Is there a need for dietary measures to further reduce LDL cholesterol in patients with type II diabetes mellitus on statin therapy?

PURPOSE: To study the need for dietary measures to further reduce LDL cholesterol in patients with type 2 diabetes mellitus on statin therapy. METHODS: A Pubmed, Embase, CINAHL and Cochrane library search was performed to identify relevant articles. After critical appraisal six articles were ranked according to relevance, validation and level of evidence. RESULTS: There were no studies performed among type II diabetics. Among patients with hypercholesterolaemia, diet led to an additional LDL reduction from 0.20 to 0.88 mmol/l, translating into 23% reduction in vascular risk. CONCLUSION: We recommend a low-fat diet on top of statin therapy in patients with type 2 diabetes mellitus assuming that effects found in hypercholesterolaemic patients also apply to type 2 diabetics.     

Inhibition of WISE Preserves Renal Allograft Function

Wnt-modulator in surface ectoderm (WISE) is a secreted modulator of Wnt signaling expressed in the adult kidney. Activation of Wnt signaling has been observed in renal transplants developing interstitial fibrosis and tubular atrophy; however, whether WISE contributes to chronic changes is not well understood. Here, we found moderate to high expression of WISE mRNA in a rat model of renal transplantation and in kidneys from normal rats. Treatment with a neutralizing antibody against WISE improved proteinuria and graft function, which correlated with higher levels of β-catenin protein in kidney allografts. In addition, treatment with the anti-WISE antibody reduced infiltration of CD68⁺ macrophages and CD8⁺ T cells, attenuated glomerular and interstitial injury, and decreased biomarkers of renal injury. This treatment reduced expression of genes involved in immune responses and in fibrogenic pathways. In summary, WISE contributes to renal dysfunction by promoting tubular atrophy and interstitial fibrosis.The development of interstitial fibrosis and tubular atrophy with ongoing inflammation is a major risk for progressive graft dysfunction eventually leading to the failure of the majority of renal transplants. Although multiple approaches are available for preventing or at least blunting immune responses, there is currently no effective treatment for the development and progression of interstitial fibrosis and tubular atrophy.¹ The formation of matrix proteins in parallel to a progressive loss of graft function is a hallmark of chronic allograft dysfunction (CAD). Several pathways, including those involving TGF-β and angiotensin receptor, have been found to promote fibrosis and thus significant efforts have been made to evaluate the potential utility of these two pathway inhibitors for CAD. TGF-β has been shown to play an important role in epithelial-mesenchymal transition (EMT), which may, in turn, promote deteriorating structural changes characteristic for CAD.² However, inhibiting TGF-β may, because of its immunomodulatory effects, carry the risk of augmenting inflammation.³ Angiotensin II (AngII) is a growth factor that activates the Smad pathway during EMT involving TGF-β.⁴ AngII receptor antagonists were shown to reduce BP, proteinuria, and fibrosis in some studies.^5,6 However, the application of AngII receptor antagonists is known to be associated with intimal hyperplasia and deteriorating renal function, thus making its application in CAD challenging.⁷Wnt signaling is tightly regulated during kidney development and plays an important role in the formation of various structures of the developing kidney.^8–11 In normal adult kidneys, Wnt signaling is progressively downregulated once the developmental phase is completed.¹² Activation of Wnt signaling has been reported in a variety of human disease processes, including interstitial pulmonary fibrosis,¹³ and in transplanted kidneys undergoing interstitial fibrosis and tubular atrophy.¹⁴ To understand the contribution of Wnt-modulator in surface ectoderm (WISE) on tubular atrophy and interstitial fibrosis, we generated a potent rat inhibitory antibody to rat WISE, allowing long-term treatment while minimizing immune responses toward the injected antibody. Prophylactic treatment with a rat anti-WISE antibody, referred to hereafter as anti-WISE, reduced inflammatory infiltration, improved renal function, and reduced structural graft deterioration over a 6-month observation period. Serum biomarker and changes in gene expression suggested improvements in tubular epithelial integrity as well as decreases in profibrotic and inflammatory pathways, respectively. The improvement in graft function in our studies was associated with increased β-catenin levels. Moreover, WISE protein modulated Wnt signaling in vitro in a context-dependent manner, and directly affected E-cadherin expression and α-smooth muscle actin (α-SMA) expression in renal epithelial cells and interstitial fibroblasts.     

Using a Delphi process to develop an effective train-the-trainers program to train health and social care professionals throughout Europe

Research has shown that developing a Train-the-Trainers (TTT) program is important if agencies are to implement guidelines, but the most effective way to deliver a TTT program remains unanswered. This article presents data from a 3-round Internet-based Delphi process, which was used to help develop consensus-based guidelines for a TTT programme to deliver to health and social care professionals throughout Europe a curriculum on traumatic stress. In Round 1, 74 experts rated the importance of statements relating to the TTT field and then reassessed their scores in the light of others' responses in subsequent rounds. Forty-one (67%) of 61 statements achieved consensus (defined as having a mean score >7 or < 3 on the 0-9 rating scales used and 70% of participants scoring 7 and above or 3 and below) for inclusion. Key TTT components included interactive and practical presentations, delivery to groups of 7-12 people over 2 days, external and local expert facilitation, course manuals, refresher courses, and supervision. The Delphi process allowed a consensus to be achieved in an area in which there are limitations in the current evidence.     

Arteriolar vascular smooth muscle cell differentiation in benign nephrosclerosis

Background Benign nephrosclerosis (bN) is the most prevalent form of hypertensive damage in kidney biopsies. It is defined by early hyalinosis and later fibrosis of renal arterioles. Despite its high prevalence, very little is known about the contribution of arteriolar vascular smooth muscle cells (VSMCs) to bN. We examined classical and novel candidate markers of the normal contractile and the pro-fibrotic secretory phenotype of VSMCs in arterioles in bN. Methods Sixty-three renal tissue specimens with bN and eight control specimens were examined by immunohistochemistry for the contractile markers caldesmon, alpha-smooth muscle actin (alpha-SMA), JunB, smoothelin and the secretory marker S100A4 and by double stains for caldesmon or smoothelin with S100A4. Results Smoothelin immunostaining showed an inverse correlation with hyalinosis and fibrosis scores, while S100A4 correlated with fibrosis scores only. Neither caldesmon, alpha-SMA nor JunB correlated with hyalinosis or fibrosis scores. Cells in the arteriolar wall were exclusively positive either for caldesmon/smoothelin or S100A4. Conclusions This is the first systematic analysis of VSMC differentiation in bN. The results suggest that smoothelin is the most sensitive marker for the contractile phenotype and that S100A4 could be a novel marker for the secretory phenotype in vivo. The other markers did not seem to differentiate these phenotypes in bN. Thus, VSMC phenotype markers should be defined in the context of the vessel segment and disease under examination. S100A4 could not only be a marker of pro-fibrotic secretory VSMCs in bN but also an important mediator of arteriolar fibrosis.     

NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency

Purpose

Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system.

Methods

Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system.

Results

Our study revealed reduced absolute numbers of mature CD56^dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia.

Conclusion

In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.

     

The topographic and systematic anatomy of the alpaca stomach

The gastric anatomy of the alpaca (Vicugna pacos) is adapted to the physiological process of ruminating and the degradation of plant cell wall contents to a great extent. Most alpaca husbandries consist of only few animals and with the still increasing number of alpacas worldwide the number of persons who are responsible for these animals is increasing as well. Despite this, little research has been done with regard to the clinical anatomy of the stomach of alpacas. Six animals were used for dissection. The vascular system of two alpacas was injected with latex milk to illustrate the course of the blood supply to the viscera. One stomach was used to prepare formalin-fixed preparations. The stomach consisted of three compartments (C1–C3) and showed two sacculated areas in C1 and another comb-like system in C2. The compartments were lined by a smooth mucosa. Only the deep cells of C2 were lined by a papillated mucosa. The main blood supply was provided by the coeliac artery which was divided into the hepatic artery and the left gastric artery, supplying abdominal organs like liver, spleen, pancreas, and the initial part of the duodenum. Literature research on the llama stomach showed that the alpaca stomachs that were used resembled each other to a very large degree. The specific design of the stomach together with its related functions and physiological processes confirm that the evolution of Tylopoda and Ruminantia took place in parallel and not in homology.     

Orbitofrontal-Striatal Structural Alterations Linked to Negative Symptoms at Different Stages of the Schizophrenia Spectrum

Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset.