bluuebunny/crossref_metadata_2025 huggingface dataset:
Twenty-Four Hour Continuous Ghrelin Infusion Augments Physiologically Pulsatile, Nycthemeral, and Entropic (Feedback-Regulated) Modes of Growth Hormone Secretion
Authors: Veldhuis Johannes D. , Reynolds George Ann , Iranmanesh Ali , Bowers Cyril Y.
Published: July 2008

Background: Ghrelin is a 28-amino acid acylated peptide that potentiates GHRH stimulation and opposes somatostatin inhibition acutely. Whether prolonged ghrelin administration can sustain physiological patterns of GH secretion remains unknown.

Hypothesis: Continuous delivery of ghrelin will amplify physiological patterns of GH secretion over 24 h.

Subjects: Men and women ages 29–69 yr, body mass indices 23–52 kg/m2, were included in the study.

Location: The study was performed at an academic medical center.

Methods: Twenty-four hour continuous sc infusion of saline vs. ghrelin (1 μg/kg·h) with frequent sampling was examined. Deconvolution and entropy analyses were performed.

Outcomes: IGF-I concentrations were determined. Basal, pulsatile, nycthemeral, and entropic measures of GH secretion were calculated.

Results: Ghrelin infusion compared with saline infusion for 24 h elevated (median) acylated ghrelin, GH, and IGF-I concentrations by 8.1-fold (P < 0.001),11-fold (P < 0.001), and 1.4-fold (P = 0.002). GH secretory-burst mass and frequency increased by 6.6-fold (P = 0.004) and 1.7-fold (P < 0.001), respectively, resulting in a 12-fold increase in pulsatile GH secretion (P < 0.001). Interpulse variability decreased significantly (P = 0.046), whereas GH secretory-burst shape and half-life did not change. The amplitude of the nycthemeral GH rhythm increased by 3.4-fold (P < 0.001), and GH patterns became more irregular (higher approximate entropy P < 0.001). Combining GHRH with ghrelin was not an additive in driving GH secretion.

Conclusions: Continuous ghrelin infusion for 24 h elevates acylated ghrelin, GH and IGF-I concentrations, and stimulates pulsatile, nycthemeral, and entropic modes of GH secretion. The consistency of outcomes in a heterogeneous cohort of adults suggests potentially broad utility of this physiological secretagogue in hyposomatotropic states.
Regulation of integrin activation through the B-cell receptor
Authors: Arana Eloisa , Harwood Naomi E. , Batista Facundo D.
Published: July 2008

Effective immune surveillance is absolutely dependent on the migration of lymphocytes throughout the body and on their successful recognition of specific antigens. Both of these functions rely on the capacity of integrins that are expressed on the surface of lymphocytes to respond in a highly regulated manner to a variety of chemokines and antigens. This Commentary is primarily concerned with the role of the B-cell integrins LFA-1 and VLA-4 in the antigen-recognition process, and summarises what is currently known about the molecular mechanisms of `inside-out' integrin activation in response to B-cell-receptor stimulation. Recent investigations have identified Vav, PI3K and small GTPases as crucial regulators of the inside-out activation of B-cell integrins. These observations are of particular interest as they allude to an underlying mechanism by which B-cell-receptor-mediated signalling is linked to cytoskeleton reorganisation and subsequent integrin activation.
Optimizing Product Line Designs: Efficient Methods and Comparisons
Authors: Belloni Alexandre , Freund Robert , Selove Matthew , Simester Duncan
Published: July 2008

We take advantage of recent advances in optimization methods and computer hardware to identify globally optimal solutions of product line design problems that are too large for complete enumeration. We then use this guarantee of global optimality to benchmark the performance of more practical heuristic methods. We use two sources of data: (1) a conjoint study previously conducted for a real product line design problem, and (2) simulated problems of various sizes. For both data sources, several of the heuristic methods consistently find optimal or near-optimal solutions, including simulated annealing, divide-and-conquer, product-swapping, and genetic algorithms.
Instruments Assessing Capacity to Manage Medications
Authors: Farris Karen B , Phillips Beth Bryles
Published: July 2008

Objective:

To review literature on instruments available for assessing the physical and cognitive ability to take medications as prescribed, which serve as a way to rule out reasons for nonadherence.

Data Sources:

A PubMed search (1950–February 2008) was conducted to identity relevant articles. Additional references were obtained from cross-referencing the bibliographies of selected articles. Only journals containing English-language articles were selected for review.

Study Selection and Data Extraction:

Articles that described a simulated assessment of medication management were obtained, irrespective of whether the assessment also contained data about medication adherence or was focused on older adults.

Data Synthesis:

Fifteen instruments were identified. Six instruments required 5 minutes or less to administer. 5 required 6–30 minutes, and 4 had no administration time data reported. A possible advantage of 3 of the instruments is that they use a subject's own medications and may therefore provide a more authentic assessment. Only 2 instruments have been tested by subjects other than the drug developers and only one has been used in 2 different populations, thereby affording soma insight into generalizability. These studies have used a variety of other validated surveys/assessments to provide an indication of construct validity, including neuropsychological batteries, caregiver reports, prospective outcomes, instrumental activities of daily living, and levels of care. One instrument determined whether Individuals could tell if refills existed, whom to contact, and resources to obtain medications. Three assessed numeracy literacy.

