Regulation of BMP-induced ectopic bone formation by Ahsg.

alpha2-HS-glycoprotein (Ahsg), also known as fetuin is a serum and bone resident glycoprotein, which binds to TGF-beta superfamily members including bone morphogenetic proteins (BMP) and inhibits dexamethasone-induced osteogenesis in bone marrow cultures in vitro. Here we demonstrate that Ahsg reduces cytokine binding to its cognate receptor in HOS osteocyte cells and suppresses intracellular signaling, while in vivo, we test the hypothesis that Ahsg-deficient mice are hyper-responsive to BMP-induced osteogenesis. Human native BMP was implanted into the hindquarter muscles of Ahsg(+/+), Ahsg(+/-) and Ahsg(-/-) mice and 4 weeks later, ossicle formation was analyzed by radiography, bone density scanning (DEXA) and histomorphometry. Alkaline phosphatase (AP) activity was measured in ossicles as a marker for bone cell differentiation, and was significantly higher in Ahsg(-/-) versus Ahsg(+/-) and/or Ahsg(+/+) mice. Ectopic ossicle size in the Ahsg(+/-) mouse was 4-fold greater than that in the wild type (Ahsg(+/+)), and intermediate to that shown in Ahsg(-/-) mouse. Bone mineral density (BMD) was lower in the Ahsg(-/+) and Ahsg(-/-) mice compared to Ahsg(+/+) littermates. The ratio of cortical to cancellous bone was found to be >2-fold higher in Ahsg(-/-) mouse in comparison to the Ahsg(+/+) mice with no significant change in the Ahsg(-/+) mouse. Finally, a significantly higher incidence of satellite ossification; small islands of immature bone, was shown in Ahsg(-/-) mice as compared to Ahsg(+/+) mice. Although Ahsg binds to TGF-beta/BMP and blocks receptor signalling, it may also sequester cytokines in matrix, thereby acting as a reservoir of osteoinductive activity when released. This may explain the non-linear relationship between ectopic bone formation characteristics and Ahsg(+/+), Ahsg(+/-) and Ahsg(-/-) genotypes, although the increase in satellite bone formation might also explain this phenomenon. Our results suggest that Ahsg may be useful for prevention of the heterotopic ossification and the regulation of osteoinductive effects of BMP used with grafts.     

Minimum effective dose of midazolam for sedation of mechanically ventilated neonates

OBJECTIVE: To determine the minimal effective dose (MED) of intravenous midazolam, required for appropriate sedation in 95% of patients, 1 h after drug administration. METHODS: A double-blind dose-finding study using the continual reassessment method, a Bayesian sequential design. Twenty-three newborn infants hospitalized in intensive care unit participated. Inclusion criteria were: (i) post-natal age <28 days, (ii) gestational age >33 weeks, (iii) intubation and ventilatory support required for respiratory distress syndrome, (iv) need for sedation (i.e. one of the six following criteria: agitation or grimacing or crying facial expression before tracheal suctioning, agitation or grimacing or crying facial expression during tracheal suctioning). Each neonate was allocated to a loading dose, ranging from 75 to 200 microg/kg, and a maintenance dose ranging from 37.5 to 100 microg/kg/h. RESULTS: The primary endpoint was the level of sedation 1 h after the onset of infusion. The sedation procedure was classified as a success if all the following clinical criteria were met: no agitation, no grimacing and no crying facial expression before as well as during tracheal suctioning. Based on the 23 patients, the final estimated probability of success was 76.9% (95% credibility interval: 56.6-91.4%) for the 200 microg/kg loading dose. no significant adverse effect was observed. CONCLUSIONS: Continual reassessment is a new approach, suitable for dose-finding study in neonates. this method overcomes some of the ethical, statistical and practical problems associated with this population. Using this method, the MED was estimated to be the 200 mug/kg loading dose of midazolam.     

Cardiopulmonary resuscitation surprise drills for assessing, improving and maintaining cardiopulmonary resuscitation skills of hospital personnel.

BACKGROUND: Cardiopulmonary resuscitation (CPR) is a sudden emergency procedure that requires a rapid and efficient response, and personnel trained in lifesaving procedures. Regular practice and training are necessary to improve resuscitation skills and reduce anxiety among the staff. Western Galilee Hospital has developed simulator programs for surprise CPR training exercises in all hospital departments and units. This study assessed the efficacy of surprise drills. METHODS: Advanced cardiac life-support instructors performed 131 surprise drills between 2003 and 2005, using a computerized simulation mannequin (SIM 4000). Nine criteria were measured and scored in the drill: reaction time, CPR according to ABC principles, calling for doctor, CPR knowledge, CPR skills, resuscitation management, staff work, resuscitation chart, and defibrillator management. Drills were evaluated, discussed, and compared with previous drills from the same department and from other departments. RESULTS: A gradual improvement was observed in the results of the drills held through 2003-2005, more significantly in the medical departments than in the surgical departments and outpatient clinics. The average score in 2005 was 77.2% (P=0.001), compared with 74% (P=0.012) in 2004 and 59% (P<0.001) in 2003. Major improved criteria were calling for doctor, staff work, CPR knowledge, and defibrillator (P<0.05). CONCLUSION: It is our belief that surprise resuscitation drills constitute an effective tool to improve performance in case of a real emergency resuscitation, both on a departmental and a general hospital level.     

