Prevalence of vertebral fractures in an urban population in Croatia aged fifty and older

Summary AIM OF THE STUDY: To establish the prevalence of vertebral fractures according to age groups, sex and vertebral level in a sample of a Croatian urban population aged 50. We also tried to establish how many people had been diagnosed with osteoporosis by their family physician. PARTICIPANTS AND METHODS: Lateral thoracic and lumbar spinal radiographs were obtained in 425 ambulatory people (156 men and 269 women) aged 50 and living in the community as a random sample of the City of Zagreb (Croatia) population. An interviewer-administered questionnaire was used to obtain information on prior traumatic vertebral fractures and whether the person had been diagnosed with osteoporosis. Vertebral fractures in the population sample were defined using the morphometric method proposed by McCloskey et al., and normal values of the ratios of dimensions in non-fractured vertebrae with the iterative algorithm described by Melton et al. RESULTS: The prevalence of individuals with vertebral fractures was 11.8% (15.8% of men and 9.7% of women), ranking Zagreb mid-scale among other European cities. The prevalence of individuals with vertebral fractures rose with age. Sixty-nine (1.24%) of 5525 analysed vertebrae had been fractured. The most common fractures were those of lower thoracic and upper lumbar vertebrae. The elderly tend to sustain multiple fractures. Forty-one (9.6%) people had been previously diagnosed as having osteoporosis. Extrapolation to the Croatian population implies that approximately 90,000 men and 77,000 women aged 50 have vertebral fractures. CONCLUSION: Vertebral osteoporotic fractures are common in the Croatian population aged 50; however, awareness of osteoporosis appears to be low.     

Serum 25‐hydroxyvitamin D levels modulate the acute‐phase response associated with the first nitrogen‐containing bisphosphonate infusion

The acute‐phase response (APR) is the most frequent side effect after the first dose of intravenous nitrogen‐containing bisphosphonates (N‐BPs). It has been demonstrated in vitro that N‐BPs stimulate γδ T‐cell proliferation and production of cytokines and that vitamin D is able to modulate them. Therefore, we have studied the relationship between bone metabolism parameters, particularly for 25‐hydroxyvitamin D [25(OH)D], and APR in patients treated with 5 mg zoledronic acid intravenously. Ninety N‐BP‐naive osteoporotic women (63.7 ± 10.6 years of age) were stratified for the occurrence of APR (APR⁺) or not (APR^–) and quantified by body temperature and C‐reactive protein (CRP). The APR⁺ women had significantly lower 25(OH)D levels than the APR^– women. Levels of 25(OH)D were normal (>30 ng/mL) in 31% of APR⁺ women and in 76% of APR^– women. The odds ratio (OR) to have APR in 25(OH)D‐depleted women was 5.8 [95% confidence interval (CI) 5.30–6.29; p < .0002] unadjusted and 2.38 (95% CI 1.85–2.81; p < .028) after multiple adjustments (for age, body mass index, CRP, calcium, parathyroid hormone, and C‐telopeptide of type I collagen). Levels of 25(OH)D were negatively correlated with postdose body temperature (r = ?0.64, p < .0001) and CRP (r = ?0.79, p < .001). An exponential increase in fever and CRP has been found with 25(OH)D levels lower than 30 ng/mL and body temperature less than 37 °C, whereas normal CRP was associated with 25(OH)D levels above 40 ng/mL. The association between post‐N‐BPs APR and 25(OH)D suggests an interesting interplay among N‐BPs, 25(OH)D, and the immune system, but a causal role of 25(OH)D in APR has to be proven by a randomized, controlled trial. However, if confirmed, it should have some practical implications in preventing APR. © 2010 American Society for Bone and Mineral Research.     

Mitral valve replacement in pregnancy: a successful strategy for fetal survival

The incidence of bacterial endocarditis (BE) during pregnancy is about 0.01%, while maternal and fetal mortality rates due to BE are 22% and 15%, respectively. Fetal survival is <15% until week 25 of gestation, and cesarean delivery is recommended before cardiopulmonary bypass in the third trimester. The case is described of a 24-year-old woman (a known drug addict), gravida 1, para 0, at week 22 of gestation, with an acute mitral valve endocarditis caused by Staphylococcus aureus. Following urgent mitral valve replacement, the strategy for fetal survival involved reducing the hemodilution and scavenging the cardioplegia solution from the right atrium, avoiding deep hypothermia to minimize rewarming, and maintaining a high pump flow rate (>2.5 l/min/m2) with a mean perfusion pressure of 70 mmHg, using pulsatile perfusion. The patient had an uneventful postoperative course, and at 34 weeks' gestation a normal newborn of 1780 g was delivered by cesarean section. No controlled clinical trials using extracorporeal circulation during pregnancy have been conducted, and reports are limited to single cases. A strategy was proposed to manage the present case of uncontrolled maternal BE at an early gestational age, by addressing several factors that would influence the outcome for both mother and baby.     

Probing Secondary Glutaminyl Cyclase (QC) Inhibitor Interactions Applying an in silico‐Modeling/Site‐Directed Mutagenesis Approach: Implications for Drug Development

Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate‐modified amyloid peptides deposited in neurodegenerative disorders such as Alzheimer’s disease. Inhibitors of QC are currently in development as potential therapeutics. The crystal structures of the potent inhibitor PBD150 bound to human and murine QC (hQC, mQC) have been described recently. The binding modes of a dimethoxyphenyl moiety of the inhibitor are significantly different between the structures, which contrasts with a similar K_i value. We show the conformation of PBD150 prone to disturbance by protein–protein interactions within the crystals. Semi‐empirical calculations of the enzyme–inhibitor interaction within the crystal suggest significant differences in the dissociation constants between the binding modes. To probe for interactions in solution, a site‐directed mutagenesis on hQC was performed. The replacement of F325 and I303 by alanine or asparagine resulted in a 800‐fold lower activity of the inhibitor, whereas the exchange of S323 by alanine or valine led to a 20‐fold higher activity of PBD150. The results provide an example of deciphering the interaction mode between a target enzyme and lead substance in solution, if co‐crystallization does not mirror such interactions properly. Thus, the study might provide implications for rapid screening of binding modes also for other drug targets.     

Susceptibility of sylvatic Triatoma infestans from Andeans valleys of Bolivia to deltamethrin and fipronil

We describe the susceptibility to deltamethrin and fipronil of four sylvatic Triatoma infestans populations from the Andean valleys of Bolivia. Fifty percent lethal doses were determined from topical application of insecticide on first instars, and mortality was assessed after 24 h for deltamethrin and 48 h for fipronil. In comparison with a reference strain from Argentina, the Bolivian populations showed deltamethrin 50 percent lethal dose ratios ranging from 1.9 to 17.4. In the case of fipronil, an insecticide never used for control of T. infestans, the Bolivian populations showed even higher variation in toxic response, with relative susceptibilities ranging from 0.5 to 139.2. However, although the sylvatic T infestans toxicological profiles differ from each other and from those of the domiciliary population studied in this work, there were no significant differences in the activities of P450 mono-oxygenases and pyrethroid esterases between the reference strain and the studied populations.     

High K+-induced contraction requires depolarization-induced Ca2+ release from internal stores in rat gut smooth muscle

Aim:

Depolarization-induced contraction of smooth muscle is thought to be mediated by Ca²⁺ influx through voltage-gated L-type Ca²⁺ channels. We describe a novel contraction mechanism that is independent of Ca²⁺ entry.

Methods:

Pharmacological experiments were carried out on isolated rat gut longitudinal smooth muscle preparations, measuring isometric contraction strength upon high K⁺-induced depolarization.

Results:

Treatment with verapamil, which presumably leads to a conformational change in the channel, completely abolished K⁺-induced contraction, while residual contraction still occurred when Ca²⁺ entry was blocked with Cd²⁺. These results were further confirmed by measuring intracellular Ca²⁺ transients using Fura-2. Co-application of Cd²⁺ and the ryanodine receptor blocker DHBP further reduced contraction, albeit incompletely. Additional blockage of either phospholipase C (U 73122) or inositol 1,4,5-trisphophate (IP₃) receptors (2-APB) abolished most contractions, while sole application of these blockers and Cd²⁺ (without parallel ryanodine receptor manipulation) also resulted in incomplete contraction block.

Conclusion:

We conclude that there are parallel mechanisms of depolarization-induced smooth muscle contraction via (a) Ca²⁺ entry and (b) Ca²⁺ entry-independent, depolarization-induced Ca²⁺-release through ryanodine receptors and IP₃, with the latter being dependent on phospholipase C activation.