appropriate therapy with dulaglutide and metformin was instituted. These overall therapeutic modifications yielded remarkable clinical advantages in terms of the glycometabolic profile, weight reduction, abdominal circumference and body mass index decrease, as well as a better quality of life, with complete resolution of the dangerous hypoglycemic episodes. CONCLUSION: In the era of new cardioprotective antidiabetic drugs, we believe the importance of the C-peptide assay should be re-evaluated in order to avoid misdiagnosis and to improve the therapeutic approach to T2D.

Xanthenylacetic Acid Derivatives Effectively Target Lysophosphatidic Acid Receptor 6 to Inhibit Hepatocellular Carcinoma Cell Growth.

Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.

Hyperhomocysteinemia is an independent risk factor of atherosclerosis in patients with metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is a clinical condition potentially promoting the development of atherosclerotic disease. To date, the clinical impact of elevated serum homocysteine (Hcy) levels in MetS is still under discussion. The aim of this cross sectional study was to evaluate the relationship between MetS and hyperhomocysteinemia and the potential role of Hcy in the pathogenesis of atherosclerotic complications of MetS. METHODS: We recruited 300 outpatients with MetS. All patients underwent a medical history collection, physical examination, blood sampling and carotid ultrasound echo-color Doppler. According to Hcy levels, MetS patients were divided into two groups: "normal" (< 10.7 µmol/l; n = 140, group 1) and "high" Hcy (≥ 10.7 µmol/l; n = 160, group 2). Comparisons between groups were made by Student's t-test or Chi-square test. The effects of potential covariates on group differences were evaluated by general linear models. The relationships between continuous variables were assessed by simple or multiple correlation and by linear regression. Multiple regression models were built to evaluate the effects of Hcy, together with other potential risk factors, on carotid atherosclerosis. RESULTS: Patients with high Hcy were predominantly male and slightly older than group 1 patients. Smokers and non-smokers exhibited similar Hcy levels, nor was a statistical relationship between pack-years and Hcy observed. Group 2 showed lower levels of folic acid, vitamin D, high density lipoprotein (HDL)-cholesterol and glomerular filtration rate (e-GFR) than group 1, but higher levels of C-peptide, uric acid and triglycerides. In all patients, Hcy was positively correlated with C-peptide and uric acid and negatively with folic acid and e-GFR. Intima-media thickness (IMT) and carotid stenosis degree were significantly higher in patients with high Hcy and a positive relationship between Hcy and both IMT and carotid stenosis was detected in all patients. Finally, Hcy atherogenic effects were independent of other well-known atherosclerosis risk factors. CONCLUSIONS: Our results highlight a link between MetS and hyperhomocysteinemia and a direct effect of Hcy on atherogenic process during MetS. Early correction of folic acid levels may contribute to prevent cardiovascular complications in MetS patients.

Metabolic syndrome and Chronic Obstructive Pulmonary Disease (COPD): The interplay among smoking, insulin resistance and vitamin D.

BACKGROUND: A close relationship between Metabolic Syndrome (MetS) and Chronic Obstructive Pulmonary Disease (COPD) has been described, but the exact nature of this link remains unclear. Current epidemiological data refer exclusively to the MetS prevalence among patients with COPD and data about the prevalence of COPD in MetS patients are still unavailable. AIM OF THE STUDY: To analyse and compare risk factors, clinical and metabolic characteristics, as well as the main respiratory function parameters, among patients affected by MetS, COPD or both diseases. PATIENTS: We recruited 59 outpatients with MetS and 76 outpatients with COPD. After medical history collection, physical examination, blood sampling for routine analysis, spirometric evaluation, they were subdivided into MetS (n = 46), MetS+COPD (n = 60), COPD (n = 29). RESULTS: A MetS diagnosis was assigned to 62% of COPD patients recruited in the COPD Outpatients Clinic of the Pneumology Department, while the COPD prevalence in MetS patients enrolled in the Internal Medicine Metabolic Disorders Outpatients Clinic was 22%. More than 60% of subjects enrolled in each Department were unaware that they suffered from an additional disease. MetS+COPD patients exhibited significantly higher C-peptide levels. We also found a positive relation between C-peptide and pack-years in all subjects and a negative correlation between C-peptide and vitamin D only in current smokers. Finally, a negative association emerged between smoking and vitamin D. CONCLUSIONS: We have estimated, for the first time, the COPD prevalence in MetS and suggest a potential role of smoking in inducing insulin resistance. Moreover, a direct effect of smoking on vitamin D levels is proposed as a novel mechanism, which may account for both insulin resistance and COPD development.

