PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia.

The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis. GPI biosynthesis is a multi-step process requiring the activity of over 25 distinct genes, most of them belonging to the phosphatidylinositol glycan (PIG) family and associated with rare neurodevelopmental disorders. PIGQ encodes the phosphatidylinositol glycan class Q protein and is part of the GPI-N-acetylglucosaminyltransferase complex that initiates GPI biosynthesis from phosphatidylinositol (PI) and N-acetylglucosamine (GlcNAc) on the cytoplasmic side of the endoplasmic reticulum (ER). Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases. We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy. Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER). Clinical features of this case broaden the phenotypic spectrum of PIGQ-related GPI deficiency, outlining the importance of glycophosphatidylinositol (GPI) anchor pathway in the pathogenesis of cerebellar ataxia.

Biallelic Variants in the Nuclear Pore Complex Protein NUP93 Are Associated with Non-progressive Congenital Ataxia.

Nuclear pore complexes (NPCs) are the gateways of the nuclear envelope mediating transport between cytoplasm and nucleus. They form huge complexes of 125 MDa in vertebrates and consist of about 30 different nucleoporins present in multiple copies in each complex. Here, we describe pathogenic variants in the nucleoporin 93 (NUP93) associated with an autosomal recessive form of congenital ataxia. Two rare compound heterozygous variants of NUP93 were identified by whole exome sequencing in two brothers with isolated cerebellar atrophy: one missense variant (p.R537W) results in a protein which does not localize to NPCs and cannot functionally replace the wild type protein, whereas the variant (p.F699L) apparently supports NPC assembly. In addition to its recently described pathological role in steroid-resistant nephrotic syndrome, our work identifies NUP93 as a candidate gene for non-progressive congenital ataxia.

Correction to: Biallelic Variants in the Nuclear Pore Complex Protein NUP93 Are Associated with Non-progressive Congenital Ataxia.

The original version of this article unfortunately contained mistake in Fig. 3 image.

EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome.

OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

Long-term neurodevelopmental outcome of children born to prospectively followed pregnancies of women with systemic lupus erythematosus and/or antiphospholipid syndrome.

Background Systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) are autoimmune diseases that affect women of childbearing age. Maternal IgG antiphospholipid antibodies (aPL) can cross the placenta during pregnancy and theoretically reach the fetal brain. Some studies showed an increased number of learning disabilities in these children. Objectives To evaluate the long-term neurodevelopmental outcome of 40 children (median age 7.4 years) born to mothers with SLE and/or APS carrying positive IgG aPL during the third trimester of pregnancy. Methods Children were checked for neurological physical exam and intellectual/cognitive functioning by the Wechsler scale for corrected age. We submitted to the mothers the Child Behavior CheckList (CBCL) and a homemade set of questions created by pediatric neurologists. Results In all children neurological physical exam and intelligence levels were found to be normal. A cognitive impairment or a discrepant cognitive profile was found in 3 (7%) and 11 (28%) children, respectively. Learning disabilities were diagnosed in 3 children (19% of school-age children), all born to mothers with triple aPL positivity. A history of epilepsy was shown in four children (10%). CONCLUSIONS: Children born to women with SLE and/or APS may need a long-term follow-up focusing on milestones of neurodevelopment in order to detect and correct any alteration as early as possible.

Clinical, biochemical and molecular characterization of prosaposin deficiency.

Prosaposin (PSAP) deficiency is an ultra-rare, fatal infantile lysosomal storage disorder (LSD) caused by variants in the PSAP gene, with seven subjects reported so far. Here, we provide the clinical, biochemical and molecular characterization of two additional PSAP deficiency cases. Lysoplex, a targeted resequencing approach was utilized to identify the variant in the first patient, while quantification of plasma lysosphingolipids (lysoSLs), assessed by liquid chromatography mass spectrometry (LC-MS/MS) and brain magnetic resonance imaging (MRI), followed by Sanger sequencing allowed to attain diagnosis in the second case. Functional studies were carried out on patients' fibroblast lines to explore the functional impact of variants. The two patients were homozygous for two different truncating PSAP mutations (c.895G>T, p.Glu299*; c.834_835delGA, p.Glu278Aspfs*27). Both variants led to a complete lack of processed transcript. LC-MS/MS and brain MRI analyses consistently provided a distinctive profile in the two children. Quantification of specific plasma lysoSLs revealed elevated levels of globotriaosylsphingosine (LysoGb3) and glucosylsphingosine (GlSph), and accumulation of autophagosomes, due to a decreased autophagic flux, was observed. This report documents the successful use of plasma lysoSLs profiling in the PSAP deficiency diagnosis, as a reliable and informative tool to obtain a preliminary information in infantile cases with complex traits displaying severe neurological signs and visceral involvement.

One-Dimensional Liquid

We compute the zero-temperature dynamical structure factor of one-dimensional liquid ^{4}He by means of state-of-the-art quantum Monte Carlo and analytic continuation techniques. By increasing the density, the dynamical structure factor reveals a transition from a highly compressible critical liquid to a quasisolid regime. In the low-energy limit, the dynamical structure factor can be described by the quantum hydrodynamic Luttinger-liquid theory, with a Luttinger parameter spanning all possible values by increasing the density. At higher energies, our approach provides quantitative results beyond the Luttinger-liquid theory. In particular, as the density increases, the interplay between dimensionality and interaction makes the dynamical structure factor manifest a pseudo-particle-hole continuum typical of fermionic systems. At the low-energy boundary of such a region and moderate densities, we find consistency, within statistical uncertainties, with predictions of a power-law structure by the recently developed nonlinear Luttinger-liquid theory. In the quasisolid regime, we observe a novel behavior at intermediate momenta, which can be described by new analytical relations that we derive for the hard-rods model.

Mitochondrial respiration and genomic analysis provide insight into the influence of the symbiotic bacterium on host trypanosomatid oxygen consumption.

Certain trypanosomatids co-evolve with an endosymbiotic bacterium in a mutualistic relationship that is characterized by intense metabolic exchanges. Symbionts were able to respire for up to 4 h after isolation from Angomonas deanei. FCCP (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone) similarly increased respiration in wild-type and aposymbiotic protozoa, though a higher maximal O2 consumption capacity was observed in the symbiont-containing cells. Rotenone, a complex I inhibitor, did not affect A. deanei respiration, whereas TTFA (thenoyltrifluoroacetone), a complex II activity inhibitor, completely blocked respiration in both strains. Antimycin A and cyanide, inhibitors of complexes III and IV, respectively, abolished O2 consumption, but the aposymbiotic protozoa were more sensitive to both compounds. Oligomycin did not affect cell respiration, whereas carboxyatractyloside (CAT), an inhibitor of the ADP-ATP translocator, slightly reduced O2 consumption. In the A. deanei genome, sequences encoding most proteins of the respiratory chain are present. The symbiont genome lost part of the electron transport system (ETS), but complex I, a cytochrome d oxidase, and FoF1-ATP synthase remain. In conclusion, this work suggests that the symbiont influences the mitochondrial respiration of the host protozoan.

Imaginary time density-density correlations for two-dimensional electron gases at high density.

We evaluate imaginary time density-density correlation functions for two-dimensional homogeneous electron gases of up to 42 particles in the continuum using the phaseless auxiliary field quantum Monte Carlo method. We use periodic boundary conditions and up to 300 plane waves as basis set elements. We show that such methodology, once equipped with suitable numerical stabilization techniques necessary to deal with exponentials, products, and inversions of large matrices, gives access to the calculation of imaginary time correlation functions for medium-sized systems. We discuss the numerical stabilization techniques and the computational complexity of the methodology and we present the limitations related to the size of the systems on a quantitative basis. We perform the inverse Laplace transform of the obtained density-density correlation functions, assessing the ability of the phaseless auxiliary field quantum Monte Carlo method to evaluate dynamical properties of medium-sized homogeneous fermion systems.

Mosquitoes in Bromeliads at Ground Level of the Brazilian Atlantic Forest: the Relationship Between Mosquito Fauna, Water Volume, and Plant Type.

Water accumulating in the axils of bromeliads provides habitat for numerous invertebrates, frequently among them, immature mosquitoes. To evaluate mosquito richness in bromeliads and the relationship between mosquito presence and biotic and abiotic variables, we performed a study in the Parque Nacional do Itatiaia, Rio de Janeiro, Brazil. Mosquitoes of genus Culex were the most abundant and varied in species richness, among which nine belonged to subgenus Microculex, Culex (Microculex) neglectus Lutz and Culex ocellatus Theobald being the most frequent species. Sabethines of genera Wyeomyia and Runchomyia were found in low numbers. Wyeomyia (Spilonympha) airosai Lane and Cerqueira and Wyeomyia (Spilonympha) finlayi Lane and Cerqueira tend to proliferate in bromeliads of the genus Bilbergia which hold less than 50 ml of water and grow either alone or with Runchomyia frontosa (Theobald). The larger the volume of water, the greater the chance of finding Culex, Anopheles as well as Wyeomyia (Phoniomyia) species, which seems to be the more generalist as it is present in different bromeliad types with a large range of plant water holding capacities.

Children born to SLE and APS mothers.

BACKGROUND: Systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) are autoimmune diseases that affect women of childbearing age. Pregnancies in these patients carry several complications such as prematurity. Maternal IgG antiphospholipid antibodies (aPL) can cross the placenta but they don't generally cause any neonatal thrombotic event. Because of the incompleteness of the fetal blood-brain barrier, aPL could theoretically reach the fetal brain. Whether this can have an effect on brain development is still under investigation. Some studies performed in children of patients with SLE and/or APS showed an increased number of learning disabilities without impairment in intelligence level. OBJECTIVES: The objectives of this article are to evaluate the neurodevelopment outcome in 30 children (median age 9 years) born to mothers with SLE and/or APS with IgG anti-beta2-glycoprotein I during the third trimester of pregnancy and found positive for the same antibodies at birth. METHODS: A neurological physical exam was performed in all children. We submitted some questionnaires to the mothers: the Child Behavior CheckList (CBCL) and a homemade set of questions obtained by a team composed of rheumatologists and pediatric neurologists. Intellectual functioning was determined by the Wechsler scale for corrected age. RESULTS: In all children neurological physical exam and intelligence levels were found to be normal but mild behavior disorders and history of neurological manifestations were shown in three children. CONCLUSIONS: Offspring of patients with SLE and/or APS are generally healthy. We and others observed the occurrence of minor neurological disorders that might be related to maternal disease or to prematurity. The limited number of the available data on this sensitive issue supports the need for further studies.

The effects of lupus and antiphospholipid antibody syndrome on foetal outcomes.

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that primarily affects women of childbearing-age. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder defined by the occurrence of venous and arterial thrombosis, often multiple, and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Recently, the long-term outcome of children born to patients with lupus and APS has become a major topic of interest both to patients and physicians. One of the major problems related to maternal disease is preterm delivery with all the consequences that this condition may bring. Prematurity may also be due to the presence of aPL; however, aPL do not generally display any thrombotic potential on neonates. Another complication may be neonatal lupus (NL), mediated by the presence of maternal antibodies (anti-Ro/SSA and anti-La/SSB). In addition, behaviour and neuropsychological outcomes have also been a matter of interest, but there are currently few data available. Beyond the biological influence of both maternal disease and autoimmune background, it is important to focus on the possible influence of maternal chronic illness on the neuropsychological development of her children. Whether aPL exposure could have a direct effect on brain development is still being debated. In children of mothers with APS, language delays have been noted and learning disabilities were described with a higher rate than the general age-school population. Several studies were performed on children born to lupus mothers: even if maternal lupus does not seem to impair intelligence levels, it may increase the occurrence of learning disabilities and particularly dyslexia in male children. To the best of our knowledge, no studies are available on the long-term outcome of children born to mothers with lupus or APS and particularly regarding the development of autoimmune diseases. Nevertheless, common experience of experts in the field is that these children do not show a significantly increased risk of displaying the same autoimmune disease as their mothers. The purpose of this paper is to answer the frequently asked questions of patients with lupus and APS who desire to become mothers, based on the little information available.

Imaginary time correlations and the phaseless auxiliary field quantum Monte Carlo.

The phaseless Auxiliary Field Quantum Monte Carlo (AFQMC) method provides a well established approximation scheme for accurate calculations of ground state energies of many-fermions systems. Here we address the possibility of calculating imaginary time correlation functions with the phaseless AFQMC. We give a detailed description of the technique and test the quality of the results for static properties and imaginary time correlation functions against exact values for small systems.

The use of abdominal muscle training, breathing exercises and abdominal massage to treat paediatric chronic functional constipation.

