CathepsinKCre mediated deletion of ßcatenin results in dramatic loss of bone mass by targeting both osteoclasts and osteoblastic cells.

It is well established that activation of Wnt/ßcatenin signaling in the osteoblast lineage leads to an increase in bone mass through a dual mechanism: increased osteoblastogenesis and decreased osteoclastogenesis. However, the effect of this pathway on the osteoclast lineage has been less explored. Here, we aimed to examine the effects of Wnt/ßcatenin signaling in mature osteoclasts by generating mice lacking ßcatenin in CathepsinK-expressing cells (Ctnnb1f/f;CtsKCre mice). These mice developed a severe low-bone-mass phenotype with onset in the second month and in correlation with an excessive number of osteoclasts, detected by TRAP staining and histomorphometric quantification. We found that WNT3A, through the canonical pathway, promoted osteoclast apoptosis and therefore attenuated the number of M-CSF and RANKL-derived osteoclasts in vitro. This reveals a cell-autonomous effect of Wnt/ßcatenin signaling in controlling the life span of mature osteoclasts. Furthermore, bone Opg expression in Ctnnb1f/f;CtsKCre mice was dramatically decreased pointing to an additional external activation of osteoclasts. Accordingly, expression of CathepsinK was detected in TRAP-negative cells of the inner periosteal layer also expressing Col1. Our results indicate that the bone phenotype of Ctnnb1f/f;CtsKCre animals combines a cell-autonomous effect in the mature osteoclast with indirect effects due to the additional targeting of osteoblastic cells.

Adenosine Receptor Blockade by Caffeine Inhibits Carotid Sinus Nerve Chemosensory Activity in Chronic Intermittent Hypoxic Animals.

Adenosine is a key excitatory neurotransmitter at the synapse between O(2)-sensing chemoreceptor cells-carotid sinus nerve (CSN) endings in the carotid body (CB). Herein, we have investigated the significance of adenosine, through the blockade of its receptors with caffeine, on the CB hypoxic sensitization induced by chronic intermittent hypoxia (CIH) in the rat. CIH animals were obtained by submitting rats during 15 days from 8:00 to 16:00 to 10 %O(2) for 40 s and 20 % O(2) for 80 s (i.e., 30 episodes/h). Caffeine (1 mM) was tested in spontaneous and 5 %O(2) evoked-CSN chemosensory activity in normoxic and CIH animals. CIH decreased basal spontaneous activity but increased significantly CSN activity evoked by acute hypoxia. Caffeine did not modify basal spontaneous activity in normoxic rats, but decreased significantly by 47.83 % basal activity in CIH animals. In addition, acute application of caffeine decreased 49.31 % and 56.01 % the acute hypoxic response in normoxic and CIH animals, respectively. We demonstrate that adenosine contributes to fix CSN basal activity during CIH, being also involved in hypoxic CB chemotransduction. It is concluded that adenosine participates in CB sensitization during CIH.

Carotid body function and ventilatory responses in intermittent hypoxia. Evidence for anomalous brainstem integration of arterial chemoreceptor input.

Obstructive sleep apnea is a frequent medical condition consisting in repetitive sleep-related episodes of upper airways obstruction and concurrent events of arterial blood hypoxia. There is a frequent association of cardiovascular diseases and other pathologies to this condition conforming the obstructive sleep apnea syndrome (OSAS). Laboratory models of OSAS consist in animals exposed to repetitive episodes of intermittent hypoxia (IH) which also develop cardiovascular pathologies, mostly hypertension. The overall OSAS pathophysiology appears to be linked to the repetitive hypoxia, which would cause a sensitization of carotid body (CB) chemoreflex and chemoreflex-driven hyperreactivity of the sympathetic nervous system. However, this proposal is uncertain because hyperventilation, reflecting the CB sensitization, and increased plasma CA levels, reflecting sympathetic hyperreactivity, are not constant findings in patients with OSAS and IH animals. Aiming to solve these uncertainties we have studied the entire CB chemoreflex arch in a rat model of IH, including activity of chemoreceptor cells and CB generated afferent activity to brainstem. The efferent activity was measured as ventilation in normoxia, hypoxia, and hypercapnia. Norepinephrine turnover in renal artery sympathetic endings was also assessed. Findings indicate a sensitization of the CB function to hypoxia evidenced by exaggerated chemoreceptor cell and CB afferent activity. Yet, IH rats exhibited marked hypoventilation in all studied conditions and increased turnover of norepinephrine in sympathetic endings. We conclude that IH produces a bias in the integration of the input arising from the CB with a diminished drive of ventilation and an exaggerated activation of brainstem sympathetic neurons.