Conclusions:

Five instruments that measure medication management capacity should be compared for potential further use, including Beckman's tasks, due to their brevity and assessment of numeracy literacy; the Medication Management Ability Assessment, Drug Regimen Unassisted Grading Scale, and Hopkins Medication Schedule because of the evidence supporting their use; and the Medication Management Instrument for Deficiencies In the Elderly because it includes an assessment of the patient's knowledge of how to obtain more medications. No brief tool is available for the primary care setting to identify individuals with medication management problems or to guide the type and amount of support required to manage medications.
Effects of AGTR1 A1166C Gene Polymorphism in Patients with Heart Failure Treated with Candesartan
Authors: Denus Simon de , Zakrzewski-Jakubiak Marcin , Dubé Marie-Pierre , Bélanger François , Lepage Serge , Leblanc Marie-Hélène , Gossard Denis , Ducharme Anique , Racine Normand , Whittom Lucette , Lavoie Joel , Touyz Rhian M , Turgeon Jacques , White Michel
Published: July 2008

Background:

The benefits of angiotensin II receptor blockers (ARBs) in patients with heart failure who are treated with standard pharmacotherapy, including an angiotensin-converting enzyme (ACE) inhibitor, were demonstrated in 2 large randomized trials. It is currently impossible to determine which patient will benefit from the addition of an ARB.

Objective:

To explore the impact of selected candidate genes on the hemodynamic, neurohormonal, and antiinflammatory effects of candesartan in patients with heart failure who are already being treated with an ACE inhibitor.

Methods:

We investigated the impact of 10 candidate genetic polymorphisms on the effects of candesartan in patients with heart failure who are treated with an ACE inhibitor. We evaluated their impact on acute (2 wk) and long-term (24 wk) changes in blood pressure and N-terminal proB-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) during treatment with candesartan.

Results:

Thirty-one patients were included. Homozygotes of the AGTR1 A1166 allele (n = 13) had a greater decrease in systolic (-9.1 ± 4.7 vs 1.1 ± 3.3 mmHg; p = 0.04 by analysis of variance [ANOVA], adjusting for dose) and diastolic blood pressure (-5.1 ± 1.5 vs 1.9 ± 1.9 mm Hg; p = 0.005 by ANOVA, adjusting for dose) compared with C1166 allele carriers (n = 18) following 2 weeks of treatment. After 6 months of treatment, C1166 carriers experienced a greater decrease in NT-proBNP (-151.4 (-207; -19.8] ng/L vs 147.3 (-61.3; 882.9] ng/L; P = 0.03) and hsCRP (-0.8 [-2.2; -0.03] mg/L) vs 0.2 [-1.8; 5.3] mg/L; p = 0.09) compared with patients carrying the AA1166 genotype. No other significant association was found.

Conclusions:

The results of this proof-of concept study provide the first evidence that the AGTR1 A1166C polymorphism could influence the response to candesartan in patients with heart failure who are receiving ACE inhibitors. Validation of these exploratory findings in larger populations is required before use of the AGTR1 A1166C genotype can be incorporated into clinical practice.
Efficacy of a Premedication Algorithm for Nonemergent Intubation in a Neonatal Intensive Care Unit
Authors: VanLooy JW , Schumacher Robert E , Bhatt-Mehta Varsha
Published: July 2008

Background:

Preventing significant oxygen desaturation and hypotension through adequate analgesia and sedation during nonemergent Intubation In neonates is desirable. However, in many neonatal intensive care units, elective intubations occur without adequate premedication. There is significant variation In the choice of premedication agen(s) and doses, and an ideal regimen for use during nonemergent intubation has not been developed.

Objective:

To evaluate the efficacy of an algorithm developed for analgesia and sedation during nonemergent Intubation in neonates.

Methods:

Prospectively collected continuous quality Improvement data on a premedication algorithm for nonemergent intubation were analyzed following institutions] review board approval. Midazolam 0.1 mg/kg and fentanyl 2 μg/kg (if the patient was not already receiving morphine for sedation) were administered prior to nonemergent intubation. Heart rate, oxygen saturation, respiration rate, mean arterial pressure, and pain scores were recorded at baseline prior to medication administration, during the procedure, and for 2 hours after the procedure. Data during laryngoscopy and until the time of lube taping were obtained from Ine bedside cardiorespiratory monitor. Additional fentanyl was allowed for more than 3 intubation attempts and rocuronium 0.6 mg/kg was allowed for more than 5 attempts. The physiological changes that occurred over time were compared with baseline. The number of attempts made, time to intubation, and medications used are presented.

Results:

Ninety evaluable patients were included. Mean ± SD birth weight and postnatal age at treatment were 2040 ± 961 g and 14 ± 17 days, respectively. Heart rate decreased and oxygen saturation Increased significantly (160 vs 154 beats/min, p = 0.01; 96.4% vs 93.8%. p = 0.002, respectively) from baseline to completion of the procedure; however, mean arterial pressure showed no significant difference (44.9 vs 44.7 mm Hg; p = 0.85; n = 68). The number of attempts at Intubation were recorded (or 66 patients; of those, 52 required 3 or fewer attempts for successful Intubation (median, 2).The lime to successful intubation was 7.2 ± 5.6 minutes (recorded in 45 pts.). Average fentanyl and midazolam doses were 1.92 ± 0.53 μg/kg and 0.096 ± 0.026 mg/kg, respectively. No patient received rocuronium.

Conclusions:

A systematic approach to premedication during nonemergent intubation successfully prevented acute physiological changes.
Indiplon: A Nonbenzodiazepine Sedative–Hypnotic for the Treatment of Insomnia
Authors: Marrs Joel C
Published: July 2008

Objective:

To review the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and adverse effects of indiplon in the treatment of transient and chronic insomnia in adult and geriatric patients.

Data Sources:

A literature search was conducted using MEDLINE (1966–May 2006), International Pharmaceutical Abstracts (1970–May 2008), and Cochrane database (2007) (or the key words indiplon or NBI-34060. References cited in the articles were reviewed for additional Information. Abstract data were included only in the absence of significant published data.

Study Selection and Data Extraction:

English-language literature reporting animal and human clinical studies was reviewed to evaluate data on the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, and adverse effects of indiplon. Clinical trials selected for inclusion were limited to those with human subjects, with the accepted Inclusion of pharmacology data in animals.

Data Synthesis:

Indiplon Is a nonbenzodiazepine sedative-hypnotic that exhibits its sedating activity through its interaction with the γ–aminobutyric acid a receptor complex. Indiplon immediate-release (IR) as well as modified-release (MR) forms have shown improvement compared with placebo in patients with DSM-IV-TR primary insomnia in various areas of subjective and objective sleep measurements. Specifically, Improvements In total sleep time, latency to persistent sleep, latency to sleep onset, wake after sleep onset, and sleep quality have been noted In clinical trials. Trials evaluating both indiplon IR and MR have so far not identified any major serious adverse effects.

Conclusions:

Limited clinical trial data exist on use of indiplon in a “true” transient insomnia patient population. Based on recent Food and Drug Administration requests, clinical trial data assessing direct comparisons of indiplon IR with other approved nonbenzodiazepine sedative–hypnotics are needed to clearly define the differences among these agents.
Hospital Admissions Associated with Adverse Drug Reactions: A Systematic Review of Prospective Observational Studies
Authors: Kongkaew Chuenjid , Noyce Peter R , Ashcroft Darren M
Published: July 2008

Objective:

To determine the prevalence of hospital admissions associated with ADRs and examine differences in prevalence rates between population groups and methods of ADR detection.

Data Sources:

Studies were identified through electronic searches of Cumulative Index to Nursing and Allied Hearth Literature. EMBASE, and MEDLINE to August 2007. There were no language restrictions.

Study Selection and Data Extraction:

A systematic review was conducted of prospective observational studies that used the World Health Organization ADR definition. Subgroup analysis examined the influence of patient age groups and methods of ADR detection on reported ADR admission rates. All statistical analyses were performed using STATA v 9.0.

Data Synthesis:

Twenty-five studies were identified including 106, 586 patients who were hospitalized; 2143 of these patients had experienced ADRs. The prevalence rates of ADRs ranged from 0.16% to 15.7%, with an overall median of 5.3% (interquartile range [IQR] 2.7–9.0%). Median ADR prevalence rates varied between age groups: for children, the ADR admission rate was 4.1% (IQR 0.16–5.3%), while the corresponding rates for adults and elderly patients were 6.3% (IQR 3.9–9.0%) and 10.7% (IQR 9.6–13.3%), respectively. ADR rates also varied depending on the methods of ADR detection employed in the different studies. Studies that employed multiple ADR detection methods, such as medical record review and patient interview, reported higher ADR admission rates compared with studies that used medical record review alone. Antiinfective drugs were most often associated with ADR admissions in children; cardiovascular drugs were most often associated with ADR admissions in adults and elderly patients.

Conclusions:

Approximately 5.3% of hospital admissions were associated with ADRs. Higher rates were found in elderly patients who are likely to be receiving multiple medications for long-term illnesses. The methods used to detect ADRs are also likely to explain much of the variation in the reported ADR prevalence rates between different studies.
Overexpression of Bone Sialoprotein Leads to an Uncoupling of Bone Formation and Bone Resorption in Mice
Authors: Valverde Paloma , Zhang Jin , Fix Amanda , Zhu Ji , Ma Wenli , Tu Qisheng , Chen Jake
Published: July 2008

The purpose of this study was to determine the effects of bone sialoprotein (BSP) overexpression in bone metabolism in vivo by using a homozygous transgenic mouse line that constitutively overexpresses mouse BSP cDNA driven by the cytomegalovirus (CMV) promoter. CMV-BSP transgenic (TG) mice and wildtype mice were weighed, and their length, BMD, and trabecular bone volume were measured. Serum levels of RANKL, osteocalcin, osteoprotegerin (OPG), TRACP5b, and PTH were determined. Bone histomorphometry, von Kossa staining, RT-PCR analysis, Western blot, MTS assay, in vitro mineralization assay, and TRACP staining were also performed to delineate phenotypes of this transgenic mouse line. Compared with wildtype mice, adult TG mice exhibit mild dwarfism, lower values of BMD, and lower trabecular bone volume. TG mice serum contained increased calcium levels and decreased PTH levels, whereas the levels of phosphorus and magnesium were within normal limits. TG mice serum also exhibited lower levels of osteoblast differentiation markers and higher levels of markers, indicating osteoclastic activity and bone resorption. H&E staining, TRACP staining, and bone histomorphometry showed that adult TG bones were thinner and the number of giant osteoclasts in TG mice was higher, whereas there were no significant alterations in osteoblast numbers between TG mice and WT mice. Furthermore, the vertical length of the hypertrophic zone in TG mice was slightly enlarged. Moreover, ex vivo experiments indicated that overexpression of BSP decreased osteoblast population and increased osteoclastic activity. Partly because of its effects in enhancing osteoclastic activity and decreasing osteoblast population, BSP overexpression leads to an uncoupling of bone formation and resorption, which in turn results in osteopenia and mild dwarfism in mice. These findings are expected to help the development of therapies to metabolic bone diseases characterized by high serum level of BSP.
Vitamin D Metabolites and Calcium Absorption in Severe Vitamin D Deficiency
Authors: Need Allan G , O'Loughlin Peter D , Morris Howard A , Coates Penelope S , Horowitz Michael , Nordin BE Christopher
Published: July 2008

