Violation of critical universality at the antiferromagnetic phase transition of YbRh2Si2.

We report on precise low-temperature specific-heat measurements, C(T), of YbRh2Si2 in the vicinity of the antiferromagnetic phase transition on a single crystal of superior quality (residual resistivity ratio of approximately 150). We observe a very sharp peak at T_{N}=72 mK with absolute values as high as C/T=8 J/mol K2. A detailed analysis of the critical exponent alpha around T_{N} reveals alpha=0.38 which differs significantly from those of the conventional universality classes in the Ginzburg-Landau theory, where alpha< or =0.11. Thermal-expansion measurements corroborate this large positive critical exponent. These results provide insight into the nature of the critical magnetic fluctuations at a temperature-driven phase transition close to a quantum critical point.

Evolution of quantum criticality in CeNi(9-x)Cu(x)Ge(4).

Crystal structure, specific heat, thermal expansion, magnetic susceptibility and electrical resistivity studies of the heavy fermion system CeNi(9-x)Cu(x)Ge(4) (0≤x≤1) reveal a continuous tuning of the ground state by Ni/Cu substitution from an effectively fourfold-degenerate non-magnetic Kondo ground state of CeNi(9)Ge(4) (with pronounced non-Fermi-liquid features) towards a magnetically ordered, effectively twofold-degenerate ground state in CeNi(8)CuGe(4) with T(N) = 175 ± 5 mK. Quantum critical behavior, [Formula: see text], is observed for [Formula: see text]. Hitherto, CeNi(9-x)Cu(x)Ge(4) represents the first system where a substitution-driven quantum phase transition is connected not only with changes of the relative strength of the Kondo effect and RKKY interaction, but also with a reduction of the effective crystal field ground state degeneracy.

Dimensional crossover of quantum critical behavior in CeCoIn5.

The nature of quantum criticality in CeCoIn5 is studied by low-temperature thermal expansion alpha(T). At the field-induced quantum critical point at H = 5 T a crossover scale T* approximately 0.3 K is observed, separating alpha(T)/T proportional, variant T(-1) from a weaker T(-1/2) divergence. We ascribe this change to a crossover in the dimensionality of the critical fluctuations which may be coupled to a change from unconventional to conventional quantum criticality. Disorder, whose effect on quantum criticality is studied in CeCoIn(5-x)Sn(x) (0 < or = x < or = 0.18), shifts T* towards higher temperatures.

The analgesic effect of pamidronate is not caused by the elevation of beta endorphin level in Paget's disease--a controlled pilot study.

INTRODUCTION: Although an analgesic effect is an essential component of the mode of action of bisphosphonates, its physiological mechanisms are still unclear. Beta-endorphin release plays an important role in the analgesic effect of both calcitonin and raloxifene. As patients with Paget's disease receive large doses of bisphosphonates within relatively short time periods, we examined whether repeated pamidronate infusion therapy would cause measurable change in beta-endorphin levels MATERIALS & METHODS: Visual analog scale (VAS) scores of pain intensity, beta-endorphin levels, and alkaline phosphatase activity of 11 patients with Paget's disease (7 with the mono- and 4 with the polyostotic form) were determined at baseline, as well as after 3 and 6 infusions (on Days 6 and 12 of treatment, respectively). Eleven untreated patients with Paget's disease (7 with the mono- and 4 with the polyostotic form) served as controls. RESULTS: It was established that in the course of pamidronate infusion therapy BE levels remained constant, whereas the values in serum alkaline phosphatase and pain intensity scores were significantly reduced. CONCLUSIONS: Although high-dose pamidronate therapy does mitigate pain substantially (as demonstrated by the reduction of VAS scores), its analgesic action is probably unrelated to the enhancement of beta-endorphin release.

Vitamin D receptor, oestrogen receptor-alpha and calcium-sensing receptor genotypes, bone mineral density and biochemical markers in Paget's disease of bone.

