Vitamin D supplementation of 4000 IU daily and cardiac function in patients with advanced heart failure: The EVITA trial.

BACKGROUND: Data regarding the effects of vitamin D on cardiac function are inconclusive. METHODS: In a post-hoc analysis of the EVITA (Effect of vitamin D on mortality in heart failure) trial, we investigated whether a daily vitamin D3 supplement of 4000 IU for three years affects echocardiography parameters like left ventricular end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), and LV ejection fraction (LVEF) in patients with advanced heart failure (HF) and 25­hydroxyvitamin D levels <75 nmol/L. Of 400 patients enrolled, 199 were assigned to vitamin D and 201 to placebo. We assessed time × treatment interaction effects using linear mixed models and analyzed in subgroups vitamin D effects at 12 and 36 months post-randomization using analysis of covariance with adjustments for baseline values. RESULTS: At baseline, values of LVEDD, LVESD, and LVEF were 67.5 ±â€¯10.5 mm, 58.9 ±â€¯12.0 mm, and 30.47 ±â€¯10.2%, respectively. There were no time × treatment interaction effects on LV echocardiographic parameters in the entire study cohort, neither at 12 months nor at 36 months post-randomization (P-values > 0.05). However, in the subgroup of patients aged ≥50 years, vitamin D treatment was associated with an increase in LVEF of 2.73% (95%CI: 0.14 to 5.31%) at 12 months post-randomization (n = 311). The increase was slightly attenuated to 2.60% (95%CI: -2.47 to 7.67%) at 36 months post-randomization (n = 242). CONCLUSION: Our data indicate that vitamin D supplementation does not significantly improve cardiac function in all patients with advanced HF. However, vitamin D probably improves LV function in HF patients aged ≥50 years.

PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias.

It has been shown that individual acute myeloid leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5-10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional-mutagenesis screen for genes cooperating with one AML initiating mutations (PML-RARA, oncogene of acute promyelocytic leukemia, APL), which allowed identification of hundreds of genetic cooperators. The cooperators are mutated at low frequency in APL or AML patients but are always abnormally expressed in a cohort of 182 APLs and AMLs analyzed. These deregulations appear non-randomly distributed and present in all samples, regardless of their associated genomic mutations. Reverse-engineering approaches showed that these cooperators belong to a single transcriptional gene network, enriched in genes mutated in AMLs, where perturbation of single genes modifies expression of others. Their gene-ontology analysis showed enrichment of genes directly involved in cell proliferation control. Therefore, the pool of PML-RARA cooperating mutations appears large and heterogeneous, but functionally equivalent and deregulated in the majority of APLs and AMLs. Our data suggest that the high heterogeneity of DNA mutations in APLs and AMLs can be reduced to patterns of gene expression deregulation of a single 'mutated' gene network.

Potential involvement of mineralocorticoid receptor activation in the pathogenesis of central serous chorioretinopathy: case report.

BACKGROUND: Recently it has been suggested that excessive glucocorticoid-dependent choroidal mineralocorticoid receptor (MR) activation may be involved in the pathogenesis of central serous chorioretinopathy (CSCR). AIM: To present a 38 year-old woman with an impressive improvement of CSCR following MR antagonist eplerenone administration. CASE REPORT: At presentation, visual acuity (VA) was 0.2 in the left eye and 1.0 in the right eye. Optical coherence tomography (OCT) of the left eye showed extended serous retinal detachment including the macular area. RESULTS: After six weeks of treatment with eplerenone (25 mg/day) total resorption of subretinal fluid with an increase in VA to 0.8 was observed. At that point the therapy with eplerenone was discontinued, with no recurrence in the left eye during five months follow-up. Two months after the discontinuation of eplerenone, subretinal fluid accumulation in the right eye was revealed by OCT. Four weeks after reintroducing the treatment with eplerenone (25 mg/day) almost total resorption of subretinal fluid in the right eye was observed. CONCLUSIONS: The effectiveness of MR antagonism in unresolved CSCR supports the hypothesis that excessive choroidal MR activation may be a potential pathological pathway leading to CSCR, and MR blockage may be an effective treatment option for CSCR. Controlled clinical trials are necessary to evaluate this therapeutic approach.

The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha.

