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Background The optimal timing of cholecystectomy for patients admitted with acute gallbladder pathology is unclear. Some studies have shown that emergency cholecystectomy during the index admission can reduce length of hospital stay with similar rates of conversion to open surgery, complications and mortality compared with a ‘delayed’ operation following discharge. Others have reported that cholecystectomy during the index acute admission results in higher morbidity, extended length of stay and increased costs. This study examined the cost-effectiveness of emergency versus delayed cholecystectomy for acute benign gallbladder disease. Methods Using data from a prospective population-based cohort study examining the outcomes of cholecystectomy in the UK and Ireland, a model-based cost–utility analysis was conducted from the perspective of the UK National Health Service, with a 1-year time horizon for costs and outcomes. Probabilistic sensitivity analysis was used to investigate the impact of parameter uncertainty on the results obtained from the model. Results Emergency cholecystectomy was found to be less costly (£4570 versus £4720; €5484 versus €5664) and more effective (0·8868 versus 0·8662 QALYs) than delayed cholecystectomy. Probabilistic sensitivity analysis showed that the emergency strategy is more than 60 per cent likely to be cost-effective across willingness-to-pay values for the QALY from £0 to £100 000 (€0–120 000). Conclusion Emergency cholecystectomy is less costly and more effective than delayed cholecystectomy. This approach is likely to be beneficial to patients in terms of improved health outcomes and to the healthcare provider owing to the reduced costs.

To examine five available software packages for the assessment of abdominal adipose tissue with magnetic resonance imaging, compare their features and assess the reliability of measurement results. Feature evaluation and test–retest reliability of softwares (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision) used in manual, semi-automated or automated segmentation of abdominal adipose tissue. A random sample of 15 obese adults with type 2 diabetes. Axial T1-weighted spin echo images centered at vertebral bodies of L2–L3 were acquired at 1.5 T. Five software packages were evaluated (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision), comparing manual, semi-automated and automated segmentation approaches. Images were segmented into cross-sectional area (CSA), and the areas of visceral (VAT) and subcutaneous adipose tissue (SAT). Ease of learning and use and the design of the graphical user interface (GUI) were rated. Intra-observer accuracy and agreement between the software packages were calculated using intra-class correlation. Intra-class correlation coefficient was used to obtain test–retest reliability. Three of the five evaluated programs offered a semi-automated technique to segment the images based on histogram values or a user-defined threshold. One software package allowed manual delineation only. One fully automated program demonstrated the drawbacks of uncritical automated processing. The semi-automated approaches reduced variability and measurement error, and improved reproducibility. There was no significant difference in the intra-observer agreement in SAT and CSA. The VAT measurements showed significantly lower test–retest reliability. There were some differences between the software packages in qualitative aspects, such as user friendliness. Four out of five packages provided essentially the same results with respect to the inter- and intra-rater reproducibility. Our results using SliceOmatic, Analyze or NIHImage were comparable and could be used interchangeably. Newly developed fully automated approaches should be compared to one of the examined software packages.

The United Kingdom National Health Service treats both elective and emergency patients and seeks to provide high quality care, free at the point of delivery. Equal numbers of emergency and elective general surgical procedures are performed, yet surgical training prioritisation and organisation of NHS institutions is predicated upon elective care. The increasing ratio of emergency general surgery consultant posts compared to traditional sub-specialities has yet to be addressed. How should the capability gap be bridged to equip motivated, skilled surgeons of the future to deliver a high standard of emergency surgical care? The aim was to address both training requirements for the acquisition of necessary emergency general surgery skills, and the formation of job plans for trainee and consultant posts to meet the current and future requirements of the NHS. Twenty nine trainees and a consultant emergency general surgeon convened as a Working Group at The Association of Surgeons in Training Conference, 2015, to generate a united consensus statement to the training requirement and delivery of emergency general surgery provision by future general surgeons. Unscheduled general surgical care provision, emergency general surgery, trauma competence, training to meet NHS requirements, consultant job planning and future training challenges arose as key themes. Recommendations have been made from these themes in light of published evidence. Careful workforce planning, education, training and fellowship opportunities will provide well-trained enthusiastic individuals to meet public and societal need.

Differentiation of embryonic stem (ES) cells generally occurs after formation of three-dimensional cell aggregates, known as embryoid bodies (EBs). This differentiation occurs following suspension culturing of EBs in media containing a high (25 mM) glucose concentration. Although high-glucose-containing media is used for maintenance and proliferation of ES cells, it has not been demonstrated whether this is a necessary requirement for EB development. To address this, we examined the growth and differentiation of EBs established in 0-mM, 5.5-mM (physiological), and 25-mM (high) glucose concentrations, through morphometric analysis and examination of gene and protein expression. The effect on EB development of supplementation with basic fibroblast growth factor (FGF2) was also studied. We report that the greatest rate of EB growth occurs in 5.5 mM glucose media. A morphological study of EBs over 104 days duration under glucose-containing conditions demonstrated the development of all three major embryonic cell types. The difference from normal human development was obvious in the lack of rostrocaudal control by the notochord. In the latest stages of development, the main tissue observed appeared to be cartilage and cells of a mesodermal lineage. We conclude that physiological glucose concentrations are suitable for the culturing of EBs, that the addition of FGF2 enhances the temporal expression of genes including POU5F1, nestin, FOXA2, ONECUT1, NEUROD1, PAX6, and insulin, and that EBs can be cultured in vitro for long periods, allowing for further examination of developmental processes. developmental biology, early development, embryo, gene regulation

It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type II diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free-fatty acid flux and inhibition of insulin-action via Randle's effect in insulin-sensitive tissues.In this review, limitations of this paradigm will be discussed and two other paradigms that may explain established links between adiposity and insulin resistance/diabetes will be presented. (A) Ectopic fat storage syndrome. Three lines of evidence support this concept. Firstly, failure to develop adequate adipose tissue mass (also known as 'lipodystrophy') results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle and the pancreatic insulin-secreting beta cell. Secondly, most obese patients also shunt lipid into the skeletal muscle, the liver and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver highly correlates with insulin resistance. Thirdly, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and therefore to accommodate an increased energy influx. Taken together, these observations support the 'acquired lipodystrophy' hypothesis as a link between adiposity and insulin resistance. Ectopic fat deposition is therefore the result of additive or synergistic effects including increased dietary intake, decreased fat oxidation and impaired adipogenesis. (B) Endocrine paradigm. This concept was developed in parallel with the 'ectopic fat storage syndrome' hypothesis. Adipose tissue secretes a variety of endocrine hormones such as leptin, interleukin-6, angiotensin II, adiponectin and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues.The novel paradigms of ectopic fat and fat cell as an endocrine organ probably will constitute a new framework for the study of the links between our obesigenic environment and the risk of developing diabetes.

Early reports suggested that resistin is associated with obesity and insulin resistance in rodents. However, subsequent studies have not supported these findings. To our knowledge, the present study is the first assessment in human subjects of serum resistin and insulin sensitivity by the insulin clamp technique. Thirty-eight nonobese subjects [age, 23 ± 4 yr; body mass index (BMI), 25.4 ± 4.3 kg/m2], 12 obese subjects (age, 54 ± 8 yr; BMI, 33.0 ± 2.5 kg/m2), and 22 obese subjects with type 2 diabetes (age, 59 ± 7 yr; BMI, 34.0 ± 2.4 kg/m2) were studied. Serum resistin concentrations were not different among nonobese (4.1 ± 1.7 ng/ml), obese (4.2 ± 1.6 ng/ml), and obese diabetic subjects (3.7 ± 1.2 ng/ml), and were not significantly correlated to glucose disposal rate during a hyperinsulinemic glucose clamp across groups. Serum resistin was, however, inversely related to insulin sensitivity in nonobese subjects only (r = −0.35; P = 0.05), although this association was lost after adjusting for percent body fat. Serum resistin was not related to percent fat, BMI, or fat cell size. A strong correlation was observed between serum resistin and resistin mRNA expression from abdominal sc adipose tissue in a separate group of obese subjects (r = 0.62; P < 0.01; n = 56). Although the exact function of resistin is unknown, we demonstrated only a weak relationship between resistin and insulin sensitivity in nonobese subjects, indicating that resistin is unlikely to be a major link between obesity and insulin resistance in humans.

BACKGROUND/AIMS The aim of the study was to investigate the clinical and microbiological effects of azithromycin as an adjunct to the non-surgical treatment of periodontitis in adults. Azithromycin is an antibiotic which is taken up by phagocytes and is released over long periods in inflamed tissue but requires a total of only three doses of 500 mg to produce its therapeutic effect. METHOD 46 patients were treated in a double-blind placebo-controlled study with assessments at weeks 0, 1, 2, 3, 6, 10 and 22. Throughout the trial measurements were made of plaque, gingival bleeding, calculus, probing pocket depths and bleeding on probing. Microbiological sampling was carried out from a selected pocket >or=6 mm at each visit. The regime employed consisted of OHI, scaling and root planing at weeks 0, 1 and 2 with reinforcement of OHI and minimal scaling at weeks 6, 10 and 22. Patients were randomly assigned to receive either azithromycin, (A), or placebo capsules, (C), 500 mg, 1x daily for 3 days at week 2. 44 patients completed the study. Mean pocket depths were analysed using analysis of covariance in 3 groups with initial pocket depth values of 1-3 mm, 4-5 mm and >or=6 mm. RESULTS The results of the microbiology have been reported in a separate paper. The clinical data showed that by week 22 a lower % of pockets initially >5 mm deep remained above that level in the 23 patients taking azithromycin (A), than the 21 taking the placebo (C), (A, 5.6%; C, 23.3%). Also at week 22, for pockets initially 4 mm or more, the test group had fewer pockets >3 mm deep (A, 26.1%; C, 44.3%), fewer failing to improve in probing depth (A, 6.6%; C, 21.6%) and fewer continuing to bleed on probing (A, 46.9%; C, 55.6%) when compared with the control group. Pocket depths initially 4-5 mm or 6-9 mm analysed by analysis of covariance showed lower mean pocket depths in the patients on azithromycin, at weeks 6, 10 and 22, (pockets initially 4-5 mm, p

BackgroundLisfranc injury is rare and the diagnosis maybe easily missed. This study reviews the experience of a single centre.MethodsA prospective review of patients with Lisfranc injuries presenting to a single surgeon with a specialist interest in foot and ankle surgery over a one year period.ResultsFive patients were identified-four men and one woman with a median age of 31 years (range 22-50 years). Presentation was a mean of 25 days after injury (range 3-56 days). The left foot was affected in three cases and the right in two. There was joint diastasis in four patients and fracture-dislocation in one. Three patients presented early and were treated by internal fixation and two presented late and were managed conservatively. Mean follow-up was eight months (range 4.5-12 months). Surgery resulted in a return to work by 6 months with no symptoms. The two patients managed conservatively continued to experience pain at 12 months and were unable to return to their original occupations.ConclusionInjury to the Lisfranc joint should be excluded in any foot injury. Early diagnosis and internal fixation appears to result in an earlier return to work when compared to nonoperative management.

Intraocular lymphoma is a rare tumour, the two main types being primary central nervous system non-Hodgkin's lymphoma (CNS-NHL) and, less commonly, systemic lymphoma that has spread to involve the eye. We present a case of a systemic NHL resulting in a serpiginous choroidopathy. To our knowledge, this presentation has not previously been reported. The diagnosis of this case was made based on the temporal relationship between the clinical activity of the choroidopathy and its response to chemotherapy. Diagnosis of intraocular lymphoma on vitreous biopsy is notoriously difficult, and this case is presented along with a review of the literature regarding vitreous biopsy and diagnostic techniques.

Maternal hyperthermia of short duration had significant short and long term effects on the developing guinea-pig eye at embryonic days 19, 21 and 23. A marked regionalisation of the heat-induced effects was observed in the developing retinae, but the lens defects were most obvious following heat at E21 and E23. Bilateral anterior pole cataracts, bipolar zonular cataracts and microphthalmia have been produced following maternal heat stress. It is suggested that these are determined by the cellular events initiated in the developing eye following the teratogenic insult.

Pixel by pixel T1 mapping of MR images has been used in conjunction with image analysis techniques to study the lumbar vertebral bone marrow of 20 patients with refractory or relapsed Hodgkin's disease prior to salvage chemotherapy, or high dose chemotherapy with autologous bone marrow rescue. Compared to 18 age matched controls, seven patients had significantly abnormal lumbar vertebral marrow T1 histograms with median, 5% and 95% centile T1 values that lay outside a three dimensional 95% probability region obtained for the normals. Six of these patients had increased areas of high T1 consistent with bone marrow involvement with lymphoma; although, only in two of them had Hodgkin's disease been detected by bilateral iliac crest bone marrow biopsy. Post-treatment studies were performed in four patients who had abnormal areas of high T1 in the lumbar vertebral bone marrow. All showed normalisation of the T1 histogram, with a reduction of T1 values to within the normal range as defined by the studies of age matched controls. T1 mapping of bone marrow offers potential for detecting bone marrow infiltrates in patients with lymphoma, and also for the assessment of treatment response. Images Figure 6 Figure 7

Guinea pigs were exposed to hyperthermia for 1 hr once or twice on day 11, 12, 13, or 14 (E11-E14) of pregnancy. The mean rectal temperatures were elevated by 3.4 degrees C-4.0 degrees C. This treatment resulted in a marked elevation of rates of resorption and developmental defects in embryos examined at day E23. The defects observed were those affecting the neural tube (NTD) (exencephaly, encephaloceles, and microphthalmia), kyphosis/scoliosis, branchial arch defects, and pericardial edema. Embryos with NTD and kyphosis/scoliosis have not been found among newborn guinea pigs to date following maternal heat exposure on days E12-E14. It appears that embryos with these defects are filtered out by resorption or abortion by days E30-E35.

