Vitamin D Deficiency Predicts Poor Clinical Outcomes in Heart Failure Patients Undergoing Cardiac Resynchronization Therapy.

BACKGROUND AND AIMS: Resynchronization therapy (CRT) improves mortality and induces reverse remodeling in heart failure (HF) patients with reduced ejection fraction and wide QRS. Nonetheless, some patients do not improve despite the optimal medical therapy and right indications for device implantation. Therefore, finding biomarkers suitable for identification of those patients is crucial. Vitamin D plays a classic hormonal role in the regulation of bone metabolism and also has physiological functions in wide range of nonskeletal tissues. Based on recent studies, low levels of vitamin D seem to directly contribute to pathogenesis and worsening of HF. We planned to assess the role of vitamin D levels on clinical outcomes of HF patients undergoing CRT. METHODS AND RESULTS: We enrolled 136 HF patients undergoing CRT. Total plasma vitamin D levels were measured at baseline and 6 months later. Primary endpoint was 5-year all-cause mortality; secondary endpoint was lack of good clinical response, defined as less than 15% increase of left ventricular ejection fraction after six months. During follow-up, 58 patients reached the primary, and 45 patients reached the secondary endpoint. Vitamin D levels less than 24.13 ng/mL predicted 5-year mortality (p = 0.045) and poor clinical response (p = 0.03) after adjusting to all significant baseline predictors. CONCLUSION: Our study showed that vitamin D deficiency has a significant impact in heart failure patients; it is an independent predictor of lack of midterm clinical response and long-term mortality in patients undergoing CRT. Therefore, monitoring vitamin D status of heart failure patients could be of clinical significance.

[Radiation therapy planning for Hodgkin lymphoma: Focus on intensity-modulated radiotherapy, gating, protons. Which techniques to best deliver radiation?] / Technique de radiothérapie du lymphome de Hodgkin : points sur la radiothérapie conformationnelle avec modulation d'intensité, le gating, la protonthérapie. Y a-t-il des techniques à favoriser ?

The optimization of radiotherapy in these young and long-lived survivors raises the question about the interest of using modern techniques to allow a better distribution of the dose. The choice of the irradiation technique must take into account the incidence of side effects related to radiation. In this context, the definition of the target volumes as well as the verification and monitoring of the delivered processing are essential. International recommendations for treatment fields are based on the "involved node radiotherapy" concept. The best irradiation technique to use remains to be defined. The use of intensity-modulated radiotherapy improves the coverage and reduces the dose to the organs at risk with a variable gain depending on the topography of the lymph nodes: upper or lower mediastinum, right or left lateralization, the techniques used. The deep inspiration breath-hold technique allows an increase of the pulmonary volume, extension of the mediastinum with an up down of the heart which make possible to move the planning target volume away from the cardiac structures. The volumetric-modulated arctherapy technique with several arches can be particularly interesting to reduce the dose to the breasts, as well as tomotherapy when bulky disease. Proton therapy with the Bragg peak specificity can play a key role in limiting doses to organs at risk, when robust planning that will take into account geometric and physical uncertainties is available. The heterogeneity of Hodgkin lymphomas in terms of volume, shape and initial location are the key elements to take into account when choosing the preferred radiotherapy technique.

[Role of radiotherapy in the treatment of NK/T-cell nasal type and primary cerebral lymphomas]. / Place de la radiothérapie dans la prise en charge des lymphomes NK/T de type nasal et primitifs cérébraux.

The head and neck are common sites for extranodal non-Hodgkin lymphomas. Radiotherapy plays an important role in the treatment of low-grade lymphomas, with curative or palliative intent. In the case of high-grade lymphomas, its combination with chemotherapy is debated. Its role is however undeniable in two specific entities: NK/T-cell lymphoma NK/T nasal type, and primary central nervous system lymphomas, which are the subject of this review.

An uncommon cause of dysuria solved by "boom-boom" radiotherapy.

