Rapid identification of atypical variant of plasma butyrylcholinesterase by PCR.

Human butyrylcholinesterase is the enzyme responsible of mivacurium and succinylcholine metabolism, which may be significantly impaired when mutation Asp70Gly is found in patients. We describe a simple PCR method for the detection of this variant. Thirteen out of sixteen patients tested after prolonged apnea were positive for the presence of this mutation (50.0% homozygotes and 31.3% heterozygotes), suggesting that this test contributes to the explanation of some clinical events and to their prevention in relatives of these patients.     

The prognostic significance of acute renal failure after renal transplantation in patients treated with cyclosporin

We studied 733 cadaveric renal transplant patients (747 transplants) under cyclosporin immunosuppression, to: (i) establish the risk profile for acute renal failure (ARF) after renal transplantation in a unit using many sub-optimal donors; (ii) assess the long-term prognostic relevance of ARF; and (iii) explore the synergistic prognostic significance of delayed graft function and acute rejection during the early post-transplant period. Transplanting from a non-heart-beating or elderly donor, protracted cold ischaemia, haemodialysis immediately before transplant surgery, poor HLA matching, and grafting to a hypersensitized recipient without residual renal function, all independently predicted delayed graft function. This delay had no detrimental effect on patient or graft survival, but prolonged ARF was associated with increased mortality from infection. Late markers of graft dysfunction (poor graft function, proteinuria, hypertension) were highly prevalent among grafts affected by ARF, specially in prolonged ARF. Delayed graft function and early acute rejection showed a definite, albeit not strong, additive impact on late graft survival, and also on the prevalence of late markers of graft dysfunction.      

Primary Immunodeficiency Syndrome in Spain: First Report of the National Registry in Children and Adults

The Spanish Registry for Primary Immunodeficiency Diseases (REDIP) was organized in 1993. One thousand sixty-nine cases of primary immunodeficiency diseases (PID) were registered in patients diagnosed between January 1980 and December 1995. PID diagnosis was made according to the World Health Organization criteria. The most frequent disorders were IgA deficiency (n = 394) and common variable immunodeficiency (n = 213), followed by severe combined immunodeficiency (n = 61), C1 inhibitor deficiency (n = 52), X-Iinked agammaglobulinemia (n = 49), IgG subclass deficiency (n = 48), and chronic granulomatous disease (n = 32). A comparative study between REDIP and data recently obtained from the European registry (ESID Report, 1995) revealed important differences between phagocytic disorders and complement deficiencies reported in both registries, 4.9 vs 8.7 and 6.0 vs 3.6, while percentages of predominantly antibody deficiencies and T cell and combined deficiencies concurred with those reported in the European registry, 69.3 vs 64.7 and 14.7 vs 20.2, respectively. The heterogeneous nature of the geographical distribution of cases submitted may indicate underdiagnosis of PID in some country areas; surprisingly, the interval between the onset of clinical symptoms and diagnosis was significant, even in immunodeficiency diseases, such as IgA deficiency, which are easy to diagnose.     

Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

From the Cover: Unlocking adults’ implicit statistical learning by cognitive depletion

Human learning is supported by multiple neural mechanisms that maturate at different rates and interact in mostly cooperative but also sometimes competitive ways. We tested the hypothesis that mature cognitive mechanisms constrain implicit statistical learning mechanisms that contribute to early language acquisition. Specifically, we tested the prediction that depleting cognitive control mechanisms in adults enhances their implicit, auditory word-segmentation abilities. Young adults were exposed to continuous streams of syllables that repeated into hidden novel words while watching a silent film. Afterward, learning was measured in a forced-choice test that contrasted hidden words with nonwords. The participants also had to indicate whether they explicitly recalled the word or not in order to dissociate explicit versus implicit knowledge. We additionally measured electroencephalography during exposure to measure neural entrainment to the repeating words. Engagement of the cognitive mechanisms was manipulated by using two methods. In experiment 1 (n = 36), inhibitory theta-burst stimulation (TBS) was applied to the left dorsolateral prefrontal cortex or to a control region. In experiment 2 (n = 60), participants performed a dual working-memory task that induced high or low levels of cognitive fatigue. In both experiments, cognitive depletion enhanced word recognition, especially when participants reported low confidence in remembering the words (i.e., when their knowledge was implicit). TBS additionally modulated neural entrainment to the words and syllables. These findings suggest that cognitive depletion improves the acquisition of linguistic knowledge in adults by unlocking implicit statistical learning mechanisms and support the hypothesis that adult language learning is antagonized by higher cognitive mechanisms.

