Intravenous ibandronate injections in postmenopausal women with osteoporosis: One‐year results from the dosing intravenous administration study

Objective

Although oral bisphosphonates are effective treatments for postmenopausal women with osteoporosis, oral dosing may be unsuitable for some patients. An efficacious intravenously administered bisphosphonate could be beneficial for such patients. Ibandronate, a potent nitrogen‐containing bisphosphonate, can be administered using extended dosing intervals, either orally or by rapid intravenous injection. The aim of this study was to identify the optimal intravenous dosing regimen for ibandronate in postmenopausal women with osteoporosis.

Methods

In a randomized, double‐blind, double‐dummy, phase III, noninferiority study, we compared 2 regimens of intermittent intravenous injections of ibandronate (2 mg every 2 months and 3 mg every 3 months) with a regimen of 2.5 mg of oral ibandronate daily, the latter of which has proven antifracture efficacy. The study group comprised 1,395 women (ages 55–80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2−L4] bone mineral density [BMD] T score less than −2.5). Participants also received daily calcium (500 mg) and vitamin D (400 IU). The primary end point was change from baseline in lumbar spine BMD at 1 year. Changes in hip BMD and in the level of serum C‐telopeptide of type I collagen (CTX) were also measured, as were safety and tolerability.

Results

At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function.

Conclusion

As assessed by BMD, intravenous injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) are at least as effective as the regimen of 2.5 mg orally daily, which has proven antifracture efficacy, and are well tolerated.

     

Ejection fraction and blood pressure are important and interactive predictors of 4-week mortality in severe acute heart failure

BACKGROUND: In acute heart failure syndromes (AHFS), the prognostic value of left ventricular ejection fraction (LVEF), although widely accepted, has been recently challenged. In contrast, blood pressure is increasingly gaining ground over LVEF as predictor of mortality. Therefore, it is not clear whether both LVEF and mean arterial pressure (MAP) are independent risk factors in patients with AHFS. METHODS AND RESULTS: The EFICA study enrolled 581 AHFS patients admitted to 60 CCU/ICUs. Survival at 4 weeks was analyzed for all cases with echocardiographic LVEF available on admission (n=355). Four-week mortality was 23%. Multivariable analysis identified lower LVEF, lower MAP and serum creatinine >1.5 mg/dl as independent correlates of mortality (respectively, OR: 1.27 per 10% decrease, CI: 1.05-1.53, p=0.012; OR: 1.30 per 10 mmHg decrease, CI: 1.15-1.48, p<0.0001; OR: 2.84, CI: 1.64-4.93, p=0.0002). LVEF interacted significantly with MAP (p<0.0001) and the subgroup analysis showed that reduced LVEF was a strong risk factor in patients with MAP 90 mmHg. CONCLUSIONS: Both LVEF and MAP are important predictors of death in severe AHFS. LVEF can provide additional prognostic information on top of MAP but mainly in patients with low MAP (相似文献   

Recent advances in the management of autoimmune pancreatitis in the era of artificial intelligence

Autoimmune pancreatitis (AIP) is a type of immune-mediated pancreatitis subdivided into two subtypes, type 1 and type 2 AIP. Furthermore, type 1 AIP is considered to be the pancreatic manifestation of the immunoglobulin G4 (IgG4)-related disease. Nowadays, AIP is increasingly researched and recognized, although its diagnosis represents a challenge for several reasons: False positive ultrasound-guided cytological samples for a neoplastic process, difficult to interpret levels of IgG4, the absence of biological markers to diagnose type 2 AIP, and the challenging clinical identification of atypical forms. Furthermore, 60% and 78% of type 1 and type 2 AIP, respectively, are retrospectively diagnosed on surgical specimens of resected pancreas for suspected cancer. As distinguishing AIP from pancreatic ductal adenocarcinoma can be challenging, obtaining a definitive diagnosis can therefore prove difficult, since endoscopic ultrasound fine-needle aspiration or biopsy of the pancreas are suboptimal. This paper focuses on recent innovations in the management of AIP with regard to the use of artificial intelligence, new serum markers, and new therapeutic approaches, while it also outlines the current management recommendations. A better knowledge of AIP can reduce the recourse to surgery and avoid its overuse, although such an approach requires close collaboration between gastroenterologists, surgeons and radiologists. Better knowledge on AIP and IgG4-related disease remains necessary to diagnose and manage patients.     

Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency: identification of four novel mutations and high prevalence of Q318X mutation

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders mainly due to defects in the steroid 21-hydroxylase (CYP21) gene. To determine the mutational spectrum in the Tunisian CAH population, the CYP21 active gene was analyzed in 51 unrelated patients using our cascade strategy (digestion by restriction enzyme, sequencing). All patients had a classical form of 21-hydroxylase deficiency. Mutations were detected in over 94% of the chromosomes examined. The most frequent mutation in the Tunisian CAH population was found to be Q318X, with large prevalence (35.3%), in contrast to 0.5-13.8% described in other series. Incidence of other mutations does not differ, as previously described: large deletions (19.6%), mutation in intron 2 (17.6%), and I172N (10.8%). Four novel mutations were found in four patients with the salt-wasting form. These four novel mutations include three point mutations that have not been reported to occur in the CYP21P pseudogene: R483W, W19X, 2669insC, and one small conversion of DNA sequence from exon 5 to exon 8. Our results have shown a good genotype/phenotype correlation in the case of most mutations. This is the first report of screening for mutations of 21-hydroxylase gene in the Tunisian population and even in the Arab population.     