BACKGROUND: Chronic lymphocytic leukaemia is a common disease affecting the hematopoietic organs. The disease remains classically indolent for years preceding a blast crisis. However, the disease can affect all parts of the body. We report here an unusual localization. CASE PRESENTATION: A 72-year-old man was followed for 2 years for an indolent chronic lymphocytic leukaemia while he presented a rapidly progressive dysuria. Prostate biopsies were performed concluding to a prostate involvement by the chronic lymphocytic leukaemia. In the absence of progression according to RAI staging system and Binet's classification, he was treated with local low-dose radiotherapy, twice 2 Gy, allowing for a rapid resolution of the symptoms. No systemic treatment was introduced, and 1 year after the completion of his treatment, he is still under watchful waiting strategy for his chronic lymphocytic leukaemia. CONCLUSION: Low-dose radiotherapy is an underused effective strategy in indolent lymphoma. In this case, urinary symptoms from a prostate involvement were relieved non-invasively at low cost.

[Prophylactic axillary radiotherapy for breast cancer]. / Radiothérapie axillaire prophylactique des cancers du sein.

Adjuvant radiotherapy, after breast conserving surgery or mastectomy for breast cancer, improves overall survival while decreasing the risk of recurrence. However, prophylactic postoperative radiotherapy of locoregional lymph nodes for breast cancer, particularly of the axillary region, is still controversial since the benefits and the risks due to axillary irradiation have not been well defined. To begin with, when performing conformal radiotherapy, volume definition is crucial for the analysis of the risk-benefit balance of any radiation treatment. Definition and contouring of the axillary lymph node region is discussed in this work, as per the recommendations of the European Society for Radiotherapy and Oncology (ESTRO). Axillary recurrences are rare, and the recent trend leads toward less aggressive surgery with regard to the axilla. In this literature review we present the data that lead us to avoid adjuvant axillary radiotherapy in pN0, pN0i+ and pN1mi patients even without axillary clearance and to perform it in some other situations. Finally, we propose an update about the potential toxicity of adjuvant axillary irradiation, which is essential for therapeutic decision-making based on current evidence, and to guide us in the evolution of our techniques and indications of axillary radiotherapy.

PAC1 receptor localization in a model nervous system: light and electron microscopic immunocytochemistry on the earthworm ventral nerve cord ganglia.

The presence and pattern of pituitary adenylate cyclase activating polypeptide (PACAP) type I (PAC1) receptors were identified by means of pre- and post-embedding immunocytochemical methods in the ventral nerve cord ganglia (VNC) of the earthworm Eisenia fetida. Light and electron microscopic observations revealed the exact anatomical positions of labeled structures suggesting that PACAP mediates the activity of some interneurons, a few small motoneurons and certain sensory fibers that are located in ventrolateral, ventromedial and intermediomedial sensory longitudinal axon bundles of the VNC ganglia. No labeling was located on large interneuronal systems such as dorsal medial and lateral giant axon systems and ventral giant axons. At the ultrastructural level labeling was mainly restricted to endo- and plasma membranes showing characteristic unequal distribution in various neuron parts. An increasing abundance of PAC1 receptors located on both rough endoplasmic reticulum and plasma membranes was seen from perikarya to neural processes, indicating that intracellular membrane traffic might play a crucial role in the transportation of PAC1 receptors. High number of PAC1 receptors was found in both pre- and postsynaptic membranes in addition to extrasynaptic sites suggesting that PACAP acts as neurotransmitter and neuromodulator in the earthworm nervous system.

A parvalbumin-containing, axosomatic synaptic network in the rat medial septum: relevance to rhythmogenesis.