Contrary to frequent claims, vitamin D insufficiency does not generally cause malabsorption of calcium because serum 1,25(OH)2D, which is the major determinant of calcium absorption, is maintained by secondary hyperparathyroidism. Nevertheless, because malabsorption of calcium has been described in osteomalacia, there must be a 25(OH)D level below which the serum 1,25(OH)2D can no longer be sustained, although it has never been defined. This paper seeks to define it. We examined the records of 3661 patients and found 319 with a serum 25(OH)D ≤40 nM, in whom calcium absorption, serum calcium, PTH, bone markers, and vitamin D metabolites had been measured. They were grouped according to their serum 25(OH)D into four categories, 0–10, 11–20, 21–30, and 31–40 nM, and differences between the groups were tested by ANOVA. Correlations between the variables were also examined. Serum calcium, 1,25(OH)2D, and calcium absorption were significantly decreased and serum PTH and alkaline phosphatase (ALP) and urine hydroxyproline were increased in those with 25(OH)D ≤10 nM. Serum ALP and urine hydroxyproline were more strongly related, inversely, to calcium absorption than to the vitamin D metabolites. We conclude that vitamin D deficiency does not reduce serum 1,25(OH)2D, and therefore calcium absorption, until the serum 25(OH)D falls to ∼10 nM. At this level, the substrate concentration seems to be insufficient to maintain the level of the dihydroxy metabolite despite secondary hyperparathyroidism. Further studies are needed to see how these changes correlate with the histological changes of osteomalacia.
Age-Dependent Demise of GNAS-Mutated Skeletal Stem Cells and “Normalization” of Fibrous Dysplasia of Bone
Authors: Kuznetsov Sergei A , Cherman Natasha , Riminucci Mara , Collins Michael T , Robey Pamela Gehron , Bianco Paolo
Published: July 2008

We studied the role of somatic mosaicism in fibrous dysplasia of bone (FD) within the context of skeletal (“mesenchymal”) stem cells by assessing the frequency of mutated colony forming unit-fibroblasts (CFU-Fs) from FD lesions, and in some cases, from unaffected sites, in a series of patients. There was a tight inverse correlation between the percentage mutant CFU-F versus age, suggesting demise of mutant stem cells caused by exuberant apoptosis noted in samples from young patients. In older patients, either partially or completely normal bone/marrow histology was observed. On in vivo transplantation, FD ossicles were generated only by cell strains in which mutant CFU-Fs were identified. Strains that lacked mutant CFU-F (but were mutation positive) failed to regenerate an FD ossicle. These data indicate that GNAS mutations are only pathogenic when in clonogenic skeletal stem cells. From these data, we have evolved the novel concept of “normalization” of FD. As a lesion ages, mutant stem cells fail to self-renew, and their progeny are consumed by apoptosis, whereas residual normal stem cells survive, self-renew, and enable formation of a normal structure. This suggests that activating GNAS mutations disrupt a pathway that is required for skeletal stem cell self-renewal.
Bone Markers Predict Cardiovascular Events in Chronic Kidney Disease
Authors: Fahrleitner-Pammer Astrid , Herberth Johann , Browning Steven R , Obermayer-Pietsch Barbara , Wirnsberger Gerhard , Holzer Herwig , Dobnig Harald , Malluche Hartmut H
Published: July 2008

Recent studies have indicated a link between bone metabolism and cardiovascular events in patients with chronic kidney disease (CKD). CKD is a major health problem worldwide. This study evaluates the role of noninvasive markers of bone metabolism in predicting cardiovascular morbidity (coronary artery disease, peripheral vascular disease, stroke) and mortality in patients with mild to severe forms of CKD. In a prospective cohort study, 627 patients with CKD were screened. To focus on bone metabolism, traditional risk factors for cardiovascular events were excluded, and 135 patients with CKD stages 1–5 were followed for 4 yr. Glomerular filtration rate was calculated by the Modification of Diet in Renal Disease formula. PTH (measured by four different assays), vitamin D 25 and 1,25, bone-specific alkaline phosphatase (BSALP), TRACP-5b, osteocalcin, serum collagen cross-link molecules, RANKL, and osteoprotegerin were determined. Predictors of cardiovascular events were evaluated by multivariable logistic regression, Kaplan-Meier survival, and Cox regression analysis. There were a total of 45 cardiovascular events (33%). Event rates were 5.6%, 29.1%, 45.2%, and 45.0% in CKD stages 1–2, 3, 4, and 5, respectively. In logistic regression, cardiovascular events were predicted only by (1) CKD stage (independent of age or sex; p < 0.001); (2) BSALP (p = 0.03); and (3) TRACP-5b (p = 0.04). Markers of bone formation (BSALP) and resorption (TRACP-5b) can serve as predictors of cardiovascular morbidity and mortality in CKD.
Practical Operationalizations of Risk Factors for Fracture in Older Women: Results From Two Longitudinal Studies
Authors: Pluijm Saskia MF , Steyerberg Ewout W , Kuchuk Natalia O , Rivadeneira Fernando F , Looman Caspar W , Van Schoor Natasja M , Koes Bart , Mackenbach Johan P , Lips Paul , Pols Huibert A
Published: July 2008

Several guidelines on osteoporosis have proposed algorithms to identify persons at high risk of fractures. Although these algorithms include well-known risk factors, it is not clear how they can best be operationalized for use in general practice. The aim of this study was to compare the predictive performance of different operationalizations of four categories of risk factors for fractures that can be used in general practice. This study included 4157 women of ≥60 yr of age (mean ± SD: 74.1 ± 9.1 yr) with a median follow-up of 8.9 yr of the Rotterdam Study and 762 women of ≥65 yr of age (mean ± SD: 76.0 ± 6.7.yr) with a median follow-up of 6.0 yr of the Longitudinal Aging Study Amsterdam (LASA). At baseline, information on four categories of risk factors was obtained, including (1) family history of hip fractures, (2) type of prior fractures, (3) low body weight/body mass index (BMI), and (4) mobility impairment. The occurrence of fragility fractures, including hip, pelvic, humerus, and wrist fractures, was used as outcome measure. We quantified the predictive performance of each risk factor by a χ2 statistic, calculated as the difference in –2 Log likelihood attributable to the risk factor, with adjustment for age and other risk factors. In the Rotterdam Study, 399 fragility fractures occurred during 31,472 person-years (PY) of follow-up. In this study, any prior fracture in the past 5 yr (χ2 = 6; p = 0.02), body weight < 64 kg (versus ≥64 kg; χ2 = 6.7; p = 0.01), BMI < 22 kg/m2 (versus ≥22 kg/m2; χ2 = 8.7; p = 0.003), and use of a walking aid (χ2 = 7.5; p = 0.004) were the most practical operationalizations of the risk factor categories, after adjustment for age and other risk factors. In LASA, 52 fragility fractures occurred during 3935 PY of follow-up. Associations were similar as in the Rotterdam Study, except that low body weight and BMI were not associated with fragility fracture. None of the usual operationalizations of family history of hip fractures was independently associated with fragility fracture in either study. Prior osteoporotic fracture, body weight <64 kg, a BMI <22 kg/m2, and the use of a walking aid are practical operationalizations of risk factors for fragility fractures. On the basis of the results of this study, a simple, practical algorithm can be developed for use in general practice.
Granulocyte Colony-Stimulating Factor Induces Osteoblast Apoptosis and Inhibits Osteoblast Differentiation
Authors: Christopher Matthew J , Link Daniel C
Published: July 2008

Long-term treatment of mice or humans with granulocyte colony-stimulating factor (G-CSF) is associated with a clinically significant osteopenia characterized by increased osteoclast activity and number. In addition, recent reports have observed a decrease in number of mature osteoblasts during G-CSF administration. However, neither the extent of G-CSF's suppressive effect on the osteoblast compartment nor its mechanisms are well understood. Herein, we show that short-term G-CSF treatment in mice leads to decreased numbers of endosteal and trabecular osteoblasts. The effect is specific to mature osteoblasts, because bone-lining cells, osteocytes, and periosteal osteoblasts are unaffected. G-CSF treatment accelerates osteoblast turnover in the bone marrow by inducing osteoblast apoptosis. In addition, whereas G-CSF treatment sharply increases osteoprogenitor number, differentiation of mature osteoblasts is impaired. Bone marrow transplantation studies show that G-CSF acts through a hematopoietic intermediary to suppress osteoblasts. Finally, G-CSF treatment, through suppression of mature osteoblasts, also leads to a marked decrease in osteoprotegerin expression in the bone marrow, whereas expression of RANKL remains relatively constant, suggesting a novel mechanism contributing to the increased osteoclastogenesis seen with long-term G-CSF treatment. In sum, these findings suggest that the hematopoietic system may play a novel role in regulating osteoblast differentiation and apoptosis during G-CSF treatment.
Bone Resorption Inhibitor Alendronate Normalizes the Reduced Bone Thickness of TRPV5−/− Mice
Authors: Nijenhuis Tom , van der Eerden Bram CJ , Hoenderop Joost GJ , Weinans Harrie , van Leeuwen Johannes PTM , Bindels René JM
Published: July 2008

TRPV5 is a Ca2+-selective channel involved in transcellular Ca2+ absorption expressed in kidney and in the ruffled border of osteoclasts. Studies in hypercalciuric TRPV5 knockout (TRPV5−/−) mice, which display significantly increased vitamin D levels, showed that TRPV5 ablation increases number and size of osteoclasts but impairs osteoclast-mediated bone resorption. The latter is not in line with the observed decreased bone thickness in TRPV5−/− mice. Bisphosphonates also inhibit osteoclast-mediated bone resorption. The aim of this study was to evaluate the effect of alendronate on the expression of the Ca2+ transporters in bone, kidney, and duodenum and, importantly, the bone phenotype in TRPV5−/− mice. Wildtype (TRPV5+/+) and TRPV5−/− mice were treated during 10 wk with 2 mg/kg alendronate or vehicle weekly and housed in metabolic cages at the end of treatment. Urine and blood samples were taken for biochemical analysis, and duodenum, kidney, and femur were sampled. Expression of Ca2+ transporters and osteoclast ruffled border transporters in bone and cultured osteoclasts was determined by QPCR analysis. Femurs were scanned using μCT, and resorption pit assays were performed in bone marrow cultures isolated from TRPV5+/+ and TRPV5−/− mice. Alendronate treatment enhanced bone thickness in TRPV5+/+ mice but also normalized the disturbed bone morphometry parameters in TRPV5−/− mice. Bone TRPV5 expression was specifically enhanced by alendronate, whereas the expression of Ca2+ transporters in kidney and intestine was not altered. The expression of the osteoclast ruffled border membrane proteins chloride channel 7 (CLC-7) and the vacuolar H+-ATPase did not differ between both genotypes, but alendronate significantly enhanced the expression and PTH levels in TRPV5−/− mice. The expression of TRPV5, CLC-7, and H+-ATPase in osteoclast cultures was not affected by alendronate. The number of resorption pits was reduced in TRPV5−/− bone marrow cultures, but the response to vitamin D was similar to that in TRPV5+/+ cultures. The alendronate-induced upregulation of TRPV5 in bone together with the decreased resorptive capacity of TRPV5−/− osteoclasts in vitro suggests that TRPV5 has an important role in osteoclast function. However, our data indicate that significant bone resorption still occurs in TRPV5−/− mice, because alendronate treatment normalized bone thickness in these mice. Thus, TRPV5−/− mice are able to rescue the resulting defect in osteoclast-mediated bone resorption, possibly mediated by the long-term hypervitaminosis D or other (non)hormonal compensatory mechanisms.
Vitamin D Depletion Induces RANKL-Mediated Osteoclastogenesis and Bone Loss in a Rodent Model
Authors: Anderson Paul H , Sawyer Rebecca K , Moore Alison J , May Brian K , O'Loughlin Peter D , Morris Howard A
Published: July 2008