Prognostic value of cardiopulmonary exercise variables in chronic heart failure patients with or without beta-blocker therapy

The prognostic value of exercise-derived variables in the prediction of mortality in patients with chronic heart failure treated by beta blockers continues to be debated. A total of 402 patients with chronic heart failure, including 255 treated with beta blockers, were included and followed for 26 +/- 20 months after the exercise test. On univariate analysis, and in contrast to peak exercise oxygen consumption, the prognostic value of the minute ventilation/carbon dioxide production slope was increased in patients receiving beta-blocker therapy. On multivariate analysis, no independent prognostic variable emerged in patients not on beta-blocker therapy. However, the model that included the circulatory power (peak oxygen uptake x systolic blood pressure), in addition to age, New York Heart Association class, and left ventricular ejection fraction, was the best 1 for patients on beta-blocker therapy. In conclusion, in patients with chronic heart failure, the circulatory power is the exercise variable with the greatest independent prognostic value, compared with the peak exercise oxygen consumption and minute ventilation/carbon dioxide production slope.     

The impact of a social network intervention on retention in Belgian therapeutic communities: a quasi-experimental study

BACKGROUND: Although numerous studies recognize the importance of social network support in engaging substance abusers into treatment, there is only limited knowledge of the impact of network involvement and support during treatment. The primary objective of this research was to enhance retention in Therapeutic Community treatment utilizing a social network intervention. AIMS: The specific goals of this study were (1) to determine whether different pre-treatment factors predicted treatment retention in a Therapeutic Community; and (2) to determine whether participation of significant others in a social network intervention predicted treatment retention. DESIGN, SETTING AND PARTICIPANTS: Consecutive admissions to four long-term residential Therapeutic Communities were assessed at intake (n = 207); the study comprised a mainly male (84.9%) sample of polydrug (41.1%) and opiate (20.8%) abusers, of whom 64.4% had ever injected drugs. Assessment involved the European version of the Addiction Severity Index (EuropASI), the Circumstances, Motivation, Readiness scales (CMR), the Dutch version of the family environment scale (GKS/FES) and an in-depth interview on social network structure and perceived social support. Network members of different cohorts were assigned to a social network intervention, which consisted of three elements (a video, participation at an induction day and participation in a discussion session). FINDINGS: Hierarchical regression analyses showed that client-perceived social support (F1,198 = 10.9, P = 0.001) and treatment motivation and readiness (F1,198 = 8.8; P = 0.003) explained a significant proportion of the variance in treatment retention (model fit: F7,197 = 4.4; P = 0.000). By including the variable 'significant others' participation in network intervention' (network involvement) in the model, the fit clearly improved (F1,197 = 6.2; P = 0.013). At the same time, the impact of perceived social support decreased (F1,197 = 2.9; P = 0.091). CONCLUSIONS: Participation in the social network intervention was associated with improved treatment retention controlling for other client characteristics. This suggests that the intervention may be of benefit in the treatment of addicted individuals.     

Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of alpha-galactosylceramides

A form of alpha-galactosylceramide, KRN7000, activates CD1d-restricted Valpha14-invariant (Valpha14i) natural killer (NK) T cells and initiates multiple downstream immune reactions. We report that substituting the C26:0 N-acyl chain of KRN7000 with shorter, unsaturated fatty acids modifies the outcome of Valpha14i NKT cell activation. One analogue containing a diunsaturated C20 fatty acid (C20:2) potently induced a T helper type 2-biased cytokine response, with diminished IFN-gamma production and reduced Valpha14i NKT cell expansion. C20:2 also exhibited less stringent requirements for loading onto CD1d than KRN7000, suggesting a mechanism for the immunomodulatory properties of this lipid. The differential cellular response elicited by this class of Valpha14i NKT cell agonists may prove to be useful in immunotherapeutic applications.     

Nitro-thiocyanobenzoic acid (NTCB) reactivity of cysteines beta100 and beta110 in porcine luteinizing hormone: metastability and hypothetical isomerization of the two disulfide bridges of its beta-subunit seatbelt

Luteinizing hormone (LH) like all other glycoprotein hormones is composed of two dissimilar subunits, alpha and beta, that are non-covalently associated. The heterodimer is stabilized by a region of the beta-subunit called the "seatbelt" because it wraps around the alpha-subunit and it is fastened by a disulfide bridge between cysteines beta26 and beta110. Although all 22 cysteines of porcine LH (pLH) are engaged in disulfide bridges, we previously showed that the free cysteine-specific reagent NTCB could react with pLH: it slowly cyanylated two cysteines in pLH and there was a close relationship between NTCB reaction with pLH and association/dissociation kinetics of its subunits. Therefore, cysteines beta26 and beta110 were considered as the best candidates for NTCB reaction. In order to identify the NTCB-reactive cysteines in pLH we have performed a mass spectroscopic analysis of the peptides released after mild basic hydrolysis of S-cyanylated pLH and its subunits. Only cysteines beta100 and beta110 were found to react with NTCB. Since these residues are not linked by a disulfide bridge in the crystallographic 3D structure of gonadotropins, it is proposed that their respective counterparts (Cysbeta93 and beta26) do not react with NTCB either because they are shielded from solvent or because they form a transient bridge. In the first hypothesis, both seatbelt bridges would be independently metastable; in the second one, a fast reversible isomerization between bridges beta26-beta110 and beta93-beta100 would occur. Such a reaction could be catalyzed by the previously recognized intrinsic protein disulfide isomerase (PDI) activity of gonadotropins.