The medial septal diagonal band complex (MS/DB), made up of cholinergic and GABAergic neurons, plays an important role in the generation of the hippocampal theta rhythm. A GABAergic neuron type in the MS/DB that has fast spiking properties was shown previously to contain parvalbumin immunoreactivity and to form axosomatic connections with unidentified somata. The aim in the current study was to determine the neurochemical identities of these target neurons. In slices and in perfused-fixed brain, staining for parvalbumin immunoreactivity first of all revealed the presence of two types of parvalbumin-positive somata in the MS/DB: medially located neurons with parvalbumin-positive basket-like terminals on them, and more laterally located neurons with fewer parvalbumin-positive contacts on them. In MS/DB slices, the terminals of fast spiking neurons filled with biocytin correspondingly made either numerous contacts that surrounded the parvalbumin-positive cell body in basket-like formation, or 1-5 contacts on a localized patch of the soma. These contacts were shown by electron microscopy to form synaptic junctions. No terminals of biocytin-filled fast spiking neurons were observed on cholinergic neurons, and dual staining in perfused-fixed brain did not reveal the presence of parvalbumin-containing terminals on cholinergic somata. Our results suggest therefore that there are two subtypes of parvalbumin-containing neuron in the MS/DB, and that these are interconnected via axosomatic synapses. The contrasting topographical organization of the two types of parvalbumin-containing neuron suggests that they may receive different types of afferent input, but this will require substantiation in future studies. We propose that generation of rhythmic activity in the MS/DB is controlled by contrasting contributions from two types of parvalbumin-positive neuron, and that the role of the cholinergic neuron is modulatory.

Reproducibility of circadian retinal and optic nerve head blood flow measurements by Heidelberg retina flowmetry.

BACKGROUND/AIM: The Heidelberg retina flowmeter (HRF) is designed to measure retinal capillary blood flow. Previous studies however showed weak reproducibility of data. The intraindividual reproducibility of circadian HRF measurements was examined in healthy subjects in three locations of the retina. METHODS: 36 healthy volunteers (27.3 (SD 4.3) years) were examined by HRF seven times a day (t0-t6). Using a default window of 10 x 10 pixels, three consecutive measurements were performed in three precise focusing planes: superficial, intermediate and deep layer, peripapillary retina, neuroretinal rim and cup, respectively. Images of identical tissue locations identified by capillary landmarks of each layer were selected to quantify the retinal microcirculation of each volunteer. Means and standard deviations of all flow results of a given subject were calculated, at t0-t6 and the coefficients of variation as a measure of reproducibility. RESULTS: The coefficients of variation ranged between 8.4% and 41.0% in the superficial layer (mean 19.8% (SD 8.4%)), 10.6%, and 43.0% in the intermediate layer (mean 24.0% (SD 8.4%)), and 9.9% and 84.0% (mean 29.6% (SD 15.8%)) in the deep layer. CONCLUSIONS: These data show the best reproducibility of measurements in the superficial layer followed by the intermediate and the deep layer. Clinically, this is an unsatisfactory intraindividual reproducibility of flow values in each studied layer.

Variability of the normalised rim/disc area quotient estimated by laser scanning tomography. A comparison with conventional planimetry.

BACKGROUND: The introduction of the laser scanning tomograph raises the possibility of the estimation of optic disc morphology in a less subjective and less time-consuming way than the conventional planimetry of fundus photography. The aim of the present study was to estimate the efficiency of the HRT method in a comparison of data collected in a glaucomatous patient group to planimetric data obtained in young normal volunteers. METHODS: Repeated rim/disc area measurements were done in 10 glaucoma patients with a Heidelberg Retina Tomograph and in a group of five young volunteers with good vision. The intra-photographic, intra-observer examination of the planimetric method was compared to the inter-photographic assessment of the HRT technique. RESULTS: The variability of the mean normalised area ratio quotient was nearly 50% less using laser scanning tomography techniques (mean rim/disc area ratio = 0.17). CONCLUSION: The results show the superiority of HRT over the conventional planimetric technique. Furthermore, the much shorter processing time and the advantages of a computer-based databank in follow-up examination with HRT provides the hope that it could replace the rather time-consuming and subjective manual planimetric technique in the examination of glaucomatous optic nerve conditions.

Differential regulation of vasopressin gene expression in the hypothalamus of endotoxin-treated 14-day-old rat.

