Outcome Measures and Biomarkers for Clinical Trials in Hereditary Spastic Paraplegia: A Scoping Review.

Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb spasticity. There is no disease-modifying treatment currently available. Therefore, standardized, validated outcome measures to facilitate clinical trials are urgently needed. We performed a scoping review of outcome measures and biomarkers for HSP to provide recommendations for future studies and identify areas for further research. We searched Embase, Medline, Scopus, Web of Science, and the Central Cochrane database. Seventy studies met the inclusion criteria, and eighty-three outcome measures were identified. The Spastic Paraplegia Rating Scale (SPRS) was the most widely used (27 studies), followed by the modified Ashworth Scale (18 studies) and magnetic resonance imaging (17 studies). Patient-reported outcome measures (PROMs) were infrequently used to assess treatment outcomes (28% of interventional studies). Diffusion tensor imaging, gait analysis and neurofilament light chain levels were the most promising biomarkers in terms of being able to differentiate patients from controls and correlate with clinical disease severity. Overall, we found variability and inconsistencies in use of outcome measures with a paucity of longitudinal data. We highlight the need for (1) a standardized set of core outcome measures, (2) validation of existing biomarkers, and (3) inclusion of PROMs in HSP clinical trials.

Varicella zoster-associated progressive lower cranial and upper cervical polyneuropathy: a case report.

BACKGROUND: Multiple cranial neuropathies carry a wide range of differential diagnoses, and when combined with cerebrospinal fluid monocytosis they often suggest an infective etiology. Reactivation of varicella zoster virus has been associated with a wide range of neurological complications. Among the cranial nerves, the upper cranial nerves (trigeminal and facial nerves) are more commonly affected; there have been some reports of lower cranial polyneuropathies resulting from varicella zoster virus reactivation. However, polyneuropathy involving both the cranial and cervical nerves is rarely reported. CASE PRESENTATION: This report highlights the case of a 64-year-old Chinese man presenting with an acute, severe dysphagia and dysphonia secondary to herpes zoster-associated progressive polyneuropathy involving the lower cranial and upper cervical nerves, without any mucocutaneous manifestations. CONCLUSIONS: To our knowledge, this is the first case of varicella zoster virus-associated cranial and cervical polyneuropathy in the literature. The report also highlights the poor sensitivity of varicella zoster virus DNA detection by polymerase chain reaction in the cerebrospinal fluid, and proposes that serology be routinely performed in such polymerase chain reaction-negative cases without a clear diagnosis.

Monogenic Parkinson's Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing.

Parkinson's disease may be caused by a single pathogenic variant (monogenic) in 5-10% of cases, but investigation of these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with a focus on genotype, phenotype, pathophysiology, and the geographic and ethnic distribution. Well-established Parkinson's disease genes include autosomal dominant forms (SNCA, LRRK2, and VPS35) and autosomal recessive forms (PRKN, PINK1 and DJ1). Furthermore, mutations in the GBA gene are a key risk factor for Parkinson's disease, and there have been major developments for X-linked dystonia parkinsonism. Moreover, atypical or complex parkinsonism may be due to mutations in genes such as ATP13A2, DCTN1, DNAJC6, FBXO7, PLA2G6, and SYNJ1. Furthermore, numerous genes have recently been implicated in Parkinson's disease, such as CHCHD2, LRP10, TMEM230, UQCRC1, and VPS13C. Additionally, we discuss the role of heterozygous mutations in autosomal recessive genes, the effect of having mutations in two Parkinson's disease genes, the outcome of deep brain stimulation, and the role of genetic testing. We highlight that monogenic Parkinson's disease is influenced by ethnicity and geographical differences, reinforcing the need for global efforts to pool large numbers of patients and identify novel candidate genes.

Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings.

Facioscapulohumeral muscular dystrophy (FSHD) is a common genetic disease of the skeletal muscle with a characteristic pattern of weakness. Facioscapulohumeral muscular dystrophy type 2 (FSHD2) accounts for approximately 5% of all cases of FSHD and describes patients without a D4Z4 repeat contraction on chromosome 4. Phenotypically FSHD2 shows virtually no difference from FSHD1 and both forms of FSHD arise via a common downstream mechanism of epigenetic derepression of the transcription factor DUX4 in skeletal muscle cells. This results in expression of DUX4 and target genes leading to skeletal muscle toxicity. Over the past decade, major progress has been made in our understanding of the genetic and epigenetic architecture that underlies FSHD2 pathogenesis, as well as the clinical manifestations and disease progression. These include the finding that FSHD2 is a digenic disease and that mutations in the genes SMCHD1, DNMT3B, and more recently LRIF1, can cause FSHD2. FSHD2 is complex and it is important that clinicians keep abreast of recent developments; this review aims to serve as an update of the clinical, genetic, and molecular research into this condition.

Intron retention enhances gene regulatory complexity in vertebrates.

BACKGROUND: While intron retention (IR) is now widely accepted as an important mechanism of mammalian gene expression control, it remains the least studied form of alternative splicing. To delineate conserved features of IR, we performed an exhaustive phylogenetic analysis in a highly purified and functionally defined cell type comprising neutrophilic granulocytes from five vertebrate species spanning 430 million years of evolution. RESULTS: Our RNA-sequencing-based analysis suggests that IR increases gene regulatory complexity, which is indicated by a strong anti-correlation between the number of genes affected by IR and the number of protein-coding genes in the genome of individual species. Our results confirm that IR affects many orthologous or functionally related genes in granulocytes. Further analysis uncovers new and unanticipated conserved characteristics of intron-retaining transcripts. We find that intron-retaining genes are transcriptionally co-regulated from bidirectional promoters. Intron-retaining genes have significantly longer 3' UTR sequences, with a corresponding increase in microRNA binding sites, some of which include highly conserved sequence motifs. This suggests that intron-retaining genes are highly regulated post-transcriptionally. CONCLUSIONS: Our study provides unique insights concerning the role of IR as a robust and evolutionarily conserved mechanism of gene expression regulation. Our findings enhance our understanding of gene regulatory complexity by adding another contributor to evolutionary adaptation.

Meta-analysis of stent-assisted coiling versus coiling-only for the treatment of intracranial aneurysms.

Endovascular coil embolization is a widely accepted and useful treatment modality for intracranial aneurysms. However, the principal limitation of this technique is the high aneurysm recurrence. The adjunct use of stents for coil embolization procedures has revolutionized the field of endovascular aneurysm management, however its safety and efficacy remains unclear. Two independent reviewers searched six databases from inception to July 2015 for trials that reported outcomes according to those who received stent-assisted coiling versus coiling-only (no stent-assistance). There were 14 observational studies involving 2698 stent-assisted coiling and 29,388 coiling-only patients. The pooled immediate occlusion rate for stent-assisted coiling was 57.7% (range: 20.2%-89.2%) and 48.7% (range: 31.7%-89.2%) for coiling-only, with no significant difference between the two (odds ratio [OR}=1.01; 95% confidence intervals [CI}: 0.68-1.49). However, progressive thrombosis was significantly more likely in stent-assisted coiling (29.9%) compared to coiling-only (17.5%) (OR=2.71; 95% CI: 1.95-3.75). Aneurysm recurrence was significantly lower in stent-assisted coiling (12.7%) compared to coiling-only (27.9%) (OR=0.43; 95% CI: 0.28-0.66). In terms of complications, there was no significant difference between the two techniques for all-complications, permanent complications or thrombotic complications. Mortality was significantly higher in the stent-assisted group 1.4% (range: 0%-27.5%) compared to the coiling-only group 0.2% (range: 0%-19.7%) (OR=2.16; 95% CI: 1.33-3.52). Based on limited evidence, stent-assisted coiling shows similar immediate occlusion rates, improved progressive thrombosis and decreased aneurysm recurrence compared to coiling-only, but is associated with a higher mortality rate. Future randomized controlled trials are warranted to clarify the safety of stent-associated coiling.

Outcomes of endovascular treatment of basilar artery occlusion in the stent retriever era: a systematic review and meta-analysis.

BACKGROUND: Stent retriever thrombectomy has recently been found to be effective for anterior circulation strokes, but its efficacy for basilar artery occlusion (BAO) is unclear. OBJECTIVE: To carry out a systematic review and meta-analysis to analyze the available evidence for the use of stent retrievers for BAO. METHODS: Two independent reviewers searched six databases for studies reporting outcomes following endovascular treatment for BAO. RESULTS: A total of 17 articles (6 prospective and 11 retrospective) were included. The weighted mean age of patients was 67 years (range 59-82) and 59% were male. Thrombolytic drugs were administered intravenously and intra-arterially in 46% (range 0-88%) and 38% (range 0-90%) of patients, respectively. Weighted pooled estimates of successful recanalization (TICI 2b-3) and good outcome (modified Rankin Scale ≤2) were 80.0% (95% CI 70.7% to 88.0%; I2=80.28%; p<0.001) and 42.8% (95% CI 34.0% to 51.8%; I2=61.83%; p=0.002), respectively. Pooled mortality was 29.4% (95% CI 23.9% to 35.3%; I2=37.01%; p=0.087). Incidence of procedure-related complications and symptomatic hemorrhage was 10.0% (95% CI 3.7% to 18.3%; I2=61.05%; p=0.017) and 6.8% (95% CI 3.5% to 10.8%; I2=37.99%; p=0.08), respectively. CONCLUSIONS: Stent retriever thrombectomy achieves a high rate of recanalization and functional independence while being relatively safe for patients with BAO. Future prospective studies with long-term follow-up are warranted.

Laparotomy vs minimally invasive laparoscopic ventriculoperitoneal shunt placement for hydrocephalus: A systematic review and meta-analysis.

Ventriculoperitoneal shunt (VPS) surgery is the most commonly used method for the treatment of hydrocephalus. Traditionally, distal catheters in the VPS surgery have been placed either through a standard small open laparotomy or via a laparoscopic technique. Although there are many studies demonstrating the benefits of a minimally invasive approach, limited research has directly compared the two techniques used in VPS surgery. The present meta-analysis aims to provide the first comprehensive review of all published observational studies and randomized controlled trials reporting outcomes of laparotomy and laparoscopy in VPS. Electronic searches were performed using six databases from their inception to February 2015. Relevant studies comparing conventional laparotomy and a laparoscopic video-guided approach in VPS were included. Data were extracted and analyzed according to predefined clinical endpoints. A total of ten studies were identified for inclusion in the present analysis. Results indicated that the laparoscopic technique was associated with a slight but significant reduction in operating time (∼ 10 min), a significantly lower rate of abdominal malposition, distal obstruction and distal shunt failure. There was no difference between the laparotomic and laparoscopic approaches in the length of hospital stay, complication rate, proximal shunt failure or infection rate. The present systematic review and meta-analysis demonstrated that the laparoscopic technique in VPS surgery is associated with reduced shunt failure and abdominal malposition compared to the open laparotomy technique, with no significant difference in rates of infection or other complications. The lack of studies with high levels of evidence may contribute to bias in our conclusions and the long-term relative merits require validation by further prospective, randomized studies.

The extremophile Nicotiana benthamiana has traded viral defence for early vigour.

A single lineage of Nicotiana benthamiana is widely used as a model plant(1) and has been instrumental in making revolutionary discoveries about RNA interference (RNAi), viral defence and vaccine production. It is peerless in its susceptibility to viruses and its amenability in transiently expressing transgenes(2,3). These unparalleled characteristics have been associated both positively and negatively with a disruptive insertion in the RNA-dependent RNA polymerase 1 gene, Rdr1(4-6). For a plant so routinely used in research, the origin, diversity and evolution of the species, and the basis of its unusual abilities, have been relatively unexplored. Here, by comparison with wild accessions from across the spectrum of the species' natural distribution, we show that the laboratory strain of N. benthamiana is an extremophile originating from a population that has retained a mutation in Rdr1 for ∼0.8 Myr and thereby traded its defence capacity for early vigour and survival in the extreme habitat of central Australia. Reconstituting Rdr1 activity in this isolate provided protection. Silencing the functional allele in a wild strain rendered it hypersusceptible and was associated with a doubling of seed size and enhanced early growth rate. These findings open the way to a deeper understanding of the delicate balance between protection and vigour.

The impact of modelling rate heterogeneity among sites on phylogenetic estimates of intraspecific evolutionary rates and timescales.

Phylogenetic analyses of DNA sequence data can provide estimates of evolutionary rates and timescales. Nearly all phylogenetic methods rely on accurate models of nucleotide substitution. A key feature of molecular evolution is the heterogeneity of substitution rates among sites, which is often modelled using a discrete gamma distribution. A widely used derivative of this is the gamma-invariable mixture model, which assumes that a proportion of sites in the sequence are completely resistant to change, while substitution rates at the remaining sites are gamma-distributed. For data sampled at the intraspecific level, however, biological assumptions involved in the invariable-sites model are commonly violated. We examined the use of these models in analyses of five intraspecific data sets. We show that using 6-10 rate categories for the discrete gamma distribution of rates among sites is sufficient to provide a good approximation of the marginal likelihood. Increasing the number of gamma rate categories did not have a substantial effect on estimates of the substitution rate or coalescence time, unless rates varied strongly among sites in a non-gamma-distributed manner. The assumption of a proportion of invariable sites provided a better approximation of the asymptotic marginal likelihood when the number of gamma categories was small, but had minimal impact on estimates of rates and coalescence times. However, the estimated proportion of invariable sites was highly susceptible to changes in the number of gamma rate categories. The concurrent use of gamma and invariable-site models for intraspecific data is not biologically meaningful and has been challenged on statistical grounds; here we have found that the assumption of a proportion of invariable sites has no obvious impact on Bayesian estimates of rates and timescales from intraspecific data.