OBJECTIVES: The significance of genetic polymorphisms in the development of Paget's disease of bone is unclear at present. METHODS: We analysed the BsmI polymorphism of the vitamin D receptor (VDR) gene, the PvuII and XbaI polymorphisms of the oestrogen receptor-alpha (ER alpha) gene, and the A986S polymorphism of the calcium-sensing receptor (CaSR) gene in 69 pagetic patients and 120 healthy subjects. We also examined the relationship of these polymorphisms with lumbar spine and femoral neck BMD as well as with biochemical parameters (serum alkaline phosphatase, osteocalcin and parathyroid hormone) in Paget's disease. RESULTS: The XbaI and PvuII genotype distributions of the ER alpha gene were significantly different between patients with Paget's disease and control subjects (P<0.001). Also, the CaSR A986S genotype frequency was significantly different between pagetic patients and controls (P<0.01). No significant effect of gene polymorphisms on BMD or biochemical parameters of bone turnover was observed. CONCLUSION: Our results suggest that the ER alpha PvuII/XbaI and CaSR A986S polymorphisms may contribute to genetic susceptibility to Paget's disease. However, further studies are required to investigate the underlying pathomechanism and to replicate the associations.

Effect of bisphosphonate treatment in patients with Paget's disease of the skull.

OBJECTIVES: Hearing loss has long been known to be a complication of Paget's disease of bone. The aim of this study was to investigate Paget's disease of the temporal bone with special attention to hearing loss. METHODS: Twenty-five patients with skull involvement were treated with either pamidronate or tiludronate. Imaging included radiography, quantitative bone scintigraphy (QBS), single photon emission computed tomography (SPECT) and high-resolution computed tomographic (HRCT) scanning. Audiometric assessment was also performed. RESULTS: Twenty-three of the 25 patients with skull involvement suffered from hearing loss. Bisphosphonate treatment resulted in a decreased serum total alkaline phosphatase (serum tAP) level and QBS ratio, and also seemed to improve the complaints of the patients. HRCT demonstrated involvement of the middle ear ossicles (n = 7), involvement of the petrous pyramids (n = 14), demineralization of the otic capsule (n = 10), porosis pericochlearis (n = 8), narrowing of the external auditory meatus (n = 12), mastoid process thickening (n = 5) and stapedial footplate thickening (n = 4). The audiometric examination did not show any significant changes 1 yr after bisphosphonate treatment. CONCLUSIONS: HRCT imaging is a well suited tool for demonstrating the complication of Paget's disease. QBS and measurement of serum tAP level may also be regarded as useful techniques for monitoring treatment. However, hearing may remain impaired in spite of the improved scintigraphy and laboratory parameters, therefore, audiometric assessment is also important in pagetic patients with skull involvement.

Prevalence of obesity in an elderly Hungarian population.

BACKGROUND: There are few cross-sectional population-based studies on obesity in Hungary. Aim of this study was to characterize the prevalence, associated diseases and metabolic laboratory parameters for obesity in men and women in Budapest, Hungary. METHODS: A random sample of 641 persons (307 males and 334 females) aged 50 years and over were recruited from a population register in Budapest. Subjects were interviewed, had height and weight measured in standard fashion. Those who were obese (BMI > 30.0 kg/m2) were matched individually with non-obese subjects. Altogether 101 pairs (48 women and 53 men pairs) were taking part and these subjects had blood taken for amount of serum glucose, lipids and uric acid. RESULTS: The mean age of men and women was 65.0 (SD = 9.1) years and 64.6 (SD = 8.9) years, respectively. The prevalence of obesity was 18.1% in men and 15.4% in women (p < 0.05). In both sexes the mean body mass index was higher at age of 50-64 years than at older ages [in men 27.2 (SD = 3.7) kg/m2 vs. 26.7 (SD = 3.3) kg/ m2, p = 0.286 and in women 26.7 (SD = 4.2) kg/m2 vs. 25.4 (SD = 4.0) kg/m2, p = 0.005]. Body mass index was higher in men than in women at all ages. In the case-control study the mean age of obese and non-obese individuals were 63.1 (SD = 7.8) years and 63.2 (SD = 7.9) years, respectively. Obesity was significantly associated with a history of diabetes mellitus (18 vs. 7%, p < 0.05) and hypertension (48 vs. 28%, p < 0.05). Compared to the non-obese, those who were obese had a higher level of serum uric acid (311 +/- 102 vs. 280 +/- 96 micromol/l, p < 0.05) and triglyceride (2.67 +/- 1.95 vs. 1.86 +/- 0.95 mmol/l, p < 0.05). CONCLUSION: The high prevalence of obesity both in elderly men and women and its strong association with chronic diseases causes economical and social burden for Hungary. Strategies and programs for weight maintenance as well as weight reduction must become a higher public health priority.