Lysophosphatidic acid receptor LPAR6 supports the tumorigenicity of hepatocellular carcinoma.

The aberrant processes driving hepatocellular carcinoma (HCC) are not fully understood. Lysophosphatidic acid receptors (LPAR) are commonly overexpressed in HCC, but their contributions to malignant development are not well established. In this report, we show that aberrant expression of LPAR6 sustains tumorigenesis and growth of HCC. Overexpression of LPAR6 in HCC specimens associated with poor survival in a cohort of 128 patients with HCC. We took a genetic approach to elucidate how LPAR6 sustains the HCC tumorigenic process, including through an expression profiling analysis to identify genes under the control of LPAR6. RNAi-mediated attenuation of LPAR6 impaired HCC tumorigenicity in tumor xenograft assays. Expression profiling and mechanistic analyses identified Pim-3 as a pathophysiologically relevant LPAR6 target gene. In nonmalignant cells where LPAR6 overexpression was sufficient to drive malignant character, Pim-3 was upregulated at the level of transcription initiation through a STAT3-dependent mechanism. A further analysis of HCC clinical specimens validated the connection between overexpression of LPAR6 and Pim-3, high proliferation rates, and poorer survival outcomes. Together, our findings establish LPAR6 as an important theranostic target in HCC tumorigenesis.

Plant-based vaccines: novel and low-cost possible route for Mediterranean innovative vaccination strategies.

A plant bioreactor has enormous capability as a system that supports many biological activities, that is, production of plant bodies, virus-like particles (VLPs), and vaccines. Foreign gene expression is an efficient mechanism for getting protein vaccines against different human viral and nonviral diseases. Plants make it easy to deal with safe, inexpensive, and provide trouble-free storage. The broad spectrum of safe gene promoters is being used to avoid risk assessments. Engineered virus-based vectors have no side effect. The process can be manipulated as follows: (a) retrieve and select gene encoding, use an antigenic protein from GenBank and/or from a viral-genome sequence, (b) design and construct hybrid-virus vectors (viral vector with a gene of interest) eventually flanked by plant-specific genetic regulatory elements for constitutive expression for obtaining chimeric virus, (c) gene transformation and/or transfection, for transient expression, into a plant-host model, that is, tobacco, to get protocols processed positively, and then moving into edible host plants, (d) confirmation of protein expression by bioassay, PCR-associated tests (RT-PCR), Northern and Western blotting analysis, and serological assay (ELISA), (e) expression for adjuvant recombinant protein seeking better antigenicity, (f) extraction and purification of expressed protein for identification and dosing, (g) antigenicity capability evaluated using parental or oral delivery in animal models (mice and/or rabbit immunization), and (h) growing of construct-treated edible crops in protective green houses. Some successful cases of heterologous gene-expressed protein, as edible vaccine, are being discussed, that is, hepatitis C virus (HCV). R9 mimotope, also named hypervariable region 1 (HVR1), was derived from the HVR1 of HCV. It was used as a potential neutralizing epitope of HCV. The mimotope was expressed using cucumber mosaic virus coat protein (CP), alfalfa mosaic virus CP P3/RNA3, and tobacco mosaic virus (TMV) CP-tobacco mild green mosaic virus (TMGMV) CP as expression vectors into tobacco plants. Expressed recombinant protein has not only been confirmed as a therapeutic but also as a diagnostic tool. Herpes simplex virus 2 (HSV-2), HSV-2 gD, and HSV-2 VP16 subunits were transfected into tobacco plants, using TMV CP-TMGMV CP expression vectors.

Interleukin-6, interleukin-1ß, and tumor necrosis factor α in menstrual effluents as biomarkers of chronic endometritis.

