Metabolic changes after surgical operations, with special reference to disturbances in protein, chloride, sodium and water metabolism after partial gastrectomy, and to the use of protein hydrolysates

(1) An investigation has been undertaken of certain post- operative metabolic disturbances in 59 surgical patients, and in 41 of these cases nitrogen balance studies were carried out. Control observations were also made on four healthy volunteers submitted to two types of food restriction, and on one patient who was not subjected to operation.(2) It was found that after gastrectomy in well- nourished subjects there was an increase in urinary nitrogen excretion which lasted for from five to eight days, the maximum loss of nitrogen being on the second to fifth days. During the same period the reduction in food intake combined with this increased excretion of nitrogen resulted in a period of negative nitrogen balance. Extension of the duration of this period of negative nitrogen balance beyond the minimum was related to protein and caloric intake or to complications, such as wound infection, broncho- pneumonia or superficial phlebitis.(3) In mal- nourished subjects there maybe no post -operative increase in urinary nitrogen excretion, or this may be much less severe than in well -nourished subjects.(4) The consumption of a high protein high calorie diet before operation has a variable effect on body weight: it is not, related in any consistent manner to nitrogen retention, and does not alter the response to operation in any significant way in well-nourished subjects. The catabolic phase is in no way diminished. An increase in the intake of calories after opera tion may accelerate the restoration of nitrogen equilibrium or positive balance. An increase in the protein intake without a proportionate increase in calories may lead to wastage of the protein. There is a physical limit to the quantity of food 'which may be eaten after gastrectomy, but this is much in excess of the diet which is usually provided.(5) The oral consumption of protein hydrolysate (such as pronutrin) was employed to increase the quantity of protein ingested. In the form at present available, such hydrolysates offer a compact means of administering protein if the patient can tolerate the smell and taste of the preparation.(6) Protein hydrolysates in the form of casydrol or amigen were administered by the intravenous route to 22 patients. In five of these detailed studies of the quantities of total nitrogen and the amino acid nitrogen excreted in the urine were made. The urinary amino acid nitrogen excretions during and after casydrol infusions were compared with those found in a control series of patients submitted to gastrectomy, and in a series of volunteers. About 60 per cent. of the amino acid nitrogen administered by the intravenous route as casydrol, and about 90 per cent. in the case of amigen, was apparently retained) in the body for metabolism. After gastrectomy, well- nourished subjects to whom casydrol or amigen was given by the intravenous route, excreted in addition to the increased quantity of nitrogen normally expected from protein catabolism, an amount of nitrogen about about equal to that administered as hydrolysate. In the remaining patients, no apparent benefit was obtained by the infusion of casydrol, except in one who was suffering from the effects of prolonged restriction of food consumption. Provided that a rate of 100 to 150 ml. per hour is not exceeded, casydrol does not cause nausea or other disturbances when administered by the intravenous route, and thrombosis and phlebitis are not more frequent than with 5 per cent, glucose solution alone. The few indications for the use of casydrol by the intravenous route which still appear to be justifiable on theoretical grounds, such as prolonged starvation or ulcerative colitis, require further examination by clinical trial.(7) Human plasma was administered to two patients as the sole source of protein. This method of supplying protein is condemned as unsound in conception and unsafe in practice.(8) After partial gastrectomy, the prevention of starvation throughout the post -operative period was achieved in three out of six patients in whom it was attempted by the administration of adequate quantities of protein and calories as milk mixture by jejunal tube or by mouth. There was still an increase in urinary nitrogen excretion, that is to say, the catabolic phase was not abolished. The negative nitrogen balance over the period of ten days after operation was, however, greatly reduced, being smaller than after any other procedure.(9) After partial gastrectomy there is usually some degree of haemodilution and increase in plasma volume indicated directly by measurement, and indirectly by reduction in haematocrit - 21 7 - haematocrit red blood corpuscles and haemoglobin concentration. There is often a reduction in plasma albumin concentration and a rise in plasma globulin concentration which may equal or exceed the change of albumin concentration. There are other and probably more important changes in the total quantities of these proteins in active circulation in the plasma. There is a contemporary shift of chloride from red blood corpuscles to plasma. There was no consistent change in plasma amino acid nitrogen, non -protein nitrogen or blood urea nitrogen concentra- tions even during or after hydrolysate infusions.(10) The observation of a reduction in urinary chloride excretion during the first six to eight days after major surgical operations led to further investigation and to a demonstration of a coincidence of reduction in urinary chloride excretion with the increased nitrogen excretion of the catabolic phase. Further investigation has revealed that following operation there is a retention in the body of chloride, sodium and water which is largely independent of the source or quantity of sodium and chloride, or the route by which they are made available.(11) There is no relationship between weight loss and nitrogen balance; this is probably due to changes in water and electrolyte balance masking the effects of nitrogen retention on loss of weight. After operation there appears to be a steady loss of body tissue which also for several days may be masked to some extent by water retention.(12) The possible clinical applications of these observations have been discussed and further hopeful lines of extension have been suggested

The Roles of Estrogen, Nitric Oxide, and Dopamine in the Generation of Hyperkinetic Motor Behaviors in Embryonic Zebrafish (Danio rerio)

Both estrogen (E2) and nitric oxide (NO) have been shown to affect motor function, in part, through regulation of dopamine (DA) release, transporter function, and the elicitation of neuroprotection/neurodegeneration of healthy neurons, as well as in neurodegenerative conditions such as Parkinson’s disease (PD). Currently, the “gold standard” treatment for PD is the use of levodopa (l-DOPA). However, patients who experience long-term l-DOPA and a monamine oxidase inhibitor (MAOI) treatment may develop unwanted side effects such as hyperkinesia which can be exacerbated by female Parkinsonian patients also on E2 replacement therapy. The current study was designed to determine whether embryonic zebrafish treated with either E2 or l-DOPA/MAOI develop a de novo-induced hyperkinetic movement disorder that relies on the NO pathway to elicit this hyperkinetic phenotype. Results from this study indicate that 5 days post-fertilization (dpf), fish treated with an l-DOPA + MAOI co-treatment or E2 elicited the development of a de novo hyperkinetic phenotype. In addition, the de novo l-DOPA + MAOI- and E2-induced hyperkinetic phenotypes are dependent on NO and E2 for its initiation and recovery. In conclusion, these findings point to the central role both NO and E2 play in the facilitation of de novo hyperkinesia

The Met Office Unified Model Global Atmosphere 6.0/6.1 and JULES Global Land 6.0/6.1 configurations

We describe Global Atmosphere 6.0 and Global Land 6.0: the latest science configurations of the Met Office Unified Model and JULES land surface model developed for use across all timescales. Global Atmosphere 6.0 includes the ENDGame dynamical core, which significantly increases mid-latitude variability improving a known model bias. Alongside developments of the model’s physical parametrisations, ENDGame also increases variability in the tropics, which leads to an improved representation of tropical cyclones and other tropical phenomena. Further developments of the atmospheric and land surface parametrisations improve other aspects of model performance, including the forecasting of surface weather phenomena. We also describe Global Atmosphere 6.1 and Global Land 6.1, which include a small number of long-standing differences from our main trunk configurations that we continue to require for operational global weather prediction. Since July 2014, GA6.1/GL6.1 has been used by the Met Office for operational global NWP, whilst GA6.0/GL6.0 was implemented in its remaining global prediction systems over the following year

Intensive versus standard physical rehabilitation therapy in the critically ill (EPICC): a multicentre, parallel-group, randomised controlled trial

Background Early physical rehabilitation in the intensive care unit (ICU) has been shown to improve short-term clinical outcomes but long-term benefit has not been proven and the optimum intensity of rehabilitation is not known. Methods We conducted a randomised, parallel-group, allocation-concealed, assessor-blinded, controlled trial in patients who had received at least 48 hours of invasive or non-invasive ventilation. Participants were randomised in a 1:1 ratio, stratified by admitting ICU, admission type and level of independence. The intervention group had a target of 90 min physical rehabilitation per day, the control group a target of 30 min per day (both Monday to Friday). The primary outcome was the Physical Component Summary (PCS) measure of SF-36 at 6 months. Results We recruited 308 participants over 34 months: 150 assigned to the intervention and 158 to the control group. The intervention group received a median (IQR) of 161 (67-273) min of physical rehabilitation on ICU compared with 86 (31-139) min in the control group. At 6 months, 62 participants in the intervention group and 54 participants in the control group contributed primary outcome data. In the intervention group, 43 had died, 11 had withdrawn and 34 were lost to follow-up, while in the control group, 56 had died, 5 had withdrawn and 43 were lost to follow-up. There was no difference in the primary outcome at 6 months, mean (SD) PCS 37 (12.2) in the intervention group and 37 (11.3) in the control group. Conclusions In this study, ICU-based physical rehabilitation did not appear to improve physical outcomes at 6 months compared with standard physical rehabilitation. Trial registration number ISRCTN 20436833

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist