A randomised study of the effect of two doses of biosynthetic human growth hormone on final height of children with familial short stature.

BACKGROUND/AIMS: The effects of biosynthetic human growth hormone (r-hGH) in children with familial short stature (FSS) are varied. We determined whether responsivity to r-hGH in FSS is dose-dependent. METHOD: Randomised trial of two doses (20 or 40 IU/m(2) body surface area/week by daily subcutaneous injection) of r-hGH in 29 (24 male, 5 female) FSS children with assessment at adult height. RESULTS: Age range at presentation was 5.1-10.5 years, height less than 1.5 standard deviation scores (SDS) below the mean, height velocity SDS greater than -1.5 and peak growth hormone response to provocative testing over 13.5 mU/l. Adult height data (SDS) at 16.5 +/- 2.1 years for the low-dose group and 16.1 +/- 1.1 years for the high-dose group (p = 0.62) were similar [low dose -1.06 (SD 0.75), high dose -1.02 (SD 0.83); p = 0.88]. The incremental effect of both doses on stature was minimal [low-dose difference in height actual-predicted 0.79 (SD 0.94), high dose 1.27 (SD 0.88); p = 0.12]. CONCLUSION: Using this r-hGH dosing schedule there were little short- or long-term effects on height in children with FSS.

Ultrafast-laser inscription of a three dimensional fan-out device for multicore fiber coupling applications.

A fan-out device has been fabricated using ultrafast-laser waveguide-inscription that enables each core of a multicore optical fiber (MCF) to be addressed by a single mode fiber held in a fiber V-groove array (FVA). By utilizing the unique three-dimensional fabrication capability of this technique we demonstrate coupling between an FVA consisting of a one-dimensional array of fibers and an MCF consisting of a two-dimensional array of cores. When coupled to all cores of the MCF simultaneously, the average insertion loss per core was 5.0 dB in the 1.55 mum spectral region. Furthermore, the fan-out exhibited low cross-talk and low polarization dependent loss.

Multiple rare earth emissions in a multicore tellurite fiber with a single pump wavelength.

A three-core tellurite glass fiber having different combinations of rare earth oxide dopants in each core has been fabricated using shaped die-extrusion. Three cores, doped with Ho(3+)-Tm(3+)-Yb(3+), Er(3+)-Ce(3+), and Tm(3+)-Yb(3+) respectively, exhibited visible upconversion (blue, green and red) and infrared emissions at 1.4 microm, 1.5 microm, 1.9 microm and 2.05 microm when pumped at a wavelength of 980 nm. The prospects for multi-band amplifiers and lasers are discussed.

Polymerization and colchicine binding. Two independent properties of tubulin.

When stored frozen in 1 M sucrose and 1 mM GTP, tubulin loses polymerizing ability exponentially. Since addition of diethiothreitol does not change the decay half-life, this decrease in activity can not be attributed to disulfide bond formation. When tubulin is stored frozen in dithiothreitol and GTP only, the decay half-life increases by a factor of four, indicating that sucrose destabilizes polymerizing ability. Frozen storage in sucrose has the opposite effect on colchicine binding, which remains at 100% for 40 days. This temporal divergence indicates that colchine binding and polymerization are two independent properties of tubulin.

Evidence for two growth steps in microtubule polymerization.

For microtubule assembly, the data reported here support an initial nucleation phase followed by a growth or elongation phase. The nucleation phase was not detected kinetically. Evidence for this step was given by the existence of the critical concentration and the dependence of the number of microtubules on oligomer concentration. Kinetic evidence indicated the existence of two consecutive steps in the growth phase of microtubules. The fast process increased and the slow one decreased with the concentration of microtubule protein. Similar kinetics were found upon recombination of tubulin oligomer and dimer which had been resolved by agarose chromatography. The fast process increased with oligomer and decreased with dimer concentration while the slow one depended positively on dimer concentration. Microtubules were formed when the oligomeric fraction only was employed. In contrast, under identical conditions, no microtubule formation was detected turbidimetrically or by electron microscopy from dimer alone. When dimer caused elongation of seed tubules, there was only one growth step with a rate constant of the same order of magnitude as the slow process for the other experiments.