AIM: The effect of muscular training, abdominal massage and diaphragmatic breathing was compared with medical treatment in a prospective randomized trial of patients with chronic functional constipation. METHOD: Patients aged 4-18 years old with functional constipation according to the Rome III criteria were randomized to physiotherapy or medical treatment. In the physiotherapy group, exercises (isometric training of the abdominal muscles, diaphragmatic breathing exercises and abdominal massage) were employed during 12 40-min sessions twice a week by a trained physiotherapist, with laxatives. Patients in the medication group were only given laxatives. Primary outcome measures were frequency of defaecation and faecal incontinence. The analysis was performed by intention-to-treat. RESULTS: After 6 weeks of treatment, the frequency of bowel movements was higher in the physiotherapy group [5.1 (2.1) days/week] than in the medication group [3.9 (2.0) days/week] (P = 0.01). The frequency of faecal incontinence was no different between the groups [3.6 (1.9) days/week vs 3.0 (2.1) days/week] (P = 0.31). CONCLUSION: The combined use of isometric training of abdominal muscles, breathing exercises and abdominal massage increased defaecation frequency after 6 weeks but faecal incontinence remained unchanged. Physiotherapy may be a useful treatment for constipation.

Follow-up of babies born to mothers with antiphospholipid syndrome: preliminary data from the European neonatal registry.

In this review preliminary data on the follow-up of 141 babies born to mothers with antiphospholipid syndrome are reported. In spite of maternal treatment, the rate of both preterm delivery and low birth weight were 16 and 17%, respectively. At birth, no clinical evidence of perinatal thrombosis was observed. Placental transfer of antiphospholipid antibodies occurred in 20, 25 and 43% of cases for lupus anticoagulant, anticardiolipin and anti-ß2-glycoprotein I antibodies, respectively. At 24 months of follow-up, four children showed behaviour abnormalities suggesting the possible need for long-term neurological evaluation in this clinical setting.

Osteoblastoma of cervical spine causing an unusual neck pain.

Osteoblastoma is a rare benign tumor of bone that accounts for approximately 1% of primary skeletal neoplasms, with around 90% of cases diagnosed in the second and third decades of life. Cervical spine is an usual localization of osteoblastoma. The main clinical manifestation in case of cervical spine location is a progressive and resistant pain, possibly accompanied by stiffness, scoliosis or other ailments, including severe neurological deficits. Owing to a non-specific clinical presentation of osteoblastoma, the delay in diagnosis is common. Osteoblastomas may have an aggressive behavior, tend to enlarge and damage the bone and adjacent structures. The treatment of choice is, therefore, a wide and complete surgical excision of the lesion in order to achieve full recovery and prevent recurrence or, in some cases, malignant transformation. In the case of persistent neck pain, not readily relieved by aspirin and possibly accompanied by stiffness, scoliosis or neurological deficits, especially in young subjects, osteoblastoma of cervical spine may be one of the diagnostic options to be considered, in order to avoid delay in diagnosis. We report the case of a 41-year-old male affected by cervical spine osteoblastoma causing a lasting neck pain.

Predictive ability of alternative models for genetic analysis of clinical mastitis.

Mastitis in cows can be defined as a binary trait, reflecting presence or absence of clinical mastitis (CM), or as a count variable, number of mastitis cases (NCM), within a defined time interval. Many different models have been proposed for genetic analyses of mastitis, and the objective of this study was to evaluate the predictive ability and sire predictions of a set of models for genetic evaluation of CM or NCM. Linear- and threshold liability models for CM, and linear, censored ordinal threshold, and zero-inflated Poisson (ZIP) models for NCM were compared in a cross-validation study. To assess the ability of these models to predict future data, records from 620492 first-lactation Norwegian Red cows, which were daughters of 3064 sires, were evaluated in a fourfold cross-validation scheme. The mean squared error of prediction was used for model comparison. All models but ordinal threshold model equally performed when comparing the overall predictive ability. This result was on average, across sick and healthy cows; however, the models behaved differently for each category of animals. For example, healthy cows were predicted better by the threshold and linear models for binary data and ZIP model, whereas for mastitic cows, the ordinal threshold model was by far the best model. Predicted sire effects and rankings of sires were highly correlated across all models. For practical purposes, the linear models are very competitive with the nonlinear models.

The role of radiation therapy in the management of non-functioning pituitary adenomas.

