Screening For Gestational Diabetes Mellitus Selectively in a University Maternity Hospital

Aims Screening for gestational diabetes mellitus (GDM) may be universal or selective based on risk factors. We audited selective screening with an Oral Glucose Tolerance Test (OGTT). Methods Clinical and laboratory details of the first 200 women who delivered a baby in 2017 were analysed. Results Based on national recommendations, 46.5% (n=93) had maternal risk factors (RF) and an additional 6.5% (n=13) had fetal RF. Nine women with RF, for unexplained reasons did not have their OGTT. Of the 95 who had their OGTT, the diagnosis of GDM was made in 27.4% (n=26). The diagnosis of GDM was made in an additional 8 women outside selective screening giving an overall incidence of 17.0%. Discussion More than half of the women needed to be screened selectively for GDM. Compliance with the national recommendations was incomplete and thus the diagnosis of GDM may be missed even in an academic setting.

Exhaust system-related burns affecting children: a UK perspective and literature review.

Burns caused by exhaust systems in children may be associated with considerable morbidity. Current epidemiological data varies, but no data are available for the UK population. We aim to identify the pattern of exhaust-related burns affecting children who presented to a regional centre for paediatric burn care in the UK. Patients who sustained burns related to exhaust mechanisms between May 2005 and August 2012 were identified via the departmental database. Data collected included patient demographics, burn injury information, management and outcomes. Thirty-nine patients sustained 43 burns from contact with exhaust mechanisms, and the majority were less than 5 years of age. 77% of the patients were male. Burns affected critical areas such as the hands and feet in 26% of cases. Most burns involved a total body surface area of ≤1% and were partial thickness in depth. Thirty-three percent of patients required operative intervention. Time to heal was less than 3 weeks in 69% of cases and 3 patients healed with hypertrophic scarring. The majority of burns were small in size and partial thickness in depth. Most were treated conservatively and healed with low complication rates. More than 1 in 5 injuries involved critical burn areas, highlighting the potential for considerable morbidity. The age profile in our study contrasted with other results worldwide. Our study highlights the need for vigilant supervision of children around motorcycles. We recommend the wearing of protective long trousers when riding motorcycles and the fitting of external shields to motorcycle exhaust pipes.

Les brûlures par pot d'échappement chez l'enfant peuvent être responsables d'une morbidité importante. Les données épidémiologiques actuelles sont variables, mais il n'y en a pas au Royaume Uni. Nous avons analysé les circonstances de survenue des brûlures par pot d'échappement touchant les enfants vus dans un CTB régional du Royaume Uni, entre mai 2005 et août 2012, retrouvés via la banque de données régionale. Les variables analysées étaient les données démographiques, le mécanisme précis de la brûlure, la prise en charge et le devenir. Trente neuf patients ont subi 43 brûlures par ce mécanisme, la majorité ayant moins de 5 ans, 77% d'entre eux étant des garçons. Les brûlures atteignaient des régions sensibles (mains, pieds) dans 26% des cas, touchaient moins de 1% de SCT dans la plupart des cas et étaient fréquemment intermédiaires. Trente neuf pour cent des patients on nécessité une intervention chirurgicale. Dans 69% des cas, la cicatrisation était obtenue en moins de 3 semaines, 3 patients ont développé une cicatrice hypertrophique. La majorité des brûlures touchent une petite surface et sont peu profondes, cicatrisant sans chirurgie ni séquelles. Plus d'une brûlure sur 5 touche des zones fonctionnelles, avec un potentiel morbide élevé. La classe d'âge touchée contraste avec les données retrouvées ailleurs et nécessite une vigilance accrue au profit des enfants lorsqu'ils sont autour de 2 roues à moteur. Nous recommandons de porter des pantalons longs et la mise en place de protections autour des pots d'échappement.

Gonadotropin-releasing hormone receptor signaling: biased and unbiased.

Gonadotropin-releasing hormone is a neuropeptide that acts via Gq coupled G-protein coupled receptors in the pituitary that mediate central control of reproduction. GnRH receptors (GnRHR) and GnRH ligands are also found in extra-pituitary sites including the CNS as well as reproductive tissues and cancer cells derived from such tissues. Much of the interest in the extra-pituitary receptors stems from the fact that they mediate anti-proliferative and/or pro-apoptotic effects and may therefore be directly targeted for cancer therapy. Type I mammalian GnRHR are atypical in that they do not bind to (or signal via) arrestins. In spite of this restriction on their signaling repertoire, there is good evidence for existence of multiple active GnRHR conformations and for activation of multiple upstream effectors (heterotrimeric and monomeric G-proteins). In this review GnRHR signaling is described, with emphasis on the relevance of functional selectivity for pharmacological characterization of GnRHR ligands, as well as its possible contribution to contextdependent GnRHR signaling and relevance for GnRHR-mediated effects on cell fate as well as GnRHR trafficking.

