Differential visceral blood flow in the hyperdynamic circulation of patients with liver cirrhosis.

BACKGROUND: With advancing liver disease and the development of portal hypertension, there are major alterations in somatic and visceral blood flow. Using phase-contrast magnetic resonance angiography, we characterised alterations in blood flow within the hepatic, splanchnic and extra-splanchnic circulations of patients with established liver cirrhosis. AIM: To compare blood flow in splanchnic and extra-splanchnic circulations in patients with varying degrees of cirrhosis and healthy controls. METHODS: In a single-centre prospective study, 21 healthy volunteers and 19 patients with established liver disease (Child's stage B and C) underwent electrocardiogram-gated phase-contrast-enhanced 3T magnetic resonance angiography of the aorta, hepatic artery, portal vein, superior mesenteric artery, and the renal and common carotid arteries. RESULTS: In comparison to healthy volunteers, resting blood flow in the descending thoracic aorta was increased by 43% in patients with liver disease (4.31 ± 1.47 vs. 3.31 ± 0.80 L/min, P = 0.011). While portal vein flow was similar (0.83 ± 0.38 vs. 0.77 ± 0.35 L/min, P = 0.649), hepatic artery flow doubled (0.50 ± 0.46 vs. 0.25 ± 0.15 L/min, P = 0.021) and consequently total liver blood flow increased by 30% (1.33 ± 0.84 vs. 1.027 ± 0.5 L/min, P = 0.043). In patients with liver disease, superior mesenteric artery flow was threefold higher (0.65 ± 0.35 vs. 0.22 ± 0.13 L/min, P < 0.001), while total renal blood flow was reduced by 40% (0.37 ± 0.14 vs. 0.62 ± 0.22 L/min, P < 0.001) and total carotid blood flow unchanged (0.62 ± 0.20 vs. 0.65 ± 0.13 L/min, P = 0.315). CONCLUSIONS: Rather than a generalised systemic hyperdynamic circulation, liver disease is associated with dysregulated splanchnic vasodilatation and portosystemic shunting that, while inducing a high cardiac output, causes compensatory extra-splanchnic vasoconstriction - the 'splanchnic steal' phenomenon. These circulatory disturbances may underlie many of the manifestations of advanced liver disease.

A national trainee-led audit of inguinal hernia repair in Scotland.

PURPOSE: This audit assessed inguinal hernia surgery in Scotland and measured compliance with British Hernia Society Guidelines (2013), specifically regarding management of bilateral and recurrent inguinal hernias. It also assessed the feasibility of a national trainee-led audit, evaluated regional variations in practise and gauged operative exposure of trainees. METHODS: A prospective audit of adult inguinal hernia repairs across every region in Scotland (30 hospitals in 14 NHS boards) over 2-weeks was co-ordinated by the Scottish Surgical Research Group (SSRG). RESULTS: 235 patients (223 male, median age 61) were identified and 96 % of cases were elective. Anaesthesia was 91 % general, 5 % spinal and 3 % local. Prophylactic antibiotics were administered in 18 %. Laparoscopic repair was used in 33 % (30 % trainee-performed). Open repair was used in 67 % (42 % trainee-performed). Elective primary bilateral hernia repairs were laparoscopic in 97 % while guideline compliance for an elective recurrence was 77 %. For elective primary unilateral hernias, the use of laparoscopic repair varied significantly by region (South East 43 %, North 14 %, East 7 % and West 6 %, p < 0.001) as did repair under local anaesthesia for open cases (North 21 %, South East 4 %, West 2 % and East 0 %, p = 0.001). Trainees independently performed 9 % of procedures. There were no significant differences in trainee or unsupervised trainee operator rates between laparoscopic and open cases. Mean hospital stay was 0.7-days with day case surgery performed in 69 %. CONCLUSIONS: This trainee-lead audit provides a contemporary view of inguinal hernia surgery in Scotland. Increased compliance on recurrent cases appears indicated. National re-audit could ensure improved adherence and would be feasible through the SSRG.

A national survey of attitudes to research in Scottish General Surgery Trainees.

