Skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) by inhibiting activation of the IGF-I signaling pathways.

We showed that unloading markedly diminished the effects of IGF-I to activate its signaling pathways, and the disintegrin echistatin showed a similar block in osteoprogenitor cells. Furthermore, unloading decreased alphaVbeta3 integrin expression. These results show that skeletal unloading induces resistance to IGF-I by inhibiting activation of the IGF-I signaling pathways at least in part through downregulation of integrin signaling. INTRODUCTION: We have previously reported that skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) with respect to bone formation. However, the underlying mechanism remains unclear. The aim of this study was to clarify how skeletal unloading induces resistance to the effects of IGF-I administration in vivo and in vitro with respect to bone formation. MATERIALS AND METHODS: We first determined the response of bone to IGF-I administration in vivo during skeletal unloading. We then evaluated the response of osteoprogenitor cells isolated from unloaded bones to IGF-I treatment in vitro with respect to activation of the IGF-I signaling pathways. Finally we examined the potential role of integrins in mediating the responsiveness of osteoprogenitor cells to IGF-I. RESULTS: IGF-I administration in vivo significantly increased proliferation of osteoblasts. Unloading markedly decreased proliferation and blocked the ability of IGF-I to increase proliferation. On a cellular level, IGF-I treatment in vitro stimulated the activation of its receptor, Ras, ERK1/2 (p44/42 MAPK), and Akt in cultured osteoprogenitor cells from normally loaded bones, but these effects were markedly diminished in cells from unloaded bones. These results were not caused by altered phosphatase activity or changes in receptor binding to IGF-I. Inhibition of the Ras/MAPK pathway was more impacted by unloading than that of Akt. The disintegrin echistatin (an antagonist of the alphaVbeta3 integrin) blocked the ability of IGF-I to stimulate its receptor phosphorylation and osteoblast proliferation, similar to that seen in cells from unloaded bone. Furthermore, unloading significantly decreased the mRNA levels both of alphaV and beta3 integrin subunits in osteoprogenitor cells. CONCLUSION: These results indicate that skeletal unloading induces resistance to IGF-I by inhibiting the activation of IGF-I signaling pathways, at least in part, through downregulation of integrin signaling, resulting in decreased proliferation of osteoblasts and their precursors.     

Treatment of essential tremor with the barbiturate T2000 (1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid).

The effect of the barbiturate T2000 (1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid; DMMDPB) on essential tremor, given in twice daily doses of 400 and 300 mg, was assessed in two brief, randomized, placebo-controlled, parallel-group, double-blinded, single-center trials in 12 and 22 patients, respectively. These trials represent the first clinical use of T2000 for a specific indication. The primary endpoint was the change in the mean scores of the treated and control groups based on the Fahn-Tolosa-Marin tremor scale. In the first study of 12 patients treated with 400 mg or placebo twice daily for 14 days, the mean change from baseline at day 14 was 19.3 (P < 0.0001) in the treated group and 9.0 (P = 0.0121) in the control group. Using a two-factor mixed ANOVA model to evaluate within group and between group changes, the effect of T2000 was significantly different from that of the placebo group (P = 0.03). In the second study of 22 patients treated with 300 mg of T2000 or placebo twice daily for 20 days, statistically significant changes were seen in treated patients compared to baseline, but the ANOVA model did not demonstrate a significant treatment effect of T2000 compared to placebo. When the treated groups from each study are compared, the 800-mg daily group is significantly different from the 600-mg daily group (P = 0.02). Some treated patients in each study, but no placebo patients, experienced marked improvement. These results support further evaluation of T2000 in the treatment of essential tremor.     

Aortenstenose

Aortic valve stenosis is the most frequent reason for prosthetic valve replacement in adults. Its incidence increases with age. Development of the most frequent form, degenerative-calcific aortic stenosis, is related to atherosclerotic risk factors. The narrowing of the aortic valve orifice leads to creation of a systolic pressure drop, the gradient, between left ventricle and ascending aorta. The pressure overload from aortic stenosis causes concentric left ventricular hypertrophy and later heart failure. Typical symptoms of severe aortic stenosis include dyspnea, angina, and dizziness or syncope. On auscultation, a loud systolic murmur over the base of the heart is apparent, which is transmitted to the carotids. The ECG often shows left ventricular hypertrophy. The most important diagnostic technique is echocardiography, which allows to measure the gradient and to calculate the orifice area, which determine the degree of severity. The development of symptoms or impaired left ventricular function in severe aortic stenosis should prompt surgical treatment by valve replacement. Truly asymptomatic patients with preserved left ventricular function should be followed conservatively.     

Nefopam, a Nonsedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold in Unanesthetized Subjects

Background: The analgesic nefopam does not compromise ventilation, is minimally sedating, and is effective as a treatment for postoperative shivering. The authors evaluated the effects of nefopam on the major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering.

Methods: Nine volunteers were studied on three randomly assigned days: (1) control (saline), (2) nefopam at a target plasma concentration of 35 ng/ml (low dose), and (3) nefopam at a target concentration of 70 ng/ml (high dose, approximately 20 mg total). Each day, skin and core temperatures were increased to provoke sweating and then reduced to elicit peripheral vasoconstriction and shivering. The authors determined the thresholds (triggering core temperature at a designated skin temperature of 34[degrees]C) by mathematically compensating for changes in skin temperature using the established linear cutaneous contributions to control of each response.

Results: Nefopam did not significantly modify the slopes for sweating (0.0 +/- 4.9[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = 0.73 +/- 0.32) or vasoconstriction (-3.6 +/- 5.0[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = -0.47 +/- 0.41). In contrast, nefopam significantly reduced the slope of shivering (-16.8 +/- 9.3[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = 0.92 +/- 0.06). Therefore, high-dose nefopam reduced the shivering threshold by 0.9 +/- 0.4[degrees]C (P < 0.001) without any discernible effect on the sweating or vasoconstriction thresholds.     

Biliopancreatic diversion with duodenal switch vs. gastric bypass for severe obesity

Conclusion In the year 2003 there is no “one best bariatric operation” for every severely obese patient. The choice of operation must be tailored to each individual patient’s needs and wishes. For the superobese patient, the patient diagnosed with intestinal metaplasia of the stomach, and for those patients who do not wish to undergo the severe dietary restrictions imposed by the RNY-GB, the BPD-DS is a valuable surgical option.     

Composantes neurosensorielles et hormonales dans l’anorexie mentale

Anorexia nervosa (AN) is often considered a multifactorial illness of unknown pathophysiology. Family and twin studies have consistently demonstrated that AN is strongly related to genetic factors. The probability of some genetic origin is 92%, genetic factors explaining around 20% of the variance. It must be remembered that 95% of the AN patients were girls or women, suggesting a role for gonadal hormonal systems and their effects on the brain and on cognitive functions. Most studies focused on the serotonin system, but other candidate genes have been suggested. At the present time, we have no evidence that women who develop AN have an adipose, metabolic, gonadal, pituitary, hypothalamic or some other dysfunctions that predispose them for the illness. It is suggested on the contrary that the symptoms of AN are physiological responses to starvation or to the response to altered body image and self-satisfaction. If this eating disorder is related to the fear of the alimentary desire of the patients, it will be easy to understand the plasma level of adiponectin, ghrelin and better understand a role for the low leptin level in the enhanced hunger. If we remember that almost 60% of these patients are engaged in a physical and mental hyperactivity, the abnormality in plasma level of cortisol, ACTH, and CRH. The decease in fat mass could explain why leptin level was low and low leptin level may explain the amenorrhea and the fall in LH, FSH, and LH–RH secretion. Moreover, anxiety, obsessive compulsive disorders and physical hyperactivity may be three interrelated factors, which could be related to serotonin and dopamine systems and in turn inhibit food intake.     

The American Association for Pediatric Ophthalmology and Strabismus workforce distribution project.

PURPOSE: To describe data sources and functional utility of the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) workforce database and associated map files. METHODS: Population data from the 2000 U.S. Census and current listings from the AAPOS and American Academy of Ophthalmology (AAO) databases were organized to demonstrate and analyze practitioner-to-population relationships for metropolitan statistical areas nationwide. An interactive map was developed to provide an intuitive graphical display of the data. RESULTS: A total of 749 active AAPOS members were distributed in 154 of 280 defined metropolitan statistical areas. Within these areas, a 0- to 20-year age subgroup varied from 17.8% to 42.6%, with an average of 30.4%. The AAPOS member-to-million-person ratio varied from 1.3 to 27, with higher numbers generally representing regions with population bases inadequately defined by Census Bureau statistical area definitions. Ratios for a majority of larger, better-defined areas ranged from 3 to 4 AAPOS members per million persons. Sizable areas with no AAPOS member presence were identified and tabulated. AAO members with a specified pediatric practice focus who were not AAPOS members were identified in 103 areas, possibly influencing patient choices and practitioner referrals for these regions. CONCLUSIONS: The AAPOS workforce database and related interactive map display practitioner and population data that may assist physicians and planners in targeting practice development and identifying potentially underserved areas.     

Polymerizable amphiphiles, 2. Micellization of 1-O-3-(4-vinylphenyl)propyl-β-D-glucopyranose

1-O-3-(4-Vinylphenyl)propyl-β-D -glucopyranose ( 1 ) undergoes in water a closed association under formation of N-mers. The unimer/N-mer association is directly visible in the Schlieren pattern of ultracentrifugal synthetic boundary experiments. Association numbers and mass-concentration-based equilibrium constants of association were calculated from the variation of N-mer concentrations with unimer concentrations and from the concentration dependence of inverse apparent average molar masses as measured by both vapor phase osmometry and sedimentation equilibrium. Association numbers were also calculated from the combination of sedimentation coefficients with diffusion coefficients, sedimentation coefficients with intrinsic viscosities, and diffusion coefficients with interinsic viscosities as well as from the dependence of apparent mass-average molar masses on inverse apparent number-average molar masses. All methods gave in general different association numbers and equilibrium constants. The effect, which was not found for other non-ionic amphiphiles, is probably due to the existence of consecutive equilibria between the unimer and a low molar mass P-mer which associates to a higher molar mass R-mer. Viscosity data are in agreement with the picture of a spherical micelle for the dominant P-mers with about 10 water molecules per glucose residue. The micellization of 1 is both enthalpy- and entropy-driven, in contrast to the micellization of 1-O-octyl-β-D -glucopyranose which is a strictly entropy-driven process.