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.     

Practice of yoga may cause damage of both sciatic nerves: a case report

Sciatic nerve traumatic damage very rarely occurs bilaterally. We describe the case of a 67-year-old woman who reported a bilateral traumatic lesion of the sciatic nerve during practice of yoga. Nerve conduction studies showed a bilateral sciatic nerve neuropathy, mostly affecting the peroneal component. Lumbar plexus MRI documented regular anatomical features of the main principal nerve roots with bilateral T2 signal alteration of roots L4, L5 and S1 that extended into the sciatic nerves showing both increase in size, probably related to chronic injury of nerves, and an alteration in diffusion signal that suggested a recent acute overlapped process.     

Improved relationship between left and right ventricular electrical activation after cardiac resynchronization therapy in heart failure patients can be quantified by body surface potential mapping

OBJECTIVES:

Few studies have evaluated cardiac electrical activation dynamics after cardiac resynchronization therapy. Although this procedure reduces morbidity and mortality in heart failure patients, many approaches attempting to identify the responders have shown that 30% of patients do not attain clinical or functional improvement. This study sought to quantify and characterize the effect of resynchronization therapy on the ventricular electrical activation of patients using body surface potential mapping, a noninvasive tool.

METHODS:

This retrospective study included 91 resynchronization patients with a mean age of 61 years, left ventricle ejection fraction of 28%, mean QRS duration of 182 ms, and functional class III/IV (78%/22%); the patients underwent 87-lead body surface mapping with the resynchronization device on and off. Thirty-six patients were excluded. Body surface isochronal maps produced 87 maximal/mean global ventricular activation times with three regions identified. The regional activation times for right and left ventricles and their inter-regional right-to-left ventricle gradients were calculated from these results and analyzed. The Mann-Whitney U-test and Kruskall-Wallis test were used for comparisons, with the level of significance set at p≤0.05.

RESULTS:

During intrinsic rhythms, regional ventricular activation times were significantly different (54.5 ms vs. 95.9 ms in the right and left ventricle regions, respectively). Regarding cardiac resynchronization, the maximal global value was significantly reduced (138 ms to 131 ms), and a downward variation of 19.4% in regional-left and an upward variation of 44.8% in regional-right ventricular activation times resulted in a significantly reduced inter-regional gradient (43.8 ms to 17 ms).

CONCLUSIONS:

Body surface potential mapping in resynchronization patients yielded electrical ventricular activation times for two cardiac regions with significantly decreased global and regional-left values but significantly increased regional-right values, thus showing an attenuated inter-regional gradient after the cardiac resynchronization therapy.     

Muscle strength and ankle mobility for the gait parameters in diabetic neuropathies

AimsTo evaluate the spatio-temporal variables of gait and the isometric muscle strength component of the ankle in patients with peripheral diabetic neuropathy. Also, verify the relationship between these variables and gait parameters.MethodsThis study involved 25 diabetic peripheral neuropathy (DPN) participants (62.4 ± 8.36 years) and 27 age-matched healthy control individuals (64.48 ± 6.21 years). The assessment of the spatio-temporal parameters of gait was performed using an electronic baropodometry treadmill. Prior to the collection data, each participant was instructed to walk on the treadmill in her/his habitual self-selected speed.ResultsDiabetic neuropathy group showed impairment of gait, with a smaller stride and length speed of the cycle, and increased duration of support time. Restricted dorsiflexion mobility and increased plantarflexion mobility were found, with a decrease in muscle strength of the dorsiflexors and plantiflexors. There was a significant relationship between plantiflexor muscle strength and the length and speed of the gait cycle. Also the muscle strengths of the plantiflexors and dorsiflexors, and the range of motion of dorsiflexion were predictors of gait performance.ConclusionsThe ankle, muscle strength and ankle mobility variables could explain changes in gait speed and range of motion in patients with DPN, allowing for the application of preventive strategies.     