Effects of cigarette smoke and hypoxia on pulmonary circulation in the guinea pig.

Cigarette smoke (CS) and chronic hypoxia (CH) can produce pulmonary hypertension. Similarities and differences between both exposures and their interaction have not been explored. The aim of the present study was to investigate the effects of CS and CH, as single factors or in combination, on the pulmonary circulation in the guinea pig. 51 guinea pigs were exposed to CS for 12 weeks and 32 were sham-exposed. 50% of the animals in each group were additionally exposed to CH for the final 2 weeks. We measured pulmonary artery pressure (P(pa)), and the weight ratio between the right ventricle (RV) and left ventricle plus the septum. Pulmonary artery contractility in response to noradrenaline (NA), endothelium-dependent vasodilatation and distensibility were evaluated in organ bath chambers. The number of small intrapulmonary vessels showing immunoreactivity to smooth muscle (SM) α-actin and double elastic laminas was assessed microscopically. CS and CH induced similar increases of P(pa) and RV hypertrophy (p<0.05 for both), effects that were further enhanced when both factors were combined. CH increased the contractility to NA (p<0.01) and reduced the distensibility (p<0.05) of pulmonary arteries. Animals exposed to CS showed an increased number of small vessels with positive immunoreactivity to SM α-actin (p<0.01) and those exposed to CH a greater proportion of vessels with double elastic laminas (p<0.05). We conclude that CH amplifies the detrimental effects of CS on the pulmonary circulation by altering the mechanical properties of pulmonary arteries and enhancing the remodelling of pulmonary arterioles.

Effects of intermittent hypoxia on blood gases plasma catecholamine and blood pressure.

Obstructive sleep apnoea syndrome (OSAS) is a disorder characterized by repetitive episodes of complete (apnoea) or partial (hypopnoea) obstruction of airflow during sleep. The severity of OSAS is defined by the apnoea hypopnoea index (AHI) or number of obstructive episodes. An AHI greater than 30 is considered severe, but it can reach values higher than 100 in some patients. Associated to the OSA there is high incidence of cardiovascular and neuro-psychiatric pathologies including systemic hypertension, stroke, cardiac arrhythmias and atherosclerosis, diurnal somnolence, anxiety and depression. In the present study we have used a model of intermittent hypoxia (IH) of moderately high intensity (30 episodes/h) to evaluate arterial blood gases and plasma catecholamines as main effectors in determining arterial blood pressure. Male rats were exposed toIH with a regime of 80s, 20% O(2) // 40s, 10%O(2), 8 h/day, 8 or 15 days.Lowering the breathing atmosphere to 10% O(2) reduced arterial blood PO(2) to 56.9 mmHg (nadir HbO(2) 86, 3%). Plasma epinephrine (E) and norepinephrine (NE) levels at the end of 8 and 15 days of IH showed a tendency to increase, being significant the increase of norepinephrine (NE) levels in the group exposed to intermittent hypoxia during 15 days. We conclude that IH causes an increase in sympathetic activity and a concomitant increase in NE levels which in turn would generate an increase in vascular tone and arterial blood pressure.

Chemoreception in the context of the general biology of ROS.

Superoxide anion is the most important reactive oxygen species (ROS) primarily generated in cells. The main cellular constituents with capabilities to generate superoxide anion are NADPH oxidases and mitochondrial respiratory chain. The emphasis of our article is centered in critically examining hypotheses proposing that ROS generated by NADPH oxidase and mitochondria are key elements in O(2)-sensing and hypoxic responses generation in carotid body chemoreceptor cells. Available data indicate that chemoreceptor cells express a specific isoform of NADPH oxidase that is activated by hypoxia; generated ROS acting as negative modulators of the carotid body (CB) hypoxic responses. Literature is also consistent in supporting that poisoned respiratory chain can produce high amounts of ROS, making mitochondrial ROS potential triggers-modulators of the CB activation elicited by mitochondrial venoms. However, most data favour the notion that levels of hypoxia, capable of strongly activating chemoreceptor cells, would not increase the rate of ROS production in mitochondria, making mitochondrial ROS unlikely triggers of hypoxic responses in the CB. Finally, we review recent literature on heme oxygenases from two perspectives, as potential O(2)-sensors in chemoreceptor cells and as generators of bilirubin which is considered to be a ROS scavenger of major quantitative importance in mammalian cells.

