Maintenance of renal function in a patient with a history of acute paroxysmal nocturnal hemoglobinuria-associated kidney injury.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disorder characterized by intravascular hemolysis, thrombosis and bone marrow failure. Acute kidney injury, including acute renal failure, have been reported in patients with PNH. We report the case of a 36-year-old male patient with PNH who developed acute kidney injury following an infection of undetermined diagnosis. Although hemolysis was initially controlled and renal function stabilized following packed red blood cell transfusion and empirical levofloxacin and prednisone, he later experienced recurrent episodes of hemolysis and hematuria requiring monthly red blood cell support. Given the high risk of thromboembolic events, treatment with standard-dose eculizumab was started. The patient's hematologic values improved, renal function was maintained, and no thromboembolic events occurred.

Serum CXCL10 levels and occurrence of thyroid dysfunction in patients treated with interferon-alpha therapy for hepatitis C virus-related hepatitis.

OBJECTIVE: Thyroid autoimmunity is a common side effect of interferon-alpha (IFN-alpha) treatment for chronic hepatitis C. There are currently no reliable parameters to predict the occurrence of thyroid dysfunctions in patients undergoing IFN-alpha therapy. CXC chemokine ligand 10 (CXCL10) is a chemokine known to play a role in both thyroid autoimmune disease and hepatitis C virus (HCV) hepatitis. DESIGN: The aim of this study was to evaluate serum CXCL10 levels in HCV patients treated with IFN-alpha in relation to the occurrence of thyroid dysfunctions. Serum CXCL10 levels were assayed in 25 HCV patients (proven to be negative for serum thyroid antibodies) before and during IFN-alpha therapy (2, 4 and 6 months) and in 50 healthy controls. HCV patients were retrospectively selected according to the occurrence of IFN-alpha-induced thyroid dysfunction and were assigned to two groups. Group I included 15 patients who did not develop thyroid antibody positivity or dysfunction; group II included ten patients who showed the appearance of serum thyroid antibodies, followed by clinically overt thyroid dysfunction. RESULTS: Patients with HCV, regardless of the development of thyroid dysfunctions, had significantly higher serum CXCL10 than controls (261.6+/-123.4 vs 80.4+/-33.6 pg/ml; P<0.00001). Pretreatment mean serum CXCL10 levels were significantly higher in Group I versus Group II (308.6+/-130.7 vs 191.1+/-69.4 pg/ml; P<0.05). Groups I and II showed different rates of favourable response to IFN-alpha treatment (33 and 90% respectively). CONCLUSION: Our results suggest that measuring serum CXCL10 before IFN-alpha treatment may be helpful for identifying those patients with higher risk to develop thyroid dysfunction, and require a careful thyroid surveillance throughout the treatment.

Intravenous neridronate for skeletal damage treatment in patients with multiple myeloma.

Almost 70-80% of the patients with Multiple Myeloma (MM) in advancer phase, of the disease show osteolytic lesions and/or pathologic fractures, with or without secondary osteoporosis. An accelerated osteoclast-mediated bone absorption is believed to be the main cause of bone damage in MM. Osteoclast can be activated by a variety of microenvironmental factors. Bisphosphonates (BF) induce the apoptosis of osteoclasts and inhibit osteoclastogenesis, thus preventing bone absorption. As well as BFs, the so-called second-generation BF (N-BF) may impair the activity of osteoclast. Neridronic acid (NER) is a N-BF molecule officially registered for the treatment of osteogenesis imperfecta. Nevertheless, NER has shown a remarkable efficacy in Paget's disease, postmenopausal osteoporosis and, most recently, in androgen deprivation-treated prostatic carcinoma. The primary endpoint of this study was to evaluate hip and spine Bone Mineral Density (BMD) modifications over the 12-month treatment with NER in a group of patients affected by MM with evidence of initial skeletal damage. Secondary endpoints were (1) changes of calcium and total Alkaline Phosphatase (tAP) plasma levels during treatment with NER and (2) tolerability of 100 mg NER monthly administration for 12 months. These data suggest that NER, if administered at these doses and timing, might allow at least for one year sustained BMD increases in patients. NER has been highly tolerated in this study. The almost complete absence of adverse effects has prompted us to reduce the time of infusions at the end of the study. In conclusion, this study provides the first data on the efficacy and safety of NER in patients with MM-induced bone damage. These initial data encourage wider phase III trials to clearly assess its efficacy in preventing skeletal-related events and its possible anti-neoplastic properties.

Association between immune thrombocytopenic purpura and chronic lymphocytic leukemia in a patient carrier of anti-hepatitis C virus antibodies.

Immune thrombocytopenic purpura (ITP) occurs in 2-3% of chronic lymphocytic leukemia (CLL) patients, whereas autoimmune thrombocytopenia is very rare before the diagnosis of lymphoma. A 67-year-old patient, was admitted to our Department because of purpura on his inferior limbs. Family history revealed arterial hypertension, a previous presence of hepatitis C virus (HCV) antibodies, with no sign of liver damage. Physical examination showed purpura of inferior limbs. Laboratory analysis revealed: marked thrombocytopenia (platelet count 5000/microL); hypogammaglobulinemia (9%, immunoglobulin-IgG 634 mg/dL); presence of HCV antibody (negative HCV-RNA); low-titer anti-nuclear antibody and anti-smooth muscle antibody (1:80); positive cryoglobulin (polycolonal, IgG-IgM, cryocrit 0.5%). Abdomen ultrasound revealed a mild liver steatosis and bone marrow aspirate megakaryocytic hyperplasia. Platelet kinetics study showed a markedly reduced platelet half-life (<1 day) with evident splenic uptake. The patient was treated with steroids, intravenous Ig and immunosuppressive agent (cyclophosphamide) with only temporary effect; a splenectomy was therefore performed with a subsequent durable increase in the platelet count. Two years later, the patient underwent a prostatectomy for prostate cancer and within the pelvic nodal screening the histological examination unexpectedly revealed features of B-cell non-Hodgkin's lymphoma, type CCL/small lymphocytic lymphoma; a bone marrow aspirate showed a monotypic CD5+, CD19+, CD23+ B-cell proliferation confirming the diagnosis of CLL. Six months later, a computed tomography scan revealed multiple pathological node enlargements (1.5-3 cm), compatible with a malignant lymphoma. The marked thrombocytopenia may have been an early expression of the lymphoproliferative disease. Otherwise, the association between CLL and ITP might reflect the underlying role of HCV infection causing an immune dysregulation responsible for both pathologies.

Pulmonary complications in diabetes mellitus: the role of glycemic control.

Insulin deficiency induces an increase in blood glucose levels that, in long run, becomes toxic for many organs and systems. Microangiopathy and derangements in the immune function are known consequences of hyperglycemia, but the way in which these systemic alterations may affect pulmonary function has been scarcely investigated. Although confirmation from large clinical trials is still to come, the diabetic disease seems to hit the pulmonary microcirculation as any other organ by increasing vessel wall thickness and impairing gas exchange, which leads to a measurable loss of function and respiratory efficiency. In addition, a diabetic lung is more susceptible to low respiratory tract infections by atypical microorganisms and more likely to host severe episodes of pneumonia than a normal, non-diabetic lung. This is a review of current knowledge on the impact of diabetes mellitus in lung health. We have paid special attention to the role of metabolic control in preventing damage to the lung by sustained hyperglycemia.

Do coronary heart disease risk factors change over time?

The stability over a 12-year period of several coronary heart disease (CHD) risk factors was evaluated in 348 individuals who had remained healthy following baseline measurements made of the same variables in 1981. CHD risk factors evaluated were fasting and post-glucose challenge (120-minute) plasma glucose and insulin concentrations, plasma triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) concentrations, and the ratio of LDL/HDL cholesterol concentrations. Approximately 40% to 60% of individuals in the highest CHD risk quartile (or lowest in the case of HDL cholesterol concentrations) in 1981 were still at highest risk in 1993. A similar proportion of individuals at lowest risk in 1981 were still in that category in 1993. At least 50% of the participants in this prospective analysis experienced a change by 1 quartile or more in each of the metabolic CHD risk factors measured, and these differences were highly statistically significant for all variables measured with the exception of the TG and HDL cholesterol concentrations. These results demonstrate that the implicit assumption in epidemiological studies that CHD risk factors at baseline remain stable may require examination.

Broad-spectrum activity of a novel antibiotic peptide against multidrug-resistant veterinary isolates.

The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) bacteria has become a medical and veterinary problem. Antimicrobial peptides (AMPs) show potential to overcome antibiotic resistance and could be used therapeutically. A novel AMP (AMP2041) was developed in silico and its microbiocidal activity against MDR clinical strains isolated from cattle (n=6), dogs (n=8), and pigs (n=20) was evaluated. AMP2041 showed strong antimicrobial activity against all Gram-positive and Gram-negative MDR clinical strains tested. Within 20 min of incubation, there was complete killing of Pseudomonas aeruginosa ATCC 27953 and a 90% reduction of colony count for Escherichia coli ATCC 25922. For Staphylococcus aureus ATCC 25923, a 90% reduction of colony count was observed within 120 min of incubation.

The BH3-mimetic ABT-737 targets the apoptotic machinery in cholangiocarcinoma cell lines resulting in synergistic interactions with zoledronic acid.

PURPOSE: In TFK-1 and EGI-1 cholangiocarcinoma cell lines, zoledronic acid (ZOL) determines an S-phase block without apoptosis. Here, we investigated the occurrence of apoptosis stigmata when ZOL is associated to the BH3-mimetic ABT-737. METHODS: In EGI-1 and TFK-1 cholangiocarcinoma cell lines untreated or treated with ABT-737 alone or in combination with ZOL, the pro-survival protein's pattern (BCL-2, BCL-XL, MCL-1, HSP72, HSP27) was investigated by biochemical criteria along with the occurrence of mitochondrial damage evaluated by cytofluorimetric analysis using a cationic dye. RESULTS: ABT-737 induced growth inhibition and significantly affected the colony-forming ability of both EGI-1 and TFK-1 cells. However, activated PARP-1 or/and caspase-3 cleavage (apoptosis markers) were detected only at the highest ABT-737 concentrations used. Combined treatment showed synergistic effect by converting the predominant cytostatic effect of ZOL into a cytotoxic one as shown by striking increment of mitochondrial harmed cells along with PARP-1 activation and caspase-3 cleavage. CONCLUSION: The lack of apoptosis following ZOL treatment in these cholangiocarcinoma cell lines appears to be multifactorial and could be ascribed to the large constitutive expression of pro-survival proteins. The efficacy of ZOL treatment requires a concomitant unleashing of apoptosis using a selective BH3-mimetic as ABT-737. The rational targeting of specific components of the apoptotic pathway may appear a useful approach to improve the treatment of refractory or relapsed cholangiocarcinoma. Combined treatment could be further explored in in vivo tumor model of cholangiocarcinoma.