Identification of brain cell types underlying genetic association with word reading and correlated traits.

Neuroimaging studies implicate multiple cortical regions in reading ability/disability. However, the neural cell types integral to the reading process are unknown. To contribute to this gap in knowledge, we integrated genetic results from genome-wide association studies for word reading (n = 5054) with gene expression datasets from adult/fetal human brain. Linkage disequilibrium score regression (LDSC) suggested that variants associated with word reading were enriched in genes expressed in adult excitatory neurons, specifically layer 5 and 6 FEZF2 expressing neurons and intratelencephalic (IT) neurons, which express the marker genes LINC00507, THEMIS, or RORB. Inhibitory neurons (VIP, SST, and PVALB) were also found. This finding was interesting as neurometabolite studies previously implicated excitatory-inhibitory imbalances in the etiology of reading disabilities (RD). We also tested traits that shared genetic etiology with word reading (previously determined by polygenic risk scores): attention-deficit/hyperactivity disorder (ADHD), educational attainment, and cognitive ability. For ADHD, we identified enrichment in L4 IT adult excitatory neurons. For educational attainment and cognitive ability, we confirmed previous studies identifying multiple subclasses of adult cortical excitatory and inhibitory neurons, as well as astrocytes and oligodendrocytes. For educational attainment and cognitive ability, we also identified enrichment in multiple fetal cortical excitatory and inhibitory neurons, intermediate progenitor cells, and radial glial cells. In summary, this study supports a role of excitatory and inhibitory neurons in reading and excitatory neurons in ADHD and contributes new information on fetal cell types enriched in educational attainment and cognitive ability, thereby improving our understanding of the neurobiological basis of reading/correlated traits.

Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities.

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10-2, threshold = 2.5 × 10-2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10-2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10-4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

Language Difficulties in School-Age Children With Developmental Dyslexia.

Developmental dyslexia (DD) is a common reading disability, affecting 5% to 11% of children in North America. Children classified as having DD often have a history of early language delay (ELD) or language impairments. Nevertheless, studies have reported conflicting results as to the association between DD-ELD and the extent of current language difficulties in children with DD. To examine these relationships, we queried the parents of school-age children with reading difficulties on their child's early and current language ability. Siblings were also examined. Children were directly assessed using quantitative tests of language and reading skills. To compare this study with the literature, we divided the sample (N = 674) into three groups: DD, intermediate readers (IR), and skilled readers (SR). We found a significant association between DD and ELD, with parents of children in the DD/IR groups reporting their children put words together later than the SR group. We also found a significant association between DD and language difficulties, with children with low reading skills having low expressive/receptive language abilities. Finally, we identified early language predicted current language, which predicted reading skills. These data contribute to research indicating that children with DD experience language difficulties, suggesting early recognition may help identify reading problems.

Genome-wide association study of word reading: Overlap with risk genes for neurodevelopmental disorders.

Reading disabilities (RD) are the most common neurocognitive disorder, affecting 5% to 17% of children in North America. These children often have comorbid neurodevelopmental/psychiatric disorders, such as attention deficit/hyperactivity disorder (ADHD). The genetics of RD and their overlap with other disorders is incompletely understood. To contribute to this, we performed a genome-wide association study (GWAS) for word reading. Then, using summary statistics from neurodevelopmental/psychiatric disorders, we computed polygenic risk scores (PRS) and used them to predict reading ability in our samples. This enabled us to test the shared aetiology between RD and other disorders. The GWAS consisted of 5.3 million single nucleotide polymorphisms (SNPs) and two samples; a family-based sample recruited for reading difficulties in Toronto (n = 624) and a population-based sample recruited in Philadelphia [Philadelphia Neurodevelopmental Cohort (PNC)] (n = 4430). The Toronto sample SNP-based analysis identified suggestive SNPs (P ~ 5 × 10-7 ) in the ARHGAP23 gene, which is implicated in neuronal migration/axon pathfinding. The PNC gene-based analysis identified significant associations (P < 2.72 × 10-6 ) for LINC00935 and CCNT1, located in the region of the KANSL2/CCNT1/LINC00935/SNORA2B/SNORA34/MIR4701/ADCY6 genes on chromosome 12q, with near significant SNP-based analysis. PRS identified significant overlap between word reading and intelligence (R2 = 0.18, P = 7.25 × 10-181 ), word reading and educational attainment (R2 = 0.07, P = 4.91 × 10-48 ) and word reading and ADHD (R2 = 0.02, P = 8.70 × 10-6 ; threshold for significance = 7.14 × 10-3 ). Overlap was also found between RD and autism spectrum disorder (ASD) as top-ranked genes were previously implicated in autism by rare and copy number variant analyses. These findings support shared risk between word reading, cognitive measures, educational outcomes and neurodevelopmental disorders, including ASD.

Mind, brain and body. Healing trauma: the way forward.

The paper explores an interdisciplinary whole person approach to healing from trauma that conserves our rich inheritance from Jung but also takes on board insights from research in the areas of attachment, trauma and the neurobiology of emotion. It is now over 20 years since insights from neurobiology began to be used to inform clinical practice. The paper reviews key insights which have emerged, along with the ways they enable therapists to help mind, brain and body to heal and the ways in which they clarify why, in clinical practice, we do what we do. Traditionally the emphasis has been on words, interpretations, and meaning-making. Currently there is greater appreciation of the affective, relational, embodied aspects of therapeutic work and the way in which these relate to traumatic early interactive experience that is held outside of human awareness. The ways in which knowledge of particular systems of connectivity inform understanding of the whole mind-brain-body relationship are examined. The way forward for clinical practice to become more focused in order to help clients to heal in mind and body is reviewed.

CHIP and Medicaid: Evolving to Meet the Needs of Children.

OBJECTIVE: To examine the evolution of Children's Health Insurance Program (CHIP) and Medicaid programs after passage of the Children's Health Insurance Program Reauthorization Act of 2009 (CHIPRA), focusing on policies affecting eligibility, enrollment, renewal, benefits, access to care, cost sharing, and preparation for health care reform. METHODS: Case studies were conducted in 10 states during 2012-which included key informant interviews and consumer focus groups-and a national survey of state CHIP program administrators was conducted in early 2013. RESULTS: Despite the recession that persisted during much of the study period, many states expanded children's coverage by raising upper income eligibility limits or by covering new groups made eligible by CHIPRA. Simplifying rules and procedures for enrollment and renewal continued to be a major priority for CHIP and Medicaid, and CHIPRA played a direct role in spurring innovation. CHIPRA's outreach grants played an important role in supporting and supplementing state outreach efforts. Important legacies of CHIPRA are the law's mandatory requirements for comprehensive dental benefits coverage and mental health parity for all types of CHIP programs. Although most states already offered generous coverage of these benefits, the mandate may have protected them from cuts during the economic downturn. Federal Maintenance of Effort rules were a crucial protection for CHIP, especially during the recession when state budget shortfalls could have led to program cuts. CONCLUSIONS: Passage of the Affordable Care Act has raised questions surrounding the future role of CHIP in a reformed health care system. A growing number of stakeholders have recommended a 2-year extension of federal CHIP funding to allow complex transition issues to be resolved.

Family members' perceptions and expectations of the use of syringe drivers: a South African study.

AIM: This study aimed to explore and gain insight into the perceptions and expectations of family members of terminally ill patients pertaining to the use of syringe drivers. BACKGROUND: There is a lack of research regarding the use of syringe drivers in Africa and, more specifically, South Africa. However, syringe drivers have been in use for around two decades in some South African settings. Some family members' ambivalence about the use of syringe drivers and the lack of research prompted this study. METHOD: A qualitative exploratory research design was used. Data was collected using semi-structured interviews, diaries, observation, and documentation. Thematic analysis and coding were used to analyse the data. RESULTS: Four main themes were identified: the rationale for the need for the syringe driver, positive perceptions pertaining to the use of the syringe driver, negative perceptions, and concerns/anxieties. The study also highlighted the challenges of drug addiction in some households when caring for terminally ill patients. CONCLUSION: The need for more continuous education and written information and support for immediate and extended family members was evident.