Traumatic respiratory insufficiency: comparison of conventional mechanical ventilation to high-frequency positive pressure with low-rate ventilation

Eleven patients suffering severe traumatic respiratory insufficiency were mechanically ventilated using a new system which combined high-frequency positive-pressure ventilation (HFPPV) with low-rate conventional mechanical ventilation (LRCMV). Ten similar patients were ventilated by conventional mechanical ventilation (CMV) with PEEP. HFPPV patients were fully conscious and cooperative during ventilation and did not need sedatives or muscle relaxants. Arterial oxygenation was significantly (p less than .005) better in HFPPV than CMV patients (89.91 +/- 10.24 vs. 78.43 +/- 11.13 torr, respectively), and pulmonary shunt was also better in the HFPPV group (13.1 +/- 4.7% vs. 20.4 +/- 6.4%, p less than .01). Moreover, inspired oxygen concentrations were lower (PaO2/FIO2 197.8 +/- 51.3 in the HFPPV group vs. 130 +/- 46.6 in the CMV group, p less than .005) and the time required for mechanical ventilation was shorter (4.2 +/- 0.91 vs. 6.1 +/- 0.8 days, p less than .1). All HFPPV patients immediately began breathing spontaneously when they were disconnected from the ventilator. We suggest this method as a better ventilatory mode for patients suffering traumatic respiratory insufficiency.     

Hemofiltration in septic ARDS. The artificial kidney as an artificial endocrine lung

Twenty-four patients with high microvascular permeability pulmonary edema were initially treated by means of conventional supportive therapy for 1-12 days. Continued deterioration was treated by predilutional hemofiltration and induced a dramatic improvement in 22/24 patients. Survival was 92%. Sieving coefficients for autacoids and middle molecular weight vasoactive peptides involved in the development of high microvascular permeability pulmonary edema were higher than 0.88 indicating that clearing from blood of these peptides during one pass through the hemofilter is similar to that obtained during one pass through the pulmonary normal microvasculature. Hemofiltration seems to be a significant breakthrough in the treatment of ARDS secondary to severe sepsis.     

Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method

OBJECTIVE: Intravenous ibuprofen (IBU) has been found to be as effective as indomethacin for the treatment of patent ductus arteriosus (PDA) in preterm infants and has been associated with fewer adverse effects in comparative phase III studies. The dose regimen used (10-5-5 mg/kg/day) was based on limited pharmacokinetic data and no phase II study was available to determine the optimal dose of IBU for this indication. The present study was designed to determine the minimum effective dose regimen (MEDR) of IBU (one course) required to close ductus arteriosus in preterm infants. METHOD: A double-blind dose-finding study was conducted using the continual reassessment method, a Bayesian sequential design. Two distinct target closure rates were initially chosen according to postmenstrual age (PMA) at birth: 80% in infants with a PMA of 27-29 weeks, and 50% in infants with a PMA < 27 weeks. Forty neonates (20 in each PMA group) with PDA were treated between days 3 and 5 of life. Four different dose regimens were tested: loading doses of 5, 10, 15 or 20 mg/kg, followed by two doses (1/2 loading dose) at 24-h intervals. Efficacy was evaluated by echocardiography 24 h after the third infusion. RESULTS: In infants with a PMA of 27-29 weeks, the estimated MEDR was 10-5-5 mg/kg with a final estimated probability of success of 77% (95% credibility interval: 56-92%). The 15-7.5-7.5 mg/kg dose regimen had a better estimated probability of success (88%, 95% credibility interval: 68-97%), but resulted in more minor renal adverse effects. In contrast, in infants with a PMA < 27 weeks, the estimated MEDR was 20-10-10 mg/kg with an estimated probability of success of 54.8% (95% credibility interval: 22-84%), whereas the conventional dose regimen resulted in a low estimated probability of success (30.6%, 95% credibility interval: 13-56%). In these infants, compared with those with a PMA of 27-29 weeks, minor renal adverse effects were more frequent from the 10-5-5 mg/kg/day dose regimen and did not appear to be clearly dose related. CONCLUSION: This study confirms that the currently recommended dose regimen (10-5-5 mg/kg) of IBU is associated with a high closure rate (80%) and few adverse effects in premature infants with a PMA of 27-29 weeks. The failure rate was much higher below 27 weeks. A higher dose regimen (20-10-10 mg/kg) might achieve a higher closure rate. However, tolerability and safety of this dose regimen should be assessed in a larger population before considering the use of these doses for ductus arteriosus closure.     