The size of adipocytes influences their function suggesting a differential responsiveness to intervention. We hypothesized that weight loss in patients with type 2 diabetes mellitus (T2DM) predominantly decreases the size of large and very-large adipocyte subfractions in parallel with beneficial changes in serum adipokines and improved insulin sensitivity. A total of 44 volunteers from the Look Action for Health in Diabetes trial, who lost weight after 1-year of intense lifestyle intervention, were included. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), size of subcutaneous abdominal adipocytes (osmium fixation), and selected serum adipokines were measured. A 13% weight loss was accompanied by 46% improvement in insulin sensitivity (increased glucose disposal rate from 5.9+/-2.2 to 8.6+/-2.7 mg/min/kg fat-free mass, P

Serial image-localized 31P magnetic resonance spectroscopy studies were performed in nine patients with newly diagnosed non-Hodgkin's lymphoma (NHL) during the early part of treatment with chemotherapy. The pre-treatment intracellular pH (pHi) of the tumours ranged from 6.97 to 7.61 for high-grade NHL (n = 3), and 7.16 to 7.39 for low-grade NHL (n = 5). A pH of 7.24 was recorded in a patient with intermediate-grade NHL. Slice-to-slice variation in tumour pHi in spectra obtained with a one-dimensional chemical shift imaging (1D-CSI) technique varied from zero to 0.5 pH units. The largest variation was seen in high-grade tumours. Slice-to-slice variation may reflect tumour heterogeneity. Alkaline shifts in tumour pHi of 0.14 to 0.45 pH units were seen in six patients following chemotherapy. Maximal change in tumour pH was related temporally to increases in the phosphodiester/beta-adenosine triphosphate ratio, and occurred before alterations in tumour size were documented. Cell death and necrosis may be associated with an alkaline shift in pHi due to cessation of H(+)-producing processes and release of basic components of proteins. An alkaline shift in tumour pHi may therefore be an early metabolic marker of response to chemotherapy.

Lumbar vertebral (LV) bone marrow proton relaxation times were measured from midline sagittal magnetic resonance images of the lumbar spine of 20 patients with refractory or relapsed Hodgkin’s disease (HD) referred for autologous bone marrow transplantation (ABMT) and 18 aged-matched normal volunteers.

Introduction Emergency surgical patients account for around half of all NHS surgical workload and 80% of surgical deaths. Few trainees opt to CCT in General Surgery, and there is no recognised subspecialty training program in Emergency General Surgery (EGS). Despite this lack of training and relevant assessment by examination, there appears to be an increasing number of EGS posts advertised. This may be associated with a reduction in the numbers of breast or vascular surgery posts that have general surgical commitments. We sought to explore changes in consultant surgeon job adverts over time. Method All consultant surgeon posts, advertised in the British Medical Journal between January 2009 and December 2014 were included. Posts in 9non-general surgical9 specialties were excluded. Data collected included specialty, region and institute of advertised post. For the purposes of statistical analysis, data was divided into two separate year bands: 2009 – 2011 and 2012 – 2014. Statistical analysis was by Chi-squared test; p Results Over the six-year study period, there were 1240 consultant job adverts in a general surgical specialty. Nine hundred and seventy-five were substantive posts; the region with the most jobs was London and the South East (n = 278). The total number of posts was 645 in 2009–11 and 595 2012–14. The most common specialties advertised were colorectal (313), breast (248), upper GI (207), pure general surgery (170) and vascular (80). There were 55 jobs advertised in EGS, either with (20) or without (35) another subspecialty. The number of EGS adverts increased significantly in 2012–14 compared to 2009–11 (p = 0.008). London and the South East were the highest recruiters to EGS posts (10% of all consultant surgeon posts advertised in the region). There was a borderline decrease in the number of breast with general surgery posts advertised (p = 0.021). Numbers of vascular with general surgery jobs and purely general surgery jobs did not change significantly over time. Conclusion This data demonstrates increasing societal need for EGS consultants over the last six years and the emergence of Emergency Surgery as a new subspecialty. The current training system in EGS on an ‘ad hoc’ basis alongside subspecialty training, may not adequately prepare newly appointed consultants. This is confounded by shortened training times in pre-existing subspecialties and introduction of EWTD. In order to meet the EGS needs of the NHS, general surgical training and the examination system need to be revised. Disclosure of interest None Declared.

OBJECTIVE: To compare the effects of a standard American diet, a traditional low-fat diet, and a low-fat diet containing the fat substitute olestra on risk factors for heart disease and diabetes. DESIGN: A 9-month, double-blind, randomized, parallel-arm, feeding study comparing three diets: (1) control (33% fat), (2) fat-reduced (FR; 25% fat), and (3) fat-substituted (FS) where olestra replaced 1/3 of dietary fat (33% lipid and 25% digestible fat). Subjects were allowed to adjust their total energy intake as desired, allowing weight to fluctuate. SUBJECTS: A total of 37 healthy, obese men (age 36.7±1.3 y; body mass index 30.8±0.4 kg/m2). MEASUREMENTS: Body weight and composition by dual-energy X-ray absorptiometry, blood pressure, serum lipids, lipoproteins, hemostatic factors, glucose, insulin, and leptin at baseline and every 3 months. RESULTS: The FS group lost 6.27 kg of body weight by 9 months vs 4.0 kg in the control and 1.79 kg in the FR groups. There was a significant diet main effect on cholesterol (P=0.002), low-density lipoprotein cholesterol (P=0.003), and triglycerides (P=0.01), all of which decreased in the FS group but not the other groups by 9 months. Apolipoprotein B (ApoB) increased in the FR and control groups but was unchanged in the FS group (diet main effect P=0.04). High-density lipoprotein (HDL) cholesterol increased in all groups over 9 months (time main effect P=0.0001). Time main effects were also observed for cholesterol, ApoA1, ApoB, Factor VII, diastolic blood pressure, and glucose. After adjustment for % fat loss at 9 months, the effects of diet on change in risk factors remained significant only for triglycerides. DISCUSSION: Consumption of a low-fat diet containing olestra for 9 months produced significant improvement in cardiovascular risk factors, an effect largely explained by weight loss. Long-term low-fat diet consumption with or without olestra does not decrease HDL cholesterol.

Adiponectin is an insulin-sensitizing hormone whose blood concentration is reduced in obesity and type 2 diabetes. Administration of recombinant adiponectin in rodents increases glucose uptake and increases fat oxidation in muscle, reduces fatty acid uptake and hepatic glucose production in liver, and improves whole body insulin resistance. The exact receptor and signaling systems are unknown, however, recent studies suggest adiponectin activates AMPK, a putative master metabolic regulator. Thus, excitement surrounds the potential for adiponectin, or a homologue of adiponectin, as pharamacotherapy agents for patients suffering from the metabolic syndrome and more particularly for individuals with insulin resistance and type 2 diabetes.

Maternal hyperthermia has been demonstrated to be a teratogen in every animal species studied, and a minimum core temperature rise of 2.5°C can produce a number of developmental defects. However, numerous embryos fail to survive to term. In the guinea-pig, heating the embryos prior to neural tube closure induces significant neural tube defects, but all embryos die within 20 days of heating. A number have aberrant cardiac development and many show spectacular pericardial effusions and congestion in the peripheral circulation. We suggest that maternal hyperthermia has interfered with neural crest migration which is a major component in the induction of these changes.

OBJECTIVE: To review the published literature regarding the effect of caloric restriction, pharmacologic intervention, and exercise to promote the loss of visceral adipose tissue (VAT) DESIGN: A review was conducted of published studies which measured VAT using computed tomography or magnetic resonance imaging before and after caloric restriction, pharmacologic therapy, or exercise. STUDIES REVIEWED: 23 separate studies were reviewed. Men represented 38% and women 63% of the 599 volunteers. There were 17 black volunteers and 30 patients with NIDDM included in these studies. MEASUREMENTS: Data regarding the baseline and change in VAT, body fat, and body weight were collected. RESULTS: Most interventions demonstrated a preferential loss of VAT regardless of the intervention applied. When expressed as percent change in VAT/percent change in body fat, a ratio can be calculated which we call the Selectivity Index (SI). When this index is applied to the literature reviewed, two observations can be made. First, the Selectivity Index is higher when baseline body fat is higher. Second, there is a direct relationship between the Selectivity Index and the baseline visceral fat ratio. These two observations suggest that individuals with greater visceral fat mass, either through an increase in the body weight or the propensity to store fat in the visceral depot, lose more visceral fat when adjusted to the loss of body fat. CONCLUSION: In conclusion, the Selectivity Index is useful to compare the ability of an intervention to specifically target the loss of AT. This simple index can serve as a benchmark for comparing intervention studies to each other.

Summary The exact timing of the introduction of the glycopeptide antibiotics teicoplanin and vancomycin in the management of the febrile neutropenic patient continues to be controversial. However, there are certain firm criteria now emerging. Bacteraemia can be eradicated with a success rate approaching 100% in cases where the organism can be identified and shown to be sensitive. Approximately 6 5% of cases of soft-tissue infection, usually occurring with the use of a Hickman or equivalent indwelling catheter, are associated with the presence on culture of Gram-positive organisms of presumed skin origin. Such infection is an indication for the early use of antibiotics with proven activity against coagulase-negative staphylococci and diptheroids. Resolution of fever in up to 50% of cases may result from using‘planned progressive therapy’: the introduction of specific Gram-positive cover in patients who have failed to respond at 48–72 h to regimens such as a ureidopenicillin or a third-generation cephalosporin with or without an amino glycoside. This approach reduces the number of patients who go on to receive empirical amphotericin B intravenously for presumed fungal infection. Using teicoplanin or vancomycin as first-line agents in the empirical treatment of first fever in febrile neutropenic patients is perhaps more controversial. Recent developments which include using quinolone-based prophylaxis more widely and introducing cytokines to reduce the period of neutropenia may increase the likelihood that a neutropenic patient's febrile episode will be due to a Gram-positive organism. The dilemma of choosing broad-spectrum monotherapy or targeted combination therapy in this situation remains unresolved. Current studies, however, should help to clarify this situation. Finally, other current studies of teicoplanin and vancomycin as prophylactic agents administered either orally or systemically, may provide additional indications for their use in the neutropenic patient.

Explants of fetal sheep pancreas transplanted into diabetic athymic mice survive for many months but there is only partial differentiation of the endocrine cells. As an alternative form of graft we examined the possibility of creating islet-like cell clusters (ICCs) by collagenase digestion of the fetal sheep pancreas, as has been described for human and porcine fetal pancreas. Such ICCs did form at the rate of 6-23 per 10 mg pancreas; their size varied between 65 and 474 μm (median 232 μm) and their insulin content was 1.6 ± 0.2 mU per 20 ICCs. Laser scanning confocal analysis showed that 4.6 ± 0.7% of the cells contained insulin. Insulin was secreted from ICCs maintained in culture at the daily rate of 2.5 mU per 30 ICCs. Arginine but not glucose or theophylline enhanced acute insulin secretion in vitro. Transplantation of up to 1000 ICCs into athymic and scid mice resulted in sparse growth of the epithelial-like cells in the graft and only partial differentiation of the endocrine cells. Hyperglycaemia in diabetic recipients was not normalized. Thus, while functioning ICCs can be created from fetal sheep pancreas, they do not appear to be appropriate for transplantation to reverse diabetes in mice.

Serum embryonic neural cell adhesion molecule (eNCAM) levels were measured at diagnosis in 92 patients with plasma cell disorders. Significantly elevated levels of serum eNCAM were detected in patients with multiple myeloma when compared to both normal controls and patients with monoclonal gammopathy of uncertain significance (MGUS). Very high levels of serum eNCAM were seen in patients with high tumour burdens. There was a significant correlation between serum eNCAM and beta 2-microglobulin (beta 2m) (r = 0.33; P = 0.002), but not between serum eNCAM and C-reactive protein or serum albumen. There was a trend towards longer survival for patients with low serum NCAM. The median survival of the low serum eNCAM group (eNCAM < 20 U/ml) was 36 months compared to 16 months for the high serum eNCAM group (log rank test chi 2 = 2.42, P = 0.1). Serum eNCAM is a new marker of tumour mass in multiple myeloma and correlates with clinical stage and beta 2m. Patients with low serum eNCAM levels may have a survival advantage. Serum eNCAM warrants further evaluation as a tumour marker and prognostic factor in multiple myeloma.

Diabetes is a chronic disorder of metabolism, which has the potential to result in the development of microvascular complications, such as retinopathy and nephropathy, many years after the onset of the disease process. This is particularly relevant to insulin-dependent diabetes, which affects the young, with blindness and renal failure occurring early in life, rather than at an advanced age, which can occur in non-insulin dependent diabetes. Until insulin dependent diabetes can be prevented, or cured by means of gene transfer, pancreatic transplantation is probably the most likely means at our disposal to normalize blood glucose levels, and thus prevent the occurrence of complications.

Chronic myelomonocytic leukaemia (CMML) is a myelodysplastic syndrome with a diverse clinical spectrum. A case of a 60 year old man with CMML who developed cardiac tamponade is reported. Cytological examination of the pericardial effusion fluid showed extramedullary haemopoiesis. Serous effusions are well recognised in association with this disease, but this seems to be the first reported case of extramedullary haemopoiesis resulting in a pericardial effusion in a patient with CMML.

In our recent studies on the effects of maternal hyperthermia on the embryonic guinea-pig, we have demonstrated two ‘teratogenic windows’ at embryonic days 13 and 21 (E13 and E21). E13 encompasses the period of the closure of the neural groove and anterior neuropore, and E21 the commencement of the cortical plate. The approximate equivalent developmental times in the human are E23-E25 and E49-E56 respectively. In the guinea-pig, maternal hyperthermia at E13 results in a high incidence of neural tube defects (NTD), many open, and associated with other defects such as microphthalmia, and scoliosis or kyphosis. The NTD were most common in the developing hindbrain and all demonstrated considerable infoldings of neural tissue, rosettes of neuroepithelial cells, outpocketings of neural tissue and large cystic cavities beneath the defect. In human examples from the Kyoto Human Embryo Collection, 16 had verified hyperthermic insults at E23-E25 and all had NTD which showed similar deformities to the guinea-pig. Most embryos with such gross defects are aborted in the early fetal period in both species.

Serial image guided 31P magnetic resonance spectroscopy (MRS) studies were performed in eight patients with non-Hodgkin's lymphoma to determine the changes in phosphorus metabolites that occur in vivo in response to chemotherapy. Pre-treatment spectral characteristics were different in high and low grade lymphoma. A larger inorganic phosphate (Pi) peak was seen in high grade NHL relative to phosphomonoesters (PME) or beta adenosine triphosphate (beta ATP), producing significant differences in the PME/Pi and Pi/beta ATP metabolite ratios, and probably reflecting a larger hypoxic cell fraction within the high grade lymphomas. Consistent metabolite changes were seen with treatment, and before reductions in tumour bulk had occurred. Alterations in tumour energetics with changes in Pi and beta ATP, and increases in phospholipid turnover reflected as an increase in the phosphodiester (PDE) resonance were detected. Changes were seen between days 10 and 27 in low grade lymphoma treated with oral alkylating therapy and between days 1 and 5 in lymphoma treated with intensive combination chemotherapy. Increases in the PDE/beta ATP metabolite ratio may be an early indicator of response to chemotherapy in human tumours. These studies illustrate the feasibility and clinical potential of image guided 31P MRS as a means of assessing response to therapy. Images Figure 1

Although the vast majority of pulmonary emboli arise from the iliac and femoral veins, we present a case that illustrates that other potential sources should be considered, especially when recurrent pulmonary emboli occur despite adequate anticoagulation. A 64 year old man presented with fever and left sided pleuritic chest pain two weeks after a laminectomy. A ventilation perfusion scan showed multiple areas of ventilation-perfusion mismatch and he was anticoagulated. Subsequently he remained well until readmission four months later with sudden onset of chest pain, dyspnoea, fever, and rigors. A pansystolic murmur was noted on examination. …

After injection of ferritin into the tibial nutrient artery of adult dogs, ferritin was seen in the interstitial fluid compartment of the tibial cortex immediately and up to 25 min after injection. The pattern of movement was consistent with bulk interstitial fluid flow influenced by hydrostatic pressure. In osteons sectioned transversely, evidence was seen of centrifugal movement of ferritin in a halo pattern around the central capillary. Haloes in the superficial part of the cortex coalesced to form a ferritin front which moved toward the periosteal surface. Movement of ferritin was delayed by appositional bone of the periosteal surface. Ferritin was seen in channels in the matrix and perivascular spaces termed “matrix prelymphatics” and “perivascular prelymphatics,” respectively, because they lacked an endothelial lining.

Image localized 31P magnetic resonance (MR) spectroscopy of the liver was performed in twelve normal volunteers and seven patients with hepatic tumours. The tumours which were clearly imaged by proton MR could also be distinguished from normal tissue because of spectral differences. The malignant tumours had significantly elevated phosphomonoester/inorganic phosphate and phosphomonoester/beta-adenosine triphosphate ratios, probably due to elevated tumour concentrations of phosphocholine and phosphoethanolamine, which are intermediates in the synthesis of membrane phospholipids. The pH values of the malignant tumours were elevated compared to normal hepatic parenchyma. Liver spectra in two patients with the commonest benign hepatic neoplasm, cavernous haemangioma, differed from both normal tissue and the malignant tumours in having a very low signal/noise ratio but apparently normal relative levels of phosphomonoester.

