Growth, behavior, and clinical findings in 27 patients with Kabuki (Niikawa-Kuroki) syndrome

This study was undertaken to document the phenotype of Kabuki (Niikawa-Kuroki) syndrome in patients from Australia and New Zealand, with particular emphasis on growth patterns, behavior, and relationship between head circumference and intellectual level. Data on 27 children and adults with Kabuki (Niikawa-Kuroki) syndrome from Australia and New Zealand were collected by questionnaire and clinical assessment. The patients ranged in age from 7 months to 36 years with a mean age of 7 years and 2 months. The mean age at diagnosis was 3(5/6) years, but in most cases, the facial phenotype was evident from infancy. The minimum birth prevalence was calculated at 1 in 86,000. Three of our patients died. Parents reported a behavior phenotype characterized by an excellent long-term memory and avoidance of eye contact. No correlation was found between head circumference and severity of intellectual disability. Eight of 14 patients over the age of 5 years were overweight or obese. Six of these eight patients had failure to thrive in infancy. One patient developed insulin-dependent diabetes mellitus in adolescence. Some individuals with Kabuki (Niikawa-Kuroki) syndrome show a characteristic growth profile with failure to thrive in infancy progressing to obesity or overweight in middle childhood or adolescence. A behavior phenotype was noted which requires further investigation. Head size is not a predictor of degree of intellectual disability.     

First messenger regulation of capacitation via G protein-coupled mechanisms: a tale of serendipity and discovery

When placed in a suitable environment, mammalian spermatozoa begin to capacitate and continue until fully capacitated; in vitro, some will 'over-capacitate' and undergo spontaneous acrosome loss, undesirable since acrosome-reacted cells are non-fertilizing. Seminal plasma contains several molecules able to bind to specific receptors on spermatozoa, thereby activating/regulating important intracellular signalling pathways. Three such 'first messengers' are fertilization promoting peptide (FPP), adenosine and calcitonin, all of which stimulate capacitation and then inhibit spontaneous acrosome reactions by regulating adenylyl cyclase (AC)/cAMP. A recent study has reported the presence in spermatozoa of several membrane-associated AC isoforms, mainly smaller in size than the corresponding ACs in somatic cells, and evidence suggests that more than one of these isoforms may be involved in responses to these first messengers. To regulate AC, FPP receptors appear to interact initially with stimulatory A(2A) adenosine receptors, which function only in uncapacitated cells, and then with inhibitory A(1) receptors, which function only in capacitated cells. In contrast, there appears to be a single population of calcitonin receptors. Responses to cholera and pertussis toxins suggest involvement of G proteins and G(s) plus several G(i) subunits have been identified in both mouse and human spermatozoa. In particular, Galpha(s) and Galpha(i2) are found in the same regions as FPP, adenosine and calcitonin receptors, supporting biochemical evidence for G protein involvement in these responses. In vivo, these first messengers could have a significant effect, helping to maximize the number of capacitated, acrosome-intact (i.e. potentially fertilizing) spermatozoa by regulating what is clearly an important signalling pathway.     

Clinical and laboratory correlates of lung disease and cancer in adults with idiopathic hypogammaglobulinaemia

Idiopathic hypogammaglobulinaemia, including common variable immune deficiency (CVID), has a heterogeneous clinical phenotype. This study used data from the national UK Primary Immune Deficiency (UKPID) registry to examine factors associated with adverse outcomes, particularly lung damage and malignancy. A total of 801 adults labelled with idiopathic hypogammaglobulinaemia and CVID aged 18–96 years from 10 UK cities were recruited using the UKPID registry database. Clinical and laboratory data (leucocyte numbers and serum immunoglobulin concentrations) were collated and analysed using uni‐ and multivariate statistics. Low serum immunoglobulin (Ig)G pre‐immunoglobulin replacement therapy was the key factor associated with lower respiratory tract infections (LRTI) and history of LRTI was the main factor associated with bronchiectasis. History of overt LRTI was also associated with a significantly shorter delay in diagnosis and commencing immunoglobulin replacement therapy [5 (range 1–13 years) versus 9 (range 2–24) years]. Patients with bronchiectasis started immunoglobulin replacement therapy significantly later than those without this complication [7 (range 2–22) years versus 5 (range 1–13) years]. Patients with a history of LRTI had higher serum IgG concentrations on therapy and were twice as likely to be on prophylactic antibiotics. Ensuring prompt commencement of immunoglobulin therapy in patients with idiopathic hypogammaglobulinaemia is likely to help prevent LRTI and subsequent bronchiectasis. Cancer was the only factor associated with mortality. Overt cancer, both haematological and non‐haematological, was associated with significantly lower absolute CD8⁺ T cell but not natural killer (NK) cell numbers, raising the question as to what extent immune senescence, particularly of CD8⁺ T cells, might contribute to the increased risk of cancers as individuals age.     

Preparation of human-mouse heterohybridomas against an immunising antigen

The production of murine monoclonal antibodies against specific antigens by hybridomas is a well utilised technique. The production of hybridomas secreting specific human antibodies would have many advantages in therapeutic applications of monoclonal antibodies. The immortalised human lymphocytes themselves would also provide valuable tools in research on lymphocyte development. Preparation of human-human hybridomas has been limited by a lack of suitable fusion partners. This protocol paper describes the production of human-mouse heterohybridomas by two independent laboratories. The purpose of this protocol is to provide a basis for the development of heterohybridoma technology in laboratories with limited hybridoma experience.     

Review: Neurodegenerative processes in temporal lobe epilepsy with hippocampal sclerosis: Clinical,pathological and neuroimaging evidence

Cognitive decline is increasingly described as a co‐morbidity of temporal lobe epilepsy (TLE). Mechanisms underlying cognitive impairment are not fully understood despite examining clinical factors, such as seizure frequency, and cellular mechanisms of excitotoxicity. We review the neuropsychometry evidence for progressive cognitive decline and examine the pathology and neuroimaging evidence supporting a neurodegenerative process in hippocampal sclerosis (HS)‐related TLE. Accelerated cognitive decline is described in groups of adult HS‐related TLE patients. Large childhood studies show early onset of seizures result in poor development of verbal memory and a hindrance in achieving cognitive potential. We discuss HS classification according to different patterns of neuronal loss and correlation to post‐temporal lobectomy cognitive outcomes in refractory TLE patients. Factors such as lateralization of HS pathology, neuronal density and subtype have correlated to cognitive outcomes with varying significance between different studies. Furthermore, alterations in neuronal maturity, regenerative capacity and aberrant connectivity appear to affect cognitive performance post‐operatively suggesting a complex multifactorial process. More recent studies have identified tau pathology being present in HS‐related TLE and correlated to post‐operative cognitive decline in some patients. A traumatic head injury‐related or novel tauopathy has been hypothesized as an underlying process. We discuss the value of prospective and cross‐sectional imaging in assessing cognition and review volumetric magnetic resonance studies with progressive ipsilateral hippocampal atrophy identified to correlate with seizure frequency. Finally, we consider the use of positron emission tomography biomarkers, such as tau tracers, and connectivity studies that may examine in vivo pathways and further explore cognitive decline in TLE.     

Natural human antibodies to pneumococcus have distinctive molecular characteristics and protect against pneumococcal disease

The molecular and functional characteristics of natural antibody from the preimmune repertoire have not been explored in detail in man. We describe seven human IgM monoclonal antibodies selected on the basis of pneumococcal polysaccharide binding that share both molecular and functional characteristics with natural antibody, suggesting a common B cell lineage origin. Unlike class-switched antibodies, which are serotype-specific, the antibodies were polyreactive and bound all pneumococcal polysaccharide capsular serotypes tested. Some bound endogenous antigens, including blood group antigens and intermediate filament proteins. All the antibodies used unmutated heavy chain V (IGHV) that are expressed at an increased frequency in the elderly and in the preimmune repertoire. The CDR3 was characterized by long length (mean aa 18.4 (+/-4.2) and selective use of IGHD6 (P < 0.001) and IGHJ6 (P < 0.01) family genes. The clones expressing IGHV1-69 and IGHV 3-21 provided significant passive protection against invasive pneumococcal disease in vivo.     

