A formula to calculate the standard liver volume in children and its application in pediatric liver transplantation

Due to a lack of available size‐matched liver grafts from children, most pediatric recipients are transplanted with technical variant grafts from adult donors. Size requirements for these grafts are not well defined, and consequences of mismatched graft sizes in pediatric liver transplantation are not known. Existing formulas for calculation of a standard liver volume are mostly derived from adults disregarding the age‐related percentual liver weight changes in children. In this study, we aimed to establish a formula for general use in children to calculate the standard liver volume. In a second step, the formula was applied in pediatric patients undergoing liver transplantation at our institution between 2000 and 2010 (n = 377). Analysis of a large number (n = 388) of autopsy data from children by regression analysis revealed a best fit for two formulas: “Formula 1,” children 0 to ≤1 year (n = 246): standard liver volume [ml] = ?143.062973 +4.274603051 * body length [cm] + 14.78817631 * body weight [kg]; “Formula 2,” children >1 to <16 years (n = 142): standard liver volume [ml] = ?20.2472281 + 3.339056437 * body length [cm] + 13.11312561 * body weight [kg]. In comparison with children receiving size‐matched organs, we found an elevated risk of liver graft failure in children transplanted with a small‐for‐size graft, whereas large‐for‐size organs seem to have no negative impact.     

Timing of Curative Treatment for Prostate Cancer: A Systematic Review

Context

Delaying definitive therapy unfavourably affects outcomes in many malignancies. Diagnostic, psychological, and logistical reasons but also active surveillance (AS) strategies can lead to treatment delay, an increase in the interval between the diagnosis and treatment of prostate cancer (PCa).

Objective

To review and summarise the current literature on the impact of treatment delay on PCa oncologic outcomes.

Evidence acquisition

A comprehensive search of PubMed and Embase databases until 30 September 2012 was performed. Studies comparing pathologic, biochemical recurrence (BCR), and mortality outcomes between patients receiving direct and delayed curative treatment were included. Studies presenting single-arm results following AS were excluded.

Evidence synthesis

Seventeen studies were included: 13 on radical prostatectomy, 3 on radiation therapy, and 1 combined both. A total of 34 517 PCa patients receiving radical local therapy between 1981 and 2009 were described. Some studies included low-risk PCa only; others included a wider spectrum of disease. Four studies found a significant effect of treatment delay on outcomes in multivariate analysis. Two included low-risk patients only, but it was unknown whether AS was applied or repeat biopsy triggered active therapy during AS. The two other studies found a negative effect on BCR rates of 2.5–9 mo delay in higher risk patients (respectively defined as any with T ≥2b, prostate-specific antigen >10, Gleason score >6, >34–50% positive cores; or D’Amico intermediate risk-group). All studies were retrospective and nonrandomised. Reasons for delay were not always clear, and time-to-event analyses may be subject to bias.

Conclusions

Treatment delay of several months or even years does not appear to affect outcomes of men with low-risk PCa. Limited data suggest treatment delay may have an impact on men with non–low-risk PCa. Most AS protocols suggest a confirmatory biopsy to avoid delaying treatment in those who harbour higher risk disease that was initially misclassified.     

Thoracic Organ Transplantation in Children: The Sahlgrenska University Hospital Experience

On the basis of the experience acquired from more than 350 thoracic organ transplantations in adults, the outcome of thoracic organ transplantations in the paediatric age group (0-17 years of age) performed consecutively from 1989 to 1998 at our centre was reviewed. Heart transplantation was performed in 27 patients, heart-lung in 6 and bilateral lung transplantation in 2 patients. The preoperative diagnosis included dilated cardiomyopathy in 17 patients, congenital heart defects in 8, hypertrophic cardiomyopathy in 2, cystic fibrosis in 1 and secondary and primary pulmonary hypertension in 5 and 2 patients, respectively. The median age at transplantation and the follow-up period were 12.7, range 0.3-18.2, and 4, range 0.1-9.2 years, respectively. No early deaths occurred after heart transplantation, but one patient died of coronary artery disease 4.8 years after transplantation. One early death occurred one week after heart-lung transplantation as a result of bleeding complications, and another patient died of obliterative bronchiolitis and pulmonary infection 2.5 years after surgery. The remaining patients are alive and have been functionally rehabilitated. In conclusion, despite a relatively small centre volume, paediatric thoracic organ transplantations can be performed with good short- and medium-term survival and good functional status can be achieved by deriving knowledge and experience from transplantations in adults and by collaboration between the various professionals involved in the caring process.     

5F-Cumyl-PINACA in ‘e-liquids’ for electronic cigarettes: comprehensive characterization of a new type of synthetic cannabinoid in a trendy product including investigations on the in vitro and in vivo phase I metabolism of 5F-Cumyl-PINACA and its non-fluorinated analog Cumyl-PINACA

Purpose

In recent years e-liquids used in electronic cigarettes have become an attractive alternative to smoking tobacco. A new trend is the use of e-liquids containing synthetic cannabinoids (SCs) instead of smoking cannabis or herbal mixtures laced with SCs. In the frame of a systematic monitoring of the online market of ‘legal high’ products, e-liquids from online retailers who also sell herbal blends were bought.

Methods

The products were analyzed by gas chromatography-mass spectrometry. In some of the e-liquids an unknown compound was detected which was identified as the SC 5F-Cumyl-PINACA (1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indazole-3-carboxamide) by nuclear magnetic resonance analysis. To investigate the phase I metabolism of this new class of compounds, 5F-Cumyl-PINACA and its non-fluorinated analog Cumyl-PINACA were incubated with pooled human liver microsomes (pHLM). Cumyl-PINACA was additionally ingested orally (0.6 mg) by a volunteer in a controlled self-experiment. To assess the relative potency of Cumyl-PINACA a set of SCs were characterized using a cAMP assay.

Results

Metabolism of 5F-Cumyl-PINACA and Cumyl-PINACA showed similarities with AM-2201 and JWH-018. The main metabolites were formed by hydroxylation at the N-pentyl side chain. The main metabolites detected in the volunteer’s urine sample were the same as in the pHLM assay. All SCs tested with the cAMP assay were full agonists at the CB₁ receptor. Cumyl-PINACA was the most potent SC among the tested compounds and showed an EC₅₀ value of 0.06 nM.

Conclusions

The increasing popularity of e-liquids particularly among young people, and the extreme potency of the added SCs, pose a serious threat to public health. To our knowledge, this is the first report describing the tentative identification of human in vivo metabolites of Cumyl-PINACA and 5F-Cumyl-PINACA.

     

The association between glucose metabolism status,diabetes severity and a history of fractures and recent falls in participants of 50 years and older—the Maastricht Study

Summary

In this cohort of relatively young and well-treated participants with type 2 diabetes, we found no association between diabetes status and a history of previous fractures and recent falls. Furthermore, no association between diabetes severity and previous fractures or recent falls was found.

Introduction

In this study, we examined the association between glucose metabolism status and historical fractures or recent falls and the effect of diabetes severity (glucose control, insulin use, and diabetes duration) on falls and fractures in the participants with type 2 diabetes.

Methods

Cross-sectional data from 2005 participants of the Maastricht Study. Falls in the past 6 months and fractures ≥age 50 were assessed by questionnaire. Glucose metabolism status (normal glucose metabolism, impaired glucose metabolism, or type 2 diabetes) was based on the oral glucose tolerance test and medication use.

Results

In the completely adjusted model, the odds for a fall were not significantly higher in those with impaired glucose metabolism status (OR (95%CI) 1.28 (0.93–1.77)) or with type 2 diabetes (OR (95%CI) 1.21 (0.80–1.81)) compared with the group with normal glucose metabolism. Within the group with type 2 diabetes, there were no significant differences with regard to reported falls between participants with HbA1c >7 % (53 mmol/mol) versus HbA1c ≤7 % (OR (95%CI) 1.05 (0.58–1.90)), insulin users versus non-insulin users (OR (95%CI) 1.51 (0.79–2.89)), and with a diabetes duration >5 versus ≤5 years (OR (95%CI) 0.52 (0.46–1.47)). Similarly, neither glucose metabolism status nor diabetes severity was associated with prior fractures.

Conclusions

Glucose metabolism status was not significantly associated with previous fractures and recent falls. In addition, in this cohort of relatively young and well-treated participants with type 2 diabetes, diabetes severity was not associated with previous fractures and recent falls.

     

17Beta-estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage

Although studies have shown that 17beta-estradiol (estradiol) normalized Kupffer cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-kappaB (NF-kappaB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-kappaB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35+/-5 mmHg approximately 90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-kappaB. This was accompanied by normalization of Kupffer cell production capacities of IL-6, TNF-alpha, macrophage inflammatory protein (MIP)-1alpha, and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer cell p38 MAPK and NF-kappaB activation, cytokine production, or the increase in circulating cytokine levels following trauma-hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-kappaB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.