OBJECTIVE: To assess the relationship between chronic endometritis (CE) and proinflammatory cytokine levels in menstrual effluents and to develop a simple noninvasive test for screening CE. DESIGN: Case-control study. SETTING: Academic center. PATIENT(S): Sixty-four women referred to our center for infertility. INTERVENTION(S): Office hysteroscopy; endometrial biopsy; collection of menstrual blood at subsequent cycle. MAIN OUTCOME MEASURE(S): Interleukin (IL) 6, IL-1ß, and tumor necrosis factor (TNF) α concentrations in menstrual effluents. RESULT(S): Thirty-six out of 64 infertile women had histologically proven CE. The remaining 28 women were included as controls. IL-6, IL-1ß, and TNF-α levels were markedly higher in menstrual effluents of women with CE compared with control subjects. Receiver operating characteristic curve analysis revealed a good CE screening capacity for all of the cytokines. The combined evaluation of either IL-6/TNF-α or IL-6/IL-1ß increased the diagnostic capacity of the test, which reached a 100% sensitivity and a negative predictive value of 100 when at least one cytokine was found to exceed its cutoff value; it also reached a 100% specificity and a positive predictive value of 100 in cases of positivity of both cytokines. Logistic regression analysis confirmed the IL-6/TNF-α-based model as a significant predictor of CE. CONCLUSION(S): Proinflammatory cytokine levels are increased in menstrual effluents of women with CE. A test dosing IL-6 and TNF-α seems to have a high screening capacity for CE.

Impairment of TLR7-dependent signaling in dendritic cells from chronic hepatitis C virus (HCV)-infected non-responders to interferon/ribavirin therapy.

BACKGROUND AND AIM: Dendritic cell (DC) dysfunction has been suggested to play a role in the weak antiviral T-cell responsiveness observed during the course of chronic hepatitis C virus (HCV) infection. This study was undertaken to evaluate whether changes in DC functions might be related to a different therapeutic outcome in HCV-infected patients. METHODS: Peripheral blood DCs (PBDCs) or monocyte-derived DCs (MoDCs) were obtained from chronic HCV-infected patients, sustained virologic responders (SVR) or non-responders (NR) to interferon/ribavirin therapy, and from healthy controls (HC). The frequency of BDCA-1+, BDCA-3+ or CD16+ myeloid DCs (mDCs) and BDCA-2+ plasmacytoid DCs (pDCs), as well as the expression of the costimulatory molecule CD86 in each PBDC subset, were evaluated by flow cytometry. MoDCs from single individuals were stimulated with TLR2, TLR3, TLR4, and TLR7 ligands and analyzed for CD86, CD83, CD40, CD80, and CD209 expression. Finally, mitogen-activated protein kinase (MAPK) phosphorylation of TLR7-triggered MoDCs was assessed by Western blotting. RESULTS: NR exhibited a reduced percentage of BDCA-1+ mDCs, as well as lower levels of CD86+ cells, in both BDCA-1+ mDCs and pDCs as compared to SVR and HC. Furthermore, MoDCs from NR displayed a defective CD86 and CD83 increase and ERK1/2 or p38-MAPK phosphorylation upon TLR7-cell triggering. CONCLUSIONS: Our data suggest that a TLR7-dependent impairment of costimulatory molecule expression caused by HCV persistence may affect DC activity in NR patients.

[An unusual case of transient loss of consciousness: the Fahr's syndrome]. / Uno strano caso di perdita transitoria di coscienza: la sindrome di Fahr.

A 69-year-old male was admitted to our Division because of repeated episodes of transient loss of consciousness and minimal cognitive and behavioural disturbances. Brain CT showed Fahr-type bilateral calcifications. Laboratory findings showed a phospho-calcium metabolism disorder consistent with the diagnosis of pseudohypoparathyroidism, whose correction led to a significant clinical improvement. This is the first case of Fahr's syndrome associated with syncope-type episodes. This observation suggests that a brain CT, as well as the search for a dysparathyroidism condition, should always carried out in all patients with unexplained recurrent episodes of loss of consciousness.

Age-related impairment of GM-CSF-induced signalling in neutrophils: role of SHP-1 and SOCS proteins.

Functional activities of mature human neutrophils are strongly influenced by the pro-inflammatory cytokine granulocyte macrophage-colony stimulating factor (GM-CSF). Accordingly, a defective response to GM-CSF might have dramatic consequences for neutrophil functions and the host defence against infections. Such an event is most likely to occur in senescence. A number of studies have, in fact, reported an impairment of the GM-CSF capacity to prime and/or to activate respiratory burst, as well as to delay apoptotic events, in neutrophils from elderly individuals. In the last 2 decades many efforts have been made to explore at molecular levels the mechanism underlying these defects. Recent studies let us depict a scenario in which an increased activity of inhibitory molecules, such as Src homology domain-containing protein tyrosine phosphatase-1 (SHP-1) and suppressors of cytokine signalling (SOCS), is responsible for the age-related failure of GM-CSF to stimulate neutrophil functions via inhibition of Lyn-, phosphoinositide 3-kinase (PI3-K)/extracellular signal-regulated kinase (ERK)- and signal transducers and activators of transcription (STAT)-dependent pathways. The control of SHP-1 and/or SOCS activity might therefore be an important therapeutic target for the restoration of normal immune responses during senescence.

Role of phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways in granulocyte macrophage-colony-stimulating factor failure to delay fas-induced neutrophil apoptosis in elderly humans.

Fas-stimulated neutrophils from elderly individuals show impaired granulocyte macrophage-colony-stimulating factor (GM-CSF)-induced apoptosis cell rescue. Herein, this defect was found to be associated with a significant reduction in GM-CSF-mediated Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Using Akt and ERK1/2 inhibitors, we demonstrated that both kinases were critical for GM-CSF antiapoptotic effects. Whereas Akt inhibition also affected GM-CSF-dependent ERK1/2 phosphorylation, ERK1/2 inhibition did not affect GM-CSF-induced Akt phosphorylation, suggesting that phosphoinositide 3-kinase (PI3-K)/Akt and ERK1/2 are activated in series and that PI3-K is located upstream of ERK1/2 along the GM-CSF-dependent signaling pathway. No age-associated changes in GM-CSF receptor expression were observed. Interestingly, both suppressors of cytokine signaling (SOCS)1 and SOCS3 proteins were significantly higher in unstimulated neutrophils from elderly individuals and, unlike in young individuals, did not further increase following GM-CSF cell triggering. These results indicate that defective PI3-K/Akt/ERK1/2 activation, likely dependent on elevated SOCS1 and SOCS3 levels, may affect the GM-CSF capacity to delay neutrophil apoptosis in elderly persons.

Impaired interleukin-12-dependent T-cell functions during aging: role of signal transducer and activator of transcription 4 (STAT4) and suppressor of cytokine signaling 3 (SOCS3).

Interleukin (IL)-12 is the major inducer of T helper cell (Th) 1-type responses. Despite a higher IL-12 production, phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC), as well as CD4(+) or CD8(+) T cells from elderly donors released interferon (IFN)-gamma amounts similar to those observed in young controls, and underwent only a slight increase in IFN-gamma production after IL-12 costimulation. These findings were not due to an age-related reduction in IL-12 receptor expression. Interestingly, no difference in PHA-triggered signal transducer and activator of transcription 4 (STAT4) phosphorylation between young and elderly donors was found, and a significant IL-12-induced STAT4 activation occurred only in PHA-preactivated cells from the younger group. The age-related defect in IL-12 signaling was STAT4-restricted as it did not involve the p38 mitogen-activated protein kinase (MAPK) pathway. Finally, suppressor of cytokine signaling 3 (SOCS3) expression was significantly higher in unstimulated cells from elderly individuals, and it did not diminish after cell stimulation. These results indicate that a defective STAT4 activation, likely dependent on elevated SOCS3 levels, is involved in the impaired IL-12-dependent T-cell functions with aging.

[Multiple extrahepatic manifestations in a patient with chronic hepatitis C treated with interferon-alfa]. / Manifestazioni extraepatiche multiple in una paziente con epatite cronica C trattata con interferone-alfa.

The case of a 61-years-old female patient with chronic hepatitis C who developed multiple consecutive extrahepatic manifestations is reported. One of these manifestations (lichen planus) appeared before HCV-related chronic hepatitis was diagnosed and treated with interferon-alpha, suggesting that it was likely associated with HCV itself. Other manifestations appeared during IFN-alpha treatment (polyarthritis) or after the end of treatment (ulcerative cholitis, sarcoidosis) implying a role for either HCV or IFN-alpha treatment in the pathogenesis of extrahepatic manifestations.

Role of defective ERK phosphorylation in the impaired GM-CSF-induced oxidative response of neutrophils in elderly humans.