In acute promyelocytic leukemia (APL) the retinoic acid receptor alpha (RARα) becomes an oncogene through the fusion with several partners, mostly with promyelocytic leukemia protein (PML), all of which have in common the presence of a self-association domain. The new fusion proteins, therefore, differently from the wild-type RARα, which forms only heterodimers with retinoic X receptor alpha, are also able to homo-oligomerize. The presence of such a domain has been suggested to be crucial for the leukemogenic potential of the chimeric proteins found in APL blasts. Whether or not any self-association domain is sufficient to bestow a leukemogenic activity on RARα is still under investigation. In this work, we address this question using two different X-RARα chimeras, where X represents the coiled-coil domain of PML (CC-RARα) or the oligomerization portion of the yeast transcription factor GCN4 (GCN4-RARα). We demonstrate that in vitro both proteins have transforming potential, and recapitulate the main PML-RARα biological properties, but CC-RARα is uniquely able to disrupt PML nuclear bodies. Indeed, in vivo only the CC-RARα chimera induces efficiently APL in a murine transplantation model. Thus, the PML CC domain represents the minimal structural determinant indispensable to transform RARα into an oncogenic protein.

Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation.

Terminal differentiation of blood cells requires the concerted action of a series of transcription factors that are expressed at specific stages of maturation and function in a cell-type and dosage-dependent manner. Leukemogenic oncoproteins block differentiation by subverting the normal transcriptional status of hematopoietic precursor cells. Pirin (PIR) is a putative transcriptional regulator whose expression is silenced in cells bearing the acute myeloid leukemia-1 eight-twenty-one (AML1/ETO) and promyelocytic leukemia/retinoic acid receptor (PML/RAR) leukemogenic fusion proteins. A role for PIR in myeloid differentiation has not to date been reported. In this study we show that PIR expression is significantly repressed in a large proportion of acute myeloid leukemias (AMLs), regardless of subtype or underlying karyotypic abnormalities. We show that PIR expression increases during in vitro myeloid differentiation of primary hematopoietic precursor cells, and that ablation of PIR in the U937 myelomonocytic cell line or in murine primary hematopoietic precursor cells results in impairment of terminal myeloid differentiation. Gene expression profiling of U937 cells after knockdown of PIR revealed increased expression of genes associated with the early phases of hematopoiesis, in particular, homeobox A (HOXA) genes. Our results suggest that PIR is required for terminal myeloid maturation, and its downregulation may contribute to the differentiation arrest associated with AML.

The effect of selective sst1, sst2, sst5 somatostatin receptors agonists, a somatostatin/dopamine (SST/DA) chimera and bromocriptine on the "clinically non-functioning" pituitary adenomas in vitro.

The aim of the work was to investigate the effects of somatostatin analogs acting selectively on sst1 (BIM-23926), sst2 (BIM-23120) and sst5 (BIM-23206) receptor subtypes on the viability of "clinically non-functioning" pituitary adenomas in vitro. The effects of native SST (SST-14), a SST/DA chimera (BIM-23A387) and a D(2)-dopamine receptor agonist bromocriptine (BC) were also examined. The study was performed on 10 surgically removed pituitary macroadenomas, diagnosed before surgery as "non-functioning". A part of each tumor was mechanically dispersed and digested with collagenase to isolate the tumoral cells. Another part of each tumor was fixed, embedded in paraffin and immunostained to reveal the pituitary hormones and SST receptor subtypes (sst1, sst2A, sst2B, sst3, sst4, sst5). The tumoral cell suspensions were incubated for 24 h with the substances mentioned above. The quantity of viable cells was estimated using the EZ4U system. The results were compared with the immunohistochemical evaluation of the hormonal profile of adenoma and the sst receptor subtype immunoreactivities present. The findings indicate that selective sst1, sst2 and sst5 receptors agonists, SST/DA chimera and D(2)-dopamine receptor agonist bromocriptine affect the viability of some, but not all, "clinically non-functioning" pituitary adenomas in vitro. The most effective was bromocriptine. The investigated somatostatin analogs including SST/DA chimera exerted roughly similar inhibitory effects. Further studies are needed to fully evaluate the potential usefulness of these compounds in the pharmacological treatment of "non-functioning" pituitary tumors.

Anti-tumoral action of octreotide and bromocriptine on the experimental rat prolactinoma: anti-proliferative and pro-apoptotic effects.

