Stiff left atrial syndrome after low‐dose radiotherapy for right breast cancer: The need for invasive hemodynamics at exercise

Stiff left atrial (LA) syndrome is a distinct phenotype of heart failure with preserved ejection fraction, characterized by predominant high LA pressure. We describe the case of a middle‐aged woman who developed exertional breathlessness during low‐dose radiotherapy for right breast cancer and who was eventually found to be affected by stiff LA syndrome. Invasive hemodynamics allowed the recognition of pathognomonic tall V waves in the wedge position during exercise, in spite of inconclusive noninvasive investigations.     

Platelet-rich plasma injections for the treatment of refractory Achilles tendinopathy: results at 4 years

Background

Chronic Achilles tendinopathy is responsible for a severe reduction in physical performance and persistent pain. There is currently a number of therapeutic options and the local administration of growth factors is an emerging treatment strategy. In particular, platelet-rich plasma (PRP) is a widely used way to provide a local regenerative stimulus for tendon healing. The aim of this study was to document the mid-term results obtained after treating recalcitrant Achilles tendinopathy with injections of high concentrate, leucocyte-rich PRP.

Materials and methods

Twenty-seven patients (mean age: 44.6 years; 22 men and 5 women) affected by chronic mid-portion Achilles tendinopathy (7 bilateral, for a total of 34 tendons), refractory to previous treatments, were enrolled. Patients were treated with three ultrasound-guided intra-tendinous injections of PRP at 2-week intervals. Patients were prospectively evaluated at baseline, and then at 2, 6, and up to a mean of 54.1 months of follow-up (minimum 30 months), using the following tools: Blanzina, VISA-A, EQ-VAS for general health, and Tegner scores.

Results

The VISA-A score showed a significant improvement: the baseline score of 49.9±18.1 increased to 62.9±19.8 at 2 months (p=0.002), with a further improvement at 6 months (84.3±17.1, p<0.0005), and stable results at 4.5 years (90.0±13.9). The EQ-VAS score also showed a similar positive trend. An evaluation of the activity level confirmed these findings, showing a significant improvement in the Tegner score over time (p=0.017 for the final evaluation). The longer duration of symptoms before treatment was associated with a slower return to sport (p=0.041).

Discussion

PRP injections produced good overall results for the treatment of chronic recalcitrant Achilles tendinopathy with a stable outcome up to a medium-term follow-up. Longer symptom duration was related with a more difficult return to sporting activity.     

The ontogeny of the endocrine pancreas in the fetal/newborn baboon

Erratic regulation of glucose metabolism including hyperglycemia is a common condition in premature infants and is associated with increased morbidity and mortality. The objective of this study was to examine histological and ultrastructural differences in the endocrine pancreas in fetal (throughout gestation) and neonatal baboons. Twelve fetal baboons were delivered at 125 days (d) gestational age (GA), 140d GA, or 175d GA. Eight animals were delivered at term (185d GA); half were fed for 5 days. Seventy-three nondiabetic adult baboons were used for comparison. Pancreatic tissue was studied using light microscopy, confocal imaging, and electron microscopy. The fetal and neonatal endocrine pancreas islet architecture became more organized as GA advanced. The percent areas of α-β-δ-cell type were similar within each fetal and newborn GA (NS) but were higher than the adults (P<0.05) regardless of GA. The ratio of β cells within the islet (whole and core) increased with gestation (P<0.01). Neonatal baboons, which survived for 5 days (feeding), had a 2.5-fold increase in pancreas weight compared with their counterparts killed at birth (P=0.01). Endocrine cells were also found in exocrine ductal and acinar cells in 125, 140 and 175d GA fetuses. Subpopulation of tissue that coexpressed trypsin and glucagon/insulin shows the presence of cells with mixed endo-exocrine lineage in fetuses. In summary, the fetal endocrine pancreas has no prevalence of a α-β-δ-cell type with larger endocrine cell percent areas than adults. Cells with mixed endocrine/exocrine phenotype occur during fetal development. Developmental differences may play a role in glucose homeostasis during the neonatal period and may have long-term implications.     

How to manage IBD in patients with infections or malignancies?

