Motile and non-motile cilia in human pathology: from function to phenotypes

Ciliopathies are inherited human disorders caused by both motile and non-motile cilia dysfunction that form an important and rapidly expanding disease category. Ciliopathies are complex conditions to diagnose, being multisystem disorders characterized by extensive genetic heterogeneity and clinical variability with high levels of lethality. There is marked phenotypic overlap among distinct ciliopathy syndromes that presents a major challenge for their recognition, diagnosis, and clinical management, in addition to posing an on-going task to develop the most appropriate family counselling. The impact of next-generation sequencing and high-throughput technologies in the last decade has significantly improved our understanding of the biological basis of ciliopathy disorders, enhancing our ability to determine the possible reasons for the extensive overlap in their symptoms and genetic aetiologies. Here, we review the diverse functions of cilia in human health and disease and discuss a growing shift away from the classical clinical definitions of ciliopathy syndromes to a more functional categorization. This approach arises from our improved understanding of this unique organelle, revealed through new genetic and cell biological insights into the discrete functioning of subcompartments of the cilium (basal body, transition zone, intraflagellar transport, motility). Mutations affecting these distinct ciliary protein modules can confer different genetic diseases and new clinical classifications are possible to define, according to the nature and extent of organ involvement. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Typical Gibbs configurations for the 1d Random Field Ising Model with long range interaction

We study a one--dimensional Ising spin systems with ferromagnetic, long--range interaction decaying as n^{-2+\a}, \a \in [0,\frac 12], in the presence of external random fields. We assume that the random fields are given by a collection of symmetric, independent, identically distributed real random variables, gaussian or subgaussian with variance $\theta$. We show that for temperature and variance of the randomness small enough, with an overwhelming probability with respect to the random fields, the typical configurations, within volumes centered at the origin whose size grow faster than any power of $\th^{-1}$, % {\bf around the origin} are intervals of $+$ spins followed by intervals of $-$ spins whose typical length is \simeq \th^{-\frac{2}{(1-2\a)}} for 0\le \a<1/2 and $\simeq e^{\frac 1 {\th^{2}}}$ for \a=1/2

Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of Fragile X Syndrome

Nutritional value of a rice-hydrolysate formula in infants with cows' milk protein allergy: a randomized pilot study.

This study was designed to assess whether a rice-hydrolysate formula allows normal growth and adequate metabolic balance in infants with cows' milk protein allergy. Infants (seven females, nine males; aged 6–14 months) were randomly assigned to receive a rice-hydrolysate formula ( n = 8) or a soy formula (control group, n = 8). Standardized growth indices ( Z scores) and biochemical parameters were evaluated during a 6-month treatment period. Infants in both groups showed normal growth patterns during the study, and no adverse reactions were seen. Mean plasma biochemical parameters were within the normal ranges, and did not differ between groups. In conclusion, rice-hydrolysate formula may be a nutritionally suitable alternative for infants with cows' milk protein allergy. Larger studies, with satisfactory power, should be undertaken to confirm these findings

Phase Transition in the 1d Random Field ising model with long range interaction

We study the one dimensional Ising model with ferromagnetic, long range interaction which decays as |i-j|^{-2+a}, 1/2< a<1, in the presence of an external random filed. we assume that the random field is given by a collection of independent identically distributed random variables, subgaussian with mean zero. We show that for temperature and strength of the randomness (variance) small enough with P=1 with respect to the distribution of the random fields there are at least two distinct extremal Gibbs measures

Antiulcer Activity of Salvadora persica on Experimental ASA-Induced Ulcer in Rats: Ultrastructural Modifications

The lyophilized decoction of Salvadora persica L. roots possesses a significant protective effect on ulceration induced by ethanol, indomethacin and cold restraint stress in rats. In this work, we study the effect of chronic intragastric administration of S. persica decoction on experimental acetylsalicylic acid (ASA)-induced ulcer in rats. The ulcer index significantly decreased (U.I. 0.9 ± 1.6; P < 0.05) after treatment with a lyophilized decoction of S. persica (500 mg/kg, os), once daily for seven days, with respect to controls (U.I. 11.4 ± 2.3). The modification of gastric mucosa was observed by transmission electronic microscopy (TEM) confirming this result. In fact, in treated rats, the mucosa recovered to normal distribution. After S. persica treatment, some changes were detected in profiles of various cytoplasm organelles of parietal cells. Particularly, the intracellular canaliculi show an enlarged lumen with an increase in the number and length of microvilli. These morphological features of ..

X-Linked Parkinsonism: phenotypic and genetic heterogeneity

X-linked parkinsonism encompasses rare heterogeneous disorders mainly inherited as a recessive trait, therefore being more prevalent in males. Recent developments have revealed a complex underlying panorama, including a spectrum of disorders in which parkinsonism is variably associated with additional neurological and non-neurological signs. In particular, a childhood-onset encephalopathy with epilepsy and/or cognitive disability is the most common feature. Their genetic basis is also heterogeneous, with many causative genes and different mutation types ranging from "classical" coding variants to intronic repeat expansions. In this review, we provide an updated overview of the phenotypic and genetic spectrum of the most relevant X-linked parkinsonian syndromes, namely X-linked dystonia-parkinsonism (XDP, Lubag disease), fragile X-associated tremor/ataxia syndrome (FXTAS), beta-propeller protein-associated neurodegeneration (BPAN, NBIA/PARK-WDR45), Fabry disease, Waisman syndrome, methyl CpG-binding protein 2 (MeCP2) spectrum disorder, phosphoglycerate kinase-1 deficiency syndrome (PGK1) and X-linked parkinsonism and spasticity (XPDS). All clinical and radiological features reported in the literature have been reviewed. Epilepsy occasionally represents the symptom of onset, predating parkinsonism even by a few years; action tremor is another common feature along with akinetic-rigid parkinsonism. A focus on the genetic background and its pathophysiological implications is provided. The pathogenesis of these disorders ranges from well-defined metabolic alterations (PGK1) to non-specific lysosomal dysfunctions (XPDS) and vesicular trafficking alterations (Waisman syndrome). However, in other cases it still remains poorly defined. Recognition of the phenotypic and genetic heterogeneity of X-linked parkinsonism has important implications for diagnosis, management, and genetic counseling. \ua9 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Lattice gas model in random medium and open boundaries: hydrodynamic and relaxation to the steady state

We consider a lattice gas interacting by the exclusion rule in the presence of a random field given by i.i.d. bounded random variables in a bounded domain in contact with particles reservoir at different densities. We show, in dimensions $d \ge 3$, that the rescaled empirical density field almost surely, with respect to the random field, converges to the unique weak solution of a non linear parabolic equation having the diffusion matrix determined by the statistical properties of the external random field and boundary conditions determined by the density of the reservoir. Further we show that the rescaled empirical density field, in the stationary regime, almost surely with respect to the random field, converges to the solution of the associated stationary transport equation

Risk of classical Kaposi sarcoma by plasma levels of Epstein-Barr virus antibodies, sCD26, sCD23 and sCD30

<p>Abstract</p> <p>Background</p> <p>To clarify the immunological alterations leading to classical Kaposi sarcoma (cKS) among people infected with KS-associated herpesvirus (KSHV).</p> <p>Methods</p> <p>In a population-based study of 119 cKS cases, 105 KSHV-seropositive controls, and 155 KSHV-seronegative controls, we quantified plasma soluble cluster of differentiation (sCD) levels and antibodies against Epstein-Barr virus nuclear antigen-1 (anti-EBNA-1) and viral capsid antigen (anti-VCA). Differences between groups in prevalence of low-tertile anti-EBNA-1 and high-tertile anti-VCA were compared by logistic regression. Continuous levels between groups and by presence of cKS co-factors among controls were compared by linear regression and Mann-Whitney-Wilcoxon methods.</p> <p>Results</p> <p>Comparisons of cKS cases to seropositive controls and of seropositive to seronegative controls revealed no significant differences. However, controls with known cKS cofactors (male sex, nonsmoking, diabetes and cortisone use) had significantly lower levels of anti-EBNA (<it>P </it>= 0.0001 - 0.07) and anti-VCA (<it>P </it>= 0.0001 - 0.03). Levels of sCD26 were significantly lower for male and non-smoking controls (<it>P</it>_adj≤ 0.03), and they were marginally lower with older age and cortisone use (<it>P</it>_adj≤ 0.09).</p> <p>Conclusions</p> <p>Anti-EBV and sCD26 levels were associated with cofactors for cKS, but they did not differ between cKS cases and matched controls. Novel approaches and broader panels of assays are needed to investigate immunological contributions to cKS.</p

A systematic review on the impact of commercially available hybrid closed loop systems on psychological outcomes in youths with type 1 diabetes and their parents

Aim: To systematically assess the impact of commercially available hybrid closed loop (HCL) systems on psychological outcomes in youths with type 1 diabetes and their parents. Methods: We performed a systematic review including studies published in the last 10 years. PICOS framework was used in the selection process, and evidence was assessed using the GRADE system. Results: A total of 215 studies were identified after duplicate removal, and 31 studies were included in this systematic review: 20 on first-generation HCL and 11 on second-generation HCL systems. According to studies with moderate- to high-level quality of evidence, HCL systems led to better, or in some studies, unchanged psychological outcomes such as distress and burden related to diabetes management, fear of hypoglycemia, quality of life, satisfaction; instead, quality of sleep was perceived as improved, although results were not confirmed in studies using actigraphy. From semi-structured interviews, answers were more homogeneous, and participants reported a positive experience and attitude towards HCL technology, which was felt to be easy to use and apt to achieve glycemic targets. Conclusions: Evidence confirms the importance of evaluating the psychosocial needs of youths with diabetes and their families when starting HCL systems and during follow-up, and to set realistic expectations of what can be achieved along with awareness of the limitations of the systems, and educate and motivate families to overcome barriers