The landscape of human genes involved in the immune response to parasitic worms.

Background: More than 2 billion individuals worldwide suffer from helminth infections. The highest parasite burdens occur in children and helminth infection during pregnancy is a risk factor for preterm delivery and reduced birth weight. Therefore, helminth infections can be regarded as a strong selective pressure.

The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K.

Background: Mutations in GDAP1 associate with demyelinating (CMT4A) and axonal (CMT2K) forms of CMT. While CMT4A shows recessive inheritance, CMT2K can present with either recessive (AR-CMT2K) or dominant segregation pattern (AD-CMT2K), the latter being characterised by milder phenotypes and later onset. The majority of the GDAP1 mutations are associated with CMT4A and AR-CMT2K, with only four heterozygous mutations identified in AD-CMT2K.

A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation.

Background: Mutations in the calcium channel voltage dependent P/Q-type alpha-1A subunit (CACNA1A) can cause different neurological disorders which share a wide range of symptoms, including episodic ataxia type 2 (EA2), familial hemiplegic migraine (FHM1) and progressive spinocerebellar ataxia (SCA6).

Objective: To describe a three generations family in which a spectrum of different phenotypes, ranging from SCA6 (proband), to EA2 (proband's mother) to FHM1 (proband's mother and proband's aunt) was found. All of the family members carried a novel CACNA1A missense mutation.

Is KIF24 a genetic risk factor for Frontotemporal Lobar Degeneration?

Linkage analysis identified a region on chromosome 9p associated with Frontotemporal Lobar Degeneration (FTLD). A detailed analysis of candidate genes lying in this region demonstrated an association with Ubiquitin Associated Protein (UBAP)1. The distribution of five Single Nucleotide Polymorphisms (SNPs) located in the chromosome 9 haplotype identified via linkage analysis, including UBAP1 rs7018487, UBAP2 rs1785506 and rs307658, and KIF24 rs17350674 and rs10814083, has been determined in a population of 284 patients diagnosed with FTLD, including 245 with behavioural variant Frontotemporal Dementia (bvFTD), 23 with Progressive Aphasia and 16 with Semantic Dementia, compared with 318 age-matched controls.

Systemic transplantation of c-kit+ cells exerts a therapeutic effect in a model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease characterized by the loss of motor neurons. Motor neuron degeneration is probably both a cell autonomous and a non-autonomous event. Therefore, manipulating the diseased microenvironment via non-neural cell replacement could be a therapeutic strategy.

Mitochondrial respiratory chain dysfunction in muscle from patients with amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a major cause of neurological disability and its pathogenesis remains elusive despite a multitude of studies. Although defects of the mitochondrial respiratory chain have been described in several ALS patients, their pathogenic significance is unclear.

Objective: To review systematically the muscle biopsy specimens from patients with typical sporadic ALS to search for possible mitochondrial oxidative impairment.

Effects of rituximab in two patients with dysferlin-deficient muscular dystrophy.

Background: The administration of rituximab (RTX) in vivo results in B-cell depletion, but evidence for multiple mechanisms of action have been reported. Surprisingly, B cell depletion produced a response in patients with polymyositis, which is characterized as a T cell-mediated autoimmune disorder with biopsy findings similar to Miyoshi myopathy (MM). Indeed, in dysferlinopathies, there is evidence of immune system involvement including the presence of muscle inflammation and a down regulation of the complement inhibitory factor, CD55.

Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy.

Infantile neuroaxonal dystrophy, INAD, is a severe progressive psychomotor disorder with infantile onset and characterized by the presence of axonal spheroids throughout the central and peripheral nervous systems. A subset of INAD patients shows also brain iron accumulation which represents instead the distinctive feature of the idiopathic neurodegeneration with brain iron accumulation, NBIA. These diseases share the same causative gene, PLA2G6, encoding iPLA2-VIA, a calcium-independent phospholipase.

Population genetics of IFIH1: ancient population structure, local selection, and implications for susceptibility to type 1 diabetes.

The human interferon induced with helicase C domain 1 (IFIH1) gene encodes a sensor of double-strand RNA involved in innate immunity against viruses, indicating that this gene is a likely target of virus-driven selective pressure. Notably, IFIH1 also plays a role in autoimmunity, as common and rare polymorphisms in this gene have been associated with type 1 diabetes (T1D). We analyzed the evolutionary history of IFIH1 in human populations.

Acute kidney injury in children: incidence and prognostic factors in critical ill patients.

Objectives: Acute kidney injury is characterized by sudden and generally revertible renal function impairment involving inability to maintain homeostasis. In pediatrics, the main causes of acute kidney injury are sepsis, use of nephrotoxic drugs and renal ischemia in critically ill patients. The incidence of acute kidney injury in these patients ranges from 20 to 30%, resulting in increased morbid-mortality, a 40 to 90% rate.

Effects of gender and posture on thoraco-abdominal kinematics during quiet breathing in healthy adults.

To investigate the effects of posture and gender on thoraco-abdominal motion and breathing pattern, 34 healthy men and women were studied by Opto-Electronic Plethysmography during quiet breathing in five different postures from seated (with and without back support) to supine position. Chest wall kinematics and breathing pattern were significantly influenced by position and gender. The progressively increased inclination of the trunk determined a progressive reduction of rib cage displacement, tidal volume, and minute ventilation and a progressive increase of abdominal contribution to tidal volume.

