Calcium requests in a primary care; An observational audit of biochemical requests and frequency of abnormal results.

BACKGROUND/AIMS: This aim of this audit was to assess the extent of serum calcium testing and the frequency of hypercalcaemia in the primary care setting. We also assessed the appropriateness of subsequent investigations with repeat serum calcium and PTH testing if hypercalcaemia was identified. METHODS: All laboratory requests for adjusted calcium and PTH samples sent from primary care in Glasgow were analysed over a 12 month period. This covered approximately 125 GP practices and a patient population of over 590,000. RESULTS: There were 78,845 requests for adjusted calcium and 2053 PTH requests from 62,745 patients aged 16-105 years (median age 57, IQ range 30 years). Of these requests 1423 (2.3%) of patients had biochemical evidence of hypercalcaemia (adjusted calcium ≥ 2.61 mmol/L). Of the 1423 patients with hypercalcaemia, 368 patients (45.8%) had a single raised calcium level that was within the normal range on repeat testing. Of the 400 patients with persistent hypercalcaemia on 2 or more samples, 210 (52.5%) had a PTH measured. Eight patients had a PTH < 2.0 pmol/L, whilst 202 (96.1%) had a PTH ≥ 2.0 pmol/L (range 2.1-106.1 pmol/L). CONCLUSIONS: Serum calcium was checked in 10.6% of the population per year within primary care. In the 2.4% with a raised calcium on initial testing, approximately half (45.8%) will normalise on repeat testing. Of those who remained persistently hypercalcaemic, only half (52.5%) had a PTH measured and the majority (96.1%) were in keeping with primary hyperparathyroidism being the most common cause of hypercalcaemia.

Creation and evaluation of full-text literature-derived, feature-weighted disease models of genetically determined developmental disorders.

There are >2500 different genetically determined developmental disorders (DD), which, as a group, show very high levels of both locus and allelic heterogeneity. This has led to the wide-spread use of evidence-based filtering of genome-wide sequence data as a diagnostic tool in DD. Determining whether the association of a filtered variant at a specific locus is a plausible explanation of the phenotype in the proband is crucial and commonly requires extensive manual literature review by both clinical scientists and clinicians. Access to a database of weighted clinical features extracted from rigorously curated literature would increase the efficiency of this process and facilitate the development of robust phenotypic similarity metrics. However, given the large and rapidly increasing volume of published information, conventional biocuration approaches are becoming impractical. Here, we present a scalable, automated method for the extraction of categorical phenotypic descriptors from the full-text literature. Papers identified through literature review were downloaded and parsed using the Cadmus custom retrieval package. Human Phenotype Ontology terms were extracted using MetaMap, with 76-84% precision and 65-73% recall. Mean terms per paper increased from 9 in title + abstract, to 68 using full text. We demonstrate that these literature-derived disease models plausibly reflect true disease expressivity more accurately than widely used manually curated models, through comparison with prospectively gathered data from the Deciphering Developmental Disorders study. The area under the curve for receiver operating characteristic (ROC) curves increased by 5-10% through the use of literature-derived models. This work shows that scalable automated literature curation increases performance and adds weight to the need for this strategy to be integrated into informatic variant analysis pipelines. Database URL: https://doi.org/10.1093/database/baac038.

Baraitser-Winter cerebrofrontofacial syndrome.

Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) (BRWS; MIM #243310, 614583) is a rare developmental disorder affecting multiple organ systems. It is characterised by intellectual disability (mild to severe) and distinctive facial appearance (metopic ridging/trigonocephaly, bilateral ptosis, hypertelorism). The additional presence of cortical malformations (pachygyria/lissencephaly) and ocular colobomata are also suggestive of this syndrome. Other features include moderate short stature, contractures, congenital cardiac disease and genitourinary malformations. BWCFF is caused by missense mutations in the cytoplasmic beta- and gamma-actin genes ACTB and ACTG1. We provide an overview of the clinical characteristics (including some novel findings in four recently diagnosed patients), diagnosis, management, mutation spectrum and genetic counselling.

Management of metastatic phaeochromocytoma and paraganglioma: use of iodine-131-meta-iodobenzylguanidine therapy in a tertiary referral centre.