[Subacute thyroiditis associated with positive antibodies to the Epstein-Barr virus]. / Tiroiditis subaguda asociada a anticuerpos positivos al virus de Epstein-Barr.

Subacute thyroiditis is an inflammatory disorder of the thyroid caused probably by viruses. It is clinically characterized by the presence of anterior cervical pain and/or painful goiter, and rarely as fever of unknown origin or as prolonged fever syndrome. We report a case of a 49-year-old female admitted to the hospital because of fever during last month, leukocytosis and accelerated erythrocyte sedimentation rate. Following observation, slight tenderness over the thyroid gland and signs of hyperthyroidism occurred. After the laboratory studies, low thyroidal radioactive iodine uptake and fine-needle aspiration cytology (FNAC) of thyroid, she was diagnosed of subacute thyroiditis with hyperthyroidism. We believe that the etiologic agent was the Epstein-Barr virus because heterophile and Epstein-Barr virus-specific antibodies were positive. The patient was treated with acetaminophen (1.500 mg/day) with prompt and complete resolution of the clinical and laboratory abnormalities. There has been no recurrence of the disease during a 1 year follow-up.

Tiroiditis subaguda asociada a anticuerpos positivos al virus de Epstein-Barr / Subacute thyroiditis associated with positive Epstein-Barr virus antibodies

Presentamos el caso clínico de una paciente de 49 años de edad que ingresó en el hospital con el diagnóstico de SFP de 1 mes de evolución, leucocitosis y aumento de la velocidad de sedimentación globular. Varios días después desarrolla molestias en región anterior del cuello y signos de hipertiroidismo. Tras los resultados de las pruebas complementarias (bioquímicos, hormonales, gammagrafía tiroidea y punción aspiración con aguja fina -PAAF- de tiroides) fue diagnosticada de Tiroiditis subaguda con hipertiroidismo. Nosotros pensamos que el agente etiológico fue el virus de Epstein-Barr ya que los anticuerpos heterófilos y específicos fueron positivos. La paciente fue tratada con paracetamol a la dosis de 1.500 mg/día con recuperación completa sin recidiva posterior tras 1 año de seguimiento (AU)

[Long-term survival in childhood acute lymphocitic leukemia (author's transl)]. / Supervivencia a largo plazo en la leucosis linfoblástica aguda infantil.

Long-term results in the treatment of 116 patients of acute lymphocitic leukemia with ages between six months and seven years are reported. A first group A, formed by 76 patients, was treated with prednisone and vincristine as induction protocol and maintenance therapy with 6-mercaptopurine or methotrexate. No neuromeningeal prophylaxis was made, except some cases in which intratecal methotrexate was applied. 27 patients are alive, 21 of them (27,6%) remain in complete remission for more than three years. A second group B, formed by 40 patients, was treated more recently; with an induction protocol composed by prednisone, vincristine and L-asparaginase. All patients in this group received cranial irradiation and intratecal methotrexate. 31 patients are alive (77,5%), 13 of them (32,5%) remain in complete remission for more than two years. The evolution period in this group B is shorter, but some features are exposed which suggest the possibility of long-term better results.

[Hodgkin's disease in small children (author's transl)]. / La enfermedad de Hodgkin en el niño en edad preescolar

17 cases of Hodgkin's disease are reported, seen in a ten year period. Age of patients oscillated between three and seven years. There was a predominance of mixed cellularity type in histologic pattern. Most of patients were diagnosed in advanced clinical stages. Primary sign of disease was presence of cervical adenopathies and there were few cases of thoracic disease. Treatment consisted in radiotherapy and chemotherapy, according to histological type and clinical stage. Survival in our serie is of 53.3% with periods of observation from six months to seven years.

[Long term evolution in Blackfan-Diamond hypoplastic anemia (author's transl)]. / Evolución a largo plazo en la anemia hipoplásica tipo Blackfan-Diamond

Six cases of Blackfan-Diamond hypoplastic anemia are reported. Five were initiated within six months of life. All cases showed intense anemia, severe reticulopenia and hypersideremia. Two of them had associated malformations. Treatment was established with Dexametasone at high doses, followed by a maintenance treatment at lower doses. A partial response was obtained in all cases. Treatment with deforroxiamine was used in order to paliate hemosiderosis. Two cases developped microangiopathic hemolitic anemia; relations with primary disease could not be determined.