Indications and expectations for neuropsychological assessment in epilepsy surgery in children and adults

In our first paper in this series (Epilepsia 2015; 56(5): 674–681), we published recommendations for the indications and expectations for neuropsychological assessment in routine epilepsy care. This partner paper provides a comprehensive overview of the more specialist role of neuropsychological assessment in the pre and postoperative evaluation of epilepsy surgery patients. The paper is in two parts. The first part presents the framework for the mandatory role of neuropsychologists in the presurgical evaluation of epilepsy surgery candidates. A preoperative neuropsychological assessment should be comprised of standardised measures of cognitive function in addition to wider measures of behavioural and psychosocial function. The results from the presurgical assessment are used to: (1) establish a baseline against which change can be measured following surgery; (2) provide a collaborative contribution to seizure characterization, lateralization and localization; (3) provide evidence‐based predictions of cognitive risk associated with the proposed surgery; and (4) provide the evidence base for comprehensive preoperative counselling, including exploration of patient expectations of surgical treatment. The second part examines the critical role of the neuropsychologist in the evaluation of postoperative outcomes. Neuropsychological changes following surgery are dynamic and a comprehensive, long‐term assessment of these changes following surgery should form an integral part of the postoperative follow‐up. The special considerations with respect to pre and postoperative assessment when working with paediatric populations and those with an intellectual disability are also discussed. The paper provides a summary checklist for neuropsychological involvement throughout the epilepsy surgery process, based on the recommendations discussed.     

Antenatal Indomethacin-Adverse Fetal Effects Confirmed

Summary: We examined the association between antenatal indomethacin exposure and adverse neonatal outcome in a matched retrospective cohort study of infants born to 72 mothers at less than 31 weeks' gestation. Indomethacin-exposed mothers were matched to controls by gestational age at delivery, antenatal corticosteroid exposure, prolonged spontaneous rupture of membranes, multiple pregnancy, thyrotrophin-releasing hormone (TRH) exposure, and neonatal sex. Peri ventricular haemorrhage was significantly increased for infants delivered within 48 hours of maternal indomethacin exposure (Grade 1 and 2 19% versus 6%, and Grades 3 and 4 28% versus 3% (p>0.03)). Persistent patent ductus arteriosus was more common in those infants delivered within 48 hours of maternal indomethacin exposure (40% versus 20% (p>0.04)). More neonates exposed to antenatal indomethacin failed to respond to postnatal indomethacin to close a patent ductus arteriosus, 60% versus 0% (p>0.04). There were no adverse effects demonstrated of indomethacin administered greater than 48 hours from delivery. We have confirmed a probable association between antenatal indomethacin administration and an increased incidence of neonatal periventricular haemorrhage, patent ductus arteriosus, and impaired renal function. The adverse neonatal effects appear to be greatest when indomethacin is administered within 48 hours of delivery. We recommend that indomethacin should be used with caution as a tocolytic agent for the treatment of preterm labour at gestations less than 31 weeks.     

Indications and expectations for neuropsychological assessment in routine epilepsy care: Report of the ILAE Neuropsychology Task Force,Diagnostic Methods Commission, 2013–2017

The International League Against Epilepsy (ILAE) Diagnostic Methods Commission charged the Neuropsychology Task Force with the job of developing a set of recommendations to address the following questions: (1) What is the role of a neuropsychological assessment? (2) Who should do a neuropsychological assessment? (3) When should people with epilepsy be referred for a neuropsychological assessment? and (4) What should be expected from a neuropsychological assessment? The recommendations have been broadly written for health care clinicians in established epilepsy settings as well as those setting up new services. They are based on a detailed survey of neuropsychological assessment practices across international epilepsy centers, and formal ranking of specific recommendations for advancing clinical epilepsy care generated by specialist epilepsy neuropsychologists from around the world. They also incorporate the latest research findings to establish minimum standards for training and practice, reflecting the many roles of neuropsychological assessment in the routine care of children and adults with epilepsy. The recommendations endorse routine screening of cognition, mood, and behavior in new‐onset epilepsy, and describe the range of situations when more detailed, formal neuropsychological assessment is indicated. They identify a core set of cognitive and psychological domains that should be assessed to provide an objective account of an individual's cognitive, emotional, and psychosocial functioning, including factors likely contributing to deficits identified on qualitative and quantitative examination. The recommendations also endorse routine provision of feedback to patients, families, and clinicians about the implications of the assessment results, including specific clinical recommendations of what can be done to improve a patient's cognitive or psychosocial functioning and alleviate the distress of any difficulties identified. By canvassing the breadth and depth of scope of neuropsychological assessment, this report demonstrates the pivotal role played by this noninvasive and minimally resource intensive investigation in the care of people with epilepsy.