INTRODUCTION: Given the importance placed on awareness and participation in research by Speciality and Training organisations, we sought to survey Scottish trainee attitudes to exposure to research practice during training and research in or out of programme. METHODS: An online survey was distributed to core and specialist trainees in general surgery in Scotland. RESULTS: Over a 4-month period, 108 trainees (75 ST/SPRs and 33 CTs) completed the survey. In their current post, most were aware of ongoing research projects (77%) and 55% were aware of trial recruitment. Only 47% attend regular journal clubs. Most believe that they are expected to present (89%) and publish (82%) during training. Most (59%) thought that participation in research is well supported. 57% were advised to undertake time out of programme research, mostly by consultants (48%) and training committee (36%). Of the 57 with time out of programme research experience, most did so in early training (37%) or between ST3-5 (47%). 28 out of the 36 (78%) without a national training number secured one after starting research. Most undertook research in a local academic unit (80%) funded by small grants (47%) or internally (33%). Most research (69%) was clinically orientated (13/55 clinical, 25/55 translational). 56% of those completing time out of programme research obtained an MD or PhD. About 91% thought that research was relevant to a surgical career. CONCLUSIONS: Most trainees believe that research is an important part of training. Generally, most trainees are exposed to research practices including trial recruitment. However, <50% attend regular journal clubs, a pertinent point, given the current 'exit exam' includes the assessment of critical appraisal skills.

Applied anatomy of the superficial branch of the radial nerve.

The superficial branch of the radial nerve (SBRN) is highly vulnerable to trauma and iatrogenic injury. This study aimed to map the course of the SBRN in the context of surgical approaches and identify a safe area of incision for de Quervain's tenosynovitis. Twenty-five forearms were dissected. The SBRN emerged from under brachioradialis by a mean of 8.31 cm proximal to the radial styloid (RS), and remained radial to the dorsal tubercle of the radius by a mean of 1.49 cm. The nerve divided into a median of four branches. The first branch arose a mean of 4.92 cm proximal to the RS, traveling 0.49 cm radial to the first compartment of the extensor retinaculum, while the main nerve remained ulnar to it by 0.64 cm. All specimens had branches underlying the traditional transverse incision for de Quervain's release. A 2.5-cm longitudinal incision proximal from the RS avoided the SBRN in 17/25 cases (68%). In 20/25 specimens (80%), the SBRN underlay the cephalic vein. In 18/25 (72%), the radial artery was closely associated with a sensory nerve branch near the level of the RS (SBRN 12/25, lateral cutaneous nerve of the forearm (LCNF) 6/25.) A longitudinal incision in de Quervain's surgery may be preferable. Cannulation of the cephalic vein in the distal third of the forearm is best avoided. The close association between the radial artery and first branch of the SBRN or the LCNF may explain the pain often experienced during arterial puncture. Particular care should be taken during radial artery harvest to avoid nerve injury.

Recurrence after totally extraperitoneal laparoscopic repair: implications for operative technique and surgical training.

BACKGROUND: The totally extraperitoneal (TEP) approach is increasingly favoured for inguinal hernia repair. The learning curve is slow with high, early recurrence rates but the exact cause of recurrence is unknown. OBJECTIVE: To determine the reasons for recurrence, identify the critical operative steps and examine the influence of surgical experience and training on results. PATIENTS AND METHODS: All patients undergoing TEP between 1993 and 2004 were included. Patients requiring re-operation for recurrence were identified and examined in detail. RESULTS: Eight surgical teams performed 1682 TEP repairs. Fifty five hernias recurred (3.27%) with a median follow-up of seven years (range 1-11 years). In six recurrences, the first repair was itself for recurrence and in 24, the initial repair was bilateral. The initial hernia was direct in 26 and indirect in 29 patients. These distributions were similar to a control sample. At re-operation, indirect recurrence was more common with 18 direct, and 37 indirect cases (P=0.020). At re-operation, when the original mesh could be identified (18 repairs), it appeared to have moved superiorly in 13 cases. Typically, recurrence occurred in 10% of a surgeon's first 20 cases, 4% of the next 60 cases and falling to below 2% thereafter. CONCLUSION: TEP repairs have a tendency for indirect recurrence even after direct repair. Meshes tend to migrate superiorly. Results suggest that recurrence occurs most often because of failure to fully expose the deep inguinal ring and/or to adequately spread the mesh inferiorly and laterally. We recommend particular attention be paid to these technical aspects. Acceptable results are obtainable after an experience of 20 cases but further improvement in results occurs as experience reaches 80 operations. With a large number of consultants having little or no experience in TEP surgery, there is an urgent need for 'hands-on' training courses so that all patients have access to TEP, particularly those with bilateral or recurrent inguinal herniae.

Effects of training and supervision on recurrence rate after inguinal hernia repair.

BACKGROUND: There is little information about the effects of operative experience and supervision of trainees on outcome in inguinal hernia surgery, one of the cornerstone operations of basic surgical training. METHODS: All primary inguinal hernia repairs carried out between 1994 and 2001 were registered prospectively in the Lothian Surgical Audit database. Subsequent problems that required re-referral were identified from this database. Patients who required reoperation for recurrence a median of 3 (range 1-7) years after surgery were identified. RESULTS: Some 4406 repairs, including 90 recurrences (2.0 per cent), were identified. Open mesh, open sutured and laparoscopic techniques were employed. Senior trainees (registrars and senior registrars) had similar recurrence rates to consultants; supervision did not affect outcome. Junior trainees (senior house officers) had similar recurrence rates to consultants as long as they were supervised by either a senior trainee or a consultant. Unsupervised junior trainees had unacceptably high recurrence rates (open mesh: relative risk (RR) 21.0 (95 per cent confidence interval (c.i.) 7.3 to 59.9), P < 0.001; open sutured: RR 16.5 (95 per cent c.i. 7.2 to 37.8), P < 0.001). CONCLUSION: Senior trainees may operate independently and supervise junior trainees, with recurrence rates equal to those of consultant surgeons. Junior trainees should be encouraged and given more practice in inguinal hernia repair with appropriate supervision.

Cocaine and amphetamine-regulated transcript mRNA regulation in the hypothalamus in lean and obese rodents.

Cocaine and amphetamine-regulated transcript (CART) mRNA and immunoreactivity are expressed abundantly in the hypothalamus. Central administration of various fragments of this neuropeptide decreases food intake in rodents. To find out whether CART might play a role in the physiological regulation of energy balance, we used in situ hybridization to investigate whether CART mRNA abundance changed in two chronic obese/fat versus lean states and after acute dietary restriction. In the first study, mice were treated with goldthioglucose to destroy glucose-responsive neurones in the ventromedial hypothalamus. This produced hyperphagia and obesity: 7 weeks after treatment, those receiving goldthioglucose weighed 70% more than the controls. CART mRNA abundance in the arcuate nucleus of goldthioglucose-treated mice was decreased by 71% compared to levels in the control mice, but CART expression was unaffected in the dorsolateral hypothalamus. In the second study, male Siberian hamsters were exposed to short days to induce a physiological winter response in which body weight decreases as fat reserves are catabolized, and food intake correspondingly declines. After 8 weeks in short days, body weight had declined by 18% relative to controls maintained in long days in a summer fat state. CART mRNA levels did not differ significantly between the two groups in any hypothalamic areas. In the third study, male Siberian hamsters, either in long days or after 12 weeks exposure to short days to induce weight loss, were subject to a 48-h period of fasting. Although photoperiod per se did not affect CART expression, fasting produced a significant decrease in CART mRNA in the arcuate nucleus of hamsters in both the long- and short-day state. We conclude that CART-producing cells are involved in energy homeostasis: the marked decrease in CART expression in the arcuate nucleus in goldthioglucose-lesioned mice may contribute to the development of obesity, and the decrease following acute dietary restriction in hamsters may reflect a compensatory mechanism to reduce caloric expenditure, but our results do not indicate that CART is involved in long-term seasonal regulation of body weight.

A comparison of enzyme-linked immunoabsorbent assays and flow cytometry techniques for the detection of HLA specific antibodies.

LATM, Quikscreen (QS), and B-Screen (QSB) are ELISA-based tests for the detection of HLA specific antibodies. FlowPRA beads are microparticles coated with HLA antigens for the detection of HLA specific antibodies by flow cytometry. The aim of this study was to evaluate the sensitivity and specificity of the LATM, QS, QSB, and FlowPRA screening tests. One hundred sixty-three sera from renal transplant patients were tested using LATM, FlowPRA, QS, and QSB. Discrepant results were further investigated using complement dependent cytotoxicity, QuikID, and PRA-STAT. When QS was compared with LATMI and FlowPRAI for the detection of HLA class I specific antibodies the overall concordance was 82.8% with no particular specificity missed by any one test. Comparing QSB with LATMII and FlowPRAII, for the detection of HLA class II specific antibodies, there was 90.7% concordance. Although the overall concordance was better for class II specific antibodies, QSB failed to detect antibodies to HLA-DQ in a number of samples from different patients. Of the methods tested, flow cytometry using FlowPRA beads appeared to be the most sensitive and specific, missing the least number of specificities. However, the ELISA methods offer the advantage of being more suitable for testing large numbers of samples in a more time- and cost-effective manner.

The application of flow cytometry to histocompatibility testing.

Flow cytometry is a powerful technique that enables the sensitive and quantitative detection of both cellular antigens and bound biological moieties. This article reviews how flow cytometry is increasingly being used as histocompatibility laboratories for the analysis of antibody specificity and HLA antigen expression. A basic description of flow cytometry principles and standardisation is given, together with an outline of clinical application in the areas of pre-transplant cross-matching, antibody screening, post-transplant antibody monitoring and HLA-B27 detection. It is concluded that flow cytometry is a useful multi-parametric analytical tool, yielding clinical benefit especially in the identification of patients at risk of early transplant rejection.

Risky business: sexual and asexual reproduction in variable environments.

Patterns of reproductive uncertainty can have an important influence on population dynamics. There is a crucial distinction between what we describe here as aggregate uncertainty (in which reproductive output in each generation is correlated among the individuals in a population) and idiosyncratic risk (in which reproductive output is independent across individuals). All else being equal, populations experiencing idiosyncratic risk enjoy a higher asymptotic growth rate than do those experiencing aggregate uncertainty. Therefore individuals in populations of the former type will have a competitive advantage over individuals in populations of the latter type. Applying this distinction to models of randomly fluctuating environments, we point out that genetic variation among offspring can serve to reduce aggregate uncertainty, transforming it into a more idiosyncratic form of risk. We show that this transformation underlies the dynamics observed in several previous models of the role of outcrossing in the evolution of sex.

A novel strategy for the detection and definition of HLA-specific antibodies in patients awaiting renal transplantation.

Conventional testing for HLA-specific antibodies employs complement-dependent cytotoxicity (CDC) which is labour intensive and dependent on a supply of viable lymphocytes. Our strategy to minimise CDC screening is initially to screen sera by ELISA (Quikscreen) to detect HLA Class I-specific antibodies. Negative sera are then screened by flow cytometry (FCS) using lymphoblastoid cell line pools to detect HLA Class II-specific antibodies. Only Quikscreen- or FCS-positive sera are then tested by CDC and, when indicated, with an ELISA kit (PRA-STAT) for specificity definition. Of 3680 sera, 886 (24.1%) were Quikscreen positive. Of the 2794 Quikscreen-negative sera, 374 (13.4%) were FCS positive. Therefore, only 1265 of the 3680 (34.3%) sera contained HLA-specific antibodies requiring specificity definition. This novel screening strategy has significantly reduced the CDC workload of the laboratory whilst enabling the detection of additional HLA-specific antibodies.

A retrospective flow cytometric crossmatch study in transplant recipients with autoreactive lymphocytotoxic antibodies.

Our previous data shows renal transplant recipients with autoreactive lymphocytotoxic antibodies to have a reduced transplant survival when compared to patients without autoantibodies. This could have been due to the presence of weak IgG antibodies inhibited by the dithiothreitol used to remove IgM antibodies in the pretransplant cytotoxicity crossmatch. That possibility was investigated in a retrospective study of 52 recipients of 57 renal transplants who were recrossmatched using a more sensitive flow cytometry crossmatch (FCXM) to detect recipient IgG antibodies to donor T and/or B cell splenic lymphocytes. Fourteen of the 57 (24%) transplants failed. Six losses were within the 1st month posttransplant and four of these were immunological failures. None of the transplant failures had a positive pretransplant FCXM. These results showed that the recipients with autoantibodies did not have pretransplant IgG anti-donor antibodies. The transplant failures did not, therefore, relate to the presence of antibodies undetected by the dithiothreitol-treated cytotoxicity crossmatch.

Expression of LFA-1 by a lymphoblastoid cell line from a patient with monosomy 21: effects on intercellular adhesion.

Monosomy 21 (M21) is a rare aneuploid condition which in certain cases leads to reduced levels of chromosome 21 gene products. We have prepared an Epstein-Barr virus lymphoblastoid cell-line (LCL) from patient with M21 who has immunological abnormalities, and analysed the expression of lymphocyte function-associated antigen-1 (LFA-1). This heterodimeric leucocyte integrin consists of CD11a (alpha) subunits non-covalently associated with CD18 (beta) subunits coded, respectively, by genes on chromosomes 16 and 21. To determine whether monosomy 21 results in decreased expression of LFA-1, monoclonal antibodies were used to compare the expression of CD11a and CD18 on the M21 LCL with LCL from trisomy 21 (Down's syndrome, T21), normal controls and a possible case of leucocyte adhesion deficiency. In addition, phorbol-ester-induced homotypic adhesion, an LFA-1-mediated effect, was compared in these LCLs. The results are consistent with a gene dosage mediated reduction of LFA-1 expression by the M21 LCL.

Efficiency in evolutionary games: Darwin, Nash and the secret handshake.

This paper considers any evolutionary game possessing several evolutionarily stable strategies, or ESSs, with differing payoffs. A mutant is introduced which will "destroy" any ESS which yields a lower payoff than another. This mutant possesses a costless signal and also conditions on the presence of this signal in each opponent. The mutant then can protect itself against a population playing an inefficient ESS by matching this against these non-signalers. At the same time, the mutants can achieve the more efficient ESS against the signaling mutant population itself. This construction is illustrated by means of the simplest possible example, a co-ordination game. The one-shot prisoner's dilemma is used to illustrate how a superior outcome which is not induced by an ESS may be temporarily but not permanently attained. In the case of the repeated prisoner's dilemma, the present argument seems to render the "evolution of co-operation" ultimately inevitable.

Monoclonal antibodies to CD18 and CD11A (LFA-1) distinguish Down's syndrome (trisomy 21) from normal lymphoblastoid cells.

To evaluate the potential of using fluorescence flow cytometry (FFC) in the diagnosis of Down's syndrome we analysed a series of Trisomy 21 lymphoid cell-lines (LCL) with a panel of monoclonal antibodies (MoAb) to the CD11a and CD18 subunits of lymphocyte function associated antigen 1 (LFA-1). In pairwise analysis of Trisomy 21 (T21) and normal LCL with 6 CD18 and 10 CD11a MoAb we found that T21 LCL could be distinguished from normal LCL with both types of MoAb, even though only the CD18 gene is duplicated in Down's syndrome. Experiments in which CD18 or CD11a were capped showed that the two subunits co-migrate on T21 and normal LCL, probably as heterodimers. This appears to explain the increased expression of CD11a on Trisomy 21 LCL. There was no evidence that T21 LCL express the other two leucocyte integrin subunits CD11b and CD11c, indicating that Trisomy 21 has little affect on tissue specific control of these molecules. In contrast, there appears to be reduced expression of an unrelated adhesion molecule LFA-3 on Trisomy 21 LCL. We discuss the relevance of these results in the diagnosis of Down's syndrome.

Liver preservation by single passage hypothermic "squirt" perfusion.

A single passage, hypothermic, intermittent squirt perfusion of the pig's liver is described which has allowed preservation of porcine livers for up to 17 hours. After preservation, orthotopically allografted livers can maintain recipient animals in good health. If this technique can be applied to clinical liver transplantation it should be possible to move livers from one hospital to another in the same way that kidneys are transported. This should increase the availability of donor livers for transplantation and avoid the serious disadvantages of moving the sick recipient just before the operation to the hospital where the donor has died.