GM-CSF-induced oxidative responses are defective in neutrophils of elderly humans. In the present study we evaluated whether this phenomenon might be related to alterations in cytokine-dependent MAPK signalling. Neutrophils obtained from elderly humans and stimulated with GM-CSF showed a significant reduction in phosphorylated ERK1/2 levels and an even higher decrease in ERK1/2 activation with respect to baseline. No changes in GM-CSF-induced p38 MAPK phosphorylation were observed. Cell pretreatment with the MEK inhibitor PD98059 determined a marked suppression of GM-CSF-induced O2- release. Interestingly, under the above experimental condition, there was no longer any difference in O2- production observed between elderly and young subjects. Furthermore, despite the fact that the p38 MAPK pathway was activated less strongly by GM-CSF, the p38 MAPK inhibitor SB203580 reduced GM-CSF-induced O2- production in the neutrophils of the elderly to levels similar to those obtained with PD98059. TNF-alpha-triggered O2- production was not altered by ageing and in fact, a similar ERK1/2 or p38 MAPK activation was found in TNF-alpha-stimulated neutrophils from elderly and young individuals. In accordance with the different potency of TNF-alpha in activating ERK1/2 and p38 MAPK, the TNF-alpha-induced oxidative responses were more sensitive to the inhibitory effects of SB203580 than to those of PD98059 in young as well as elderly subjects. These results suggest that, along the GM-CSF-dependent ERK signalling pathway, a step proximal to MEK1/2 but distal to the connection with the p38 MAPK module likely becomes defective as a feature of age. The consequent decline in ERK1/2 activation could potentially account for the GM-CSF-dependent impairment of the neutrophil respiratory burst that occurs with ageing.

Asymptomatic systemic sarcoidosis arising 5 years after IFN-alpha treatment for chronic hepatitis C: a new challenge for clinicians.

Interferon (IFN)-induced sarcoidosis is well documented. Herein, we report the case of a patient with chronic hepatitis C (CHC) who developed IFN-alpha-induced sarcoidosis. The clinical features of this case make it unique among all cases so far described. The patient was, in fact, asymptomatic for sarcoidosis, and the disease, characterized by liver and lung granulomatosis, was discovered by chance during the CHC follow-up. The diagnosis was made 5 years after IFN-alpha discontinuation. A pathogenetic role for IFN-alpha in our patient is supported by a liver biopsy performed before the therapy with IFN-alpha was started, showing no evidence of granulomatous localizations. This case suggests that the incidence of sarcoidosis during IFN-alpha treatment is underestimated. A search for clinical and laboratory findings typical of the disease, as well as a liver biopsy, should always be included in the follow-up of CHC patients undergoing therapy with IFN-alpha.

APC-dependent impairment of T cell proliferation in aging: role of CD28- and IL-12/IL-15-mediated signaling.

The age-related impairment of phytohaemagglutinin (PHA)-triggered peripheral blood mononuclear cell (PBMC) proliferation was paralleled by an expansion of CD28 (-) T lymphocytes with a poor capacity to undergo lectin-induced blastogenesis. However, both CD28 (-) and CD28 (+) T cells isolated from aged individuals exhibited a significant reduction of proliferative response to PHA in comparison with young controls, this implies that the CD28-mediated signaling is not the only defective pathway in the elderly. Thus, PBMC or T cell subsets plus monocytes from aged donors were stimulated with PHA and assayed for the production of, or the response to cytokines known to regulate T cell functions. Results can be so summarized: (i). interleukin (IL)-2 as well as IL-10 release was unaffected by age; (ii). in both groups of subjects, IL-15 concentrations were similar to those spontaneously released by PBMC; (iii). surprisingly, IL-12 p70 and IL-12 p40 production by PBMC was markedly increased in the aged group; (iv) in spite of this finding and of the experimental outcome that IFN-gamma synthesis was almost completely dependent on IL-12. PBMC from old individuals did not release higher amounts of IFN-gamma in comparison with young controls; (v). moreover, only a slight increase in IFN-gamma production was observed in PBMC cultures from the aged group as a result of IL-12 and/or IL-15 costimulation; (vi) at the same time, even though IL-12 as well as IL-15 were necessary for an efficient T cell proliferation, the addition of exceeding doses of cytokines proved to be ineffective in enhancing the proliferative outcome of PBMC or of both CD28 (+) and CD28 (-) T cells in the aged group. Taken together, the data outline the role of CD28 and IL-12/IL-15 signaling impairment in T cell proliferative deficiency during senescence.