The association between increased risk of hip fracture and low vitamin D status has long been recognized. However, the level of vitamin D required to maintain bone strength is controversial. We used a rodent model of vitamin D depletion to quantify the 25-hydroxyvitamin D (25D) levels required for normal mineralization. Six groups of 10-wk-old male Sprague-Dawley rats (n = 42) were fed a diet containing 0.4% calcium and various levels of dietary vitamin D3 for 4 mo to achieve stable mean serum 25D levels ranging between 10 and 115 nM. At 7 mo of age, animals were killed, and the histomorphometry of distal and proximal femora and L2 vertebra was analyzed. Total RNA was extracted from whole femora for real-time RT-PCR analyses. In the distal femoral metaphysis, trabecular bone mineral volume (BV/TV) showed a significant positive association with circulating 25D levels (r2 = 0.42, p < 0.01) in the animals with serum 25D levels between 20 and 115 nM. Osteoclast surface (Oc.S) levels were positively associated with RANKL:OPG mRNA ratio, higher in groups with lower serum 25D levels, and were independent of serum 1,25D levels. Serum 25D levels <80 nM gave rise to osteopenia as a result of increased osteoclastogenesis, suggesting that levels of 25D >80 nM are needed for optimal bone volume. These data indicate that serum 25D levels are a major determinant of osteoclastogenesis and bone mineral volume and are consistent with the levels of 25D recommended to reduce the risk of fracture in humans.
Diagnostic performance of rapid tests for detection of fecal calprotectin and lactoferrin and their ability to discriminate inflammatory from irritable bowel syndrome
Authors: Otten Charlotte M.T. , Kok Liselotte , Witteman Ben J.M. , Baumgarten Ruben , Kampman Ellen , Moons Karel G.M. , de Wit Niek J.
Published: July 2008

: Ruling out somatic bowel disease, such as inflammatory bowel disease (IBD), is an important goal in the management of abdominal complaints. Endoscopy is commonly used but is invasive and expensive. Mucosal inflammation in IBD can be detected through fecal biomarkers, though the present enzyme-linked immunoabsorbent assay (ELISA) tests require laboratory facilities. We validated the diagnostic performance of two new fecal rapid tests (FRTs) for the detection of calprotectin and lactoferrin and assessed their potential to differentiate IBD from irritable bowel syndrome (IBS).

: The calprotectin and lactoferrin FRTs and ELISA tests were performed on the fecal samples of 114 patients referred for endoscopy, 80% of whom had IBS and 20% IBD, and validated against the endoscopic diagnosis.

: The sensitivity and negative predictive value of the calprotectin FRT were both 100%, whereas they were 78% and 95%, respectively, for the lactoferrin FRT. The specificity and positive predictive value were slightly higher for the lactoferrin FRT. Both FRTs had similar diagnostic accuracy as the corresponding ELISA tests.

: The calprotectin and lactoferrin rapid tests are as good as the ELISA tests in detecting colonic inflammation. Given their simple use, FRTs can support the non-invasive exclusion of IBD, notably in primary care.

Clin Chem Lab Med 2008;46:1275–80.
Fetal hemoglobin: assessment of glycation and acetylation status by electrospray ionization mass spectrometry
Authors: Davison Andrew S. , Green Brian N. , Roberts Norman B.
Published: July 2008

: Electrospray ionization mass spectrometry (ESI-MS) can be used for the measurement of glycated adult hemoglobin. Here, we describe the evaluation of ESI-MS for measurement of glycated (GHbF) and acetylated (AcHbF) fetal hemoglobin and the identification by mass of different chains of fetal hemoglobin.

: Blood samples were diluted in an acidic denaturing solvent, desalted with AG 50W-X8 resin and introduced directly into the mass spectrometer. Resulting mass spectra were processed to determine the percentage of GHbF and AcHbF and the γ-chain masses.

: The procedure yielded reproducible quantitative assay of GHbF and AcHbF, with coefficients of variation <4.9%. Measurement of α-chain glycation was similarly reproducible and is suggested as an alternative marker of glycemic control. Marked increases in glycation occurred in dried spot blood samples, which were related to duration of storage, temperature and glucose concentration. Molecular masses of fetal hemoglobin chains were also determined and in 42 neonates studied, two types A and B were identified, two-thirds were type A with γ-chain masses corresponding to

: ESI-MS can be used for the estimation of GHbF and AcHbF and the accurate measurement of fetal γ-chain masses. The use of whole blood is preferred for analysis.

