Effects of heterozygosity for the E180 splice mutation causing growth hormone receptor deficiency in Ecuador on IGF-I, IGFBP-3, and stature.

CONTEXT & OBJECTIVE: The Ecuadorian GH receptor deficiency (GHRD)/Laron syndrome population is the only large cohort with a single GHR mutation (E180 splice), permitting identification of numerous carrier and noncarrier first-degree relatives, to ascertain effects of heterozygosity on GH-dependent IGF-I and IGFBP-3 concentrations and on growth. DESIGN: First-degree relatives (n=212) of GHRD patients had specimens taken for IGF-I, IGFBP-3, and GHR genotyping. Normal statured (n=40) and short statured (n=40) unrelated controls had measurement of IGF-I, IGFBP-3, and stature. RESULTS: There were no significant differences between heterozygous and homozygous normal relatives in IGF-I or IGFBP-3 standard deviation scores (SDS). Heterozygous relatives had lower mean height SDS than did homozygous normals, but with extensive overlap between genotype groups in both child and adult relatives. Height SDS in general did not relate to IGF-I or IGFBP-3 concentrations. CONCLUSIONS: GH-dependent IGF-I and IGFBP-3 secretion is not affected by heterozygosity for the E180 splice mutation that causes GHRD/Laron syndrome in the Ecuadorian population. Heterozygosity is associated with reduction in mean statural SDS, but this is not sufficient to be clinically important and not mediated through measurable differences in circulating IGF-I or IGFBP-3 related to genotype.     

In vitro evaluation of ablation parameters of normal and fibrous aorta using smooth excimer laser coronary angioplasty

A modified exeimer laser energy delivery system was used to irradiate 100 segments of normal and fibrous aorta in vitro. The laser beam was scanned into 8 fiber bundles consisting of 50 fibers each resulting in a reduction of the applied pulse energy. The total repetition rate was increased to 150 Hz in order to keep the repetition rate per fiber bundle close to 20 Hz and to minimize thermal injury. The results demonstrate that effective ablation (etch rate per 8 pulses > 2.0 μm) occurred at an energy fluency of 50 mJ/mm² in both normal and fibrous aorta. Tissue damage (carbonization, tissue separation, fissures, cracks, and vacuolization) was in a range of 100 ± 28 to 152 ± 30 μm for normal aorta and in a range of 57 ± 35 to 110 ± 39 μm for fibrous aorta. We conclude that effective ablation of normal and fibrous human aorta can be achieved by the application of smooth excimer laser coronary angioplasty. This improvement of excimer laser technology may result in a reduction of shock wave- and cavitation-induced damage leading to a reduction of tissue injury. However, this awaits further in vitro and in vivo confirmation. © 1993 Wiley-Liss, Inc.     

Differentiation of Streptococcus uberis from Streptococcus parauberis by polymerase chain reaction and restriction fragment length polymorphism analysis of 16S ribosomal DNA.

Streptococcus uberis type II has been proposed recently as a separate species designated Streptococcus parauberis (A. M. Williams and M. D. Collins, J. Appl. Bacteriol. 68:485-490, 1990). Differentiation of S. parauberis from S. uberis has been possible only by DNA-DNA hybridization or 16S rRNA sequencing, since the biochemical and serological characteristics of the two species are indistinguishable. A simple and reliable technique was developed for differentiating S. parauberis (S. uberis type II [ATCC 13386]) from S. uberis (S. uberis type I [ATCC 9927, ATCC 13387, and ATCC 27958]) by restriction fragment length polymorphism (RFLP) analysis of 1.4-kb 16S ribosomal DNA (rDNA). Oligonucleotide primers complementary to 16S rRNA genes were used to amplify 16S ribosomal gene fragments from genomic DNA by polymerase chain reaction. The 1.4-kb 16S rDNA fragment was digested with ScaI, NspI, DdeI, and AvaII restriction endonucleases. Restriction fragments produced by all four restriction endonucleases were characteristic for each species. RFLP analysis of 16S rDNA from 24 "S. uberis" isolates obtained from mammary secretions of dairy cows indicated that all 24 isolates were indeed S. uberis.     

