Assessing the psychometric properties of quality of life measures in individuals with amyotrophic lateral sclerosis: a systematic review.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. There are many patient-reported outcome measures (PROMs) for measuring quality of life (QoL) and health-related QoL (HRQoL) within this population; however, there is limited consensus regarding which are most valid, reliable, responsive, and interpretable. This systematic review assesses the psychometric properties and interpretability of QoL and HRQoL PROMs for individuals with ALS. METHODS: This review was conducted following the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) methodology for systematic reviews of PROMs. MEDLINE, EMBASE, and CINAHL databases were searched. Studies were included if their aim was to evaluate one or more psychometric properties or the interpretability of QoL or HRQoL PROMs in individuals with ALS. RESULTS: We screened 2713 abstracts, reviewed 60 full-text articles, and included 37 articles. Fifteen PROMs were evaluated including generic HRQoL (e.g., SF-36), ALS-specific HRQoL (e.g., ALSAQ-40), and individualized QoL (e.g., SEIQoL) measures. Evidence for internal consistency and test-retest reliability were acceptable. For convergent validity, 84% of hypotheses were met. For known-groups validity, outcomes were able to distinguish between healthy cohorts and other conditions. Responsiveness results ranged from low to high correlations with other measures over 3-24 months. Evidence for content validity, structural validity, measurement error, and divergent validity was limited. CONCLUSION: This review identified evidence in support of the ALSAQ-40 or ALSAQ-5 for individuals with ALS. These findings can guide healthcare practitioners when selecting evidence-based QoL and HRQoL PROMs for patients and provide researchers with insight into gaps in the literature.

COVID-19 cross-sectional study in Maricá, Brazil: The impact of vaccination coverage on viral incidence.

Population surveillance in COVID-19 Pandemic is crucial to follow up the pace of disease and its related immunological status. Here we present a cross-sectional study done in Maricá, a seaside town close to the city of Rio de Janeiro, Brazil. Three rounds of study sampling, enrolling a total of 1134 subjects, were performed during May to August 2021. Here we show that the number of individuals carrying detectable IgG antibodies and the neutralizing antibody (NAb) levels were greater in vaccinated groups compared to unvaccinated ones, highlighting the importance of vaccination to attain noticeable levels of populational immunity against SARS-CoV-2. Moreover, we found a decreased incidence of COVID-19 throughout the study, clearly correlated with the level of vaccinated individuals as well as the proportion of individuals with detectable levels of IgG anti-SARS-CoV-2 and NAb. The observed drop occurred even during the introduction of the Delta variant in Maricá, what suggests that the vaccination slowed down the widespread transmission of this variant. Overall, our data clearly support the use of vaccines to drop the incidence associated to SARS-CoV-2.

Development and applicability of a ready-to-use PCR system for GMO screening.

With the growing number of GMOs introduced to the market, testing laboratories have seen their workload increase significantly. Ready-to-use multi-target PCR-based detection systems, such as pre-spotted plates (PSP), reduce analysis time while increasing capacity. This paper describes the development and applicability to GMO testing of a screening strategy involving a PSP and its associated web-based Decision Support System. The screening PSP was developed to detect all GMOs authorized in the EU in one single PCR experiment, through the combination of 16 validated assays. The screening strategy was successfully challenged in a wide inter-laboratory study on real-life food/feed samples. The positive outcome of this study could result in the adoption of a PSP screening strategy across the EU; a step that would increase harmonization and quality of GMO testing in the EU. Furthermore, this system could represent a model for other official control areas where high-throughput DNA-based detection systems are needed.

Novel hybrid DHPM-fatty acids: synthesis and activity against glioma cell growth in vitro.

