Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins.

Osteoporosis is associated with both atherosclerosis and vascular calcification. No mechanism yet explains the parallel progression of these diseases. Here, we demonstrate that osteoclasts (OCL) depend on lipoproteins to modulate cellular cholesterol levels and that this controls OCL formation and survival. Removal of cholesterol in OCL via high-density lipoprotein or cyclodextrin treatment dose-dependently induced apoptosis, with actin disruption, nuclear condensation and caspase-3 activation. One mechanism linked to the induction of OCL apoptosis was the cell-type-specific failure to induce HMG-CoA reductase mRNA expression, suggesting an absence of feedback regulation of de novo cholesterol biosynthesis. Furthermore, cyclodextrin treatment substantially suppressed essential M-CSF and RANKL-induced survival signaling pathways via Akt, mTOR and S6K. Consistent with these findings, cholesterol delivery via low-density lipoprotein (LDL) significantly increased OCL viability. Interestingly, OCLs from the LDL receptor (LDLR)-/- mouse exhibited reduced size and lifespan in vitro. Remarkably, LDLR+/+ OCL in lipoprotein-deficient medium phenocopied LDLR-/- OCL, while fusion and spreading of LDLR-/- OCL was rescued when cholesterol was chemically delivered during differentiation. With hyperlipidemia being associated with disease of the vascular system and bone, these findings provide novel insights into the selective lipoprotein and cholesterol dependency of the bone resorbing cell. Cell Death and Differentiation (2004) 11, S108-S118. doi:10.1038/sj.cdd.4401399 Published online 12 March 2004

Heliox improves gas exchange during high-frequency ventilation in a pediatric model of acute lung injury.

Because heliox has a lower density as compared with air, we postulated that heliox would improve gas exchange during high-frequency oscillatory ventilation (HFOV) in a model of acute lung injury. In a prospective, cross-over trial, we studied 11 piglets with acute lung injury created by saline lavage. With initial conditions of permissive hypercapnia (Pa(CO(2)) 55-80 mm Hg), each piglet underwent HFOV with a fixed mean airway pressure, pressure oscillation, and ventilatory frequency. The following gas mixtures were used: oxygen-enriched air (60% O(2)/40% N(2)) and heliox (60% O(2)/ 40% He and 40% O(2)/60% He). Compared with oxygen-enriched air, the 40% and 60% helium gas mixtures reduced Pa(CO(2)) by an average of 10.5 and 20.3 mm Hg, respectively. A modest improvement in oxygenation was seen with the 40% helium mixture. We conclude that heliox significantly improves carbon dioxide elimination and modestly improves oxygenation during HFOV in a model of acute lung injury. On the basis of test lung data and plethysmography measurements, we also conclude that heliox improves carbon dioxide elimination primarily through increased tidal volume delivery. Although heliox improved gas exchange during HFOV in our model, increased tidal volume delivery may limit clinical applicability.

Tidal volumes for ventilated infants should be determined with a pneumotachometer placed at the endotracheal tube.

Many ventilators measure expired tidal volume (VT) without compensation either for the compliance of the ventilator circuit or for variations in the circuit setup. We hypothesized that the exhaled VT measured with a conventional ventilator at the expiratory valve would differ significantly from the exhaled VT measured with a pneumotachometer placed at the endotracheal tube. To investigate this we studied 98 infants and children requiring conventional ventilation. We used linear regression analysis to compare the VT obtained with the pneumotachometer with the ventilator-measured volume. An additional comparison was made between the pneumotachometer volume and a calculated effective VT. For infant circuits (n = 70), our analysis revealed a poor correlation between the expiratory VT measured with the pneumotachometer and the ventilator-measured volume (r(2) = 0.54). Similarly, the expiratory VT measured with the pneumotachometer did not correlate with the calculated effective volume (r(2) = 0.58). For pediatric circuits (n = 28), there was improved correlation between the expiratory VT measured with the pneumotachometer and both the ventilator-measured volume and the calculated effective VT (r(2) = 0.84 and r(2) = 0.85, respectively). The data demonstrate a significant discrepancy between expiratory VT measured at a ventilator and that measured with a pneumotachometer placed at the endotracheal tube in infants. Correcting for the compliance of the ventilator circuit by calculating the effective VT did not alter this discrepancy. In conventionally ventilated infants, exhaled VT should be determined with a pneumotachometer placed at the airway.

Deadspace to tidal volume ratio predicts successful extubation in infants and children.

OBJECTIVE: Using a modification of the Bohr equation, single-breath carbon dioxide capnography is a noninvasive technology for calculating physiologic dead space (V(D)/V(T)). The objective of this study was to identify a minimal V(D)/V(T) value for predicting successful extubation from mechanical ventilation in pediatric patients. DESIGN: Prospective, blinded, clinical study. SETTING: Medical and surgical pediatric intensive care unit of a university hospital. PATIENTS: Intubated children ranging in age from 1 wk to 18 yrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-five patients were identified by the pediatric intensive care unit clinical team as meeting criteria for extubation. Thirty minutes before the planned extubation, each patient was begun on pressure support ventilation set to deliver an exhaled tidal volume of 6 mL/kg. After 20 mins on pressure support ventilation, an arterial blood gas was obtained, V(D)/V(T) was calculated, and the patient was extubated. Over the next 48 hrs, the clinical team managed the patient without knowledge of the preextubation V(D)/V(T) value. Of the 45 patients studied, 25 had V(D)/V(T) < or =0.50. Of these patients, 24 of 25 (96%) were successfully extubated without needing additional ventilatory support. In an intermediate group of patients with V(D)/V(T) between 0.50 and 0.65, six of ten patients (60%) successfully extubated from mechanical ventilation. However, only two of ten patients (20%) with a V(D)/V(T) > or =0.65 were successfully extubated. Logistic regression analysis revealed a significant association between lower V(D)/V(T) and successful extubation. CONCLUSIONS: A V(D)/V(T) < or =0.50 reliably predicts successful extubation, whereas a V(D)/V(T) >0.65 identifies patients at risk for respiratory failure following extubation. There appears to be an intermediate V(D)/V(T) range (0.51-0.65) that is less predictive of successful extubation. Routine V(D)/V(T) monitoring of pediatric patients may permit earlier extubation and reduce unexpected extubation failures.

M-CSF neutralization and egr-1 deficiency prevent ovariectomy-induced bone loss.

Increased stromal cell production of M-CSF, an event caused by enhanced phosphorylation of the nuclear protein Egr-1, is central to the mechanism by which estrogen (E2) deficiency upregulates osteoclast (OC) formation. However, the contribution of enhanced M-CSF production to the bone loss induced by E2 deficiency remains to be determined. We found that treatment with an Ab that neutralizes M-CSF in vivo completely prevents the rise in OC number, the increase in bone resorption, and the resulting bone loss induced by ovariectomy (ovx). We also found that adult, intact Egr-1-deficient mice, a strain characterized by maximally stimulated stromal cell production of M-CSF, exhibit increased bone resorption and decreased bone mass. In these mice, treatment with anti-M-CSF Ab restored normal levels of bone resorption, thus confirming that increased M-CSF production accounts for the remodeling abnormalities of Egr-1-deficient mice. Consistent with the failure of ovx to further increase M-CSF production in Egr-1-deficient mice, ovx neither increased bone resorption further, nor caused bone loss in these animals. In summary, the data demonstrate that E2 deficiency induces M-CSF production via an Egr-1-dependent mechanism that is central to the pathogenesis of ovx-induced bone loss. Thus, Egr-1 and M-CSF are critical mediators of the bone sparing effects of E2 in vivo.

Parathyroid hormone and prostaglandin E2 preferentially increase luciferase levels in bone of mice harboring a luciferase transgene controlled by elements of the pro-alpha1(I) collagen promoter.

Type I collagen is the major extracellular protein in bone, tendons, ligaments, and skin. DNA elements of the mouse pro-alpha1 (I) collagen promoter were shown to drive the bone-selective expression of a luciferase transgene. We examined whether this expression can be used to evaluate the effect of anabolic agents on bone formation in vivo. Treatment of either intact males, intact females, or ovariectomized (ovx) mice with 80 microg/kg/day of human parathyroid hormone (hPTH), for 5 to 11 days increased luciferase levels in tibiae by two- to threefold compared with vehicle-treated mice. The increases were tissue specific, as no changes in skin luciferase expression were observed. Treatment with prostaglandin E2, a potent bone anabolic agent, for 11 days also increased expression of the transgene in bone, but not in skin. Treatment with dihydrotestosterone (DHT) for 11 days increased luciferase activity in skin, but not in bone. Histomorphometric analysis revealed that 28-day treatment with PTH increased bone formation; 60-day treatment of OVX mice with DHT did not. These findings show a correlation between bone formation and the expression of a transgene driven by DNA elements of the mouse pro-alpha1 (I) collagen promoter, suggesting that this expression can be used as an indicator and provide a faster readout for the ability of agents to stimulate bone formation in this mouse strain.

Enhanced MR in the acute phase of Wernicke encephalopathy.

MR in a patient with Wernicke encephalopathy showed enhancement in the mamillary bodies and inferior quadrigeminal plate. These findings pointed to the correct diagnosis, which can be difficult to make in patients who are not alcoholics.

Methadone maintenance detoxification fear: a study of its components.

These studies added three hypothesized fear components to the Detoxification Fear Survey Schedule (DFSS-14) and compared its psychometric properties to the original. Two disparate methadone maintenance populations (N = 226) were used in scale development. Thirty-one items and three factors emerged. A validation sample (N = 159) from two diverse methadone maintenance populations yielded a 27-item scale that discriminated between interview-diagnosed detoxification fear and non-fear (91.8% and 85.4% correctly classified). Finally, in methadone maintenance patients from three disparate programs in which the prevalence of detoxification fear was known, the DFSS-27 and DFSS-14 were compared. The DFSS-27 showed substantially improved sensitivity. The DFSS-27 seems a useful screen for detoxification fear in methadone maintenance, may aid intervention planning, and may prove a useful interventions outcome measure.

[Hormonal evaluation in the diagnosis of obesity associated with "primary empty sella"]. / Valutazione ormonale nella diagnosi di obesità associata a "primary empty sella".

To determine whether obesity associated with "primary empty sella" (PES) had a characteristic hormonal pattern, we evaluated the hormonal profile in 24 simple obese and 19 obese-PES women. The latter group showed a significant delta-GH and LH impaired levels as well as plasma beta-EP significantly higher. Hence, the beta-EP measurement could be used to predict the hormonal response in these women.

Intellectual ability of children after perinatal cytomegalovirus infection.

The intellectual ability of 16 children who had not had congenital cytomegalovirus (CMV) infection, but acquired it before the age of six months, was compared with that of two other groups: one comprising 32 children who had had CMV-excreting mothers but who were not infected themselves: the other comprising 18 healthy controls. Serial audiological, ophthalmological and psychometric examinations were performed. The only statistically significant difference found was that the children with acquired CMV infection had lower mean arithmetic scores. The results suggest that healthy term infants who acquire early CMV infection are not at increased risk of intellectual impairment.

[Ambulatory radicular myelography with iopamidol]. / Radicolomielografia ambulatoriale con Iopamidolo.

The appearance of side effects was monitored in 70 selected patients who underwent radiculography and myelography. After the examination, a rapid return to normal activity was recommended. In accordance with literature, no greater incidence of side effects was found in patients who were allowed to get up soon after myelography or radiculography, than in patients confined to bed for some hours. These results are essentially attributable to the low toxicity of the contrast medium used in this study (Iopamidol), and to an adequate hydratation of the patients after examination.

Clinical-angiographic correlations in 132 patients with megadolichovertebrobasilar anomaly.

We have found numerous case reports, but no systematic study of the megadolichovertebrobasilar anomaly ( MDVBA ). The purpose of this paper is to evaluate the relationships between arterial shifts of the vertebro-basilar system and neurological findings in the posterior fossa in our series of 132 cases. We found a high percentage (77.3%) of angiographic-clinical correlations having evaluated the arterial shifts, measured in mm, of the vertebro-basilar system in a frontal and a sagittal plane and concluded that the greater the degree of dislocation, the greater the number of positive cases. Nevertheless it is not possible to predetermine the presence of particular neurosymptomatology related to arterial dislocation degrees.

CT in syringomyelia: three different aspects.

Three different CT aspects of patients with myelographic and clinical syringomyelia patterns are presented. In the first the CT pattern was atypical. The second case is a typical example of opacification of the cavity after contrast enhancement and the third shows re-formation of the cavity 7 years after surgical damage.