Vision therapy as part of neurorehabilitation after acquired brain injury - a clinical study in an outpatient setting.

Introduction: Oculomotor (OM) functions may be affected by acquired brain injury (ABI). The ability to benefit from rehabilitation or to perform daily activities may be affected by OM dysfunctions and associated symptoms. The purpose of this study was to investigate the effects of vision therapy (VT) as part of neurorehabilitation after ABI.Materials and Methods: The study included two groups of outpatients (median 49.5-52.0 years, range 27-67) admitted to neurorehabilitation due to moderate to severe ABI. One group received VT while the other group served as controls to monitor the course of OM dysfunctions without VT.Results: The intervention group showed significant improvements in convergence (Z = 2.26, p = .02), vergence facility (Z = -2.16, p = .03) and vergence reserves (Z = -2.44, p < .01 and t = -4.47, DF = 15, p < .01) along with a significant reduction in vision-related symptoms (Z = 2.97, p < .01).Discussion: We conclude that OM issues were frequent and that targeted VT, as part of neurorehabilitation, can be an efficient treatment resulting in improved functions and reduced symptoms. Further study will be required to understand how improved functions link to performance and satisfaction with everyday activities.

Performance and digestive function of broiler chickens given grit in the diet.

1. A series of experiments were carried out to study the effect of grit on broiler performance, gizzard development and fate of grit in the digestive tract. 2. In Experiment 1, performance, gizzard weight and content of grit in the gizzard of broiler chickens given access to granite-type grit was investigated. In Experiment 2, the effect of grit stones on performance and gizzard development was assessed in diets with or without whole wheat. 3. In Experiment 3, the effect of grit in the form of zeolite, granite or marble on gizzard development and digestive tract grinding and passage was studied in diets with or without whole wheat. 4. Grit stones had no effect on performance of broiler chickens, which may be explained by the fact that grit stones did not stimulate gizzard development to the same extent as with other structural materials. 5. The lack of stimulation is at least partly due to the fact that a majority of the grit stones eaten pass through the small intestine without being retained in the gizzard. 6. Grit in the form of marble reduced feed intake and weight gain.

Additive manufacturing of bioactive and biodegradable porous iron-akermanite composites for bone regeneration.

Advanced additive manufacturing techniques have been recently used to tackle the two fundamental challenges of biodegradable Fe-based bone-substituting materials, namely low rate of biodegradation and insufficient bioactivity. While additively manufactured porous iron has been somewhat successful in addressing the first challenge, the limited bioactivity of these biomaterials hinder their progress towards clinical application. Herein, we used extrusion-based 3D printing for additive manufacturing of iron-matrix composites containing silicate-based bioceramic particles (akermanite), thereby addressing both of the abovementioned challenges. We developed inks that carried iron and 5, 10, 15, or 20 vol% of akermanite powder mixtures for the 3D printing process and optimized the debinding and sintering steps to produce geometrically-ordered iron-akermanite composites with an open porosity of 69-71%. The composite scaffolds preserved the designed geometry and the original α-Fe and akermanite phases. The in vitro biodegradation rates of the composites were improved as much as 2.6 times the biodegradation rate of geometrically identical pure iron. The yield strengths and elastic moduli of the scaffolds remained within the range of the mechanical properties of the cancellous bone, even after 28 days of biodegradation. The composite scaffolds (10-20 vol% akermanite) demonstrated improved MC3T3-E1 cell adhesion and higher levels of cell proliferation. The cellular secretion of collagen type-1 and the alkaline phosphatase activity on the composite scaffolds (10-20 vol% akermanite) were, respectively higher than and comparable to Ti6Al4V in osteogenic medium. Taken together, these results clearly show the potential of 3D printed porous iron-akermanite composites for further development as promising bone substitutes. STATEMENT OF SIGNIFICANCE: Porous iron matrix composites containing akermanite particles were produced by means of multi-material additive manufacturing to address the two fundamental challenges associated with biodegradable iron-based biomaterials, namely very low rate of biodegradation and insufficient bioactivity. Our porous iron-akermanite composites exhibited enhanced biodegradability and superior bioactivity compared to porous monolithic iron scaffolds. The murine bone cells proliferated on the composite scaffolds, and secreted the collagen type-1 matrix that stimulated bony-like mineralization. The results show the exceptional potential of the developed porous iron-based composite scaffolds for application as bone substitutes.

Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

Preimplantation genetic screening in women of advanced maternal age caused a decrease in clinical pregnancy rate: a randomized controlled trial.

BACKGROUND: Advanced maternal age (AMA) is an important parameter that negatively influences the clinical pregnancy rate in IVF, in particular owing to the increased embryo aneuploidy rate. It has thus been suggested that only transferring euploid embryos in this patient group would improve the pregnancy rate. The purpose of this study was to test whether employing preimplantation genetic screening (PGS) in AMA patients would increase the clinical pregnancy rate. METHODS: We conducted a two-center, randomized controlled trial (RCT) to analyze the outcome of embryo transfers in AMA patients (>or=38 years of age) after PGS using FISH analysis for chromosomes X, Y, 13, 16, 18, 21 and 22. The PGS group was compared with a control group. The primary outcome measure was clinical pregnancy rate after 6-7 weeks of gestation per randomized patient. RESULTS: The study was terminated early as an interim analysis showed a very low conditional power of superiority for the primary outcome. Of the 320 patients calculated to be included in the study, 56 and 53 patients were randomized into the PGS and control groups, respectively. The clinical pregnancy rate in the PGS group was 8.9% (95% CI, 2.9-19.6%) compared with 24.5% (95% CI, 13.8-38.3%) in the control group, giving a difference of 15.6% (95% CI, 1.8-29.4%, P = 0.039). CONCLUSIONS: Although the study was terminated early, this RCT study provides evidence against the use of PGS for AMA patients when performing IVF. TRIAL REGISTRATION NUMBER: ISRCTN38014610.

Application of metaphase HR-CGH and targeted Chromosomal Microarray Analyses to genomic characterization of 116 patients with mental retardation and dysmorphic features.

Recent advances in molecular cytogenetics enable identification of small chromosomal aberrations that are undetectable by routine chromosome banding in 5-20% of patients with mental retardation/developmental delay (MR/DD) and dysmorphism. The aim of this study was to compare the clinical usefulness of two molecular cytogenetic techniques, metaphase high-resolution comparative genomic hybridization (HR-CGH) and targeted array CGH, also known as Chromosomal Microarray Analysis (CMA). A total of 116 patients with unexplained mild to severe MR and other features suggestive of a chromosomal abnormality with apparently normal or balanced karyotypes were analyzed using HR-CGH (43 patients) and/or CMA (91 patients). Metaphase HR-CGH detected seven interstitial deletions (16.3%). Rare deletions of chromosomes 16 (16p11.2p12.1) and 8 (8q21.11q21.2) were identified. Targeted CMA revealed copy-number changes in 19 of 91 patients (20.8%), among which 11 (11.8%) were clinically relevant, 6 (6.5%) were interpreted as polymorphic variants and 2 (2.1%) were of uncertain significance. The changes varied in size from 0.5 to 12.9 Mb. In summary, our results show that metaphase HR-CGH and array CGH techniques have become important components in cytogenetic diagnostics, particularly for detecting cryptic constitutional chromosome imbalances in patients with MR, in whom the underlying genetic defect is unknown. Additionally, application of both methods together increased the detection rates of genomic imbalances in the tested groups.

EFNS guideline on diagnosis and management of post-polio syndrome. Report of an EFNS task force.

Post-polio syndrome (PPS) is characterized by new or increased muscular weakness, atrophy, muscle pain and fatigue several years after acute polio. The aim of the article is to prepare diagnostic criteria for PPS, and to evaluate the existing evidence for therapeutic interventions. The Medline, EMBASE and ISI databases were searched. Consensus in the group was reached after discussion by e-mail. We recommend Halstead's definition of PPS from 1991 as diagnostic criteria. Supervised, aerobic muscular training, both isokinetic and isometric, is a safe and effective way to prevent further decline for patients with moderate weakness (Level B). Muscular training can also improve muscular fatigue, muscle weakness and pain. Training in a warm climate and non-swimming water exercises are particularly useful (Level B). Respiratory muscle training can improve pulmonary function. Recognition of respiratory impairment and early introduction of non-invasive ventilatory aids prevent or delay further respiratory decline and the need for invasive respiratory aid (Level C). Group training, regular follow-up and patient education are useful for the patients' mental status and well-being. Weight loss, adjustment and introduction of properly fitted assistive devices should be considered (good practice points). A small number of controlled studies of potential-specific treatments for PPS have been completed, but no definitive therapeutic effect has been reported for the agents evaluated (pyridostigmine, corticosteroids, amantadine). Future randomized trials should particularly address the treatment of pain, which is commonly reported by PPS patients. There is also a need for studies evaluating the long-term effects of muscular training.

Comparison of seven measures of sickness absence based on data from three counties in Sweden.

The objective was to compare the applicability of and results provided by the two measures of sickness absence used most often within the Swedish social insurance administration (that is, unadjusted sick-leave rate and adjusted sick-leave rate) and five measures suggested by epidemiological researchers. Data consisted of four cross-sectional data sets of registry sick-leave data covering four separate years (1997-2000) in three counties. In total 454,000 persons qualified for sickness insurance and aged 20-64 years were included. The two measures used within the social insurance administration and three of the five measures suggested by epidemiological researchers revealed sex-related dissimilarities in absence patterns that indicated that women had more sickness absence than men. However, in marked contrast to those results, two of the epidemiologically based measures (i.e., length of sickness absence and duration of sickness absence) instead showed highly comparable rates of sick leave for men and women, and such information is seldom obtained, albeit definitely of importance, when trying to make a correct assessment of sickness absence. The measure of sickness absence that is used influences the findings and should therefore be chosen with care. Complementing the measures used in the social insurance administration by five measures suggested by epidemiological researchers provided a more informative and comprehensive picture of sickness absence in a population. Further investigations into the effect of using different measures is needed, as well as international consensus on what to call different measures.

Polio Patients in Northern Italy, a 50 Year Follow-up.

BACKGROUND: Poliomyelitis was before the immunization an important medical problem. Nowadays polio prior patients (PP) suffer from polio sequelae or have developed post-polio-syndrome (PPS) with increasing paresis, pain and fatigue. OBJECTIVES: To analyze the medical situation 50 years after acute polio. The degree of paresis was compared between the recovery 1952-1961 and 2012.The prevalence of patients fulfilling the criteria for PPS was estimated. METHOD: The study was performed in Italy. Included were PP with rehabilitation after acute polio 1952-1961 and in 2012. During the years PP underwent yearly evaluation. A thorough neurological examination was performed in 2012. A telephone interview with questions concerning pain, paresis, fatigue, walking aids and concomitant diseases was performed in 2012. The patients were divided in two groups, if they fulfilled the criteria for PPS or not. RESULTS: Included were 67(94%) patients receiving rehabilitation after acute poliomyelitis and 2012. 78% were walkers, half of the PPS used wheelchair. Eight out of ten suffered from pain. Four out of ten fulfilled the PPS criteria. Pain was slightly more common in PPS. CONCLUSION: Female gender, fatigue and wheelchair dependency were significantly more common in PPS while pain was common in both groups.

Recombinant human follicle-stimulating hormone is capable of exerting a biological effect in the adult hypophysectomized rat by reducing the numbers of degenerating germ cells.

There is considerable controversy as to whether FSH can, under normal circumstances, exert an effect to promote spermatogenesis in the adult rat. Recombinant human FSH (rhFSH) was used to answer a more limited question relating to whether FSH is capable of exerting a biological effect in promoting adult spermatogenesis. Can a pure preparation of FSH prevent the regressive changes seen after hypophysectomy (Hx) in a short term experiment? To answer this question, five groups of adult rats were used as follows: pituitary-intact animals, 3-day hypophysectomized (Hx), 3-day Hx given 3 mg testosterone propionate (T)/day for 7 days, 3-day Hx given 22 IU rhFSH for 7 days, and 3-day Hx given saline vehicle for 7 days. Testis weight, seminiferous tubule diameter, analysis of four degenerating germ cell types, the relative amount of lipid, and the levels of FSH receptors showed that FSH could, in a significant manner, prevent the regressive changes accompanying Hx. FSH was not as effective as T in doing so, because the FSH values were always intermediate between T-maintained animals and those after long term Hx. The Leydig cell was eliminated as a possible source of FSH-stimulated T promotion of spermatogenesis, given that morphometry and tissue T assays indicated that no additional production of T was elicited by rhFSH. The assay system used to enumerate degenerating germ cells proved a very sensitive indicator of the ability of hormones to maintain cell viability in short term experiments. The data not only show that FSH can exert a biological effect, but that this effect is qualitatively similar to that seen after the administration of T in terms of the maintenance of viability of specific germ cell types. A hypothesis is presented whereby FSH and T, although the former acting by a second messenger system and the latter by binding to nuclear receptors, can stimulate the genome to exert similar qualitative effects promoting the viability of germ cells.

Prolactin regulation of pim-1 expression: positive and negative promoter elements.

The lactogen-dependent rat Nb2 lymphoma is a useful model to investigate PRL signaling pathways that lead to regulation of gene transcription. A primary mechanism coupled to PRL receptor (PRLR) activation in Nb2 cells involves phosphorylation by Jak-family tyrosine kinases of one or more signal transducers and activators of transcription (Stat) factors which subsequently bind to gamma-interferon activation sequences (GAS) within promoter regions of target genes. However, it is presently unclear whether this mechanism is operative as a means for regulating PRL-induced gene expression to the exclusion of other signaling pathways. Previously, we reported that PRL directly stimulated rapid expression of the protooncogene, pim-1, at the mRNA and protein levels in lactogen-dependent Nb2-11 cells. In the present study, experiments were conducted to evaluate signaling mechanisms by which PRL regulates transcription of pim-1. Toward this end, a 1,268-bp segment upstream of the transcription initiation site of the 5'-pim-1 promoter and a series of deletion mutants were ligated upstream of the chloramphenicol acetylase transferase (CAT) gene in an expression vector that was introduced into FDC/Nb2 cells, a premyeloid line that stably expresses the intermediate form of the PRLR. Analysis of PRL-treated cultures indicated that two elements [distal (DE), -427 to -336 bp and proximal (PE), - 104 to -1] but not several GAS or GAS-like sequences were required for hormone activation of the pim-1 promoter. Moreover, treatment of Nb2-11 cells with PRL activated protein binding to these elements assessed by gel mobility shift assay. Deoxyribonuclease I (DNase I) protection experiments revealed a motif containing a nuclear factor-1 (NF-1, -224 to -217 bp) half-site that was hydrolyzed when exposed to extracts from PRL-treated cells but protected by proteins from unstimulated cells. Gel mobility shift analysis of this sequence showed decreased protein binding after PRL stimulation. It is concluded that the PRLR initiates pim-1 transcription by a mechanism that involves transcriptional activation by factors that stimulate the DE- and PE-sites and derepress a NF-1-containing element. Moreover, this mechanism appears to be independent of an interaction between Stat transcription factors and GAS-like elements present within the promoter.

Muscle biopsy, macro EMG, and clinical characteristics in patients with schizophrenia.

BACKGROUND: In a previous study of motor unit properties in patients with schizophrenia, muscle fiber histologic and electrophysiologic abnormalities were observed. The present study was designed to compare patients with schizophrenia with healthy control subjects with regard to muscle fiber histology and motor unit function. A second objective was to relate these variables to clinical characteristics. METHODS: Twelve patients with first-episode schizophrenia and fifteen patients with chronic schizophrenia (DSM-III-R) and 27 matched control subjects were included in the study. Muscle biopsies were performed either in m. tibialis anterior or m. vastus lateralis. Electromyographic recordings (macro EMG) were made from the m. tibialis anterior motor units. Psychiatric ratings included the PANSS and extrapyramidal side effects. RESULTS: Seven of the muscle biopsy specimens from the patients and one from the control subjects were classified as abnormal (p =.049). The most frequent abnormality was atrophic muscle fibers. Eight patients and no control subjects exhibited pathological macro EMG (p =.032). The findings were present in chronic as well as in first-episode patients with schizophrenia. CONCLUSIONS: In approximately 50% of the patients, neuromuscular abnormalities were found either in the muscle biopsy or the macro EMG investigations. The results indicate that either a common pathologic process or different pathological processes are at hand in the neuromuscular system in patients with schizophrenia. The findings are compatible with a disturbed cell membrane function.

Influence of pentobarbital on metoprolol plasma levels.

Induction of microsomal enzymes with barbiturates in rats has little effect on the metabolism of metoprolol, compared with propranolol and alprenolol, which undergo extensive hepatic extraction in animals and man. Our study was designed to examine whether the metabolism of metoprolol is inducable by barbiturate in man. In 8 healthy subjects the area under the plasma concentration/time curve after 0.1 gm metoprolol was reduced by a mean of 32% after treatment with 0.1 gm pentobarbital at bedtime for 10 days. There was considerable interindividual variability in the reduction after pentobarbital treatment (2% to 46%).

Influence of pentobarbital on effect and plasma levels of alprenolol and 4-hydroxy-alprenolol.

Six healthy subjects were given placebo and a single oral 0.2-gm dose of alprenolol (Aptin) before and after 0.1 gm pentobarbital at bedtime for 10 days. The plasma concentrations of alprenolol and its metabolite 4-hydroxy-alprenolol and the inhibition of exercise tachycardia were studied for 7 hr after the alprenolol. Alprenolol and 4-hydroxy-alprenolol plasma levels were decreased by about 40% by pentobarbital but plasma half-lives were unchanged. The inhibition of exercise tachycardia during a 7-hr period was reduced from 14.0% to 10.7% by pentobarbital. The reduction was proportional to the decreased drug plasma levels. There was a significant contribution of the metabolite to alprenolol effect. The estimation of relative potency of metabolite against parent compound was 0.9 before pentobarbital and 1.9 after pentobarbital.

Muscle fiber atrophy in leg muscles after botulinum toxin type A treatment of cervical dystonia.

Previous electrophysiologic studies on the effects of local injections of botulinum toxin type A (BTX-A) have indicated impaired neuromuscular transmission in distant muscles. To further study possible distant effects of repeated BTX-A injections, we obtained percutaneous muscle biopsies of the vastus lateralis muscle from 11 patients with cervical dystonia. We examined the biopsies with histopathology and morphometry, and compared them with age-matched healthy controls. There was an increased frequency of angular atrophic type IIB fibers in the patient group, and the mean size of IIB fibers was significantly smaller (p < 0.05). In addition, there was a negative correlation between accumulated dose of botulinum toxin and relative size of type IIA fibers (p < 0.05). We postulate that the observed atrophy is due to distant effects of botulinum toxin causing progressive denervation-like changes in non-treated muscle. This observation calls for further, prospective studies of the long-term effects of the treatment.

C4342T-mutation in the SCN4A gene on chromosome 17q in a Swedish family with paramyotonia congenita (Eulenburg)--correlations with clinical, neurophysiological and muscle biopsy data.