The E. coli endotoxin 0111 B4, a lipopolysaccharide (LPS), in a dose of 200 ng/kg body weight/50 microl artificial cerebrospinal fluid (CSF) was given intracisternally to 14-day-old rats. Four hours later CSF, blood and urine were sampled, and consecutive brain sections from the hypothalamic area of the brain were prepared for in situ hybridization. The LPS treatment resulted in a significant (p<0.001) pleocytosis and an elevation of the protein content of the CSF. There were no changes observed in the chemical parameters of the CSF, plasma, blood or urine, i.e. vasopressin (VP) levels, osmolality, Na+ and K+ concentrations, glucose level, pH, bicarbonate or PaCO2, PaO2 values. LPS injection, however, resulted in a significantly (p<0.01) increased VP mRNA level (121% of the control value) in the supraoptic nuclei (SON), but not in the paraventricular nuclei (PVN), as compared to controls. Our findings suggest an early effect of LPS on VP gene expression selectively in the SON of 14-days-old rats. This animal model might be suitable for studying the regulation of VP gene expression and the role of this peptide in the pathogenesis of bacterial meningitis in pediatric patients.

Retinopathy induced in mice by targeted disruption of the rhodopsin gene.

Retinitis pigmentosa (RP) represents the most common mendelian degenerative retinopathy of man, involving death of rod photoreceptors, cone cell degeneration, retinal vessel attenuation and pigmentary deposits. The patient experiences night blindness, usually followed by progressive loss of visual field. Genetic linkage between an autosomal dominant RP locus and rhodopsin, the photoreactive pigment of the rod cells, led to the identification of mutations within the rhodopsin gene in both dominant and recessive forms of RP. To better understand the functional and structural role of rhodopsin in the normal retina and in the pathogenesis of retinal disease, we generated mice carrying a targeted disruption of the rhodopsin gene. Rho-/- mice do not elaborate rod outer segments, losing their photoreceptors over 3 months. There is no rod ERG response in 8-week-old animals. Rho+/- animals retain the majority of their photoreceptors although the inner and outer segments of these cells display some structural disorganization, the outer segments becoming shorter in older mice. These animals should provide a useful genetic background on which to express other mutant opsin transgenes, as well as a model to assess the therapeutic potential of re-introducing functional rhodopsin genes into degenerating retinal tissues.

IgA autoantibodies against human eye muscle antigen detected by western blotting and immunohistochemical methods in Graves' disease.

The presence of IgA autoantibodies against human eye muscle was investigated in 40 patients with Graves' disease (33 had ophthalmopathy). IgA anti-eye muscle antibodies could be demonstrated in sera of patients using western blotting and immunohistochemical methods. For the detection of sera possessing autoantibodies against eye muscle antigen the indirect immunosorbent assay had been used. IgA anti-eye muscle antibodies could be demonstrated in 25 cases and IgG types in 16 cases out of 40 patients. These anti-muscle autoantibodies were associated with eye muscle rather than skeletal muscle, the number of positive cases with the latter being 5/40 for IgG and 2/40 for IgA. Immunoreactive bands of IgA autoantibodies against eye cytosol were found at 84, 64, 45, 40 and 25-23 kDa in 22, 2, 16, 2 and 18 cases, respectively. A difference was observed in the staining of IgG and IgA types of autoantibodies by immunohistochemical analysis of eye muscle tissue. The IgA anti-eye muscle antibodies reacted with muscle fibers and the IgG types showed staining on endomysium. No sera of Graves' disease patients gave staining on skeletal muscle tissue. The results supported the presence of IgA anti-human eye muscle antibodies in patients with Graves' ophthalmopathy, which might play a relevant role in the development of eye disease.

Appearance and some neurochemical features of nitrergic neurons in the developing quail digestive tract.

Using immunocytochemistry, NADPH-diaphorase (NADPHd) histochemistry and electron microscopy, the appearance of nitrergic enteric neurons in different digestive tract regions of the embryonic, neonatal and adult quail was studied in whole mounts and sections. NADPHd was first expressed by embryonic day 4-5 in two distinct locations, namely the mesenchyme of the gizzard primordium and at the caeco-colonic junction. At embryonic day 6, nitrergic neurons had already begun to form a myenteric nerve network in the wall of the proventriculus, gizzard and proximal part of the large intestine and by embryonic day 9, a myenteric network was visualized along the entire digestive tract of the quail. At the level of the stomach, this network was confined to the area covered by the intermediate muscles. By embryonic day 12-13, the NADPHd-positive myenteric neurons in the wall of the distal parts of the blind-ending paired caeca also became organized into ganglia. From this developmental stage on, a submucous nitrergic nerve network, sandwiched between the lamina muscularis mucosae and the luminal side of the outer muscle layer, became prominent in the proventriculus and intestinal walls. In the adult quail, only a minority of the NADPHd-positive neurons stained for vasoactive intestinal polypeptide (VIP) along the intestine. VIP-immunoreactive (IR) cell bodies were frequent in the myenteric plexus but not in the submucous plexus, whereas there were considerable numbers of NADPHd-positive neurons in both these plexuses. Nitrergic fibres were also observed in the outer muscle layer, but were almost absent from the lamina muscularis mucosa and lamina propria, in contrast to the dense VIP-ergic innervation encircling the bases of the intestinal crypts.