Isoelectronic perturbations to f-d-electron hybridization and the enhancement of hidden order in URu2Si2

Electrical resistivity measurements were performed on single crystals of URu_2–xOs_xSi₂ up to x = 0.28 under hydrostatic pressure up to P = 2 GPa. As the Os concentration, x, is increased, 1) the lattice expands, creating an effective negative chemical pressure P_ch(x); 2) the hidden-order (HO) phase is enhanced and the system is driven toward a large-moment antiferromagnetic (LMAFM) phase; and 3) less external pressure P_c is required to induce the HO→LMAFM phase transition. We compare the behavior of the T(x, P) phase boundary reported here for the URu_2-xOs_xSi₂ system with previous reports of enhanced HO in URu₂Si₂ upon tuning with P or similarly in URu_2–xFe_xSi₂ upon tuning with positive P_ch(x). It is noteworthy that pressure, Fe substitution, and Os substitution are the only known perturbations that enhance the HO phase and induce the first-order transition to the LMAFM phase in URu₂Si₂. We present a scenario in which the application of pressure or the isoelectronic substitution of Fe and Os ions for Ru results in an increase in the hybridization of the U-5f-electron and transition metal d-electron states which leads to electronic instability in the paramagnetic phase and the concurrent formation of HO (and LMAFM) in URu₂Si₂. Calculations in the tight-binding approximation are included to determine the strength of hybridization between the U-5f-electron states and the d-electron states of Ru and its isoelectronic Fe and Os substituents in URu₂Si₂.

The heavy-fermion superconducting compound URu2Si2 is known for its second-order phase transition into the so-called “hidden-order” (HO) phase at a transition temperature T0 ≈17.5 K. Extensive investigation of the phase space in proximity to the HO phase transition has provided a detailed picture of the electronic and magnetic structure of this unique phase (1–42). However, more than three decades after the initial characterization of URu2Si2 (1–3), the order parameter for the HO phase is still unidentified.Most perturbations to the URu2Si2 compound have the effect of suppressing HO. The application of an external magnetic field (H) suppresses the HO phase (41, 43) and many of the chemical substitutions (x) at the U, Ru, or Si sites that have been explored significantly reduce T0, even at modest levels of substituent concentration (44–52). At present, only three perturbations are known to consistently enhance the HO phase in URu2Si2: 1) external pressure P, 2) isoelectronic substitution of Fe ions for Ru, and 3) isoelectronic substitution of Os ions for Ru. Upon applying pressure P, the HO phase in pure URu2Si2 is enhanced (6) and the system is driven toward a large-moment antiferromagnetic (LMAFM) phase (53). The HO→LMAFM phase transition is identified indirectly by a characteristic “kink” at a critical pressure Pc ≈1.5 GPa in the T0 (P) phase boundary (18, 53, 54) and also directly by neutron diffraction experiments, which reveal an increase in the magnetic moment from μ ∼ (0.03±0.02)μB/U in the HO phase to μ ∼ 0.4 μB/U in the LMAFM phase (13, 55, 56).Recent reports indicate that the isoelectronic substitution of Fe ions for Ru in URu2Si2 replicates the T0(P) behavior in URu2Si2 (57–59). An increase in x in URu2−xFexSi2 enhances the HO phase and drives the system toward the HO→LMAFM phase transition at a critical Fe concentration xc ≈0.15 (58, 60). The decrease in the volume of the unit cell due to substitution of smaller Fe ions for Ru may be interpreted as a chemical pressure, Pch, where the Fe concentration x can be converted to Pch (x) (57, 59). In addition, the induced HO→LMAFM phase transition in URu2−xFexSi2 occurs at combinations of x and P that consistently obey the additive relationship: Pch(x) + Pc ≈1.5 GPa (57, 59). These results have led to the suggestion that Pch is equivalent to P in affecting the HO and LMAFM phases (58, 59).Reports of the isoelectronic substitution of larger Os ions for Ru have shown that an increase in x in URu2−xOsxSi2 1) expands the volume of the unit cell, thus creating an effective negative chemical pressure (Pch ≤0); 2) enhances the HO phase; and 3) drives the system toward a similar HO→LMAFM phase transition at a critical Os concentration of xc ≈0.065 (60–62). These results are contrary to the expectation that a negative Pch would lead to a suppression of HO and complicate the view of chemical pressure as a mechanism affecting the evolution of phases in URu2Si2.In this paper, we report on the behavior of the T(x, P) boundary for the URu2−xOsxSi2 system based on ρ(T) measurements of single crystals of URu2−xOsxSi2 as a function of Os concentration x and applied pressure P. The T(x, P) phase boundary observed here for the URu2−xOsxSi2 system (57–59) is compared to that of the URu2−xFexSi2 system and also with the behavior of T(P) in pure URu2Si2. As an explanation for the enhancement of HO toward the HO→LMAFM phase transition, we suggest a scenario in which each of the perturbations of Os substitution, Fe substitution, and pressure P favors delocalization of the 5f electrons and increases the hybridization of the uranium 5f-electron and transition metal (Fe, Ru, Os) d-electron states. To avoid an ad hoc explanation of the effect of increasing the Os concentration x in URu2−xOsxSi2, compared to the effects of pressure P and Fe substitution, we explain how pressure P, Fe substitution, and Os substitution are three perturbative routes to enhancement of the U-5f- and d-electron hybridization. The importance of the 5f- and d-electron hybridization to the emergence of HO/LMAFM is presented in the context of the Fermi surface (FS) instability that leads to a reconstruction and partial gapping of the FS during the transition from the paramagnetic (PM) phase to the HO and LMAFM phases (2, 6, 20, 22, 24–26, 37, 38, 63).In an effort to further understand the effect of isoelectronic substitution on the 5f- and d-electron hybridization, calculations in the tight-binding approximation were made for compounds from the series UM2Si2 (M = Fe, Ru, and Os). The calculations indicate that the degree of hybridization is largely dependent on the magnitude of the difference between the binding energy of the localized U-5f electrons and that of the transition metal d electrons.     

