Ventilator Dependency in ALS: Management, Disease Progression, and Issues of Coping

The natural progression of amyotrophic lateral sclerosis (ALS) leads to respiratory fail ure and death. Artificial ventilation can prolong the course, leading to extreme degrees of weakness and dependence. Little specific information is available to counsel ALS patients about making the decision for artificial ventilation. In order to gain more infor mation, we visited four ventilator-dependent ALS patients and their primary caregivers. We determined the neurologic state and level of function of the patients and inter viewed their primary caregivers to assess medical care and management needs (both social and financial) and how they were being met. We also administrated question naires to assess the psychological well-being of both patient and primary caregiver and how the relationship between the patient and primary caregiver changed under these circumstances. Key Words: ALS—Artificial ventilation—Disease progression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68609/2/10.1177_154596839601000306.pd

Inventory of the marine soft bottom macrofauna of São Sebastião Channel, southeastern Brazilian continental shelf

Analysis of macrofauna from 91 quantitative soft-bottom samples (from five surveys) obtained in the São Sebastião Channel at depths ranging from 2 to 45 m yielded 431 species from a total of 38,630 individuals. The present contribution gives a list of the species found in the area and their depth distribution and sedimentary preferences (granulometric characteristics of the sites where they occurred). This is the first complete inventory of the subtidal invertebrate soft-bottom fauna of the São Sebastião Channel, a peculiar marine area under crescent human impact.

Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

UNLABELLED:Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p<or=0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Delta7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p<or=0.0036) and maximum ulnar CMAP scores (p<or=0.0001) increased significantly. CONCLUSIONS:While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects. TRIAL REGISTRATION:ClinicalTrials.gov

SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy

Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007).This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials.Clinicaltrials.gov NCT00227266

Angiogenic factors: role in esophageal cancer, a brief review

Esophageal cancer has an aggressive behavior with rapid tumor mass growth and frequently poor prognosis; it is known as one of the most fatal types of cancer worldwide. The identification of potential molecular markers that can predict the response to treatment and the prognosis of this cancer has been subject of a vast investigation in the recent years. Among several molecules, various angiogenic factors that are linked to the tumor development, growth, and invasion, such as VEGF, HGF, angiopoietin-2, IL-6, and TGF-B1, were investigated. In this paper, the authors sought to review the role of these angiogenic factors in prognosis and hypothesize how they can be used as a treatment target.info:eu-repo/semantics/publishedVersio

SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Cerebellar Hypoplasia and Dysmorphia in Neurofibromatosis Type 1

Unidentified bright objects (UBO) and tumors are well-known cerebellar abnormalities in neurofibromatosis type 1 (NF1). Literature reports on malformative cerebellar anomalies in neurofibromatosis type 1 (NF1), however, are scant. We retrospectively studied the clinical and neuroimaging findings of 5 patients with NF1 (4 females, age 6 to 29 years at last follow-up) and cerebellar anomalies. Cerebellar symptoms on neurological examination were mild or even not evident whereas learning disabilities were more or less pronounced in four patients. Two patients had cerebellar hypoplasia (diffusely enlarged cerebellar interfoliar spaces) and three cerebellar dysmorphias involving mainly one cerebellar hemisphere. In NF1, malformative cerebellar anomalies are rare (estimated prevalence of about 1 %), but most likely underestimated and easily overlooked, because physicians tend to focus on more prevalent, obvious, and well-known findings such as optic pathway gliomas, other tumors, and UBO. This kind of cerebellar anomaly in NF1 has most likely a malformative origin, but the exact pathogenesis is unknown. The individual clinical significance is difficult to determine. We suggest that cerebellar anomalies should be systematically evaluated in neuroimaging studies of NF1 patients

FIGURE 3 in On the taxonomy of Apistobranchus species (Polychaeta: Apistobranchidae) from the Antarctic

FIGURE 3. Apistobranchus glacierae (Martel Inlet). Scanning electron micrographs. Adult (A–H). Juvenile (I). A. Anterior end, ventral view, ciliated prostomium and ventral band, mouth, palps. B. Dorsal view, nuchal organ, only interramal cirri on setiger 1. C. Bottle-shaped notopodium, post-setal lamelae from setiger 4. D. Dorsal view, ciliated interramal cirri and notopodium, anterior neurosetae. E–F. Splintered limbate setae. G. Limbate and capillary setae. H. Dorsal view, post-setal lamelae of setigers 5–8. I. Difference in post-setal lamelae morphology. Abbreviations: anc, anterior neurosetae; cvb, ciliated ventral band; irc, interramal cirri; mth, mouth; neu, neuropodium; ntp, notopodium; nuc, nuchal organ; palp, palp; pros, prostomium; psl, post-setal lamellae. Scales: A, C, I, 100 µm; B, D, G, H, 30 µm; E, F, 10 µm.Published as part of &lt;i&gt;Varella Petti, Mồnica A., Nonato, Edmundo F., Bromberg, Sandra, Gheller, Paula F., Paiva, Paulo Cesar &amp; Corbisier, N., 2007, On the taxonomy of Apistobranchus species (Polychaeta: Apistobranchidae) from the Antarctic, pp. 51-59 in Zootaxa 1440 (1)&lt;/i&gt; on page 55, DOI: 10.11646/zootaxa.1440.1.4, &lt;a href="http://zenodo.org/record/10087931"&gt;http://zenodo.org/record/10087931&lt;/a&gt

Trophic structure of benthic communities in the Cabo Frio upwelling system (southeastern Brazilian shelf): a temporal study using stable isotope analysis

In Brazil, coastal upwelling is observed in 7 areas along the southeastern/southern\ud region and is most pronounced near Cabo Frio, Rio de Janeiro. This region is exposed to moderate seasonal Ekman-driven upwelling that brings cold water with increased nutrient levels nearshore and is more frequent and intense during the austral spring and summer, primarily due to the prevalence of northeasterly winds. Our aim was to verify the influence of this upwelling on the benthic trophic structure of the inner and outer shelf off Cabo Frio through measurements of stable nitrogen (15N) and carbon (13C) isotopes. We identified 1 main pathway of organic matter (OM) transfer from the base to the top of the food web, as observed from the tendencies of the 13C\ud and 15N values. The isotopic signatures of benthic consumers exhibited temporal and spatial variability, with no interaction between them. As the result of a time lag, only consumers (mostly decapod carnivores) appeared to reflect the assimilation of 15N-depleted and 13C-enriched OM produced and deposited during strong upwelling that occurred 4 mo earlier. Therefore, the intensity and period of the upwelling phenomenon were important for detecting upwelling in benthic food webs. Lighter nitrogen and heavier carbon isotopes were found on the inner shelf. Consumers may have exploited OM of different quality on the inner and outer shelf due to differences in sediment,\ud hydrodynamics, mineralisation and assimilation of 13C-enriched microphytobenthos. Nevertheless, 4 trophic levels were estimated in the benthic communities of the continental shelf offthe Cabo Frio upwelling system, independent of period or area