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males.

Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.

VEGF haplotypes are associated with increased risk to progressive supranuclear palsy and corticobasal syndrome.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are in the spectrum of tauopathies and recognized to have a strong genetic background. It has been widely reported that MAPT tau haplotype H1 is a genetic risk factor in both conditions, but no other genetic determinants have so far been proposed. Recently, vascular endothelial growth factor (VEGF) haplotypes were reported to confer risk to frontotemporal dementia (FTD).

Ex vivo expansion of human circulating myogenic progenitors on cluster-assembled nanostructured TiO2.

Ex vivo expansion of hematopoietic stem cells has been explored in the fields of stem cell biology, gene therapy and clinical transplantation. Recently, we demonstrated the existence of a circulating myogenic progenitor expressing the CD133 antigen. The relative inability of circulating CD133+ stem cells to reproduce themselves ex vivo imposes substantial limitations on their use for clinical applications in muscular dystrophies.

A cortically blind patient with preserved visual imagery.

Background/objective: The loss or preservation of visual imagery in patients with cortical blindness may be helpful in resolving the controversial roles assigned by some researchers to the early visual cortex during the process of visual imagery.

Patient And Methods: Here we report a patient with complete permanent cortical blindness coupled with denial of the blindness (Anton syndrome) as a result of bilateral occipital infarction.

Results: Interestingly, the patient's ability to visualize objects, color, and spatial imagery was preserved, although cerebral computed tomography, magnetic resonance imaging, and positron emission tomography scans detected what was likely complete bilateral damage to the primary visual cortex.

Polymorphisms in the CPB2 gene are maintained by balancing selection and result in haplotype-preferential splicing of exon 7.

The CPB2 gene encodes thrombin-activatable fibrinolysis inhibitor (TAFI), a hepatically secreted zymogen acting as a molecular link among coagulation, fibrinolysis, and inflammation. Variants in CPB2 have been associated with several human conditions. We resequenced and analyzed the two regions carrying previously known nonsynonimous single-nucleotide polymorphisms (Ala147Thr and Ile325Thr) and variants affecting transcript stability.

Genome-wide identification of susceptibility alleles for viral infections through a population genetics approach.

Viruses have exerted a constant and potent selective pressure on human genes throughout evolution. We utilized the marks left by selection on allele frequency to identify viral infection-associated allelic variants. Virus diversity (the number of different viruses in a geographic region) was used to measure virus-driven selective pressure.

The m.12316G>A mutation in the mitochondrial tRNA Leu(CUN) gene is associated with mitochondrial myopathy and respiratory impairment.

Mitochondrial disorders are often associated with mutations in mitochondrial tRNA. Independent observation of the same molecular defect in unrelated subjects is a generally required proof of pathogenicity. A sporadic case of chronic external ophthalmoplegia (cPEO) with ragged red fibres (RRFs) has been previously related to an m.

The role of protozoa-driven selection in shaping human genetic variability.

Protozoa exert a strong selective pressure in humans. The selection signatures left by these pathogens can be exploited to identify genetic modulators of infection susceptibility. We show that protozoa diversity in different geographic locations is a good measure of protozoa-driven selective pressure; protozoa diversity captured selection signatures at known malaria resistance loci and identified several selected single nucleotide polymorphisms in immune and hemolytic anemia genes.

GRN variability contributes to sporadic frontotemporal lobar degeneration.

Mutations in the progranulin gene (GRN) are responsible for familial FTLD with ubiquitin pathology (FTLD-U). However, there are controversial data regarding the contribution of GRN variability to sporadic FTLD. We carried out an association study in 265 patients, who did not carry a GRN causal mutation, and 375 age-matched controls.

FUS/TLS genetic variability in sporadic frontotemporal lobar degeneration.

Two hundred and fifty one Italian patients with sporadic frontotemporal lobar degeneration (FTLD) and 259 age-matched controls were tested for association with the tagging single nucleotide polymorphisms (SNPs) rs741810 and rs1052352 in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS). Only patients negative for GRN mutations were included. Considering each SNP alone, no differences in either allelic or genotypic frequencies between patients and controls were found (P > 0.

Genetic variability in the ACE gene region surrounding the Alu I/D polymorphism is maintained by balancing selection in human populations.

Objective: Angiotensin-converting enzyme plays a critical role in the maintenance of cardiovascular homeostasis. Extensive research has aimed at identifying ACE genetic variants responsible for variation in enzyme plasma concentrations and associated with human diseases. These efforts have been hampered by the extensive linkage disequilibrium across the gene and the identity or location of the functional polymorphism(s) is at presently unknown.

Embryonic stem cell-derived neural stem cells improve spinal muscular atrophy phenotype in mice.

Spinal muscular atrophy, characterized by selective loss of lower motor neurons, is an incurable genetic neurological disease leading to infant mortality. We previously showed that primary neural stem cells derived from spinal cord can ameliorate the spinal muscular atrophy phenotype in mice, but this primary source has limited translational value. Here, we illustrate that pluripotent stem cells from embryonic stem cells show the same potential therapeutic effects as those derived from spinal cord and offer great promise as an unlimited source of neural stem cells for transplantation.