Using automated imaging to interrogate gonadotrophin-releasing hormone receptor trafficking and function.

Gonadotrophin-releasing hormone (GnRH) acts via seven transmembrane receptors on gonadotrophs to stimulate gonadotrophin synthesis and secretion, and thereby mediates central control of reproduction. Type I mammalian GnRHR are unique, in that they lack C-terminal tails. This is thought to underlie their resistance to rapid homologous desensitisation as well as their slow rate of internalisation and inability to provoke G-protein-independent (arrestin-mediated) signalling. More recently it has been discovered that the vast majority of human GnRHR are actually intracellular, in spite of the fact that they are activated at the cell surface by a membrane impermeant peptide hormone. This apparently reflects inefficient exit from the endoplasmic reticulum and again, the absence of the C-tail likely contributes to their intracellular localisation. This review is intended to cover some of these novel aspects of GnRHR biology, focusing on ways that we have used automated fluorescence microscopy (high content imaging) to explore GnRHR localisation and trafficking as well as spatial and temporal aspects of GnRH signalling via the Ca(2+)/calmodulin/calcineurin/NFAT and Raf/MEK/ERK pathways.

Encoding and decoding mechanisms of pulsatile hormone secretion.

Ultradian pulsatile hormone secretion underlies the activity of most neuroendocrine systems, including the hypothalamic-pituitary adrenal (HPA) and gonadal (HPG) axes, and this pulsatile mode of signalling permits the encoding of information through both amplitude and frequency modulation. In the HPA axis, glucocorticoid pulse amplitude increases in anticipation of waking, and, in the HPG axis, changing gonadotrophin-releasing hormone pulse frequency is the primary means by which the body alters its reproductive status during development (i.e. puberty). The prevalence of hormone pulsatility raises two crucial questions: how are ultradian pulses encoded (or generated) by these systems, and how are these pulses decoded (or interpreted) at their target sites? We have looked at mechanisms within the HPA axis responsible for encoding the pulsatile mode of glucocorticoid signalling that we observe in vivo. We review evidence regarding the 'hypothalamic pulse generator' hypothesis, and describe an alternative model for pulse generation, which involves steroid feedback-dependent endogenous rhythmic activity throughout the HPA axis. We consider the decoding of hormone pulsatility by taking the HPG axis as a model system and focussing on molecular mechanisms of frequency decoding by pituitary gonadotrophs.

A clinical risk score to predict 3-, 5- and 10-year survival in patients undergoing surgery for Dukes B colorectal cancer.

BACKGROUND: The prognosis of patients with Dukes stage B colorectal cancer is unpredictable and there is continuing interest in simply and reliably identifying patients at high risk of developing recurrence and dying of their disease. The aim of this study was to devise a clinical risk score to predict 3-, 5- and 10-year survival in patients undergoing surgery for Dukes stage B colorectal cancer. METHODS: A total of 1350 patients who underwent surgery for Dukes stage B colorectal cancer between 1991 and 1994 in 11 hospitals in Scotland were included in the analysis. RESULTS: On follow-up, 926 patients died of whom 479 died of their cancer. At 10 years, cancer-specific survival was 61% and overall survival was 38%. On multivariate analysis, age ≥75 (hazard ratio (HR) 1.45, 95% confidence interval (CI) 1.15-1.82, P=0.001), emergency presentation (HR 1.59, 95% CI 1.27-1.99, P<0.001) and anastomotic leak (HR 2.17, 95% CI 1.24-3.78, P<0.01) were independently associated with cancer-specific survival in colon cancer. On multivariate analysis, only age ≥75 (HR 1.58, 95% CI 1.14-2.18, P<0.01) was associated with cancer-specific survival in rectal cancer. Age, presentation and anastomotic leak hazards could be simply added to form a clinical risk score from 0 to 2 in colon cancer. In patients with Dukes B stage colon cancer, the cancer-specific survival at 5 years for patients with a cumulative score 0 was 81%, 1 was 67% and 2 was 63%. The cancer-specific survival rate at 10 years for patients with a clinical risk score of 0 was 72%, 1 was 58% and 2 was 53%. CONCLUSION: The results of this study, in a mature cohort, introduce a new simple clinical risk score for patients undergoing surgery for Dukes B colon cancer. This provides a solid foundation for the examination of the impact of additional factors and treatment on prediction of 3-, 5- and 10-year cancer-specific survival.

Trafficking and signalling of gonadotrophin-releasing hormone receptors: an automated imaging approach.

Gonadotrophin-releasing hormone (GnRH) is a neuropeptide that mediates central control of reproduction by stimulating gonadotrophin secretion from the pituitary. It acts via 7 transmembrane region (7TM) receptors that lack C-terminal tails, regions that for many 7TM receptors, are necessary for agonist-induced phosphorylation and arrestin binding as well as arrestin-dependent desensitization, internalization and signalling. Recent work has revealed that human GnRH receptors (GnRHR) are poorly expressed at the cell surface. This apparently reflects inefficient exit from the endoplasmic reticulum, which is thought to be increased by pharmacological chaperones (non-peptide GnRHR antagonists that increase cell surface GnRHR expression) or reduced by point mutations that further impair GnRHR trafficking and thereby cause infertility. Here, we review recent work in this field, with emphasis on the use of semi-automated imaging to interrogate compartmentalization and trafficking of these unique 7TM receptors.

The impact of young age on cancer-specific and non-cancer-related survival after surgery for colorectal cancer: 10-year follow-up.

BACKGROUND: It has been reported that although young patients present with more advanced disease, when adjusted for stage, cancer-specific survival is not different after surgery for colorectal cancer. However, few studies have examined non-cancer survival in young patients and 10-year survival has rarely been reported. Moreover, the largest study included patients of old age as a comparator. The aim of this study was to compare cancer-specific and non-cancer-related survival at 10 years in a young age cohort and a middle age cohort in patients undergoing surgery for colorectal cancer. METHODS: Two thousand and seventy seven patients who underwent surgery for colorectal cancer between 1991 and 1994 in 11 hospitals in Scotland were included in the study. Ten-year cancer-specific and non-cancer-related survival and the hazard ratios (HR) were calculated according to age groups (<45/45-54/55-64/65-74 years). RESULTS: On follow-up, 1066 patients died of their cancer and 369 died of non-cancer-related causes. At 10 years, overall survival was 32%, cancer-specific was 45%, and non-cancer-related survival was 72%. On multivariate analysis of all factors, sex (HR 0.77, 95% CI 0.68-0.88, P<0.001), mode of presentation (HR 1.64, 95% CI 1.44-1.87, P<0.01), Dukes' stage (HR 2.69, 95% CI 2.49-2.90, P<0.001), and specialisation (HR 1.24, 95% CI 1.04-1.44, P<0.01) were independently associated with cancer-specific survival. On multivariate analysis of all factors, age (HR 2.46, 2.04-2.97, P<0.001), sex (HR 0.56, 0.45-0.70, P<0.001), and deprivation (HR 1.16, 1.10-1.24, P<0.001) were independently associated with non-cancer-related survival. CONCLUSION: The results of this study confirm that young age does not have a negative impact on cancer-specific survival. Moreover, they show that, with 10-year follow-up, young age does not have a negative impact on non-cancer-related survival.

Involvement of PKC alpha and G-protein-coupled receptor kinase 2 in agonist-selective desensitization of mu-opioid receptors in mature brain neurons.

BACKGROUND AND PURPOSE: The ability of an agonist to induce desensitization of the mu-opioid receptor (MOR) depends upon the agonist used. Furthermore, previous data suggest that the intracellular mechanisms underlying desensitization may be agonist-specific. We investigated the mechanisms underlying MOR desensitization, in adult mammalian neurons, caused by morphine (a partial agonist in this system) and DAMGO (a high-efficacy agonist). EXPERIMENTAL APPROACH: MOR function was measured in locus coeruleus neurons, by using whole-cell patch-clamp electrophysiology, in rat and mouse brain slices (both wild-type and protein kinase C (PKC)alpha knockout mice). Specific isoforms of PKC were inhibited by using inhibitors of the receptors for activated C-kinase (RACK), and in vivo viral-mediated gene-transfer was used to transfect neurons with dominant negative mutants (DNMs) of specific G-protein-coupled receptor kinases (GRKs). KEY RESULTS: Morphine-induced desensitization was attenuated by using RACK inhibitors that inhibit PKCalpha, but not by other isoform-specific inhibitors. Further, the PKC component of morphine-induced desensitization was absent in locus coeruleus neurons from PKCalpha knockout mice. The PKC-enhanced morphine-induced desensitization was not affected by over-expression of a GRK2 dominant negative mutant (GRK2 DNM). In contrast, DAMGO-induced MOR desensitization was independent of PKC activity but was reduced by over-expression of the GRK2 DNM but not by that of a GRK6 DNM. CONCLUSIONS AND IMPLICATIONS: In mature mammalian neurons, different MOR agonists can induce MOR desensitization by different mechanisms, morphine by a PKCalpha-mediated, heterologous mechanism and DAMGO by a GRK-mediated, homologous mechanism. These data represent functional selectivity at the level of receptor desensitization.