Human learning is thought to be supported by the interactions between two basic memory systems of the brain, namely declarative and nondeclarative memory (1). Declarative memory is characterized by voluntary, explicit, attention-based processes, such as recall and recognition of facts/events, and is mediated by medial-temporal lobe and prefrontal cortex structures (2). Nondeclarative memory, also referred to as procedural memory, on the other hand is part of implicit memory and includes the acquisition of a heterogeneity of skills, habits, and procedures. It is mediated by basal ganglia, cerebellar, and neocortical structures, as well as parts of the prefrontal cortex [e.g., Broca''s area (3–5)].Accumulating evidence supports a competitive relationship between these two memory systems during human skill learning. Suppression of the declarative memory system by interventions like repetitive transcranial magnetic stimulation (TMS), distraction tasks, alcohol consumption, hypnosis, intake of benzodiazepines, or cognitive fatigue, can actually enhance performance in implicit, perceptual-motor learning tasks such as the serial-reaction time task (6–11) or intuitive reasoning tasks (12). These findings suggest that higher-level cognitive functions associated with declarative memory and supported by the prefrontal cortex can interfere with behavior that is naturally driven by implicit learning processes (13). However, it remains unresolved whether competing memory systems also affect implicit statistical learning abilities that are critical for the early, rapid acquisition of language in infants (14). This is an important question, as it could explain why infants and children pick up languages with less effort than adults (cf “What don’t we know?”) (15).Language acquisition involves many different memory and learning processes that are dependent on both procedural and declarative memory (2, 16). The first step for infants acquiring language is to gain knowledge about the phonological structure in one’s spoken language system, the probabilistic constraints on how speech sounds combine (i.e., phonotactic learning), and the segments of continuous speech (i.e., word forms) (17). Word form learning takes place already in the first 12 months of life and is an important precursor to vocabulary acquisition (i.e., mapping form to meaning) and more complex language acquisition (e.g., grammar) later in development (18). In the present study, we focus on statistical learning mechanisms that contribute to word segmentation and thus novel word form learning in the early stages of language acquisition.Statistical learning is generally known as the ability to pick up on patterns in the environment through extraction of frequent regularities and distributional properties. The term was first introduced in the field of cognitive psychology by the work of Saffran, Aslin, and Newport (1996) (19), who demonstrated that infants of only 8-mo-old can extract word boundaries and segment novel word forms from a continuous stream of speech sounds with no other cue than the transitional probabilities between syllables. Later, this learning was also demonstrated in older children and adults (20, 21) and across different domains (e.g., music and grammar) or modalities (e.g., auditory, visual, and motor) (22, 23), indicating that statistical learning is a largely continuous and domain-general learning mechanism for skill acquisition across the human life span.In a typical statistical learning experiment, participants are repeatedly exposed to patterned stimuli such as consonant strings from an artificial grammar, or recurrent syllable triplets. Learning is then typically assessed postexposure by using a two-alternative forced-choice recognition task in which triplets from the exposure stream are pitted against foils. Participants have to indicate which of the two triplets sounded most familiar, and above-chance accuracy is taken as indication of learning. Since statistical learning occurs without any instruction or intention to learn, it is often assumed to result in implicit memory representations (24). This view is also supported by the evidence that statistical learning occurs in infants and even in sleeping neonates (25). However, in recent work, Batterink and colleagues demonstrated that even without intention to learn, adults acquire mainly explicit knowledge of the novel word forms during statistical learning (26–29). This can be derived from the observation that participants’ performance was above chance when they were confident remembering the triplet but at chance when they were unconfident. Knowledge is implicit when participants lack awareness of what they have learned. This means that if participants perform also above chance when they are unconfident, knowledge is inferred to be implicit (30). In contrast, if they perform at chance level when confidence is low, no implicit knowledge is gained. Although statistical learning may produce additional implicit knowledge that cannot be assessed by the recognition and memory judgement tasks (e.g., ref. 28), Batterink’s earlier findings show that adults store the acquired word knowledge mainly in the explicit memory system.We and others have proposed that cognitive development and maturation of the prefrontal areas negatively affect language acquisition, such as word form or grammar learning (31–35). For instance, we showed that children outperform adults on the Hebb repetition learning paradigm (32, 33), a memory paradigm in which participants are asked to immediately recall syllable sequences that consist of hidden repeated word forms. Interestingly, in a follow-up study, we found that cognitive depletion by TMS to the left dorsolateral prefrontal cortex (DLPFC), an area closely related to declarative memory and cognitive control, enhanced Hebb performance in adult participants (34). This suggests that late-developing prefrontal cognitive mechanisms can induce changes in efficiently acquiring sequential language information from the environment, a finding that is largely in line with previously reported evidence in skill learning (13). Recently, we corroborated this idea further by showing enhanced phonotactic constraint learning in adults under cognitive fatigue (35). Based on these findings, we hypothesize that the higher cognitive control system could reduce access to implicit memory processes in adults, thereby making them less efficient in language acquisition relative to infants and children. This idea is in line with the well-known less-is-more hypothesis that attributes developmental changes in language acquisition, such as phonology and grammar, to maturational changes in attention and memory capacities (36–38). In our previous work, participants were explicitly asked to memorize (34) or produce (35) syllable sequences and thus exposure to the novel language was not passive, or “infant like.” Moreover, we did not separate implicit and explicit memory representations. Thus it remains unresolved how higher-order cognitive functions affect acquisition of implicit linguistic knowledge during passive listening to continuous speech using statistical learning mechanisms that support infant language acquisition (23, 39).The aim of the current study was to directly address this question using the auditory statistical learning paradigm. In particular, we aimed to determine whether a temporary depletion of the higher cognitive control system, using two different interventions, can unlock adults’ implicit statistical learning processes that serve infant word segmentation. To investigate this, we exposed young adults to continuous streams of syllables with, unknown to them, repeating three-syllable pseudowords, while watching a silent film. In the first experiment, inhibitory continuous theta-burst stimulation was used to induce a long-lasting disruption in left DLPFC or a control site prior to exposure, similar to the method used in Smalle et al., 2017 (34). In the second experiment, participants first performed an effortful dual working-memory task under high– or low–cognitive-load( HCL and LCL, respectively) conditions, which induces cognitive fatigue that hampers subsequent cognitive performance (7, 35, 40), or did not perform a cognitive load task prior to the language exposure (control or no-load condition). Our primary measure of statistical learning was the offline recognition of the hidden words, which was assessed 15 min after exposure. This was combined with a memory judgement procedure, which measured how confident the participants were that they remembered the hidden words. This task dissociates explicit versus implicit memory representations (e.g., refs. 27–29, 41). In both experiments, electroencephalography (EEG) was also measured during the 20-min language exposure in order to investigate an online perceptual component as second independent measure of statistical learning. Research has shown that the steady-state response of the brain shows a decrease at the frequency of individual syllables and an increase at the rhythm of three-syllable words while listening to continuous sound streams that consist of repeating three-syllable structures. This shift in neural entrainment indicates online statistical learning of novel words as a function of auditory exposure (29). Overall, we predicted that TMS-induced disruption of the DLPFC (in experiment 1) and cognitive fatigue (in experiment 2) would enhance statistical language learning and especially strengthen implicit memory representations for the hidden novel words.     

Current and novel injectable hydrogels to treat focal chondral lesions: Properties and applicability

Focal chondral lesions and early osteoarthritis (OA) are responsible for progressive joint pain and disability in millions of people worldwide, yet there is currently no surgical joint preservation treatment available to fully restore the long term functionality of cartilage. Limitations of current treatments for cartilage defects have prompted the field of cartilage tissue engineering, which seeks to integrate engineering and biological principles to promote the growth of new cartilage to replace damaged tissue. Toward improving cartilage repair, hydrogel design has advanced in recent years to improve their utility. Injectable hydrogels have emerged as a promising scaffold due to their wide range of properties, the ability to encapsulate cells within the material, and their ability to provide cues for cell differentiation. Some of these advances include the development of improved control over in situ gelation (e.g., light), new techniques to process hydrogels (e.g., multi‐layers), and better incorporation of biological signals (e.g., immobilization, controlled release, and tethering). This review summarises the innovative approaches to engineer injectable hydrogels toward cartilage repair. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:64–75, 2018.