Evidence against tubulin oligomer dissociation to tubulin dimer at assembly temperatures.

Chromatography of microtubule protein through 8% agarose at 4 and 31 degrees C demonstrated that tubulin oligomer was not dissociated to tubulin dimer and microtubule associated proteins by assembly temperatures. During chromatography, formation of microtubules was prevented by using 10 microM podophyllotoxin and/or 25 microM GTP. In the presence of 25 microM GTP, tubulin oligomer at 31 degrees C and microtubule protein retained the ability to polymerize. Evidence against dimer formation from tubulin oligomer was also obtained via a turbidity study of the initial events (the first 90 s) of microtubule assembly.

Growth hormone treatment in idiopathic short stature: a preliminary analysis of cardiovascular effects.

Growth hormone (GH) hypersecretion is associated with an increased incidence of hypertension and cardiac hypertrophy, resulting in excess cardiovascular morbidity and mortality. Abnormalities in the renin-angiotensin-aldosterone (RAA) system have been reported in acromegaly and in normal adults treated with recombinant human GH. The RAA system was investigated in prepubertal children with idiopathic short stature during treatment with recombinant human GH in doses up to 40 IU/m2/week. In addition, left ventricular size and function were assessed by serial echocardiography over an initial 12-month period. Modest and transient increases in blood pressure and body weight were observed during the first 7 days of GH treatment, but this was not accompanied by activation of the RAA system. Echocardiographic parameters of left ventricular size and function remained within the normal range for age and body size. Short-term GH treatment of idiopathic short stature was thus not associated with an increase in risk factors known to be associated with later cardiovascular morbidity. Longer follow-up studies will be required to confirm the safety of high-dose GH in this respect.

Serum insulin-like growth factor 1 in congenital heart disease.

Serum insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), and a range of growth and nutritional variables were investigated in 62 infants with congenital heart disease and healthy controls. Infants with congenital heart disease were small, underweight, and had a reduced energy intake. Serum IGF-1 and IGFBP-3 concentrations were significantly reduced. Decreased IGF-1 and IGFBP-3 levels are observed in nutritional deficiency; similar findings in congenital heart disease suggest that undernutrition contributes to the poor growth of these infants. Serial measurements of serum IGF-1 and IGFBP-3 may be helpful in monitoring the effect of nutritional treatment in congenital heart disease.

Serially multiplexed point sensor for the detection of high humidity in passive optical networks.

We describe a fiber-optic sensor capable of detecting high humidity. The device is constructed from standard telecommunications single-mode fiber and is compatible with deployment in a serial array, permitting interrogation by optical time-domain reflectometry for network monitoring. The sensors exhibit a reversible change in insertion loss between their dry (lossy) and humid (transmissive) states. The loss can be tailored to take any value; the current devices were designed to change by approximately 2.5 dB at a wavelength of 1.31 mum. The sensors are simple to construct and are compatible with installation in an existing passive optical network. The transduction mechanism is based on the humidity-induced change in refractive index in a polymer overlay on a polished half-block single-mode fiber device.

Stabilization of microtubules by GTP analogues.

We recently demonstrated that the nonhydrolyzable analogues of GTP (GMPPCP and GMPPNP) and ATP support the elongation phase of tubulin assembly and are incorporated into the E-site of polymerized tubulin. In this report we studied the stability of microtubules containing GTP analogues by examining length redistributions after shearing at polymer steady state. The mean length of a population of microtubules containing GMPPCP increased only by 37% over a 150 min time period after shearing. Microtubules which contained 70% ATP and 30% GDP at the E-site increased in length by 88%. In contrast, the mean length of microtubules assembled in the presence of GTP increased by 410% in the same time period. These results suggest that microtubules containing GMPPCP or ATP at their ends are stabilized from depolymerization.

Blood pressure and the renin-angiotensin-aldosterone system in children receiving recombinant human growth hormone.