Vitamin D-dependent non-type 1, non-type 2 rickets in a 3-month-old Cornish Rex kitten.

UNLABELLED: CASE PRESENTATION AND ASSESSMENT: A 3-month-old female Cornish Rex kitten was found to have non-painful swelling of the carpal and tarsal regions when presented for routine neutering. The kitten was smaller in stature and less active than its siblings and, according to the owner, had a bunny-hopping gait, was reluctant to climb stairs and strained during defecation. Radiography of the affected limbs and a subsequent radiographic survey of the entire skeleton demonstrated features consistent with rickets. The three littermates were clinically and radiographically normal. As a nutritionally complete diet was being fed, it seemed most likely that the kitten had an inborn error related to vitamin D metabolism. Serum biochemistry demonstrated reduced total alkaline phosphatase activity and increased concentrations of parathyroid hormone. Concentrations of 1,25- and 25-hydroxycholecalciferol were markedly reduced, confirming the diagnosis of rickets. TREATMENT: The kitten was treated with calcitriol, administered orally once daily, and improved rapidly both clinically and radiologically. Serial laboratory studies suggested that the error in vitamin D metabolism was transient, and, at the time of writing, as an adult, the cat appears to require no ongoing replacement calcitriol therapy. CLINICAL RELEVANCE: This case emphasises the value of examining a full 'calcium profile' via a human or veterinary reference laboratory, and a favourable prognosis in some kittens with rickets makes such investigations worthwhile. Even when finances preclude detailed investigation, trial therapy using a nutritionally complete diet and physiological doses of calcitriol or cholecalciferol is inexpensive and can produce a good response.

Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat.

A 3-year-old Ragdoll cat was referred for investigation of polyuria, polydipsia, vomiting, weight loss and hypercalcaemia. Serum biochemical abnormalities included total and ionised hypercalcaemia and hypophosphataemia. Following clinical investigations a diagnosis of idiopathic hypercalcaemia was made. Because of the severity of the hypercalcaemia and the associated clinical signs, treatment for hypercalcaemia was commenced with pamidronate. Major electrolyte abnormalities were detected but, remarkably, were accompanied by minimal clinical signs. The cat was subsequently treated with oral alendronate and is clinically normal 15 months later. Reports of the use of bisphosphonates in cats are limited and close monitoring of patients is recommended.

Do standard measures of deprivation reflect health inequalities in older people?

The objective of the study is to examine the relationship between different deprivation indicators and both self-rated health and emergency admission rates of older people to determine which indicators best predict the health of people in this age group. The method employed an ecological study design using data from all 100 neighbourhoods in Sheffield in 2004 and analysing relationships in three age groups 50-64, 65-74 and over 75 years. Analysis was performed using Pearson correlation coefficient. For people aged 50-64 years, receipt of income support was the best predictor of poor self-reported health (R=0.85). For people aged 64-75 years, lack of formal educational qualifications showed the strongest relationship with poor health (R=0.88), although there was still a significantly strong relationship between poor self-rated health and both non-property ownership (R=0.8) and receipt of income support (R=0.7) in this age group. For people aged 75 years and over, lack of formal qualifications showed the strongest relationship (R=0.6, P<0.001). This was reinforced by a strong relationship between this indicator and emergency admission rates. In conclusion, caution should be used when using conventional deprivation/poverty measures to select older populations to be targeted for services. Our analysis has shown that the deprivation indicator that correlates best with the subjective health rating of people aged 75+ is educational qualification.

Parathyroid hormone assay predicts hypocalcaemia after total thyroidectomy.

BACKGROUND: Postoperative parathyroid gland function after total thyroidectomy (TT) has traditionally been monitored by the measurement of serum calcium concentrations. The purpose of this study is to determine whether measurement of parathyroid hormone (PTH) concentrations in the early postoperative period accurately predicts patients at risk of developing hypocalcaemia. METHODS: A prospective cohort study of patients undergoing TT was carried out. PTH concentrations were measured preoperatively and at 4 and 23 h postoperatively. Serum calcium concentration was measured preoperatively and twice daily for 48 h after surgery. RESULTS: One hundred patients undergoing TT were recruited into the study in the period June 2004 to July 2005. Benign multinodular goitre was the most common indication for surgery (77%). The incidence of temporary hypocalcaemia (Ca < 2.0 mmol/L) was 18%. The mean PTH concentration at 4 h after surgery was 22.3 ng/L and was not significantly different from the 23-h concentration of 23.2 ng/L (P = 0.18). A PTH concentration of < or = 3 ng/L measured at 4 h after surgery had a sensitivity, specificity and likelihood ratio of 0.71, 0.94 and 11.3, respectively, for predicting postoperative hypocalcaemia. The accuracy of a single PTH concentration at 4 h was good for predicting hypocalcaemia (area under receiver-operator characteristic curve 0.90; confidence interval 0.81-0.96). There was no significant difference in accuracy between the 4- and 24-h PTH concentrations (P = 0.14). CONCLUSIONS: A single measurement of PTH concentration in the early postoperative period after TT reliably predicts patients who are likely to develop hypocalcaemia. This approach facilitates early discharge and may decrease the need for multiple postoperative blood tests.

The effect of fluoride administration on rat serum osteocalcin expression during orthodontic movement.

INTRODUCTION: Osteocalcin is a bone protein that has been used to mark bone turnover. The precise role of this protein in bone remodeling has not been fully elucidated; however, it was shown to be instrumental in the activation of osteoclastic bone resorption via its effect on osteoblasts. Fluoride influences bone growth by acting as a mitogenic agent for osteoblasts. In this study, we used a rodent model to determine the effects of fluoride administration on systemic osteocalcin during orthodontic tooth movement. METHODS: Thirty-two 8-week-old female Wistar rats were divided into 4 groups. The first experimental group (n = 10) was fed a normal laboratory diet and distilled water (MilliQ). The second experimental group (n = 10) had the same diet with the addition of fluoridated water. All animals in both groups had 100-g nickel-titanium coil springs secured to their mandibular incisors and left first molars to instigate orthodontic tooth movement for 14 days. The third (n = 6) and fourth (n = 6) groups were the controls. These animals did not undergo orthodontic tooth movement and were given fluoridated (100 ppm sodium fluoride) and nonfluoridated water ad libitum. Phlebotomy was performed via the lateral tail vein before placement of the orthodontic appliances, and final blood samples were obtained via cardiac puncture after the rats were killed 2 weeks later. Serum was isolated from the samples after centrifuging at each stage of phlebotomy, and an enzyme-linked immunosorbent assay (ELISA) was subsequently performed to determine osteocalcin levels in the various sample groups. RESULTS: Orthodontic tooth movement with high, continuous forces was found to have a positive, statistically significant correlation with serum osteocalcin expression in the rodent model. The use of fluoride as a variable was found to increase the mean osteocalcin concentration, but this was not statistically significant. CONCLUSIONS: Further understanding of the biological implications of increased osteocalcin expression requires additional research into the local expression of this protein in the gingival crevice during orthodontic movement.

Intraoperative parathyroid hormone measurement during minimally invasive parathyroidectomy: does it "value-add" to decision-making?

BACKGROUND: Routine use of intraoperative parathyroid hormone levels (IOPTH) during minimally invasive parathyroidectomy (MIP) has been challenged simply because the test works best when needed least, ie, once a solitary adenoma has been resected, and is less accurate with multiple gland disease. It has also been shown not to be cost-effective. The aim of this study was to determine if IOPTH "value-added" to decision-making during MIP. STUDY DESIGN: The study group comprised 100 consecutive patients with sporadic hyperparathyroidism and an unequivocally positive sestamibi scan who were undergoing MIP in our unit from June 2004 until October 2005, from whom blood was collected for parathyroid hormone measurement preoperatively, preexcision, and at 10 and 30 minutes postremoval. No action was taken on the results of the test. RESULTS: Ninety-eight patients were cured by MIP alone. Two patients had persistent hyperparathyroidism, one of whom was cured with subsequent open reexploration and removal of a second adenoma, and the other remains hypercalcemic despite additional open neck exploration. IOPTH in both patients failed to fall in retrospect, only the first would have been cured by conversion at the time of operation. The value-added accuracy of IOPTH was really only 1%. In an additional nine patients, IOPTH at 10 minutes had failed to fall by > 50% from the highest level, those patients (9%) would have been subjected to an unnecessary conversion on the basis of a false-negative result. CONCLUSIONS: IOPTH does not substantially value-add to decision-making during MIP. Most patients will be cured with appropriate selection for MIP based on preoperative localization studies.

Arithmetic processing in children with spina bifida: Calculation accuracy, strategy use, and fact retrieval fluency.

Three studies compared 98 children with spina bifida myelomeningocele (SBM)-a disorder associated with high rates of math disability and spatial deficits-to 94 typically developing children on multidigit subtraction and cognitive addition tasks. Children with SBM were classified into those with reading decoding and math disability, only math disability, and no reading or math disability. Study 1 showed that visual-spatial errors in multidigit arithmetic were not elevated in children with SBM. In Study 2, deficits in accuracy, speed, and strategy-use in single-digit addition characterized groups with math disability regardless of reading status. Accuracy and speed on single-digit addition was strongly related to performance on multidigit subtraction. A math-level matching design in Study 3 revealed less mastery of math facts by the group with SBM. The results are discussed with reference to cognitive and neuropsychological models of math disability.

The dreaming mind-brain: a Jungian perspective.

In this paper I discuss the nature and role of dream and the dreaming process in Jungian clinical practice in the light of neuroscience. Insights from contemporary neuroscience support rather than contest Jung's view that emotional truth, not censorship or disguise, underpins the dreaming process. I use clinical material to illustrate how work with dreams within the total interactive experience of the analytic dyad enables the development of the emotional scaffolding necessary for the development of 'mind'. Large scale evidence-based research reveals that dreaming is caused by brain activity during sleep that is both biochemically and regionally different from that of waking states. Recent imaging studies confirm that dreams are the mind's vehicle for the processing of emotional states of being, particularly the fear, anxiety, anger or elation that often figure prominently. Dream sleep is understood as also being the guardian of memory, playing a part in forgetting, encoding and affective organization of memory. In the clinical section of the paper I let a series of dreams speak for themselves, revealing the emotionally salient concerns of the dreamer, weaving past and present, transference and reality together in a way that demonstrates the healthy attempt of the brain-mind to come to terms with difficult emotional experience from the past. The dreams become dreamable as part of the meaning-making process of analysis.

Surgery for hyperparathyroidism: does morphology or function matter most?