We described the first synthesis of fatty acid 3,4-dihydropyrimidinones (DHPM-fatty acids) using the Biginelli multicomponent reaction. Antiproliferative activity on two glioma cell lines (C6 rat and U-138-MG human) was also reported. The novel DHPM-fatty acids reduced glioma cell viability relative to temozolomide. Hybrid oxo-monastrol-palmitic acid was the most potent, reducing U-138-MG human cell viability by ca. 50% at 10 µM. In addition, the DHPM-fatty acids showed a large safety range to neural cells, represented by the organotypic hippocampal culture. These results suggest that the increased lipophilicity of DHPM-fatty acids offer a promising approach to overcoming resistance to chemotherapy and may play an important role in the development of new antitumor drugs.

JRC GMO-Matrix: a web application to support Genetically Modified Organisms detection strategies.

BACKGROUND: The polymerase chain reaction (PCR) is the current state of the art technique for DNA-based detection of Genetically Modified Organisms (GMOs). A typical control strategy starts by analyzing a sample for the presence of target sequences (GM-elements) known to be present in many GMOs. Positive findings from this "screening" are then confirmed with GM (event) specific test methods. A reliable knowledge of which GMOs are detected by combinations of GM-detection methods is thus crucial to minimize the verification efforts. DESCRIPTION: In this article, we describe a novel platform that links the information of two unique databases built and maintained by the European Union Reference Laboratory for Genetically Modified Food and Feed (EU-RL GMFF) at the Joint Research Centre (JRC) of the European Commission, one containing the sequence information of known GM-events and the other validated PCR-based detection and identification methods. The new platform compiles in silico determinations of the detection of a wide range of GMOs by the available detection methods using existing scripts that simulate PCR amplification and, when present, probe binding. The correctness of the information has been verified by comparing the in silico conclusions to experimental results for a subset of forty-nine GM events and six methods. CONCLUSIONS: The JRC GMO-Matrix is unique for its reliance on DNA sequence data and its flexibility in integrating novel GMOs and new detection methods. Users can mine the database using a set of web interfaces that thus provide a valuable support to GMO control laboratories in planning and evaluating their GMO screening strategies. The platform is accessible at http://gmo-crl.jrc.ec.europa.eu/jrcgmomatrix/ .

Pulsed electromagnetic field and exercises in patients with shoulder impingement syndrome: a randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVE: To evaluate the effects of pulsed electromagnetic field (PEMF) and exercises in reducing pain and improving function and muscle strength in patients with shoulder impingement syndrome (SIS). DESIGN: Double-blind, randomized controlled trial with a 3-month posttreatment follow-up. SETTING: Outpatient rehabilitation of a public hospital. PARTICIPANTS: Patients (N=56) between 40 and 60 years of age, with a diagnosis of SIS, were randomly assigned to receive active PEMF (n=26; mean age, 50.1y) or placebo PEMF (n=30; mean age, 50.8y). INTERVENTIONS: After 3 weeks of active or placebo PEMF, both groups performed the same program of exercises that focused on shoulder strengthening. MAIN OUTCOME MEASURES: A visual analog scale, the University of California/Los Angeles shoulder rating scale, the Constant-Murley shoulder score, and handheld dynamometry for muscle strength were used as outcome measures at baseline (pretreatment), at 3 weeks (after active or placebo PEMF), at 9 weeks (postexercise), and at 3 months posttreatment. RESULTS: Patients in the active PEMF group had a higher level of function and less pain at all follow-up time frames compared with baseline (P<.05). However, the placebo PEMF group had increased function and reduced pain only at the 9-week and 3-month follow-ups (P<.05)-that is, after performing the associated exercises. For the shoulder dynamometry, the active PEMF group had increased strength for lateral rotation at 9 weeks (P<.05), and increased strength for medial rotation at 9 weeks and 3 months (both P<.05) when compared with baseline. There was no significant difference for shoulder strength in the placebo PEMF group (P>.05), as well as no significant differences (P>.05) for all outcome measures. CONCLUSIONS: The combination of PEMF and shoulder exercises is effective in improving function and muscle strength and decreasing pain in patients with SIS. However, these results should be carefully interpreted because of the lack of differences between groups.

A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation.

Individuals with congenital disorders of glycosylation (CDG) have recessive mutations in genes required for protein N-glycosylation, resulting in multi-systemic disease. Despite the well-characterized biochemical consequences in these individuals, the underlying cellular defects that contribute to CDG are not well understood. Synthesis of the lipid-linked oligosaccharide (LLO), which serves as the sugar donor for the N-glycosylation of secretory proteins, requires conversion of fructose-6-phosphate to mannose-6-phosphate via the phosphomannose isomerase (MPI) enzyme. Individuals who are deficient in MPI present with bleeding, diarrhea, edema, gastrointestinal bleeding and liver fibrosis. MPI-CDG patients can be treated with oral mannose supplements, which is converted to mannose-6-phosphate through a minor complementary metabolic pathway, restoring protein glycosylation and ameliorating most symptoms, although liver disease continues to progress. Because Mpi deletion in mice causes early embryonic lethality and thus is difficult to study, we used zebrafish to establish a model of MPI-CDG. We used a morpholino to block mpi mRNA translation and established a concentration that consistently yielded 13% residual Mpi enzyme activity at 4 days post-fertilization (dpf), which is within the range of MPI activity detected in fibroblasts from MPI-CDG patients. Fluorophore-assisted carbohydrate electrophoresis detected decreased LLO and N-glycans in mpi morphants. These deficiencies resulted in 50% embryonic lethality by 4 dpf. Multi-systemic abnormalities, including small eyes, dysmorphic jaws, pericardial edema, a small liver and curled tails, occurred in 82% of the surviving larvae. Importantly, these phenotypes could be rescued with mannose supplementation. Thus, parallel processes in fish and humans contribute to the phenotypes caused by Mpi depletion. Interestingly, mannose was only effective if provided prior to 24 hpf. These data provide insight into treatment efficacy and the broader molecular and developmental abnormalities that contribute to disorders associated with defective protein glycosylation.

A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency.

Congenital disorder of glycosylation (PMM2-CDG) results from mutations in pmm2, which encodes the phosphomannomutase (Pmm) that converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P). Patients have wide-spectrum clinical abnormalities associated with impaired protein N-glycosylation. Although it has been widely proposed that Pmm2 deficiency depletes M1P, a precursor of GDP-mannose, and consequently suppresses lipid-linked oligosaccharide (LLO) levels needed for N-glycosylation, these deficiencies have not been demonstrated in patients or any animal model. Here we report a morpholino-based PMM2-CDG model in zebrafish. Morphant embryos had developmental abnormalities consistent with PMM2-CDG patients, including craniofacial defects and impaired motility associated with altered motor neurogenesis within the spinal cord. Significantly, global N-linked glycosylation and LLO levels were reduced in pmm2 morphants. Although M1P and GDP-mannose were below reliable detection/quantification limits, Pmm2 depletion unexpectedly caused accumulation of M6P, shown earlier to promote LLO cleavage in vitro. In pmm2 morphants, the free glycan by-products of LLO cleavage increased nearly twofold. Suppression of the M6P-synthesizing enzyme mannose phosphate isomerase within the pmm2 background normalized M6P levels and certain aspects of the craniofacial phenotype and abrogated pmm2-dependent LLO cleavage. In summary, we report the first zebrafish model of PMM2-CDG and uncover novel cellular insights not possible with other systems, including an M6P accumulation mechanism for underglycosylation.

Força do manguito rotador em indivíduos com síndrome do impacto comparado ao lado assintomático / Rotator cuff strength in subjects with shoulder impingement syndrome compared with the asymptomatic side

OBJETIVO: Avaliar a força muscular de rotação interna, externa e elevação dos ombros sintomáticos comparado aos assintomáticos, associando a força muscular à função da articulação. MÉTODOS: Quarenta e oito indivíduos com diagnóstico de SIO unilateral foram avaliados quanto a força muscular isométrica do ombro sintomático e assintomático (utilizando um dinamômetro isométrico manual), além de serem avaliados quanto a função utilizando a escala de Constant-Murley. Os indivíduos foram distribuídos em 2 grupos: grupo 1 = 35 a 49 anos; grupo 2 = 50 a 65 anos. RESULTADOS: Foi encontrada redução da força de rotação interna, externa e elevação no ombro sintomático, comparado ao lado assintomáticos (p< 0,0001), mas não foi observada redução da força de rotação medial nos sujeitos do grupo 1. Também observamos que a força muscular é diretamente proporcional a função do ombro, onde indivíduos com pouca força do manguito rotador apresentam menor função. CONCLUSÃO: A SIO causa diminuição da força muscular de rotação interna, externa e elevação comparado ao lado assintomático, além de causar diminuição da função do ombro. A redução da função é proporcional a diminuição da força muscular do manguito rotador. Nível de Evidência III, Estudo analítico.

OBJECTIVE: To evaluate the strength of internal rotation, external rotation and elevation of the shoulders of symptomatic compared with asymptomatic patients, associating muscle strength with joint function. METHODS: Forty-eight individuals diagnosed with unilateral SIS were evaluated in relation to isomeric muscle strength of symptomatic and asymptomatic shoulders (using a hand-held isometric dynamometer), in addition to evaluating function using the Constant-Murley scale. The subjects were divided into 2 groups: group 1 = 35 to 49 years, group 2 = 50 to 65 years. RESULTS: A reduction in strength of internal rotation, external rotation and elevation of the symptomatic shoulder were found, compared with the asymptomatic side (p <0.0001), but there was no reduction in the strength of medial rotation in the subjects of group 1. It was observed that muscle strength is directly proportional to shoulder function, with individuals with little strength of the rotator cuff having less function. CONCLUSION: SIS causes decreased muscle strength of internal rotation, external rotation and elevation compared with the asymptomatic side. It also causes decreased shoulder function. The reduced function is proportional to the decrease in muscle strength of the rotator cuff. Level of evidence: level III, analytical study.

Hydractinia allodeterminant alr1 resides in an immunoglobulin superfamily-like gene complex.

Allorecognition, the ability to discriminate between self and nonself, is ubiquitous among colonial metazoans and widespread among aclonal taxa. Genetic models for the study of allorecognition have been developed in the jawed vertebrates, invertebrate chordate Botryllus, and cnidarian Hydractinia. In Botryllus, two genes contribute to the histocompatibility response, FuHC and fester. In the cnidarian Hydractinia, one of the two known allorecognition loci, alr2, has been isolated, and a second linked locus, alr1, has been mapped to the same chromosomal region, called the allorecognition complex (ARC). Here we isolate alr1 by positional cloning and report it to encode a transmembrane receptor protein with two hypervariable extracellular regions similar to immunoglobulin (Ig)-like domains. Variation in the extracellular domain largely predicts fusibility within and between laboratory strains and wild-type isolates. alr1 was found embedded in a family of immunoglobulin superfamily (IgSF)-like genes, thus establishing that the ARC histocompatibility complex is an invertebrate IgSF-like gene complex.

Progressive colonization and restricted gene flow shape island-dependent population structure in Galápagos marine iguanas (Amblyrhynchus cristatus).

BACKGROUND: Marine iguanas (Amblyrhynchus cristatus) inhabit the coastlines of large and small islands throughout the Galápagos archipelago, providing a rich system to study the spatial and temporal factors influencing the phylogeographic distribution and population structure of a species. Here, we analyze the microevolution of marine iguanas using the complete mitochondrial control region (CR) as well as 13 microsatellite loci representing more than 1200 individuals from 13 islands. RESULTS: CR data show that marine iguanas occupy three general clades: one that is widely distributed across the northern archipelago, and likely spread from east to west by way of the South Equatorial current, a second that is found mostly on the older eastern and central islands, and a third that is limited to the younger northern and western islands. Generally, the CR haplotype distribution pattern supports the colonization of the archipelago from the older, eastern islands to the younger, western islands. However, there are also signatures of recurrent, historical gene flow between islands after population establishment. Bayesian cluster analysis of microsatellite genotypes indicates the existence of twenty distinct genetic clusters generally following a one-cluster-per-island pattern. However, two well-differentiated clusters were found on the easternmost island of San Cristóbal, while nine distinct and highly intermixed clusters were found on youngest, westernmost islands of Isabela and Fernandina. High mtDNA and microsatellite genetic diversity were observed for populations on Isabela and Fernandina that may be the result of a recent population expansion and founder events from multiple sources. CONCLUSIONS: While a past genetic study based on pure FST analysis suggested that marine iguana populations display high levels of nuclear (but not mitochondrial) gene flow due to male-biased dispersal, the results of our sex-biased dispersal tests and the finding of strong genetic differentiation between islands do not support this view. Therefore, our study is a nice example of how recently developed analytical tools such as Bayesian clustering analysis and DNA sequence-based demographic analyses can overcome potential biases introduced by simply relying on FST estimates from markers with different inheritance patterns.

Development of 10 highly-polymorphic microsatellite markers in the vulnerable Galápagos land iguanas (genus Conolophus).

The two species of Galápagos land iguanas (Conolophus subcristatus and C. pallidus) are listed as 'vulnerable' species by the International Union for the Conservation of Nature (IUCN Red List; http://www.iucnredlist.org). Here, we report on the isolation and characterization of 10 microsatellite markers using 562 individuals sampled on all Galápagos islands where Conolophus species occur today. We show that these 10 loci are highly polymorphic and display diagnostic alleles for five out of the six island populations. These markers will be useful for Conolophus population genetic analyses as well as for guiding ongoing captive breeding programmes.

Population genetics of Galápagos land iguana (genus Conolophus) remnant populations.

The Galápagos land iguanas (genus Conolophus) have faced significant anthropogenic disturbances since the 17th century, leading to severe reduction of some populations and the extinction of others. Conservation activities, including the repatriation of captive-bred animals to depleted areas, have been ongoing since the late 1970s, but genetic information has not been extensively incorporated. Here we use nine species-specific microsatellite loci of 703 land iguanas from the six islands where the species occur today to characterize the genetic diversity within, and the levels of genetic differentiation among, current populations as well as test previous hypotheses about accidental translocations associated with early conservation efforts. Our analyses indicate that (i) five populations of iguanas represent distinct conservation units (one of them being the recently discovered rosada form) and could warrant species status, (ii) some individuals from North Seymour previously assumed to be from the natural Baltra population appear related to both Isabela and Santa Cruz populations, and (iii) the five different management units exhibit considerably different levels of intrapopulation genetic diversity, with the Plaza Sur and Santa Fe populations particularly low. Although the initial captive breeding programmes, coupled with intensive efforts to eradicate introduced species, saved several land iguana populations from extinction, our molecular results provide objective data for improving continuing in situ species survival plans and population management for this spectacular and emblematic reptile.

Embryonic chimerism does not induce tolerance in an invertebrate model organism.

In colonial marine invertebrates, allorecognition restricts somatic fusion and thus, chimerism, to histocompatible individuals. Little is understood, however, about how invertebrates respond to chimerism formed across histocompatibility barriers or whether embryonic exposure to histoincompatible cells induces allotolerance. We here evaded natural allorecognition barriers by generating well mixed embryonic chimeras of Hydractinia symbiolongicarpus (Cnidaria:Hydrozoa) and developed molecular markers to detect chimerism in both histocompatible and histoincompatible settings. Histocompatible chimeras exhibited markedly higher growth rates and survivorship than histoincompatible pairings. Histoincompatible chimeras were unstable, with chimerism being undetectable by 4 wk of age. In contrast, colonies generated from histocompatible pairings remained chimeric at markedly higher frequencies and longer durations. Histoincompatible chimeras that lost detectable chimerism retained the fusibility/rejection characteristics of the remaining component of the chimera but not that of the lost component. Chimerism across histocompatibility barriers in an invertebrate model organism was unstable and did not induce tolerance.