OBJECTIVE: We investigated the effect of growth hormone (GH) treatment on salt and water metabolism and the renin-angiotensin-aldosterone system in children with short stature. DESIGN: Randomized, controlled study. PATIENTS: Twenty-nine short, pre-pubertal children referred to two specialist growth clinics for further assessment. MEASUREMENTS: Serial measurements of blood pressure, body weight, plasma renin activity (PRA), aldosterone, electrolytes, insulin and insulin-like growth factor I (IGF-I) have been made following the initiation of GH treatment. RESULTS: A small and transient increase in systolic blood pressure was observed during the first week of GH treatment. The increase in blood pressure over baseline was -1.1 mmHg in controls compared to +11.5 and +3.0 mmHg in children receiving standard (20 units/m2/week) and high dose (40 units/m2/week) GH respectively (P = 0.004). Over the same time interval body weight also tended to increase with GH compared with controls. These changes were greater in those children receiving the lower dose of GH and were not significantly related to age or prior GH status. PRA did not change with GH treatment. Although plasma aldosterone concentration tended to increase with GH, maximal values did not differ from controls and all remained within our normal range. Plasma IgF-I levels were increased by a similar amount in both treatment groups (1.5 and 1.12 U/ml compared to 0.44 U/ml in controls at 4 months). No difference in plasma insulin concentration was noted after 7 days of GH. CONCLUSIONS: In contrast to adult subjects, treatment with high dose GH in childhood is not associated with activation of the renin-angiotensin-aldosterone system. Clinical signs consistent with transient salt and water retention are observed with GH therapy, however, suggesting either a direct effect of GH or of IGF-I on renal tubular function. Blood pressure, plasma renin activity and plasma aldosterone levels were not increased after more prolonged GH therapy. These data suggest that high dose GH therapy in childhood is unlikely to be associated with the increased risk of hypertension seen in adults with GH hypersecretion.

Ineffective dental and surgical treatment associated with atypical facial pain.

Patients with atypical facial pain (AFP) are subject to ineffective dental and surgical procedures for their pain complaints. Twenty-one of fifty-eight patients (36.2 percent) with AFP had sixty-five dental and surgical treatments, with only one patient showing less pain as a result of the treatment. While the majority of patients (69 percent) with AFP suffered from a psychiatric illness, fourteen (24 percent) of the patients referred for AFP had a specific medical or dental disorder that was causal in their pain complaints. There is a trend for the AFP patient with a psychiatric diagnosis to receive more ineffective treatments than those AFP patients for whom a specific medical or dental diagnosis was made. Patients with AFP should receive conservative dental and medical treatment and a psychiatric assessment before dental and surgical procedures are contemplated.

Sodium and other inorganic growth requirements of bacteroides amylophilus.

Bacteroides amylophilus has growth requirements for Na(+), PO(4) (3-), K(+), and small quantities of Mg(2+). No requirement could be shown for Ca(2+) in media previously found growth-yield-limiting for Bacteroides succinogenes. Deletion of Co(2+), Mn(2+), Cl(-), or SO(4) (2-) did not affect growth. Quantitative studies indicate that Na(+), K(+), and PO(4) (3-) have differing effects on the growth of B. amylophilus. A concentration of sodium and potassium ions affects both growth rate and growth yield, whereas a phosphate concentration markedly affects growth yield, but affects growth rate only slightly, if at all. The sodium requirement of B. amylophilus is absolute. It cannot be replaced by K(+), Li(+), Rb(+), or Cs(+). The latter three monovalent cations are toxic to B. amylophilus if supplied to the organism at Na(+)-replacing concentrations. K(+) is inactive at similar concentrations. The K(+) requirement of B. amylophilus may be satisfied by Rb(+). The concentration of Na(+) required by B. amylophilus for abundant growth suggests that B. amylophilus should be considered a slightly halophilic organism. The results suggest that Na(+) may be a more frequent requirement among terrestial bacteria obtained from relatively low-salt environments than has been previously believed.

Stabilization of tubulin by deuterium oxide.

Tubulin is an unstable protein when stored in solution and loses its ability to form microtubules rapidly. We have found that D2O stabilizes the protein against inactivation at both 4 and 37 degrees C. In H2O-based buffer, tubulin was completely inactivated after 40 h at 4 degrees C, but in buffer prepared in D2O, no activity was lost after 54 h. Tubulin was completely inactivated at 37 degrees C in 8 h in H2O buffer, but only 20% of the activity was lost in D2O buffer. Tubulin also lost its colchicine binding activity at a slower rate in D2O. The deuterated solvent retarded an aggregation process that occurs during incubation at both temperatures. Inactivation in H2O buffer was partially reversed by transferring the protein to D2O buffer; however, aggregation was not reversed. The level of binding of BisANS, a probe of exposed hydrophobic sites in proteins, increases during the inactivation of tubulin. In D2O, the rate of this increase is slowed somewhat. We propose that D2O has its stabilizing effect on a conformational step or steps that involve the disruption of hydrophobic forces. The conformational change is followed by an aggregation process that cannot be reversed by D2O. As reported previously [Ito, T., and Sato, H. (1984) Biochim. Biophys. Acta 800, 21-27], we found that D2O stimulates the formation of microtubules from tubulin. We also observed that the products of assembly in D2O/8% DMSO consisted of a high percentage of ribbon structures and incompletely folded microtubules. When these polymers were disassembled and reassembled in H2O/8% DMSO, the products were microtubules. We suggest that the combination of D2O and DMSO, both stimulators of tubulin assembly, leads to the rapid production of nuclei that lead to the formation of ribbon structures rather than microtubules.

Fiber-optic Sagnac interferometer for noncontact structural monitoring in power plant applications.

The design of a noncontact fiber-optic sensor is described for the detection of acoustic emission for structural integrity monitoring in high-temperature power plant applications. The sensor is based on a Sagnac interferometer and produces an output proportional to target velocity, without the need for active phase stabilization. It is inherently insensitive to low-frequency perturbations of the instrument or the target and incorporates an environmentally insensitive downlead, which may be of arbitrary length. It is shown that the sensor is capable of meeting the specifications for structural integrity monitoring of high-temperature power plant components based on acoustic emission detection and has a velocity resolution of 50 nm s(-1) Hz(-1/2).

Transient deformation measurement with electronic speckle pattern interferometry and a high-speed camera.

To the best of our knowledge, transient deformations have been measured in real time with microsecond temporal resolution for the first time with speckle pattern interferometry. The short exposure period and high framing rate of a high-speed camera at as many as 40,500 frames per second allow low-power continuous-wave laser illumination and fiber-optic beam delivery to be used. We have applied the technique to measure both harmonic vibration and transient deformation.

Wavelength dependence of bending loss in monomode optical fibers: effect of the fiber buffer coating.

The bend-induced optical loss in a monomode fiber has been studied as a continuous function of wavelength in the range 1.2-1.6 microm. The loss was observed to be an oscillatory function of wavelength. These observations were explained by using a model based on interference between the guided core mode in the fiber and a "whispering gallery" mode ejected from the core by the bend. The wavelengths of the minima in the oscillatory function were accurately predicted by the model when the propagation of optical power in the fiber buffer coating was taken into account.

Phase-demodulation error of a fiber-optic Fabry-Perot sensor with complex reflection coefficients.

The influence of reflector losses attracts little discussion in standard treatments of the Fabry-Perot interferometer yet may be an important factor contributing to errors in phase-stepped demodulation of fiber optic Fabry-Perot (FFP) sensors. We describe a general transfer function for FFP sensors with complex reflection coefficients and estimate systematic phase errors that arise when the asymmetry of the reflected fringe system is neglected, as is common in the literature. The measured asymmetric response of higher-finesse metal-dielectric FFP constructions corroborates a model that predicts systematic phase errors of 0.06 rad in three-step demodulation of a low-finesse FFP sensor (R = 0.05) with internal reflector losses of 25%.