The FGFR4-G388R Polymorphism Promotes Mitochondrial STAT3 Serine Phosphorylation to Facilitate Pituitary Growth Hormone Cell Tumorigenesis

Pituitary tumors are common intracranial neoplasms, yet few germline abnormalities have been implicated in their pathogenesis. Here we show that a single nucleotide germline polymorphism (SNP) substituting an arginine (R) for glycine (G) in the FGFR4 transmembrane domain can alter pituitary cell growth and hormone production. Compared with FGFR4-G388 mammosomatotroph cells that support prolactin (PRL) production, FGFR4-R388 cells express predominantly growth hormone (GH). Growth promoting effects of FGFR4-R388 as evidenced by enhanced colony formation was ascribed to Src activation and mitochondrial serine phosphorylation of STAT3 (pS-STAT3). In contrast, diminished pY-STAT3 mediated by FGFR4-R388 relieved GH inhibition leading to hormone excess. Using a knock-in mouse model, we demonstrate the ability of FGFR4-R385 to promote GH pituitary tumorigenesis. In patients with acromegaly, pituitary tumor size correlated with hormone excess in the presence of the FGFR4-R388 but not the FGFR4-G388 allele. Our findings establish a new role for the FGFR4-G388R polymorphism in pituitary oncogenesis, providing a rationale for targeting Src and STAT3 in the personalized treatment of associated disorders

The effect of platelet‐rich plasma as a scaffold in regeneration/revitalization endodontics of immature permanent teeth assessed using 2‐dimensional radiographs and cone beam computed tomography: a randomized controlled trial

Aim: To assess the outcomes of platelet‐rich plasma as a scaffold in regenerative/revitalization endodontics (RET) using cone beam computed tomography (CBCT) and 2‐dimensional radiographs. Methodology: Twenty‐six healthy patients with mean age of 12.66 ± 4.47, and immature permanent anterior teeth with necrotic pulps, were randomly allocated to two groups, whereby RET was performed using platelet‐rich plasma (PRP, test group) and blood clot (BLC, control group). Changes in root length (RL), root dentinal thickness (RDT), apical foramen width (AFW) and radiographic root area (RRA), were assessed using both radiographic methods, whilst changes in periapical area diameter (PAD) were assessed using CBCT, over a period of 12 months. T ‐test and chi‐square/Fisher’s exact tests were used to compare continuous and categorical data between BLC and PRP groups, respectively. Changes in RL, RDT, AFW, RRA and PAD were examined by comparing the two groups (PRP versus BLC) using multilevel modelling, considering the clustering effect of repeated measures of several teeth originating from the same participant. Results: Changes in RL, RDT, AFW, RRA and PAD, over time, were found to be significant for both groups. There was, however, no difference between the RET techniques (PRP versus BLC), using both radiographic and CBCT methods. The results of both assessment techniques (CBCT and 2‐dimensional radiographic methods) were highly consistent (overall ICC ranged between 0.80 and 0.94). In addition, a significant effect of baseline PAD was found on RL, RRA and AD at 12 months (RL effect = −0.68, P < 0.001; RRA effect = −1.91, P = 0.025; AD effect = 0.08, P = 0.024). Conclusion: The current study highlights successful and comparable clinical and radiographic outcomes of RET techniques using PRP and BLC. Standardized and calibrated 2‐dimensional radiographic assessment was as effective as CBCT in assessing RET outcomes; therefore, the routine use of CBCT in RET is not recommended. Although an effect of baseline periapical lesion diameter on root development outcomes, at 12 months, were observed, more studies are recommended in order to assess such an effect

Symptomatic cerebral oedema during treatment of diabetic ketoacidosis: effect of adjuvant octreotide infusion

<p>Abstract</p> <p>Introduction</p> <p>A potentially lethal complication of diabetic ketoacidosis (DKA) in children is brain oedema, whether caused by DKA itself or by the therapeutic infusion of insulin and fluids.</p> <p>Case presentation</p> <p>A 10-year old previously healthy boy with DKA became unconscious and apnoeic due to cerebral oedema (confirmed by abnormal EEG and CT-scan) during treatment with intravenous fluids (36 ml/h) and insulin (0.1 units/kg/h). He was intubated and artificially ventilated, without impact on EEG and CT-scan. Subsequently, adjuvant infusion of octreotide was applied (3.5 μg/kg/h), suppressing growth hormone (GH) and IGF-1 production and necessitating the insulin dose to be reduced to 0.05 - 0.025 units/kg/h. The brain oedema improved and the boy made a full recovery.</p> <p>Conclusion</p> <p>Co-therapy with octreotide was associated with a favourable outcome in the present patient with DKA and cerebral oedema. Whether this could be ascribed to the effects of octreotide on the insulin requirement or on the GH/IGF-axis remains to be elucidated.</p

NrCAM, a neuronal system cell-adhesion molecule, is induced in papillary thyroid carcinomas

NrCAM (neuron-glia-related cell-adhesion molecule) is primarily, although not solely, expressed in the nervous system. In the present study, NrCAM expression was analysed in a series (46) of papillary thyroid carcinomas (PTCs) and paired normal tissues (NT). Quantitative reverse transcriptase (QRT)-PCR revealed that NrCAM expression was upregulated in all PTCs compared to normal thyroid, whatever the stage or size of the primary tumour. NrCAM transcript levels were 1.3- to 30.7-fold higher in PTCs than in NT. Immunohistochemistry (IHC) confirmed that the expression of NrCAM was considerably higher in tumours (score 2+/3+) than in adjacent normal paratumoural thyroid tissue. The NrCAM protein was detected in all but three (93.3%) PTC samples, and it was mainly cytoplasmic; in some cases there was additional membranous localisation – basolateral and partly apical. In the normal thyroid and tissues surrounding tumours, focal NrCAM immunolabelling was seen only in follicles containing tall cells, where staining was restricted to the apical pole of thyrocytes. Western blot analysis corroborated the QRT–PCR and IHC results, showing higher NrCAM protein levels in PTCs than in paired NT. The level of overexpression of the NrCAM mRNA in tumourous tissue appeared to be independent of the primary tumour stage (pT) or the size of the PTC. These data provide the first evidence that NrCAM is overexpressed in human PTCs at the mRNA and protein levels, whatever the tumour stage. Thus, the induction and upregulation of NrCAM expression could be implicated in the pathogenesis and behaviour of papillary thyroid cancers

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe