First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes – Chapter 1: update on national regulatory frameworks pertinent to clinical islet xenotransplantation

Islet xenotransplantation represents an attractive solution to overcome the shortage of human islets for use in type 1 diabetes. The wide‐scale application of clinical islet xenotransplantation, however, requires that such a procedure takes place in a specifically and tightly regulated environment. With a view to promoting the safe application of clinical islet xenotransplantation, a few years ago the International Xenotransplantation Association (IXA) published a Consensus Statement that outlined the key ethical and regulatory requirements to be satisfied before the initiation of xenotransplantation studies in diabetic patients. This earlier IXA Statement also documented a disparate regulatory landscape among different geographical areas. This situation clearly fell short of the 2004 World Health Assembly Resolution WHA57.18 that urged Member States “to cooperate in the formulation of recommendations and guidelines to harmonize global practices” to ensure the highest ethical and regulatory standards on a global scale. In this new IXA report, IXA members who are active in xenotransplantation research in their respective geographic areas herewith briefly describe changes in the regulatory frameworks that have taken place in the intervening period in the various geographic areas or countries. The key reassuring take‐home message of the present report is that many countries have embraced the encouragement of the WHO to harmonize the procedures in a more global scale. Indeed, important regulatory changes have taken place or are in progress in several geographic areas that include Europe, Korea, Japan, and China. Such significant regulatory changes encompass the most diverse facets of the clinical application of xenotransplantation and comprise ethical aspects, source animals and product specifications, study supervision, sample archiving, patient follow‐up and even insurance coverage in some legislations. All these measures are expected to provide a better care and protection of recipients of xenotransplants but also a higher safety profile to xenotransplantation procedures with an ultimate net gain in terms of international public health.     

Urinary fibrogenic cytokines ET-1 and TGF-β1 are associated with urinary angiotensinogen levels in obese children

Background

Fibrogenic cytokines are recognized as putative drivers of disease activity and histopathological deterioration in various kidney diseases. We compared urinary transforming growth factor β1 (U-TGF-β1) and endothelin 1 (U-ET-1) levels across body mass index classes and assessed their association with the level of urinary angiotensinogen (U-AGT), a biomarker of intrarenal renin–angiotensin–aldosterone system (RAAS).

Methods

The was a cross-sectional evaluation of 302 children aged 8–9 years. Ambulatory blood pressure (BP), insulin resistance (HOMA-IR), aldosterone level and renal function were evaluated. U-ET-1, U-TGF-β1 and U-AGT levels were determined by immunoenzymatic methods.

Results

Obese children presented with the lowest levels of U-ET-1 and U-TGF-β1, but the difference was only significant for U-ET-1. In obese children, the median levels of both U-ET-1 and U-TGF-β1 tended to increase across tertiles (T1–T3) of U-AGT (U-ET-1: T1, 19.9 (14.2–26.3); T2, 32.5 (23.3–141.6); T3, 24.8 (18.7–51.5) ng/g creatinine, p?=?0.007; U-TGF-β1: T1, 2.2 (1.8–4.0); T2, 4.3 (2.7–11.7); T3, 4.9 (3.8–10.1) ng/g creatinine, p?=?0.004]. In multivariate models, in the obese group, U-ET-1 was associated with HOMA-IR and aldosterone and U-AGT levels, and U-TGF-β1 was associated with U-AGT levels and 24 h-systolic BP.

Conclusions

Whereas the initial hypothesis of higher levels of urinary fibrogenic cytokines in obese children was not confirmed in our study, both TGF-β1 and U-ET-1 levels were associated with U-AGT level, which likely reflects an early interplay between tissue remodeling and RAAS in obesity-related kidney injury.

     

Bacterial DNA Induces the <Emphasis Type="Italic">Complement</Emphasis> System Activation in Serum and Ascitic Fluid from Patients with Advanced Cirrhosis

Translocation of intestinal bacteria to ascitic fluid is, probably, the first step in the development of spontaneous bacterial peritonitis in patients with cirrhosis. Proteins of the complement system are soluble mediators implicated in the host immune response to bacterial infections and its activation has been traditionally considered to be an endotoxin-induced phenomenon. The aim of this study was to compare the modulation of these proteins in response to the presence of bacterial DNA and/or endotoxin in patients with advanced cirrhosis and ascites in different clinical conditions. Groups I and II consisted of patients without/with bacterial DNA. Group III included patients with spontaneous bacterial peritonitis and Group IV with patients receiving norfloxacin as secondary long-term prophylaxis of spontaneous bacterial peritonitis. Serum and ascitic fluid levels of endotoxin and truncated residues of the complement system were measured by ELISA. The complement system is triggered in response to bacterial DNA, as evidenced by significantly increased levels of C3b, membrane attack complex, and C5a in patients from Groups II and III compared with patients without bacterial DNA (Group I) and those receiving norfloxacin (Group IV). Gram classification did not further differentiate the immune response between patients within groups II and III, even though endotoxin levels were, as expected, significantly higher in patients with bacterial DNA from gram-negative microorganisms. The complement protein activation observed in patients with bacterial DNA in blood and ascitic fluid is indistinguishable from that observed in patients with spontaneous bacterial peritonitis and may occur in an endotoxin-independent manner.     

