A shorter time to the first treatment may be predicted by the absolute number of regulatory T-cells in patients with Rai stage 0 chronic lymphocytic leukemia

Regulatory T-cells (Tregs) are increased in chronic lymphocytic leukemia(CLL) and correlates with clinical and biological features of active/progressive disease. However, little is known about their ability to predict the time to first treatment (TFT). We evaluated 75 patients with Rai stage 0 CLL, in whom the absolute number of Tregs was determined at diagnosis, and correlated to main clinical and biological features, as well as to the need of receiving any specific therapy during the course of the disease. After a median follow-up of 30 months, 12 patients(16%) required therapy at some time from the diagnosis. Treated patients showed a significant higher number of peripheral white blood cells and B-lymphocytes, platelet count, cases with unmutated immunoglobulin heavy chain status, and high-risk cytogenetic abnormalities,as well as lower hemoglobin values, than patients who did not need therapy. A greater number of circulating Tregs was detected in treated patients (P < 0.001). Multivariate analysis confirmed that the absolute number of Tregs was an independent predictor of TFT in these patients, the best predictive cut-off being 41/mL. These data show that the absolute Tregs cell number is able to identify Rai stage 0 CLL patients at higher risk of requiring therapy.     

Physical contact with endothelial cells through β1- and β2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells

Background

Chronic lymphocytic leukemia B cells display prolonged survival in vivo, but when cultured in vitro rapidly undergo spontaneous apoptosis. We hypothesize that interactions with endothelial cells in infiltrated tissues and during recirculation may have a pathogenic role in chronic lymphocytic leukemia.

Design and Methods

We evaluated apoptosis of leukemic cells after co-culture on a monolayer of human umbilical vein endothelial cells with addition of fludarabine and antibodies that block adhesion. Then, we compared microarray-based gene expression profiles between leukemic cells at baseline and after co-culture.

Results

We found that the endothelial layer protected leukemic cells from apoptosis inducing a 2-fold mean decrement in apoptotic cells after 2 days of co-culture. Moreover, the endothelial layer decreased the sensitivity of chronic lymphocytic leukemia B cells to fludarabine-induced apoptosis. Physical contact with endothelium mediated by both β₁- and β₂- integrins is essential for the survival advantage of leukemic cells. In particular, blocking CD106 on endothelial cells or CD18 on leukemic B cells led to the almost complete abrogation of the survival advantage (>70% inhibition of viability). However, a reduction of apoptosis was also measured in leukemic cells cultured in conditioned medium collected after 2 days of co-culture, implying that survival is partially mediated by soluble factors. Overall, the contact with endothelial cells modulated 1,944 genes in chronic lymphocytic leukemia B cells, establishing a peculiar gene expression profile: up-regulation of angiogenesis-related genes, an increase of genes involved in TGFβ and Wnt signaling pathways, secretion of cytokines recruiting stromal cells and macrophages and up-regulation of anti-apoptotic molecules such as Bcl2 and Survivin.

Conclusions

Our study supports the notion that endothelial cells are major players in the chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly supports survival, protects from drug-induced apoptosis and extensively modifies the gene expression profile of leukemic cells.     

Ultrasound and color Doppler in nephrology. Technology and applications

Advances in digital technology in the last decades have led to a fast development of ultrasound technology. Ultrasound information originating from stationary structures or red blood cells moving into the vessels can be visualized with different imaging modalities. Conventional B-mode sonography provides anatomical details based on acoustic impedance differences. Gray-scale sonography represents the structural echoes as brightness points. Based on the Doppler effect, vascular scattering can be represented as spectral wave velocity depending on time (velocity/time curve), or as dual-scale color mapping depending on the changes in average blood velocity. The flow-in is depicted in red and the flow-out in blue. The analysis of the vascular scattering enhanced by infusion of contrast agents is the basis of contrast-enhanced harmonic imaging. The perfusional pattern of tissues allows the differential diagnosis of expansive lesions. Tissue strain analysis provides a new dimension of diagnostic information. It is used in elastographic imaging to describe relative physical tissue stiffness properties. Tissue stiffness information is complementary to and independent of the acoustic impedance information provided by B-mode imaging as well as the vascular flow information provided by Doppler imaging. Adjacent tissue elements may appear identical using conventional B-mode or Doppler imaging. When stress (axial force) is applied to tissues, they show different degrees of deformation. Comparing the baseline and stress image information, each tissue element may be labeled by its relative stiffness. A lighter shade indicates relatively soft tissue (elastic), while a darker shade indicates relatively stiff tissue (non-elastic).     

Ultrasound and color Doppler applications in nephrology. The normal kidney: anatomy, vessels and congenital anomalies

Gray-scale ultrasound is the diagnostic technique of choice in patients with suspected or known renal disease. Knowledge of the normal and abnormal sonographic morphology of the kidney and urinary tract is essential for a successful diagnosis. Conventional sonography must always be complemented by Doppler sampling of the principal arterial and venous vessels. B-mode scanning is performed with the patient in supine, prone or side position. The kidney can be imaged by the anterior, lateral or posterior approach using coronal, transverse and oblique scanning planes. Morphological parameters that must be evaluated are the coronal diameter, the parenchymal thickness and echogenicity, the structure and state of the urinary tract, and the presence of congenital anomalies that may mimic a pseudomass. The main renal artery and the hilar-intraparenchymal branches of the arterial and venous vessels should be accurately evaluated using color Doppler. Measurement of intraparenchymal resistance indices (IP, IR) provides an indirect and quantitative parameter of the stiffness and eutrophic or dystrophic remodeling of the intrarenal microvasculature. These parameters differ depending on age, diabetic and hypertensive disease, chronic renal glomerular disease, and interstitial, vascular and obstructive nephropathy.     

Nigral involvement and nigrostriatal dysfunction in Huntington's disease: Evidences from an MRI and SPECT study

BackgroundHuntington disease (HD) is pathologically characterized by a selective neurodegeneration of vulnerable populations of neurons, with an early marked neuronal loss and atrophy in the neostriatum. Dopaminergic innervations of neostriatal neurons originate in the substantia nigra pars compacta. Few studies investigated the neuronal loss and the functional role of the substantia nigra in modulating clinical features in HD.Methods12 patients and 12 age-matched controls underwent SPECT scans with ¹²³I-FP-CIT and a 1.5 T MRI scan with inversion recovery technique. The association between both clinical and neuropsychological features and striatal uptake and volume of substantia nigra was explored.ResultsStriatal (p < 0.05), caudate (p < 0.05), and putaminal (p < 0.01) uptake was significantly lower in patients with respect to controls. Further, the volume of substantia nigra was reduced in HD when compared to controls (p < 0.01). No relationship between the volume of SN and tracer striatal uptake was found as well as between clinical and neuropsychological features with the SPECT and MRI results.ConclusionsOur results confirm that the degeneration of nigrostriatal pathway may occur in symptomatic HD patients. If confirmed by larger studies, the lack of any kind of correlation between clinical and neuropsychological features with striatal uptake and volume of substantia nigra suggests that motor and cognitive aspects in HD are not directly related to nigrostriatal degeneration.     

Intra-hospital Transport of Brain-Injured Patients: A Prospective, Observational Study

Introduction

Discrepant data exist regarding the incidence and severity of clinical problems related to intra-hospital transport of brain-injured patients and no consensus exists whether modern-day intra-hospital transport represents a safe or potentially problematic environment for neurointensive care unit (NICU) patients.

Methods

We examined the incidence of clinical complications and physiological derangements that occurred in 160 neurologically injured patients (90 males, 70 females, mean age 57 ± 17 years) who underwent intra-hospital transport (288 cases, 237 scheduled, 51 unscheduled) for computed tomography scans.

Results

Our findings indicate that (1) at least one significant complication (predominantly hemodynamic) occurred in over one-third (36 %) of all transports (p = n.s scheduled vs. unscheduled) necessitating the deployment of interventions designed to treat changes in arterial pressure (2) despite the presence of trained medical personnel and availability of specialized equipment, intra-cranial pressure was not adequately monitored during transports (especially in patients with intra-cranial hypertension prior to transport) (3) intra-hospital transfer was associated with minor but statistically significant clinical changes, including a reduction in arterial partial pressure of oxygen ( $ {\text{Pa}}_{{{\text{O}}_{ 2} }} $ )/inspired oxygen fraction ( $ {\text{Fi}}_{{{\text{O}}_{ 2} }} $ ) (only in the scheduled transport population), decreased arterial lactate levels (scheduled transport population), lowered body temperature (scheduled transport population), and increased arterial partial pressure of carbon dioxide ( $ {\text{Pa}}_{{{\text{CO}}_{ 2} }} $ ) (scheduled transport population).

Conclusions

Intra-hospital transport of brain-injured NICU patients may present some hazards even if performed by skilled personnel with specialized equipment. In Trauma Centers such as ours, an improvement in the frequency of neuromonitoring [intra-cranial pressure (ICP) and end-tidal CO₂ ( $ {\text{ET}}_{{{\text{CO}}_{ 2} }} $ )] during transport is recommended.     

Case report: use of thienopyridines in a patient with acquired idiopathic thrombotic thrombocytopenic purpura

Thienopyridines are commonly used anti-platelet drugs that may be associated with the development of secondary, drug-induced thrombotic thrombocytopenic purpura (TTP), a rare but potentially life threatening condition. We report the case of a 70?year-old man with a history of recurrent idiopathic TTP episodes who was treated with clopidogrel and then ticlopidine for thromboprophylaxis after percutaneous coronary intervention. Treatment was successful with no signs of TTP recurrence. Platelet counts and ADAMTS13 activity levels remained normal for months after the initiation of anti-platelet therapy, with no reappearance of anti-ADAMTS13 autoantibodies. This report demonstrates that thienopyridines do not necessarily induce TTP in patients with a history of TTP who are in disease remission.     

Stroke and renal dysfunction: are we always conscious of this relationship?

Cerebrovascular disease may represent an important clinical presentation of atherosclerosis in chronic kidney disease (CKD), and atherosclerosis is frequently encountered in CKD. In fact, kidney disease is now considered a risk factor for development of cardiovascular disease. Although guidelines for primary prevention of stroke have been recently published, CKD is hardly mentioned. Based on a series of available studies, we analyzed the relationship between reduced renal function, end-stage renal disease (ESRD), and stroke. Reduced renal function and risk of stroke appear to be related to the highest risk of patients on dialysis treatment. Primary and secondary prevention of stroke should be encouraged in participants with renal dysfunction.