The appearance of direct contacts between Auerbach's plexus and smooth muscle cells in the small intestine of the chicken during in ovo development.

Direct contacts between the neural cell bodies of Auerbach's ganglia and the longitudinal smooth muscle cells in the chicken small intestine were demonstrated by electron microscopy during the second half of embryonic development. The possible functional explanation of these contacts is discussed.

Ultrastructure of the developing myenteric plexus of chicken small intestine.

The present ultrastructural study established the main morphological events that occur during the myenteric plexus formation in the chicken duodenum from the 7th day of incubation (E7) up to hatching, with special attention to the appearance of different axon profiles and synaptic contacts. Transmission electron microscopy revealed that the compartmentalization of the enteric mesenchyma into outer and inner zones precedes the sequential morphological maturation of the crest derived cells during myenteric plexus formation. On E7, a slender neuropil was present in the migrating cell clusters, but all the crest derived cells were uniform. In the following stages, the neuronal and enteroglial cells were distinguishable. The first significant sign of neuronal maturation was the morphological heterogeneity in the vesicle population on E11. Progressive changes in the synaptogenesis were identified, and the axosomatic synapses were characteristic around hatching. On E18, a transient direct muscle-ganglion contact with the circular muscle layer was observed, in addition to the permanent ganglionar contact to the longitudinal layer of the muscularis externa.

Relationship between appearance of GABA, fluorogenic monoamines and cytochrome oxidase activity during prenatal morphogenesis of chick myenteric plexus.

The basic histology of the developing embryonic gut wall of the chick was examined on haematein and eosin-stained paraffin sections. In parallel with this, the ontogenic sequence of myenteric plexus formation was followed on whole mounts after NADH diaphorase histochemistry. The presence of nerve elements was verified also by electron microscopy. The appearance of enteric gamma-aminobutyric acid-containing neurons, as an example of an intrinsic inhibitory neuronal system, was studied by using an antiserum against the gamma-aminobutyric acid glutaraldehyde bovine serum albumin conjugate. The development of noradrenergic innervation as an extrinsic inhibitory supply was followed by means of a glyoxylic acid-induced fluorescence method. Cytochrome oxidase activity was detected histochemically. Three consecutive steps of the morphogenesis of the myenteric plexus were revealed; first the appearance of a cellular crest at the mesenteric border on embryonic day 9; second the migration and clustering of nerve cells between embryonic days 10 and 16; then the elongation of neurites on embryonic days 16 and 21. Immunoreactive and also fluorescent fibres were first detected on the 14th day of incubation, while immunopositive cell bodies appeared only after hatching. In the early stages the cytochrome oxidase activity was restricted to the perikarya, while at the end of embryonic development the activity also appeared in the ganglionic neuropile. On the basis of these observations, we concluded that there is a close time relation between the morphogenesis and the biochemical and functional maturation of the myenteric plexus.

[Effect of physical training on children after reconstructive heart surgery]. / Fizikai tréning hatása rekonstrukciós szívmütéten átesett gyermekekre.

The authors composed a programme of physical training for children with congenital valvular defect. The training programme was applied before and after the heart operation. Two years after a successful reconstructive heart operation the fitness condition of 40 children was examined. The average age of the children was 8.0 +/- 3.6 years. Twenty of the children participated and 20 did not participate in the programme. The physical condition of the children who took part in the training was found to be significantly better than that of the others without training.