Coffin–Siris Syndrome with obesity,macrocephaly, hepatomegaly and hyperinsulinism caused by a mutation in the ARID1B gene

Coffin–Siris Syndrome (CSS, MIM 135900) is a rare genetic disorder, and mutations in ARID1B were recently shown to cause CSS. In this study, we report a novel ARID1B mutation identified by whole-exome sequencing in a patient with clinical features of CSS. We identified a novel heterozygous frameshift mutation c.1584delG in exon 2 of ARID1B ({"type":"entrez-nucleotide","attrs":{"text":"NM_020732.3","term_id":"297207098","term_text":"NM_020732.3"}}NM_020732.3) predicting a premature stop codon p.(Leu528Phefs*65). Sanger sequencing confirmed the c.1584delG mutation as a de novo in the proband and that it was not present either in her parents, half-sister or half-brother. Clinically, the patient presented with extreme obesity, macrocephaly, hepatomegaly, hyperinsulinism and polycystic ovarian syndrome (PCOS), which have previously not been described in CSS patients. We suggest that obesity, macrocephaly, hepatomegaly and/or PCOS may be added to the list of clinical features of ARID1B mutations, but further clinical reports are required to make a definite conclusion.     

Chromogranin a induces the biogenesis of granules with calcium- and actin-dependent dynamics and exocytosis in constitutively secreting cells

Chromogranins are a family of acidic glycoproteins that play an active role in hormone and neuropeptide secretion through their crucial role in secretory granule biogenesis in neuroendocrine cells. However, the molecular mechanisms underlying their granulogenic activity are still not fully understood. Because we previously demonstrated that the expression of the major component of secretory granules, chromogranin A (CgA), is able to induce the formation of secretory granules in nonendocrine COS-7 cells, we decided to use this model to dissect the mechanisms triggered by CgA leading to the biogenesis and trafficking of such granules. Using quantitative live cell imaging, we first show that CgA-induced organelles exhibit a Ca(2+)-dependent trafficking, in contrast to native vesicle stomatitis virus G protein-containing constitutive vesicles. To identify the proteins that confer such properties to the newly formed granules, we developed CgA-stably-expressing COS-7 cells, purified their CgA-containing granules by subcellular fractionation, and analyzed the granule proteome by liquid chromatography-tandem mass spectrometry. This analysis revealed the association of several cytosolic proteins to the granule membrane, including GTPases, cytoskeleton-based molecular motors, and other proteins with actin- and/or Ca(2+)-binding properties. Furthermore, disruption of cytoskeleton affects not only the distribution and the transport but also the Ca(2+)-evoked exocytosis of the CgA-containing granules, indicating that these granules interact with microtubules and cortical actin for the regulated release of their content. These data demonstrate for the first time that the neuroendocrine factor CgA induces the recruitment of cytoskeleton-, GTP-, and Ca(2+)-binding proteins in constitutively secreting COS-7 cells to generate vesicles endowed with typical dynamics and exocytotic properties of neuroendocrine secretory granules.     

CAESAR: a new tool to assess relatives’ experience of dying and death in the ICU

Purpose

To develop an instrument designed specifically to assess the experience of relatives of patients who die in the intensive care unit (ICU).

Methods

The instrument was developed using a mixed methodology and validated in a prospective multicentre study. Relatives of patients who died in 41 ICUs completed the questionnaire by telephone 21 days after the death, then completed the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised and Inventory of Complicated Grief after 3, 6, and 12 months.

Results

A total of 600 relatives were included, 475 in the main cohort and 125 in the reliability cohort. The 15-item questionnaire, named CAESAR, covered the patient’s preferences and values, interactions with/around the patient and family satisfaction. We defined three groups based on CAESAR score tertiles: lowest (≤59, n = 107, 25.9 %), middle (n = 185, 44.8 %) and highest (≥69, n = 121, 29.3 %). Factorial analysis showed a single dimension. Cronbach’s alpha in the main and reliability cohorts was 0.88 (0.85–0.90) and 0.85 (0.79–0.89), respectively. Compared to a high CAESAR score, a low CAESAR score was associated with greater risks of anxiety and depression at 3 months [1.29 (1.13–1.46), p = 0.001], post-traumatic stress-related symptoms at 3 [1.34 (1.17–1.53), p < 0.001], 6 [OR = 1.24 (1.06–1.44), p = 0.008] and 12 [OR = 1.26 (1.06–1.50), p = 0.01] months and complicated grief at 6 [OR = 1.40 (1.20–1.63), p < 0.001] and 12 months [OR = 1.27 (1.06–1.52), p = 0.01].

Conclusions

The CAESAR score 21 days after death in the ICU is strongly associated with post-ICU burden in the bereaved relatives. The CAESAR score should prove a useful primary endpoint in trials of interventions to improve relatives’ well-being.

     

ORIF versus arthroplasty for open proximal humerus fractures: Nationwide Inpatient Sample data between 1998 and 2013

Background

Limited data exists in analyzing open reduction and internal fixation (ORIF) and arthroplasty in the management of open proximal humerus fractures. We analyzed differences in hospital course between these procedures, patient demographics, complication rate, length of stay, hospital charges, and mortality rate.

Materials and methods

This is a retrospective review of the Nationwide Inpatient Sample database. ICD-9 codes identified patients hospitalized for open proximal humerus fractures from 1998 to 2013 who underwent ORIF or shoulder arthroplasty (hemi-, total, or reverse). Demographics and in-hospital complications were compared. Logistic regression controlling for age, gender, and Deyo index tested the impact of ORIF vs ARTH on any complications.

Results

Seven hundred thirty patients were included (ORIF, n?=?662 vs ARTH, n?=?68). ORIF patients were younger (p?<?0.001), more likely to be males (p?<?0.001), and had a lower Deyo score (p?=?0.012). Both groups had comparable complication rates (21.4% vs 18.0%, p?=?0.535), lengths of stay (7.86 days vs 7.44 days, p?=?0.833), hospital charges ($76,998 vs $64,133, p?=?0.360), and mortality rates (0.2% vs 0%, p?=?0.761). Type of surgery was not a predictor of any complications (OR?=?0.67 [95% CI 0.33–1.35], p?=?0.266), extended length of stay (OR?=?1.01 [95% CI 0.58–1.78], p?=?0.967), or high hospital charges (OR?=?1.39 [95% CI 0.68–2.86], p?=?0.366).

Conclusion

We revealed no differences in hospital course between ORIF and arthroplasty for management of open proximal humerus fractures. Although differences in demographics existed, no differences in complication rates, length of stay, hospital charges and mortality rates were noted. Future studies can evaluate the long-term outcomes of these procedures.

Level of evidence

Level III.

     

Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking

The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 × 10⁻⁸). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed α-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N=5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders.     

Micromorphological and hardness analyses of human and bovine sclerotic dentin: a comparative study

The purpose of this study was to test the hypothesis that both human and bovine sclerotic dentin have similar hardness properties, in addition to similar micromorphological characteristics. Sixteen teeth (8 human and 8 bovine) exhibiting exposed dentin in the incisal edge and showing characteristics typical of sclerosis were used. Vickers surface microhardness testing was conducted. Three areas of the dentin surface of each specimen were selected. All teeth were processed for scanning electron microscopy in order to estimate the amount (in percentage) of solid dentin on the sclerotic dentin surface. The data were compared by Student's t test (α = 0.05). The micromorphological and microhardness data were compared by Pearson's linear correlation test (α = 0.05). The mean percentages of solid dentin of human and bovine sclerotic dentin were similar (human 90.71 ± 0.83 and bovine 89.08 ± 0.81, p = 0.18). The mean microhardness value (VHN) of human sclerotic dentin was significantly higher than that of bovine sclerotic dentin (human 45.26 ± 2.92 and bovine 29.93 ± 3.83, p = 0.006). No correlation was found between the microhardness values and the amount of solid dentin in the sclerotic dentin, irrespective of the species considered (human R2 = 0.0240, p = 0.714; bovine R2 = 0.0017, p = 0.923; and combined R2 = 0.038, p = 0.46). We concluded that although both bovine and human sclerotic dentin present a similar amount of solid tissue, human sclerotic dentin presents higher microhardness than bovine sclerotic dentin.