Pseudosarcoma in Paget's disease.

The authors describe the case of a male patient who had had Paget's disease since 1973 which led to the diffuse swelling of the proximal femur in 1993. The elevated alkaline phosphatase level and the destructive lytic lesions on the X-ray of the femur raised the possibility of malignancy. The bone scan showed increased accumulation in the proximal part of the left femur. On the MR the low T1 and the elevated T2 signal intensity suggested malignity despite that in some regions signals typical of adipose tissue could also be seen, which is usually interpreted as a sign of benignity. In the histological specimens no signs of malignant tumour cells were identified. The patient received bisphosphonate treatment which decreased his pain and swelling and also the alkaline phosphatase level. The patient died because of a rapidly progressing retroperitoneal fibrosarcoma and lung metastasis in 1996. The autopsy did not prove any malignant transformation of Paget's disease of bone in the proximal femur.

Inhibition of platelet integrin alpha(IIb)beta(3) by peptides that interfere with protein kinases and the beta(3) tail.

alpha-Thrombin stimulation of human platelets initiates inside-out signaling to integrin alpha(IIb)beta(3) (glycoprotein IIb/IIIa), resulting in the exposure of ligand binding sites. In the present study, the regulation of alpha(IIb)beta(3) via protein kinases was investigated in platelets permeabilized with streptolysin O by introducing peptides that interfere with these enzymes and with possible regulatory domains in the cytosolic tail of the beta(3) subunit. Compared with intact platelets, the permeabilized platelets preserved >80% of the aggregation, secretion, and alpha(IIb)beta(3) ligand binding capacity. The peptide YIYGSFK, a substrate for Src kinases, inhibited alpha-thrombin-induced ligand binding to alpha(IIb)beta(3), but a reversed peptide with Y-->F substitutions (KFSGFIF) had no effect. Ligand binding to alpha(IIb)beta(3) was also inhibited by the peptide RKRCLRRL, which binds irreversibly to the catalytic domain of protein kinase C. Peptides corresponding to parts of the protein C inhibitor and beta(2)-glycoprotein I were used as negative controls and failed to interfere with ligand binding. Possible target domains for protein kinases are present in the cytoplasmic tail of the beta(3) subunit. The LLITIHDR peptide, matching the membrane-proximal domain of beta(3) (residues 717 to 724), had no effect, but NNPLYKEA (residues 743 to 750), EATSTFTN (residues 749 to 756), and TNITYRGT (residues 755 to 762), which mimicked overlapping domains of the carboxy-terminal part of beta(3), reduced alpha-thrombin-induced ligand binding by 60+/-4%, 97+/-1%, and 97+/-2% (n=3) at 500 micromol/L peptide, respectively. These observations indicate that Src kinases and protein kinase C take part in inside-out signaling to integrin alpha(IIb)beta(3) and identify target domains in beta(3) that contribute to the regulation of this integrin.

The antiovulatory potential of progesterone antagonists correlates with a down-regulation of progesterone receptors in the hypothalamus, pituitary and ovaries.