Complication and local recurrence rate after endoscopic resection of large high-risk colorectal adenomas of ≥3 cm in size

Purpose

Endoscopic resection is a widely used technique for treatment of large colorectal adenomas, but few data are available including only lesions larger than ≥2 cm. The aim of this study is to evaluate the complication and recurrence rate after endoscopic resection of high-risk colorectal adenomas ≥3 cm in size.

Methods

Retrospective analysis of a prospectively maintained database of patients undergoing polypectomy of large colorectal polyps of ≥3 cm.

Results

In 341 patients, 360 colorectal adenomas with a mean size of 3.9 cm were resected endoscopically. In 25 patients, a complication including 22 delayed bleedings (6.5 %) and three perforations (0.9 %) occurred. Single-variate analysis showed an increasing risk of complications for larger adenomas (3.9 vs. 4.6 cm; p?≤?0.05). Two hundred twelve patients with 224 adenomas had undergone at least one documented follow-up endoscopy with a medium follow-up period of 16 months. In 95 resected lesions (42.4 %), a residual adenoma occurred in the first follow-up colonoscopy (n?=?88, 92.6 %) or a recurrent adenoma occurred after at least one negative follow-up colonoscopy (n?=?7, 7.4 %). In multivariate analysis, risk factors were lesion size, sessile growth pattern, and the performing endoscopist. The complication and recurrence rate correlated inversely between endoscopists.

Conclusions

The present study is the largest study showing complication and recurrence rates after colorectal polypectomy of advanced colorectal adenomas of ≥3 cm in size. Polyp size was identified as the most important risk factor for complications. For the first time, this study shows that the complication rate after colorectal polypectomy of large adenomas is correlated inversely with the residual and/or recurrence rate.

     

Structure of cerebral arterioles in cystathionine beta-synthase-deficient mice

We examined effects of hyperhomocysteinemia on structure and mechanics of cerebral arterioles. We measured plasma total homocysteine (tHcy) and pressure, diameter, and cross-sectional area of the vessel wall in maximally dilated cerebral arterioles in heterozygous cystathionine beta-synthase-deficient (CBS(+/-)) mice and wild-type (CBS(+/+)) littermates that were provided with drinking water that was unsupplemented (control diet) or supplemented with 0.5% L-methionine (high-methionine diet). Plasma tHcy was 5.0+/-1.1 micro mol/L in CBS(+/+) mice and 8.3+/-0.9 micro mol/L in CBS(+/-) mice (P<0.05 versus CBS(+/+) mice) fed the control diet. Plasma tHcy was 17.2+/-4.6 micro mol/L in CBS(+/+) mice and 21.2+/-3.9 micro mol/L in CBS(+/-) mice (P<0.05) fed the high-methionine diet. Cross-sectional area of the vessel wall was significantly increased in CBS(+/-) (437+/-22 micro m(2)) mice fed control diet and CBS(+/+) (442+/-36 micro m(2)) and CBS(+/-) (471+/-46 micro m(2)) mice fed high-methionine diet relative to CBS(+/+) (324+/-18 micro m(2)) mice fed control diet (P<0.05). During maximal dilatation, the stress-strain curves in cerebral arterioles of CBS(+/-) mice on control diet and CBS(+/+) and CBS(+/-) mice on high-methionine diet were shifted to the right of the curve in cerebral arterioles of CBS(+/+) mice on control diet, an indication that distensibility of cerebral arterioles was increased in mice with elevated levels of plasma tHcy. Thus, hyperhomocysteinemia in mice was associated with hypertrophy and an increase in distensibility of cerebral arterioles. These findings suggest that hyperhomocysteinemia promotes cerebral vascular hypertrophy and altered cerebral vascular mechanics, both of which may contribute to the increased incidence of stroke associated with hyperhomocysteinemia.