OBJECTIVES: The purpose of the study was to compare the effects of bromocriptine (BC) - D-2 receptor agonist and octreotide (OCT) - somatostatin analog on the tumor weight, prolactin (PRL) secretion, cell proliferation and apoptosis in the diethylstilboestrol (DES)-induced rat prolactinoma. MATERIAL AND METHODS: Male four-week Fisher 344 rats were used in the experiment. The animals were implanted subcutaneously (s.c.) with capsules containing DES. Six weeks after the implantation the rats were given OCT (2 x 25 microg/animal/24 h s.c.) or BC (3 mg/kg b.w./24 h s.c.) for 10 days. The incorporation of bromodeoxyuridine (BrDU) into the tumor cell nuclei was used as an index of cell proliferation (labeling index - LI). The labeling of nuclear DNA fragmentation according to the TUNEL method was considered as an index of apoptosis (AI). PRL was measured by radioimmunoassay (RIA). RESULTS: It has been found that OCT and BC significantly decreased the tumor weight and LI of tumor cells to the same extent. Both OCT and BC suppressed the PRL levels, but the inhibitory effect of BC was stronger than that of OCT. BC and OCT significantly enhanced the number of apoptotic cells in the tumor, but the pro-apoptotic effect of BC was more pronounced. The joint treatment exerted additive effects on tumor mass reduction, PRL secretion and cell proliferation, but OCT attenuated the pro-apoptotic effect of BC. CONCLUSIONS: Summing up, both OCT and BC inhibit PRL secretion and cell proliferation. The anti-tumoral action of BC, and to some extent the action of OCT, is also connected with induction of apoptosis.

Angiotensins II and IV stimulate the rat adrenocortical cell proliferation acting via different receptors.

OBJECTIVE: The effects of angiotensins II (Ang II) and IV (Ang IV,3-8 fragment of angiotensin II) on the adrenocortical cell proliferation have been investigated in the rat. METHODS: The male adult Wistar rats were injected subcutaneously with saline, captopril or captopril together with either Ang II or Ang IV. A part of animals received additionally losartan - an antagonist of AT1 subtype of angiotensin receptors. Bromodeoxyuridine (BrDU) incorporation into cell nuclei was used as the index of cell proliferation. RESULTS: It was found that both Ang II and Ang IV increased the BrDU labeling in the adrenal cortex of captopril-pretreated rats. This effect involved mainly the zona glomerulosa cells. The proliferogenic effect of Ang II was blocked by AT1 receptor antagonist losartan. In contrast, losartan did not block the effect of Ang IV. CONCLUSION: Both Ang II and Ang IV stimulate the adrenocortical cell proliferation in the rat, but they act via different receptors - AT1 in the case of Ang II and non-AT1 (probably AT4) in the case of Ang IV.

[Transient ST segment elevation after electrical cardioversion of atrial fibrillation]. / Przemijajace uniesienie odcinka ST elektrokardiogramu po kardiowersji elektrycznej migotania przedsionków.

In 50 patients (30F, 20M), aged 47 +/- 8 who underwent artificial heart valve implantation, the transient ST segment elevation (uST) of at least 0.1 mV on ECG immediately after electrical cardioversion (KE) of atrial fibrillation (MP) was evaluated. uST of 2 +/- 0.7 mV, lasting for 1.5 +/- 0.8 minutes was observed in 52% of cases (15F, 9M). Occurrence of uST correlated significantly with the following parameters: enlarged left atrium, high values of energy delivered during KE, history of more than cardiosurgical operation. Inversely, uST did not depend on duration of MP, efficacy of KE, BMI and the time span between the operation and KE.

[The frequency of cytomegalovirus infection (CMV) in patients immunocompromised patients with malignant and nonmalignant blood disorders]. / Czestosc zakazenia wirusem cytomegalii (CMV) u chorych z niedoborem immunologicznym w przebiegu zlosliwych i niezlosliwych chorób krwi.

Studies on CMV infection were carried out in a group of 110 patients, aged from 15 to 78 (average 38), treated in the Department of Haematology. During the course of observation most of the patients were examined repeatedly. Diagnosis was based on serology (CFT, ELISA) and virus isolation from the clinical material. Primary infection (seroconversion) was confirmed in 4 (21%) out of 19 seronegative patients. Seropositive patients comprised 83 per cent. Active CMV infection was determined in 20 (22%) of those patients.

[Apoptosis (programmed cell death) in the immune system and hemopoiesis]. / Apoptoza (programowana smierc komórki) w ukladzie immunologicznym i hemopoezie.

Apoptosis, or programmed cell death, is a series of controlled sequential events resulting in the demise of cells without evoking an inflammatory response. Although first described 20 years ago, this phenomenon evokes now renewed interest in this phenomenon, particularly in the light of our greater understanding of cellular signalling pathways and their genetic control. This is especially pertinent to haemopoiesis and overall maintenance of a functional immune system.