In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to the mdx mousemodel of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR-Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force.This work establishes CRISPR-Cas9-based genome editing as a potential therapy to treat DMD.Muscular Dystrophy Association (Award MDA277360)National Institutes of Health (U.S.) (Grant 5DP1-MH100706)National Institutes of Health (U.S.) (Grant R01DK097768

In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the CRISPR/Cas9 system to the mdx mouse model of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR/Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force. This work establishes CRISPR/Cas9-based genome editing as a potential therapy to treat DMD

Comparison of Heterologous Neutralizing Antibody Responses of Human Immunodeficiency Virus Type 1 (HIV-1)- and HIV-2-Infected Senegalese Patients: Distinct Patterns of Breadth and Magnitude Distinguish HIV-1 and HIV-2 Infections

Neutralizing antibody responses against heterologous isolates in human immunodeficiency virus type 1 (HIV-1) and HIV-2 infections were compared, and their relationships with established clinical markers of progression were examined. Neutralizing responses against 7 heterologous primary isolates and 1 laboratory strain were compared between 32 untreated HIV-1-infected subjects and 35 untreated HIV-2-infected subjects using a pseudotyped reporter virus assay. The breadth of the neutralizing response, defined as the proportion of panel viruses positively neutralized by patient plasma, was significantly greater among HIV-2-infected subjects than among HIV-1-infected subjects. Notably, for fully one-third of HIV-2 subjects, all viruses were effectively neutralized in our panel. Magnitudes of responses, defined as reciprocal 50% inhibitory concentration (IC(50)) titers for positive reactions, were significantly greater among HIV-1-infected subjects than among HIV-2-infected subjects. When plasma samples from HIV-1 patients were tested for cross-neutralization of HIV-2 and vice versa, we found that these intertype responses are very rare and their prevalences comparable in both HIV-1 and HIV-2 infection. The significantly higher magnitude of heterologous responses for HIV-1 compared to HIV-2 prompted us to examine associations with viremia, which is known to be significantly higher in HIV-1 infection. Importantly, there was a significant positive correlation between the IC(50) titer and viral load within both the HIV-1 and HIV-2 groups, suggesting heterologous antibodies may be driven by viral replication. We conclude that HIV-2 infection is characterized by a broad, low-magnitude intratype neutralization response, while HIV-1 is characterized by a narrower but higher-magnitude intratype response and that a significant positive association between the IC(50) titer and viremia is common to both HIV-1 and HIV-2 infections

Factors Associated With Pulmonary Tuberculosis-HIV Co-Infection in Treatment-Naive Adults in Jos, North Central Nigeria

Background: Co-infection with tuberculosis and human immunodeficiency virus (TB-HIV) remains a major global health problem, with about 1.1 million new cases of TB in HIV-positive persons reported in 2011; 79% of the reported cases were amongst patients living in Africa. Advanced immune suppression remains the most important risk factor for tuberculosis in those with HIV, but epidemiological and clinical factors have also been identified. We sought to determine the prevalence and factors associated with pulmonary tuberculosis (PTB) in antiretroviral therapy (ART)- naive HIV-infected patients seeking HIV care services at a tertiary health facility in North Central Nigeria. Methods: We compared clinical and laboratory data for 218 HIV-1 positive adults with and without a diagnosis of pulmonary tuberculosis. Results from univariate analyses informed the selection of predictors to conduct multivariate analysis to determine which factors were associated with presence of PTB-HIV co-infection. Results: The prevalence of PTB-HIV co-infection in the evaluated cohort was 9.6%. Lower CD4+ cell count and the presence of oropharyngeal candidiasis were independently associated with PTB-HIV co-infection. CD4+ cell count was strongly associated with PTB-HIV co-infection (p=0.002) with the odds of co-infection reduced by 85% in those with a CD4+ cell count >100 cells/mm3 compared to those with <100 cells/ mm3. There was a strong association between oropharyngeal candidiasis and PTB-HIV co-infection, where the odds of co-infection are about 4.5 times higher in those with oropharyngeal candidiasis than those without candidiasis (p=0.008). Conclusion: PTB was prevalent among HIV patients seeking care in our setting. Severe immune suppression and oropharyngeal candidiasis were associated with PTB-HIV co-infection in our patients at presentation. Potential implications for severe immune suppression and advanced HIV disease are a poor clinical outcome and further spread of PTB. Strategies to encourage the early diagnosis of both HIV and TB should be considere

Motor neuronopathy with dropped hands and downbeat nystagmus: A distinctive disorder? A case report

BACKGROUND: Eye movements are clinically normal in most patients with motor neuron disorders until late in the disease course. Rare patients are reported to show slow vertical saccades, impaired smooth pursuit, and gaze-evoked nystagmus. We report clinical and oculomotor findings in three patients with motor neuronopathy and downbeat nystagmus, a classic sign of vestibulocerebellar disease. CASE PRESENTATION: All patients had clinical and electrodiagnostic features of anterior horn cell disease. Involvement of finger and wrist extensors predominated, causing finger and wrist drop. Bulbar or respiratory dysfunction did not occur. All three had clinically evident downbeat nystagmus worse on lateral and downgaze, confirmed on eye movement recordings using the magnetic search coil technique in two patients. Additional oculomotor findings included alternating skew deviation and intermittent horizontal saccadic oscillations, in one patient each. One patient had mild cerebellar atrophy, while the other two had no cerebellar or brainstem abnormality on neuroimaging. The disorder is slowly progressive, with survival up to 30 years from the time of onset. CONCLUSION: The combination of motor neuronopathy, characterized by early and prominent wrist and finger extensor weakness, and downbeat nystagmus with or without other cerebellar eye movement abnormalities may represent a novel motor neuron syndrome