BACKGROUND: Phaeochromocytoma (phaeo) and paraganglioma (PGL) are rare conditions, which are malignant in up to 30%. Optimal treatment is controversial, but in patients with metastatic iodine-131-meta-iodobenzylguanidine ((123)I-MIBG) avid tumours, we offer (131)I-MIBG therapy. We summarize response rates, survival and safety in a cohort of such patients treated with (131)I-MIBG in our centre from 1986 to 2012. DESIGN/METHODS: Retrospective analysis of the case notes of patients with metastatic phaeo/PGL who received (131)I-MIBG was undertaken; patients underwent clinical, biochemical and radiological evaluation within 6 months of each course of (131)I-MIBG therapy. RESULTS: Twenty-two patients (9 males) were identified, 12 with metastatic PGL and 10 with phaeo. Overall median follow-up time after first dose of (131)I-MIBG was 53 months. In total, 68 doses of (131)I-MIBG were administered; average dose was 9967 MBq (269.4 mCi). After the first dose, >50% of patients demonstrated disease stability or partial response; progressive disease was seen in 9%. A subset of patients underwent repeated treatment with the majority demonstrating partial response or stable disease. No life-threatening adverse events were reported, but three patients developed hypothyroidism and two developed ovarian failure after repeated dosing. Five-year survival after original diagnosis was 68% and median (+inter quartile range) survival from date of diagnosis was 17 years (7.6-26.4) with no difference in survival according to diagnosis (P < 0.1). CONCLUSIONS: (131)I-MIBG is well tolerated and associates with disease stabilization or improvement in the majority of patients with metastatic phaeo/PGL. However, stronger conclusions on treatment effectiveness are limited by lack of a directly comparable 'control group' as well as an alternative 'gold standard' treatment.

Prior D1 dopamine receptor stimulation is required to prime D2-mediated striatal Fos expression in 6-hydroxydopamine-lesioned rats.

Repeated dopamine agonist administration to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway potentiates behavioral and neuronal activation in response to subsequent dopamine agonist treatment. This response sensitization has been termed "priming" or "reverse-tolerance". Our prior work has shown that three pretreatment injections of the mixed D1/D2 agonist apomorphine (0.5 mg/kg) into 6-hydroxydopamine-lesioned rats permits a previously inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to induce robust contralateral rotation and striatal Fos expression in striatoentopeduncular "direct" pathway neurons. These striatal neurons typically express D1 but not D2 receptors. Because apomorphine acts as an agonist at both D1 and D2 receptors, the present study sought to determine whether D1, D2, or concomitant D1/D2 receptor stimulation was required to prime D2-mediated contralateral rotation and striatal Fos expression. Twenty-one days following unilateral stereotaxic injection of 6-hydroxydopamine into the medial forebrain bundle, rats received three pretreatment injections, at three- to six-day intervals, with either: the mixed D1/D2 agonist apomorphine, the D1 agonist SKF38393, the D2 agonist quinpirole, or a combination of SKF38393 + quinpirole. Ten days following the third pretreatment injection, 6-hydroxydopamine-lesioned rats were challenged with the D2 agonist quinpirole (0.25 mg/kg). Pretreatment with SKF38393 (10 mg/kg), quinpirole (1 mg/kg) or SKF38393 (1 mg/kg) + quinpirole (0.25 mg/kg) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to induce robust contralateral rotation which was similar in magnitude to that observed following apomorphine priming. However, only pretreatment with SKF38393 (10 mg/kg) or SKF38393 (1 mg/kg) + quinpirole (0.25 mg/kg) permitted the same dose of quinpirole (0.25 mg/kg) to induce striatal Fos expression. These results demonstrate that while prior stimulation of D1, D2 or D1/D2 receptors can effectively prime D2-mediated contralateral rotation, prior stimulation of D1 receptors is required to prime D2-mediated striatal Fos expression. This study demonstrates that priming of 6-hydroxydopamine-lesioned rats with a D1 agonist permits a subsequent challenge with a D2 agonist to produce robust rotational behavior that is accompanied by induction of immediate-early gene expression in neurons that comprise the "direct" striatal output pathway. These responses are equivalent to the changes observed in apomorphine-primed 6-hydroxydopamine-lesioned rats challenged with D2 agonist. In contrast, D2 agonist priming was not associated with D2-mediated induction of striatal immediate-early gene expression even though priming of D2-mediated rotational behavior was not different from that observed following priming with apomorphine or D1 agonist. Therefore, while priming-induced alterations in D2-mediated immediate early gene expression in the "direct" striatal output pathway may contribute to the enhanced motor behavior observed, such changes in striatal gene expression do not appear to be required for this potentiated motor response in dopamine-depleted rats.