The impact of old age on cancer-specific and non-cancer-related survival following elective potentially curative surgery for Dukes A/B colorectal cancer.

Previous studies have suggested that survival following surgery for colorectal cancer is poorer in the elderly. However, the findings were inconsistent and none of the studies adjusted for case mix. The aim of this study was to establish whether there were age-related differences in cancer (colorectal)-specific and non-cancer (colorectal)-related survival in patients undergoing elective potentially curative resection for Dukes stage A/B colorectal cancer. One thousand and forty three patients who underwent elective potentially curative resection for Dukes' A/B colorectal cancer between 1991 and 1994 in 11 hospitals in Scotland were included in the study. Ten year cancer-specific and non-cancer-related survival and the hazard ratios were calculated according to age groups (<64; 65-74/>74 years). On follow-up 273 patients died of their cancer and 328 died of non-cancer-related causes. At 10 years, overall survival was 45%, cancer specific was 70% and non-cancer-related survival was 64%. On multivariate analysis of all factors, age (HR 1.38, 95% CI 1.18-1.62, P<0.001), sex (HR 1.74, 95% CI 1.36-2.23, P<0.001), site (HR 1.42, 95% CI 1.11-1.81, P<0.01) and Dukes' stage (HR 1.71, 1.19-2.47, P<0.01) were independently associated with cancer-specific survival. On multivariate analysis of all factors, age (HR 2.14, 1.84-2.49, P<0.001), sex (HR 1.43, 1.15-1.79, P<0.01) and deprivation (HR 1.30, 1.09-1.55, P<0.01) were independently associated with non-cancer-related survival. The results of this study show that increasing age impacts negatively both on cancer-specific and non-cancer-related survival following elective potentially curative resection for node-negative colorectal cancer. However, the effect of increasing age is greater on the non-cancer-related survival. These results suggest that cancer-specific and non-cancer-related mortality should be considered separately in survival analysis of these cancer patients.

Effect of intraoperative fluid optimisation on renal function in patients undergoing emergency abdominal surgery: a randomised controlled pilot study (ISRCTN 11799696).

BACKGROUND: Emergency abdominal surgery carries a high risk of postoperative morbidity and mortality. Goal directed therapy has been advocated to improve outcome in high-risk surgery. The aim of the present pilot study was to examine the effect of goal directed therapy using fluid alone on postoperative renal function and organ failure score in patients undergoing emergency abdominal surgery. METHODS: This prospective randomised pilot study included patients over the age of 50 undergoing emergency abdominal surgery. In the intervention group pulse pressure variation measurements were used to guide fluid boluses of 6% Hydroxyethylstarch 130/0.4. The control group received standard care. Serum urea, creatinine and cystatin C levels were measured prior to and at the end of surgery and postoperatively on day 1, day 3 and day 5. RESULTS: Thirty patients were recruited. One patient died prior to surgery and was excluded from the analysis. The intervention group received a median of 750 ml of hydroxyethylstarch. The peak values of postoperative urea were 6.9 (2.7-31.8) vs. 6.4 (3.5-11.5)mmol/l (p=0.425), creatinine 100 (60-300) vs. 85 (65-150) micromol/l (p=0.085) and cystatin C 1.09 (0.66-4.94) vs. 1.01 (0.33-2.29)mg/dl (p=0.352) in the control and intervention group, respectively. CONCLUSIONS: In the present pilot study replacing the identified fluid deficit was not associated with a change in renal function. These results do not preclude that goal directed therapy using fluid alone may have an effect on renal function but they would suggest that the effect size of fluid optimisation alone on renal function is small.

The relationship between tumour proliferative activity, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer.

BACKGROUND: The aim of the present study was to examine the relationship between Ki-67, C-reactive protein and cancer-specific survival in patients undergoing resection for colorectal cancer. METHOD: One hundred and forty-seven patients undergoing potentially curative resection for colorectal cancer had preoperative C-reactive protein concentrations and tumour Ki-67 labelling index measured. RESULTS: On univariate analysis, age (P < 0.001), Dukes stage (P < 0.001), C-reactive protein (P < 0.001) and expression of Ki-67 (< 0.01) were associated with poorer cancer-specific survival. Ki-67 labelling index and C-reactive protein were correlated (r(s) = 0.172, P = 0.037). On multivariate analysis, age (HR 1.96, 95% CI 1.26-3.04, P = 0.003), Dukes stage (HR 4.38, 95% CI 2.11-9.09, P < 0.001) and C-reactive protein (HR 4.09, 95% CI 2.04-8.24, P < 0.001) retained significance. CONCLUSION: Increased tumour proliferation is associated with a systemic inflammatory response and poor cancer-specific survival in patients undergoing potentially curative surgery for colorectal cancer.

Preoperative but not postoperative systemic inflammatory response correlates with survival in colorectal cancer.

BACKGROUND: The aim of the present study was to evaluate the relationship between the preoperative and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for colorectal cancer. METHODS: One hundred and eighty patients with colorectal cancer were studied. Circulating concentrations of C-reactive protein (CRP) were measured before surgery and in the immediate postoperative period. RESULTS: The peak in CRP concentration occurred on day 2 (P < 0.001). During the course of the study 59 patients died, 30 from cancer and 29 from intercurrent disease. Day 2 CRP concentrations were dichotomized. In univariable analysis, advanced tumour node metastasis stage (P = 0.002), a raised preoperative CRP level (P < 0.001) and the presence of hypoalbuminaemia (P = 0.043) were associated with poorer cancer-specific survival. CONCLUSION: Preoperative but not postoperative CRP concentrations are associated with poor tumour-specific survival in patients undergoing potentially curative resection for colorectal cancer.

Evaluation of the relationship between the systemic inflammatory response and cancer-specific survival in patients with primary operable breast cancer.

The relationship between the systemic inflammatory response (as evidenced by elevated C-reactive protein and lowered albumin concentrations), clinico-pathologic status and relapse-free, cancer-specific and overall survival was examined in patients with invasive primary operable breast cancer (n=300). The median follow-up of the survivors was 46 months. During this period, 37 patients relapsed and 25 died of their cancer. On multivariate analysis, only tumour size (P<0.05), albumin (P<0.01) and systemic treatment (P<0.0001) were significant independent predictors of relapse-free, cancer-specific and overall survival. Lower serum albumin concentrations (

Postoperative serum urea is associated with 30-day mortality in patients undergoing emergency abdominal surgery.

BACKGROUND: Emergency abdominal surgery carries considerable postoperative morbidity and mortality. Hypovolaemia is considered to be a cause of renal hypoperfusion, which is associated with a decreased clearance of serum urea and creatinine. This study examines whether the perioperative serum urea and creatinine concentrations are predictors of mortality in patients undergoing emergency abdominal surgery. METHODS: Consecutive patients (n=300) who underwent emergency abdominal surgery were studied. Age- and sex-specific reference intervals were used for the data analysis. Patients with incomplete biochemical (n=51) or mortality data (n=31) or with pre-existing renal failure (n=9) were excluded from the analysis. RESULTS: 209 patients were analysed, of whom 162 (78%) remained alive and 47 (22%) died following surgery. The non-survivors were older (P<0.05), had undergone more extensive surgery (P<0.001) and were more likely to have been admitted to the intensive care unit (P<0.001). The serum urea concentration was higher preoperatively (P<0.05) and on day one postoperatively (P<0.001) in the non-survivors. On multivariate logistic regression analysis, age (odds ratio [OR] 3.27, 95% confidence interval [CI] 1.43-7.47, P<0.005), severity of surgery (OR 2.21, 95% CI 1.14-4.29, P<0.019), admission to intensive care (OR 0.54, 95% CI 0.11-0.54, P<0.001), seniority of anaesthetist (OR 0.50, 95% CI 0.27-0.90, P<0.022) and day one urea (OR 3.33, 95% CI 1.39-7.99, P<0.007) were independently associated with 30-day mortality. CONCLUSIONS: These results indicate that an increased serum urea concentration, but not serum creatinine concentration, in the postoperative period is associated with an increase in 30-day mortality in patients undergoing emergency abdominal surgery.