BACKGROUND: With minimally invasive parathyroidectomy (MIP) not all enlarged parathyroid glands are necessarily removed, and intraoperative measurement of parathyroid hormone levels (IO-PTH) does not necessarily predict multiple enlarged glands. The aim of this study was to compare morphology with function, using Ca(2+)-regulated PTH secretion. METHODS: PTH secretion was determined by perifusion: (1) cells from 12 normal parathyroids were compared with 14 parathyroid adenomas; (2) functional characteristics (PTH secretion, sestamibi uptake, IO-PTH decrease) were correlated with morphologic characteristics; (3) PTH secretion as a predictor of IO-PTH decrease was determined in 7 patients with 2 enlarged parathyroids. RESULTS: (1) There were significant differences between normal and pathological parathyroid cells consistent with reduced sensitivity to Ca(2+). Maximum secretion rates for normal and adenomatous cells were, respectively, 3.9 +/- 0.4 fg min(-1) cell(-1) and 2.0 +/- 0.4 fg min(-1) cell(-1) (P = .002) and minimum secretion rates, 0.7 +/- 0.1 fg min(-1) cell(-1) and 0.4 +/- 0.1 fg min(-1) cell(-1) (P = .008). However, the IC(50) value for Ca(2+) was elevated in adenomatous cells indicating an apparent loss of extracellular Ca(2+) sensitivity being 1.1 +/- 0.02 mmol/L for normal and 1.2 +/- 0.02 mmol/L for adenomatous cells (P = .02). (2) There was no overall correlation between PTH secretion and gland morphology. (3) In 5 of 7 cases, PTH secretion correctly predicted the decrease in IO-PTH. CONCLUSION: Parathyroid adenomas generally exhibit abnormal PTH secretory function; however, enlarged parathyroid glands that do not contribute to the biochemical changes of hyperparathyroidism do exist, and, in these cases, cellular secretory function is a useful predictor of IO-PTH dynamics.

Undoing dissociation. Affective neuroscience: a contemporary Jungian clinical perspective.

In the last ten years both analysts and neuroscientists have begun to challenge the analytic world to explore the analytic view of the mind in relation to knowledge emerging from the field of neuroscience. I find that 'in many ways it is Jung's understanding of the mind, the human condition, and the self, that is most compatible with the insights that are emerging from neuroscience today' (Wilkinson 2004, p. 84). In this paper I consider the insights that neuroscience has to offer us as we seek to work with those patients whose early experience has diminished their capacity to be 'in mind' and with it their capacity for reflective self-function, whose defences are dissociative, whose need has been to keep unbearable experience at bay, out of mind. I look first at dissociationist theory and its development, then focus on the insights to be gained from neuroscience with regard to early trauma and its effect on the encoding and recall of memory. Finally, I turn to the nature of cure and argue that hemispheric integration is the key to undoing dissociation and the prelude to individuation.

L-amino acids regulate parathyroid hormone secretion.

Parathyroid hormone (PTH) secretion is acutely regulated by the extracellular Ca(2+)-sensing receptor (CaR). Thus, Ca(2+) ions, and to a lesser extent Mg(2+) ions, have been viewed as the principal physiological regulators of PTH secretion. Herein we show that in physiological concentrations, l-amino acids acutely and reversibly activated the extracellular Ca(2+)-sensing receptor in normal human parathyroid cells and inhibited parathyroid hormone secretion. Individual l-amino acids, especially of the aromatic and aliphatic classes, as well as plasma-like amino acid mixtures, stereoselectively mobilized Ca(2+) ions in normal human parathyroid cells in the presence but not the absence of the CaR agonists, extracellular Ca(2+) (Ca(2+)(o)), or spermine. The order of potency was l-Trp = l-Phe > l-His > l-Ala > l-Glu > l-Arg = l-Leu. CaR-active amino acids also acutely and reversibly suppressed PTH secretion at physiological ionized Ca(2+) concentrations. At a Ca(2+)(o) of 1.1 mm and an amino acid concentration of 1 mm, CaR-active amino acids (l-Phe = l-Trp > l-His = l-Ala), but not CaR-inactive amino acids (l-Leu and l-Arg), stereoselectively suppressed PTH secretion by up to 40%, similar to the effect of raising Ca(2+)(o) to 1.2 mm. A physiologically relevant increase in the -fold concentration of the plasma-like amino acid mixture (from 1x to 2x) also reversibly suppressed PTH secretion in the Ca(2+)(o) concentration range 1.05-1.25 mm. In conclusion, l-amino acids acutely and reversibly activate endogenous CaRs and suppress PTH secretion at physiological concentrations. The results indicate that l-amino acids are physiological regulators of PTH secretion and thus whole body calcium metabolism.