Infections and malignancies are a major issue for clinicians in the management of patients with IBD because of concerns about the safety of drugs currently used in treatment, including immunosuppressive agents, steroids and tumor necrosis factor (TNF) antagonists. Infections are strongly associated with IBD both in their etiopathogenesis and in their clinical course. A number of viral infections, tuberculosis and other therapy-related infections create challenges for the successful management of intestinal disease with immunosuppressive agents or TNF antagonists. Recently published guidelines offer a strong support to deal with these issues. Major concern about IBD patients with malignancies is related to the consequences of chemotherapy on the intestinal disease, the risk of maintaining immunosuppressant or anti-TNF therapy after the diagnosis of malignancy and the management of a clinical relapse of IBD in patients with a recent diagnosis of malignancy. Further research is required to optimize strategies for IBD patients with malignancies. At the moment, all therapeutic choice is made on an individual basis, with an integrative multidisciplinary approach.     

Assessment of central adrenal insufficiency in children and adolescents with Prader-Willi syndrome

Objective A recent study evidenced by metyrapone test a central adrenal insufficiency (CAI) in 60% of Prader–Willi syndrome (PWS) children. These results were not confirmed in investigations with low [Low‐Dose Tetracosactrin Stimulation Test (LDTST), 1 μg] or standard‐dose tetracosactrin stimulation tests. We extended the research by LDTST in paediatric patients with PWS. Design Cross‐sectional evaluation of adrenal stress response to LDTST in a PWS cohort of a tertiary care referral centre. Patients Eighty‐four children with PWS. Measurements Assessment of adrenal response by morning cortisol and ACTH dosage, and 1‐μg tetracosactrin test. Response was considered appropriate when cortisol reached 500 nm ; below this threshold, patients were submitted to a second test. Responses were correlated with the patients’ clinical and molecular characteristics to assess genotype–phenotype correlation. Results Pathological cortisol peak responses to the LDTST were registered in 12 patients (14·3%) who had reduced basal (169·4 ± 83·3 nm ) and stimulated (428·1 ± 69·6 nm ) cortisol levels compared to patients with normal responses (367·1 ± 170·6 and 775·9 ± 191·3 nm , P < 0·001). Body mass index standard deviation score was negatively correlated with basal and peak cortisol levels (both P < 0·001), and the patients’ ages (P < 0·001). In patients with deletion on chromosome 15, the cortisol peak was significantly lower than that in uniparental disomy (UPD) cases (P = 0·030). At multiple regression analysis, the predictors of peak response were basal cortisol, age, and UPD subclass (r² = 0·353, P < 0·001). Standard‐dose (250 μg) tetracosactrin test confirmed CAI in 4/12 patients (4·8% of the cohort). Conclusions Our results support the hypothesis that, albeit rare, CAI may be part of the PWS in childhood.     

L-citrulline Prevents Alveolar and Vascular Derangement in a Rat Model of Moderate Hyperoxia-induced Lung Injury

Background

Moderate normobaric hyperoxia causes alveolar and vascular lung derangement in the newborn rat. Endogenous nitric oxide (NO), which promotes lung growth, is produced from the metabolism of l-arginine to l-citrulline in endothelial cells. We investigated whether administering l-citrulline by raising the serum levels of l-arginine and enhancing NO endogenous synthesis attenuates moderate hyperoxia-induced lung injury.

Methods

Newborn rats were exposed to FiO₂?=?0.6 or room air for 14?days to induce lung derangement and then were administered l-citrulline or a vehicle (sham). Lung histopathology was studied with morphometric features. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis. Lung vascular endothelial growth factor (VEGF), nitric oxide synthase (eNOS), and matrix metalloproteinase 2 (MMP2) gene and protein expressions were assessed.

Results

Serum l-arginine rose in the L-citr?+?hyperoxia group (p?=?0.05), as well as the Von Willebrand factor stained vessels count (p?=?0.0008). Lung VEGF immune staining, localized on endothelial cells, was weaker in the sections under hyperoxia than the l-citr?+?hyperoxia and room air groups. This pattern was comparable with the VEGF gene and protein expression profiles. Mean alveolar size increased in the untreated hyperoxia and sham-treated groups compared with the groups reared in room air or treated with l-citrulline under exposure to hyperoxia (p?=?0.0001). Lung VEGF and eNOS increased in the l-citrulline-treated rats, though this treatment did not change MMP2 gene expression but regulated the MMP2 active protein, which rose in BALF (p?=?0.003).

Conclusions

We conclude that administering l-citrulline proved effective in improving alveolar and vascular growth in a model of oxygen-induced pulmonary damage, suggesting better lung growth and matrix regulation than in untreated groups.     

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.