Mapping of hormones and cortisol responses in patients after Lyme neuroborreliosis

<p>Abstract</p> <p>Background</p> <p>Persistent symptoms after treatment for neuroborreliosis are common for reasons mainly unknown. These symptoms are often unspecific and could be caused by dysfunctions in endocrine systems, an issue that has not been previously addressed systematically. We therefore mapped hormone levels in patients with previous confirmed Lyme neuroborreliosis of different outcomes and compared them with a healthy control group.</p> <p>Methods</p> <p>Twenty patients of a retrospective cohort of patients treated for definite Lyme neuroborreliosis were recruited 2.3 to 3.7 years (median 2.7) after diagnosis, together with 23 healthy controls. Lyme neuroborreliosis patients were stratified into two groups according to a symptom/sign score. All participants underwent anthropometric and physiological investigation as well as an extensive biochemical endocrine investigation including a short high-dose adrenocorticotropic hormone stimulation (Synacthen^®) test. In addition to hormonal status, we also examined electrolytes, 25-hydroxy-vitamin D and interleukin-6.</p> <p>Results</p> <p>Eight patients (40%) had pronounced symptoms 2-3 years after treatment. This group had a higher cortisol response to synacthen as compared with both controls and the Lyme neuroborreliosis patients without remaining symptoms (p < 0.001 for both comparisons). No other significant differences in the various baseline biochemical parameters, anthropometric or physiological data could be detected across groups.</p> <p>Conclusions</p> <p>Apart from a positive association between the occurrence of long-lasting complaints after Lyme neuroborreliosis and cortisol response to synacthen, no corticotropic insufficiency or other serious hormonal dysfunction was found to be associated with remaining symptoms after treatment for Lyme neuroborreliosis.</p

Measurement of νˉμ\bar{\nu}_{\mu} and νμ\nu_{\mu} charged current inclusive cross sections and their ratio with the T2K off-axis near detector

We report a measurement of cross section $\sigma(\nu_{\mu}+{\rm nucleus}\rightarrow\mu^{-}+X)$ and the first measurements of the cross section $\sigma(\bar{\nu}_{\mu}+{\rm nucleus}\rightarrow\mu^{+}+X)$ and their ratio $R(\frac{\sigma(\bar \nu)}{\sigma(\nu)})$ at (anti-)neutrino energies below 1.5 GeV. We determine the single momentum bin cross section measurements, averaged over the T2K $\bar{\nu}/\nu$-flux, for the detector target material (mainly Carbon, Oxygen, Hydrogen and Copper) with phase space restricted laboratory frame kinematics of $\theta_{\mu}$500 MeV/c. The results are $\sigma(\bar{\nu})=\left( 0.900\pm0.029{\rm (stat.)}\pm0.088{\rm (syst.)}\right)\times10^{-39}$ and $\sigma(\nu)=\left( 2.41\ \pm0.022{\rm{(stat.)}}\pm0.231{\rm (syst.)}\ \right)\times10^{-39}$in units of cm$^{2}$/nucleon and$R\left(\frac{\sigma(\bar{\nu})}{\sigma(\nu)}\right)= 0.373\pm0.012{\rm (stat.)}\pm0.015{\rm (syst.)}$.Comment: 18 pages, 8 figure

Measuring the atmospheric neutrino oscillation parameters and constraining the 3+1 neutrino model with ten years of ANTARES data

The ANTARES neutrino telescope has an energy threshold of a few tens of GeV. This allows to study the phenomenon of atmospheric muon neutrino disappearance due to neutrino oscillations. In a similar way, constraints on the 3+1 neutrino model, which foresees the existence of one sterile neutrino, can be inferred. Using data collected by the ANTARES neutrino telescope from 2007 to 2016, a new measurement of m2 32 and 23 has been performed | which is consistent with world best- t values | and constraints on the 3+1 neutrino model have been derived.Centre National de la Recherche Scienti que (CNRS)Commissariat a l' energie atomique et aux energies alternatives (CEA)Commission Européenne (FEDER fund and Marie Curie Program)Institut Universitaire de France (IUF)IdEx program and UnivEarthS Labex program at Sorbonne Paris Cité (ANR-10-LABX-0023 and ANR-11-IDEX-0005-02)Labex OCEVU (ANR-11-LABX-0060) and the A*MIDEX project (ANR-11-IDEX-0001-02)Région ÎIle-de- France (DIM-ACAV)Région Alsace (contrat CPER)Région Provence-Alpes-Côte d'Azur, Département du Var and Ville de La Seyne-sur-MerBundesministerium für Bildung und Forschung (BMBF)Istituto Nazionale di Fisica Nucleare (INFN)Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO)Council of the President of the Russian Federation for young scientists and leading scientific schools supporting grantsExecutive Unit for Financing Higher Education, Research, Development and Innovation (UEFISCDIÇ)Ministerio de Economía y Competitividad (MINECO): Plan Estatal de Investigación (refs. FPA2015-65150-C3-1-P, -2-P and -3-P, (MINECO/FEDER))Severo Ochoa Centre of Excellence and Red Consolider MultiDark (MINECO), and Prometeo and Grisolía programs (Generalitat Valenciana)Ministry of Higher Education, Scienti c Research and Professional Trainin