Effective control of persistent hyperparathyroidism with cinacalcet in renal allograft recipients

Background. Cinacalcet rapidly normalizes serum calcium and reduces intact parathyroid hormone (PTH) levels in renal transplant patients with hypercalcaemia and persistent hyperparathyroidism. The aim of this study is to evaluate the 6 months efficacy of cinacalcet and the effect of cinacalcet withdrawal on serum calcium and PTH in such patients. Furthermore, the impact of cinacalcet on bone turnover and quality of life was assessed. Methods. Twelve renal allograft recipients with hypercalcaemia due to persistent hyperparathyroidism were treated with cinacalcet for 26 weeks. Cinacalcet was then withdrawn to check for recurrence of hypercalcaemia. Results. Cinacalcet maintained normocalcaemia in all patients from week 4 to 26, and PTH significantly decreased and remained suppressed. Serum phosphate increased, whereas the serum calcium-phosphate product remained unchanged. The excretion of calcium and phosphate in the 24 h urine had tendency to decrease. After cinacalcet was withdrawn, hypercalcaemia recurred rapidly and PTH increased to baseline values. Renal function remained stable, proteinuria was unchanged and no allograft rejection was observed. During treatment with cinacalcet, total and bone-specific alkaline phosphatase increased, whereas the urinary deoxypyridinoline-creatinine ratio did not change significantly, suggesting enhanced bone formation. Quality of life assessed at weeks 10 and 26 remained unchanged compared with baseline. Conclusions. In conclusion, continued treatment with cinacalcet is required to maintain long-term normocalcaemia and to suppress the enhanced PTH production in renal transplant recipients with persistent hyperparathyroidis

Excellent agreement between genetic and hydrogen breath tests for lactase deficiency and the role of extended symptom assessment

Clinical manifestations of lactase (LCT) deficiency include intestinal and extra-intestinal symptoms. Lactose hydrogen breath test (H2-BT) is considered the gold standard to evaluate LCT deficiency (LD). Recently, the single-nucleotide polymorphism C/T−13910 has been associated with LD. The objectives of the present study were to evaluate the agreement between genetic testing of LCT C/T−13910 and lactose H2-BT, and the diagnostic value of extended symptom assessment. Of the 201 patients included in the study, 194 (139 females; mean age 38, range 17-79 years, and 55 males, mean age 38, range 18-68 years) patients with clinical suspicion of LD underwent a 3-4h H2-BT and genetic testing for LCT C/T−13910. Patients rated five intestinal and four extra-intestinal symptoms during the H2-BT and then at home for the following 48h. Declaring H2-BT as the gold standard, the CC−13910 genotype had a sensitivity of 97% and a specificity of 95% with a κ of 0·9 in diagnosing LCT deficiency. Patients with LD had more intense intestinal symptoms 4h following the lactose challenge included in the H2-BT. We found no difference in the intensity of extra-intestinal symptoms between patients with and without LD. Symptom assessment yielded differences for intestinal symptoms abdominal pain, bloating, borborygmi and diarrhoea between 120min and 4h after oral lactose challenge. Extra-intestinal symptoms (dizziness, headache and myalgia) and extension of symptom assessment up to 48h did not consistently show different results. In conclusion, genetic testing has an excellent agreement with the standard lactose H2-BT, and it may replace breath testing for the diagnosis of LD. Extended symptom scores and assessment of extra-intestinal symptoms have limited diagnostic value in the evaluation of L

A Systematic Review of Medication Adherence Thresholds Dependent of Clinical Outcomes

