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Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19). We see no difference in signature between cases and controls, providing no support for a common etiological role of MZ twinning in NTDs. The strong associations therefore continue to await elucidation.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) refractory to conventional therapy can lead to marked disability and represents a therapeutic challenge.
To report five cases of treatment-refractory disabling CIDP treated with autologous hematopoietic stem cell transplantation (AHSCT).
This was a retrospective cohort study from a tertiary care referral center for both neuromuscular disease and AHSCT. Patients with CIDP treated with AHSCT between 2008 and 2020 were included. All patients had major persistent and disabling neuropathic deficits despite combinations of intensive immunosuppressive therapy. The primary outcome measures were: Medical Research Council sum score, Overall Neuropathy Limitations Scale and requirement for ongoing CIDP immunotherapy after transplantation. We also analyzed safety outcomes by documenting all severe AHSCT-related complications.
Five patients with refractory CIDP underwent AHSCT. Three were classified as manifesting a typical syndrome, two were classified as the multifocal Lewis Sumner variant. The mean age at time of CIDP diagnosis was 33.4 years (range 24–46 years), with a median delay of 46 months (range 21–135 months) between diagnosis and AHSCT. The median follow-up period was 41 months. All five patients were able to wean off CIDP-related immunotherapy. Marked improvements in Medical Research Council scale and overall Neuropathy Limitations Scale were noted in 4/5 patients. One patient with longstanding neurogenic atrophy showed no improvement in disability scales. There were no treatment-related deaths or critical illnesses.
AHSCT can achieve marked sustained clinical improvement of refractory CIDP and may allow for weaning off long-term complex immunotherapies.
We implemented universal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing of patients undergoing surgical procedures as a means to conserve personal protective equipment (PPE). The rate of asymptomatic coronavirus disease 2019 (COVID-19) was <0.5%, which suggests that early local public health interventions were successful. Although our protocol was resource intensive, it prevented exposures to healthcare team members.
Iodine intake affects the occurrence of thyroid disorders. However, the association of iodine intake with longevity remains to be described. This led us to perform a 20 years’ follow-up on participants from the Randers–Skagen (RaSk) study. Residents in Randers born in 1920 (n 210) and Skagen born in 1918–1923 (n 218) were included in a clinical study in 1997–1998. Mean iodine content in drinking water was 2 µg/l in Randers and 139 µg/l in Skagen. We collected baseline data through questionnaires, performed physical examinations and measured iodine concentrations in spot urine samples. Income data were retrieved from Danish registries. We performed follow-up on mortality until 31 December 2017 using Danish registries. Complete follow-up data were available on 428 out of 430 of participants (99·5 %). At baseline, the median urinary iodine concentration was 55 µg/l in Randers and 160 µg/l in Skagen residents. Participants were long-term residents with 72·8 and 92·7 % residing for more than 25 years in Randers and Skagen, respectively. Cox regression showed that living in Skagen compared with Randers was associated with a lower hazard ratio (HR) of death in both age- and sex-adjusted analyses (HR 0·60, 95 % CI 0·41, 0·87, P = 0·006), but also after adjustment for age, sex, number of drugs, Charlson co-morbidity index, smoking, alcohol and income (HR 0·60, 95 % CI 0·41, 0·87, P = 0·008). Residing in iodine-replete Skagen was associated with increased longevity. This indicates that long-term residency in an iodine-replete environment may be associated with increased longevity compared with residency in an iodine-deficient environment.
This chapter provides detailed practical information about testing for sperm antibodies and interpretation of the results of various antibody tests. It also briefly reviews our knowledge about anti-sperm antibodies (ASA) in males and females and outlines several lines of evidence regarding the predisposing factors for sperm immunity in men and women.
Forensic psychiatry in Europe is a specialty primarily concerned with individuals who have either offended or present a risk of doing so, and who also suffer from a psychiatric condition. These mentally disordered offenders (MDOs) are often cared for in secure psychiatric environments or prisons. In this guidance paper we first present an overview of the field of forensic psychiatry from a European perspective. We then present a review of the literature summarising the evidence on the assessment and treatment of MDOs under the following headings: The forensic psychiatrist as expert witness, risk, treatment settings for mentally disordered offenders, and what works for MDOs. We undertook a rapid review of the literature with search terms related to: forensic psychiatry, review articles, randomised controlled trials and best practice. We searched the Medline, Embase, PsycINFO, and Cochrane library databases from 2000 onwards for adult groups only. We scrutinised publications for additional relevant literature, and searched the websites of relevant professional organisations for policies, statements or guidance of interest. We present the findings of the scientific literature as well as recommendations for best practice drawing additionally from the guidance documents identified. We found that the evidence base for forensic-psychiatric practice is weak though there is some evidence to suggest that psychiatric care produces better outcomes than criminal justice detention only. Practitioners need to follow general psychiatric guidance as well as that for offenders, adapted for the complex needs of this patient group, paying particular attention to long-term detention and ethical issues.
Oxidative stress has been suggested to increase after electroconvulsive therapy (ECT), a treatment which continues to be the most effective for severe depression. Oxidative stress could potentially be mechanistically involved in both the therapeutic effects and side effects of ECT.
We measured sensitive markers of systemic and central nervous system (CNS) oxidative stress on DNA and RNA (urinary 8-oxodG/8-oxoGuo, cerebrospinal fluid 8-oxoGuo, and brain oxoguanine glycosylase mRNA expression) in male rats subjected to electroconvulsive stimulations (ECS), an animal model of ECT. Due to the previous observations that link hypothalamic–pituitary–adrenal (HPA)-axis activity and age to DNA/RNA damage from oxidation, groups of young and middle-aged male animals were included, and markers of HPA-axis activity were measured.
ECS induced weight loss, increased corticosterone (only in middle-aged animals), and decreased cerebral glucocorticoid receptor mRNA expression, while largely leaving the markers of systemic and CNS DNA/RNA damage from oxidation unaltered.
These results suggest that ECS is not associated with any lasting effects on oxidative stress on nucleic acids neither in young nor middle-aged rats.
Let Sn,n≥1, be the successive sums of the payoffs in the classical St. Petersburg game. The celebrated Feller weak law states that Sn∕(nlog2n)→ℙ1 as n→∞. In this paper we review some earlier results of ours and extend some of them as we consider an asymmetric St. Petersburg game, in which the distribution of the payoff X is given by ℙ(X=srk-1)=pqk-1,k=1,2,…, where p+q=1 and s,r>0. Two main results are extensions of the Feller weak law and the convergence in distribution theorem of Martin-Löf (1985). Moreover, it is well known that almost-sure convergence fails, though Csörgő and Simons (1996) showed that almost-sure convergence holds for trimmed sums and also for sums trimmed by an arbitrary fixed number of maxima. In view of the discreteness of the distribution we focus on `max-trimmed sums', that is, on the sums trimmed by the random number of observations that are equal to the largest one, and prove limit theorems for simply trimmed sums, for max-trimmed sums, as well as for the `total maximum'. Analogues with respect to the random number of summands equal to the minimum are also obtained and, finally, for joint trimming.
Despite the ecological relevance of tropical reefs, information on species composition and coverage on sandstone reefs is very scarce. Most studies on reef systems have been conducted for true coral reefs, ecosystems that show calcareous formations with extensive coral cover and diversity. The aim of this study was to analyse the coverage of benthic assemblages in a submerged sandstone reef (22–24 m) in a relatively non-explored region (Tropical South-western Atlantic). In this area, filamentous algae (43.6%) and sponges (19.6%) are the main components of the benthic reef assemblages. Other benthic reef fauna (ascidians, corals and zoanthids) showed lower coverage, although their importance may vary depending on the area. A negative correlation between filamentous algae and slow-growing reef-building organisms (calcareous algae) was observed. High sand coverage (19.6%) over the reef revealed a high rate of silting. A low coral diversity (only two resilient species) was quantified, and most of the coral colonies were small-sized. The results provide a baseline assessment for a poorly known ecosystem with turbid-water benthic communities and higher sea-surface temperatures near the Earth's equator.
Few studies have investigated developmental strengths and weaknesses within the cognitive profile of children and adolescents with fragile X syndrome (FXS), a single-gene cause of inherited intellectual impairment. With a prospective longitudinal design and using normalized raw scores (Z scores) to circumvent floor effects, we measured cognitive functioning of 184 children and adolescents with FXS (ages 6 to 16) using the Wechsler Scale of Intelligence for Children on one to three occasions for each participant. Participants with FXS received lower raw scores relative to the Wechsler Scale of Intelligence for Children normative sample across the developmental period. Verbal comprehension, perceptual organization, and processing speed Z scores were marked by a widening gap from the normative sample, while freedom from distractibility Z scores showed a narrowing gap. Key findings include a relative strength for verbal skills in comparison with visuospatial–constructive skills arising in adolescence and a discrepancy between working memory (weakness) and processing speed (strength) in childhood that diminishes in adolescence. Results suggest that the cognitive profile associated with FXS develops dynamically from childhood to adolescence. Findings are discussed within the context of aberrant brain morphology in childhood and maturation in adolescence. We argue that assessing disorder-specific cognitive developmental profiles will benefit future disorder-specific treatment research.
Monozygotic (MZ) twins provide a natural system for investigating developmental plasticity and the potential epigenetic origins of disease. A major difference in the intrauterine environment between MZ pairs is whether they share a common placenta or have separate placentas. Using DNA methylation measured at >400,000 points in the genome on the Illumina HumanMethylation450 array, we demonstrate that the co-twins of MZ pairs (average age of 14) that shared a common placenta (n = 18 pairs) have more similar DNA methylation levels in blood throughout the genome relative to those with separate placentas (n = 16 pairs). Functional annotation of the genomic regions that show significantly different correlation between monochorionic (MC) and dichorionic (DC) MZ pairs found an over-representation of genes involved in the regulation of transcription, neuronal development, and cellular differentiation. These results support the idea that prenatal environmental exposures may have a lasting effect on an individual's epigenetic landscape, and the potential for these changes to have functional consequences.
Hypertension is associated with an increased risk of dementia and
depression with uncertain longitudinal associations with brain
To examine lifetime blood pressure as a predictor of brain structure in
A total of 190 participants (mean age 69.3 years) from the Whitehall II
study were screened for hypertension six times (1985–2013). In 2012–2013,
participants had a 3T-magnetic resonance imaging (MRI) brain scan. Data
from the MRI were analysed using automated and visual measures of global
atrophy, hippocampal atrophy and white matter hyperintensities.
Longitudinally, higher mean arterial pressure predicted increased
automated white matter hyperintensities (P<0.002).
Cross-sectionally, hypertensive participants had increased automated
white matter hyperintensities and visually rated deep white matter
hyperintensities. There was no significant association with global or
Long-term exposure to high blood pressure predicts hyperintensities,
particularly in deep white matter. The greatest changes are seen in those
with severe forms of hypertension, suggesting a dose–response
Monozygotic (MZ) twins form an important system for the study of biological plasticity in humans. While MZ twins are generally considered to be genetically identical, a number of studies have emerged that have demonstrated copy-number differences within a twin pair, particularly in those discordant for disease. The rate of autosomal copy-number variation (CNV) discordance within MZ twin pairs was investigated using a population sample of 376 twin pairs genotyped on Illumina Human610-Quad arrays. After CNV calling using both QuantiSNP and PennCNV followed by manual annotation, only a single CNV difference was observed within the MZ twin pairs, being a 130 KB duplication of chromosome 5. Five other potential discordant CNV were called by the software, but excluded based on manual annotation of the regions. It is concluded that large CNV discordance is rare within MZ twin pairs, indicating that any CNV difference found within phenotypically discordant MZ twin pairs has a high probability of containing the causal gene(s) involved.
With the growing interdependence between medicine and technology, the prospect of connecting machines to the human brain is rapidly being realized. The field of neuroprosthetics is transitioning from the proof of concept stage to the development of advanced clinical treatments. In one area of brain-machine interfaces (BMIs) related to the motor system, also termed ‘motor neuroprosthetics’, research successes with implanted microelectrodes in animals have demonstrated immense potential for restoring motor deficits. Early human trials have also begun, with some success but also highlighting several technical challenges. Here we review the concepts and anatomy underlying motor BMI designs, review their early use in clinical applications, and offer a framework to evaluate these technologies in order to predict their eventual clinical utility. Ultimately, we hope to help neuroscience clinicians understand and participate in this burgeoning field.
Genes in the TGF9 signaling pathway play important roles in the regulation of ovarian follicle growth and ovulation rate. Mutations in three genes in this pathway, growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and the bone morphogenetic protein receptor B 1 (BMPRB1), influence dizygotic (DZ) twinning rates in sheep. To date, only variants in GDF9 and BMP15, but not their receptors transforming growth factor ß receptor 1 (TGFBR1), bone morphogenetic protein receptor 2 (BMPR2) and BMPR1B, have been investigated with respect to their roles in human DZ twinning. We screened for rare and novel variants in TGFBR1, BMPR2 and BMPR1B in mothers of dizygotic twins (MODZT) from twin-dense families, and assessed association between genotyped and imputed variants and DZ twinning in another large sample of MODZT. Three novel variants were found: a deep intronic variant in BMPR2, and one intronic and one non-synonymous exonic variant in BMPRB1 which would result in the replacement of glutamine by glutamic acid at amino acid position 294 (p.Gln294Glu). None of these variants were predicted to have major impacts on gene function. However, the p.Gln294Glu variant changes the same amino acid as a sheep BMPR1B functional variant and may have functional consequences. Six BMPR1B variants were marginally associated with DZ twinning in the larger case-control sample, but these were no longer significant once multiple testing was taken into account. Our results suggest that variation in the TGF9 signaling pathway type II receptors has limited effects on DZ twinning rates in humans.