Clin Chem Lab Med 2008;46:1230–8.
Analyse und Synthese eines Temperaturregelkreises mit Hilfe der harmonischen Balance (Analysis and Synthesis of a Temperature Control System Using Describing Functions)
Authors: Rehrl Jakob , Horn Martin
Published: July 2008

Im vorliegenden Aufsatz wird die rechnergestützte Simulation des Temperaturregelkreises einer klimatechnischen Anlage beschrieben. Ziel der Untersuchungen ist es, durch Anwenden der Methode der harmonischen Balance das in realen Anlagen beobachtete Auftreten von unerwünschten Dauerschwingungen mathematisch nachzuweisen und in weiterer Folge durch gezielte Maßnahmen zu verhindern.
Sättigende weiche strukturvariable Regelung (Saturated Soft Variable-structure Control)
Authors: Buhl Michael , Joos Philipp , Lohmann Boris
Published: July 2008

Der Beitrag beschreibt eine weiche strukturvariable Regelung mit dem Ziel, lineare Strecken mit Stellgrößenbegrenzung nahezu zeitoptimal in eine Ruhelage zu überführen. Dazu werden gezielt Reglerverstärkungen verwendet, die in großen Bereichen des Zustandsraums zu einer Sättigung der Stellgröße führen. Dynamik und Robustheit der Regelung können über zwei Parameter in transparenter Weise eingestellt werden; der numerische Aufwand ist vergleichsweise gering.
Algebraische Ableitungsschätzung im Kontext der Rekonstruierbarkeit (Algebraic Time-derivative Estimation in the Context of Reconstructibility)
Authors: Reger Johann , Jouffroy Jérôme
Published: July 2008

Das von Fliess und Sira Ramírez vorgeschlagene algebraische Verfahren zur Schätzung von Zeitableitungen gemessener Signale wird aus klassischen Resultaten der Optimalschätzung hergeleitet. Insbesondere wird anhand einfacher Rechnungen gezeigt, wie sich das algebraische Verfahren als ein Sonderfall der Zustandsrekonstruktion mit Hilfe von Rekonstruierbarkeits-Gramschen ergibt. Abschließend werden Verbindungen zu weiteren Verfahren hergestellt, wie Least-Squares und dem Kalman-Filter, sowie kurz Implikationen für die Praxis erörtert.
Ereignisgesteuerte kontinuierliche Systeme – Eigenschaften und Entwurfsprobleme (Discretely Controlled Continuous Systems – Properties and Design Problems)
Authors: Hellfeld Marcus , Schild Axel , Lunze Jan , Schwarz Wolfgang , Krupar Jörg
Published: July 2008

Der Beitrag behandelt die Klasse der ereignisgesteuerten kontinuierlichen Systeme, einer wichtigen Unterklasse der hybriden dynamischen Systeme. An Beispielen wird gezeigt, dass derartige Systeme in vielen Anwendungen in Form eines Regelkreises aus einer kontinuierlichen Strecke und einem diskreten Regler auftreten. Die Systemfunktion wird durch diskrete Stelleingriffe des Reglers erzielt, die zwischen den verschiedenen Betriebsmodi der Strecke umschalten und damit eine Änderung der Streckendynamik bewirken. Es werden ein allgemeines, modulares Modell vorgeschlagen, wichtige Eigenschaften dieser Systemklasse hervorgehoben und relevante Analyse- und Entwurfsaufgaben abgeleitet.
Dietary factors associated with plasma high molecular weight and total adiponectin levels in apparently healthy women
Authors: Yannakoulia Mary , Yiannakouris Nikos , Melistas Labros , Fappa Evaggelia , Vidra Nikoletta , Kontogianni Meropi D , Mantzoros Christos S
Published: July 2008

Objective

Our aim was to investigate associations between dietary factors and high molecular weight (HMW) as well as total adiponectin in a sample of apparently healthy adult Mediterranean women.

Design and methods

Two hundred and twenty women were enrolled in this study. Anthropometric and body composition measurements were performed in all subjects. Fasting blood samples were taken; HMW and total adiponectin concentrations were measured. Food intake was evaluated using 3-day food records. The frequency of consumption of several food groups was approximately quantified in terms of number of servings per day. Furthermore, dietary intakes of betaine, choline, and free choline were estimated.

Results

Women in the highest HMW adiponectin tertile had higher fruit intake compared with those with lower levels, after adjusting for potential confounders (P=0.04). On the contrary, dietary betaine and choline intakes were not different among HMW adiponectin tertiles. In linear models, fruit consumption, controlling for biological and lifestyle variables, was significantly related to HMW adiponectin (partial r=0.15, P=0.04), but the association with total adiponectin did not reach statistical significance (partial r=0.11, P=0.12). A significant negative correlation between total adiponectin and refined cereals was also observed (partial r=−0.16, P=0.03).

Discussion

This is the first study that evaluates associations between dietary factors and HMW adiponectin levels. The associations found are moderate and indicate that, after multivariate adjustment, fruit consumption is related to HMW adiponectin in both linear and nonlinear models.
Tumour necrosis factor-α-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx
Authors: Kim Hyo-Eun , Choi Sung-E , Lee Soo-Jin , Lee Ji-Hyun , Lee Youn-Jung , Kang Sang Sun , Chun Jaesun , Kang Yup
Published: July 2008

The present study was undertaken to determine how tumour necrosis factor-α (TNF-α) elicits the inhibition of glucose-stimulated insulin secretion (GSIS) in rat insulinoma cells (INS)-1 β-cells. TNF-α pretreatment did not change the expression levels of insulin, PDX-1, glucose transporter 2, glucokinase, KATP channels, Ca2+ channels, and exocytotic molecules and, furthermore, did not reduce the glucose-stimulated ATP level. On the other hand, TNF-α reduced the glucose-stimulated influx of Ca2+. The TNF-α treatment was thought to activate c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-κB inflammatory signals, since TNF-α increased phospho-JNK and phospho-p38 and reduced IκB levels. Inhibitors of these signaling pathways prevented the TNF-α-induced reduction of the Ca2+ influx and GSIS. Overexpression of MEKK3, a possible mediator from the TNF-α receptor to the JNK/p38 and NK-κB signaling cascade, increased the levels of phospho-JNK, phospho-p38, and NF-κB, and reduced the glucose-stimulated Ca2+ influx and GSIS. The reduction of the Ca2+ influx and GSIS in MEKK3-overexpressing INS-1 cells was also prevented by inhibitors of JNK, p38, and NF-κB. These data demonstrate that TNF-α inhibits GSIS by reducing the glucose-stimulated Ca2+ influx, possibly through the activation of JNK and p38 MAPK and NF-κB inflammatory signals. Thus, our findings suggest that the activation of stress and inflammatory signals can contribute to the inhibition of GSIS in the development of diabetes.
Micro- and macro-mechanical behaviour of DEM crushable materials
Authors: Bolton M. D. , Nakata Y. , Cheng Y. P.
Published: July 2008

This paper provides a micro-mechanical commentary on the macroscopic behaviour observed in DEM simulations of the compression of individual crushable grains, and of triaxial tests on assemblies of both crushable and uncrushable grains. A fragmentation ratio is defined to describe the bond breakage processes, and the significance of other micro-mechanical parameters such as sliding contacts ratio, average coordination number, deviator fabric, and internal energies per unit volume is discussed. Three different modes of grain damage were observed: asperity breakage, internal shear cracking, and internal tensile cracking leading to fast fracture. Energy balances both for the compression of a single grain, and for triaxial tests on assemblies of grains, showed that the loss of elastic energy due to bond breakage was a negligible fraction of the significantly enhanced dissipation encountered with crushable materials. This extra dissipation was associated with frictional sliding triggered by the creation of new degrees of freedom among the breaking fragments. Different modes of grain breakage were found to be representative of different regions of soil states of stress defined with respect to the virgin compression line. The secondary role of elastic grain deformability, increasing coordination number but reducing dilatancy, has also been demonstrated.
Evaluation of effluent toxicity as an indicator of aquatic life condition in effluent-dominated streams: A pilot study
Authors: Diamond Jerry , Stribling James , Bowersox Marcus , Latimer Henry
Published: July 2008

The types and quality of data needed to determine relationships between chronic whole effluent toxicity (WET) test results and in-stream biological condition were evaluated using information collected over a 1.5-y period from 6 different sites across the United States. A data-quality-objectives approach was used that included several proposed measurement quality objectives (MQOs) that specified desired precision, bias, and sensitivity of methods used. The 6 facilities used in this study (4 eastern and 2 western United States) all had design effluent concentrations >60% of the stream flow. In addition to at least quarterly chronic Ceriodaphnia dubia, Pimephales promelas (fathead minnow), and Selenastrum capricornutum (green algae) WET tests, other tests were conducted to address MQOs, including splits, duplicates, and blind positive and negative controls. Macroinvertebrate, fish, and periphyton bioassessments were conducted at multiple locations upstream and downstream of each facility. The test acceptance criteria of the US Environmental Protection Agency (USEPA) were met for most WET tests; however, this study demonstrated the need to incorporate other MQOs (minimum and maximum percent significant difference and performance on blind samples) to ensure accurate interpretation of effluent toxicity. More false positives, higher toxicity, and more “failed” (noncompliant) tests were observed using no-observed-effect concentration (NOEC) as compared to the IC25 endpoint (concentration causing ≥25% decrease in organism response compared to controls). Algae tests often indicated the most effluent toxicity in this study; however, this test was most susceptible to false positives and high interlaboratory variability. Overall, WET test results exhibited few relationships with bioassessment results even when accounting for actual effluent dilution. In general, neither frequency of WET noncompliance nor magnitude of toxicity in tests were significantly related to differences in biological condition upstream and downstream of a discharge. Periphyton assessments were most able to discriminate small changes downstream of the effluent, followed by macroinvertebrates and fish. Although sampling methods were robust, more replicate samples collected upstream and downstream of each facility were needed to increase detection power. In general, macroinvertebrate and periphyton assessments together appeared to be sufficient to address project objectives.
Porphyromonas gingivalis Infection Accelerates Intimal Thickening in Iliac Arteries in a Balloon‐Injured Rabbit Model
Authors: Zhang Ming‐Zhu , Li Chao‐Lun , Jiang Yun‐Tao , Jiang Wei , Sun Ying , Shu Rong , Liang Jing‐Ping
Published: July 2008

Background: Current epidemiologic data suggest that a localized infection (periodontitis) can disseminate into the distant tissues, and subgingival bacteria can migrate in the bloodstream, thereby contributing to independent systemic disease processes. To test this hypothesis, we investigated the effect of repeated systemic inoculations with Porphyromonas gingivalis (Pg) on intimal hyperplasia in iliac arteries in a rabbit model of balloon injury.

Methods: One week after single balloon injury to the iliac artery, 30 male New Zealand rabbits were randomly assigned to intravenous inoculation with 100 μl live Pg (107 colony‐forming units; n = 15) or vehicle (n = 15) once weekly for 4, 8, or 12 consecutive weeks. Arteries were fixed by perfusion and removed for analysis of neointimal lesion formation. We measured intimal and medial lesion areas in iliac artery cross‐sections as well as the intimal/medial ratio (I/M). We also analyzed Pg 16S ribosomal DNA amplification with polymerase chain reaction, systemic proinflammatory mediators with enzyme‐linked immunosorbent assay, and immunolocalization of macrophages in the balloon‐injured arteries.

Results: At 12 weeks, iliac intimal hyperplasia was accelerated, and I/M was significantly increased in Pg‐inoculated animals (I/M 3.961 ± 0.536 in the Pg group versus 3.585 ± 0.353 in the control animals; P <0.01). Pg‐inoculated animals also had significant increases in macrophage infiltration at 12 weeks, C‐reactive protein levels at all time points, and interleukin‐6 levels at 12 weeks. Moreover, Pg ribosomal DNA was found in the injured arteries of Pg‐inoculated animals, but only after 12 weeks.

Conclusion: Long‐term systemic challenge with Pg, an oral pathogen, may accelerate intimal hyperplasia in balloon‐injured iliac arteries.