Normal reference ranges of antithrombin,protein C and protein S: Effect of sex,age and hormonal status

Introduction

Antithrombin (AT), protein C (PC) and protein S (PS) deficiencies are risk factors for venous thromboembolism. Overlapping values between heterozygous carriers and normal individuals often make a correct classification of a deficiency difficult. The aim of this study was to investigate the effect of sex, age, menopause and hormone therapy on natural anticoagulant plasma levels in a large group of healthy individuals, and to evaluate the need of separate reference ranges.

Materials and Methods

AT and PC were measured with a chromogenic assay, antigenic free PS with an ELISA test. To evaluate the effect of sex, age, oral contraception, hormonal status (and their interaction) on AT, PC and PS levels, linear regression models were used. Biological relevance and the value of the normal deviate z were chosen as rules to decide for separate reference ranges.

Results

The study population consisted of 1837 healthy adult individuals (741 men, 1096 women), aged 18-85 years (median age: 44 years). In men AT levels decreased after the age of 50 years. Men had higher levels of PS than women, particularly at young ages. In women, after correction for menopause, only PC levels increased with age. Menopause affected AT and PS, but not PC levels. Oral contraceptive intake was associated with a decrease of AT and PS, and an increase of PC levels.

Conclusions

For AT, PC and PS, sex- and age-specific normal reference ranges can be useful, in order to better discriminate true carriers of a natural anticoagulant deficiency.     

Parry Romberg Syndrome associated with chronic facial pain

Parry Romberg Syndrome (PRS) is a rare condition of unknown cause and pathophysiology. It is characterized by progressive facial hemiatrophy, and neurological abnormalities are found in 20% of cases. We describe a 50-year-old woman with PRS and severe neurological involvement (lateralised epileptic seizure activity and facial pain refractory to medication). Pain intensity and frequency was reduced and control of epileptic crises was improved using levetiracetam as an additional therapy. In previous published cases associated with facial pain, the most frequent diagnoses were migraine and trigeminal neuralgia. Our findings suggest that in this patient PRS-related persistent pain has peculiar features possibly attributed to the underlying musculoskeletal abnormalities.     

Hepatocyte growth factor (HGF) and hemodialysis: physiopathology and clinical implications

Hepatocyte growth factor (HGF) is a pleiotropic cytokine which exerts a variety of effects on several cells, being involved in the regulation of many biological processes, such as inflammation, tissue repair, morphogenesis, angiogenesis, tumour propagation, immunomodulation of viral infections and cardio-metabolic activities. Patients undergoing regular hemodialysis (HD) present elevated levels of HGF, mainly due to the leukocyte activation associated with HD treatment. High HGF levels might account for specific clinical features of HD patients, i.e. mild liver damage in course of HCV-infection and high cardiovascular risk profile. Moreover, in patients with acute kidney injury, the induction of HGF may represent a crucial step to promote renal recovery, which can have important prognostic consequences in the short and long-term. In this review we discuss the mechanisms underlying HGF production in HD patients, the role of HGF in this particular patient population and the potential clinical implications derived from the study of HGF in HD patients.     

Glassy cell carcinoma of the endometrium: a case report and review of the literature

Glassy cell carcinomas are composed of malignant cells showing a "ground glass" cytoplasm, distinct cell membranes, and large nuclei with prominent nucleoli. To our knowledge, only 12 cases of glassy cell endometrial carcinomas (EGCC) have been reported until now. A 63-year-old patient complaining of irregular vaginal bleeding underwent hysteroscopy-guided biopsy revealing a well-differentiated endometrial endometrioid adenocarcinoma. The patient underwent left salpingo-oophorectomy, total abdominal hysterectomy, and pelvic lymphadenectomy. The final diagnosis was FIGO stage IB poorly differentiated endometrial adenosquamous carcinoma with > 90% of glassy tumor cells. The patient is alive, with no evidence of disease for 69 months after diagnosis. We describe an additional case of EGCC and review the data of the literature, emphasizing the need to strictly define the criteria for the diagnosis and the potential usefulness of assessing biologic parameters for the prognostic characterization of this rare entity.