Ageing and Toll-like receptor expression by innate immune cells in chronic human schistosomiasis

There has been no systematic study of the immune response of individuals aged over 60 years living in Schistosomiasis mansoni-endemic areas, although senescence is reportedly associated with susceptibility to infection and progressive decline in immune function. We have shown previously, in two endemic areas in Minas Gerais, Brazil, that the frequency of individuals aged over 60 years with chronic schistosomiasis is no longer negligible. Moreover, several elderly individuals who have always lived in these endemic areas stay protected from infection. An important question for studies of ageing and disease control in developing countries is which differences in the immunological profile of these negatively tested (non-infected) individuals can account for their resistance to either infection or reinfection. We show, in the present study, that non-infected (negative) elderly individuals develop innate immune mechanisms of protection that replace the age-associated decline in T cell function. Non-infected elderly individuals from endemic areas of schistosome infection present an increase in the frequency of the natural killer (NK) CD56(low) subset of NK cells expressing Toll-like receptors (TLR)-1, -2, -3 and -4 as determined by flow cytometry analysis. In addition, the proportion of dendritic cells expressing TLR-1 is elevated as well as the frequency of monocytes expressing TLR-1 and -4. These results suggest that TLR expression by cells of the innate immune system may be related to the negative status of infection in some elderly individuals who are constantly exposed to S. mansoni. Developing mechanisms of protection from infection may represent a biomarker for healthy ageing in this population.     

Calibration and validation of toxicokinetic-toxicodynamic models for three neonicotinoids and some aquatic macroinvertebrates

Ecotoxicology - Exposure patterns in ecotoxicological experiments often do not match the exposure profiles for which a risk assessment needs to be performed. This limitation can be overcome by...     

The launch of opicapone for Parkinson’s disease: negatives versus positives

Introduction: Opicapone is a novel, third generation COMT inhibitor approved for the treatment of Parkinson’s disease. Safety and tolerability data is critical to determine the benefit-harm balance and anticipate therapeutic adherence.

Areas covered: This review evaluates the tolerability and safety profile of opicapone. These data were extracted from all published clinical trials, including preclinical, phase I, phase II and phase III studies as well as postmarketing data. Opicapone was safe and well tolerated, with frequencies of treatment-emergent adverse events similar to placebo.

Expert opinion: Opicapone have shown a good safety and tolerability profile. This adds to its proven efficacy and convenient once-daily administration, supporting a role of opicapone as a first-line therapy for motor complications in Parkinson’s disease patients.     

USE OF CERVICAL VERTEBRAL DIMENSIONS FOR ASSESSMENT OF CHILDREN GROWTH

Objective:

The purpose of this study was to investigate whether skeletal maturation using cephalometric radiographs could be used in a Brazilian population.

Material and Methods:

The study population was selected from the files of the Oral Radiological Clinic of the Dental School of Piracicaba, Brazil and consisted of 128 girls and 110 boys (7.0 to 15.9 years old) who had cephalometric and hand-wrist radiographs taken on the same day. Cervical vertebral bone age was evaluated using the method described by Mito and colleagues in 2002. Bone age was assessed by the Tanner-Whitehouse (TW3) method and was used as a gold standard to determine the reliability of cervical vertebral bone age. An analysis of variance and Tukey''s post-hoc test were used to compare cervical vertebral bone age, bone age and chronological age at 5% significance level.

Results:

The analysis of the Brazilian female children data showed that there was a statistically significant difference (p<0.05) between cervical vertebral bone age and chronological age and between bone age and chronological age. However no statistically significant difference (p>0.05) was found between cervical vertebral bone age and bone age. Differently, the analysis of the male children data revealed a statistically significant difference (p<0.05) between cervical vertebral bone age and bone age and between cervical vertebral bone age and chronological age (p<0.05).

Conclusions:

The findings of the present study suggest that the method for objectively evaluating skeletal maturation on cephalometric radiographs by determination of vertebral bone age can be applied to Brazilian females only. The development of a new method to objectively evaluate cervical vertebral bone age in males is needed.     

Preoperative extracorporeal membrane oxygenation for postinfarction ventricular septal defect: Case series of three patients with a literature review

The mortality rate after the development of postinfarction ventricular septal defect (VSD) remains high, despite progress in pharmacologic therapy, invasive cardiology, and surgical techniques. We present three cases of preoperative venoarterial extracorporeal membrane oxygenation as a bridge to reparative surgical repair in patients with cardiogenic shock who would otherwise require emergent cardiac surgery with an associated risk. Two patients were discharged, whereas the third patient died due to pulmonary artery rupture after a right ventricular assist device implantation, despite the fact that he had a successful bridge to reparative surgery and VSD repair. Finally, a review of the current literature concerning the use of preoperative venoarterial extracorporeal membrane oxygenation as a bridge to reparative surgery is provided.     

Antinociceptive activity of Syzygium cumini leaves ethanol extract on orofacial nociception protocols in rodents

Context: Syzygium cumini (L.) Skeels (Myrtaceae) is a tree with dark purple fruits, popularly known as “jambolão” or “jambolan”. In folk medicine, this plant is used for the treatment of diabetes and inflammatory conditions.

Objective: We investigated the antinociceptive effect of ethanol extract (EE) from S. cumini leaves on orofacial nociception.

Material and methods: The antinociceptive effects of the EE obtained from the leaves of S. cumini were evaluated in mice using formalin- and glutamate-induced orofacial nociception.

Results: ESI-MS/MS analyses demonstrated that major constituents in the analyzed samples coincided with the mass of the phenolic acids and flavonoids. In pharmacological approach, pre-treatment with EE (100, 200, or 400?mg/kg, p.o.) significantly reduced (p?p?G-nitro-l-arginine (l-NOARG). The extract, all doses, also caused a marked inhibition (p?p?Conclusions: We can suggest that the antinociceptive effect of the EE is mediated by peripheral mechanisms, possibly involving K_ATP channels and the nitric oxide pathways. These effects appear to be related to the presence of flavonoids compounds, such as quercetin.