These studies analyze the regulation of progesterone receptors (PRs) in central and peripheral tissues with the aim of further understanding mechanistically the inhibition of ovulation by progesterone antagonists (PA). Therefore, it was of interest to investigate the influence of the progesterone receptor antagonist, Onapristone (ON), on PRs in the ovary, pituitary (PT), and hypothalamus (HYP), since ON effectively inhibits ovulation in rats. For this study PMSG/hCG-primed immature and adult female rats were treated with ON. Immunohistochemistry was used for the detection of PRs. Progesterone (P4) and estradiol (E2) levels were determined by RIA. PR expression in the ovaries of immature rats was not detectable until after hCG administration. In these animals, ON caused a reduction in the staining intensity of PR in the tertiary follicles at the time when the preovulatory P4-surge was inhibited (6 h post hCG). Adult rats treated for 15 days with ON showed a decreased PR expression in PT and HYP. At this time (proestrus, 7 p.m.) the P4 and E2 levels are significantly lowered. These results suggest that after treatment with ON the expression of PR is reduced in the ovary, PT and HYP. The regulation of PR in the ovary seems to be less dependent on estrogens than on LH. Thus, it is conceivable that the reduced PR expression after ON treatment may be a result of decreased LH sensitivity in the ovary. In the pituitary and hypothalamus, PR expression is stimulated by estrogens and progesterone, and therefore the fall in the P4 and E2 levels in ON-treated animals may be responsible for the reduced PR expression in PT and HYP, and may contribute to the antiovulatory effect of ON. We therefore conclude that the mechanism of the antiovulatory potency of progesterone antagonists is based on a reduced preovulatory P4-production and PR expression in the ovary and also on the down-regulation of PR in the anterior pituitary and hypothalamus.

Effects of partial versus pure antiestrogens on ovulation and the pituitary-ovarian axis in the rat.

The present study was undertaken to compare the effects of the pure antiestrogen ZM 182780 (ZM) and the partial agonist tamoxifen (TAM) on ovulation and peripheral hormone levels in the rat. Adult female rats were treated with ZM (5 mg/kg/d) or TAM (5 mg/kg/d) and sacrificed at varying times during the estrous cycle. ZM and TAM were able to inhibit ovulation to nearly the same extent (60% and 70%, respectively). ZM induced a persistent diestrus whereas TAM led to a mixed picture in the vaginal smear. Both antiestrogens suppressed the preovulatory surge of LH, FSH and progesterone but had no effect on basal FSH values. In contrast to TAM, ZM caused an increase in basal levels of LH. Moreover, basal and preovulatory levels of estradiol and androgens were increased by ZM. By contrast, TAM decreased basal and preovulatory values of LH, estradiol, and androgens. These data suggest that ZM inhibits not only the positive but also negative feedback effect of estrogens and TAM seems to inhibit only the positive feedback. Moreover, it is conceivable that the suppressed preovulatory progesterone surge induced by ZM and TAM could be responsible for the antiovulatory effect.

Differential involvement of tyrosine and serine/threonine kinases in platelet integrin alphaIIbbeta3 exposure.

The relative contributions of protein tyrosine kinases (PTKs) and protein kinase C isoenzymes (PKCs), a family of serine/threonine kinases, in integrin alpha(IIb)beta3 (glycoprotein IIb/IIIa) exposure are the subject of much controversy. In the present study we measured the effect of the PTK inhibitor herbimycin A and the PKC inhibitor bisindolylmaleimide I on 125I-fibrinogen binding to alpha(IIb)beta3 and on aggregation/secretion induced by different agonists. Dose-response studies showed complete inhibition of alpha(IIb)beta3 exposure by 30 micromol/L (ADP stimulation) and 35 to 40 micromol/L (alpha-thrombin stimulation) herbimycin A. In contrast, inhibition of exposure by bisindolylmaleimide I varied from none (for ADP and epinephrine), to 30% (for platelet-activating factor), and to approximately 80% (for alpha-thrombin). Studies with a submaximal dose of herbimycin A (approximately 50% inhibition of the ADP-response) and a maximal dose of bisindolylmaleimide I showed that optical aggregation had a similar sensitivity to the inhibitors as alpha(IIb)beta3 exposure with minimal interference by secreted ADP. Thus, the relative contributions of tyrosine and serine/threonine kinases in alpha(IIb)beta3 exposure and aggregation differ among the different agonists, with an exclusive role for PTKs in ADP- and epinephrine-induced responses and a role for both PTKs and PKCs in responses induced by platelet-activating factor and alpha-thrombin.

Signal transduction through trimeric G proteins in megakaryoblastic cell lines.

The biogenesis of trimeric G proteins was investigated by measurement of the expression of alpha-subunits in the megakaryoblastic cell lines MEG-01, DAMI, and CHRF-288-11, representing stages of increasing maturation, and compared with platelets. Megakaryoblasts and platelets contained approximately equal amounts of Gi alpha-1/2, Gi alpha-3, Gq alpha, and G12 alpha protein. Maturation was accompanied by (1) downregulation of mRNA for Gs alpha and disappearance of iloprost-induced Ca2+ mobilization, (2) upregulation of the long form of Gs alpha protein (Gs alpha-L) and an increase in iloprost-induced cAMP formation, and (3) upregulation of G16 alpha mRNA and G16 alpha protein and appearance of thromboxane A2-induced signaling (Ca2+ mobilization and stimulation of prostaglandin I2-induced cAMP formation). Gz alpha protein was absent in the megakaryoblasts despite weak expression of Gz alpha mRNA in DAMI and relatively high levels of Gz alpha mRNA and Gz alpha protein in platelets. These findings reveal major changes in G protein-mediated signal transduction during megakaryocytopoiesis and indicate that G16 alpha couples the thromboxane receptor to phospholipase C beta.

The antiovulatory effect of the antiprogestin onapristone could be related to down-regulation of intraovarian progesterone (receptors).

The present study was undertaken to investigate intraovarian mechanism(s) for the antiovulatory effect of Onapristone (ON), because antiprogestins possessing the same antiprogestational activity and inhibiting the preovulatory LH surge to the same extent differ in their antiovulatory potency. Ovulation was induced by treating immature female rats with pregnant mare serum gonadotropin (PMSG) for folliculogenesis and hCG for the induction of ovulation. The animals were treated twice with ON (200 mg/kg 42 h and 48 h after PMSG) and killed at different times. The ovulation rate was assessed by counting the number of ova in the fallopian tubes and uteri. Blood and ovaries were collected for radioimmunoassay (RIA) of steroid hormones and histological analysis for 3beta-hydroxysteroid dehydrogenase (3beta-HSDH), 17beta-hydroxysteroid dehydrogenase (17beta-HSDH), progesterone (PR), estrogen (ER) and androgen (AR) receptors. Treatment with ON totally blocked ovulation and the progesterone (P4) surge was significantly diminished in comparison to the control (6-8 h post-hCG), whereas androgen levels remained unaffected. The decreased P4 concentrations correlated well with a reduced staining intensity of 3beta-HSDH in granulosa cells of tertiary follicles. Moreover, we observed a down-regulation of PR in granulosa cells of tertiary follicles. Additionally, in secondary and tertiary follicles the expression of AR between 0 and 6 h after hCG was reduced. These results suggest that the antiovulatory effect of the antiprogestin ON is related to down-regulation of intraovarian progesterone, caused by attenuated 3beta-HSDH activity and PR expression. One can thus assume that intraovarian P4 is an important factor for the induction of ovulation. An effect of ON on the staining intensity of 17beta-HSDH in theca and granulosa cells could not be observed at any time. In conclusion, the inhibition of ovulation induced by the antiprogestin, ON, could be related to decreased intraovarian progesterone production through reduced 3beta-HSDH activity and the down-regulation of PR.

The antiovulatory activity of progesterone antagonists is not correlated to their antiprogestational potency in the rat.