Plasma oxprenolol concentrations were measured in six young healthy female volunteers after single oral dosing with a 16/260 oxprenolol Oros system on three separate occasions. Reproducibility was assessed by comparing individual plasma profiles, areas under the curve, peak concentrations and times to peak. Plasma concentration-time profiles were consistent with an extended duration of drug release from the Oros system. Individual and mean profiles on the three occasions were similar, and no significant differences in mean plasma levels, or derived pharmacokinetic parameters, were detected. The mean amount of drug in eight systems recovered from faeces corresponded to 11% of the dose. Individual amounts were related to the total transit time of the system through the body. The 16/260 Oros system functioned reproducibly within the gastrointestinal tract, and in vivo absorption mirrored in vitro drug release.

The influence of beta-adrenoceptor blockade on the free fatty acid (FFA) response during and after submaximal exercise was studied in a group of normal volunteers. The study showed that the exercise-induced rise in serum FFA concentrations seen with placebo was reduced after pretreatment with propranolol. Furthermore, the palmitic, stearic, oleic and linoleic acid responses showed progressive attenuation with increasing doses of propranolol. Different beta blockers were studied using comparable doses: metoprolol and nadolol had little effect and produced FFA profiles that were similar to placebo whereas the changes on pindolol were comparable with those on propranolol.

Fifteen consecutive patients with refractory or relapsed Hodgkin's disease (HD) referred for autologous bone marrow transplantation (ABMT) underwent quantitative magnetic resonance (MR) studies of the lumbar vertebral bone marrow. Markedly elevated lumbar vertebral marrow T1 values suggestive of bone marrow involvement with HD were seen in four patients, two of whom had no evidence of HD on bilateral iliac crest bone marrow biopsy. Serial studies showed normalisation of T1 values in the post-transplant period. T1 relaxation rate correlated positively with time to engraftment following ABMT and a significant correlation (r = 0.73, 0.02 greater than P greater than 0.01) between T2 relaxation rate and granulocyte and macrophage colony forming units (CFU-GM) of processed bone marrow was seen. This preliminary study illustrates the potential role of quantitative MRI both in the pre-transplant assessment of patients considered for ABMT and in the post-transplant evaluation of tumour response when marrow involvement with HD is present. Images Figure 3

1. Plasma ammonia and heart rate were measured in normal volunteers before, during and after an exercise test following administration of placebo, propranolol, pindolol, metoprolol and nadolol. 2. Small changes in plasma ammonia occurred during exercise after placebo. However, all four β-adrenoceptor antagonists produced considerably greater rises. This effect was most marked after propranolol with the response to pindolol, metoprolol and nadolol being similar and intermediate between placebo and propranolol. 3. Resting heart rate was reduced by all the β-adrenoceptor antagonists except pindolol. Exercise induced changes in heart rate were significantly reduced to a similar degree by all the β-adrenoceptor antagonists.

Thirty patients with various hematologic disorders and 15 healthy control subjects underwent quantitative magnetic resonance (MR) imaging of the lumbar spine with spin-echo techniques. Images of patients with infiltrative bone marrow disorders showed significantly more prolonged T1 times than those of control subjects (P less than .001). It was not possible to distinguish different diffuse infiltrative bone marrow disorders on the basis of T1 values. Aplastic anemia could be distinguished from normality because of significantly shortened T1 (P less than .001). A significant correlation was seen between T1 and bone marrow cellularity (r = .74, P less than .001). T2 was of no value in the characterization of bone marrow disorders. Quantitative MR imaging dose not improve the diagnostic potential of bone marrow imaging in the detection of diffuse marrow infiltrates.

Higher AUC and Cmax values were obtained for metoprolol, oxprenolol and propranolol in groups receiving the low-dose oestrogen-ethinyl oestradiol oral contraceptive, but statistical significance was reached only with metoprolol AUC. The oral contraceptive had the opposite effect on acebutolol AUC and Cmax but this was not significant. The oral contraceptive had no detectable effects on the tmax and t 1/2 values of any of the beta-adrenoceptor blockers.

Summary We present a case of sarcoidosis complicated by total alopecia and a myopathy occurring in a young West Indian woman. There was a very satisfactory response to oral steroids.

Summary Submucosal dissection of the oesophagus is a rare oesophageal disorder. We report a patient who had recurrent episodes of dissection and achalasia. Both recurrence and the association with achalasia are to our knowledge unique.

Changes in plasma ammonia in response to exercise with and without pretreatment with propranolol have been studied. A standardised submaximal treadmill exercise test was used to assess the effects of placebo or propranolol 40 mg, 80 mg, or 160 mg twice daily given in random order for 3 days, the last dose being taken 90 min before exercise. After placebo the mean incremental rise in plasma ammonia in response to exercise was 16 mumol X 1(-1). The corresponding rise after propranolol 40 mg was 56 mumol X 1(-1) (p less than 0.01). All three doses of propranolol produced similar effects on plasma ammonia and exercise heart rates.