Surgical removal of non-functioning pituitary adenoma (NFPA) is the first-choice therapeutic option, but radical removal of the tumor cannot be accomplished in all patients. The best strategy to prevent regrowth of NFPA is still a matter of debate. Adjuvant radiotherapy is very effective in reducing recurrence rate after incomplete removal of NFPA, but concerns still exist about long-term toxicity of radiation. Different modalities have been developed to irradiate the pituitary region. One major distinction is between radiation techniques that deliver the total dose in multiple sessions using 3 fixed radiation beams and radiosurgical equipment that delivers the total dose to the target volume in a single treatment session. Progression-free survival of patients with NFPA treated by adjuvant radiotherapy is well above 90% at 5 yr in most studies and diminishes only slightly at 10 yr. Very few studies have a more prolonged follow-up. In comparison, the 5- and 10-yr estimated recurrence rate without adjuvant radiotherapy ranged from 15% to 51% and from 44% to 78%, respectively. Complications of radiation include rare but severe side-effects, such as secondary brain neoplasm, optic neuropathy, cerebrovascular accidents, and more frequent but less severe complications, such as pituitary deficiency. Optimal management of patients with residual or recurring NFPA after surgical debulking can be achieved through the judicious use of different treatment options, necessitating close cooperation between neurosurgeons, endocrinologists, and radiation oncologists.

Role of the energy sensor adenosine monophosphate-activated protein kinase in the regulation of immature gonadotropin-releasing hormone neuron migration.

BACKGROUND: The 5'-AMP-activated protein kinase (AMPK) plays a fundamental role in regulating energy homeostasis as well as feeding and metabolism, through central and peripheral actions. AMPK is activated by conditions causing ATP depletion and by different metabolic molecules, such as adiponectin and AMPK agonist, such as 5-aminoimidazole- 4-carboxamide-1-ß-D-ribofuranoside (AICAR). AMPK activation has also been shown to affect the migration of different cell types and to participate in the central control of reproductive function, although information concerning AMPK and the development of the hypothalamic reproductive compartment is lacking. AIM: To explore whether AMPK activation by globular adiponectin (gAdipo) and AICAR may affect the migratory ability of GnRH neurons. MATERIALS AND METHODS: We used GN11 immature GnRH neurons (in vitro model system), RT-PCR and Western blot analysis, and Boyden's chamber assay. RESULTS: gAdipo did not affect FBS-stimulated migration of GN11 cells and activated AMPK through the mandatory phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Akt, which also interact one to each other. AICAR treatment inhibited FBS-stimulated GN11 cell migration, through a long-lasting activation of AMPK. A downstream activation of ERK1/2 by AICAR was also observed and inhibition of ERK1/2 amplified AICAR-induced inhibition of migration. CONCLUSIONS: The direct, but not the indirect, activation of AMPK appears to negatively affect FBSinduced GN11 cell migration, suggesting that the final balance between pro-migratory and anti-migratory actions may also depend upon the specific sequence of intracellular signals activated by one agent.

[Fine specificity of anti-ß2glycoprotein I antibodies in systemic autoimmune diseases is mostly directed against domain 1]. / La fine specificità degli anticorpi anti-ß2 glicoproteina I nelle malattie autoimmune sistemiche è prevalentemente diretta verso il dominio 1.

OBJECTIVE: Anti-ß2 GPI are a formal laboratory criterion for the antiphospholipid syndrome (APS). They were demonstrated to be a risk factor for thrombosis and fetal losses but can also be detected in patients with systemic autoimmune disease (SAD), in healthy adults individuals and pre-school children. It has been suggested that different subpopulations of anti-ß2GPI may carry different pathogenetic potential: autoantibodies against Domain1 seem to be associated with thrombosis; autoantibodies against Domain4/5 have been identified in patients with non-thrombotic conditions. METHODS: We studied 48 patients with SAD (32 systemic lupus erythematosus, 16 undifferentiated connettive tissue disease), 64 patients with APS, 57 one-year-old healthy children born to mother with SAD, 33 children with atopic dermatitis. All subjects were IgG anti-ß2 GPI positive. The specificity of anti-ß2 GPI was investigated using ELISA research products containing recombinant ß2 GPI D1 and D4/5 antigens. Cut-off values are calculated as 95th percentile on 100 NHD. IgG anti-ß2 GPI were tested at a validated home-made ELISA routinely performed in our laboratory. No thrombotic events were recordered in patients with SAD and in both groups of children. RESULTS: Patients with SAD and APS showed prevalent reactivity for D1 while children in both groups preferentially recognize D4/5. CONCLUSIONS: IgG anti-ß2 GPI against D1 seem to cluster in patients with systemic autoimmune conditions. Their pathogenic potential in determine APS manifestations may be mitigated by adequate prophylaxis.