Losartan and lercanidipine attenuate low-density lipoprotein oxidation in patients with hypertension and type 2 diabetes mellitus: a randomized,prospective crossover study

OBJECTIVES: Lipoprotein oxidation, dyslipidemia, and hypertension are important underlying causes of accelerated atherosclerosis in patients with diabetes mellitus. The potential of antihypertensive medications to reduce lipid oxidation is, therefore, an important determinant in the choice of agents for patients with diabetes mellitus. The aim of this study was to compare the lowering effect of a new dihydropyridine calcium antagonist, lercanidipine, with that of the first angiotensin-receptor blocker, losartan, on low-density lipoprotein (LDL) oxidation. METHODS: Forty patients in metabolically stable condition who had type 2 diabetes mellitus with hypertension were studied in this single-blind, randomized, prospective crossover study, comprising 2 treatment periods of 16 weeks each, separated by a 4-week washout period. LDL oxidation was evaluated by dialdehyde analysis by means of the thiobarbituric acid-reactive substances assay with and without cupric sulfate, as well as determination of conjugated dienes in the LDL lipid extract. RESULTS: Lercanidipine and losartan both significantly reduced the propensity of the serum to oxidize LDL (P =.001). With one method of estimation (conjugated dienes), the effect of lercanidipine was superior to that of losartan (P =.04). Losartan lowered urinary albumin excretion but lercanidipine did not. CONCLUSIONS: Both lercanidipine and losartan attenuate LDL oxidation in patients with type 2 diabetes mellitus and hypertension. This observation may offer insight into the mechanisms of the therapeutic effects of these agents in patients with diabetes mellitus.     

The relationship between selflessness levels and the severity of anorexia nervosa symptomatology

This study examined the relationship of selflessness, the tendency to ignore one's own needs and interests and serve others, to the severity of anorexia nervosa (AN) symptomatology. Measures of selflessness, perfectionism, obsessiveness, self‐esteem, disordered eating, body dissatisfaction, drive for thinness and general symptomatology were completed by 205 women with a history of AN (ANh) in various stages of illness and recovery (42 ill, 90 partially recovered and 78 recovered) and 238 female controls. The ANh women's scores on the Selflessness Scale declined significantly as the severity of current pathology decreased. Recovered anorexics scored similarly to female controls. Assertion of one's own needs and interests may be an integral component of recovery from AN, and should be emphasized in therapy. Copyright © 2006 John Wiley & Sons, Ltd and Eating Disorders Association.     

The effects of long-term testosterone,gonadotropin-releasing hormone agonist and pimozide treatments on testicular development and luteinizing hormone levels in juvenile and early maturing striped bass,Morone saxatilis

The present study was conducted to test the responsiveness of the juvenile male reproductive axis to hormonal stimulation and to compare it to that of early maturing males. Long-term treatments with various combinations of T, GnRHa and pimozide did not result in an increased incidence of early maturing males, but did stimulate spermatogenesis slightly in juvenile fish. In early maturing males, the treatments appeared to be inhibitory since they resulted in a reduction of the GSI and a lower incidence of spermiating males. In early maturing males, pituitary LH content was elevated by GnRHa treatments alone while in juvenile males a combination of T and GnRHa was needed to increase the levels of LH in the pituitary. Thus, T may play an important role during puberty by potentiating the effects of GnRH on LH synthesis. In both juvenile and early maturing males, plasma LH levels could be increased only by high doses of GnRHa (in combination with T). Therefore, LH synthesis and release probably require different levels of GnRH stimulation. A GnRH challenge (single injection of 50 microg GnRHa/kg) at the end of the experiment resulted in a dramatic elevation of plasma LH levels in almost all animals. This finding demonstrates that pituitaries from juvenile and early maturing males were responsive to GnRHa stimulation, even after long-term hormonal treatments. The addition of pimozide did not affect the T- and GnRHa-induced increase in pituitary LH content but inhibited the release of LH in response to a GnRHa challenge. In conclusion, high doses of GnRHa in combination with T can increase plasma LH levels in juvenile males but do not induce complete testicular maturation. Factors other than T, GnRHa or LH are probably involved in the induction and completion of spermatogenesis.