Progesterone antagonists often differ in regard to their potency to block ovulation in rats although they may possess similar 'antiprogestational' (abortive) activity. Therefore, the questions arose as to: (a) whether antiovulatory and antiprogestational effects (on endometrial and mammary gland parameters) of antiprogestins correlate at all; and (b) which mechanism(s) may be responsible for their ability to abolish ovulation. To answer these questions we set out to compare the influences of two progesterone antagonists, Onapristone (ON) a very potent and ZK 136798 only a weak inhibitor of ovulation, to assess changes on the one hand on typical progestational actions and on the other hand on factors known to regulate ovulation. For this purpose immature PMSG/hCG primed and adult female rats and infantile female rabbits were treated either with ON, ZK 136798 or vehicle in different treatment schedules. In these investigations ON and ZK 136798 showed similar antiprogestational activities on the progesterone-induced development of mammary glands (rats) and the secretory transformation of endometrium (rabbits). ON blocked an induced or a spontaneous ovulation, whereas ZK 136798 only revealed a very weak antiovulatory effect. Both ON and ZK 136798 stimulated basal levels of LH, estradiol, and testosterone, whereas the preovulatory LH surge was decreased to the same extent. Interestingly, in contrast to ZK 136798, ON reduced the preovulatory increase in progesterone secretion. These results clearly indicate: (a) that antiovulatory potency and antiprogestational activity may not be correlated in the rat; and (b) that decreased preovulatory levels of progesterone following treatment with ON may play an important role in intraovarian mechanism(s) contributing to a blocking of ovulation.

Molecular characterization of the Anopheles gambiae 2L telomeric region via an integrated transgene.

A Drosophila P-element derivative (pUChsneo) integrated into the telomeric region of the left arm of the second chromosome of Anopheles gambiae was used to clone the proximally flanking An. gambiae sequences. Molecular analyses revealed that the pUChsneo construct was partially duplicated and had integrated into a subterminal minisatellite. This satellite has a repeat unit of 820 bp and is located exclusively at the tip of 2L. No sequence similarity to subterminal minisatellites from other dipterans was detected, but some structural features such as tandem subrepeats are shared. The end of the chromosome was mapped with respect to restriction sites in pUChsneo at approximately generation 100 after the integration event. Considering inevitable terminal nucleotide loss due to incomplete DNA replication, we conclude that the chromosome end must have undergone a dramatic elongation process since it was mapped in generation 23.

DNA organization and polymorphism of a wild-type Drosophila telomere region.

Telomeres at the ends of linear chromosomes of eukaryotes protect the chromosome termini from degradation and fusion. While telomeric replication/elongation mechanisms have been studied extensively, the functions of subterminal sequences are less well understood. In general, subterminal regions can be quite polymorphic, varying in size from organism to organism, and differing among chromosomes within an organism. The subterminal regions of Drosophila melanogaster are not well characterized today, and it is not known which and how many different components they contain. Here we present the molecular characterization of DNA components and their organization in the subterminal region of the left arm of chromosome 2 of the Oregon RC wild-type strain of D. melanogaster, including a minisatellite with a 457bp repeat length. Two distinct polymorphic arrangements at 2L were found and analyzed, supporting the Drosophila telomere elongation model by retrotransposition. The high incidence of terminal chromosome deficiencies occurring in natural Drosophila populations is discussed in view of the telomere structure at 2L.

Identification of alpha-subunits of trimeric GTP-binding proteins in human platelets by RT-PCR.

In a search for new alpha-subunits of trimeric GTP-binding proteins in human platelets, we prepared leucocyte-free platelet concentrates and analyzed total RNA for areas homologous to known alpha-subunits. RT-PCR based on two degenerate primers revealed the expected band of 495 base pairs and an additional band of 540 base pairs reflecting the alternative splice product of Gs alpha. Following subcloning in pGEM-T vector and sequencing, we identified the alpha-subunits Gi alpha-2 and Gs alpha-S of the regulating GTP-binding proteins of adenyl cyclase as well as Gz alpha whose function is unknown, confirming earlier immunological identification. In addition, we identified Gs alpha-L (differing from Gs alpha-S by an insertion of 45 base pairs), G16 alpha, (a member of the pertussis toxin insensitive Gq-family), and two new variants of both Gs alpha-S and Gs alpha-L each containing a C-A-G triplet. With G16 we have identified another candidate for pertussis-toxin insensitive signal transduction in platelets. The C-A-G containing sequences of Gs alpha lead to an insertion of a Ser-residue, which results in the consensus sequence of a phosphorylation site for protein kinase C (Ser-X-Lys), making these variants candidates for protein kinase C-sensitive cyclic AMP formation.