Genetic analysis of the adult muscle sodium channel alpha-subunit, SCN4A gene on chromosome 17q, was performed by means of PCR technique in a Swedish family with paramyotonia congenita (Eulenburg) (PMC). The mutation was found in four family members and consisted of a C to T transition affecting the fourth domain of the sodium channel protein. This mutation has earlier been described in other families with paramyotonia congenita. All family members carrying the mutation had cold-induced paradoxical myotonia, myotonic bursts on EMG, and a type IIB atrophy on muscle biopsy. Three of them had slight CK elevation and two had episodes of paralysis. On the basis of clinical findings in this family, persistent proximal muscle weakness, myopathic EMG abnormalities, a type IIB atrophy on muscle biopsy and no symptoms but other signs of muscle affection, were earlier suggested as clinical features of PMC. However, genetic analysis revealed that family members with these symptoms and findings did not have the mutation, indicating that these features are not due to PMC.

Charcot-Marie-Tooth disease--muscle biopsy findings in relation to neurophysiology.

Nine patients with Charcot-Marie-Tooth disease with reduced motor nerve conduction velocity (MNCV), i.e. type 1 (CMT1), demyelinating form, and nine patients with Charcot-Marie-Tooth disease with normal or near-normal MNCV, i.e. type 2 (CMT2), axonal form, were subjected to percutaneous muscle biopsy from the anterior tibial muscle in order to characterize histopathological abnormalities and evaluate differences between the two groups. Data from the biopsies were compared with those from 18 age- and sex-matched healthy controls. Muscle biopsies from the CMT1 patients exhibited angular atrophic fibres that were scattered or in small groups, findings commonly described as neuropathic. Muscle biopsies from the CMT2 patients exhibited atrophic fibres that were rounded or elongated in groups and hypertrophic fibres with central nuclei and fibre splitting. There were also increased amounts of connective tissue, 'whorled fibres', degeneration and signs of regeneration, findings commonly regarded as myopathic. In conclusion, muscle biopsies from patients with CMT1 and CMT2 showed markedly different histopathological abnormalities. Possible underlying mechanisms are discussed.

Welander distal myopathy is not linked to other defined distal myopathy gene loci.

Welander distal myopathy is an autosomal dominant disorder with late onset that affects extensor muscles of the hands and the feet. The disorder is considered as the most prevalent of the distal myopathies and is almost only seen in Sweden and in some parts of Finland. On clinical, morphological and genetical grounds the disorder is clearly separated from other distal myopathies. We have performed linkage analysis with the MLINK program in a total of six families with microsatellite markers dispersed throughout the genome and report exclusion for the localisation of the gene of 64% of the human genome. These studies have clearly separated Welander distal myopathy from previously mapped forms of distal myopathy such as the Miyoshi myopathy by excluding linkage to chromosome 2. The region on 14q that has been suggested to house the gene of the distal myopathy described by Laing et al. (Am J Hum Genet 1995;56:422-7), has as well been excluded by several markers.

Welander hereditary distal myopathy, a molecular genetic comparison to hereditary myopathies with inclusion bodies.

Welander distal myopathy (WDM) is an autosomal dominant disorder with late onset predominantly affecting distal extensor muscles of the hands and the feet. The disorder is considered as the most common of the distal myopathies but is almost only seen in Sweden and some parts of Finland. The finding of rimmed vacuoles in muscle biopsies from patients with moderate and severe symptoms constitutes one similarity with hereditary inclusion body myopathy (HIBM) sparing the quadriceps as described by Argov and Yarom [Argov Z, Yarom R. J Neurol Sci 1984;64:33-43]. The question has been raised whether some of the different forms of distal myopathy might be allelic. In previous reports the gene defects for HIBM and autosomal recessive hereditary distal myopathy with rimmed vacuoles (DMRV) have been mapped to chromosome 9pl-q1. The Finnish tibial muscular dystrophy (TMD) that displays similar histopathological findings has recently been linked to chromosome 2q. We have investigated the regions of interest with dispersed microsatellite markers in four well-described pedigrees, and this study now excludes the regions on chromosome 9pl-q1 and 2q from linkage to WDM both by haplotype analysis and linkage analysis with the MLINK program. WDM, showing morphological similarities with HIBM, is clearly separated from the disorders mapped to chromosomes 9 and 2 on clinical and genetical grounds.