Background: In pharmacotherapy, the achievement of a target clinical outcome requires a certain level of medication intake or adherence. Based on Haynes's early empirical definition of sufficient adherence to antihypertensive medications as taking ≥80% of medication, many researchers used this threshold to distinguish adherent from non-adherent patients. However, we propose that different diseases, medications and patient's characteristics influence the cut-off point of the adherence rate above which the clinical outcome is satisfactory (thereafter medication adherence threshold). Moreover, the assessment of adherence and clinical outcomes may differ greatly and should be taken into consideration. To our knowledge, very few studies have defined adherence rates linked to clinical outcomes. We aimed at investigating medication adherence thresholds in relation to clinical outcomes.Method: We searched for studies that determined the relationship between adherence rates and clinical outcomes in the databases PubMed, EmbaseⓇ and Web of Science™ until December 2017, limited to English-language. Our outcome measure was any threshold value of adherence. The inclusion criteria of the retrieved studies were (1) any measurement of medication adherence, (2) any assessment of clinical outcomes, and (3) any method to define medication adherence thresholds in relation to clinical outcomes. We excluded articles considered as a tutorial. Two authors (PB and IA) independently screened titles and abstracts for relevance, reviewed full-texts, and extracted items. The results of the included studies are presented qualitatively.Result: We analyzed 6 articles that assessed clinical outcomes linked to adherence rates in 7 chronic disease states. Medication adherence was measured with Medication Possession Ratio (MPR, n = 3), Proportion of Days Covered (PDC, n = 1), both (n = 1), or Medication Event Monitoring System (MEMS). Clinical outcomes were event free episodes, hospitalization, cortisone use, reported symptoms and reduction of lipid levels. To find the relationship between the targeted clinical outcome and adherence rates, three studies applied logistic regression and three used survival analysis. Five studies defined adherence thresholds between 46 and 92%. One study confirmed the 80% threshold as valid to distinguish adherent from non-adherent patients.Conclusion: The analyzed studies were highly heterogeneous, predominantly concerning methods of calculating adherence. We could not compare studies quantitatively, mostly because adherence rates could not be standardized. Therefore, we cannot reject or confirm the validity of the historical 80% threshold. Nevertheless, the 80% threshold was clearly questioned as a general standard

Excellent agreement between genetic and hydrogen breath tests for lactase deficiency and the role of extended symptom assessment

Clinical manifestations of lactase (LCT) deficiency include intestinal and extra-intestinal symptoms. Lactose hydrogen breath test (H2-BT) is considered the gold standard to evaluate LCT deficiency (LD). Recently, the single-nucleotide polymorphism C/T(-13910) has been associated with LD. The objectives of the present study were to evaluate the agreement between genetic testing of LCT C/T(-13910) and lactose H2-BT, and the diagnostic value of extended symptom assessment. Of the 201 patients included in the study, 194 (139 females; mean age 38, range 17-79 years, and 55 males, mean age 38, range 18-68 years) patients with clinical suspicion of LD underwent a 3-4 h H2-BT and genetic testing for LCT C/T(-13910). Patients rated five intestinal and four extra-intestinal symptoms during the H2-BT and then at home for the following 48 h. Declaring H2-BT as the gold standard, the CC(-13910) genotype had a sensitivity of 97% and a specificity of 95% with a κ of 0.9 in diagnosing LCT deficiency. Patients with LD had more intense intestinal symptoms 4 h following the lactose challenge included in the H2-BT. We found no difference in the intensity of extra-intestinal symptoms between patients with and without LD. Symptom assessment yielded differences for intestinal symptoms abdominal pain, bloating, borborygmi and diarrhoea between 120 min and 4 h after oral lactose challenge. Extra-intestinal symptoms (dizziness, headache and myalgia) and extension of symptom assessment up to 48 h did not consistently show different results. In conclusion, genetic testing has an excellent agreement with the standard lactose H2-BT, and it may replace breath testing for the diagnosis of LD. Extended symptom scores and assessment of extra-intestinal symptoms have limited diagnostic value in the evaluation of LD

Gender-related differences in patients presenting with suspected acute coronary syndromes: clinical presentation, biomarkers and diagnosis

Objectives: Gender differences in patients presenting with suspected acute coronary syndromes (ACS) have not yet been fully characterized. The aim of this study was to assess gender-related disparities in clinical profiles, biomarkers and diagnoses of patients with suspected ACS. Methods: This single-centre, prospective cohort study included 377 consecutive patients presenting with suspected ACS to the emergency department. Suspected ACS was defined as a request for conventional troponin T (c-cTnT) measurements on clinical grounds. Results: Women were older than men (p = 0.004), and had a lower prevalence of known coronary artery and peripheral vascular disease (p < 0.05). c-cTnT was positive in 8% of female and in 14% of male patients (p = 0.16), TIMI risk score and cardiac biomarkers including c-cTnT, hs-cTnT, myoglobin, creatine kinase, N-terminal pro-brain natriuretic peptide, myeloid-related protein 8/14 and pregnancy-associated plasma protein A were lower in women (p < 0.05). Women were less frequently diagnosed with ACS (30 vs. 51%), and were not referred for urgent coronary angiography as often as men (p < 0.001). In multivariate analysis, female gender was associated with a lower referral for coronary angiography (HR 0.41, 95% CI 0.23-0.78, p = 0.006). Conclusions: In patients with suspected ACS, women presented with different biomarker profiles, and were less often diagnosed with ACS and referred to coronary angiography

Proposal of standardization to assess adherence with medication records: methodology matters

Medication adherence is the process by which patients take their medication as prescribed and is an umbrella term that encompasses all aspects of medication use patterns. Ambiguous terminology has emerged to describe a deviation from prescribed regimen, forcing the European ABC Project to define 3 phases of medication use: initiation, implementation, and discontinuation. However, different measures of medication adherence using medication records are currently available that do not always distinguish between these phases. The literature is lacking standardization and operationalization of the assessment methods.; To propose a harmonization of standards as well as definitions of distinct measures and their operationalization to quantify adherence to medication from medication records.; Group discussions and consensus process among all coauthors. The propositions were generated using the authors' experiences and views in the field of adherence, informed by theory.; The concepts of adherence measures within the new taxonomy were harmonized, and the standards necessary for the operationalization of adherence measures from medication records are proposed. Besides percentages and time-to values, the addition of a dichotomous value for the reinitiation of treatment is proposed. Methodological issues are listed that should be disclosed in studies on adherence.; The possible impact of the measures in adherence research is discussed. By doing this, the results of future adherence research should gain in accuracy. Finally, studies will become more transparent, enabling comparison between studies

Deliberate removal of T cell help improves virus-neutralizing antibody production

The B cell response to lymphocytic choriomeningitis virus is characterized by a CD4(+) T cell-dependent polyclonal hypergammaglobulinemia and delayed formation of virus-specific neutralizing antibodies. Here we provide evidence that, paradoxically, because of polyclonal B cell activation, virus-specific T cell help impairs the induction of neutralizing antibody responses. Experimental reduction in CD4(+) T cell help in vivo resulted in potent neutralizing antibody responses without impairment of CD8(+) T cell activity. These unexpected consequences of polyclonal B cell activation may affect vaccine strategies and the treatment of clinically relevant chronic bacterial, parasitic and viral infections in which hypergammaglobulinemia is regularly found

Endothelium-derived Vasoactive Factors and Hypertension: Possible Roles in Pathogenesis and as Treatment Targets

Endothelial cells regulate vascular tone by releasing various contracting and relaxing factors including nitric oxide (NO), arachidonic acid metabolites (derived from cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases), reactive oxygen species, and vasoactive peptides. Additionally, another pathway associated with the hyperpolarization of the underlying smooth muscle cells plays a predominant role in resistance arteries. Endothelial dysfunction is a multifaceted disorder, which has been associated with hypertension of diverse etiologies, involving not only alterations of the L-arginine NO-synthase–soluble guanylyl cyclase pathway but also reduced endothelium-dependent hyperpolarizations and enhanced production of contracting factors, particularly vasoconstrictor prostanoids. This brief review highlights these different endothelial pathways as potential drug targets for novel treatments in hypertension and the associated endothelial dysfunction and end-organ damage

The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis.

The gene encoding for Epstein-Barr virus-induced G-protein-coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7α,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied. We found increased mRNA expression of EBI2 and oxysterol-synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated levels of 25-hydroxylated oxysterols, including 7α,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2 &lt;sup&gt;-/-&lt;/sup&gt; mice in the IL-10 colitis model. The colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2 &lt;sup&gt;-/-&lt;/sup&gt; mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures. In summary, we report induction of the EBI2-7α,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7α,25-dihydroxycholesterol axis in IBD pathogenesis